U.S. patent application number 14/812652 was filed with the patent office on 2016-06-02 for salts of lorcaserin with optically active acids.
The applicant listed for this patent is Arena Pharmaceuticals, Inc.. Invention is credited to William Lucas Betts, III, Anthony C. Blackburn, Jaimie Karyn Rueter, Yun Shan, Anna Shifrina, Scott Stirn.
Application Number | 20160151381 14/812652 |
Document ID | / |
Family ID | 44653551 |
Filed Date | 2016-06-02 |
United States Patent
Application |
20160151381 |
Kind Code |
A1 |
Blackburn; Anthony C. ; et
al. |
June 2, 2016 |
SALTS OF LORCASERIN WITH OPTICALLY ACTIVE ACIDS
Abstract
Salts of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
with optically active acids, and pharmaceutical compositions
comprising them that are useful for, inter alia, weight
management.
Inventors: |
Blackburn; Anthony C.; (San
Diego, CA) ; Betts, III; William Lucas; (San Diego,
CA) ; Rueter; Jaimie Karyn; (San Diego, CA) ;
Shan; Yun; (San Diego, CA) ; Shifrina; Anna;
(San Diego, CA) ; Stirn; Scott; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Arena Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
44653551 |
Appl. No.: |
14/812652 |
Filed: |
July 29, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13820126 |
Aug 8, 2013 |
9248133 |
|
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PCT/US11/49935 |
Aug 31, 2011 |
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14812652 |
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61402580 |
Sep 1, 2010 |
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Current U.S.
Class: |
514/217.01 |
Current CPC
Class: |
A61K 31/55 20130101;
C07D 223/16 20130101; A61K 45/06 20130101; A61K 31/155 20130101;
A61P 43/00 20180101; A61P 3/04 20180101 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 45/06 20060101 A61K045/06; A61K 31/155 20060101
A61K031/155 |
Claims
1-50. (canceled)
51. A method for weight management, comprising administering to an
individual in need thereof a therapeutically effective amount of a
salt selected from:
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-camsylate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyroglutamate salt; and
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate salt; and pharmaceutically acceptable solvates and
hydrates thereof.
52. The method of claim 51, wherein the weight management comprises
one or more of: weight loss, maintenance of weight loss, decreased
food consumption, increasing meal-related satiety, reducing
pre-meal hunger, and reducing intra-meal food intake.
53. The method of claim 51, wherein the method for weight
management is a method of decreasing food intake.
54. The method of claim 51, wherein the method for weight
management is a method of inducing satiety.
55. The method of claim 51, wherein the method for weight
management is a method of controlling weight gain.
56. The method of claim 51, wherein the method for weight
management is a method of treating obesity.
57. The method of claim 51, as an adjunct to a reduced-calorie
diet.
58. The method of claim 51, wherein the individual in need of
weight management is selected from: an obese patient with an
initial body mass index .gtoreq.30 kg/m.sup.2; and an overweight
patient with an initial body mass index .gtoreq.27 kg/m.sup.2 in
the presence of at least one weight-related comorbid condition.
59. The method of claim 58, wherein the weight-related comorbid
condition is selected from: hypertension, dyslipidemia, and type 2
diabetes.
60. The method of claim 51, further comprising administering a
second anti-obesity agent to the individual.
61. The method of claim 60, wherein the second anti-obesity agent
is selected from: chlorphentermine, clortermine, phenpentermine,
and phentermine, and pharmaceutically acceptable salts, solvates,
and hydrates thereof.
62. The method of claim 51, further comprising administering an
anti-diabetes agent to the individual.
63. The method of claim 62, wherein the anti-diabetes agent is
metformin.
64. The method of claim 51, wherein the salt is
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-camsylate salt.
65. The method of claim 51, wherein the salt
is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt.
66. The method of claim 51, wherein the salt is
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt.
67. The method of claim 51, wherein the salt is
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt.
68. The method of claim 51, wherein the salt is
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate salt.
69. The method of claim 51, wherein the salt is
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyroglutamate salt.
70. The method of claim 51, wherein the salt
is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate salt.
71. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to salts of
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with
optically active acids, and pharmaceutical compositions comprising
them that are useful for, inter alia, weight management.
BACKGROUND OF THE INVENTION
[0002] Obesity is a life-threatening disorder in which there is an
increased risk of morbidity and mortality arising from concomitant
diseases such as type II diabetes, hypertension, stroke, cancer and
gallbladder disease.
[0003] Obesity is now a major healthcare issue in the Western World
and increasingly in some third world countries. The increase in
numbers of obese people is due largely to the increasing preference
for high fat content foods but also the decrease in activity in
most people's lives. Currently about 30% of the population of the
USA is now considered obese.
[0004] Whether someone is classified as overweight or obese is
generally determined on the basis of their body mass index (BMI)
which is calculated by dividing body weight (kg) by height squared
(m2). Thus, the units of BMI are kg/m.sup.2 and it is possible to
calculate the BMI range associated with minimum mortality in each
decade of life. Overweight is defined as a BMI in the range 25-30
kg/m.sup.2, and obesity as a BMI greater than 30 kg/m.sup.2 (see
table below).
TABLE-US-00001 Classification Of Weight By Body Mass Index (BMI)
BMI CLASSIFICATION <18.5 Underweight 18.5-24.9 Normal 25.0-29.9
Overweight 30.0-34.9 Obesity (Class I) 35.0-39.9 Obesity (Class II)
>40 Extreme Obesity (Class III)
[0005] As the BMI increases there is an increased risk of death
from a variety of causes that are independent of other risk
factors. The most common diseases associated with obesity are
cardiovascular disease (particularly hypertension), diabetes
(obesity aggravates the development of diabetes), gall bladder
disease (particularly cancer) and diseases of reproduction. The
strength of the link between obesity and specific conditions
varies. One of the strongest is the link with type 2 diabetes.
Excess body fat underlies 64% of cases of diabetes in men and 77%
of cases in women (Seidell, Semin Vasc Med, 5:3-14 (2005)).
Research has shown that even a modest reduction in body weight can
correspond to a significant reduction in the risk of developing
coronary heart disease.
[0006] There are problems however with the BMI definition in that
it does not take into account the proportion of body mass that is
muscle in relation to fat (adipose tissue). To account for this,
obesity can also be defined on the basis of body fat content:
greater than 25% in males and greater than 30% in females.
[0007] Obesity considerably increases the risk of developing
cardiovascular diseases as well. Coronary insufficiency,
atheromatous disease, and cardiac insufficiency are at the
forefront of the cardiovascular complications induced by obesity.
It is estimated that if the entire population had an ideal weight,
the risk of coronary insufficiency would decrease by 25% and the
risk of cardiac insufficiency and of cerebral vascular accidents
would decrease by 35%. The incidence of coronary diseases is
doubled in subjects less than 50 years of age who are 30%
overweight. The diabetes patient faces a 30% reduced lifespan.
After age 45, people with diabetes are about three times more
likely than people without diabetes to have significant heart
disease and up to five times more likely to have a stroke. These
findings emphasize the inter-relations between risks factors for
diabetes and coronary heart disease and the potential value of an
integrated approach to the prevention of these conditions based on
the prevention of obesity (Perry, I. J., et al., BMJ 310, 560-564
(1995)).
[0008] Diabetes has also been implicated in the development of
kidney disease, eye diseases and nervous system problems. Kidney
disease, also called nephropathy, occurs when the kidney's "filter
mechanism" is damaged and protein leaks into urine in excessive
amounts and eventually the kidney fails. Diabetes is also a leading
cause of damage to the retina at the back of the eye and increases
risk of cataracts and glaucoma. Finally, diabetes is associated
with nerve damage, especially in the legs and feet, which
interferes with the ability to sense pain and contributes to
serious infections. Taken together, diabetes complications are one
of the nation's leading causes of death.
[0009] The first line of treatment is to offer diet and life style
advice to patients such as reducing the fat content of their diet
and increasing their physical activity. However, many patients find
this difficult and need additional help from drug therapy to
maintain results from these efforts.
[0010] Most currently marketed products have been unsuccessful as
treatments for obesity because of a lack of efficacy or
unacceptable side-effect profiles. The most successful drug so far
was the indirectly acting 5-hydroxytryptamine (5-HT) agonist
d-fenfluramine (Redux.TM.) but reports of cardiac valve defects in
up to one third of patients led to its withdrawal by the FDA in
1998.
[0011] In addition, two drugs have been launched in the USA and
Europe: Orlistat (Xenical.TM.) a drug that prevents absorption of
fat by the inhibition of pancreatic lipase, and Sibutramine
(Reductil.TM.), a 5-HT/noradrenaline re-uptake inhibitor. However,
side effects associated with these products may limit their
long-term utility. Treatment with Xenical.TM. is reported to induce
gastrointestinal distress in some patients, while Sibutramine has
been associated with raised blood pressure in some patients.
[0012] Serotonin (5-HT) neurotransmission plays an important role
in numerous physiological processes both in physical and in
psychiatric disorders. 5-HT has been implicated in the regulation
of feeding behavior. 5-HT is believed to work by inducing a feeling
of satiety, such that a subject with enhanced 5-HT stops eating
earlier and fewer calories are consumed. It has been shown that a
stimulatory action of 5-HT on the 5-HT.sub.2C receptor plays an
important role in the control of eating and in the anti-obesity
effect of d-fenfluramine. As the 5-HT.sub.2C receptor is expressed
in high density in the brain (notably in the limbic structures,
extrapyramidal pathways, thalamus and hypothalamus i.e. PVN and
DMH, and predominantly in the choroid plexus) and is expressed in
low density or is absent in peripheral tissues, a selective
5-HT.sub.2C receptor agonist can be a more effective and safe
anti-obesity agent. Also, 5-HT.sub.2C knockout mice are overweight
with cognitive impairment and susceptibility to seizure.
[0013] It is believed that the 5-HT.sub.2C receptor may play a role
in obsessive compulsive disorder, some forms of depression, and
epilepsy. Accordingly, agonists can have anti-panic properties, and
properties useful for the treatment of sexual dysfunction.
[0014] In sum, the 5-HT.sub.2C receptor is a receptor target for
the treatment of obesity and psychiatric disorders, and it can be
seen that there is a need for selective 5-HT.sub.2C agonists which
safely decrease food intake and body weight.
[0015] The present invention pertains to certain salts of the
selective 5-HT.sub.2C-receptor agonist
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and
pharmaceutical compositions comprising them. Like many
pharmaceutically useful compounds,
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine contains an
asymmetric carbon atom and thus it can exist as different optical
isomers. Optical isomers of pharmaceutically useful compounds may
posses significantly different physiological activity and
therefore, compounds useful for resolving mixtures of optical
isomers are needed. One method of resolving pharmaceutically useful
compounds containing one or more asymmetric carbon atom is by the
formation of diastereoisomeric salts. Once resolved, such salts are
useful for preparing pharmaceutical compositions directly, without
the need for further processing the resolved pharmaceutically
useful compound to another salt form, or to the free base or free
acid.
[0016] One aspect of the present invention pertains to optically
active acid salts of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound
1), and are useful for, inter alia, weight management, including
weight loss and the maintenance of weight loss. Compound 1 is
disclosed in PCT patent publication WO2003/086303, which is
incorporated herein by reference in its entirety.
##STR00001##
[0017] Various synthetic routes to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, its
related salts, enantiomers, crystalline forms, and intermediates,
have been reported in PCT publications, WO 2005/019179, WO
2006/069363, WO 2007/120517, WO 2008/070111, WO 2009/111004, and in
U.S. provisional application 61/396,752 each of which is
incorporated herein by reference in its entirety.
[0018] Combinations of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with
other agents, including without limitation, phentermine, and uses
of such combinations in therapy are described in WO 2006/071740,
which is incorporated herein by reference in its entirety
[0019] The following United States provisional applications are
related to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine:
61/402,578; 61/403,143; 61/402,580; 61/402,628; 61/403,149;
61/402,589; 61/402,611; 61/402,565; 61/403,185; each of which is
incorporated herein by reference in its entirety.
[0020] The following applications are related to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and have
the same filing date as the subject application: Attorney Reference
Number 178.WO1, a PCT application which claims priority to U.S.
provisional applications 61/402,578 and 61/403,143; Attorney
Reference Number 186.WO1, a PCT application which claims priority
to U.S. provisional applications 61/402,628 and 61/403,149;
Attorney Reference Number 187.WO1, a PCT application which claims
priority to U.S. provisional application 61/402,589; Attorney
Reference Number 188.WO1, a PCT application which claims priority
to U.S. provisional application 61/402,611; and Attorney Reference
Number 192.WO1, a PCT application which claims priority to U.S.
provisional applications 61/402,565 and 61/403,185; each of which
is incorporated herein by reference in its entirety.
[0021] (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hydrochloride (lorcaserin hydrochloride) is an agonist of the
5-HT.sub.2C receptor and shows effectiveness at reducing obesity in
animal models and humans. In December 2009, Arena Pharmaceuticals
submitted a New Drug Application, or NDA, for lorcaserin to the
FDA. The NDA submission is based on an extensive data package from
lorcaserin's clinical development program that includes 18 clinical
trials totaling 8,576 patients. The pivotal phase 3 clinical trial
program evaluated nearly 7,200 patients treated for up to two
years, and showed that lorcaserin consistently produced significant
weight loss with excellent tolerability. About two-thirds of
patients achieved at least 5% weight loss and over one-third
achieved at least 10% weight loss. On average, patients lost 17 to
18 pounds or about 8% of their weight. Secondary endpoints,
including body composition, lipids, cardiovascular risk factors and
glycemic parameters improved compared to placebo. In addition,
heart rate and blood pressure went down. Lorcaserin did not
increase the risk of cardiac valvulopathy. Lorcaserin improved
quality of life, and there was no signal for depression or suicidal
ideation. The only adverse event that exceeded the placebo rate by
5% was generally mild or moderate, transient headache. Based on a
normal BMI of 25, patients in the first phase 3 trial lost about
one-third of their excess body weight. The average weight loss was
35 pounds or 16% of body weight for the top quartile of patients in
the second phase 3 trial.
[0022] In view of the growing demand for compounds useful in the
treatment of disorders related to the 5-HT.sub.2C receptor,
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine has
emerged has an important new compound. Accordingly, new salts and
pharmaceutical compositions of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and
processes for their preparation are needed. The salts and processes
described herein help meet these and other needs.
SUMMARY OF THE INVENTION
[0023] A priori, it is difficult to predict with confidence which
salts of a particular compound will be solid, stable, and readily
isolable. Salts of chiral amines with optically active acids are no
exception. It is only through diligent experimentation that a
stable, solid-state salt may be discovered; once that salt is
in-hand however, the artisan of ordinary skill is equipped to
resolve its diastereoisomers. In the course of preparing the salts
of the present invention, many salt-forming agents commonly used in
the pharmaceutical industry (see e.g. Berge, et al., Journal of
Pharmaceutical Sciences, 66:1-19 (1977)) were investigated.
DL-lactate, D-gluconate, and D-lactobionate salts of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine were
prepared, but in contrast to the crystalline salts of the present
invention, they failed to crystallize.
[0024] One aspect of the present invention pertains to certain
optically active acid salts of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound
1) and pharmaceutically acceptable solvates and hydrates
thereof.
[0025] One aspect of the present invention pertains to certain
optically active acid salts of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Compound
1.
[0026] One aspect of the present invention pertains to salts
selected from:
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1
S)-(+)-10-camsylate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyroglutamate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate salt; and
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
di-camphorate salt; and pharmaceutically acceptable solvates and
hydrates thereof.
[0027] One aspect of the present invention pertains to
pharmaceutical compositions comprising a salt of the present
invention and a pharmaceutically acceptable carrier.
[0028] One aspect of the present invention pertains to processes
for preparing a pharmaceutical composition comprising admixing a
salt of the present invention, and a pharmaceutically acceptable
carrier.
[0029] One aspect of the present invention pertains to bulk
pharmaceutical compositions suitable for the manufacture of dosage
forms for weight management, comprising a salt of the present
invention, and a pharmaceutically acceptable carrier.
[0030] One aspect of the present invention pertains to processes
for preparing bulk pharmaceutical compositions suitable for the
manufacture of dosage forms for weight management, comprising
admixing a salt of the present invention, and a pharmaceutically
acceptable carrier.
[0031] One aspect of the present invention pertains to methods for
weight management, comprising administering to an individual in
need thereof, a therapeutically effective amount of a salt or a
pharmaceutical composition of the present invention.
[0032] One aspect of the present invention pertains to the use of
salts of the present invention in the manufacture of a medicament
for weight management in an individual.
[0033] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of treatment of the human or animal body by therapy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1: PXRD of Compound 1 (1S)-(+)-10-Camsylate Salt, Form
I.
[0035] FIG. 2: DSC and TGA of Compound 1 (1S)-(+)-10-Camsylate
Salt, Form I.
[0036] FIG. 3: DMS of Compound 1 (1S)-(+)-10-Camsylate Salt, Form
I.
[0037] FIG. 4: PXRD of Compound 1 Hemi-L-Malate Salt, Form I.
[0038] FIG. 5: DSC and TGA of Compound 1 Hemi-L-Malate Salt, Form
I.
[0039] FIG. 6: DMS of Compound 1 Hemi-L-Malate Salt, Form I.
[0040] FIG. 7: PXRD of Compound 1 L-Glutamate Salt, Form I.
[0041] FIG. 8: DSC and TGA of Compound 1 L-Glutamate Salt, Form
I.
[0042] FIG. 9: DMS of Compound 1 L-Glutamate Salt, Form I.
[0043] FIG. 10: PXRD of Compound 1 L-Aspartate Salt, Form I.
[0044] FIG. 11: DSC and TGA of Compound 1 L-Aspartate Salt, Form
I.
[0045] FIG. 12: DMS of Compound 1 L-Aspartate Salt, Form I.
[0046] FIG. 13: PXRD of Compound 1 Hemimucate Salt, Form I.
[0047] FIG. 14: DSC and TGA of Compound 1 Hemimucate Salt, Form
I.
[0048] FIG. 15: DMS of Compound 1 Hemimucate Salt, Form I.
[0049] FIG. 16: PXRD of Compound 1 Pyroglutamate Salt, Form I.
[0050] FIG. 17: DSC and TGA of Compound 1 Pyroglutamate Salt, Form
I.
[0051] FIG. 18: DMS of Compound 1 Pyroglutamate Salt, Form I.
[0052] FIG. 19: PXRD of Compound 1 Glucuronate Salt, Form I.
[0053] FIG. 20: DSC and TGA of Compound 1 Glucuronate Salt, Form
I.
[0054] FIG. 21: DMS of Compound 1 Glucuronate Salt, Form I.
[0055] FIG. 22: PXRD of Compound 1 Di-camphorate Salt Solvate, Form
I.
[0056] FIG. 23: DSC and TGA of Compound 1 Di-camphorate Salt
Solvate, Form I.
[0057] FIG. 24: DMS of Compound 1 Di-camphorate Salt Solvate, Form
I.
DETAILED DESCRIPTION
[0058] It should be appreciated that certain features of the
invention, which are, for clarity, described in the context of
separate embodiments, can also be provided in combination in a
single embodiment. Conversely, various features of the invention
which are, for brevity, described in the context of a single
embodiment, can also be provided separately or in any suitable
subcombination.
DEFINITIONS
[0059] For clarity and consistency, the following definitions will
be used throughout this patent document.
[0060] The term "agonist" refers to a moiety that interacts with
and activates a receptor, such as the 5-HT.sub.2C serotonin
receptor, and initiates a physiological or pharmacological response
characteristic of that receptor.
[0061] The term "individual" refers to both humans and non-human
mammals. Non-human mammals include but are not limited to rodents
such as mice and rats, etc. rabbits, dogs, cats, swine, cattle,
sheep, horses, and non-human primates such as monkeys and apes,
etc. The term "pharmaceutical composition" refers to a composition
comprising at least one active ingredient; including but not
limited to Compound 1 and pharmaceutically acceptable salts,
solvates and hydrates thereof, whereby the composition is amenable
to investigation for a specified, efficacious outcome in a mammal
(for example, without limitation, a human). Those of ordinary skill
in the art will understand and appreciate the techniques
appropriate for determining whether an active ingredient has a
desired efficacious outcome based upon the needs of the
artisan.
[0062] The term "therapeutically effective amount" refers to the
amount of active compound or pharmaceutical agent that elicits the
biological or medicinal response in a tissue, system, animal,
individual or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician or caregiver or by
an individual, which includes one or more of the following:
[0063] (1) Preventing the disease, for example, preventing a
disease, condition or disorder in an individual that may be
predisposed to the disease, condition or disorder but does not yet
experience or display the pathology or symptomatology of the
disease;
[0064] (2) Inhibiting the disease, for example, inhibiting a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., arresting further development
of the pathology and/or symptomatology); and
[0065] (3) Ameliorating the disease, for example, ameliorating a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., reversing the pathology
and/or symptomatology).
[0066] The term "treatment" as used herein refers to one or more of
the following:
[0067] (1) prevention of a disease, for example, prevention of a
disease, condition or disorder in an individual that may be
predisposed to the disease, condition or disorder but does not yet
experience or display the pathology or symptomatology of the
disease;
[0068] (2) inhibition of a disease, for example, inhibition of a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., arresting further development
of the pathology and/or symptomatology); and
[0069] (3) amelioration of a disease, for example, amelioration of
a disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., reversing the pathology
and/or symptomatology).
[0070] Whether an individual is in need of treatment is a judgment
made by a caregiver (e.g. nurse practitioner, physician, physician
assistant, nurse, etc. in the case of humans; veterinarian in the
case of animals, including non-human mammals) that an individual or
animal requires or will benefit from treatment. This judgment is
made based on a variety of factors that are in the realm of a
caregiver's expertise, but that includes the knowledge that the
individual or animal is ill, or will become ill, as the result of a
disease, condition or disorder that is treatable by Compound 1 and
pharmaceutically acceptable salts, solvates and hydrates thereof.
Accordingly, Compound 1 and pharmaceutically acceptable salts,
solvates and hydrates thereof can be used in a protective or
preventive manner; or Compound 1 and pharmaceutically acceptable
salts, solvates and hydrates thereof can be used to alleviate,
inhibit or ameliorate a disease, condition or disorder.
