HK1109399A - Phenylpiperazines with a combination of affinity for dopamine -d2 receptors and serotonin reuptake sites - Google Patents

Description

Simultaneous para-dopamine-D2Phenylpiperazines with affinity for the receptor and the 5-hydroxytryptamine reuptake site

The invention relates to a group of dual-function modes: 5-hydroxytryptamine reuptake inhibition and dopamine-D inhibition₂Novel phenylpiperazine derivatives having affinity for receptors, and to processes for the preparation of these compounds. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament providing a beneficial effect. The advantageous effects are disclosed herein or are apparent to those skilled in the art from the specification and technical common sense. The invention also relates to the use of a compound of the invention for the preparation of a medicament for the treatment or prevention of a disease or condition. More specifically, the present invention relates to a novel use for treating a disease or condition disclosed herein or apparent to those skilled in the art from the specification and general knowledge of the technology. In an embodiment of the invention, certain compounds disclosed herein are useful for the preparation of a medicament for the treatment of conditions involving dopamine-D₂A receptor and a site of 5-hydroxytryptamine reuptake or a disease that can be treated by manipulation of these targets.

Known from WO01/014330 as dopamine-D₂A dual action phenylpiperazine derivative of an antagonist and a 5-hydroxytryptamine reuptake inhibitor. This combination is useful in the treatment of schizophrenia and other psychotic disorders, thereby enabling a more complete treatment of all disease symptoms (e.g., positive and negative symptoms).

Oxime derivatives of halophenylpiperazinyl-alkyl ketones having useful pharmacological activity, in particular as analgesics, anti-inflammatory agents and myospasmolytics, have been disclosed in patent specification GB1378080 (1974).

The object of the present invention is to provide a composition further having dopamine-D₂Dual action compounds of an antagonist and a 5-hydroxytryptamine reuptake inhibitor.

The present invention relates to compounds of general formula (1) and tautomers, stereoisomers and N-oxides thereof, as well as pharmacologically acceptable salts, hydrates and solvates of the compounds of formula (1) and tautomers, stereoisomers and N-oxides thereof:

wherein:

m and n are independently 1, 2, 3, 4, 5, 6, 7 or 8,

x is 0, 1, 2 or 3,

R₂is halogen, branched or straight chain alkyl (C)_1-6) Phenyl, benzyl, branched or straight chain alkoxy (C)_1-6) A trifluoromethyl group or a cyano group,

R₃and R₄Independently represent hydrogen, alkyl (C)_1-6) A phenyl group, a benzyl group or an acetyl group,

the group Q is selected from the structural fragments A-N

Wherein:

y is 1, 2 or 3,

R₁is halogen, branched or straight chain alkyl (C)_1-6) Phenyl, benzyl, branched or straight chain alkoxy (C)_1-6) Trifluoromethyl or cyano.

Prodrugs of the above compounds are within the scope of the invention. Prodrugs are therapeutic agents that are inactive by themselves but are convertible to one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules that are used to overcome some of the obstacles to the use of the parent drug molecule. These include, but are not limited to, solubility, permeability, stability, pre-systemic metabolism (presystemic metabolism) and targeting limitations (Medicinal Chemistry: Principles and practice, 1994, ISBN 0-85186-494-5, Ed., F.D. King, p.215; J.Stella, "Prodrugs as therapeutics",Expert Opin.Ther. Patents14(3), 277-280, 2004; ettmayer et al, "Lessonslated from labeled and encapsulated primers", J.Med.chem., 47, 2393-. Prodrugs, i.e., compounds that are metabolized to compounds having formula (1) when administered to a human by any known route, are encompassed by the present invention. In particular, this relates to compounds having primary or secondary amino groups or hydroxyl groups. These compounds can be reacted with organic acids to give compounds of formula (1) in which there are additional groups that are easily removed after administration, such as, but not limited to, amidines (amidines), enamines, Mannich bases (Mannich bases), hydroxy-methylene derivatives, O- (acyloxymethylene carbamate) derivatives, carbamates, esters, amides or enaminones (enaminones).

