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Field of the invention The present invention relates to new modulators of dopamine neurotransmission, and more specifically to new substituted 4-(phenyl N-alkyl)-piperazines and 4-(phenyl N-alkyl)-piperidines, and use thereof.
Background of the Invention Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopa¬mine in the brain has been intensely explored. To date, it is well established that dopamine is essential in sev¬eral aspects of brain function including motor, cogni¬tive, sensory, emotional and autonomous (e.g. regulation of appetite, body temperature, sleep) functions. Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, both neurologic and psychiatric disorders are treated with medications based on interac¬tions with dopamine systems and dopamine receptors in the brain.
Drugs that act, directly or indirectly, at central dopamine receptors are commonly used in the treatment of neurologic and psychiatric disorders, e.g. Parkinson's disease and schizophrenia. Currently available dopaminer¬gic pharmaceuticals have severe side effects, such as ex¬trapyramidal side effects and tardive dyskinesia in dopa¬minergic antagonists used as antipsychotic agents, and dyskinesias and psychoses in dopaminergic agonists used as anti-Parkinson's agents. Therapeutic effects are un¬satisfactory in many respects. To improve efficacy and reduce side effects of dopaminergic pharmaceuticals, novel dopamine receptor ligands with selectivity at spe¬cific dopamine receptor subtypes or regional selectivity
are sought for. In this context, also partial dopamine receptor agonists, i.e. dopamine receptor ligands with some but not full intrinsic activity at dopamine recep¬tors, are being developed to achieve an optimal degree of stimulation at dopamine receptors, avoiding excessive do¬pamine receptor blockade or excessive stimulation.
Compounds belonging to the class of substituted 4-(phenyl-K-alkyl)-piperasine and substituted 4-{phenyl-N-alkyl)-piperidines have been previously reported. Among these compounds, some are inactive in the CKS, some dis¬play serotonergic or mixed serotonergic/dopaminergic pharmacological profiles while some are full or partial dopamine receptor agonists or antagonists with high af¬finity for dopamine receptors,
A number of 4-phenylpiperazines and 4-phenyl-piperidine derivatives are known and described, for exam¬ple Costall et al. European J. Pharm. 31, 94, (1975), Mewshaw et al. Bioorg. Med. Chem. Lett., 8, 295, (1998). The reported compounds are substituted 4-phenyl-piperazine"s, most of them being 2-, 3- or 4-OH phenyl substituted and displaying DA autoreceptor agonist properties.
Fuller R. W. et al, J. Pharmacol. Exp. Therapeut. 218, 636, (1981) disclose substituted piperazines (e.g. 1-(m-trifluoro-methylphenyl)piperazine) which reportedly act as serotonin agonists and inhibit serotonin uptake. Fuller R. W. et al, Res. Commun. Chem. Pathol. Pharmacol. 17, 551, (1977) disclose the comparative effects on the 3,4-dihydroxy-phenylacetic acid and Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) disclose the comparative effects on the 5-hydroxyindole acetic acid concentration in rat brain by 1-(p-chlorophenol)-piperazine.
Boissier J. et al Chem Abstr, 61:10691c, disclose disubstituted piperazines. The compounds are reportedly adrenolytics, antihypertensives, potentiators of barbitu¬rates, and depressants of the central nervous system.
A number of different substituted piperazines have been published as ligands at S-HTi receptors, for example Giennon R.A. et al J. Med. Chem., 31, 1966, (1988), van Steen B.J., J. Med. Chem., 36, 2751, (1993), Mokrosz, J. et al. Arch. Pharm. (Weinhein) 328, 143-148 (1995), and Dukat M.-L., J. Med. Chem., 39, 4017, (1996). Giennon R. A. discloses, in international patent applications WO 93/00313 and WO 91/09594 various amines, among them sub¬stituted piperazines, as sigma receptor ligands. Clinical studies investigating the properties of sigma receptor ligands in schizophrenic patients have not generated evi¬dence of antipsychotic activity, or activity in any other CMS disorder. Two of the most extensively studied selec¬tive sigma receptor antagonists, BW234U (rimcazole) and BMY14802, have both failed in clinical studies in schizo¬phrenic patients (Borison et al, 1991, Psychopharmacol Bull 27(2): 103-106; Gewirtz et al, 1994, Neuropsycho-pharmacology 10:37-40).
Further, WO 93/04684 and GB 2027703 also desciribe specific substituted piperazines useful in the treatment of CNS disorders.
Summary of the invention The object of the present invention is to provide new pharmaceutically active compounds, especially useful in treatment of disorders in the central nervous system, which do not have the disadvantages of the above de¬scribed substances.
In the work leading to the present invention, it was found that it is desired to provide substances with spe¬cific pharmacological properties, namely substances that have modulating effects on dopamine neurotransmission. These properties have not been described earlier, and they are not possible to obtain with the earlier known compounds. The compounds according to the present inven¬tion have a very surprising and interesting duallstic do¬paminergic action profile with antagonist-like effects on
on brain neurochemistry and mild agonist-like effects on normal behavior, but they induce inhibition of behavior in states of hyperactivity.
The present invention thus relates to new 3-substi¬tuted 4-{phenyl-N-alkyl} piperazines and 3-substituted 4-(phenyl-N-alkyl) piperidines in the form of free base or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds and use of said compounds in therapy.
One subject of the invention is to provide new com¬pounds for therapeutic use, and more precisely compounds for modulation of dopaminergic systems in the mammalian brain, including human brain.
Another subject of the invention is to provide com¬pounds with therapeutic effects after oral administra¬tion.
More precisely, the present invention relates to 3-substituted 4-(phenyl N-alkyl)-piperazine and 4-(phenyl-N-alkyl) -piperidine compounds of Formula 1:
and pharmaceutically acceptable salts thereof,
wherein:
X Is selected from the group consisting of K, CH, and C,
however X may only be C when the compound comprises a
double bond at the dotted line;
Ri is selected from the group consisting of OS02CF3*
OSO2CH3, SOR3, SO2R3, COR3, NO2, and CONHR3, wherein R3 is
as defined below, and when X is CH or C R1 may also be
selected from the group consisting of CFs, CN, F, C1, Br,
and I ;
R2 is selected from the group consisting of C1-C4 alkyls,
allyls, CHzSCHj, CH2CH2OCH3, CH2CH2CH2F, CH2CF3, 3,3,3-
trifluoropropyl, 4,4,4-trifluorobutyl, and -(CH:)-Ra,
wherein R is as defined below;
R3 is selected from the group consisting of C1-C3 alkyls,
CF3, and N(R2)2, wherein R2 is as defined above;
R4 is selected from the group consisting of Cs-Cg cycloal-
kyls, 2-tetrahydrofurane and 3-tetra-hydrofurane.
The compounds according to the present invention possess dopamine-modulating properties and are useful in treating numerous central nervous system disorders in¬cluding both psychiatric and neurological symptoms.
Diseases in which compounds with modulating effects on dopaminergic systems may be beneficial are in disor¬ders related to ageing, for preventing bradykinesia and depression and for the improvement of mental functions. They may also be used to improve cognitive functions and related emotional disturbances in neurodegenerative and developmental disorders as well as after brain damage.
The compounds according to the invention can be used to improve all symptoms of psychosis, including schizo¬phrenia and schizophreniform disorders as well as drug induced psychotic disorders. The compounds according to the invention may also be used in behavioral disorders usually first diagnosed in infancy, childhood, or adoles¬cence as well as in impulse control disorders. Also, speech disorders such as stuttering may improve. They may also be used for treating substance abuse disorders as well as disorders characterized by misuse of food.
Mood and anxiety disorders, personality disorders, and conversion hysteria may also be treated with the com¬pounds according to the invention.
Neurological indications include the treatment of Huntington's disease and other movement disorders as well as movement disorders induced by drugs. Restless legs and related disorders as well as narcolepsy may also be treated with compounds included according to the inven¬tion. They may also improve mental and motor function in Parkinson's disease, and in related parkinsonian syn-
dromes. They may also be used to ameliorate tremor of different origins. They may be used in the treatment of headaches and used to improve brain function following vascular or traumatic brain injury. Moreover, they may be used to relieve pain in conditions characterized by in¬creased muscle tone,
The compounds according to the present invention have unexpectedly been found to act specifically on dopa¬minergic systems in the brain. They have effects on bio¬chemical indices in the brain with the characteristic features of selective dopamine antagonists, e.g. produc¬ing increases in concentrations of dopamine metabolites.
