OA16618A - Novel fumarate salts of a histamine H3 receptor antagonist. - Google Patents
Novel fumarate salts of a histamine H3 receptor antagonist. Download PDFInfo
- Publication number
- OA16618A OA16618A OA1201100499 OA16618A OA 16618 A OA16618 A OA 16618A OA 1201100499 OA1201100499 OA 1201100499 OA 16618 A OA16618 A OA 16618A
- Authority
- OA
- OAPI
- Prior art keywords
- cyclohexylmethyl
- ethyl
- methylpyrrolidin
- tetrahydroisoquinoline
- sulfonamide
- Prior art date
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- 238000000034 method Methods 0.000 claims abstract description 22
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Abstract
The disclosure relates to fumarate salts of 2(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide, to pharmaceutical compositions thereof, processes for making the same, and methods of use thereof.
Description
The présent invention relates to novel fumarate sait forms of 2-(cyclohexylmethyl)-A/-(2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and pharmaceutical compositions thereof. This invention also relates to processes for the préparation of such sait forms and pharmaceutical compositions, and to methods of use thereof for the prévention and treatment of diseases related to the histamine H3 receptors.
BACKGROUND OF THE INVENTION
The histamine H3 receptors are found ïn the central and peripheral nervous Systems. The administration of histamine H3 receptor ligands may influence the histamine levels or the sécrétion of neurotransmitters in the brain and the periphery and thus can be useful in the treatment of several disorders, including Alzheimer's disease and other dementias, obesity, central nervous system disorders such as vigilance and sleep disorders, narcolepsy, Parkinson’s disease, attention-deficit hyperactivity disorder, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive disorders, dépréssion, anxiety, cardiovascular disorders, and gastrointestinal disorders.
To illustrate, a number of studies in the literature hâve demonstrated the cognitive enhancing properties of histamine H3 receptors antagonists in rodent models (See, e.g., Giovannini et al., Behav. Brain Res., 104, 147-155 (1999)). These reports further suggest that antagonists and/or inverse agonists could be useful for the treatment of cognitive impairments in neurological diseases such as Alzheimer's disease and related neurodegenerative disorders. Alzheimer's disease is the most common cause of dementia in the elderly, and is often characterized with one or more symptoms such as memory loss, confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, withdrawal of the sufferer, and loss of motor control.
2-(Cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl)-1,2,3,4-tetrahydroisoquinoline-7sulfonamide, which has the structure of Formula (I):
is a potent histamine H3 receptor antagonist with inverse agonist properties. The préparation, physical properties and bénéficiai pharmacological properties of 2-(cyclohexylmethyl)-/\/-{2[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide are described in, for example, W02005/118547 (also US2007/0105834). In W02005/118547, 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide is described as being in the free base form, which is a viscous oil, or in the form of an oxalate sait, which has low crystallinity and thermal stability.
Although it is known that the préparation of sait forms may improve the physical or pharmaceutical properties of a pharmaceutically active compound, it is not possible to predict which sait forms may possess advantages for a particular purpose prior to the actual préparation and characterization of the sait form. In particular, such advantages, in a nonlimiting manner could include, physical forms of the sait in that it provides better processability, solubility or shelf life stability, just to name a few. Other advantages may also include biological properties such as improved bioavailability, reduced adverse reactions at the Gl tract (for example irritation of the Gl tract, partial dégradation of the compound, etc.), or better deliverabilîty of the drug to the intended target site among other advantages.
The présent invention therefore provides fumarate salts of 2-(cyclohexylmethyl)-/V-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide which exhibit advantageous properties which differentiate the fumarate salts from the base form of 2(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide itself, and over other sait forms of 2-(cyclohexylmethyl)-/V-(2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide known in the art.
Furthermore, the crystallinity and stability profile of the difumarate monohydrate sait of 2(cyclohexylmethyl)-A/-(2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3l4-tetrahydroisoquinoline-7sulfonamide make this solid form unpredictably and particularly useful as a médicament.
-3SUMMARY OF THE INVENTION
Accordingly, the présent invention is directed to the fumarate salts of 2-(cyclohexylmethyl)-/\/-{2[(2S)-1 -methyIpyrrolîdin-2-yl]ethyI}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide. The présent invention is also directed to novel crystalline forms of the fumarate salts of 2-(cyclohexylmethyl)A/-(2-[(2S)-1 -methylpyrrolidrn-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide.
One aspect of the invention is the difumarate monohydrate sait of 2-(cyclohexylmethyl)-A/-{2[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (designated the difumarate monohydrate sait), represented by Formula (II):
Another aspect of the invention is the difumarate sait of 2-(cyclohexylmethyl)-N-(2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,213,4-tetrahydroisoquinoline-7-sulfonamide difumarate sait), represented by Formula (III):
(designated the
Another aspect of the invention is the monofumarate sait of 2-(cyclohexylmethyl)-N-(2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (designated the monofumarate sait), represented by Formula (IV):
/7
Another aspect of the invention is the hemifumarate dihydrate sait of 2-(cyc!ohexylmethyl)-/V-{2[(2S)-1-methylpyrrolidin“2-ylJethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (designated “the hemifumarate dihydrate sait), represented by Formula (V):
OH (V).
Another aspect of the invention is the hemifumarate sait of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methy lpyrrolidin-2-y l]ethyl}-1 .Z.S^-tetrahydroisoquinoline-y-sulfonamide (designated “the hemifumarate sait), represented by Formula (VI):
OH (VI).
Another aspect of the présent invention is a pharmaceutical composition comprising one or more compounds of the invention and a pharmaceutically acceptable carrier.
Another aspect of the invention is a pharmaceutical composition prepared by formulating one or more compounds of the invention with one or more pharmaceutically acceptable carriers.
Another aspect of the invention is a process for preparing a pharmaceutical composition of 2(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2“yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide comprising formulating one or more compounds of the invention with one or more pharmaceutically acceptable diluents.
Another aspect of the présent invention is a method of treating a pathology in which a histamine H3 receptor antagonist provides a therapeutic benefit.
CS
-5The présent invention is more fully discussed with the aid of the following figures and detailed description below.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray powder diffractogram of crystalline 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate of the présent invention.
Figure 2 is a Fourier Transform Infrared (FTIR) spectrum of 2-(cyclohexylmethyl)-/V-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate of the présent invention.
Figure 3 is a Differential Scanning Calorimetry - Thermal Gravimétrie Analysis and Mass Spectrometry (DSC-TGA-MS) thermogram of 2-(cyclohexylmethyl)-N-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate of the présent invention.
Figure 4 is an X-ray powder diffractogram of crystalline 2-(cyclohexylmethy()-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate of the présent invention.
Figure 5 is an X-ray powder diffractogram of crystalline 2-(cyclohexylmethyl)-A/-(2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate of the présent invention.
Figure 6 is an overlay of DSC-TGA thermograms of 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1 methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide monofumarate, and 2-(cyclohexylmethyl)-W-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate of the présent invention.
Figure 7 is an overlay of X-ray powder diffractograms of crystalline 2-(cyclohexylmethyl)-/V-{2[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2l3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate and crystalline 2-(cyclohexy lmethyl)-A/-{2-[(2S)-1 -methylpy rrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate of the présent invention.
-6Figure 8 is the dynamic vapor sorption (DVS) water sorption profile of 2-(cyclohexylmethyl)-/V{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3l4-tetrahydroisoquinoline-7-sulfonamide difumarate and corresponding 2-(cyclohexy I methy Ι)-Λ/-{2- [(2 S)-1 -met h y I py rro lidi n-2-y I Jethy I}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate of the présent invention.
Figure 9 is the DVS hydgroscopicity profile of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate and corresponding 2-(cyclohexylmethyl)-A/-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate of the présent invention.
DETAILED DESCRIPTION OFTHE INVENTION
Définitions and Abbreviations
As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to hâve the following meanings:
| DMF | A/,A/-dimethy!formamide |
| ETOH | éthanol |
| g | gram |
| HPLC | high performance liquid chromatography |
| mg | milligram |
| mL | milliliter |
| uL | microliter |
| MTBE | tert-butyl methyl ether |
| NMR | nuclear magnetic résonance |
| RH | relative humidity |
As used above, and throughout the description of the invention, various terms used herein shall hâve the generally accepted meanings in the art. More particularly, the following terms, unless otherwise indicated, shall generally be understood to hâve the following meanings.
