# Patent

## Title
Phenylpiperazines

## Abstract

The invention relates to a novel group of phenylpiperazines having interesting pharmacological properties such as a high affinity for the dopamine D2 receptor and/or the serotonin reuptake site, and the ability to treat conditions related to disturbances in the dopaminergic and/or the serotonergic systems such as aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition, disturbances of memory, Parkinson's disease, schizophrenia, and psychotic disorders.
The invention relates to a group of novel phenylpiperazine derivatives of the formula (I):




wherein:

    
    
        X is a group of formula 1, 2, 3, 4, 5, 6, or 7 as defined in the text,
        m has the value 2 to 6;
        n has the value 0–2;
        R5 and R6 are independently H or alkyl (1–3C); or R5+R6 represent a group —(CH2)—p wherein p has the value 3–5, and
        R7 is alkyl (1–3C), alkoxy (1–3C), halogen or cyano; or R6+R7 (R7 at position 7 of the indole group) represent a group —(CH2)q wherein q has the value 2–4,

and salts thereof.

## Background
The invention relates to a group of novel phenylpiperazine derivatives of the formula (I):




wherein:

    
    
        X is 1) a group of the formula
    
    






wherein

    
    
        S1 is hydrogen or halogen,
        S2 and S3 are independently hydrogen, alkyl (1–6C), phenyl or benzyl,
        S4 represents two hydrogen atoms or an oxo group,
        S5 is H or alkyl (1–4C), and
        Y is CH2, O or S,

or 2) a group of the formula

    
    






wherein S1 has the above meaning and R is H, alkyl (1–4C), alkoxyalkyl (2–6C), alkenyl (2–4C) or alkynyl (2–4C),

or 3) a group of the formula





wherein S1 has the above meaning and Z is CH2, O or NH,

or 4) a group of the formula





wherein S1 has the above meaning,

or 5) a group of the formula





wherein S1 has the above meaning and A is O or NH, linked to the piperazine ring with position 5 or 8,

or 6) a group of the formula





wherein S1 has the above meaning and S6 and S7 represent hydrogen atoms or an oxo group,

or 7) a group of the formula





wherein one of the dotted lines can represent a double bond, S1 has the above meaning, and

    
    
        P, T, and Q are independently nitrogen or NH

or P and T are independently nitrogen or NH and Q is CH or CH2 

or P and Q are independently nitrogen or NH and T is CH, CH2, C—CH3 or CH—CH3 

or P is nitrogen or NH, and T and Q are independently CH or CH2 

        or P is nitrogen or NH, T is CH or CH2 and Q is sulphur
        m has the value 2 to 6;
        n has the value 0–2;
        R5 and R6 are independently H or alkyl (1–3C); or R5+R6 represent a group —(CH2)—p wherein p has the value 3–5, and
        R7 is alkyl (1–3C), alkoxy (1–3C), halogen or cyano; or R6+R7 (R7 at position 7 of the indole group) represent a group —(CH2)q wherein q has the value 2–4,

and salts thereof, which show high affinity for the dopamine D2-receptor and are good serotonin reuptake inhibitors (SRI's).

    
    


Preferred compounds of the invention are compounds having formula (I) wherein X represents a group of the formula (1), (2) or (3), wherein the symbols have the meanings given above and the salts thereof.
Especially preferred are compounds having formula (I) wherein X is the group with the formula (1) wherein S1=H, S2=CH3, S3=H, S4=oxo, S5=H and Y is oxygen, m is 3, R5=R6=hydrogen, n is 0 or 1 and R7 is 5-fluoro,
and the salts thereof.
It has been found that the compounds according to the invention show high affinity for both the dopamine D2 receptor and the serotonin reuptake site. This combination is useful for the treatment of schizophrenia and other psychotic disorders which enables a more complete treatment of all disease symptoms (e.g. positive symptoms and negative symptoms).
However, some of the compounds having formula (I) show (partial) agonist activity at dopamine receptors making them particularly suitable for the treatment of Parkinson's disease.
The compounds show activity as antagonists at dopamine D2 receptors as they potentially antagonize apomorphine-induced climbing behaviour in mice. The compounds also show activity as inhibitors of serotonin reuptake, as they potentiate 5-HTP induced behaviour in mice.
The compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g. the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61–67) and antidepressants or anxiolytics (e.g. suppression of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989, 97: 147–148).
In contrast to clinically relevant dopamine D2 receptor antagonists the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal side effects than existing antipsychotic agents.
The inhibitory activity of serotonin reuptake inherent in these compounds may be responsible for the therapeutic effects observed in behavioural models sensitive to either antidepressants or anxiolytics.
The compounds can be used for the treatment of affections or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotonergic systems, for example: aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, Parkinson's disease, and in particular schizophrenia and other psychotic disorders.
Pharmacologically acceptable acids with which the compounds of the invention can form suitable acid addition salts are for example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphthalene sulphonic acid.
When the compounds comprise a centre of chirality both the racemic mixture and the individual enantiomers belong to the invention.
The compounds and their acid addition salts can be brought into forms suitable for administration by means of suitable processes using auxiliary substances such as liquid and solid carrier materials.
The compounds having formula (I) can be prepared by reaction of a compound of the formula