N-oxides of the above compounds are within the scope of the present invention. The tertiary amines may or may not produce N-oxide metabolites. N-oxidation occurs to a degree from trace to near quantitative conversion. N-oxideMay be more or less active than their corresponding tertiary amines. While N-oxides are readily reduced chemically to their corresponding tertiary amines, in the human body this occurs to varying degrees. Some N-oxides are reduced to the corresponding tertiary amines in near quantitative amounts, in other cases the conversion is only a trace reaction or even completely absent. (M.H.Bickel: "The pharmacological and Biochemistry of N-oxides",Pharmaco-logical Reviews， 21(4)，325-355，1969)。

preferred compounds of the present invention are compounds having formula (1) and tautomers, stereoisomers and N-oxides thereof, wherein m is 1, N is 2, 3, 4 or 5, x is 1, R is 1, and pharmacologically acceptable salts, hydrates and solvates of the compounds of formula (1) and tautomers, stereoisomers and N-oxides thereof₂Is 4-fluoro or 4-trifluoromethyl, R₃And R₄Independently represents hydrogen or methyl, the group Q is selected from the structural fragment A, D, F or N, y is 1, and R₁Is a branched or straight chain alkoxy group (C)_1-3)。

It has been found that the compounds according to the invention exhibit dopamine D activity₂Both the receptor and the 5-hydroxytryptamine reuptake site have high affinity. The compound appears as dopamine D₂Receptor antagonists are active because they potentially antagonize apomorphine (apomorphine) -induced mouse climbing behavior. The compounds also show activity as 5-hydroxytryptamine reuptake inhibitors, as they potentiate 5-HTP induced behavior in mice. The compounds are useful in therapeutic models for clinically relevant antipsychotic sensitivity (e.g., conditioned avoidance response; Van der Heyden)&Bradford, behav. brainres, 1988, 31: 61-67) and treatment models sensitive to antidepressants or anxiolytics (e.g., stress-induced vocalization); van der Poel et al, Psycho-pharmacology, 1989, 97: 147-148) is active. Clinically relevant dopamine D₂In contrast to receptor antagonists, the compounds induce the immobility of rodentsThe predisposition to the disorder is small and therefore less extrapyramidal side effects may be induced compared to existing antipsychotics. The intrinsic 5-hydroxytryptamine reuptake inhibitory activity of these compounds may lead to the therapeutic effects observed in behavioral models sensitive to antidepressants or anxiolytics. The compounds may be used for the treatment of central nervous system disorders or diseases which are caused by disorders of the dopaminergic or 5-hydroxytryptamine systems, such as aggression (aggregations), anxiety disorders (anxiety disorders), autism (autism), vertigo (vertigo), depression, cognitive or memory disorders, Parkinson's disease, in particular schizophrenia (schizophrenia), and other psychotic disorders.

General description of the Synthesis

The synthesis of all piperazine derivatives in this patent can be performed as described in scheme 1 for the preparation of compound 3. The starting phenylpiperazine can be as described in EP 0189612: hartog, J et al, 1985: 'New pharmaceutical compositions having a pathological section'; feenstra, r.w.; de Moes, J.P; hofma, j.; kling, h.; kuipers, W; long, s.k.; tulp, m.t.m.; van der Heyden, j.a.m and Kruse, c.g.; ' New 1-ary1-4- (biarylmethyl) piperazines antistatic masking subpamine D₂ receptorand serotonin 5HT_1A receptor affinities.Bioorg.&Med. chem. Lett., 2001, 11, 2345-. Alkylphenyl ketone derivative 2 is commercially available.

^aReagents and conditions: (i) DIPEA, KI, CH₃CN, refluxing; (ii) h₂NO-CH₂CH₂NH₂2HCl, DIPEA, EtOH, reflux

The choice of a particular synthetic method depends on factors known to those skilled in the art, such as the compatibility of the functional group with the reagents used, the possibility of using protecting groups, catalysts, activating and coupling reagents, and the final structural characteristics present in the final compound prepared.

Pharmaceutically acceptable salts can be obtained by standard procedures well known to those skilled in the art, for example by mixing a compound of the invention with a suitable acid, for example an inorganic acid such as hydrochloric acid or an organic acid.

Pharmaceutical preparation

The compounds of the invention may be converted into a form suitable for administration by conventional means using excipients such as liquid or solid carrier materials. The pharmaceutical compositions of the present invention may be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or regionally (topically). They may be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gels), or suppositories. Suitable excipients for these formulations are pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavoring agents, coloring and/or buffering substances. Usual adjuvants which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol, and solvents, such as sterile water and mono-or polyhydric alcohols, such as glycerol.

The compounds of the present invention are generally administered as pharmaceutical compositions which are important and novel embodiments of the present invention due to the presence of the compounds, particularly the specific compounds disclosed herein. The types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions and other types disclosed herein or apparent to those skilled in the art from the specification and general knowledge of the art. In an embodiment of the invention, there is provided a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical composition of the invention. Associated with these containers may be written materials, such as instructions for use, or indicia dictated by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which indicia reflect approval by the agency for manufacture, use or sale for human or veterinary administration.

