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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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  • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention relates to hydroxy-substituted aryl sulfamide derivatives, which are monoamine reuptake inhibitors, compositions containing these derivatives, and methods of their use for the prevention and treatment of diseases or disorders including vasomotor symptoms, depression disorders, endogenous behavioral disorders, cognitive disorders, sexual dysfunction, or pain conditions, in particular vasomotor symptoms.
• Vasomotor symptoms are the most common symptoms associated with menopause, occurring in 60% to 80% of all women following natural or surgically-induced menopause. VMS are likely an adaptive response of the central nervous system (CNS) to declining sex steroids. To date, the most effective therapies for VMS are hormone-based treatments, including estrogens and/or some progestins. Hormonal treatments are very effective at alleviating VMS, but they are not appropriate for all women.
• VMS are caused by fluctuations of sex steroid levels and can be disruptive and disabling in both males and females.
• a hot flush can last up to thirty minutes and vary in their frequency from several times a week to multiple occurrences per day.
• the patient experiences a hot flush as a sudden feeling of heat that spreads quickly from the face to the chest and back and then over the rest of the body. It is usually accompanied by outbreaks of profuse sweating, and may sometimes occur several times an hour, and it often occurs at night. Hot flushes and outbreaks of sweats occurring during the night can cause sleep deprivation.
• Hot flushes may be even more severe in women treated for breast cancer for several reasons. Many survivors of breast cancer are given tamoxifen, the most prevalent side effect of which is hot flush, and many women treated for breast cancer undergo premature menopause from chemotherapy Women with a history of breast cancer are also generally been denied estrogen therapy because of concerns about potential recurrence of breast cancer (Loblui, et al., Lancet, 2000, 356(9247): 2059-2063).
• estrogen treatment e.g. estrogen replacement therapy
• relieves the symptoms establishes the link between these symptoms and an estrogen deficiency.
• estrogen deficiency For example, the menopausal stage of life is associated with a wide range of other acute symptoms as described above and these symptoms are generally estrogen responsive.
• estrogens may stimulate the activity of both the norepinephrine (NE) and/or serotonin (5-HT) systems ( J. Pharmacology & Experimental Therapeutics, 1986, 236(3) 646-652). It is hypothesized that estrogens modulate NE and 5-HT levels providing homeostasis in the thermoregulatory center of the hypothalamus. The descending pathways from the hypothalamus via brainstem/spinal cord and the adrenals to the skin are involved in maintaining normal skin temperature. The action of NE and 5-HT reuptake inhibitors is known to impinge on both the CNS and peripheral nervous system (PNS).
• PNS peripheral nervous system
• the pathophysiology of VMS is mediated by both central and peripheral mechanisms and, therefore, the interplay between the CNS and PNS may account for the efficacy of dual acting SRI/NRIs in the treatment of thermoregulatory dysfunction.
• the physiological aspects and the CNS/PNS involvement in VMS may account for the lower doses proposed to treat VMS (Loblui, et al., Lancet, 2000, 356:2059-2063; Stearns et al., JAMA, 2003, 289:2827-2834) compared to doses used to treat the behavioral aspects of depression.
• the interplay of the CNS/PNS in the pathophysiology of VMS supports the claims that the norepinephrine system could be targeted to treat VMS.
• VMS are most commonly treated by hormone therapy, some patients cannot tolerate estrogen treatment (Berendsen, Maturitas, 2000, 36(3): 155-164, Fink et al., Nature, 1996, 383(6598): 306).
• hormone replacement therapy is usually not recommended for women or men with or at risk for hormonally sensitive cancers (e.g. breast or prostate cancer).
• non-hormonal therapies e.g. fluoxetine, paroxetine [SRIs] and clonidine
• WO9944601 discloses a method for decreasing hot flushes in a human female by administering fluoxetine.
• ⁇ 2 Adrenergic receptors play a role in thermoregulatory dysfunctions (Freedman et al., Fertility & Sterility, 2000, 74(1): 20-3). These receptors are located both pre- and post-synaptically and mediate an inhibitory role in the central and peripheral nervous system. There are four distinct subtypes of the adrenergic ⁇ 2 receptors, i.e., are ⁇ 2A , ⁇ 2B , ⁇ 2C and ⁇ 2D (Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Ther., 1995, 68: 175).
• a non-select ⁇ 2 -adrenoceptor antagonist, yohimbine induces a flush and an ⁇ 2 -adrenergic receptor agonist, clonidine, alleviates the yohimbine effect (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193(2): 129-35, Freedman et al., Fertility & Sterility, 2000, 74(1): 20-3).
• Clonidine has been used to treat hot flush. However, using such treatment is associated with a number of undesired side effects caused by high doses necessary to abate hot flush described herein and known in the related arts.
• neuropathic pain i.e., diabetic neuropathy and post-herpetic neuralgia
• fibromyalgia include off-label use of the tricyclic (TCA) antidepressants (e.g., amytriptyline) and anticonvulsants (e.g., gabapentin) (Collins et al., J. Pain Symptom Manage.
• TCA tricyclic
• antidepressants e.g., amytriptyline
• anticonvulsants e.g., gabapentin
• noradrenergic pathway A major component of this descending pain inhibitory system involves the noradrenergic pathway (Zhuo, et al., Brain Research 1991; 550:35-48; Holden, et al. Neuroscience 1999; 91: 979-990). It is assumed that norepinephrine (NE), and to a lesser extent serotonin (5-HT) reuptake inhibitor NRIs and SRIs, attenuate pain by preventing presynaptic reuptake of NE/5-HT leading to increased postsynaptic NE/5-HT levels and sustained activation of this descending pain inhibitory pathway.
• NE norepinephrine
• 5-HT serotonin
• the present invention provides novel compounds and compositions containing these compounds directed to these and other important uses.
• the present invention is directed to aryl sulfamide derivatives, which are monoamine reuptake inhibitors, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions, including, inter alia, vasomotor symptoms (such as hot flush), sexual dysfunction (such as desire-related or arousal-related dysfunction), gastrointestinal disorders and genitourinary disorder (such as stress incontinence or urge incontinence), chronic fatigue syndrome, fibromyalgia syndrome, depression disorders (such as major depressive disorder, generalized anxiety disorder, panic disorder, attention deficit disorder with or without hyperactivity, sleep disturbance, and social phobia), diabetic neuropathy, pain, and combinations thereof.
• vasomotor symptoms such as hot flush
• sexual dysfunction such as desire-related or arousal-related dysfunction
• gastrointestinal disorders and genitourinary disorder such as stress incontinence or urge incontinence
• chronic fatigue syndrome fibromyalgia syndrome
• depression disorders such as major depressive disorder, generalized anxiety disorder, panic disorder,
• One aspect of the invention provides a compound of formula I:
• composition comprising:
• Another aspect of the invention provides a method for treating or preventing a condition selected from the group consisting of a vasomotor symptom, sexual dysfunction, gastrointestinal disorder, genitourinary disorder, chronic fatigue syndrome, fibromyalgia syndrome, depression disorder, endogenous behavioral disorder, cognitive disorder, diabetic neuropathy, pain, and combinations thereof in a subject in need thereof, comprising the step of:
• Another aspect of the invention provides a process for the preparation of a compound of formula I:
• the compound of formula IA is formed by:
• the compound of formula IB is formed by:
• the compound of formula IC is prepared by:
• the compound of formula ID is prepared by:
• the compound of formula IE is prepared by:
• Norepinephrine transporter is abbreviated NET.
• hNET Human norepinephrine transporter
• SERT Sterotonin transporter
• Human serotonin transporter is abbreviated hSERT.
• NRI Norepinephrine reuptake inhibitor
• SNRI Selective norepinephrine reuptake inhibitor
• SRI Sterotonin reuptake inhibitor
• SSRI Selective serotonin reuptake inhibitor
• Norepinephrine is abbreviated NE.
• Subcutaneous is abbreviated sc.
• treat includes preventative (e.g., prophylactic), curative or palliative treatment.
• an effective amount refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to treatment of a given disease or disorder.
• An effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects.
• “effective amount” refers to the amount of compound or composition of compounds that would increase norepinephrine levels to compensate in part or total for the lack of steroid availability in subjects subject afflicted with a vasomotor symptom. Varying hormone levels will influence the amount of compound required in the present invention. For example, the pre-menopausal state may require a lower level of compound due to higher hormone levels than the peri-menopausal state.