under basic conditions with a compound of the formula





in which formulae the symbols have the meanings given above, and L is a so-called leaving group such as a halogen atom or a mesylate group.

The piperazine compounds having formula (II) can be obtained as described in EP 0138280, EP 0189612 and/or EP 0900792, or in an analogous manner.
The preparation of the piperazines having formula (II) can be carried out as indicated in schemes (i)–(iv) below. Some of the routes result in optically pure piperazine derivatives.
















The starting compounds having formula (III) can be prepared according to methods known for analogues compounds, as described for example in Organic Process Res. and Dev. 1997 (1), 300–310.
The invention will now be illustrated by means of the following Examples:


EXAMPLE 1
Preparation of Compound a,i (See Scheme i)
Step 1 (scheme i): To a solution of chloronitrocatechol (6.45 g, 34 mmol) in dry DMSO (50 ml) was added powdered NaOH (2.72 g, 68 mmol). After stirring for 30 minutes a solution was added of R-glycerolketal mesylate (8.0 g, 38 mmol) in DMSO (20 ml) and this mixture was heated at 80° C. during 24 hours. After cooling to room temperature the reaction mixture was poured into water (200 ml), acidified with 1 N HCl and extracted with methyl t-butylether. The organic fraction was washed with water and dried on MgSO4. After removal of the drying agent and the solvent in vacuo, the resulting oil was subjected to flash chromatografy (SiO2, eluent PE/aceton=3/1). Yield 9.29 g (90%) of the S-ketal.
Step 2 (scheme i): To a solution of the S-ketal (31 g, 102 mmol) in acetic acid (120 ml) was added 35% HBr in acetic acid (80 ml) and this mixture was rotated for 2 hours on a rotavapor in a waterbath of 50° C. The reaction mixture was diluted with ethanol (96%, 250 ml), cooled in a salt/ice mixture and then NaOH (50% in water, 250 ml) was added slowly, keeping the temperature below 15° C. After adding ethanol (250 ml) and water (250 ml) the reaction mixture was stirred at room temperature for 16 hours. Then concentrated HCl (about 300 ml) and water were added and the mixture extracted with ethyl acetate. After washing the organic fraction with 5% NaHCO3 (4×500 ml), the solvent was removed in vacuo and the resulting oil was subjected to flash chromatografy (SiO2, eluent PE/aceton=3/1). Yield 20.5 g (81%) of the R-benzodioxane as a yellow oil.
Step 3 (scheme i): To a solution of R-benzodioxane (20 g, 81 mmol) in DMF (200 ml) was added KOH (4.56 g, 81 mmol). After cooling the red solution in ice/aceton dimethyl sulfate (23 ml) was added and the reaction mixture was stirred for 1.5 hours at room temperature. Then more KOH (4.56 g, cooling) was added and the mixture was stirred at room temperature for 16 hours. After adding water (700 ml), the product was extracted with ethyl acetate. The ethyl acetate was removed in vacuo and the resulting oil was subjected to flash chromatografy (SiO2, eluent PE/aceton=4/1) yielding R-methoxymethylbenzodioxane (12.3 g, 58%) as a yellow oil. [α]D25=−97° (methanol).
Step 4 (scheme i): To a solution of R-methoxymethylbenzodioxane (5 g, 19 mmol) in ethanol (100 ml) and ethyl acetate (50 ml) was added a catalytic amount of 10% Pd/C and the solution was shaken under atmospheric H2 pressure at room temperature. After the calculated amount of H2 was taken up by the reaction mixture, the catalyst was removed by filtration and the filtrate was concentrated in vacuo. Yield 3.7 g (100%) of the corresponding anilino-compound.
Step 5 (scheme i): The anilino-compound (4 g, 2 mmol) and BCEA, i.e. HN(CH2CH2Cl)2.HCl (3.7 g, 2 mmol) were dissolved in chlorobenzene (100 ml). The mixture was heated to 150° C. for 16 hours, concentrated in vacuo and purified by flash chromatografy (SiO2, dichloromethane/methanol/ammonium hydroxide=92/7.5/0.5). Yield 3.67 g (68%) of the piperazine a,i.
EXAMPLE 2
Preparation of Compound No. 126
The route is described above, i.e. reaction of compound (II) with compound (III). The mesylates of formula (III) were prepared from the corresponding alcohols by standard procedures, e.g. with MsCl/Et3N.
A mixture of the piperazine a,i (3,6 g, 13,6 mmol), the 5-fluoro indole-mesylate (4,1 g, 15,1 mmol), triethylamine (2 ml) and a catalytic amount of KI in CH3CN (100 ml) was heated under reflux during 18 hours after which the reaction mixture was concentrated in vacuo and purified by chromatografy (SiO2, dichloromethane/methanol/ammonium hydroxide=92/7.5/0.5). Yield 3,77 of the free base (oil). The free base was dissolved in ethanol and 1 equivalent of fumaric acid in ethanol was added. After removal of the solvent compound no. 126 was obtained (4,3 g, 57%). [α]D25=−2° (methanol)
