4-(4-Chlorophenyl)-1236-tetrahydro-1(1H-124-triazol-1-yl)butty)pyrideine and salts thereof; pharmaceutical compositions and method of treating psychoses utilizing same

Preparation of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine

A mixture of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (48.5 g, 0.21 mol), 1-(4-chlorobutyl)triazole (35 g, 0.21 mol), acid carbonate of potassium (105 g, 1.05 mol) and sodium iodide (6 g) in acetonitrile (500 ml) is heated under reflux for 24 hours. Once it is cold, water is added and the two phases are separated. The organic phase is dried with anhydrous sodium sulfate and is evaporated under reduced pressure. 54.5 g of a product are obtained which, when recrystallized in acetonitrile, yields 51 g (77%) of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine of m.p. 101-3° C.

IR (KBr, cm −1 ): 2930, 2775, 2737, 1509, 1493, 1381, 1271, 1141, 1091, 1010, 961, 847, 828, 680

1 H-NMR [300 MHz, CDCl 3 , 25° C., δ(ppm)]: 1.56 (quint, J=7.5 Hz, 2H); 1.97 (quint, J=7.5 Hz, 2H); 2.40-2.70 (a.c., 4H); 2.66 (t, J=5.7 Hz, 2H); 3.10 (d, J=3 Hz, 2H), 4.21 (t, J=7.0 Hz, 2H); 6.04 (s, 1H); 7.20-7.35 (m, 4H); 7.94 (s, 1H); 8.06 (s, 1H)

Preparation of the hydrochloride of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine

A solution of ethanol/hydrochloric acid (6.8 ml, 6 N) is added to a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine (11.5 g, 36.3 mmol) in absolute ethanol (50 ml) cooled on an ice bath. After a few minutes ethyl ether (200 ml) is added and a precipitate appears, which is filtered, washed with cold ethanol and dried, yielding 12 g (93%) of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine hydrochloride of m.p. 165-6° C.

IR (KBr, cm −1 ): 2951, 2505 (b.a.) 1502, 1494, 1275, 1136, 1098, 1013, 810, 686

1 H-NMR [300 MHz, DMSO-d 6 , 25° C., δ(ppm)]: 1.73 (m, 2H); 1.83 (m, 2H); 2.70 (m, 1H); 2.85 (m, 1H); 3.10-3.20 (a.c., 3H); 3.54 (m, 1H); 3.73 (m, 1H); 3.88 (m, 1H), 4.22 (t, J=6.6 Hz, 2H); 6.20 (s, 1H); 7.42 (AB, J=8.6 Hz, 2H); 7.49 (AB, J=8.6 Hz, 2H); 7.97 (s, 1H); 8.59 (s, 1H)

Preparation of the citrate of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine

A solution of citric acid monohydrate (33.8 g, 0.16 mol) in water (30 ml) is added to a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine (51 g, 0.16 mol) in absolute ethanol (350 ml) at 40° C. After about 20 minutes a precipitate appears, which is filtered after cooling to room temperature, washed with cold ethanol and dried, yielding 68.9 g (84%) of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine citrate of m.p. 133-4° C.

IR (KBr, cm −1 ): 3384 (b.a.), 3200-2200 (b.a.) 1726, 1702, 1594, 1432, 1221, 1131, 802

1 H-NMR [300 MHz, DMSO-d 6 , 25° C., δ(ppm)]: 1.54 (m, 2H); 1.83 (m, 2H); 2.54 (AB, J=15 Hz, 2H); 2.63 (AB, J=15 Hz, 2H); 2.82 (m, 2H); 3.03 (m, 2H); 3.20-3.50 (a.c., 4H); 4.21 (t, J=6.8 Hz, 2H); 6.20 (s, 1H); 7.40 (AB, J=8.8 Hz, 2H); 7.48 (AB, J=8.8 Hz, 2H); 7.97 (s, 1H); 8.52 (s, 1H)

Preparation of the fumarate of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1-1,2,4-triazol-1-yl)butyl]pyridine

A solution of fumaric acid (0.464 g, 4 mmol) in absolute ethanol (10 ml) is added to a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine (1.26 g, 4 mmol) in isopropanol (12 ml) at 40° C. After about 20 minutes a precipitate appears, which is filtered after cooling to room temperature, washed with cold ethanol and dried, yielding 1.65 g (93%) of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine fumarate of m.p. 156-9° C.

