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HK1098128A1 - New crystalline form v of agomelatine, a process for its preparation and pharmaceutical compositions containing it - Google Patents

New crystalline form v of agomelatine, a process for its preparation and pharmaceutical compositions containing it Download PDF

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Publication number
HK1098128A1
HK1098128A1 HK07104583.8A HK07104583A HK1098128A1 HK 1098128 A1 HK1098128 A1 HK 1098128A1 HK 07104583 A HK07104583 A HK 07104583A HK 1098128 A1 HK1098128 A1 HK 1098128A1
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Prior art keywords
crystalline form
agomelatine
formula
compound
disorders
Prior art date
Application number
HK07104583.8A
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Chinese (zh)
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HK1098128B (en
Inventor
Coquerel Gérard
Linol Julie
Souvie Jean-Claude
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Les Laboratoires Servier
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
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    • A—HUMAN NECESSITIES
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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Abstract

Crystalline form V of agomelatine (I) is new. Crystalline form V of agomelatine ((I); N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide) having powder X-ray diffraction diagram, measured using a diffractometer (copper anticathode) and expressed in terms of inter-planar distance d (8.979-3.239 A[deg]), Bragg's angle 2 theta (9.84-27.51 degrees), intensity and relative intensity (15-100 percentage with respect to the most intense), is new. Independent claims are included for: (1) the preparation of (I); and (2) a composition comprising (I) and, inert and non-toxic carriers. ACTIVITY : Hypnotic; Tranquilizer; Antidepressant; Cardiovascular-Gen.; Sedative; Muscular-Gen.; Immunomodulator; Neuroleptic; Anorectic; Anticonvulsant; Antidiabetic; Antiparkinsonian; Nootropic; Antimigraine; Neuroprotective; Endocrine-Gen.; Contraceptive; Cytostatic. MECHANISM OF ACTION : Melatoninergic receptor agonist.

