Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use

Abstract

Compounds of the general formula Iwherein rings B, C, D and E may be present or not and, when present, are combined with A as A+C, A+E, A+B+C, A+B+D, A+B+E, A+C+E, A+B+C+D or A+B+C+D+E, rings B, C and E being aliphatic whereas ring D may be aliphatic or aromatic / heteroaromatic, and wherein X is —(CH2)m—, in which m is an integer 1-3, to form a ring E or, when E is absent, a group R1 bound to the nitrogen atom, wherein R1 is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 3 carbon atoms, cycloalkyl(alkyl) groups of 3 to 5 carbon atoms (i.e. including cyclopropyl, cyclopropylmethyl, cyclobutyl and cyclobutylmethyl) and wherein Y is —(CH2)n—, in which n is an integer 1-3, to form a ring C or when C is absent, a group R2 bound to the nitrogen atom, wherein R2 is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms, cycloalkyl(alkyl) groups of 3 to 7 carbon atoms, alkenyl or alkylnyl groups of 3 to 6 carbon atoms, arylalkyl, heteroarylalkyl having 1 to 3 carbon atoms in the alkyl moiety, whilst the aryl / heteroaryl nucleus may be substituted, provided that when rings B, C, D and E are absent NR1R2 is different from dimethylamino, N-methyl-N-ethylamino, N-methyl-N-propynyl-amino, N-methyl-N-propylamino and N-hydroxipropyl-N-methylamino, and salts thereof with pharmaceutically acceptable acids or bases are disclosed as well as the use of such compounds for the manufacturing of pharmaceutical compositions for the treatment of Parkinson's disease, psychoses, Huntington's disease, impotence, renal failure, heart failure or hypertension, such pharmaceutical compositions and methods of treating Parkinson's disease and schizophrenia.

Description

[0001]This application is a divisional of application Ser. No. 10 / 258,014 filed Oct. 18, 2002 now U.S. Pat. No. 6,683,087, which is a 371 of PCT / SE01 / 00840, filed Apr. 17, 2001.FIELD OF THE INVENTION[0002]The present invention relates to new chemical compounds representing a new prodrug principle for the generation of catecholamines, in particular catecholethylamines, to processes for their preparation, pharmaceutical compositions containing them and their use in therapy.BACKGROUND ART[0003]Neurodegenerative diseases are becoming more prevalent with the aging population. One particular neurodegenerative disease which typically has its onset between the ages of 50 and 80 years of age is Parkinson's disease. Parkinson's disease is a disorder of the brain which is characterized by tremor and difficulty with walking, movement, and coordination.[0004]Parkinson's disease appears to be caused by a progressive deterioration of dopamine-containing neurons in the substantia nigra zona compact...

AI Technical Summary

Benefits of technology

The present invention provides new prodrugs that can be metabolized in vivo to a catecholamine derivative that is a potent dopamine receptor ligand with agonist, partial agonist, inverse agonist, and antagonist effects. These prodrugs have been found to be useful for the treatment of various diseases such as Parkinson's disease, schizophrenia, Huntington's disease, impotence, renal failure, heart failure, hypertension, and sexual stimulation disorders. The prodrugs can be used as therapeutic agents or in the preparation of pharmaceutical compositions.

Problems solved by technology

Insufficient dopamine is thought to disturb the balance between dopamine and other neurotransmitters such as acetylcholine.

When such dopamine levels are reduced, nerve cells cannot properly transmit impulses, resulting in a loss of muscle control and function.

Currently, there is no known cure for Parkinson's disease.

However, their clinical use is limited because they have low or no bioavailability (high first-pass effect).

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