OA18216A - Novel polymorphic form of N-[2-(6-fluoro-LHindol-3-YI)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) benzylamine hydrochloride for the treatment of Alzheimer's. - Google Patents
Novel polymorphic form of N-[2-(6-fluoro-LHindol-3-YI)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) benzylamine hydrochloride for the treatment of Alzheimer's. Download PDFInfo
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- OA18216A OA18216A OA1201700002 OA18216A OA 18216 A OA18216 A OA 18216A OA 1201700002 OA1201700002 OA 1201700002 OA 18216 A OA18216 A OA 18216A
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- OAPI
- Prior art keywords
- ethyl
- fluoro
- indol
- benzylamine hydrochloride
- tetrafluoropropoxy
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- -1 N-[2-(6-fluoro-1H-indol-3yl)ethyl]-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride Chemical compound 0.000 claims abstract description 27
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Abstract
The present invention relates to a novel polymorphic form of N-[2-(6-fluoro-1H-indol-3yl)ethyl]-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
Description
NOVEL POLYMORPHIC FORM OF N-[2-(6-FLUORO-LH-INDOL-3-YL)ETHYL]-3-(2,2,3,3TETRAFLUOROPROPOXY)BENZYLAMINE HYDROCHLORIDE FOR THE TREATMENT OF ALZHEIMER'S
FIELD OF THE INVENTION
The présent invention relates to a novel polymorphie form of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
BACKGROUND OF THE INVENTION
The incidence of Alzheimer's disease is expected to increase through the year 2050 with an estimated prevalence of 11 to 16 million cases. Currently, two classes of médications are FDA approved for managing symptoms of Alzheimer’s disease - acetylcholinesterase inhibitors (AChEls) and an Nmethyl-D-aspartase (NMDA) receptor antagonist. AChEls are commonly used as initial treatment on diagnosis. The AChEls - donepezil, rivastigmine, galantamine, and tacrine - are indicated for mild-tomoderate Alzheimer’s disease; only donepezil is approved for the severe stage.
AChEls do not help everyone who has Alzheimer's disease and in fact are not efficacious in many patients. Considering that AChEls and memantine hâve only a modest symptomatic effect, and cannot prevent Alzheimer’s disease décliné and slow disease progression, there is a high unmet need for more effective symptomatic treatments and for a disease modifÿing/slowing thérapies.
The use of sélective 5-HT6 receptor antagonists to treat cognitive dysfunction has been suggested and is based on several Unes of reasoning. For example, sélective 5-HT6 receptor antagonists hâve been shown to modulate cholinergic and glutamatergic neuronal function. The activity of sélective 5-HT6 receptor antagonists has been demonstrated in animal models of cognitive function. Since the disclosure ofthe firstsélective 5-HT6 receptorantagonists, there hâve been several reports on the activity of these sélective compounds in in-vivo models of cognitive function. N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, CAS number 467458-02-2, (herein also referred to as “Lu AE58054”) is a 5-HT6 receptor antagonist and its chemical structure is depicted below:
The synthesis of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, its use for the treatment of Alzheimer’s disease, and pharmaceutical compositions comprising this compound are disclosed in U.S. Patent No. 7,157,488 (“the ‘488 patent”). The ‘488 patent further describes the préparation of the hydrochloride sait of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine.
N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine can be produced according to the method described in WO 11/76212.
By using the methods in the ‘488 patent and in WO 11/76212, the N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is obtained as a solid.
Pharmaceutical solids can exist in amorphous, glass or crystalline states. Furthermore crystalline materials can be found as hydrates or other solvatés. If such a compound can exist in more than one crystalline arrangement (polymorphie form) the compound is said to show polymorphism.
In order to be able to provide an active pharmaceutical ingrédient of high and reproducible quality and with well-defined biological activity, it is désirable to hâve the active pharmaceutical ingrédient in the most thermodynamically stable form.
The inventors of the présent invention hâve found a new and thermodynamically stable form of the hydrochloride sait of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.
SUMMARY OF THE INVENTION
The présent invention relates to polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
The invention further relates to a process preparing polymorphieform III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride comprising:
a. capturing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride from a suspension of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine in an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C.
The invention further relates to a process for preparing polymorphieform lll of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride comprising:
a. adding polymorphie form I, form II, amorphous or a mixture ofthe forms of N-[2-(6fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C to produce a suspension;
b. capturing polymorphieform lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
The invention further relates to a process for preparing polymorphie form lll of N-[2-(6-fluoro-IH indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride comprising:
a. seeding a suspension of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C with polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride;
b. capturing polymorphieform lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
The invention further relates to a process for preparing polymorphie form lll of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride comprising:
a. adding polymorphie form I, form II, amorphous or a mixture ofthe forms of N-[2-(6fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, heptane, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C to produce a suspension;
b. seeding with polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride at a température below 60°C;
c. capturing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
The invention further relates to polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride for use as a médicament, a pharmaceutical composition comprising polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride and a method of treating Alzheimeris disease as adjunctive therapy to acetylcholinesterase treatment comprising administering an effective daily dose of polymorphie form III of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to a patient in need of such treatment.
BRIEF DESCRIPTION OF THE FIGURES
FIGURE 1 : X-ray powder diffractogram of polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
FIGURE 2: X-ray powder diffractogram calculated from the crystal structure of polymorphie form I.
FIGURE 3: X-ray powder diffractogram of polymorphie form II of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
FIGURE 4: X-ray powder diffractogram calculated from the crystal structure of polymorphie form II.
FIGURE 5: X-ray powder diffractogram of polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
FIGURE 6: Shows crystal packing of polymorphieform I and form II of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
FIGURE 7: X-ray powder diffractograms of polymorphie form III (lower curve) and mixture of polymorphieform III and polymorphieform IV (upper curve).
FIGURE 8: FTIR spectrum of polymorphie form III
FIGURE 9: FTIR spectrum of polymorphie form I
FIGURE 10: FTIR spectra of two batches of polymorphie form III shown in the spectral région 11301050 cm’1.
FIGURE 11: FTIR spectra of two batches of polymorphie form III (marked with “HI”) and one spectrum of polymorphie form I (marked with “I”) shown in the spectral région 1130-1050 cm'1.