[0071] The term "weight management" as used herein refers to
controlling body weight and in the context of the present invention
is directed toward weight loss and the maintenance of weight loss
(also called weight maintenance herein). In addition to controlling
body weight, weight management includes controlling parameters
related to body weight, for example, BMI, percent body fat and
waist circumference. For example, weight management for an
individual who is overweight or obese can mean losing weight with
the goal of keeping weight in a healthier range. Also, for example,
weight management for an individual who is overweight or obese can
include losing body fat or circumference around the waist with or
without the loss of body weight.
[0072] The term "maintenance of weight loss" or "weight
maintenance" as used herein refers to preventing, reducing or
controlling weight gain after weight loss. It is well known that
weight gain often occurs after weight loss. Weight loss can occur,
for example, from dieting, exercising, illness, drug treatment,
surgery or any combination of these methods, but often an
individual that has lost weight will regain some or all of the lost
weight. Therefore, weight maintenance in an individual who has lost
weight can include preventing weight gain after weight loss,
reducing the amount of weigh gained after weight loss, controlling
weight gain after weight loss or slowing the rate of weight gain
after weight loss.
[0073] The term "optically active acid salt" as used herein means a
salt in which the anion is derived from the deprotonation of an
optically active acid. The following table provides certain
non-limiting examples of optically active acids.
TABLE-US-00002 Chemical Name Structure (1S)-(+)-10-camphorsulfonic
acid ##STR00002## L-malic acid ##STR00003## L-glutamic acid
##STR00004## L-aspartic acid ##STR00005## mucic acid ##STR00006##
pyroglutamatic acid ##STR00007## glucuronic acid ##STR00008##
(1R,3S)-(+)-camphoric acid ##STR00009## D-gluconic acid
##STR00010## L-lactic acid ##STR00011## L-tartaric acid
##STR00012## D-glycero-D-gulo-heptonic acid ##STR00013##
D-lactobionic acid ##STR00014## L-mandelic acid ##STR00015##
(D)-(+)-pantothenic acid ##STR00016## dibenzoyl-L-tartaric acid
##STR00017## Di-p-toluoyl-L-tartaric acid ##STR00018##
(S)-2-phenylpropionic acid ##STR00019## L-N-acetylphenylalanine
##STR00020## (1R)-(+)-3-bromocamphor-8-sulfonic acid ##STR00021##
(S)-2,3-isopropylideneglycerol hemiphthalate ##STR00022##
Diacetyl-L-tartaric acid ##STR00023## N-tosyl-L-glutamic acid
##STR00024## (1S)-(-)-Camphanic acid ##STR00025##
[0074] The term "diastereoisomeric" as used herein refers to the
relationship between stereoisomers that are not enantiomers.
Similarly, the term "diastereoisomeric salts" as used herein refers
to the relationship between salts that comprise both a chiral anion
and a chiral cation, wherein the salts are stereoisomers but are
not enantiomers.
[0075] For example, in a salt consisting of an anion with one
chiral center and a cation with one chiral center, there are four
possible stereoisomers of the salt: [0076] A. (R)-anion-(R)-cation;
[0077] B. (R)-anion-(S)-cation; [0078] C. (S)-anion-(R)-cation; and
[0079] D. (S)-anion-(S)-cation.
[0080] In this example each salt has one enantiomeric salt and two
diastereoisomeric salts. The various relationships between the four
salts above is shown in the following table:
TABLE-US-00003 Salt Enantiomer of salt Diastereoisomers of salt A D
B and C B C A and D C B A and D D A B and C
[0081] By way of further example, in a salt consisting of an anion
with two chiral centers and a cation with one chiral center, there
are eight possible stereoisomers of the salt: [0082] E.
(R,R)-anion-(R)-cation; [0083] F. (R,R)-anion-(S)-cation; [0084] G.
(R,S)-anion-(R)-cation; [0085] H. (R,S)-anion-(S)-cation; [0086] I.
(S,R)-anion-(R)-cation; [0087] J. (S,R)-anion-(S)-cation; [0088] K.
(S,S)-anion-(R)-cation; and [0089] L. (S,S)-anion-(S)-cation.
[0090] In this example each salt has one enantiomeric salt and six
diastereoisomeric salts. The various relationships between the
eight salts above is shown in the following table:
TABLE-US-00004 Salt Enantiomer of Salt Diastereoisomers of Salt E L
F, G, H, I, J, and K F K E, G, H, I, J, and L G J E, F, H, I, K,
and L H I E, F, G, J, K, and L I H E, F, G, J, K, and L J G E, F,
H, I, K, and L K F E, G, H, I, J, and L L E F, G, H, I, J, and
K
Salts of the Present Invention
[0091] The present invention is directed, inter alia, to solid,
stable, and readily isolable salts of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and
pharmaceutically acceptable solvates and hydrates thereof. The
solid state properties of the crystalline forms of salts the
present invention are summarized infra.
[0092] One aspect of the present invention pertains to salts
selected from:
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-camsylate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyroglutamate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate salt; and
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
di-camphorate salt; and pharmaceutically acceptable solvates and
hydrates thereof.
[0093] One aspect of the present invention pertains to salts
selected from:
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-camsylate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyroglutamate salt; and
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate salt; and pharmaceutically acceptable solvates and
hydrates thereof.
[0094] One aspect of the present invention pertains to salts
selected from:
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-camsylate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyroglutamate salt;
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate salt; and
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
di-camphorate salt solvate.
[0095] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
di-camphorate salt solvate.
[0096] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-camsylate salt.
[0097] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt.
[0098] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt.
[0099] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt.
[0100] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate salt.
[0101] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyroglutamate salt.
[0102] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate salt.
[0103] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
di-camphorate salt solvate.
[0104] One aspect of the present invention pertains to
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-camsylate salt.
[0105] One aspect of the present invention pertains to
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malate
salt.
[0106] One aspect of the present invention pertains to
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamate
salt.
[0107] One aspect of the present invention pertains to
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartate
salt.
[0108] One aspect of the present invention pertains to
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucate
salt.
[0109] One aspect of the present invention pertains to
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamate
salt.
[0110] One aspect of the present invention pertains to
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronate
salt.
[0111] One aspect of the present invention pertains to
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphorate
salt solvate.
[0112] One aspect of the present invention pertains to
(.+-.)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-camsylate salt.
[0113] One aspect of the present invention pertains to
(.+-.)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt.
[0114] One aspect of the present invention pertains to
(.+-.)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt.
[0115] One aspect of the present invention pertains to
(.+-.)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt.
[0116] One aspect of the present invention pertains to
(.+-.)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate salt.
[0117] One aspect of the present invention pertains to
(.+-.)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyroglutamate salt.
[0118] One aspect of the present invention pertains to
(.+-.)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate salt.
[0119] One aspect of the present invention pertains to
(.+-.)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
di-camphorate salt solvate.
[0120] One aspect of the present invention pertains to
(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-camsylate salt.
[0121] One aspect of the present invention pertains to
(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt.
[0122] One aspect of the present invention pertains to
(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt.
[0123] One aspect of the present invention pertains to
(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt.
[0124] One aspect of the present invention pertains to
(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate salt.
[0125] One aspect of the present invention pertains to
(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyroglutamate salt.
[0126] One aspect of the present invention pertains to
(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate salt.
[0127] One aspect of the present invention pertains to
(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
di-camphorate salt solvate.
[0128] One aspect of the present invention pertains to
pharmaceutical compositions comprising a salt of the present
invention.
[0129] One aspect of the present invention pertains to process for
preparing a pharmaceutical composition comprising admixing a salt
of the present invention and a pharmaceutically acceptable
carrier.
[0130] One aspect of the present invention pertains to methods for
weight management, comprising administering to an individual in
need thereof, a therapeutically effective amount of a salt of the
present invention.
[0131] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for weight management in an individual.
[0132] One aspect of the present invention pertains to salts of the
present invention, for use in a method of treatment of the human or
animal body by therapy.
[0133] One aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management.
[0134] One aspect of the present invention pertains to salts of the
present invention, for use in a method of weight loss.
[0135] One aspect of the present invention pertains to salts of the
present invention, for use in a method of maintenance of weight
loss.
[0136] One aspect of the present invention pertains to salts of the
present invention, for use in a method of decreasing food
consumption.
[0137] One aspect of the present invention pertains to salts of the
present invention, for use in a method of increasing meal-related
satiety.
[0138] One aspect of the present invention pertains to salts of the
present invention, for use in a method of reducing pre-meal
hunger.
[0139] One aspect of the present invention pertains to salts of the
present invention, for use in a method of reducing intra-meal food
intake.
[0140] One aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management further
comprising a reduced-calorie diet.
[0141] One aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management further
comprising a program of regular exercise.
[0142] One aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management further
comprising a reduced-calorie diet and a program of regular
exercise.
[0143] One aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in an
obese patient with an initial body mass index .gtoreq.30
kg/m.sup.2.
[0144] One aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in an
overweight patient with an initial body mass index .gtoreq.27
kg/m.sup.2 in the presence of at least one weight related co-morbid
condition.
[0145] One aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in an
overweight patient with an initial body mass index .gtoreq.27
kg/m.sup.2 in the presence of at least one weight related co-morbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0146] On aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in an
individual with an initial body mass index .gtoreq.30
kg/m.sup.2.
[0147] On aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in an
individual with an initial body mass index .gtoreq.27 kg/m.sup.2.
On aspect of the present invention pertains to salts of the present
invention, for use in a method of weight management in an
individual with an initial body mass index .gtoreq.27 kg/m.sup.2 in
the presence of at least one weight related co-morbid
condition.
[0148] On aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in an
individual with an initial body mass index .gtoreq.27 kg/m.sup.2 in
the presence of at least one weight related co-morbid condition
selected from: hypertension, dyslipidemia, cardiovascular disease,
glucose intolerance, and sleep apnea.
[0149] On aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in an
individual with an initial body mass index .gtoreq.25
kg/m.sup.2.
[0150] On aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in an
individual with an initial body mass index .gtoreq.25 kg/m.sup.2 in
the presence of at least one weight related co-morbid
condition.
[0151] On aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in an
individual with an initial body mass index .gtoreq.25 kg/m.sup.2 in
the presence of at least one weight related co-morbid condition
selected from: hypertension, dyslipidemia, cardiovascular disease,
glucose intolerance, and sleep apnea.
[0152] One aspect of the present invention pertains to salts of the
present invention, for use in a method of weight management in
combination with phentermine
Crystalline Salts
[0153] Polymorphism is the ability of a substance to exist as two
or more crystalline phases that have different arrangements and/or
conformations of the molecules in the crystal lattice. Polymorphs
show the same properties in the liquid or gaseous state but they
may behave differently in the solid state.
[0154] Besides single-component polymorphs, drugs can also exist as
salts and other multicomponent crystalline phases. For example,
solvates and hydrates may contain an API host and either solvent or
water molecules, respectively, as guests. Analogously, when the
guest compound is a solid at room temperature, the resulting form
is often called a cocrystal. Salts, solvates, hydrates, and
cocrystals may show polymorphism as well. Crystalline phases that
share the same API host, but differ with respect to their guests,
may be referred to as pseudopolymorphs of one another.
[0155] Solvates contain molecules of the solvent of crystallization
in a definite crystal lattice. Solvates, in which the solvent of
crystallization is water, are termed hydrates. Because water is a
constituent of the atmosphere, hydrates of drugs may be formed
rather easily.
[0156] Recently, polymorph screens of 245 compounds revealed that
about 90% of them exhibited multiple solid forms. Overall,
approximately half the compounds were polymorphic, often having one
to three forms. About one-third of the compounds formed hydrates,
and about one-third formed solvates. Data from cocrystal screens of
64 compounds showed that 60% formed cocrystals other than hydrates
or solvates. (G. P. Stahly, Crystal Growth & Design (2007),
7(6), 1007-1026.) The present invention is directed, inter alia, to
crystalline salts of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and
hydrates and solvates thereof. The crystalline forms of the salts
of the present invention can be identified by unique solid state
signatures with respect to, for example, differential scanning
calorimetry (DSC), X-ray powder diffraction (PXRD), and other solid
state methods. Further characterization with respect to water or
solvent content of the crystalline salts of the present invention
can be gauged by any of the following methods for example,
thermogravimetric analysis (TGA), DSC and the like. For DSC, it is
known that the temperatures observed will depend upon sample
purity, the rate of temperature change, as well as sample
preparation technique and the particular instrument employed. Thus,
the values reported herein relating to DSC thermograms can vary by
about .+-.6.degree. C. The values reported herein relating to DSC
thermograms can also vary by about .+-.20 joules per gram. For
PXRD, the relative intensities of the peaks can vary, depending
upon the sample preparation technique, the sample mounting
procedure and the particular instrument employed. Moreover,
instrument variation and other factors can often affect the
2.theta. values. Therefore, the peak assignments of diffraction
patterns can vary by about .+-.0.2.degree.2.theta.. The relative
intensities of the reported peaks can also vary. For TGA, the
features reported herein can vary by about .+-.5.degree. C. The TGA
features reported herein can also vary by about .+-.2% weight
change due to, for example, sample variation. Further
characterization with respect to hygroscopicity of the crystalline
salt can be gauged by, for example, dynamic moisture sorption
(DMS). The DMS features reported herein can vary by about .+-.5%
relative humidity. The DMS features reported herein can also vary
by about .+-.5% weight change. The deliquescence relative humidity
(DRH) measurements by water activity meter are sensitive to sample
quality and quantity. The DRH measurements reported herein can vary
by about .+-.5% RH.
Compound 1 (1S)-(+)-10-Camsylate Salt.
[0157] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1
S)-(+)-10-camsylate salt, Form I (Compound 1 (1 S)-(+)-10-camsylate
salt, Form I). The physical properties of Compound 1
(1S)-(+)-10-camsylate salt, Form I are summarized in Table 1
below.
TABLE-US-00005 TABLE 1 Compound 1 (1S)-(+)-10-Camsylate Salt, Form
I PXRD FIG. 1: Peaks of >20% relative intensity at 9.93, 11.58,
14.90, 15.32, 16.45, 16.88, 18.25, 18.57, 20.97, 23.14, and 25.44
.degree.2.theta. TGA FIG. 2: about 0.2% weight loss up to about
150.degree. C. DSC FIG. 2: extrapolated onset temperature:
176.degree. C.; enthalpy of fusion 92 J/g DMS FIG. 3: 0.49% weight
increase out to 90% RH
[0158] Form I of Compound 1 (1S)-(+)-10-camsylate salt held
residual solvent or a small amount of water. The small weight loss
by TGA (0.215%) is too small to be a stoichiometric solvate; it may
be a mixture of anhydrous solvated crystal phases. The melting
onset by DSC was 176.degree. C.
[0159] Form I of Compound 1 (1S)-(+)-10-camsylate salt was
non-hygroscopic by DMS analysis, picking up about 0.49% out to and
including the 90% RH hold at 25.degree. C. The DRH was determined
to be 99.8% RH by water activity measurement of a saturated aqueous
solution with excess solid at 25.degree. C.
[0160] Certain X-ray powder diffraction peaks for Form I of
Compound 1 (1S)-(+)-10-camsylate salt are shown in Table 2
below.
TABLE-US-00006 TABLE 2 Pos. (.degree.2.theta.) Rel. Int. (%) 9.93
33.89 11.58 38.89 13.15 2.15 14.08 8.07 14.43 12.50 14.90 24.42
15.32 25.17 16.45 46.36 16.88 26.94 17.57 7.59 18.25 100.00 18.57
44.04 19.89 5.97 20.97 41.20 21.36 5.76 21.56 10.34 22.54 17.03
23.14 25.60 23.28 16.29 24.58 6.00 24.90 10.60 25.30 14.05 25.44
23.97 25.82 8.07 26.41 2.45 26.92 8.25 27.56 8.59 28.18 6.81 28.51
3.91 29.06 1.78 29.52 0.89 30.05 3.29 30.86 5.09 31.11 3.09 31.88
4.87 32.02 3.96 32.75 5.23 33.23 8.73 33.29 8.45 34.01 2.81 34.32
5.81 34.79 1.47 35.31 5.87 36.24 2.66 36.93 4.84 37.61 5.57 38.09
6.29 38.76 1.26 39.20 1.78
[0161] One aspect of the present invention is directed to a
Compound 1 (1S)-(+)-10-camsylate salt having an X-ray powder
diffraction pattern comprising a peak, in terms of 2.theta., at
about 18.25.degree.. In some embodiments, the crystalline form has
an X-ray powder diffraction pattern comprising a peak, in terms of
2.theta., at about 16.45.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
peaks, in terms of 2.theta., at about 18.25.degree. and about
16.45.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 18.25.degree. and about 18.57.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
18.25.degree., about 16.45.degree., and about 18.57.degree.. In
some embodiments, the crystalline form has an X-ray powder
diffraction pattern comprising peaks, in terms of 2.theta., at
about 18.25.degree., about 16.45.degree., about 18.57.degree.,
about 20.97.degree., about 11.58.degree., about 9.93.degree., and
about 16.88.degree.. In some embodiments, the crystalline form has
an X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 18.25.degree., about 16.45.degree., about
18.57.degree., about 20.97.degree., about 11.58.degree., about
9.93.degree., about 16.88.degree., about 23.14.degree., about
15.32.degree., and about 14.90.degree.. One aspect of the present
invention is directed to a Compound 1 (1S)-(+)-10-camsylate salt
having an X-ray powder diffraction pattern comprising one or more
peaks listed in Table 2. In some embodiments, the crystalline form
has an X-ray powder diffraction pattern substantially as shown in
FIG. 1, wherein by "substantially" is meant that the reported peaks
can vary by about .+-.0.2.degree.2.theta., and also that the
relative intensities of the reported peaks can vary.
[0162] In some embodiments, the Compound 1 (1S)-(+)-10-camsylate
salt has a differential scanning calorimetry thermogram comprising
an endotherm with an extrapolated onset temperature between about
160.degree. C. and about 190.degree. C. In some embodiments, the
Compound 1 (1S)-(+)-10-camsylate salt has a differential scanning
calorimetry thermogram comprising an endotherm with an extrapolated
onset temperature at about 176.degree. C. In some embodiments, the
Compound 1 (1S)-(+)-10-camsylate salt has a differential scanning
calorimetry thermogram comprising an endotherm with an associated
heat flow of about 92 joules per gram. In some embodiments, the
Compound 1 (1S)-(+)-10-camsylate salt has a differential scanning
calorimetry thermogram substantially as shown in FIG. 2, wherein by
"substantially" is meant that the reported DSC features can vary by
about .+-.6.degree. C. and by about .+-.20 joules per gram.
[0163] In some embodiments, the Compound 1 (1S)-(+)-10-camsylate
salt has a thermogravimetric analysis profile substantially as
shown in FIG. 2, wherein by "substantially" is meant that the
reported TGA features can vary by about .+-.5.degree. C. and by
about .+-.2% weight change.
[0164] In some embodiments, the Compound 1 (1S)-(+)-10-camsylate
salt has a dynamic moisture sorption profile substantially as shown
in FIG. 3, wherein by "substantially" is meant that the reported
DMS features can vary by about .+-.5% relative humidity and by
about .+-.5% weight change.
[0165] Form I of Compound 1 (1S)-(+)-10-camsylate salt can be
prepared by any of the suitable procedures known in the art for
preparing crystalline polymorphs. In some embodiments Form I of
Compound 1 (1S)-(+)-10-camsylate salt can be prepared as described
in Example 1. In some embodiments, Form I of Compound 1
(1S)-(+)-10-camsylate salt can be prepared by slurrying crystalline
Compound 1 (1S)-(+)-10-camsylate salt containing one or more
crystalline forms other than Form I. In some embodiments, Form I of
Compound 1 (1S)-(+)-10-camsylate salt can be prepared by
recrystallizing crystalline Compound 1 (1S)-(+)-10-camsylate salt
containing one or more crystalline forms other than Form I.
Compound 1 Hemi-L-Malate Salt
[0166] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-malate salt, Form I (Compound 1 hemi-L-malate salt, Form I).
The physical properties of Compound 1 hemi-L-malate salt, Form I
are summarized in Table 3 below.
TABLE-US-00007 TABLE 3 Compound 1 Hemi-L-Malate Salt, Form I PXRD
FIG. 4: Peaks of .gtoreq.25% relative intensity at 7.18, 10.84,
11.7932, 15.09, 19.14, 19.36, 20.34, 20.45, 21.26, 21.97, and 23.25
.degree.2.theta. TGA FIG. 5: less than 0.3% weight loss up to about
120.degree. C. DSC FIG. 5: extrapolated onset temperature about
156.degree. C.; enthalpy of fusion 106 J/g DMS FIG. 6:
deliquescence between 80 and 90% RH
[0167] Compound 1 hemi-L-malate salt, Form I was crystalline and
melted with an onset temperature of 155-156.degree. C. It
demonstrated deliquescence between 80 and 90% RH by DMS
analysis.
[0168] Certain X-ray powder diffraction peaks for Form I of
Compound 1 hemi-L-malate salt are shown in Table 4 below.
