KR20000005412A - Piperazine and piperidine compounds - Google Patents

Abstract

PURPOSE: Piperazine and piperidine compounds and a preparation method thereof are provided, which compounds show high affinity for both the dopamine D2 and serotonin 5-HT1A receptors CONSTITUTION: The compounds are represented by the formula a, wherein A is a heterocyclic group of 5-7 ring atoms which contains 1-3 heteroatoms from the group O, N and S; R1 is a hydrogen or fluorine atom; R2 is an alkyl group of C1-C4, an alkoxy group of C1-C4 or an oxo group; p is 0, 1 or 2; Z is a carbon or nitrogen atom; the dotted line is a single bond when Z is nitrogen, and a single or double bond when Z is carbon; R3 and R4 independently are a hydrogen atom or an alkyl group of C1-C4; n is 1 or 2; R5 is a halogen atom, a hydroxy group, an alkoxy group of C1-C4 or an alkyl group of C1-C4; q is 0, 1, 2 or 3; Y is a phenyl, furanyl or thienyl group which can be substituted with 1-3 substituents from the group consisting of a hydroxy group, a halogen atom, an alkoxy group of C1-C4, an alkyl group of C1-C4l, a cyano group, an aminocarbonyl group, and a mono- or di-alkylaminocarbonyl group of C1-C4.

Description

Piperazine and Piperidine Compounds

The present invention relates to a group of novel piperazine and piperidine compounds with interesting pharmacological properties.

It has been found that the compounds of formula a and salts thereof have interesting pharmacological properties.

In the above formula,

A is a 5-7 membered heterocyclic group having 1 to 3 heteroatoms from the O, N and S groups,

R ₁ is hydrogen or fluoro,

R ₂ is C _1-4 -alkyl, C _1-4 -alkoxy or oxo group,

p is 0, 1 or 2,

Z is carbon or nitrogen,

The dashed line is a single bond when Z is nitrogen, a single bond or a double bond when Z is carbon,

R ₃ and R ₄ are independently hydrogen or C _1-4 -alkyl,

n is 1 or 2,

R ₅ is halogen, hydroxy, C _1-4 -alkoxy or C _1-4 -alkyl,

q is 0, 1, 2 or 3,

Y is 1 to 3 substituents from hydroxy, halogen, C _1-4 -alkoxy, C _1-4 -alkyl, cyano, aminocarbonyl, mono- or di-C _1-4 -alkylaminocarbonyl group Phenyl, furanyl or thienyl which may be substituted by.

Preferred compounds according to the invention are those in which A is a group of the formulas b to m together with a phenyl group, wherein R ₁ , (R ₂ ) p, R ₃ , R ₄ , (R ₅ ) q ', Y and Z are as defined above. And a compound of formula a wherein n is 1 and salts thereof.

A is a group of formula (b) or a hetero ring with a phenyl group or a group of formula (l) substituted by an oxo group, Y is phenyl which may be substituted as mentioned above, n is 1, R ₃ and R ₄ are hydrogen, and R ₅ is hydroxy, methoxy or halogen, q is 0 or 1, are particularly preferred compounds and their salts of the formula Z a is nitrogen.

Particular preference is given to compounds of the formula a in which A is a group of formula l in which a heterocyclic ring is substituted with an oxo group together with a phenyl group, q is 0 and Y is phenyl, and salts thereof.

It is known from EP 0650964 that compounds of the following formula, in which phenyl groups and / or heterocyclic groups and / or piperazine groups, can be substituted, act on the central nervous system by binding to the 5-HT receptor.

In the above formula,

R ₀ is C _1-4 -alkyl.

In particular, these compounds bind to the subtypes of 5-HT-receptors, namely 5-HT _1A and 5-HT _1D receptors.

Surprisingly, it was found that the compounds according to the invention have high affinity for both dopamine D ₂ and serotonin 5-HT _1A receptors (pKi 7.0 to 9.5 for both receptor types). This combination is useful for the treatment of schizophrenia and other mental disorders, and allows more complete treatment of all disease symptoms (eg positive symptoms, negative symptoms and cognitive deficits).

Compounds exhibit a variety of activities as agonists or antagonists that are partial to dopamine D _2- , D ₃ -and D ₄ -receptors. Some compounds exhibit agonist-like effects on dopamine receptors, which strongly antagonize apomorphine-induced climbing behavior in mice (less than an ED ₅₀ value of 1 mg / kg, oral administration). Compounds exhibit various activities as 5-HT _1A receptor agonists and lead to different intensities in terms of serotonin behavioral symptoms.

Compounds may be used in clinically related antipsychotics (e.g. conditional avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31: 61-67), antidepressants (e.g. parallax enhancement of low rat response; van Hest et al., Psychopharmacology, 1992, 107; 474-479) and in therapeutic models susceptible to anxiolytics (e.g. stress-induced vocal suppression; van der Poel et al., Psychopharmacology, 1989, 97: 147-148). Active.