DETAILED DESCRIPTION OF THE INVENTION
Previous to the présent invention; two polymorphie modifications ofthe N-[2-(6-fIuoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride were known. Polymorphie form I which was found to be the thermodynamically stable form at low température (below about 60°C) and polymorphieform II which is the thermodynamically stable form at high température (above about 60°C). Polymorphie form II has a melting point, as determined by Differential scanning calorimetry (DSC) at 171 °C. Polymorphieform I transforms into polymorphieform II upon heating in the température range 120-140°C, thus a melting point of polymorphie form I could not be determined. The crystal structures of both polymorphie forms were determined using single crystal X-ray analysis. The structural parameters are given in table 1 below:
| Polymorphie form I | Polymorphie form II |
| C20H20F5N2O+.Cr | C20H20F5N2O+.Cr |
| Mr = 434.83 | Mr = 434.83 |
| T =298 (2) K | T= 298 (2) K |
| Monoclinic, P2\ | Orthorhombic, Pbca |
| a = 7.3776 (3) Â | «= 10.529 (3)Â |
| b = 7.0709 (3) Â | b = 9.569 (3) Â |
| c = 38.3480 (19) Â | c = 41.398 (10) Â |
| beta= 94.103 (1)° | — |
| K= 1995.34 (15) Â3 | F= 4171 (2) Â3 |
| Z = 4 | Z=8 |
| Dx = 1.447 Mg m’3 | Dx= 1.385 Mgm'3 |
Table 1 - Structural parameters of polymorphie form I and form II of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
The crystal packing differs significantly in the two polymorphie forms (Figure 6).
Crystallization experiments hâve been performed in the search for other polymorphie modifications without success. Ail experiments resulted in polymorphieform I and form II, depending on the température. It was therefore surprising to find a new and thermodynamically more stable form that based on DSC is very similarto polymorphieform [ (it also transforms into polymorphieform II by heating in the température range 120°C-140°C), and has many low-angle reflections in common with polymorphie form I in X-ray powder diffractogram (XRPD), but also differ significantly in other reflections.
Despite previous unsuccessful attempts to find new polymorphie forms of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride, the inventors ofthe présent invention hâve found a way to produce a new polymorphie form of N-[2-(6-fluoro4H-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride, in the following referred to as polymorphie form III.
It has been found that in the température range where polymorphieform III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is the thermodynamically stable polymorphieform, it is easierto produce polymorphieform I and II of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafIuoropropoxy)benzylamine hydrochloride. In summary polymorphieform I and form II of N[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride hâve a kinetic advantage over polymorphie form lll which is the thermodynamically stable form making this polymorphie form more difficult to produce.
Polymorphieform lll is particular advantageous in that it is the most thermodynamically stable form of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
The présent invention is further described in the embodiments 1 to 42 (E(1) to E(42)) below:
E(1): Polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
E(2): The polymorphie form according to (E1) characterized by an X-Ray powder diffractogram showing peaks atthe following 20-angles: 4.63°, 6.94°, 13.89°, 17.26° and 19.97°.
E(3): The polymorphie form according to (E2) further characterized by an X-Ray powder diffractogram showing peaks atthefollowing 20-angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.95°, 19.97°, 22.53° and 23.65°.
E(4): The polymorphie form according to (E3) further characterized by an X-Ray powder diffractogram showing peaks at the following 20-angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.07°, 18.49°, 18.95°, 19.47°, 19.97°, 20.53°, 21.83°, 22.53°, 23.27°, 23.65° and 28.91°.
E(5): The polymorphie form according to (E1), wherein said compound exhibits an X-Ray powder diffractogram as shown in figure 5.
E(6): A process for preparing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride comprising:
capturing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride from a suspension of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C.
E(7): A process for preparing polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride comprising:
a) adding polymorphie I, form II, amorphous or a mixture of the forms of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C to produce a suspension;
b) capturing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
E(8): A process for preparing polymorphieform III of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride comprising:
a) seeding a suspension of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C with polymorphie form III of N-[2-(6-fIuoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride;
b) capturing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
E(9): A process for preparing polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride comprising:
a) adding polymorphie I, form II, amorphous or a mixture of the forms of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, heptane, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C to produce a suspension;
b) seeding with polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride at a température below 60°C;
c) capturing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
E(10): The process according to any of the (E6) to (E9) wherein the mixture of organic solvents is such that crystallization occurs below 60°C.
E(11 ): The process according to any of the (E6) to (E9), wherein the organic solvent is a mixture of acetone and heptane in the ratio 1:4.
E(12): The process according to any of the (E6) to (E9), wherein the organic solvent is a mixture of methanol and toluene in the ratio 1:4.
E(13): A compound according to any of the (E1) to (E5) for use as a médicament.
E(14): A pharmaceutical composition comprising a compound according to any of the (E1) to (E5).
E(15): The pharmaceutical formulation according to (E14) comprising pharmaceutically acceptable carriers or diluents.
E(16): A method of treating Alzheimer’s disease as adjunctive therapy to acetylcholinesterase treatment comprising administering an effective daily dose of a compound according to any of the E(1 ) to E(5) to a patient in need of such treatment.
E(17): The method according to E(16), wherein the effective daily dose administered to the patient of said compound is between about 5 and about 120 mg.
E(18): The method according to E(16), wherein the effective daily dose administered to the patient of said compound is between about 30 and about 60 mg
E(19): The method of according to any of E(16) to E(18), wherein the acetylcholinesterase inhibitor is donepezil.
E(20): The method according to any of E(16) to E(18), wherein the acetylcholinesterase inhibitor is rivastigmine.
E(21): The method according to any of E(16) to E(18), wherein the acetylcholinesterase inhibitor is galantamine.
E(22): The method according to any of E(16) to E(18), wherein the acetylcholinesterase inhibitor is tacrine.
E(23): A method of treating a disease or disorder selected from dementia in Parkinson’s disease, Huntington’s chorea and Down’s syndrome comprising administering an effective daily dose of a compound according to any of E(1) to E(5)to a patient in need of such treatment
E(24): A method of treating a disease or disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including dépréssion, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, spécifie phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson’s disease, epilepsy, convulsions, migraine (including migraine headache), substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazépines, cocaïne, sédatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington’s Chorea, cognitive déficits subséquent to cardiac bypass surgery and grafting, stroke, cérébral ischemia, spinal cord trauma, head trauma, périnatal hypoxia, cardiac arrest, hypoglycémie neuronal damage, vascular dementia, multi-infarct dementia, amylotrophic latéral sclerosis, and multiple sclerosis comprising administering an effective daily dose of a compound according to any of E(1 ) to E(5) to a patient in need of such treatment
E(25): A compound according to any of E(1) to E(5) for use in treating Alzheimer’s disease as adjunctive therapy to acetylcholinesterase treatment.