EXAMPLE 3
Preparation of Compound b,ii (See Scheme ii)
Step 1 (scheme ii): A solution of the aminophenol (37.3 g, 198 mmol), S-lactic acid methyl ester (20 ml) and triphenylphosphine (58 g, 220 mmol) in THF (2000 ml) was cooled in ice/salt (temperature<10° C.). Then a solution of azodicarboxic acid ester (DIAD, 43 ml, 218 mmol) in THF (400 ml) was added slowly. After stirring at room temperature for 18 hours the reaction mixture was concentrated in vacuo and ethanol (500 ml) and 36% HCl (125 ml) were added to the residue. The mixture was heated to 100° C. (development of gas). After cooling the compound was isolated by filtration and washed with 96% ethanol (about 100 ml). Yield 42 g (87%).
Step 2 (scheme ii): This step is similar to step 4 described in scheme i.
Step 3 (scheme ii): This step is similar to step 5 described in scheme i, resulting in the formation of the piperazine b,ii.
EXAMPLE 4
Preparation of Compound No. 89
The route is described above, i.e. reaction of compound (II) with compound (III). The reaction is carried out as described in example 2, starting with the piperazine b,ii. Yield 58% of compound no. 89, [α]D25=−24° (methanol).
EXAMPLE 5
Preparation of Coumpound c,iii (See Scheme iii)
Step 1 (scheme iii): A solution of the benzomorpholinone (10 g, 41 mmol; see scheme ii, step 1) and powdered KOH (2.3 g, 41 mmol) in DMF (100 ml) was cooled in ice (temperature<10° C.). After adding 1 equivalent of MeI (2.55 ml, 41 mmol) the reaction mixture was stirred at room temperature for about 1.5 hours and then poured into water. The precipitate was filtered off, washed with water and dried. Yield 10 g (95%) of the NCH3-compound, mp. 191–192; [α]D25=+7.5° (in THF)
Step 2 (scheme iii): This step is similar to step 4 described in scheme i.
Step 3 (scheme iii): This step is similar to step 5 described in scheme i, resulting in the formation of the piperazine c,iii.
EXAMPLE 6
Preparation of Compound No. 121
The route is described above, i.e. reaction of compound (II) with compound (III). The reaction is performed as described in example 2, starting with the piperazine c,iii. Yield 44% of compound no. 121, [α]D25=−28° (methanol).
EXAMPLE 7
Preparation of Compound d,iv (See Scheme iv)
Step 1 (scheme iv): Pyridine (81 ml, 1 mol) was added to a solution of 2-hydroxy-5-chloroaniline (143.5 g, 1 mol) in dry CH2Cl2. The mixture was cooled in ice (temperature<10° C.) and then a solution of 2-bromo-2-methyl-propionylbromide (163 ml, 1 mol) in CH2Cl2 (100 ml) was added slowly. The mixture was stirred at room temperature for 18 hours and was poured into CH2Cl2 (5000 ml) and water (2000 ml). The organic layer was washed with water, dried and concentrated in vacuo till about 1 liter. The precipitate was filtered off, washed with CH2Cl2 and dried. Yield 231 g (79%) of the bromocompound, mp. 172° C.
Step 2 (scheme iv): To a suspension of the bromocompound (60 g, 205 mmol) in water (95 ml) was added slowly under ice cooling concentrated sulfuric acid (7 ml) followed by 70% HNO3 (16 ml) and stirring was continued for 2 hours at room temperature. After cooling in ice water the precipitate was filtered off, washed with water and purified by chromatografy (SiO2, methyl t-butylether). Yield 49 g (71%) of the nitrocompound.
Step 3 (scheme iv): To a solution of the nitrocompound (49 g, 145 mmol) in DMF (500 ml) was added K2CO3. This mixture was heated for one hour at 150° C., then cooled and poured into a mixture water/ethyl acetate. The organic fraction was washed with sodium bicarbonate (5% in water) HCl (2N) and water respectively. The solvent was removed in vacuo and the residue was purified by flash chromatografy (SiO2, methyl t-butylether/PE=1/1). Yield 23 g (62%).
Step 4 (scheme iv): This step is similar to step 4 described in scheme i.
Step 5 (scheme iv): This step is similar to step 5 described in scheme i, leading to the formation of the piperazine d,iv.
EXAMPLE 8
Preparation of Compound No. 115
The route is described above, i.e. reaction of compound (II) with compound (III). The reaction is performed as described in example 2, starting with the piperazine d,iv. Yield 20% of compound no. 115.
The compounds listed in the following tables have been prepared according to the method of the above examples.
























