TW200815341A - Pharmaceutically and veterinarily suitable salt - Google Patents

Abstract

An improved pharmaceutical and veterinarily acceptable salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide and compositions thereof, is described.

Description

200815341 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a modified 2,3-dichloro-N-cyclopentyl-N-[(3S)-5-indrolridin-3-yl group. Medicinal and veterinary acceptable salts of decylamine and its constituents. [Prior Art 3 Background] Compound 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzylindole 10 amine has serotonin and norepinephrine reuptake inhibition The activity of the agent can therefore be used in a variety of therapeutic areas. For example, the present compounds are useful in the treatment of conditions involving modulation of the function of a monoamine transporter, particularly in the treatment of conditions in which inhibition of reuptake of serotonin or norepinephrine is involved. In addition, the present compounds are useful for conditions involving inhibition of both serotonin and norepinephrine, such as urinary incontinence. In addition, the present compounds are intended for use in conditions that preferentially inhibit reabsorption of one of the positive adrenaline or serotonin over the reabsorption of the other, such as pain, fibromyalgia, attention deficit hyperactivity disorder (ADHD), and Depression. International Patent Application Publication No. WO2004/110995 discloses that a monoamine reuptake inhibitor comprises 2,3-dioxapentyl-N-nbilorizine-3-yl-tuberamine. It has unexpectedly been found that 2,3-dichloro-indole-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide has several advantages, thus making it suitable. For the preparation of pharmaceutically and veterinary acceptable formulations. It has thus been found that this particular salt form has a unique combination of good formulation properties, making it particularly suitable for the preparation of pharmaceutical and veterinary acceptable formulations using 5 200815341. A variety of these properties will be discussed later in the tables 1, 2A and 2B. C invention content:! SUMMARY OF THE INVENTION 5 According to the present invention, a hemi-citrate salt of 2,3-dichloroA-cyclopentyl_N-[(3S)-pyrrolidinyl-3-yl]benzamide is provided. In a preferred embodiment, the 2,3-dichloro-N-indolyl-N-[(3S)-indolyl-3-yl]benzylamine sulphate is halogenated by powder ( The PXRD) pattern is characterized by the use of CuKal X light radiation (wavelength = 1.54 〇 562 angstroms) to show 2 Θ main peaks at 129, 10 15 · 0, 15.2, 18 · 4, and 20 · 0 degrees (± 〇. 1 degree 2Θ). This embodiment is further characterized by differential scanning calorimetry (DSC) scoring, which is shown at a peak endothermic rate of 2i3 °c. In still another aspect of the present invention, there is provided a 2,3-dichlorocyclopentyl-N-[(3S)_%trolidine-3-yl]benzamide amine citrate together with a medicinal or beast A pharmaceutically acceptable or veterinary acceptable composition of a pharmaceutically acceptable diluent or carrier. In particular, the present invention provides a lozenge comprising a 2,3-dioxa_N_cyclopentyl-N-[(3S)-咣 咬 _3_ benzyl] benzalkonium hemi-citrate mixed with an excipient Formulation. A preferred formulation comprises the 2,3-dioxa_N_cyclopentyl 2 〇·Ν-[(33)·吼吼 -3-3· Γ Γ 醯 半 半 半 、 、, compression aids such as Microcrystalline cellulose, an additive that provides gloss to a tablet, such as anhydrous dibasic calcium phosphate, a disintegrating agent such as sodium starch glycolate, and a lubricant such as magnesium stearate. Further, the present invention provides a capsule formulation comprising a mixed excipient of 2,3_diox_N_cyclopentyl_N_[(3S)-pyridin-3-yl]nodosylidene citrate. Preferably, the formulation of 200815341 comprises the semi-citrate, inert diluent, disintegrating agent and lubricant as hereinbefore described. Further, the present invention provides 2,3-dichloro-N-cyclopentyl N_[(3S)_々t-r-[3-yl]] decylamine hemi-citrate as a sterile aqueous solution for parenteral administration. Preferably, such solutions contain from 1% to 4% by weight of propylene glycol, and preferably also contain sufficient sodium chloride to avoid hemolysis, for example comprising about 1°/〇w/v sodium chloride. 2,3-Dichloro-N-cyclopentyl-N-[(3S)"pyrrolidyl-1 yl]thretonamine hemi-citrate is useful because it has pharmacological activity in mammals including humans. It can be used for the treatment or prevention of a condition in which the regulation of monoamine transporter function 10 is involved, more particularly a condition involving inhibition of serotonin or norepinephrine reuptake, and a condition involving inhibition of serotonin and norepinephrine reuptake Thus, 2,3·di-N-cyclopentyl-N-[(3S)-pyrrolidinyl-3-yl]benzamide can be used to treat urinary incontinence, such as true stress type urine. Incontinence 15 (GSI), stress urinary incontinence (SUI), or urinary incontinence in the elderly; overactive bladder (OAB) 'includes abnormal hair dysfunction, secondary to neurological diseases (eg, Parkinson's disease, multiple sclerosis) , spinal cord injury and stroke) and urinary muscle hyperactivity and secondary urinary bladder dysfunction (such as benign prostatic hypertrophy (BpH), ureteral constriction or restenosis); urinary muscle activity; The combination of the aforementioned 20 conditions (such as stress type urinary incontinence combined with overactive bladder) caused by urinary loss And lower urinary tract symptoms, such as frequent urination and forced urinary. The term OAB is intended to cover both wet-type OAB and dry-type OAB. There is a pharmacological activity in the above, 2,3-dichloro-N-cyclopentyl-N-[ (3S)-Pipi each bite _3-yl] benzalkonium hexanoate can also be used to treat depression such as weight 7 200815341 type depression, recurrent depression, single episode depression, secondary symptom type Symptoms of depression, depression in cancer patients, depression in patients with Parkinson's disease, depression after myocardial infarction, depression in children, depression in child abuse, depression in infertile women, depression after isolation, menstruation Pre-irritation and convulsions for the elderly 5 syndrome. In view of the aforementioned pharmacological activities, 2,3-dichloro-N-cyclopentyl _N_[(3S) 吼 咬 -3--3-yl] decylamine hemi-citrate is also available. For the treatment of cognitive disorders such as dementia, especially degenerative dementia (including Alzheimer's disease, Alzheimer's disease, Pick's disease, Huntington's disease, Parkinson's disease and 10 CJD ( Creutzfeldt-Jakob disease)) and vascular dementia (including multiple infarct dementia) and occupying lesions with intracranial space Dementia associated with trauma, infection and related conditions (including HIV infection), metabolism, toxins, tissue hypoxia and vitamin deficiency; mild cognitive impairment associated with aging, especially age-related memory impairment (AAMI), insomnia 15 cognitive decline associated with aging and aging (ARCD); psychiatric disorders such as schizophrenia and snoring; anxiety disorders such as generalized anxiety disorder, phobia (eg, phobia, social phobia and simple phobia), panic Symptoms, obsessive-compulsive disorder, post-traumatic stress disorder, mixed anxiety and depression; personality disorders such as avoidance personality disorder and phonetic deficit hyperactivity disorder (ADHD); sexual dysfunction such as early onset ejaculation 2 (MED), male Erectile dysfunction (MED) and female sexual dysfunction (FSD) (eg female arousal disorder (FSAD)); premenstrual syndrome; seasonal affective disorder (SAD); dietary disorders such as anorexia nervosa and bulimia nervosa; Obesity; appetite suppression; chemical dependence due to cancer or substance abuse, such as nicotine, alcohol, coca, heroin, 8 200815341 Phenobairbital and stupidity, 5 10 15 chemical dependence caused by J's cheek addiction; withdrawal syndrome, such as withdrawal syndrome that may be due to the aforementioned chemical dependence; paste such as partial turn, sputum Shape = slow = paroxysmal migraine, headache associated with vascular disorders, headache and tension headache associated with withdrawal syndrome due to chemical dependence; pain; Bajinsen's _ such as Parkinson's Dementia of the disease, neurological drugs-induced Parkinson's disease and delayed dyskinesia; endocrine disorders, such as hyperprolactin in the blood; vasospasm f, such as the gray tube stenosis of the cerebral vascular bed; cerebellar dysmotility; Syndrome; plucking cockroaches; stealing cockroaches; emotional instability; pathological crying; sleep disorders (snoring) and shock. ADHD is of particular interest in the aforementioned conditions. The diagnosis of ADHD is based on clinical evaluation (M. Dulcan et al.; eight 111 people (^ (1 Child and Adolescent Psychiatry, Oct. 1997, 36 (10 SuPPl), 85s_121s; National Institutes of Health, 1998) a "ADHD The main Wei is the persistent pattern of inattention and/or hyperactivity-impulse, which compares the frequency and severity observed by typical individuals at the comparative level of development. (Diagnosis and statistics of mental disorders (DSM-IV) ), American Psychiatric Association, Washington, DC, 1994. In order to cut off ADHD, patients must demonstrate that ADHD symptoms are caused by a deficiency before the age of 7 and that symptoms must be in at least two contexts (eg, school [or workplace] And family) for more than six months (refer to DSM-IV). In view of the aforementioned pharmacological activity, 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzyl Indoleamine hemi-citrate can also be used to treat a variety of other conditions or conditions, including hypotension; gastrointestinal disorders (involving changes in gastrointestinal motility and secretion) such as intestinal fistula (IBS), intestinal obstruction (eg postoperative intestinal obstruction) And defeat 20 200815341 intestinal obstruction during blood disease), stomach cramps (such as sugar Sick gastroparesis), digestive 〉 beiyang, gastroesophageal reflux disease (GORD or synonym GERD), flatulence and stagnation of b-intestinal disease, such as dyspepsia (eg non-ulcerative dyspepsia (NUD)) And non-cardiac chest pain (Nccp); and fibromyalgia syndrome. There is a time in the aforementioned pharmacological activity, 2,3-digas-N-cyclopentyl-N_[(3S)_吼洛唆-3-yl] thrift Aminosemisyl citrate can also be used to treat pain. 10 15 Sweat pain is an important protective mechanism designed to warn of an external environment that may present a risk of noxious stimuli. The system operates via a specific set of primary sensory neurons, and It is activated by noxious stimuli through the peripheral conduction mechanism (Ref., 1999, Ρπ^·N_biol., 57, l-164 for its review). These sensory fibers are called pain receptors, and this sensory fiber is slow. The characteristic small-diameter axons of conduction velocity. The pain receptors are programmed, duration and quality due to their local anatomical organization:: The location of the stimulus. _ The system appears in the pain nerve fibers, including the large type, ie A , dimension (with 雠) and C fiber (without _). The activity produced by the input is directly transmitted in (4) _ complex _, or transmitted to the f-side bottom hypothala through the smear, and then transmitted to the cortex to produce pain in the cortex. 2 Usually classified as acute Or chronic. The beginning of acute pain is short (usually 12 weeks or less). It is usually associated with factors such as specific injuries and is often sharp and severely painful. It is caused by hand=疚特纽, (4)Μ(四) This type of pain occurs after a beta injury. Acute pain usually does not cause any lasting psychological reaction. Conversely, chronic pain is a long-term pain, typical duration (four) (four) 20 200815341 months, resulting in significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g., painful diabetic neuropathy, post-herpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, joint pain, and chronic postoperative pain. 5 When the body tissue is physically injured due to illness or trauma, the characteristics of pain receptor activation are altered, and sensitization is localized around the wound site and centered around the pain receptor. These effects may result in increased pain perception. For acute pain, these mechanisms can be used to enhance protective performance and thus make the repair process even more feasible. Normally, once injured, the sensitivity will return to normal. However, in a variety of chronic pain states, it is still too sensitive after the healing process, often due to neurological injuries. Such injuries often result in sensory nerve fiber abnormalities associated with incompatibility and abnormal activity (Woolf & Salter, 2000, Science, 288, 1765-1768). 