MXPA00011147A - Phenylsulfonamide-phenylethylamines useful as dopamine receptors - Google Patents

Abstract

Compounds of formula (I) and their pharmaceutically acceptable slats having selective dopamine D3 receptor activity suitable for treating central nervous system disorders. In formula (I) R1 is independently H or a C1-C8 alkyl including isomeric forms thereof;R2 is H, C1-C3 alkyl, a halogen, OCH3, OCF3, CF3, CN, SCH3 or NHCOCH3;and R3 is H, C1-C3 alkyl, a halogen, OCH3, OCF3, CF3, CN, SCH3 or NHCOCH3.

Description

FENILSULFONAMIDA-FENILETILAMINAS USEFUL AS RECEPTORS OF DOPAMINE FIELD OF THE INVENTION The present invention is directed to a novel chemical structure of phenylsulfonamide- (phenylethylamine), wherein the phenylsulfonamide is optionally substituted. The compound and its pharmaceutically acceptable salts are preferably linked to the dopamine D3 receptor and, therefore, are useful in the treatment of CNS disorders, such as schizophrenia, Parkinson's disease, tardive dyskinesia, obsessive-compulsive disorders, depression and anxiety. .

BACKGROUND OF THE INVENTION The dopamine D3 receptor was recently cloned by Sokoloff et al. (Nature, 347, 146 (1990)). Raising the hypothesis that this receptor subtype is important in the action of anti-psychotics. Interestingly, this receptor shows a relatively high abundance in regions of the brain associated with emotional and cognitive functions. Compounds with this profile may be useful in the treatment of CNS disorders, for example schizophrenia, mania, depression, geriatric disorders, drug addiction and abuse, Parkinson's disease, anxiety disorders, sleep disorders, alterations in circadian rhythm and dementia.