Yet, dopamine receptor antagonists characteristi¬cally suppress behavioral activity and induce catalepsy, while the compounds of this invention show no, or only limited, inhibitory effects on spontaneous locomotion. In contrast they may induce a slight behavioral activation with concomitant increases in small-scale movements, e.g. stops in the center of the behavior recording arena, similar to that induced by dopaminergic agonists. The be¬havioral activation is limited, not reaching the profound increases in activity induced by direct or indirect dopa¬minergic agonists. On the other hand, the preferred sub¬stances reduce the increase in activity induced by direct or indirect dopaminergic agonists, i.e. d-amphetamine and congeners.
Thus, the compounds of this invention surprisingly show an interesting dualistic dopaminergic action profile with antagonist like effects on brain neurochemistry and mild agonist like effects on normal behavior, but inhibi¬tion of behavior in states of hyperactivity. The action profile suggests modulatory effects on dopaminergic func¬tions, clearly different from known compounds belonging to these chemical classes or effects anticipated of typi¬cal dopamine receptor antagonists or agonists from these or other chemical classes.
Given the involvement of dopamine in a large variety of CNS functions and the clinical shortcomings of pres¬ently available pharmaceuticals acting on dopamine sys¬tems, the novel class of dopaminergic modulators pre¬sented in this invention may prove superior to presently known dopaminergic compounds in the treatment of several disorders related to dysfunctions of the CNS, in terms of efficacy as well as side effects.
Some coKipounds according to the invention have been found to have surprisingly good pharmacokinetic proper¬ties including high oral bioavailability. They are thus suitable for the preparation of orally administered phar¬maceuticals. There is no guidance in the prior art how to obtain compounds with this effect on dopamine systems in the brain.
Detailed Description of the Invention Pharmacology
Evidence is available that neurotransmission in the CNS is disturbed in psychiatric and neurologic diseases. In many instances, for example in schizophrenia or Park¬inson's disease, pharmacotherapies based on antagonism or agonism at dopamine receptors are useful, but not opti¬mal. In recent years much efforts have been put on find¬ing novel and selective ligands for dopamine receptor subtypes (Di, D2, D3, D4, D5) with the aim to improve effi¬cacy and reduce side effects.
The present invention offers another principle for novel therapeutics based on interactions with dopamine systems. The compounds according to the invention have effects on brain neurochemistry similar to antagonists at dopamine D2 receptors. In contrast to currently used do¬pamine receptor antagonists the compounds according to the invention show no or limited inhibitory effects on spontaneous locomotion. They may induce behavioral acti¬vation with concomitant increases in small-scale move¬ments, e.g. stops in the center of the behavior recording
8
arena, similar to that induced by dopaminergic agonists. The behavioral activation is limited, not reaching the profound increases in activity induced by direct or indi¬rect dopamine receptor agonists. Surprisingly, the pre¬ferred substances can actually reduce the increase in ac¬tivity induced by direct or indirect dopaminergic ago¬nists, i.e. d-amphetamine and congeners.
The preferred structures are substituted in the meta position on the aromatic ring. An example of such a com¬pound is methanesulfonic acid 3-(l-propyl-piperidin-4-yl)-phenyl ester, which is shown in Example 14 below. In rat, this compound increases 3,4-dihydroxyphenylacetic acid in the striatum from 1265 ± 74 {controls) to 3208 + 236 ng/g tissue at 50 pmol/kg s.c. in combination with a slight increase in behavioral activity; 1485 ± 328 cm/30 min (controls) to 2126 ± 240 cm/30 min at 50 pmol/kg s.c, n=4. Another preferred example of a compound ac¬cording to the invention is 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, further illustrated in Example 6. In rat, this compound increases 3,4-dihydroxy-phenylacetic acid in the striatum from 914 + 19 (controls) to 1703 ± 19 ng/g tissue at 50 pmol/kg s.c. This increase in dopa¬mine turnover is followed by a trend towards an increase in motor activity from 2030 ± 299 cm/60 min to 2879 ± 398 cm/60 min p = 0.14. In animals habituated to the motili-tymeter box the compound described in Example 5, 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, increases behavioral activity from 476 ± 279 cm/60 min (controls) to 1243 ± 72 cm/60 min, p
In addition, the compound described in Example 6, 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, has the preferred ability to reduce behavioral activation induced by both d-amphetamine (1.5 mg/kg s.c.) and dizolcipine (Mk-801, 0,7 mg/kg i.p.). d-Amphetamine hyperactivity is
reduced from 10694 ± 2165 cm/60 min to 1839 ± 344 cm/60min, p
Unlike the somewhat similar compounds described in WO91/09594, the compound of Example 6, 4-(3-methane-sulfonyl-phenyl)-1-propyl-piperidine, lacks affinity at the sigma receptor,
In order to demonstrate the surprising effects of the compounds according to the invention, some of the compounds have been compared to similar compounds accord¬ing to prior art. The compounds used for comparison with the compounds according to the invention in the compara¬tive examples are thus not compounds according to the in¬vention since they do not exhibit the desired properties.
Comparative example 1: 4-(4-methanesulphonyl-phenyl)-1-propyl piperidine illustrates that substitution in the para position yields inactive compounds. 4-{4-methanesulphonyl-phenyl)-1-propyl piperidine has no ef¬fect on 3,4-dihydroxyphenyl-acetic acid in the striatum as demonstrated in the neurochemical experiment; 988 ± 70 (controls) ng/g tissue and 928 ± 61 ng/g tissue at 50 pmol/kg s.c. 4-(4-methanesulphonyl-phenyl)-1-propyl pi¬peridine does not have the properties desired according to the invention.
Comparative example 2: To further illustrate the im¬portance of the substitition on the aromatic ring for the desired properties, 4-phenyl-l-propyl-piperidine is dem¬onstrated to lack activity in the behavioral assay in the non-pre-treated rat, 36611494 cm/60 min, controls, to 2553 ± 471 cm/60 min, p>0.05, n = 4, at 33 jimol/kg and
10
lacks effects on 3,4-dihydroxyphenyl-acetic acid in the striatum as demonstrated in the neurochemical experiment; 1027 ± 31 (controls) ng/g tissue and 1190 ± 70 ng/g tis¬sue at 33 uraol/kg s.c, p > 0.05., 4-phenyl~l-propyl-piperidine] also lacks the desired inhibition of behav¬ioral activity in the d-amphetamine stimulated {17295 + 4738 cm/6Q min, d-amphetamine, to 13764 ± 2919 cm/60 min, n = 4, p » 0.05 at 33 pmol/kg.
Cornparative example 3: Further, l-phenyl-4-propyl-piperazine, described as sigma receptor binding compound in WO91/09594, is found to reduce behavioral activity in the non-pre-treated animal, from 3370 ± 227, controls, to 1923 ± 204 cm/60 min, n = 4, p
Comparative example 4: Substitution in the ortho po¬sition as exemplified by 1-(2-methoxy-phenyl)-4-pi:opyl piperazine yields a compound which increases 3,4-dihydroxyphenylacetic acid in the striatum from 1028 ± 9 (controls) ng/g tissue to 3836 ± 65 ng/g tissue at 50 pmol/kg s.c, p
Comparative example 5: The properties of the sub-stituent in the meta position are important, l-propyl-4-{3-triflouro-methyl-phenyl) piperazine increases 3,4-dihydroxyphenyl-acetic acid in the striatum from 1066 ± 46 (controls) ng/g tissue to 3358 ± 162 ng/g tissue at 50 pmol/kg s.c, p
Comparative example 6: Further, the compound of 3-(4-Propyl-piperazine-l-yl)-benzonitrile increases 3,4-dihydroxyphenyl-acetic acid in the striatum from 1432 ± 57 (controls) ng/g tissue to 4498 ± 243 ng/g tissue at
11
100 pmol/kg s.c, p
Comparative example 7: Another example of the impor¬tance of the substituent is preparation 14 which has no effect on 3,4-dihydroxy-phenyl-acetic acid in the stria¬tum; 1121 ± 36 (controls) ng/g tissue to 1169 ± 42 ng/g tissue at 50 pmol/kg s.c.