• the effective amount of components of the present invention will vary from patient to patient not only with the particular compound, component or composition selected, the route of administration, and the ability of the components (alone or in combination with one or more additional active agents) to elicit a desired response in the individual, but also with factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of being of the patient, and the severity of the pathological condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. Dosage regimens may be adjusted to provide the improved therapeutic response.
• the compounds of the present invention are administered at a dosage and for a time such that the number of hot flushes is reduced as compared to the number of hot flushes prior to the start of treatment.
• Such treatment can also be beneficial to reduce the overall severity or intensity distribution of any hot flushes still experienced, as compared to the severity of hot flushes prior to the start of the treatment.
• the compounds of the present invention are administered at a dosage and for a time sufficient to treat the symptom or condition.
• compounds of formula I, or a pharmaceutically acceptable salt thereof may be administered, preferably, at a dosage of from about 0.1 mg/day to about 1500 mg/day, dosed one or two times daily, more preferably from about 1 mg/day to about 200 mg/day and most preferably from about 1 mg/day to 100 mg/day for a time sufficient to reduce and/or substantially eliminate the number and/or severity of hot flushes or symptom or condition of the sexual dysfunction, gastrointestinal disorder, genitourinary disorder, chronic fatigue syndrome, fibromyalgia syndrome, depression disorder, diabetic neuropathy, or pain.
• composition component
• composition of compounds component
• compound component
• drug drug
• pharmacologically active agent active agent or “medicament”
• modulation refers to the capacity to either enhance or inhibit a functional property of a biological activity or process; for example, receptor binding or signaling activity. Such enhancement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway and/or may be manifest only in particular cell types.
• the modulator is intended to comprise any compound; e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein, and is preferably small molecule, or peptide.
• inhibitor refers to any agent that inhibits, suppresses, represses, or decreases a specific activity, such as norepinephrine reuptake activity.
• the term “inhibitor” is intended to comprise any compound; e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein (preferably small molecule or peptide) that exhibits a partial, complete, competitive and/or inhibitory effect on mammalian (preferably the human) norepinephrine reuptake or both serotonin reuptake and the norepinephrine reuptake, thus diminishing or blocking (preferably diminishing) some or all of the biological effects of endogenous norepinephrine reuptake or of both serotonin reuptake and the norepinephrine reuptake.
• the compounds of formula I may be prepared in the form of pharmaceutically acceptable salts.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic salts and organic salts.
• Suitable non-organic salts include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most preferred is the hydrochloride salt.
• administering means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.
• subject refers to an animal including the human species that is treatable with the compounds, compositions, and/or methods of the present invention.
• subject or “subjects” is intended to refer to both the male and female gender unless one gender is specifically indicated.
• patient comprises any mammal which may benefit from treatment or prevention of a disease or disorder, such as a human, especially if the mammal is female, either in the pre-menopausal, peri-menopausal, or post-menopausal period.
• patient includes female animals including humans and, among humans, not only women of advanced age who have passed through menopause but also women who have undergone hysterectomy or for some other reason have suppressed estrogen production, such as those who have undergone long-term administration of corticosteroids, suffer from Cushing's syndrome or have gonadal dysgenesis.
• patient is not intended to be limited to a woman.
• “Side effect” refers to a consequence other than the one(s) for which an agent or measure is used, as one or more adverse effects produced by a drug, especially on a tissue or organ system other then the one sought to be benefited by its administration.
• the term “side effect” may refer to such conditions as, for example, vomiting, nausea, sweating, and hot flushes (Janowsky, et al., Journal of Clinical Psychiatry, 1984, 45(10 Pt 2): 3-9).
• Vasomotor symptoms include, but are not limited to, hot flushes (flushes), insomnia, sleep disturbances, mood disorders, irritability, excessive perspiration, night sweats, fatigue, and the like, caused by, inter alia, thermoregulatory dysfunction.
• hot flush (sometimes called “hot flash”) is an art-recognized term that refers to an episodic disturbance in body temperature typically consisting of a sudden skin flushing, usually accompanied by perspiration in a subject.
• premature menopause or “artificial menopause” refer to ovarian failure of unknown cause that may occur before age 40. It may be associated with smoking, living at high altitude, or poor nutritional status. Artificial menopause may result from oophorectomy, chemotherapy, radiation of the pelvis, or any process that impairs ovarian blood supply.
• pre-menopausal means before the menopause
• peri-menopausal means during the menopause
• post-menopausal means after the menopause.
• Oxidectomy means removal of an ovary or ovaries and can be effected according to Merchenthaler et al., Maturitas, 1998, 30(3): 307-316.
• sexual dysfunction includes, but is not limited to, conditions relating to disorders of sexual desire and/or arousal.
• gastrointestinal and genitourinary disorders includes irritable bowel syndrome, symptomatic GERD, hypersensitive esophagus, nonulcer dyspepsia, noncardiac chest pain, biliary dyskinesia, sphincter of Oddi dysfunction, incontinence (i.e., urge incontinence, stress incontinence, genuine stress incontinence, and mixed incontinence, including the involuntary voiding of feces or urine, and dribbling or leakage or feces or urine which may be due to one or more causes including but not limited to pathology altering sphincter control, loss of cognitive function, overdistention of the bladder, hyperreflexia and/or involuntary urethral relaxation, weakness of the muscles associated with the bladder or neurologic abnormalities), interstitial cystitis (irritable bladder), and chronic pelvic pain (including, but not limited to vulvodynia, prostatodynia, and
• CFS chronic fatigue syndrome
• FMS fibromyalgia syndrome
• FMS and other somatoform disorders include FMS and other somatoform disorders, including FMS associated with depression, somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder, and somatoform NOS.
• FMS and other somatoform disorders are accompanied by physiological symptoms selected from a generalized heightened perception of sensory stimuli, abnormalities in pain perception in the form of allodynia (pain with innocuous stimulation), abnormalities in pain perception in the form of hyperalgesia (increased sensitivity to painful stimuli), and combinations thereof.
• depression disorder includes major depressive disorder, generalized anxiety disorder, panic disorder, attention deficit disorder with or without hyperactivity, sleep disturbance, social phobia, and combinations thereof.
• a cognitive disorder includes changes or defects in alertness; mild cognitive impairment (MCI), characterized by problems with memory, language, or other mental functions which is severe enough to be noticeable or be detected by tests, but not serious enough to significantly interfere with daily life; cognitive disorder NOS (not otherwise specified), characterized by a syndrome of cognitive impairment that does not meet the criteria for delerium, dementia or amnesic disorders; age-related cognitive decline (ARCD); and cognitive arousal (such as increased arousal states).
• MCI mild cognitive impairment
• NOS not otherwise specified
• a cognition disorder can be ideopathic, or can be caused by a variety of other factors such as a congenital defect, alcohol or drug addiction, transient or permanent pharmacologic effects of drugs, organic or infectious disease (e.g., Alzheimer's disease, Parkinson's disease, AIDS), trauma (e.g., brain injury, stroke) or advanced age.
• an “endogenous behavioral disorder” includes attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD, including adult and pediatric forms of predominantly inattentive, predominantly hyperactive, or combined types), obsessive-compulsive disorder (OCD), oppositional or oppositional explosive defiant disorder (ODD/OEDD), anxiety and panic disorders (APD) and temper, rage and outburst behavior disorder (TROBD).
• ADD/ADHD attention deficit disorder/attention deficit hyperactivity disorder
• OCD obsessive-compulsive disorder
• ODD oppositional or oppositional explosive defiant disorder
• APD anxiety and panic disorders
• temper rage and outburst behavior
• pain includes both acute and chronic nociceptic or neuropathic pain, which includes centralized pain, peripheral pain, or combination thereof.
• the term includes many different types of pain, including, but not limited to, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, and combinations thereof, such as lower back pain, atypical chest pain, headache such as cluster headache, migraine, herpes neuralgia, phantom limb pain, pelvic pain, myofascial face pain, abdominal pain, neck pain, central pain, dental pain, opioid resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, peripheral neuropathy and diabetic neuropathy, post-operative pain, and pain which is co-morbid with nervous system disorders described herein.
• acute pain refers to centralized or peripheral pain that is intense, localized, sharp, or stinging, and/or dull, aching, diffuse, or burning in nature and that occurs for short periods of time.
