JP2011001308A - Deuterated carbostyril compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a deuterated aripiprazole and intermediates for producing the same.SOLUTION: A compound represented by formula (I) and a salt thereof are disclosed. The hepta deuteriums-substituted compound of aripiprazole has substantially the same pharmacological action and safety as aripiprazole, and the compound has the site of action of metabolism by dehydrogenation which is substituted with deuteriums and additionally has deuteriums on the adjacent benzene ring, and accordingly exhibits in vivo behavior different from the reported deuterated aripiprazole, for example, the metabolic rate by dehydrogenation is further retarded and, as a result, the duration of action as a drug is extended.

Description

  The present invention relates to deuterated carbostyril compounds useful as pharmaceuticals and intermediates for the production of pharmaceutical compounds.

  Although many of the carbon compounds do not change the basic physicochemical properties even when the hydrogen atom (H) is replaced with a deuterium atom (D), it is known that various changes occur in biological activity. . In addition to the basic activity, the short C–D bond also makes a meaningful change in the size of the molecule for the living body, and it also has an effect on pharmaceutical properties. Among biological activities, the metabolic rate in vivo, particularly involving the cleavage of the C—H bond, often results in a large difference because the dissociation energy of the C—H bond and the C—D bond is different. For example, the amino acid phenylalanine undergoes metabolism in vivo and is converted to tyrosine, but the elimination of hydrogen (H) from the intermediate of the reaction is significantly more than deuterium (D) and tritium (T). It is known to be fast (this phenomenon is called the isotope effect).

  On the other hand, aripiprazole (aripiprazole: 7- [4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy] -3,4-dihydro-2 (1H) -quinolinone) is a third-generation antipsychotic It is an atypical antipsychotic that is classified (Japanese Patent Laid-Open No. 2-191256). It acts on the mesolimbic system and the midbrain cortex in the brain to regulate dopamine stimulation, thus treating schizophrenia and the like Widely used in Aripiprazole is metabolized in the liver, but is known to undergo dehydrogenation and hydroxylation mainly by cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6), and N-dealkylation by CYP3A4. The main metabolite in plasma is dehydrogenated form (dehydroaripiprazole: 7- [4-4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy) -2 (1H) -quinolinone), steady state (administration) On day 14), the ratio of AUC of dehydroaripiprazole to unchanged is about 27%. Furthermore, metabolites in which the aromatic ring is oxidized have been detected, particularly in in vivo tests on monkeys.

  Attempts have been made to control the metabolic rate of aripiprazole using the above isotope effect. For example, US Patent Publication 2008 / 0299216A1 discloses derivatives of aripiprazole randomly deuterated as a mixture. In addition, International Publication WO2008 / 24481 discloses a derivative in which the 3rd and 4th positions of the quinolinone skeleton of aripiprazole and the 4th position of the butoxy group are deuterated. However, these publications do not disclose compounds in which the benzene ring portion of the quinoline skeleton is deuterated, and there is no suggestion or teaching regarding the metabolic rate of such compounds.

Japanese Patent Laid-Open No. 2-191256 US Patent Publication 2008 / 0299216A1 International Publication WO2008 / 24481

  An object of the present invention is to provide a deuterated aripiprazole and an intermediate for production thereof.

  The present inventor has intensively studied to provide a deuterated aripiprazole which has not been reported so far, a compound in which all of the hydrogen atoms of the quinoline skeleton are substituted with deuterium, and an intermediate for the production thereof. As a result, the obtained hepta-deuterium substitute showed a different in vivo behavior from aripiprazole and the previously reported deuterated aripiprazole (International Publication WO2008 / 24481), and the metabolism due to oxidation was significantly delayed. In addition to changes in AUC, favorable excretion from renal bile, etc., reduction of toxicity due to metabolites, reduction of cholelithiasis-like findings including metabolites, and changes in body distribution including brain It has been found that it has preferable properties such as. The present invention has been completed based on the above findings.

