HK1062645B - Tartrate salts of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene - Google Patents

Description

5, 8, 14-triazatetracyclo [10.3.1.02，11.04，9]Tartrate salt of (E) -hexadeca-2 (11), 3, 5, 7, 9-pentaene

The invention relates to 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadec-2 (11), 3, 5, 7, 9-pentaene

And pharmaceutical compositions thereof. In particular, the present invention relates to the L-tartrate salt of the compound, and to various polymorphs of the L-tartrate salt, including two different anhydrous polymorphs (herein referred to as forms A and B) and a hydrate polymorph (herein referred to as form C). In addition, the invention also relates to 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-D-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene and its various polymorphs, D, L-tartrate salt of the compound and its polymorphs, and meso-tartrate salt of the compound and its polymorphs.

The compound 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadeca-2 (11), 3, 5, 7, 9-pentaene is capable of binding to neuronal specific receptor sites for nicotinic acetylcholine and can be used to modulate cholinergic functioning. The compounds are useful for the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, diarrhea (celiac disease), cystitis (pouchitis), vasoconstriction, anxiety, panic disorder (systemic disorder), depression, bipolar disorder (bipolar disorder), autism, sleep disorder, jet lag (jet lag), myoatrophyAmyotrophic Lateral Sclerosis (ALS), cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., due to alcohol, barbiturates, vitamin deficiency, restorative drugs (cognitive drug), lead, arsenic, mercury), disease-induced cognitive impairment (e.g., due to alzheimer's disease (alzheimer's), vascular dementia (vasular dementia), parkinson's disease, multiple sclerosis, AIDS, (large) encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, pick's disease, korsakoff's syndrome and forehead (front) and subcortical dementia (subcortical dementia)), hypertension, bulimia, anorexia, obesity, cardiac arrhythmia, hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy (progessus subarachnoid palsy), chemical dependence and addiction (e.g., to tobacco products (and/or tobacco products)), chemical dependence and addiction, Alcohol, benzodiazepines, barbiturates, opiates or cocaine dependence and addiction), headache, migraine, stroke, Traumatic Brain Injury (TBI), obsessive-compulsive disorder (OCD), psychosis, huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multiple sclerosis dementia, age-related cognitive decline, epilepsy, including seizure deficiency epilepsy, Attention Deficit Hyperactivity Disorder (ADHD), Tourette's Syndrome, in particular nicotine dependence, addiction and withdrawal, including use in smoking cessation therapy.

The tartrate salts of the present invention may be used in pharmaceutical compositions in combination with antidepressants (e.g., tricyclic antidepressants or 5-hydroxytryptamine reuptake inhibition antidepressants (SRIs)) to treat cognitive decline and depression with AD, PD, stroke, huntington's chorea or Traumatic Brain Injury (TBI); may also be used in combination with muscarinic agonists to stimulate central muscarinic and nicotinic receptors for the treatment of, for example, ALS, cognitive dysfunction, age-related cognitive decline, AD, PD, stroke, Huntington's chorea and TBI; it can also be used in combination with neurotrophic factors such as NGF to maximize cholinergic enhancement for treatment of, for example, ALS, cognitive dysfunction, age-related cognitive decline, AD, PD, stroke, Huntington's chorea and TBI; or in combination with an agent that slows or prevents AD, wherein examples of agents that slow or prevent AD include: cognitive enhancers, amyloid aggregation inhibitors, secretase inhibitors, tau (tau) kinase inhibitors, neuronal anti-inflammatory agents and estrogenic therapeutic agents.

Compounds that bind to neuronal nicotinic receptor sites are mentioned in WO99/35131 (corresponding to U.S. patent application No. 09/402,010 filed on 28.9.1999 and U.S. patent application No. 09/514,002 filed on 25.2.25.2000.1999) published 15.7.15.1999, including 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadec-2 (11), 3, 5, 7, 9-pentaene and its hydrochloride. The applicants of the above applications are the same as the applicants of the present application and the disclosures of these documents, which are hereby incorporated by reference in their entirety, generally mention pharmaceutically acceptable acid addition salts of the compounds.

The L-tartrate salts of the invention exhibit properties including high solid state stability and compatibility with certain pharmaceutical formulation excipients which make them superior to 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]Known salts of hexadec-2 (11), 3, 5, 7, 9-pentaene. In addition, the properties exhibited by the D-tartrate salt and the D, L-tartrate salt also make them suitable for pharmaceutical formulation use.

Brief Description of Drawings

FIG. 1 is a 5, 8, 14-triazatetracyclo [10.3.1.0 ] form A^2，11.0^4，9]-powder X-ray diffraction pattern of the anhydrous L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene (linear counts per second on the y-axis; X is degrees at 2 theta angle).

FIG. 2 is a 5, 8, 14-triazatetracyclo [10.3.1.0 ] form B^2，11.0^4，9]Anhydrous L-value of hexadeca-2 (11), 3, 5, 7, 9-pentaenePowder X-ray diffraction pattern of the tartrate salt (y-axis is linear counts per second; X is degrees 2 theta angle).

FIG. 3 is a C-form of 5, 8, 14-triazatetracyclo [10.3.1.0 ]^2，11.0^4，9]-hexadec-2 (11), powder X-ray diffraction pattern of hydrate of the L-tartrate salt of 3, 5, 7, 9-pentaene (y-axis linear counts per second; X is degrees at 2 theta angle).

FIG. 4A is 5, 8, 14-triazatetracyclo [10-3.1.0 ] form B^2，11.0^4，9]Theoretical powder X-ray diffraction pattern of the anhydrous L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene (linear counts per second on the y-axis; X is degrees at 2 θ angle). FIG. 4B is a C-form of 5, 8, 14-triazatetracyclo [10.3.1.0 ]^2，11.0^4，9]Theoretical powder X-ray diffraction pattern of L-tartrate hydrate of hexadec-2 (11), 3, 5, 7, 9-pentaene (linear counts per second on the y-axis; X is degrees 2 theta angle).

FIG. 5A is a representation of 5, 8, 14-triazatetracyclo [10.3.1.0 ] form B^2，11.0^4，9]-a superposition of the theoretical powder X-ray diffraction pattern (lower line) of the anhydrous L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene and the actually measured powder X-ray diffraction pattern (upper line) (linear counts per second on the y-axis; X in degrees 2 theta). FIG. 5B is a C-form 5, 8, 14-triazatetracyclo [10.3.1.0 ]^2，11.0^4，9]-hexadec-2 (11), superposition of the measured powder X-ray diffraction pattern (upper line) of the L-tartrate hydrate of 3, 5, 7, 9-pentaene and the theoretical powder X-ray diffraction pattern (lower line) (y-axis linear counts per second; X is degrees at 2 theta angle).

FIG. 6 shows 5, 8, 14-triazatetracyclo [10.3.1.0 ] type A (lower line), type B (middle line) and type C (upper line)^2，11.0^4，9]-X-ray diffraction pattern of L-tartrate powder of hexadec-2 (11), 3, 5, 7, 9-pentaene (y-axis linear counts per second; X is degrees 2 theta).

FIGS. 7A, 7B and 7C are 5, 8, 14-triazatetracyclo [10.3.1.0 ] forms A, B and C, respectively^2，11.0^4，9]-sixteen-2 (11), 3, 5, 7,solid state of 9-pentaene L-tartrate¹³C NMR spectra were determined by cross-polarized magic angle spinning (CPMAS) method in a 7mm wide-aperture magic angle spinning (WBMAS) probe using a Bruker Avance DRX 500MHz NMR spectrometer at 295K. Marked with an asterisk (^*) The peak of (a) is a spin side band, which shifts along both sides of the true peak (central band) at multiple peaks of spin frequency.

FIG. 8A is a representation of 5, 8, 14-triazatetracyclo [10.3.1.0 ] form B^2，11.0^4，9]-X-ray crystal structure (absolute configuration) of the anhydrous L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene. FIG. 8B is a C-form of 5, 8, 14-triazatetracyclo [10.3.1.0 ]^2，11.0^4，9]-X-ray crystal structure (absolute configuration) of hydrate of L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene.

FIGS. 9A, 9B and 9C are 5, 8, 14-triazatetracyclo [10.3.1.0 ] forms A, B and C, respectively^2，11.0^4，9]-differential scanning calorimetry of L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene.

FIGS. 10A and 10B are, respectively, X-and Y-form 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]Powder X-ray diffraction pattern of the D, L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene (linear counts per second on the y-axis; X in degrees 2 θ)

FIGS. 11A and 11B are, respectively, X-and Y-form 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-differential scanning calorimetry of L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene.

Summary of The Invention

The invention relates to 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]Tartrate salt of hexadec-2 (11), 3, 5, 7, 9-pentaene. The tartrates of the present invention include L-tartrate, D, L-tartrate and meso-tartrate.

The invention relates in particular to 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene.

In one embodiment of the invention, 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]The L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene is anhydrous L-tartrate salt, referred to herein as form a. The tartrate form a is characterized in that: the main X-ray diffraction pattern peaks are expressed in terms of 2 θ and d-spacing measured in copper radiation (within the error range indicated) as follows:

2 theta angle (± 0.2)	d value (_) 0.2
		6.1	14.5
12.2	7.2
		13.0	6.8
14.7	6.0
		16.8	5.3
19.4	4.6
		21.9	4.1
24.6	3.6

The form a L-tartrate crystals are characterized in that: the melting point was determined to be about 223 ℃ by differential scanning calorimetry with a rate of 5 degrees/minute ramp heating. Form a is also characterized by: when using solid state¹³C NMR cross-polarization magic angle spin technique showed the following major resonance peaks (. + -. 0.1ppm) from 100ppm low field (adamantane standard peak 29.5 ppm): 178.4, 149.3, 147.4, 145.1 and 122.9 ppm.

In another embodiment of the invention, 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]The L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene is another anhydrous L-tartrate polymorph, referred to herein as form B. Form B of L-tartrate is characterized in that: the main X-ray diffraction pattern peaks are expressed in terms of 2 θ and d-spacing as determined by copper radiation as follows (within the error range indicated):

2 theta angle (± 0.2)	d value (_) 0.2
		5.9	15.0
12.8	6.9
		14.4	6.1
15.3	5.8
		16.9	5.2
17.2	5.2
		21.8	4.1
23.8	3.7
		25.1	3.5

Form B of the L-tartrate salt has a single crystal X-ray structure (absolute configuration) as shown in figure 8A. The B-type crystal is an orthorhombic system and belongs to the space group of P2(1), 2, (1), 2 and 1. The type B crystal is also characterized in that: the melting point was determined to be about 215 ℃ by differential scanning calorimetry with a rate of 5 degrees/minute ramp heating. In addition, the type B crystal is also characterized in that: its water solubility was about 156mg/ml and its natural pH in aqueous solution was about 3.3. In addition, form B crystals have a hygroscopicity of about 0.2% at 90% relative humidity.

