# Patent

## Title
Piperazine, piperidine and tetrahydropyridine derivatives and their pharmaceutical use

## Abstract

Novel piperazine, piperidine and tetrahydropyridine derivatives comprising a dibenzofurane moiety are provided herein, as well as pharmaceutical compositions comprising same and therapeutic uses thereof.

## Background
RELATED APPLICATIONS
This application is a division of U.S. patent application Ser. No. 13/322,572 filed on Nov. 28, 2011, which is a National Phase of PCT Patent Application No. PCT/IL2010/000418 having International filing date of May 26, 2010, which claims the benefit of priority of U.S. Provisional Patent Application No. 61/181,331 filed on May 27, 2009. The contents of the above applications are all incorporated by reference as if fully set forth herein in their entirety.


FIELD AND BACKGROUND OF THE INVENTION
The present invention, in some embodiments thereof, relates to a novel family of compounds and uses thereof to treat disorders such as central nervous system disorders, and more particularly, but not exclusively, novel compounds comprising a piperazine, piperidine or tetrahydropyridine moiety.
Piperazine derivatives which act on the central nervous system (CNS) are known in the art. For example, EP 512755 describes piperazine derivatives having high binding affinity to 5-HT receptors. Recently, piperazine derivatives (and also other nitrogen-containing six-membered rings, such as piperidine), which are substituted at positions 1 and 4 with a fused ring heterocyclic and phenyl groups, respectively, were described in WO 08/117,269. The compounds disclosed in WO 08/117,269 are reported to bind to dopamine and 5-HT receptors and to be useful in the treatment of various CNS disorders.
DESCRIPTION OF EMBODIMENTS OF THE INVENTION
The invention relates to a class of compounds of formula (I):




wherein:

Y1 and Y2 are independently CH, C(R1) or N;

X is N, CH or C, with the proviso that when X is C, then the broken line represents a chemical bond;

R1, R2 and R3 are independently selected from the group consisting of C1-C5 alkyl, —OH, —SH, halogen, alkoxy, namely, —O(C1-C5alkyl), —NR42, NO2, —CN.

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2 or 3; and

p is 0, 1, 2, 3 or 4.

It is understood that when m, n, or p equals 0, then the free positions at the relevant ring are occupied by hydrogen atoms.
The compounds of formula I have been found to posses high binding affinity for dopamine and serotonin receptors. The compounds are accordingly useful in the treatment of various CNS disorders, as discussed in more detail below.
Preferably, X in formula I is nitrogen. More specifically, preferred sub-classes of compounds provided by the present invention are represented by formulas Ia, Ib, Ic, Id and Ie (in the formulas depicted below, the substituents on the dibenzofuran system have the meanings as set forth above):




wherein m is 0, 1, 2 or 3, more preferably 0, 1 or 2, and when m is other than 0, then R1 is preferably selected from the group consisting of hydroxy, alkoxy (specifically —OCH3 or —OC2H5), halogen and cyano.

The compounds of formula I may be prepared by reacting a piperazine, piperidine or 1,2,3,6-tetrahydropyridine derivative of formula II (or an acid addition salt thereof),




with dibenzofurane of formula III:





wherein X, Y1, Y2, R1, R2, R3 m, n and p are as hereinabove defined and L is a suitable leaving group such as halogen, (specifically chlorine or bromine), p-toluene sulfonate or mesylate). Thus, the reaction involves the formation of a tertiary amine by alkylation of a secondary amine (of formula II) with alkyl halide, tosylate or mesylate (of formula III). The reaction may be conveniently carried out in a solvent, which may be selected from the group consisting of dimethylformamide; ethers such tetrahydrofuran; acetonitrile, ketones such as acetone and methyl ethyl ketone; and halogenated hydrocarbons. The reaction is carried out in the presence of a base, which may be either an inorganic base (alkali or alkaline earth metal carbonate, alkali metal hydrogen carbonate and sodium hydroxide) or an organic base (trialkyl amine, such as triethylamine; or pyridine). dimethylformamide and triethylamine are generally the preferred solvent and base, respectively, employed in the reaction.