TABLE-US-00008 TABLE 4 Pos. (.degree.2.theta.) Rel. Int. (%) 7.18
33.59 9.41 12.07 10.84 100.00 11.79 88.54 13.78 3.71 14.34 2.76
15.09 31.06 16.36 4.57 16.77 7.82 18.76 21.71 19.14 26.02 19.36
26.41 19.87 11.41 20.34 29.98 20.45 28.55 20.94 19.62 21.26 39.19
21.64 20.60 21.97 42.90 23.01 23.35 23.25 26.66 23.61 23.48 24.19
18.55 25.16 13.20 25.69 9.53 26.58 6.73 26.92 12.21 27.65 7.52
28.20 4.75 28.81 6.71 29.50 3.72 29.88 5.71 30.43 4.91 32.75 6.12
33.68 3.88 34.02 3.72 35.16 6.57 35.95 4.32 36.85 1.25 37.53 1.99
38.11 1.54 39.1250 2.61
[0169] One aspect of the present invention is directed to a
Compound 1 hemi-L-malate salt having an X-ray powder diffraction
pattern comprising a peak, in terms of 2.theta., at about
10.84.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising a peak, in terms of
2.theta., at about 11.7932.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
peaks, in terms of 2.theta., at about 10.84.degree. and about
11.7932.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 10.84.degree. and about 21.97.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
10.84.degree., about 11.7932.degree., and about 21.97.degree.. In
some embodiments, the crystalline form has an X-ray powder
diffraction pattern comprising peaks, in terms of 2.theta., at
about 10.84.degree., about 11.7932.degree., about 21.97.degree.,
about 21.26.degree., about 7.18.degree., about 15.09.degree., and
about 20.34.degree.. In some embodiments, the crystalline form has
an X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 10.84.degree., about 11.7932.degree., about
21.97.degree., about 21.26.degree., about 7.18.degree., about
15.09.degree., about 20.34.degree., about 20.45.degree., about
23.25.degree., and about 19.36.degree.. One aspect of the present
invention is directed to a Compound 1 hemi-L-malate salt having an
X-ray powder diffraction pattern comprising one or more peaks
listed in Table 4. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern substantially as shown in FIG. 4,
wherein by "substantially" is meant that the reported peaks can
vary by about .+-.0.2.degree.2.theta., and also that the relative
intensities of the reported peaks can vary.
[0170] In some embodiments, the Compound 1 hemi-L-malate salt has a
differential scanning calorimetry thermogram comprising an
endotherm with an extrapolated onset temperature between about
140.degree. C. and about 170.degree. C. In some embodiments, the
Compound 1 hemi-L-malate salt has a differential scanning
calorimetry thermogram comprising an endotherm with an extrapolated
onset temperature at about 156.degree. C. In some embodiments, the
Compound 1 hemi-L-malate salt has a differential scanning
calorimetry thermogram comprising an endotherm with an associated
heat flow of about 106 joules per gram. In some embodiments, the
Compound 1 hemi-L-malate salt has a thermogravimetric analysis
profile substantially as shown in FIG. 5, wherein by
"substantially" is meant that the reported TGA features can vary by
about .+-.5.degree. C. and by about .+-.2% weight change.
[0171] In some embodiments, the Compound 1 hemi-L-malate salt has a
differential scanning calorimetry thermogram substantially as shown
in FIG. 5, wherein by "substantially" is meant that the reported
DSC features can vary by about .+-.6.degree. C. and by about .+-.20
joules per gram.
[0172] In some embodiments, the Compound 1 hemi-L-malate salt has a
dynamic moisture sorption profile substantially as shown in FIG. 6,
wherein by "substantially" is meant that the reported DMS features
can vary by about .+-.5% relative humidity and by about .+-.5%
weight change.
[0173] Form I of Compound 1 hemi-L-malate salt can be prepared by
any of the suitable procedures known in the art for preparing
crystalline polymorphs. In some embodiments Form I of Compound 1
hemi-L-malate salt can be prepared as described in Example 2. In
some embodiments, Form I of Compound 1 hemi-L-malate salt can be
prepared by slurrying crystalline Compound 1 hemi-L-malate salt
containing one or more crystalline forms other than Form I. In some
embodiments, Form I of Compound 1 hemi-L-malate salt can be
prepared by recrystallizing crystalline Compound 1 hemi-L-malate
salt containing one or more crystalline forms other than Form
I.
Compound 1 L-Glutamate Salt
[0174] One aspect of the present invention pertains to a
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt (Compound 1 L-glutamate salt). In some
embodiments, the
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-glutamate salt is Form I (Compound 1 L-glutamate salt, Form I).
The physical properties of Form I of Compound 1 L-glutamate salt
are summarized in Table 5 below.
TABLE-US-00009 TABLE 5 Compound 1 L-Glutamate Salt, Form I PXRD
FIG. 7: Peaks of .gtoreq.20% relative intensity at 5.79, 16.88,
17.63, 18.06, 18.24, 20.25, 21.27, 21.78, 22.46, 23.73, and 25.59
.degree.2.theta. TGA FIG. 8: about 0.25% weight loss up to about
124.degree. C. DSC FIG. 8: extrapolated onset temperature about
187.degree. C.; enthalpy of fusion 288 J/g DMS FIG. 9:
non-hygroscopic, about 0.1% weight gain out 90% RH
[0175] Compound 1 L-glutamate salt, Form I had a melting onset of
187.degree. C. A large portion of the salt, a degradant or
component, was lost prior to melting, based on the TGA result. The
salt was anhydrous and non-hygroscopic.
[0176] Certain X-ray powder diffraction peaks for Form I of
Compound 1 L-glutamate salt are shown in Table 6 below.
TABLE-US-00010 TABLE 6 Pos. (.degree.2.theta.) Rel. Int. (%) 5.79
31.50 10.61 8.24 11.59 10.80 12.83 1.38 15.22 17.13 16.88 24.59
17.63 99.12 18.06 41.01 18.24 29.49 19.07 5.69 20.25 47.15 21.27
34.93 21.78 80.76 22.46 23.35 22.92 13.91 23.73 49.50 25.59 100.00
26.00 19.27 26.98 5.80 27.36 2.03 28.32 13.14 28.94 2.08 29.2382
7.91 29.5508 2.11 30.2671 13.89 30.6035 4.84 31.20 5.22 31.96 2.89
32.61 5.41 32.94 10.36 33.62 1.96 34.31 3.53 34.93 2.03 35.24 7.29
35.60 11.62 36.66 18.40 37.03 10.33 37.25 8.52 37.54 5.74 38.17
4.11 38.49 5.75 38.76 4.61 39.10 3.60
[0177] One aspect of the present invention is directed to a
Compound 1 L-glutamate salt having an X-ray powder diffraction
pattern comprising a peak, in terms of 2.theta., at about
25.59.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising a peak, in terms of
2.theta., at about 17.63.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
peaks, in terms of 2.theta., at about 25.59.degree. and about
17.63.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 25.59.degree. and about 21.78.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
25.59.degree., about 17.63.degree., and about 21.78.degree.. In
some embodiments, the crystalline form has an X-ray powder
diffraction pattern comprising peaks, in terms of 2.theta., at
about 25.59.degree., about 17.63.degree., about 21.78.degree.,
about 23.73.degree., about 20.25.degree., about 18.06.degree., and
about 21.27.degree.. In some embodiments, the crystalline form has
an X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 25.59.degree., about 17.63.degree., about
21.78.degree., about 23.73.degree., about 20.25.degree., about
18.06.degree., about 21.27.degree., about 5.79.degree., about
18.24.degree., and about 16.88.degree.. One aspect of the present
invention is directed to a Compound 1 L-glutamate salt having an
X-ray powder diffraction pattern comprising one or more peaks
listed in Table 6. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern substantially as shown in FIG. 7,
wherein by "substantially" is meant that the reported peaks can
vary by about .+-.0.2.degree.2.theta., and also that the relative
intensities of the reported peaks can vary.
[0178] In some embodiments, the Compound 1 L-glutamate salt has a
differential scanning calorimetry thermogram comprising an
endotherm with an extrapolated onset temperature between about
170.degree. C. and about 200.degree. C. In some embodiments, the
Compound 1 L-glutamate salt has a differential scanning calorimetry
thermogram comprising an endotherm with an extrapolated onset
temperature at about 187.degree. C. In some embodiments, the
Compound 1 L-glutamate salt has a differential scanning calorimetry
thermogram comprising an endotherm with an associated heat flow of
about 288 joules per gram. In some embodiments, the Compound 1
L-glutamate salt has a thermogravimetric analysis profile
substantially as shown in FIG. 8, wherein by "substantially" is
meant that the reported TGA features can vary by about
.+-.5.degree. C. and by about .+-.2% weight change.
[0179] In some embodiments, the Compound 1 L-glutamate salt has a
differential scanning calorimetry thermogram substantially as shown
in FIG. 8, wherein by "substantially" is meant that the reported
DSC features can vary by about .+-.6.degree. C. and by about .+-.20
joules per gram.
[0180] In some embodiments, the Compound 1 L-glutamate salt has a
dynamic moisture sorption profile substantially as shown in FIG. 9.
By "substantially" is meant that the reported DMS features can vary
by about .+-.5% relative humidity and by about .+-.5% weight
change.
[0181] Form I of Compound 1 L-glutamate salt can be prepared by any
of the suitable procedures known in the art for preparing
crystalline polymorphs. In some embodiments Form I of Compound 1
L-glutamate salt can be prepared as described in Example 3. In some
embodiments, Form I of Compound 1 L-glutamate salt can be prepared
by slurrying crystalline
[0182] Compound 1 L-glutamate salt containing one or more
crystalline forms other than Form I. In some embodiments, Form I of
Compound 1 L-glutamate salt can be prepared by recrystallizing
crystalline Compound 1 L-glutamate salt containing one or more
crystalline forms other than Form I.
Compound 1 L--Aspartate Salt
[0183] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-aspartate salt, Form I (Compound 1 L-aspartate salt, Form I). The
physical properties of Compound 1 L-aspartate salt, Form I are
summarized in Table 7 below.
TABLE-US-00011 TABLE 7 Compound 1 L-Aspartate Salt, Form I PXRD
FIG. 10: Peaks of .gtoreq.25% relative intensity at 8.49, 13.40,
15.28, 16.43, 16.55, 19.45, 20.80, 21.22, 22.08, 22.38, 23.29, and
29.85 .degree.2.theta. TGA FIG. 11: 54.9% weight from about
140.degree. C. to about 200.degree. C. DSC FIG. 11: extrapolated
onset temperature about 174.degree. C. DMS FIG. 12: hygroscopic at
70% RH and deliquescent above 70% RH
[0184] Form I of Compound 1 L-aspartate salt was an anhydrous
crystal phase that melted at 173.9.degree. C. It displayed
back-to-back endothermic events corresponding to simultaneous loss
of a degradant or a component of the salt, and melting. The TGA
showed a large step transition (weight-loss), thus DSC endothermic
events are accompanied by volatilization of some portion of the
sample.
[0185] DMS showed it to be slightly hygroscopic at 70% RH and
deliquescent above 70% RH, picking up 28% weight during the 80% RH
hold, 45% of its weight in water out to and including the 90% RH
hold at 25.degree. C.
[0186] Certain X-ray powder diffraction peaks for Form I of
Compound 1 L-aspartate salt are shown in Table 8 below.
TABLE-US-00012 TABLE 8 Pos. (.degree.2.theta.) Rel. Int. (%) 5.12
1.93 8.49 89.49 12.75 4.03 13.40 71.47 14.20 4.37 15.28 68.22 16.43
35.18 16.55 35.20 16.96 6.96 17.49 5.41 17.98 3.56 19.45 29.32
20.80 64.93 21.22 100.00 21.69 20.38 22.08 45.99 22.38 36.19 23.29
45.28 23.56 7.19 24.33 17.79 25.18 6.08 25.56 7.58 26.33 15.10
26.66 9.03 26.88 21.72 27.71 1.47 28.27 7.21 28.60 13.17 29.85
56.07 30.49 24.42 31.14 9.83 31.38 24.01 32.29 2.26 33.06 11.70
33.98 4.21 34.23 10.10 34.82 10.62 35.02 8.80 36.40 8.61 36.60 8.18
37.01 2.54 37.35 3.76 37.67 2.82 38.13 4.28 38.43 7.61 38.74 4.65
39.43 3.29
[0187] One aspect of the present invention is directed to a
Compound 1 L-aspartate salt having an X-ray powder diffraction
pattern comprising a peak, in terms of 2.theta., at about
21.22.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising a peak, in terms of
2.theta., at about 8.49.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
peaks, in terms of 2.theta., at about 21.22.degree. and about
8.49.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 21.22.degree. and about 13.40.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
21.22.degree., about 8.49.degree., and about 13.40.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
21.22.degree., about 8.49.degree., about 13.40.degree., about
15.28.degree., about 29.85.degree., about 29.85.degree., and about
22.08.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 21.22.degree., about 8.49.degree., about
13.40.degree., about 15.28.degree., about 29.85.degree., about
29.85.degree., about 22.08.degree., about 23.29.degree., about
22.38.degree., and about 16.55.degree.. One aspect of the present
invention is directed to a Compound 1 L-aspartate salt having an
X-ray powder diffraction pattern comprising one or more peaks
listed in Table 8. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern substantially as shown in FIG. 10,
wherein by "substantially" is meant that the reported peaks can
vary by about .+-.0.2.degree.2.theta., and also that the relative
intensities of the reported peaks can vary.
[0188] In some embodiments, the Compound 1 L-aspartate salt has a
differential scanning calorimetry thermogram comprising an
endotherm with an extrapolated onset temperature between about
160.degree. C. and about 190.degree. C. In some embodiments, the
Compound 1 L-aspartate salt has a differential scanning calorimetry
thermogram comprising an endotherm with an extrapolated onset
temperature at about 174.degree. C. In some embodiments, the
Compound 1 L-aspartate salt has a thermogravimetric analysis
profile substantially as shown in FIG. 11, wherein by
"substantially" is meant that the reported TGA features can vary by
about .+-.5.degree. C. and by about .+-.2% weight change.
[0189] In some embodiments, the Compound 1 L-aspartate salt has a
differential scanning calorimetry thermogram substantially as shown
in FIG. 11, wherein by "substantially" is meant that the reported
DSC features can vary by about .+-.6.degree. C. and by about .+-.20
joules per gram.
[0190] In some embodiments, the Compound 1 L-aspartate salt has a
dynamic moisture sorption profile substantially as shown in FIG.
12, wherein by "substantially" is meant that the reported DMS
features can vary by about .+-.5% relative humidity and by about
.+-.5% weight change.
[0191] Form I of Compound 1 L-aspartate salt can be prepared by any
of the suitable procedures known in the art for preparing
crystalline polymorphs. In some embodiments Form I of Compound 1
L-aspartate salt can be prepared as described in Example 4. In some
embodiments, Form I of Compound 1 L-aspartate salt can be prepared
by slurrying crystalline Compound 1 L-aspartate salt containing one
or more crystalline forms other than Form I. In some embodiments,
Form I of Compound 1 L-aspartate salt can be prepared by
recrystallizing crystalline Compound 1 L-aspartate salt containing
one or more crystalline forms other than Form I.
Compound 1 Hemimucate Salt.
[0192] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemimucate, Form I (Compound 1 hemimucate salt, Form I). The
physical properties of Compound 1 hemimucate salt, Form I are
summarized in Table 9 below.
TABLE-US-00013 TABLE 9 Compound 1 Hemimucate Salt, Form I PXRD FIG.
13: Peaks of >4% relative intensity at 5.06, 10.06, 14.57,
15.90, 18.60, 18.89, 20.92, 21.46, 21.63, 22.74, 23.0980, and 25.61
.degree.2.theta. TGA FIG. 14: 56% weight loss from about
175.degree. C. to about 215.degree. C. DSC FIG. 14: extrapolated
onset temperature: 208.degree. C.; enthalpy of fusion 358 J/g DMS
FIG. 15: 0.255% weight increase out to 90% RH
[0193] Form I of Compound 1 hemimucate salt exhibited a melting
onset at 208.degree. C. The large heat of fusion (357.5 J/g shown
in FIG. 14) was due in large part to vaporization of more than half
of the sample, indicating the salt melts with degradation.
[0194] Compound 1 hemimucate salt was essentially non-hygroscopic,
picking up only 0.26% weight in water out to and including the 90%
RH hold at 25.degree. C.
[0195] Certain X-ray powder diffraction peaks for Form I of
Compound 1 hemimucate salt are shown in Table 10 below.
TABLE-US-00014 TABLE 10 Pos. (.degree.2.theta.) Rel. Int. (%) 5.06
100.00 10.06 9.14 10.62 0.26 11.67 1.51 12.08 0.05 14.08 1.50 14.57
11.53 15.07 0.53 15.90 6.75 18.01 1.55 18.60 28.58 18.89 8.11 20.12
0.24 20.92 13.14 21.46 4.96 21.63 8.25 22.29 2.45 22.74 4.12 23.10
4.24 23.86 0.41 24.27 3.09 25.22 3.81 25.61 4.48 26.44 1.12 26.85
1.86 27.37 1.54 27.88 1.72 28.29 0.75 28.92 3.11 29.28 1.36 30.37
2.29 31.44 1.06 31.60 1.04 32.29 0.96 32.64 0.49 33.30 1.90 34.00
0.39 34.40 0.59 35.18 0.40 35.42 0.52 36.17 0.39 36.78 0.21 37.65
1.54 38.12 1.29 38.51 0.37
[0196] One aspect of the present invention is directed to a
Compound 1 hemimucate salt having an X-ray powder diffraction
pattern comprising a peak, in terms of 2.theta., at about
5.06.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising a peak, in terms of
2.theta., at about 18.60.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
peaks, in terms of 2.theta., at about 5.06.degree. and about
18.60.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 5.06.degree. and about 20.92.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
5.06.degree., about 18.60.degree., and about 20.92.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
5.06.degree., about 18.60.degree., about 20.92.degree., about
14.57.degree., about 10.06.degree., about 21.63.degree., and about
18.89.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 5.06.degree., about 18.60.degree., about
20.92.degree., about 14.57.degree., about 10.06.degree., about
21.63.degree., about 18.89.degree., about 15.90.degree., about
21.46.degree., and about 25.61.degree.. One aspect of the present
invention is directed to a Compound 1 hemimucate salt having an
X-ray powder diffraction pattern comprising one or more peaks
listed in Table 10. In some embodiments, the crystalline form has
an X-ray powder diffraction pattern substantially as shown in FIG.
13, wherein by "substantially" is meant that the reported peaks can
vary by about .+-.0.2.degree.2.theta., and also that the relative
intensities of the reported peaks can vary.
[0197] In some embodiments, the Compound 1 hemimucate salt has a
differential scanning calorimetry thermogram comprising an
endotherm with an extrapolated onset temperature between about
190.degree. C. and about 220.degree. C. In some embodiments, the
Compound 1 hemimucate salt has a differential scanning calorimetry
thermogram comprising an endotherm with an extrapolated onset
temperature at about 208.degree. C. In some embodiments, the
Compound 1 hemimucate salt has a differential scanning calorimetry
thermogram comprising an endotherm with an associated heat flow of
about 358 joules per gram. In some embodiments, the Compound 1
hemimucate salt has a differential scanning calorimetry thermogram
substantially as shown in FIG. 14, wherein by "substantially" is
meant that the reported DSC features can vary by about
.+-.6.degree. C. and by about .+-.20 joules per gram.
[0198] In some embodiments, the Compound 1 hemimucate salt has a
thermogravimetric analysis profile substantially as shown in FIG.
14, wherein by "substantially" is meant that the reported TGA
features can vary by about .+-.5.degree. C. and by about .+-.2%
weight change.
[0199] In some embodiments, the Compound 1 hemimucate salt has a
dynamic moisture sorption profile substantially as shown in FIG.
15, wherein by "substantially" is meant that the reported DMS
features can vary by about .+-.5% relative humidity and by about
.+-.5% weight change.
[0200] Form I of Compound 1 hemimucate salt can be prepared by any
of the suitable procedures known in the art for preparing
crystalline polymorphs. In some embodiments Form I of Compound 1
hemimucate salt can be prepared as described in Example 5. In some
embodiments, Form I of Compound 1 hemimucate salt can be prepared
by slurrying crystalline Compound 1 hemimucate salt containing one
or more crystalline forms other than Form I. In some embodiments,
Form I of Compound 1 hemimucate salt can be prepared by
recrystallizing crystalline Compound 1 hemimucate salt containing
one or more crystalline forms other than Form I.
Compound 1 Glucuronate Salt.
[0201] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
glucuronate, Form I (Compound 1 glucuronate salt, Form I). The
physical properties of Compound 1 glucuronate salt, Form I are
summarized in Table 11 below.
TABLE-US-00015 TABLE 11 Compound 1 Glucuronate Salt, Form I PXRD
FIG. 16: Peaks of 10 > % relative intensity at 5.59, 12.54,
16.46, 17.41, 18.40, 20.48, 20.69, 22.12, 26.66, 27.53, 27.85, and
29.57 .degree.2.theta. TGA FIG. 17: about 20% weight loss from
about 150.degree. C. to about 165.degree. C. DSC FIG. 17:
extrapolated onset temperature: 164.degree. C.; enthalpy of fusion
124 J/g DMS FIG. 18: 0.16% weight increase out to 90% RH
[0202] Compound 1 glucuronate salt was an anhydrous crystalline
material with melting onset of .about.164.degree. C. Based on rapid
weight loss of about 20% starting just prior to the melting onset,
this salt melted with degradation. It was non-hygroscopic by DMS
picking up about 0.16% out to and including the 90% RH hold at
25.degree. C.
[0203] Certain X-ray powder diffraction peaks for Form I of
Compound 1 glucuronate salt are shown in Table 12 below.
TABLE-US-00016 TABLE 12 Pos. (.degree.2.theta.) Rel. Int. (%) 5.59
71.04 11.10 1.23 12.54 55.77 13.43 2.10 14.79 5.71 16.46 100.00
17.41 42.46 18.09 7.55 18.40 58.29 19.10 1.99 20.48 55.27 20.69
30.98 22.12 22.45 22.90 8.02 23.98 3.46 24.20 4.29 24.68 9.76 25.13
6.41 25.94 2.74 26.66 10.40 27.26 5.26 27.53 10.09 27.85 14.59
28.19 7.69 28.64 2.99 29.39 9.66 29.57 12.34 30.47 5.19 31.42 9.83
31.98 5.74 32.84 6.85 33.55 5.41 34.78 3.60 35.28 4.12 35.68 4.57
37.18 5.03 37.42 6.79 38.44 4.53 38.68 4.38 39.21 5.43 39.58
4.06
[0204] One aspect of the present invention is directed to a
Compound 1 glucuronate salt having an X-ray powder diffraction
pattern comprising a peak, in terms of 2.theta., at about
16.46.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising a peak, in terms of
2.theta., at about 5.59.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
peaks, in terms of 2.theta., at about 16.46.degree. and about
5.59.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 16.46.degree. and about 18.40.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
16.46.degree., about 5.59.degree., and about 18.40.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
16.46.degree., about 5.59.degree., about 18.40.degree., about
12.54.degree., about 20.48.degree., about 17.41.degree., and about
20.69.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 16.46.degree., about 5.59.degree., about
18.40.degree., about 12.54.degree., about 20.48.degree., about
17.41.degree., about 20.69.degree., about 22.12.degree., about
27.85.degree., and about 29.57.degree.. One aspect of the present
invention is directed to a Compound 1 glucuronate salt having an
X-ray powder diffraction pattern comprising one or more peaks
listed in Table 12. In some embodiments, the crystalline form has
an X-ray powder diffraction pattern substantially as shown in FIG.
