FIELD OF THE INVENTION

The present invention relates to the compounds of formula (I), pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment of hyperkinetic diseases and disorders, such as tardive dyskinesia, by administration of such compounds to a warm-blooded animal in need thereof.

Synonyms: Dihydrotetrabenazine; DTBZ; DHTBZ

Synonyms: d6-Dihydrotetrabenazine; d6-DTBZ; d6-DHTBZ

BACKGROUND OF THE INVENTION

The involuntary movement and repetitive body movement are typical symptoms of hyperkinetic movement disorder caused by exposure of long-term medication with dopamine amine blocking agents, such as antipsychotic agents. The actual mechanism of hyperkinetic movement disorder is still not clear. Previous data support hypothesis of upregulation and supersensitiveness of dopamine receptor, like D2, resulting in chronic reduction of dopaminergic neurotransmission and causing the hyperkinetic movement disorder.

The hyperkinetic movement could start with chewing, affected normal speech, breathing, movement disorder and balance. In some severe cases, it will result in self-injury, laceration and inability for the normal life. Tardive dyskinesia (TD) is one of the family of hyperkinetic movement disorder and generally is characterized by involuntary hyperkinetic movement in orofacial area and choreoathetoid disorder in the limbs and trunk. In general, TD can be developed by long-term exposure of antipsychotic drugs and often persists even after discontinuation of treatment.

Vesicular monoamine transporter-2 (VMAT2) is a membrane protein that transports the monoamine such as dopamine, serotonin, histamine and norepinephrine from presynaptic into synaptic vesicle. 3-isobutyl-9,10,dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one, also known as tetrabenazine (TBZ, XENAZINE®) is a potent (IC50is 3.2 nM, Scherman, et al., Proc. Natl. Acad. Sci. USA, 1983, 80, 584-588) and reversible VMAT2 inhibitor and has been used as treatment of hyperkinetic movement disorders, for example chorea associated with Huntington's disease and TD. However, some TBZ off-target related side effects including depression, sedation, drowsiness, dizziness, insomnia, akathisia and parkinsonism were observed and reported. Therefore, a strict RISK Evaluation and Mitigation Strategy (REMS) of XENAZINE® was issued and personalized dosing, dose titration and management of medication associated side effects are required.

TBZ is a racemic mixture and presents two chiral centers. It can be rapidly and extensively metabolized to its reduced form, 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, known as dihydrotetrabenzaine (DHTBZ). Due to the nature of racemic mixture, DHTBZ can be presented as four isomers, (±)-α-DHTBZ and (±)-β-DHTBZ, where the extent to which isomer can be highly variable between patients (Mehvar et al., Drug Metab. and Dispos., 1987, 15, 250-255). Among these isomers, the (+)-α-DHTBZ or 2R, 3R, 11bR-DHTBZ is considered as the major active metabolite and exhibits excellent VMAT2 binding and off-target selectivity. On the other hand, other stereoisomers present variable pharmacology effects such as weak to moderate VMAT2 binding and high affinity to some off-target receptors (Grigoriadis et al., J. Pharmacol. Exp. Ther., 2017, 361, 454-461). TBZ has been approved as hyperkinetic disorder medication; however, variable bioavailability due to the complexity of TBZ metabolism through extensive first pass effect and off-target phenomenon can result in variable inter-patient therapeutic results. Also, the short half-life and low bioavailability could cause more dosing frequency, three times per day.

The off-target effect of TBZ caused by complex racemic metabolites can result in several serious side effects, including suicidality, depression, sedation, drowsiness, dizziness, insomnia, akathisia and parkinsonism. The genotyping of individuals could exhibit different degrees of metabolism of TBZ to generate variable concentration levels of each metabolite. Also, due to the genotyping issue, the dose titration of TBZ is required.

Since the serious side effects associated with TBZ are related to the complexity of metabolism where the generated isomeric metabolites can be highly variable from patient to patient. The poor off-target selectivity of some metabolites have been shown to be responsible for these serious side effects. Therefore, the problems associated with the stereochemical metabolites can possibly be avoided by administration of the metabolite or its derivative in a single stereoisomer form.

(S)-2-amino-3-methyl-butyric acid (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl (Valbenazine, VBZ, INGREZZA®) described in U.S. Pat. No. 8,039,627 is a prodrug with valine substitution on the single stereoisomer (+)-(α)-DHTBZ. A prodrug is a pharmacological substance (drug) that is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into its active parent drug. Administrating a prodrug of a single stereoisomer can provide the merit by avoiding exposure to all stereoisomer metabolites of dihydrotetrabenazine (DHTBZ). As disclosed in U.S. Pat. No. 8,039,627, VBZ [(+)-(α)-DHTBZ conjugated with valine, an amino acid] showed VAMT2 binding affinity, Ki, of 187 nM. The VBZ is less potent than (+)-(α)-DHTBZ, but is still quite a strong inhibitor for VMAT2.