15 Clinical pain will occur when there is discomfort and abnormal sensitivity in the patient's symptoms. The patient is quite different. There may be multiple pain symptoms. These pain symptoms include: 1) spontaneous pain 'this pain can be dull, burning or stinging; 2) exaggerated pain response (hyperalgesia) to noxious stimuli; and 3) from normal harmless stimuli Pain produced (pain abnormalities - Meyer et al., 20 1994, Pain Textbook, 13_44). Although patients with various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may vary and therefore require different treatment strategies. Depending on the pathophysiology, pain can be divided into a number of different subtypes, including pain receptor pain, inflammatory pain, and neuropathic pain. 11 200815341 Seeing that X body pain is induced by tissue damage, or by four stimuli that may cause knowledge. The afferent afferent system is activated by the pain and body conduction of the injured part. (4) The pain receptors that are activated by the human chordate, and the same degree of neural crest. Then go up through the spinal bundle, #继到脑, 5 10 15 20 to see the pain in the big fine (Meyer et al., 1994, Pain Textbook, 13_44). Activation of pain and body activates two types of human neurofibrillar. Qianle's fiber transmission is fast, responsible for sharp pain and tingling, and without (four) c fiber, the rate of transmission Ixk, and the transmission of pure pain or phase. Moderate to severe acute pain g-pain is caused by central nervous system trauma, deformation/sprain, and burning. The main features of muscle infarction and acute pancreatitis pain, postoperative pain (any similar surgery = Lai), post-traumatic pain, renal colic, cancer pain and back pain: cancer pain can be chronic pain such as tumor-related pain (eg "Bone pain, fU or visceral pain" or pain associated with cancer treatment (eg, broad 22:, V syndrome, postoperative pain syndrome, or 2 groups after radiation therapy). Cancer _ may occur in chemotherapy, New Zealand treatment, hormone therapy f: caused. Back pain may be naturally relieved due to herniated discs or broken two =:, _ joints, muscles around the spine or posterior tibia. However, in some patients, back pain persists for 12 weeks w«, special wealth can be discarded. Hyperthermia pain is currently caused by pain or pain caused by __ _ lesions or dysfunction. The gods are caused by trauma and disease. Thus, "neuropathic pain" :: more: the cause of the disease. These conditions include heart m, diabetic neuropathy, post-neuralgia, tri-neural nerves 200815341 pain, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and chronic alcoholism Pain caused by hypofunction of the sputum, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological because it does not have a protective effect. It is often present after the original cause has disappeared and often lasts for many years, significantly reducing the quality of life of patients (w〇〇lf and Mannion, 1999, lancet) , 353, 1959-1964). Symptoms of neuropathic pain are difficult to treat because patients with the same disease may also be diversified (Woolf & Decosterd, 1999, Pain 10 Supp6, S141_S147; Woolf and Mannion, 1999, Thorn, 353, 1959-1964). Neuropathic pain includes spontaneous pain, spontaneous pain can be continuous pain, and paroxysmal pain or abnormally stimulating pain such as hyperalgesia (increased sensitivity to noxious stimuli and analgesia) is harmless to normal. Stimulation Sensitive 15 The inflammatory process is a complex series of biochemical events and cellular events that are activated in response to tissue stings or foreign bodies, resulting in swelling and pain (Levine and Taiwo '1994, Pain Textbook, 45-56). Joint pain is the most common inflammatory pain. Rheumatoid disease is the most common chronic inflammatory disease in developed countries, and rheumatoid arthritis is the most common cause of disability. 20 due to rheumatoid arthritis The disease is unknown, but the current hypothesis suggests that genetic and microbiological factors are important (Grennan & Jayson, 1994, Pain Textbook, 397_4〇7). It is estimated that there are almost 6,000 million Americans with symptomatic osteoarthritis (0A) or degenerative joint disease. Most patients are over 60 years old and are expected to age with the population. The number of patients may increase to 40 million in 200815341, thus becoming a considerable public health problem (H〇uge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Pain Textbook, 387- 395). Most patients with osteoarthritis seek treatment because of pain. Arthritis has a significant impact on psychosocial and physical functions. Arthritis is known to be the leading cause of end-stage disease disability. Ankylosing spondylitis It is also a kind of rheumatism, which causes arthritis of the spine joints and secret joints. It consists of continuous lifelong intermittent episodes to severe chronic diseases 'attacks (four) vertebrae's peripheral joints and other body organs, etc. 10 15 Li Yi. (4) Recording pain For visceral pain, including pain associated with inflammatory bowel disease (_ visceral pain is a kind of visceral phase __, covering the organs of the abdominal cavity. These organs include sexual organs, spleen and Digestive system; points: The pain associated with the internal organs can be divided into digestive (four) silk non-filial; visceral visceral pain. Common gastrointestinal (GI) disorders that cause pain include functional bowel disease (Gang and inflammatory bowel disease) Gastrointestinal disorders include a wide variety of disease states that are currently only moderately controlled, including gastroesophageal reflux, dyspepsia, intestinal fistula (IBS), and functional abdominal pain syndrome (FAps) in the immediate sense; In other words, including Crohn's disease% and ulcerative colitis, all of them have visceral pain. Other types of internal pain include dysmenorrhea, bladder fire, and pain caused by long-term pancreatic pain and pelvic pain. It should be noted that several types of pain have multiple _ generations (4), which can be classified as more than variable components. Another painful stylistic component and other types of neuropathic pain include... 20 200815341 • Pain caused by musculoskeletal disorders, ridges; ^. Pain caused by pain, including myalgia, fibromuscular m, push acupoints, serum vaginal, g , &, m $ , rheumatism) joint lesions, non-articular rheumatism, muscle contraction lesions, glycogen, sclerotomy, and purulent myositis; • visceral and vascular pain, blush rabbit, ^ Caused by angina pectoris, myocardial infarction, pain in the sacral flap, Raynaud's phenomenon, sclerosis, and bone (4) ischemia • headaches such as her face and migraine without warning, and a headache , tension headaches, discomfort headaches, and headaches associated with vascular conditions; and facial pains include toothache, earache, scalded oral syndrome, and myofascial fascia pain. Conditions of particular interest to 7 people include urinary incontinence such as mixed urinary loss π GSI and SUI, pain; fibromyalgia; adh〇 and depression. The present invention further provides 2,3-dichloro-N-cyclopentyl_N_[(3S)-pyrrolidine-15-3-yl] decylamine hemi-citrate for human treatment of urinary incontinence, pain, fibromuscular muscle The use of pain, hyperactivity and depression. More particularly, the present invention further provides 2,3-dioxa-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide amine citrate for the treatment of urinary incontinence such as true stress type Urinary incontinence (GSI), stress urinary incontinence (SUI), or urinary incontinence in the elderly; overactive bladder (oab), including idiopathic type 20 urinary muscle instability, secondary to neurological diseases (eg, Parkinson's disease, multiple Sexual sclerosis, spinal cord injury and stroke) and excessive urinary muscle activity and secondary urinary muscle activity secondary to bladder efflux obstruction (eg benign prostatic hypertrophy (BPH), ureteral constriction or restenosis); Urinary incontinence due to a combination of the aforementioned conditions (eg, stress-type urinary incontinence combined with overactive bladder); and lower urinary tract 15 200815341 symptoms such as frequent urination and forced urination. The OAB-word is intended to cover both wet OAB and dry 0AB. The present invention further provides 2,3-dichloro-N-cyclopentyl-N-[(3S)-indenylpyridin-3-yl]benzamide amine citrate for use in animals, particularly in dogs, for the treatment of urinary incontinence. 5 The present invention provides a method for preparing 2,3-dichloro-indole-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzylamine sulphate by allowing 2,3- Dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide is reacted with citric acid in an inert solvent, and the hemic citrate is recovered. A preferred inert solvent is isopropanol (IPA). 10 The present invention also encompasses all suitable isotopic variations of 2,3-dichloro-N-cyclopentyl-N-[(3S)-indenyl-3-yl] benzinamide hemi-citrate. The isotopic variation of 2,3-digas-N-cyclopentyl-N-[(3S)^pyridin-3-yl]benzylamine sulphate is defined as where at least one atomic system has the same atom The atom of the order is replaced, but the atomic quantity of the atom is different from the atomic quantity seen in nature. 15 Examples of isotopes which can be incorporated into 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzylamine sulphate include hydrogen, carbon, nitrogen and Oxygen isotopes such as 2H, 3H, 13C, 14C, 15N, 170, and 180. 2,3·di-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzylamine Several isotopic variations of the citric acid salt, such as compounds in which a radioisotope such as 3H or 14C is incorporated, can be used for drug and/or enzyme matrix tissue distribution studies. The tritiated isotope, i.e., the 3H and carbon-14 isotopes, i.e., 14C, is preferred because it is easy to prepare and easy to detect. In addition, substitution with an isotope such as gas, i.e., 2H, may provide several therapeutic advantages due to higher metabolic stability, such as prolonged half-life or reduced dosage requirements in vivo. Isotope change of 2,3-dichloro-N-cyclopentyl 16 200815341 -N-[(3S)-pyrrolidin-3-ylbenzyl benzalkonium citrate is usually carried out via conventional procedures such as the following examples and The procedure described in the Preparations was prepared using isotopic changes of the appropriate reagents. Although the free-form base form of 2,3-di-n-cyclo-pentyl-N-[(3S)-indolyl-3-yl]benzylamine 5 is active, it is actually used for formulation purposes. The system is administered as a pharmaceutically and/or veterinary acceptable acid salt. Several different possible pharmaceutically acceptable salt forms of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzylamine have been identified. It is especially found that acid addition salts containing pharmaceutically and/or veterinary acceptable anions are suitable, such as hydrochloric acid 10 salt, hydrobromide salt, hemiethane-1,2-disulfonate (semi-disulfonic acid salt). Salt), ethane-1,2-disulfonate (ethanedisulfonate), fumarate, D-tartrate, L-tartrate, acetate and hemisulfate. For easy formulation of pharmaceutically and/or veterinary acceptable salts of 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl] benzamide, the following must be met Fourteen physical and chemical standards: (1) good solubility; (2) appropriate stability; (3) non-hygroscopicity; (4) good processing properties on pharmaceutical or veterinary blending. It has been found that although a plurality of salts as described above can satisfy a number of such criteria, none of the salts other than the preferred semi-citrate salt are observed to meet all criteria and provide the desired chemical stability and physical stability. Thus, it has been found that 2,3-dichloro20-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide amine has a number of advantages, making it particularly suitable for use. A pharmaceutical formulation of 2,3-dioxa-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide was prepared. Salts having a compounding advantage of the compounds of the present invention include: hydrochloride, hydrobromide, hemi-ethanedisulfonate, ethanedisulfonate, fumarate, L-tartrate, D-tartrate, 17 200815341 Acetate and hemisulfate. The hemi-ethanedisulfonate can be prepared according to the method disclosed in Example 1 of International Patent Application PCT/IB/5/〇〇3643 (published as Jun. 1, 2006, w. 2006/056884). The salt of the additional 2,3-dichloro-4-cyclopentyl good [(3s)-pyrrolidin-3-yl] decylamine can be prepared according to the acid addition salt production method known in the art, or according to the following (in the example) 3 to Example u) Preparation of the method specified in detail. For example, if appropriate, other salts of 2,3-dioxa_N_cyclopentyl _n_[(3s) _^r- ridin-3-yl] decylamine are conveniently via the solution of the compound with the desired acid Or prepared by mixing with a base. These other salts may be precipitated from the solution; they may be collected by filtration or may be recovered by evaporation to remove the solvent. Table 1 illustrates the selection of combinations of advantageous formulation properties of the salt forms according to the [Example 2] of the present invention, including non-hygroscopic and non-solvent properties. Table 1 Properties Semi-citrate crystallinity 1 Crystallographic thermal event 2 206 ° C (Sample A (Example 2A) - Figure 4) 213 ° C (Sample B (Example 2) - Figure 5) Solvate / Hydrate 3 ^ Non-solvent hygroscopicity 4 Non-hygroscopicity 2 The crystallinity measured by PXRD is described in detail later. 15 3 Determine the melting point by DSC according to the procedure discussed in Figures 4 and 5 below. The solvent/hydration system was evaluated by thermogravimetric analysis (TGA). The thermogravimetric analysis was performed using Texas Instruments (Ding 8 11 〇 111 ^ plus) -1 ^ 8 D 0 0 2950 instrument, and the 6.3 mg sample was measured in the open Weight loss in the platinum plate. The sample was purged with a nitrogen gas oven to 2 Torr. The rate of [:/min 4 hours is heated from ambient temperature to 300 °C. 20 Hygroscopicity was evaluated using Surface Measurement Systems Ltd's Dynamic Distillation Equipment Model DVS-1. The analysis was carried out at 30 ° C using a nitrogen flow of 200 cm 3 /i. The adsorption of water and the desorption of water were measured in the range of 〇% to 90% relative humidity (RH), using an interval of 15% RH. The humidity is exposed to at least 2 hours, or the rate of change to exposure is less than 0.0003%/min (average over 25 10 minutes). The sample weight was 12.6 mg. The samples were weighed using CAHND-200, a seven-digit record balance that is part of the integration of the instrument. 18 200815341 Table 2A and Table 2B show the results of a laboratory scale investigation based on the salt form of the present invention [Example 2A] compared to the formulation properties of other salt forms.