Comp.









S6 +






no
X
m
Y
R5
R6
(R7)n
R
Z
A
S7
P
T
Q
Remarks






























1
form
2
3
—
H
H
H
2-CH2OH
—
—
—
—
—
—
S1 = H


2

1
3
CH2
H
H
H
—
—
—
—
—
—
—
S1–S5 = H


3

3
3
—
H
H
H
—
O
—
—
—
—
—
S1 = H


4

3
4
—
H
H
H
—
O
—
—
—
—
—
S1 = H


5

3
4
—
H
H
H
—
O
—
—
—
—
—
S1 = H


6

3
3
—
H
CH3
H
—
O
—
—
—
—
—
S1 = H


7

2
3
—
H
H
H
3-CH2OH
—
—
—
—
—
—
S1 = H


8

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo,

















S1 = S2 = S3 = S5 = H


9

1
3
O
H
H
H
—
—
—
—
—
—
—
S1–S5 = H


10

4
3
—
H
H
H
—
—
—
—
—

—
S1 = H


11

1
3
CH2
H
H
H
—
—
—
—
—
—
—
S1, S3–S5 = H

















S2 = CH3





















12

3
3
—
H
—(CH2)3—
—
O
—
—
—
—
—
S1 = H






















13

2
3
—
H
H
H
3-CH2OH
—
—
—
—
—
—
S1 = H*





















14

1
3
CH2
—(CH2)4
H
—
—
—
—
—
—
—
S1–S5 = H






















15

3
3
—
H
H
5-OCH3
—
O
—
—
—
—
—
S1 = H


16

1
3
CH2
CH3
H
5-Cl
—
—
—
—
—
—
—
S1–S5 = H


17

3
3
—
CH3
H
5-Cl
—
O
—
—
—
—
—
S1 = H


18

1
3
CH2
H
H
5-Br
—
—
—
—
—
—
—
S1–S5 = H


19

3
3
—
H
H
5-Br
—
O
—
—
—
—
—
S1 = H


20

1
2
CH2
H
H
H
—
—
—
—
—
—
—
S1–S5 = H


21

1
3
CH2
H
H
5-F
—
—
—
—
—
—
—
S1–S5 = H


22

3
3
—
H
H
5-F
—
O
—
—
—
—
—
S1 = H


23

3
3
—
H
H
H
—
CH2
—
—
—
—
—
S1 = H


24

5
3
—
H
H
H
—
—
O
—
—
—
—
S1 = H; position 8


25

1
3
CH2
H
H
7-Cl
—
—
—
—
—
—
—
S1–S5 = H


26
form
3
3
—
H
H
7-F
—
O
—
—
—
—
—
S1 = H


27

1
3
CH2
H
H
7-F
—
—
—
—
—
—
—
S1–S5 = H


28

3
3
—
H
H
7-Cl
—
O
—
—
—
—
—
S1 = H


29

3
3
—
H
H
7-CH3
—
O
—
—
—
—
—
S1 = H


30

2
3
—
H
H
H
2-CH2OCH3
—
—
—
—
—
—
S1 = H


31

7
3
—
H
H
H
—
—
—
—
N
CH2
CH2
S1 = H


32

1
3
CH2
H
H
6-Cl
—
—
—
—
—
—
—
S1–S5 = H


33

3
3
—
H
H
6-Cl
—
O
—
—
—
—
—
S1 = H


34

3
3
—
H
H
5-CN
—
O
—
—
—
—
—
S1 = H


35

1
3
CH2
H
H
5-CN
—
—
—
—
—
—
—
S1–S5 = H


36

1
3
CH2
H
H
4-Cl
—
—
—
—
—
—
—
S1–S5 = H


37

3
3
—
H
H
4-Cl
—
O
—
—
—
—
—
S1 = H


38

1
6
CH2
H
H
H
—
—
—
—
—
—
—
S1–S5 = H


39

1
5
CH2
H
H
H
—
—
—
—
—
—
—
S1–S5 = H


40

1
3
CH2
H
H
H
—
—
—
—
—
—
—
S1–S4 = H S5 = CH3


41

1
3
S
H
H
H
—
—
—
—
—
—
—
S4 = oxo,

















S1–S3 = S5 = H


42

6
3
—
H
H
H
—
—
—
oxo
—
—
—
S1 = H


43

1
3
S
H
H
H
—
—
—
—
—
—
—
S1–S5 = H


44

6
3
—
H
H
H
—
—
—
H2
—
—
—
S1 = H


45

1
4
CH2
H
H
H
—
—
—
—
—
—
—
S1–S5 = H


46

1
3
CH2
H
H
6-F
—
—
—
—
—

—
S1–S5 = H


47

3
3
—
H
H
6-F
—
O
—
—
—
—
—
S1 = H


48

7
3
—
H
H
H
—
—
—
—
N
CH
NH
S1 = H


49

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo, S2 = CH3,

