In contrast to clinically involved dopamine D ₂ receptor antagonists, the compounds described have a lower propensity to induce ankylosing in rodents and likewise less induction of side effects than the existing antipsychotics.

The 5-HT _1A receptor antagonism inherent in these compounds may be due to the lowered propensity to effect effects extrapyramidal and the therapeutic effects observed in behavioral models that are sensitive to antidepressants or anxiolytics.

The compound may be used for central nervous system effects or diseases caused by disorders in the dopamine functional or serotonin functional systems, such as Parkinson's disease, aggressiveness, anxiety disease, autism, dizziness, depression, cognitive or memory deficiency and especially schizophrenia and It may be useful for the treatment of other mental disorders.

Suitable acids that can form pharmaceutically acceptable acid addition salts with the compound include, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and organic acids, such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p- Toluene sulfonic acid, methanesulfonic acid and natralene-sulfonic acid.

The compounds of the present invention can be formulated in dosage forms in a useful manner using auxiliary materials such as liquid and solid carrier materials.

The compounds of the present invention can be obtained according to the methods A to E described below. Piperazine, homopiperazine and piperidine used in the process are compounds of Formulas I-H to XIX-H, wherein Formulas I-XIX are as follows.

The synthesis of piperidine XVIII-H and XIX-H used in the preparation of the compounds of the invention is similar to the method described in WO 94-GB 1507.

The synthesis of piperazine used in the preparation of the compounds of the invention is described in EP0189612, except for XI-H, XIII-H and XV-H (see below).

Homopiperazine XI-H and piperazine XIII-H and XV-H are novel and their preparation is shown below (Scheme A.i-A.iii).

XI-H Manufacturing:

Manufacture XIII-H:

Steps 1-3 (Scheme A.ii):

7-nitro-indoles are described in S. M. Parmerter et al., J. Am. Chem. Soc. 80, (1958), 4621-2, and steps 1, 2 and 3 perform similarly to the synthesis described in EP 0650964.

XV-H manufacture:

Steps 1 to 3 of Scheme A.i and step 1 of Scheme A.iii are described in detail in the Examples, and the methods of steps 2 and 3 of Scheme A.iii are similar to those described in EP0189612.

The H-atoms of the N-H residues of compounds I-H to XIX-H can be replaced with group Q by five different chemical pathways (A, B, C, D and E, see below) to prepare compounds of the invention. Q1 to Q34 are as follows.

Synthetic Path A

Compounds A1-A14 and A16-A28 are prepared according to the synthetic methods shown in Scheme A1 (see below). Compounds of formula QX in acetonitrile with Et (i-Pr) ₂ N serving piperazine (IH-VI-H and VIII-H-XVII-H) as bases, wherein X is Cl, Br, OMs ) And in some cases add KI. Et ₃ N may be used in place of Et (i-Pr) ₂ N.

The following synthetic routes B to E are not limited to the production of piperazine, and can be used for the production of piperidine.

Synthetic Path B

Compounds can also be prepared according to the synthetic methods shown in Scheme B1 (see below). Piperazine I-H is reacted with 2-phenyl-phenol and formaldehyde in EtOH.

Synthetic Path C

Compounds C1-C4 are prepared according to the synthetic methods shown in Scheme C1 (see below). Phenylpiperazine is reacted with some meta-substituted phenyl-benzoic acid chlorides to yield the corresponding amides. The amide is reduced to compounds C1-C4 using LiAlH ₄ .

Compounds C2 and C3 are prepared as shown in Scheme C2.

Composite path D

Compounds D1-D18 and D21-D23 are prepared according to the synthetic methods shown in Scheme D1 (see below). Arylboronic acid is reacted with aromatic bromide in the presence of a catalytic amount of Pd (PPh ₃ ) ₄ under basic conditions. The so-called "Suzuki" reaction yields CC coupled final product D.

Compounds D19 and D20 are prepared according to the modified synthetic method shown in Scheme D2.

After carrying out the Suzuki reaction mentioned above, the protective benzyl group is removed by standard hydrolysis steps (e.g. hot concentrated HCl) by a further hydrolysis step (Method E2 (Scheme E2)).

Synthetic Path E

Compounds E2 and E3 are prepared according to the synthetic methods shown in Scheme E1. Although the intermediates are different, the same Suzuki reaction is applied as described in synthetic route D.

Compound E1 is prepared according to the modified synthetic method shown in Scheme E2. A further step to the synthesis method shown in Scheme E1 is the hydrolysis of the protective benzyl group.

The preparation of the compounds of formula a and a number of intermediate compounds thereof will be described in detail in the following examples.