Comparative example 8: The physicochemical proper¬ties of the substituent on the basic nitrogen is also im¬portant for the desired profile. It is not possible to use any substituent, which is exemplified by 1-phenethyl-4-{3-trifluoromethyl-phenyl)-piperazine described as a Sigma receptor ligand in WO 91/09594 and WO 93/00313 which has some effects on 3,4-dihydroxyphenylacetic acid in the striatum; 852 ± 33 (controls) to 1406 ± 77 ng/g tissue at 50 pmol/kg s.c, p
Comparative example 9: In addition, l-benzyi-4-i3-methanesulfonyl-phenyl)-piperidine and 3-(l-benzyl-piperidin-4-yl)-phenol, compounds with benzylic substitu¬tion on the basic nitrogen, both has the undesired prop-
12
erty to interact with serotonin systems in the brain. 1-Benzyl-4-(3-methanesulfonyl-phenyl)-piperidine increases 5-hydroxyindoleacetic acid in the striatum from 428±20 (controls) to 487 + 7 ng/g tissue at 50 pmol/kg s.c, p
Comparative example 10: Substitution on the basic nitrogen according to 2-[4-(3-methanesulfonyl-phenyl)-piperazin-1-ylJ-ethanoi] (described in GB 2027703} ren¬ders compounds which are inactive in the behavioral ac¬tivity test; 3238 ± 1089 cm/60 min (controls) to 3782 ± 962 Gm/60 min. at 33 uraol/kg s.c, n=4, p > 0,05, as well as in the neurochemical test; effects on 3,4-dihydroxyphenylacetic acid in the striatum; 1158 ± 126 (controls) to 1239 + 162 ng/g tissue at 33 umol/kg s.c, n = 4, p > 0.05.
The compounds according to the invention are espe¬cially suitable for treatment of disorders in the central nervous system, and particularly for treatment of dopa¬mine mediated disorders. They may, e.g. used to amelio¬rate symptoms of mood disorders, in obesitas as an an¬orectic agent and in other eating disorders, to improve cognitive functions and related emotional disturbances, to improve cognitive and motor dysfunctions associated with developmental disorders, to improve all symptoms of schizophrenia and schizophreniform disorders as well as other psychoses, to improve ongoing symptoms as well as to prevent the occurrence of new psychotic episodes, to
13
regulate pathological disorders due to intake of food, coffee, tea, tobacco, alcohol, addictive drugs etc.
The compounds according to the invention can thus be used to treat symptoms in e.g.:
- schizophrenia and other psychotic disorders, such as catatonic, disorganized, paranoid, residual or differen¬tiated schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psy¬chotic disorder; shared psychotic disorder; psychotic disorder due to a general medical condition with delu¬sions and/or hallucinations;
- mood disorders, such as depressive disorders , e.g., dysthymic disorder or major depressive disorder; bipolar disorders, e.g., bipolar I disorder, bipolar II disorder, and cyclothymic disorder; mood disorder due to a general medical condition with depressive, and/or manic features; and substance-induced mood disorder;
- anxiety disorders, such as acute stress disorder, ago¬raphobia without history of panic disorder, anxiety dis¬order due to general medical condition, generalized anxi¬ety disorder, obsessive-compulsive disorder, panic disor¬der with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, specific phobia, social phobia, and substance-induced anxiety disorder;
- eating disorders, such as anorexia nervosa, bulimia nervosa, and obesitas;
- sleep disorders, such as dyssomnias, e.g., breathing-related sleep disorder, circadian rhythm sleep disorder, hypersomnia, insomnia, narcolepsy, and "jet lag";
- impulse-control disorders not elsewhere classified, such as intermittent explosive disorder, kleptomania, pathological gambling, pyromania, and trichotillomania;
- personality disorders, such as paranoid, schizoid or schizotypal disorder; antisocial, borderline, histrionic, and narcissistic disorder; and avoidant, dependent, ob¬sessive-compulsive disorder;
14
- medication-induced movement disorders, such as neuro¬leptic induced parkinsonism, neuroleptic malignant syn¬drome, neuroleptic induced acute and tardive dystonia, neuroleptic induced akathisia, neuroleptic induced tardive dyskinesia, medication induced tremor, and medi¬cation induced dyskinesias;
- substance-related disorders, such as abuse, dependence, anxiety disorder, intoxication, intoxication delirium, psychotic disorder, psychotic disorder with delusions, mood disorder, persisting amnestic disorder, persisting dementia, persisting perception disorder, sexual dysfunc¬tion, sleep disorder, withdrawal, and withdrawal delirium due to use ore misuse of alcohol, amphetamine (or am¬phetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencycli-dine (or phencyclidine-like substances!, sedative sub¬stances, hypnotic substances, and/or anxiolytic sub¬stances;
- disorders usually first diagnosed in infancy, child¬hood, or adolescence, such as mental retardation; learning disorders; motor skills disorders, e.g. develop¬mental coordination disorder; communication disorders, e.g. expressive language disorder, phonological disorder, receptive-expressive language disorder and stuttering; pervasive developmental disorders, e.g. Asperger's disor¬der, autistic disorder, childhood disintegrative disor¬der, and Rett's disorder; attention-deficit and disrup¬tive behavior disorders, e.g. attention-
deficit/hyperactivity disorder, conduct disorder, and op¬positional defiant disorder; feeding and eating disorders of infancy or early childhood, e.g. feeding disorder of infancy or early childhood, pica, rumination disorder; tic disorders, e.g. chronic motor or vocal tic disorder, and Tourette's disorder; other disorders of infancy, childhood, or adolescence, e.g. selective mutism, and stereotypic movement disorder;
15
- delirium, dementia, amnestic and other cognitive disor¬ders, such as Alzheimer's, Creutzfeldt-Jakob disease, dead trauma, Huntington's disease, HIV disease, Pick's disease, and diffuse Lewy body dementia;
- conversion hysteria;
- conditions connected to normal aging, such as distur¬bances in motor functions and mental functions;
- Parkinson's Disease and related disorders, such as mul¬tiple system atrophies, e.g. striatonigral degeneration, olivopontocerebellar atrophy, and shydrager syndrome; progressive supranuclear palsy; corticobasal degenera¬tion; and vascular parkinsonism;
- tremors, such as essential, orthostatic, rest, cerebel¬lar, and secondary tremor
- headaches, such as migraine, cluster headache, tension type headache, and paroxysmal headache;
- movement disorders, such as dyskinesias, e.g. in den-eral medicine condition, secondary to trauma or vascular insult, hemiballism, athetosis, Sydenham's chorea, and paroxysmal; dystonias; Ekbom's syndrome [restless legs); Wilson's Disease; Hallerworden-Spatz disease;
- rehabilitation medicine, e.g. to improve rehabilitation after vascular or traumatic brain injury;
- pain in conditions characterized by increased muscular tone, such as fibromyalgia, myofascial syndrome, dysto¬nia, and parkinsonism; as well as
- conditions related to the above that fall within the larger categories but does not meet the criteria of any specific disorder within those categories.
Synthesis
The synthesis of the present compounds is carried out by methods that are conventional for the synthesis of related known compounds. The syntheses of compounds in Formula 1, in general, comprise the reaction of an inter¬mediate that supplies the alkyl group with an intermedi-
16
ate piperidine or piperazine that supplies the amine group of Formula 2:
A convenient method of synthesis of the present com¬pounds is by use of an alkyl iodide {e.g. 1-propyl-iodide). Alternatively, other leaving groups besides io¬dide may be used on the alkyl group, of course, such as sulfonates, particularly methanesulfonate or toluenesul-fonate, bromo and the like. The alkyl intermediate is re¬acted with the appropriate amine in the presence of any convenient acid scavenger. The usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanola-mines. The reaction medium for such reactions may be any convenient organic solvent which is inert to the basic conditions; acetonitrile, esters such as ethylacetate and the like and halogenated alkane solvents are useful. Usu¬ally the reactions will be carried out at elevated tem¬peratures such as from ambient temperature to the reflux temperature of the reaction mixture, particularly from SCC to about lOOC.
Another convenient method of synthesis of the pre¬sent compounds involves reductive amination with an amine of Formula 2:
with an aldehyde or ketone, either in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride or followed by reduction, e.g. us-
groups besides iodide may be used on the alkyl group, of course, such as sulfonates, particularly methanesulfonate or toluenesulfonate, bromo and the like. The alkyl inter¬mediate is reacted with the appropriate amine in the presence of any convenient acid scavenger. The usual bases such as alkali metal or alkaline earth metal car¬bonates, bicarbonates and hydroxides are useful acid scavengers, as are some organic bases such as trial-kylamines and trialkanolamines. The reaction is performed in a suitable solvent such as n-butanol by heating at about 50-150°C.
18
zerovalent transition metal catalyst such as Pd or Ni, according to known method [Tetrahedron Letters, vol 37, 1996, 4453-4466, J. Org. Chem., vol. 51, 1996, 1133-1135).