SUMMARY OF THE INVENTION In one aspect, the present invention is directed to pharmaceutically acceptable compounds and salts of Formula I: R1 is independently H or a C-C8 alkyl, including isomeric forms thereof. R2 is H, C1-C3 alkyl, including isomeric forms thereof, halogens (preferably Cl, F and Br), OCH3, OCF3, CF3, CN, SCH3 or NHCOCH3; and R3 is H, CJ.-C3 alkyl, including isomeric forms thereof, halogens (preferably Cl, F and Br), OCH3, OCF3, CF3, CN, SCH3 or NHCOCH3. In Formula I, it is demonstrated that the ethyl amine entity is either in the meta position or in the para position, to form any isomer. In another aspect, the present invention is a method for treating schizophrenia by administration to a patient suffering from schizophrenia of a therapeutically effective amount of a compound of Formula I. The compounds of Formula I can be administered to a patient suffering from schizophrenia, mania, depression, geriatric disorders, drug addiction and abuse, Parkinson's disease, disorders of sleep, disorders in the circadian rhythm, anxiety disorders or dementia. The compounds can be administered in an amount from about 0.25 mg to about 100 mg / person. In another aspect, the present invention is directed to a method for treating disorders in the central nervous system associated with the activity of the dopamine D3 receptor in a patient in need of this treatment, which comprises administering to the patient a therapeutically effective amount of a compound of Formula I to alleviate this disorder. Typically, the compound of Formula I is administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent. In another aspect, the present invention is directed to a pharmaceutical composition, for treating disorders of the central nervous system, associated with the activity of the dopamine D3 receptor, comprising an effective amount of a compound of Formula I with a pharmaceutically acceptable carrier or diluent DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to pharmaceutically acceptable compounds or salts of Formula I, as depicted above in either the racemic or pure enantiomer forms. The compounds are selective for the dopamine D3 receptor and have only a moderate affinity for the dopamine D2 receptor. Where "alkyl" is from one to eight or three, depending on the specified carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomeric forms thereof "Halogens" refers to the fluorine atoms, chlorine, bromine and iodine. The pharmaceutically acceptable salts include salts of both inorganic and organic acids. Preferred pharmaceutically acceptable salts include salts of the following acids: methanesulfonic, hydrochloric, bromydipic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric or malic. The compounds of Formula I are orally or parenterally active. In oral form, the compounds of Formula I can be delivered in solid dosage forms, such as tablets or capsules or cansupplied in liquid dosage forms, such as elixirs, syrups or suspensions as is known to those skilled in the art. It is preferred that the compounds of Formula I be supplied in solid dosage form and that this be a tablet. Typically, the compounds of Formula I can be delivered in an amount of about 0.5 mg to about 250 mg / person, one to three times a day. Preferably, from about 5 to about 50 mg / day in divided doses. The exact dosage and frequency of administration depends on the particular Formula I compound used, the particular condition or condition to be treated, the severity of the condition to be treated, age, weight, physical condition. general of the particular patient, of other medications that the patient may be taking, as is well known to those skilled in the art and can be determined more accurately by measuring the level or concentration in blood of the active compound in the patient's blood and / or the patient's response to the particular condition being treated. Thus, the compounds present, together with a pharmaceutically acceptable carrier, diluent or buffer, can be administered in an amount effective therapeutic or pharmacological treatment to alleviate the disorder of the central nervous system with respect to the diagnosed physiological condition. The compounds can be administered intravenously, intramuscularly, topically, transdermally, such as for example by epidermal patches, in oral or buccal form to humans or other vertebrates. The compositions of the present invention may be presented for administration to humans and other vertebrates in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, oil emulsions. in water and water in oil containing the right amounts of the compound, suppositories and in suspensions or fluid solutions. For oral administration, unit dosage forms can be prepared either solid or fluid. To prepare solid compositions such as tablets, the compound can be mixed with conventional ingredients, such as talcum, magnesium stearate, dicalcium phosphate, aluminum magnesium silicate, calcium sulfate, starch, lactose, acacia, methylcellulose and functionally pharmaceutical diluents or excipients. Similar. The capsules are prepared mixing the compound with an inert pharmaceutical diluent and filling with the mixture a hard gelatin capsule of the appropriate size. The soft gelatin capsules were prepared by machine encapsulation of a pulp of the compound with a vegetable oil, light liquid petrolatum or other inert oil that is acceptable. Fluid unit dosage forms can be prepared for oral administration, such as syrups, elixirs, and suspensions. The forms can be dissolved in an aqueous carrier together with sugar, aromatic flavoring agents and preservatives to form a syrup. The suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent, such as acacia, tragacanth, methylcellulose and the like. For parenteral administration, fluid unit dosage forms can be prepared using the compound and a sterile vehicle. In the preparation of the solutions, the compound can be dissolved in water for injection and sterilized by filtration before filling and sealing a suitable vial or vial. Adjuvants, such as local anesthetic agents, preservatives and buffers can dissolve in the vehicle. The composition can be frozen after filling the vial and the water removed in vacuo. The lyophilized powder can then be sealed in the vial and reconstitute before use.

Binding Data of the Examples: Competent binding experiments used eleven dilutions of test compounds of Formula I competing with [3 H] -5- (dipropylamino) -5,6-dihydro-4H-imidazo (4, 5) , 1-ij) quinolin-2 (1H) -one (R-enantiomer) ("86170") (62 Ci / mmol, 2nM) and [3 H] -spiperone ("SPI") (107 Ci / mmol, 0.5 nM ) for binding sites D2 and D3, respectively. (Lahti, R.A., Eur. J. Pharmacol., 202, 289 (1991)). In each experiment, cloned rat receptors expressed in CH0-K1 cells were used. (Chio, C.L., Nature, 343, 266 (1990); and Huff, R.M., Mol.Pharmacol., 45, 51-60 (1993)). The results are shown in Table I.