The “difumarate monohydrate sait, as used herein, is meant to describe the difumarate monohydrate sait of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide that may be characterized using distinguishing data as described herein. Exemplary data is found in Figures 1, 2, 3 and 8. The difumarate monohydrate sait of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide is also synonymously called 2-(cyclohexylmethyl)-N-{216618
-7[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate hydrate and 2-(cyclohexylmethyl)-A/-{2-[(2S)-1 -methylpy rrolidin-2-y l]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.
The difumarate sait, as used herein, is meant to describe the difumarate sait of 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2l3,4-tetrahydroÎsoquinoline-7sulfonamide that may be characterized using distinguishing data as described herein. Exemplary data is found in Figures 4 and 8. The difumarate sait of 2-(cyclohexylmethyl)-A/-{2[(2S)-1 -methylpy rrolrdin-2-yf]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide is also synonymously called 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate, anhydrous 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpy rrolidi n-2-y l]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate, 2(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide difumarate anhydrate, and the difumarate anhydrate.
The “monofumarate sait, as used herein, is meant to describe the monofumarate sait of 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2l3,4-tetrahydroisoquinoline-7sulfonamide that may be characterized using distinguishing data as described herein. Exemplary data is found in Figures 5 and 6. The monofumarate sait of 2-(cyclohexylmethyl)-A/{2-[(2S)-1 -methylpy rrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide is also synonymously called 2-(cyclohexylmethyl)-A/-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide monofumarate.
The “hemifumarate sait, as used herein, is meant to describe the hemifumarate sait of 2(cyclohexylmethyl)-/V-{2-f(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide that may be characterized using distinguishing data as described herein. Exemplary data is found in Figures 6, 7, and 9. The hemifumarate sait of 2-(cyclohexylmethyl)A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1l2,3,4-tetrahydroisoquinoline-7-sulfonamide is also synonymously called 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1.2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate, 2-(cyclohexylmethyl)-/V-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dehydrate, anhydrous 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinolîne-7-sulfonamide hemifumarate, and the hemifumarate anhydrate sait.
The hemifumarate dihydrate sait, as used herein, is meant to describe the hemifumarate dihydrate sait of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide that may be characterized using distinguishing data as described herein. Exemplary data is found in Figures 6, 7 and 9. The hemifumarate dihydrate
-8salt of 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide is also synonymously called 2-(cyclohexylmethyl)-/V-{2[(2S)-1-methylpyrrolidin-2-yl]ethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate.
“Compounds of the invention, as used herein, is meant to describe 2-(cyclohexylmethyl)-A/-{2[(2S)-1 -methyl py rrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolîdin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate, 2-{cyclohexylmethyl)-A/-{2-[(2S)-1 methylpy rrolidi n-2-yl]et hy I}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamîde hemifumarate, and 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate.
Treating or “treatment means to alleviate or partially alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to slow the appearance of symptoms of the named disorder or condition. The compounds and compositions of this invention are useful in treating a pathology in which a histamine H3 receptor antagonist provides a therapeutic benefit. For example, the treatment of Alzheimer’s disease may include reversing disease progression, improving memory and/or cognition; and slowing the loss of memory and/or cognition.
“Patient includes both human and other mammals.
“Pharmaceutically effective amount is meant to describe an amount of a compound, composition, médicament or other active ingrédient effective in producing the desired therapeutic effect.
The présent invention provides a process for the manufacture of the 2-(cyclohexylmethyl)-A/-{2[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate of formula (II), said process comprising the steps of contacting, under elevated température or at ambient température, 2-(cyclohexylmethyl)-/V-{2-[(2S)-1 -methylpyrrolidin-2y!]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide dissolved in a suitable solvent or in a mixture of solvents, with fumaric acid, optîonally dissolved in a solvent or in a mixture of solvents, and isolating the precipitated solid, for example by filtration or removal of the solvent. In one embodiment, about two moles of fumaric acid are reacted per mole of 2(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamîde. In another embodiment, greater than two moles of fumaric acid are reacted per
Q16618
-9mole of
2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3.4tetrahydroisoquinoline-7-sulfonamide.
Suitable solvents to dissolve 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1.2.3.4- tetrahydroisoquinoline-7-sulfonamîde for performing the sait formation comprise alcohols, for example methanol, éthanol, 1- or 2-propanol, isomeric alcohols of butanol, isomeric alcohols of pentanol, and isomeric alcohols of hexanol, like 2-methyl-4-pentanol; ketones like acetone; ethers, for example tetrahydrofuran and dioxane; acetic acid esters, for example ethyl acetate; organic acids, for example acetic acid; amides, for example N-methylpyrrolidinone and nitriles, for example acetonitrile; and mixtures thereof including mixtures comprising water.
Also provided is a process for preparing 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate comprising contacting 2-(cyclohexylmethyl)-/V-{2-[2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate with water,
Another aspect of the invention, îs the process for preparing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl)-1,2,3l4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate comprising exposing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamrde difumarate to above about 10% relative humidity at around ambient température, wherein ambient température ranges from 20 to 25 “C.
A particular aspect of the invention is 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate in crystalline form. The crystalline form of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1.2.3.4- tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate described in this spécification is referred to as 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate Form I. In one aspect of the invention, the crystalline form of 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate exhibits an X-ray diffraction pattern comprising peaks at about 5.31, 5.84, 7.00, and 8.67 degrees 2-theta.
Another particular aspect of the invention is a process for preparing 2-(cyclohexylmethyl)-/\/-{2[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate rn crystalline form.
To obtain 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate in crystalline form, 216618
-ιο(cyclohexylmethyl)-/V-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide is dissolved in a suitable solvent or in a mixture of solvents, including but not limited to methanol, éthanol, isopropanol, acetonitrile, acetone, and water with fumaric acid, optionally dissolved in a solvent or in a mixture of solvents, and isolating the precipitated solid, for example by filtration or removal of the solvent by vacuum drying. In one embodiment, 1 mole of fumaric acid is reacted per mole of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide. In another embodiment, two moles of fumaric acid are reacted per mole of 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide.
For a better control of the crystallization, it is possible to provide a step of initiating the crystallization, carried out by seeding the reaction medium with a small amount of 2(cyclohexylmethyl)-/V-{2-((2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide difumarate monohydrate previously obtained in crystalline form, such as described above. For this seeding, it is possible to use, for example, a weight percentage of 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide difumarate monohydrate between 0.05% and 5% relative to the total amount of 2(cyclohexylmethyl)-/V-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethy l}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide in base form to be reacted. For example, about 0.1 wt % of 2-(cyclohexylmethyl)A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate could be used relative to the total amount of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide in base form to be reacted.
Another aspect of the invention is 2-(cyclohexylmethyl)-W-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate. This difumarate sait is particularly useful for the préparation of the difumarate monohydrate sait.
A particular aspect of the invention is 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2l3,4-tetrahydroisoquinoline-7-sulfonamide difumarate in crystalline form. The crystalline form of 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate described in this spécification is referred to as 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2l3,4-tetrahydroisoquinoline-7sulfonamide difumarate Form I. In one aspect of the invention, the crystalline form of 2(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide difumarate exhibits an X-ray diffraction pattern comprising peaks at about 5.21, 5.67, 7,06, and 11.34 degrees 2-theta,
-IIThe présent invention also provides a process for preparing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1methylpyrrolidin-2-yi]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate, comprising dehydrating 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.
In one aspect of the invention, a process for preparing 2-(cyclohexylmethyl)-N-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate comprises exposing 2-(cyc!ohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate to low relative humidity, for example below about 10% humidity for two or more hours at around ambient température, wherein ambient température ranges from 20 to 25 °C.
In another aspect of the invention, a process for preparing 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate comprises heating 2-(cyclohexylmethyl)-/V-(2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate above about 75°C.
In another aspect of the invention, a process for preparing 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate comprises heating 2-(cyclohexylmethyl)-/V-(2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate above room température, for example above about 40°C, at low relative humidity, for example below about 10% humidity.