Table 2A Salt Semi-Citrate (Example 2A) HC1 (Example 3) HBr (Example 4) Hemi-disulfonic acid salt (Example 5) Ethylenediate salt (Example 6) Crystallinity Crystalline Crystalline Crystallization Crystallization heat event Endothermic peak 206〇C Multiple endothermic peaks 45°C, 90 〇C, 143〇C Multiple endothermic peaks 67〇C, 73〇C, 96〇C, 140〇C Endothermic peak 220°C Endothermic peak 134 °C Solvent Compound / hydrate NS S* S* S* S*

Table 2B Salt Semi-Citrate (Example 2A) Fumarate (Example 7) L-Tartrate (Example 8) D-Tartrate (Example 9) Hemisulfate (Example 10) Acetate (Example 11) Crystallinity Crystalline Crystalline Crystallization There are several disordered crystallographic crystallization events. Bright endothermic peaks 206°C Multiple endothermic peaks 79〇C, 202 °C Multiple endothermic peaks 30-100 〇C, 138 〇C, 154〇C - Endothermic Peak 123〇C Innumerable endothermic peaks 69 〇C, 81〇C Solvate/hydrate NS NS * S - S* S* NS : Non-solvent S: Solvent $ indicates the weight loss crystallinity of the solvent loss, Thermal events and solvent/hydration were determined according to the methods indicated above (Table 1). Table 2A and Table 2B indicate that among all the salts tested, only 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide sulphate Combination with excellent properties of the next 15 columns: desired crystallinity; single distinct endothermic peak; non-solvent. Since the higher melting point is easy to process, the thermal result is positive. 19 200815341 The compounds of the invention may be administered alone or as part of a combination therapy. If a combination of therapeutic agents is administered, the active ingredient may be administered sequentially or separately in separate pharmaceutical formulations or in a combination pharmaceutical formulation. Examples of suitable adjunctive therapeutic agents include: • Dental floss analgesics such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, force Ivaii〇rphan, methandone, meperidine, fentanyl, cocaine, codeine (c〇deine), dihydrococoa Because of 10 (dihydrocodeine), oxyc〇d〇ne, hydrocodone, pr0p0Xyphene, nalmefene, nalorphine,洛oxone, naltrexone, buprenorphine, butorphanol, naibuphine, or pentazocine; • non-steroidal resistance Inflammatory drugs (NSAID) such as aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, Flufenisal, flurbiprofen, Ibrahim 20 (ib Uprofen), indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, Meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, ol 20 200815341 rassinazine, OXaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or left beauty Zomepirac; 5 • Barbiturate tranquilizers such as amobarbital, aprobarbital, butabarbital, butatarbital (butabital), mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, color Secobarbital, talbutal, theamylal, Thipentental; benzodiazepines with calming effects such as chlordiazepoxide, clorazepate, diazepam, flurazepam , lorazepam, 15 oxazepam, temazepam, or triazolam; • antagonists with a calming effect such as diphenhydramine , pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine; • tranquilizers such as glutethimide, beauty Meprobamate, methaqualone, or dichloralphenazone; • Skeletal muscle relaxants such as baclofen, carrisopod 21 200815341 (carisoprodol), Chl〇rzoxazone, cyclobenzaprine, meth〇carbamol, or orphrenadine; • NMDA receptor antagonists such as Dai Messo Fang 5 (dextromethorphan) ((+)-3-hydroxy --N-methylmorphinane or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinane), ketamine, memantine, oral 卩Each. Combination of Lin, Quinine, Wu_4_(bendylmethyl)-2-acridinecarboxylic acid, budipine, EN-3231 (MorphiDex, morphine and Daizuome) ), topiramate, neramexane or perzinfotel including NR2B antagonists such as ifenprodil, traveloprodil or (·) ·(ΙΙ)-6-{2-[4-(3-Fluorophenyl)-4-hydroxy-1-acridinyl H-hydroxyethyl-3,4-dihydro-2(1H)-porphyrin Ketones; • α-adrenergic agents such as doxazosin, tamsulosin, clonidine, quanfacine, dexamethasamine Dexmetatomidine), modafinil, phentolamine, terazasin, prazasin or 4-amino-6,7-dimethoxy-2-( 5-methanesulfonylamino-1,2,3,4-tetrazolyl 17-chaline-2-yl)-5-(2-吼°定基)唆11坐琳; 20 • tricyclic anti-drug agent Desipramine, imipramine, amitriptyline or nortriptyline; A twitching agent such as carbamazepine, lamotrigine, topiratmate, or phenate hydrochloride 22 200815341 (valproate); • tachykinin (NK) antagonists are particularly NK- 3. NK-2 or NK-1 antagonists such as (aR, 9R)_7_[3,5·贰(trifluoromethyl)]]8,9,1011_tetrahydro_9_methyl-5-(4 -Methylphenyl)-7Η-[1,4]diindolo[2,lg][l,7]-naphthyridine 5 -6,13-di-(丁八1<:_637), 5- [[(211,38)-2-[(111)_1_[3,5-Wu(trifluoromethyl)benzyl]ethoxy-3-(4-fluorophenyl)-4)-indolyl]- Methyl]-l,2-dihydro-3Η·1,2,4-disa-3--(ΜΚ-869), aprepitant, laneitant, dapitan ( Dapitent) or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-nonylamino]-2-phenyl acridine (2S, 3S); Agents such as oxybutynin, tolterodine, pr〇piverine, tr〇pSium chloride, and darifenacin Solifenacin, long: Mifan^ buckle 11^6141^), and Iptorpion (ipratr〇pium); COX-2 selective inhibitors such as ciec〇xib, rfefecoxib, parecoxib, valdecoxib, 彳拉拉考希Deracoxib), etoricoxib, or iumirac〇xib; • coal tar analgesics especially for paraCetam〇l; • neuroleptics such as lepredid (droperidol), chlorPromazine, haloperidol, perphenazine, thi〇ridazine, mesoridazine,提福皮拉辛 (tri^|u〇perazine), fluphenazine, ci〇zapine, olanzapine, riSperid〇ne, mat Passioni 23 200815341 (ziprasidone), quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, ilo Iloperidone, perospirone, raclopride, zotepine, must 5 Bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, irifansin Eplivanserin), osanetant, rimonabant, meclinertant, Miraxion, or sarizotan; • vanilloid-like receptors Agent (such as resinferatoxin) or a vanilloid receptor antagonist (such as capsazepine) i • β-adrenergic agent such as pu 〇pran〇l〇 l); 15 • Local anesthetics such as mexiletine; • Pibe steroids such as dexamethasone; • 5-HT receptor agonists or antagonists especially 5-11 butyl 18/11) Agents such as eletriptan, sumatriptan, narazidetan (atdptan), zomimimittan (z〇lmitriptan) or rizatriptan 20 (rizatriptan); ·5·ΗΤ2α Receptor antagonists such as R(+)_a_(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenethyl)]-4_acridine methanol (MDL1〇〇9 〇7); • biliary test (in the test) analgesics such as ispnicollin 24 200815341 amine (RJR-2403), (magic _5_(2_吖 基 methoxy)_2_gas pyridine (ABT 594) or test; • Tramadol; • PDEV inhibitor such as 5-[2-ethoxy-5-(4-methyl-1-indolyl-sulfonyl 5 I group) Methyl-3-n-propyl-1,6-dihydro-7H-port is more than saliva[4,3-d]. Michidine 1 ketone (sildenafil), (6R, 12aR)_2, 3,6,7,12,12a-A hydrogen-2-methyl-6-(3,4-methylene II Oxyphenyl)·吼啡和[2,,Γ·· 6,^% pyridine[3,4-b]吲哚-丨,4_dione (IC-35丨 or Tadalafi (tadalafil) ))), 2-[2-ethoxy-5-(4-ethyl)-phenylidenesulfonyl)-phenyl]_5_methyl10·7-propyl_3H-flavored and 5,lf][l,2,4] three tillage-4-ketone (vardenafi1), 5-(5-ethylindol-2-butoxy-3-acridinyl)-3- Ethyl-2-(1-ethyl-3-indolyl)-2,6-dihydro-711-pyrazolo[4,34]pyrimidin-7-one, 5-(5-ethenyl- 2-propoxy-3-indolyl)-3-ethyl-2-(1-isopropyl-3-indolyl)-2,6-dihydro-7Η"pyrazole[4,3 -d]pyrimidin-7-one, 5-[2_ethoxy.5_(4-15ethylindole. well-1-ylsulfonyl)acridin-3-yl]-3-ethyl-2_[ 2-methoxyethyl]-2,6-dihydro-7-hydrazino[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amine Base]-2-[(2S)_2-(transmethyl) hydrazine. Each bite_ι_基]_N-decamper-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7.keto-3-propyl-6,7-dihydrol -1H"biazo[4,3-d]pyrimidin-5-yl)[2-(1.methyloxaridin-2-yl)20ethyl]-4-propoxybenzenesulfonamide • α-2-δ ligands such as gabapentin, pregabalin, 3-methylgabapentin, (1α 3α 5α) (3-amino-methyl-two-ring) [3·2·0]heptan-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-mercapto-heptanoic acid, (3S,5R)-3-amino-5-A Base-heptanoic acid, (3S,5R)_3_amino group_5_methyl_xin 25 200815341 acid, (2S, 4s)_4_(3-chlorophenoxy) valine, (2S, 4S)-4_ (3-fluorophenoxy) aminic acid, [(1R,5R,6S)·6·(aminomethyl)bicyclo[3.2.0]heptyl]acetic acid ' 3-(1-aminomethyl) -cyclohexylmethyloxadiazole_5-one, C-[1-(1H-tetras-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-amino Methyl 5-yl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl·octanoic acid, (3S,5R)-3-amino group _ 5-methyl-decanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3S,4R,5R)-3-amino-4,5-dimethyl -heptanoic acid, and (3S,4R,5R)-3-amino-4,5-dimethyl-octanoic acid; • cannabis; 10 • metabolism of alanine subtype 1 receptor (mGluRl) antagonist • serotonin reuptake inhibitors such as sertraline, color left serotonin metabolites to serotonin, fluoxetine, fluoxetine (fuxiidine to methyl metabolite), fofosamin (f|uvoxainine), paroxetine 'cital〇pram, chitanofan metabolites to 15 甲希坦罗潘, escitalopram, d,l - D-l-Fenfluramine, femoxetine, ifoxetine, cytopine (Cyan〇 (j〇thiepin), litoxetine, 达达丁丁) Puxiding ((130〇6 to 1^), Nifa Zuodong (1^[32〇(1〇1^), cericlamine, and trazodone; 2〇 • Adrenalin reuptake inhibitors such as maprotinline, lofepramine, mirtazepine, oxaprotiline, fezolamine, and Moxidin Tomoxetine), mianserin, buproprion, buppyin metabolite hydroxy buppeine, 26 200815341 nomifensine and vil〇xazine Vivalan, especially for selective norepinephrine reuptake inhibitors such as reboxetine, especially (S, S) _ repboxedin; • serotonin-norepinephrine double reuptake inhibition Agents such as venlafaxine, venlafaxine metabolites 去 _ venlafaxine, clomipramine, imipramine metabolite normethacamine, Duloxetine, milnacipran, and imipramine; • Inducible nitric oxide synthase (iN0S) inhibitors such as s_[2_^10-aminoethyl)amine ]ethyl]-L-salcynan, S-[2-[(l-iminoethyl)amino]ethyl]-4,4-one-keto-cysteine, S-[ 2-[(l-iminoethyl)amino]ethyl]_2-methyl-L-cysteine, (2s,5Z)_2-amino-2-methyl-7-[(l -Iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-1-( 5-thiazolyl)-butyl]thio]_5_ gas. Bis-pyridonitrile, 15 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]chlorobenzonitrile, (2S,4R)-2 -Amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]_5_thiobutanol, 2-[[(lR,3S)-3-amino-4- Hydroxy-1-(5-hydrazinyl)-butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1r,3S)_3_amino]-4-hydroxyl 1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)20ethyl]phenyl]nonanylcarboxylate Amine or sulfoethyl disulfide; • Acetylcholinesterase inhibitors such as Dopnepezil; • Prostaglandin E2 subtype 4 (EP4) antagonists such as N-[({2- [4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]acridine-yl)phenyl]ethyl}amino)-carbonyl]-4- Methylbenzenesulfonamide or chloro-2-(3-fluorophenoxy) 27 200815341 acridine-3-yl]carbonyl}amino)ethyl]benzoic acid; • leukotriene B4 antagonist such as 1-( 3-biphenyl-4-ylmethyl-winter-hydroxyl-bit. End-7-yl)-cyclopentanecarboxylic acid (cp-1〇5696), 5-[2-(2-carboxyethyl)-3- [6-(4-Methoxyphenyl)-5E-hexenyl]oxyphenoxy]-pentanoic acid 5 (ONO-4057) or DPC-11870, 5-lipoxygenase inhibitors such as zileut〇n, 6_[(3-gas_5-[4-methoxy-3,4,5,6-tetrahydro-2H-furan- 4-yl])phenoxy-methyl]-1-mercapto-2-indanone (ZD-2138) or 2,3,5-trimethyl-6·(3-pyridylfluorenyl)- 1,4-benzoquinone (CV-6504); 10 • Sodium channel blockers such as lidocaine; • 5-HT3 antagonists such as Ondanxi (on (jansetron), Gnissi left ( Granisetron), tropisetron, azasetron, dolasetron, or axissetron; • estrogen agonist or selective estrogen receptor Modulators (eg hormone I5 supplementation therapy (HRT) or lasofoxifene; • alpha-adrenergic receptor agonists such as phenylpropanolamine or R_45〇; • dopamine receptor agonists (eg apo) Morphine, its teachings as a drug can be referred to US-A-5945117), including dopamine D2 receptor agonists (eg, premiprixal, Pharmacia 20 uPj〇hn compound number PNU95666; Or ropinir〇 (ropinir〇le); • PGE1 agonist (eg Apsta Di (alpr〇stadi...; and its pharmaceutically acceptable salts and solvates. In still another aspect, the present invention provides a biscitrate comprising 2,3_di-N-cyclopentyl-N-[(3S)-indolyl-3-benzyl]benzamide, together with a 28 200815341 A composition of an additional therapeutic agent. For human use, 2,3-dichlorocyclopentyl-indole-[(38)-pyrrolidine, 3-aminobenzamide hemi-citrate can be administered alone, but for humans, it is usually used for humans. Appropriate pharmaceutical dosage for the route of administration and standard pharmaceutical practice = 5 diluent or carrier mixed dose. For example, 2,3-dichloro-7-cyclopentyl-indole _[(35) "better than _3_ yl] tartamine semi-citrate can be used as tablets, capsules (including soft gelatin capsules), jujube The round, bar, solution, or suspension dosage form is administered orally, orally or sublingually, and the dosage form may contain a flavoring or coloring agent for immediate release, delayed release, modified release, sustained release, Dual release, controlled release, or pulsatile delivery. 2,3-dioxacyclopentyl-N-[(3S)-pyridinium-3-yl]benzamide sulphate can also be permeable to the sponge Intra-injection administration. 