• chronic pain refers to centralized or peripheral pain that is intense, localized, sharp, or stinging, and/or dull, aching, diffuse, or burning in nature and that occurs for extended periods of time (i.e., persistent and/or regularly reoccurring), including, for the purposes of the present invention, neuropathic pain and cancer pain.
• Chronic pain includes neuropathic pain, hyperalgesia, and/or allodynia.
• neuropathic pain refers to chronic pain caused by damage to or pathological changes in the peripheral or central nervous systems.
• pathological changes related to neuropathic pain include prolonged peripheral or central neuronal sensitization, central sensitization related damage to nervous system inhibitory and/or exhibitory functions and abnormal interactions between the parasympathetic and sympathetic nervous systems.
• neuropathic pain A wide range of clinical conditions may be associated with or form the basis for neuropathic pain including, for example, diabetes, post traumatic pain of amputation (nerve damage cause by injury resulting in peripheral and/or central sensitization such as phantom limb pain), lower back pain, cancer, chemical injury, toxins, other major surgeries, peripheral nerve damage due to traumatic injury compression, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, or viral or bacterial infections such as shingles or human immunodeficiency virus (HIV), and combinations thereof.
• neuropathic pain is a condition secondary to metastatic infiltration, adiposis dolorosa, burns, central pain conditions related to thalamic conditions
• hypoalgesia refers to pain where there is an increase in sensitivity to a typically noxious stimulus.
• allodynia refers to an increase in sensitivity to a typically non-noxious stimulus.
• the term “visceral pain” refers to pain associated with or resulting from maladies of the internal organs, such as, for example, ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, and combinations thereof.
• maladies of the internal organs such as, for example, ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, and combinations thereof.
• female-specific pain refers to pain that may be acute and/or chronic pain associated with female conditions.
• groups of pain include those that are encountered solely or predominately by females, including pain associated with menstruation, ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of a follicular or corpus luteum cyst, irritation of the pelvic viscera, uterine fibroids, adenomyosis, endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abdominal adhesions, anatomic distortion of the pelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelvic congestion or referred pain from non-gynecological causes, and combinations thereof.
• Alkyl refers to an optionally substituted, saturated straight, branched, or cyclic hydrocarbon having from about 1 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 1 to about 8 carbon atoms or 1 to 6 carbon atoms (C 1 -C 6 ) being preferred, and with from about 1 to about 4 carbon atoms, herein referred to as “lower alkyl”, being more preferred.
• Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl, cyclopropyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
• a branched alkyl group has at least 3 carbon atoms (e.g., an isopropyl group), and in various embodiments, has up to 6 carbon atoms, i.e., a branched lower alkyl group.
• a branched alkyl group has at least 3 carbon atoms (e.g., an isopropyl group), and in various embodiments, has up to 6 carbon atoms, i.e., a branched lower alkyl group.
• Examples of branched lower alkyl groups include, but are not limited to:
• Alkenyl refers to an alkyl group of at least two carbon atoms having one or more double bonds, wherein alkyl is as defined herein. Preferred alkenyl groups have from 2 to 6 carbon atoms (C 2 -C 6 ). Alkenyl groups can be optionally substituted.
• Alkynyl refers to an alkyl group of at least two carbon atoms having one or more triple bonds, wherein alkyl is as defined herein. Preferred alkynyl groups have from 2 to 6 carbon atoms (C 2 -C 6 ). Alkynyl groups can be optionally substituted.
• Alkylenyl refers to the subsets of alkyl, alkenyl, alkynyl and aryl groups, respectively, as defined herein, including the same residues as alkyl, alkenyl, alkynyl, and aryl but having two points of attachment within a chemical structure.
• C 1 -C 6 alkylenyl examples include methylenyl (—CH 2 —), ethylenyl (—CH 2 CH 2 —), propylenyl (—CH 2 CH 2 CH 2 —), and dimethylpropylenyl (—CH 2 C(CH 3 ) 2 CH 2 —).
• examples of C 2 -C 6 alkenylenyl include ethenylenyl (—CH ⁇ CH— and propenylenyl (—CH ⁇ CH—CH 2 —).
• Examples of C 2 -C 6 alkynylenyl examples include ethynylenyl (—C ⁇ C—) and propynylenyl (—C ⁇ C—CH 2 —).
• arylenyl groups include phenylenyl
• arylenyl groups contain 6 carbon atoms (C 6 ).
• Halo refers to chloro, bromo, fluoro, and iodo.
• Aryl refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system having from about 5 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 6 to about 10 carbons (C 6 -C 10 ) being preferred.
• Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl.
• Heteroaryl refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system that includes at least one, and preferably from 1 to about 4 heteroatom ring members selected from sulfur, oxygen and nitrogen. Heteroaryl groups can have, for example, from about 3 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 4 to about 10 carbons being preferred.
• heteroaryl groups include, for example, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
• Heterocyclic ring refers to a stable 4- to 12-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring that is saturated, partially unsaturated or unsaturated (aromatic), and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above defined heterocyclic rings is fused to a benzene ring.
• the nitrogen and sulfur heteroatoms may optionally be oxidized.
• the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
• heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen atom in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds one, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than two.
• heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4H-carbazolyl, ⁇ -, ⁇ -, or ⁇ -carbolinyl, chromanyl, chromenyl, cinnolinyl, de
• Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
• Alkoxy refers to the group R—O— where R is an alkyl group, as defined herein. Preferred alkoxy groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
• Arylalkyl refers to the group R′—R— where R′ is an aryl group, as defined herein, and R is an alkyl group, as defined herein. Preferred arylalkyl groups have from 7 to 16 carbon atoms (C 7 -C 16 ).
• Heteroarylalkyl refers to the group R′′-R— where R′′ is a heteroaryl group, as defined herein, and R is an alkyl group, as defined herein.
• Heteroarylmethyl refers to the group R′′—CH 2 — where R′′ is a heteroaryl group, as defined herein.
• Alkanoyloxy refers to the group R—C( ⁇ O)—O— where R is an alkyl group, as defined herein, of 1 to 5 carbon atoms (C 1 -C 5 ).
• Alkylsulfoxide refers to as used herein, refers to —S( ⁇ O)—R′, where R′ is alkyl, as defined herein.
• Preferred alkysulfoxide groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
• Arylsulfoxide refers to as used herein, refers to —S( ⁇ O)—R′, where R′ is aryl, as defined herein.
• Preferred arylsulfoxide groups have from 6 to 10 carbon atoms (C 6 -C 10 ).
• Alkylsulfone refers to —S( ⁇ O) 2 —R′, where R′ is alkyl, as defined herein.
• Preferred alkylsulfone groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
• Arylsulfone refers to —S( ⁇ O) 2 —R′, where R′ is aryl, as defined herein. Preferred arylsulfone groups have from 6 to 10 carbon atoms (C 6 -C 10 ).
• Alkylsulfonamide refers to —NR—S( ⁇ O) 2 —R, where each R is independently, alkyl, as defined above, or the NR part may also be NH.
• Preferred alkylsulfonamide groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
• Arylsulfonamide refers to —NR—S( ⁇ O) 2 —R′, where R is H or alkyl, as defined herein, and R′ is aryl, as defined herein. Preferred arylsulfonamide groups have from 6 to 10 carbon atoms (C 6 -C 10 ).
• Heteroarylsulfonamide refers to —NR—S( ⁇ O) 2 —R′′, where R is H or alkyl, as defined herein, and R′′ is aryl, as defined herein.
• Alkylamido refers to —NR—C( ⁇ O)—R′, where each R is independently, alkyl, as defined above, or the NR part may also be NH.
• Preferred alkylamido groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
• Arylamido refers to —NR—C( ⁇ O)—R′′, where R is H or alkyl, as defined herein, and R′′ is aryl, as defined herein. Preferred arylamido groups have from 6 to 10 carbon atoms (C 6 -C 10 ).
• Phenylamido refers to —NR—C( ⁇ O)-phenyl, where R is H or alkyl, as defined above.
• substituent groups independently include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl, formyl, alkyl, perfluoroalkyl, alkylamino, dialkylamino, alkoxy, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, alkylthio, aryl, heteroaryl, a heterocyclic ring, cycloalkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, alkenyl, alkynyl, arylalkyl, aryloxy,
• Substituent groups that have one or more available hydrogen atoms can in turn optionally bear further independently selected substituents, to a maximum of three levels of substitutions.
