HK1116486A - Novel salt form of a dopamine agonist - Google Patents

Description

Novel salt forms of dopamine agonists

The present invention relates to novel salt forms of the dopamine agonist 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl) pyridin-2-amine (I):

more particularly, the invention relates to 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di- (1S) -camphorsulfonate (di-S-camphorsulfonate) and to intermediates used in the preparation of the salt, to processes for preparing compositions containing the salt, and to uses of the salt.

According to the description of international patent application WO2004/052372, compounds of formula (I) have been shown to be selective D3 agonists useful for the treatment and/or prevention of sexual dysfunction (e.g. Female Sexual Dysfunction (FSD), in particular Female Sexual Arousal Disorder (FSAD), and male sexual dysfunction, in particular Male Erectile Dysfunction (MED)). Male sexual dysfunction as referred to herein is intended to include ejaculatory abnormalities such as premature ejaculation, orgasm deficiency (inability to achieve orgasm) or desire disorders such as hypoactive sexual desire disorder (HSDD: lack of sexual interest). Female sexual dysfunction as referred to herein is intended to include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder. The compounds are also useful for the treatment of neuropsychiatric disorders and neurodegenerative diseases.

The free base form of the compound 5- [ (2R, 5S) -5 methyl-4-propylmorpholin-2-yl ] pyridin-2-amine has a low melting point and is deliquescent. These properties make the compound a less than ideal choice for incorporation into pharmaceutical formulations.

Remarkably, it has been found that 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate has the advantage of being able to formulate it as a necessary property for a drug. I.e. it is not deliquescent, it has a high melting point, and it is non-hygroscopic and it is in crystalline form.

Furthermore, 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate has the following additional advantageous properties that make it more suitable for use in conditions used for the manufacture of pharmaceutical products on a commercial scale, namely:

it did not dehydrate after 3.5 hours at 0% Relative Humidity (RH) at 30 ℃. Drug hydrates would generally be expected to dehydrate within hours of exposure to 0% RH. Furthermore, dehydration was observed at 85 ℃ when a sample of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate was heated in a 0% RH gas stream. This temperature is much higher than would normally be expected for a hydrated salt. Such kinetic stability is desirable to allow the compound to be successfully milled prior to formulation.

Many hydrates are not stable under the severe vacuum drying conditions required for isolation of the drug. However, the monohydrate of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate will be stable because it will remain as low as 10mbar when exposed to reduced partial pressure at 40 ℃.

The present invention includes the following embodiments:

a)5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate:

b) a compound according to a) in the form of a monohydrate.

c) Compounds according to b) having characteristic main peaks with a2 theta in their powder X-ray diffraction pattern of 6.3, 12.7, 15.1, 16.3 and 25.6 degrees.

d) A compound according to a), b) or c) having an enantiomeric excess of at least 80%.

e) A compound according to d) having an enantiomeric excess of at least 95%.

f) A pharmaceutical composition comprising 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate and a pharmaceutically acceptable diluent or carrier.

g) The pharmaceutical composition according to f), wherein the 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate is in the form of the monohydrate.

h) A process for the preparation of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate comprising reacting a compound of formula (X) with (1S) -10-camphorsulfonic acid in a suitable solvent.

i) The process according to h), wherein the solvent is acetone/water.

j) The process according to i), wherein the amount of water used is in the range of 0.7L to 1L of water per Kg of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine.

k) The process according to i), wherein the amount of water used is in the range of 0.8 to 0.9L of water per Kg of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine.

l) compounds of formula (VII) and pharmaceutically acceptable salts and solvates thereof.

Depending on atmospheric conditions (temperature and humidity), the compounds of the invention may exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is used when the solvent is water. Thus, the invention additionally includes pharmaceutically acceptable solvates of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate and 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate monohydrate.

The currently accepted classification system for organic hydrates is that of defining separation sites, channels or metal ion coordinated hydrates-seePolymorphism in Pharmaceutical Solids byK.R.Moms(Ed.H.G.Brittain，Marcel Dekker，1995)。

An isolation site hydrate is a hydrate in which water molecules are isolated from each other by inserting organic molecules so that they cannot come into direct contact. In channel hydrates, water molecules are located in lattice channels, where they are adjacent to other water molecules. In the metal ion complex hydrate, water molecules are bonded to the metal ions.

When solvent or water is intimately bound, the complex will have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound (as in channel solvates and hygroscopic compounds), the water/solvent content will depend on the humidity and drying conditions. Under these circumstances, non-stoichiometry is normal.

Also included within the scope of the invention are multi-component complexes (in addition to salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-receptor inclusion complexes) and co-crystals. The latter is generally defined as a crystalline complex of neutral molecular components bound together by non-covalent interactions, but may also be a complex of a neutral molecule with a salt. Co-crystals can be prepared by solution crystallization, by recrystallization from solvents, or by physically grinding the ingredients together-see Chem commu, 17, 1889-. For an overview of multicomponent complexes see J Pharm Sci, 64(8), 1269-1288, by Haleblian (8.1975).

The invention also includes all polymorphic forms and crystal habit of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate and 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate.

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate and its monohydrate, wherein one or more of the atoms are replaced by the following atoms: which have the same atomic number but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in compounds of the invention include hydrogen isotopes (e.g. hydrogen isotopes)²H and³H) carbon isotopes (e.g. of the formulae¹¹C、¹³C and¹⁴C) nitrogen isotopes (e.g. of the formula¹³N and¹⁵n), isotopes of oxygen (e.g. of the formula¹⁵O、¹⁷O and¹⁸o) and isotopes of sulfur (e.g. of sulfur³⁵S)。

Certain isotopically-labeled compounds of the present invention (e.g., those comprising a radioactive isotope) are useful in drug and/or substrate tissue distribution studies. Radioisotope tritium (i.e. tritium³H) And carbon-14 (i.e.¹⁴C) Are particularly useful for this purpose because they are easy to incorporate and the means of detection is simple.

With heavier isotopes such as deuterium (i.e.²H) Substitution may result in specific therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or a reduction in the necessary dose, and is therefore preferred in some circumstances.

Using positron-emitting isotopes (e.g. of the type¹¹C、¹⁸F、¹⁵O and¹³n) substitution can be used to detect substrate receptor occupancy in Positron Emission Tomography (PET) studies.

Isotopically-labelled compounds of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate can generally be prepared by conventional techniques well known to those skilled in the art, or by procedures analogous to those described in the accompanying experiments, using an appropriate isotopically-labelled reagent in place of the unlabelled reagent previously used.

Pharmaceutically acceptable solvates according to the invention include those wherein the crystallization solvent may be isotopically substituted (e.g. D)₂O、d₆-acetone, d₆-DMSO).

5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate monohydrate can be prepared according to the following scheme. Those skilled in the art will recognize other synthetic methods that may be equally practical.

Scheme 1

The 2-amino-5 bromopyridine may be reacted with 2, 5-hexanedione and p-toluenesulfonic acid under Dean-Stark conditions in a suitable solvent such as heptane to give the protected bromopyridine (II). And then (II) treating bromopyridine (II) with n-butyllithium in a suitable solvent (e.g., tert-butyl methyl ether) at low temperature. The amide (III) solution is then added to produce the chloroketone (IV). And then (iii) reductive conversion of the ketone to epoxide (V) by use of a suitable reducing agent (e.g. sodium borohydride) in a suitable solvent (e.g. tetrahydrofuran); followed by treatment with a suitable base, such as sodium hydroxide. (iv) Nucleophilic attack of epoxide (V) with (S) - (+) -2-amino-1-propanol (VI) in a suitable solvent (e.g. tetrahydrofuran) at elevated temperatures produces amine (VII). And (v) converting amine (VII) to compound (VIII) by reductive alkylation with propionaldehyde in the presence of a suitable reducing agent, such as sodium triacetoxyborohydride. (vi) Deprotection with hydroxylamine in a suitable solvent (e.g. ethanol) at high temperature converts compound (VIII) to compound (IX). (vii) Cyclization of compound (IX) under acidic conditions produces compound (X). (viii) Finally, 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate (XI) is produced by reacting compound (X) with (1S) -10-camphorsulfonic acid in a suitable solvent such as acetone/water followed by crystallization of the salt.

5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate and its polymorphs and pharmaceutically acceptable solvates are useful as selective D3 agonists for the treatment of disease.

Accordingly, in a first additional embodiment, the present invention provides the use of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate and its polymorphs and pharmaceutically acceptable solvates in medicine.

5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate and its polymorphs and pharmaceutically acceptable solvates may be particularly useful in the treatment of female sexual dysfunction, male erectile dysfunction, pain, neurodegeneration, depression and psychosis.

Accordingly, in a second additional embodiment, the present invention provides the use of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate and its polymorphs and pharmaceutically acceptable solvates in the manufacture of a medicament for the treatment and/or prevention of sexual dysfunction; suitable conditions include Female Sexual Dysfunction (FSD), in particular Female Sexual Arousal Disorder (FSAD), and male sexual dysfunction (FSD), in particular Male Erectile Dysfunction (MED). Male sexual dysfunction as referred to herein is intended to include ejaculatory abnormalities, such as premature ejaculation, orgasm deficiency (inability to achieve orgasm), or desire disorders, such as hypoactive sexual desire disorder (HSDD: lack of sexual interest). Female sexual dysfunction as described herein is intended to include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder.

In a third additional embodiment, the present invention provides the use of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate and its polymorphs and pharmaceutically acceptable solvates for the preparation of a medicament for the treatment of male erectile dysfunction.

In a fourth additional embodiment, the present invention provides the use of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate and its polymorphs and pharmaceutically acceptable solvates for the preparation of a medicament for the treatment of female sexual dysfunction, in particular female sexual arousal disorder and hypoactive sexual disorder.

The salts of the invention are also useful in the treatment of pain, particularly (but not exclusively) chronic nociceptive pain.

Physiological pain is a protective mechanism intended to warn of danger from potentially harmful stimuli from the external environment. This system is activated by noxious stimuli through a specific set of primary sensory neurons acting and via an extrinsic turnover guidance mechanism (reviewed in Millan, 1999, prog. neurobiol., 57, 1-164). These sensory fibers are called nociceptors and are characterized by small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration, and quality of noxious stimuli and, by their projection on the topological tissue of the spinal cord, encode the location of the stimuli. Nociceptors are found on nociceptive nerve fibers, of which there are two main types: a-delta fibers (myelinated) and C fibers (unmyelinated). After complex processing in the dorsal horn, nociceptor input produces activity that is transferred to the ventral basal thalamus, either directly or through the brainstem junctional nucleus, and then to the cortex where a painful sensation is produced.