In practice, the solvent and the base are charged into a reaction vessel, following which the starting materials of formulas II and III are added and allowed to dissolve under stirring. The starting materials may be used in equimolar amounts, but it may be preferable to apply the starting material of formula II in a 1.5 molar excess. The reaction may be carried out under room temperature or possibly under heating. The reaction reaches completion after about 16 hours. The product of formula I may then be isolated from the reaction mixture by means of known procedures. More specifically, upon removal of the solvent by means of evaporation under reduced pressure, an the product of formula I may be recovered as an oily material which can be purified by means of silica gel column chromatography.
The reactants of formula II and III which participate in the synthetic pathway described above are commercially available, or may be prepared by conventional methods.
Regarding the starting material of formula III, a dibenzofurane system is most generally represented by the following formula:




where the numbers 1-4 and 6-9 represent positions in which substituents may be provided. As indicated before, in the starting material of formula III, which is operative according to the present invention in the preparation of the end product of formula I, position 4 is occupied by the group —CH2L (wherein L is a leaving group). The starting material of formula III may be obtained by reducing a corresponding aldehyde, to form a dibenzofurane derivative having —CH2OH group attached at position 4, and subsequently converting said alcohol to the starting material of formula III, wherein the leaving group L is halogen, such as chlorine or bromine, as illustrated by the following sequential reaction scheme:





The reduction of the aldehyde of formula (V) to form the primary alcohol of formula (IV) may be conveniently accomplished in the presence of a hydride source, namely, a complex metal hydride, such as sodium borohydride or lithium aluminum hydride. A suitable solvent to employed in the reaction is typically a short chain alkanol, specifically methanol or ethanol. The primary alcohol intermediate is isolated from the reaction mixture and is subsequently treated with a halide source, such as thionyl chloride or various phosphorous halides. The conversion of the alcohol (IV) into the corresponding haloalkane (III).
The compounds the invention were tested for dopamine (D2, D3 and D4.4) receptors binding activity and 5-HT1A receptor binding activity according to the procedures described in WO 08/117,269; the compounds of the invention were found to be potent ligands of said receptors. The compounds of the invention may be used in the treatment of CNS disorders in mammals, especially human. Of particular interest is the use of the compounds of the invention as anti-dyskinetic agents. Dyskinesia is a serious side effect associated with L-DOPA treatment of patients with Parkinson's disease. An in vivo study given below demonstrates that the compounds of the invention exhibit activity against L-DOPA induced dyskinesia in parkinsonian rats.
The invention also provides a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers. The composition may be provided either in a solid or liquid form, or a mixture of solid and liquid.
Suitable solid compositions include tablets, capsules, caplets, powders, granulates, sachets, lozenges and pastilles. Examples of excipients which are combined with the active ingredient to produce the composition include (but are not limited to) diluents or fillers (e.g. lactose, microcrystalline cellulose, pregelatinized starch), binders (e.g. carbopol, povidone, xanthan gum), lubricants (e.g. magnesium stearate), glidants (e.g. talc, colloidal silicon dioxide) and disintegrants (e.g. alginic acid, carboxymethylcellulose, carboxymethyl starch, croscarmellose sodium, sodium starch glycolate).
Solid unit dosage forms (e.g., tablets or capsules) may be manufactured by a variety of different methods, as are well known in the art, including a direct compression using a tablet punch. As an alternative to direct compression, the active ingredient and excipients may be combined by dry blending, and then subjected to dry granulation prior to tablet compression. A further alternative method is to utilize wet granulation, in which at least some of the excipients, together with the active ingredient, are blended and then further mixed in the presence of a granulation liquid. Following aggregation of the various powders, the aggregates (i.e. granules) are then sized by screening or milling, dried and used to produce a tablet. The tablet may be finally coated.
Solid formulation blends for loading into capsules (such as soft gelatin capsules) may be prepared by dry blending, or by wet or dry granulation prior to being introduced into said capsules.
Suitable liquid compositions include, inter alia, solutions, suspensions and syrups, in which solvents (e.g. water, an organic solvent) emulsifying agents (e.g. carbomer, cetyl alcohol, gelatin), flavoring agents (e.g. vanillin, fruit acids, menthol), sweeteners (e.g. sucrose, fructose, aspartame, saccharin) and preservatives may be present together with the active compound of formula I.
In addition to orally-administrable compositions, the compounds of the invention may be formulated into sterile solution for intravenous or intramuscular injection.
Further information relating to the preparation of solid, liquid and gel dosage forms that are suitable for use in the present invention may be obtained from any standard pharmaceutical reference work, such as Remington's Pharmaceutical Science (Martin E W [1995], Mack Publishing Company, 19th ed.).
A further aspect of the invention relates to the use of a compound of formula I set forth herein above in the preparation of a medicament, e.g., for the treatment of CNS disorders in a mammal, and more specifically, for the treatment of dyskinesia.
The present invention also relates to a method for treating CNS disorders in a patient, comprising administering a therapeutically effective amount of a compound of formula I. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the disorder being treated, and the particular compound being used. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day. The compounds of Formula I according to this invention may be administered orally or parenterally.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph illustrating the results of an in vivo activity study in which a compound of the invention was tested as an anti-diskinesia agent.