The catalyst, preferably Pd will have the ability to form ligand complex and undergo oxidative addition. Typi¬cal Pd catalysts will be Pd2(dba)3 (wherein dba refers to di-benzylidene acetone), Pd(PPh3)4c Pd{0Ac)2, or PdCl2[P(o-tol)aJs and typical phosphine ligands will be BINAP, P(o-tol)3, dppf, or the like. The usual bases such as alkali metal or alkaline earth metal carbonates, bi-carbonates and alkyloxides are useful acid scavengers, as are some organic bases such as trialkylamines and trial-kanolamines. The reaction medium for such reactions may be any convenient organic solvents, which are inert to the basic conditions; acetonitrile, toluene, dioxane, NMP (N-methyl-2-pyrrolidone), DME (dimethoxyethane), DHF (N,N-dimethylformamide}, DMSO (dimethylsulfoxide) and THF (tetrahydrofuran) solvents are useful. Usually the reac¬tions will be carried out at elevated temperatures such as from ambient temperature to the reflux temperature of
the reaction mixture, particularly from 50°C to about 120°C.
Compounds of the Formula 1 wherein K = N is also ac¬complished by reacting compounds of Formula 6 with an aryl substituted with a leaving group (e.g. F or CI) via nucleophilic aromatic displacement reactions in the pres¬ence of a base as explained above.
Compounds of the Formula 1 wherein X = CH is also accomplished by transition metal catalyzed cross-coupling reaction, known as, for example, Suzuki and Stille reac¬tions, to those skilled in the art.
The reaction may be carried out between compounds of Formula 8:
wherein Y is, for example, a dialkylborane, dialkenylbo-rane or boronic acid (e.g. BEta, B(0H)2 (dotted lines can be double bonds)) or a trialkyltin (e.g. SnMes, SnBuj) , and an aryl substituted with a leaving group of Formula 7:
(for definition of 2, see above) in the presence of a base and a zerovalent transition metal catalyst such as Pd or Ni, according to known methods (Chem. Pharm. Bull., vol 33, 1985, 4755-4763, J. Am. Chem. Soc., vol, 109, 1987, 5478-5486., Tetrahedron Lett., vol. 33, 1992, 2199-2202). In addition, Y can also be a zink- or magnesium-halide group (e.g. ZnCle, ZnBr2, Znl2, MgBrj, Mglj) accord¬ing to known methods (Tetrahedron Lett., vol. 33, 1992, 5373-5374, Tetrahedron Lett., vol. 37, 1996, 5491-5494).
The catalyst, preferably Pd will have the ability to form ligand complex and undergo oxidative addition. The definition of ligands, bases and solvents, is mentioned above.
Alternatively, the transition metal catalyzed cross-coupling reaction can be performed with the opposite sub¬stitution pattern:
with an heteroaryl/alkenyl substituted with an leaving group of Formula 10:
in the presence of a base and a zerovalent transition metal catalyst such as Pd or Wi, according known methods discussed in the previous paragraph. Compounds of Formula 11:
can be prepared by catalytic hydrogenation of the tetra-hydropyridine or pyridine from the previous paragraph, using standard methods known in the art, generally with palladium on carbon, Pt02, or Raney nickel as the cata¬lyst . The reaction is performed in an inert solvent, such as ethanol or ethyl acetate, either with or without a protic acid, such as acetic acid or HCl. When the pyri¬dine ring is quaternized with an alkyl group the ring can be partly reduced by NaBH4 or NaCNBH, yielding the tetra-
hydropyridine analog which can further be reduced with catalytic hydrogenation,
Another convenient method of syntheses of compounds of the Formula 1, wherein X = CH is also accomplished by treating arylhalides of Formula 7:
■Z (7)
wherein Z is CI, Br, or I, with alkyllithium reagents.
■Z (7)
wherein Z is CI, Br, or I, with alkyllithium reagents, for example, butyllithiiim, sec-butyllithinm or tert-butyl-lithium, preferably butyllitium or Mg (grignard re¬action) in an inert solvent. Suitable solvents include, for example ether or tetrahydrofuran, preferably tetrahy-drofuran. Reaction temperatures range from about -llOC to about eCc. The intermediate lithium anions or magne¬sium anions thus formed may then be further reacted with a suitable electrophile of Formula 12:
wherein A is defined as a protecting group like t-Boc (tert-butoxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl) or a an alkylgroup like benzyl. The intermediates of Formula 13:
which are formed require that the hydroxy group be re¬moved so as to result in compounds of Formula 1 [X=CH).
This step may be accomplished by one of several standard methods known in the art. For example, a thio-
carbonyl derivative [for example a xanthate) may be pre¬pared and removed by a free radical process, of which are known to those skilled in the art. Alternatively, the hy-droxyl group may be removed by reduction with a hydride source such as triethylsilane under acidic conditions, using such as, for example, trifluoroacetic acid or boron trifluoride. The reduction reaction can be performed neat or in a solvent, such as methylene chloride, A further alternative would be to first convert the hydroxyl group to a suitable leaving group, such as tosylate or chlo¬ride, using standard methods. The leaving group is then removed with a nuclGophilic hydride, such as, for exam¬ple, lithium aluminium hydride. This last reaction is performed typically in an inert solvent, such as, ether or tetrahydrofuran.
Another alternative method for removing the hydroxyl group is to first dehydrate the alcohol to an olefin with a reagent such as Burgess salt (J, Org, Chera., vol 38, 1973, 26) followed by catalytic hydrogenation of the dou¬ble bond under standard conditions with a catalyst such as palladium on carbon. The alcohol may also be dehy¬drated to the olefin by treatment with acid such as p-toluenesulfonic acid or trifluoroacetic acid.
The protecting group, h, is removed under standard conditions known by those skilled in the art. For exam¬ple, t-Boc cleavages are conveniently carried out with trifluoroacetic acid either neat or in combination with methylene chloride. F-moc is conveniently cleaved off with simple bases such as, ammonia, piperidine, or mor-pholine, usually in polar solvents such as DMF and aceto-nitrile. When A is Cbz or benzyl, these are conveniently cleaved off under catalytic hydrogenation conditions. The benzyl group can also be cleaved off under N-dealkylation conditions such as treatment with a-chloroethyl chloro-formate {J. Org. Chem., vol 49, 1984, 2081-2082).
It is further possible to convert a radical Ri in a compound of the Formula 1 into another radical Ri, e.g.
by oxidizing methylsulfide to methylsulfone (for example by m-chloroperoxybenzoic acid), substitution of a tri-flate or halide group with a cyano group (for example palladium catalyzed cyanation), substitution of triflate or halide group with a ketone (for example palladium catalyzed Heck reaction with taiatyl vinyl ether) , substi¬tution of a triflate or halide group with a carboxamide (for example, palladium catalyzed carbonylation), or cleaving an ether by, for example, converting a methoxy group into the corresponding hydroxyl derivate, which can further be converted into the corresponding mesylate or triflate. The terms mesylate and triflate refers to OSOzCHa, CH3SO3 or OSO2CF3, CF3SO3, respectively.
In summary, the general process for preparing the
As used herein the term C1-C4 alkyl refers to an al-kyl containing 1-4 carbon atoms in any isomeric form. The various carbon moieties are defined as follows: Alkyl re¬fers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl.
The term cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cy-clopentyl, cyclohexyl.
The term "patient" used herein refers to an individ¬ual in need of the treatment according to the invention.
The term "treatment" used herein relates to both treatment in order to cure or alleviate a disease or a condition, and to treatment in order to prevent the de¬velopment of a disease or a condition. The treatment may either be performed in an acute or in a chronic way.
Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds according to the invention. Illus¬trative acids are sulfuric/ nitric, phosphoric, hydro¬chloric, citric, acetic, lactic, tartaric, palmoic, eth¬ane disulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid. These salts are read¬ily prepared by methods known in the art.
The pharmaceutical composition containing a compound according to the invention may also comprise substances used to facilitate the production of the pharmaceutical preparation or the administration of the preparations. Such substances are well known to people skilled in the art and may for example be pharmaceutically acceptable adjuvants, carriers and preservatives.
In clinical practice the compounds used according to the present invention will normally be administered orally, rectally, or by injection, in the form of pharma¬ceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier. The carrier may be a solid, semisolid or liquid preparation. Usually the ac¬tive substance will constitute betvfeen 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by a weight for preparations intended for injec-
tion and between 0.2 and 50% by weight for preparations suitable for oral administration.