Example 1

Method A1 (Scheme A1):

1.0 g (4.3 mmol) of piperazine III-H and 1.2 g (4.7 mmol) of Q1-Br are added to 20 ml of CH ₃ CN, and 0.52 g (5.1 mmol) of Et ₃ N and a small amount of KI are added. The reaction mixture is stirred and refluxed for 16 h under a nitrogen atmosphere. After cooling the mixture, the solvent is removed in vacuo and the obtained residue is dissolved in CH ₂ Cl ₂ and washed with 0.5N NaOH and brine (twice). The organic fractions are dried over MgSO ₄ . After removing the desiccant, the solvent is removed in vacuo to give a residue. Flash column chromatography (SiO ₂ , eluent: CH ₂ Cl ₂ / MeOH 99/1) affords compound A11 (free base, see Table A1). The residue is dissolved in ether and 1 equivalent of 1N HCl / EtOH is added. Precipitation gave 0.98 g (2.3 mmol, 53%) of pure A11.HCl. Melting point: 228 to 230 ° C. ¹ H-NMR (CDCl _3, δ): 2.18 (m, 2H), 3.09 (broad, 2H), 3.3-3.7 (broad cluster, 6H), 4.21 (m, 4H), 4.30 (s, 2H), 6.59 (dd, J = 1 and 8 Hz, 1H), 6.71 (dd, J = 1 and 8 Hz, 1H), 6.82 (t, J = 8 Hz, 1H), 7.37 (m, 1H), 7.47 (m, 2H), 7.53 (t, J = 8 Hz, 1H), 7.62-7.74 (cluster, 4H), 7.90 (t, J = 2 Hz, 1H), 12.9 (braod, 1H).

According to the synthetic method described above, compounds A1-A14 and A16-A28 are prepared by similar routes (see Table A1). Compound A15 is prepared from compound A14 by reducing with LiAlH ₄ / THF similarly to method A5 (see below, the reduction of A14 is performed at reflux instead of room temperature).

Intermediates Used for Path A

Intermediate Q-X:

Q2-OH, Q3-OH and Q5-OH to Q9-OH: Example (Q2-OH), see Scheme A2:

Arylboronic acid is reacted with aromatic bromide in the presence of a catalytic amount of Pd (PPh ₃ ) ₄ under basic conditions. The so-called "Suzuki" reaction yields CC coupled intermediate Q-OH. The applied boronic acid is readily available through the corresponding bromide (D. Janietz et al., Synthesis, (1993), 33 and references cited therein).

Method A2 (Scheme A2):

10 ml of dimethoxy-ethane is refluxed under a nitrogen atmosphere and the solvent is cooled. 0.85 ml (1.43 g, 8.8 mmol) of 2-bromo-thiophene is added and nitrogen is bubbled through the solution for 10 minutes. 0.4 g (0.35 mmol, 0.04 equiv) of Pd (PPh ₃ ) ₄ is added to the solution. After stirring for 10 minutes, 1.25 g (8.2 mmol) of 3- (hydroxymethyl) -phenylboronic acid dissolved in 8.5 ml of 2N Na ₂ CO ₃ / H ₂ O and about 2 ml of EtOH are added to the reaction mixture. The reaction mixture is heated, refluxed for 4 hours and then the heating is stopped and the reaction stirred for 16 hours at room temperature. The precipitate formed is filtered through celite and the filtrate is washed with EtOAc / H ₂ O. The filtrate is extracted with EtOAc and the combined organic fractions are dried over MgSO ₄ . After removing the desiccant the filtrate is obtained and the solvent is evaporated to give 2.1 g of oil. Flash chromatography (SiO _2, eluent: methyl tert-butyl-ether / hexane 1/1) yields 0.85 g (4.5 mmol, 51%) of the desired product Q2-OH.

In a similar manner, the following meta-substituted benzyl alcohol Q-OH is prepared by combining the aromatic bromide and boronic acid given in Table A2.

All Q-OH mentioned in Table A2 are converted to the corresponding mesylate via standard processes (e.g., MsCl and Et ₃ N in EtOAc). However, for Q8-OH and Q9-OH, the corresponding mesylate is not obtained, but due to workup with 2N HCl the corresponding chlorides Q8-Cl and Q9-Cl are obtained. Q8-Cl and Q9-Cl are excellent alkylating agents in the reaction shown in Scheme A1.

Intermediate Q1-Br (see Scheme A3):

Meta-phenyl-toluene (S ₁ = H) is brominated under the action of N-bromosuccinimide (NBS) in the presence of a catalytic amount of dibenzoylperoxide.