Another aspect of the invention is 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate. A particular aspect of the invention is 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide monofumarate in crystalline form. The crystalline form of 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide monofumarate described in this spécification is referred to as 2-(cyclohexylmethyl)/V-{2-[(2S)-1-methylpynOlidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate Form I. In one aspect of the invention, the crystalline form of 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yljethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide monofumarate exhibits an X-ray diffraction pattern comprising peaks at about 3.37, 6.70, 13.36, 14.83, 15.88, and 17.65 degrees 2-theta.
The présent invention also provides a process for preparing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoqurnoline-7-sulfonamide monofumarate, comprising contacting, under elevated température or at ambient température 216618
-I2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide dissolved in a suitable solvent or in a mixture of solvents, with one équivalent of fumaric acid, optionally dissolved in a solvent or in a mixture of solvents, and isolating the precipitated difumarate monohydrate solid, for example by filtration or removal of the solvent. The monofumarate sait may be obtained after successive crystallizations from the mother liquor.
Suitable solvents to dissolve 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide for performing the monofumarate sait formation comprise alcohols, for example methanol, éthanol, 1- or 2-propanol, isomeric alcohols of butanol, isomeric alcohols of pentanol, and isomeric alcohols of hexanol, like 2-methyl-4pentanol; ketones like acetone; ethers, for example tetrahydrofuran and dioxane; acetic acid esters, for example ethyl acetate; organic acids, for example acetic acid; amides, for example N-methylpyrrolidinone and nïtriles, for example acetonitrile; and mixtures thereof including mixtures comprising water.
Another aspect of the invention is 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1.21314- tetrahydroisoquinoline-7-sulfonamide hemifumarate. A particular aspect of the invention is 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide hemifumarate in crystalline form. The crystalline form of 2-(cyclohexylmethyl)-A/-{2[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate described in this spécification is referred to as 2-(cyclohexylmethyl)-A/-(2-[(2S)-1methylpyrrolidin-2-yl]ethyl)-1,2,3,4-tetrahydroisoquinoline-7“Sulfonamide hemifumarate Form I. In one aspect of the invention, the crystalline form of 2-(cyclohexylmethyl)-/V-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate exhibits an X-ray diffraction pattern comprising peaks at about 3.61, 7.22, 7.96, 8.21, 9.01, 10.82, and 15.66 degrees 2-theta.
The présent invention also provides a process for preparing 2-(cyclohexylmethyl)-A/-{2-((2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate, comprising the steps of contacting, under elevated température or at ambient température, 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide dissolved in a suitable solvent or in a mixture of solvents, with fumaric acid, optionally dissolved in a solvent or in a mixture of solvents, and isolating the precipitated solid, for example by filtration or removal of the solvent, and drying. The hemifumarate sait may be obtained after successive crystallizations from the mother liquor.
Suitable solvents to dissolve 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1.21314- tetrahydroisoquinoline-7-sulfonamide for performing the hemifumarate sait formation
Q16618
-13comprise alcohols, for example methanol, éthanol, 1- or 2-propanol, isomeric alcohols of butanol, isomeric alcohols of pentanol, and isomeric alcohols of hexanol, like 2-methyl-4pentanol; ketones like acetone; ethers, for example tetrahydrofuran and dioxane; acetic acid esters, for example ethyl acetate; organic acids, for example acetic acid; amides, for example N-methylpyrrolidinone and nitriles, for example acetonitrile; and mixtures thereof including mixtures comprising water.
The présent invention also provides a process for preparing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1(2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate, comprising dehydrating 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate.
In one aspect of the invention, a process for preparing 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate comprises exposing 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate to low relative humidity, for example below about 10% humidity for two or more hours.
In another aspect of the invention, a process for preparing 2-(cyclohexylmethyl)-/V-{2-[(2S}-1methylpyrrolidin-2-yl]ethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate comprises heating 2-(cyclohexy Imethy l)-A/~{2-[(2S)-1 -methy lpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamïde hemifumarate dihydrate above about ambient températures, wherein ambient température ranges from about 20 to about 25°C.
In another aspect of the invention, a process for preparing 2-(cyclohexylmethyl)-A/-{2-((2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate comprises heating 2-(cyclohexylmethyl)-A/-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate above room température, for example above about 40°C, at low relative humidity, for example below about 19% humidity.
Another aspect of the invention is 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate. A particular aspect of the invention is 2-(cyclohexy Imethy Ι)-Λ/-{2-[(2 S)-1 -m ethy Ipy rrol id in-2-y IJethy I}-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate in crystalline form. The crystalline form of 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate described in this spécification is referred to as 2-(cyciohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate Form I. In one aspect of the
-14invention. the crystalline form of 2-(cyclohexylmethyl)-M-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate exhîbits an X-ray diffraction pattern comprising peaks at about 3.49, 6.93, 8.46, 10.34, 13.25, 13.75, and 15.40 degrees 2-theta.
The présent invention also provides a process for preparing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate comprising contacting 2-(cyclohexylmethyl)-/V-{2-[2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate with water.
Another aspect of the invention, is the process for preparing 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydrofsoquinoline-7-sulfonamide hemifumarate dihydrate comprising exposing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-ylJethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate to above about 20% relative humidity at around ambient température, wherein ambient température ranges from 20 to 25 °C.
The présent invention provides pharmaceutical compositions comprising 2-(cyclohexylmethyl)A/-{2-[(2S)-1-methylpyrrolidin-2'yl]ethyl}-1l2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate in combination with a pharmaceutically acceptable carrier. In one aspect of the invention, the pharmaceutical composition comprises crystalline 2-(cyclohexylmethyl)-/V-{2[( 2 S)-1 -methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate in combination with a pharmaceutically acceptable carrier.
The présent invention also provides pharmaceutical compositions comprising 2(cyclohexylmethyl)-A/-{2-{(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide difumarate in combination with a pharmaceutically acceptable carrier. In one aspect of the invention, the pharmaceutical composition comprises crystalline 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide difumarate in combination with a pharmaceutically acceptable carrier.
The présent invention also provides pharmaceutical compositions comprising 2(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidîn-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide monofumarate in combination with a pharmaceutically acceptable carrier. In one aspect of the invention, the pharmaceutical composition comprises crystalline 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide monofumarate in combination with a pharmaceutically acceptable carrier.
-ISThe présent invention also provides pharmaceutical compositions comprising 2(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2l3l4-tetrahydroisoquinoline-7sulfonamide hemifumarate in combination with a pharmaceutically acceptable carrier. In one aspect of the invention, the pharmaceutical composition comprises crystalline 2(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3l4-tetrahydroisoquinoline-7sulfonamide hemifumarate in combination with a pharmaceutically acceptable carrier.
The présent invention also provides pharmaceutical compositions comprising 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1l2,3,4-tetrahydroisoquinoline-7sulfonamide hemifumarate dihydrate in combination with a pharmaceutically acceptable carrier. In one aspect of the invention, the pharmaceutical composition comprises crystalline 2(cyclohexylmethyi)-N-{2-[(2S)-1-methylpyrrolldin-2-yl]ethyl}-1l2l3,4-tetrahydrotsoquinoline-7sulfonamide hemifumarate dihydrate in combination with a pharmaceutically acceptable carrier.
Another aspect of the invention is a pharmaceutical composition prepared by formulating the difumarate monohydrate sait with one or more pharmaceutically acceptable carriers.
Another aspect of the invention is a pharmaceutical composition prepared by formulating the difumarate sait with one or more pharmaceutically acceptable carriers.
Another aspect of the invention is a pharmaceutical composition prepared by formulating the monofumarate sait with one or more pharmaceutically acceptable carriers.
Another aspect of the invention is a pharmaceutical composition prepared by formulating the hemifumarate sait with one or more pharmaceutically acceptable carriers.
Another aspect of the invention is a pharmaceutical composition prepared by formulating the hemifumarate dihydrate sait with one or more pharmaceutically acceptable carriers.
The présent invention also provides a process for preparing a pharmaceutical composition comprising formulating the difumarate monohydrate sait with one or more pharmaceutically acceptable diluents.
The présent invention also provides a process for preparing a pharmaceutical composition comprising formulating the difumarate sait with one or more pharmaceutically acceptable diluents.
-I6The présent invention also provides a process for preparing a pharmaceutical composition comprising formulating the monofumarate sait with one or more pharmaceutically acceptable diluents.
