CN1187124A - Use of phenoxy pyridine derivatives for treatment of illnesses caused by disorders of dopamine system - Google Patents

Abstract

The present invention relates to the purposes of the compound shown in formula I, wherein: R ¹ represents hydrogen, lower alkyl, halogen, lower alkoxy or nitro; R ² represents hydrogen, lower alkyl, trifluoromethyl; and R ³ represents hydrogen, lower alkyl, trifluoromethyl, benzyl, hydroxy lower alkyl, lower alkoxy, lower alkylcarbonylamino, carbonyl lower alkyl, benzyl, di-lower alkylaminocarbonyl, carbonylamino; Or amino-carbonyl-amino, or R ² and R ³ can also collectively represent a condensed benzene ring and R ⁴ represent hydrogen or halogen, which also includes the use of pharmaceutically acceptable salts thereof. These compounds can be used to control and prevent diseases caused by the disorder of the dopamine system, and can also be used to produce corresponding drugs.

Description

Use of phenoxypiperidine derivatives for treating diseases caused by dopamine system disorders

The present invention relates to aromatic ethers, especially phenoxypyridine derivatives with the following general formula, and pharmaceutically acceptable salts thereof:

in

^R represents hydrogen, lower alkyl, halogen, lower alkoxy or nitro;

^R represents hydrogen, lower alkyl or trifluoromethyl; and

R ³ represents hydrogen, lower alkyl, trifluoromethyl, benzyl, hydroxy lower alkyl, lower

  Alkoxy, lower alkylcarbonylamino, carbonyl lower alkyl, benzyl, di-lower alkane

      Aminocarbonyl, carbonylamino; or amino-carbonyl-amino, or

^R2 and ^R3 can also together represent a fused benzene ring

and

R ⁴ represents hydrogen or halogen

These compounds and their salts are known. Their preparation and their use as anti-inflammatory, antiallergic, antitussive, and analgesic agents have been described in DE-OS 1964421.

Herein, "lower alkyl" means a straight or branched lower alkyl group of 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, butyl, pentyl and the like. "Lower alkoxy" means a lower alkyl ether group in which the lower alkyl group is as previously described. For example, methoxy, ethoxy, isopropoxy and the like. Halogen refers to chlorine, bromine, fluorine and iodine. The aforementioned halogen atoms are preferably fluorine and chlorine.

It has now been surprisingly found that these compounds can be used to control or prevent diseases caused by disturbances of the dopamine system. At this point they are classified as psychiatric drugs such as those used in the treatment of schizophrenia. Therefore the object of the present invention is to use the compounds of formula I to treat or prevent mental diseases caused by disturbance of the dopamine system and to use these compounds as the active ingredient of medicines to produce medicines for the above-mentioned therapeutic purposes and especially medicines containing these compounds drug.

The novel pharmacological properties of these compounds are based on a highly selective affinity for neuroreceptors, especially for the dopamine _D4 receptor. Therefore, when using them, one can expect their side effects to be much milder than those of the known classic central antipsychotics, such as haloperidol. Haloperidol is a recognized drug that binds to _D2 and _D3 receptors. It has been found that in schizophrenia, the density of _D2 and _D3 receptors increases by about 10%, while at the same time the density of _D4 receptors increases by more than 600% (TiPS, July 1994, vol.15, p.264-70 ).

The compounds of the invention are characterized by their ability to bind to the _D4 receptor.

Furthermore, it is expected that these compounds should have better selectivity for the _D4 receptor over the _D2 receptor.

CHO cells (Chinese hamster ovary cells) were used in the experiments.

Crude membranes were isolated from _D4 -CHO and _D2 -CHO cells by ultracentrifugation and stored at -80°C. Homogenize with buffer (50 mM Tris, 1 mM EDTA, 5 mM KCl, 1.5 mM CaCl ₂ , 4 mM MgCl ₂ , pH 7.4) after thawing at room temperature with 200 pM [ ³ H]-spipperidone and gradually increase the concentration The test compound (1×10 ^-11 M-1×10 ^-4 M) was incubated for 90 minutes, and the non-specific binding was established by incubation with 1×10 ^-5 M(+)-butaramo. Unbound radioligand was filtered out with a GF/C glass filter, and radioactivity of the conjugate was measured by scintillation in a Packard Topcount liquid scintillation counter.