Pain can be generally classified as acute or chronic. Acute pain starts suddenly and is of short duration (usually within 12 weeks or less). It is often associated with a particular cause (e.g., a particular injury) and is acute and severe. It is the kind of pain that can occur following a particular injury caused by surgery, dental procedures, strain or sprain. Acute pain generally does not cause a persistent psychological response. In contrast, chronic pain is chronic pain that usually lasts more than three months and causes serious psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, post-treatment neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-operative pain.

When severe damage is caused to body tissue by disease or trauma, the characteristics of nociceptor activation are altered and there is nociception both peripherally (located around the injury) and centrally (where nociceptors terminate). These effects lead to an increased sensation of pain. In acute pain, these mechanisms can be used to promote protective behavior that better enables the repair process to occur. Normal is expected to be the return of sensitivity to normal when the injury heals. However, in many chronic pain conditions, hypersensitivity is much longer than the recovery process and it is usually caused by nervous system injury. This injury often leads to abnormalities in the sensory nerve fibers associated with maladaptive and abnormal behavior (Woolf & Salter, 2000, Science, 288, 1765-.

Clinical pain occurs when the patient has symptoms characterized by discomfort and abnormal sensitivity. Patients tend to be very different and may present with multiple pain symptoms. These symptoms include: 1) spontaneous pain, which may be dull, burning or stinging; 2) exaggerated pain response to noxious stimuli (hyperalgesia); and 3) Pain resulting from normally harmless stimuli (touchness Pain-Meyer et al, 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may differ, and thus may require different treatment strategies. Pain can therefore also be divided into a number of different subtypes, including nociceptive, inflammatory and neuropathic pain, according to different pathophysiology.

Nociceptive pain is caused by tissue damage, or by intense stimuli that may cause damage. The transduction of stimuli by nociceptors at the site of injury activates the introduction of pain and, in its termination phase, the activation of neurons in the spinal cord. And then up the spinal cord tract to the brain where Pain is felt (Meyer et al, 1994, Textbook of Pain, 13-44). Activation of nociceptors can activate both types of afferent nerve fibers. Myelinated a-delta fibers transmit rapidly and respond to a sensation of acutely and tingling, while unmyelinated C fibers transmit at a slow rate and convey dull or aching pain. Moderate to severe acute nociceptive pain is a major characteristic of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), post-traumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain, such as tumor-related pain (e.g., bone pain, headache, facial pain, or visceral pain) or pain associated with cancer therapy (e.g., post-chemotherapy syndrome, chronic post-operative pain syndrome, or post-radiation therapy syndrome). Cancer pain can also result from chemotherapy, immunotherapy, hormonal therapy, or radiotherapy. Back pain can be caused by herniated or ruptured intervertebral discs, or abnormalities of lumbar facet joints, sacral joints, paraspinal muscles, or posterior longitudinal ligaments. Back pain can be eliminated naturally, but in some patients with back pain lasting more than 12 weeks, it becomes a particularly debilitating chronic condition.

Neuropathic pain is currently defined as pain that is induced or caused by a primary injury or dysfunction of the nervous system. Nerve damage can result from trauma and disease, and thus the term "neuropathic pain" encompasses a number of conditions with different causes. These disorders include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain, and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and vitamin deficiency. Neuropathic pain is pathological in that it does not have a protective function. It is often evident after the initial cause is eliminated (usually for years), severely reducing the quality of life of the patient (Woolf and Mannion, 1999, Lancet, 353, 1959-. Symptoms of neuropathic Pain are difficult to treat because they are often heterogeneous even among patients with the same disease (Woolf & Decoster, 1999, Pain supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). This includes spontaneous pain, which may be continuous, episodic, or abnormally provoked, such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally innocuous stimuli).

Inflammatory processes are a complex series of biochemical and molecular events that are activated in response to tissue damage or the presence of foreign substances, which cause swelling and Pain (Levine and Taiwo, 1994, textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatism is one of the most common chronic inflammatory disorders in developed countries, whereas rheumatoid arthritis is a common cause of disability. The exact cause of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-. It has been estimated that about one thousand six million Americans suffer from symptomatic Osteoarthritis (OA) or degenerative joint disease, most of which are over the age of 60 years, and that the population is expected to increase to four million with increasing age, making this a very important public health problem (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-. Due to the accompanying pain, most osteoarthritis patients seek medical attention. Arthritis has a great influence on psychosocial and physiological functions and is known to be a major cause of disability in the later years. Ankylosing spondylitis is also a rheumatic disease that causes spondyloarthritis and sacral osteoarthritis. It varies from intermittent episodes of back pain throughout life to a severe chronic disease that erodes the spine, peripheral joints, and other body organs.

Another type of inflammatory pain is visceral pain including that associated with Inflammatory Bowel Disease (IBD). Visceral pain is pain associated with the viscera, including organs within the abdominal cavity. These organs include the sexual organs, spleen and part of the digestive system. Visceral associated pain can be divided into digestive visceral pain and non-digestive visceral pain. Common include painful Gastrointestinal (GI) diseases, including functional enteritis (FBD) and Inflammatory Bowel Disease (IBD). These GI diseases include a wide range of disease states that are currently only moderately controlled, including gastroesophageal reflux, dyspepsia, Irritable Bowel Syndrome (IBS) and Functional Abdominal Pain Syndrome (FAPS) for FBD, and Crohn's disease, ileitis and ulcerative colitis for IBD, all of which regularly produce visceral pain. Other types of visceral pain include pain associated with dysmenorrhea, cystitis and pancreatitis, as well as pelvic pain.

It should be noted that some types of pain have multiple etiologies and can therefore be classified in more than one context, such as back pain and cancer pain having both nociceptive and neuropathic components.

Other types of pain include:

pain caused by musculoskeletal diseases including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, muscular dystrophy, glycogen breakdown, polymyositis, and pyomyositis;

cardiac and vascular pain, including pain caused by angina pectoris, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, sclerodoma and skeletal muscle ischemia;

headaches such as migraine (including migraine with aura and migraine without aura), cluster headache, mixed headache of tension-type headaches, and headache associated with vascular disease; and

orofacial pain, including toothache, earache, burning mouth syndrome, and temporomandibular myofascial pain.

Thus, in a fifth preferred embodiment, the present invention also provides the use of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate and its polymorphs and pharmaceutically acceptable solvates for the manufacture of a medicament for the treatment or prevention of pain. The invention further provides the use of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate and its polymorphs and pharmaceutically acceptable solvates for the preparation of a medicament for the treatment or prevention of chronic nociceptive pain.

In a sixth preferred embodiment of the present invention, the present invention also provides the use of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate, and polymorphs and pharmaceutically acceptable solvates thereof, for the preparation of a medicament for the treatment of neuropsychiatric disorders or neurodegenerative diseases; suitable conditions may include hypertension, neurodegeneration, psychosis, depression (e.g., depression in cancer patients, depression in Parkinson's patients, depression after myocardial infarction, sub-complex depression, depression in infertile women, major depression, child abuse induced depression, postpartum depression, and splenic dysphoric geriatric syndrome), single-episode or recurrent major depression, dysthymia, depressive neurosis and psychofunctional depression, depression with depression (including anorexia, weight loss, insomnia, early-wake insomnia, or bradykinesia); atypical depression (or reactive depression) includes appetite enhancement, lethargy, psychomotor agitation or excitation, seasonal affective disorder, and childhood depression; bipolar disorders or manic depression, such as bipolar I disorder, bipolar II disorder, and cyclothymia; a behavioral disorder; destructive behavioral disorders; trichotillomania, Attention Deficit Hyperactivity Disorder (ADHD); behavioral disorders associated with mental retardation, autism; borderline personality disorder; avoidant personality disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias (e.g., specific animal phobias, social anxiety disorder, social phobia), obsessive-compulsive disorder, stress disorders (including post-traumatic stress disorder and acute stress disorder), and generalized anxiety disorder; unstable emotion, pathological crying; schizophrenia and other psychoses, such as schizophreniform psychosis, schizoaffective psychosis, delusional disorder, brief psychotic disorder, shared psychosis, psychosis with delusions and hallucinations, psychotic anxiety disorder associated with psychosis, psychotic mood disorder, e.g., major depressive disorder; mood disorders associated with psychosis such as acute mania, and depression associated with bipolar disorder; mood disorders associated with schizophrenia; eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity; dyskinesias such as akinesia, dyskinesias (including familial paroxysmal dyskinesias), spasticity, Tourette's syndrome, Scott syndrome, PALSYS and akinesia-rigidity syndrome; extrapyramidal movement disorders such as drug therapy induced movement disorders, for example, anti-neuropathic drug-induced parkinsonism, anti-neuropathic drug malignant syndrome, anti-neuropathic drug-induced acute dystonia, anti-neuropathic drug-induced acute akathisia, anti-neuropathic drug-induced tardive dyskinesia, and drug therapy-induced postural tremor; chemical dependence and addiction (e.g., dependence on or addiction to alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbital) and behavioral addiction, e.g., gambling; and ocular diseases such as glaucoma and ischemic retinopathy; restless leg syndrome, Huntington's disease, multiple sclerosis, mild cognitive impairment, Down's syndrome, stroke, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, cerebral amyloid angiopathy, delirium, dementia, age-related cognitive decline (ARCD) and amnesia, as well as other cognitive or neurodegenerative diseases, such as Parkinson's Disease (PD), Huntington's Disease (HD), Alzheimer's disease, senile dementia, dementia of Alzheimer's type, memory disorders, loss of executive function, vascular dementia, dementia of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, multi-infarct dementia, alcoholic dementia or dementia associated with other drugs, dementia associated with intracranial tumors or brain trauma, dementia associated with Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, HIV or AIDS-associated dementia, diffuse lewy body type Alzheimer's disease, frontotemporal dementia with parkinson's disease (FTDP), head trauma, spinal cord injury, demyelinating diseases of the nervous system, peripheral neuropathy, pain, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, multiple sclerosis, dyskinesias associated with dopamine agonist therapy, mental retardation, learning disorders (including reading disorders, mathematical disorders, or disorders of writing expression); age-related cognitive decline, amnesia, neuroleptic-induced parkinsonism, tardive dyskinesia, and acute and chronic neurodegenerative disorders; premenstrual syndrome, fibromyalgia syndrome, stress incontinence, endocrine disorders (e.g., hyperprolactinemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal disorders (involving changes in motility and secretion), cluster headache, migraine, pain, chronic paroxysmal migraine, headache (associated with vascular disease), sleep disorders (cataplexy), and shock.