Form B of the L-tartrate salt is further characterized by: when using solid state¹³C NMR cross-polarization magic angle spin technique showed the following major resonance peaks (. + -. 0.1ppm) from 100ppm low field (adamantane standard peak 29.5 ppm): 179.2, 178.0, 147.4, 145.2, 144.4, 124.8 and 122.5 ppm.

In another embodiment of the invention, the L-tartrate salt of 5, 8, 14-triazatetracyclo [10.3.1.02, 11.04, 9] -hexadeca-2 (11), 3, 5, 7, 9-pentaene is the hydrate L-tartrate salt, herein referred to as form C. Form C tartrate is characterized in that: the main X-ray diffraction pattern peaks are expressed in terms of 2 θ and d-spacing as determined by copper radiation as follows (within the error range indicated):

2 theta angle (± 0.2)	d value (_) 0.2
		5.9	15.1
11.8	7.5
		16.5	5.4
21.2	4.2
		23.1	3.8
23.8	3.7
		26.5	3.4

The crystalline form C of hydrate L-tartrate has a single crystal X-ray structure as shown in figure 8B. Further, the C-type hydrate is a monoclinic system and belongs to the space group P2 (1). The type C crystal is also characterized in that: the initial solid-solid transition point was about 72 ℃ and the initial melt transition point was about 220 ℃ as determined by differential scanning calorimetry with a rate of 5 degrees/minute ramp heating. Form C crystals have the same water solubility as form B crystals because form B crystals are converted to form C hydrates upon exposure to 100% relative humidity.

The form C crystals of L-tartrate are characterized in that: when using solid state¹³C NMR cross-polarization magic angle spin technique showed the following major resonance peaks (. + -. 0.1ppm) from 100ppm low field (adamantane standard peak 29.5 ppm): 179.0, 176.1, 147.5, 144.5 and 124.6 ppm.

Another embodiment of the invention relates to 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]D-tartrate salt of hexadec-2 (11), 3, 5, 7, 9-pentaene. In particular, the present invention relates to three polymorphic forms of D-tartrate (referred to herein as A ', B ' and C ') which exhibit the same X-ray diffraction characteristics, hygroscopicity, water content and thermal properties as L-tartrate forms A, B and C.

In another embodiment, the invention relates to 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]The D, L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene, specifically to two polymorphs, an anhydrate (herein referred to as form X) and a hydrate (herein referred to as form Y).

Form X, D, L-tartrate is characterized in that: the peaks of the main X-ray diffraction pattern are expressed in terms of 2 theta and d-spacing measured with copper radiation as follows (within the indicated error range):

2 theta angle (± 0.2)	d value (_) 0.2
		6.0	14.6
11.9	7.4
		15.0	5.9
17.1	5.2
		22.1	4.0
24.5	3.6

The form X-D, L-tartrate is further characterized in that: its initial melting transition point is about 212 deg.c.

Form Y of the D, L-tartrate salt is characterized by the following (within the indicated error range) major X-ray diffraction pattern peaks measured with copper radiation:

2 theta angle (± 0.2)	d value (_) 0.2
		6.2	14.2
12.0	7.4
		15.2	5.8
18.1	4.9
		24.0	3.7
25.1	3.5

The form Y D, L-tartrate is further characterized in that: the initial solid-solid transition point is about 131 ℃ and the initial melt transition point is about 217 ℃.

Another embodiment of the present invention is directed to a process for preparing a compositionA pharmaceutical composition comprising 5, 8, 14-triazatetracyclo [10.3.1.0 ] in type A, B or C^2，11.0^4，9]-hexadeca-2 (11), at least one polymorph of the D, L-tartrate polymorph of 3, 5, 7, 9-pentaene and a pharmaceutically acceptable carrier or excipient for use in the treatment of inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spasmodic dystonia, chronic pain, acute pain, diarrhea, capsulitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, Amyotrophic Lateral Sclerosis (ALS), cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., due to alcohol, barbiturates, vitamin deficiencies, recreational drugs, lead, arsenic, mercury), disease-induced cognitive impairment (e.g., caused by Alzheimer's disease (presenile dementia), vascular dementia, Parkinson's disease, multiple sclerosis, AIDS, (macro) encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, pick's disease, Korsakoff's syndrome and frontal and subcortical dementia), hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, hyperchlorhydria, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addiction (e.g., to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioid-or cocaine dependencies and addictions), headache, migraine, stroke, Traumatic Brain Injury (TBI), obsessive compulsive and behavioral disorders (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, headache, migraine, cerebral apoplexy, Traumatic Brain Injury (TBI), obsessive-compulsive disorders (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multiple sclerosis dementia, age-related cognitive decline, epilepsy, including petit-deficit epilepsy, Attention Deficit Hyperactivity Disorder (ADHD), and Tourette's syndrome. In another more preferred embodiment of the invention, the pharmaceutical composition is for use in the treatment of nicotine dependence, addiction and withdrawal; most preferably for smoking cessation therapy.

The invention also relates to a pharmaceutical composition for use as described in the preceding paragraph, which contains 5, 8,14-Triazatetracyclo [10.3.1.0^2，11.0^4，9]-any one of D-tartrate, D, L-tartrate or meso-tartrate of hexadeca-2 (11), 3, 5, 7, 9-pentaene.

The invention also relates to methods of treating: inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum, and crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, diarrhea, cystitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, Amyotrophic Lateral Sclerosis (ALS), cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., due to alcohol, barbiturates, vitamin deficiency, recreational drugs, lead, arsenic, mercury), disease-induced cognitive impairment (e.g., due to alzheimer's disease (alzheimer's dementia), vascular dementia, parkinson's disease, multiple sclerosis, AIDS, (large) encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, Pick's disease, Korsakoff syndrome and frontal and subcortical dementia), hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, hyperacidity, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependence and addiction (e.g., dependence and addiction to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, Traumatic Brain Injury (TBI), Obsessive Compulsive Disorder (OCD), psychosis, huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multiple sclerosis dementia, age-related cognitive decline, epilepsy, including petit-deficit epilepsy, Attention Deficit Hyperactivity Disorder (ADHD), and tourette's syndrome, comprising: administering to a patient in need thereof a therapeutically effective amount of A, B or 5, 8, 14-triazatetracyclo [10.3.1.0 ] form C^2，11.0^4，9]-any one of L-tartrate salts of hexadeca-2 (11), 3, 5, 7, 9-pentaene, preferably form B. Another more preferred embodiment of the invention relates toA method of treating nicotine dependence, addiction and withdrawal, in particular to a method of smoking cessation treatment, comprising: administration of A, B or a C-type 5, 8, 14-triazatetracyclo [10.3.1.0 ] to a patient in need thereof^2，11.0^4，9]-any one of L-tartrate salts of hexadeca-2 (11), 3, 5, 7, 9-pentaene, preferably form B.

The invention also relates to a method of treating a disease as described in the preceding paragraph comprising: administering A, B or a C-form 5, 8, 14-triazatetracyclo [10.3.1.0 ] to a patient in need thereof^2，11.0^4，9]Any one of D-tartrate, D, L-tartrate or meso-tartrate of hexadeca-2 (11), 3, 5, 7, 9-pentaene.

The term "treating" as used herein when used as a verb means and includes: reversing, alleviating or inhibiting the progression of, or preventing a disease, disorder, condition, or one or more symptoms thereof. The term "treatment" when used as a noun refers to the act of treating as described above.

The invention also relates to the preparation of 5, 8, 14-triazatetracyclo [10.3.1.0 ] form A^2，11.0^4，9]-L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene, comprising the steps of:

(i) reacting 5, 8, 14-triazatetracyclo [10.3.1.0 ] in a suitable solvent^2，11.0^4，9]-hexadec-2 (11), 3, 5, 7, 9-pentaene is contacted with 1 to 2 equivalents of L-tartaric acid; and

(ii) the crystals formed were collected.

In a preferred embodiment of the invention relating to the above process, 1.1 equivalents of L-tartaric acid are used and tartaric acid is added to the solution containing the free base. In a preferred form of the method, the contacting step is allowed to proceed for less than 2 hours. In a more preferred embodiment of the invention with respect to the above process, the contacting step, i.e. step "(i) above, is allowed to proceed at above 45 ℃. In another preferred embodiment of the present invention relating to the above process, the suitable solvent is selected from the group consisting of：(C₁-C₆) Alkyl alcohol, (C)₁-C₆) Alkyl ketone or (C)₁-C₆) Alkyl ether, acetonitrile and (C)₁-C₆) Alkyl esters (e.g., ethyl acetate, isopropyl acetate, etc.). More preferably, the suitable solvent is methanol or ethanol.

The present invention also relates to a process for the preparation of form a' D-tartrate comprising the above steps (i) and (ii) as described for the preparation of form a L-tartrate salt, but wherein D-tartaric acid is used in place of L-tartaric acid in step (i).

The invention also relates to the preparation of 5, 8, 14-triazatetracyclo [10.3.1.0 ] form B^2，11.0^4，9]-L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene, comprising the steps of:

(i) reacting 5, 8, 14-triazatetracyclo [10.3.1.0 ] in a suitable solvent^2，11.0^4，9]-hexadec-2 (11), 3, 5, 7, 9-pentaene with about 1 to about 2.3 equivalents of L-tartaric acid; and

(ii) the crystals formed were collected.

In a preferred embodiment of the present invention involving the above process, about 1.1 to about 2.2 equivalents, more preferably 1.1 equivalents of L-tartaric acid are used and then the free base solution is added to the solution containing L-tartaric acid. In a preferred embodiment of the process, the contacting step is allowed to proceed for at least 1 hour, more preferably at least 2 hours, most preferably greater than 12 hours. In a preferred embodiment, the suitable solvent is selected from: (C)₁-C₆) Alkanol, (C)₁-C₆) An alkanone or (C)₁-C₆) Alkyl ether, acetonitrile and (C)₁-C₆) Alkyl esters (e.g., ethyl acetate, isopropyl acetate, and the like). More preferably, the suitable solvent is methanol or ethanol, most preferably methanol.

The present invention also relates to a process for the preparation of form B' D-tartrate comprising the above steps (i) and (ii) as described for the preparation of form B L-tartrate, but using D-tartaric acid instead of L-tartaric acid in step (i).

Another aspect of the invention relates to the preparation of 5, 8, 14-triazatetracyclo [10.3.1.0 ] form C^2，11.0^4，9]-L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene, comprising the steps of:

(i) allowing 5, 8, 14-triazatetracyclo [10.3.1.0 ] in type A or B^2，11.0^4，9]-L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene in contact with water; and

(ii) the crystals formed were collected.