To produce pharmaceutical preparations containing the compound according to the invention in the form of dosage units for oral application, the selected corapound may be mixed with a solid excipient, e.g. lactose, sac¬charose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose deriva¬tives, a binder such as gelatine or polyvinyl-pyrrolidine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arable, gelatine, talcum, ti¬tanium dioxide, and the like. Alternatively, the tablet can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or differ¬ent amounts of the active compound.
For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or poly-ethylene glycol. Hard gelatine capsules may con¬tain granules of the active substance using either the mentioned excipients for tablets e.g. lactose, saccha¬rose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.
Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of supposi¬tories comprising the active substance in a mixture with a neutral fatty base, or gelatine rectal capsules com¬prising the active substance in admixture with vegetable oil or paraffin oil. Liquid preparations for oral appli-
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The invention is further illustrated in the examples below, which in no way are intended to limit the scope of the invention.
Example 1; 1- (3-Methanesulfonyl-phenyl)-4-propyl-piperazine
A suspension of 1-[3-raethanesulfonyl-phenyl)-piperazine (350 mg) and ground K2CO3 (403 mg) was stirred in CH3CN (25 mL) at room temperature. 1-Iodo-propane (712 pL) was added. The mixture was refluxed overnight. The reaction mixture was filtered and the volatilea were evaporated in vacuum. The oily residue was chromatogra-phed on a silica column with MeOH:CH2Cl2 (1:30 (v/v) ) as eiuent. Collection of the fractions containing pure prod¬uct and evaporation of the solvent afforded pure l-(3-methanesulfonyl-phenyl)-4-propyl-piperazine (220 mg). The amine was converted into the HCl salt and recrystallized from ethanol/diethylether; m,p. 233'C MS m/z {relative intensity, 70 eV) 282 (M*, 30), 254 (15), 253 (bp), 210 (17), 70 (21).
The following compounds according to Examples 2-11 were prepared in a manner similar to the one described in Example 1.
Example 2; l-Propyl-4-(3-Triflupromethanesulfonyl-phenyl)-piperazine
MS m/z (relative intensity, 70 eV) 336 [M+, 16), 307 (bp), 77 (18) , 70 (38), 56 (23) .
Example 3: 1- [3-(4-Propyl-piperazin-l-yl)-phenyl]-ethanone
Beginning with 1-(3-Piperazin-l-yl-phenyl)-ethanone and n-Pr-X; m.p. 119°C (oxalate), MS m/z (rel. intensity, 70 eV) 246 (M+, 10), 217 (33), 132 (18), 70 (bp), 56 (41); Rf 0.23 (EtOAc).
Example 4: l-Propvl-4-(3-trifluoromethyl~phenyaj piperidine
Beginning with 4-(3-TrifluoroniGthyl-phenyl)-piperidine and n-Pr-I: m.p. igs-C (HCl), MS m/z (rel. in¬tensity, 70 eV) 271 (M+, 4), 243 (16), 242 (bp), 159 (13), 70 (49) .
Example 5: l-ButYl-4-(3-trifluoromethyl-phenyl)-piperidine
Beginning with 4-(3-Trifluoromethyl-phenyl)-piperidine and n-Bu-Br: m.p. 222 "C (HCl), MS m/z (rel. intensity, 70 eV) 285 {M+, 3), 243 (12), 242 (bp), 70 (51), 56 (17).
Example 6: 4-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine
m.p. 200'C (HCl) MS m/z (relative intensity, 70 eV) 281 (M+, 5), 252 (bp), 129 (20), 115 (20), 70 (25.
Example 7: 4-(3-Methane3ulfonyl-phenyl)-1-propyl-l,2,3, 6-tetrahydro-pyridine
Beginning with 4-(3-methanesulfonyl-phenyl)-1,2,3, 6-tetrahydro-pyridine and iodopropane: MS m/z (relative in¬tensity, 70 eV) 279 (M+. 26), 250 (bp), 171 (6), 128 (12), 115 (8) .
Example 8: 4-(3-Methanesulfonyl-phenyl)-l-ethyl-piperidine
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and iodoethane: m.p. 158 °C (HCl). MS m/z (rel. intensity, 70 eV) 267 (M+, 20), 252 (bp), 130 (10), 115 (12), 84 (20);
Example 9: 1-Isopropy1-4-(3-methanesulfouyl-phenyll-piperidine
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and i-propylbromide: m.p. 220 °C (HCl); MS ra/z
(rel. intensity, 70 eV) 281 (M+, 4), 266 (bp), 187 (5), 129 (5j, 115 (5)
Example 10: 4~(3-Methanesulfonyl-phenyl)-1-butyl-piperidine
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and n-BuCl. MS m/z (eel. intensity, 70 eVj 295 (M+, 3), 252 (bp), 130 (5), 115 (3), 70 (8).
Example 11: l-Isobutyl-4-(3-methanesulfonyI-phenyl)-piperidine
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and i-butylbromide; m.p. 212 "C (HCl); MS m/z (rel. intensity, 70 eV) 295 (M+, 1), 252 (80), 129 (40), 115 (50), 70 (bp).
Example 12; 3-(l-PrQpyl-piperidln-4-yl)-benzonitrile
A solution of 3-(l-propyl-piperidin-4-yl)-benzamide
(350 mg) and POCI3 (326 pL) in dry DMF (6 ml) was heated at SCC for 3 h under an argon atmosphere. Evaporation of the solvent yielded a dark, oily residue, which was dis¬solved in water. The solution was basified and extracted with CH2C12. The combined organic phases were dried
(MgS04) , filtered and evaporated. The oily residue was chromathographed on a silica column with MeOH:CH2Cl2 (1:19
(v/v)1 as Gluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure 3-{l-Propyl-piperidin-4-yl)-benzonitrile (127 mg). The amine was converted into the fumarate salt and recrystal-lized from ethanol/diethylether: m.p. 122'C; MS m/z
(relative intensity, 70 eV) 228 (M+, 2), 199 (42), 129
(26), 70 (bp) 56 (53).
Example 13; l-sec-Butyl-4-(3-methanesulfonyl-phenyl)-piperidine
4- (3-inethanesulfonyl-phenyl) -piperidine hydrochlo¬ride (20 mg), glacial acetic acid (4.4 mg) and 2-butanone
(5.1 mg) were mixed in 1,2-dichloroethane (5 mL). Sodium trxacetoxyborohydride (23.5 mg) was added to the solution and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5 h (G.L.C. analysis in¬dicated a complete reaction). The reaction was quenched with saturated aqueous NaHCOs and the product was ex¬tracted with CHzClz. The combined organic phases were dried (MgSO) , filtered, and the solvent was evaporated to afford l-sec-butyl-4-(3-methanesulfonyl-phenyl)-piperidine as an oily residue. The product was chroma-tographed on a silica coluitm with CH2Cl2:MeOH (9:1 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure amine (15 mg, 71%); MS m/z (relative intensity, 70 eV) 295 (M+, 1), 280 (7), 266 (bp), 187 (4), 129 (4).
Example 14: Methanesulfonic acid 3~(l-propyl-piperidin-4-yl)-phenyl ester
A solution of 3-(l-propyl-piperidin-4-yl)-phenol
(340 mg) and triethylamine (187 mg) in 20 ml of CHaClj was cooled to CC. Then methanesulfonyl chloride (194 mg) dissolved in 10 ml of CH2CI2 was added dropwise. The reac¬tion mixture was allowed to reach room temperature and then stirred for 2,5 h at 25 "C. The reaction was finally quenched with water. The organic layer was separated and washed with 10% HCl and then 10% Na2C03.
After drying {MgS04) the solvent was removed under reduced pressure. The residue was chromathographed on a silica column using MeOH:CH2Cl2 (1:9 (v/v)) as eluent. The fractions containing pure methanesulfonic acid 3-(l-propyl-piperidin-4-yl)-phenyl ester were collected, and the solvent was removed in vacuum, affording 206 mg of the title compound, (MS m/z (rel. intensity, 70 eV) 297
(M+, 3), 268 (bp), 189 (24), 131 (13), 79 (16);
The following compounds in Examples 15 ~ 19 were prepared in a manner similar to the one described in Ex¬ample 14.