In another embodiment, the present invention also includes the above use, wherein the 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate is in the monohydrate form.

Activity at the dopamine D3 receptor can be determined by using the methods described in WO2004/052372 (incorporated herein by reference). Using this assay, 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate monohydrate was found to have a functional potency at the D3 receptor expressed as 21nM at EC50 and a 476-fold selectivity for D3 over D2. Selectivity was calculated as the D2EC50 value divided by the D3 EC50 value.

Suitable assays for determining the utility of the compounds of the invention in a variety of pain conditions are described below:

neuropathic pain

The activity of a compound in treating neuropathic pain can be determined according to the following test protocol.

Animals: male Sprague Dawley rats were housed in groups. All animals were kept in a 12 hour light/dark cycle (7: 00 full light in the morning) with food and water ad libitum. All experiments were performed by an uninformed observer according to Home Office Animals (Scientific Procedures) Act 1986.

Chronic Constrictive Injury (CCI) to neuropathic pain

Sciatic nerve CCI was performed as described by Bennett and Xie (Bennett GJ, Xie YK. A peripheral mononeuropathy inventers of pain sensing like glucose in man. pain: 33: 87-107, 1988). Animals were anesthetized with a 2% isoflurane/O2 mixture. The right rear thigh was shaved and wiped with 1% iodine. The animals were then moved onto a constant temperature blanket during this procedure and anesthesia was maintained via the nose cone during the procedure. The skin is cut along the femoral line. The general sciatic nerve was exposed to the middle of the femur by blunt dissection through the biceps femoris. The nerve closest to the sciatic trifurcation was released by inserting forceps down the nerve and gently lifting the nerve off the thigh for about 7 mm. Using forceps, the suture was pulled out from under the nerve and a simple knot was tied until a slight obstruction was felt, and then a double knot was tied. This operation was repeated until 4 threads (filaments 4-0) were loosely tied around the nerve at a spacing of about 1 mm. The incision was closed in each layer and the wound was treated with topical antibiotics.

Streptozotocin (STZ) causes diabetic neuropathy in rats

Diabetes was triggered by a single intraperitoneal injection of streptozotocin (50mg/kg), freshly dissolved in 0.9% sterile saline. Streptozotocin injection elicits reproducible mechanical allodynia within 3 weeks, which can last for at least 7 weeks (Chen SR and Pan HL.hypersensitivity of Spinetoramic Trace nerves associates With neurological Neuropathic Pain in amines.J. neurophysol 87: 2726-2733, 2002).

Assessment of static and dynamic allodynia

Static allodynia

Animals were habituated to the test cage at the bottom of the wire before assessment of allodynia. Von Frey hairs (Stoelting, Wood Dale, Illinois, USA) were applied by ascending force (0.6, 1, 1.4, 2, 4, 6,8, 10, 15 and 26g) on the plantar surface of the hind paw to assess static allodynia. Each von Frey hair was applied to the paw for up to 6 seconds, or until a retraction reaction occurred. Once the paw-withdrawal response to the von frey hair was established, the paw was retested, starting with the filament below the filament that produced withdrawal, and then using the remaining filaments in a sequence of decreasing forces until no withdrawal occurred. The maximum force 26g lifts the paw and initiates the reaction, thus representing a cut-off point. Both hind paws of each animal were tested in this manner. The minimum force to initiate the reaction was recorded as the Paw Withdrawal Threshold (PWT) in grams. If the animal responds to a stimulus of less than or equal to 4g, which is not harmful to the naive rats, it is defined as the presence of static allodynia (Field MJ, Bramwell S, Hughes J, Singh L.Detectionf static and dynamic components of mechanical allodynia in rat models of neuropathic pain pa: are the signal by diagnostic patient physiological pain, 1999; 83: 303-11).

Dynamic allodynia

Dynamic allodynia was assessed by tapping the plantar surface of the hind paw with a cotton swab. To avoid recording general motor activity, the procedure was carefully performed in fully habituated (that had no mobility) rats. At least two measurements were taken at each time point, and the mean value represents Paw Withdrawal Latency (PWL). If no response is shown within 15 seconds, the procedure is terminated and the animal is assigned the paw withdrawal time. Painful withdrawal is often accompanied by repeated flinching or licking of the paw. If the animal responds to cotton stimuli within 8 seconds of the start of the stroke, dynamic allodynia is considered to be present (Field et al, 1999).

Nociceptive pain

The activity of the compounds in treating nociceptive pain was determined according to the following assay.

Hot plate

Experimental procedure: male Sprague Dawley rats were placed on a hotplate (Ugo Basile, Italy) maintained at 55 ℃. + -. 5 ℃. The time between placing the animal on the hot plate and licking the forepaw or hindpaw, shaking or jumping off the surface is measured. Baseline measurements were taken and animals were re-evaluated after dosing. The off-time of the hot plate latency was set to 20 seconds to prevent tissue damage.

Ovariohysterectomy (OVX)

Experimental procedure: female Sprague Dawley rats were placed in an anesthesia chamber and anesthetized with a 2% isoflurane/O2 mixture. Anesthesia is maintained during surgery via the nose cone. OVX was performed along the white line by midline incision (length 2cm) while the animals were placed on the heat blanket. The uterine ovarian ligaments and cervix are ligated with 5-0 silk using a single clamp technique. The ovaries and uterus were then removed. The abdominal wall was closed using 4 simple interrupted sutures and the skin was sutured using 4 wound clips. Immediately after surgery, animals were placed in a separate plexiglas chamber. Once the animals recovered from anesthesia, abdominal postures were recorded at each time point at 30 minute intervals. The postures recorded were a humpback posture, abdominal muscle contraction associated with inward movement of hind limbs, body extension and lower abdominal squat against the ground. Each behavior is recorded as a gesture.

Brennan

Experimental procedure: male Sprague Dawley rats were placed in an anesthesia chamber and anesthetized with a 2% isoflurane/O2 mixture. Anesthesia is maintained during surgery via the nose cone. The plantar surface of the right hind paw was cleaned with 50% ethanol. A1 cm long longitudinal incision was made through the plantar skin and fascia of the foot, starting with a 11 gauge blade extending from 0.5cm from the proximal edge of the heel toward the toes. The plantar muscle was lifted with forceps and cut longitudinally with the muscle origin and muscle attachment intact. After light pressure hemostasis, the skin was sutured with two simple sutures of braided silk.

Mono-iodoacetate (MIA) induced OA model

Male Sprague Dawley (SD, Japan SLC orCharles River Japan) rats of 6 weeks of age were anesthetized with pentobarbital. Injection sites were shaved and cleaned with 70% ethanol. Mu.l MIA solution or saline was injected into the right knee using a 29G needle. Rats were trained 7, 14, 19 and 20 days after MIA injection to measure weight-bearing without their stress (WB). The WB of each of the two hind paws was measured twenty-one days after MIA injection and the WB deficiency was calculated to be 10.2. The WB deficiency value is defined as a "pre value". The experimental groups were arranged on average taking into account the pre and pre values (pre value). After application of the test compound or vehicle, WB of each of the two hind paws was measured.

Cancer pain model

Adult male C3H/HeN mice (Nihon SLC, Shizuoka, Japan) were used for these experiments. Mice were housed in an animal feeding room (maintained at 22 ℃ C., with 12 hour alternating light/dark cycles) according to the guidelines of the National institute of Health, and were provided with food and water ad libitum. The method of injection of the sarcoma used has been described. After general anesthesia with inhaled isoflurane (2%), a superficial incision was made in the skin overlying the patella using Mora scissors. The patellar ligament is then dissected to expose the distal femoral condyle. A 30 gauge needle was inserted into the medullary canal at the level of the ankle socket to create a primary core path. After the primary core is formed, an access bone is created using a 29 gauge needleThe final path of (2). A 0.5mm recess was then made on the pneumatic dental high speed handpiece head using a half-round file for mechanical retention of the dental resin filling. Then 20. mu.l of alpha-minimal basal medium (Sigma; sham injection) or 20. mu.l of alpha-minimal basal medium containing 1X 10 was injected using a 29 gauge needle and 25cc syringe⁵2472 Culture Medium for osteolytic sarcoma cells (American Type Culture Collection, Rockville, Maryland; sarcoma injection). To prevent the cells from leaking out of the bone, the injection site was blocked with dental resin and then rinsed extensively with filtered water. Wound closure was accomplished using an automated wound closure clip (becton dickinson, San Jose, California). The wound closure clips were removed on day 5 to avoid interfering with the behavioral testing.

Assessment of static and dynamic allodynia

Static allodynia

Procedures for neuropathic pain as described above.

Dynamic allodynia

Procedures for neuropathic pain as described above.

Radiant heat jaw retraction

Experimental procedure: hot paw withdrawal was assessed using the rat plantar test (Ugo Basile, Italy) according to a modified method of Hargreaves et al, 1988. Rats were habituated to a device consisting of three independent plexiglas boxes placed on an elevated glass table. A moving radiant heat source was positioned under the table and focused on the rear paw, recording Paw Withdrawal Latency (PWL). There was an automatic cut-off point at 22.5 seconds to avoid tissue damage. Two hind paws of each animal were recorded 2-3 times PWL, the mean of which represents the baseline of the right and left hind paws. The apparatus was calibrated to obtain a PWL of about 10 seconds.

Load bearing

Experimental procedure: animals were tested for hypersensitivity using a "incapacitator" (Linton Instruments, dis, Norfolk, u.k.) in weight-bearing experiments. The forelimbs of the rats were placed against the plexiglas slope and hindlimb weight distribution was measured by means of force sensors under each hind paw. Each animal was placed in the apparatus and the weight load applied by the hind paw was recorded. The difference in weight bearing was calculated by subtracting the ipsilateral (injured) paw from the weight bearing of the contralateral paw (normal), and this constitutes the raw data.

Inflammatory pain

The activity of a compound in the treatment of inflammatory pain can be measured according to the following test method.

CFA-induced rat weight deficit

Male 7-week-old SD rats were fasted overnight. The right hind paw pad of the rat was injected with CFA (300. mu.g of Mycobacterium Tuberculosis (Mycobacterium Tuberculosis) H37 RA (Difco laboratories) in 100. mu.L of liquid paraffin (Wako)). Two days after CFA administration, changes in hindpaw weight distribution between the left (ipsilateral) and right (contralateral) limbs were measured as pain indices using a Linton incapacitation tester (UK). Test compounds suspended in 0.1% mc (wako) were administered orally in a volume of 1mL per 100g body weight. Each animal was placed in the apparatus and the weight load exerted by the paw before dosing, 1, 2 and 4 hours after dosing was measured.