In a preferred embodiment of the present invention relating to the above process, the contacting of step (i) comprises: the crystals of form A or B are slurried with water and then an organic solvent is added to facilitate precipitation of the form C product. In a more preferred embodiment of the process, the organic solvent used to facilitate precipitation is methanol, ethanol or acetonitrile.

The present invention also relates to a process for the preparation of form C D-tartrate comprising the steps (i) and (ii) as described above for the preparation of form C L-tartrate, but using form A 'or B' D-tartrate in place of form A or B L-tartrate in step (i).

The invention also relates to the preparation of X-type 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]A process for the D, L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene, comprising the steps of:

(i) reacting 5, 8, 14-triazatetracyclo [10.3.1.0 ] in a suitable solvent^2，11.0^4，9]-hexadec-2 (11), 3, 5, 7, 9-pentaene with about 1 to about 2.3 equivalents of D, L-tartaric acid; and

(ii) the crystals formed were collected.

In a preferred embodiment of the present invention relating to the above process, about 2.2 equivalents of D, L-tartaric acid are used and the free base solution is then added to the solution containing D, L-tartaric acid. In a preferred embodiment of the method, the contacting step is allowed to proceed for at least 2 hours, more preferably at least 2 hours, most preferably at least 24 hours.

In another preferred embodiment of the present invention, which relates to the above process for preparing form X crystals, the suitable solvent is an anhydrous or near anhydrous solvent selected from the group consisting of: (C)₁-C₆) Alkanol, (C)₁-C₆) An alkanone or (C)₁-C₆) Alkyl ether, acetonitrile and (C)₁-C₆) Alkyl esters (e.g., ethyl acetate, isopropyl acetate, and the like). More preferably, the suitable solvent is ethanol.

The invention also relates to the preparation of the Y-type 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]A process for the D, L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene, comprising the steps of:

(i) reacting 5, 8, 14-triazatetracyclo [10.3.1.0 ] in a suitable solvent^2，11.0^4，9]-hexadec-2 (11), 3, 5, 7, 9-pentaene with about 1 to about 2.3 equivalents of D, L-tartaric acid; and

(ii) the crystals formed were collected.

In a preferred embodiment of the present invention relating to the above process, about 2.2 equivalents of D, L-tartaric acid are used and the free base solution is then added to the solution containing D, L-tartaric acid. In a preferred embodiment of the method, said contacting step is allowed to proceed for at least 2 hours, more preferably at least 12 hours, most preferably at least 24 hours.

In another preferred embodiment of the above process of the present invention involving the preparation of Y-form crystals, the suitable solvent is selected from the group consisting of the following solvents in admixture with water: (C)₁-C₆) Alkanol, (C)₁-C₆) Alkanones or (C)₁-C₆) Alkyl ether, acetonitrile and (C)₁-C₆) Alkyl esters (e.g., ethyl acetate, isopropyl acetate, and the like). More preferably, a suitable solvent is ethanol mixed with water, most preferably 20% aqueous ethanol.

Detailed Description

The compound 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadeca-2 (11), 3, 5, 7, 9-pentaene is a nicotinic partial agonist and is useful in the treatment of a variety of CNS diseases, disorders and conditions, including, inter alia, nicotine dependence, addiction and withdrawal.

Although in general, 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]Salts of hexadeca-2 (11), 3, 5, 7, 9-pentaene are all crystalline, but most salts are too hygroscopic to be useful as pharmaceutical formulations. 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]The L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene is very poorly hygroscopic, highly water soluble and has a high melting point, these properties, and its relative inactivity with common excipients, make it very suitable for use in pharmaceutical formulations. 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]The D-tartrate, D, L-tartrate and meso-tartrate salts of hexadeca-2 (11), 3, 5, 7, 9-pentaene also show advantageous properties.

L-tartrate has three possible forms: two anhydrous forms and one hydrate form. In both anhydrous forms, form a and B, form a is a dynamic polymorph that, under appropriate conditions, converts to thermodynamically stable form B crystals. The hydrate form C, L-tartrate, is a monohydrate and is relatively stable in the ambient environment. Under vacuum and moderate temperature conditions, form C crystals will maintain 1 equivalent of water for at least 1 day (e.g., 24 hours in a vacuum oven at 45 ℃), but will eventually lose water and convert to form B anhydrate over some period of time (e.g., 48 hours or more). At low humidity, form B crystals are the most stable polymorph. Thus, 5, 8, 14-triazatetracyclo [10.3.1.0 ] is useful in pharmaceutical preparations^2，11.0^4，9]The L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene, form B crystals appear to be the most suitable and stable polymorph.

As noted above, polymorph form A is an anhydrous dynamic polymorph that, under appropriate conditions, converts to thermostable polymorph form BAnd (4) crystal form substances. The form A polymorph can be obtained synthetically, for example, by reacting 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadec-2 (11), 3, 5, 7, 9-pentaene free base is contacted with about 1 equivalent of L-tartaric acid in methanol or ethanol, with little or no time to equilibrate. The 5, 8, 14-triazatetracyclo [10.3.1.0 ] is substituted by a substituent^2，11.0^4，9]Hexadec-2 (11), 3, 5, 7, 9-pentaene and L-tartaric acid, initially yielded the form a polymorph, but after continued or prolonged stirring of the reaction mixture, the form B polymorph began to form. The rate of polymorph form B formation can be increased if at least a 2-fold or greater stoichiometric excess of L-tartaric acid is used (i.e., 2.2 equivalents of L-tartaric acid are used to form polymorph form B faster than 1.1 equivalents of L-tartaric acid alone), and the reaction allowed to proceed for more than two hours, preferably at least one day or more. When 2.2 equivalents are used, the conversion to form B polymorph is generally complete after 5 hours of reaction. In contrast, the conversion takes more than 20 hours when 1.1 equivalents are applied. In any case, complete conversion to form B polymorph is generally obtained if the reaction is carried out at 20-25 ℃ for 48 hours.

The temperature of the L-tartrate salt forming reaction also affects the isolation of form a or form B polymorph, since forms a and B can be thermally interconverted. Salt formation reactions at temperatures above 45 ℃ give polymorph form a. In contrast, salt formation reactions carried out below 45 ℃ give predominantly polymorph form B. Additionally, form B is formed by stirring polymorph form A in methanol at temperatures below 40 ℃.

Although any number of solvents may be used, including too many lower alcohols. Preferably, form B polymorph is obtained in high yield using methanol, which provides a high filtration rate of the crystalline material and direct formation of form B polymorph. The solubility of both the free base and L-tartaric acid in methanol is higher than that of other lower alkanols.

By following a specific order of addition, wherein 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-sixteen-2 (11), 3The rate of formation of polymorph form B can be increased by adding the free base of 5, 7, 9-pentaene to the L-tartaric acid solution. In order to maximize the actual concentration of L-tartaric acid in the reaction, a solution of the free base in methanol may be added to a solution of 1.1 or more equivalents of L-tartaric acid at 20 c, and the desired anhydrous polymorph form B isolated directly, the conversion of which is complete within 2 hours.

A preferred process for preparing anhydrous polymorph form B comprises: to a vessel free of particulates (speck-free) was added 1.1-2.2 equivalents of L-tartaric acid and methanol (4-50 volumes), the mixture was stirred until dissolved, and the resulting solution was then filtered in a particulate-free manner into a crystallization vessel. Stirring the 5, 8, 14-triazatetracyclo [10.3.1.0 ] in a vessel at a temperature of 0 to 50 deg.C, more preferably 20 to 25 deg.C^2，11.0^4，9]Hexadec-2 (11), 3, 5, 7, 9-pentaene free base (1.0 equiv) and methanol (4-50 vol) until dissolved. Then, the obtained 5, 8, 14-triazatetracyclo [10.3.1.0 ] is subjected to condensation polymerization for a time of about 1 minute to 2 hours, preferably about 30 minutes or longer^2，11.0^4，9]-hexadeca-2 (11), 3, 5, 7, 9-pentaene free base solution was added to the tartaric acid solution. The product is stirred at a temperature of 0-40 deg.C, more preferably 20-25 deg.C, for 1-48 hours, more preferably about 1 hour, and then separated by filtration. The product is dried, typically under vacuum at 20-60 deg.C, more preferably 35-45 deg.C, to provide 5, 8, 14-triazatetracyclo [10.3.1.0 ] form B^2，11.0^4，9]-L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene.

Both form a and form B anhydrous crystals can be converted to form C monohydrate by exposure to 100% Relative Humidity (RH) or stirring in water. Polymorph form C can most easily be prepared as follows: the polymorph form a or B is dissolved in water at 20-50 c, then an organic solvent incapable of dissolving the salt, preferably methanol, ethanol or acetonitrile, is added thereto and the mixture is allowed to stir for 1-30 minutes, preferably about 10 minutes. The white form C product precipitated and was filtered off and allowed to air dry.

It should be noted that: when exposed to 100% RH humidity, form B will change to form C within 2 days. In contrast, polymorph form C readily converts to polymorph form B when exposed to 0% relative humidity for substantially the same amount of time. However, hydrate form C dehydrates more slowly when placed under conditions below 50% RH, which was confirmed by experiments at 23% and 43% RH. Nevertheless, at RH greater than 60%, both form B and form C crystals are relatively stable over a period of months, as shown by experiments at 75% and 87% relative humidity.

Further, the form A crystal can be obtained from the form C crystal by the following method: form C crystals are dissolved in a hot organic solvent, preferably ethanol, at or near boiling temperature, preferably at about 75 deg.C, and then stirred for 10 minutes to 3 hours, preferably 30 minutes. The mixture was filtered hot and the crystals were collected and dried under vacuum at 45 ℃ to give polymorph form a.

5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-hexadec-2 (11), the D-tartrate salt of 3, 5, 7, 9-pentaene has three polymorphs (a ', B ' and C ') which have the same X-ray diffraction, hygroscopicity, water content and thermal properties as the L-tartrate form A, B and C, respectively; and are prepared by the same procedures as the corresponding L-tartrate polymorphs except that D-tartaric acid is used in place of L-tartaric acid in these procedures.

Preparation of 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-anhydrous polymorph (form X) of D, L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene comprising the steps of: at a temperature of 20 ℃ to the reflux temperature of the solvent, the 5, 8, 14-triazatetracyclo [10.3.1.0 ]^2，11.0^4，9]-hexadec-2 (11), 3, 5, 7, 9-pentaene and about 1 to about 2.3 equivalents, preferably 2.2 equivalents of D, L-tartaric acid are dissolved in a suitable solvent, preferably in anhydrous ethanol, for at least 2 hours, more preferably at least 12 hours, most preferably at least 24 hours; the resulting crystals were collected, the product washed with solvent and air dried. Preparation of hydrate polymorph of D, L-tartrate salt in similar manner(form Y) except that a solvent mixed with water is used, preferably a mixture of ethanol and water, more preferably 20% ethanol in water. In addition, meso-tartrate salts may be prepared in a similar manner to the D, L-tartrate salts.