16, wherein by "substantially" is meant that the reported peaks can
vary by about .+-.0.2.degree.2.theta., and also that the relative
intensities of the reported peaks can vary.
[0205] In some embodiments, the Compound 1 glucuronate salt has a
differential scanning calorimetry thermogram comprising an
endotherm with an extrapolated onset temperature between about
150.degree. C. and about 180.degree. C. In some embodiments, the
Compound 1 glucuronate salt has a differential scanning calorimetry
thermogram comprising an endotherm with an extrapolated onset
temperature at about 164.degree. C. In some embodiments, the
Compound 1 glucuronate salt has a differential scanning calorimetry
thermogram comprising an endotherm with an associated heat flow of
about 124 joules per gram. In some embodiments, the Compound 1
glucuronate salt has a differential scanning calorimetry thermogram
substantially as shown in FIG. 17, wherein by "substantially" is
meant that the reported DSC features can vary by about
.+-.6.degree. C. and by about .+-.20 joules per gram.
[0206] In some embodiments, the Compound 1 glucuronate salt has a
thermogravimetric analysis profile substantially as shown in FIG.
17, wherein by "substantially" is meant that the reported TGA
features can vary by about .+-.5.degree. C. and by about .+-.2%
weight change.
[0207] In some embodiments, the Compound 1 glucuronate salt has a
dynamic moisture sorption profile substantially as shown in FIG.
18, wherein by "substantially" is meant that the reported DMS
features can vary by about .+-.5% relative humidity and by about
.+-.5% weight change.
Form I of Compound 1 glucuronate salt can be prepared by any of the
suitable procedures known in the art for preparing crystalline
polymorphs. In some embodiments Form I of Compound 1 glucuronate
salt can be prepared as described in Example 6. In some
embodiments, Form I of Compound 1 glucuronate salt can be prepared
by slurrying crystalline Compound 1 glucuronate salt containing one
or more crystalline forms other than Form I. In some embodiments,
Form I of Compound 1 glucuronate salt can be prepared by
recrystallizing crystalline Compound 1 glucuronate salt containing
one or more crystalline forms other than Form I.
Compound 1 Pyrogluconate Salt.
[0208] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
pyrogluconate, Form I (Compound 1 pyrogluconate salt, Form I). The
physical properties of Compound 1 pyrogluconate salt, Form I are
summarized in Table 13 below.
TABLE-US-00017 TABLE 13 Compound 1 Pyrogluconate Salt, Form I PXRD
FIG. 19: Peaks of >12% relative intensity at 6.78, 14.69, 16.50,
16.95, 17.61, 18.40, 18.80, 20.66, 22.72, 22.99, 24.47, and 27.84
.degree.2.theta. TGA FIG. 20: No significant weight loss prior to
melting DSC FIG. 20: extrapolated onset temperature: 139.degree.
C.; enthalpy of fusion 70.8 J/g DMS FIG. 21: 17-24% weight increase
at 70% RH, about 50% weight increase at 90% RH
[0209] Form I of Compound 1 pyrogluconate salt was a crystalline
solid with a small broad endotherm prior to a melting endotherm
with an onset at 139.degree. C. and heat of fusion of 70.8 J/g.
Prior to the melting onset there was minimal weight loss by TGA and
upon melting there was a gradual and complete weight loss,
indicating the isolated crystal phase was not a solvate.
[0210] Compound 1 pyroglutamate salt, Form I was hygroscopic above
approximately 50% RH, picking up during the adsorption cycle nearly
17% water at 70% RH, nearly 50% water out to and including the 90%
RH hold at 25.degree. C. and still gaining weight after 2 h at 90%
RH. The sample subsequently retained much of the water, even down
to 10% RH. The sample after removal from the dynamic
moisture-sorption analyzer was a sticky oil, so no further analysis
was performed.
[0211] Certain X-ray powder diffraction peaks for Form I of
Compound 1 pyrogluconate salt are shown in Table 14 below.
TABLE-US-00018 TABLE 14 Pos. (.degree.2.theta.) Rel. Int. (%) 6.78
100.00 8.23 1.01 8.81 0.12 9.81 1.29 11.46 10.49 13.52 8.13 14.69
12.51 14.93 0.29 15.64 0.69 16.50 13.75 16.95 29.48 17.61 19.64
18.40 28.95 18.80 42.64 19.34 9.09 19.64 4.51 19.74 4.37 20.31 6.19
20.66 25.68 21.43 9.44 22.20 2.03 22.72 21.94 22.99 15.93 24.47
26.51 24.66 6.06 25.11 4.29 25.65 1.49 25.95 2.44 26.31 0.97 26.77
9.30 27.15 3.37 27.84 15.61 27.95 9.89 28.79 1.85 29.39 10.02 29.66
2.60 30.20 1.19 30.72 5.02 31.41 4.47 32.37 1.31 32.47 1.18 32.88
1.48 33.53 4.21 33.93 1.51 34.12 3.03 34.21 3.29 34.77 0.82 35.08
0.22 35.57 3.35 36.30 0.45 36.55 1.29 36.89 1.92 37.49 2.67 38.05
1.53 38.57 0.08 39.05 0.39 39.25 0.16 39.78 1.97
[0212] One aspect of the present invention is directed to a
Compound 1 pyrogluconate salt having an X-ray powder diffraction
pattern comprising a peak, in terms of 2.theta., at about
6.78.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising a peak, in terms of
2.theta., at about 18.80.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
peaks, in terms of 2.theta., at about 6.78.degree. and about
18.80.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 6.78.degree. and about 16.95.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
6.78.degree., about 18.80.degree., and about 16.95.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
6.78.degree., about 18.80.degree., about 16.95.degree., about
18.40.degree., about 24.47.degree., about 20.66.degree., and about
22.72.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 6.78.degree., about 18.80.degree., about
16.95.degree., about 18.40.degree., about 24.47.degree., about
20.66.degree., about 22.72.degree., about 17.61.degree., about
22.99.degree., and about 27.84.degree.. One aspect of the present
invention is directed to a Compound 1 pyrogluconate salt having an
X-ray powder diffraction pattern comprising one or more peaks
listed in Table 14. In some embodiments, the crystalline form has
an X-ray powder diffraction pattern substantially as shown in FIG.
19, wherein by "substantially" is meant that the reported peaks can
vary by about .+-.0.2.degree.2.theta., and also that the relative
intensities of the reported peaks can vary.
[0213] In some embodiments, the Compound 1 pyrogluconate salt has a
differential scanning calorimetry thermogram comprising an
endotherm with an extrapolated onset temperature between about
120.degree. C. and about 150.degree. C. In some embodiments, the
Compound 1 pyrogluconate salt has a differential scanning
calorimetry thermogram comprising an endotherm with an extrapolated
onset temperature at about 139.degree. C. In some embodiments, the
Compound 1 pyrogluconate salt has a differential scanning
calorimetry thermogram comprising an endotherm with an associated
heat flow of about 73 joules per gram. In some embodiments, the
Compound 1 pyrogluconate salt has a differential scanning
calorimetry thermogram substantially as shown in FIG. 20, wherein
by "substantially" is meant that the reported DSC features can vary
by about .+-.6.degree. C. and by about .+-.20 joules per gram.
[0214] In some embodiments, the Compound 1 pyrogluconate salt has a
thermogravimetric analysis profile substantially as shown in FIG.
20, wherein by "substantially" is meant that the reported TGA
features can vary by about .+-.5.degree. C. and by about .+-.2%
weight change.
[0215] In some embodiments, the Compound 1 pyrogluconate salt has a
dynamic moisture sorption profile substantially as shown in FIG.
21, wherein by "substantially" is meant that the reported DMS
features can vary by about .+-.5% relative humidity and by about
.+-.5% weight change.
[0216] Form I of Compound 1 pyrogluconate salt can be prepared by
any of the suitable procedures known in the art for preparing
crystalline polymorphs. In some embodiments Form I of Compound 1
pyrogluconate salt can be prepared as described in Example 7. In
some embodiments, Form I of Compound 1 pyrogluconate salt can be
prepared by slurrying crystalline Compound 1 pyrogluconate salt
containing one or more crystalline forms other than Form I. In some
embodiments, Form I of Compound 1 pyrogluconate salt can be
prepared by recrystallizing crystalline Compound 1 pyrogluconate
salt containing one or more crystalline forms other than Form
I.
Compound 1 Di-Camphorate Salt Solvate.
[0217] One aspect of the present invention pertains to
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
di-camphorate salt solvate, Form I (Compound 1 di-camphorate salt
solvate, Form I). The physical properties of Compound 1
di-camphorate salt solvate, Form I are summarized in Table 15
below.
TABLE-US-00019 TABLE 15 Compound 1 Di-camphorate Salt Solvate, Form
I PXRD FIG. 22: Peaks of >25% relative intensity at 7.39, 7.80,
8.91, 13.01, 15.01, 15.20, 15.58, 15.70, 17.83, 23.00, and 23.25
.degree.2.theta. TGA FIG. 23: 4.135% weight loss up to about
110.degree. C. DSC FIG. 23: extrapolated onset temperature:
90.degree. C.; enthalpy of fusion 55 J/g DMS FIG. 24: 1.8% weight
increase out to 90% RH
[0218] Form I of Compound 1 di-camphorate salt solvate showed a
broad melting onset at approximately 90.degree. C. and an enthalpy
of fusion of 55 J/g by DSC. By TGA the sample lost approximately 4%
of its weight during melting/desolvation and continued to lose
weight after the melt.
[0219] During DMS analysis of Compound 1 di-camphorate salt solvate
the sample gained up to 1.8% weight in water out to and including
the 90% RH hold at 25.degree. C. Hysteresis was evident on the
desorption isotherm. The sample lost over 1.2% weight on the
desorption phase at 25.degree. C. and 10% RH, which had not been
removed during the drying step at 40.degree. C. and .about.1% RH.
After DMS analysis the sample remained a white solid, and the PXRD
pattern of this material was consistent with the original material
indicating that the crystalline phase did not change.
[0220] Certain X-ray powder diffraction peaks for Form I of
Compound 1 di-camphorate salt solvate are shown in Table 16
below.
TABLE-US-00020 TABLE 16 Pos. (.degree.2.theta.) Rel. Int. (%) 7.39
35.15 7.80 43.69 8.91 27.48 10.46 14.91 10.86 6.49 12.56 13.13
13.01 34.99 14.61 21.92 15.01 29.30 15.20 35.92 15.58 66.15 15.70
100.00 17.83 52.03 18.60 10.25 19.69 16.79 20.22 9.67 20.95 23.04
21.40 9.52 21.75 13.25 22.21 5.09 22.72 10.43 23.00 31.07 23.25
26.41 24.37 5.27 24.70 5.87 25.78 14.42 26.73 4.39 27.73 4.76 28.52
3.94 30.00 3.04 30.43 3.17 32.71 2.08 35.07 2.00 37.30 3.13
[0221] One aspect of the present invention is directed to a
Compound 1 di-camphorate salt solvate having an X-ray powder
diffraction pattern comprising a peak, in terms of 2.theta., at
about 15.70.degree.. In some embodiments, the crystalline form has
an X-ray powder diffraction pattern comprising a peak, in terms of
2.theta., at about 15.58.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
peaks, in terms of 2.theta., at about 15.70.degree. and about
15.58.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 15.70.degree. and about 17.83.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising peaks, in terms of 2.theta., at about
15.70.degree., about 15.58.degree., and about 17.83.degree.. In
some embodiments, the crystalline form has an X-ray powder
diffraction pattern comprising peaks, in terms of 2.theta., at
about 15.70.degree., about 15.58.degree., about 17.83.degree.,
about 7.80.degree., about 15.20.degree., about 7.39.degree., and
about 13.01.degree.. In some embodiments, the crystalline form has
an X-ray powder diffraction pattern comprising peaks, in terms of
2.theta., at about 15.70.degree., about 15.58.degree., about
17.83.degree., about 7.80.degree., about 15.20.degree., about
7.39.degree., about 13.01.degree., about 23.00.degree., about
15.01.degree., and about 8.91.degree.. One aspect of the present
invention is directed to a Compound 1 di-camphorate salt solvate
having an X-ray powder diffraction pattern comprising one or more
peaks listed in Table 16. In some embodiments, the crystalline form
has an X-ray powder diffraction pattern substantially as shown in
FIG. 22, wherein by "substantially" is meant that the reported
peaks can vary by about .+-.0.2.degree.2.theta., and also that the
relative intensities of the reported peaks can vary.
[0222] In some embodiments, the Compound 1 di-camphorate salt
solvate has a differential scanning calorimetry thermogram
comprising an endotherm with an extrapolated onset temperature
between about 75.degree. C. and about 105.degree. C. In some
embodiments, the Compound 1 di-camphorate salt solvate has a
differential scanning calorimetry thermogram comprising an
endotherm with an extrapolated onset temperature at about
90.degree. C. In some embodiments, the Compound 1 di-camphorate
salt solvate has a differential scanning calorimetry thermogram
comprising an endotherm with an associated heat flow of about 55
joules per gram. In some embodiments, the Compound 1 di-camphorate
salt solvate has a differential scanning calorimetry thermogram
substantially as shown in FIG. 23, wherein by "substantially" is
meant that the reported DSC features can vary by about
.+-.6.degree. C. and by about .+-.20 joules per gram.
[0223] In some embodiments, the Compound 1 di-camphorate salt
solvate has a thermogravimetric analysis profile substantially as
shown in FIG. 23, wherein by "substantially" is meant that the
reported TGA features can vary by about .+-.5.degree. C. and by
about .+-.2% weight change.
[0224] In some embodiments, the Compound 1 di-camphorate salt
solvate has a dynamic moisture sorption profile substantially as
shown in FIG. 24, wherein by "substantially" is meant that the
reported DMS features can vary by about .+-.5% relative humidity
and by about .+-.5% weight change.
[0225] Form I of Compound 1 di-camphorate salt solvate can be
prepared by any of the suitable procedures known in the art for
preparing crystalline polymorphs. In some embodiments Form I of
Compound 1 di-camphorate salt solvate can be prepared as described
in Example 8. In some embodiments, Form I of Compound 1
di-camphorate salt solvate can be prepared by slurrying crystalline
Compound 1 di-camphorate salt solvate containing one or more
crystalline forms other than Form I. In some embodiments, Form I of
Compound 1 di-camphorate salt solvate can be prepared by
recrystallizing crystalline Compound 1 di-camphorate salt solvate
containing one or more crystalline forms other than Form I.
[0226] One aspect of the present invention pertains to processes
for preparing a pharmaceutical composition comprising admixing a
crystalline salt of the present invention, and a pharmaceutically
acceptable carrier.
[0227] One aspect of the present invention pertains to processes
for preparing a bulk pharmaceutical composition comprising admixing
a crystalline salt of the present invention, and a pharmaceutically
acceptable carrier.
[0228] One aspect of the present invention pertains to methods for
weight management, comprising administering to an individual in
need thereof, a therapeutically effective amount of a crystalline
salt of the present invention.
[0229] One aspect of the present invention pertains to the use of
crystalline salts of the present invention, in the manufacture of a
medicament for weight management in an individual.
[0230] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of treatment of
the human or animal body by therapy.
[0231] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management.
[0232] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
loss.
[0233] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of maintenance
of weight loss.
[0234] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of decreasing
food consumption.
[0235] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of increasing
meal-related satiety.
[0236] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of reducing
pre-meal hunger.
[0237] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of reducing
intra-meal food intake.
[0238] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management further comprising a reduced-calorie diet.
[0239] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management further comprising a program of regular exercise.
[0240] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management further comprising a reduced-calorie diet and a program
of regular exercise.
[0241] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in an obese patient with an initial body mass index
.gtoreq.30 kg/m.sup.2.
[0242] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in an overweight patient with an initial body mass index
.gtoreq.27 kg/m.sup.2 in the presence of at least one weight
related co-morbid condition. One aspect of the present invention
pertains to crystalline salts of the present invention, for use in
a method of weight management in an overweight patient with an
initial body mass index .gtoreq.27 kg/m.sup.2 in the presence of at
least one weight related co-morbid condition selected from:
hypertension, dyslipidemia, cardiovascular disease, glucose
intolerance, and sleep apnea.
[0243] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in an individual with an initial body mass index
.gtoreq.30 kg/m.sup.2.
[0244] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in an individual with an initial body mass index
.gtoreq.27 kg/m.sup.2.
[0245] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in an individual with an initial body mass index
.gtoreq.27 kg/m.sup.2 in the presence of at least one weight
related co-morbid condition.
[0246] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in an individual with an initial body mass index
.gtoreq.27 kg/m.sup.2 in the presence of at least one weight
related co-morbid condition selected from:
[0247] hypertension, dyslipidemia, cardiovascular disease, glucose
intolerance, and sleep apnea.
[0248] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in an individual with an initial body mass index
.gtoreq.25 kg/m.sup.2.
[0249] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in an individual with an initial body mass index
.gtoreq.25 kg/m.sup.2 in the presence of at least one weight
related co-morbid condition.
[0250] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in an individual with an initial body mass index
.gtoreq.25 kg/m.sup.2 in the presence of at least one weight
related co-morbid condition selected from: hypertension,
dyslipidemia, cardiovascular disease, glucose intolerance, and
sleep apnea.
[0251] One aspect of the present invention pertains to crystalline
salts of the present invention, for use in a method of weight
management in combination with phentermine
Optical Resolution
[0252] Despite the large number of elaborate enantioselective
syntheses for the preparation of a single enantiomer to achieve
industrial and scientific goals, the separation and purification of
enantiomers (components of racemic compounds) is also
necessary.
[0253] Methods for resolving optical isomers include, without
limitation, spontaneous resolution, induced crystallization,
resolution by formation of diastereoisomers, resolution by
formation of non-covalent diastereoisomers, resolution by
diastereoisomeric salt formation, resolution by diastereoisomeric
complex formation, half equivalent methods of resolution,
separation by crystallization, separation by distillation,
separation by supercritical fluid extraction, resolution with
mixtures of resolving agents, resolution with a derivative of the
target compound, enantioselective chromatography, resolution by
formation of covalent diastereoisomers, resolution by substrate
selective reaction, kinetic resolution without enzymes, kinetic
resolution by enzyme catalysis, resolution by hydrolytic and redox
enzymes, kinetic and thermodynamic control, resolutions combined
with second-order asymmetric transformations, and enrichment of
partially resolved mixtures (Fogassy et al. Optical resolution
methods. Organic & Biomolecular Chemistry, (2006), 4(16),
3011-3030).
[0254] Resolution by diastereoisomeric salt formation is a popular
method for the resolution of bases. For example, dibenzoyl tartaric
acid (DBTA) and di-p-toluoyl tartaric acid (DPTA) are often used to
separate chiral bases (Kozma et al., Chirality, 1999, 11, 373). An
intermediate of the potent anticancer agent flavopyridol was
resolved with (R,R)-DBTA (Kim et al. J. Med. Chem., 2000, 43,
4126). cis-1-Amino-2-indanol, an intermediate for indinavir, was
resolved with (S)-2-phenylpropionic acid (Sakurai and Sakai,
Tetrahedron: Asymmetry, 2003, 14, 411),
3-methylamino-1-(2-thienyflpropan-1-ol, an intermediate for
duloxetine, was resolved with (S)-mandelic acid (Sakurai et al.,
Tetrahedron: Asymmetry, 2003, 14, 3713). Optimum conditions for the
resolution of N-methylamphetamine with DPTA (molar ratio, solvent,
etc.) were elaborated (Kozma et al., Chirality, 1999, 11, 373). A
similar investigation involving N-acetyl-phenylalanine as the
resolving agent for a series of benzodiazepines was recently
reported (Burnouf et al., J. Med. Chem., 2000, 43, 4850).
Camphorsulfonic acid was the resolving agent for a metabolite
[1-(3-hydroxy-4-methylphenyl)-2-methyl-3-(1-piperidyl)-propanone]
of tolperisone (Mint et al., Tetrahedron: Asymmetry, 2000, 11,
1323). Tolperisone enantiomers show different biological profiles:
while the R enantiomer is a bronchodilator, the S enantiomer is a
central muscle relaxant. (1R)-(+)-3-bromocamphor-8-sulfonic acid
[(R)-BRCS] is also an efficient resolving agent e.g. for a
tetrahydroquinoline intermediate of the antibacterial agent
flumequine (Balint et al., Tetrahedron: Asymmetry, 1999, 10, 1079).
Resolution of .beta.,.gamma.-unsaturated amines with
(S)-2,3-isopropylideneglycerol hemiphthalate is remarkable in that
the chiral center of the resolving agent is separated by six bonds
from the carboxyl group (Pallavicini et al., Tetrahedron:
Asymmetry, 2000, 11, 4017).
[0255] (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
can be prepared via fractional crystallization resolution of the
hemi-L-tartrate salt of
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Example 5).
Lorcaserin,
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hydrochloride, can be prepared by converting
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemi-L-tartrate salt to the free base and then treating with
HCl.
[0256] In view of the growing demand for compounds useful in the
treatment of disorders related to the 5-HT.sub.2C receptor, new
salt forms of racemic
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, with
optically active counterions are needed as intermediates in the
preparation of the corresponding hydrochloride salt. Salt forms of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with
optically active counterions are also useful for directly preparing
pharmaceutical compositions for the treatment of weight loss. In
such compositions the API is a salt form of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with an
optically active counterion. Salt forms of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with
optically active counterions can be prepared by treating Compound 1
with optically active acids, or by resolving salt forms of racemic
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with
optically active counterions into their diastereoisomers using
techniques well-known to one of ordinary skill in the art.