Example 15; Methanesulfonic acid 3-tl-ethyl-pipericiin-4-yl)-phenyl ester
Beginning with 3-(l-ethyl-piperidin-4-yl)-phenol and methanesuifonyl chloride. MS m/z (rel. intensity, 70 eV) 283 (M+, 6), 268 (bp), 189 (54), 131 (20), 79 (70);
Example 16: MethanesulEonic acid 3-(l-butyI-pipericlin-4-yl)-phenyl ester
Beginning with 3-(l-butyl-piperidin-4-yl}-phenol and methanesulfonyl chloride. MS m/z (rel. intensity, 70 eV) 311 {M+, 3), 268 (bp), 189 (20), 131 (18), 79 (12);
Example 17: Methanesulfonic acid 3-(4-propyl-piperazin-l-yl)-phenyl ester
Beginning with 3- {4-propyl-piperazin-l-yl)-phenol and methanesulfonyl chloride; m.p 143-144 °C (fumarate); MS m/z (rel. intensity, 70 eV) 298 (M+, 35), 269 (95), 121 (25), 84 (30), 70 (bp);
Example 18: Trifluoro-methanesulfonic acid 3-(l-prQpyl-piperidin-4-yl)-phenyl ester
Beginning with 3-(l-propyl-piperidin-4-yl)-phenol and triflic anhydride MS m/z (rel. intensity, 70 eV) 351 (M+, 4), 322 (65), 189 (30), 131 (20), 69 (bp) .
Example 19: Trifluoro-inethanesulfonic acid 3-(l-ethyI-piperidin-4-yl)-phenyl ester
Beginning with 3-(l-ethyl-piperidin-4-yl)-phenol and triflic anhydride: MS in/z (rel. intensity, 70 eV) 337 (M+, 4), 322 (65), 189 (30), 131 (20), 69 (bp).
Example 20 1-[3-(l-Propyl-piperidin-4-yl)-phenyl]-ethanone
To a stirred solution of trifluoro-methanesulfonic acid 3-(l-propyl-piperidin-4~yl)-phenyl ester (300 mg) in DMF {4 ml) under argon atm at r.t. was subsequently added NEt3 (356 \ih) , butyl vinyl ether (823 pL) , 1,3-bis(diphenylphosphino)propane (50 mg), and Pd[0Ac)2 (19 mg). The reaction mixture was then heated to 80°C and af¬ter 2 h the reaction was stopped. 5 % Hydrochloric acid solution (6 ml) was added and the combined mixture stirred for 45 min. Then CH2CI2 was added and the phases were separated. The aqueous layer was then extracted with CH2C12. The combined organic phases were dried (MgS04) , filtered and evaporated to dryness. The crude product was purified by flash chromatography (MeOH;CH2Cl2 (1:9 (v/v)). Collection of the fractions containing pure product and evaporation of the solvent afforded pure l-[3-(1-Propyl-piperidin-4-yl)-phenyl]-ethanone {35 mg). MS m/z (rel. intensity, 70 eV) 245 (M+, 4), 216 (bp), 100 (19), 70 (36), 57 (13) .
Example 21: l-Propyl-4-(3-trifluoromethylsulfonylphenyl)-1,2,3,6-tetrahydropyridine
4-(3-Trifluoromethylsulfonylphenyl)-Pyridine (0.3 g) was dissolved in 1-iodo-propane (2 ml) and heated to 100°C for 2 h. Then the voilatiles were evaporated and the residue redissolved in abs EtOH (20 ml) and NaBH4 (340 mg) was addded portions wise at - 20'C. The mixture was then allowed to reach r.t. and stirred over night. To the mixture was added 10% NasCOa solution (20 ml). The aqueous layer was extracted with CH2C12 and the combined organic phases were dried {MgS04), filtered and evapo¬rated to dryness. The crude product was purified by flash chromatography (MeOH:CH2Cl2 (1:9 (v/v)). Collection of the fractions containing pure product and evaporation of the solvent afforded pure l-propyl-4-(3-trifluoromethyl¬sulfonylphenyl) -1, 2, 3, 6-tetrahydropyridine (150 mg). MS
m/z frel. intensity, 70 eV) 333 (M+, 21), 305 (16), 304 (bp), 171 (14), 128 (14). Rf 0.55 (MeOH)
Example 22: l-PrQpyl-4(3-trifluoromethylsulfonylphenyl)-piperidine
Beginning with l-propYl-4-(3-tEi£luorQmethyl-sulfonyl'phenyl)-1,2,3,6-tetrahydropyridine, 1-Propyl-4(3-trifluoro-methylsulfonylphenyl)-piperidine was recov¬ered by the procedure described in Preparation 9. MS m/z (relative intensity, 70 eV) 335 {M+, 3), 307 (17), 306 (bp), 173 (26), 70 (10).
Example 23: l-Allyl-4-(3-methanesulfonyl-phenyl)-piperidine
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and allylbromide, the titled compound was re¬covered by the procedure described in Example 1. MS m/z {relative intensity, 70 eV) 279 (M+, 74), 96 (bp), 82 (98), 68 (74), 55 (93). Rf = 0.42 (MeOH, 0.08 (EtOAc).
Example 24: 4-(3-Methanesulfonyl-phenyl)-1-(tetrahydro-furan-2-ylmethyl)-piperidine
Beginning with 4-{3-methanesulfonyl-phenyl)-piperidine and tetrahydrofurfuryl chloride, the titled compound was recovered by the procedure described in Ex¬ample 1. MS m/z (relative intensity, 70 eV) 323 (M+, 1}, 252 (bp), 129 (9), 115 (6), 70 (17). Rf = 0.3 (MeOH, 0.03 (EtOAc).
Syntheses of intermediates used in the above Exam¬ples are described in the preparations below.
Preparation 1: 4-Hydroxy-4-(3-methylsulfanyl-phenyl)-piperidin-l-carboxylic acid tert-butyl ester
l-Bromo-3-methylsulfanyl-benzene (5.0 g, 24.6 mmol) was dissolved in dry THF (40 ml) and cooled to -78'c un¬der a stream of Argon (g). n-BuLi (12.8 ml, 2.5 M in hex-
ane, 31.9 itimol) was added dropwise via syringe and the reaction mixture was stirred for an additional 30 min at -78°C, then the temperature was increased to Cc for 5 min and then decreased to -ISC. l-tert-Butoxycarbonyl-4-pipertdone (5.4 q, 27.06 mitiol) dissolved in dry THF (30 ml) was added via syringe. The reaction mixture was al¬lowed to reach room temperature and then stirred for 1 hour, and finally quenched with saturated ammonium chlo¬ride solution (30 ml). The mixture was extracted several times with EtOAc and the combined organic phases were dried (MgS04) , filtered and evaporated to dryness. The oily residue was chromatho-graphed on a silica column us¬ing CH2Cl2:MeOH (19:1 (v/v)) as eluent, yielded 4-hydroxy-4-(3-methylsulfanyl-phenyl)-piperidin-1-carboxylic acid tert-butyl ester (6 g, 76 %). MS m/z (relative intensity, 70 eV) 323.1 (M+, 6), 223.0 (11), 178.0 (7), 152 (3), 57.0 (bp), 56 130).
Preparation 2: l-Benzyl-4-(S-methoxy-phenyl)-piperidin-4-ol
Beginning with B-bromoanisole (5 g) and l-benzyl-4-piperidone (5.5 g), 4.58 g of l-benzyl-4-(3-methoxy-phenyl)-piperidin-4-ol was recovered by the procedure de¬scribed in Preparation 1, MS m/z (relative intensity, 70 eV) 297 (K+, B), 279 (13), 206 (28), 146 (17), 91 (bp).
Preparation 3: l-Benzyl-4-(3-trifluoromethyl-phenyl)-piperidin-4-ol
Beginning with 3-trifluoromethyl-iodobensene (3 g) and l-benzyl-4-piperidone (2.1 g), 1.75 g of the title compound was recovered by the procedure described in preparation 1. MS m/z (rei. intensity, 70 eV) 335 (M+, 29), 244 (22), 146 (19), 91 (bp), 56 (19).
Preparation 4: 4-Q-Methylsulfanyl-phenyl)-1,2,3,6-tetrahydro-pyridine
4-Hydroxy-4-(3~methylsulfanyl-phenyl)-piperidin-1-carboxylic acid tert-butyl ester (3.97 g) was dissolved in CH2CI2 (500 ml) and trifluoroacetic acid (80 ml) was added in one portion. The mixture was refluxed for one hour and then washed with two portions of 10%-Na2CO3, dried (MgS04) , filtered and evaporated to dryness. Yield 2.07 g. MS m/2 (relative intensity, 70 eV) 205 (M+, 73), 158 (44), 129 (95), 128 (80), 82 (bp).