TABLE 1 IC50 VALUES OF THE UNION DATA TO THE RECEIVER Example # Receptor Ki (nM) 1 D2-DOP-CLON 629 D3-DOP-CLON 3.7 D2-DOP-CLON 1069 D3-DOP-CLON 34 D2-DOP-CLON 760 D3-DOP-CLON 14.26 D2-DOP-CLON 677 D3-D0P-CLON 18 D2-D0P-CL0N 2390 D3-D0P-CL0N 28 D2-DOP-CLON 2176 D3-DOP-CLON 165 D2-DOP-CLON 623 D3-DOP-CLON 14 D2-DOP-CLON 1529 D3-DOP-CLON 33 D2 -DOP-CLON 645 D3-DOP-CLON 54 D2-DOP-CLON 1075 D3-DOP-CLON 111 Scheme 1: Scheme 2: 7: a H 8: F3CO H ^ kuf 9: F Cl 10: Br H 11: F3C H Scheme 3: D ArS02Q 2) TFA 14: X = H, Y = F 15: X = CI, Y = H In procedure 1 (Scheme 1), 4-nitrofenethylamine (1) was dipropyllated with bromopropane, followed by catalytic hydrogenation of palladium on carbon from the nitro entity to produce 2. The addition of functional groups of the aromatic amine with aryl sulfonyl chlorides using procedure 2 provided analogs 3 and 4 of dipropylamine. The analogs of monopropyl amine were synthesized using procedures 3 and 4, as shown in scheme 2. In the procedure, 3,4-nitrofenethylamine (1) was acylated with propionyl chloride and this amide was selectively reduced with borano. The resulting secondary amine was protected as the BOC-carbamate followed by catalytic hydrogenation with palladium on carbon from the nitro portion to produce 5.

Using procedure 4, the aromatic amine was treated with aplsulfonyl chlorides, followed by BOC deprotection of the secondary amine with trifluoroacetic acid to provide analogs 6, 7, 8, 9, 10 and 11 monopropylamine. The metaubstituted phenethylamines were synthesized in procedures 5 and 4, as shown in scheme 3. In procedure 5, 3-nitrophenethyl alcohol (12) was subjected to sulfonylation with methanesulfonyl chloride and used to alky1-ammopropane. The resulting secondary amine was protected as the BOC-carbamate, followed by catalytic hydrogenation with palladium on carbon from the nitro portion to produce 13. Using procedure 4, the aromatic amine was treated with aplsulfonyl chlorides, followed by the BOC deprotection. the secondary amine with tpfluoroacetic acid to provide analogues 14 and 15 of monopropylamma.

EXAMPLE 1: Procedure 1- Preparation of 2- (4-ammophenol) et? L-1-dipropylamine (2) 2- (4-N? Trophenyl) ethylamine hydrochloride (3.9 g), potassium carbonate ( 2 eq), bromopropane (6 eq), and dimethylformamide (40 mL) were stirred at room temperature All night long. The solvent was concentrated in vacuo and the residue fractionated between diethyl ether and water. The ether layer was washed with brine and the solvent removed in vacuo. The residue was subjected to flash chromatography. (dichloromethane / ethyl acetate / hexane) to provide 2.9 g of an oil. This oil was catalytically hydrogenated in ethanol with palladium on 10% carbon to provide 2.2 g of the title compound as an oil.

Method 2: Preparation of 2- [4- (4-chlorobenzenesulfonamido) phenyl] ethyl-1-dipropylamine (3). To 2- (4-aminophenyl) ethyl-1-dipropylamine (0.40 g), triethylamine (3 eq) and THF (5 mL) was added 4-chlorobenzenesulfonyl chloride (0.40 g) in THF (3 mL). After 16 hours, it was partitioned between diethyl ether and saturated aqueous sodium bicarbonate. The ether layer was washed with brine and the solvent removed in vacuo. The residue was subjected to flash chromatography (dichloromethane / ethyl acetate / hexane) to provide 0.6 g of the title compound as an oil. The hydrochloride salt was crystallized from methanol / diethylether to provide a solid with m.p. of 74-78 ° C.

EXAMPLE 2: Preparation of 2 - [4- (4-acetamidobenzensulfonamido) phenyl] et? l-1-d? prop? lamma (4). To the 2- (4-ammophene?) Et? -1-d? Prop? Lam? Na was added 4-acetam? Dobenzensulfonyl chloride using procedure 2 to provide the title compound. The hydrochloride salt was crystallized from methanol / diethylether to provide a solid with m.p. of 248-250 ° C.