で表される化合物又はその塩が提供される。 That is, according to the present invention, the following formula (I):

Or a salt thereof is provided.

（式中、Xは脱離基を示す）で表される化合物又はその塩が提供される。これらの化合物又はそれらの塩は、上記式(I)で表される化合物の製造用中間体として有用である。 From another point of view, according to the present invention, the following formula (II) or formula (III):

(Wherein X represents a leaving group) or a salt thereof is provided. These compounds or their salts are useful as intermediates for producing the compounds represented by the above formula (I).

From still another aspect, the present invention provides a medicament, preferably an antipsychotic, comprising the compound represented by the above formula (I) or a physiologically acceptable salt thereof as an active ingredient.
Further, the use of the compound represented by the above formula (I) or a salt thereof for the manufacture of the above medicament and a method for treating and / or preventing mental illness such as schizophrenia, mania, depression, or manic depression A method comprising administering to a mammal, including a human, a therapeutically and / or prophylactically effective amount of a compound represented by the above formula (I) or a physiologically acceptable salt thereof is provided by the present invention. The

Furthermore, according to the present invention, there is provided a process for producing a compound represented by formula (I), comprising the following steps
(1) 7-hydroxy-3,3,4, dihydro-1H-quinolin-2-one is deuterated in the presence of a metal catalyst and a deuterated solvent and a hydrogen molecule to form 7-hydroxy-3,3,4, Producing 4,5,6,8-heptaduterio-2 (1H) -quinolinone;
(2) Convert 7-hydroxy-3,3,4,4,5,6,8-heptaduterio-2 (1H) -quinolinone obtained in step (1) above to the compound of formula (II) Steps; and
(3) A method comprising the step of reacting a compound of formula (II) with 1- (2,3-dichlorophenyl) piperazine to convert to a compound of formula (I) is provided.
As the metal catalyst, for example, a palladium carbon catalyst can be used, and as the deuterated solvent, for example, heavy water can be used.

  The hepta deuterium-substituted compound of aripiprazole provided by the present invention has substantially the same pharmacological action and safety as aripiprazole, and is adjacent to the deuterium substitution of the metabolic action point by dehydrogenation. Since deuterium is also present on the benzene ring, it exhibits in vivo behavior different from that of the previously reported deuterated aripiprazole (International Publication WO2008 / 24481) .For example, the metabolic rate due to dehydrogenation is further delayed. As a result, it has the characteristic that the action time as a medicine is prolonged. For example, since the metabolism due to oxidation is significantly delayed, in addition to sustained activity, changes in AUC, favorable excretion from renal bile, etc., and reduction in toxicity due to metabolites, cholelithiasis including metabolites It causes a decrease in appearance and changes in the body distribution including the brain. In particular, it is known that aripiprazole also oxidizes the benzene ring that constitutes the quinolone ring in the metabolic process. The hepta deuterated compound of the present invention delays the metabolic rate in this pathway, thereby prolonging the action time. I can expect.

  In addition, the compound represented by the formula (II) of the present invention can be produced with good yield in one step from a non-deuterated quinolinone derivative which is inexpensive and easily available. Therefore, by using this compound of formula (II) as an intermediate for production, the compound of formula (I) can be produced much cheaper and more easily than deuterated aripiprazole described in, for example, International Publication WO2008 / 24481 There is a feature that can be.

In the above formulas (I) to (III), hydrogen atoms (H) other than deuterium represented by D are omitted.
In the compounds represented by the formulas (I) to (III), an acid addition salt can be used as a salt. For example, mineral salts such as hydrochloride, sulfate, hydrobromide, tartrate, maleate, etc. Organic acid salts such as acid salts, malic acid salts, p-toluenesulfonic acid salts, and methanesulfonic acid salts can be used, but are not limited thereto. Preferably, hydrochloride or the like can be used.