Carrageenan-induced mechanical hyperalgesia in rats

Male 4-week-old SD rats were fasted overnight. Lambda carrageenan (0.1mL of 1% w/v saline solution, Zushikagaku) was injected intraplantarly. Test compounds (0.1% methylcellulose in 1ml per 100g body weight) were administered orally 5.5 hours after carrageenan injection. Paw withdrawal thresholds (grams) were measured by an analgesia meter (Ugo Basile) 3.5, 4.5, 6.5 and 7.5 hours after carrageenan injection. (Randalll L.O. & Selitto I.J., Arch.int.Pharmacodyn.111, 409-419, 1957)

Carrageenan-induced thermal hyperalgesia (CITH) in rats

Thermal hyperalgesia was assessed using the rat plantar test (Ugo Basile, Italy) according to the modified method of Hargreaves et al, 1988. In brief, rats were habituated to a device consisting of three separate plexiglas boxes on a glass table. A moving radiant heat source is located under the table and focused on the target paw. Three PWLs were recorded for two hind paws of each animal, the mean of which represents the baseline for the left and right hind paws. The apparatus was calibrated to obtain a PWL of about 10 seconds for the naive mice. To avoid tissue damage, a cut-off point of 22.5 seconds was used. Lambda carrageenan was injected intraplantarly into the right hindpaw (100. mu.l, 20mg/ml) and a baseline recording of PWL was made 2 hours after dosing.

Visceral pain

The activity of the compounds in the treatment of visceral pain can be measured according to the following test methods.

Several modes can be used to determine whether a compound is effective in treating a visceral disorder. These models include the LPS model (Eutamene H et al, J Pharmacol Exp Ther 2000295 (1): 162-7), the TNBS model (Diop L. et al, Gastroenterology 1999, 116, 4 (2): A986), the IBD model (Clemett D, Markham A, Drugs 2000 Apr; 59 (4): 929-56), the pancreatic pain model (Isla AM, Hosp Med 2000 Jun; 61 (6): 386-9), and the visceral non-digestible pain model (Boucher M et al, Jurol 2000 Jul; 164 (1): 203-8).

TNBS-induced chronic visceral allodynia in rats

In an experimental model of colonic distension in conscious rats, prior injection of trinitrobenzenesulfonesulfonic acid (TNBS) into the proximal colon lowered the visceral pain threshold.

Materials and methods: male Sprague-Dawley rats were used. Animals were housed in three cages per conditioned environment (20. + -. 1 ℃ C., 50. + -. 5% humidity, light 8:00 am to 8:00 pm). On day 0 under anesthesia (ketamine 80mg/kg, i.p.; acepromazine 12mg/kg, i.p.), TNBS (50mg/kg in 30% ethanol) or saline (1.5ml/kg) was injected into the proximal colon wall (1 cm from the cecum). Animals were individually housed in polypropylene cages after surgery and kept in a controlled environment (20 + -1 deg.C, 50 + -5% humidity, light 8:00 am to 8:00 pm) for 7 days. On day 7 after TNBS administration, a balloon (5-6cm long) was inserted transanally and held in place by sticking a catheter to the base of the tail (5 cm from the tip of the balloon to the anus). Test compounds were administered orally 1 hour prior to the colonic distension cycle (gradual expansion of the balloon from 0mm Hg to 75mm Hg in 5mm Hg steps, each distension step lasting 30 seconds). Each colon expansion cycle is controlled by a standard barostat. The threshold (mm Hg) corresponds to the pressure that produces the first abdominal contraction, and the inflation cycle can then be terminated. Colonic threshold was determined after four cycles of expansion on the same animal.

LPS-induced hypersensitivity of rat rectum

Intraperitoneal injection of bacterial Lipopolysaccharide (LPS) has been shown to elicit rectal hyperalgesia in conscious rats.

Materials and methods: the animals were prepared surgically for electromyography (electromyography): rats were anesthetized by intraperitoneal injection of acepromazine (0.6mg/kg) and ketamine (120 mg/kg). Three sets of electrodes (three per set) were implanted into the external oblique musculature of the abdomen (just above the inguinal ligament). The electrodes are threaded out behind the neck and protected by a glass tube attached to the skin. Animals were individually rested in polypropylene cages and placed in a temperature controlled room (21 ℃). Food (UAR pellets, epicay, France) and water were provided ad libitum.

Myoelectricity scanning and recording are started five days after the operation. The electrical activity of the abdominal striated muscle was recorded using an electroencephalograph scanner (Mini VIII Alvar, Paris, France) with a short time constant (0.03s) and a paper speed of 3.6cm/min to remove low frequency signals (< 3 Hz).

Expansion procedure: rats were placed in plastic tubes (6cm diameter x 25cm length) where they could not move, escape or turn around, thus avoiding balloon damage. Animals were acclimated to the procedure for four days prior to rectal distension to minimize stress response in the experiment. The balloon used for inflation is an arterial embolectomy catheter (Fogarty, Edwards Laboratories Inc.). Rectal distension was performed by inserting a balloon (2cm diameter x 2cm long) into the rectum (1 cm from the anus) and securing the catheter at the base of the tail. The balloon was gradually inflated with warm water from 0ml to 1.2ml at 0.4ml per step, each inflation step lasting 5 minutes. To detect possible leaks, the volume of water introduced into the balloon is checked at the end of inflation by complete removal with a syringe.

The compounds of the present invention may be administered alone or in combination with one or more other drugs. Generally, it is administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than a compound of the invention. The choice of excipient will depend primarily on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Suitable auxiliary active agents that may be used in combination with the compounds of the present invention include:

1) naturally occurring or synthetic prostaglandins or esters thereof. The prostaglandins useful herein include compounds such as alprostadil, prostaglandin E₁Prostaglandin E₀13, 14-dihydroprostaglandin E₁Prostaglandin E₂Epostinol, natural synthetic and semi-synthetic prostaglandins and derivatives thereof (including those described in US6,037,346 and/or WO-00033825 (incorporated herein by reference in their entirety) granted 3.14.2000), PGE₀、PGE₁、PGA₁、PGB₁、PGF₁Alpha, 19-hydroxy-PGA₁19-hydroxy-PGB₁、PGE₂、PGB₂19-hydroxy-PGA₂19-hydroxy-PGB₂、PGE₃Alpha, carboprost (carboprost) tromethamine, dinoprost (dinoprost) tromethamine, dinoprostone (dinoprostone), Ripoprost (lipoprost), Gimeraprost (gemeprost), Metroprost (metenoprost), Sulprost (sulprostune), tiaprost (tiaprost) and moxisyclate (moxisylate).

2) Alpha-adrenoceptor antagonist compounds, also known as alpha-adrenoceptors or alpha-receptors or alpha-blockers. Compounds suitable for use herein include: alpha-adrenoceptor blockers (the disclosures of which relate to alpha-adrenoceptors are incorporated herein by reference) as described in PCT application WO99/30697 published at 14/6/1998, which include selective alpha 1-adrenoceptors or alpha 2-adrenoceptor blockers and non-selective adrenoceptor blockers, suitable alpha 1-adrenoceptor blockers include: phentolamine (phentolamine), phentolamine mesylate (phentolamine), trazodone (trazodone), alfuzosin (alfuzosin), indoramine (indoramin), naftopidil (naftopidil), tamsulosin (tamsulosin), dapiprazole (dapiprazole), phenoxybenzamine (phenoxybenzamine), idazoxan (idazoxan), efaraxan (efaraxan), yohimbine (yohimbine), rauwolfa (rauwoolfa) alkaloid, Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL89.0591, doxazosin (doxazosin), terazoxazine (terazoabab), abanoquine (prazoquinone) and (prazosin) azosin; α 2-blocker blockers from US6,037,346 (3.3.14.2000): dibenarine (dibenanine), tolazoline (tolazoline), and tramazosin (trimazosin); alpha-adrenergic receptors as described in U.S. patents 4,188,390, 4,026,894, 3,511,836, 4,315,007, 3,527,761, 3,997,666, 2,503,059, 4,703,063, 3,381,009, 4,252,721, and 2,599,000 (each of which is incorporated herein by reference); an α 2-adrenoceptor blocker comprising: clonidine (clonidine), papaverine (papaverine), papaverine hydrochloride, optionally a cariogenic agent (caritonic agent) such as pirxamine (pirxamine).

3) NO-donor (NO-agonist) compounds. NO donor compounds suitable for use herein include organic nitrates, such as mono-, di-or tri-nitrates or organic nitrates, including glyceryl trinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, butanetetranitrate, Sodium Nitrosoferricyanide (SNP), 3-morpholino-ketoimine molsidomine (3-morpholinoside salts), S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, isoamyl nitrite, linsidomine (linsidomine), linsidomine hydrochloride, (SIN-1) S-nitroso-N-cysteine, diazeniumdiolate (diazenium diolates), (NONONAtes), 1, 5-pentane dinitrate, L-arginine, ginseng, red date (zizphifuctus), molsidomine, Re-2047, nitrosylated macystilyne (nitrosylated maxisylate) derivatives, such as NMI-678-11 and NMI-937 as described in published PCT application WO 0012075;

4) potassium channel openers or modulators. Potassium channel openers/modulators suitable for use herein include nicorandil, cromokaline, levocromakaline, lemakalim, pimaridine, cliazoxide, minoxidil, bracon-nectoxin, glyburide, 4-aminopyridine, BaCl₂；

5) A vasodilator. Vasodilators suitable for use herein include nimodipine (nimodipine), pinadil (pinacidil), cyclandelate (cyclandelate), isoxsuprine (isoxsuprine), chloroprumazine, Rec 15/2739, trazodone;

6) a thromboxane a2 agonist;

7) a CNS active agent;

8) an ergot alkaloid; suitable ergot alkaloids are described in us patent 6,037,346, granted on 14.3.2000 and include acetyldihydroergotamine (acetergamine), bromoergoline (brazergoline), bromoergouride (bromerguride), cyanoergoline (ciargoline), dicentropicrine (delorgotrile), disulerine (disulergine), ergonovine maleate (ergonovine maleate), ergotamine tartrate (ergotamine tartrate), ethiprole (ethisulergine), lergotonitrile (lergitale), ergodiethylamine (lysergide), mersulgine (mesurgine), mergoline (metergoline), methylergotamine (metergtamine), nicerinate (pergolide), golide (pergolide), proppergolide (pimpergolide), progolide (properguride), and terguride (terguride);

9) compounds that modulate the action of natriuretic factors, particularly atrial natriuretic factors (also known as atrial natriuretic peptides), type B and type C natriuretic factors, such as inhibitors or neutral endopeptidases;