E(26): The compound according to E(25), wherein the dose of said compound is between about 5 and about 120 mg.
E(27): The compound according to E(25), wherein the dose of said compound is between about 30 and about 60 mg.
E(28): The compound according to any of E(25)-E(27), wherein the acetylcholinesterase inhibitor is donepezil.
E(29): The compound according to any of E(25)-E(27), wherein the acetylcholinesterase inhibitor is rivastigmine.
E(30): The compound according to any of E(25)-E(27), wherein the acetylcholinesterase inhibitor is galantamine.
E(31): The compound according to any of E(25)-E(27), wherein the acetylcholinesterase inhibitor is tacrine.
E(32): A compound according to any of E(1 )-E(5) for use in treating a disease or disorder selected from dementia in Parkinson’s disease, Huntington’s chorea and Down’s syndrome.
E(33): A compound according to any of E(1 )-E(5) for use in treating a disease or disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including dépréssion, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, spécifie phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson’s disease, epilepsy, convulsions, migraine (including migraine headache), substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazépines, cocaïne, sédatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimeris disease and AIDSinduced dementia), Huntington’s Chorea, cognitive déficits subséquent to cardiac bypass surgery and grafting, stroke, cérébral ischemia, spinal cord trauma, head trauma, périnatal hypoxia, cardiac arrest, hypoglycémie neuronal damage, vascular dementia, multi-infarct dementia, amylotrophic latéral sclerosis, and multiple sclerosis.
E(34): Use of a compound according to any of E(1 )-E(5) for the manufacture of a médicament for treating Alzheimer’s disease as adjunctive therapy to acetylcholinesterase treatment.
E(35): The use according E(34), wherein the dose of said compound is between about 5 and about 120 mg.
E(36): The use according to E(34), wherein the dose of said compound is between about 30 and about 60 mg.
E(37): The use according to any of E(34) to E(36), wherein the acetylcholinesterase inhibitor is donepezil.
E(38): The use according to any of E(34) to E(36), wherein the acetylcholinesterase inhibitor is rivastigmine.
E(39): The use according to any of E(34) to E(36), wherein the acetylcholinesterase inhibitor is galantamine.
E(40):The use according to any of E(34) to E(36), wherein the acetylcholinesterase inhibitor is tacrine.
E(41 ): Use of a compound according to any of E(1 ) to E(5) for the manufacture of a médicament for treating a disease or disorder selected from dementia in Parkinson’s disease, Huntington’s chorea and Down’s syndrome.
E(42): Use of a compound according to any of E(1 ) to E(5)for the manufacture of a médicament for treating a disease or disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including dépréssion, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, spécifie phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson’s disease, epilepsy, convulsions, migraine (including migraine headache), substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazépines, cocaïne, sédatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington’s Chorea, cognitive déficits subséquent to cardiac bypass surgery and grafting, stroke, cérébral ischemia, spinal cord trauma, head trauma, périnatal hypoxia, cardiac arrest, hypoglycémie neuronal damage, vascular dementia, multi-infarct dementia, amylotrophic latéral sclerosis, and multiple sclerosis.
E(43): The process according to any of E(6) to E(10) wherein the suspension is prepared at a température about 50°C, such as 45-55°C.
E(44): The process according to any of E(6) to E(10) wherein the suspension is prepared at a température below 50°C.
E(45): The polymorphie form according to (E1) characterized by an FTIR spectrum having relative strong band intensity atthe following band positions [cm-1]: 3426,1586,1089, 762 and a shoulder at 1099 cm’1.
E(46): The polymorphie form according to (E1) characterized by an FTIR spectrum in the spectral région 1130-1050 cm-1 as shown in figure 10.
il
E(47): A pharmaceutical composition prepared from polymorphieform III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
E(48): A pharmaceutical composition prepared from polymorphieform III of N-[2-(6-fiuoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride characterized by an X-Ray powder diffractogram showing peaks atthe following 20-angles: 4.63°, 6.94°, 13.89°, 17.26° and 19.97°.
E(49): A pharmaceutical composition prepared from polymorphie form III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride characterized by an X-Ray powder diffractogram showing peaks atthefollowing 20-angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.95°, 19.97°, 22.53° and 23.65°.
E(50): A pharmaceutical composition prepared from polymorphie form III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride characterized by an X-Ray powder diffractogram showing peaks at the following 20-angles: : 4.63°, 6.94°, 13.89°, 17.26°, 18.07°, 18.49°, 18.95°, 19.47°, 19.97°, 20.53°, 21.83°, 22.53°, 23.27°, 23.65° and 28.91°.
E(51): A pharmaceutical composition prepared from polymorphieform III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride characterized by an X-Ray powder diffractogram as shown in figure 5
E(52): A pharmaceutical composition prepared from polymorphieform III of N-[2-(6-fIuoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride characterized byan FTIRspectrum having strong band intensity at the following band positions [cm'1]: 3426,1586,1089, 762 and a shoulder at 1099 cm’1.
E(53): A pharmaceutical composition prepared from polymorphieform III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride characterized byan FTIRspectrum in the spectral région 1130-1050 cm-1 as shown in figure 10.
Définitions
N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine is “Lu AE58054”. Lu AE58054 is a 5-HT6 receptor antagonist and its chemical structure is depicted below:
Polymorphieform lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is characterized by an X-Ray powder diffractogram (XRPD) showing peaks at the following 20-angles: 4.63°, 6.94°, 13.89°, 17.26° and 19.97°, more specifically at the following 20angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.95°, 19.97°, 22.53° and 23.65° and even more specifically at the following 20-angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.07°, 18.49°, 18.95°, 19.47°, 19.97°, 20.53°, 21.83°, 22.53°, 23.27°, 23.65° and 28.91°.
Polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is characterized by an X-Ray powder diffractogram showing peaks at the following 20angles: 4.62°, 6.95°, 13.90°, 17.40°, 20.15° and 24.97°.
Polymorphieform II of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is characterized by an X-Ray powder diffractogram showing peaks at the following 20angles: 4.29°, 8.56°, 12.84°, 15.34°, 17.92° and 28.75°.