S1 = S3 = S5 = H


50

1
3
CH2
H
H
H
—
—
—
—
—
—
—
S4 = oxo,

















S1–S3 = S5 = H


51
form
3
3
—
H
C2H5
5-CN
—
O
—
—
—
—
—
S1 = H


52

3
3
—
H
H
H
—
NH
—
—
—
—
—
S1 = H


53

7
3
—
H
H
H
—
—
—
—
N
C(CH3)
NH
S1 = H


54

7
3
—
H
H
H
—
—
—
—
NH
N
CH
S1 = H


55

7
3
—
H
H
H
—
—
—
—
N
N
NH
S1 = H


56

1
3
CH2
H
H
4-F
—
—
—
—
—
—
—
S1–S5 = H


57

3
3
—
H
H
4-F
—
O
—
—
—
—
—
S1 = H


58

1
3
CH2
H
H
7-Br
—
—
—
—
—
—
—
S1–S5 = H


59

3
3
—
H
H
7-Br
—
O
—
—
—
—
—
S1 = H


60

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo, S1 = 7-Cl,

















S2 = S3 = S5 = H


61

2
3
—
H
H
5-F
2-CH2OCH3
—
—
—
—
—
—
S1 = H


62

1
3
CH2
H
H
5,7-F2
—
—
—
—
—
—
—
S1–S5 = H


63

3
3
—
H
H
5,7-F2
—
O
—
—
—
—
—
S1 = H


64

2
3
—
H
H
7-F
2-CH2OCH3
—
—
—
—
—
—
S1 = H


65

5
3
—
H
H
H
—
—
NH
—
—
—
—
S1 = H; position 5


66

5
3
—
H
H
5-F
—
—
NH
—
—
—
—
S1 = H; position 5


67

5
3
—
H
H
7-F
—
—
NH
—
—
—
—
S1 = H; position 5


68

2
3
—
H
H
H
3-CH2OCH3
—
—
—
—
—
—
S1 = H


69

2
3
—
H
H
H
2-CH2OCH3
—
—
—
—
—
—
S1 = H


70

2
3
—
H
H
5-F
2-CH2OCH3
—
—
—
—
—
—
S1 = H


71

2
3
—
H
H
5-F
3-CH2OCH3
—
—
—
—
—
—
S1 = H


72

2
3
—
H
H
7-F
3-CH2OCH3
—
—
—
—
—
—
S1 = H


73

2
3
—
H
H
7-F
2-CH2OCH3
—
—
—
—
—
—
S1 = H


74

1
3
S
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo,

















S1–S3 = S5 = H


75

2
3
—
H
H
H
3-CH2OC3H7
—
—
—
—
—
—
S1 = H


76
form.
2
3
—
H
H
5-F
3-CH2OC3H7
—
—
—
—
—
—
S1 = H


77

2
3
—
H
H
H
3-CH2OCH2C≡CH
—
—
—
—
—
—
S1 = H


78

2
3
—
H
H
5-F
3-CH2OCH2C≡CH
—
—
—
—
—
—
S1 = H


79

2
3
—
H
H
7-F
3-CH2OCH2C≡CH
—
—
—
—
—
—
S1 = H


80

2
3
—
H
H
H
3-CH2OCH2CH2OCH3
—
—
—
—
—
—
S1 = H


81

2
3
—
H
H
5-F
3-CH2OCH2CH2OCH3
—
—
—
—
—
—
S1 = H


82

2
3
—
H
H
7-F
3-CH2OCH2CH2OCH3
—
—
—
—
—
—
S1 = H


83

1
3
S
H
H
5-F
—
—
—
—
—
—
—
S1–S5 = H


84

1
3
S
H
H
H
—
—
—
—
—
—
—
S2 = CH3,

















S1 = S3–S5 = H


85

1
3
S
H
H
H
—
—
—
—
—
—
—
S4 = oxo, S2 = CH3,

















S1 = S3 = S5 = H


86

7
3
—
H
H
H
—
—
—
—
N
CH
S
S1 = H


87

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo, S2 = CH3,

















S1 = S3 = S5 = H


88

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo, S2 = CH3,

















S1 = S3 = S5 = H


89

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo, S2 = CH3,

















S1 = S3 = S5 = H


90

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo, S2 = CH3,

















S1 = S3 = S5 = H


91

1
3
O
H
H
7-F
—
—
—
—
—
—
—
S4 = oxo, S2 = CH3,

