10) compounds that inhibit angiotensin converting enzyme (e.g., enalapril (enapril)), and combined inhibitors of angiotensin converting enzyme and neutral endopeptidase, such as omatralat (omapatrilat);

11) angiotensin receptor antagonists such as losartan (losartan);

12) substrates for NO-synthases, such as L-arginine;

13) calcium channel blockers such as amlodipine (amlodipine);

14) endothelin receptor antagonists and inhibitors, or endothelin converting enzyme;

15) cholesterol lowering agents such as statins (e.g. atorvastatin)/Lipitor (Lipitor) -trade mark) and fenofibrate (fibrate);

16) antiplatelet and antithrombotic agents, such as tPA, uPA, warfarin (warfarin), hirudin (hirudin) and other thrombin inhibitors, heparin (heparin), inhibitors of the prothrombin activating factor;

17) insulin potentiating agents, such as, for example, rilysin (rezulin) and hypoglycemic agents such as glipizide (glipizide);

18) acetylcholinesterase inhibitors such as donezipil;

19) steroidal or non-steroidal anti-inflammatory agents;

20) estrogen receptor modulators and/or estrogen agonists and/or estrogen antagonists, preferably raloxifene (raloxifene) or lasofoxifene (lasofoxifene), (-) -cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol and pharmaceutically acceptable salts thereof, the preparation of which is detailed in WO 96/21656;

21) PDE inhibitors, more particularly PDE2, 3, 4, 5, 7 or 8 inhibitors, preferably PDE2 or PDE5 inhibitors, most preferably PDE5 inhibitors (see below), preferably with an IC50 against the corresponding enzyme of less than 100nM (under conditions where the PDE3 and 4 inhibitors are administered only locally or by injection into the penis);

22) vascular-acting intestinal proteins (VIP), VIP mimetics, VIP analogues, more specifically mediated by one or more of the VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide), VIP receptor agonists or VIP analogues (e.g. Ro-125-1553) or VIP fragments, one or more of alpha-adrenoceptor antagonists in combination with VIP (e.g. ying-cony (invicor), Aviptadil (Aviptadil));

23) melanocortin receptor (especially of the MC3 or MC4 subtype) agonists or modulators or melanocortin enhancers, for example compounds as claimed in melanotan II (melantotan II), PT-14, PT-141 or WO-09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-00114879, WO-00113112, WO-09954358;

24) 5-hydroxytryptamine receptor agonists, antagonists or modulators, more specifically agonists, antagonists or modulators of the 5HT1A (including VML670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO-09902159, WO-00002550 and/or WO-00028993;

25) testosterone replacement agents (including dehydroandrostenedione), testosterone (Tostrelle), dihydrotestosterone, or testosterone implants;

26) estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (mpa) (i.e. as a combination), or estrogen and methyltestosterone hormone replacement therapy agents (e.g. HRT, in particular bimatolein (Premarin), cinstein (Cenestin), oestroemium (Oestrofeminal), eiquine (Equin), emtrice (Estrace), norkunmi (estrofefem), elstrom (ellestesolo), estimat (estriong), estodel (eastaderm) TTS, eastraadm Matrix, demeritin (Dermestril), prolifex (primhausen), proleak (preempropro), prolibak (prim), prolimiger (primique), estentist), estotest (estoteracil), tilonene (Tibolone));

27) modulators of norepinephrine, dopamine, and/or serotonin carriers, such as bupropion (bupapion), GW-320659;

28) a purinergic receptor agonist and/or modulator;

29) neurokinin (NK) receptor antagonists including those described in WO-09964008;

30) an opioid receptor agonist, antagonist or modulator, preferably an ORL-1 receptor agonist;

31) an oxytocin receptor agonist, antagonist or modulator, preferably a selective oxytocin agonist or modulator;

32) cannabinoid receptor modulators;

33) SEP inhibitors (SEPi), e.g. having an IC of at least less than 100 nanomolar (more preferably at least less than 50 nanomolar)₅₀The SEPi of (1).

Preferably, the SEP inhibitors of the invention have a 30-fold, more preferably 50-fold, selectivity for SEP over neutral endopeptidase NEP EC 3.4.24.11 and Angiotensin Converting Enzyme (ACE). It is also preferred that the SEPi has a 100-fold greater selectivity than endothelin-converting enzyme (ECE).

34) Antagonists or modulators of NPY (particularly of the Y1 and Y5 subtypes) receptors.

35) Sex hormone binding globulin antagonists or modulators that inhibit estrogen and/or androgen binding.

36) An inhibitor of arginase II and an inhibitor of arginase II,

37) vasopressin receptor agonists, antagonists or modulators, preferably selective for the V1a receptor

38) PDE5 inhibitors. Suitable PDE5 inhibitors include: 5- [ 2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (sildenafil), especially sildenafil citrate; (6R, 12aR) -2, 3, 6, 7, 12, 12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6, 1] pyrido [3, 4-b ] indole-1, 4-dione (IC-351 or tadalafil); 2- [ 2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5, 1-f ] [1, 2, 4] triazin-4-one (vardenafil)); 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one; 5- (5-acetyl-2-propoxy-3-pyridyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one; 5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ 2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one; 4- [ (3-chloro-4-methoxybenzyl) amino ] -2- [ (2S) -2- (hydroxymethyl) pyrrolidin-1-yl ] -N- (pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide (TA-1790); 3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4, 3-d ] pyrimidin-5-yl) -N- [2- (1-methylpyrrolidin-2-yl) ethyl ] -4-propoxybenzenesulfonamide (DA 8159) and pharmaceutically acceptable salts thereof.

39) A selective dopamine D4 receptor agonist, for example 2- [ (4-pyridin-2-ylpiperazin-1-yl) methyl ] -1H-benzimidazole (ABT 724).

40) One or more Selective Serotonin Reuptake Inhibitors (SSRIs), for example dapoxetine (dapoxetine), paroxetine (parooxetine), 3- [ (dimethylamino) methyl ] -4- [4- (methylthioalkyl) phenoxy ] benzenesulfonamide (example 28 of WO 0172687), 3- [ (dimethylamino) methyl ] -4- [ 3-methyl-4- (methylthioalkyl) phenoxy ] benzenesulfonamide (example 12 of WO 0218333), N-methyl-N- ({3- [ 3-methyl-4- (methylthioalkyl) phenoxy ] -4-pyridyl } methyl) amine (example 38 of PCT application No. PCT/IB 02/01032).

41) One or more NEP inhibitorsA formulation, preferably wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor of EC 3.4.24.11, more preferably the selective NEP inhibitor is a selective inhibitor of EC 3.4.24.11, having an IC of less than 100nM₅₀(e.g. opuritrilate (ompatrilat), lapatrilat (sampatrilat)), suitable NEP inhibitor compounds are those described in EP-A-1097719; IC50 values for NEP and ACE can be obtained using published patent application EP1097719-A1 [0368 ]]To [0376]Segment said segment method determination;

42) melanocortin receptor agonists (e.g., melanotan II and PT141) and selective MC3 and MC4 agonists (e.g., THIQ).

43) Monoamine transport inhibitors, such as noradrenaline (noradrenaline) reuptake inhibitors (NRI), including selective NRI such as reboxetine (reboxetine), in either the racemic (R, R/S, S) or optically pure (S, S) enantiomeric form, such as (S, S) -reboxetine.

By cross-reference to a compound contained in a patent and patent application that is useful in the present invention we mean a therapeutically active compound as defined in the claims (especially claim 1) and the specific examples (all incorporated herein by reference). The patents and patent applications cited above are incorporated herein by reference.

If a combination of active agents is administered, they may be administered simultaneously, separately or sequentially.

Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods of making them can be found in Remington's pharmaceutical Sciences, 19 th edition (Mack Publishing Company, 1995), which is incorporated herein by reference.

The compounds of the invention may be administered orally. Oral administration includes swallowing (whereby the compound enters the gastrointestinal tract) and/or buccal, lingual or sublingual administration whereby the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid, semi-solid and liquid systems, such as lozenges; soft or hard capsules containing multiparticulates or nanoparticles, liquid, semi-solid or solid matrices or powders; lozenges (including liquid-filled lozenges); chewable tablets; gelling; a fast-dispersing dosage form; a film; an ovoid; spraying agent; and buccal patch/mucoadhesive.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations are useful as fillers in soft and hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations can also be prepared by reconstitution of solids (e.g., from caplets).

The compounds of the present invention are also useful in fast dissolving, fast disintegrating dosage forms, such as those described by Liang and Chen (2001) in Expert Opinion in Therapeutic Patents, 11(6), 981-.

For lozenge dosage forms, the drug may constitute from 0.5% to 80% by weight of the dosage form, more typically from 1% to 60% by weight of the dosage form, depending on the dosage. In addition to the drug, lozenges generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant will comprise from 1 to 25 weight percent, preferably from 5 to 20 weight percent of the dosage form.

Binders are commonly used to impart adhesive properties to lozenge formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Lozenges may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

Lozenges may also optionally contain surfactants (e.g., sodium lauryl sulfate and polysorbate 80) and glidants (e.g., silicon dioxide and talc). When present, the surfactant may constitute from 0.2% to 5% by weight of the lozenge and the glidant may constitute from 0.2% to 1% by weight of the lozenge.

Lozenges generally contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricant typically constitutes from 0.25% to 10%, preferably from 0.5% to 3% by weight of the lozenge.

Other possible ingredients include antioxidants, coloring agents, flavoring agents, preservatives, and taste-masking agents.

Exemplary lozenges comprise up to 80% of a drug, from about 10% to about 90% by weight of a binder, from about 0% to about 85% by weight of a diluent, from about 2% to about 10% by weight of a disintegrant, and from about 0.25% to about 10% by weight of a lubricant.

The lozenge mixture can be compressed into lozenges either directly or by roller compression. The lozenge mixture or part of the mixture may be wet granulated, dry granulated or melt granulated, melt congealed or extruded prior to tableting. The final formulation may comprise one or more layers, and may or may not be coated; it may even be encapsulated.

The formulation of the troches is described in Pharmaceutical Dosage Forms: tablets, Vol.1, by H.Lieberman and L.Lachman (Marcel Dekker, New York, 1980), which is incorporated herein by reference.

Consumable oral films for human or veterinary use are typically soft, water-soluble or water-swellable film dosage forms that dissolve rapidly or are capable of adhering to mucous membranes and typically comprise a compound of the present invention, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation may perform more than one function.