The table below shows the binding of some compounds that selectively bind to the _D4 receptor. _{Ki is} the binding constant representing the affinity of the compound for the _D4 receptor. Measured by [ ³ H]-spiperidone. Ligands can affect the calculation results of this method.

Table 1 Cpd. No. R ¹ R ² R ³ R ⁴ K _i atD4[nM] 1 h _CH3 h h <100 2 h h _CH3 h <100 3 h h CF ₃ h <100 4 h h -CH ₂ OH h <100 5 h h -OCH ₃ h <100 6 h h -NHCOCH ₃ h <100 7 h h -COCH ₃ h <100 8 _{CH3 CH3} h h <100 9 Cl h -NHCOCH ₃ h <100 10 h R ² and R ³ together represent a benzene ring h <100 11 h CF ₃ h f <100 12 h h -CONH ₂ f <100 13 h h -NHCONH ₂ f <100 14 h h -NHCOCH ₃ Cl <100

Table 1 illustrates specific active compounds, which are the following compounds: 1. 1-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-3-m-tolyloxy-propane- 2-alcohol 2.1-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-3-o-tolyloxy-propan-2-ol 3.1-(4-benzene Base-3,6-dihydro-2H-pyridin-1-yl)-3-(3-trifluoromethylphenoxy)-propan-2-ol 4.1-(2-hydroxymethylphenoxy )-3-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-propan-2-ol 5.1-(2-methoxyphenyl)-3-(4- Phenyl-3,6-dihydro-2H-pyridin-1-yl)-propan-2-ol 6. N-[2-[2-hydroxyl-3-(4-phenyl-3,6-dihydro -2H-pyridin-1-yl)-propoxy]-phenyl]-acetamide 7. 1-[2-[2-hydroxyl-3-(4-phenyl-3,6-dihydro-2H- Pyridin-1-yl)-propoxy]-phenyl]-ethanone 8. 1-(3,4-dimethylphenoxy)-3-(4-phenyl-3,6-dihydro- 2H-pyridin-1-yl)-propan-2-ol 9. N-[5-chloro-2-[2-hydroxyl-3-(4-phenyl-3,6-dihydro-2H-pyridine-1 -yl)-propoxy]-phenyl]-acetamide 10.1-(naphthalene-1-oxyl)-3-(4-phenyl-3,6-dihydro-2H-pyr-1-yl )-propan-2-ol 11. 1-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-3-(3-trifluoromethyl-phenoxy

Base)-propan-2-ol 12. 2-[3-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-hydroxypropoxy]-

Benzamide 13. [2-[3-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-hydroxypropoxy]-

Phenyl]-urea 14. N-[2-[3-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-hydroxypropoxy

base]-phenyl]-acetamide

Compounds according to formula I and their pharmaceutically acceptable salts can be used as medicines. For example, in the form of a pharmaceutical preparation. The pharmaceutical preparations can be taken orally, such as tablets, coated tablets, sugar pills, hard and soft capsules, solutions, emulsions or suspensions. In addition, rectal administration, such as administration in the form of suppositories, or parenteral administration, such as administration in the form of injections,

In the manufacture of pharmaceutical preparations containing compounds of formula I and pharmaceutically acceptable salts thereof, pharmaceutically inert, inorganic or organic carriers may be used. For example, as carriers for tablets, coated tablets, sugar pills and hard capsules, lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like can be used. Suitable carriers for soft capsules may be, for example, vegetable oils, waxes, animal fats, semi-solid and liquid polyols, etc.; however, due to the nature of the active ingredient, no carrier is usually required for soft capsules. Carriers for the production of solutions and syrups, such as water, polyols, sucrose, invert sugar, glucose, etc. Alcohols, polyalcohols, glycerin, vegetable oils, etc. can be used as solubilizers for the preparation of water-soluble injections of water-soluble salts of compounds of formula I, but this is not a necessary rule. Suitable carriers for suppositories are natural or hardened oils, waxes, tallow, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavor enhancers, salts for varying the osmotic pressure, buffers, coatings or antioxidants. It may also contain other therapeutically valuable substances.