Hydrates and Solvates
[0257] It is understood that when the phrase "pharmaceutically
acceptable salts, solvates, and hydrates" or the phrase
"pharmaceutically acceptable salt, solvate, or hydrate" is used
when referring to compounds described herein, it embraces
pharmaceutically acceptable solvates and/or hydrates of the
compounds, pharmaceutically acceptable salts of the compounds, as
well as pharmaceutically acceptable solvates and/or hydrates of
pharmaceutically acceptable salts of the compounds. It is also
understood that when the phrase "pharmaceutically acceptable
solvates and hydrates" or the phrase "pharmaceutically acceptable
solvate or hydrate" is used when referring to compounds described
herein that are salts, it embraces pharmaceutically acceptable
solvates and/or hydrates of such salts.
[0258] It will be apparent to those skilled in the art that the
dosage forms described herein may comprise, as the active
component, either a salts or crystalline form thereof as described
herein, or a solvate or hydrate thereof. Moreover, various hydrates
and solvates of the salts or crystalline form thereof described
herein will find use as intermediates in the manufacture of
pharmaceutical compositions. Typical procedures for making and
identifying suitable hydrates and solvates, outside those mentioned
herein, are well known to those in the art; see for example, pages
202-209 of K. J. Guillory, "Generation of Polymorphs, Hydrates,
Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical
Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New
York, 1999.
[0259] Accordingly, one aspect of the present invention pertains to
methods of administering hydrates and solvates of salts or
crystalline forms thereof described herein and/or their
pharmaceutically acceptable salts, that can be isolated and
characterized by methods known in the art, such as,
thermogravimetric analysis (TGA), TGA-mass spectroscopy,
TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl
Fisher titration, high resolution X-ray diffraction, and the like.
There are several commercial entities that provide quick and
efficient services for identifying solvates and hydrates on a
routine basis. Example companies offering these services include
Wilmington PharmaTech (Wilmington, Del.), Avantium Technologies
(Amsterdam) and Aptuit (Greenwich, Conn.).
Isotopes
[0260] The present disclosure includes all isotopes of atoms
occurring in the present salts and crystalline forms thereof.
Isotopes include those atoms having the same atomic number but
different mass numbers. One aspect of the present invention
includes every combination of one or more atoms in the present
salts and crystalline forms thereof that is replaced with an atom
having the same atomic number but a different mass number. One such
example is the replacement of an atom that is the most naturally
abundant isotope, such as .sup.1H or .sup.12C, found in one the
present salts and crystalline forms thereof, with a different atom
that is not the most naturally abundant isotope, such as .sup.2H or
.sup.3H (replacing .sup.1H), or .sup.11C, .sup.13C, or .sup.14C
(replacing .sup.12C). A salt wherein such a replacement has taken
place is commonly referred to as being isotopically-labeled.
Isotopic-labeling of the present salts and crystalline forms
thereof can be accomplished using any one of a variety of different
synthetic methods know to those of ordinary skill in the art and
they are readily credited with understanding the synthetic methods
and available reagents needed to conduct such isotopic-labeling. By
way of general example, and without limitation, isotopes of
hydrogen include .sup.2H (deuterium) and .sup.3H (tritium).
Isotopes of carbon include .sup.11C, .sup.13C, and .sup.14C.
Isotopes of nitrogen include .sup.13N and .sup.15N. Isotopes of
oxygen include .sup.15O, .sup.17O, and .sup.18C. An isotope of
fluorine includes .sup.18F. An isotope of sulfur includes .sup.35S.
An isotope of chlorine includes .sup.36Cl. Isotopes of bromine
include .sup.75Br, .sup.76Br, .sup.77Br, and .sup.82Br. Isotopes of
iodine include .sup.123I, .sup.124I, .sup.125I, and .sup.131I.
Another aspect of the present invention includes compositions, such
as, those prepared during synthesis, preformulation, and the like,
and pharmaceutical compositions, such as, those prepared with the
intent of using in a mammal for the treatment of one or more of the
disorders described herein, comprising one or more of the present
salts and crystalline forms thereof, wherein the naturally
occurring distribution of the isotopes in the composition is
perturbed. Another aspect of the present invention includes
compositions and pharmaceutical compositions comprising salts and
crystalline forms thereof as described herein wherein the salt is
enriched at one or more positions with an isotope other than the
most naturally abundant isotope. Methods are readily available to
measure such isotope perturbations or enrichments, such as, mass
spectrometry, and for isotopes that are radio-isotopes additional
methods are available, such as, radio-detectors used in connection
with HPLC or GC.
Pharmaceutical Compositions
[0261] A further aspect of the present invention pertains to
pharmaceutical compositions comprising one or more salts according
to any of the salt embodiments disclosed herein and one or more
pharmaceutically acceptable carriers. Some embodiments pertain to
pharmaceutical compositions comprising a salt according to any of
the salt embodiments disclosed herein and a pharmaceutically
acceptable carrier. Some embodiments pertain to pharmaceutical
compositions comprising any subcombination of salts according to
any of the salt embodiments disclosed herein.
[0262] Another aspect of the present invention pertains to methods
of producing pharmaceutical compositions comprising admixing one or
more salts according to any of the salt embodiments disclosed
herein and one or more pharmaceutically acceptable carriers. Some
embodiments pertain to a method of producing a pharmaceutical
composition comprising admixing a salt according to any of the salt
embodiments disclosed herein and a pharmaceutically acceptable
carrier. Some embodiments pertain to a methods of producing
pharmaceutical compositions comprising admixing any subcombination
of salts according to any of the salt embodiments disclosed herein
and a pharmaceutically acceptable carrier.
[0263] Formulations may be prepared by any suitable method,
typically by uniformly mixing the active salt(s) with liquids or
finely divided solid carriers, or both, in the required proportions
and then, if necessary, forming the resulting mixture into a
desired shape.
[0264] Conventional excipients, such as binding agents, fillers,
acceptable wetting agents, tabletting lubricants and disintegrants
may be used in tablets and capsules for oral administration. Liquid
preparations for oral administration may be in the form of
solutions, emulsions, aqueous or oily suspensions and syrups.
Alternatively, the oral preparations may be in the form of dry
powder that can be reconstituted with water or another suitable
liquid vehicle before use. Additional additives such as suspending
or emulsifying agents, non-aqueous vehicles (including edible
oils), preservatives and flavorings and colorants may be added to
the liquid preparations. Parenteral dosage forms may be prepared by
dissolving the salt of the invention in a suitable liquid vehicle
and filter sterilizing the solution before filling and sealing an
appropriate vial or ampule. These are just a few examples of the
many appropriate methods well known in the art for preparing dosage
forms.
[0265] The salts of the present invention can be formulated into
pharmaceutical compositions and bulk pharmaceutical compositions
suitable for the manufacture of dosage forms using techniques well
known to those in the art. Suitable pharmaceutically-acceptable
carriers, outside those mentioned herein, are known in the art; for
example, see Remington, The Science and Practice of Pharmacy,
20.sup.th Edition, 2000, Lippincott Williams & Wilkins,
(Editors: Gennaro et al.)
[0266] While it is possible that, for use in the prophylaxis or
treatment, a salt of the invention may, in an alternative use, be
administered as a raw or pure chemical, it is preferable however to
present the salt or active ingredient as a pharmaceutical
formulation or composition further comprising a pharmaceutically
acceptable carrier.
[0267] Pharmaceutical formulations include those suitable for oral,
rectal, nasal, topical (including buccal and sub-lingual), vaginal
or parenteral (including intramuscular, subcutaneous and
intravenous) administration or in a form suitable for
administration by inhalation, insufflation or by a transdermal
patch. Transdermal patches dispense a drug at a controlled rate by
presenting the drug for absorption in an efficient manner with
minimal degradation of the drug. Typically, transdermal patches
comprise an impermeable backing layer, a single pressure sensitive
adhesive and a removable protective layer with a release liner. One
of ordinary skill in the art will understand and appreciate the
techniques appropriate for manufacturing a desired efficacious
transdermal patch based upon the needs of the artisan.
[0268] The salts of the invention, together with a conventional
adjuvant, carrier, or diluent, may thus be placed into the form of
pharmaceutical formulations and unit dosages thereof and in such
form may be employed as solids, such as tablets or filled capsules,
or liquids such as solutions, suspensions, emulsions, elixirs, gels
or capsules filled with the same, all for oral use, in the form of
suppositories for rectal administration; or in the form of sterile
injectable solutions for parenteral (including subcutaneous) use.
Such pharmaceutical compositions and unit dosage forms thereof may
comprise conventional ingredients in conventional proportions, with
or without additional active compounds or principles and such unit
dosage forms may contain any suitable effective amount of the
active ingredient commensurate with the intended daily dosage range
to be employed.
[0269] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are capsules, tablets,
powders, granules or a suspension, with conventional additives such
as lactose, mannitol, corn starch or potato starch; with binders
such as crystalline cellulose, cellulose derivatives, acacia, corn
starch or gelatins; with disintegrators such as corn starch, potato
starch or sodium carboxymethyl-cellulose; and with lubricants such
as talc or magnesium stearate. The active ingredient may also be
administered by injection as a composition wherein, for example,
saline, dextrose or water may be used as a suitable
pharmaceutically acceptable carrier.
[0270] Salts of the present invention or a solvate, hydrate or
physiologically functional derivative thereof can be used as active
ingredients in pharmaceutical compositions, specifically as
5-HT.sub.2C-receptor modulators. The term "active ingredient" as
defined in the context of a "pharmaceutical composition" and is
intended to mean a component of a pharmaceutical composition that
provides the primary pharmacological effect, as opposed to an
"inactive ingredient" which would generally be recognized as
providing no pharmaceutical benefit.
[0271] The dose when using the salts of the present invention can
vary within wide limits and as is customary and is known to the
physician, it is to be tailored to the individual conditions in
each individual case. It depends, for example, on the nature and
severity of the illness to be treated, on the condition of the
patient, on the salt employed or on whether an acute or chronic
disease state is treated or prophylaxis conducted or on whether
further active compounds are administered in addition to the salts
of the present invention. Representative doses of the present
invention include, but are not limited to, about 0.001 mg to about
5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about
1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about
0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001
mg to about 25 mg. Multiple doses may be administered during the
day, especially when relatively large amounts are deemed to be
needed, for example 2, 3 or 4 doses. Depending on the individual
and as deemed appropriate from the patient's physician or caregiver
it may be necessary to deviate upward or downward from the doses
described herein.
[0272] The amount of active ingredient, or an active salt or
derivative thereof, required for use in treatment will vary not
only with the particular salt selected but also with the route of
administration, the nature of the condition being treated and the
age and condition of the patient and will ultimately be at the
discretion of the attendant physician or clinician. In general, one
skilled in the art understands how to extrapolate in vivo data
obtained in a model system, typically an animal model, to another,
such as a human. In some circumstances, these extrapolations may
merely be based on the weight of the animal model in comparison to
another, such as a mammal, preferably a human, however, more often,
these extrapolations are not simply based on weights, but rather
incorporate a variety of factors. Representative factors include
the type, age, weight, sex, diet and medical condition of the
patient, the severity of the disease, the route of administration,
pharmacological considerations such as the activity, efficacy,
pharmacokinetic and toxicology profiles of the particular salt
employed, whether a drug delivery system is utilized, on whether an
acute or chronic disease state is being treated or prophylaxis
conducted or on whether further active compounds are administered
in addition to the salts of the present invention and as part of a
drug combination. The dosage regimen for treating a disease
condition with the salts and/or compositions of this invention is
selected in accordance with a variety factors as cited above. Thus,
the actual dosage regimen employed may vary widely and therefore
may deviate from a preferred dosage regimen and one skilled in the
art will recognize that dosage and dosage regimen outside these
typical ranges can be tested and, where appropriate, may be used in
the methods of this invention.
[0273] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations. The daily dose can be
divided, especially when relatively large amounts are administered
as deemed appropriate, into several, for example 2, 3 or 4 part
administrations. If appropriate, depending on individual behavior,
it may be necessary to deviate upward or downward from the daily
dose indicated.
[0274] The salts of the present invention can be administrated in a
wide variety of oral and parenteral dosage forms. It will be
obvious to those skilled in the art that the following dosage forms
may comprise, as the active component, either a salt of the
invention or a solvate or hydrate of a salt of the invention.
[0275] For preparing pharmaceutical compositions from the compounds
of the present invention, the selection of a suitable
pharmaceutically acceptable carrier can be either solid, liquid or
a mixture of both. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0276] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component.
[0277] In tablets, the active component is mixed with the carrier
having the necessary binding capacity in suitable proportions and
compacted to the desire shape and size.
[0278] The powders and tablets may contain varying percentage
amounts of the active salt. A representative amount in a powder or
tablet may contain from 0.5 to about 90 percent of the active salt;
however, an artisan would know when amounts outside of this range
are necessary. Suitable carriers for powders and tablets are
magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter and
the like. The term "preparation" is intended to include the
formulation of the active salt with encapsulating material as
carrier providing a capsule in which the active component, with or
without carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets and lozenges can be used
as solid forms suitable for oral administration.
[0279] For preparing suppositories, a low melting wax, such as an
admixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool and thereby to
solidify.
[0280] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
sprays containing in addition to the active ingredient such
carriers as are known in the art to be appropriate.
[0281] Liquid form preparations include solutions, suspensions and
emulsions, for example, water or water-propylene glycol solutions.
For example, parenteral injection liquid preparations can be
formulated as solutions in aqueous polyethylene glycol solution.
Injectable preparations, for example, sterile injectable aqueous or
oleaginous suspensions may be formulated according to the known art
using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable
solution or suspension in a nontoxic parenterally acceptable
diluent or solvent, for example, as a solution in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0282] The compounds according to the present invention may thus be
formulated for parenteral administration (e.g. by injection, for
example bolus injection or continuous infusion) and may be
presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with an added
preservative. The pharmaceutical compositions may take such forms
as suspensions, solutions, or emulsions in oily or aqueous vehicles
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents. Alternatively, the active ingredient may
be in powder form, obtained by aseptic isolation of sterile solid
or by lyophilization from solution, for constitution with a
suitable vehicle, e.g. sterile, pyrogen-free water, before use.
[0283] Aqueous formulations suitable for oral use can be prepared
by dissolving or suspending the active component in water and
adding suitable colorants, flavors, stabilizing and thickening
agents, as desired.
[0284] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, or other well-known
suspending agents. Also included are solid form preparations which
are intended to be converted, shortly before use, to liquid form
preparations for oral administration. Such liquid forms include
solutions, suspensions and emulsions. These preparations may
contain, in addition to the active component, colorants, flavors,
stabilizers, buffers, artificial and natural sweeteners,
dispersants, thickeners, solubilizing agents and the like.
[0285] For topical administration to the epidermis the salts
according to the invention may be formulated as ointments, creams
or lotions, or as a transdermal patch.
[0286] Ointments and creams may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening
and/or gelling agents. Lotions may be formulated with an aqueous or
oily base and will in general also contain one or more emulsifying
agents, stabilizing agents, dispersing agents, suspending agents,
thickening agents, or coloring agents.
[0287] Formulations suitable for topical administration in the
mouth include lozenges comprising active agent in a flavored base,
usually sucrose and acacia or tragacanth; pastilles comprising the
active ingredient in an inert base such as gelatin and glycerin or
sucrose and acacia; and mouthwashes comprising the active
ingredient in a suitable liquid carrier.
[0288] Solutions or suspensions are applied directly to the nasal
cavity by conventional means, for example with a dropper, pipette
or spray. The formulations may be provided in single or multi-dose
form. In the latter case of a dropper or pipette, this may be
achieved by the patient administering an appropriate, predetermined
volume of the solution or suspension. In the case of a spray, this
may be achieved for example by means of a metering atomizing spray
pump.
[0289] Administration to the respiratory tract may also be achieved
by means of an aerosol formulation in which the active ingredient
is provided in a pressurized pack with a suitable propellant. If
the salts of the present invention or pharmaceutical compositions
comprising them are administered as aerosols, for example as nasal
aerosols or by inhalation, this can be carried out, for example,
using a spray, a nebulizer, a pump nebulizer, an inhalation
apparatus, a metered inhaler or a dry powder inhaler.
Pharmaceutical forms for administration of the salts of the present
invention as an aerosol can be prepared by processes well known to
the person skilled in the art. For their preparation, for example,
solutions or dispersions of the salts of the present invention in
water, water/alcohol mixtures or suitable saline solutions can be
employed using customary additives, for example benzyl alcohol or
other suitable preservatives, absorption enhancers for increasing
the bioavailability, solubilizers, dispersants and others and, if
appropriate, customary propellants, for example include carbon
dioxide, CFCs, such as, dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane; and the like.
The aerosol may conveniently also contain a surfactant such as
lecithin. The dose of drug may be controlled by provision of a
metered valve.
[0290] In formulations intended for administration to the
respiratory tract, including intranasal formulations, the salt will
generally have a small particle size for example of the order of 10
microns or less. Such a particle size may be obtained by means
known in the art, for example by micronization. When desired,
formulations adapted to give sustained release of the active
ingredient may be employed.
[0291] Alternatively the active ingredients may be provided in the
form of a dry powder, for example, a powder mix of the salt in a
suitable powder base such as lactose, starch, starch derivatives
such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone
(PVP). Conveniently the powder carrier will form a gel in the nasal
cavity. The powder composition may be presented in unit dose form
for example in capsules or cartridges of, e.g., gelatin, or blister
packs from which the powder may be administered by means of an
inhaler.
[0292] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0293] Tablets or capsules for oral administration and liquids for
intravenous administration are preferred compositions.
[0294] Some embodiments of the present invention include a method
of producing a pharmaceutical composition for "combination-therapy"
comprising admixing at least one salt according to any of the salt
embodiments disclosed herein, together with at least one known
pharmaceutical agent as described herein and a pharmaceutically
acceptable carrier.
[0295] It is noted that when the salts of the present invention are
utilized as active ingredients in a pharmaceutical composition,
these are not intended for use only in humans, but in other
non-human mammals as well. Indeed, recent advances in the area of
animal health-care mandate that consideration be given for the use
of active agents, such as 5-HT.sub.2C-receptor modulators, for the
treatment of a 5-HT.sub.2C-receptor-associated disease or disorders
in companionship animals (e.g., cats, dogs, etc.) and in livestock
animals (e.g., cows, chickens, fish, etc.). Those of ordinary skill
in the art are readily credited with understanding the utility of
such salts in such settings.
[0296] One aspect of the present invention pertains to methods for
weight management, comprising administering to an individual in
need thereof, a therapeutically effective amount of a
pharmaceutical composition of the present invention.
[0297] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of treatment of the human or animal body by therapy.
[0298] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management.
[0299] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight loss.
[0300] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of maintenance of weight loss.
[0301] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of decreasing food consumption.
[0302] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of increasing meal-related satiety.
[0303] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of reducing pre-meal hunger.
[0304] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of reducing intra-meal food intake.
[0305] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management further comprising a reduced-calorie
diet.
[0306] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management further comprising a program of regular
exercise.
[0307] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management further comprising a reduced-calorie
diet and a program of regular exercise.
[0308] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in an obese patient with an initial
body mass index .gtoreq.30 kg/m.sup.2.
[0309] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in an overweight patient with an
initial body mass index .gtoreq.27 kg/m.sup.2 in the presence of at
least one weight related co-morbid condition.
[0310] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in an overweight patient with an
initial body mass index .gtoreq.27 kg/m.sup.2 in the presence of at
least one weight related co-morbid condition selected from:
hypertension, dyslipidemia, cardiovascular disease, glucose
intolerance, and sleep apnea.
[0311] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.30 kg/m.sup.2.
[0312] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.27 kg/m.sup.2.
[0313] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.27 kg/m.sup.2 in the presence of at least one
weight related co-morbid condition.
[0314] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.27 kg/m.sup.2 in the presence of at least one
weight related co-morbid condition selected from: hypertension,
dyslipidemia, cardiovascular disease, glucose intolerance, and
sleep apnea.
[0315] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.25 kg/m.sup.2.
[0316] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.25 kg/m.sup.2 in the presence of at least one
weight related co-morbid condition. One aspect of the present
invention pertains to pharmaceutical compositions of the present
invention, for use in a method of weight management in an
individual with an initial body mass index .gtoreq.25 kg/m.sup.2 in
the presence of at least one weight related co-morbid condition
selected from: hypertension, dyslipidemia, cardiovascular disease,
glucose intolerance, and sleep apnea.
[0317] One aspect of the present invention pertains to
pharmaceutical compositions of the present invention, for use in a
method of weight management in combination with phentermine.
Indications
[0318] Obesity is a life-threatening disorder in which there is an
increased risk of morbidity and mortality arising from concomitant
diseases such as, but not limited to, type II diabetes,
hypertension, stroke, certain forms of cancers and gallbladder
disease.
[0319] Obesity has become a major healthcare issue in the Western
World and increasingly in some third world countries. The increase
in the number of obese people is due largely to the increasing
preference for high fat content foods but also, and this can be a
more important factor, the decrease in activity in most people's
lives. In spite of the growing awareness of the health concerns
linked to obesity the percentage of individuals that are overweight
or obese continues to increase. The most significant concern, from
a public health perspective, is that children who are overweight
grow up to be overweight or obese adults, and accordingly are at
greater risk for major health problems. Therefore, it appears that
the number of individuals that are overweight or obese will
continue to increase.
[0320] Whether someone is classified as overweight or obese is
generally determined on the basis of his or her body mass index
(BMI) which is calculated by dividing body weight (kg) by height
squared (m.sup.2). Thus, the units for BMI are kg/m.sup.2. BMI is
more highly correlated with body fat than any other indicator of
height and weight. A person is considered overweight when they have
a BMI in the range of 25-30 kg/m.sup.2, whereas a person with a BMI
over 30 kg/m.sup.2 is classified as obese. Obesity is further
divided into three classes: Class I (BMI of about 30 to about 34.9
kg/m.sup.2), Class II (BMI of about 35 to 39.9 kg/m.sup.2) and
Class III (about 40 kg/m.sup.2 or greater); see Table below for
complete classifications.