The compounds of the invention may be water soluble or water insoluble. The water soluble compound typically comprises from 0.5 wt% to 80 wt%, more typically from 20 wt% to 50 wt% of the solute. The low solubility compound may comprise a higher proportion of the composition, typically up to 88% by weight of the solute. Alternatively, the compounds of the invention may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, co-solvents (including oils), emollients, fillers, anti-foaming agents, surfactants, and taste-masking agents.

The films of the present invention are typically prepared by evaporative drying of a liquid film that has been applied to a release backing or paper. This can be done in a drying oven or drying tunnel (typically a combined coating dryer), or by freeze drying or vacuum pumping.

Solid formulations for oral administration may be formulated for immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release.

Suitable modified release formulations for the purposes of the present invention are described in U.S. Pat. No. 6,106,864. Other suitable delivery techniques (e.g., high energy dispersion and penetration and coating of granules) can be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001), which is incorporated herein by reference. The use of chewing gum to achieve controlled release is described in WO00/35298, which is incorporated herein by reference.

The compounds of the invention may also be administered directly into the bloodstream, into muscles or into internal organs. Suitable means for parenteral administration include intravenous injection, intraarterial injection, intraperitoneal injection, intravertebral injection, intraventricular injection, intraurethral injection, intrasternal injection, intracranial injection, intramuscular injection, intrasynovial injection, and subcutaneous injection. Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors, and injection techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably having a pH of from 3 to 9), but for some applications they may more suitably be formulated as sterile non-aqueous solutions or in dry form together with a suitable carrier, for example sterile pyrogen-free water.

Preparation of parenteral formulations under sterile conditions (e.g., by freeze-drying) can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of the present invention used in the preparation of injectable solutions can be enhanced by the use of appropriate formulation techniques, such as the incorporation of solubilizing agents.

Formulations for parenteral administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. The compounds of the invention may thus be formulated as suspensions or as solids, semisolids or thixotropic liquids for administration (which serve as implant reservoirs providing modified release of the active compound). Examples of such formulations include drug-coated stents and semi-solids and suspensions containing drug-loaded poly (dl-lactic-co-glycolic) acid (PGLA) microspheres.

The compounds of the invention may also be applied topically, transdermally (intra) or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, emulsions, solutions, creams, ointments, loose powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include ethanol, water, mineral oil, liquid paraffin, white paraffin, glycerol, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated, see for example Finnin and Morgan (10.1999) J Pharm Sci, 88(10), 955-958, which are incorporated herein by reference.

Other means of topical administration include by electroporation, iontophoresis, sonophoresis, and microneedle or needleless (e.g., Powderject)^TM、Bioject^TMEtc.) for delivery by injection.

Formulations for topical administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release.

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (which may be present alone, for example, in a mixture with lactose, as a mixture), or in the form of particles of a component of the mixture, for example, in admixture with a phospholipid such as phosphatidylcholine), from a dry powder inhaler, or as a spray from a pressurised container, pump, spray, nebuliser (preferably a nebuliser using electrohydrodynamics to produce a fine spray), with or without the use of a suitable propellant (such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3,3, 3-heptafluoropropane), or as nasal drops. For intranasal use, the powder may comprise a bioadhesive, such as chitosan or cyclodextrin.

The pressurized container, pump, sprayer, nebulizer or atomizer contains a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol or other solvent suitable for dispersing, dissolving or prolonging the release of the active agent, a propellant as a solvent, and optionally a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronized to a suitable size (typically less than 5 microns) for delivery by inhalation. This may be accomplished by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, or spray drying.

Capsules (e.g., made of gelatin or hydroxypropylmethyl cellulose), foaming agents and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base (e.g., lactose or starch), and a performance modifying agent (e.g., 1-leucine, mannitol or magnesium stearate). Lactose may be in anhydrous or monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Suitable formulations of solutions for use in a nebulizer that generates a fine spray using electrohydrodynamics may contain from 1 μ g to 20mg of a compound of the invention per actuation, and the actuation volume may vary from 1 μ l to 100 μ l. A typical formulation may comprise a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Other solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavouring agents (e.g. menthol and levomenthol) or sweetening agents (e.g. saccharin or saccharin sodium) may be added to the formulations of the invention intended for inhalation/intranasal administration.

Formulations for inhalation/intranasal administration may be formulated as immediate release agents and/or as modified release agents by use of, for example, PGLA. Modified release formulations include delayed, sustained, pulsed, controlled, directed, and programmed release.

For dry powder inhalers and aerosols, the dosage units can be determined by means of valves which are able to deliver a measured quantity. The unit of the invention is generally arranged to administer a metered dose or "puff" containing a compound of the invention.

The compounds of the invention may be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated as immediate release and/or modified release agents. Modified release formulations include delayed, sustained, pulsed, controlled, directed, and programmed release.

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of micronized suspensions or drops of solutions in isotonic, pH adjusted, sterile saline. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and microparticulate or vesicular systems, such as niosomes or liposomes. Polymers (e.g. cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid), fibrous polymers (e.g. hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose) or heteropolysaccharide polymers (e.g. agarose gel) may be blended with preservatives (e.g. benzalkonium chloride). Such formulations may also be delivered by iontophoresis. Formulations for ocular/nasal administration may be formulated as immediate release and/or modified release agents. Modified release formulations include delayed, sustained, pulsed, controlled, directed, and programmed release.

The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability when used in any of the above modes of administration.

For example, drug-cyclodextrin complexes have generally found utility in most dosage forms and methods of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrins may be used as an auxiliary additive, i.e. as a carrier, diluent or solubiliser. The most commonly used for these purposes are alpha-, beta-and gamma-cyclodextrins, examples of which can be found in international patent application nos. WO 91/11172, WO94/02518 and WO 98/55148, which are incorporated herein by reference.

Whenever it is desired to administer a combination of active compounds for the purpose of, for example, treating a particular disease or condition, the scope of the present invention includes that two or more pharmaceutical compositions, at least one of which comprises a compound of the present invention, may conveniently be combined in the form of a kit, which is suitable for co-administration of the compositions.

The kit of the invention thus comprises two or more separate pharmaceutical compositions, at least one of which comprises a compound of the invention, and means for separately preserving the compositions, such as a container, a portion bottle or a portion foil packet. One example of such a kit is the well-known blister pack used for packaging tablets, capsules, and the like.

The kits of the invention are particularly suitable for administering different dosage forms (e.g., oral and parenteral dosage forms), for administering separate compositions at different dosage intervals, or for titrating separate compositions against one another. To assist compliance with a predetermined course of treatment, the kit typically contains instructions for administration, along with so-called memory aids.

Drawings

FIG. 1 shows a schematic view of a

Isothermal gravimetric analysis of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate monohydrate at 40 ℃, 45 ℃, 80 ℃ and 85 ℃. The material was maintained at the selected temperature with a nitrogen flow of 0% RH. 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate was dehydrated at 85 ℃ at 0% RH. At 30 ℃/0% RH significant hydrate loss occurs.

FIG. 2

Water absorption of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate monohydrate at 30 ℃. The adsorption at 90% RH was 0.316% (w/w) of the dry weight. This value relates to unbound water and does not include water contained in the crystal lattice.

FIG. 3

The water absorption of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate was compared with the free base, di-D-tartrate and hydrobromide at 30 ℃.

FIG. 4

Simulated PXRD pattern of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate.

FIG. 5

The true PXRD pattern for 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate.

FIG. 6

DSC thermogram of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate.

Experiment of

Differential Scanning Calorimetry (DSC): differential scanning calorimetry was performed using a Perkin Elmer Diamond DSC in aluminum dishes with wells and lids. Approximately 3mg of the sample was heated at 20 ℃ per minute in the range of 30 ℃ to 250 ℃ under a nitrogen purge.

Thermogravimetric analysis (TGA): the reaction was carried out using a model 2950 TA apparatus. Approximately 8mg of the sample was maintained at the assay temperature in an open dish for at least 30 minutes under a 0% RH nitrogen flow. The results represent the dynamic stability of the hydrate over the exposure time of the sample.

Dynamic vapor adsorption (DVS): DVS-1 model automatic adsorption analyzer. Manufactured by surface measurements Systems ltd. The solids (10-20mg) were exposed to a controlled relative humidity (% RH) environment and the change in weight was recorded after a period of time. Humidity was from 0% to 90% to 0% RH in 15% RH steps. An adsorption rate of 0.0005%/minute was required at each humidity before exposure to the next humidity in the process. When the sample is deliquescent, equilibrium adsorption cannot always be achieved.

Powder X-ray diffraction (PXRD): PXRD patterns were obtained using a Bruker-AXS ltd. d5000 powder X-ray diffractometer (equipped with an autosampler, theta-theta goniometer, an autosampler slit, a secondary monochromator and a scintillation counter). The samples were analyzed as a thin layer of powder on a silicon wafer sample holder. The sample was rotated while being irradiated with copper K- α 1X-rays (wavelength: 1.5406 angstroms) using an X-ray tube (which was operated at 40kv/40 mA). The analysis was performed with a goniometer (which operates in a continuous mode setting of 5 seconds counts per 0.02 ° step over a2 θ angle range of 2 ° to 55 °).

The obtained 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate peak is compared to the peak from the single crystal structure calculation map.

2 theta Angle and relative Strength of simulated powder spectra Using Accelrys Materials Studio^TMReflex Powder Diffraction Module [2.2 edition ]]Calculated from the single crystal structure. Suitable simulation parameters in each case are:

wavelength 1.540562 Å (Cu Ka)

Polarization factor of 0.5

Pseudo-Voigt spectrum (U ═ 0.01, V ═ 0.001, W ═ 0.002)

As known to those skilled in the art, the relative intensities of the various peaks in the tables given below may vary depending on factors such as the directional effect of the crystals in the X-ray beam, or the purity of the material being analyzed, or the degree of crystallization of the sample. The position of the peak may also vary due to changes in the sample height, but the position of the peak remains substantially as defined in the following table.

The skilled person will also understand that using different wavelength measurement wavelengths will produce different displacements according to the Bragg equation (n λ ═ 2d sin θ).

Such other PXRD patterns generated by the use of other wavelengths are considered to be other representations of the PXRD pattern of the crystalline material of the present invention and are therefore within the scope of the present invention.

The compounds of the invention can be synthesized according to the following procedures. Where the preparation is carried out on different scales, giving a process which is suitable for carrying out both large-scale and small-scale syntheses. The following abbreviations and definitions are used:

TBME Tert-butyl methyl Ether

DCM dichloromethane

IPA isopropyl alcohol

Peak of mass m/z

HCl hydrochloric acid

NaOH sodium hydroxide

MS Mass Spectrometry

m multiplet

q quartet peak

s single peak

t triplet peak

br width

Kg kilogram

L liter

g

CDCl₃Deuterated chloroform

ppm parts per million

NMR spectra were obtained using a Varian Inova 300MHz spectrometer by dissolving the sample in a suitable solvent.

