PHENOXY PIPERAZINE DERIVATIVES FOR TREATING DISORDERS OF THE DOPAMINE SYSTEM

Abstract: The invention is concerned with compounds of general formula (I) wherein R<1> and R<3> each independently signify hydrogen, aryl, carbamoyl, lower-alkyl-carbonyl, lower-alkyl, halogen, lower-alkyl-carbonyl-amino, lower-alkenyl-carbonyl-amino, amino, arylamino, aryloxy, nitro, aryl-acetyl, lower-alkanoyl-lower-alkyl, alkyl-sulphonyl-amino, ureido or furan-2-yl-carbonyl-amino and R<2> signifies hydrogen, lower-alkyl, trifluoromethyl, halogen, lower-alkoxy, lower-alkyl-carbonyl or lower-alkyl-carbonyl-amino or R<1> and R<2> together can be -OCH2O-, -O(CH2)2O- or -(CH2)3-, R<4> signifies hydrogen, halogen, hydroxy, lower-alkyl, lower-alkoxy or nitro, R<5> signifies hydrogen, halogen or lower-alkoxy, R<6> signifies hydrogen, lower-alkyl, halogen, hydroxy, amino, lower-alkoxy, trifluoromethyl, nitro or lower-alkyl-carbonyl-amino and R<7> signifies hydrogen or lower-alkyl-carbonyl, as well as pharmaceutically acceptable salts of compounds of formula (I), for the treatment or prevention of illnesses which are caused by disorders of the dopamine system, and, respectively, for the production of corresponding medicaments.

Description: PHENOXY PIPERAZINE DERIVATIVES FOR TREATING DISORDERS OF THE DOPAMINE SYSTEM The invention is concerned with aromatic ethers, especially phenoxy-piperazine derivatives of the general formula wherein R 1 and R 3 each independently signify hydrogen, aryl, carbamoyl, lower-alkyl-carbonyl, lower-alkyl, halogen, lower- alkyl-carbonyl-amino, lower-alkenyl-carbonyl-amino, amino, arylamino, aryloxy, nitro, aryl-acetyl, lower- alkanoyl-lower-alkyl, alkyl-sulphonyl-amino, ureido or furan-2-yl-carbonyl-amino and R 2 signifies hydrogen, lower-alkyl, trifluoromethyl, halogen, lower-alkoxy, lower-alkyl-carbonyl or lower-alkyl-carbonyl-amino or R 1 and R 2 together can be -OCH 2 0-, -0(CH 2 )2θ- or -(CH 2 )3-, R 4 signifies hydrogen, halogen, hydroxy, lower-alkyl, lower-alkoxy or nitro, R 5 signifies hydrogen, halogen or lower-alkoxy, R 6 signifies hydrogen, lower-alkyl, halogen, hydroxy, amino, lower-alkoxy, trifluoromethyl, nitro or lower- alkyl-carbonyl-amino and R 7 signifies hydrogen or lower-alkyl-carbonyl, as well as pharmaceutically acceptable salts of compounds of formula I. These compounds and salts are known. The manufacture of the aforementioned compounds as well as their use as antihyper- tensive agents is described in DE-OS 1964423. As used herein, the term "lower alkyl" denotes straight or branched chain lower alkyl of 1 to 6 carbon atoms, for example, methyl, ethyl or isopropyl, butyl, pentyl and the like. The term "lower alkoxy" denotes alkyl ether groups in which the lower alkyl is as described above, for example, methoxy, ethoxy, isopropoxy, and the like. The term "halogen" denotes chlorine, bromine, fluorine and iodine. Of the halogens, fluorine and chlorine are prepared. The amino group, is desired, can be substituted by lower alkyl of 1 to 6 carbon atoms, such as, for example, methyl-, ethyl-, propyl-, butyl-, or pentyl-amino and the like. The term "lower alkenyl" denotes straight and branched chain olefinic unsaturated hydrocarbon groups having from 2 to 6 carbon atoms. The term "aryl" denotes phenyl or phenyl bearing a lower alkyl of 1 -4 carbon atoms. Of these, p-tolyl is preferred. It has now surprisingly been found that these compounds can be used in the control or prevention of illnesses which are caused by disorders of the dopamine system. Thereto there belong psychotic illnesses such as e.g. schizophrenia. The object of the present invention is accordingly the use of compounds of formula I for the treatment or prevention of psychotic illnesses which are caused by disorders of the dopamine system and the use of these compounds as active ingredients in the production of medicaments for the said purpose as well as medicaments containing these compounds. The novel pharmacological properties of these compounds follow from a high selective affinity to a