Method A3 (Scheme A3)

Q1-Br: 3 g (29.8 mmol) 3-phenyl-toluene and 5.3 g (29.8 mmol) N-bromo-succinimide (NBS) are dissolved in 30 ml CCl ₄ . A small amount of dibenzoylperoxide is added and the reaction mixture is refluxed for 10 hours. During this time additional small amounts of dibenzoylperoxide are added. After cooling, the reaction mixture is diluted with CCl ₄ and water. The above system is made alkaline with 2N NaOH and stirred. The organic layer is washed with 1N NaOH and water and dried over MgSO ₄ . After removing the desiccant, the solvent is removed in vacuo to yield 8.0 g of residue. The residue is purified by column chromatography (SiO ₂ , eluent: Et ₂ O / petroleum ether 1/9) to give 5.3 g (21.5 mmol, 72%) of pure intermediate Q1-Br.

For Q10-Br, the desired 2-fluoro-5-phenyl-toluene (S ₁ = F) was obtained from phenylboronic acid and 2-fluoro-5-bromo-toluene according to the Suzuki method, similar to Method A2. (See Scheme A3).

Q4:

Example (Q4-OH) (see Scheme A4):

Under the action of MeI / KOtBu 3-phenyl-4-hydroxy-benzoic acid (see the method of US Pat. No. 4873367) was dimethylated to give the corresponding methoxy-benzoic acid methyl ester, which was then reduced (LiAlH ₄ ) to Q4-. OH is obtained.

Method A4 (Scheme A4):

Step 1: Dissolve 4.0 g (19 mmol) of 3-phenyl-4-hydroxy-benzoic acid in 70 ml of DMF, add 4.6 g (41 mmol) of KOtBu and stir the mixture for 30 minutes. Then 3.0 g (21 mmol) of MeI are added and the reaction mixture is stirred for 14 hours at room temperature, during which one additional equivalent of MeI is added. The solvent is removed in vacuo to afford a residue, which is dissolved in EtOAc. The solution is shaken with 2N NaOH. The organic fraction is dried over Na ₂ S0 ₄ . After removing the desiccant and solvent, 3.65 g (16.0 mmol, 84%) of 3-phenyl-4-methoxy-benzoic acid methyl ester is obtained which is quite pure. This batch is used without further purification for the reduction described in Method A5.

Method A5 (Scheme A4):

Step 2: Add 0.68 g (18 mmol) of LiAlH ₄ to 20 ml of dry THF and stir under nitrogen atmosphere. 3.65 g (16.0 mmol) of 3-phenyl-4-methoxybenzoic acid methyl ester dissolved in 60 ml of dry THF are added dropwise to the LiAlH ₄ / THF mixture. Stir at room temperature for 1 hour. The reaction mixture is cooled (ice / water) and 0.7 ml of water and 1.4 ml of 2N NaOH mixed with THF are added. The mixture is refluxed for 10 minutes and filtered to remove salts. The salt is washed with hot THF and the wash is combined with the filtrate. The solvent is removed in vacuo to yield 3.1 g (14.5 mmol, 90%) of fairly pure Q4-OH. This batch is used without further purification to prepare mesylate Q4-OMs and in the method shown in Scheme A1 to afford compound A8.

Example 2

Method B1 (Scheme B1):

3.74 g (17.0 mmol) of piperazine IH and 3.0 g (17.0 mmol) of 2-phenyl-phenol are dissolved in 80 ml of anhydrous EtOH. While stirring the solution, 2.0 ml (24.0 mmol) of 37% CH ₂ O / H ₂ O was added and stirring continued for 48 hours. The reaction mixture is then concentrated in vacuo to afford a residue, which is subjected to flash column chromatography (SiO ₂ , eluent: CH ₂ Cl ₂ / petroleum ether 1/1). The unreacted 2-phenyl-phenol portion was separated and the eluent was changed from 100% CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 99/1 to give 1.70 g (4.2 mmol, 25%) of compound B1 as the free base. To obtain. Melting point: 174 to 175 ° C. ¹ H-NMR (CDCl ₃ , δ): 2.65 (cluster, 8H), 3.83 (s, 2H), 4.27 (m, 4H), 6.48 (dd, J = 1.5 and J = 8 Hz, 1H), 6.59 (dd , J = 1.5 and J = 8 Hz, 1H), 6.76 (t, J = 8 Hz, 1H), 6.87 (t, J = 8 Hz, 1H), 7.05 (dd, J = 1.5 and J = 8 Hz, 1H), 7.28 (dd, J = 1.5 and J = 8 Hz, 1H), 7.32 (m, 1H), 7.42 (t, J = 8 Hz, 2H), 7.61 (m, 2H), 11.4 (broad s, 1H).