Mass spectra were obtained using an LC-MS system combined with a Thermo-Finnigan Surveyor HPLC system and a Thermo Finnigan LCQ ion trap mass spectrometer.

5-bromo-2- (2, 5-dimethylpyrrol-1-yl) pyridine

2-amino-5-bromopyridine (6.0Kg, 34.7 moles), 2, 5-hexanedione (4.35Kg, 38.2 moles), and p-toluenesulfonic acid (12g) were dissolved in heptane (36L) and refluxed under Dean Stark conditions overnight. The instrument was set to distill and heptane (18L) was removed by distillation. The mixture was cooled to 20 ℃ over 60 minutes. Seeds were added and the mixture was granulated for 2 hours at 20 ℃ and then at 5 ℃ overnight. The product was collected by filtration, washed with heptane (2 × 6L) and dried in vacuo at 45 ℃ overnight. Yield 80% (7.0Kg) δ_H(CDCl₃ 300MHz)2.20(6H，s)、5.95(2H，s)、7.15(1H，d)、7.95(1H，d)、8.70(1H，s)ppm。MS m/z 253(MH⁺Br isotope).

2-chloro-1- [6- (2, 5-dimethylpyrrol-1-yl) pyridin-3-yl]Ethanones

A solution of 5-bromo-2- (2, 5-dimethylpyrrol-1-yl) pyridine (1.00Kg 3.98 moles) in TBME (7.5L) was cooled to-70 ℃. N-butyllithium (2.5N in hexane; 1.73L, 4.32 moles) was added dropwise over 1 hour, maintaining the temperature between-74 ℃ and-69 ℃. The mixture was then stirred at a temperature between-74 ℃ and-69 ℃ for a further 15 minutes. A solution of 2-chloro-N-methoxy-N-methylacetamide (0.65Kg, 4.72 moles) in TBME (3.0L) was then added dropwise over 100 minutes,the temperature is maintained between-73 ℃ and-67 ℃. The resulting mixture was then stirred for an additional 100 minutes at a temperature between-73 ℃ and-67 ℃. 2N HCl (5.0L) was then added dropwise over 45 minutes, allowing the temperature to rise from-70 ℃ to 17 ℃ during the addition. TBME (4.0L) and water (2.0L) were added to the resulting suspension and the mixture was stirred until the phases separated. Before concentration in vacuo, water (2.0L) and aqueous NaHCO were used₃The organic layer was washed (0.13 Kg in 2.0L of water) followed by water (2.0L). IPA (1.50L) was added to the residue and the mixture was heated to reflux. The mixture was then allowed to cool to room temperature and stirred overnight, after which it was cooled to 8-12 ℃ for 1 hour. The product was collected by filtration, washed with IPA (2X 0.1L) and dried overnight in vacuo at 45 ℃. Yield 78.8% (0.78Kg), delta_H(CDCl₃，300MHz)2.20(6H，s)、4.70(2H，s)、5.95(2H，s)、7.35(1H，d)、8.40(1H，dd)、9.15(1H，d)ppm。MS m/z 249(MH⁺)。

2- (2, 5-dimethylpyrrol-1-yl) -5-oxiranylpyridines

To a suspension of sodium borohydride (0.17Kg, 4.36 moles) in 1, 4-dioxane was added water (1.08Kg) dropwise at 16 ℃ and the resulting solution was stirred at room temperature. 2-chloro-1- [6- (2, 5-dimethylpyrrol-1-yl) pyridin-3-yl is added over 1 hour]A solution of ethanone (1.08Kg, 4.35 moles) in tetrahydrofuran (2.16L) was stirred at room temperature for 45 minutes. When all 2-chloro-1- [6- (2, 5-dimethylpyrrol-1-yl) pyridin-3-yl]Upon consumption of the ethanone, the reaction mixture was cooled to 19 ℃ and treated with concentrated HCl (36% w/w) (1.08L) for 40 minutes. The mixture was cooled to 11 ℃ and NaOH (32% w/w) was added over 45 minutes, maintaining the temperature at 25 ℃. The mixture was then allowed to granulate at room temperature overnight. When all the chlorohydrin intermediate was consumed, DCM (5.0L) and water (5.0L) were added and the mixture was stirred until the phases separated. The aqueous phase was extracted with DCM (2.50L) and the combined fractions were washed with water (2X 1.0L)The organic phase was concentrated in vacuo. Yield 98% (0.92Kg) delta_H(CDCl₃，300MHz)2.10(6H，s)、2.90(1H，dd)、3.25(1H，dd)、4.00(1H，dd)、5.90(2H，s)、7.20(1H，d)、7.70(1H，dd)、8.40(1H，d)ppm。MS m/z 215(MH⁺)。

(2S) -2- [ { (RS) -2- [6- (2, 5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl]-2-hydroxyethyl } propane Amino group]Propan-1-ol

A mixture of 2- (2, 5-dimethylpyrrol-1-yl) -5-oxiranylpyridine (0.65Kg, 3.04 mol) and (S) - (+) -2-amino-1-propanol (0.30Kg, 3.95 mol) in toluene (6.50L) was heated to reflux overnight. The reaction mixture was cooled to room temperature, DCM (6.5L) and water (1.30L) were added and the phases were allowed to separate. To the organic layer was added sodium triacetoxyborohydride (0.96Kg, 4.56 moles), followed by dropwise addition of propionaldehyde (0.48L, 6.68 moles) and glacial acetic acid (0.17L, 3.04 moles) at a temperature below 30 ℃. The reaction mixture was stirred at room temperature for 1 hour until quenched with water (1.20L) and aqueous potassium carbonate (1.00Kg in 3.23Kg water), and the phases were separated. The aqueous phase was extracted with DCM (1.20L) and the combined organic phases were washed with water (0.60L), then water (0.30L) and concentrated in vacuo. Yield 89% (0.89Kg, material isolated at about 70% purity) delta_H(CDCl₃，300MHz)0.8-1.0(6H，m)、1.50-1.70(2H，m)、2.10(6H，s)、2.50-3.15(5H，m)、3.50(2H，dd)、4.80(1H，dd)、5.90(2H，s)、7.20(1H，m)、7.80-7.90(1H，m)、8.60(1H，m)ppm。MS m/z 332(MH⁺). The intermediate amine is characterized by delta_H(CDCl₃，300MHz)1.10(3H，t)、2.10(6H，s)、2.7-3.2(3H，m)、3.45(1H，m)、3.70(H，dd)、4.85(1H，m)、5.90(2H，s)、7.20(1H，d)、7.90(1H，dd)、8.60(1H，d)ppm。MS m/z 290(MH⁺)。

(2S)-2-[{(RS) -2- [6- (2, 5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl]-2-hydroxyethyl } amino group] Propan-1-ol

To a suspension of sodium borohydride (4.11Kg, 109 moles) in tetrahydrofuran (140 liters) at 15 deg.C was added water (15.0L) and the resulting solution was stirred at 15 deg.C. 2-chloro-1- [6- (2, 5-dimethylpyrrol-1-yl) pyridin-3-yl is added over 40 minutes]A solution of ethanone (30.0Kg, 120.6 moles) in tetrahydrofuran (100L) and water (15L). The resulting solution was stirred at 15 ℃ for 60 minutes. When all 2-chloro-1- [6- (2, 5-dimethylpyrrol-1-yl) pyridin-3-yl]Upon consumption of the ethanone, the reaction mixture was treated with concentrated HCl (27% w/w, 47Kg) for 80 minutes, maintaining the temperature below 30 ℃. The mixture was cooled to 15 ℃ and NaOH (34% w/w, 79kg) was added over 60 minutes, maintaining the temperature below 30 ℃. The mixture was then granulated at 20 ℃ overnight. When all the chlorohydrin intermediates were consumed, the aqueous phase was separated. DCM (150L) and water (140L) were added and the mixture was stirred until the phases separated. The organic phase was washed with water (2X 30L). (S) - (+) -2-amino-1-propanol (17.2Kg, 229 moles) and tetrahydrofuran (15L) were added over 20 minutes. The instrument was set up for distillation and DCM was replaced with tetrahydrofuran to give a final volume of 160 l. The reaction mixture was refluxed overnight. After cooling to room temperature, DCM (150L) was added and the mixture was washed with water (3 × 30L). The set-up was distilled and tetrahydrofuran and DCM were replaced with acetonitrile to give a final volume of 84 litres. Alpha-trifluorotoluene (300L) was added over 60 minutes and the mixture was cooled to 5 ℃ over 8 hours and granulated at 5 ℃ for 6 hours. The product was collected by filtration, washed with α α α -trifluorotoluene (2 × 30L) and dried under vacuum at 45 ℃ overnight. Yield 65% (22.7Kg) delta_H(CDCl₃，300MHz)1.10(3H，t)、2.10(6H，s)、2.7-3.2(3H，m)、3.45(1H，m)、3.70(H，dd)、4.85(1H，m)、5.90(2H，s)、7.20(1H，d)、7.90(1H，dd)、8.60(1H，d)ppm。MS m/z 290(MH⁺). The intermediate epoxide is characterized by δ_H(CDCl₃，300MHz)2.10(6H，s)、2.90(1H，dd)、3.25(1H，dd)、4.00(1H，dd)、5.90(2H，s)、7.20(1H，d)、7.70(1H，dd)、8.40(1H，d)ppm。MS m/z 215(MH⁺)。

(2S) -2- [ { (RS) -2- [6- (2, 5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl]-2-hydroxyethyl } propane Amino group]Propan-1-ol

(2S) -2- [ { (RS) -2- [6- (2, 5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl ] was added in 0 min at 20 ℃]-2-hydroxyethyl } amino group]Propanal (5.02Kg, 86.4 moles) was added to propan-1-ol (22.7Kg, 78.6 moles) in DCM (123L). The resulting solution was stirred at 20 ℃ for 2 hours then allowed to settle and then added to a suspension of sodium triacetoxyborohydride (25.8Kg, 122 moles) in DCM (123L) over 90 minutes maintaining the temperature below 30 ℃. The reaction mixture was stirred at 20 ℃ for 1 hour, after which the reaction was quenched with aqueous potassium carbonate solution (36.4Kg in 136L of water) and the phases were allowed to separate. The organic phase was washed with water (2X 23L). The set-up was distilled and DCM (190L) was removed by distillation to give a final volume of 45 litres. The mixture was cooled to 20 ℃. Yield 100% (51.1Kg, 50.9% w/w in DCM). Delta_H(CDCl₃，300MHz)0.8-1.0(6H，m)、1.50-1.70(2H，m)、2.10(6H，s)、2.50-3.15(5H，m)、3.50(2H，dd)、4.80(1H，dd)、5.90(2H，s)、7.20(1H，m)、7.80-7.90(1H，m)、8.60(1H，m)ppm。MS m/z 332(MH⁺)。