Good stability, minimal or no VMAT2 binding, and suitable hydrolysis rate to release active drug are the key parameters in development of long acting depot of DHTBZ derivative. Although some prior arts have demonstrated chemical modification on hydroxyl containing DHTBZ, the resulting properties associated with esterified compounds varied significantly and unpredictably. For example, those described in Harriott et al, Prog. Med. Chem., 2018, 57, 87-111, Aranda et al. Euro. J. Med. Chem., 1990, 25, 369-374 and Kilbourn et al. Chirality, 1997, 9, 59-62, have shown that the hydroxyl group in DHTBZ could be utilized to form different ester modifications of DHTBZ. Aranda disclosed a caproic acid ester of DHTBZ (see page 370 of Aranda, Compound No. 6) and Kilbourn disclosed an acetic acid ester of DHTBZ (see page 60 of Kilbourn, right hand column). However, these types of compounds are not suitable for use as prodrugs of DHTBZ. As disclosed in the response to the Examiner's rejection for patent application Ser. No. 11/937,445 on Apr. 1, 2011, when tested in human liver assay, no conversion of these compounds to (+)-α-DHTBZ was observed; only VBZ, a valine modified DHTBZ, can release the active (+)-α-DHTBZ. It appears that modification with short chain (C2 and C6) aliphatic carboxylic acid would make liberation of active parent drug inefficient. Thus, neither of these prior art compounds would function as a substitute for (+)-α-DHTBZ since administration of the same fails to generate the active metabolite.

Aranda reports a VMAT2 binding affinity (EC50) for the caproic acid ester of 8.1±3.3 nM compared to 6.7±1.1 nM for (+)-(α)-DHTBZ (see Table 1, page 370). This corresponds to a Ki of 5.7 nM for the caproic acid ester compared to 4.7 nM for (+)-(α)-DHTBZ (see 16 of the Declaration). The acetate ester of Kilbourn was found to have a Ki of 16 nM compared to 5.3 nM for (+)-(α)-DHTBZ (see 17 of the Declaration). The acetate ester of Kilbourn (C2) showed lower affinity than the caproic acid ester of Aranda (C6), i.e., 16 nM vs 5.7 nM. It appears that the longer the carbon chain of the esters, the stronger the inhibitor for VAMT2. Both caproic acid ester and acetate esters are potent VAMT2 inhibitors with comparable potency (Ki) to that of (+)-(α)-DHTBZ. Therefore, these esters disclosed in Kilbourn (C2) and Aranda (C6) are not suitable for use as prodrugs. It also seems that increasing carbon chain length of the (+)-(α)-DHTBZ esters from C2 to C6 would not lead to a lower potency for VMAT2.

Although the VBZ is a successful oral dosage form, it has to be taken daily for a long time. It's still relative potent to VMAT2 receptor and not ideal for use as a prodrug. Therefore there is still a need for a much longer acting dosage form which can significantly reduce dosing frequency and improved compliance. There is also a need for a modified drug to have a lower potency to VMAT2 than VBZ.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I) including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof.



wherein R1is —C(═O)O-alkyl, carbonate ester, or —C(═O)-alkyl, ester, or —C(═O)N-alkyl, carbamate ester and wherein R2is —CH3or —CD3. The alkyl ester can contain saturated or unsaturated C12to C26alkyl carbon. The alkyl carbon chain can have either a straight, branched, noncyclic, cyclic or substituted structure.

Specifically, the present invention provides the conjugations of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)-α-DHTBZ) and (2S, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)-β-DHTBZ) compounds, as well as the modification method of these compounds, use, and pharmaceutical compositions containing the same.

The compounds of formula (I) of the present invention has both good chemical and physical stability, minimal or no VMAT2 binding and acceptable ester hydrolysis rate.

The compounds of formula (I) of the present invention can achieve a broad spectrum of therapeutic applications, and may be used as the inhibitor for vesicular monoamine transporter 2 (VMAT2) receptor and its associated disease, such as the family of hyperkinetic movement disorder diseases.

The compounds of formula (I) of the present invention are designed to deliver the active DHTBZ in a controlled manner with less variable plasma concentration and pharmacokinetics (PK) profile, which can limit the off-target effect to provide an improved safety profile to patients. In addition, the formula (I) is the alkyl esterification of (+)-DHTBZ ((+)-α-DHTBZ) and (+)-(β-DHTBZ)), where the alkyl esterification containing C12to C26alkyl ester. The present invention provides method for the conjugation of (+)-DHTBZ with fatty acid by reacting the hydroxyl group in (+)-DHTBZ with carboxyl group in fatty acid moiety. The compounds of formula (I) of the present invention provide low aqueous solubility (e.g., less than 100 mcg/mL), suitable VMAT2 inhibition (K more than 100 nM). The compounds of formula (I) of the present invention can be administrated to a subject in need and the active DHTBZ is released after hydrolysis of the conjugate within tissue environment. The hydrolysis can be conducted via enzymatic or chemical pathway or in the combination of both pathways.

The present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).