• the term “optionally substituted alkyl” is intended to mean an alkyl group that can optionally have up to four of its hydrogen atoms replaced with substituent groups as defined above (i.e., a first level of substitution), wherein each of the substituent groups attached to the alkyl group can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a second level of substitution), and each of the substituent groups of the second level of substitution can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a third level of substitution).
• substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
• substituent “arylalkoxycabonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.
• impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
• impermissible substitution patterns are well known to the skilled artisan.
• C 1-6 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 alkyl.
• the term “5-9 membered heteroaryl group” is specifically intended to individually disclose a heteroaryl group having 5, 6, 7, 8, 9, 5-9, 5-8, 5-7, 5-6, 6-9, 6-8, 6-7, 7-9, 7-8, and 8-9 ring atoms.
• protecting group or “G p ” with respect to amine groups, hydroxyl groups and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art, such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999) which can be added or removed using the procedures set forth therein.
• Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
• a reagent such as, but not limited to,
• Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; carbamates; e.g. BOC; imides, such as phthalimide, Fmoc, Cbz, PMB, benzyl, and dithiosuccinimide; and others.
• Examples of protected or capped sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
• activated or “an activating group” or “G a ” as used herein indicates having an electrophilic moiety bound to a substituent, capable of being displaced by a nucleophile.
• activating groups are halogens, such as Cl, Br or I, and F; triflate; mesylate, or tosylate; esters; aldehydes; ketones; epoxides; and the like.
• An example of an activated group is acetylchloride, which is readily attacked by a nucleophile, such as piperidine group to form a N-acetylpiperidine functionality.
• deprotecting refers to removal of a protecting group, such as removal of a benzyl or BOC group bound to an amine. Deprotecting may be preformed by heating and/or addition of reagents capable of removing protecting groups. In preferred embodiments, the deprotecting step involves addition of an acid, base, reducing agent, oxidizing agent, heat, or any combination thereof.
• One preferred method of removing BOC groups from amino groups is to add HCl in ethyl acetate.
• Many deprotecting reactions are well known in the art and are described in Protective Groups in Organic Synthesis, Greene, T. W., John Wiley & Sons, New York, N.Y., (1st Edition, 1981), the entire disclosure of which is herein incorporated by reference.
• One aspect of the invention provides a compound of formula I:
• each R 1 is H.
• R 2 is:
• each R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of H, alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido.
• R 9 is F.
• R 5 , R 6 , R 7 and R 8 are H.
• R 5 is H or F
• R 6 is H or F
• R 7 is H or F
• R 8 is H or F
• R 9 is H or F.
• R 5 , R 6 , R 7 , R 8 and R 9 are H, halo, alkyl or alkoxy.
• R 3 is alkyl. More particularly, methyl.
• R 4 is H.
• m is an integer from 2 to 6. More particularly, m is 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, or 4 to 5. In another embodiment, m is 1, m is 2, m is 3, m is 4, m is 5 or m is 6.
• ring A comprises all carbon atoms.
• R 2 is pyridinyl, methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or quinolinyl.
• R 2 is phenyl, fluoro-phenyl, difluoro-phenyl, trifluoro-phenyl, chloro-phenyl, fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl trifluoromethoxy-phenyl, methyl-fluoro-phenyl, methoxy-fluoro-phenyl, or naphthyl.
• the compound is selected from the group consisting of:
• Another aspect of the invention provides a compound selected from the group consisting of:
• said pharmaceutically acceptable salt is a hydrochloride or dihydrochloride.
• composition comprising:
• Another aspect of the invention provides a method for treating or preventing a condition selected from the group consisting of a vasomotor symptom, sexual dysfunction, gastrointestinal disorder, genitourinary disorder, chronic fatigue syndrome, fibromyalgia syndrome, depression disorder, endogenous behavioral disorder, cognitive disorder, diabetic neuropathy, pain, and combinations thereof in a subject in need thereof, comprising the step of:
• the vasomotor symptom is hot flush.
• the sexual dysfunction is desire-related or arousal-related.
• the gastrointestinal disorder or the genitourinary disorder is stress incontinence or urge incontinence.
• the condition is chronic fatigue syndrome.
• the condition is fibromyalgia syndrome.
• the condition is a depression disorder selected from the group consisting of major depressive disorder, generalized anxiety disorder, panic disorder, attention deficit disorder with or without hyperactivity, sleep disturbance, social phobia, and combinations thereof.
• the disorder is an endogenous behavioral disorder or a cognitive disorder.
• the condition is diabetic neuropathy.
• the condition is pain.
• the pain is acute centralized pain, acute peripheral pain, or a combination thereof.
• the pain is chronic centralized pain, chronic peripheral pain, or a combination thereof.
• the pain is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or a combination thereof.
• the neuropathic pain is associated with diabetes, post traumatic pain of amputation, lower back pain, cancer, chemical injury, toxins, major surgery, peripheral nerve damage due to traumatic injury compression, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, viral infection, bacterial infection, metastatic infiltration, adiposis dolorosa, burns, central pain conditions related to thalamic conditions, or a combination thereof.
• the neuropathic pain is post-herpetic neuralgia.
• the visceral pain is associated with ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, or a combination thereof.
• the pain is female-specific pain.
• norepinephrine activity in the hypothalamus or in the brainstem can be elevated by (i) blocking the activity of the NE transporter, (ii) blocking the activity of the presynaptic adrenergic ⁇ 2 receptor with an antagonist, or (iii) blocking the activity of 5-HT on NE neurons with a 5-HT 2a antagonist.
• the compounds of the invention are also useful to prevent and treat pain.
• the pain may be, for example, acute pain or chronic pain.
• the pain may also be centralized or peripheral.
• Examples of pain that can be acute or chronic and that can be treated in accordance with the methods of the present invention include inflammatory pain, musculoskeletal pain, bony pain, lumbosacral pain, neck or upper back pain, visceral pain, somatic pain, neuropathic pain, cancer pain, pain caused by injury or surgery such as burn pain or dental pain, or headaches such as migraines or tension headaches, or combinations of these pains.
• a pain caused by inflammation may also be visceral or musculoskeletal in nature.
• the compounds useful in the present invention are administered in mammals to treat chronic pain such as neuropathic pain associated for example with damage to or pathological changes in the peripheral or central nervous systems; cancer pain; visceral pain associated with for example the abdominal, pelvic, and/or perineal regions or pancreatitis; musculoskeletal pain associated with for example the lower or upper back, spine, fibromyalgia, temporomandibular joint, or myofascial pain syndrome; bony pain associated with for example bone or joint degenerating disorders such as osteoarthritis, rheumatoid arthritis, or spinal stenosis; headaches such migraine or tension headaches; or pain associated with infections such as HIV, sickle cell anemia, autoimmune disorders, multiple sclerosis, or inflammation such as osteoarthritis or rheumatoid arthritis.
• chronic pain such as neuropathic pain associated for example with damage to or pathological changes in the peripheral or central nervous systems; cancer pain; visceral pain associated with for example the abdominal, pelvic, and/or
• the compounds useful in this invention are used to treat chronic pain that is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain or inflammatory pain or combinations thereof, in accordance with the methods described herein.
• Inflammatory pain can be associated with a variety of medical conditions such as osteoarthritis, rheumatoid arthritis, surgery, or injury.
• Neuropathic pain may be associated with for example diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, or nerve damage cause by injury resulting in peripheral and/or central sensitization such as phantom limb pain, reflex sympathetic dystrophy or postthoracotomy pain, cancer, chemical injury, toxins, nutritional deficiencies, or viral or bacterial infections such as shingles or HIV, or combinations thereof.
• the methods of use for compounds of this invention further include treatments in which the neuropathic pain is a condition secondary to metastatic infiltration, adiposis dolorosa, burns, or central pain conditions related to thalamic conditions.
• somatic pain that can be treated in accordance with the methods of the present invention include pains associated with structural or soft tissue injury experienced during surgery, dental procedures, burns, or traumatic body injuries.
• visceral pain that can be treated in accordance with the methods of the present invention include those types of pain associated with or resulting from maladies of the internal organs such as ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, or biliary tract disorders, or combinations thereof.
• the pain treated according to the methods of the present invention may also be related to conditions of hyperalgesia, allodynia, or both. Additionally, the chronic pain may be with or without peripheral or central sensitization.
• the compounds useful in this invention may also be used to treat acute and/or chronic pain associated with female conditions, which may also be referred to as female-specific pain.
