Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-09
2001-09-18
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S150000
Reexamination Certificate
active
06291494
ABSTRACT:
DESCRIPTION
1. Technical Field
The present invention relates to new 2-amino-thiazol-fused 2-aminoindans and 2-aminotetralins and their use. More particularly, the present invention relates to (basic)N-substituted and (basic)-N,N-disubstituted derivatives of 2,6-di-amino-thiazolo[4,5-f]indan, 2,7-di-amino-thiazolo[4,5-g]-tetralin and 2,7-di-amino-thiazolo[5,4-g]-tetralin having pharmacologically valuable properties, acid addition salts thereof, pharmaceutical compositions containing them and their use in the preparation of medicaments.
2. Background Art
Numerous tetrahydro-benzothiazoles are known from the literature. Thus, U.S. Pat. No. 4,337,343 describes 4,5,6,7-tetrahydro-benzothiazoles which are substituted in the 2 position by a hydrogen atom or an alkyl group and in the 4, 5 or 6 position by an alkylaminoalkyl group and have an effect on the circulation, U.S. Pat. No. 4,208,420 describes 4,5,6,7-tetrahydro-benzothiazoles which are substituted in the 2 position by a hydrogen atom or an alkyl group and the 4,5 or 6 position by an alkylamino group and have, inter alia, a stimulatory effect on the sympathetic nervous system and act as regulators of the cerebral vascular system, and DE-A-2.136.233 describes 4,5,6,7-tetrahydro-benzothiazoles ureido or thioureido group and have virustatic properties. optionally substituted ureido of thioureido group and have virustatic properties.
The tetrahydrobenzothiazole Pramipexol® (Mirapex) is presently marketed as a drug against Parkinson's disease (pat. appl. Griss et al., EP 186087 A1 860702; See also Schneider and Mireau, JMC 1987, 30, 494-498).
However, 2-aminothiazole-fused 2-aminoindans and 2-aminoteralins, of the type claimed in this invention (Formula 1 below), have not been described before.
A CAS ONLINE search in the registry file on Jun. 9, 1998 gave no hits on the following truncated structures, thus supporting the fact that the compounds claimed in Formula 1 below are new. Compounds searched and not found in CAS ONLINE (substructure searches; in these searches the indane and tetralin ring system hydrogens were specified and only the two “free site” substituents were allowed to be any substituent possible in CAS ONLINE):
SUMMARY OF THE INVENTION
In one aspect the subject invention is related to new 2-aminothiazol-fused 2-aminoindans and 2-aminotetralins of the general formula (Formula 1):
wherein R
1
and R
2
, which may be identical or different are selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms, (alkyl)cycloalkyl groups of 3 to 7 carbon atoms, alkenyl or alkynyl groups of 3 to 6 carbon atoms, arylalkyl groups having 1 to 3 carbon atoms in the alkyl moiety, whilst the aryl nucleus may be substituted (e.g. by fluorine, chlorine or bromine atoms or a sulfonyloxy (e.g. a triflate)group), and n and m are both 1 (2-aminothiazol-fused 2-aminoindans; Formula 1a):
or n is 2 and m is 1 (2-aminothiazol-fused 2-aminotetralins; Formula 1b):
or n is 1 and m is 2 (2-aminothiazol-fused 2-aminotetralins; Formula 1c):
and the enantiomers ant the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids.
Compounds of general Formula 1 have valuable pharmacological properties, particularly an effect on the dopaminergic system of the central nervous system and/or the circulation.
According to another aspect, the present invention relates to pharmaceutical compositions containing as an active substance a compound of Formula 1 or a physiologically acceptable acid addition salt thereof, optionally together with one or more inert carriers and/or diluents.
According to a further aspect, the present invention relates to the use of a compound of Formula 1 or a physiologically acceptable acid addition salt thereof for preparing a drug having an effect on the dopaminergic system of the central nervous system and/or the circulation, e.g. for treating dopamine receptor related central nervous neuro-psychiatric diseases, circulatory disorders, schizophrenia, Parkinson's disease, Parkinsonism or drug abuse, in particular alcohol and/or cocaine abuse.