The présent invention also provides a process for preparing a pharmaceutical composition comprising formulating the hemifumarate sait with one or more pharmaceutically acceptable diluents.
The présent invention also provides a process for preparing a pharmaceutical composition comprising formulating the hemifumarate dihydrate sait with one or more pharmaceutically acceptable diluents.
The compounds of the invention may be administered in pharmaceutically acceptable dosage forms to humans and other mammals by topical or systemic administration, including oral, inhalational, rectal, nasal, buccal, sublingual, vaginal, colonie, parentéral (including subeutaneous, intramuscular, intravenous, intradermal, intrathecal and épidural), intracisternal and intraperitoneal. It will be appreciated that the particular route may vary with for example the physiological condition of the récipient.
“Pharmaceutically acceptable dosage forms” refers to dosage forms of the compounds of the invention, and includes, for example, tablets, dragées, powders, élixirs, syrups, liquid préparations, including suspensions, sprays, inhalants tablets, lozenges, émulsions, solutions, granules, capsules and suppositories, as well as liquid préparations for injections, including liposome préparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest édition.
A particular aspect of the invention provides for the compounds of the invention to be administered in the form of a pharmaceutical composition.
Pharmaceutically acceptable carriers include at least one component selected from the group comprising pharmaceutically acceptable carriers, diluents, coatings, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsîfying agents, stabilizing agents, suspending agents, isotonie agents, sweetening agents, flavoring agents, perfuming agents, coloring agents, antibacterial agents, antifungal agents, other therapeutic agents, lubricating agents, adsorption delaying or promoting agents, and dispensing agents, depending on the nature of the mode of administration and dosage forms.
-17Exemplary suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxîde, bentonite, agar-agar and tragacanth, or mixtures of these substances.
Exemplary antibacterial and antifungal agents for the prévention of the action of microorganisms include parabens, chlorobutanol, phénol, sorbic acid, and the like.
Exemplary isotonie agents include sugars, sodium chloride, and the like.
Exemplary adsorption delaying agents to prolong absorption include aluminum monostearate and gelatin.
Exemplary adsorption promoting agents to enhance absorption include dimethyl sulfoxide and related analogs.
Exemplary diluents, solvents, vehicles, solubilizing agents, stabilizing agents, emulsifiers and émulsion stabilizers, include water, chloroform, sucrose, éthanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol, 1,3-butylene glycol, glycerol, polyethylene glycols, dimethylformamide, Tween® 60, Span® 60, cetostearyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate, fatty acid esters of sorbitan, vegetable oils (such as cottonseed oil, groundnut oil, olive oil, castor oil and sesame oil) and injectable organic esters such as ethyl oleate, and the like, or suitable mixtures of these substances.
Exemplary excipients include lactose, milk sugar, sodium citrate, calcium carbonate and dicalcium phosphate.
Exemplary disintegrating agents include starch, alginic acids and certain complex silicates.
Exemplary lubricants include magnésium stéarate, sodium lauryl sulfate, talc, as well as high molecular weight polyethylene glycols.
Pharmaceutical compositions of the présent invention suitable for oral administration may be presented as discrète units such as a solid dosage form, such as capsules, cachets or tablets each containing a predetermined amount of the active ingrédient, or as a powder or granules; as a liquid dosage form such as a solution or a suspension in an aqueous liquid or a nonaqueous liquid, or as an oil-in-water liquid émulsion or a water-in-oil liquid émulsion. The active ingrédient may also be presented as a bolus, electuary or paste.
-I8“Solid dosage form means the dosage form of a compound of the invention is in solid form, for example capsules, tablets, pills, powders, dragées or granules. In such solid dosage forms, a compound of the invention is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or: (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, (i) lubrîcants, as for example, talc, calcium stéarate, magnésium stéarate, solid polyethylene glycols, sodium lauryl sulfate, (j) opacifying agents, (k) buffering agents, and agents which release a compound of the invention in a certain part of the intestinal tract in a delayed manner.
A tablet may be made by compression or molding, optionally with one or more accessory ingrédients. Compressed tablets may be prepared by compressing in a suitable machine the active ingrédient în a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubrîcants such as magnésium stéarate, sodium lauryl sulfate and talc may be used. A mixture of the powdered compounds moistened with an inert liquid diluent may be molded in a suitable machine to make molded tablets. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingrédient therein.
Solid compositions may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.
If desired, and for more effective distribution, the compound can be microencapsulated in. or attached to, a slow release or targeted delivery Systems such as a biocompatible, biodégradable polymer matrices (e.g., poly(d,l-lactide co-glycolide)), liposomes, and microspheres and subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer. The compound may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of stérile solid
-19compositions which can be dissolved in stérile water, or some other stérile injectable medium immediately before use.
“Liquid dosage form means the dose of the active compound to be administered to the patient is in liquid form, for example, pharmaceutically acceptable émulsions, solutions, suspensions, syrups and élixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as solvents, solubilizing agents and emulsifiers.
When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
Pharmaceutical compositions suitable for topical administration means formulations that are in a form suitable to be administered topically to a patient. The formulation may be presented as a topical ointment, salves, powders, sprays and inhalants, gels (water or alcohol based), creams, as is generally known in the art, or incorporated into a matrix base for application in a patch, which would allow a controlled release of the compound through the transdermal barrier. When formulated in an ointment, the active ingrédients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingrédients may be formulated in a cream with an oil-in-water cream base. Formulations suitable for topical administration in the eye include eye drops wherein the active ingrédient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingrédient. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingrédient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingrédient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingrédient in a suitable liquid carrier.
The oily phase of the émulsion pharmaceutical composition may be constituted from known ingrédients, in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. In a particular embodiment, a hydrophilic emulsifier is included together with a lipophilie emulsifier that acts as a stabilizer. Together, the emulsifier(s) with, or without, stabilizer(s) make up the emulsifying wax, and together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
If desired, the aqueous phase of the cream base may include, for example, a least 30% w/w of a polyhydric alcohol, Le. an alcohol having two or more hydroxyl groups such as, propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)
-20and mixtures thereof. The topical formulations may desirably include a compound that enhances absorption, or pénétration of the active ingrédient through the skin, or other affected areas.
The choice of suitable oils or fats for a composition is based on achieving the desired properties. Thus a cream should particularly be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stéarate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used. These may be used alone or in combination depending on the properties required. Alternative^, high melting point lipids such as white soft paraffin and/or liquid paraffin or other minerai oils can be used.
Pharmaceutical compositions suitable for rectal or vaginal administrations mean formulations that are in a form suitable to be administered rectally or vaginally to a patient and containing at least one compound of the invention. Suppositories are a particular form for such formulations that can be prepared by mixing a compound of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary températures but liquid at body température and therefore, melt in the rectum or vaginal cavity and release the active component.
Pharmaceutical compositions administered by injection may be by transmuscular, intravenous, intraperitoneal, and/or subcutaneous injection. The compositions of the présent invention may be formulated in liquid solutions, in particular in physiologically compatible buffers such as Hank’s solution or Ringer's solution. In addition, the compositions may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms are also included. The formulations are stérile and include émulsions, suspensions, aqueous and nonaqueous injection solutions, which may contain suspending agents and thickening agents and anti-oxidants, buffers, bacteriostats and solutés which render the formulation isotonie, and hâve a suitably adjusted pH, with the blood of the intended récipient.
Pharmaceutical compositions of the présent invention suitable for nasal or inhalational administration are in a form suitable to be administered nasally or by inhalation to a patient. The composition may contain a carrier, in a powder form, having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in incréments of 5 microns such as 30 microns, 35 microns, etc.). Suitable compositions wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingrédient. Compositions suitable for aérosol
-2Iadministration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers or any suitable dry powder inhaler.
Actual dosage levels of active ingredient(s) in the compositions of the invention may be varied so as to obtain an amount of active ingredient(s) that is (are) effective to obtain a desired therapeutic response for a particular composition and method of administration for a patient. A selected dosage levei for any particular patient therefore dépends upon a variety of factors including the desired therapeutic effect, the route of administration, the desired duration of treatment, the etiology and severity of the disease, the patients condition, weight, sex, diet and âge, the type and potency of each active ingrédient, rates of absorption, metabolism and/or excrétion and other factors.