Preparation 5: l-Benzyl-4-(3-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine
Beginning with l-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-ol (4,5 g) and trifluoroacetic acid (80 ml), 3.5 g of l-benzyl-4-(3-methaxy-phenyl)-1,2,3,6-tetrahydro-pyridine was recovered by the procedure de¬scribed in Preparation 4, MS m/z (relative intensity, 70 eV) 279 (M+, 35), 145 (13), 115 (15), 91 (bp), 65 (22).
Preparation 6: l-Benzyl-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine
Beginning with l-Benzyl-4-(3-trifluoromethyl-phenyl)-piperidin-4-ol (1.74 g), 1.44 g of the title com¬pound was recovered by the procedure described in prepa¬ration 4 (neat CF3COOH) . MS m/z (rel. intensity, 70 eV) 317 (M+, 71), 226 (13), 172 (15), 91 (bp), 65 (17).
Preparation 7: 4-(3~Methylsulfanyl-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid methyl ester
4-(3-Methyl3ulfanyl-phenyl)-1,2,3,6-tetrahydro-pyridine (2 g) and NEt3 (1 g) were dissolved in CH2CI2 (75 ml) and cooled to OC. Methyl chloroformate (0.96 g) dis¬solved in CH2CI2 (20 ml) was added dropwise and the reac¬tion mixture was then allowed to reach room temperature. After an additional two hours at room temperature the re¬action mixture was washed with 10% Na2C03 solution, dried
(MgS04), filtered and concentrated by evaporation. The oily residue was chromatographed on a silica column using CH2Cl2:MeOH (19:1 {v/v)) as eluent, 4-[3-methylsulfanyl-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid methyl ester (1.4 g). MS m/z (relative intensity, 70 eV) 263 (M+ 45), 248 (89), 129 (83), 128 (bp), 59 (96).
Preparation 8: 4-(3-Methanesulfonyl-phenyl)-3,6-dihydro-2H~pyridine-l-carboxylic acid methyl ester
4-(3-Methylsulfanyl-phenyi)-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester (1.4g) was dissolved in CH3C12 (150 ml) and cooled to 0°C. m-Chloroperoxybenzoic acid {2.48 g) was added portions wise and the mixture was stirred at room temperature for three hours. The result¬ing clear solution was washed with 10%-Na2CO3 solution, dried (MgSO) , filtered and concentrated by evaporation and yielding an oily residue (1.3 g). MS m/z (relative intensity, 70 eV) 295 (M+, 19), 280 (56), 129 (70), 128 (89), 59 (bp).
Preparation 9: 4-(3-Methanesulfonyl-phenyl)-piperidin-1-carboxylic acid methyl ester
4'(3-Methanesulfonyl-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid methyl ester (2.0 g) was dis¬solved in methanol (40 ml). Concentrated hydrochloric acid (2 ml) and Pd/C (500 rag) were added. The resulting mixture was hydrogenated under a hydrogen gas pressure (50 psi) for 8 h and then filtered through a pad of ce-lite. The solvent was evaporated in vacuum and the resi¬due was purified by flash chromatography (CHaCl?: MeOH, 3:1 (v/v)). Yield 0.92 g MS m/z (relative intensity, 70 eV) 297 (M+, 54), 282 (62), 238 (bp), 115 (92), 56 (93).
Preparation 10: 4-(3-Methoxy-phenyl)-piperidine
Beginning with l-Ben2yl-4-(3-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine (5.1 g) and 900 mg Pd/C, 1.7 g of 4-{3-Methoxy-phenyl)-piperidine was recovered by the
procedure described in Preparation 9. The oily residue Was purified by flash chromatography (SiOj, CHaClsiMeOH, 3:1 (v/v) with 1 % NEts) to give the pure title compound. MS m/z (relative intensity, 70 eV) 191 {M+, 75), 160 (60), 83 (55), 57 (80), 56 (bp).
Preparation II: 4-(3-Trifluoromethyl-phenyl)-piperidine
Beginning with l-Benzyl-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine [1.44 g), 1 g of the title compound as HCl salt was recovered by the procedure described in preparation 9. ra.p. 202°C (HCl); MS m/z {rel. intensity, 70 eV) 229 (M+, 44), 228 (33), 83 (12), 57 (54), 56 (bp).
Preparation 12: 4-(S-Methanesulfonyl-phenyl-piperidine
4-(3-Methanesulfonyl-phenyl)-piperidin-1-carboxylic acid methyl ester (0.92 g) dissolved in ethanol (15 ml) and 8 M HCl (40 ml) was refluxed for 12 hours. The mix¬ture was then evaporated in vacuum to dryness. Yield 0.85 g MS m/z (relative intensity, 70 eV) 239 (M+, 59), 238 (50), 69 (20), 57 (79), 56 (bp).
Preparation 13: 3-Piperidin-4-yl-phenol.
4-(3-Methoxy-phenyl)-piperidine (1.7 q) was dis¬solved in 48-% HBr [60 ml) and stirred at 120 "C under an Argon-atmosphere for 3 h. The excess of HBr was then evaporated and absolute ethanol added and evaporated. This procedure was repeated several times to yield dry Crystals of 3-piperidin-4-yl-phenol x HBr (2.3 g). MS m/z
(relative intensity, 70 eV) 177 (M+, bp), 176 (23), 91
(14), 57 (44), 56 (60).
Preparation 14: 3-(l-Propyl-piperidin-4-yl)-phenol x HBr
Beginning with 3-piperidin-4-yl-phenol x HBr (300 mg) and n-propyl iodide (200 mg), 340 mg o£ 3-(l-propyl-piperidin-4-yl)-phenol was recovered by the procedure de¬scribed in Example 1. The HBr salt was prepared to pro-
vide the title compound. MS m/z {rel. intensity, 70 GV) 219 (M+, 21), 190 (bp), 119 (22), 91 (30), 70 (63); m.p. 181-184 "C (HEr).
Preparation 15: 3- (l-Ethyl--piperidin-4-yl) -phenol
Beginning with 3-piperidin-4-yl-phenol x HBr (200 mg) and Ethyl iodide (121 rag), 120 mg of 3-(l-ethyl-piperidin-4-yl)-phenol was recovered by the procedure de¬scribed in Example 1. MS m/z (rel. intensity, 70 eV) 205 (M+, 12), 190 (bp), 119 (36), 91 (22), 70 (87).
Preparation 16: 3-(l-Butyl-piperidin-4-yl)-phenol
Beginning with 3-piperidin-4-yl-phenol x HBr (200 mg) and n-butyl chloride (73 mg), 118 mg of 3-(l-butyl-piperidtn-4-yl)-phenol was recovered by the procedure de¬scribed in Example 1. MS m/z (rel. intensity, 70 eV) 233 (M+, 6), 190 (bp), 119 (42), 91 (26), 70 (45).
Preparation 17: 1-(3-Methanesulfonyl-phenyl)-piperazine A mixture of 1-bromo-3-methanesulfonyl-benzene
(0.8g), piperazine (1 g), sodium tert-butoxide (0.5 g) BINAP (42 mg) and [Pd2(dba)3 (38 mg) in toluene (7 ml) was heated under argon at 80 °C for 24 h. After cooling to roomtemperature, the solvent was evaporated to dryness. The crude material was purified by flash chromatography on silica gel using EtOAc, Yield 0.48 g: MS m/z (rel. in¬tensity, 70 eV) 240 {M+, 17), 199 (12), 198 (bp), 119
(9), 56 (7) .
Preparation 18: 1- (3-Trifluoromethanesulfonyl-phenyl)-piperazine
Beginning with 3-bromo-trifluoromethanesulfonyl-benzene and piperazine, the titled cmp was recovered by the procedure described in Preparation 17. MS m/z [rel. intensity, 70 eV) 294 (M+, 22), 252 (bp), 119 (32), 104 (10), 56 (15). (451.
Preparation 19: 1-(3-Piperazin-l-yl-phenyl)-ethanone
Beginning with 3-bromo-acetophenone and piperazine, the titled cmp was recovered by the procedure described in Preparation 17. MS ra/z (rel. intensity, 70 eV} 204 (M+, 51, 152 (35), 77 (30), 57 (35), 56 (bpl.