Ail XRPD data given herein are indicated as ± 0.10 (°2θ).
The solids of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride obtained by the methods in the ‘488 patent and in WO 11/76212 are polymorphieform I and form II.
A therapeutically effective amount of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adéquate to accomplish this is defined as a therapeutically effective amount. Effective amounts for each purpose will dépend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine expérimentation, by constructing a matrix of values and testing different points in the matrix, which is ail within the ordinary skills of a trained physician.
The term treatment and treating as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prévention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (préventive) and therapeutic (curative) treatment are two separate aspects of the invention. The patient to be treated is preferably a mammal, in particular a human being.
Typically, the treatment of the présent invention will involve daily administration of the compounds of the présent invention. This may involve once daily administration, or administration twice a day or even more frequently.
A therapeutically effective dose of polymorphie form III of N-[2-(6-fiuoro-IH-indol-3-yI)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride is an amount sufficient to provide an observable therapeutic benefit compared to baseline clinically observable signs and symptoms of Alzheimer’s disease as measured by ADAS-cog, and Alzheimer’s disease-related dementia treated in connection with the combination therapy.
Immediate-release is meant to include a conventional release, in which release of the drug starts immediately after administration. As used herein, the term immédiate release includes dosage forms that allow the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug. The objective is for the drug to be released rapidly after administration, for example for it to be possible to release at least 80% of the anti-dementia drug within approximately 30 minutes after commencement of dissolution in a dissolution test.
The term “acetylcholinesterase inhibitor” is known to those skilled in art and includes compounds selected from the group consisting of donepezil, rivastigmine, galantamine and tacrine. The FDA approved dosages of the acetylcholinesterase inhibitor are encompassed by the instant invention. For example, the methods cover the dosages of donepezil shown to be effective in controlled clinical trials of the treatment of mild to moderate Alzheimer’s disease are 5 mg or 10 mg administered orally once per day. A 23 mg orally once daily dose of donepezil is also approved for treating moderate to severe Alzheimer’s disease.
The term “daily” means a given, continuous twenty-four (24) hour period.
The term dose is used herein to mean administration of polymorphie form III of the N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in one dosage form to the patient being treated. In some embodiments, the dose is a single oral formulation. In some embodiments, the dose is formulated as a tablet, a capsule, a pill, or a patch administered to the patient
The term “effective daily dose” means the total amount of polymorphieform III of the N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride administered to a patient in need of therapy in a continuous, twenty-four (24) hour period. As a non-limiting example used herein solely to illustrate the meaning of the term, an effective daily dose of 90 mg shall mean and include administering a single dose of 90 mg in a twenty four hour period, administering two doses of 45 mg each within a twenty four hour period, and administering three doses of 30 mg each in a twenty four hour period, and so on. When administering polymorphieform III of the N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in such a manner, i.e. more than once in a twenty four hour period, such administrations can be spread evenly through the twenty four hour period or even be administered simultaneously or nearly so.
The term dose range as used herein refers to an upper and a lower limit of an acceptable variation of the amount of agent specified. Typically, a dose of the agent in any amount within the specified range can be administered to patients undergoing treatment.
Pharmaceutical compositions
In one embodiment, the présent invention relates to pharmaceutical composition comprising polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
In a further embodiment, the présent invention relates to pharmaceutical formulation comprising polymorphieform III of the N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and pharmaceutically acceptable carriers or diluents
The présent invention further provides a pharmaceutical composition comprising a therapeutically effective amount of polymorphie form III of the N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochlorideand optionally a pharmaceutically acceptable carrier or diluent. Polymorphieform III ofthe N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 22nd Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 2013.
Suitable pharmaceutical carriers include inert solid diluents or fillers, stérile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, agar, pectin, acacia, stearic acid and lower alkyl ethers of cellulose com starch, potato starch, talcum, magnésium stéarate, gélatine, lactose, gums, and the like. Other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingrédients.
The pharmaceutical compositions formed bycombining polymorphieform III ofthe N-[2-(6-fiuoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may be presented in dosage form by methods known in the art of pharmacy.
Formulations ofthe présent invention suitable for oral administration may be presented as discrète units such as capsules or tablets, each containing a predetermined amount ofthe active ingrédient, and which may include one or more suitable excipients. The orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-inwater or water-in-oil liquid émulsion. If a solid carrier is used for oral administration, the préparation may be tabletted, placed in a hard gélatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
Without limiting the scope of the invention, an example of an immédiate release formulation of a once daily 30 mg dose of polymorphieform III ofthe N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride is the following:
Polymorphieform III of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride 32.75mg
Calcium Phospohate Dibasic 222.0mg
Colloïdal Slilcon Dioxide NF (Aerosil 200) 3.900mg
Magnésium Sterate NF (Vegatable Grade) 1.300mg
The formulation can be encapsulated e.g. in a Gelatin Capsule Size #3.
In a similar manner, pharmaceutical compositions may be prepared comprising the administration of polymorphieform III ofthe N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride wherein the dose ranges administered are between about 5 mg and about 120 mg.
Methods of treatment
Provided herein is a combination therapy useful for the treatment of mild, moderate and severe Alzheimer's disease, as well as symptoms associated with mild to moderate Alzheimer’s disease. As discussed below, the methods provided herein hâve a number of advantages.
The term Alzheimer's disease refersto a progressive disease ofthe human central nervous system. It is manifested by dementia typically in the elderly, by disorientation, loss of memory, difficulty with language, calculation, or Visual- spatial skills, and by psychiatrie manifestations. It is associated with degenerating neurons in several régions ofthe brain. The term dementia as used herein includes, but is not restricted to, Alzheimer's dementia with or without psychotic symptoms.
In a particular embodiment, the therapeutic methods provided herein are effective for the treatment of mild, moderate and severe Alzheimer's disease in a subject. Phases of Alzheimer's further include moderately severe cognitive décliné, also referred to as moderate or mid-stage Alzheimer's disease; severe cognitive décliné, also referred to as moderately severe or mid-stage Alzheimer's disease; and very severe cognitive décliné, also referred to as severe or late-stage Alzheimer’s disease. Moderately severe cognitive décliné is characterized by major gaps in memory and déficits in cognitive function emerge. Atthis stage, some assistance with day-to-day activities becomes essential. In severe cognitive décliné, memory difficulties continue to worsen, signifïcant personality changes may emerge and affected individuals need extensive help with customary daily activities. Late stage Alzheimer's disease or very severe cognitive décliné is the final stage ofthe disease when individuals lose the ability to respond to their environment, the ability to speak and, ultimately, the ability to control movement.