Total daily dose of a compound of this invention administered to a patient in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily and particularly 0.01 to 10 mg/kg/day. For example, in an adult, the doses are generally from about 0.01 to about 100, particularly about 0.01 to about 10, mg/kg body weight per day by inhalation, from about 0.01 to about 100, particularly 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.01 to about 50, particularly 0.01 to 10, mg/kg body weight per day by intravenous administration. The percentage of active ingrédient in a composition may be varied, though it should constitute a proportion such that a suitable dosage shall be obtained. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. Obviously, several unit dosage forms may be administered at about the same time. A dosage may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much lower maintenance doses adéquate. For other patients, it may be necessary to hâve long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requîrements of each particular patient. For other patients, it may be necessary to prescribe not more than one or two doses per day.
The formulations can be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the pharmaceutically active ingrédient with the carrier that constitutes one or more accessory Ingrédients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingrédient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
-22The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the stérile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from stérile powders, granules and tablets of the kind previously described.
The pharmaceutical compositions of the présent invention preferably contain a pharmaceutically effective amount of a compound of the invention. In determining the effective amount or dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, âge, and general health; the spécifie disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the mode of administration; the bioavailability characteristics of the préparation administered; the dose regimen selected; the use of concomitant médication; and other relevant circumstances.
The pharmaceutical compositions of the présent invention can be administered with other therapeutic and/or prophylactic agents and/or médicaments that are not medically incompatible therewith.
All components of the présent compositions must be pharmaceutically acceptable. As used herein, a “pharmaceutically acceptable” component is one that is suitable for use with humans and/or other animais without undue adverse side effects (such as toxicity, irritation and allergie response) commensurate with a reasonable benefit/risk ratio.
The présent invention further relates to the use of the pharmaceutical compositions of the invention in medicine.
2-(Cyclohexylmethyl)-N-(2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide is a potent histamine H3 receptor antagonist and, as such, can be used in the treatment of pathologies in which a histamine H3 receptor antagonist provides a therapeutic benefit. In particular, the compounds of the invention can be used in the treatment of obesity, diabètes, central nervous system diseases such as vigilance and sleep disorders, narcolepsy, Alzheimer's disease and other dementias, Parkinson's disease, attention-deficit hyperactivity disorder, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive disorders, dépréssion, and anxiety. The states of dépréssion and anxiety include, for example, anxieties of anticipatory type (before a surgical procedure, before a dental treatment, etc), anxiety caused by alcohol or drug dependency or withdrawal, mania, seasonal affective disorders, migraines and nausea. The compounds of the invention can also be used in the
-23treatment of sexual dysfunction, dizziness and travel sickness. The compounds of the invention can also be used in the treatment of cardiovascular disorders and gastrointestinal disorders.
An aspect of the invention is a method of treating pathologies in which a histamine H3 receptor antagonist provides a therapeutic benefit, which comprises administering to a patient in need of said treatment a pharmaceutically effective amount of a compound selected from the group consistîng of 2-(cy clohexylmethy l)-A/-{2-[(2S)-1 -methylpyrrolidin-2-y l]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, 2-(cyclohexylmethyl)-/V-{2-[(2S)1 -methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate, 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolÎdin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide monofumarate, 2-(cyclo h exy Imethy I)-A/-{2-[(2 S)-1 -methylpy rrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate, and 2-(cyclohexylmethyl)-/V-{2[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2l3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate or a pharmaceutically effective amount of a pharmaceutical composition of the présent invention.
Another aspect of the invention is a method of treating pathologies in which a histamine H3 receptor antagonist provides a therapeutic benefit, which comprises administering to a patient in need of said treatment a pharmaceutically effective amount of 2-(cyclohexylmethyl)-/\/-{2-[(2S)1 -methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.
In a particular aspect, the présent invention provides a method of treating a central nervous system disease, which comprises administering to a patient in need of said treatment a pharmaceutically effective amount of a compound selected from the group consisting of 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1(2,3,4-tetrahydroisoquinoline-7sulfonamide difumarate hydrate, 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1.2.3.4- tetrahydroisoquinoline-7-sulfonamide difumarate, 2-(cyclohexylmethyî)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, 2(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide hemifumarate, and 2-(cyclohexylmethyl)-N-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-
112.3.4- tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate, or a pharmaceutically effective amount of a pharmaceutical composition of the présent invention.
In another particular aspect, the présent invention provides a method of treating a central nervous system disease, which comprises administering to a patient in need of said treatment a pharmaceutically effective amount of 2-(cyclohexylmethyl)-A/-(2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.
O
-24A particular aspect of the invention is a method of treating a disease or disorder selected from the group consisting of obesity, diabètes, vigilance disorders, sleep disorders, narcolepsy, Alzheimer's disease, dementia, Parkinson's disease, attention-deficit hyperactivity disorder, memory disorders, learning disorders, epilepsy, schizophrénie, moderate cognitive disorders, dépréssion, anxiety, sexual dysfunction, dizziness, and travel sickness, which comprises administering to a patient in need of said treatment a pharmaceutically effective amount of a compound selected from the group consisting of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3l4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate, 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1 methylpyrrolidin-2-yl]ethy I}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide hemifumarate, and 2-(cyclohexylmethyl)-A/-(2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate, or a pharmaceutically effective amount of a pharmaceutical composition of the présent invention.
Another particular aspect of the invention is a method of treating Alzheimer's disease which comprises administering to a patient in need of said treatment a pharmaceutically effective amount of a compound selected from the group consisting of 2-(cyclohexylmethyl)-N-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate, 2-(cyclohexylmethyl)-/V-{2-[(2S)-1 methy Ipy rrolidin-2-y l]ethyl}-1,213,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, 2(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide hemifumarate, and 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate, or a pharmaceutically effective amount of a pharmaceutical composition of the présent invention.
Another particular aspect of the invention is a method of treating Alzheimer's disease which comprises administering to a patient in need of said treatment a pharmaceutically effective amount of 2-(cyclohexylmethyl)-N-{2-[(2S)-1 -methylpyrrolidi n-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.
An aspect of the présent invention is the use of a compound selected from the group consisting of 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,213,4-tetrahydroisoquinoline7-sulfonamide difumarate monohydrate, 2-(cyclohexylmethyl)-/V-{2-I(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate, 2-(cyclohexylmethyl)-A/-{2
-25[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2l3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide hemifumarate, and 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}1,2$3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate, in the manufacture of médicinal products for the treatment of pathologies in which a histamine H3 receptor antagonist provides a therapeutic benefit.
Another aspect of the invention is the use 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide dîfumarate monohydrate, 2(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide dîfumarate, 2-(cyclohexylmethyl)-/V-(2-[(2S)-1 -met h y I py rrol idin-2-y l]et hy I}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide monofumarate, 2-(cyclohexylmethyl)-A/-{2-[(2S)-1 methylpyrrolidin-2-yl]ethyl}-1,2,3l4-tetrahydroisoquinoline-7-sulfonamide hemifumarate, and 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide hemifumarate dihydrate for the treatment of pathologies in which a histamine H3 receptor antagonist provides a therapeutic benefit.
Another aspect ofthe invention is the use 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,314-tetrahydroisoquinolîne-7-sulfonamide dîfumarate monohydrate, 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide dîfumarate, 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide monofumarate, 2-(cyclohexylmethyl)-/V-{2-f(2S)-1 methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate, and 2(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydfoisoquinoline-7sulfonamide hemifumarate dihydrate for the treatment of a disease or disorder selected from the group consisting of obesity, diabètes, vigilance disorders, sleep disorders, narcolepsy, Alzheimer's disease, dementia, Parkinson’s disease, attention-deficit hyperactivity disorder, memory disorders, learning disorders, epilepsy, schizophrenia, moderate cognitive disorders, dépréssion, anxîety, sexual dysfunction, dizziness, and travel sickness.
The préparation and properties of the compounds of the invention are described in the following experimental section. Suitable 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide starting material for the herein described procedures includes, but is not limited to, 2-(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide prepared by the procedures described in W02005/118547.
Example 1: Préparation of2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate
2-(Cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroîsoquinoline-7-sulfonamide (318 mg, 0.756 mmol) was dissolved in methanol (3 mL). Fumaric acid solution (29 mg/3 mL, 2.1 équivalents) was added. The mixture was dried at room température under vacuum. The recovered solid was dissolved in isopropanol (1 mL). One milliliter of ethyl acetate was added and the solution was placed in refrigerator. The solids were collected by vacuum filtration.