• groups of pain include those that are encountered solely or predominately by females, including pain associated with menstruation, ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of a follicular or corpus luteum cyst, irritation of the pelvic viscera, uterine fibroids, adenomyosis, endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abdominal adhesions, anatomic distortion of the pelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelvic congestion or referred pain from non-gynecological causes.
• Another aspect of the invention provides a process for the preparation of a compound of formula I:
• the compound of formula IA is formed by:
• the activating step comprises:
• the compound of formula IB is formed by:
• the deprotecting step comprises:
• the acid is hydrochloric acid (HCl).
• the compound of formula IC is prepared by:
• the oxidizing step is performed in the presence of sodium periodate (NaIO 4 ) and ruthenium chloride (RuCl 3 ).
• the compound of formula ID is prepared by:
• the reacting step is performed in the presence of triethylamine (Et 3 N).
• the compound of formula IE is prepared by:
• the reacting step is performed in the presence of sodium cyanoborohydride (NaCNBH 3 ) and acetic acid (AcOH).
• the reacting step :
• Some of the compounds of the present invention may contain chiral centers and such compounds may exist in the form of stereoisomers (i.e. enantiomers or diastereomers).
• the present invention includes all such stereoisomers and any mixtures thereof including racemic mixtures. Racemic mixtures of the stereoisomers as well as the substantially pure stereoisomers are within the scope of the invention.
• the term “substantially pure,” as used herein, refers to at least about 90 mole %, more preferably at least about 95 mole %, and most preferably at least about 98 mole % of the desired stereoisomer is present relative to other possible stereoisomers.
• Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein.
• HPLC high performance liquid chromatography
• Jacques, et al. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron, 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds , (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions , p. 268 (E. L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972), the entire disclosures of which are herein incorporated by reference.
• the present invention includes prodrugs of the compounds of formula I.
• “Prodrug,” as used herein, means a compound which is convertible in vivo by chemical or metabolic means (e.g. by hydrolysis) to a compound of formula I.
• Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology , vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed).
• the compounds of formula I may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• the solvated forms are considered equivalent to the unsolvated forms for the purpose of the present invention.
• the compounds of the present invention may be prepared in a number of ways well known to those skilled in the art.
• the compounds can be synthesized, for example, by the methods described below, or variations thereon as appreciated by the skilled artisan. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.
• protecting groups may contain protecting groups during the course of synthesis.
• Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention.
• Protecting groups that may be employed in accordance with the present invention may be described in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991, the entire disclosure of which is herein incorporated by reference.
• the compounds of this invention contain chiral centers, providing for various stereoisomeric forms such as diastereomeric mixtures, enantiomeric mixtures as well as optical isomers.
• the individual optical isomers can be prepared directly through asymmetric and/or stereospecific synthesis or by conventional chiral separation of optical isomers from the enantiomeric mixture.
• an appropriate fluoronitroarene 1 may be substituted with an aryl amine using a base under standard conditions to provide an aminonitroarene 2.
• a base such as sodium hydride in DMF or an organometallic base such as butyllithium in THF.
• Reduction of the nitro group in structure 2 is accomplished under standard conditions using hydrogen and a suitable catalyst such as palladium or Raney nickel to provide a dianiline 3.
• Nitro reduction is a common transformation and one could employ a number of alternative procedures including reduction conditions using metal salts such as aqueous HCl with tin(II) chloride or aqueous ammonium chloride with zinc metal.
• the dianiline 3 is then treated a suitable sulfate containing reagent to form arylsulfamide of structure 4.
• 3 was heated with sulfamide in diglyme to provide the cyclized product 4.
• the acidic nitrogen is then combined with a suitably substituted side chain providing products 5 or 6 defending on the structure of the desired side chain.
• An effective method for attaching the side chain to sulfamide 4 is the Mitsunobu reaction in which an alcohol is activated and displaced by treating with a phosphine and an activating reagent.
• typical conditions for effecting the attachment of the sulfamide to the alcohol containing side chain were treatment with diisopropyl azodicarboxylate and triphenylphosphine in THF.
• Another suitable method for accomplishing side chain attachment is direct nucleophilic substitution of a leaving group containing side chain with the sulfamide and can be facilitated by addition of a base in a suitable solvent.
• compounds of structure 5 with a bromine containing side chain were treated with an excess of the desired amine to provide the desired compounds of formula I.
• An alternative method for the synthesis of compounds of formula I is possible from 6 where the side chain is attached with the amine present in protected form (the protecting group is represented by the letter P). Any suitable amine protecting group, t-butoxycarbonyl in a typical example, may be used. The protecting group is then removed, in the case of t-butoxycarbonyl using an acid such as hydrochloric acid, to give compounds of formula I.
• an aryl boronic acid forms an aryl-nitrogen bond in the presence of a transition metal salt such as copper(II) acetate to provide 6.
• a transition metal salt such as copper(II) acetate
• Subsequent deprotection of the protecting group P in 6 affords compounds of formula I.
• the protecting group t-butoxycarbonyl was useful for this purpose and is readily removed using an acid such as hydrochloric acid to give compounds of formula I.
• dianiline 3 can be treated with an aldehyde using standard reductive amination conditions giving substituted dianiline 11. Condensation of this with thionyl chloride under basic conditions gives the sulfonylurea 12 which can be readily oxidized utilizing a variety of conditions to the sulfamide 13. Treatment of this with hydrogen chloride unmasks the diol 14 which is converted to the tosylate 15 under basic conditions. When treated with potassium carbonate this is readily converted to the epoxide 16 which can be treated with an excess of the desired amine to provide the desired compounds of formula 17.
• sulfamide 4 prepared as in Scheme 1, can be readily alkylated with an epoxide containing a leaving group including but not limited to bromide, tosylate or mesylate providing compounds of structure 16.
• a leaving group including but not limited to bromide, tosylate or mesylate
• compounds of structure 16 were treated with an excess of the desired amine to provide the desired compounds of formula 1.
• compositions comprising:
• the compound of formula I, or a pharmaceutically acceptable salt thereof will be present at a level of from about 0.1%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition, based on the total weight of the pharmaceutical composition.
• the compound of formula I, or a pharmaceutically acceptable salt thereof will be present at a level of at least about 1%, by weight, based on the total weight of the pharmaceutical composition. More preferably, the compound of formula I, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 5%, by weight, based on the total weight of the pharmaceutical composition.
• the compound of formula I, or a pharmaceutically acceptable salt thereof will be present at a level of at least about 10%, by weight, based on the total weight of the pharmaceutical composition. Yet even more preferably, the compound of formula I, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 25%, by weight, based on the total weight of the pharmaceutical composition.
• compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is herein incorporated by reference.
• Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
• the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
• Applicable solid carriers can include one or more substances that may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
• the carrier is a finely divided solid that is in admixture with the finely divided active ingredient.
• the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain up to about 99% of the active ingredient.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
• Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
• the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
• the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators.
• suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
• cellulose derivatives preferably sodium carboxymethyl cellulose solution
• alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols
• oils e.g. fractionated coconut oil and arachis oil
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
• Liquid pharmaceutical compositions for parenteral administration which are sterile solutions or suspensions, can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
• the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
• the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
• the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
• the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
• the compounds useful in the present invention may be administered to a mammal with one or more other pharmaceutical active agents such as those agents being used to treat any other medical condition present in the mammal.
• pharmaceutical active agents include pain relieving agents, anti-angiogenic agents, anti-neoplastic agents, anti-diabetic agents, anti-infective agents, or gastrointestinal agents, or combinations thereof.
• the one or more other pharmaceutical active agents may be administered in a therapeutically effective amount simultaneously (such as individually at the same time, or together in a pharmaceutical composition), and/or successively with one or more compounds of the present invention.
• combination therapy refers to the administration of two or more therapeutic agents or compounds to treat a therapeutic condition or disorder described in the present disclosure, for example hot flush, sweating, thermoregulatory-related condition or disorder, or other condition or disorder.
• a therapeutic condition or disorder described in the present disclosure for example hot flush, sweating, thermoregulatory-related condition or disorder, or other condition or disorder.
• Such administration includes use of each type of therapeutic agent in a concurrent manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
• the route of administration may be any enteral or parenteral route which effectively transports the active compound of formula I, or a pharmaceutically acceptable salt thereof, to the appropriate or desired site of action; such as oral, nasal, pulmonary, transdermal, such as passive or iontophoretic delivery, or parenteral, e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intrathecal, intra-articular, intranasal, ophthalmic solution or an ointment.