2,3-Digas-N-cyclopentyl-N-[(3S)_%[:l-pyridin-3-yl]benzamide sulphate can also be passed through a fast dispersing dosage form or fast The dosage form is administered in a dissolved form. 15 These tablets may contain excipients such as microcrystalline cellulose, chylomicron, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn starch, Potato starch, or tree potato powder); disintegrating agents such as sodium glycolate, cross-linked sodium silicate, and some miscible citrates; and granulation binders such as polyethylene 吼Bite _, thiopropyl Mercapto cellulose 20 (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and acacia gum. In addition, it can include lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc. Solid compositions of a similar form may also be used as fillers in gelatin capsules. Preferred excipients in this regard include chylomicron, starch, fiber 29 200815341 sucrose or sucrose 1 polyethylene glycol For use in aqueous suspensions and/or elixirs, the compounds of the invention and their pharmaceutically acceptable salts may be combined with various sweetening or flavoring agents, colorants or dyes; with emulsifying and/or suspending agents, And a combination of a diluent, such as water, ethanol, propylene glycol, and glycerin, and a combination thereof. - The modified release type and the pulsatile release dosage form may contain an immediate release dosage form together with an excipient which acts as a release rate modifier. The release rate modifying agent is coated on the body of the device and/or included in the device body. Release rate modifiers include, but are not exclusively limited to, propyl propyl cellulose, methyl cellulose, (7) carboxyl groups. Methyl cellulose sodium, ethyl fiber , cellulose acetate, polyethylene oxide, yellow gum, Carbomer, ammonium methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, phthalate The hydroxypropyl decyl cellulose 'methacrylic acid copolymer and mixtures thereof. The modified release dosage form and the pulsatile release dosage form may contain a release rate 15 modified excipient or a combination thereof. The release rate modifying excipient may Exist in the dosage form, that is, in the matrix, and/or on the dosage form, that is, on the surface of the coating. The Rapid Dispersion or Dissolving Formulation Formulation (FDDF) may contain the following ingredients: Aspartame, Sweet Potassium , citric acid, cross-linked methylcellulose sodium, cross-linked 20-dimensional (cr〇sp〇vidone), diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropyl methylcellulose, stearic acid Magnesium amide, mannitol, methyl methacrylate, mint flavoring agent, polyethylene glycol, fumed oxygen, cerium oxide, sodium starch glycolate, sodium stearyl succinate, sorbitol, Xylitol. The words "dispersion or dissolution" as used herein indicate that the FDDF system has a dependency on the solubility of the drug used in the application of 30 200815341, that is, when the drug is insoluble, a rapidly dispersing dosage form can be prepared; and when the drug is soluble, it can be prepared quickly. Dissolve Qi J ^1. 2,3 -Dichloro-N- 戍 戍 - -N-[(3S) - 比 ϋ ϋ -3- -3- 基 基 半 半 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Intra-arterial, intra-abdominal, intrathecal, intraventricular, intraurethral, intrathoracic, intracranial, intramuscular or subcutaneous routes; or may be administered by infusion techniques. For such parenteral administration, the best use is in the form of a sterile aqueous solution which may contain other substances such as a sufficient amount of salt or glucose to render the solution and the blood isotonic. The aqueous solution 10 should be suitably buffered (preferably buffered to pH 3 to pH 9) if desired. The preparation of an appropriate parenteral formulation under sterile conditions is conveniently accomplished by skilled artisans using standard pharmaceutical techniques. For oral and parenteral administration to patients, 2,3-dioxa_N-cyclopentyl-N-[(3S)-la-rrolidine-3-yl]benzylamine citrate Usually 15 lines are from 10 mg to 500 mg (administered in a single dose or in divided doses). Such as 'for example, '2,3-diqi-Ν- 戍 戍 _ _N_[(3S)-n 洛 咬 -3--3-yl] benzyl hydrazine citrate tablets or capsules, if appropriate Containing 5 mg to 250 mg of active compound for single or two or more administrations. The physician will determine the actual dose that will be most appropriate for the individual patient and the dose will vary with the age, weight and response of the particular patient. The aforementioned doses are examples of the average case. Of course, there may be individual cases where a higher dose range or a lower dose range is preferred, and such is also within the scope of the invention. Those skilled in the art understand that 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide hemi-citrate can be used in the treatment of certain diseases (including PE). A single dose is administered on a "as needed" basis (ie, if required or if required by 31 200815341). EXAMPLE I Formulation Formulations Tablet formulations typically contain from about 0.01 mg to 500 mg of 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide half lemon The acid salt, tablet 5 filling weight is in the range of 50 mg to 1000 mg. An example of a formulation of 10 mg of lozenge: Ingredient %w/w Example 2 of citric acid 10.000* 10 Lactose 64.125 Starch 21.375 Crosslinked thiol cellulose sodium 3.00 Magnesium stearate 1.500 *This amount is typically based on the drug The activity is adjusted and is based on the weight of the free base 15 . 2,3-Dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzylamine sulphate can also be administered intranasally or by inhalation, conveniently presented Dry powder inhaler or aerosol spray dosage form for administration from a pressurized container, pump, spray or atomizer using a suitable propellant such as dichlorodifluoromethane, tri-fluoromethane, or two gas Tetrafluoroethane, hydrofluorocarbon such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade name]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [commodity Name]), carbon dioxide or other suitable gas. In the case of pressurized aerosols, the unit dose can be measured by installing a valve to measure the quantity measured. Pressurized container, pump, solution «Floating liquid, such as #用化化器 may contain active compound 2 with a lubricant, such as oleic acid sorbet. For use in: capsules and cards with = human input: _ if made of gelatin) can be formulated into a powder mixture of σ and appropriate powdery bases such as lactose. "------------------------------------------------------ 3-Based] decylamine hemi-citrate is delivered to the patient. The total amount of spray is 10 daily; it is in the range of 1 to 50 mg, and can be administered in a single dose or more commonly divided into multiple doses throughout the day. 2,3-one gas _N-cyclopentyl _n-[(3S)_h than sputum _3-yl] sulphate sulphate citrate can also be formulated to be administered through a nebulizer. The formulation for the nebulizer device may contain the following ingredients as a solubilizer, emulsifier or suspending agent··water, ethanol, 15 glycol, glycerin, propylene glycol, low molecular weight polyethylene glycol, sodium carbonate, carbon fluoride , polyethylene glycol ethers, sorbitan trioleate, oleic acid. In addition, 2,3-dichloro-N-cyclopentyl-N-[(3S)·indolyl-3-yl]benzamide hemi-citrate can also be administered as a suppository or pessary dosage form, or It is applied topically in the form of a gel, a syrup, a lotion, a solution, a cream, an ointment, or a spreader. The 2,3-dicyclopentyl-N-[(3S)-indolyl-3-yl]benzylamine sulphate can also be administered transdermally or transdermally via the use of a dermal patch. The compounds can also be administered via the ocular, pulmonary or rectal route. For ophthalmology, the compound can be formulated into an isotonic, pH-adjusted, sterile saline solution of micronized suspension; or it can be formulated into aseptic, pH-adjusted sterile water adjusted by 33 200815341, and preserved as needed A dosage form such as a chlorinated benzidine group is administered. In addition, the compound can be formulated in various creams. For topical application to the skin, 2,3-dichlorocyclopentyl hydrazine _[(38)^pyrrolidin-3-yl]benzamide sulphate can be formulated to contain active compounds in frequency or dissolved in Suitable anti-poor agents for the mixture of species or mixtures of minerals: mineral oil, liquid paraffin, white soft paraffin, propylene glycol, polyoxyethylene dioxane compound, emulsified hydrazine and water. κ 10 15 20 In addition, the compound may be formulated as a suitable lotion or cream, for example, in a mixture of one or more of the following: sorbitan stearate, polyethylene glycol, liquid paraffin, P〇lysorbate 60, cetyl S-type, wax, green wax-based stearyl alcohol, 2_octanoyl dialkyl alcohol, alcohol and water. 2,3· Di-N-cyclopentyl-N-[(3S)- 咄-pyridinyl] citrate succinate can also be used in combination with cyclodextrin. It is known that a cyclodextrin can form a package/donor body and a non-occluded body complex with a drug molecule. The complexation of the drug-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability and/or stability of the drug molecule. Drug-cyclodextrin complexes are commonly used in most dosage forms and most of the drug routes. As an alternative to direct compounding of the drug, cyclodextrin can be used as an auxiliary additive, for example as a carrier, diluent or solubilizer. The use of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, and suitable examples are described in WCM^91/11172, WO-A-94/02518 and WO-A-98/55148. For oral or parenteral administration, the daily dose of the compound is from 0.01 mg/kg to 30 mg/kg (administered in a single dose or in divided doses), and 34 200815341 is preferably administered at 0. 01 mg. /kg to 5 mg / kg range. Thus, Ginger knows that S has 1 to gram of _4 grams of compound, if appropriate for a single or two or more evening administration. In summary, the physician will determine the actual dose that is most appropriate for any particular patient, and the dose will vary with the age, weight, and response of that particular patient. The dosages are of course only exemplified by the average case, and some cases may be suitable for higher doses or lower doses, which are also within the scope of the invention. It is better to give it by oral administration. The beast is used on the west, 2,3_dichloro-N-cyclopentyl-yi[(38)^pyridyl]-decylamine and half-lemon _ is based on the positive (four) medical practice and is appropriately dosed 10 The veterinarian will determine the most appropriate dosing schedule and route of administration for a particular animal. Thus, according to still another aspect, the present invention provides a citrate containing 2,3-dichloro-N-cyclopentyl-N-[(3S)-indenylpyridine-3-yl]benzamide, and a pharmaceutical A pharmaceutical formulation that can be used as an adjuvant, diluent, and carrier. 15 The foregoing compositions may conveniently be presented in the form of a pharmaceutical formulation, such that a pharmaceutical formulation comprising a composition as hereinbefore defined, together with a pharmaceutically acceptable adjuvant, diluent or carrier, constitutes a further aspect of the invention. The individual components of such compositions may be administered sequentially or simultaneously in separate pharmaceutical formulations or combination pharmaceutical formulations. 20 When 2,3·di-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide-semi-citrate combination second therapeutic agent is used, the dose of each compound It will be different from the dose when the compound is used alone. The appropriate dosage is conveniently determined by the skilled artisan. BRIEF DESCRIPTION OF THE DRAWINGS 35 200815341 The following figures are intended to illustrate the invention; Figure 1: 2,3-digas-N-cyclopentyl-N-[(3S)-pyrrolidine-3-yl] A powder X-ray diffraction pattern calculated from the amine hemi citrate. Figure 2: 2,3-Dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]nodal 5 amine hemi-citrate, sample A [Example 2A] measured A powder X-ray diffraction pattern was obtained (using a Bmker-AXS ltd D5000 powder X-ray diffractometer). Figure 3: 2,3-dioxacyclopentyl-N-[(3S)-indolyl-3-yl]nosylamine hemi-citrate, sample B [Example 2] measured powder X Light diffraction pattern 10 (using the Booker-AXS D4 powder X-ray diffractometer). Figure 4: DSC temperature record of 2,3-digas-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzylamine citrate sample A [Example 2A] (Using the Texas Instruments Q1000 Differential Scanning Calorimeter). Figure 5: DSC temperature record of 2,3-dichloro-indole·cyclopentyl-N-[(3S)-pyrrolidin-3-yl]pyrene 15 amine semi-citrate sample B [Example 2] (Using a Perkin Elmer Diamond Differential Scanning Calorimeter). C application mode: j Detailed description of the preferred examples Preparation examples and examples: 20 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide It can be prepared by the method disclosed in the international patent application publication WO2004/110995 and the international patent application PCT/IB05/003643 (published as WO 2006/056884 on June 1, 2006), or as described later: To tie. C indicates. Rapid column chromatography was performed using Merck 36 200815341 (Merck) Oxygen Gel 60 (9385). Solid phase extraction (SPE) chromatography was performed using a Varian Mega Bond Elut (Si) cartridge (Anachem) under a vacuum of 15 mm Hg. Layer chromatography (TLC) was performed on a Merck's 60-well plate (5729) in 5 rows. J: The site was measured using a Gallenkamp MPD350 device and was uncorrected. The Varian-Unity Inova 300MHz and 400MHz Nmr spectrometers or the Mercury 400MHz nmr spectrometer are used. The mass spectrometry system uses the Finnigan voyager. (Navigator) Single quadrupole electrospray mass spectrometer 10 or Fenigan aQa APCI mass spectrometer Preparation Example 1: Preparation of (3S>3-Aminopyrrolidine-1-carboxylic acid tert-butyl ester