  The compound represented by the above formula (I) (7- [4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy] -3,4-dihydro-3,3,4,4,5 , 6,8-heptaduterio-2 (1H) -quinolinone) is a compound represented by the above formula (II) (7-hydroxy-3,3,4,4,5,6,8-heptaduterio- 2 (1H) -quinolinone) is easily produced by derivatizing the compound represented by the above formula (III) and further substituting the leaving group X with 4- (2,3-dichlorophenyl) piperazine. can do. In formula (III), as X, for example, a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyl group, and a methanesulfonyl group can be used, and X is preferably a bromine atom.

The compound represented by the formula (II), for example, using 7-hydroxy-3,4-dihydro-1H-quinolin-2-one as a raw material compound, the method of Sakuji et al. (Sajiki et al., Tetrahedron Letters, 46, pp.6995-6998, 2005; Journal of Synthetic Organic Chemistry, 65, pp.1179-1189, 2007), acting a small amount of hydrogen molecules (H ₂ ) in the presence of metal catalyst and deuterated solvent By doing so, hydrogen atoms at the 3rd, 4th, 5th, 6th and 8th positions of the quinoline ring can be substituted with deuterium. The reaction may be performed at a temperature of about 80 to 150 ° C. for several hours to several days. The structure of the deuterated compound and the substitution position with deuterium can be easily confirmed by ¹ H-NMR and ¹³ C-NMR. Although the deuteration rate is not particularly limited, it is, for example, 90% or more, preferably 95% or more, more preferably 98% or more.By repeating the above reaction as necessary, the deuteration rate can be further increased. Enhanced compounds can be produced.

  As the catalyst, for example, a metal catalyst used for normal catalytic hydrogenation, such as a palladium catalyst, a platinum catalyst, a nickel catalyst, a cobalt catalyst, or an iridium catalyst, can be used, and these metal catalysts can be activated carbon or an inert inorganic compound. A catalyst supported on an inert carrier such as can be preferably used. Preferably, a palladium carbon catalyst or the like can be used.

Examples of the deuterated solvent include heavy water (D ₂ O), heavy methanol, heavy ethanol, heavy propanol, heavy isopropanol, heavy butanol, heavy tert-butanol, heavy pentanol, heavy hexanol, heavy heptanol and the like. In addition to alcohols, organic solvents such as heavy carboxylic acids such as heavy formic acid, heavy acetic acid, heavy propionic acid, heavy butyric acid, heavy isobutyric acid, heavy valeric acid, heavy isovaleric acid, and heavy pivalic acid can be used. The deuteration rate of these deuterated solvents is not particularly limited, but it is preferable to use, for example, 90% or more, preferably 95% or more, more preferably 98% or more. Of these, it is preferable to use heavy water from the viewpoints of environment and workability. In addition to a deuterated solvent, an aprotic solvent or a hydrophobic solvent can also be added. Depending on the reaction conditions, partially deuterated solvents such as CH ₃ OD and C ₂ H ₅ OD can be used.

  Deuterated compound of formula (II) is used to react with 1,4-dibromobutane or 1-bromo-4-chlorobutane to induce compound of formula (III) and further desorb By substituting the group X with 4- (2,3-dichlorophenyl) piperazine, the compound represented by the formula (I) can be easily produced, but an example of the reaction together with the above deuteration reaction step Specific examples are given in the examples of this specification. Accordingly, those skilled in the art will appropriately select raw material compounds, reaction reagents, and reaction conditions with reference to the description of the above general synthesis method and the specific production methods of the examples, and make appropriate modifications or alterations as necessary. Thus, the compound of formula (I) can be easily produced.

  Since the compound represented by the formula (I) of the present invention has substantially the same pharmacological action and safety as aripiprazole, various psychiatric disorders for which aripiprazole is effective, such as schizophrenia, Efficacy for gonorrhea, depression, manic depression, etc. The medicament of the present invention can be used according to the indication, usage, and volume of aripiprazole, and is in the form of an appropriate pharmaceutical composition, for example, a pharmaceutical composition for oral administration or a pharmaceutical composition for parenteral administration. Administration to mammals including humans is possible. With regard to aripiprazole, JP-A-2-191256 describes indications, usage, capacity, and the like, and the above publication is included as a disclosure of the present invention by reference.