S1 = S3 = S5 = H


92

1
3
O
H
H
7-F
—
—
—
—
—
—
—
S4 = oxo, S2 = CH3,

















S1 = S3 = S5 = H


93

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo, S2 = phenyl,

















S1 = S3 = S5 = H


94

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo, S2 = phenyl,

















S1 = S3 = S5 = H


95

1
3
O
H
H
7-F
—
—
—
—
—
—
—
S4 = oxo, S2 = phenyl,

















S1 = S3 = S5 = H


96

2
3
—
H
H
H
3-CH2OCH2CH═CH2
—
—
—
—
—
—
S1 = H


97

2
3
—
H
H
5-F
3-CH2OCH2CH═CH2
—
—
—
—
—
—
S1 = H


98

2
3
—
H
H
7-F
3-CH2OCH2CH═CH2
—
—
—
—
—
—
S1 = H


99

2
3
—
H
H
H
2-CH2OCH2C≡CH
—
—
—
—
—
—
S1 = H


100

2
3
—
H
H
5-F
2-CH2OCH2C≡CH
—
—
—
—
—
—
S1 = H


101
form.
2
3
—
H
H
7-F
2-CH2OCH2C≡CH
—
—
—
—
—
—
S1 = H


102

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo, S2 = C3H7,

















S1 = S3 = S5 = H


103

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo, S2 = C3H7,

















S1 = S3 = S5 = H


104

1
3
O
H
H
7-F
—
—
—
—
—
—
—
S4 = oxo, S2 = C3H7,

















S1 = S3 = S5 = H


105

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo,

















S2 = S5 = CH3,

















S1 = S3 = H


106

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo,

















S2 = S5 = CH3,

















S1 = S3 = H


107

1
3
O
H
H
7-F
—
—
—
—
—
—
—
S4 = oxo,

















S2 = S5 = CH3,

















S1 = S3 = H


108

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo, S2 = benzyl,

















S1 = S3 = S5 = H


109

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo, S2 = benzyl,

















S1 = S3 = S5 = H


110

1
3
O
H
H
7-F
—
—
—
—
—
—
—
S4 = oxo, S2 = benzyl,

















S1 = S3 = S5 = H


111

2
3
—
H
H
H
3-CH2OCH2C≡CCH3
—
—
—
—
—
—
S1 = H


112

2
3
—
H
H
H
2-CH2OCH2C≡CCH3
—
—
—
—
—
—
S1 = H


113

2
3
—
H
H
5-F
2-CH2OCH2C≡CCH3
—
—
—
—
—
—
S1 = H


114

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo,

















S2 = S3 = CH3,

















S1 = S5 = H


115

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo,

















S2 = S3 = CH3,

















S1 = S5 = H


116

2
3
—
H
H
H
3-CH2OCH3
—
—
—
—
—
—
S1 = H


117

2
3
—
H
H
5-F
3-CH2OCH3
—
—
—
—
—
—
S1 = H


118

2
3
—
H
H
5-F
3-CH2OCH3
—
—
—
—
—
—
S1 = H


119

2
3
—
H
H
H
3-CH2OCH3
—
—
—
—
—
—
S1 = H


120

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo,

















S2 = S5 = CH3,

















S1 = S3 = H


121