As already mentioned, medicaments comprising a compound according to formula I or a pharmaceutically acceptable salt thereof and therapeutically neutral excipients, as well as processes for the production of said medicaments, are also objects of the present invention. The method comprises the preparation of one or more compounds of formula I or a pharmaceutically acceptable salt thereof, and one or more therapeutically valuable substances, and one or more therapeutically The active carrier is mixed into the administration form. The dosage may be adjusted within wide limits and in particular cases altered to suit particular needs. In short, a dosage of about 1-1000 mg per day should be appropriate.

Finally, as mentioned above, the use of compounds according to formula I and pharmaceutically acceptable salts thereof for the production of medicines, especially for the production of medicines for the control and prevention of diseases caused by disturbances of the dopamine system, is also an object of the present invention.

Example A

Tablets containing the following ingredients are produced in a generic manner:

mg/tablet

Active ingredient 100

Lactose powder 95

white cornstarch 35

Polyvinylpyrrolidone 8

Sodium Carboxymethyl Starch 10

Magnesium stearate 2

Tablet weight 250

Example B

Tablets containing the following ingredients are produced in a generic manner:

mg/tablet

Active ingredient 200

Lactose powder 100

white cornstarch 64

Polyvinylpyrrolidone 12

Sodium Carboxymethyl Starch 20

Magnesium stearate 4

Tablet Weight 400

Example C

Prepare capsules containing the following ingredients:

Active ingredient 50

Crystalline lactose 60

Microcrystalline Cellulose 34

Talc 5

Magnesium stearate 1

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The active ingredients with appropriate particle size, lactose crystals and microcrystalline cellulose are evenly mixed. After sieving, talc and magnesium stearate are also added to the mixture and mixed evenly. Finally, the mixture is filled into hard capsules of appropriate size.

Claims (10)

1. Compound shown by formula I and on pharmaceutics acceptable salt, be used to control and prevent because caused disease of disorders of dopamine system and the purposes that is used to produce relative medicine;

   Wherein

   

   R ¹Expression hydrogen, low alkyl group, halogen, lower alkoxy or nitro; R ²Expression hydrogen, low alkyl group, trifluoromethyl; And R ³Expression hydrogen, low alkyl group, trifluoromethyl, benzyl, hydroxyl low-grade alkyl is low

   The level alkoxyl, the low alkyl group carbonyl amino, the carbonyl low alkyl group, benzyl, two is low

   The level alkyl amino-carbonyl, carbonylamino; Or amino-carbonyl-amino, perhaps R ²And R ³Also can represent jointly thick and phenyl ring; And R ⁴The expression hydrogen or halogen.
2. 2. according to the purposes of the chemical compound of the formula I of claim 1, R wherein ¹Expression hydrogen, R ²Expression hydrogen or trifluoromethyl, R ³Expression hydrogen, carbonyl amino or acetylamino, R ⁴The expression fluorine or chlorine.
3. 3. according to the purposes of claim 1, said chemical compound is 1-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-yl]-3-(3-4-trifluoromethylphenopendant)-propan-2-ol.
4. 4. according to the purposes of claim 1, said chemical compound is N-[2-[3-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-yl]-2-hydroxyl-propoxyl group]-phenyl]-acetamide.
5. 5. according to the purposes of claim 1, said chemical compound is 2-[3-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-yl]-2-hydroxyl-propoxyl group]-phenyl]-Benzoylamide.
6. 6. according to any one purposes of claim 1-5, be used for the treatment of psychosis.
7. 7. according to the purposes of claim 6, be used for the treatment of schizophrenia.
8. 8. according to the purposes in any among the claim 1-7, the dosage of chemical compound wherein is 1-1000mg/ days the dosage that instructs.
9. 9. medicine that is used for the disease that caused by disorders of dopamine system, it contains chemical compound and the inert carrier of treatment among among the claim 1-5 any one.
10. 10. treatment and prevention be because the method for the disease that causes of disorders of dopamine system, and this method comprises and gives effective dose, the chemical compound among the claim 1-5 in any.