Differential scanning calorimetry

Differential Scanning Calorimetry (DSC) studies of 5, 8, 14-triazatetracyclo [10.3.1.0 ] forms A, B and C^2，11.0^4，9]-solid-state thermal behaviour of hexadec-2 (11), 3, 5, 7, 9-pentaene L-tartrate. The traces of form a, form B and form C are shown in fig. 9A, 9B and 9C, respectively. These DSC thermograms are produced by Mettler Toledo DSC 821^e(STAR^eSystem) is obtained. Generally, 1-10mg samples were prepared in coiled aluminum pans (crimped aluminum pans) with small pinholes. The measurement was carried out at a heating rate of 5 ℃/min within a temperature range of 30-300 ℃.

As can be seen in fig. 9A, the form a L-tartrate has an initial melt transition temperature of 223 c, a corresponding melting point peak of 225 c (decomposition), and a temperature ramp rate of 5 c/min. As shown in FIG. 9B, the form B L-tartrate had an initial dissolution transition point of 215 ℃ and a melting point peak of 218 ℃ (decomposition) at a temperature rising rate of 5 ℃/min. As shown in fig. 9C, the solid-solid transition point of form C, L-tartrate hydrate, which is considered to be equivalent to the loss of water from the crystal lattice, was 73 ℃ and the peak was 76 ℃. It was also observed that the initial melting-transition point was 220 ℃ and the melting point peak was 223 ℃ (decomposition).

The X-and Y-form 5, 8, 14-triazatetracyclo [10.3.1.0 ] s were also investigated by DSC^2，11.0^4，9]-solid state thermal behaviour of hexadeca-2 (11), 3, 5, 7, 9-pentaene D, L-tartrate. As shown in FIG. 11A, the starting melting transition point of form X, D, L-tartrate (anhydrous) is 212 ℃. In FIG. 11B, a differential scanning calorimetry scan of form Y, D, L-tartrate shows an initial solid-solid transition point of 131 ℃ and a melting point peak of 137 ℃. The solid-solid transition point is considered to correspond to or be associated with a loss of water from the crystal lattice. The initial melting transition point of the Y-form was also observed to be 217 ℃ with concomitant decomposition.

However, the person skilled in the art will note that: in the DSC measurement, the actual measurement starting temperature and peak temperature are changed to some extent depending on the heating rate, crystal shape and purity, and many measurement parameters.

Powder X-ray diffraction pattern

Using radiation containing copper (CuK)_α) Powder X-ray diffraction patterns of A, B and form C L-tartrate were collected by a Bruker D5000 diffractometer (Bruker AXS, Madison, Wisconisn) with fixed slits (1.0, 0.6mm) and a Kevex solid detector. Data was collected at a 2 theta range of 3.0 to 40.0 degrees in steps of 0.04 degrees and time intervals of 1.0 second.

The X-ray powder diffraction pattern (relative intensity: 0.500) of form A L-tartrate was measured with a copper anode at a wavelength of 1 (1.54056. ANG.) and a wavelength of 2 (1.54439. ANG.). 2 theta ranges between 3.0-40.0 degrees in steps of 0.04 degrees, time intervals of 1.00, smooth width of 0.300 and threshold of 1.0.

The diffraction peaks of form A of L-tartrate at the diffraction angles (2. theta.) in the measured powder X-ray diffraction analysis are shown in Table I. However, the relative intensity may vary with crystal size and crystal morphology. Fig. 1 shows the powder diffraction pattern actually measured.

TABLE I A powder X-ray diffraction Pattern with diffraction line intensities and peak positions for form L-tartrate

2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)
									6.1	14.5	73.3	20.6	4.3	16.8	30.8	2.9	5.6
11.8	7.5	6.1	21.9	4.1	100.0	32.0	2.8	5.8
									12.2	7.2	15.8	22.6	3.9	9.1	32.5	2.8	8.9
13.0	6.8	23.9	23.9	3.7	13.4	34.0	2.6	6.0
									14.7	6.0	14.6	24.6	3.6	29.2	34.8	2.6	6.9
16.8	5.3	99.5	27.2	3.3	10.5	35.2	2.5	8.8
									17.6	5.0	11.7	27.7	3.2	6.1	37.0	2.4	6.9
18.3	4.8	7.0	28.8	3.1	8.0	37.5	2.4	8.6
									19.0	4.7	14.4	29.4	3.0	5.3	38.2	2.4	6.5
19.4	4.6	28.4	29.8	3.0	15.9	-	-	-

Table II lists the 2 θ, d-spacing and relative intensities for form A. The listed data are computer generated data.

TABLE II intensity and Peak position of form A L-tartrate

2 theta angle	d value (_)	I (relative value)
			6.1	14.5	73.3
12.2	7.2	15.8
			13.0	6.8	23.9
14.7	6.0	14.6
			16.8	5.3	99.5
19.4	4.6	28.4
			21.9	4.1	100.0
24.6	3.6	29.2

The X-ray powder diffractogram of the salt form B was determined using the same equipment and with the same parameters as for the determination of form A. In the measured type B powder X-ray diffraction analysis, diffraction peaks at diffraction angles 2. theta. are shown in Table III. However, these relative intensities may also vary with crystal size and morphology. The diffraction pattern of the powder actually measured is shown in FIG. 2.

TABLE III powder X-ray diffraction Pattern with diffraction line intensities and peak positions for form B L-tartrate salt

2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)
									5.9	15.0	57.0	19.1	4.6	11.1	29.1	3.1	8.6
11.7	7.5	8.2	20.7	4.3	6.3	29.7	3.0	4.9
									12.8	6.9	27.2	21.1	4.2	6.0	31.9	2.8	11.9
14.4	6.1	23.2	21.8	4.1	100.0	34.6	2.6	7.2
									15.3	5.8	4.9	23.8	3.7	26.9	34.9	2.6	5.5
16.4	5.4	23.0	24.3	3.7	10.5	35.6	2.5	5.0
									16.9	5.2	41.8	25.1	3.5	15.8	37.3	2.4	5.4
17.2	5.2	49.3	25.8	3.4	11.4	38.8	2.3	5.4
									17.8	5.0	6.8	26.9	3.3	6.6	-	-	-

18.7

4.7

5.6

27.8

3.2

8.7

-

-

-

Table IV lists the 2 θ, d-spacing and relative intensities for form B. The listed data are computer generated data.

TABLE IV intensity and Peak position of L-tartrate form B

2 theta angle	d value (_)	I (relative value)
			5.9	15.0	57.0
12.8	6.9	27.2
			14.4	6.1	23.2
15.3	5.8	4.9
			16.9	5.2	41.8
17.2	5.2	49.3
			21.8	4.1	100.0
23.8	3.7	26.9
			25.1	3.5	15.8

The X-ray powder diffractogram of the salt form C was determined using the same equipment and with the same parameters as for the determination of form A. In the measured C-type powder X-ray diffraction analysis, diffraction peaks at diffraction angles 2. theta. are shown in Table V. However, these relative intensities may also vary with crystal size and morphology. The diffraction pattern of the powder actually measured is shown in FIG. 3.

TABLE V C powder X-ray diffraction Pattern with diffraction line intensities and peak positions for form L-tartrate

2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)
									5.9	15.1	85.5	23.8	3.7	78.5	32.1	2.8	8.7
11.8	7.5	49.4	26.1	3.4	11.6	33.5	2.7	5.9
									13.1	6.8	14.4	26.5	3.4	65.8	35.8	2.5	10.0
14.5	6.1	9.2	27.0	3.3	9.6	36.0	2.5	13.0
									16.5	5.4	97.4	27.9	3.2	5.8	37.0	2.4	5.7
17.5	5.1	10.0	28.9	3.1	9.5	37.9	2.4	11.5

18.8	4.7	7.0	29.3	3.0	27.3	-	-	-
									20.3	4.4	8.2	29.9	3.0	33.0	-	-	-
21.2	4.2	100.0	31.3	2.9	6.7	-	-	-
									23.1	3.8	35.0	31.6	2.8	9.0	-	-	-

Table VI lists the 2 θ, d-spacing and relative strengths for form C. The listed data are computer generated data.

TABLE VI intensities and Peak positions of form C L-tartrate

2 theta angle	d value (_)	I (relative value)
			5.9	15.1	85.5
11.8	7.5	49.4
			16.5	5.4	97.4
21.2	4.2	100.0
			23.1	3.8	35.0
23.8	3.7	78.5
			26.5	3.4	65.8

As shown in fig. 6, the superposition of the X-ray powder diffraction patterns observed for A, B and form C L-tartrate shows that there are some shifts in the X-ray powder diffraction peaks and that the various crystalline forms have different powder diffraction fingerprints.

The X-ray powder diffraction pattern of the X-form (anhydrous) D, L-tartrate salt was measured using the same equipment and the same parameters as those used for the measurement of form A. In the X-ray powder X-ray diffraction analysis measured, diffraction peaks at diffraction angles 2. theta. are shown in Table VII. However, these relative intensities may also vary with crystal size and morphology. The actually measured powder diffraction pattern is shown in fig. 10A.

TABLE VII powder X-ray diffraction patterns with diffraction line intensities and peak positions for form X, D-tartrate

2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)
									6.0	14.6	100.0	18.3	4.8	10.3	27.5	3.2	3.7
10.9	8.1	3.8	18.7	4.8	4.8	28.2	3.2	4.4
									11.5	7.7	13.0	19.6	4.5	6.0	31.8	2.8	11.7

11.9	7.4	38.0	22.1	4.0	49.5	37.2	2.4	4.0
									13.6	6.5	18.4	24.5	3.6	24.5	37.3	2.4	3.7
14.1	6.3	8.8	25.3	3.5	4.3
									15.0	5.9	27.6	25.6	3.5	3.9
17.1	5.2	49.2	26.4	3.4	11.8

Table VIII lists the 2 θ, d-spacing and relative intensities for type X. The listed data are computer generated data.

TABLE VIII intensity and Peak position of form X D, L-tartrate

2 theta angle	d value (_)	I (relative value)
			6.0	14.6	100.0
11.9	7.4	38.0
			15.0	5.9	27.6
17.1	5.2	49.2
			22.1	4.0	49.5
24.5	3.6	24.5

The X-ray powder diffraction pattern of the Y-form (hydrate) D, L-tartrate was determined using the same equipment and the same parameters as for the A-form L-tartrate. In the measured Y-type powder X-ray diffraction analysis, diffraction peaks at diffraction angles (2. theta.) are shown in Table IX. However, these relative intensities may also vary with crystal size and morphology. The actually measured powder diffraction pattern is shown in fig. 10B.