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example. In the examples, elemental analysis values were measured by thermal conductivity. In the elemental analysis based on thermal conductivity, H ₂ O and D ₂ O are not distinguished from each other and a composition value as D = 1 is given, so the calculated value was calculated as D = 1.
Example 1
Pentadeuterated aripiprazole ((7- [4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy] -3,4-dihydro-3,3,4,4,5, 6,8-heptaduterio-2 (1H) -quinolinone) was prepared.

(a) Synthesis of compound 3
7-Hydroxy-3,4-dihydro-1H-quinolin-2-one (2) 252.3 mg (1.509 mmol) and 10% Pd / C (27.8 mg) were placed in a sealed tube and D ₂ O (6 cm ³ ) Was added to make a suspension, and after H ₂ gas was blown in, it was quickly sealed and heated and stirred at 110-120 ° C. for 72 hours. After cooling to room temperature and removing the catalyst by Celite filtration, the filtrate was evaporated under reduced pressure to obtain crude compound 3 (255.8 mg, 100%). As a result of ¹ H NMR measurement, the crude compound 3 maintained a purity that could be used for the next synthesis reaction without purification. Recrystallization from ethanol / water gave Compound 3 as colorless needles.

¹ H NMR (DMSO-d ₆ ) δ ppm 2.35 (0.04H, s), 2.69 (0.04H, s), 6.30 (0.02H, s), 6.32 (0.02H, s), 6.91 (0.02H, s) , 9.33 (1H, br s), 9.91 (1H, s)
¹³ C NMR (DMSO-d ₆ ) δ ppm 22.6-24.2 (m), 29.6-31.2 (m), 101.5-102.6 (m), 108.0-109.0 (m), 113.5, 127.4-128.4 (m), 138.9, 156.3, 172.3
LRMS (EI) m / z 170 (M +; 100%), 142 (50), 128 (13), 114 (25), 97 (7), 85 (7), 69 (12), 54 (15)
C ₉ H ₂ D ₇ NO ₂
Calculated: C, 63.51; H, 5.33; N, 8.23
Found: C, 63.56; H, 5.59; N, 8.17

(b) Synthesis of Compound 4Compound 3 (252.3 mg, 1.482 mmol) was dissolved in acetone (5 ml), and potassium carbonate (255.6 mg, 1.849 mmol) and 1,4-dibromobutane (1.6238 g, 7.521 mmol) were dissolved. In addition, the mixture was heated to reflux for 17 hours. After cooling to room temperature, the residue obtained by filtration through celite and concentration under reduced pressure of the filtrate was subjected to silica gel column chromatography (BW-200, 15 g, elution solvent; 20% → 40% → 60% ethyl acetate / n-hexane. ) To obtain 347.3 mg (1.138 mmol, 75%) of compound 4. Recrystallization from ethanol gave Compound 4 as colorless needles.

Melting point 110.5-111 ℃ (ethanol)
¹ H NMR (CDCl ₃ ) δ ppm 1.87-1.98 (2H, m), 2.00-2.11 (2H, m), 2.59 (0.04H, s), 2.87 (0.04H, s), 3.48 (2H, t, J = 6.6 Hz), 3.97 (2H, t, J = 6.1 Hz), 6.36 (0.02H, s), 6.51 (0.02H, s), 7.04 (0.02H, s), 8.58 (1H, br s)
¹³ C NMR (CDCl ₃ ) δ ppm 23.6-24.2 (m), 27.9, 29.5, 30.0-30.6 (m), 33.5, 67.0, 101.5-102.3 (m), 107.9-108.6 (m), 115.6, 127.8-128.5 (m), 138.0, 158.2, 171.8
LRMS (EI) m / z 304 (M +; 13%), 170 (34), 135 (51), 97 (18), 55 (100)
C ₁₃ H ₉ D ₇ BrNO ₂
Calculated: C, 51.16; H, 5.28; N, 4.59
Found: C, 51.24; H, 5.36; N, 4.55