TABLE-US-00021 Classification Of Weight By Body Mass Index (BMI)
BMI CLASSIFICATION <18.5 Underweight 18.5-24.9 Normal 25.0-29.9
Overweight 30.0-34.9 Obesity (Class I) 35.0-39.9 Obesity (Class II)
>40 Extreme Obesity (Class III)
[0321] As the BMI increases for an individual there is an increased
risk of morbidity and mortality relative to an individual with
normal BMI. Accordingly, overweight and obese individuals (BMI of
about 25 kg/m.sup.2 and above) are at increased risk for physical
ailments such as, but not limited to, high blood pressure,
cardiovascular disease (particularly hypertension), high blood
cholesterol, dyslipidemia, type II (non-insulin dependent)
diabetes, insulin resistance, glucose intolerance,
hyperinsulinemia, coronary heart disease, angina pectoris,
congestive heart failure, stroke, gallstones, cholescystitis and
cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and
respiratory problems, some types of cancer (such as endometrial,
breast, prostate, and colon), complications of pregnancy, poor
female reproductive health (such as menstrual irregularities,
infertility, irregular ovulation), diseases of reproduction (such
as sexual dysfunction, both male and female, including male
erectile dysfunction), bladder control problems (such as stress
incontinence), uric acid nephrolithiasis, psychological disorders
(such as depression, eating disorders, distorted body image, and
low self esteem). Research has shown that even a modest reduction
in body weight can correspond to a significant reduction in the
risk of developing other ailments, such as, but not limited to,
coronary heart disease. As mentioned above, obesity increases the
risk of developing cardiovascular diseases.
[0322] Coronary insufficiency, atheromatous disease, and cardiac
insufficiency are at the forefront of the cardiovascular
complications induced by obesity. The incidence of coronary
diseases is doubled in subjects less than 50 years of age who are
30% overweight. The diabetes patient faces a 30% reduced lifespan.
After age 45, people with diabetes are about three times more
likely than people without diabetes to have significant heart
disease and up to five times more likely to have a stroke. These
findings emphasize the inter-relations between risks factors for
type 2 diabetes and coronary heart disease and the potential value
of an integrated approach to the prevention of these conditions
based on the prevention of obesity [Perry, I. J., et al. BMJ 310,
560-564 (1995)]. It is estimated that if the entire population had
an ideal weight, the risk of coronary insufficiency would decrease
by 25% and the risk of cardiac insufficiency and of cerebral
vascular accidents by 35%.
[0323] Diabetes has also been implicated in the development of
kidney disease, eye diseases and nervous-system problems. Kidney
disease, also called nephropathy, occurs when the kidney's "filter
mechanism" is damaged and protein leaks into urine in excessive
amounts and eventually the kidney fails. Diabetes is also a leading
cause of damage to the retina and increases the risk of cataracts
and glaucoma. Finally, diabetes is associated with nerve damage,
especially in the legs and feet, which interferes with the ability
to sense pain and contributes to serious infections. Taken
together, diabetes complications are one of the nation's leading
causes of death.
[0324] The first line of treatment for individuals that are
overweight or obese is to offer diet and life style advice, such
as, reducing the fat content of their diet and increasing their
physical activity. However many patients find these difficult to
maintain and need additional help from drug therapy to sustain
results from these efforts.
[0325] Most currently marketed products have been unsuccessful as
treatments for obesity owing to a lack of efficacy or unacceptable
side-effect profiles. The most successful drug so far was the
indirectly acting 5-hydroxytryptamine (5-HT) agonist d-fenfluramine
(Redux.TM.) but reports of cardiac valve defects in up to one third
of the patient population led to its withdrawal by the FDA in
1998.
[0326] The 5-HT.sub.2C receptor is recognized as a well-accepted
receptor target for the treatment of obesity, psychiatric, and
other disorders. See, for example, Halford et al., Serotonergic
Drugs Effects on Appetite Expression and Use for the Treatment of
Obesity, Drugs 2007; 67 (1): 27-55; Naughton et al., A Review Of
The Role Of Serotonin Receptors In Psychiatric Disorders. Human
Psychopharmacology (2000), 15(6), 397-415.
[0327] (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hydrochloride (lorcaserin hydrochloride) is an agonist of the
5-HT.sub.2C receptor and shows effectiveness at reducing obesity in
animal models and humans. In a phase 3 human clinical trial
evaluating the safety and efficacy of lorcaserin for weight
management, statistical significance (p<0.0001) was achieved on
all three of the hierarchically ordered co-primary endpoints for
patients treated with lorcaserin versus placebo. Treatment with
lorcaserin was generally very well tolerated. An assessment of
echocardiograms indicated no apparent drug-related effect on the
development of US Food and Drug Administration (FDA)-defined
valvulopathy over the two-year treatment period. The hierarchically
ordered endpoints were the proportion of patients achieving 5% or
greater weight loss after 12 months, the difference in mean weight
loss compared to placebo after 12 months, and the proportion of
patients achieving 10% or greater weight loss after 12 months.
Compared to placebo, using an intent-to-treat last observation
carried forward (ITT-LOCF) analysis, treatment with lorcaserin was
associated with highly statistically significant (p<0.0001)
categorical and average weight loss from baseline after 12 months:
47.5% of lorcaserin patients lost greater than or equal to 5% of
their body weight from baseline compared to 20.3% in the placebo
group. This result satisfied the efficacy benchmark in the most
recent FDA draft guidance. Average weight loss of 5.8% of body
weight, or 12.7 pounds, was achieved in the lorcaserin group,
compared to 2.2% of body weight, or 4.7 pounds, in the placebo
group. Statistical separation from placebo was observed by Week 2,
the first post-baseline measurement. 22.6% of lorcaserin patients
lost greater than or equal to 10% of their body weight from
baseline, compared to 7.7% in the placebo group. Lorcaserin
patients who completed 52 weeks of treatment according to the
protocol lost an average of 8.2% of body weight, or 17.9 pounds,
compared to 3.4%, or 7.3 pounds, in the placebo group
(p<0.0001).
[0328] In addition, the 5-HT.sub.2C receptor is also involved in
other diseases, conditions and disorders, such as, obsessive
compulsive disorder, some forms of depression, and epilepsy.
Accordingly, 5-HT.sub.2C receptor agonists can have anti-panic
properties, and properties useful for the treatment of sexual
dysfunction. In addition, 5-HT.sub.2C receptor agonists are useful
for the treatment of psychiatric symptoms and behaviors in
individuals with eating disorders such as, but not limited to,
anorexia nervosa and bulimia nervosa. Individuals with anorexia
nervosa often demonstrate social isolation. Anorexic individuals
often present symptoms of being depressed, anxious, obsession,
perfectionistic traits, and rigid cognitive styles as well as
sexual disinterest. Other eating disorders include, anorexia
nervosa, bulimia nervosa, binge eating disorder (compulsive eating)
and ED-NOS (i.e., eating disorders not otherwise specified--an
official diagnosis). An individual diagnosed with ED-NOS possess
atypical eating disorders including situations in which the
individual meets all but a few of the criteria for a particular
diagnosis. What the individual is doing with regard to food and
weight is neither normal nor healthy.
[0329] The 5-HT.sub.2C receptor plays a role in Alzheimer Disease
(AD). Therapeutic agents currently prescribed for Alzheimer's
disease (AD) are cholinomimetic agents that act by inhibiting the
enzyme acetylcholinesterase. The resulting effect is increased
levels of acetylcholine, which modestly improves neuronal function
and cognition in patients with AD. Although, dysfunction of
cholinergic brain neurons is an early manifestation of AD, attempts
to slow the progression of the disease with these agents have had
only modest success, perhaps because the doses that can be
administered are limited by peripheral cholinergic side effects,
such as tremors, nausea, vomiting, and dry mouth. In addition, as
AD progresses, these agents tend to lose their effectiveness due to
continued cholinergic neuronal loss.
[0330] Therefore, there is a need for agents that have beneficial
effects in AD, particularly in alleviating symptoms by improving
cognition and slowing or inhibiting disease progression, without
the side effects observed with current therapies. Therefore,
serotonin 5-HT.sub.2C receptors, which are exclusively expressed in
brain, are attractive targets.
[0331] Another disease, disorder or condition that can is
associated with the function of the 5-HT.sub.2C receptor is
erectile dysfunction (ED). Erectile dysfunction is the inability to
achieve or maintain an erection sufficiently rigid for intercourse,
ejaculation, or both. An estimated 20-30 million men in the United
States have this condition at some time in their lives. The
prevalence of the condition increases with age. Five percent of men
40 years of age report ED. This rate increases to between 15% and
25% by the age of 65, and to 55% in men over the age of 75
years.
[0332] Erectile dysfunction can result from a number of distinct
problems. These include loss of desire or libido, the inability to
maintain an erection, premature ejaculation, lack of emission, and
inability to achieve an orgasm. Frequently, more than one of these
problems presents themselves simultaneously. The conditions may be
secondary to other disease states (typically chronic conditions),
the result of specific disorders of the urogenital system or
endocrine system, secondary to treatment with pharmacological
agents (e.g. antihypertensive drugs, antidepressant drugs,
antipsychotic drugs, etc.) or the result of psychiatric problems.
Erectile dysfunction, when organic, is primarily due to vascular
irregularities associated with atherosclerosis, diabetes, and
hypertension.
[0333] There is evidence for use of a serotonin 5-HT.sub.2C agonist
for the treatment of sexual dysfunction in males and females. The
serotonin 5-HT.sub.2C receptor is involved with the processing and
integration of sensory information, regulation of central
monoaminergic systems, and modulation of neuroendocrine responses,
anxiety, feeding behavior, and cerebrospinal fluid production
[Tecott, L. H., et al. Nature 374: 542-546 (1995)]. In addition,
the serotonin 5-HT.sub.2C receptor has been implicated in the
mediation of penile erections in rats, monkeys, and humans.
[0334] In summary, the 5-HT.sub.2C receptor is a validated and
well-accepted receptor target for the prophylaxis and/or treatment
of 5-HT.sub.2C mediated receptor diseases and disorders, such as,
obesity, eating disorders, psychiatric disorders, Alzheimer
Disease, sexual dysfunction and disorders related thereto. It can
be seen that there exists a need for selective 5-HT.sub.2C receptor
agonists that can safely address these needs. The present invention
is directed to these, as well as other, important ends.
[0335] One aspect of the present invention pertains to methods for
weight management, comprising administering to an individual in
need thereof, a therapeutically effective amount of a salt, a
pharmaceutical composition, or a dosage form of the present
invention.
[0336] One aspect of the present invention pertains to methods for
weight management, comprising administering to an individual in
need thereof, a therapeutically effective amount of a salt or a
pharmaceutical composition of the present invention.
[0337] In some embodiments, the weight management comprises weight
loss.
[0338] In some embodiments, the weight management comprises
maintenance of weight loss.
[0339] In some embodiments, the weight management comprises
decreased food consumption.
[0340] In some embodiments, the weight management comprises
increasing meal-related satiety.
[0341] In some embodiments, the weight management comprises
reducing pre-meal hunger.
[0342] In some embodiments, the weight management comprises
reducing intra-meal food intake.
[0343] In some embodiments, the weight management further comprises
a reduced-calorie diet. In some embodiments, the weight management
further comprises a program of regular exercise.
[0344] In some embodiments, the weight management further comprises
both a reduced-calorie diet and a program of regular exercise.
[0345] In some embodiments, the individual in need of weight
management is an obese patient with an initial body mass index
.gtoreq.30 kg/m.sup.2.
[0346] In some embodiments, the individual in need of weight
management is an overweight patient with an initial body mass index
.gtoreq.27 kg/m.sup.2 in the presence of at least one weight
related comorbid condition.
[0347] In some embodiments, the individual in need of weight
management is an overweight patient with an initial body mass index
.gtoreq.27 kg/m.sup.2 in the presence of at least one weight
related comorbid condition selected from: hypertension,
dyslipidemia, cardiovascular disease, glucose intolerance, and
sleep apnea.
[0348] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.30
kg/m.sup.2.
[0349] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.27
kg/m.sup.2.
[0350] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.27 kg/m.sup.2 in
the presence of at least one weight related comorbid condition.
[0351] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.27 kg/m.sup.2 in
the presence of at least one weight related comorbid condition
selected from: hypertension, dyslipidemia, cardiovascular disease,
glucose intolerance, and sleep apnea.
[0352] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.25
kg/m.sup.2.
[0353] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.25 kg/m.sup.2 in
the presence of at least one weight related comorbid condition.
[0354] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.25 kg/m.sup.2 in
the presence of at least one weight related comorbid condition
selected from: hypertension, dyslipidemia, cardiovascular disease,
glucose intolerance, and sleep apnea.
[0355] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 20
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0356] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 20
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0357] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 21
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0358] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 21
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0359] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 22
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0360] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 22
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0361] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 23
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0362] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 23
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0363] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 24
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0364] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 24
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0365] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 25
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0366] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 25
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0367] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 26
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0368] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 26
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0369] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 27
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0370] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 27
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0371] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 28
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0372] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 28
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0373] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 29
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0374] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 29
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0375] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 30
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0376] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 30
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0377] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 31
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0378] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 31
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0379] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 32
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0380] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 32
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0381] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 33
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0382] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 33
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0383] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 34
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0384] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 34
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0385] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 35
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0386] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 35
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0387] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 36
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0388] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 36
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0389] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 37
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0390] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 37
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0391] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 38
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0392] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 38
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0393] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 39
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0394] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 39
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0395] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 40
kg/m.sup.2 in the presence of at least one weight related comorbid
condition.
[0396] In some embodiments, the individual in need of weight
management has an initial body mass index .gtoreq.about 40
kg/m.sup.2 in the presence of at least one weight related comorbid
condition selected from: hypertension, dyslipidemia, cardiovascular
disease, glucose intolerance, and sleep apnea.
[0397] In some embodiments, the method for weight management
further comprises administering phentermine to the individual.
[0398] One aspect of the present invention pertains to methods for
the treatment of a disorder related to 5-HT.sub.2C receptor
activity in an individual, comprising administering to an
individual in need thereof, a therapeutically effective amount of a
salt or a pharmaceutical composition of the present invention.
[0399] One aspect of the present invention pertains to methods for
the treatment of obesity, comprising administering to an individual
in need thereof, a therapeutically effective amount of a salt or a
pharmaceutical composition of the present invention.
[0400] In some embodiments, the method for the treatment of obesity
further comprises the administration or prescription of
phentermine.
[0401] In some embodiments, the method for the treatment of obesity
further comprises gastric electrical stimulation.
[0402] One aspect of the present invention pertains to methods for
inducing weight loss, BMI loss, waist circumference loss or body
fat percentage loss, comprising administering to an individual in
need thereof, a therapeutically effective amount of a salt or a
pharmaceutical composition of the present invention.
[0403] One aspect of the present invention pertains to methods for
inducing weight loss, BMI loss, waist circumference loss or body
fat percentage loss in an individual in preparation of the
individual for bariatric surgery, comprising administering to an
individual in need thereof, a therapeutically effective amount of a
salt or a pharmaceutical composition of the present invention.
[0404] One aspect of the present invention pertains to methods for
maintaining weight loss, BMI loss, waist circumference loss or body
fat percentage loss in an individual, comprising administering to
an individual in need thereof, a therapeutically effective amount
of a salt or a pharmaceutical composition of the present
invention.
[0405] One aspect of the present invention pertains to methods for
maintaining weight loss, BMI loss, waist circumference loss or body
fat percentage loss in an individual following bariatric surgery,
comprising administering to an individual in need thereof, a
therapeutically effective amount of a salt or a pharmaceutical
composition of the present invention.
[0406] One aspect of the present invention pertains to methods for
inducing satiety in an individual, comprising administering to an
individual in need thereof, a therapeutically effective amount of a
salt or a pharmaceutical composition of the present invention.
[0407] One aspect of the present invention pertains to methods for
decreasing food intake in an individual, comprising administering
to an individual in need thereof, a therapeutically effective
amount of a salt or a pharmaceutical composition of the present
invention.
[0408] One aspect of the present invention pertains to methods for
decreasing hunger in an individual, comprising administering to an
individual in need thereof, a therapeutically effective amount of a
salt or a pharmaceutical composition of the present invention.
[0409] One aspect of the present invention pertains to methods for
decreasing food cravings in an individual, comprising administering
to an individual in need thereof, a therapeutically effective
amount of a salt or a pharmaceutical composition of the present
invention.
[0410] One aspect of the present invention pertains to methods for
increasing intermeal interval in an individual, comprising
administering to an individual in need thereof, a therapeutically
effective amount of a salt or a pharmaceutical composition of the
present invention.
[0411] One aspect of the present invention pertains to methods for
the treatment of a disorder selected from: schizophrenia, anxiety,
depression, psychoses and alcohol addiction, comprising
administering to an individual in need thereof, a therapeutically
effective amount of a salt or a pharmaceutical composition of the
present invention.
[0412] In some embodiments, the disorder is schizophrenia.
[0413] In some embodiments, the disorder is anxiety.
[0414] In some embodiments, the disorder is depression.
[0415] In some embodiments, the disorder is psychoses.
[0416] In some embodiments, the disorder is alcohol addiction.
[0417] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for weight management in an individual.
[0418] In some embodiments, the weight management comprises weight
loss.
[0419] In some embodiments, the weight management comprises
maintenance of weight loss.
[0420] In some embodiments, the weight management comprises
decreased food consumption.
[0421] In some embodiments, the weight management comprises
increasing meal-related satiety.
[0422] In some embodiments, the weight management comprises
reducing pre-meal hunger.
[0423] In some embodiments, the weight management comprises
reducing intra-meal food intake.
[0424] In some embodiments, the weight management further comprises
a reduced-calorie diet.
[0425] In some embodiments, the weight management further comprises
a program of regular exercise.
[0426] In some embodiments, the weight management further comprises
both a reduced-calorie diet and a program of regular exercise.
[0427] In some embodiments, the individual is an obese patient with
an initial body mass index 30 kg/m.sup.2.
[0428] In some embodiments, the individual is an overweight patient
with an initial body mass index .gtoreq.27 kg/m.sup.2 in the
presence of at least one weight related comorbid condition.
[0429] In some embodiments, the individual is an overweight patient
with an initial body mass index .gtoreq.27 kg/m.sup.2 in the
presence of at least one weight related comorbid condition selected
from: hypertension, dyslipidemia, cardiovascular disease, glucose
intolerance, and sleep apnea.
[0430] In some embodiments, the individual has an initial body mass
index .gtoreq.30 kg/m.sup.2.
[0431] In some embodiments, the individual has an initial body mass
index .gtoreq.27 kg/m.sup.2.
[0432] In some embodiments, the individual has an initial body mass
index .gtoreq.27 kg/m.sup.2 in the presence of at least one weight
related comorbid condition.
[0433] In some embodiments, the individual has an initial body mass
index .gtoreq.27 kg/m.sup.2 in the presence of at least one weight
related comorbid condition selected from: hypertension,
dyslipidemia, cardiovascular disease, glucose intolerance, and
sleep apnea.
[0434] In some embodiments, the individual has an initial body mass
index .gtoreq.25 kg/m.sup.2.
[0435] In some embodiments, the individual has an initial body mass
index .gtoreq.25 kg/m.sup.2 in the presence of at least one weight
related comorbid condition.
[0436] In some embodiments, the individual has an initial body mass
index .gtoreq.25 kg/m.sup.2 in the presence of at least one weight
related comorbid condition selected from: hypertension,
dyslipidemia, cardiovascular disease, glucose intolerance, and
sleep apnea.
[0437] In some embodiments, the medicament for weight management is
used in combination with phentermine.
[0438] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for a disorder related to 5-HT.sub.2C receptor activity in an
individual.
[0439] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for the treatment of obesity in an individual.
[0440] In some embodiments, the treatment of obesity further
comprises the administration or prescription of phentermine
[0441] In some embodiments, the treatment of obesity further
comprises gastric electrical stimulation.
[0442] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for inducing weight loss, BMI loss, waist circumference loss or
body fat percentage loss in an individual.
[0443] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for inducing weight loss, BMI loss, waist circumference loss or
body fat percentage loss in an individual in preparation of the
individual for bariatric surgery.
[0444] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for maintaining weight loss, BMI loss, waist circumference loss or
body fat percentage loss in an individual.
[0445] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for maintaining weight loss, BMI loss, waist circumference loss or
body fat percentage loss in an individual following bariatric
surgery.
[0446] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for inducing satiety in an individual.
[0447] One aspect of the present invention pertains to the use of
salts, or crystalline forms of the present invention, in the
manufacture of a medicament for decreasing food intake in an
individual.
[0448] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for decreasing hunger in an individual.
[0449] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for decreasing food cravings in an individual.
[0450] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for increasing intermeal interval in an individual.
[0451] One aspect of the present invention pertains to the use of
salts of the present invention, in the manufacture of a medicament
for the treatment of a disorder selected from: schizophrenia,
anxiety, depression, psychoses and alcohol addiction in an
individual.
[0452] In some embodiments, the disorder is schizophrenia.
[0453] In some embodiments, the disorder is anxiety.
[0454] In some embodiments, the disorder is depression.
[0455] In some embodiments, the disorder is psychoses.
[0456] In some embodiments, the disorder is alcohol addiction.
[0457] One aspect of the present invention pertains to salts of the
present invention, for use in a method of treatment of a disorder
related to 5-HT.sub.2C receptor activity in an individual.
[0458] One aspect of the present invention pertains to salts of the
present invention, for use in a method of treatment of obesity in
an individual.
[0459] In some embodiments, the method of treatment of obesity
further comprises the administration or prescription of
phentermine.
[0460] In some embodiments, the method of treatment of obesity
further comprises gastric electrical stimulation.
[0461] One aspect of the present invention pertains to salts of the
present invention, for use in a method of inducing weight loss, BMI
loss, waist circumference loss or body fat percentage loss in an
individual.
[0462] One aspect of the present invention pertains to salts of the
present invention, for use in a method of inducing weight loss, BMI
loss, waist circumference loss or body fat percentage loss in an
individual in preparation of the individual for bariatric
surgery.
[0463] One aspect of the present invention pertains to salts of the
present invention, for use in a method of maintaining weight loss,
BMI loss, waist circumference loss or body fat percentage loss in
an individual.