EXAMPLES
Preparation 1
Preparation of 4-(chloromethyl) Dibenzofuran (A starting material of Formula III)




a) Dibenzofuran-4-ylmethanol
1 g (5.1 mmol) of Dibenzofuran-4-carboxaldehyde is dissolved in 5 ml of ethanol. 0.24 g of NaBH4 is then added portionwise to the stirred solution during a period 20 minutes. The solution is maintained under stirring at room temperature for 2 hours, following which the solvent is evaporated. The residue obtained is treated with water, and aqueous layer is then extracted with ether. Evaporation of the organic phase yielded 0.90 g of Dibenzofuran-4-ylmethanol.
b) 4-(chloromethyl) Dibenzofuran
Thionyl chloride (6 ml) is added to a solution of Dibenzofuran-4-ylmethanol (0.9 g). The solution is refluxed for 1 hour. Excess of reagent is evaporated to yield 4-(chloromethyl) Dibenzofuran (0.97 g).
Example 1 (L32)
4-(chloromethyl) Dibenzofuran (0.34 g, 1.7 mmol) and 1-(2-ethoxyphenyl)piperazine hydrochloride (0.62 g, 2.55 mmol) are added to a stirred solution of N,N Dimethylformamide (5 ml) and triethylamine (1 ml). The solution formed is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure and the crude residue obtained was chromatographed on silica gel with eluant hexane:ethyl acetate (90% Hexane/10% Ethyl Acetate). Following recrystallization from hexane, the product was collected in a solid form (120 mg).
H1NMR: 1.10 (t, 3H), 2.82 (t, 2H), 3.27 (t, 2H), 4.02 (s, 2H), 4.21 (q, 2H) 7.10-8.05 (m, 10H, arom).
Example 2 (L33)
4-(chloromethyl) Dibenzofuran (0.34 g, 1.7 mmol) and 1-(3-hydroxyphenyl) piperazine (0.50 gr. (2.55 mmol) are added to a stirred solution of N,N Dimethylformamide (5 ml) and triethylamine (1 ml). The solution formed is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure and the crude residue obtained is chromatographed on silica gel with eluant hexane:ethyl acetate (80% Hexane/20% Ethyl Acetate). Following recrystallization from hexane, the product is collected in a solid form (390 mg).
H1NMR: 2.84 (t, 2H), 3.31 (t, 2H), 4.07 (s, 2H), 6.92-7.91 (m, 11H, arom).
Example 3 (L34)
4-(chloromethyl) Dibenzofuran (0.34 g, 1.7 mmol) and 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (0.50 g) are added to a stirred solution of N,N Dimethylformamide (5 ml) and triethylamine (1 ml). The solution formed is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure and the crude residue obtained is chromatographed on silica gel with eluant hexane:ethyl acetate (90% Hexane/10% Ethyl Acetate). Following recrystallization from hexane, the product is collected in a solid form (100 mg).
H1NMR: 2.78-3.95 (m, 6H), 4.03 (s, 2H), 4.55 (m, 1H) (6.93-8.82 (m, 12H, arom)
Example 4 (L105)
4-(chloromethyl) Dibenzofuran (1 g, 5 mmol) and 4-phenyl piperidine (1.2 g, 7.55 mmol) are added to a stirred solution of N,N Dimethylformamide (10 ml) and triethylamine (2 ml). The solution formed is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure and the crude residue obtained is chromatographed on silica gel with eluant hexane:ethyl acetate (90% Hexane/10% Ethyl Acetate) to give the product (195 mg)
H1NMR: 2.18-3.88 (m, 9H, piperidine), 4.03 (s, 2H), (6.90-8.72 (m, 12H, arom)
Example 5 (L106)
4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 2-thiazole piperazine (1 g, 6 mmol) are added to a stirred solution of N,N Dimethylformamide (10 ml) and triethylamine (2 ml). The solution formed is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure to give a crude residue, which is chromatographed on silica gel with eluant hexane:ethyl acetate (90% Hexane/10% Ethyl Acetate) to afford the product (204 mg).
H1NMR: 2.86 (t, 2H), 3.28 (t, 2H), 4.03 (s, 2H), (6.92-8.89 (m, 9H, arom)
Example 6 (L107)
4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 1-(−2-methoxyphenyl) piperazine hydrochloride (1.4 g, 6 mmol) are added to a stirred solution of N,N Dimethylformamide (10 ml) and triethylamine (2 ml). The solution formed is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure to give a crude residue, which is chromatographed on silica gel with eluant hexane:ethyl acetate (90% Hexane/10% Ethyl Acetate) to afford the product (411 mg).
H1NMR: 2.81 (t, 2H), 3.21 (t, 2H), 4.02 (s, 2H), 4.21 (s, 3H) 7.09-8.09 (m, 10H, arom).
Example 7 (L108)
4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 1-(−2-pyridyl) piperazine (0.8 g, 5 mmol) are added to a stirred solution of N,N Dimethylformamide (10 ml) and triethylamine (2 ml). The solution formed is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure to give a crude residue, which is chromatographed on silica gel with eluant hexane:ethyl acetate (80% Hexane/20% Ethyl Acetate) to afford the product (223 mg).
H1NMR: 2.87 (t, 2H), 3.25 (t, 2H), 4.1 (s, 2H), 7.09-8.17 (m, 10H, arom).
Example 8 (L109)
4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 1-(−2-cyanophenyl) piperazine (0.9 g, 5 mmol) are added to a stirred solution of N,N-Dimethylformamide (10 ml) and triethylamine (2 ml). The solution formed is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure to give a crude residue, which is chromatographed on silica gel with eluant hexane:ethyl acetate (90% Hexane/20% Ethyl Acetate) to afford the desirable product (180 mg)
H1NMR: 2.86 (t, 2H), 3.28 (t, 2H), 4.05 (s, 2H), 6.96-7.97 (m, 11H, arom).
Example 9 (L110)
4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 1-(−2-pyrimidyl) piperazine (1 g, 6 mmol) are added to a stirred solution of N,N Dimethylformamide (10 ml) and triethylamine (2 ml). The solution formed is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure to give a crude residue, which is chromatographed on silica gel with eluant hexane:ethyl acetate (80% Hexane/20% Ethyl Acetate) to afford the product (503 mg)
H1NMR: 2.84 (t, 2H), 3.27 (t, 2H), 4.1 (s, 2H), 7.04-8.27 (m, 9H, arom).
Example 10
The compounds of Examples 1, 3, 4 and 9 were tested for their 5-HT1A receptor binding activity and dopamine (D2, D3 and D4.4) receptors binding activity according to the protocols set forth above. The percentage inhibition of labeled ligand binding caused by the indicated few test ligand compound of the invention at different concentrations of said test ligand is shown in Table I.