In another embodiment, the patient to be treated by the combination therapy of the invention has an MMSE score between 12 and 22. MMSE refers to the Mini-Mental State Examination used in the cognitive assessment community.
In one embodiment, the présent invention relates to a method of treating Alzheimer’s disease as adjunctive therapy to acetylcholinesterase treatment comprising administering an effective daily dose of polymorphieform lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride a patient in need of such treatment. In a further embodiment, the effective daily dose administered to the patient of polymorphieform lll of N-[2-(6fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is between about 5 and about 120 mg. In a further embodiment, the effective daily dose administered to the patient of polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,317 tetrafluoropropoxy)benzylamine hydrochloride is between about 30 and about 60 mg. In a further embodiment, the acetylcholinesterase inhibitor is donepezil. In a further embodiment, the acetylcholinestérase inhibitor is rivastigmine. In a further embodiment, the acetylcholinesterase inhibitor is galantamine. In a further embodiment, the acetylcholinesterase inhibitor is tacrine.
In one embodiment, the présent invention relates to a method of treating a disease or disorder selected from dementia in Parkinson’s disease, Huntington’s chorea and Down’s syndrome comprising administering an effective daily dose of polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to a patient in need of such treatment.
In one embodiment, the présent invention relates to a method of treating a disease or disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including dépréssion, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, spécifie phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson’s disease, epilepsy, convulsions, migraine (including migraine headache), substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazépines, cocaïne, sédatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimeris disease and AIDSinduced dementia), Huntington’s Chorea, cognitive déficits subséquent to cardiac bypass surgery and grafting, stroke, cérébral ischemia, spinal cord trauma, head trauma, périnatal hypoxia, cardiac arrest, hypoglycémie neuronal damage, vascular dementia, multi-infarct dementia, amylotrophic latéral sclerosis, and multiple sclerosis comprising administering an effective daily dose of polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to a patient in need of such treatment
In one embodiment, the présent invention relates to polymorphie form III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for use in treating Alzheimer’s disease as adjunctive therapy to acetylcholinesterase treatment. In a further embodiment, the dose of polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride is between about 5 and about 120 mg. In a further embodiment, the dose of polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3 tetrafluoropropoxy)benzylamine hydrochloride is between about 30 and about 60 mg. In a further embodiment, the acetylcholinesterase inhibitor is donepezil. In a further embodiment, the acetylcholinesterase inhibitor is rivastigmine. In a further embodiment, the acetylcholinesterase inhibitor is galantamine. In a further embodiment, the acetylcholinesterase inhibitor is tacrine.
In one embodiment, the présent invention relates to polymorphie form III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for use in treating a disease or disorder selected from dementia in Parkinson’s disease, Huntington’s chorea and Down’s syndrome.
In one embodiment, the présent invention relates to polymorphie form III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for use in treating a disease or disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including dépréssion, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, spécifie phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specifïed (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson’s disease, epilepsy, convulsions, migraine (including migraine headache), substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazépines, cocaïne, sédatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, leaming disorders, dementia (including Alzheimerts disease and AIDS-induced dementia), Huntington's Chorea, cognitive déficits subséquent to cardiac bypass surgery and grafting, stroke, cérébral ischemia, spinal cord trauma, head trauma, périnatal hypoxia, cardiac arrest, hypoglycémie neuronal damage, vascular dementia, multi-infarct dementia, amylotrophic latéral sclerosis, and multiple sclerosis.
In one embodiment, the présent invention relates to use of polymorphie form III of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for the manufacture of a médicament for treating Alzheimer’s disease as adjunctive therapy to acetylcholinesterase treatment. In a further embodiment, the dose of polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride is between about 5 and about 120 mg. In a further embodiment, the dose of polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride is between about 30 and about 60 mg. In a further embodiment, the acetylcholinesterase inhibitor is donepezil. In a further embodiment, the acetylcholinesterase inhibitor is rivastigmine. In a further embodiment, the acetylcholinesterase inhibitor is galantamine. In a further embodiment, the acetylcholinesterase inhibitor is tacrine.
In one embodiment, the présent invention relates to use of polymorphie form III of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for the manufacture of a médicament for treating a disease or disorder selected from dementia in Parkinson’s disease, Huntington’s chorea and Down’s syndrome.
In one embodiment, the présent invention relates to use of polymorphie form III of N-[2-(6-fIuoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for the manufacture of a médicament for treating a disease or disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including dépréssion, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, spécifie phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson’s disease, epilepsy, convulsions, migraine (including migraine headache), substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazépines, cocaïne, sédatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington’s Chorea, cognitive déficits subséquent to cardiac bypass surgery and grafting, stroke, cérébral ischemia, spinal cord trauma, head trauma, périnatal hypoxia, cardiac arrest, hypoglycémie neuronal damage, vascular dementia, multi-infarct dementia, amylotrophic latéral sclerosis, and multiple sclerosis.
EXPERIMENTAL SECTION
X-Ray powder diffractoqrams (XRPD)
X-Ray powder diffractograms (XRPD) were measured on a PANalytical X’Pert PRO X-Ray Diffractometer using CuKa-ι radiation. The samples were measured in reflection mode in the 20-range 3-40° using an X’celerator detector. Diffraction data are indicated ± 0.10 (°20).
IR spectra obtained by Fourier transform infrared spectroscopy (FTIR)
The infrared spectra (IR spectra) are recorded on a TENSOR 27 FTIR spectrometerfrom BRUKER equipped with an attenuated total réflectance (ATR) unit with a diamond single reflecting element. The spectra are obtained using a spectral resolution of 1 cm’1 and 32 scan. IR bands given are indicated as ± 1 cm'1.
Example 1 : Synthesis of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride
The synthesis of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride can be found in U.S. Patent No. 7,157,488, which is hereby incorporated by reference in its entirety. See e.g. column 109, line 1 through column 110, line 3 for a synthesis starting with commercially available 6-fluoroindole.