IR (KBr, cm −1 ): 2940 (b.a.), 2418, 1697, 1508, 1496, 1272, 1162, 678

1 H-NMR [300 MHz, DMSO-d 6 /TFA, 25° C., δ(ppm)]: 1.65 (m, 2H); 1.82 (m, 2H); 2.74 (m, 2H); 3.18 (m, 3H); 3.61-3.76 (a.c, 2H); 3.95 (m, 1H); 4.26 (t, J=6.6 Hz, 2H); 6.21 (s, 1H); 6.61 (s, 2H) ; 7.50 (AB, J=8.5 Hz, 2H); 7.43 (AB, J=8.5 Hz, 2H); 8.18 (s, 1H); 8.78 (s, 1H)

Preparation of the sulfate of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine

A solution of 96% sulfuric acid (0.196 g) in isopropanol (2 ml) is added to a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine (0.63 g, 2 mmol) in isopropanol (6 ml) cooled on an ice bath. After a few minutes a precipitate appears, which is filtered, washed with cold ethanol and dried, yielding 0.74 g (90%) of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine sulfate of m.p. 164-6° C.

IR (KBr, cm −1 ): 2958 (b.a.), 2570 (b.a.), 1536, 1492, 1430, 1112, 983, 803, 617

1 H-NMR [300 MHz, DMSO-d 6 /TFA, 25° C., δ(ppm)]: 1.66 (m, 2H); 1.85 (m, 2H); 2.74 (m, 2H); 3.19 (m, 3H); 3.61-3.76 (a.c., 2H); 3.98 (m, 1H); 4.28 (t, J=6.6 Hz, 2H); 6.21 (s, 1H); 7.50 (AB, J=8.6 Hz, 2H); 7.43 (AB, J=8.6 Hz, 2H); 8.26 (s, 1H); 8.89 (s, 1H)

Preparation of the phosphate of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine

A solution of 85% phosphoric acid (0.225 g, 2 mmol) in isopropanol (1 ml) is added to a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine (0.63 g, 2 mmol) in isopropanol (6 ml) cooled on an ice bath. After a few minutes a precipitate appears, which is filtered, washed with cold ethanol and dried, yielding 0.77 g (93%) of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine phosphate of m.p. 146-8° C.

IR (KBr, cm −1 ): 3422 (b.a.), 1508, 1492, 1274, 1094, 1059, 1011, 943, 808

1 H-NMR [300 MHz, DMSO-d 6 /TFA, 25° C., δ(ppm)]: 1.65 (m, 2H); 1.84 (m, 2H); 2.74 (m, 2H); 3.18 (m, 3H); 3.61-3.78 (a.c., 2H); 3.96 (m, 1H); 4.25 (t, J=6.6 Hz, 2H); 6.22 (s, 1H); 7.51 (AB, J=8.6 Hz, 2H); 7.43 (AB, J=8.6 Hz, 2H); 8.08 (s, 1H); 8.66 (s, 1H)

Preparation of the methanesulfonate of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine

A solution of methanesulfonic acid (0.63 g, 2 mmol) in acetone (1 ml) is added to a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine (0.63 g, 2 mmol) in acetone (5 ml) at 40° C. After about 20 minutes a precipitate appears, which is filtered after cooling to room temperature, washed with cold ethanol and dried, yielding 0.66 g (80%) of 4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-[4-(1H-1,2,4-triazol-1-yl)butyl]pyridine methanesulfonate of m.p. 130-2° C.

IR (KBr, cm −1 ): 3432 (b.a.), 2934 (b.a.), 2584, 1508, 1494, 1239, 1194, 1058, 784

1 H-NMR [300 MHz, DMSO-d 6 /TFA, 25° C., δ(ppm)]: 1.65 (m, 2H); 1.83 (m, 2H); 2.39 (s, 3H); 2.74 (m, 2H); 3.19 (m, 3H); 3.61-3.78 (a.c., 2H); 3.98 (m, 1H); 4.27 (t, J=6.6 Hz, 2H); 6.21 (s, 1H); 7.50 (AB, J=8.5 Hz, 2H); 7.43 (AB, J=8.5 Hz, 2H); 8.21 (s, 1H); 8.83 (s, 1H)

Pharmacological investigation of the antipsychotics comprises a wide range of tests with the aim of establishing both the antipsychotic activity in its aspects of efficacy against the stated positive symptoms and negative manifestations of schizophrenia, and the capacity to induce undesirable extrapyramidal effects. Within this range of tests, two of them stand out as most used in the evaluation of antipsychotics: antagonism of the climbing activity induced by apomorphine and the induction of catalepsy. Activity against the negative manifestations is identified by demonstrating activation of brain areas involved in cognitive processes, such as the medial area of the prefrontal cortex.

Antagonism of the climbing activity induced by apomorphine in the mouse [T. G. Heffner et al., J. Pharmacol. Exp. Ther., 1989, 251, 105] is one of the tests that most clearly define antipsychotic activity, both of the typical antipsychotics and of the atypical antipsychotics.