TABLE I





Compound,






1micrMol
5-HT1A binding
D2 binding
D3 binding
D4 binding



















L-33
43.4
75%
78.2
77.7


L-109
73.5
68.7
63.2
64.9


L-107
86.7
96%
33.7
78


L-105
42.2
93.8
44.5
69.1









The results demonstrate that the compounds of the invention strongly bind to both D2, D3 and D4 dopamine and 5-HT1A receptors.
Example 11
In the following study, the compound of Example 2 was tested for its in vivo activity against L-DOpA induced dyskinesia in parkinsonian rats (the model is the L-DOPA-induced abnormal involuntary movements (AIMS) in the 6-hydroxydopamine (6-OHDA) lesion rat model).
Rats were unilaterally lesioned with (6-OHDA) in medial forebrain bundle. Three weeks later, rats were injected with apomorphine (0.1 mg/kg s.c.) and numbers of contralateral turns were counted using a rotameter. Two weeks after the apomorphine test, rats showing marked turning activity were selected and split into 2 groups:
The experimental group, which received the compound of Example 2, and the control group, which received the injection medium for said compound (CMC in saline); n=5 and 3 respectively.
All animals were treated daily with L-dopa/carbidopa (25/6 mg/kg respectively) and dyskinetic movements were scored commencing day 5. Compounds were administered in escalating dose, at daily doses shown below, commencing day 11 of L-dopa treatment: 1 mg/kg—11th day, 1 mg/kg—12th, 2 mg/kg—15th, 2 mg/kg—16th. On the 17th day, the rats of the control group were injected with propranolol (10 mg/kg in saline), whereas the rats of the experimental group were injected with saline. On the 18th and 19th day all rats were treated with L-dopa/carbidopa only.
The following dyskinetic movements were scored: dystonic posturing, head and upper body movements, forelimb, locomotion, trunk, orolingual. Movements were scored according to the protocol shown in Table II.