TABLE IX powder X-ray diffraction patterns of form Y D, L-tartrate with diffraction line intensities and peak positions

2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)	2 theta angle	d value (_)	I (relative value)
									4.1	21.4	5.2	17.3	5.1	18.6	26.1	3.4	8.5
6.2	14.2	100.0	18.1	4.9	32.2	27.5	3.2	17.9
									10.9	8.1	7.8	18.7	4.7	7.1	29.3	3.0	7.4
11.5	7.7	23.1	19.9	4.5	24.7	29.7	3.0	8.4
									12.0	7.4	39.1	21.1	4.2	7.0	30.3	2.9	11.7

12.5	7.1	4.6	21.7	4.1	11.0	31.5	2.8	17.4
									13.5	6.5	16.6	22.5	4.0	5.4	35.8	2.5	6.4
14.4	6.1	14.7	23.2	3.8	12.2	36.7	2.4	4.5
									15.0	5.9	16.4	24.0	3.7	52.7	37.3	2.4	4.6
15.2	5.8	32.7	25.1	3.5	75.1	39.1	2.3	5.4
									15.6	5.7	9.6	25.5	3.5	10.3

Table X lists the 2 θ, d-spacing and relative intensities for the Y-form. The listed data are computer generated data.

TABLE X Y intensity and Peak position of form D, L-tartrate

2 theta angle	d value (_)	I (relative value)
			6.2	14.2	100.0
12.0	7.4	39.1
			15.2	5.8	32.7
18.1	4.9	32.2
			24.0	3.7	52.7
25.1	3.5	75.1

Single crystal X-ray analysis

Single crystals of form B and C L-tartrate were obtained and studied by X-ray diffraction. For each crystal form, representative crystals were studied and a 1_ data set (max sin θ/λ ═ 0.5) was collected on a Siemens R4RA/v diffractometer. From the International Tables for X-Ray Crystallography (Birmingham: Kynoch Press, 1974) volume IV, 55, 99And page 149 acquires the atomic scattering factor. Single crystal X-ray data were collected at room temperature. All crystallographic calculations were aided by SHELXTL^TMsystem (SHELXTL^TMReference Manual, Version 5.1, Bruker AXS, Madison, Wis 1997). The relevant crystal data collection and processing for form B crystals is summarized in Table XI below and for form C crystals in Table XII below.

For the two crystal forms, trial structures are obtained by a direct method and then refined by a conventional method. The difference map (difference map) shows two molecules of crystal water per salt molecule. The position of hydrogen is calculated as much as possible. The hydrogen atoms on the nitrogen and oxygen atoms are located by a difference Fourier technique. The hydrogen parameter is added to the structure factor calculation but not processed. The displacements calculated in the least squares process are each less than 0.1 of the corresponding standard deviation. For the B form crystals, the final R-index was 3.25%. For the C-type structure, the final R-index was 3.47%. The final difference fourier does not show the disappearance or dislocation of electron density. The modified structures were drawn using the SHELXTL mapping software package, as shown in FIGS. 8A (type B) and 8B (type C). The absolute configuration is based on the use of L (+) -tartaric acid.

Table XIII shows the atomic coordinates (. times.10) of the form B crystals⁴) And corresponding isotropic shift parameter (\ u)²×10³). Table XIV lists the measured bond lengths [ \ u ] for the B-form crystals]Angle of harmony key [ ° ]]. Table XV lists the anisotropy Shift parameter (\ u) for type B crystals²×10³) In order to calculate an anisotropic shift factor index of the form: -2 pi²[h²a^*2U₁₁+...+2hka*b*U₁₂]. Finally, the hydrogen coordinates (× 10) of the form B crystals are shown in the following Table XVI⁴) And isotropic shift parameter (\ u)²×10³)。

Table XVII shows the atomic coordinates (. times.10) of the C-type crystal⁴) And isotropic shift parameter (\ u)²×10³). Table XVIII shows the measured bond length [ \ u ] for the C-type crystals]Angle of harmony key [ ° ]]. Table XIX lists the anisotropy Shift parameters of form C crystals (_²×10³) In order to calculate an anisotropic shift factor index of the form: -2 pi²[h²a^*2U₁₁+...+2hka*b*U₁₂]. Finally, the hydrogen coordinates (× 10) of form C crystals are shown in Table XX below⁴) And isotropic shift parameter (\ u)²×10³)。

TABLE XI Crystal Structure data and measurement parameters for form B L-tartrate

Parameter(s)	Form B of L-tartrate
		Empirical molecular weight crystal system space group crystal size, mmDensity rho Z temperature wavelength absorption coefficient F (000) calculated by abc alpha gamma beta volume is reflected and collected to obtain independent reflection processing method data/reflections/parameter FFinal R index of goodness of fit [ I > 2 ε (I) above]Absolute structural parameter maximum diffraction peaks and pores	CHNCHO361.35 orthogonal P2(1)2(1) 0.01 × 0.08 × 0.107.0753(5) _7.7846(5) _29.870(2) _90 ° -645.21 (19) \\ u1.459g/cm4298(2)K1.54178_0.944mm76034901318[R(int)＝0.0542]FFull matrix least squares 1318/0/2510.856R1 ═ 0.0325, wR2 ═ 0.06380.0031(3)0.115 and-0.150 e \u

TABLE XII crystal structure data and measurement parameters for form C L-tartrate

Parameter(s)	Form C of L-tartrate hydrate
		Empirical molecular weight crystal system space group crystal size, mmDensity rho Z temperature wavelength absorption coefficient F (000) reflection calculated by X-ray Code (Code) abc alpha gamma beta volume collects independent reflection processing method data/reflections/parameter FFinal R index of goodness of fit [ I > 2 ε (I) above]Absolute structural parameter maximum diffraction peaks and pores	CHNCHO·HO379.37 monoclinic P2(1) 0.04X 0.38X 0.30F 6117.5120-29.854-7.671-90 degree, 90.40 degree, 1720.3 degree1.465g/cm4298(2)K1.54178_0.974mm80019831817[R(int)＝0.0224]FFull matrix least squares 1817/0/5281.028R1 ═ 0.0347, wR2 ═ 0.08340.0(3)0.168 and-0.230 e \u

TABLE XIII atomic coordinates of type B crystals (. times.10)⁴) And an equivalent isotropic shift parameter (\ u)²×10³) U (eq) is defined as orthogonal U_ij1/3 tensor

	x	y	z	U(eq)
					N(1)C(2)C(3)N(4)C(5)C(6)C(7)C(8)C(9)C(10)C(11)C(12)C(13)C(14)N(15)C(16)C(20)O(21)O(22)C(23)O(24)C(25)O(26)C(27)O(28)O(29)	8211(8)8968(8)8093(11)6431(8)5624(9)6502(8)5676(8)4007(8)3107(7)3890(8)2865(7)891(6)1397(7)3510(6)3597(5)1962(6)7858(9)9522(5)6680(4)7033(6)5062(4)8063(6)7763(4)7520(6)7065(4)7681(4)	10638(7)9093(11)7629(9)7715(6)9313(8)10752(9)12396(7)12557(6)11097(7)9495(7)14122(6)13347(6)11686(6)14823(6)13405(5)12183(5)6393(6)6116(4)5324(4)8162(5)8318(4)9486(5)9176(4)11321(6)11655(4)12417(4)	12233(1)12235(2)12047(2)11853(1)11834(2)12025(2)11985(1)11762(2)11572(1)11605(1)11634(1)11573(1)11315(1)11182(1)10838(1)10838(1)10523(1)10603(1)10349(1)10623(1)10542(1)10339(1)9873(1)10465(2)10852(1)10148(1)	61(1)72(2)75(2)64(1)50(1)49(1)48(1)41(1)42(1)49(1)44(1)53(1)46(1)43(1)39(1)46(1)37(1)47(1)47(1)32(1)44(1)31(1)35(1)35(1)43(1)47(1)

TABLE XIV form B L-tartrate bond lengths (. alpha.) and bond angles [ ° ]

Length of the bond
				N(1)-C(2)N(1)-C(6)C(2)-C(3)C(3)-N(4)N(4)-C(5)C(5)-C(10)C(5)-C(6)C(6)-C(7)C(7)-C(8)C(8)-C(9)C(8)-C(11)C(9)-C(10)C(9)-C(13)C(11)-C(14)	1.316(6)1.362(6)1.413(7)1.314(7)1.370(6)1.411(6)1.403(7)1.412(6)1.361(6)1.421(6)1.511(6)1.368(6)1.504(6)1.526(5)	C(11)-C(12)C(12)-C(13)C(13)-C(16)C(14)-N(15)N(15)-C(16)C(20)-O(21)C(20)-O(22)C(20)-C(23)C(23)-O(24)C(23)-C(25)C(25)-O(26)C(25)-C(27)C(27)-O(28)C(27)-O(29)	1.532(6)1.547(6)1.531(5)1.510(5)1.498(5)1.221(5)1.288(5)1.525(6)1.420(5)1.521(5)1.428(5)1.526(6)1.227(5)1.281(5)
Key angle
				C(2)-N(1)-C(6)N(1)-C(2)-C(3)N(4)-C(3)-C(2)C(3)-N(4)-C(5)N(4)-C(5)-C(10)N(4)-C(5)-C(6)C(10)-C(5)-C(6)N(1)-C(6)-C(5)N(1)-C(6)-C(7)C(5)-C(6)-C(7)C(8)-C(7)-C(6)C(7)-C(8)-C(9)C(7)-C(8)-C(11)C(9)-C(8)-C(11)C(10)-C(9)-C(8)C(10)-C(9)-C(13)C(8)-C(9)-C(13)C(9)-C(10)-C(5)C(8)-C(11)-C(14)C(8)-C(11)-C(12)	115.0(5)123.9(5)121.8(5)116.0(5)118.3(6)121.5(6)120.2(6)121.8(6)117.8(6)120.3(5)119.0(5)120.7(5)131.5(5)107.7(4)121.2(5)129.8(5)108.7(5)118.6(5)110.7(4)101.6(4)	C(14)-C(11)-C(12)C(11)-C(12)-C(13)C(9)-C(13)-C(16)C(9)-C(13)-C(12)C(16)-C(13)-C(12)N(15)-C(14)-C(11)C(16)-N(15)-C(14)N(15)-C(16)-C(13)O(21)-C(20)-O(22)O(21)-C(20)-C(23)O(22)-C(20)-C(23)O(24)-C(23)-C(25)O(24)-C(23)-C(20)C(25)-C(23)-C(20)O(26)-C(25)-C(23)O(26)-C(25)-C(27)C(23)-C(25)-C(27)O(28)-C(27)-O(29)O(28)-C(27)-C(25)O(29)-C(27)-C(25)	107.9(3)100.2(3)110.0(4)100.8(4)108.2(4)110.6(4)115.7(3)111.2(3)126.1(5)119.4(5)114.5(5)108.5(3)114.8(4)108.6(3)111.0(3)111.2(3)112.0(4)125.4(4)119.8(4)114.7(4)