Preparation 20: 3-(l-Propyl-piperidin--4-yl)-benzoic acid methyl ester
A mixture of trifluoro-methanesulfonic acid 3-(1-propyl-piperidin-4-yl)-phenyl ester (1.2 g) , triethyl amine (0.9 g), MeOH (5.4 ml), Pd(0Ac)2 (25 mg) and 1,3-bis(di-phenyl-phosphino)propane {45 mg) in 15 ml DMSO was stirred at room temperature for 15 min. A stream of CO (g) was passed through the solution for 4-5 min., and then the reaction vessel was placed under a sligthly positive pressure of CO (g). The temp was increased to 70'C. After 5h the reaction was allowed to cool to r.t. Water was then added, and the aqueous solution was ex¬tracted with five portions of ethyl acetate and the com¬bined organic phases were dried (MgSO) , and evaporated. The residue was chromathographed on a silica column using MeOH; CH2CI2 (1:9 (v/vj) as eluent. The fractions contain¬ing pure titled compound were collected, and the solvent was removed in vacuum, affording 650 mg of the titled compound. (MS m/z (rel. intensity, 70 eV) 261 {M+, 5), 233 (16), 232 (bp), 161 (5), 70 (20)
Preparation 21: 3- (l-Propyl-piperidin-4-yl)-benzamide
A solution of 3-{l-Propyl-piperidin-4-yl)-benzoic acid methyl ester (0.6 g) and formamide (320 pL) in DMF (9 ml) was heated to 100 °C under a blanket of argon. So¬dium methoxi'de in methanol (30%, 770 pL) was added drop-wise and after Ih, GC analysis revealed the complete ab¬sence of starting material and indicated the titled com¬pound as the sole product. After cooling, CH2C12 was added and the resulting solution was filtered through a pad of celite and evaporated to dryness. The residue was chro-
mathographed on a silica column using MeOH: CHsCls (1:3 (v/v)) as eluent. The fractions containing pure titled compound were collected, and the solvent was removed in vacuum, affording 400 mg of the titled compound, m.p. 182'C {oxalate) (MS m/z [rel. intensity, 70 eV) 246 (M+, 4), 217 (bp), 131 (19), 100 (22), 70 (63).
Preparation 22: 4-Q-Trifluoromethylsulfonyl-phenyl)-pyridine
l-Bromo-3-trifluOromethylsulfonyl benzene (580 mg) and 4-pyridine-boronic acid (275 mg) was dissolved in toluene (5 ml) and abs EtOH [5 ml). To the mixture was then added Na2C03 (424 mg) and Pd(PPh3)4 (119 mg) under an atmosphere of Argon. The resulting mixture was heated to 90 "C for 18 h. Then CH2CI2 was added and the organic phase was washed with water and dried [MgS04) , filtered and evaporated to dryness. The residue was then used without any further purification. (MS m/z (rel. inten¬sity, 70 eV) 287 (M+, 33), 218 (22), 154 (bp), 127 (56), 69 (27) .
The following tests were used for evaluation of the compounds according to the invention.
In vivo test: Behavior
For behavioral testing, the animals were placed in separate motility meter boxes 50X50X50 cm equipped with an array of 16x16 photocells (Digiscan activity monitor, RKYZM (16) TAO, Omnitech Electronics, USA), connected to an Omnitech Digiscan analyzer and a Apple Macintosh com¬puter equipped with a digital interface board (NB DIO-24, National Instruments, USA). Behavioral data from each mo¬tility meter box, representing the position (center of gravity) of the animal at each time, were recorded at a sampling frequency of 25 Hz and collected using a custom written LABView application. The data from each record¬ing session were analyzed with respect to distance trav-
A1
eled and small-scale movements, e.g. stops in the center of the behavior recording arena, during the recording session. To determine stops in the center, velocity at each time point is calculated as the distance traveled since the preceding sample divided by the time elapsed since the preceding sample, The number of stops is then calculated as the number of times that the velocity changes from a non-zero value to zero. The number of stops in the center of the behavioral recording arena is calculated as the number of stops occurring at a position at least ten centimeters from the edges of the recording arena. For behavioral testing of habituated rats, the animals were placed in the motility meter boxes 30 min¬utes before the administration of test compound. Each be¬havioral recording session lasted 60 or 30 minutes, starting immediately after the injection of test com¬pound. Similar behavioral recording procedures was ap¬plied for non-habituated rats, habituated rats and drug pre-treated rats. Rats pre-treated with d-amphetamine are given the dose 1,5 mg/kg s.c. 5 min before the behavioral session in the motility meter. Rats pre~treated with dizolcipine (Mk-801) are given the dose 0,7 mg/kg i.p. 90 min before the behavioral session in the motility meter.
In vivo test: Neurochemistry
After the behavioral activity sessions the rats were decapitated and their brains rapidly taken out and put on an ice-cold petri-dish. The limbic forebrain, the stria¬tum, the frontal cortex and the remaining hemispheral parts of each rat were dissected and frozen. Each brain part was subsequently analyzed with respect to its con¬tent of monoamines and their metabolites. The monoaminer-gic indices analyzed were dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and noradrenaline (NA). All mono-aminergic indices in the dissected tissue were analyzed
by means of HPLC with electrochemical detection as de¬scribed by Svensson K, et al. , 1986, Naunyn-Schmiedeberg's Arch Pharmacol 334: 234-245 and references cited therein.
In vivo test: Pharmacokinetics in the rat
To determine oral availability (F) and plasma half life (tl/2) of test compounds according to the invention experiments performed in the rat were undertaken. On day one rats were implanted with one catheter in the jugular vein and one catheter in the carotid artery under keta-mine anesthesia. On day three test compound is injected either orally or in the jugular vein catheter. Blood sam¬ples are collected during 8 hours from the arterial catheter. The blood samples were heparinized and centri-fuged. Plasma is collected from the centrifuged samples and frozen. The levels of test compound were subsequently determined in each sample by means of gas chromatography-mass spectrometry (Hewlett-Packard 5972MSD). The plasma samples, taken from the rats of the Sprague-Dawley strain, (0.5 ml) were diluted with water (0.5 ml), and 30 pmol (50 \il) of ( (-)-S-3-[3-Ethylsulfonylphenyl)-N-n-propyl-piperidine as internal standard was added. The pH was adjusted to 11.0 by the addition of 25 \il saturated Na2C03. After mixing, the samples were extracted with 4 ml dichloromethane by shaking for 20 min. The organic layer was, after centrifugation, transferred to a smaller tube and evaporated to dryness under a stream of nitrogen and subsequently redissolved in 40 jil toluene for GC-MS analysis. A standard curve over the range of 1-500 pmol was prepared by adding appropriate amounts of test com¬pound to blank plasma samples. GC was performed on a HP-Ultra 2 capillary column (12m x 0.2 mm ID), and 2 pi was injected in the splitless mode. The GC temperature was held at 90°C for 1 minute following injection, and was then increased by 30°C/min to the final temperature of 290°C. Each sample was run in duplicate. The lowest de-
tectable concentration of test compound was generally found to be 1 pmol/ml.
WE CLAIM:
1. A 3-substituted 4-(phenyl-N-alkyl)-piperidine compound of Formula 1:
R1 is selected from the group consisting of OSO2CF3, OSO2CH3, SOR3, SO2R3,
COCH3, COCH2CH3 and COCF3, wherein R3 is as defined below;
R2 is selected from the group consisting of C1-C4 alkyls, allyl, CH2CH2OCH3,
CH2CH2CH2F, CH2CF3, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl;
R3 is selected from the group consisting of C1-C3 alkyis, CF3 and N(CH3)2,
wherein R2 is as defined above;
or a pharmaceutically acceptable salt thereof.
2. The compound as claimed in claim 1, wherein R, is selected from the group
consisting of OSO2CF3, OSO2CH3, SO2CH3, SO2CF3, COCH3 and
S02N(CH3)2.
3. The compound as claimed in claim 1 or 2, wherein R2 is selected from the group consisting of n-propyl and ethyl.
4. The compound as claimed in any one of the claims 1 to 3, wherein Ri is SO2CH3, and R2 is n-propyl.
5. The compound as claimed in any one of the claims 1 to 4, wherein said
compound is 4-(3-methanesulfonyl-phenyl)-l-propyl-piperidine.
6. A pharmaceutical composition comprising a compound as claimed in any one
of the claims 1 to 5 and one or more pharmaceutically acceptable carriers or
diluents.
7. The pharmaceutical composition as claimed in claim 6, formulated for oral
administration.
8. The pharmaceutical composition as claimed in claim 7, formulated as a tablet.
9. The pharmaceutical composition as claimed in claim 7, formulated as a
capsule.
10. The pharmaceutical composition as claimed in claim 6, formulated for
administration by injection.
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