Description

New crystalline form V of agomelatine, process for its preparation and pharmaceutical compositions containing it
Technical Field
The present invention relates to a new crystalline form V of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (I):
a process for its preparation and pharmaceutical compositions containing it.
Background
Agomelatine, or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide, has valuable pharmacological properties.
It does have a dual profile, on the one hand, it is an agonist of receptors of the melatoninergic system and, on the other hand, it is 5-HT2CAn antagonist of the receptor. These properties make it active in the central nervous system, more particularly in the treatment of major depression (severe depression), seasonal affective disorder, sleep disorders, cardiovascular disease, digestive system disease, insomnia and fatigue due to jet lag, appetite disorders and obesity.
Agomelatine, its preparation and its therapeutic use are described in european patent specification EP 0447285.
In view of the pharmaceutical value of the compound, it is important to obtain the compound in good purity, in a well-defined crystalline form and with excellent reproducibility, as a result of which valuable properties are exhibited in terms of dissolution and formulation and which are sufficiently stable that it can be stored for a long time without specific requirements on temperature, light, humidity or oxygen level.
Patent specification EP 0447285 describes the eight-step preparation of agomelatine starting from 7-methoxy-1-tetralone. However, the document does not specify the conditions for obtaining agomelatine exhibiting these characteristics in a reproducible manner.
Disclosure of Invention
The applicant has now developed a new synthetic process which makes it possible to obtain agomelatine in a well-defined, highly reproducible crystalline form which exhibits, inter alia, valuable characteristics in terms of dissolution and formulation.
More specifically, the present invention relates to crystalline form V of the compound of formula (I) characterized by the following powder X-ray diffraction diagram, measured using a siemens D5005 diffractometer (copper on cathode), expressed as interplanar spacing D, bragg 2 θ angle, intensity and relative intensity (expressed as a percentage of the most intense rays):
the invention also relates to a process for the preparation of the crystalline form V of the compound of formula (I), characterized in that agomelatine is subjected to so-called "high-energy" mechanical milling. In the crystallization process of the present invention, it is possible to use the compound of formula (I) obtained by any method.
The invention also relates to another process for the preparation of the crystalline form V of the compound of formula (I), characterized in that agomelatine is heated until complete melting, then immediately placed at room temperature and simultaneously added in small amounts of the newly prepared crystalline form V of the compound of formula (I), and the mixture is cooled until crystallization is complete. Preferably, in the second crystallization process of the present invention, agomelatine melts at 110 ℃. The amount of form V added in the second process of the invention is preferably between 1/100 and 1/50 by weight of agomelatine. In the second crystallization process of the present invention, it is possible to use the compound of formula (I) obtained by any method.
The advantage of obtaining such a crystalline form is that it allows the preparation of pharmaceutical formulations having a consistent and reproducible composition, as a result of which valuable properties are exhibited in terms of dissolution, which is particularly beneficial when the formulation is intended for oral administration.
Pharmacological studies of the crystalline form V thus obtained have demonstrated its important activity in the central nervous system and in the microcirculation, which has led to the establishment of crystalline form V of agomelatine useful in the treatment of the following disorders: stress, sleep disorders, anxiety, major depression, seasonal affective disorders, cardiovascular disease, digestive system disease, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraine, memory loss, alzheimer's disease and cerebral circulation disorders. In another field of activity, it is indicated that crystalline form V of agomelatine is useful in the treatment of sexual dysfunction, has ovulation-inhibiting and immunomodulating properties and is useful in the treatment of cancer.
Crystalline form V of agomelatine is preferably used for the treatment of major depressive disorder, seasonal affective disorder, sleep disorders, cardiovascular disease, insomnia and fatigue due to jet lag, appetite disorders and obesity.
The invention also relates to a pharmaceutical composition comprising crystalline form V of agomelatine as active ingredient, together with one or more suitable inert non-toxic excipients. Among the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, such as tablets or dragees, granules, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and disintegratable pastes.
Useful dosages are adjusted according to the nature and severity of the disorder, the route of administration, and the age and weight of the patient. The dose varies between 0.1mg and 1g per day, administered one or more times.
Detailed Description
The following examples illustrate the invention but do not limit it in any way.
Example 1: crystalline form V of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide
100g N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide was ground in a mechanical grinding mill of the variable speed high energy planetary mill type for about 6 hours, and the resulting solid was characterized by the following powder X-ray diffraction pattern, measured using a Siemens D5005 diffractometer (copper on cathode) and expressed as interplanar spacing D, Bragg 2 theta angle, intensity and relative intensity (expressed as a percentage of the most intense ray):
example 2: crystalline form V of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide
4g N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide was placed in a vented incubator at 110 ℃. After 1 hour at 110 ℃ the product is immediately left at room temperature and 0.05g of the structurally pure crystalline form V of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide obtained by high-energy mechanical milling are used. After 5 minutes, the crystallization was complete and the solid obtained was characterized by the following powder X-ray diffraction diagram, measured using a siemens D5005 diffractometer (copper vs. cathode) and expressed in interplanar spacing D, bragg 2 θ angle, intensity and relative intensity (expressed as a percentage of the strongest rays):
example 3: pharmaceutical composition
A formulation for making 1000 tablets, each tablet containing a 25mg dose:
the
A
.
The
The
The
.
.
Example 4: pharmaceutical composition
A formulation for making 1000 tablets, each tablet containing a 25mg dose:
the
A
.
.
The
.
.