Table XV type B crystal isotropic shift parameter (\\ u)²×10³) (the isotropic shift factor index form is: -2 pi²[h²a*²U₁₁+...+2hka*b*U₁₂])

	U	U	U	U	U	U
							N(1)C(2)C(3)N(4)C(5)C(6)C(7)C(8)C(9)C(10)C(11)C(12)C(13)C(14)N(15)C(16)C(20)O(21)O(22)C(23)O(24)C(25)O(26)C(27)O(28)O(29)	63(4)54(4)79(5)78(4)65(4)41(4)51(4)45(4)46(4)54(4)49(3)45(4)42(3)43(3)35(3)42(3)48(4)30(2)44(2)26(3)33(2)35(3)35(2)22(3)53(2)74(2)	70(4)114(6)78(5)54(4)45(4)69(5)56(5)41(4)40(4)52(5)43(3)63(4)49(3)39(3)41(3)51(3)30(4)41(2)22(2)28(3)33(2)25(3)32(2)40(4)36(2)27(2)	50(3)49(4)66(4)60(3)39(3)36(3)38(3)38(3)40(3)41(3)38(3)50(3)48(3)46(3)40(2)44(3)33(3)68(2)73(2)42(3)68(2)32(3)38(2)42(4)41(2)41(2)	12(2)20(4)14(4)8(3)5(3)8(3)3(3)4(3)12(3)8(3)-1(3)6(3)11(3)-3(3)7(2)6(3)9(3)3(2)-5(2)0(2)-10(2)-7(2)-5(1)-7(3)-7(2)5(2)	-2(3)-3(3)-6(4)-9(3)-3(3)-9(3)-2(3)1(3)9(3)-5(3)1(3)7(3)-3(3)2(2)3(2)-4(3)10(3)-5(2)-2(2)7(2)4(2)-1(2)3(2)-8(3)2(2)7(2)	8(3)8(5)30(5)13(3)6(4)1(4)-5(4)-3(4)-4(4)-14(4)-1(3)3(3)-4(3)-1(3)-2(2)-2(3)-6(4)7(2)2(2)0(3)1(2)4(3)-1(2)1(3)2(2)4(2)

TABLE XVI type B Crystal Hydrogen coordinates (× 10)⁴) And isotropic shift parameter (\ u)²×10³)

	x	y	z	U(eq)
					H(2A)H(3A)H(7A)H(10A)H(11A)H(12A)H(12B)H(13A)H(14A)H(14B)H(15A)H(15B)H(16A)H(16B)H(23A)H(24A)H(25A)H(26A)H(29A)	10149871062643292288776295372263647483600(70)4860(70)230289472704680(70)94196710(70)7180(60)	8958657613354854615004140921309710840157041534414000(60)12850(60)111561271384277400(60)93559120(70)13930(80)	1236712062121081148011868113981185811321110821121310578(14)10867(14)10672106881093910401(15)103979841(17)10298(14)	80808080808080808080808080808080B08080

TABLE XVII atomic coordinates of type C crystals (× 10)⁴) And an equivalent isotropic shift parameter (\ u)²×10³) U (eq) is defined as orthogonal U_ij1/3 tensor

		x	y		z	U(eq)
							N(1)C(2)C(3)N(4)C(5)C(6)C(7)C(8)C(9)C(10)C(11)C(12)N(13)C(14)C(15)C(16)C(1X)O(2X)O(3X)C(4X)O(5X)C(6X)O(7X)C(8X)O(9X)O(10X)O(1W)N(51)C(52)C(53)N(54)C(55)C(56)C(57)C(58)C(59)C(60)C(61)C(62)N(63)C(64)C(65)C(66)C(1Y)O(2Y)O(3Y)C(4Y)O(5Y)C(6Y)O(7Y)C(8Y)O(9Y)O(10Y)O(2W)		-159(7)-239(10)1241(10)2878(7)3033(8)1520(7)1723(7)3381(7)4905(7)4759(8)6537(7)7003(7)5380(6)4292(7)4011(7)5826(8)1541(7)1182(4)361(5)3457(6)3649(5)4282(7)3348(4)6296(7)7172(5)6935(5)3226(6)3493(6)3598(9)2114(9)494(7)289(8)1799(7)1574(8)-95(8)-1609(7)-1436(7)-3249(8)-3717(7)-2088(6)-1014(7)-765(7)-2599(8)-2999(7)-3633(5)-3884(5)-986(6)-53(4)-163(7)-328(5)1746(7)2954(5)2085(5)54(6)	10186(3)10333(3)10446(3)10415(3)10257(3)10141(3)99679902(3)10018(3)10194(3)9881(3)9395(3)9102(3)9171(3)9668(3)9887(3)7444(3)7444(2)7474(2)7425(3)7280(2)7881(3)8230(2)7900(3)7560(2)8241(2)7996(2)6295(3)6141(3)6031(3)6065(3)6228(3)6340(3)6528(2)6593(3)6472(2)6295(3)6621(3)7097(3)7392(3)7329(3)6828(3)6612(3)8598(3)8257(2)8934(2)8611(3)8261(2)9070(3)9219(2)9048(3)9023(2)9039(2)8500(2)		-1642(7)-58(10)959(9)368(6)-1310(8)-2302(8)-4007(7)-4622(7)-3648(7)-2016(8)-4655(7)-4191(7)-4292(6)-5922(7)-6277(7)-6550(8)-5634(8)-7182(5)-4418(5)-4997(7)-3247(5)-5336(7)-4482(5)-4948(7)-5428(5)-4266(5)-924(5)3311(7)4922(9)5890(8)5313(7)3651(7)2642(8)950(8)320(7)1339(7)2965(9)334(8)850(7)720(6)-916(6)-1308(7)-1564(7)27(7)745(5)-462(5)-356(7)523(5)-16(7)1725(5)-658(8)572(5)-2209(5)4066(5)	45(1)52(2)50(2)42(1)33(2)30(2)32(2)25(1)25(1)36(2)31(2)33(2)27(1)29(1)28(1)41(2)23(1)36(1)38(1)24(1)32(1)25(1)28(1)22(1)37(1)35(1)37(1)43(1)47(2)45(2)43(1)30(1)30(2)32(2)27(1)25(1)35(2)32(2)33(2)26(1)29(1)30(1)36(2)26(1)35(1)34(1)20(1)28(1)23(1)33(1)24(1)36(1)37(1)39(1)

TABLE XVIII bond length (. alpha.) and bond angle [ ° ] of form C L-tartrate

Key length (C type)
				N(1)-C(2)N(1)-C(6)C(2)-C(3)C(3)-N(4)N(4)-C(5)C(5)-C(6)C(5)-C(10)C(6)-C(7)C(7)-C(8)C(8)-C(9)C(8)-C(15)C(9)-C(10)C(9)-C(11)C(11)-C(12)C(11)-C(16)C(12)-N(13)N(13)-C(14)C(14)-C(15)C(15)-C(16)C(1X)-O(2X)C(1X)-O(3X)C(1X)-C(4X)C(4X)-O(5X)C(4X)-C(6X)C(6X)-O(7X)C(6X)-C(8X)C(8X)-O(10X)C(8X)-O(9X)	1.294(8)1.369(7)1.396(10)1.316(8)1.377(8)1.407(8)1.421(9)1.417(8)1.349(8)1.407(8)1.526(8)1.362(8)1.511(8)1.534(8)1.545(8)1.501(7)1.504(6)1.525(8)1.528(8)1.216(6)1.295(6)1.518(7)1.417(6)1.517(8)1.419(7)1.541(7)1.240(7)1.267(7)	N(51)-C(52)N(51)-C(56)C(52)-C(53)C(53)-N(54)N(54)-C(55)C(55)-C(60)C(55)-C(56)C(56)-C(57)C(57)-C(58)C(58)-C(59)C(58)-C(65)C(59)-C(60)C(59)-C(61)C(61)-C(62)C(61)-C(66)C(62)-N(63)N(63)-C(64)C(64)-C(65)C(65)-C(66)C(1Y)-O(3Y)C(1Y)-O(2Y)C(1Y)-C(4Y)C(4Y)-O(5Y)C(4Y)-C(6Y)C(6Y)-O(7Y)C(6Y)-C(8Y)C(8Y)-O(10Y)C(8Y)-O(9Y)	1.320(8)1.375(7)1.365(9)1.317(8)1.373(8)1.410(8)1.417(8)1.424(8)1.355(8)1.431(8)1.514(8)1.360(8)1.515(8)1.518(9)1.539(8)1.511(7)1.508(6)1.537(8)1.533(8)1.259(7)1.254(7)1.543(8)1.424(6)1.526(8)1.413(7)1.521(8)1.219(6)1.306(7)
Key angle (C type)
				C(2)-N(1)-C(6)N(1)-C(2)-C(3)N(4)-C(3)-C(2)C(3)-N(4)-C(5)N(4)-C(5)-C(6)N(4)-C(5)-C(10)C(6)-C(5)-C(10)N(1)-C(6)-C(5)N(1)-C(6)-C(7)C(5)-C(6)-C(7)C(8)-C(7)-C(6)C(7)-C(8)-C(9)C(7)-C(8)-C(15)C(9)-C(8)-C(15)C(10)-C(9)-C(8)C(10)-C(9)-C(11)C(8)-C(9)-C(11)C(9)-C(10)-C(5)C(9)-C(11)-C(12)C(9)-C(11)-C(16)C(12)-C(11)-C(16)N(13)-C(12)-C(11)C(14)-N(13)-C(12)	115.5(6)124.4(7)122.2(6)115.6(5)121.1(6)119.0(5)119.8(6)121.3(6)118.9(5)119.9(5)118.8(5)121.9(5)130.5(5)107.4(5)120.9(5)130.2(5)108.7(5)118.7(5)108.9(5)101.6(5)107.9(5)110.8(5)113.6(4)	C(52)-N(51)-C(56)N(51)-C(52)-C(53)N(54)-C(53)-C(52)C(53)-N(54)-C(55)N(54)-C(55)-C(60)N(54)-C(55)-C(56)C(60)-C(55)-C(56)N(51)-C(56)-C(55)N(51)-C(56)-C(57)C(55)-C(56)-C(57)C(58)-C(57)-C(56)C(57)-C(58)-C(59)C(57)-C(58)-C(65)C(59)-C(58)-C(65)C(60)-C(59)-C(58)C(60)-C(59)-C(61)C(58)-C(59)-C(61)C(59)-C(60)-C(55)C(59)-C(61)-C(62)C(59)-C(61)-C(66)C(62)-C(61)-C(66)N(63)-C(62)-C(61)C(64)-N(63)-C(62)	115.6(5)123.4(6)123.6(6)116.0(5)119.6(5)120.4(5)120.0(5)121.0(6)118.8(5)120.1(5)119.0(5)120.4(5)131.4(5)107.9(5)121.9(5)130.8(5)107.1(5)118.7(5)109.2(5)102.4(5)109.8(5)109.8(5)114.9(4)
Key angle (C type)