neuroreceptor, especially to the doρamine-D4 receptor. Thereby, it can be expected that when these compounds are used significantly fewer side effects will occur than in the case of known classical neuroleptic agents, e.g. haloperidol, which, as is known, bind to the D2 or D3 receptor. It has been found that in the case of schizophrenia the D2 and D3 receptor density increases by about 10%, while it can increase in the case of the D4 receptor by about 600% (TiPS, July 1994, vol. 15, p. 264-70). Test description The compounds were characterized by their binding behaviour at the D4 receptor. Compounds, which, moreover, were expected to have a good selectivity, were compared with respect to their D receptor activity. CHO cells (Chinese Hamster Ovary) were used in the test. Crude membranes were isolated by ultracentrifugation from D4-CHO and D2-CHO cells and were stored at -80°C. After thawing and homogenizing in a buffer solution (50 mM Tris, 1 mM EDTA, 5 mM KCI, 1.5 mM CaCI∑, 4 mM MgCl2, pH 7.4) they were incubated at room temperature for 90 minutes with 200 pM [ 3 H]spiperone and an increasing concentration (1 x l O" 1 1 M to 1 x 10 -4 M) of test compound. A non-specific binding was established by incubating in the presence of 1 x 10 -5 M (+)- butaclamol. The unbound radioiigand was removed by filtration through a GF/C glass filter and the bound radioactivity was determined by scintillation in a Packard TopCount. The following Table shows the binding behaviour of some selected compounds at the D4 receptor. The Ki value is a binding constant which shows the affinity of the compounds to the D4 receptor. It was determined using 3H- spiperone. The calculation of the value was effected with ligand. Table 1 Particularly active compounds are set forth in Table 1 These are the following compounds: 1 1 -Phenoxy-3-(4-phenyl-piperazin-l -yl)-propan-2-ol; 2 1 -(2-Amino-phenoxy)-3-(4-phenyl-piperazin-1 -yl)-propan- 2-ol; 3 1 -[2-[2-Hydroxy-3-(4-phenyl-piperazin-1 -yl)-proρoxy]- phenyl]-ethanone; 4 2-[2-Hydroxy-3-(4-ρhenyl-piperazin-1 -yl)-propoxyJ- benzamide; 5 1 -[4-(4-Chloro-phenyl)-piperazin-1 -yl]-3-(3-trifluoro- methyl-phenoxy)-propan-2-ol; 6 N-[2-[2-Hydroxy-3-(4-o-tolyl-piperazin-1 -yl)-propoxy]- phenyi]-acetamide; 7 N-[2-[2-Hydroxy-3-[4-(2-trifluoromethyl-phenyl)- piperazin-1 -yl]-propoxy]phenyl]-acetamide; 8 N-[2-[2-Hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-1 -yl]- propoxy]-phenyl]-acetamide; 9 [+]-1 -(2-Amino-phenoxy)-3-[4-(2-methoxy-phenyl)- piperazin-1 -yl]-propan-2-ol; 10 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 -yl]- propoxy]-phenyl]-acetamide; 1 1 [+]-N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 - y!]-propoxy]phenyl]-acetamide; 1 [-]-N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 - yl]-propoxy]phenyl]-acetamide; 13 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 -yl]- propoxy]-phenyl]-propionamide; 14 Hexanoic acid [2-[2-hydroxy-3-[4-(2-methoxy-phenyl)- piperazin-1 -yl]propoxy]-phenyl]-amide; 1 5 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 -yl]- propoxy]-phenyl]-2,2-dimethyl-propionamide; 16 [+]-(E)-But-2-enolic acid [2-[2-hydroxy-3-[4-(2-methoxy- phenyl)-piperazin-1 -yl]-propoxy]-phenyl]-amide; 17 Furan-2-carboxylic acid [2-[2-hydroxy-3-[4-(2-methoxy- phenyl)-piperazin-1 -yl]-propoxy]-phenyl]-amide; 18 [2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 -yl]- propoxy]-phenyl]-urea; 19 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 -yl]- propoxy]-5-methyl-phenyl]-acetamide; 20 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 -yl]- propoxy]-4-methyl-phenyl]-acetamide; 21 N-[2-[3-[4-(2-Ethoxy-phenyl)-piperazin-1 -yi]-2-hydroxy- propoxy]-phenyl]propionamide; 22 1 -(2-Amino-ρhenoxy)-3-[4-(2-nitro-phenyl)-piperazin-1 - yl]-propan-2-ol; 30 Ethyl 2-(2-acetylamino-phenoxy)-1 -[4-(2-methoxy- phenyl)-piperazin-1 -ylmethyl]-acetate and 31 Ethyl [+]-2-(2-acetylamino-phenoxy)-1 -[4-(2-methoxy- phenyl)-piperazin-1 -ylmethyl]-acetate. The following Table 2 clearly shows the selectivity of some compounds with respect to the D 2 