2N hydrochloric acid (aqueous solution) (21.81 liters, 43.62 moles) was added to (3S)-3.aminopyrrolidine^3.76 kg, 43.62 mol) to methyl15 alcohol (18·8) at 0 °C over 1 hour. Li) solution. The reaction was stirred for 15 minutes at which time a solution of b〇c2 (9.52 kg, 43.62 m) in decyl alcohol (3.8 L) was added while maintaining the reaction mixture at 5 ° C or below. Hey. The reaction mixture was allowed to warm to room temperature over 2 hours, at which time methanol was removed by distillation under reduced pressure. The pH of the obtained aqueous solution was adjusted to less than 6 using 2N hydrochloric acid (aqueous solution), and then washed with hydrazine (7.52 liters), and the organic phase was separated and discarded. The aqueous phase was cooled to 5 ° C, basified with aqueous potassium carbonate (6. 63 kg, 48 m.s., 7.52 liters of water) and the product was extracted with di-methane (DCM) (3 X 18.8 L). The combined DCM layer was washed with water (7 52 liters) and solvent was distilled, 37 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 31.2 Moule, 71%). 'H NMR (MeOD? 400MHz) 8 : 1.45 (br s?9H)? 1.69 (m, lH), 2.05 (m, lH), 3.03 (m, lH), 3.33 (m, lH), 3.49 (m, 3H) 5 1 by Fluorochem available from TCI Japan, Preparation Example 2: (3S)_3-(cyclopentylamino)pyrrolidine-1-carboxylic acid tert-butyl vinegar

As detailed in Preparation 1 of WO 2006/056884, cyclopenta-10 (12.7 ml, 143 mmol) was added to the (3S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (26). The mixture was stirred at room temperature under nitrogen for 1.5 hours under a mixture of methanol and toluene 3:1 (600 ml: 200 ml). The reaction mixture was then evaporated to 50 mL, and then evaporated and evaporated. The residue obtained was taken up in methanol (250 ml), cooled to &lt;RTI ID=0.0&gt;&gt; After the reaction was completed, water (50 ml) was added and the solvent was evaporated. The residue was diluted with an additional amount of water (150 mL) and extracted thrice with dichloromethane (250 mL). The organic phase was combined, dried (MgSO4) 1H NMR (CDC13? 400MHz) 6 : 1.18 (brs?lH)? 1.28 (m52H)? 1.44 (s, 9H), 1.52 (m, 2H), 1.67 (m, 3H), 1.83 (m, 2H), 2.05 ( m,lH),2 38 200815341 • 98(m,lH),3.08(m,lH), 3.30(m,2H), 3.45(m,lH),3.58(m,lH); MS APCrm/z 255 [ MH]+ Preparation 2A: Another method for the preparation of (3S)-3-(cyclopentylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (3S)-3_aminopyrrolidine-1- A solution of the butyl carboxylic acid in IPA (about 5.81 kg, 31.2 mol of a total of about 15 liters of IPA) was diluted with isoamyl alcohol (ΙΡΑ1) (11.7 liters). The cyclopentanone (2.62 kg, 31.2 mol) was added over a period of 30 minutes, the temperature did not rise above 30 ° C, and the residue after the addition was washed with isopropanol (3 L). This imine reaction mixture was stirred at room temperature for at least 5 hours. NaBH4 (1.3 kg, 34.3 mol) was cooled to 5 ° C in a slurry of tert-butylmethyl _ (ΤΒΜΕ) (11. 62 liters) and IPA (3 liters). At this rate, methanol (5.2 liters) was added to maintain the reaction. The temperature is below 10 °C. The imine solution in IPA was then added to the sodium hydride sodium mixture at a reaction temperature maintained below 5 ° C and the line was washed with IPA (3 liters). The reaction mixture was then warmed to room temperature and stirred for at least 8 hours. Care was taken to quench the reaction with water (11.6 L) and then diluted with TBME (11.6 L), at which time the phases were separated. The organic phase was washed with water (I 6 liters), and the combined aqueous washing solution was extracted back with hydrazine (11.6 liters). Then, the combined layer is evaporated to oil under reduced pressure, the oil is dissolved in acetic acid, and then evaporated once again to obtain the standard oil of the standard compound (7.75 kg is equivalent to 7 61 kg of product, 39.9 mol, 96%). ). Preparation Example 3 · (3S)-3-(cyclopentylamino) 吼 σ 定 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

(^^-(cyclopentylamino) bromide-indole-carboxylic acid terpene vinegar ^ in kilograms, 29.9 moles in ethyl acetate (38 liters) solution was cooled to 〇〇c, at this time A solution of toluenesulfonic acid (5.69 kg, 29.9 mol) in ethyl acetate (85·4 L). The slurry was stirred at 〇C for 1 hour, allowed to warm to room temperature and stirred overnight. After filtration and washing with ethyl acetate (7·6 liters), EtOAc (EtOAc: EtOAc (EtOAc) 6 : 1.49(s59H)?1.68 - 1.83(br 10 m,6H), 2.18(br m,3H), 2.38 (br s,4H), 3.44 _ 3.63(br m,4H), 3.77(m,lH) , 3.92 (m, lH), 7.24 (d, J = 7.9 Hz, 2H), 7.72 (d, J = 7. 9 Ηζ, 2 Η) Preparation 4: (3S)-3-[cyclopentyl (2,3) -Dimethyl benzhydryl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester

As detailed in Preparation 2 of WO 2006/056884, triethylamine (24 ml, 170 mmol) was added to the amine of Preparation 2 (36.1 g, 142 mmol) in dichloromethane under nitrogen. (350 ml) solution. The reaction mixture was cooled to 〇 ° C, and 2,3-dichlorobenzhydrin chloride (29.8 g, 142 mmol) was added dropwise to 40 2008 15341 di- methane to maintain the temperature below 5 °C. The reaction mixture was then stirred for 6 hours, then water (200 mL) was added and the organic phase was separated. The aqueous layer was then extracted with dioxane (250 mL). The combined organic phases were washed with 2M aqueous sodium hydroxide and 10% EtOAc. The crude product was purified by column chromatography eluting with EtOAc EtOAc (EtOAc:EtOAc:EtOAc 82.4%). 1H NMR (CDCl3? 400MHz? rotamers) 5 : 1.43-1.47 (d, 9H)? 1.56_1.66 (m, 5H), 1.79 (m, 0.5H), 1.98 (m, 3H), 2.37 (m, lH) , 2.92 (m, 0.5H), 3.15 (m, 0.5H), 3.40 (m, lH), 3.58 (m, 1.5H), 3.74 (m, 2H), 10 3.97 (m, lH), 7.10 (m) , lH), 7.24 (m, lH), 7.46 (d, lH); MS APCI+ m/z 427 [MH]+and m/z 327[MH-Boc]+ Preparation 4A: (3S)-3-[ Another method for the preparation of cyclopentyl (2,3-dioxabenzhydryl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester 15 sodium hydroxide solution ([2M aqueous solution], 31.4 liters, 62.8 moles Addition to the compound of Preparation Example 3 (3 s)-3-(cyclopentylamino) indole bite 1 - tartrate tert-butyl tosylate (10 · 48 kg, 24.6 mol) in toluene (34.54 liters) of the stirred slurry. The two-phase mixture is cooled to 〇 it, 2,3-dichlorobenzamide (5 66 kg '27.0 mol) in toluene (54 liters) and toluene container wash (3 liters) The reaction temperature is not more than 15 (the rate is added. Let the resulting mixture drop to ν 5 j day to keep warm to room temperature, at this time separate the phases. The organic phase is hydrochloric acid (Tao ' M. 4 L ' M. 4 Molar And water (M * liter) washing recorded under reduced pressure by adding and steaming to remove another portion of toluene (2 liters) and azeotropic drying. The title product is maintained in toluene solution (38.25 kg solution containing ι〇· 4 kg yield 41 200815341, 24.3 mol, 99%). Example 1: 2,3·dichloro-indole-cyclopentyl-N-[(3S)-pyrrolidinyl]benzamide

As detailed in Example 1 of WO 2006/056884, the title product (from the 5 base base) of the third butoxycarbonyl (Boc) protected product of Preparation 4 (46 g, 107 mmol) was dissolved under nitrogen. The mixture was treated with trifluoroacetic acid (85 mL, 1 M) and dichloromethane was then evaporated. The reaction mixture was then stirred at room temperature for 4 hours, then evaporated and evaporated under reduced pressure. The residue obtained was taken up in dioxane (400 ml) and washed with 1M aqueous sodium hydroxide (2 mL). The organic phase was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to azeotropic distillation with ethyl acetate (10-times), and then dried under reduced pressure to give the title product as a solid as a gum, 34 g (97%). Example 2: 2,3-dioxacyclopentyl-N-[(3S)_pyrobityl-3-yl] hydrazine 15 alternative method of amine toluene (4.4 liters) added to the aforementioned (3S)-3-[ A solution of cyclopentyl (2,3-dioxabenzhydryl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (Preparation Example 4A) in toluene was cooled to 〇 ° C. Trifluoroacetic acid (TFA) (13.85 kg, 121.5 mol, 5 eq.) was added, the addition rate was maintained at a low temperature of m15 ° C, and the line was washed with a stupid (5 20 liters). The reaction mixture was heated to 45 ° C for 3 hours. Upon completion of the reaction, TFA was removed by two vacuum distillations and replaced with toluene (2 x 20 liters), and 2 x 2 liters of distillate was collected and discarded. The toluene solution was cooled to room temperature and tested with aqueous sodium hydroxide 42 200815341 ([2M], 36.4 liters, 36.4 m) until the aqueous phase was above pH 1 〇. The phases were separated and the product was extracted back into aqueous hydrochloric acid ([1M], 31.2 liters, 31.2 moles). The organic phase was further extracted with water (1 〇·4 liters) in combination with a hydrochloric acid extract. The acidic aqueous phase is washed with toluene (10·4 liters) and then with aqueous sodium hydroxide.

5 ([5Μ] ’ 10.4 liters '52 murs) to the south of pjj 9. The aqueous phase was extracted with τβμΕ (2 X 31·2 liters). The combined organic phase was washed with water (2 〇·8 liters). The τβμΕ was replaced with hydrazine (2 χ 20 liters) under reduced pressure to give the title compound as a jpA solution (26.2 kg solution, 6.95 kg product, 21.2 mol, 87%). H NMR (MeOD, 300MHz) 5 : 1.37 - 1.98 (br m, 8H), 2.07 -10 2.42 (br m, 2H), 2.84 - 3.03 (br m, 2H), 3.36 (m, 2H), 3.77 (m, lH), 3.96 (m, lH), 7.27 (m, lH), 7.41 (br t, J = 7.9 Hz, 1H) 7 62 (br d, J = 8.0 Hz, lH), κ Example 2 Preparation of 2,3_二气善环戊基善[(3s)_ 口比罗基基]benzylhydrazine 15 amine semi-citrate

One / contiguous acid (2 · 04 kg ' 〇 · 5 equivalents) in water (2 liters) solution added to 2,3 _ 2 〇 one (four) one nuclear pentyl l [(3S) - 吼 mouth each bite -3- Base 醯 醯 自由 free state test (6. 95 rose to above 25 ^. 20 thousand ^, 1 when #) in isopropanol (35 liters) solution, the rate of addition so that the internal temperature will not get the slurry at 25 ° C was stirred for 2 hours, followed by distillation of 43 200815341. The filter cake was dried by suction, washed with isopropanol (20.8 L) and again as dry as possible. The wet product was dried under reduced pressure at 50 ° C overnight to obtain (S)-2,3-dichlorohepta-cyclopentyl-N-[(3S)·pyrrolidin-3-yl] decylamine hemi-citrate , white solid (7.7 kg, 86%). NMR (MeOD? 300MHz) 8 : 1.37 - 2.04 (br m? 8H) 52.49 (m, 2H), 2.69 (d, J = 15 · 2 Ηζ, 1 Η), 2 · 78 (d, J = 15 · 2 Ηζ, 1 Η ), 3·27 (m, lH), 3.56 (m, lH), 3.75 (br m, 3H), 4.29 (m, lH), 7_33 (m, lH), 7·43 (br t, J = 7.9) Hz, lH), 7.64 (br* d, J = 7·9Ηζ, 1Η)· Example 2A: 2,3-Dichloro-s-cyclopentyl-N-[(3S)-indolyl-3-yl]benzyl Preparation of guanamine semi-citrate

宁 citric acid (303⁄4 g, 〇·ΐ6 mmol, 〇·5 equivalent) in methanol (2 ml) 5 / gluten solution added to - gas cyclopentyl-N-[(3S)-吼洛 bite- A 3-benzyl]benzylamine hydrochloride free assay (10 mg mg, 〇 _32 mmol) in methanol (25 mL). The solvent was removed under reduced pressure and the residue was crystallisjjjjjjjj Dehydration under solid pressing to obtain (S)-2,3- 20 benzylamine citrate hemi-citrate, solid washed with isopropyl-(2 ml) and reduced with H-chlorocyclopentyl-N- [(3S)-吼洛ϋ定_3· [, is a white solid. 44 200815341 lH NMR (400 MHz, MeOH-A) 5: 7.65 (1H, d), 7.43 (1H, dd), 7.30 (lH, dd), 4.34 (lH, m), 3.85-3.68 (3H, m), 3.52 (lH, m), 3.26 (lH, m), 2.72 (2H, dd), 2.60-2.42 (2H, m), 1.95 (lH, m), 1.92-1.65 (3H, m), 1.65 -1.40 (4H, m). Example 3: Preparation of 2,3-dioxa-N-cyclopentyl-N-[(3S)--pyrrolidin-3-yl]benzylguanamine hydrochloride

10 aqueous hydrochloric acid solution (0.32 ml, 1.0 M, 0.32 mmol, 1.0 equivalent) added to 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzidine A solution of the amine free base (105 mg, 0.32 mmol) in methanol (2.5 mL). The solvent was evaporated under reduced pressure. crystall crystal crystal crystal crystal crystal crystal The solid was washed with diisopropyl ether (2 mL) and dehydrated under reduced pressure to give (S) 2,3-dichloro-N-cyclopentyl-N-[(3S)-indrolidine-3- Benzobenzamide hydrochloride is a colorless crystal. NMR (400 MHz? MeOH-^) 5: 7.65 (1H, d), 7.43 (1H, dd), 7.30 (1H, dd), 4.34 (1H, m), 3.85-3.68 (3H, m), 3.52 ( lH,m ), 3.26 (lH,m), 2.60-2.42 (2H,m), 1.95 (lH,m),1.92-1.65 (3H,m), 20 1.65-1.40(4H,m)· 45 200815341 Examples 4 : Preparation of 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide amine hydrobromide

Aqueous hydrobromic acid solution (0.32 ml, 1.0 M, 0.32 mmol, 1.0 eq.) was added to 2,3-dichloro-indole- lysyl-N-[(3S)- 吼 咬 -3 - A solution of the free amine (105 mg, 0.32 mmol) in methanol (2.5 mL). The solvent was evaporated under reduced pressure. crystall crystal crystal crystal crystal crystal crystal The solid was washed with diisopropyl ether (2 mL) and dried under reduced pressure to afford (S)-2,3-dichloro-indole-cyclopentyl-N-[(3S) -Based benzinamide hydrobromide salt, which is a colorless crystal. NMR (400 MHz, MeOH-A) 8: 7.65 (1H, d), 7.43 (1H, dd), 7.30 (1H, dd), 4.34 (1H, m), 3.85-3.68 (3H, m), 3.52 ( lH, m ), 3.26 (lH, m), 2.60-2.42 (2H, m), 1.95 (lH, m), 1.92-1.65 (3H, m), 15 1.65-1.40 (4H, m). Example 5 · Preparation of 2,3-digas-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide amine hemi-ethanedisulfonate

46 200815341 1,2-ethanedisulfonic acid (30 mg, 0.16 mmol, 0.5 eq.) in decyl alcohol (2 mL) was added to 2,3-dichloro-indole- 哀 戊 戊 基 Ν [ [ [ (38)-σΗ: a solution of the free-form base (105 mg, 0.32 mmol) in methanol (2.5 mL). The solvent was evaporated under reduced pressure. The solid was washed with diisopropyl ether (2 ml) and dried under reduced pressure to give (S)-2,3-dichloro-indole-cyclopentyl-N-[(3S)-indrolidine-3- Benzobenzamide heptanesulfonic acid salt, as a white solid. lR NMR (400 MHz? MeOH-^) 5: 7.65 (1H, d), 7.43 (1H, dd), 7.30 (lH, dd), 4.34 (lH, m), 3.85-3.68 (3H, m), 3.52 (lH, m 10 ), 3.26 (lH, m), 3.22 (2H, s), 2.60-2.42 (2H, m), 1.95 (lH, m), 1.92-1. 65 (3H, m), 1.65-1.40 (4H, m). Example 6: Preparation of 2,3-dioxa-N-cyclopentyl-N-[(3S)·pyrrolidin-3-yl]benzylamine ethanedisulfonate