N(13)-C(14)-C(15)C(16)-C(15)-C(14)C(16)-C(15)-C(8)C(14)-C(15)-C(8)C(15)-C(16)-C(11)O(2X)-C(1X)-O(3X)O(2X)-C(1X)-C(4X)O(3X)-C(1X)-C(4X)O(5X)-C(4X)-C(6X)O(5X)-C(4X)-C(1X)C(6X)-C(4X)-C(1X)O(7X)-C(6X)-C(4X)O(7X)-C(6X)-C(8X)C(4X)-C(6X)-C(8X)O(10X)-C(8X)-O(9X)O(10X)-C(8X)-C(6X)O(9X)-C(8X)-C(6X)

110.8(4)108.6(5)101.6(4)109.8(4)99.7(4)123.7(5)121.2(5)115.1(5)113.4(4)114.0(4)107.5(4)112.0(4)111.8(4)113.7(4)125.6(5)119.3(5)115.1(5)

N(63)-C(64)-C(65)C(58)-C(65)-C(66)C(58)-C(65)-C(64)C(66)-C(65)-C(64)C(65)-C(66)-C(61)O(3Y)-C(1Y)-O(2Y)O(3Y)-C(1Y)-C(4Y)O(2Y)-C(1Y)-C(4Y)O(5Y)-C(4Y)-C(6Y)O(5Y)-C(4Y)-C(1Y)C(6Y)-C(4Y)-C(1Y)O(7Y)-C(6Y)-C(8Y)O(7Y)-C(6Y)-C(4Y)C(8Y)-C(6Y)-C(4Y)O(10Y)-C(8Y)-O(9Y)O(10Y)-C(8Y)-C(6Y)O(9Y)-C(8Y)-C(6Y)

110.6(4)101.8(4)109.1(4)108.9(5)99.3(4)125.2(5)116.1(5)118.7(5)112.3(4)111.8(4)112.7(4)114.1(4)113.9(4)106.7(4)123.7(5)121.4(5)114.9(5)

TABLE isotropic Shift parameter (\ u) for form XIX C crystals²×10³) (the isotropic shift factor index form is: -2 pi²[h²a*²U₁₁+...+2hka*b*U₁₂])

	U	U	U	U	U	U
							N(1)C(2)C(3)N(4)C(5)C(6)C(7)C(8)C(9)C(10)C(11)C(12)N(13)C(14)C(15)C(16)C(1X)O(2X)O(3X)C(4X)O(5X)C(6X)O(7X)C(8X)O(9X)O(10X)O(1W)N(51)C(52)C(53)N(54)C(55)C(56)C(57)C(58)C(59)C(60)C(61)C(62)N(63)C(64)C(65)C(66)C(1Y)O(2Y)O(3Y)C(4Y)O(5Y)C(6Y)O(7Y)	42(4)53(5)63(5)59(4)44(4)27(3)30(4)28(4)27(3)33(4)30(3)22(3)27(3)26(3)24(3)42(4)23(3)28(2)19(2)19(3)29(2)20(3)21(2)21(3)19(2)26(2)28(2)29(3)44(4)50(5)53(4)34(4)28(4)30(4)32(4)22(3)25(3)26(3)25(3)25(3)36(3)35(3)42(4)23(3)21(2)19(2)18(3)21(2)23(3)32(2)	46(4)51(5)40(4)30(3)19(3)25(4)36(4)27(3)20(3)32(4)26(4)44(4)32(3)34(4)29(4)41(4)19(3)56(3)69(3)30(3)34(2)28(3)25(2)30(4)43(3)35(3)47(3)47(4)46(4)48(4)40(3)28(3)25(3)34(4)24(4)21(3)32(4)30(4)35(4)27(3)33(4)33(4)32(4)38(4)42(3)41(3)22(3)31(2)30(3)37(3)	46(4)52(5)49(4)37(3)35(4)39(4)30(4)19(3)29(4)44(4)38(4)34(3)21(3)27(3)30(3)39(4)28(4)25(2)26(2)24(3)33(2)26(3)36(2)16(3)49(3)45(2)35(2)54(4)51(5)35(4)37(3)27(3)36(4)32(4)24(3)33(4)49(4)40(4)38(4)27(3)18(3)21(3)33(4)17(3)43(2)44(3)21(3)30(2)17(3)31(3)	-8(3)-5(4)-2(4)-8(3)1(3)1(3)-1(3)1(2)4(3)-8(3)0(3)0(3)1(2)-4(3)7(3)5(3)-1(3)-7(2)8(2)5(3)5(2)-1(3)-3(2)-2(3)-10(2)-10(2)-9(2)7(3)11(4)2(3)4(3)5(3)-5(3)4(3)-1(3)0(3)3(3)2(3)4(3)-2(2)2(3)-5(3)-6(3)-1(3)11(2)11(2)3(2)3(2)4(3)-3(2)	4(3)9(4)19(4)-7(3)-8(3)3(3)-10(3)-4(3)-9(3)-14(3)-1(3)0(3)0(2)-11(3)-5(3)7(3)8(3)-2(2)5(2)-1(2)-5(2)2(2)5(2)1(2)-1(2)-7(2)1(2)-3(3)-9(4)-4(3)5(3)4(3)2(3)7(3)5(3)1(3)10(3)-6(3)0(3)5(2)8(3)3(3)-6(3)-6(2)5(2)3(2)-1(2)-2(2)1(2)6(2)	0(3)3(4)11(4)11(3)9(3)3(3)4(3)3(3)0(3)-4(3)-6(3)0(3)1(2)-1(3)-2(3)-2(3)1(3)-1(2)2(2)1(3)8(2)1(3)4(2)5(3)4(2)-1(2)-1(2)8(3)4(3)10(4)8(3)3(3)2(3)3(3)-1(3)-2(3)-3(3)-6(3)-2(3)1(2)1(3)6(3)2(3)0(3)-2(2)8(2)4(3)4(2)7(3)7(2)
C(8Y)	23(3)	16(3)	33(4)	3(3)	-2(3)	-4(2)

	U	U	U	U	U	U
							O(9Y)O(10Y)O(2W)	19(2)28(2)32(2)	61(3)57(3)50(3)	27(2)24(2)35(3)	-9(2)4(2)7(2)	-6(2)6(2)-2(2)	5(2)1(2)3(2)

TABLE XX hydrogen coordinates of type C crystals (× 10)⁴) And isotropic shift parameter (\ u)²×10³)

	x	y	z	U(eq)
					H(2)H(3)H(7)H(10)H(11)H(12A)H(12B)H(13X)H(13Y)H(14A)H(14B)H(15)H(16A)H(16B)H(3XX)H(4X)H(5XX)H(6X)H(7XX)H(1WX)H(1WY)H(52)H(53)H(57)H(60)H(61)H(62A)H(62B)H(63X)H(63Y)H(64A)H(64B)H(65)H(66A)H(66B)H(4Y)H(5YX)H(6Y)H(7YX)H(9YX)H(2WX)H(2WY)	-1359106673257707541789674995710(100)4660(100)31474897320257156570-980(110)40823350(100)41443230(100)2060(110)4280(110)472023292559-2435-4250-4647-4158-2480(100)-1300(100)141-162016-2509-3358-860-140(100)-797-100(110)4230(110)1040(110)-990(110)	103661054698991027210086928493838750(30)9130(30)9025903597201019097127490(30)72087550(30)79368210(30)8070(30)8050(30)61065927660562206416721171017730(30)7360(30)7470747167776308678885538240(30)92869020(30)8990(30)8370(30)8380(30)	4352094-4690-1377-4476-4990-3021-4290(90)-3380(100)-5797-6903-7264-6996-7324-4900(90)-5730-2600(100)-6589-3240(100)-390(90)-270(100)542370192863610511872035650(90)1730(100)-772-1889-2307-2010-2329-16071670(100)-7572280(100)40(90)4630(100)4830(100)	808080808080808080808080808080808080808080808080808080808080808080808080808080808080

Using SHELXTL^TMXFOG and XPOW computer programs provided in computer program libraries obtain single crystal data from each of the B-and C-type tartrates and calculate powder X-ray diffraction patterns for the B-and C-type crystals. The calculated powder plot for form B is shown in fig. 4A. The calculated powder plot for form C is shown in fig. 4B.

The measured B-mode powder pattern is compared to the calculated pattern and the results are shown in the superimposed powder X-ray diffraction pattern of FIG. 5A. The lower graph of the graph corresponds to the calculated powder plot (calculated from the single crystal results) and the upper graph corresponds to the representative experimental powder plot. The results of the overall mutual match between the two figures show that: the powder samples were consistent with the corresponding single crystal structure.

The measured type C powder pattern was compared to the calculated pattern and the results are shown in the superimposed powder X-ray diffraction pattern of FIG. 5B. The lower graph of the graph corresponds to the calculated powder plot (calculated from the single crystal results) and the upper graph corresponds to the representative experimental powder plot. The results of the overall mutual match between the two figures show that: the powder samples were consistent with the corresponding single crystal structure.

Solid state NMR

Characterization of 5, 8, 14-triazatetracyclo [10.3.1.0 ] forms A, B and C using solid state NMR techniques^2，11.0^4，9]-L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene.

Approximately 300mg of the sample was tightly packed in a 7mm ZrO spinner. Bruker 7mmWBMAS probe collection on a wide-bore Bruker Avance DRX 500MHz NMR spectrometer at 295K¹³And (4) C spectrum. The sample was spun at 7 kHz. The cross-polarized contact time was set to 1 ms. A total of 512 scans were obtained for most samples over about 30 minutes of acquisition time. The methyl signal of the highest field was set at 29.5ppm using adamantane as external standard as spectral reference.

A. Of B-and C-type crystals¹³The CPMAS spectra are shown in fig. 7A, 7B and 7C, respectively. The samples shown perform reasonably well from a solid state spectral property point of view. The resolution is good and the sensitivity is acceptable. The spectral properties of all compounds were each significantly different, indicating that: solid state NMR can easily distinguish small physical/chemical property differences between samples.

All of FIGS. 7A, 7B and 7C are marked with an asterisk: (^*) The peaks of (a) are both spin sidebands. Such spin sidebands are located at multiple spin frequencies on either side of the actual peak (central band). The spin speed was set at 7kHz, which converted to 55.7ppm at 500 MHz. The intensity of the sidebands depends on the spin speed(the higher the velocity, the lower the sideband intensity) and the magnitude of the anisotropy contribution to the chemical shift of a given carbon atom. Experiments using different spin speeds can easily be separated from the central zone. Carbonyl and aromatic carbon atoms tend to have strong sidebands because they have large chemical shift anisotropy. CH and CH₂type-C atoms producing relatively small spin sidebands, methyl (CH)₃) No sideband is generally generated.

