Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-10-03
2002-05-07
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C548S221000, C548S490000, C548S152000, C548S525000, C549S049000, C549S058000, C549S471000, C549S462000, C546S139000, C546S152000, C514S307000, C514S311000, C514S367000, C514S415000, C514S422000, C514S444000, C514S469000, C514S065000
Reexamination Certificate
active
06384281
ABSTRACT:
This application is a 371 of PCT/GB00/01294 filed Apr. 4, 2000.
This invention relates to novel compounds having pharmaceutical properties.
Certain aminoalkyl bicycloheptanes having a pharmacological effect on the central nervous system, are disclosed in British Patent 1 586 249. Also, British Patents 1 444 717 and 1 549 174 describe aminoalkyl bicyclooctyl derivatives with similar properties.
The compounds of the invention are of the following formula:
in which R
1
and R
2
are each hydrogen or C
1-4
alkyl, or
R
1
and R
2
together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, said group being optionally substituted with 1 to 3 C
1-4
alkyl substituents,
R
3
is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted, and n is 1 or 2;
or a salt or ester thereof.
The compounds of the invention and their pharmaceutically acceptable salts and esters are indicated for use in the treatment of disorders of the central nervous system.
In the above formula (I), R
1
and R
2
are preferably hydrogen or C
1-4
alkyl.
A C
1-4
alkyl group can be methyl, ethyl, or propyl, and can be branched or unbranched and includes isopropyl and tert. butyl. Preferably R
1
and R
2
are each hydrogen, methyl or ethyl, and especially hydrogen or methyl. The —NR
1
R
2
group is most preferably —N(CH
3
)
2
or —NH(CH
3
).
Compounds of formula (I) are preferably bicycloheptyl derivatives (n is 1).
The R
3
substituent is attached to the bicyclo ring at certain positions on the substituent, and examples of R
3
groups are a-naphthyl, &bgr;-naphthyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl, 2-, 3-, 5- or 6-benzofuranyl, 2- or 5-benzothiazolyl, 2-, 3-, 6- or 7-quinolinyl or 3-, 6- or 7-isoquinolinyl. A naphthyl group is preferably &bgr;-naphthyl. Preferred R
3
substituents are &bgr;-naphthyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl and 2-, 3-, 5- or 6-benzofuranyl.
The R
3
group can also be substituted, substitution being in one or both rings, with one or more, preferably 1 to 3, substituents. Preferred substituents include C
1-4
alkyl, C
1-4
alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, —NR′R″ and —CONR′R″ where R′ and R″ are each hydrogen or C
1-4
alkyl.
A preferred value of R
3
is optionally substituted &bgr;-naphthyl, and especially unsubstituted &bgr;-naphthyl.
A further preferred value of R
3
is optionally substituted 2-, 3-,5- or 6-benzothienyl.
As indicated above, it is possible to prepare salts of the compound of the invention and such salts are included in the invention. Such salts are preferably the pharmaceutically acceptable, non-toxic salts. Of special interest are acid addition salts, in particular those with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, maleic, fumaric, tartaric or citric acid.
In addition to the pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.
It will be appreciated that when a substituent on an R
3
group is acidic such as, for example, a carboxy group, the opportunity exists for esters. These can be aliphatic or aromatic, being preferably alkyl esters derived from C
1-4
alkanols, especially methyl and ethyl esters. An example of an ester substituent is —COOR′ where R′ is C
1-4
alkyl.
The compounds of the invention contain asymmetric carbon atoms as indicated by asterisks in the following structures:
This asymmetry gives rise to cis- and trans-isomers as well as, in the case of the bicycloheptyl derivatives, exo- and endo-forms. Thus the bicycloheptyl derivatives exist as trans exo, trans endo, cis exo and cis endo forms, and in each instance R and S enantiomers. In the case of the bicyclooctyl derivatives, there are cis and trans derivatives only, each of which exist in R and S enantiomeric form. The compounds can be prepared as racemic mixtures and can conveniently be used a such, but individual isomers can be isolated by conventional techniques, or are preferably prepared by chiro-selective methods. Both racemic mixtures and individual isomers are included in the present invention.
A preferred group of compounds of formula (I) above is one in which R
1
and R
2
are each hydrogen or C
1-4
alkyl, and R
3
is optionally substituted &bgr;-naphthyl.
A further preferred group of compounds of formula (I) is one in which R
1
and R
2
are each hydrogen or C
1-4
alkyl, and R
3
is optionally substituted benzothienyl.
A preferred group of compounds of the invention can be represented as follows:
in which R
1
and R
2
are each hydrogen or C
1-4
alkyl, R
4
and R
5
are each C
1-4
alkyl, C
1-4
alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, —NR′R″ or —CONR′R″, where R′ and R″ are each hydrogen or C
1-4
alkyl, and p and q are each 0 or 1 to 3, such that the sum of p and q is preferably 0 or 1 to 3; or a salt thereof. When the naphthyl group is substituted there is preferably a single substituent at the 6-position. Of the above compounds of formula (Ia), the most preferred are the unsubstituted compounds in which p and q are both 0, and furthermore the compounds in which n is 1, the bicycloheptyl derivatives, are most preferred.
A further preferred group of compounds of the invention can be represented as follows:
in which R
1
and R
2
are each hydrogen or C
1-4
alkyl, and R
6
is C
1-4
alkyl, C
1-4
alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, —NR R″ or —CONR″, where R′ and R″ are each hydrogen or C
1-4
alkyl, and p is 0 or 1 to 3; or a salt thereof. When p is 2 or 3, the substituents can be different.
A further preferred group of compounds of the invention can be represented as follows:
where the bicyclo group is attached at the 5- or 6-position, and in which R
1
and R
2
are each hydrogen or C
1-4
alkyl, and R
6
is C
1-4
alkyl, C
1-4
alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, —NRR′R″ or —CONR′R″, where R′ and R″ are each hydrogen or C
1-4
alkyl, and p is 0, 1 or 2; or a salt thereof. When p is 2, the substituents can be different.
As examples of compounds of the invention, and their pharmaceutically acceptable salts, in isomeric or racemic form, there are included:
N,N-Dimethyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine
N-Methyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine
[(3-(6-Methoxy-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1-Benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1-Benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1H-Indol-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(6-Fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(6-Fluoro-2-naphthylbicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1-Benzothien-7-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamnine
[3-(1-Benzothien-4-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1-Benzothien-6-yl)bicyclo[2.2.1]hept-2-yl]-N, N-dimethylmethanamine
[3-(3-Methoxy-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(6-Fluoro-1-benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
N,N-Dimethyl-[3-(2-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine
N,N-Dimethyl-[3-(3-methyl-1-benzothien-5-yl)b
Keenan Martine
Milutinovic Sandra Ginette
Tupper David Edward
Barts Samuel
Eli Lilly and Company
Gaylo Paul J.
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