Pharmacological methods

para-dopamine-D₂In vitro affinity of receptors

Using i.cresse, r.schneider and s.h.snyder: "[³H]Determination of Compound Paopamine-D in the receptor binding assay described by Spiroperoid platelets receptors in rat pituitary and blue ", Eur.J.Pharmacol., 46, 377-381, 1977₂The affinity of the receptor.

In vitro affinity for the site of 5-hydroxytryptamine reuptake

With e.habert et al: "Characterisation of³H]-paroxetinibindto rate biological membranes ", Eur.J. Pharmacol, 118, 107-114, 1985, to determine the affinity of a compound for the site of 5-hydroxytryptamine reuptake.

Dosage form

Determination of Compounds of the invention on dopamine-D as described above₂Receptor and 5-hydroxytryptamine reuptake site affinity. The theoretical minimum effective dose can be estimated from the binding affinities determined for a defined compound of formula (1). At a value equal to measured K_iAt a concentration of compound of two times the value, 100% of the receptors may be occupied by compound. Assuming ideal bioavailability, this concentration is converted to mg compound/kg patient, resulting in the theoretical minimum effective dose. Pharmacokinetic, pharmacodynamic and other considerations may shift the actual dosage administered to higher or lower values. A suitable dose is 0.001-1000mg/kg, preferably 0.1-100mg/kg, of patient body weight.

Treatment of

The term "treatment" as used herein refers to any treatment of a condition or disease in a mammal, preferably a human, including: (1) preventing the disease or condition from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed with the disease, (2) inhibiting the disease or condition, i.e., arresting its development, (3) alleviating the disease or condition, i.e., causing regression of the disease, or (4) alleviating the disease-induced condition, i.e., arresting the disease condition.

The preparation of the compounds of formula (1) is now described in more detail in the following examples.

Examples

Example 1: materials and methods

DMSO-D on a Bruker Avance DRX600 instrument (600MHz), a Varian UN400 instrument (400MHz), or a Varian VXR200 instrument (200MHz)₆Or CDCl₃As solvent and tetramethylsilane as internal standard, record¹H and¹³c NMR spectrum. Chemical shifts are given in ppm (delta scale) from tetramethylsilane low magnetic field. The coupling constants (J) are expressed in Hz. Flash chromatography was carried out on silica gel 60(0.040-0.063mm, Merck). Column chromatography was carried out using silica gel 60(0.063-0.200mm, Merck). The melting points were determined on a B ü chi B-545 melting point apparatus. Mass spectra were recorded on a Micromass QTOF-2 instrument with MassLynx application software for data acquisition and reconstruction. Complete the excimer ion [ M + H ]]⁺Accurate mass measurement.

Example 2: synthesis of specific Compounds

The synthesis of compound 3 is a two-step reaction starting from 4- (2, 3 dihydro-1, 4 benzodioxin-5-yl) -1-piperazine (3 i). 15mmol of piperazine (3i) were suspended in 125ml of acetonitrile and 2 equivalents of diisopropylethyl-amine (DIPEA) were added. After stirring for 5 minutes at room temperature, 1 equivalent (15mmol) of 5-chloro-1- (4-trifluoromethyl-phenyl) -pentan-1-one was added followed by 1 equivalent of sodium iodide. The mixture was stirred at 80 ℃ for 20 hours. The solvent was removed by evaporation and the residue was dissolved in 100ml dichloromethane.

The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography, thus obtaining 6.4mmol of the keto-derivative 3ii, which was dissolved in 30ml of methanol. To this solution 1 equivalent of O- (2-aminoethyl) -hydroxylamine di-HCl salt was added and the mixture was heated at 80 ℃ for 12 hours. After evaporation of the solvent, the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and the solvent was evaporated to give a residue, which was purified by column chromatography. After addition of 3 equivalents of HCl in ethanol to the pure material, the tri HCl-salt of compound 3 was obtained.

mp.156-60 ℃; the total yield is 15%.