[0464] One aspect of the present invention pertains to salts of the
present invention, for use in a method of maintaining weight loss,
BMI loss, waist circumference loss or body fat percentage loss in
an individual following bariatric surgery.
[0465] One aspect of the present invention pertains to salts of the
present invention, for use in a method of inducing satiety in an
individual.
[0466] One aspect of the present invention pertains to salts of the
present invention, for use in a method of decreasing food intake in
an individual.
[0467] One aspect of the present invention pertains to salts of the
present invention, for use in a method of decreasing hunger in an
individual.
[0468] One aspect of the present invention pertains to salts of the
present invention, for use in a method of decreasing food cravings
in an individual.
[0469] One aspect of the present invention pertains to salts of the
present invention, for use in a method of increasing intermeal
interval in an individual.
[0470] One aspect of the present invention pertains to salts of the
present invention, for use in a method of treatment of a disorder
selected from: schizophrenia, anxiety, depression, psychoses and
alcohol addiction in an individual.
[0471] In some embodiments, the disorder is schizophrenia.
[0472] In some embodiments, the disorder is anxiety.
[0473] In some embodiments, the disorder is depression.
[0474] In some embodiments, the disorder is psychoses.
[0475] In some embodiments, the disorder is alcohol addiction.
[0476] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of treatment of the human or animal body by therapy.
[0477] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management.
[0478] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight loss.
[0479] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of maintenance of weight loss.
[0480] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of decreasing food consumption.
[0481] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of increasing meal-related satiety.
[0482] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of reducing pre-meal hunger.
[0483] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of reducing intra-meal food intake.
[0484] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management further comprising a reduced-calorie
diet.
[0485] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management further comprising a program of regular
exercise.
[0486] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management further comprising a reduced-calorie
diet and a program of regular exercise.
[0487] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an obese patient with an initial
body mass index .gtoreq.30 kg/m.sup.2.
[0488] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an overweight patient with an
initial body mass index .gtoreq.27 kg/m.sup.2 in the presence of at
least one weight related co-morbid condition.
[0489] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an overweight patient with an
initial body mass index .gtoreq.27 kg/m.sup.2 in the presence of at
least one weight related co-morbid condition selected from:
hypertension, dyslipidemia, cardiovascular disease, glucose
intolerance, and sleep apnea.
[0490] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.30 kg/m.sup.2.
[0491] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.27 kg/m.sup.2.
[0492] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.27 kg/m.sup.2 in the presence of at least one
weight related co-morbid condition.
[0493] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.27 kg/m.sup.2 in the presence of at least one
weight related co-morbid condition selected from: hypertension,
dyslipidemia, cardiovascular disease, glucose intolerance, and
sleep apnea.
[0494] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.25 kg/m.sup.2.
[0495] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.25 kg/m.sup.2 in the presence of at least one
weight related co-morbid condition.
[0496] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in an individual with an initial body
mass index .gtoreq.25 kg/m.sup.2 in the presence of at least one
weight related co-morbid condition selected from: hypertension,
dyslipidemia, cardiovascular disease, glucose intolerance, and
sleep apnea.
[0497] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in combination with phentermine
[0498] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of treatment of a disorder related to 5-HT.sub.2C receptor
activity in an individual.
[0499] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of treatment of obesity in an individual.
[0500] In some embodiments, the method of treatment of obesity
further comprises the administration or prescription of
phentermine.
[0501] In some embodiments, the method of treatment of obesity
further comprises gastric electrical stimulation.
[0502] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of inducing weight loss, BMI loss, waist circumference loss
or body fat percentage loss in an individual.
[0503] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of inducing weight loss, BMI loss, waist circumference loss
or body fat percentage loss in an individual in preparation of the
individual for bariatric surgery.
[0504] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of maintaining weight loss, BMI loss, waist circumference
loss or body fat percentage loss in an individual.
[0505] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of maintaining weight loss, BMI loss, waist circumference
loss or body fat percentage loss in an individual following
bariatric surgery.
[0506] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of inducing satiety in an individual.
[0507] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of decreasing food intake in an individual.
[0508] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of decreasing hunger in an individual.
[0509] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of decreasing food cravings in an individual.
[0510] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of increasing intermeal interval in an individual.
[0511] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of treatment of a disorder selected from: schizophrenia,
anxiety, depression, psychoses and alcohol addiction in an
individual.
[0512] In some embodiments, the disorder is schizophrenia.
[0513] In some embodiments, the disorder is anxiety.
[0514] In some embodiments, the disorder is depression.
[0515] In some embodiments, the disorder is psychoses.
[0516] In some embodiments, the disorder is alcohol addiction.
[0517] One aspect of the present invention pertains to methods for
weight management, comprising administering to an individual in
need thereof, a therapeutically effective amount of a salt or a
pharmaceutical composition of the present invention.
[0518] In some embodiments, the weight management comprises one or
more of: weight loss, maintenance of weight loss, decreased food
consumption, increasing meal-related satiety, reducing pre-meal
hunger, and reducing intra-meal food intake.
[0519] In some embodiments, the weight management is as an adjunct
to diet and exercise.
[0520] In some embodiments, the individual in need of weight
management is selected from: an obese patient with an initial body
mass index .gtoreq.30 kg/m.sup.2; an overweight patient with an
initial body mass index .gtoreq.27 kg/m.sup.2 in the presence of at
least one weight related comorbid condition; an overweight patient
with an initial body mass index .gtoreq.27 kg/m.sup.2 in the
presence of at least one weight related comorbid condition; wherein
the weight related co-morbid condition is selected from:
hypertension, dyslipidemia, cardiovascular disease, glucose
intolerance, and sleep apnea.
[0521] In some embodiments, the method further comprises
administering a second anti-obesity agent to the individual.
[0522] In some embodiments, the second anti-obesity agent is
selected from: chlorphentermine, clortermine, phenpentermine, and
phentermine, and pharmaceutically acceptable salts, solvates, and
hydrates thereof.
[0523] In some embodiments, the method further comprises
administering an anti-diabetes agent to the individual.
[0524] In some embodiments, the anti-diabetes agent is
metformin.
[0525] One aspect of the present invention pertains to uses of a
salt of the present invention, in the manufacture of a medicament
for weight management in an individual.
[0526] In some embodiments, the weight management comprises one or
more of: weight loss, maintenance of weight loss, decreased food
consumption, increasing meal-related satiety, reducing pre-meal
hunger, and reducing intra-meal food intake.
[0527] In some embodiments, the medicament is used as an adjunct to
diet and exercise.
[0528] In some embodiments, the individual in need of weight
management is selected from: an obese patient with an initial body
mass index .gtoreq.30 kg/m.sup.2; an overweight patient with an
initial body mass index .gtoreq.27 kg/m.sup.2 in the presence of at
least one weight related comorbid condition; and an overweight
patient with an initial body mass index .gtoreq.27 kg/m.sup.2 in
the presence of at least one weight related comorbid condition;
wherein the weight related co-morbid condition is selected from:
hypertension, dyslipidemia, cardiovascular disease, glucose
intolerance, and sleep apnea.
[0529] In some embodiments, the medicament is used in combination
with a second anti-obesity agent.
[0530] In some embodiments, the second anti-obesity agent is
selected from: chlorphentermine, clortermine, phenpentermine, and
phentermine, and pharmaceutically acceptable salts, solvates, and
hydrates thereof.
[0531] In some embodiments, the medicament is used in combination
with an anti-diabetes agent.
[0532] In some embodiments, the medicament is used in combination
with an anti-diabetes agent; wherein the anti-diabetes agent is
metformin.
[0533] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of treatment of the human or animal body by therapy.
[0534] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management.
[0535] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management; wherein the weight management
comprises one or more of: weight loss, maintenance of weight loss,
decreased food consumption, increasing meal-related satiety,
reducing pre-meal hunger, and reducing intra-meal food intake.
[0536] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use as an
adjunct to diet and exercise for weight management.
[0537] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management; wherein the individual in need of
weight management is selected from: an obese patient with an
initial body mass index .gtoreq.30 kg/m.sup.2; an overweight
patient with an initial body mass index .gtoreq.27 kg/m.sup.2 in
the presence of at least one weight related comorbid condition; and
an overweight patient with an initial body mass index .gtoreq.27
kg/m.sup.2 in the presence of at least one weight related comorbid
condition; wherein the weight related co-morbid condition is
selected from: hypertension, dyslipidemia, cardiovascular disease,
glucose intolerance, and sleep apnea.
[0538] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in combination with a second
anti-obesity agent.
[0539] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in combination with a second
anti-obesity agent selected from: chlorphentermine, clortermine,
phenpentermine, and phentermine, and pharmaceutically acceptable
salts, solvates, and hydrates thereof.
[0540] One aspect of the present invention pertains to salts and
pharmaceutical compositions of the present invention, for use in a
method of weight management in combination with an anti-diabetes
agent; wherein the anti-diabetes agent is metformin.
Combination Therapies
[0541] The salts of the present invention can be used in
combination with suitable pharmaceutical agents.
[0542] In some embodiments the salts of the present invention can
be used in combination with a second anti-obesity agent.
Anti-obesity agents include, for example, adrenergic reuptake
inhibitors, apolipoprotein-B secretion/microsomal triglyceride
transfer protein inhibitors, .beta.3 adrenergic receptor agonists,
bombesin agonists, cannabinoid 1 receptor antagonists,
cholescystokinin-A agonists, ciliary neutrotrophic factors,
dopamine agonists, galanin antagonists, ghrelin receptor
antagonists, glucagon-like peptide-1 receptor agonists,
glucocorticoid receptor agonists or antagonists, histamine-3
receptor antagonists or reverse agonists, human agouti-related
proteins, leptin receptor agonists, lipase inhibitors, MCR-4
agonists, melanin concentrating hormone antagonists,
melanocyte-stimulating hormone receptor analogs, monoamine reuptake
inhibitors, neuromedin U receptor agonists, neuropeptide-Y
antagonists, orexin receptor antagonists, stimulants,
sympathomimetic agents, thyromimetic agents, and urocortin binding
protein antagonists.
[0543] In some embodiments, the second anti-obesity agent is
selected from: 4-methylamphetamine, 5-HTP, amfecloral,
amfepentorex, amfepramone, aminorex, amphetamine, amphetaminil,
atomoxetine, benfluorex, benzphetamine, bromocriptine, bupropion,
cathine, cathinone, cetilistat, chlorphentermine, ciclazindol,
clobenzorex, cloforex, clominorex, clortermine, dapiclermin,
dehydroepiandrosterone, dehydroepiandrosterone analogues,
dexmethylphenidate, dextroamphetamine, dextromethamphetamine,
difemetorex, dimethylcathinone, dinitrophenol, diphemethoxidine,
ephedra, ephedrine, ethylamphetamine, etolorex, fenbutrazate,
fencamfamine, fenethylline, fenproporex, fludorex, fluminorex,
furfenorex, galactomannan, glucomannan, ibipinabant, indanorex,
khat, L-dopa, leptin, a leptin analog, levopropylhexedrine,
lisdexamfetamine, L-phenylalanine, L-tryptophan, L-tyrosine,
N-[[trans-4-[(4,5-dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cycloh-
exyl]methyl]methanesulfonamide, manifaxine, mazindol, mefenorex,
metformin, methamphetamine, methylphenidate, naloxone, naltrexone,
oleoyl-estrone, orlistat, otenabant, oxyntomodulin, P57, pemoline,
peptide YY, phendimetrazine, phenethylamine, phenmetrazine,
phenpentermine, phentermine, phenylpropanolamine, pipradrol,
prolintane, propylhexedrine, pseudoephedrine, pyrovalerone,
radafaxine, reboxetine, rimonabant, setazindol, sibutramine,
simmondsin, sterculia, surinabant, synephrine, taranabant,
tesofensine, topiramate, viloxazine, xylopropamine, yohimbine,
zonisamide, and zylofuramine, and pharmaceutically acceptable
salts, solvates, and hydrates thereof.
[0544] In some embodiments, the second anti-obesity agent is
selected from: 4-methylamphetamine, amfecloral, amfepentorex,
amfepramone, aminorex, amphetamine, amphetaminil, atomoxetine,
benfluorex, benzphetamine, bupropion, cathine, cathinone,
chlorphentermine, ciclazindol, clobenzorex, cloforex, clominorex,
clortermine, dexmethylphenidate, dextroamphetamine,
dextromethamphetamine, difemetorex, dimethylcathinone,
diphemethoxidine, ephedra, ephedrine, ethylamphetamine, etolorex,
fenbutrazate, fencamfamine, fenethylline, fenproporex, fludorex,
fluminorex, furfenorex, indanorex, khat, levopropylhexedrine,
lisdexamfetamine, manifaxine, mazindol, mefenorex, methamphetamine,
methylphenidate, pemoline, phendimetrazine, phenethylamine,
phenmetrazine, phenpentermine, phentermine, phenylpropanolamine,
pipradrol, prolintane, propylhexedrine, pseudoephedrine,
pyrovalerone, radafaxine, reboxetine, setazindol, sibutramine,
synephrine, taranabant, tesofensine, viloxazine, xylopropamine, and
zylofuramine, and pharmaceutically acceptable salts, solvates, and
hydrates thereof.
[0545] In some embodiments, the second anti-obesity agent is
selected from: chlorphentermine, clortermine, phenpentermine, and
phentermine, and pharmaceutically acceptable salts, solvates, and
hydrates thereof.
[0546] In some embodiments the salts of the present invention can
be used in combination with an anti-diabetes agent. Anti-diabetes
agents include, for example, DPP-IV inhibitors, biguanides,
alpha-glucosidase inhibitors, insulin analogues, sulfonylureas,
SGLT2 inhibitors, meglitinides, thiazolidinediones, anti-diabetic
peptide analogues, and GPR119 agonists.
[0547] In some embodiments, the anti-diabetes agent is selected
from: sitagliptin, vildagliptin, saxagliptin, alogliptin,
linagliptin, phenformin, metformin, buformin, proguanil, acarbose,
miglitol, voglibose, tolbutamide, acetohexamide, tolazamide,
chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide,
dapagliflozin, remigliflozin, sergliflozin, and
4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-
-yloxy]-piperidine-1-carboxylic acid isopropyl ester.
[0548] In some embodiments, the anti-diabetes agent is a DPP-IV
inhibitor selected from the following compounds and
pharmaceutically acceptable salts, solvates, and hydrates thereof:
3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a-
]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;
1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile;
(1S,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[-
3.1.0]hexane-3-carbonitrile;
2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyri-
midin-1-ylmethyl]benzonitrile;
8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-
-2-ylmethyl)xanthine;
1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid;
4(S)-fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino-
]acetyl]pyrrolidine-2(S)-carbonitrile;
1-[(2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[-
2,1-a]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one;
(2S,4S)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acetylpyrr-
olidine;
8-(cis-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-methyl-7-(3-methyl--
but-2-enyl)-1-(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione;
1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)-
pyrrolidin-3-yl)-5,5difluoropiperidin-2-one;
(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
-1(2H)-yl)methyl)-4-fluorobenzonitrile;
5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-
-tetrazol-5-yl)10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic
acid bis-dimethylamide;
((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidi-
n-2-yl)(thiazolidin-3-yl)methanone;
(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-flu-
oropyrrolidine-2-carbonitrile;
6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-
-1,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione;
2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,-
4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile;
(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidin-
e-2-carbonitrile;
(2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acety-
l}-pyrrolidine-2-carbonitrile;
(3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-y-
l)pyrrolidin-2-yl)methanone;
(2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrroli-
dine-2-carbonitrile;
(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl-
)glycyl}pyrrolidine-2-carbonitrile; and
(1S,6R)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin--
7
(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3-en-1-amine
[0549] In some embodiments, the anti-diabetes agent is an
alpha-glucosidase inhibitor selected from the following compounds
and pharmaceutically acceptable salts, solvates, and hydrates
thereof:
(2R,3R,4R,5R)-4-((2R,3R,4R,5S,6R)-5-((2R,3R,4S,5S,6R)-3,4-dihydroxy-6-met-
hyl-5-((1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamin-
o)tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2-
H-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal;
(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol;
and
(1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)c-
yclohexane-1,2,3,4-tetraol.
[0550] In some embodiments, the anti-diabetes agent is a
sulfonylurea selected from the following compounds and
pharmaceutically acceptable salts, solvates, and hydrates thereof:
N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carb-
oxamide);
5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-met-
hoxybenzamide; and
3-ethyl-4-methyl-N-(4-(N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)p-
henethyl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide.
[0551] In some embodiments, the anti-diabetes agent is an SGLT2
inhibitor selected from the following compounds and
pharmaceutically acceptable salts, solvates, and hydrates thereof:
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)t-
etrahydro-2H-pyran-3,4,5-triol; ethyl
((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-1-isopropyl--
5-methyl-1H-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl
carbonate; and ethyl
((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)te-
trahydro-2H-pyran-2-yl)methyl carbonate.
[0552] In some embodiments, the anti-diabetes agent is a
meglitinide selected from the following compounds and
pharmaceutically acceptable salts, solvates, and hydrates thereof:
(S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butylamino)-2-oxo-
ethyl)benzoic acid;
(R)-2-((1r,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoic
acid; and
(S)-2-benzyl-4-((3aR,7aS)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-
-oxobutanoic acid.
[0553] In some embodiments, the anti-diabetes agent is a biguanide
selected from the following compounds and pharmaceutically
acceptable salts, solvates, and hydrates thereof: metformin,
phenformin, buformin, and proguanil.
[0554] In some embodiments, the anti-diabetes agent is
metformin.
[0555] In some embodiments, the anti-diabetes agent is a GPR119
agonist selected from the GPR119 agonists disclosed in the
following PCT applications: WO2006083491, WO 2008081204,
WO2009123992, WO2010008739, WO2010029089, and WO2010149684.
[0556] In some embodiments, the anti-diabetes agent is
4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-
-yloxy]-piperidine-1-carboxylic acid isopropyl ester.
[0557] In some embodiments, the anti-diabetes agent is
5-(4-(4-(3-fluoro-4-(methylsulfonyl)phenoxy)butan-2-yl)piperidin-1-yl)-3--
isopropyl-1,2,4-oxadiazole.
[0558] Other anti-obesity agents, and anti-diabetes agents
including the agents set forth infra, are well known, or will be
readily apparent in light of the instant disclosure, to one of
ordinary skill in the art. It will be understood that the scope of
combination therapy of the salts of the present invention with
other anti-obesity agents and with anti-diabetes agents is not
limited to those listed above, but includes in principle any
combination with any pharmaceutical agent or pharmaceutical
composition useful for the treatment of overweight, obese, and
diabetic individuals.
[0559] One aspect of the present invention pertains to salts of the
present invention, characterized in that the salts is administered
in conjunction with a second anti-obesity agent as described
herein.
[0560] One aspect of the present invention pertains to salts of the
present invention, characterized in that the salt is administered
in conjunction with an anti-diabetes agent as described herein.
[0561] One aspect of the present invention pertains to salts of the
present invention for use in combination with a second anti-obesity
agent for use in weight management.
[0562] One aspect of the present invention pertains to salts of the
present invention for use in combination with an anti-diabetes
agent for use in weight management and the treatment of
diabetes.
[0563] One aspect of the present invention pertains to methods of
weight management in an individual in need thereof, comprising
administering to the individual a salt of the present invention and
a second anti-obesity agent wherein the salt and the second
anti-obesity agent are administered to the individual
simultaneously, separately, or sequentially.
[0564] One aspect of the present invention pertains to methods of
weight management and treating diabetes in an individual in need
thereof, comprising administering to the individual a salt of the
present invention and an anti-diabetes agent wherein the salt and
the anti-diabetes agent are administered to the individual
simultaneously, separately, or sequentially.
[0565] One aspect of the present invention pertains to methods of
weight management in an individual in need thereof, wherein the
individual has been or is being treated with a second anti-obesity
agent, the method comprising administering to the individual a
therapeutically effective amount of a salt of the present
invention.
[0566] One aspect of the present invention pertains to methods of
weight management and treatment of diabetes in an individual in
need thereof, wherein the individual has been or is being treated
with an anti-diabetes agent, the method comprising administering to
the individual a therapeutically effective amount of a salt of the
present invention.
[0567] One aspect of the present invention pertains to anti-obesity
agents, characterized in that the anti-obesity agent is
administered in conjunction with a salt of the present invention.
One aspect of the present invention pertains to anti-diabetes
agents, characterized in that the anti-diabetes agent is
administered in conjunction with a salt of the present
invention.
[0568] One aspect of the present invention pertains to anti-obesity
agents for use in combination with a salt of the present invention
for use in weight management.
[0569] One aspect of the present invention pertains to
anti-diabetes agents for use in combination with a salt of the
present invention for use in weight management and the treatment of
diabetes.
[0570] One aspect of the present invention pertains to methods of
weight management in an individual in need thereof, comprising
administering to the individual an anti-obesity agent and a salt of
the present invention wherein the anti-obesity agent and the salt
are administered to the individual simultaneously, separately, or
sequentially.
[0571] One aspect of the present invention pertains to methods of
weight management and treating diabetes in an individual in need
thereof, comprising administering to the individual an
anti-diabetes agent and a salt of the present invention wherein the
anti-diabetes agent and the salt are administered to the individual
simultaneously, separately, or sequentially.
[0572] One aspect of the present invention pertains to methods of
weight management in an individual in need thereof, wherein the
individual has been or is being treated with a salt of the present
invention, the method comprising administering to the individual a
therapeutically effective amount of a second anti-obesity
agent.
[0573] One aspect of the present invention pertains to methods of
weight management and treatment of diabetes in an individual in
need thereof, wherein the individual has been or is being treated
with a salt of the present invention, the method comprising
administering to the individual a therapeutically effective amount
of an anti-diabetes agent.
[0574] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of noncritical parameters which can be changed or modified
to yield essentially the same results.
EXAMPLES
[0575] The following examples are provided to further define the
invention without, however, limiting the invention to the
particulars of these examples. The compounds and salts thereof
described herein, supra and infra, are named according to the CS
ChemDraw Ultra Version 7.0.1, AutoNom version 2.2, or CS ChemDraw
Ultra Version 9.0.7. In certain instances common names are used and
it is understood that these common names would be recognized by
those skilled in the art.