• the administration of compound of formula I, or pharmaceutically acceptable salt thereof, with other active ingredients may be separate, consecutive or simultaneous.
• Step 1 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.45 g, 1.7 mmol) was dissolved in tetrahydrofuran (20 mL) and triphenylphosphine (0.54 g, 2 mmol) was added followed by 3-buten-1-ol (0.16 mL, 1.87 mmol) and diisopropyl azodicarboxylate (0.39 g, 2 mmol). The mixture was stirred for 18 hours at 23° C.
• Step 2 1-(but-3-enyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.44 g, 1.64 mmol) was dissolved in CH 2 Cl 2 (10 mL) at 23° C. 3-chlorobenzoperoxoic acid (1.02 g, 3.9 mmol) was added and the mixture allowed to stir for 18 h then filtered and concentrated. The residue was diluted with EtOAc and washed with 10% NaHCO 3 solution then brine. After drying with Na 2 SO 4 the solution was concentrated then 300 mg of the residue was dissolved in 10 mL of MeNH 2 solution (8M in EtOH).
• Step 3 Approximately 300 mg of racemic 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol was dissolved in 4 mL of methanol. 200 ⁇ L of the resulting solution was repetitively injected onto the Supercritical Fluid Chromatography instrument, and the baseline resolved enantiomers were separately collected using the conditions described below. The chiral purity of each enantiomer was determined under the same Supercritical Fluid Chromatography conditions using a 250 mm ⁇ 4.6 mm ID column at 2.0 mL/min flow rate using Chiralpak AS-H 5 Analytical Supercritical Fluid Chromatography (Berger Instruments, Inc. Newark, Del.). Both enantiomers were found to be >99.9% enantiomerically pure.
• Step 1 To a solution of N1-(2-fluorophenyl)benzene-1,2-diamine, 1, (1 g, 5 mmol) in methanol (100 mL) was added the aldehyde (0.72 g, 5 mmol) followed by acetic acid (0.12 mL, 2 mmol) and sodium cyanoborohydride (3.15 g, 50 mmol). The reaction was stirred for 8 hour at 23° C. then NaHCO 3 solution (50 mL) added. The mixture was extracted with EtOAC (3 ⁇ ) and the combined organic layers washed with brine, dried (Na 2 SO 4 ) and concentrated. The residue was purified via HPLC (SFC, 10% MeOH in CO 2 , 20 ⁇ 250 mm Kromasil CN) to afford 0.74 g (68%) of the desired product 2 as a clear oil.
• HPLC SFC, 10% MeOH in CO 2 , 20 ⁇ 250 mm Kromasil CN
• Step 2 To a solution of 2 (0.53 g, 1.6 mmol) in THF (20 mL) at 0° C. was added triethylamine (0.68 mL, 4.8 mmol) followed by thionyl chloride (0.17 ml, 2.4 mmol) dropwise. The reaction was allowed to stir for 0.5 h then diluted with EtOAc and washed with water and brine. After drying with Na 2 SO 4 the solution was concentrated then purified via Isco chromatography (Redisep, silica, gradient 0-50% EtOAc) to afford 0.56 g (93%) of 3 as a clear oil.
• Step 3 3 (0.46 g, 1.22 mmol) was dissolved in acetonitrile/water (1:1, 20 mL) at 0° C. Sodium Periodate (0.39 g, 1.8 mmol) was added followed by RuCl 3 .(H 2 O) x (11 mg, catalytic) and the mixture was stirred for 1 h then filtered through Celite. The mixture was diluted with EtOAc, washed with water and brine then dried with Na 2 SO 4 and concentrated. The residue was purified via Isco chromatography (Redisep, silica, gradient 0-50% EtOAc) to afford 0.45 g (94%) of 4 as a clear oil.
• Step 4 4 (0.425 g, 1.1 mmol) was dissolved in THF (20 mL) at 23° C. 2N HCl (10 mL) was added dropwise and the mixture was stirred for 4 h then a saturated solution of NaHCO 3 added slowly. The mixture was extracted with CH 2 Cl 2 (4 ⁇ ) and the combined layers washed with brine, dried with Na 2 SO 4 and concentrated. The residue was purified via Isco chromatography (Redisep, silica, gradient 0-100% EtOAc) to afford 0.325 g (85%) of 5 as a clear oil.
• Step 5 5 (0.29 g, 0.82 mmol) was dissolved in CH 2 Cl 2 (15 mL) at 0° C. Triethylamine (0.14 mL, 0.99 mmol) was added followed by p-toluenesulfonyl chloride (0.17 g, 0.9 mmol). The mixture was stirred at 0° C. for 1 hour then allowed to warm to 23° C. over 6 h. The reaction was washed with water, a 10% HCl solution, NaHCO 3 and brine. After drying with Na 2 SO 4 and concentration, the residue was purified via Isco chromatography (Redisep, silica, gradient 0-60% EtOAc) to afford 0.229 g (55%) of 6 as a clear oil.
• Step 6 6 (0.2 g, 0.4 mmol) was dissolved in MeOH/THF (1:1, 10 mL) at 23° C. Potassium carbonate (0.06 g, 0.43 mmol) was added and the reaction was stirred at 23° C. for 18 hour then diluted with CH 2 Cl 2 (20 mL). The reaction was washed with water, dried over Na 2 SO 4 , concentrated and purified via Isco chromatography (Redisep, silica, gradient 0-50% EtOAc) to afford 0.08 g (60%) of 7 as a clear oil.
• Step 7 7 (0.08 g, 0.23 mmol) was dissolved in MeNH 2 solution (8M in EtOH, 10 mL). The solution was heated to 60° C. for 1 hour. The reaction mixture was cooled and concentrated then loaded directly onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-100% of 10% 7M ammonia in MeOH/dichloromethane) to afford 0.08 g (95%) of 8 as a foamy oil. This was dissolved in CH 2 Cl 2 (5 mL) and HCl added (4N in dioxane, 0.11 mL). After stirring for 30 minutes at 23° C.
• Step 1 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.5 g, 1.9 mmol) was dissolved in acetone (5 mL) and potassium carbonate (0.52 g, 3.8 mmol) was added followed by S( ⁇ )-4-bromo-1,2-epoxybutane (0.57 g, 3.8 mmol). The mixture was stirred for 18 hours at 50° C. in a sealed vial then diluted with EtOAc (100 mL) and washed with water (2 ⁇ ), brine then dried (Na 2 SO 4 ). After concentration the residue was dissolved in 10 mL of MeNH 2 solution (8M in EtOH).
• Step 1 1-(but-3-enyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.44 g, 1.64 mmol) was dissolved in CH 2 Cl 2 (10 mL) at 23° C. 3-chlorobenzoperoxoic acid (1.02 g, 3.9 mmol) was added and the mixture allowed to stir for 18 h then filtered and concentrated. The residue was diluted with EtOAc and washed with 10% NaHCO 3 solution then brine. After drying with Na 2 SO 4 the solution was concentrated then 50 mg of the residue was dissolved in 2 mL of NH 3 solution (7M in MeOH).
• Step 1 In an analogous manner to example 3B, (2S)-4-[3-(2-fluoro, 4-((2-(trimethylsilyl)ethoxy)methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol was prepared from 1-(4-bromobutyl)-3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine (33% in ethanol).
• Step 3 The product from Step 1 was dissolved in 9:1 ether:methanol and 2N HCl in ether added. After allowing to stand overnight a solid formed which was remover by filtration to afford 3-fluoro-4- ⁇ 3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl ⁇ phenol hydrochloride.
• Example 6 was prepared using 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 4-penten-1-ol analogous to the conditions used in example 1.
• Example 7 was prepared using 1-(2-fluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and ammonia analogous to the conditions used in step 2 of example 1.
• Example 8 was prepared using 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 4-penten-1-ol analogous to the conditions used in example 1.
• Example 9 was prepared using 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 4-penten-1-ol analogous to the conditions used in example 1
• Example 10 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and ethylamine analogous to the conditions used in step 2 of example 1.
• Example 11 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and dimethylamine analogous to the conditions used in step 2 of example 1.
• Example 12 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and isopropylamine analogous to the conditions used in step 2 of example 1.
• Example 13 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 1.
• Example 14 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and t-butylamine analogous to the conditions used in step 2 of example 1.
• Example 15 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and methylamine analogous to the conditions used in step 2 of example 1.
• Example 16 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and methylamine analogous to the conditions used in step 2 of example 1.