According to a still further aspect, the present invention relates to a process for preparing a pharmaceutical composition characterized in that a compound of Formula 1 or a physiologically acceptable salt thereof is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are represented by Formula 1 or a pharmaceutically acceptable salt thereof as shown above. The compounds may be used in a method for treating mammals, especially humans, suffering from dopamine generated central nervous system disorders (e.g. schizophrenia, Parkinson's disease, Tourette's Syndrome, MBD, hyperprolactinemia and drug abuse (e.g. abuse of alcohol or cocaine)) by administering a therapeutically effective amount of a Formula 1 compound.
In the structural Formula 1, the carbon content of various hydrocarbon-containing moieties is indicated by expressing that the moiety contains “i to j carbon atoms”. Thus, a “1 to 7 carbon atoms” alkyl refers to straight and branched alkyls of one to seven carbon atoms, inclusive, including isomers thereof such as methyl, ethyl, propyl and isopropyl.
Cycloalkyl are three to seven carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term “halogen” includes fluoro, chloro, bromo and iodo.
As examples of the definitions of the group —NR
1
R
2
this group represents an amino, methyl-amino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isoamylamino, n-hexylamino, n-heptylamino, dimethylamino, di-ethylamino, di-n-propylamino, di-n-butylamino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-isopropylamino, 2,2,2-trifluoro-ethylamino, 3,3,3-trifluoro-propylamino, 2-fluoro-ethylamino, 3-fluoro-propylamino, allylamino, buten-2-ylamino, hexen-2-ylamino, diallylamino, N-methyl-allylamino, N-ethyl-allylamino, N-n-propyl-allylamino, N-n-butyl-allylamino, propargylamino, buten-2-ylamino, hexen-2-ylamino, dipropargylamino, N-methyl-propargylamino, N-ethyl-propargylamino, cyclopropylamino, cyclobutylamino, cyclo-pentylamino, cyclobexylamino, cycloheptylamino, N-methyl-cyclohexylamino, N-ethyl-cyclohexylamino, benzylamino, chlorobenzylamino, bromobenzylamino, 1-phenylethylamino, 2-phenylethylamino, 2-phenyl-n-propylamino, 3-phenyl-n-propylamino, N-methyl-benzylamino, N-ethyl-benzylamino, N-ethyl-p-chlorobenzylamino, N-ethyl-2-phenylethylamino, N-allyl-benzylamino, N-allyl-p-chlorobenzylamino, n-propyl-phenylethylamino, n-propyl-2-thienylethylamino, n-propyl-3-thienylethylamino group.
As further examples of the group “arylalkyl”, this group represents an alkyl part of 1-3 carbon atoms, where the aryl part can be taken from (substituted) phenyl, 1- or 2-naphtyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furanoyl, 2- or 4-imidazolyl and 1-imidazolin-2-one, the three last given as structural formulas for clarity:
Pharmaceutically acceptable salts means salts useful for administering the compounds of this invention or useful forms the compounds may take in vitro and in vivo and include the acid addition salts with e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid. Alkyl sulfonic acids (e.g. CH
3
SO
3
H) are also suitable for the salt formation. These salts may be in hydrated form.
Particularly preferred compounds of general Formula 1 are, however, the compounds of general Formula 1, wherein
R
1
represents a hydrogen atom, an alkyl or F-alkyl group having 1 to 3 carbon atoms or an allyl group,
R
2
represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a haloalkyl group having 1-6 carbon atoms, an allyl, propargyl, phenylethyl, 2-thienylethyl, 3-thienylethyl, cyclopropylmethyl group, and the acid addition salts thereof, particularly the physiolo
Andrén Per Erik
Carlsson Per Arvid Emil
Dijkstra Durk
Gunne Lars
Van Vliet Leonard Alexander
McDermott & Will & Emery
Stockton Laura L.
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