(2S) -2- [ { (RS) -2- [ 6-aminopyridin-3-yl]-2-hydroxyethyl } (propyl) amino]Propan-1-ol

(2S) -2- [ { (R, S) -2- [6- (2, 5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl ] -2-hydroxyethyl } propylamino ] propan-1-ol (0.90Kg, 2.71 mol), hydroxylamine hydrochloride (0.56Kg, 8.05 mol), ethanol (5.20L) and water (0.45L) were mixed and heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. Water (1.50L) was added and the suspension was cooled to 5 ℃. The resulting suspension was added portionwise to a mixture of concentrated hydrochloric acid (36% w/w, 0.25L) and water (3.10L). DCM (1.00L) was added and the phases were allowed to separate. The aqueous phase was washed with DCM (2X 0.40L), then mixed with DCM (1.60L) and basified with NaOH 10N (1.45L). The phases were separated and the aqueous phase was extracted with DCM (1.60L) and the combined organic phases were washed with NaOH 1.4N (0.70L), NaOH 0.9N (0.55L), water (0.50L, water (0.25L) and concentrated in vacuo to 87% yield (0.55 Kg).

(2S) -2- [ { (RS) -2- [6- (2, 5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl ] -2-hydroxyethyl } propylamino ] propan-1-ol (51.1Kg, 50.9% w/w in DCM, 78.5 moles), hydroxylamine hydrochloride (16.4Kg, 236 moles), sodium bicarbonate (3.30Kg, 39.3 moles) and ethanol (136L) were mixed. The set-up was distilled and DCM was replaced with ethanol to give a final volume of 130 l. The reaction mixture was cooled to room temperature and kept at that temperature overnight. The reaction mixture was heated to reflux and stirred at reflux for 10.5 hours, then cooled to room temperature. The set-up was subjected to vacuum distillation and the ethanol was replaced with water to give a final volume of 120 litres. The mixture was cooled to room temperature and granulated overnight. The by-product was separated by filtration and washed with water (13L). The filtrate was acidified with HCl (22% w/w, 13.2Kg) and washed with DCM (3X 26L), then mixed with DCM (78L), water (39L) and basified with NaOH (40% w/w, 38.7 Kg). The phases were separated and the aqueous phase was extracted with DCM (52L) and the combined organic phases were washed with NaOH (4.4% w/w, 14.6Kg) and water (2X 9L). Yield 93% (196.3Kg, 9.5% w/w in DCM).

δ_H(CDCl₃，300 MHz)、0.85(3H，t)、0.95(3H，m)1.40-1.60(2H，m)、2.40-2.80(4H，m)、2.95-3.10(1H，m)、3.40(1H，d)、3.45(1H，d)、4.45(2H，br)、4.55(1H，m)、6.50(1H，d)、7.45(1H，d)、8.00(1H，s)ppm。MS m/z254(MH⁺)。

5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl]Pyridin-2-ylamine (Compound A) and 5- [ (2S, 5S) - 5-methyl-4-propylmorpholin-2-yl]Pyridin-2-ylamine (Compound B)

A solution of (2S) -2- [ { (2RS) -2- [ 6-aminopyridin-3-yl ] -2-hydroxyethyl } (propyl) amino ] propan-1-OL (0.50 Kg, 1.97 mol) in DCM (1.OL) was added portionwise to concentrated sulfuric acid (98% w/w) (1.10L) maintaining the temperature below 25 ℃. The mixture was stirred at room temperature for 1 hour and then cooled to between 5 ℃ and 10 ℃. Water (2.0L) was added dropwise and the phases were allowed to separate. The aqueous phase was washed with DCM (0.5L) and added dropwise to a solution of NaOH (1.71Kg) in water (11.0L). DCM (1.5L) was added and the phases were allowed to separate. The aqueous phase was extracted with DCM (0.5L) and the combined organic phases were washed with water (o.5l), then water (2 × 0.25L) and concentrated in vacuo. The yield was 82% (0.38 Kg).

A solution of (2S) -2- [ { (2RS) -2- [ 6-aminopyridin-3-yl ] -2-hydroxyethyl } (propyl) amino ] propan-1-ol in DCM (9.04% w/w, 340.6Kg, 122 moles) was added to concentrated sulfuric acid (98% w/w, 119.4Kg, 1217 moles) over 3.5 hours, maintaining the temperature below 30 ℃. The mixture was stirred at room temperature for 1 hour and then cooled to 5 ℃. Water (145L) was added over 2 hours, the temperature was maintained at 30 ℃ and the phases were allowed to separate. DCM (92L) and aqueous ammonia (35% w/w, 130Kg, 2678 moles) were added to the aqueous phase over 2 hours, maintaining the temperature below 30 ℃. After separation of the phases, the aqueous phase was extracted with DCM (31L) and the organic phase was washed with water (2X 16L). The set-up was distilled and DCM was replaced with acetone to give a final volume of 120 l. The yield was 92.5% (123.3Kg, 21.5% w/w in acetone).

δ_H(CDCl₃300 MHz), 0.85(3H, 2t), 1.00(3 hx 0.45, d, diastereomer a), 1.10(3H simple extract)0.55, d, diastereomer B)1.40-1.60(2H, m), 2.20-2.90(5H, m), 3.30-3.90(2H, m), 4.20(2H, br), 4.20-4.30(1H, m), 6.50(1H, m), 7.45(1H, m), 8.05(1H, m) ppm. MS m/z 236 (MH)⁺). The ratio of diastereomer A to diastereomer B was determined_H1.00ppm and delta_HThe 1.10ppm signal ratio was determined by 1H-NMR.

5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl]pyridin-2-Aminedi- ((1S-10-Camsylate) A Hydrate of calcium and magnesium

To a solution of 5- [ (2S, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine and 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine (2.62Kg, 11.1 moles) in acetone (31.4L) was added a solution of (1S) -10-camphorsulfonic acid (5.11Kg, 22.0 moles) in water (2.29L) and acetone (5.24L). The solution was stirred at 20 ℃ for 15 minutes, seed crystals were added and the mixture was granulated at 20 ℃ overnight. The product was collected by filtration, washed with acetone (2X 2.6L) and dried under vacuum at 40 ℃ overnight. Yield 34% (2.71 Kg).

To a solution of 5- [ (2S, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine and 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine (143.7Kg, 21.5% w/w in acetone, 131 moles) in acetone (343L) was added a solution of (1S) -10-camphorsulfonic acid (63.3Kg, 256 moles) in water (24L). The solution was stirred at 20 ℃ for 15 minutes, seed crystals were added and the mixture was granulated at 20 ℃ overnight. The product was collected by filtration, washed with acetone (62L) and dried under vacuum at 45 ℃ overnight. Yield 37.8% (35.6 Kg).

δ_H(CDCl₃，300MHz)0.7(6H，s)、0.9(3H，t)、1.05(6H，s)、1.2-1.35(7H，m)、1.5-1.75(2H，m)、1.8(2H，d)、1.8-1.9(2H，m)、1.95(2H，m)、2.25(2H，m)、2.40(2H，d)、2.55-2.7(2H，m)、2.90(2H，d)、2.95-3.35(5H，m)、3.65(1H，m)、4.10(1H，m)、4.7(1H，m)、7.0(1H，d)、7.95(2H，m)、8.15(2H，br)、9.8(2H，br)ppm。MS m/z 236(MH⁺)。

From 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl]pyridin-2-Aminodi-S-Camphorsulfonate Mono Characteristic PXRD peak of hydrate calculation map

Main characteristic peaks:

2-theta angle (degree)	Strength (%)	2-theta angle (degree)	Strength (%)
				6.3	27.3	17.6	9.9
10.9	75.9	18.0	15.9
				12.3	18.3	18.8	15.4
12.7	10.7	19.3	29.6
				14.0	15.0	21.7	13.5
14.4	10.2	21.9	25.9
				15.1	100.0	22.4	32.2
16.3	68.8	23.2	35.0
				16.4	28.0	23.5	20.4
16.6	22.1	25.6	9.4
				17.3	31.6	27.9	8.5

5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl]pyridin-2-Aminodi-S-Camphosulfonate monohydrate Characteristic PXRD peak of substance

2-theta angle (degree)	Strength (%)	2-theta angle (degree)	Strength (%)
				6.3	90.6	25.6	100.0
10.9	6.1	27.2	15.8
				12.7	98.3	28.5	7.6
14.0	23.1	32.3	6.1
				15.1	58.4	34.7	9.7
16.3	23.6	38.7	8.8
				17.3	12.4	39.7	10.5
19.1	7.1	39.8	6.0

2-theta angle (degree)	Strength (%)	2-theta angle (degree)	Strength (%)
				19.8	24.5	41.1	7.1
21.7	5.8	46.9	10.5
				23.2	10.2	47.0	6.0

Claims (12)

1.5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate:

2. a monohydrate form of the compound of claim 1.

3. The compound of claim 2, having characteristic main peaks at 6.3, 12.7, 15.1, 16.3 and 25.6 degrees 2 Θ on a powder X-ray diffraction pattern obtained using copper K- α 1X-ray (wavelength of 1.54056 angstroms).

4. A pharmaceutical composition comprising 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-aminedi-S-camphorsulfonate and a pharmaceutically acceptable diluent or carrier.

5. The pharmaceutical composition according to claim 4, wherein 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate is in the form of a monohydrate.

6. A compound according to any one of claims 1 to 3 for use in medicine.

7. Use of a compound according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of sexual dysfunction.

8. Use according to claim 7, wherein the sexual dysfunction is male erectile dysfunction or female sexual dysfunction.

9. Use of a compound according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of a neuropsychiatric disorder or a neurodegenerative disease.

10. A process for the preparation of 5- [ (2R, 5S) -5-methyl-4-propylmorpholin-2-yl ] pyridin-2-amine di-S-camphorsulfonate monohydrate comprising reacting a compound of formula (X) in a suitable solvent

With (1S) -10-camphorsulfonic acid.

11. The process of claim 10 wherein the solvent is acetone/water.

12. A compound of formula (VII)

And pharmaceutically acceptable salts and solvates thereof.