• Example 17 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and methylamine analogous to the conditions used in step 2 of example 1.
• Example 18 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and dimethylamine analogous to the conditions used in step 2 of example 1.
• Example 19 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and isopropylamine analogous to the conditions used in step 2 of example 1.
• Example 20 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and isopropylamine analogous to the conditions used in step 2 of example 1.
• Example 21 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 1.
• Example 22 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and t-butylamine analogous to the conditions used in step 2 of example 1.
• Example 23 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and t-butylamine analogous to the conditions used in step 2 of example 1.
• Example 24 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and ethylamine analogous to the conditions used in step 2 of example 1.
• Example 25 was prepared using 1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and ethylamine analogous to the conditions used in step 2 of example 1.
• Example 26 was prepared using 1-(2-fluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 1.
• Example 27 was prepared using 1-(2-methylphenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 1.
• Example 28 was prepared using 1-(2,4-difluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 1.
• Example 29 was prepared using 1-(2,5-difluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 1.
• Example 30 was prepared using 1-(2,6-difluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 1.
• Example 31 was prepared using 1-(3-methoxyphenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 1.
• This compound was prepared using 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine analogous to the conditions used in example 3B.
• This compound was prepared using 1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine analogous to the conditions used in example 3B.
• This compound was prepared using 1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine analogous to the conditions used in example 3B.
• This compound was prepared using 1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine analogous to the conditions used in example 3B.
• This compound was prepared using 1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine analogous to the conditions used in example 3B.
• This compound was prepared using 1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine analogous to the conditions used in example 3B.
• This compound was prepared using 1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine analogous to the conditions used in example 3B.
• This compound was prepared using 1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine analogous to the conditions used in example 3B.
• This compound was prepared using 1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, S( ⁇ )-4-bromo-1,2-epoxybutane and methylamine analogous to the conditions used in example 3B.
• Step 1 1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.15 g, 0.5 mmol) was dissolved in acetone (5 mL) and potassium carbonate (0.14 g, 1.0 mmol) was added followed by (R)-2-(oxiran-2-yl)ethyl 4-tosylate (0.24 g, 1.0 mmol). The mixture was stirred for 18 hours at 50° C. in a sealed vial then diluted with EtOAc (100 mL) and washed with water (2 ⁇ ), brine then dried (Na 2 SO 4 ).
• This compound was prepared using 1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to the conditions used in example 41.
• This compound was prepared using 1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to the conditions used in example 41.
• This compound was prepared using 1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to the conditions used in example 41.
• This compound was prepared using 1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to the conditions used in example 41.
• This compound was prepared using 1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to the conditions used in example 41.
• This compound was prepared using 1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to the conditions used in example 41.
• This compound was prepared using 1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to the conditions used in example 41.
• Step 1 In an analogous manner to Example 3B, 1-(2-fluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with cyclobutylamine (1 mL, 12 mmol) in methanol to give (2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.59 g, 44%).
• HRMS calcd for C 20 H 24 FN 3 O 3 S+H + , 406.15952; found (ESI, [M+H] + Obs'd), 406.1591.
• Step 1 In an analogous manner to Example 3B, 1-(2-fluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with cyclopentylamine (1.2 mL, 12 mmol) in methanol to give (2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.67 g, 49%).
• HRMS calcd for C 21 H 26 FN 3 O 3 S+H + , 420.17517; found (ESI, [M+H] + Obs'd), 420.1746. HP
• Step 1 In an analogous manner to Example 3B, 1-(2-fluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with cyclohexylamine (1.4 mL, 12 mmol) in methanol to give (2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol which was treated with 1N hydrochloric acid in ether to give hydrochloride salt as a white solid (0.84 g, 59%).
• HRMS calcd for C 22 H 28 FN 3 O 3 S+H + , 434.19082; found (ESI, [M+H] + Obs'd), 434.1902. HP
• Step 1 In an analogous manner to Example 3B, 1-(2-fluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with cyclohexylamine (1.4 mL, 12 mmol) in methanol to give (2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(isopropylamino)butan-2-ol which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.74 g, 57%).
• HRMS calcd for C 19 H 24 FN 3 O 3 S+H + , 394.15952; found (ESI, [M+H] + Obs'd), 394.1590.
• Step 1 In an analogous manner to Example 3B, 1-(2-fluorophenyl)-3- ⁇ 2-[(2S)-oxiran-2-yl]ethyl ⁇ -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with 30-40% ethylamine in methanol to give (2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol which was treated with 1N hydrochloric acid in ether to give a white hydrochloride salt (0.74 g, 59%). MS (ES) m/z 379.9 ([M+H] + ). HPLC retention time: 7.0 min.
• hNET Assay Procedure Protocol A Inhibition of [ 3 H] NE Uptake into Cloned Human NE Transporters (MDCK Cells) (“hNET Uptake”)
• the hNET uptake assay procedure was used to screen for compounds that inhibit the reuptake of norepinephrine and to determine IC 50 values for compounds identified as hNET reuptake inhibitors.
• NE uptake studies were performed using MDCK cells stably expressing human norepinephrine transporter (hNET) (See Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature. 350:350-354) cultured in growth medium containing high glucose DMEM (Gibco, Cat. No. 11995), 10% FBS (dialyzed, heat-inactivated, US Bio-Technologies, Lot FBD1129HI) and 500 ⁇ g/ml G418 (Gibco, Cat. No. 10131). Cells were seeded at 300,000/T75 flask, and split twice weekly.
• DMEM high glucose DMEM
• FBS dialyzed, heat-inactivated, US Bio-Technologies, Lot FBD1129HI
• 500 ⁇ g/ml G418 Gabco, Cat. No. 10131
• All uptake experiments were performed in 96-well plates (Falcon Optilux, cat #353947) in a total volume of 250 ⁇ l/well. MDCK cells were plated at 50,000 cells/well. At the time of the assay, the media was removed, and 200 ⁇ l assay buffer (25 mM Hepes, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl 2 , 1.2 mM MgSO 4 .7H 2 O, 2 mg/ml glucose, 0.2 mg/ml ascorbic acid, 1 ⁇ M pargyline, pH 7.4) was added to each well. 25 ⁇ l of each test compound was subsequently added to plates in triplicate and incubated at 37° C. for 5 minutes.
• assay buffer 25 mM Hepes, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl 2 , 1.2 mM MgSO 4 .7H 2 O, 2 mg/ml glucose, 0.2 mg
• test compounds were dissolved in 100% DMSO and diluted in 4% DMSO/H 2 O, and assayed using a 7-point dose response curve (1 nM-10 ⁇ M).
• 25 ⁇ l of [ 3 H] NE (74.9 Ci/mmol, Perkin Elmer, Boston, Mass.) was added to all wells and incubated at 37° C. for an additional 5 minutes. Non-specific uptake was defined by 20 ⁇ M desipramine.
• the final concentrations of [ 3 H] NE was 16 nM, respectively.
• the reaction was terminated by aspiration and washed with ice cold 50 mM Tris (pH 7.4).
• the plates were left to air dry for roughly 30 min, and MDCK cells were lysed by the addition of 25 ⁇ l of 0.25 M NaOH. 100 ⁇ l of Microscint-20 were added to each well (Packard, Perkin Elmer, Boston, Mass.), and the plates were counted using a TopCount (Perkin Elmer, Downer's Grove, Ill.) liquid scintillation counter.
• TopCount Perkin Elmer, Downer's Grove, Ill.
• % Inhibition of uptake ((mean cpm control wells ⁇ each cpm drug well)/(mean cpm control wells ⁇ non-specific wells) ⁇ 100.
• IC 50 values were calculated using a Prism® nonlinear regression program where % inhibition is plotted versus concentration of inhibitor.
• hNET Assay Procedure Protocol B Cell Based Norepinephrine (NE) Reuptake Assay Using the Recombinant Human Norepinephrine Transporter (hNET) (“hNET Uptake”)
• the hNET uptake assay procedure was used to screen for compounds that inhibit the reuptake of norepinephrine and to determine IC 50 values for compounds identified as hNET reuptake inhibitors.
• hydrochloride salts of compounds were dissolved in solution and 25 ⁇ l aliquots of compound solution at a 1 ⁇ M or 10 ⁇ M final concentration delivered directly to cells.
• stock compounds were prepared at 10 mM from powder. The stock solution was diluted according to compound testing range. Typically, the compound testing range was from 6 nM to 6 ⁇ M by half log dilutions.