Compound number Piperazine Q salt Melting point ℃ B1 I 11 base 174 to 175

Example 3

Method C1 (Scheme C1):

Step 1: 0.8 g (3.4 mmol) of 3- (3-methoxy-phenyl) benzoic acid are dissolved in 15 ml of anhydrous THF and 0.65 ml of Et ₃ N under a nitrogen atmosphere. The solution is cooled to 0 ° C. and 0.42 ml of i-ButO (CO) Cl is added with stirring. After 30 minutes, 0.71 g (3.2 mmol) of IH dissolved in 5 ml of dry THF is added to the solution. The reaction mixture is warmed to rt and stirred for 16 h. The reaction mixture is then treated with 2N NaOH and the biphasic system is extracted with EtOAc. The organic fraction is dried over magnesium sulfate. After the desiccant is removed and the solvent is removed in vacuo, the residue is obtained and subjected to column chromatography (SiO ₂ , eluent: EtOAc / petroleum ether 1/1). Yield: 0.75 g (1.7 mmol, 52%) of corresponding amide.

Step 2: 0.9 g of LiAlH ₄ is suspended in 20 ml of dry THF, the suspension is brought to reflux temperature and 0.7 g (1.6 mmol) of amide (product of step 1) dissolved in 15 ml of dry THF is added to the suspension. Reflux for 15 minutes and the reaction mixture is cooled (ice / water) and 0.9 g of water is added very carefully dropwise. 1.8 ml 2N NaOH and 0.9 g of water are added and the mixture is brought back to reflux for 20 minutes. Cool to room temperature, filter to give a residue, wash with EtOAc. The combined filtrates and washes are dried over magnesium sulfate. The desiccant is removed and the solvent is removed in vacuo to give a residue which is subjected to column chromatography (SiO ₂ , eluent: EtOAc). Yield: 0.57 g (1.4 mmol, 85%) of pure free base C1. It is dissolved in EtOAc and converted to its HCl salt by addition of 1 equivalent of 1N HCl / MeOH. Yield: 0.50 g of pure C1.HCl. Melting point: 165 to 167 ° C (decomposition). ¹ H-NMR (CDCl ₃ , δ): 3.24 (broad, 2H), 3.42-3.58 (cluster, 4H), 3.64-3.84 (broad, 2H), 3.90 (s, 3H), 4.26 (m, 4H), 4.30 (s, 2H), 6.67 (broad d, J = 8Hz, 2H), 6.79 (t, J = 8Hz, 1H), 6.93 (m, 1H), 7.23 (m, 2H), 7.38 (t, J = 8 Hz, 1H), 7.52 (t, J = 8 Hz, 1H), 7.65 (broad d, J = 8 Hz, 1H), 7.69 (broad d, J = 8 Hz, 1H), 7.92 (broad s, 1H), 13.2 ( broad, 1H).

Method C2 (Scheme C2):

Steps 1 and 2: These reactions are similar to steps 1 and 2 of scheme C1 (Scheme C1).

Step 3: 1.1 g (2.4 mmol) of acetic acid ester are suspended in 150 ml of EtOH and 15 ml of water and 1.5 g (37.5 mmol) of NaOH are added. The reaction mixture is stirred for 16 hours and EtOH is removed under vacuum. The remaining fractions are treated with saturated NH ₄ Cl solution and extracted with CH ₂ Cl ₂ . The combined organic fractions are washed with saturated NaHCO ₃ solution and dried over magnesium sulfate. After the desiccant is removed and the solvent is removed in vacuo, 0.97 g (2.3 mmol, 97%) of residue containing the corresponding pure phenol derivative is obtained.

Step 4: 0.98 g (2.3 mmol) of phenol derivative (obtained in step 3) are dissolved in 15 ml of acetone and 1.5 g of K ₂ CO ₃ is added. While stirring, 0.3 ml of (CH ₃ ) ₂ SO ₄ is added and the reaction mixture is refluxed for 2 hours. After the reaction mixture is brought to room temperature, the solvent is removed in vacuo. 30 ml of water is added to the remaining fractions and the mixture is boiled for 45 minutes. After cooling the mixture, it is extracted with CH ₂ Cl ₂ and the organic fractions are dried over magnesium sulfate. After the desiccant is removed and the solvent is removed in vacuo, 0.95 g (2.2 mmol, 96%) of the corresponding pure O-methylated phenolic derivative is obtained.

The synthesis of compound C4 is similar to that described for C2.

Table C summarizes the compounds.

Compound number Piperazine Q salt Melting point ℃ C1 I 6 HCl 165 to 167 (decomposition) C2 I 12 base 197 to 198 C3 I 4 HCl Greater than 148 (decomposition) C4 XIV 12 HCl 255 to 257

Intermediates Used for Path C

3- (3-methoxy-phenyl) -benzoic acid (Scheme C3) is described in W. G. Dauben et al., J. Am. Chem. Soc., 75, (1953), 4969-73. 3-Phenyl-4-acetoxy-benzoic acid (Scheme C3) is prepared from 3-phenyl-4-hydroxy-benzoic acid according to standard methods (Scheme C3). The synthesis of 3-phenyl-4-hydroxy-benzoic acid is described in US Pat. No. 4873367.