Example 2: Préparation of 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate prepared with seeding step
2-(Cyclohexylmethyl)-A/-(2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide (43.7 g, 104 mmol) was dissolved in 95% éthanol (200 mL) with warming on a steam bath. Fumaric acid (23.8 g, 203 mmol, 1.95 équivalents) was added, rinsing the flask with 95% éthanol (50 mL). The mixture was heated with swirling to near boiling on the steam bath until ail of the fumaric acid dissolved. The solution was removed from the steam bath and allowed to stir at room température. When the température of the solution reached 48°C, it was seeded with previously isolated 2-(cyclohexylmethyl)-A/-(2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate. The mixture was allowed to cool and by 27.7 °C, it had largely set up. After standing over the weekend, the mixture was cooled in an ice bath. The solids were collected and washed with ice-cold 95% éthanol (175 mL). After air-drying overnight, the clumps were partially broken up to give a colorless solid: 58.4 g (84 % yield).
The difumarate monohydrate sait was recrystallized from 95% éthanol (350 mL), seeding with previously isolated 2-(cyclohexylmethyl)-A/-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate and stirring whîle cooling to room température. The mixture became very thick, finally setting up enough that stirring effectively stopped. After standing at room température overnight, the mixture was cooled in ice bath and the solids were collected by filtration. The filtrate was washed through the filter cake with ice-cold 95% éthanol (50 mL). The filter cake was then washed with ice-cold éthanol (125 mL) and air-dried overnight to give the desired product as a colorless solid: 49.84 g (72% yield).
Example 3: Préparation of2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate
2-(Cyclohexylmethyl)-A/-(2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate (solid, 50 mg) was heated at a
O
-27linear rate of 1.8°C/minute to 80°C at ambient RH and held for 50 minutes to yield the difumarate sait.
Example 4: Préparation of 2-(cyclohexylmethyl)-N-(2-[(2S)-1-methylpyrrolidrn-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate anhydrate
2-(Cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate (17.19 g, 25.7 mmol) was suspended in about 225 mL of water. Potassium carbonate (15.3 g, 111 mmol) was added, and the mixture was extracted into ethyl acetate. The organic extract was washed twice with water. An additional 5 mL of brine was added to the 2nd wash to break up the émulsion. The liquid was concentrated in vacuo. Acetone (about 50 mL) was added and the material was concentrated in vacuo. The residue was dissolved in 60 mL of acetone, and polish filtered into a flask (2 x 20 mL rinses), A solution of the fumaric acid (2.98 g, 25,7 mmol) in 100 mL of acetone and 20 mL of 95% éthanol was added with stirring. The solution turned permanently cloudy at the end of the addition with the séparation of a clear oil. The material was heated briefly on a steam bath to boiling, then about 15 mL of 95% EtOH was added to dissolve the oil. The material was stirred at room température overnight. The precipitated solids were filtered and washed with 50 mL of acetone containing 10% éthanol (95%). The cake was air dried for about 6 hours in the hood, and gave 4.17 g of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.
After standing, additional crystals formed in the filtrate. The crystals were collected and washed with acetone containing a small amount of 95% éthanol to give, after air drying, 1,08 g of white needles. The isolated material is 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate.
Example 5: Préparation of2-(cyclohexylmethyl)-W-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate
2-(Cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl)-1,2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate anhydrate (solid, 10 mg) was allowed to stand at 25°C and 60% RH for 2 hours. After 2 hours the sample had fully transformed to the hemifumarate dihydrate sait.
Example 6: Préparation of2-(Cyclohexylmethyl)-W-(2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate
Fumaric acid (1.86 g, 16 mmol) was added to 2-(cyclohexylmethyl)-N-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (6.7 g, 16 mmol). DMF (10 mL) and water (500 pL) were added to the mixture, and the solids were dissolved by warming on a steam bath. Isopropyl acetate (30 mL) was added gradually while heating on a steam bath. The heat was removed, and material oiled out. The mother liquors were decanted. About 100 mL MTBE were added to the residual oil, which was stirred for several hours until the mixture was a uniform slurry. A solid was collected and washed with MTBE. The solid was harvested and dried by vacuum filtration on a Büchner funnel. NMR shows a 1.9:1 ratio of fumaric acid to base. The solid was air-dried over night.
Additional material crystallized from the DMF/isopropyl acetate mother liquors. After réfrigération, more material separated as an oil. The mixture was rewarmed to room température to redissolve most of the oil. The solids were collected and washed with a little isopropyl acetate. The wash was combined with the mother liquors. The solid was air dried over night. Yield of 0.95 grams.
More material crystallized from the remaining mother liquor. The solids were collected and air was drawn through cake for 7a hour. Yield 0.7 grams. NMR shows a ratio of 1:1 fumaric acid to base indicating the monofumate sait.
The compounds of the invention are analyzed by the following analytical methods.
FourierTransform Infrared Spectroscopy (FTIR)
Fourier Transform IR spectra were obtained using a Nicolet Magna-IR Spectrometer 55 attached to a Nicolet Nic-Plan FT-IR microscope. Data acquisition and parameter settings were controlled by Omnic 7.2 software. The samples were placed on a KBr disk and scanned from 4000 cm'1 to 400 cm'1, 32 times. A spectral resolution of 4 cm'1 was used.
The FTIR spectra of the compound prepared generally according Example 2 (see Figure 2) confirmed sait formation and is consistent with the chemical structure of 2-(cyclohexylmethyl)-/V[2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate. Table 1 gives the characteristic wavenumbers for 2-(cyclohexylmethyl)-A/-{2[( 2S)-1 -methyl py rrol id tn-2-yl] ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate. The multiple strong bands présent in the région of 2800 to 2000 cm'1 arise from overtone and combination stretching vibrations of the protonated amine group, consistent with amine sait formation. The C-0 stretching vibrations (1650-1550 cm’1) characteristic of the carboxylate ion may be considered consistent with salts formed from fumaric acid.
-29Table 1 : Characteristic wavenumbers for 2-(cyclohexylmethyl)-M-{2[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide difumarate monohydrate
| Wavenumber (cm'1 +/-1 cm'1) |
| 3436 |
| 3243 |
| 3049 |
| 2930 |
| 2851 |
| 2656 |
| 2587 |
| 2504 |
| 1698 |
| 1647 |
| 1634 |
| 1580 |
| 1449 |
| 1332 |
| 1302 |
| 155 |
| 983 |
Differential Scanning Calorimetry - Thermal Gravimétrie Analysis and Mass Spectrometry (DSC-TGA-MS)
Thermal analysis of the compounds of the invention is performed using a TA Instruments Model
Q-600 Simultaneous Differential Scanning Calorimeter/Thermal Gravimétrie Analyzer (DSC10 TGA) under a dry hélium atmosphère (100 mL/min) înterfaced to a Pfeiffer Quadstar mass spectrometer (DSC-TGA-MS) using a capillary held at 200°C. The DSC-TGA température is calibrated using an indium standard and MS with water vapor. MS détection was by a secondary électron multiplier. The compound powder is transferred to an aluminum pan (TA Instruments part number 900793.901). The thermogram is acquired at a linear heating rate of 15 10°C per minute.
-30Therma! analysis for the dîfumarate monohydrate sait (Figure 3) shows a loss of water (about 3.3%) during heating up from ambient room température to about 100°C. The anhydrous phase, created upon the loss of water, melts at 113 to 123°C under these conditions.
Figure 6 is an overlay of the thermal (DSC-TGA) profiles of the monofumarate sait with the hemifumarate dihydrate sait and the dîfumarate monohydrate sait. The DSC of the monofumarate sait shows the melt of the crystalline phase at an onset of 129°C. The melting température of the monofumarate sait is unique compared to that of the anhydrous dîfumarate sait (onset 113°C) and anhydrous hemifumarate sait (onset 137°C) salts.
The DSC of the hemifumarate dihydrate sait shows a broad endotherm concomitant with water évolution followed by melt endotherms at onsets of 113°C (minor) and 137’C (major). The 137°C melt is unique to the hemifumarate anhydrate sait while the minor melting endotherm is consistent with the observed melting température of the dîfumarate anhydrate sait.