Claims (6)

1. Crystalline form V of agomelatine of formula (I):
characterized by the following powder X-ray diffraction pattern, determined using a diffractometer with copper on cathode and expressed in interplanar spacing d, bragg 2 theta angle, intensity and relative intensity, expressed as a percentage of the most intense ray:
2. process for the preparation of the crystalline form V of the compound of formula (I) according to claim 1, characterized in that agomelatine is subjected to so-called "high energy" mechanical milling.
3. Process for the preparation of the crystalline form V of the compound of formula (I) according to claim 1, characterized in that agomelatine is heated until complete melting, then immediately placed at room temperature and simultaneously added in small amounts of the newly prepared crystalline form V of the compound of formula (I), and the mixture is cooled until crystallization is complete.
4. A pharmaceutical composition comprising the crystalline form V of agomelatine according to claim 1 as active ingredient in association with one or more pharmaceutically acceptable inert non-toxic carriers.
5. Use of the crystalline form V of the compound of formula (I) according to claim 1 in the manufacture of a medicament for the treatment of melatoninergic disorders.
6. Use of crystalline form V of a compound of formula (I) according to claim 1 in the manufacture of a medicament for the treatment of: sleep disorders, stress, anxiety, seasonal affective disorder or major depression, cardiovascular disease, digestive system disease, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, alzheimer's disease, cerebral circulation disorders, sexual dysfunction, use as ovulation inhibitors and immunomodulators, and cancer.
HK07104583.8A 2005-08-03 2007-04-30 New crystalline form v of agomelatine, a process for its preparation and pharmaceutical compositions containing it HK1098128B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0508278A FR2889523B1 (en) 2005-08-03 2005-08-03 NOVEL CRYSTALLINE FORM V OF AGOMELATIN, PROCESS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
FR0508278 2005-08-03

Publications (2)

Publication Number Publication Date
HK1098128A1 true HK1098128A1 (en) 2007-07-13
HK1098128B HK1098128B (en) 2009-05-22

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IL177173A0 (en) 2006-12-10
NO20063517L (en) 2007-02-05
PE20070365A1 (en) 2007-06-02
EP1752443A1 (en) 2007-02-14
BRPI0603059A (en) 2007-08-14
TWI359128B (en) 2012-03-01
CU20060153A7 (en) 2012-04-15
TW200736199A (en) 2007-10-01
WO2007015004A3 (en) 2007-03-22
EP2277857A3 (en) 2011-06-01
RS52423B (en) 2013-02-28
CA2555115C (en) 2013-12-10
ZA200606453B (en) 2007-12-27
HRP20120779T1 (en) 2012-10-31
IL177173A (en) 2011-10-31
MXPA06008789A (en) 2007-02-02
EA011030B1 (en) 2008-12-30
NO336967B1 (en) 2015-12-07
CR8529A (en) 2006-12-07
CY1113011T1 (en) 2016-04-13
ES2391406T3 (en) 2012-11-26
AR057715A1 (en) 2007-12-12
FR2889523B1 (en) 2007-12-28
MY139902A (en) 2009-11-30
AP2006003695A0 (en) 2006-08-31
CN1907958A (en) 2007-02-07
EA200601273A1 (en) 2007-02-27
JO2793B1 (en) 2014-03-15
CN100448843C (en) 2009-01-07
WO2007015004A2 (en) 2007-02-08
EP1752443B1 (en) 2012-07-11
SI1752443T1 (en) 2012-10-30
FR2889523A1 (en) 2007-02-09
CA2555115A1 (en) 2007-02-03
MA28451B1 (en) 2007-03-01
AU2006203342A1 (en) 2007-02-22
JP2007056017A (en) 2007-03-08
DK1752443T3 (en) 2012-10-22
SG130110A1 (en) 2007-03-20
ME02026B (en) 2012-11-06
UA83720C2 (en) 2008-08-11
JP4575337B2 (en) 2010-11-04
NZ548864A (en) 2008-03-28
PL1752443T3 (en) 2012-11-30
AU2006203342B2 (en) 2012-07-19
PT1752443E (en) 2012-07-25
EP2277857A2 (en) 2011-01-26
SA06270255B1 (en) 2010-06-13
GT200600346A (en) 2007-02-28
ECSP066715A (en) 2007-03-29
AP2486A (en) 2012-10-03

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