Procedure 3. Preparation of 2- (4-ammophene?) Et? L-1- (tert-butoxycarbonyl) propylamine (5). To the 2- (4-n-trophenyl) ethylamine hydrochloride (5.0 g), tpetilamma (2.5 eq) and THF (50 mL) was added propionyl chloride (2.5 mL). After 18 hours, the solution was fractionated between diethyl ether and water and the ether layer was washed with 2N hydrochloric acid, water, aqueous bicarbonate and brine. The solvent was removed in vacuo and the residue was subjected to flash chromatography (methanol / d chloromethane) to provide 3.3 g of a solid. This was dissolved in THF, borane-dimethyl sulfide (1.5 eq) was added and refluxed at 17 hours. It was then refluxed with 2N hydrochloric acid (20 mL) for 75 minutes and the mixture was extracted with diethyl ether. The aqueous layer was basified with sodium hydroxide and this basic aqueous layer was extracted with diethyl ether / THF and the ether layer was washed with brine. The solvent was removed under vacuum to provide 3.1 g of an oil. To this oil was added THF (40 mL) and di-tert-butyldicarbonate (1.1 eq). After 45 minutes, the solvent was removed in vacuo and the residue was subjected to flash chromatography (dichloromethane / ethyl acetate / hexane) to provide 4.4 g of an oil. This oil was catalytically hydrogenated in ethanol with palladium on 10% carbon to provide 3.7 g of the title compound, as an oil.

EXAMPLE 3: Method 4: Preparation of 2- [4- (2,4-dichlorobenzensulfonamido) phenyl] ethyl-1-propylamine (6). To 2- (4-aminophenyl) ethyl-1- (tert-butoxycarbonyl) propylamine (0.50 g), triethylamine (1.5 eq), and THF (5 mL) was added 2,4-dichlorobenzenesulfonyl chloride (0.49 g). After 19 hours it was partitioned between diethyl ether and saturated aqueous sodium bicarbonate. The ether layer was washed with brine and the solvent removed in vacuo. The residue was subjected to flash chromatography (dichloromethane / ethyl acetate / hexane) to provide 0.6 g of a solid. Trifluoroacetic acid (3 mL) was added; after 90 minutes it was removed under vacuum and the residue partitioned between diethyl ether / THF and saturated aqueous sodium bicarbonate. The ether layer was washed with brine, the solvent was removed in vacuo and the residue was subjected to flash chromatography (ammonium hydroxide in methanol / dichloromethane) to give the title compound as a solid with m.p. from 165-168 ° C.

EXAMPLE 4: Preparation of 2- [4- (4-chlorobenzensulfonamido) phenyl] ethyl-1-propylamine (7). Using procedure 4, 2- (4-aminophenyl) ethyl-1- (tert-butoxycarbonyl) propylamine was added 4-chlorobenzenesulfonyl chloride to give the title compound as a solid, m.p. of 137-140 ° C.

EXAMPLE 5: Preparation of 2- [4- (4-trifluoromethoxybenzensulfonamido) phenyl] ethyl-1-propylamine (8). Using procedure 4, 2- (4-aminophenyl) ethyl-1- (tert-butoxycarbonyl) propylamine was added 4-trifluoromethoxybenzenesulfonyl chloride to give the title compound as a solid with m.p. of 151-154 ° C.

EXAMPLE 6: Preparation of 2- [4- (2-chloro-4-fluorobenzensulfonamido) phenyl] ethyl-1-propylamine (9). Using procedure 4, a 2- (4- aminophenyl) ethyl-1- (tert-butoxycarbonyl) propylamine was added 2-chloro-4-fluorobenzenesulfonyl chloride to give the title compound as a solid with m.p. from 165-167 ° C.

EXAMPLE 7: Preparation of 2- [4- (4-bromobenzensulfonamido) phenyl] ethyl-1-propylamine (10). Using procedure 4, 2- (4-aminophenyl) ethyl-1- (tert-butoxycarbonyl) ropylamine was added 4-bromobenzenesulfonyl chloride to give the title compound as a solid with m.p. 141-143 ° C.

EXAMPLE 8: Preparation of 2- [4- [(4-trifluoromethyl) benzenesulfonamido] phenyl] ethyl-1-propylamine (11). Using procedure 4, 2- (4-aminophenyl) ethyl-1- (tert-butoxycarbonyl) propylamine was added 4- (trifluoromethyl) benzenesulfonyl chloride to give the title compound as a solid with m.p. from 172-174 ° C.

EXAMPLE 9: Preparation of 2- [3- (2-fluorobenzensulfonamido) phenylethyl-1-propylamine (12).