(c) Synthesis of compound 1
1- (2,3-dichlorophenyl) piperazine (5) (182.9 mg, 0.791 mmol) and compound 4 (193.8 mg, 0.635 mmol) are dissolved in acetonitrile (3 cm ³ ) and potassium carbonate (286.2 mg, 2.071 mmol) And potassium iodide (25.4 mg, 0.152 mmol) was added, and it heated and refluxed for 3 hours. After cooling to room temperature, H ₂ O (20 cm ³ ) was added, extracted four times with chloroform, dried over anhydrous sodium sulfate, and the solvent was concentrated. The obtained residue was purified by silica gel column chromatography (BW-200, 12 g, elution solvent; 0% → 1% → 2% → 5% methanol / ethyl acetate) to obtain 264.4 mg (0.580 mmol, 91 %)Obtained. Recrystallization from acetonitrile gave Compound 1 as colorless needle crystals.

¹ H NMR (CDCl ₃ ) δ ppm 1.65-1.88 (4H, m), 2.45-2.53 (2H, m), 2.57-2.71 (4.04H, m), 2.86 (0.04H, m), 3.02-3.14 (4H , m), 3.97 (2H, br t, J = 6 Hz), 6.36 (0.02H, s), 6.52 (0.02H, s), 6.92-6.99 (1H, m), 7.04 (0.02H, s), 7.11-7.18 (2H, m), 8.52 (1H, br s, NHC = O)
¹³ C NMR (CDCl ₃ ) δ ppm 23.4, 23.7-24.3 (m), 27.2, 30.1-30.7 (m), 51.2 (2C), 53.2 (2C), 58.1, 67.7, 101.5-102.3 (m), 107.9- 108.6 (m), 115.2, 118.4, 124.3, 127.2, 127.8-128.5 (m), 128.3, 133.7, 138.0, 151.0, 158.3, 172.3
LRMS (EI) m / z 454 (M +; 8%), 285 (19), 243 (100), 200 (8), 173 (11),
141 (6), 112 (7), 84 (44).
C ₂₃ H ₂ 0D ₇ Cl ₂ N ₃ O ₂
Calculated: C, 60.66; H, 5.98; N, 9.23
Found: C, 60.54; H, 6.09; N, 9.17

Claims (6)

Formula (I) below:

Or a salt thereof. A pharmaceutical comprising the compound represented by the above formula (I) or a physiologically acceptable salt thereof as an active ingredient. The following formula (II) or formula (III):

(Wherein X represents a leaving group) or a salt thereof. A compound represented by formula (II) or formula (III) according to claim 3 for use as an intermediate for the production of a compound represented by formula (I) according to claim 1. It is a manufacturing method of the compound represented by the formula (I) of Claim 1, Comprising: The following processes:
(1) 7-hydroxy-3,3,4, dihydro-1H-quinolin-2-one is deuterated in the presence of a metal catalyst and a deuterated solvent and a hydrogen molecule to form 7-hydroxy-3,3,4, Producing 4,5,6,8-heptaduterio-2 (1H) -quinolinone;
(2) Convert 7-hydroxy-3,3,4,4,5,6,8-heptaduterio-2 (1H) -quinolinone obtained in step (1) above to the compound of formula (II) Steps; and
(3) A method comprising a step of reacting a compound of formula (II) with 1- (2,3-dichlorophenyl) piperazine to convert to a compound of formula (I). 6. The method according to claim 5, wherein a palladium carbon catalyst is used as the metal catalyst and heavy water is used as the deuterated solvent.