The synthesis of compound 7 is a two-step reaction starting from 2-isopropyloxy-phenylpiperazine (7 i). 4.2mmol of phenylpiperazine 7i were suspended in 40ml of acetonitrile. 2 equivalents of DIPEA, 1 equivalent of 4-chloro-1- (4-trifluoromethyl-phenyl) -butan-1-one and 1 equivalent of potassium iodide were added. The mixture was refluxed overnight and the solvent was evaporated the next day. The residue was purified by column chromatography to give 2.5mmol of pure keto-compound 7ii, which was dissolved again in 30ml of ethanol (100%). 1 equivalent of O- (2-aminoethyl) hydroxylamine di-HCl salt and 1 equivalent of pyridine are added. The mixture was heated at 80 ℃ for 4 hours. After evaporation of the solvent the residue was purified by column chromatography, thus obtaining 2mmol of orange oil. The oily substance was dissolved in ethanol, and 1 equivalent of fumaric acid was added. After evaporation, the amorphous fumarate salt of compound 7 was obtained; the total yield is 50%

The synthesis of compound 8 is a two-step reaction starting from 4- (2, 3 dihydro-1, 4 benzodioxin-5-yl) -1-piperazine (3 i). 3.5mmol of phenylpiperazine (3i) were suspended in 40ml of acetonitrile. 2 equivalents of DIPEA, 1 equivalent of 6-chloro-1- (4-trifluoromethyl-phenyl) -hexan-1-one and 1 equivalent of potassium iodide were added. The mixture was refluxed overnight and the solvent was evaporated the next day. The residue was purified by column chromatography to give 1.7mmol of pure keto-compound 8ii, which was again dissolved in 10ml ethanol (100%). 1 equivalent of O- (2-aminoethyl) hydroxylamine di HCl salt was added and the mixture was heated at 80 ℃ for 4 hours. After evaporation of the solvent the residue was purified by column chromatography, thus obtaining 1.6mmol of yellow oil. The oily substance was dissolved in ethanol, and 2 equivalents of fumaric acid were added. Evaporation gave compound 8 as amorphous fumarate; the total yield is 45%.

The synthesis of compound 9 starts from a two-step reaction of 4- (2, 3 dihydro-1, 4 benzodioxin-5-yl) -1-piperazine. Compound 3ii (30mmol) was dissolved in 20ml of methanol. To this solution 1 equivalent of O- (N-methyl-2-aminoethyl) -hydroxylamine di-HCl salt was added and the mixture was heated at 80 ℃ for 5 hours. After evaporation of the solvent, the residue was dissolved in dichloromethane and washed with sodium bicarbonate solution and then brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated to give a residue, which was purified by column chromatography. Adding 1 equivalent of an ethanolic solution of fumaric acid to the purified material, followed by evaporation of the solvent to give the fumarate salt of compound 9; the total yield is 15%.

The synthesis of compound 10 is a two-step reaction starting from 4- (2, 3 dihydro-1, 4 benzodioxin-5-yl) -1-piperazine (3 i). 6mmol of phenylpiperazine 3i were suspended in 40ml of acetonitrile. 2 equivalents of DIPEA, 1 equivalent of 7-chloro-1- (4-trifluoromethyl-phenyl) -heptan-1-one and 1 equivalent of potassium iodide were added. The mixture was refluxed overnight and the solvent was evaporated the next day. The residue was purified by column chromatography to give 4.2mmol of pure keto-compound 10ii, which was again dissolved in 25ml of ethanol (100%). 1 equivalent of O- (2-aminoethyl) hydroxylamine di-HCl salt was added and the mixture was heated at 80 ℃ for 4 hours. After evaporation of the solvent the residue was purified by column chromatography, thus obtaining 2mmol of a yellow oil. The oily substance was dissolved in ethanol, and 1.5 equivalents of fumaric acid were added. After evaporation, amorphous fumarate salt of compound 10 was obtained; the total yield is 35%.

TABLE 1 Compounds of the general formula (1)

Wherein Q may be one of the structural fragments A-N

Compound (I)	y	R1	Q	x	R2	R3	R4	n	m	mp(℃)
3	-	-	A	1	4-CF3	H	H	3	1	156-160
											4	1	2-OMe	N	1	4-F	H	H	2	1	150-152
5	-	-	F	1	4-CF3	H	H	3	1	158
											6	-	-	D	1	4-CF3	H	H	3	1	153-154
7	1	OCH(Me)2	N	1	4-CF3	H	H	2	1	Amorphous form
											8	-	-	A	1	4-CF3	H	H	4	1	Amorphous form
9	-	-	A	1	4-CF3	Me	H	3	1	Amorphous form
											10	-	-	A	1	4-CF3	H	H	5	1	Amorphous form
11	1	2-OMe	N	1	4-CF3	H	H	5	1	Amorphous form

The synthesis of specific compounds as described above is intended to further illustrate the invention in more detail. They are not to be considered in any way as limiting the scope of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Example 3: formulations of Compound 3 for animal research

For oral (p.o.) administration: to the desired amount (0.5-5mg) of solid compound 3 in a glass tube was added some glass beads and the solid was crushed by vortexing for 2 minutes. After addition of 1ml of a solution of 1% methylcellulose and 2% (v/v) of Poloxamer188(Lutrol F68) in water, the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1N). The remaining particles in suspension are further suspended with an ultrasonic bath.