X-Ray Power Diffractometry (XRPD)
X-ray powder diffractometry is performed on a Siemens-Bruker D5000 diffractometer, using the parafocusing Bragg-Brentano (theta-two-theta)-type geometry. The compound of the invention, as a powder, is deposited on a single-crystal silicon wafer, eut according to the (510) crystallographic orientation. Copper K-alpha radiation (1.54056 angstroms), emitted from a copper anticathode tube (45kV/40mA) is used as the x-ray source, with Cu K-beta radiation filtered out using a reflected beam monochromator. A scintillation counter is used for détection. A divergence slit of 0.6 mm, an anti-scatter slit of 0.6 mm, a monochromator slit of 0.1 mm, and detector slit of 0.6 mm are used. The diffraction pattern is obtained using the following conditions: at least 2.0 to 30.0 degree Scan in angle 2-theta, 1.0 second count time per step, 0.02 degree step size, under ambient conditions of pressure, température, and relative humidity except as noted. Above ambient températures were achieved by heating the sample at a linear rate of 0.03 to 0.06°C/second.
The XRPD spectra (Figure 1) confirmed that the 2-(cyclohexylmethyl)-A/-{2-[(2S)-1methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide dîfumarate monohydrate was crystalline.
Based on the XRPD patterns, the crystalline dîfumarate anhydrate sait (Figure 4) has a unique XRPD pattern compared to the crystalline dîfumarate monohydrate sait.
Figure 5 is an XRPD pattern of the crystalline monofumarate sait. The data show that the
-3Imonofumarate sait crystal structure is unique comparée! to the crystal structures of the difumarate, difumarate monohydrate, hemifumarate and hemifumarate dihydrate salts.
Figure 7 is an overlay of the XRPD patterns of the crystalline hemifumarate and the crystalline hemifumarate dihydrate salts. The XRPD pattern of the hemifumarate dihydrate sait and corresponding hemifumarate anhydrate sait are largely unique compared to the difumarate monohydrate, difumarate anhydrate and monofumarate salts.
A person skilled in the art will recognize that the peak locations could be slightly affected by différences in sample height. The peak locations described herein are thus subject to a variation of plus or minus (+/-) 0.15 degrees 2-theta. The relative intensities may change dependîng on the crystal size and morphology.
Table 2 sets forth the characteristic peak locations, d-spacings and relative intensities for the powder x-ray diffraction pattern for the difumarate monohydrate sait.
Table 2: Characteristic XRPD Peak locations and Relative Intensities of the Difumarate Monohydrate Sait
| Measured Angle | Calculated Spacing | Relative |
| Degrees 2Θ | d value | Intensity |
| +/-0.15° 20 | (Angstroms) | (%) |
| 5.31 | 16.62 | 7.1 |
| 5.84 | 15.12 | 69.6 |
| 7.00 | 12.62 | 27.4 |
| 8.67 | 10.19 | 11.3 |
| 11.71 | 7.55 | 6.5 |
| 13.99 | 6.33 | 8.3 |
| 17.17 | 5.16 | 13.1 |
| 17.59 | 5.04 | 20.8 |
| 18.45 | 4.81 | 100 |
| 19.32 | 4.59 | 13.1 |
| 21.05 | 4.22 | 15.5 |
| 21.69 | 4.09 | 25.0 |
In particular, the peaks at 5.31, 5.84, 7.00, and 8.67 (expressed in degrees 2-theta +/-0.15 degree) are characteristic of the difumarate monohydrate sait.
-32Table 3 sets forth the characteristic peak locations, d-spacings and relative intensities for the powder x-ray diffraction pattern for the difumarate sait.
Table 3: Characteristic XRPD Peak locations and Relative Intensities of the Difumarate Sait
| Measured Angle | Calculated Spacing | Relative |
| Degrees 2Θ | d value | Intensity |
| +/- 0.15° 28 | (Angstroms) | (%) |
| 5.21 | 16.94 | 17.6 |
| 5.67 | 15.57 | 38.3 |
| 7.06 | 12.51 | 24.3 |
| 11.34 | 7.79 | 36.0 |
| 11.70 | 7.56 | 26.6 |
| 13.24 | 6.68 | 9.0 |
| 14.17 | 6.25 | 7.7 |
| 17.01 | 5.21 | 67.1 |
| 17.46 | 5.08 | 35.6 |
| 17.80 | 4.98 | 26.6 |
| 18.54 | 4.78 | 100 |
| 20.87 | 4.25 | 52.3 |
| 21.36 | 4.16 | 51.4 |
| 22.75 | 3.90 | 59.9 |
| 23.68 | 3.76 | 14.9 |
| 24.15 | 3.68 | 20.3 |
| 25.53 | 3.49 | 24.3 |
In particular, the peaks at 5.21, 5.67, 7.06, and 11.34 (expressed in degrees 2-theta +/-0.15 10 degrees 2-theta) are characteristic of the difumarate sait.
Table 4 sets forth the characteristic peak locations, d-spacings and relative intensities for the powder x-ray diffraction pattern for the monofumarate sait.
Table 4: Characteristic XRPD Peak Locations and Relative
Intensities of the Monofumarate Sait
| Measured Angle | Calculated Spacing | Relative |
| Degrees 26 | d value | Intensity |
| +/-0.15° 2Θ | (Angstroms) | (%) |
| 3.37 | 26.24 | 33.9 |
| 6.70 | 13.19 | 13.2 |
| 13.36 | 6.62 | 11.1 |
| 14.83 | 5.97 | 22.4 |
| 15.88 | 5.58 | 29.9 |
| 17.65 | 5.02 | 100 |
| 18.16 | 4.88 | 34.5 |
| 18.84 | 4.71 | 18.4 |
| 19.45 | 4.56 | 18.4 |
| 19.87 | 4.46 | 35.6 |
| 21.52 | 4.13 | 35.1 |
| 22.09 | 4.02 | 37.4 |
| 22.52 | 3.95 | 29.9 |
| 23.06 | 3.85 | 51.7 |
| 24.42 | 3.64 | 15.5 |
| 25.81 | 3.45 | 13.8 |
ln partîcular, the peaks at 3.37, 6.70, 13.36, 14.83, 15.88, and 17.65 (expressed in degrees 2theta +/-0.15 degrees 2-theta) are characteristic of the monofumarate sait.
Table 5 sets forth the characteristic peak locations, d-spacings and relative intensities for the powder x-ray diffraction pattern for the hemifumarate sait.
-34Table 5: Characteristic XRPD Peak Locations and Relative
Intensities of the Hemifumarate Sait
| Measured Angle | Calculated Spacing | Relative |
| Degrees 2Θ | d value | Intensity |
| +/- 0.15° 2Θ | (Angstroms) | (%) |
| 3.61 | 24.48 | 3.9 |
| 7.22 | 12.24 | 2.3 |
| 7.96 | 11.10 | 4.5 |
| 8.21 | 10.76 | 7.3 |
| 9.01 | 9.80 | 2.3 |
| 10.82 | 8.17 | 3.9 |
| 11.93 | 7.41 | 1.8 |
| 12.60 | 7.02 | 2.2 |
| 14.10 | 6.28 | 2.5 |
| 14.82 | 5.97 | 2.3 |
| 15.66 | 5.66 | 100 |
| 16.19 | 5.47 | 9.1 |
| 16.47 | 5.38 | 40.7 |
In particular, the peaks at 3.61, 7.22, 7.96, 8.21, 9.01, 10.82, and 15.66 (expressed in degrees 2-theta +/-0.15 degrees 2-theta) are characteristic of the hemifumarate sait.
Table 6 sets forth the characteristic peak locations, d-spacings and relative intensities for the powder x-ray diffraction pattern for the hemifumarate dihydrate sait.