1,2-ethanedisulfonic acid (61 mg, 0.32 mmol, 1.0 eq.) in methanol (2 mL) was added to 2,3 - 2 gas-N- ί 戍-N-[(3S) - A solution of each of the 11-but-3-yl]benzylamine amine free base (105 mg, 0.32 mmol) in methanol (2.5 mL). The solvent was evaporated under reduced pressure and the residue was crystallised from ethyl acetate (5 ml). The solid was dehydrated under reduced pressure to obtain (S)-2,3-dichloro-indole-cyclopentyl 47 200815341 -N_[(3S)-pyridin-3-yl]benzamide ethanedisulfonate, It is a white solid. !H NMR (400 MHz 5 MeOH-^) 8 : 7.65 (1H, d), 7.43 (1H, dd), 7.30 (1H, dd), 4.34 (1H, m), 3.85-3.68 (3H, m), 3.52 ( lH, m ), 3.26 (lH, m), 3.22 (4H, s), 2.60-2.42 (2H, m), 1.95 (lH, m), 1.92-1. 5 65 (3H, m), 1.65 -1.40 (4H, m)· Example 7: Preparation of 2,3-digas-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzylamine-fumarate

10 Add the solution of fumaric acid (37 mg, 0.32 mmol, 1.0 eq.) to methanol (2 liter) to 2,3 -digas-N-d-pentyl-N-[(3S)-π A solution of the piroxicam-3_yl]benzylamine amine free base (105 mg, 0.32 mmol) in methanol (2.5 mL). The solvent was evaporated under reduced pressure and the crystall The solid was dehydrated under reduced pressure to obtain (S)-2,3-dichloro-indole-cyclopentyl-N-[(3S)-indolyl-3-yl]benzylamine sulfonate, It is a white solid. lH NMR (400 MHz, MeOH-A) 5: 7.65 (1H, d), 7.43 (1H, dd), 7.30 (1H, dd), 6.70 (2H, s), 4.34 (lH, m), 3.85-3.68 (3H,m), 3.52(lH,m), 3.26(lH,m), 2.60-2.42(2H,m),1.95(lH,m),1.92-l· 20 65(3H,m),1.65- 1.40(4H,m). 48 200815341 Example 8: 2,3·Dichloro-indole-yttrium-N-[(3S)-σ-pyridin-3-yl]-tanning amine L-tartrate preparation

n L-(+)-H02CCH(0H)CH(0H)C02H L-(+)-tartaric acid (48 mg, 0.32 mmol, 1.0 eq.) in methanol (25 mL) was added to 2,3 - A solution of the free-form base (105 mg, 0.32 mmol) in methanol (2.5 mL). The solvent was evaporated under reduced pressure and the residue was crystallised from ethyl acetate (5 ml). The solid was dehydrated under reduced pressure to give (S)-2,3-dichloro-indole-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzylamine L-tartrate as a white solid. 10 !H NMR (400 MHz? MeOH-^) §: 7.65 (lH, d), 7.43 (lH, dd), 7.30 (lH, dd), 4.40 (2H, s), 4.34 (lH, m), 3.85 -3.68(3H,m), 3.52(lH,m), 3.26(lH,m), 2.60-2.42(2H,m),1.95(lH,m),l.92-1. 65(3H,m) , 1.65-1.40 (4H, m)· 15 Example 9 : 2,3-dichloro-N-cyclopentyl_N-[(3S)-fluorenyl-3-yl]benzamide D·tartrate preparation

D_(一)-tartaric acid (48 mg, 0.32 mmol, 1.0 eq.) in methanol (2 49 200815341 ml) was added to 2,3-dichloro-indole-cyclopentyl_N_[(3S)•pyrrolidine_ The solvent was removed by evaporation of EtOAc (EtOAc) (EtOAc) The solid is dehydrated under reduced pressure to obtain (s)_2,3_digas_Ν_cyclopentyl 5-N-[(3S)" than slightly biting _3_yl]benzylamine D-tartrate, white solid. Iji NMR (400 MHz? MeOH-^) 8 : 7.65 (lH?d)? 7.43 (lH, dd), 7.3 〇 (lH, dd), 4.40 (2H, s), 4.34 (lH, m), 3.85- 3.68^ 3.52(lHM3.26(lH?m)?2.60-2.42(2H?m)a.95(lH?m)?1.92-l. Example 10 · 2,3_mono-N-cyclopentyl-N -[(3S)-pyrrolidine_3_yl]benzamide amine sulphate preparation

Aqueous ruthenium (6 ml, 1.0 M, 0.16 mmol, 〇 5 eq.) was added to the 2,3-dichloro-N-cyclopentyl-N_[ (3S)-吼 吼 _ 3- 3- 基 基 基 。 。 。 。 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( The solvent was evaporated under reduced pressure. The solid was dehydrated under reduced pressure to obtain (S) 2,3-dichlorocyclopentyl-N-[(3Sh pyrrrolidin-3-yl)benzylamine hemisulfate as a crystalline white solid. 50 200815341 NMR (400 MHz? MeOH-^) 8 ·· 7.65 (lH, d), 7.43 (lH5dd) 57.30 (lH5dd)? 4.34 (lH?m)? 3.85-3.68 (3H5m) 53.52 (lH? m), 3.26 ( lH, m), 2.60-2.42 (2H, m), 1.95 (lH, m), 1.92_1.65 (3H, m), 1.6 5-1.40 (4H, m) · Example 11: 2,3-dichloro Preparation of -N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzylguanamine acetate

10 Aqueous acetic acid (0.32 ml, 1.0 M, 0.32 mmol, 1.0 eq.) in methanol (2 mL) was added to 2,3-dichloro-N-cyclopentyl-N-[(3S)- fluorene A solution of the pyridine-3-yl]benzylamine amine free base (105 mg, 0.32 mmol) in methanol (2.5 mL). The solvent was evaporated under reduced pressure. The solid was dehydrated under reduced pressure to obtain (S)-2,3-dichloro-N-cyclopentyl15-N-[(3S)-indolyl-3-yl]benzylamine acetate, which was crystalline. White solid. !H NMR (400 MHz, MeOH-A) 5: 7.65 (1H, d), 7.43 (1H, dd), 7.30 (1H, dd), 4.34 (lH, m), 3.85 - 3.68 (3H, m) , 3.52 (lH, m), 3 • 26 (lH, m), 2.60-2.42 (2H, m), 1.96 (3H, m), 1.95 (lH, m), 1.92-1.65 (3 20 H, m), 1.65-1.40 (4H, m). 51 200815341 Determining the properties of 2,3-dichloro-indole·cyclopentyl-N-[(3S)-indolyl-3-yl] decylamine hemi-citrate by PXRD and DSC analysis (a) PXRD analysis (1) Calculated value simulated powder X-ray diffraction pattern (Fig. 1) was measured at room temperature by using the "Reflective Powder Diffraction" module of Accelrys Materials Studio [3rd Edition]. The single crystal structure of 2,3-dichloro-N-cyclopentyl-N-[(3S)-indolyl-3-yl]benzamide was determined. The relevant calculation parameters in each case are: Wavelength = 1.540562 angstroms (Cu κα 〇 Polarization factor = 0.5 Pseudo_Voigt Profile) (U=0.0i, V=-0.001, w=0.002) The powder X-ray diffraction peaks with a strength higher than 20% and their 2 Θ values are shown in Table 3. Table 3 2,3-Dichloro-indole-cyclopentyl-N-[(3S)-indolyl-3-yl The calculated PXRD peak data is 2Θ/degree relative intensity/% 2Θ/degree relative intensity 8.6 20.0 18.5 25.7 12.9 100.0 19.5 28.7 14.5 33.1 20.0 75.7 15.0 49.9 21.2 33.6 15.2 36.8 22.5 32.7 15.6 22.5 23.5 23.8 16.9 20.6 25.4 25.2 18.4 41.3 27.3 25.4 52 200815341 As known by the crystallographic technicians of the Thermal Technology, the relative intensities of the peaks in a given table vary due to a number of factors, such as the directional influence of the crystal in the beam, or analysis. The purity of the material or the crystallinity of the sample. The peak position can also be migrated to obtain the change in sample orientation, but the peak position in the given table will remain as defined in the qualitative. The crystallurgical technician of the enthusiasm is also aware of Measurements using different wavelengths will be based on the Bragg equation - ηλ = 2 (1 sin Θ different displacements are obtained. The additional PXRD pattern produced by using other wavelengths is regarded as another representative map of the PXRD pattern of the crystalline material of the present invention, and thus also falls within the scope of the present invention. (ii) Measurement of the value of '3 gas cyclopentyl-N-[(3S)-吼 slightly bite-3-yl] benzinamide semi-limus acid salt [sample A] powder calender pattern (Fig. 2) Use Buick (test er_ (8) around (four) to obtain the calculation of the towel system using powdered α quartz (ICDD 4 Bu 1〇45) standard. The data is at room temperature at 2 degrees and the angle is 2 degrees 40 degrees before the wood is used 0 〇 2 degrees The size of the class is collected. The data is collected for 3.5 seconds in each class. The obtained powder has a relative intensity of more than 2%, and the 2 Θ±〇·1 degree is shown in Table 4. The powder χ light diffraction pattern is aligned to further calibrate the peak position. 20 53 200815341 Table 4 2,3-Dichloro-N-cyclopentyl-indole __, each red group] sulphonamide