Example 4

Method D1 (Scheme D1):

0.4 g (2.8 mmol) of 4-bromo-phenol is dissolved in 5 ml of toluene under a nitrogen atmosphere. To the solution was added 97.5 mg (0.084 mmol, 0.03 equivalent) of Pd (PPh ₃ ) _4, 2.8 ml of 2N Na ₂ CO ₃ and 1.0 g (2.8 mmol) of boronic acid d1 (S ₅ = H) dissolved in 5 ml of hot ethanol. . The resulting mixture is stirred vigorously at 90 ° C. for 4 hours. The reaction mixture is brought to room temperature and then diluted with EtOAc and a small amount of water. Extract with EtOAc, combine the combined organic fractions with brine and dry over magnesium sulfate. The desiccant is removed and the solvent is removed in vacuo, then 1.52 g of residue are obtained and subjected to column chromatography (SiO ₂ , eluent: EtOAc / petroleum ether 1/1). Yield: 0.53 g (1.3 mmol, 47%) of pure free base D22. The free base is converted from its dihydrochloride salt (crystallized from EtOAc / ether). Yield: D22.HCl. Melting point: 222 to 227 ° C. ¹ H-NMR (d ₆ -DMSO / CDCl ₃ 4/1, δ): 3.14-3.30 (broad cluster, 4H), 3.34-3.56 (broad cluster, 4H), 4.23 (m, 4H), 4.42 (d, J = 4 Hz, 2H), 6.46-6.58 (cluster, 2H), 6.73 (t, J = 8 Hz, 1H), 6.89 (m, 2H), 7.47 (t, J = 7 Hz, 1H), 7.52-7.66 (cluster , 4H), 7.99 (t, J = 1 Hz, 1H), 9.40 (broad, OHN ⁺ HH ₂ O), 11.5 (broad, 1H).

According to the synthetic method given above, the following compounds are prepared.

Intermediates Used for Path D

Bromides used in Schemes D1 and D2 are readily obtained or commercially available by standard methods. Boronic acids applied to Schemes D1 and D2 are readily available through the corresponding bromide (Scheme D3) (D. Janietz et al., Synthesis, (1993), 33, and references thereof).

The bromide used (S ₅ = H, OCH ₂ Ph, Scheme D3) is synthesized similarly to the method described in Method E3 (Scheme E3).

Example 5

Method E1 (Scheme E1):

5.1 g (12.0 mmol) of 1-[(2-methoxy-5-bromo-phenyl) methyl] -4- (2,3-dihydro-1,4-benzodioxin-5-yl) piperazine It is dissolved in 20 ml of toluene and 12 ml of 2N Na ₂ CO ₃ / H ₂ O and 0.45 g (0.39 mmol, 0.03 equiv) of Pd (PPh ₃ ) ₄ are added. 1.46 g (12.0 mmol) of phenyl-boronic acid dissolved in 3 ml of hot EtOH are added to the solution. The reaction mixture is stirred vigorously at a temperature of 85 ° C. After 4 hours, the ideal reaction mixture is brought to room temperature and the organic (toluene) fraction is separated. The aqueous layer is extracted with EtOAc. The combined toluene- and EtOAc fractions are washed with water and brine respectively and the organic fractions are dried over sodium sulfate. The desiccant is removed and the solvent is removed in vacuo, then the residue is obtained and subjected to column chromatography (SiO ₂ , eluent: EtOAc / petroleum ether 1/2). The separated pure free base of E2 is dissolved in EtOAc / EtOH 1/1 and the solution is treated with 1 equivalent of 1N HCl / EtOH. Yield: 1.43 g (3.2 mmol, 26%) E2.HCl. Melting point: 240 to 242 ° C. (decomposition). ¹ H-NMR (d 6 -DMSO / CDCl ₃ 4/1, δ): 3.1-3.3 (cluster, 4H), 3.48 (cluster, 4H), 3.93 (s, 3H), 4.23 (m, 4H), 4.41 ( d, J = 5 Hz, 2H), 6.48 (dd, J = 1 Hz, J = 8 Hz, 1H), 6.55 (dd, J = 1 Hz, J = 8 Hz, 1H), 6.73 (t, J = 8 Hz, 1H), 7.20 (d, J = 9Hz, 1H), 7.32 (m, 1H), 7.40 (t, J = 8Hz, 2H), 7.71 (m, 2H), 7.75 (dd, J = 2Hz, J = 9Hz, 1H) , 8.04 (d, J = 2 Hz, 1 H), 11.1 (broad, 1 H).