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo,

















S2 = S5 = CH3,

















S1 = S3 = H


122

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo,

















S2 = S5 = CH3,

















S1 = S3 = H


123

1
3
O
H
H
H
—
—
—
—
—
—
—
S4 = oxo,

















S2 = S5 = CH3,

















S1 = S3 = H


124

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo, S1 = 7-Cl,

















S2 = S3 = S5 = CH3


125

1
3
O
H
H
5-F
—
—
—
—
—
—
—
S4 = oxo, S1 = H,

















S2 = S3 = S5 = CH3


126

2
3
—
H
H
5-F
3-CH2OCH3
—
—
—
—
—
—
S1 = H





*R7 is linked to position 7 of the indole group



















Comp.





no
Salt or free base
MP (° C.)
[α]D25 (in methanol)


















1
fumarate
 192–4
—


2
2-HCl
 239–41
—


3
free base
 203–4
—


4
′′
 170–1
—


5
3. fumarate
 98
—


6
free base
 175–6
—


7
4/3. fumarate
 140–3
—


8
free base
 189–90
—


9
fumarate
 200–1
—


10
3/2. fumarate
 190–1
—


11
1⁄2. fumarate
 210–2 (dec.)
—


12
free base
 165–7
—


13
free base
 70–1
—


14
fumarate
 208
—


15
free base
amorph
—


16
2. fumarate
amorph
—


17
free base
amorph
—


18
fumarate
>225 (dec.)
—


19
fumarate
>170 (dec.)
—


20
free base
amorph
—


21
1⁄2. fumarate
>245 (dec)
—


22
1⁄2. fumarate
>165 (glass)
—


23
free base
 176–7
—


24
free base
amorph
—


25
1⁄2. fumarate
amorph
—


26
3⁄4. fumarate
amorph
—


27
1⁄2. fumarate
>240 (dec)
—


28
4/5. fumarate
amorph
—


29
′′
amorph
—


30
3/2. fumarate
glass
—


31
5/4. fumarate
 188–190
—


32
1⁄2. fumarate
>230 (dec)
—


33
fumarate
amorph
—


34
fumarate
 150–2
—


35
1⁄2. fumarate
 247–8 (dec)
—


36
1⁄2. fumarate
>240 (dec)
—


37
fumarate
amorph
—


38
HCl
amorph
—


39
HCl
amorph
—


40
HCl
 220–4
—


41
HCl
>250 (dec)
—


42
1⁄2. fumarate
 214–7 (dec)
—


43
1⁄2. fumarate
 240–3
—


44
1⁄2. fumarate
 220–2 (dec)
—


45
HCl
amorph
—


46
fumarate
 223–5
—


47
2/3. fumarate
 200–2
—


48
free base
glass
—


49
free base
 196–7
—


50
free base
 181–2
—


51
1⁄2. fumarate
 138.5–41
—


52
free base
 190–5 (dec)
—


53
free base
glass
—


54
free base
glass
—


55
free base
glass
—


56
1⁄2. fumarate
 185–6
—


57
fumarate
 210–1 (dec)
—


58
2. fumarate
amorph
—


59
free base
amorph
—


60
1⁄2. fumarate
>250
—


61
fumarate
glass
—


62
1⁄2. fumarate
 245–7
—


63
3/2. fumarate
 175–8
—


64
fumarate
glass
—


65
free base
 220–4 (dec)
—


66
free base
 234–6 (dec)
—


67
free base
>280
—


68
HCl
glass
—


69
fumarate
glass
+28 (free base), R-conf.