• 25 ⁇ l of compound solution at the specified concentrations was added to the plates containing cells.
• a DMSO stock of desipramine was prepared at 10 mM in DMSO and diluted for a final concentration of 20 ⁇ M to determine the non-specific reuptake.
• the radioligand in this assay is 3 H-norepinephrine (NE) (PerkinElmer; NET678; 40-80 Ci/mmol) was delivered at approximately 16 nM final concentration for both single point testing and compound IC 50 determinations.
• NE 3 H-norepinephrine
• MDCK-Net6 cells stably transfected with human hNET (See Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature. 350:350-354) was maintained in growth media [high glucose DMEM (Gibco Cat. 11995), 10% FBS (dialyzed, heat-inactivated, Sigma, dialysed, heat inactivated, Lot# K 0922 or equivalent) 1 ⁇ Pen/Strep, and 500 ⁇ g/ml G418 (Gibco Cat. 10131)]. Cells were plated at 300,000/T75 flask and cells were split twice weekly.
• Cells were plated at 3,000 cells/well on day 1 in BD Falcon Microtest 96-well sterile cell culture plates, Optilux White/Clear Bottom TC plate (VWR; # 62406-466 or equivalent) in growth media and maintained in a cell incubator (37° C., 5% CO 2 ). On Day 2, cells were removed from the cell incubator and the growth media is replaced by 200 ⁇ l of assay buffer (25 mm HEPES 120 mM NaCL; 5 mM KCl; 2.5 mM CaCl 2 ; 1.2 mM MgSO 4 ; 2 mg/ml glucose (pH 7.4, 37° C.)) containing 0.2 mg/ml ascorbic acid and 1 ⁇ M parglyine.
• assay buffer 25 mm HEPES 120 mM NaCL; 5 mM KCl; 2.5 mM CaCl 2 ; 1.2 mM MgSO 4 ; 2 mg/ml glucose (pH 7.4, 37° C.)
• Microscint 20 (PerkinElmer; #87-051101) was added to the plates and the plates were sealed with film tape and replaced on the shake table for a minimum of 10 min. The plates were counted in a TopCount counter (PerkinElmer).
• each compound plate contained at least 3 control wells (maximum NE reuptake determinant) and 3 non-specific wells determined by adding 20 ⁇ M of desipramine (minimum NE reuptake determinant). Determination of active compounds were calculated using a Microsoft Excel spread sheet applying the following formula:
• % inhibition [1 ⁇ ((mean cpm test compound wells ⁇ mean cpm non-specific wells)/(mean cpm control wells ⁇ mean cpm non-specific wells))] ⁇ 100
• IC 50 determination raw cpm values were generated in a data file from the TopCount counter. The data was organized Microsoft Excel and transferred into PRIZM graphing and statistical program, which calculated the estimated IC 50 value. Calculation of IC 50 values was made using non-linear regression analysis with a sigmoidal dose response with variable slope. The statistical program used wells containing 3 H norepinephrine only as the maximal NE reuptake determinant and wells containing 3 H norepinephrine plus 20 ⁇ M desipramine as the minimal NE reuptake determinant (non-specific determinant). Estimation of the IC 50 value is completed on a log scale and the line is fit between the maximal and minimal NE reuptake values. In the event that the highest test concentration does not exceed 50% reuptake inhibition, data will be reported as percent maximal NE reuptake at the highest concentration tested.
• NE uptake (Protocol B) Example IC 50 (nM) 1 7.3 2 2.68 3 1.35 3A 3B 4 8.73 5 4 6 186 7 32 8 109 9 465 10 196 11 481 12 2255 13 9 14 853 15 2 16 3 17 252 18 278 19 2294 20 1158 21 6 22 3243 23 765 24 148 25 193 26 13 27 358 28 214 29 34 30 13 31 292 32 4 33 4 34 43 35 3 36 18 37 146 38 64 39 28 40 25 41 9 42 394 43 10 44 100 45 328 46 294 47 61 48 143 49 415 50 3833 51 5019 52 2118 53 104
• DMSO stock solutions of test compounds were prepared at 0.5 mM concentration.
• Diluted solutions of test compounds were prepared by adding 50 uL of each DMSO stock solution to 200 uL of acetonitrile to make 0.1 mM solutions in 20% DMSO/80% acetonitrile.
• Rat liver microsomal solution was prepared by adding 1.582 mL of concentrated rat liver microsomes (20 mg/mL protein concentration) to 48.291 mL of pre-warmed (to 37° C.) 0.1M potassium phosphate buffer (pH 7.4) containing 127 uL of 0.5 M EDTA to make a 0.6329 mg/mL (protein) microsomal solution.
• the method for this radioligand binding assay was modified from the methods supplied with hDAT membranes (catalog number RBHDATM; Perkin Elmer Life Analytical Sciences), and those modifications are listed within this method section.
• Frozen membrane samples from a cell line that expresses hDAT were diluted to 7.5 ml in binding buffer (50 mM Tris-HCl; pH 7.4, 100 mM NaCl), homogenized with a tissue-tearer (Polytron PT 120° C., Kinematica AG) and delivered at a volume of 75 ⁇ l to each well of a polypropylene 96-well plate.
• the binding reaction was run in polypropylene 96-well plates (Costar General Assay Plate, Cat. No.
• mazindol is a DA transporter inhibitor with a 50% inhibitory concentration (IC 50 ) value of 18.0 ⁇ 6.0 nM in the present assays.
• IC 50 inhibitory concentration
• Data from wells containing mazindol (10 uM) were used to define non-specific (NSB) hDAT binding (minimum hDAT binding). Total binding is defined by addition of 5 ⁇ l of binding buffer alone in the presence of [ 3 H] WIN-35,428.
• Stock solutions of compounds to be tested were prepared in DMSO at concentrations of 10 mM to 10 uM.
• test compounds were diluted in assay buffer according to test range (100,000 to 10 nM) ensuring a maximal DMSO concentration of less than 0.5% in the assay reaction wells.
• Homogenized membranes were pre-incubated with test compounds for 20 min at 4° C. before the initiation of the binding reaction.
• the binding reaction is initiated by addition of 25 ⁇ l of 3 [H]-WIN 35,428 diluted in binding buffer.
• the final concentration of 3 [H]-WIN 35,428 delivered was 10 nM.
• the plate containing the radioligand binding reactions were incubated for 2 h at 4° C. on a shaking table (Bellco, Vineland, N.J.) at 3 revolutions per minute.
• the MultiScreen-FB opaque 96-well filtration plates contained Millipore glass fiber filters (Millipore glass fiber B, Cat. No.
• MAFBN0B MAFBN0B
• the plates were presoaked with 0.5% polyethylenimine (PEI; Sigma Cat. No. P-3143) in water for a minimum of two hours at room temperature to reduce nonspecific binding of 3 [H]-WIN 35,428 during the harvest procedure.
• PEI polyethylenimine
• the PEI solution is aspirated from the filter plates using a vacuum manifold. Aliquots of each reaction (90 ⁇ l of each 100 ⁇ l reaction well) were transferred from the reaction plates to the filter plates using a Zymark Rapid Plate-96 automated pipette station. The binding reaction is terminated by vacuum filtration through the glass fiber filters.
• the filter plates were aspirated at 5-10 inches of Hg, and the wells are washed 9 times with 200 ⁇ l wash buffer (50 mM Tris-HCl, 0.9% NaCl, pH 7.4; 4° C.) using a 12 channel aspiration/wash system. Plastic bottom supports are removed from the filter plates and the plates are placed in plastic liners. A 100 ⁇ l aliquot of scintillation fluid was added to each well and the top of each plate is sealed with adhesive film. The plates are vigorously shaken at 5 rpm for 10-15 minutes to ensure adequate equilibration of aqueous to solvent partitioning. The collection of raw counts per minute (cpm) data was done using a Wallac Microbeta counter (Perkin Elmer).
• IC 50 values were made using the transformed-both-sides logistic dose response program that uses mean cpm values from wells representing maximum binding (total)(assay buffer) and mean cpm values from wells representing minimum binding (NSB, 10 ⁇ M mazindol). Estimation of the IC 50 values was completed on a log scale and the line was fit between the maximum and minimum binding values.
• the K i value for these studies was determined by dividing the IC 50 value by a factor of 2.4 to account for the concentration of 3 [H]-WIN 35,428 used in the assay.

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