The induction of catalepsy in rats [J. Robert et al., J. Pharmacol. Exp. Ther., 1986, 239, 124] is a parameter that is commonly employed for determining the ability of antipsychotics to induce extrapyramidal effects. The typical antipsychotics are those which, in spite of being very powerful in specific tests of antipsychotic activity, induce extrapyramidal effects, and this is detected in the catalepsy test. The best known of the typical antipsychotics is haloperidol, whereas the best known of the atypical antipsychotics is clozapine.

The compound of Example 2 demonstrated an antipsychotic activity similar to that of clozapine (DE-50=14 mg/kg, i.p.) with complete absence of cataleptic effects at doses up to 80 mg/kg, s.c. This contrasts with the results for haloperidol, which although possessing good antipsychotic activity (DE-50=0.13 mg/kg, i.p.), has very high cataleptic activity, of the same order as the antipsychotic (DE-50=0.14 mg/kg, s.c.).

Therefore the advantage of the compound of Example 2 relative to the typical antipsychotics, such as haloperidol, is that as well as notable antipsychotic activity it does not induce catalepsy, which indicates absence of extrapyramidal effects. Comparing it with clozapine, an atypical antipsychotic that is of limited use owing to possible induction of agranulocytosis, we see that the compound of Example 2 has the same profile of antipsychotic activity, both of potency an d of absence of induction of extrapyramidal effects.

Induction of the Protein c-fos in Various Brain Areas in the Rat

The results of this study confirm the antipsychotic activity and the absence of extrapyramidal effects of the compound of Example 2. In addition they indicate its activity against the negative symptom of schizophrenia, demonstrating both antipsychotic potency and potency against the negative symptoms, greater than clozapine.

Acute treatment with various antipsychotics is characterized by the induction of the protein c-fos, owing to the rapid induction off the c-fos gene in various areas of the limbic and extrapyramidal systems [M. Dragunow et al., Neuroscience, 1990, 37, 287-294; J. C. Miller, J. Neurochem., 1990, 54, 1453-1455; A. Y. Deutch et al., Mol. Cell. Neurosci., 1992, 3, 332-341; T. V. Nguyen et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 4270-4274; G. S. Robertson and H. C. Fibinger, Neuroscience, 1992, 46, 315-328]. The patterns of induction of the protein depend on whether the antipsychotic is typical or atypical [G. S. Robertson et al., J. Pharmacol. Exp. Ther., 1994, 271, 1058-1066; G. S. Robertson and H. C. Fibinger, Neuroscience, 1992, 46, 315-328]. These changes in expression of c-fos can be investigated by extraction of the proteins from the brain areas of interest, and analysis of the levels by electrophoresis (Western blot).

Acute treatment with the compound of Example 2, at a dose of just 20 mg/kg s.c., induced a significant increase in the levels of Fos in the nucleus accumbens and in the medial area of the prefrontal cortex (118% and 134% of the group injected with saline, respectively). On the other hand the levels of Fos did not change significantly in the dorsolateral groove on administering the compound of Example 2 (104% of the saline group).

The administration of clozapine exhibited some similar effects, both in the prefrontal cortex (134%) and in the nucleus accumbens and in the dorsolateral groove (118% and 110%), but we must emphasize that a much higher dose was determined for it (30 mg/kg, s.c.).

Control of immunoreactivity of the Fos protein by acute treatment

The nucleus accumbens is the only brain region in which the expression of c-fos increases after administration of any of the known antipsychotics, suggesting that it might be a critical site for antipsychotic activity.

On the other hand, only the administration of few atypical antipsychotics induces an increase in the number of immunoreactive cells of the Fos type, in the medial zone of the prefrontal cortex. It has been suggested that hypofrontality is associated with the negative symptoms of schizophrenia [K. F. Berman et al., Arch. Gen. Psychiatry, 1986, 43, 126-135; D. R. Weinberger, Trends Neurosci., 1988, 8, 367-370], hence the antipsychotics capable of increasing expression of c-fos in this brain area will be active in the treatment of the negative signs.

Both effects are observed both with clozapine and with the compound of Example 2, but at different doses (30 and 20 mg/kg, s.c., respectively), thus demonstrating that the compound of Example 2 is more powerful than clozapine in both effects, both in relation to antipsychotic activity and in relation to activity against the negative symptoms of schizophrenia

On the other hand, the compound of Example 2 does not induce any significant change in levels of Fos in the dorsolateral groove, which is an indication that it is without extrapyramidal side effects, at the same dose that it displays antipsychotic effects and moreover with possible efficacy against the negative symptoms of schizophrenia.

In human therapy, the dose of administration of the compounds of the present invention is a function of the severity of the disorder to be treated. Normally it will be between 1 and 100 mg/day. The compounds of the invention, with a suitable pharmaceutical formulation, will be administered by various routes such as oral, transdermal, parenteral, subcutaneous, intranasal, intramuscular or intravenous. As an example, the following is the pharmaceutical composition of a tablet containing a product of the invention.