TABLE II







HEAD AND


OROLINGUAL



DYSTONIC
UPPER BODY
LIMB
LOCOMOTIVE
& OROFACIAL


SCORE
POSTURING
MOVEMENTS
MOVEMENTS
MOVEMENTS
MOVEMENTS







0-4
head and body
head
abnormal,
locomotion
empty jaw



turning towards
movements
purposeless
movements
movements,



the side
and
movements
contralaterally to
contralateral



contralateral
choreiform
of the forelimb
the lesion
tongue



to the lesion
twisting
and digits

protrusion




of the neck
contralateral to

tremor of face




and upper
the lesion

muscles,




body


gritting of the







teeth


0
absent of
movements
absent of
movements


0.5
light or single
very weak or
weak forelimb
~1 rotation
single opening


very
turning of the
single
swings
in 1 minute
of the mouth,


weak
head towards
head


single tongue


or
the side
movements


protrusion,


single
contralateral



tremor of face


movements
to the lesion



muscles,



with angle



gritting of teeth



of bias about



30°


1
turning of the
frequent little
forelimb
~2-5
hardly seen, but


weak
head
head
movements
rotations
permanent


movements
at the point of
movements
along
in 1 minute
jaw movements



the forelimb

the ground of

with



(angle of bias

the case

close mouth,



about 90°)

or distinct,

rare tongue





but rare

protrusion





movements with





lifted





forelimb


2
turning of the
moderate and
steady moderate
~6-10
permanent jaw


moderate
head
distinctly seen
movements
rotations
movements


movements
at the point of
head
with lifted
in 1 minute
with a little



the back paw
movements and
forelimb

opening



(angle of bias
choreiform


mouth,



about 150°)
twisting


more often




of the neck


tongue







protrusion


3
turning of the
strong head
fast plentiful
~11-18
permanent jaw


strong
head
movements
movements
rotations
movements


movements
at the point of
and choreiform
with lifted
in 1 minute
with a broadly



the tail
twisting
forelimb

opening



(angle of bias
of the neck and


mouth,



about 180°)
upper body


frequent tongue







protrusion


4
turning of the
strong head
rapid
more than


very
head
movements,
movements of
18 rotations


strong
over the tail
choreiform
lifted forelimb
in a minute


movements
with the
twisting
with large scale



angle bias
of the neck



more than 180°
and upper




body,




throwing




back the head









The results are presented in FIG. 1, AIM score is shown for the relevant treatment days (for the sum of all movements indicated in Table II together). A strong anti-dyskinetic effect is observed on the 16th day, in which day the compound of the invention was administered (for the second time in succession) at a daily dose of 2 mg/kg. It is noted that Propanolol, which was given to the control group in a dose of 10 mg/kg on the 17th day, reduced the abnormal involuntary movements.

## Claims

1. A compound of the general formula Id or the general formula Ie:



wherein:
R1, R2 and R3 are independently selected from the group consisting of C1-C5 alkyl, —OH, —SH, halogen, alkoxy, NO2, and —CN;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, 2 or 3; and
p is 0, 1, 2, 3 or 4.

2. A compound according to claim 1, wherein m is 0, 1, 2 or 3, and R1 is selected from the group consisting of hydroxy, alkoxy, halogen and cyano.

3. A compound according to claim 1, wherein R1 is hydroxy.

4. A compound according to claim 1, wherein m is 1.

5. A compound according to claim 1, wherein n is 0 and p is 0.

6. A pharmaceutical composition comprising a compound as defined in claim 1 in combination with one or more pharmaceutically acceptable carriers.

7. A method for treating CNS dyskinesia in mammals, comprising administering to said mammal a therapeutically effective amount of the compound defined in claim 1.

8. A compound of formula I:



wherein:
Y1 and Y2 are independently CH, C(R1) or N;
X is CH or C, with the proviso that when X is C, then the broken line represents a chemical bond;
R1, R2 and R3 are independently selected from the group consisting of C1-C5 alkyl, —OH, —SH, halogen, alkoxy, NO2, and —CN;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, 2 or 3; and
p is 0, 1, 2, 3 or 4.

9. A compound according to claim 8, having the formulas Id or Ie:

10. A compound according to claim 8, wherein m is 0, 1, 2 or 3, and R1 is selected from the group consisting of hydroxy, alkoxy, halogen and cyano.

11. A compound according to claim 8, wherein R1 is hydroxy.

12. A compound according to claim 8, wherein m is 1.

13. A compound according to claim 8, wherein n is 0 and p is 0.

14. A pharmaceutical composition comprising a compound as defined in claim 8 in combination with one or more pharmaceutically acceptable carriers.

15. A method for treating CNS dyskinesia in mammals, comprising administering to said mammal a therapeutically effective amount of the compound defined in claim 8.