Method E2 (Scheme E2):

3.0 g (5.9 mmol) of O-benzyl protected compound E1 are dissolved in 35 ml of concentrated HCl and the mixture is stirred and brought to reflux temperature. After 45 minutes, an additional 30 ml of concentrated HCl is added and the reflux is continued for 45 minutes. The reaction mixture is then brought to room temperature and the solvent is removed in vacuo. The residue is treated with saturated NaHCO ₃ solution and extracted with EtOAc. The organic fraction is washed with brine and dried over magnesium sulfate. The desiccant is removed and the solvent is removed in vacuo, then the residue is obtained and flash column chromatography (SiO ₂ , eluent: CH ₂ Cl ₂ / MeOH 95/5). The free base of E1 is separated and converted to its HCl salt by treatment with 1N HCl / EtOH. Recrystallization from EtOH / H ₂ O affords 1.45 g (3.2 mmol, 54%) of pure E1.HCl.

The compounds mentioned above are summarized in Table E.

Compound number Piperazine Q salt Melting point ℃ E1 I 13 HCl Greater than 190 (decomposition) E2 I 14 HCl 240 to 242 (decomposition) E3 XIV 15 HCl 271 to 273 (decomposition)

Intermediate Used for Path E

The bromide used in the Suzuki reaction shown in Scheme E1 can be synthesized from phenyl-piperazine and the desired substituted 3-bromo-phenyl-methyl-X intermediate, wherein X is Cl, Br or OMs. Scheme E3).

Method E3 (Scheme E3):

6.6 g (23.0 mmol) of (2-methoxy-5-bromo-phenyl) -methyl-bromide and 5.4 g (21 mmol) of IH.HCl were added to 80 ml of CH ₃ CN, 5.2 g (51.0 mmol) of Et ₃ N and Add a small amount of KI. The reaction mixture is stirred and kept at reflux for 16 hours. The reaction mixture is then filtered and the filtrate is concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , eluent: EtOAc / petroleum ether 1/2) to give pure 1-[(2-methoxy-5-bromo-phenyl) methyl] -4- (2,3-dihydro 5.1 g (12.2 mmol, 58%) of -1,4-benzodioxin-5-yl) piperazine are obtained.

The applied boronic acid is readily available through the corresponding bromide (D. Janietz et al., Synthesis, (1993), 33 and references cited therein).

Preparation of Intermediate XI-H according to Scheme A.i:

Step 1 (Scheme A.i):

1- (phenylmethyl) -hexahydro-5H-1,4-di-azepin-5-one [Dickerman et al., J. Org. Chem., 19, (1954), 1855-61] 5.1 g (25 mmol) and 7.39 g (37.5 mmol) of 7-bromobenzfuran were dried from 3.45 g (25 mmol) of K ₂ CO ₃ and 0.48 g (2.5 mmol) of CuI. ) Into the flask and stir the mixture while heating at 120 ° C. for 90 hours. After the reaction mixture was brought to room temperature, 40 ml of toluene was added. The suspension is filtered through celite and the residue is washed with hot toluene. The combined washes and filtrates were evaporated in vacuo to afford 12.4 g of brown oil. The oil is diluted with CH ₂ Cl ₂ and treated with 2N NaOH, NaHCO ₃ (saturated) and water. The organic fraction is dried over magnesium sulfate. After removing the desiccant and evaporating the solvent under vacuum, 11.7 g of brown oil is obtained. The residue was flash column chromatography (SiO ₂ , eluent: CH ₂ Cl ₂ / MeOH 98/2) to give 5.7 g (83%) of the desired product.

Step 2 (Scheme A.i):

5.9 g (18.6 mmol) of the product of Step 1 dissolved in 40 ml of dry THF are added dropwise to a mixture of 2.14 g (55.8 mmol) of LiAlH _{4 in} 100 ml of Et ₂ O and stirring is continued for 3 hours. The reaction mixture is then treated with 2.1 ml of water, 4.2 ml of 2N NaOH and 2.4 ml of water in THF, respectively. After stirring for 2 hours, the mixture is filtered through celite and the residue is washed with THF and CH ₂ Cl ₂ , respectively. The combined washes and filtrates are evaporated in vacuo to give 5.4 g of brown oil. The residue was flash chromatographed (SiO ₂ , eluent: CH ₂ Cl ₂ / MeOH 98/1) to give 4.83 g (85%) of diazepine homologue.