70
fumarate
glass
+28 (free base), R-conf.


71
fumarate
glass
—


72
fumarate
glass
—


73
fumarate
glass
+25 (free base), R-conf.


74
free base
 212.5–14.5
—


75
fumarate
glass
—


76
fumarate
glass
—


77
fumarate
glass
—


78
fumarate
glass
—


79
fumarate
glass
—


80
fumarate
glass
—


81
fumarate
glass
—


82
fumarate
glass
—


83
fumarate
amorph
—


84
free base
amorph
—


85
free base
amorph
—


86
1⁄2. fumarate
 218–20
—


87
free base
glass
−26 R-conf.


88
free base
glass
+27 S-conf.


89
free base
glass
−24 R-conf.


90
free base
glass
+24 S-conf.


91
free base
 184–5
−25 R-conf.


92
free base
 181–3
+25 S-conf.


93
free base
glass
—


94
free base
glass
—


95
free base
glass
—


96
free base
 70–3
—


97
free base
 73–5
—


98
fumarate
glass
—


99
fumarate
glass
+39 (free base), R-conf.


100
fumarate
glass
+36 (free base), R-conf.


101
fumarate
glass
+37 (free base), R-conf.


102
free base
 158–60
—


103
free base
 181–2
—


104
free base
 174–6
—


105
free base
glass
—


106
free base
glass
—


107
free base
glass
—


108
free base
glass
—


109
free base
 207–10 (dec)
—


110
free base
 197–9 (dec)
—


111
fumarate
glass
—


112
fumarate
glass
+31 (free base), R-conf


113
fumarate
glass
+31 (free base), R-conf


114
free base
 191–4
—


115
free base
 190–2
—


116
free base
amorph
 0 S-conf.


117
fumarate
amorph
   S-conf.


118
free base
amorph
   R-conf.


119
free base
amorph
 0 R-conf.


120
free base
amorph
−31 R-conf.


121
free base
amorph
−28 R-conf.


122
free base
amorph
+28 S-conf.


123
free base
amorph
+32 S-conf.


124
free base
amorph
—


125
free base
amorph
—


126
fumarate
amorph
 −2 R-conf.

## Claims

1. A compound of the formula (I):




wherein:
X is 1) a group of the formula





wherein
S1 is hydrogen or halogen,
S2 and S3 are independently hydrogen, alkyl (1–6C), phenyl or benzyl,
S4 represents two hydrogen atoms or an oxo group,
S5 is H or alkyl (1–4C), and
Y is CH2, O or S, and
m has the value 2 to 6;
n has the value 0–2;
R5 and R6 are independently H or alkyl (1–3C); or R5+R6 represent a group —(CH2)—p wherein p has the value 3–5, and
R7 is alkyl (1–3C), alkoxy (1–3C), halogen or cyano; or R6+R7 (R7 at position 7 of the indole group) represent a group —(CH2)q wherein q has the value 2–4,

an enantiomer thereof, or a salt of any of the foregoing.

2. A compound as claimed in claim 1, wherein m is 3, R5=R6=H, n is 0 or 1, and R7 is 5-fluoro, an enantiomer thereof, or a salt of any of the foregoing.

3. A method for preparing a compound, an enantiomer thereof, or a salt of any of the foregoing as claimed in claim 1, comprising reacting a compound having formula (II)




under basic conditions with a compound having formula (III)




in which formulae the symbols having the meanings given in claim 1, and L is a leaving group,
to yield the compound, the enantiomer thereof, or the salt of any of the foregoing as claimed in claim 1.

4. A pharmaceutical composition comprising at least one compound as claimed in claim 1, an enantiomer thereof, or a salt of any of the foregoing and at least one auxiliary substance.

5. A method of preparing a composition as claimed in claim 4, comprising mixing the at least one compound, an enantiomer thereof, or a salt of any of the foregoing with the at least one auxiliary substance.

6. A method of treating at least one central nervous system disorder in a human or animal patient in need of such treating, comprising administering at least one compound as claimed in claim 1, an enantiomer thereof, a salt of any of the foregoing, or a combination of the foregoing to the patient in an amount effective for the treating,
wherein the at least one central nervous system disorder is chosen from anxiety disorders, depression, Parkinson's disease, and schizophrenia.

7. The method of claim 6, in which the at least one central nervous system disorder is chosen from schizophrenia.