Example 2: Préparation of polymorphie form lll of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride mL of a solvent or solvent mixture is added into a glass vial together with polymorphie form I of N-[2(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. The added amount of compound is determined by the expected solubility in the relevant solvent or solvent system. If a clear solution is obtained anti-solvent and/or additional polymorphie form I of N-[2-(6-fiuoro-IH-indol3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochlorideis added until it is a suspension at the relevant température. The suspension is slurred fora prolonged period oftime. The resuit ofthe slurry experiment is evaluated by filtering off the solid material and measuring XRPD on the isolated solid.
Slurry in a toluene/acetonitrile solvent mixture at 50°C:
mL of a toluene/acetonitrile (4:1) solvent mixture was added into a glass vial and 100mg polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. The resulting suspension was heated to 50°C. A clear solution was obtained and another 50 mg was added. The suspension was stirred for one month at 50°C. Polymorphie form lll of N-[2-(6-fluoroIH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained as evaluated byXRPD.
Slurry in an acetone/heptane solvent mixture at 50°C:
mL of an acetone/heptane (1:4) solvent mixture was added into a glass vial and 100mg polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. The resulting suspension was heated to 50°C. The suspension was stirred for one week at 50°C. Polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was obtained as evaluated by XRPD.
Slurry in a methanol/toluene solvent mixture at 50°C:
mL of a methanol/toluene (1:9) solvent mixture was added into a glass vial and 10Omg polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. Afterstirring another 1 mL ofthe anti-solvent (toluene) was added + 50mg polymorphieform I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. Stirring resulted in a clear solution and 1 mLof toluene was added and additional 50mg polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. Stirring still resulted in a clear solution and the total volume of 8 mL was divided into two. To the 4 mL solutions another 1 mL of toluene was added and additional 50mg polymorphie form I of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. The resulting suspension was heated to 50°C. A clear solution was obtained and substance was added until a suspension was obtained. The suspension was stirred for one week at 50°C. Polymorphie form III of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained as evaluated by XRPD.
Slurry in isopropyl acetate at 50°C:
mL of isopropyl acetate was added into a glass vial and 50mg polymorphie form I of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. The resulting suspension was heated to 50°C. A clear solution was obtained and another 50 mg polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. Substance was added until a suspension was obtained at 50°C. The suspension was stirred for one week at 50°C. Polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was obtained as evaluated by XRPD.
Slurry in ethyl acetate at 50°C:
mL of ethyl acetate was added into a glass vial and 150mg polymorphie form I of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. The resulting suspension was heated to 50°C on a thermal stirrer plate. A clear solution was obtained and 50mg polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. Polymorphie form I of N-[2-(6-fiuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was added until a suspension was obtained. The suspension was stirred for one month at 50°C. Polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained as evaluated by XRPD.
Polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is transformed into polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride when slurred at 50°C. As no solvaté is formed, this shows that polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride is less soluble and therefore thermodynamically stable at 50°C.
Slurry in isopropyl acetate at 25°C:
mL of isopropyl acetate was added into a glass vial and 50mg polymorphie form I of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. The suspension was stirred for one month at 25°C. Polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was obtained as evaluated by XRPD.
Slurry in dichloromethane at 25°C:
mL of dichloromethane was added into a glass vial and 50mg polymorphie form I of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafiuoropropoxy)benzylamine hydrochloride was added. The suspension was stirred for one month at25°C. Polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was obtained as evaluated by XRPD.
Slurry in 2-butanol at 25°C:
mL of 2-butanol was added into a glass vial and 10Omg polymorphie form I of N-[2-(6-fluoro-IH-indol3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. The suspension was stirred for one month at 25°C. Polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was obtained as evaluated by XRPD.
Polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is transformed into polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride when slurred at 25°C. As no solvaté is formed, this shows that polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride is less soluble and therefore thermodynamically stable at 25°C.
Slurry in a methanol/toluene solvent mixture at 5°C:
mL of a methanol/toluene (1:9) solvent mixture was added into a glass vial and 100mg polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added. Afterstirring another 1 mL ofthe anti-solvent (toluene) was added + 50mg polymorphieform I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafIuoropropoxy)benzylamine hydrochloride. Stirring resulted in a clear solution and 1 mL of toluene was added and additional 50mg polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. Stirring still resulted in a clear solution and the total volume of 8 mL was divided into two. To the 4 mL solutions another 1 mL of toluene was added and additional 50mg polymorphie form I of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. The saturated supematant together with a small amount of solid from the obtained suspension was transferred to a glass vial and stirred in the refrigerator at 5°C forthree month. Polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained as evaluated by XRPD.
Polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is transformed into polymorphie form III of N-[2-(6-fiuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride when slurred at 5°C. As no solvaté is formed, this shows that polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is less soluble and therefore thermodynamically stable at 5°C.
Example 3: Préparation of polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride by seeding
Polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride(3858 g) in a mixture of acetonitrile (4.55kg) and toluene (5 kg) was warmed to 80°C to obtain a clear solution. The solution was then cooled to 45°C before seeding with polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride(4.8g) and then cooled further to 42°C. After 18 hours a portion of toluene (7.2kg) was added, followed by additional toluene portion (16.7 kg) and stirred at approximately. 45°C for 3 days, cooled and filtered to give polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride which was washed with toluene (3.9 kg). The compound was dried to give polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafIuoropropoxy)benzylamine hydrochloride (3.722 kg).
Polymorphie form I of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride (40g) in toluene (480 mL) under an atmosphère of nitrogen was heated to 110°C before cooling slowly down to 52°C. The suspension was then seeded with polymorphieform lll of N-[2-(6fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and stirred ovemight. A small sample of the suspension was taken cooled and filtered; the solid obtained was analyzed by XRPD to be polymorphieform II of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride. The température of the suspension was lowered to 45°C before seeding with polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride and stirred ovemight. A small sample of the suspension was taken cooled and filtered; the solid obtained was analyzed by XRPD to be polymorphieform II of N[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. The suspension at 45°C was seeded with polymorphie form lll of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and stirred for two days. A small sample of the suspension was taken cooled and filtered; the solid obtained was analyzed by XRPD to be a mixture of polymorphieform II and lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride. The température of the suspension was lowered to 40°C before seeding with polymorphie form lll of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride and stirred ovemight. A small sample of the suspension was taken cooled and filtered; the solid obtained was analyzed by XRPD to be a mixture of polymorphie form II and lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. Acetonitrile (50 mL) was added before seeding with polymorphieform lll of N-[2-(6fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and stirred ovemight at 40°C. A small sample of the suspension was taken cooled and filtered; the solid obtained was analyzed byXRPDto polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yI)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride with traces of polymorphie form I.