Using procedure 4, to 2- (3-aminophenyl) ethyl-1- (tert-butoxycarbonyl) propylamine (13) was added 2-fluorobenzenesulfonyl chloride to give the title compound as a solid with m.p. 165-169 ° C.

EXAMPLE 10: Preparation of 2- [3- (3-chlorobenzenesulfonamido) phenyl] ethyl-1-propylamine (13). Using procedure 4, to 2- (3-aminophenyl) ethyl-1- (tert-butoxycarbonyl) propylamine (13) was added 4,3-chlorobenzenesulfonyl chloride to give the title compound as a solid of m.p. 145-148 ° C.

Method 5: Preparation of 2- (3-aminophenyl) ethyl-1- (tert-butoxycarbonyl) propylamine (13). To 2- (3-nitrophenyl) ethyl alcohol (5.0 g) in acetonitrile (60 mL), in an ice bath, were added triethylamine (1.2 eq) and methanesulfonyl chloride (1.1 eq). After 25 minutes propylamine (10 eq) was added and the solution was refluxed for 15 hours. The solvent was removed in vacuo; the hydrochloric acid salt was formed and then crystallized from ethanol / hexane. To this was added THF (70 mL), triethylamine (1.1 eq) and di-tert-butyldicarbonate (1.1 eq). After 60 minutes, the solvent was removed in vacuo and the residue was partitioned between 2N hydrochloric acid and diethyl ether. The ether layer was washed with water, with aqueous sodium bicarbonate and with brine and the solvent was removed in vacuo. The residue was subjected to flash chromatography (ethyl acetate / hexane) to provide 10.9 g of an oil. This oil was catalytically hydrogenated in ethanol with palladium on 10% carbon to provide 7.8 g of the title compound as an oil.

Claims (12)

1. CLAIMS: 1. The use of a compound for the manufacture of a medicament for treating a central nervous system disorder associated with dopamine D3 receptors, wherein the compound has Formula I. wherein each R1 is independently H or C? _? alkyl; and R2 and R3 are independently H, C? _3 alkyl, halogen, 0CH3, OCF3, CF3, CN, SCH3 or NHCOCH3; or a pharmaceutically acceptable salt thereof.
2. 2. The use according to claim 1, wherein each R1 is independently H or Cj.-6 alkyl.
3. 3. The use according to claim 1 or 2, wherein R2 and R3 are each Cl.
4. 4. The use according to claim 1 or 2, wherein R2 is H and R3 is Cl.
5. 5. A compound of Formula I according to any of claims 1 to 4, wherein R3 is OCF3.
6. 6. A compound of Formula I according to any of claims 1 to 4, wherein at least R1 is alkyl, excluding 2- [2- (benzenesulfonamido) phenyl] ethyl-1- methylamine and 2- [4- (4-methoxybenzenesulfonamido) phenyl] ethyl-1-diethylamine.
7. 7. A compound according to claim 5 or 6, wherein one R1 is propyl.
8. 8. A compound according to claim 5 or 7, wherein one R2 is H and R3 is OCF3.
9. 9. A compound according to claim 5, which is: 2- [4- (4-chlorobenzenesulfonamido) phenyl] ethyl-1-dipropylamine; 2- [4- (2, -dichlorobenzensulfonamido) phenyl] ethyl-1-propylamine; 2- [4- (4-chlorobenzenesulfonamido) phenyl] ethyl-1-propylamine; 2- [4- (2-chloro-4-fluorobenzensulfonamido) phenyl] ethyl-1-propylamine; 2- [4- (4-bromobenzensulfonamido) phenyl] ethyl-1-propylamine; 2- [4- [(4-trifluoromethyl) benzenesulfonamido] phenyl] ethyl-1-propylamine; 2- [3- (2-fluorobenzensulfonamido) phenyl] ethyl-1-propylamine; or 2- [3- (3-chlorobenzenesulfonamido) phenyl] ethyl-1-propylamine.
10. 10. A compound according to claim 5, which is: 2- [4- (4-trifluoromethoxybenzenesulfonamido) phenyl] ethyl-1-propylamine. The use according to claim 1, wherein the compound is according to any of claims 5 to 10. 12. 2- (4-ammophenyl) ethyl-1- (tert-butoxycarbonyl) propylamine.