A. 5, 8, 14-triazatetracyclo [10.3.1.0 ] forms B and C^2，11.0^4，9]The main formants of the solid-state carbon spectrum of hexadec-2 (11), 3, 5, 7, 9-pentaene (low field starting from 100ppm, ± 0.1ppm) are shown in table XXI.

TABLE XXI types 5, 8, 14-triazatetracyclo [10.3.1.0 ] A, B and C^2，11.0^4，9]Predominantly solid L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene¹³C-NMR formants (only low fields starting from 100ppm are listed) (based on adamantane 29.5ppm)

Type AC (ppm) solid state	Type BC (ppm) solid state	C typeC (ppm) solid state
			178.4	179.2	179.0
149.3	178.0	176.1
			147.4	147.4	147.5
145.1	145.2	144.5
			122.9	144.4	124.6
	124.8
				122.5

The modes of administration of the L-tartrate, D, L-tartrate and meso-tartrate salts (herein "active salts") of the present invention include: oral, transdermal (e.g., using a patch), nasal, sublingual, rectal, parenteral, or topical administration. Transdermal and oral administration are preferred. Most desirably, these salts are administered in a dose of about 0.01mg to about 1500mg per day, preferably about 0.1 to about 300mg per day, in one or more divided doses, although this may vary if desired, depending on the weight and health of the patient being treated and the route of administration chosen. However, it is most desirable to use a dosage of about 0.001 to about 10mg/kg body weight/day. However, the dosage may also vary depending on the weight and health of the patient to be treated, the respective response to the drug, the type of pharmaceutical formulation selected, the duration of administration and the interval between administrations. In some cases, dosages below the lower limit of the aforesaid range may be employed in higher than adequate amounts, while in other cases, larger dosages may be employed without causing any harmful side effects, provided that: these larger doses are first divided into several smaller doses throughout the day.

These active salts may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by any of several routes as previously described. More specifically, the active salts may be administered in a wide variety of different dosage forms, for example, they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges (lozenes), troches (troches), hard candies, powders, sprays, creams, ointments (salves), suppositories, gels (jellies), gels (gels), pastes, lotions, ointments, aqueous suspensions, solutions for injection, elixirs, syrups, and the like. These carriers include solid diluents or fillers, sterile aqueous bases and various non-toxic organic solvents. In addition, the oral pharmaceutical compositions may also be suitably sweetened and/or flavored. Generally, the active compound is present in the dosage form at a concentration level of about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine; examples of disintegrants are starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates; examples of granulation binders are polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may also be used for tableting. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this regard include sucrose or lactose (milk sugar) and polymeric polyethylene glycols. When aqueous suspensions and/or elixirs are used for oral administration, the active ingredient may also be combined with various sweetening or flavoring agents and coloring matter, as well as emulsifying and/or suspending agents and diluents such as water, ethanol, polyethylene glycol, glycerin and various combinations thereof if desired.

For parenteral administration, solutions of the active salts in sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solution should be suitably buffered (preferably to a pH greater than 8) and the liquid diluent first rendered isotonic, if necessary. These aqueous solutions are also suitable for intravenous injection. The oil solution is suitable for intra-articular, intramuscular and subcutaneous administration. The preparation of all such solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

The active salts may also be administered topically, which may be accomplished by standard pharmaceutical practice in the form of creams, patches, gels, pastes, ointments and the like.

Examples

The following examples illustrate the methods and compounds of the present invention. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described.

Example 1

5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene (anhydrous polymorph form B)

To a particle-free vessel, L-tartaric acid (780 g, 1.1 eq.) and methanol (7.5L) were added. The contents of the vessel were stirred until a solution formed and no particulate filtration (free solution and specific free filtered) to crystalline volumeIn the device. The 5, 8, 14-triazatetracyclo [10.3.1.0 ] is substituted by a substituent^2，11.0^4，9]Hexadec-2 (11), 3, 5, 7, 9-pentaene free base (992 g) and methanol (7.5L) were dissolved in the vessel and the temperature of the resulting mixture was maintained at 20-25 ℃. The 5, 8, 14-triazatetracyclo [10.3.1.0 ] ring is removed in about 45 minutes^2，11.0^4，9]-hexadeca-2 (11), 3, 5, 7, 9-pentaene free base solution was added via funnel to L-tartaric acid solution, making the solution free of particles and fibers. The product was stirred at 20-25 ℃ overnight and isolated by filtration. Vacuum drying the product at 35-45 deg.C to obtain B-type 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]-L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene (molecular weight 361.36)1618.4g (95.4%). Melting point 210.5 ℃; the B-form crystal was confirmed by powder X-ray diffraction.

Example 2

5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]L-tartrate salt of hexadeca-2 (11), 3, 5, 7, 9-pentaene (anhydrous polymorph form A)

Adding 5, 8, 14-triazatetracyclo [10.3.1.0 ] to the reactor^2，11.0^4，9]Hexadec-2 (11), 3, 5, 7, 9-pentaene free base (2 g; 0.0095mole, 1.0 equiv.) and methanol (60mL, 30 mL/g). The mixture was stirred at 20-25 ℃ until complete dissolution. Another reactor containing a solution of L-tartaric acid (1.55g, 0.0103mole, 1.1 equiv) in methanol (60mL, 30mL/g) was heated to reflux (e.g., 60-66 ℃ C.) in methanol. The free base solution was added to the L-tartaric acid solution at methanol reflux temperature for 20 minutes. The resulting slurry was cooled to 20-25 ℃ over 1 hour. The reaction mixture was stirred for about 2 hours and then the product was isolated by filtration. The solid product was washed with methanol (10mL) and dried at 30-35 deg.C under vacuum to give 3.3g (97%) of 5, 8, 14-triazatetracyclo [10.3.1.0 ] A^2，11.0^4，9]-L-tartrate salt of hexadec-2 (11), 3, 5, 7, 9-pentaene free base. Form a crystals were identified by PXRD compared to standard samples.

Example 3

C-type 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]L-tartrate salt of hexadec-2 (11), 3, 5, 7, 9-pentaene (type C)

Preparation of form C CP-526,555-18 from form A or form B polymorphs:

form B L-tartrate (. about.5 g) was dissolved in water (10 to 15ml) and acetonitrile (200-. The resulting slurry was stirred for 10 minutes and filtered. The wet cake was air dried. The product was determined by NIR spectroscopy, DSC and PXRD analysis. This process can be carried out using form a to give a form C product.

Example 4

5, 8, 14-triazatetracyclo [10.3.1.0 ] form A^2，11.0^4，9]L-tartrate salt of hexadec-2 (11), 3, 5, 7, 9-pentaene (type A)

Preparation of form a from polymorph form C: the C form of L-tartrate (. about.2 g) was added to 200-300mL of hot ethanol (. about.75 ℃ C.) and stirred for 30 minutes. The samples were filtered hot and then dried in a vacuum oven at 45 deg.C (housevacuum). The material was determined to be polymorph form a by NIR spectroscopy, DSC and PXRD analysis.

Claims (15)

1. A compound which is 5, 8, 14-triazatetracyclo [10.3.1.0^2，11.0^4，9]Tartrate salt of hexadec-2 (11), 3, 5, 7, 9-pentaene.

2. The compound of claim 1 which is the L-tartrate salt and is the anhydrous L-tartrate salt.

3. The compound of claim 2, characterized primarily by: a powder X-ray diffraction pattern expressed in 2 theta measured using copper radiation having at least one peak selected from the group consisting of 6.1, 16.8 and 21.9.

4. The compound of claim 2, characterized primarily by: the powder X-ray diffraction pattern, expressed in terms of 2 θ and d-spacing, measured with copper radiation, has the following main peaks:

2 theta angle d value (_) 6.1 14.5 12.2 7.2 13.0 6.8 14.7 6.0 16.8 5.3 19.4 4.6 21.9 4.1 24.6 3.6

5. A compound according to claim 3, characterized in that: solid state¹³The C NMR spectrum had resonance peaks at 178.4, 145.1 and 122.9 ppm.

6. The compound of claim 2, characterized primarily by: a powder X-ray diffraction pattern expressed in 2 θ as measured by copper radiation having at least one peak selected from 5.9 and 21.8.

7. The compound of claim 2, characterized primarily by: the powder X-ray diffraction pattern, expressed in terms of 2 θ and d-spacing, measured with copper radiation, has the following main peaks:

2 theta angle d value (_) 5.9 15.0 12.8 6.9 14.4 6.1 15.3 5.8 16.9 5.2 17.2 5.2 21.8 4.1 23.8 3.7 25.1 3.5

8. The compound of claim 6, characterized primarily by: solid state¹³The C NMR spectrum had major resonance peaks at 179.2, 178.0, 144.4, 124.8 and 122.5 ppm.

9. The compound of claim 1 which is the L-tartrate salt and hydrate.

10. The compound of claim 9, characterized in that: a powder X-ray diffraction pattern expressed in 2 theta measured using copper radiation having at least one peak selected from the group consisting of 11.8, 16.5, 23.1 and 26.5.

11. The compound of claim 9, characterized in that: the powder X-ray diffraction pattern expressed in terms of 2 θ and d-spacing, as determined by copper radiation, has the following major peaks:

2 theta angle (± 0.2) d value (_) 0.2 5.9 15.1 11.8 7.5 16.5 5.4 21.2 4.2 23.1 3.8 23.8 3.7 26.5 3.4

12. The compound of claim 10, characterized by: solid state¹³The C NMR spectrum had major resonance peaks at 179.0, 176.1, 147.5 and 144.5 ppm.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1, 2, 3, 6, 9 and 10.

14. The use of a compound according to any one of claims 1, 2, 3, 6, 9 and 10 for the manufacture of a medicament for the treatment of: inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, diarrhea, cystitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis, cognitive dysfunction, drug/toxin-induced cognitive impairment due to alcohol, barbiturates, vitamin deficiencies, maintenance drugs, lead, arsenic or mercury; cognitive impairment induced by illnesses resulting from Alzheimer's disease, senile dementia, vascular dementia, Parkinson's disease, multiple sclerosis, AIDS, encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, pick's disease, Korsakoff's syndrome, frontal dementia or subcortical dementia, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, hyperchlorhydria, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addiction to nicotine, tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine, headache, migraine, stroke, traumatic brain injury, obsessive-compulsive disorders, psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multiple sclerosis dementia, age-related cognitive decline, epilepsy, including petit-mal epilepsy, attention deficit hyperactivity disorder, and Tourette's syndrome.

15. The use of a compound according to any one of claims 1, 2, 3, 6, 9 and 10 for the manufacture of a medicament for the treatment of nicotine dependence, addiction and withdrawal.