Polymorphie form I of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride (40g) in isopropyl acetate (480 mL) under an atmosphère of nitrogen was heated to 81 °C to give a clear solution before cooling slowly down to 50°C then seeded with polymorphie form III of N[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and stirred overnight. A small sample ofthe suspension was taken cooled and filtered; the solid obtained was analyzed byXRPD to be polymorphie form II of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride with traces of polymorphieform I or III. The température ofthe suspension was lowered to 45°C before seeding with polymorphieform III of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and stirred overnight. A small sample ofthe suspension wastaken cooled and filtered; the solid obtained was analyzed byXRPDto be polymorphie form II of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride with traces of polymorphie form I or III. The suspension at 45°C was seeded with polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and stirred forthree days. A small sample ofthe suspension wastaken cooled and filtered; the solid obtained was analyzed by XRPD to be to be polymorphie form II of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride with traces of polymorphie form I/III. The suspension at 45°C was seeded with polymorphie form III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and stirred for six days. A small sample of the suspension was taken cooled and filtered; the solid obtained was analyzed by XRPD to be polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. The solution was cooled to 5°C and isolated by filtration, dried under reduced pressure to give polymorphieform III of N-[2-(6-fiuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride (37.6 g).
Heating polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafiuoropropoxy)benzylamine hydrochloride in toluene as describe above will resuit in the formation of polymorphie form II upon cooling from 110°C as polymorphie form II is the most stable at températures above 60°C, and more easily formed than the polymorphieform III. Lowering the température and adding acetonitrile to the slurry and thereby getting a higher solubility, resulted in polymorphieform III. The traces of polymorphieform I could be obtained when evaporating the solvent during filtration indicating that polymorphie form I is more easily formed compared to polymorphie form lll at lowertempératures.
Polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride(49 g), in a mixture of acetonitrile (74 mL) and toluene (74 mL) was warmed to 84°C to obtain a clear solution under a nitrogen atmosphère. The solution was slowly cooled to 45°C over approximately 1 hour before seeding with polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3(2,2,3,3-tetrafIuoropropoxy)benzylamine hydrochloride (100mg) and stirred between 41-43°Cfor approximately 1.5 hours. Toluene (200mL) was slowly added maintaining the température between 4043 °C. The suspension was then warmed slowly to 50 °C and stirred at this température for 17 hours. The suspension was then slowly cooled to 31 °C and filtered and washed with a mixture of toluene (162 mL) and acetonitrile (18 mL). The compound was dried to give polymorphieform lll of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride (44.8g ).
Example 4: Evaporation crystallization experiments
4.5 mL ethyl acetate and 45mg of polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was added to a glass vial and stirred for a few minutes to obtain a clear solution. The solution was divided in three.
A 1/3 ofthe solution was kept at 25°C, without cap, for more rapid évaporation resulting in polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
A 1/3 ofthe solution was kept at 50°C, without cap, for more rapid évaporation resulting in polymorphie form II of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
A 1/3 ofthe solution was kept at 50°C, with a cap with a pinhole, for slow évaporation resulting in polymorphie form II of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
mL of a 2 butanone/heptane (1:4) solvent mixture and 45mg of polymorphie form I of N-[2-(6-fluoroIH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was added to a glass vial and stirred for a few minutes resulting in a suspension. 1 mL of 2-butanone was added but solid material was still observed. 1 mL of the solution was removed and 1 mL of 2-butanone was added and a clear solution was obtained. The solution was divided in three.
A 1/3 of the solution was kept at 25°C, without cap, for more rapid évaporation resulting in polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
A 1/3 of the solution was kept at 50°C, without cap, for more rapid évaporation resulting in polymorphie form II of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafiuoropropoxy)benzylamine hydrochloride.
A 1/3 of the solution was kept at 50°C, with a cap with a pinhole, for slow évaporation resulting in polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.
Evaporation of the solvent from a solution of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride at 25°C and 50°C results in the formation of polymorphie form I and II and not form III. The results of these experiments indicate that polymorphie form I and form Il of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride hâve a kinetic advantage over polymorphieform III which is the thermodynamically stable form atthese températures.
Example 5: Relative stability of polymorphie form 1, Il and III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafIuoropropoxy)benzylamine hydrochloride
A saturated solution was prepared by heating 1.6 mL isopropyl acetate and 0.4 mL heptane to 70°C and adding 50mg of polymorphie form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride. Stirring for two hours and then left non-stirred at 70°C ovemight resulted in a saturated solution where solid material could be seen.
The supematant was divided into two ampoules and kept at 60°C and 70°C.
5mg of polymorphie form I, Il and III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was added to the 60°C solution and left stirring at 60°C for one and four days, respectively. Evaluation after one day resulted in a mixture of polymorphie form II and III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and polymorphie form I has vanished. Evaluation after four days resulted in polymorphie form 11 of N-[2-(628 fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and traces of polymorphie form III.
2.5mg of polymorphieform I, Il and III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was added to the 70°C solution and left without stirring at 70°C for three days. Evaluation resulted in polymorphie form II and I of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and polymorphie form III has vanished.
Polymorphieform I, Il and III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride were mixed in equal amounts and slurred in isopropyl acetate at 60°C. After one day it is only a mixture of polymorphie form II and III of N-[2-(6-fluoro-IH-indol3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride while polymorphie form I has vanished. Afterfour days it can be seen that polymorphieform III ofthe N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetraf)uoropropoxy)benzylamine hydrochloride is transforming into polymorphie form
II. This shows that polymorphie form I of N-[2-(6-fluoro-IH-indoI-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride is less stable than polymorphie form III and polymorphie form II is thermodynamically stable at this température. The fact that the transformation is slow indicates that it is close to the transition température between polymorphie form II and III of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. At 70°C the transformation is faster and a suspension of equal amounts of polymorphieform I, Il and III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride left without stirring will tum into polymorphie form II in three days. This shows that polymorphie form II of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is thermodynamically stable at 70°C.