[0576] Powder X-ray Diffraction (PXRD) studies were conducted using
an X'Pert PRO MPD powder diffractometer (PANalytical, Inc.; EQ0233)
with a Cu source set at 45 kV and 40 mA, Cu(K.alpha.) radiation and
an X'Celerator detector. Samples were placed on a PXRD sample plate
either as-is or ground slightly to reduce the size of large
particles or crystals. Data were collected with the samples
spinning from 5.degree. to 40.degree.2.theta.. Data were analyzed
by X'Pert Data Viewer software, version 1.0a, to determine
crystallinity and/or crystal form, and by X'Pert HighScore
software, version 1.0b, to generate the tables of PXRD peaks.
[0577] Differential scanning calorimetry (DSC) studies were
conducted using a TA Instruments, Q2000 (EQ1980) at heating rate
10.degree. C./min. The instruments were calibrated by the vendor
for temperature and energy using the melting point and enthalpy of
fusion of an indium standard.
[0578] Thermogravimetric analyses (TGA) were conducted using a TA
Instruments TGA Q5000 (EQ1982) at heating rate 10.degree. C./min.
The instrument was calibrated by the vendor using Alumel and Nickel
Curie points for the furnace temperature and a standard weight for
the balance.
[0579] Dynamic moisture-sorption (DMS) studies were conducted using
a dynamic moisture-sorption analyzer, VTI Corporation, SGA-100,
equipment #0228. Samples were prepared for DMS analysis by placing
5 mg to 20 mg of a sample in a tared sample holder. The sample was
placed on the hang-down wire of the VTI balance. A drying step was
run, typically at 40.degree. C. and 0.5-1% RH for 1-2 h. The
isotherm temperature is 25.degree. C. Defined % RH holds typically
ranged from 10% RH to 90% RH or 95% RH, with intervals of 10 to 20%
RH. A % weight change smaller than 0.010% over a specified number
of minutes (typically 10-20), or up to 2 h, whichever occurs first,
is required before continuing to the next % RH hold. The water
content of the sample equilibrated as described above was
determined at each % RH hold.
[0580] If saturated in water with excess solid, a deliquescing
compound or salt thereof equilibrated in a closed system at a given
temperature produces a % RH in that closed system that is equal to
its deliquescing % RH (DRH) at that temperature. Fractional
relative humidity is equal to water activity (a.sub.w) in the vapor
phase and at equilibrium in a closed system, the a.sub.w in an
aqueous solution is equal to the aw in the vapor phase above the
solution (see Equation 1).
-78- Equation 1
[0581] A water activity meter was used to measure DRH for selected
salts described herein. The instrument used for this study is a
Decagon Devices AquaLab 4TE water activity meter, equipment #2169.
This instrument is designed with temperature control and a small
headspace above the enclosed sample to establish equilibrium
between solution and vapor phases quickly. Measured a.sub.w values
at 25.degree. C. for samples of aqueous-saturated Compound 1 salts
with excess solid were multiplied by 100% to get DRH values in %
RH.
[0582] Acquity ultra performance liquid chromatography (UPLC) from
Waters was used for solubility and stoichiometry determination.
Instrument number is SY-EQ 1889. UPLC was equipped with Acquity PDA
detector. UPLC mobile phase solvent A was 0.1% TFA in DI-water,
solvent B was 0.1% TFA in acetonitrile. The mobile phase gradient
as shown in the table below:
TABLE-US-00022 Time (min) Flow (mL/min) % A % B Curve 0.600 95.0
5.0 2.00 0.600 5.0 95.0 6 2.50 0.600 5.0 95.0 6 2.75 0.600 95.0 5.0
1 5.00 0.000 95.0 5.0 11
[0583] Column temperature was 40.+-.5.degree. C. Acquity UPLC.RTM.
HSS T3 1.8 .mu.m, 2.1.times.50 mm column was used.
[0584] A known amount of sample was dissolved in water and analyzed
by UPLC. The weight percent of Compound 1 in the salt samples was
determined by comparing the UV signal to that of a standard,
Compound 1 hydrochloride salt hemihydrate, or Compound 1 free base.
The percentage of Compound 1 or the percentage of the counterion
determined was compared to the theoretical values to establish the
stoichiometry.
Example 1
Preparation of Form I of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(1S)-(+)-10-Camsylate Salt (Compound 1 (1S)-(+)-10-Camsylate Salt,
Form I)
[0585] The title salt was prepared by the dropwise addition of 1
mole equivalent of .about.3.6 M aqueous (1S)-(+)-10-camphorsulfonic
acid to a solution of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in
acetonitrile with vigorous stirring Immediate precipitation was
observed and the solid was collected by filtration and washed with
isopropyl alcohol.
[0586] The DRH of the title salt was determined to be 99.8% RH by
water activity measurement of a saturated aqueous solution with
excess solid at 25.degree. C., indicating that it was not
deliquescent.
[0587] A known amount of the title salt was dissolved in water and
analyzed by UPLC. The amount of Compound 1 in the salt sample was
determined to be 39.7%. This is slightly lower than the theoretical
value, 45.7%. Solubility of the title salt in water was determined
by UPLC to be 20 mg/mL, with a final pH of 7.
[0588] The powder X-ray diffraction pattern of the title salt is
shown in FIG. 1. Thermal analysis (TGA and DSC) of the title salt
is shown in FIG. 2. DMS analysis of the title salt is shown in FIG.
3.
Example 2
Preparation of Form I of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Hemi-L-malate Salt (Compound 1 Hemi-L-malate Salt, Form I)
[0589] The title salt was prepared by the dropwise addition of
L-malic acid (0.5 eq.), either in solution in hot MeOH or as a
solid, to a solution of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in
isopropyl acetate. The mixture was heated to .about.60.degree. C.
and held at that temperature for .about.1 h. The mixture was then
allowed to cool to room temperature and stirred for 1-3 days. The
solid product was isolated by vacuum filtration and dried on the
filter or in an oven at 40.degree. C. for. An attempt to make a 1:1
salt produced a mixture of mono-L-malate and hemi-L-malate
salts.
[0590] The DRH of the title salt was measured by water activity
determination for a saturated aqueous solution with excess solid to
be 89.9% RH at 25.degree. C.
[0591] A known amount of the title salt was dissolved in water and
analyzed by UPLC. The amount of Compound 1 in the sample was 76.5%.
This is in acceptable agreement with the theoretical amount for a
hemi-L-malate salt of Compound 1, 74.5%. Aqueous solubility of the
title salt was 486.3 mg/mL, final pH 6.0.
[0592] The powder X-ray diffraction pattern of the title salt is
shown in FIG. 4. Thermal analysis (TGA and DSC) of the title salt
is shown in FIG. 5. DMS analysis of the title salt is shown in FIG.
6.
Example 3
Preparation of Form I of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-Glutamate Salt (Compound 1 L-Glutamate Salt, Form I)
Method 1
[0593] The title salt was prepared by addition of L-glutamic acid
(0.5-1 eq.) in hot EtOH/H.sub.2O (.about.2:1) to a solution of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in
isopropyl acetate, followed by evaporation of the solvent overnight
to produce a solid. The solid was slurried in isopropyl acetate and
then isolated by filtration.
Method 2
[0594] The title salt was prepared by addition of a solution of
L-glutamic acid (1 eq.) in hot H.sub.2O to a solution of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. The
product crystallized without the need for evaporation or the
solvent.
[0595] The products of both methods produced crystalline solids
with essentially the same PXRD pattern.
[0596] The DRH of the title salt was measured by water activity
determination for a saturated aqueous solution with excess solid to
be 98.3% RH at 25.degree. C.
[0597] A known amount of the title salt was dissolved in water and
analyzed by UPLC. The amount of Compound 1 in the sample was
59-60%. This is in acceptable agreement with calculated amount,
57.1%. Aqueous solubility of the title salt was 176.2 mg/mL, with a
final pH 5.5.
[0598] The powder X-ray diffraction pattern of the title salt is
shown in FIG. 7. Thermal analysis (TGA and DSC) of the title salt
is shown in FIG. 8. DMS analysis of the title salt is shown in FIG.
9.
Example 4
Preparation of Form I of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
L-Aspartate Salt (Compound 1 L-Aspartate Salt, Form I)
[0599] The title salt was prepared by addition of a solution of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in either
acetone or acetonitrile to one equivalent of aspartic acid solid.
The mixture was heated to 50.degree. C. then slow-cooled and
stirred overnight.
[0600] A known amount of the title salt was dissolved in water and
analyzed by UPLC. The amount of Compound 1 in the sample was 59.5%.
This is in good agreement with the theoretical value, 61.7%.
Aqueous solubility of the title salt was 42 mg/mL. The final pH of
a near saturated solution of this salt was 4.82.
[0601] The powder X-ray diffraction pattern of the title salt is
shown in FIG. 10. Thermal analysis (TGA and DSC) of the title salt
is shown in FIG. 11. DMS analysis of the title salt is shown in
FIG. 12.
Example 5
Preparation of Form I of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Hemimucate (Compound 1 Hemimucate Salt, Form I)
[0602] The title compound was synthesized from
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2
equivalents) and mucic acid (1 equivalent) in THF, acetone or IPA
(.about.10 mg/mL) with 4% water.
[0603] A known amount of Compound 1 hemimucate salt, was dissolved
in methanol and analyzed by UPLC. The percent of Compound 1 in the
salt sample was determined to be 64.4%. This is close to the
theoretical percent Compound 1 in a 1:0.5 Compound 1 hemimucate
salt (65.1%).
[0604] The aqueous solubility of Compound 1 hemimucate was
determined to be 0.85 mg/mL at a pH of 1.48.
[0605] The powder X-ray diffraction pattern of the title salt is
shown in FIG. 13. Thermal analysis (TGA and DSC) of the title salt
is shown in FIG. 13. DMS analysis of the title salt is shown in
FIG. 15.
Example 6
Preparation of Form I of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Glucuronate Salt (Compound 1 Glucuronate Salt, Form I)
[0606] The title salt was prepared by addition of a molar
equivalent of D-glucuronic acid to a solution of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in
isopropanol, acetonitrile, ethyl acetate, or acetone at 60.degree.
C. D-glucuronic acid, dissolved in the corresponding solvent at
60.degree. C., was added dropwise with vigorous stirring.
Precipitation occurred immediately and the suspension was allowed
to cool and stir overnight. The resulting solid was recovered by
filtration and dried in a fume hood overnight.
[0607] A known amount of Compound 1 glucuronate salt was dissolved
in methanol and analyzed by UPLC. The percentage of Compound 1 in
the salt sample was determined to be 56.9%. This is slightly higher
than the theoretical percentage of Compound 1 in an anhydrous
Compound 1 glucuronate salt (50.2%).
[0608] The solubility of Compound 1 glucuronate in water was
determined by UPLC to be 2.5 mg/mL, with a final pH of 6.80.
[0609] The powder X-ray diffraction pattern of the title salt is
shown in FIG. 16. Thermal analysis (TGA and DSC) of the title salt
is shown in FIG. 17. DMS analysis of the title salt is shown in
FIG. 18.
Example 7
Preparation of Form I of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Pyroglutamate Salt (Compound 1 Pyroglutamate Salt, Form I)
[0610] The title salt was prepared by combining one equivalent of
pyroglutamic acid with
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in ethyl
acetate at 60.degree. C. then cooling slowly and stirring
overnight. The resulting white solid was isolated by filtration and
dried.
[0611] A known amount of Compound 1 pyroglutamate was dissolved in
methanol and analyzed by UPLC. The percentage of Compound 1 in the
salt sample was determined to be 61.1%. This is close to the
theoretical percentage of Compound 1 in a 1:1 Compound 1
pyroglutamate salt, (60.3%).
[0612] The aqueous solubility of Compound 1 pyroglutamate was
determined to be >161.5 mg/mL at pH 3.94.
[0613] The powder X-ray diffraction pattern of the title salt is
shown in FIG. 19. Thermal analysis (TGA and DSC) of the title salt
is shown in FIG. 20. DMS analysis of the title salt is shown in
FIG. 21.
Example 8
Preparation of Form I of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Di-camphorate Salt Solvate (Compound 1 Di-camphorate Salt Solvate,
Form I)
[0614] The title salt was prepared by combining equal molar amounts
of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and
(1R,3S)-(+)-camphoric acid in ethyl acetate with 4% water. The
solution was heated to 50.degree. C. then slowly cooled. Upon
cooling the sample was a clear solution and did not change after
addition of MTBE. The sample was evaporated to a clear oil which
formed a white solid after standing at room temperature.
[0615] A known amount of Compound 1 di-camphorate salt (solvated)
was dissolved in methanol and analyzed by UPLC. Percent of Compound
1 in the salt sample was determined to be 28.9%. This is close to
the theoretical percent Compound 1 in a Compound 1 di-camphorate
hydrate, 31.9%.
[0616] The aqueous solubility of Compound 1 di-camphorate salt
solvate was determined to be 38.6 mg/mL (12.3 mg/mL of the free
base) at a pH of 5.2.
[0617] The powder X-ray diffraction pattern of the title salt is
shown in FIG. 22. Thermal analysis (TGA and DSC) of the title salt
is shown in FIG. 23. DMS analysis of the title salt is shown in
FIG. 24.
Example 9
Preparation of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Hydrochloride Salt Hemihydrate, Form III
Step A: Preparation of
8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
[0618] To a reactor equipped with overhead agitation, jacket
temperature control, a nitrogen inlet, and a caustic scrubber vent
were charged, in the specified order,
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride (1.00
kg, 3.72 mol), aluminum chloride (0.745 kg, 5.58 mol), and
1,2-dichlorobenzene (2.88 kg). The stirred reactor contents were
heated to 125-130.degree. C., and stirring was continued at that
temperature for 14-18 h. At 60-70.degree. C., a dark colored
solution was obtained. After reaction completion (<1.0% starting
material by HPLC peak area) had been verified, the stirred reactor
contents were cooled to 30-35.degree. C. To a second reactor vented
to a caustic scrubber was charged purified water (1.60 L) and
silica gel (0.160 kg). The Friedel-Crafts reaction mixture was
transferred from the first reactor to the second reactor
sufficiently slowly to maintain the stirred contents of the second
reactor at <60.degree. C. After the transfer is completed, the
next step may be executed without any hold period. The silica gel
was filtered on a medium to coarse filter element at 55-60.degree.
C., and the filtered solids were subsequently washed with purified
water (800 mL) preheated to 50-60.degree. C. The combined mother
and wash liquor filtrates were cooled to 20-25.degree. C. with
vigorous agitation. Then the stirring was stopped, and the phases
were allowed to separate at 20-25.degree. C. (Process volume peaked
at this point at 5.68 L). Three phases separated after 1-2 hours of
standing. The lowest layer was drained to waste disposal. This dark
layer consisted mostly of 1,2-dichlorobenzene (1.64 kg, 1.33 L) at
pH 3-4. About 1% of the product was lost to this layer. The
remaining two phases were allowed to stand without agitation for
another 2-4 h. The lower layer was drained and saved (Layer A).
This light colored phase (2.64 kg, 2.00 L, pH 2-3) contained
.about.90% 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine. The
upper layer (2.24 kg of a turbid water phase at pH 0-1) contains
.about.1-4% 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine and
remained in the reactor for back-extraction. The reactor was
charged with cyclohexane (1.10 kg) and then 30% aqueous NaOH (2.44
kg, 18.3 mol). The resulting mixture (5.60 L) was stirred
vigorously for 30 min at room temperature. The stirring was
stopped, and the phases were allowed to separate for 25-40 min. If
the pH of the lower (aqueous) phase was >13, it was drained to
waste disposal. Otherwise, more 30% aqueous NaOH was added, and
this extraction was repeated. At pH 14, the aqueous phase contains
<0.1% 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine free
base. The remaining upper (organic) phase from the reactor was
drained and saved (Layer B). The reactor was rinsed with purified
water and followed by a suitable organic solvent to remove residual
salts. The lower, light-colored product phase (the middle of the
original three phases, Layer A) and the upper phase (organic, Layer
B) were returned to the reactor. To the stirred reactor contents
was added 30% aqueous NaOH (1.60 kg, 12.0 mol). The reactor
contents were stirred vigorously for 0.5 hours. The stirring was
discontinued and the phases were allowed to separate over 15-30
minutes. The lower (aqueous) layer was drained to waste disposal.
To the upper (organic) phase remaining in the reactor was added
purified water (2.40 kg). The reactor contents were stirred
vigorously at 60-65.degree. C. for 0.5 h. The stirring was
discontinued, and the phases were allowed to separate at
60-65.degree. C. over 1.5-2 h. The lower (aqueous) layer was
drained to waste disposal. With a reactor jacket temperature of
55-60.degree. C., solvent from the upper (organic) layer was
removed by vacuum distillation at pressures starting at 115-152
torr and falling to 40 torr. The crude product,
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine as the free
base, was obtained as a yellow to brown oil distillation
residue.
Step B: Preparation of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Hemitartrate Salt
[0619] The distillation residue from Step A (crude
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine as the free
base) was dissolved in acetone (0.400 kg). The resulting solution
was drained and weighed to assay the
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine content by
HPLC. Results of the assay were used to calculate charges of
acetone, L-tartaric acid, and water. The quantities indicated below
are typical for achievement of the target
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine:acetone:L-tartaric
acid:water mole ratio of 1.00:9.6:0.25:3.6 prior to addition of
seed crystals. More acetone (1.415 kg) was added to the reactor and
the stirred reactor contents were heated to 47-52.degree. C. To the
resulting solution was added a solution of L-tartaric acid (0.1223
kg, 0.815 mol) in purified water (0.211 kg) at a steady rate over
5-15 min. A thin suspension formed during the addition but then
redissolved when the mixture temperature was reestablished at
50.degree. C. Hemitartrate seed crystals (0.80 g) were added to the
50.degree. C. solution to achieve cloudiness and to initiate
nucleation. Nucleation was allowed to continue for 2-3 h with
agitation at 47-52.degree. C. Acetone (0.473 kg) was added to the
reactor while the stirred reactor contents were maintained at
50.degree. C. The resulting suspension was cooled to 0-5.degree. C.
slowly over 3-5 h. Stirring was continued at 0.degree. C. for
another 1-3 h. The resulting white precipitate was collected on a
medium-to-fine filter element and then washed with a mixture of
acetone (0.900 kg) and purified water (0.054 kg). The enantiomeric
excess (ee) of the wet cake was determined
[0620] If the ee was <98%, the wet cake was transferred back
into the reactor and reslurried in a mixture of acetone (1.90 kg)
and purified water (0.400 kg) at 55-60.degree. C. for 0.5-1 h. If
dissolution had not been achieved after one h, then water
(approximately 0.160 kg) was added until a clear solution was
achieved. The resulting mixture was then cooled to 0-5.degree. C.
slowly over 2-3 h. Stirring at 0.degree. C. was continued for
another 3-5 h. The resulting white precipitate was collected on a
medium-to-fine filter element and then washed with acetone (0.400
kg) at 0-4.degree. C.
[0621] The washed solid product (296 g wet) was dried at
60-65.degree. C. under full vacuum for 15-20 hours. The yield of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemitartrate salt, with about 99.7% ee and 7.5 wt. % water content,
was 295 g (27.1% based on racemic
2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride and
corrected for product water content).
Step C: Preparation of
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Hydrochloride Salt Hemihydrate, Form III
[0622] To a reactor equipped with overhead agitation and a nitrogen
inlet was charged, in the specified order,
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hemitartrate (1.00 kg containing 7.5 wt % water, 1.71 mol),
potassium carbonate (0.508 kg, 3.68 moles), ethyl acetate (2.68
kg), and purified water (2.68 kg). The resulting mixture was
stirred at 20-25.degree. C. for 30-40 min, and then the phases were
allowed to separate over 0.5-1 h. The lower (aqueous) phase was
drained to waste disposal. Purified water (2.68 kg) was added to
the reactor, and the resulting mixture was vigorously stirred for
10-20 min. The phases were allowed to separate over 1-1.5 h. The
lower (aqueous) phase was drained to waste disposal. With the
reactor contents at a temperature of 40-45.degree. C., the solvent
was removed by vacuum distillation at pressures falling from 153
torr to 46 torr. The residue was cooled to 20-25.degree. C. Ethyl
acetate (3.81 kg) was charged to the reactor, and the distillation
residue was dissolved with stirring. The water content of the
resulting solution was verified by Karl Fischer analysis to be
<0.8 wt. %. The solution was filtered through a polishing
filter. The reactor was rinsed through the filter with ethyl
acetate (2.33 kg) previously verified by Karl Fischer analysis to
have <0.05 wt. % water content. Both the solution and rinse
filtrates were charged back into the reactor. Purified water (39.9
g) was added to the reactor. The stirred reactor contents were
cooled to 0-5.degree. C., and then HCl gas (19.0 g, 0.521 mol) was
added while the stirred reactor contents were maintained at
0-5.degree. C.
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hydrochloride salt hemihydrate seed crystals (1.33 g) were added to
the stirred reactor contents to initiate nucleation at 0-5.degree.
C. The remaining HCl gas (107.6 g, 2.95 mol) was charged to the
reactor at a steady rate over at least 1.5-2 h while the stirred
reactor contents were maintained at 0-5.degree. C. The resulting
suspension was stirred at 0-5.degree. C. for 2 h. The resulting
white precipitate was collected on a medium-to-fine filter element.
The reactor and then the filtered solid product were washed with
ethyl acetate (1.33 kg). The wet cake (ca. 867 g) was dried at full
vacuum and 33-37.degree. C. for 20 h or until the cake temperature
had been stable for 4 hours, whichever occurred first. The
resulting (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hydrochloride salt hemihydrate (3.7 wt. % water content, 14.7%
chloride content, <0.01% ROI, >99.6% ee, >99% HPLC purity,
and <0.1% wrong isomer content) was obtained in a yield of about
741 g (89.9%).
[0623] Those skilled in the art will recognize that various
modifications, additions, substitutions, and variations to the
illustrative examples set forth herein can be made without
departing from the spirit of the invention and are, therefore,
considered within the scope of the invention.
* * * * *