Table 6: Characteristic XRPD Peak Locations and Relative Intensities of the Hemifumarate
Dihydrate Sait
| Measured Angle | Calculated Spacing | Relative |
| Degrees 2Θ | d value | Intensity |
| +/- 0.15° 2Θ | (Angstroms) | (%) |
| 3.49 | 25.29 | 4.5 |
| 6.93 | 12.75 | 2.7 |
| 8.46 | 10.45 | 12.1 |
| 10.34 | 8.55 | 4.0 |
| 13.25 | 6.68 | 1.9 |
| 13.75 | 6.43 | 2.4 |
| 15.40 | 5.75 | 100.0 |
| 15.77 | 5.61 | 4.6 |
| 16.61 | 5.33 | 7.2 |
| 16.86 | 5.25 | 14.3 |
| 17.21 | 5.15 | 10.3 |
| 17.84 | 4.97 | 5.0 |
| 18.20 | 4.87 | 7.4 |
| 18.55 | 4.78 | 4.7 |
| 18.86 | 4.70 | 6.7 |
| 19.11 | 4.64 | 5.7 |
| 19.75 | 4.49 | 9.4 |
| 20.07 | 4.42 | 7.0 |
ln particular, the peaks at 3.49, 6.93, 8.46, 10.34, 13.25, 13.75, and 15.40 (expressed in degrees 2-theta +/-0.15 degrees 2-theta) are characteristic of the hemifumarate dihydrate sait.
Dynamîc Vapor Sorption
The water sorption profile of a compound of the invention is determined using a SMS Instruments Dynamîc Vapor Sorption Analyzer (DVS) Model DVS-Advantage. Relative humidity (RH) and weight are calibrated using standards. The powder of the relevant compound of the invention is loaded and dried at 0% RH for 3 hours prior to starting the experiment. The RH is 10 stepped from 0.1 to 94.4% in 11 steps. The specimen weight is considered constant at each step when percent mass change is less than 0.01% over a 5-minute interval with a minimum absolute équilibration time of 15 minutes and maximum équilibration time of 180 minutes.
Figure 8 is the DVS profile of the difumarate monohydrate sait and corresponding difumarate 15 sait and numerical data is shown in Table 7. The profile shows that the difumarate monohydrate sait is stable from 10% to 94%RH at 25°C.
-36Table 7: Numerical DVS data for the difumarate monohydrate sait and the corresponding difumarte sait
| Sample (%RH) | Change in Mass (%) - dry | |
| Sorption | Desorption | |
| 0.6 | 0.0 | 0.0 |
| 10.2 | 2.8 | 2.9 |
| 19.6 | 2.9 | 2.9 |
| 29.4 | 3.0 | 3.0 |
| 38.5 | 3.0 | 3.0 |
| 48.5 | 3.0 | 3.0 |
| 57.5 | 3.1 | 3.1 |
| 67.1 | 3.1 | 3.1 |
| 77.0 | 3.1 | 3.2 |
| 87.0 | 3.2 | 3.2 |
| 94.2 | 3.3 | 3.3 |
Figure 9 is the DVS profile of the hemifumarate dihydrate and corresponding hemifumarate salts and numerical data is shown in Table 8. The profile shows that the hemifumarate monohydrate sait is stable from 19% to 92%RH at 25°C.
Table 8: Numerical DVS data for the hemifumarate dihydrate and the corresponding hemifumarte sait
| Sample (%RH) | Change in Mass (%) - dry | |
| Sorption | Desorption | |
| 0.6 | 0.00 | 0.00 |
| 10.1 | 0.25 | 0.56 |
| 19.4 | 3.53 | 6.71 |
| 29.0 | 3.87 | 6.85 |
| 37.8 | 6.50 | 6.89 |
| 47.7 | 6.89 | 6.97 |
| 56.4 | 7.01 | 7.10 |
| 65.7 | 7.13 | 7.21 |
| 75.3 | 7.32 | 7.33 |
-3784.8 7.68 7.66
92.0 8.31 8.25
Stability Testing
1. Storage at 60°C and ambient RH for two weeks.
Approximately 400 mg of the difumarate monohydrate sait was weighed into a scintillation vial and placed into an oven set to 60°C. The sample was tested for appearance, then diluted with éthanol to approximately 1 mg/mL and analyzed for related substances and optical enantiomer by HPLC.
After storage at 60°C for 14 days, the difumarate monohydrate sait showed no observable change in physical form by XRPD and DSC-TGA. The difumarate monohydrate appears to be physically stable under these storage conditions. With respect to chemical stability, the difumarate monohydrate sait appears to be stable in the solid state with a minimal increase in impurity levels and no observable change in appearance.
2. Storage at 60°C/80% RH and ambient RH for two weeks.
A glass desiccation chamber was pre-equilibrated overnight with a saturated KBr solution to 79,3%RH within an 80°C oven. Approximately 400 mg of the difumarate monohydrate was weighed into a scintillation vial and placed into the chamber, which was then sealed to maintain the environment. Samples were tested for appearance, then diluted with éthanol to approximately 1 mg/mL and analyzed for related substances and optical enantiomer by HPLC.
After storage at 60°C/80% RH for 14 days, the difumarate monohydrate sait showed no observable change in physical form by XRPD and DSC-TGA. The difumarate monohydrate sait appears to be physically stable under these storage conditions. With respect to chemical stability, the difumarate monohydrate sait appears to be stable in the solid state with a minimal increase in impurity levels and no observable change in appearance.
3. Storage at 80°C/80% RH for 4 days
A glass desiccation chamber was pre-equilibrated overnight with a saturated KBr solution to 79.3%RH within an 80°C oven. Approximately 100 mg of the difumarate monohydrate sait was weighed into respective scintillation vials and these vials were placed into the chamber, which was then sealed to maintain the environment. The sample was tested on day 4 for appearance, then diluted with éthanol to approximately 1 mg/mL and analyzed by HPLC versus a control (time 0) sample.
or
-38After storage at 80°C/80% RH for 4 days, the dîfumarate monohydrate sait was stable in the solid state with no observable chemical change.
Claims (15)
- What is claimed is:1. A compound selected from the group consisting of:
- 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide dîfumarate monohydrate;2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl)-1<2,3,4-tetrahydroisoquinoline-7sulfonamide dîfumarate;2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide monofumarate;2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3l4-tetrahydroisoquinoline-7sulfonamide hemifumarate; and2-(cyclohexylmethyl)-A/-(2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide hemifumarate dihydrate.2. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
- 3. A pharmaceutical composition prepared by formulating a compound according to claim 1 with one or more pharmaceutically acceptable carriers.
- 4. A process for preparing a pharmaceutical composition comprising formulating a compound according to claim 1 with one or more pharmaceutically acceptable diluents.
- 5. The compound 2-(cyclohexylmethyl)-/V-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide dîfumarate monohydrate according to claim 1.
- 6. The compound according to claim 5 in crystalline form.
- 7. A pharmaceutical composition comprising the compound according to claim 5 and a pharmaceutically acceptable carrier.
- 8. A pharmaceutical composition prepared by formulating the compound according to claim5 with one or more pharmaceutically acceptable carriers.
- 9. A process for preparing a pharmaceutical composition comprising formulating the compound according to claim 5 with one or more pharmaceutically acceptable diluents.
- 10. The compound 2-(cyclohexylmethyl)-/V-{2-[(2S)-1 -methyIpyrrolidin-2-yI]ethyI}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide difumarate according to claim 1, in crystalline form.
- 11. The compound 2-(cyclohexylmethyl)-/V-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide monofumarate according to claim 1, in crystalline form.
- 12. The compound 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate according to claim 1, in crystalline form.
- 13. The compound 2-(cyclohexylmethyl)-A/-{2-f(2S)-1 -methyIpyrrolidin-2-yIJethyI}-1,2,3,4tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate according to claim 1, in crystalline form.
- 14. A process for the manufacture of the 2-(cyclohexylmethyl)-/V-(2-[(2S)-1-methylpyrrolidin2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate comprising the steps of contacting, under elevated température or at ambient température, 2(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7sulfonamide dissolved in a suitable solvent or in a mixture of solvents, with fumaric acid, optionally dissolved in a solvent or in a mixture of solvents; and isolating the precipitated solid.
- 15. Use of the compound according to claim 1 for the treatment of a disease or disorder selected from the group consisting of obesîty, diabètes, vigilance disorders, sleep disorders, narcolepsy, Alzheimer's disease, dementia, Parkinsorïs disease, attention-deficit hyperactivity disorder, memory disorders, learning disorders, epilepsy, schizophrénie, moderate cognitive disorders, dépréssion, anxiety, sexual dysfunction, dizziness, and travel srckness.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/220,683 | 2009-06-26 | ||
| FR0959110 | 2009-12-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA16618A true OA16618A (en) | 2015-12-01 |
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