Step 3 (Scheme A.i):

4.83 g (15.8 mmol) of the product of step 2 are stirred in 65 ml of 1,2-dichloroethane. At 2-4 ° C. under a nitrogen atmosphere, 2.3 g (15.8 mmol) of Cl (CO) O (CHCl) CH ₃ (“ACE-chloride”) dissolved in 25 ml of 1,2-dichloroethane are added dropwise to the solution for 10 minutes. . The reaction mixture is refluxed for 10 hours. The reaction mixture is then concentrated in vacuo to give 5.1 g of residue. The residue is diluted with methanol and the resulting solution is refluxed for 16 hours. The reaction mixture is brought to room temperature, then the solvent is removed in vacuo to yield 4.2 g of residue which is subjected to flash column chromatography (SiO ₂ , eluent: CH ₂ Cl ₂ / MeOH / NH ₄ OH 92 / 7.5 / 0.5). Yield: 2.8 g (82%) of 1- (7-benzfuranyl) -hexa-hydro-1,4-diazepine.

Preparation of XV-H (see Scheme A.iii):

Step 1 (Scheme A.iii):

3.94 g (21.9 mmol) of 7-nitro-2-benzoxazolinone (European Patent 0189612 and references cited therein) are dissolved in 40 ml of DMSO and 1.72 g (26.2 mmol) of 85% KOH powder are added. While stirring and cooling (water), 3.72 g (26.2 mmol) of MeI dissolved in 6 ml of DMSO was added dropwise over 10 minutes. Stirring is continued at room temperature for 16 hours during which time additional amount of MeI (0.5 g) is added. After completion of the reaction, the reaction mixture is diluted with water and extracted with CH ₂ Cl ₂ . The combined organic fractions are washed with water and brine respectively and the organic fractions are dried over magnesium sulfate. The desiccant is removed and the solvent is evaporated in vacuo to give 4.1 g of solid. Flash column chromatography (SiO ₂ , eluent: CH ₂ Cl ₂ ) affords 3.6 g (85%) of pure 3-methyl-7-nitro-2-benzoxazolinone.

Claims (9)

Compounds of formula a and salts thereof. Formula a In the above formula, A is a 5-7 membered heterocyclic group having 1 to 3 heteroatoms from the O, N and S groups, R ₁ is hydrogen or fluoro, R ₂ is C _1-4 -alkyl, C _1-4 -alkoxy or oxo group, p is 0, 1 or 2, Z is carbon or nitrogen, The dashed line is a single bond when Z is nitrogen, a single bond or a double bond when Z is carbon, R ₃ and R ₄ are independently hydrogen or C _1-4 -alkyl, n is 1 or 2, R ₅ is halogen, hydroxy, C _1-4 -alkoxy or C _1-4 -alkyl, q is 0, 1, 2 or 3, Y is 1 to 3 substituents from hydroxy, halogen, C _1-4 -alkoxy, C _1-4 -alkyl, cyano, aminocarbonyl, mono- or di-C _1-4 -alkylaminocarbonyl group Phenyl, furanyl or thienyl which may be substituted by. A compound according to claim 1, wherein A is a group of formulas b to m together with a phenyl group, and R ₁ , (R ₂ ) p, R ₃ , R ₄ , (R ₅ ) q, Y and Z are defined in claim ₁ And n is 1 and salts thereof. Formula b Formula c Formula d Chemical formula e Formula f Chemical formula g Formula h Formula i Formula j Formula k Formula l Chemical formula m 3. A compound according to claim 2, wherein A is a group of formula (b) or a hetero ring with a phenyl group is a group of formula (l) substituted by an oxo group, Y is phenyl which may be substituted as mentioned in claim 1, and Z is Compounds that are nitrogen and salts thereof. _4. Compounds and salts thereof as claimed in claim 3, wherein R ₃ and R ₄ are hydrogen, R ₅ is hydrogen, hydroxy, methoxy or halogen and Y is as defined in claim 3. 5. The compound and salt thereof according to claim 4, wherein A is a group of formula l wherein A is a phenyl group and a heterocyclic ring is substituted with an oxo group, R ₅ is hydrogen, and Y is phenyl. a) reacting a compound of Formula n with a compound of Formula 1, b) reacting a compound of Formula n with a compound of Formula 2 and formaldehyde, or c) reacting a compound of Formula n with a compound of Formula 3 and then reducing the keto-group, d) reacting a compound of formula o with a compound of formula 4, or e) A process for preparing a compound of formula a as defined in claim 1 comprising reacting a compound of formula p with a compound of formula 5. Y-Br B (OH) ₂ -Y In the above formula, R ₁ , R _2, R _3, R ₄ , R ₅ , A, Z, Y, p, q and n are as defined in claim 1, X is an exit group. A pharmaceutical composition containing as active ingredient at least one compound as defined in claim 1. A method of making a pharmaceutical composition as defined in claim 7 comprising formulating the compound of claim 1 in a suitable dosage form. A method of treating CNS disease, including using the compound of claim 1.