For intraperitoneal (i.p.) administration: to the desired amount (0.5-15mg) of solid compound 3 in glass was added some glass beads and the solid was crushed by vortexing for 2 minutes. After addition of 1ml of a solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended by vortexing for 10 minutes. Finally the pH was adjusted to 7.

Example 4: results of pharmacological tests

In the following table is shown according to the abovedopamine-D obtainable by the described protocol₂And 5-hydroxytryptamine reuptake receptor affinity data.

TABLE 2 in vitro affinity of the Compounds of the invention

	Affinity in vitro
				dopamine-D2	5-HT reuptake
Compound (I)	pKi	pKi
			3	8.3	8.2
4	8.6	7.3
			5	8.2	8.3
6	6.6	8.3
			7	8.1	7.0
8	8.3	8.0
			9	8.4	7.5
10	8.4	8.5
			11	8.3	8.3

Claims (10)

1. A compound of the general formula (1) and tautomers, stereoisomers and N-oxides thereof, and pharmacologically acceptable salts, hydrates and solvates of the compound of the formula (1) and tautomers, stereoisomers and N-oxides thereof:

wherein:

m and n are independently 1, 2, 3, 4, 5, 6, 7 or 8,

x is 0, 1, 2 or 3,

R₂is halogen, branched or straight chain alkyl (C)_1-6) Phenyl, benzyl, branched or straight chain alkoxy (C)_1-6) A trifluoromethyl group or a cyano group,

R₃and R₄Independently represent hydrogen, alkyl (C)_1-6) A phenyl group, a benzyl group or an acetyl group,

the group Q is selected from the structural fragments A-N

Wherein:

y is 1, 2 or 3,

R₁is halogen, branched or straight chain alkyl (C)_1-6) Phenyl, benzyl, branched or straight chain alkoxy (C)_1-6) Trifluoromethyl or cyano.

2. A compound of the general formula (1) as claimed in claim 1, wherein m is 1, N is 2, 3, 4 or 5, x is 1, R is 1, and tautomers, stereoisomers and N-oxides thereof, and pharmacologically acceptable salts, hydrates and solvates of the compound of the formula (1) and tautomers, stereoisomers and N-oxides thereof₂Is 4-fluoro or 4-trifluoromethyl, R₃And R₄Independently represents hydrogen or methyl, the group Q is selected from the structural fragment A, D, F or N, y is 1, R₁Is a branched or straight chain alkoxy group (C)_1-3)。

3. A compound as claimed in claim 1 selected from the group consisting of tautomers, stereoisomers and N-oxides thereof, and pharmacologically acceptable salts, hydrates and solvates of the compounds of formula (1) and tautomers, stereoisomers and N-oxides thereof:

y R₁ Q x R₂ R₃ R₄ n m - - A 1 4-CF₃ H H 3 1 1 2-OMe N 1 4-F H H 2 1 - - F 1 4-CF₃ H H 3 1 - - D 1 4-CF₃ H H 3 1 1 OCH(Me)₂ N 1 4-CF₃ H H 2 1 - - A 1 4-CF₃ H H 4 1 - - A 1 4-CF₃ Me H 3 1 - - A 1 4-CF₃ H H 5 1 1 2-OMe N 1 4-CF₃ H H 5 1

wherein the symbols represent those in formula (1):

and structural fragment A, D, F or N:

4. a pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable adjuvant, and, as active ingredient, a pharmacologically active amount of at least one compound according to one of claims 1 to 3 or a salt thereof.

5. A process for the preparation of a composition as claimed in claim 4, characterized in that at least one compound according to one of claims 1 to 3 or a salt thereof is brought into a form suitable for administration.

6. A compound as claimed in any one of claims 1 to 3, or a salt thereof, for use as a medicament.

7. The use of a compound as claimed in any of claims 1 to 3 for the preparation of a pharmaceutical composition for the treatment of CNS disorders.

8. The use as claimed in claim 7, characterized in that the disorders are aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, Parkinson's disease, schizophrenia and other psychotic disorders.

9. The use as claimed in claim 7, characterized in that the disease is depression.

10. The use as claimed in claim 7, characterized in that the diseases are schizophrenia and other psychotic disorders.