l±i TC/ί! tt&gt;fe Γ I 2Θ/degree relative intensity/% 8.6 36.5 8.7 42.0 12.9 22.9 14.5 22.0 15.0 24.0 16.9 27.2 17.3 24.3 17.4 29.5 18.4 24.7 19.5 24.3 20.0 100.0 21.7 59.4 21.7 61.2 227? 23.5 25.3 26.1 26.1 26.3 27.3 30.3 33.1 35.4 39.6 39.7 Relative Strength /%^ 20.9 29.9 41.0 35.1 45.8 24.0 41.0 25.4 20.2 20.0 23.1 28.6 5 $External '2,3·Dichloro·Ν.Cyclopentyl _Ν_[(斗比批3_ The powder calendering pattern (Fig. 3) obtained from the brewing amine hemi-citrate [sample Β] was obtained using a Buick-AXS light diffractometer equipped with an automatic sample replacement. n, θ__ corner, automatic beam divergence crack and pSD Vantec, the tester is prepared to be analyzed by mounting the sample on a low background cavity Shihua 10 wafer test piece. Irradiated with copper κ-od X-ray (wavelength = 1.5406 angstroms), the X-ray tube was operated at 4 〇 kV/35 mA. The analysis was performed in a continuous mode set with a goniometer, and a count of 0.2 seconds per 18-degree class was performed. 2 至 to 55 ° 2 Θ range. The relative intensity of more than 25% of the resulting powder X-ray diffraction peak Its 20 value ± 〇 1 degree is shown in Table 5. The peak position can be further calibrated by aligning with the powder X-ray diffraction pattern calculated as shown in Figure 1. 54 200815341 Table 4 2,3_Dichloronasal ring戊基善[(38)-吼略咬_3-基]节||Ammonia citrate [Sample B] Measured PXRD spike data 2Θ/degree 8.5 12.9 14.5 15.0 15.1 17.2 18.4 15.5 19.5 20.0 21.2 21.6 22.5 23.5 Relative strength /% 41.9 97.5 32.9 52.0 35.7 49.9 56.8 39.3 40.1 100.0 40.8 86.1 45.5 44.2 2Θ / degree 23.5 25.3 26.0 26.0 26.4 26.5 26.9 27.3 27.5 30.3 31.2 39.5 39.6 Relative strength /% 44.1 52.6 73.5 77.8 41.6 41.1 38.0 61.6 26.3 32.9 29.8 37.2 30.3 5 (b) DSC analysis The DSC temperature record (Fig. 4) consists of 2.382 mg of 2,3-dichlorocyclononyl_N_[(3S)-pyrrolidinyl] guanamine citrate A sample of the salt [Sample A] was calculated using a Texas Instruments 卩1〇〇〇 differential scanning calorimeter in an aluminum pan. The sample was purged at 50 cm 3 /min under a nitrogen atmosphere to a temperature of 3 ° C per 300 ° C to 300 ° C. A distinct melt endotherm peak was observed at 206 ° C followed by multiple decomposition events. In addition, the 'DSC temperature record chart (Fig. 5) is a 3.088 mg 2,3-dichloro-N-% amyl group [(3S) using a diamond differential scanning calorimeter from a Perkins Emma company. _P is more than a pyridin-3-yl] decylamine hemi-citrate [sample B] 15 f. The sample was purged in a nitrogen furnace atmosphere at 4 〇 cubic centimeters per minute. The enthalpy was 2 乂 per knife (the rate was heated from ambient temperature to 3 〇 (rc. at 213. 〇 彳 $ 彳 _ body absorption peak, then For multiple decomposition events, η% peak temperature is increased by Na.c 55 200815341 (Fig. 4) to 2i3°c (Fig. 5) due to possible sample B (Fig. 5) relative to sample A (p. 4)) The purity is increased instead of the indicated form. Bioactive pharmacologically active part 2,3-dichloro-N-cyclopentyl-N-[(3S)4 lysine I base] 5 benzyl amine The activity is described in the International Patent Application No. PCT/IB05/003643 (published as WO 2006/056884 on June 1, 2006). Example 1 of the case shows NRIKI = 15 nM and SRIKi = 5 mM. The NRIKI and SRIKi of the example compounds were determined as follows. The compounds were subjected to scintillation proximal assay (SPA) technology, which inhibited the selective radioactive ligand to human serotonin and norepinephrine transporter (SERT and NET, respectively). Binding ability to test biological activity. SPA binding system uses radioligand 3H-citalopram (citalopram) and 3H-nisoxetine (nisoxetine) The human membrane cDNA (hSERT, hNET) encoding SERT or NET is subjected to SPA binding reaction to a cell membrane preparation prepared by human cDNA (hSERT, hNET) cell line 15. i) Cell culture method can express human fetal kidney cells of various transport factors (HEK-293) is a continuous cell culture medium (reference culture 20 base and buffer composition) maintained in a 225 cm2 flask at 37 ° C in the presence of 5% carbon dioxide in a humid atmosphere at 37 ° C. The cell line was subcultured by a 90% confluent monolayer at a ratio of 1:3-1: 4. To harvest the cells, the growth medium was removed from the monolayer and the cells were co-cultured with a cell lysis solution (Sigma). To show the dissociation phenomenon. The cells were then knocked out from the bottom of the flask and granulated for storage by granules at 56 200815341 before further use (in _8 (rc frozen storage). ii) Cell membrane preparation, I field pellets in ice On the ice, i. After 10 minutes of oral culture, use a hand-held homogenizer to individually homogenize the four-human ^ 10 seconds. Then homogenize at 1 〇 75 X g at 4. Centrifuge for 2 。 minutes. Then collect the supernatant and maintain the supernatant. The primary cells and the nuclear pellets (P1) were again homogenized, and then re-homogenized and centrifuged using the aforementioned conditions, and the supernatant 10 was collected and pooled with the supernatant obtained by the first centrifugation. The supernatant was centrifuged at 35,000 x g for 3 minutes at 4 °C, the supernatant was discarded, and the pellet (P2) was again suspended in 13⁄4 liter of membrane preparation buffer relative to the amount of cells originally filled per milliliter. The protein concentration is then determined and the membrane suspension is finally frozen in the set amount and stored at _8 (rc for assay analysis using 15 iii) assay analysis method A. Determination of the optimal assay conditions for individual membrane batches SPA bead types vary by transport factor, wheat germ agglutinin coated yttrium citrate (YSi WGA) SPA beads for hSERT assay analysis, and 20 WGA coated polyvinyl toluene (PVT WGA) SPA beads Granules are used for hNET assay analysis. The optimum concentration of beads and membranes was determined for each batch of membrane used. Specific deuterated radioligands of each transport factor were used (3H-hitanropone for hSERT and 3H-nisoxetine for hNET). The free radioligand concentration determined by the assay is expressed as a percentage of the total free radioligand concentration 57 200815341 to calculate the depletion estimate of the radioligand. The depletion of the radioligand in the assay for the two transport factors was less than 3 〇 % to ensure that sufficient radioactive ligand was available for binding. The depletion of the radioligand can also be used to select the best assay conditions for use when using a new batch of membrane. 5 The affinity of the radioligand for the individual transporter is based on the selected protein concentration and the concentration of the beads on each batch of membrane; This is achieved by measuring the concentration of the free state radioligand that is occupied by the 〇 concentration, which is the 50% transport factor binding site. The average KD of the radioligand for each batch of membrane was determined from at least three separate assays. Subsequent KD uses the contour data of the membrane batch for all assays to allow determination of the Κι values of the compounds studied using Cheng &amp; Pruss ff (Cheng YC and Rrus ff WH, resulting in 50 enzyme reactions) The relationship between the inhibition constant of % inhibition (Κι) and the concentration of inhibitor. Biochem Pharmacol 1973; 22 ·· 2099-3108). 15 B. Characterization of the assay protocol Preparation of the bead/membrane complex The membrane was thawed on ice and added to a predetermined amount of beads in the assay buffer suspension. The impurities were pre-coupled for 2 hours on a shaker by culturing a predetermined amount of protein f per milligram of beads at the temperature of the generation. 20 as pure/frequency at 865 X g away ^ 5 minutes. The obtained pellets were resuspended in the m-salt and heavy (four) silk steps. The final pellet is then resuspended in assay assay buffer at the specific concentration required for final assay analysis. Preparation of Ligand [H] Radioligand preparations were diluted in assay buffer to obtain a final final assay concentration below the equilibrium dissociation constant (kd). Preparation of Compound Plates All test compounds were prepared from dry samples at a concentration of 4 mM at 100% dimethyl hydrazine (DMSO). The compound was diluted in 0.75% DMSO in double distilled water 5 to obtain a suitable test concentration in a 384-well plate to obtain a final volume of 2 μL. The final assay analysis buffer is added to the specific well of the plate, allowing subsequent measurement of the binding of the total radioligand. In addition, 20 microliters of a high concentration compound which was assayed for each transport factor was subsequently added to a predetermined well to determine 10 non-specific binding (NSB). flUOXetine (l〇pM final assay analysis indifference) was used for hSERT, and desipramine (40 pM final assay concentration) for hNET. For individual transport factor assays, 20 microliters of the specific radioactive ligand prepared was added to each well of the final assay plate (containing the compound solution). Subsequently, 20 microliters of the corresponding bead/membrane complex is added to each well of the final assay plate to ensure thorough mixing of the suspension. The panels were sealed at room temperature for 1 hour with shaking. The plate was then incubated for another 6 hours, adapted to the dark, and then read. C. Data Analysis 20 The assay analysis window (specificity) of each plate was calculated by deducting the average NSB readings (counted per minute or expressed in cpm) from the average of the total combined readings. Subsequent cpm readings per well (net of average NSB) are expressed as a percentage of the plate window to determine the amount of radioligand bound to the transport factor. These values are plotted against the concentration of the test compound, and the bending inhibition concentration is applied. 59 200815341 The curve is obtained using a four-parameter logistic equation and a free-matching parameter matching data to obtain a redundant 5 〇 value (5 〇 % specific binding in the neurotransmitter transport factor inhibition). The concentration of the desired compound). The inhibition dissociation 5 constant (Ki) value was then calculated from the iCs 〇 value using the Cheng-Prusoff equation. After determining the individual values of the test compound, the total geometric mean is calculated, along with a 95% confidence interval and an n value, where n is the total number of individual heart values. Iv) medium and buffer

hSERT cell growth medium 10 DMEM, 10% (w/v) dialysis FCS 2 mM L-glutamine (diluted from 200 mM stock) 25 mM HEPES (diluted from 1 Μ stock)

250 μg/3⁄4 liter of genetecin hNET cell growth medium 15 DMEM, 10% (w/v) FCS 2 mM L-glutamine (diluted from 200 mM stock) 25 mM HEPES (diluted from 1 Μ stock) 250 Microgram/ml Gene Timothy Membrane Preparation Buffer 20 20 mM HEPES (obtained by re-steaming water from 1 Μ stock), ρΗ 7.4 at room temperature, stored in the next generation, dissolved in 5Q ml buffer before use. Intact protease inhibitor ingot. Assay assay buffer (1.5 times final assay concentration) 30 mM HEPES (diluted with heavy distilled water from 丨 "feedstock"), and 1 (10) 200815341 mM NaCl (diluted with 5 liters of re-distilled water), pH 7.4 stored at room temperature 4〇C. I: Simple description of the figure 3 Fig. 1: 2,3_Dichloro-N-cyclopentyl_N-[(3S)-indolyl-3-yl]peptidom 5 amine half-screw The calculated powder X-ray diffraction pattern of citrate. Figure 2: 2,3_digas_N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl] decylamine half lemon Acidate, sample A [Example 2A] measured powder X-ray diffraction pattern (using Bruker-AXS ltd D5000 powder X-ray diffractometer). 10 Figure 3: 2, 3 - Digas-N-cyclopentyl-N-[(3S)-indolyl-3-yl]nosylamine hemi-citrate, sample B [Example 2] measured powder X-ray diffraction pattern (Using the Buick-AXS D4 powder X-ray diffractometer). Figure 4: 2,3_Dichloro-N-cyclopentyl-N-[(3S)"bileridyl-methylene-benzylamine amide half DSC temperature record of citrate sample A [Example 2A] (using a Texas Instruments 15 Q1000 differential scanning calorimeter). Figure 5: DSC temperature record of 2,3_dichloro-indole_cyclopentyl-N-[(3S)"bistidine-3-yl]benzamide amine citrate sample B [Example 2] (Using Perkin Elmer Diamond Differential Scanning Calorimeter) [Main Component Symbol Description]

Claims (1)

200815341 X. Patent application scope: 匕 A 2,3-dichloro-cyclopentyl_N_[(3S)·pyrrolidinyl] decylamine citrate. 2. The compound of claim 1 is characterized by a powder calender diffraction pattern 5 (PXRD) pattern which exhibits a main peak at 12.9 when measured using Cu Κα radiation (wavelength - 1.5406 angstroms). 15.0, 15.2, H4, and 2〇_〇2Θ±0·1 degrees. 3. A pharmaceutical or veterinary composition comprising a compound as claimed in claim 1 or 2 together with a pharmaceutically or veterinary acceptable diluent or carrier 10 and additional optional excipients. 4. The composition of claim 3, which is in the form of a tablet. 5. The composition of claim 4, wherein the additional selectivity is an additive, a disintegrating agent, and a lubricant that are derived from a compression aid, a gloss to the tablet. 15 6. The composition of claim 3, which is in the form of a capsule. 7. The composition of claim 6 wherein the additional selective excipient is selected from the group consisting of inert diluents, dried disintegrating agents, and lubricants. 8. A sterile aqueous solution comprising a compound as described in claim 2 or 2 and suitable for parenteral administration. 9. A compound of claim 1 or 2, which is used in the treatment of urinary incontinence, pain, fibromyalgia, attention deficit hyperactivity disorder (ADHD), or sorrow. 10. The compound of claim 9 is for use in the treatment of urinary incontinence. 62 200815341 11. A compound according to claim 1 or 2 for use in the treatment of urinary incontinence in animals. 12. The compound of claim 10 or 11, wherein the urinary incontinence is true urinary incontinence (GSI), stress urinary incontinence (SUI), or urinary incontinence in an elderly or 5 animal. 13. Use of a compound as claimed in claim 1 or 2 for the manufacture of a medicament for the treatment of urinary incontinence, pain, fibromyalgia, ADHD, or depression in humans. 14. For the purposes of claim 13 of the patent application, it is used for the treatment of urinary incontinence. 15. Use of a compound as claimed in claim 1 or 2 for the manufacture of an animal urinary incontinence treatment. 16. The use of claim 14 or 15 wherein the urinary incontinence is true urinary incontinence (GSI), stress urinary incontinence (SUI), or urinary incontinence in the elderly or dysfunction. 63