Example 6: Solubility in organic solvents
Thermodynamic solubility of polymorphieform I and III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride was measured by shaking an excess amount ofthe two polymorphie forms in the organic solvent in a sealed container at room température (about 23°C). After equilibrium was attained, a sample was withdrawn, the solid filtered or centrifuged off and the clear filtrate/supematant was assayed by HPLC at 217nm. The precipitate was evaluated by XRPD to détermine the polymorphie form.
Table 2: Solubility of polymorphieform lll and form I of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride in organic solvents.
| Solvent | Solubility - polymorphie form III [mg base/mL] | Solubility-polymorphie form I [mg base/mL] |
| 2-butanol | 9.3 | 10.5 |
| Isopropanol | 24.5 | 25.2 |
| Isopropyl acetate | 3.0 | 3.4 |
Solubility experiments in organic solvents show that polymorphie form lll of N-[2-(6-fluoro-IH-indol-35 yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is slightly less soluble and therefore thermodynamically stable at room température (about 23°C).
Example 7: Préparation of a mixture of polymorphie form lll and polymorphie form IV.
A saturated solution of éthanol and polymorphie form lll of N-[2-(6-fluoro-1 H-indol-3-yl)ethyl]-3-(2,2,3,310 tetrafluoropropoxy)benzylamine hydrochloride is prepared at room température. The slurry is left to equilibrate under constant stirring. A small sample ofthe slurry containing both liquid and solid material is taken out with a pipette and left to evaporate.
A mixture of polymorphie form lll and polymorphieform IV of N-[2-(6-fIuoro-1 H-indol-3-yl)ethyl]-3(2,2,3,3-tetrafIuoropropoxy)benzylamine hydrochloride was obtained as evaluated by XRPD (figure 7).
Characteristic polymorphie form IV XRPD peaks are listed below (±0.10 (°2θ)):
17.52, 17.73,19.20,19.72, 20.30, 21.60, 23.07, 23.87, 26.41
Example 8: FTIR spectra of polymorphie form III and polymorphie form I.
The IR spectra of polymorphie form I and polymorphie form III were recorded as described above.
| Band position [cm'1] | Relative band intensity | |
| Polymorphie form I | Polymorphie form III | |
| 3425 | 3426 | Strong |
| 2951 | 2951 | Medium |
| 2800 | 2800 | Medium |
| 2749 | 2749 | Medium |
| 1631 | 1631 | Medium |
| 1586 | 1586 | Strong |
| 1451 | 1452 | Strong |
| 1099 | Shoulder | |
| 1092 | 1089 | Very strong |
| 879 | 880 | Medium |
| 762 | 762 | Strong |
Table 3: FTIR band positions and relative intensity for polymorphie form I and polymorphie form III.
Claims (19)
- Claims:1. Polymorphieform lll of N-[2-(6-fIuoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tet.rafluoropropoxy)benzylamine hydrochloride, characterized byanX-Ray powder diffractogram showing peaks atthe following 20-angles: 4.63°, 6.94°, 13.89°, 17.26° and 19.97°.
- 2. The polymorphie form according to claim 1 further characterized by an X-Ray powder diffractogram showing peaks at the following 20-angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.95°, 19.97°, 22.53° and 23.65°.
- 3. The polymorphie form according to claim 1, wherein said compound exhibits a X-Ray powder diffractogram as shown in figure 5
- 4. A process for preparing polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride comprising:a. capturing polymorphieform lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride from a suspension of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C.
- 5. A process for preparing polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride comprising:a. adding polymorphie I, form II, amorphous or a mixture of the forms of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafiuoropropoxy)benzylamine hydrochloride to an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C to produce a suspension;b. capturing polymorphieform lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
- 6. A process for preparing polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzyiamine hydrochloride comprising:a. seeding a suspension of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile, proprionitrile, acetone, methanol, éthanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C with polymorphie form lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride;*Ib. capturing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
- 7. A process for preparing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride comprising:a. adding polymorphie I, form II, amorphous or a mixture of the forms of N-[2-(6-fluoro-IHindol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to an organic solvent selected from the listof acetonitrile, proprionitrile, acetone, methanol, éthanol, heptane, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a température below 60°C to produce a suspension;b. seeding with polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride at a température below 60°C;c. capturing polymorphieform III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride.
- 8. The process according to any of the claims 4-7, wherein the organic solvent is a mixture of acetone and heptane in the ratio 1:4.
- 9. The process according to any ofthe claim 4-7, wherein the organic solvent is a mixture of methanol and toluene in the ratio 1:4.
- 10. A compound according to any of the claims 1 -3 or 19 for use as a médicament.
- 11. A pharmaceutical composition comprising a compound according to any ofthe claims 1-3 or 19.
- 12. A compound according to any ofthe claims 1-3 or 17 for use in treating Alzheimer’s disease as adjunctive therapy to acetylcholinesterase treatment.
- 13. The compound according to claim 12, wherein the dose of said compound is between about 30 and about 60 mg.
- 14. Use of a compound according to any ofthe claims 1-3 or 17 forthe manufacture of a médicament for treating Alzheimer’s disease as adjunctive therapy to acetylcholinesterase treatment.
- 15. The use according to claim 14, wherein the dose of said compound is between about 30 and about 60 mg.
- 16. The process according to any of claims 4 to 7 wherein the suspension is produced in the température range 45°C - 55°C.
- 17. Polymorphieform lll of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3tetrafluoropropoxy)benzylamine hydrochloride, characterized byan FTIRspectrum having relative strong band intensity atthefollowing band positions [cm'1]: 3426,1586,1089, 762 and a shoulder at 1099 cm’1.
- 18. A pharmaceutical composition prepared from polymorphieform III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride, wherein polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is characterized by an X-Ray powder diffractogram showing peaks at the following 20-angles:5 4.63°, 6.94°, 13.89°, 17.26°, 18.95°, 19.97°, 22.53° and 23.65°.
- 19. A pharmaceutical composition prepared from polymorphie form III of N-[2-(6-fluoro-IH-indol-3yl)ethyl]-3-(2,2,3,3-tetrafiuoropropoxy)benzylamine hydrochloride, wherein the polymorphie form III of N-[2-(6-fluoro-IH-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is characterized by an FTIR spectrum having strong band intensity at the10 following band positions [cm-1]: 3426,1586,1089, 762 and a shoulder at 1099 cm'1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA201400369 | 2014-07-04 |
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| OA18216A true OA18216A (en) | 2018-09-04 |
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