receptor, expressed by the ratio of the Ki values at the D4 receptor and at the D2 receptor. Table 2 The compounds of formula I and pharmaceutically accept¬ able salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parent- erally, e.g. in the form of injection solutions. The compounds of formula I and pharmaceutically accept¬ able salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsi- fiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances. As mentioned earlier, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises by bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, a daily dosage of about 1 mg to 1000 mg should be appropriate. Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutically usable salts thereof for the production of medicaments, especially for the control or prevention of illnesses which are caused by disorders of the dopamine system, is also an object of the invention. Example A Tablets of the following composition are produced in the usual manner: mα/tablet Active ingredient 100 Powd. lactose 95 White corn starch 35 Polyvinylpyrrolidone 8 Na carboxymethyl starch 10 Magnesium stearate 2 Tablet weight 250 Example B Tablets of the following composition are produced in the usual manner: mα/tablet Active ingredient 200 Powd. lactose 100 White corn starch 64 Polyvinylpyrrolidone 12 Na carboxymethyl starch 20 Magnesium stearate 4 Tablet weight 400 Example C Capsules of the following composition are produced: mα/capsule Active ingredient 50 Cryst. lactose 60 Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150 The active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are homo¬ geneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatine capsules of suitable size.

Claims: Claims 1. The use of compounds of the general formula wherein R 1 and R 3 each independently signify hydrogen, aryl, carbamoyl, lower-alkyl-carbonyl, lower-alkyl, halogen, lower- alkyl-carbonyl-amino, lower-alkenyl-carbonyl-amino, amino, arylamino, aryloxy, nitro, aryl-acetyl, lower- alkanoyl-lower-alkyl, alkyl-sulphonyl-amino, ureido or furan-2-yl-carbonyl-amino and R 2 signifies hydrogen, lower-alkyl, trifluoromethyl, halogen, lower-alkoxy, lower-alkyl-carbonyl or lower-alkyl-carbonyl-amino or R 1 and R 2 together can be -OCH 2 0-, -0(CH 2 )2θ- or -(CH 2 )3-, R 4 signifies hydrogen, halogen, hydroxy, lower-alkyl, lower-alkoxy or nitro, R 5 signifies hydrogen, halogen or lower-alkoxy, R 6 signifies hydrogen, lower-alkyl, halogen, hydroxy, amino, lower-alkoxy, trifluoromethyl, nitro or lower- alkyl-carbonyl-amino and R 7 signifies hydrogen or lower-alkyl-carbonyl, as well as of pharmaceutically acceptable salts of compounds of formula I for the treatment or prevention of illnesses which are caused by disorders of the dopamine system and, respectively, for the production of corresponding medicaments. 2. The use in accordance with claim 1 of compounds of general formula I defined in claim 1 in which R 1 signifies hydrogen or methyl, R 2 signifies hydrogen, trifluoromethyl or methyl, R 4 signifies hydrogen, hydroxy or halogen, R5 signifies hydrogen and R 3 , R 6 and R 7 have the significance set forth in claim 1 . 3. The use in accordance with claim 1 or 2 in psychotic 5 illnesses. 4. The use in accordance with claim 3 in schizophrenia. 5. The use in accordance with any one of claims 1 -4 with o a reference to a dosage of 1 mg to 1000 mg per day. 6. A medicament for use in illnesses which are caused by disorders of the dopamine system, containing a compound according to claim 1 or 2 and a therapeutically inert carrier. 5 7. A method for the treatment or prevention of illnesses which are caused by disorders of the dopamine system, which method comprises the administration of an effective dosage of a compound according to claim 1 or 2. 0 * * *

Inventors: GODEL THIERRY, HARTMAN DEBORAH, RIEMER CLAUS, GODEL, THIERRY, HARTMAN, DEBORAH, RIEMER, CLAUS
Applicants: HOFFMANN LA ROCHE, F. HOFFMANN-LA ROCHE AG
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61P25, A61P43, C07D295, C07D307