Imidazole derivatives having affinity for &agr;2 receptors

Details Imidazole derivatives having affinity for &agr;2 receptors Imidazole derivatives having affinity for &agr;2 receptors

2001-07-16

2002-11-12

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S400000, C548S341100, C548S345100

Reexamination Certificate

active

06479530

ABSTRACT:

The present invention relates to substituted 4(5)-(1-indanyl and 1-indanylmethyl and 1-indanylmethylen)imidazoles and 4(5)-[1-(1,2,3,4-tetrahydronaphthyl and 1,2,3,4-tetrahydronaphthylmethyl and 1,2,3,4-tetrahydronaphthylmethylen]imidazoles and to their isomers, pharmaceutically acceptable salts and esters. It also relates to their preparation, use and to pharmaceutical compositions containing them.
The compounds of the invention have affinity for alpha2 receptors most of them being very selective alpha2 agonists. Accordingly, they are useful in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances (such as tobacco and narcotics) and different neurological, musculoskeletal, psychiatric and cognition disorders as well as sedative and analgesic agents, nasal decongestants, and adjuncts to anaesthesia.
Gregory G. B., et al describe in J. Org. Chem. (1990), 55, 1479-1483 a new synthesis step for 1-phenylalkyl-1-(4-imidazolyl)-1,2,3,4-tetrahydronaphthalene derivatives which are useful as nonpeptide antagonists of the angiotensin II receptor.
The imidazole derivatives of the invention are either compounds of formula I
n is 0 or 1
R
1
is hydrogen or C
1
-C
4
-alkyl
R
2
is hydrogen or R
2
and R
3
together form a double bond
R
3
is hydrogen or C
1
-C
4
-alkyl or R
2
and R
3
together form a double bond
R
4
is hydrogen, C
1
-C
4
-alkyl, hydroxy or C
1
-C
4
-alkoxy
R
5
is hydrogen or C
1
-C
4
-alkyl or R
4
and R
5
together with the carbon atom to which they are attached form a carbonyl group
R
6
, R
7
and R
8
are each the same or different and are independently hydrogen, C
1
-C
4
-alkyl or C
2
-C
4
-alkenyl, C
3
-C
7
-cycloalkyl, hydroxy, C
1
-C
4
-alkoxy, C
1
-C
4
-hydroxyalkyl, thiol, C
1-4
-alkylthio, C
1-4
-alkylthiol, halogen, trifluoromethyl, nitro or optionally substituted amino
X is —CHR
9
—(CHR
10
)
m
—
m is 0 or 1
and R
9
and R
10
are each the same or different and are independently hydrogen or C
1
-C
4
-alkyl;
or a pharmaceutically acceptable ester or salt thereof.
The terms as employed herein have the following meanings: A halogen is e.g. chlorine, bromine or fluorine, preferably it is chlorine or fluorine. The C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy and C
2
-C
4
-alkenyl etc. groups may be branched or straight chain groups. C
3
-C
7
-Cycloalkyl is a saturated cyclic hydrocarbon group having preferably 3 to 5 carbon atoms. Optionally substituted amino is an amino group which is unsubstituted or substituted with a C
1
-C
4
-alkyl group.
When m=n=0
R
3
is preferably hydrogen,
R
4
is preferably hydrogen, hydroxy or C
1
-C
4
-alkoxy, such as ethoxy,
R
5
is preferably hydrogen, or R
4
and R
5
form, together with the carbon atom to which they are attached, a carbonyl group.
R
6
is preferably hydrogen, C
1
-C
4
-alkyl or C
1
-C
4
-alkoxy, such as methyl, ethyl, t-butyl, methoxy or hydroxy. For example, R
6
may be C
1
-C
4
-alkyl at position 4, 5 or 6, a C
1
-C
4
-alkoxy at position 5, 6 or 7, or hydroxy at position 5 or position 7.
More preferably R
6
is hydrogen, 4-methyl, 6-methyl or 7-methoxy.
R
7
is preferably at position 5, 6 or 7.
R
7
is preferably hydrogen or C
1
-C
4
-alkyl, such as, for example methyl or t-butyl. For example R
7
may be a C
1
-C
4
-alkyl at position 5, 6 or 7, such as 5-methyl, 7-methyl or 6-t-butyl.
More preferably R
7
is hydrogen.
R
8
is preferably at position 6 or 7.
R
8
is preferably hydrogen, hydroxy or C
1
-C
4
-alkoxy, such as methoxy. For example, R
8
may be a C
1
-C
4
-alkoxy at position 6, such as 6-methoxy, or 6-hydroxy or 7-hydroxy.
R
9
is preferably hydrogen or methyl.
When n=1 and m=0
R
1
is preferably hydrogen or methyl.
R
2
, R
3
, R
4
, R
5
and R
9
are preferably hydrogen,
R
6
is preferably hydrogen, halogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, such as, for example, methyl or t-butyl, methoxy or hydroxy. R
6
is preferably at position 4, 5 or 6. For example, R
6
may be a C
1
-C
4
-alkyl at position 4, 5 or 6, such as 4- or 5-methyl or 5-t-butyl or a C
1
-C
4
-alkoxy at position 5 or 6, such as 5- or 6-methoxy, or 4-, 5- or 6-hydroxy. R
6
may be halogen at position 5 or 6, such as 5- or 6-fluoro.
More preferably R
6
is 4-, 5- or 6-hydroxy.
R
7
is preferably at position 5, 6 or 7.
R
7
is preferably hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy or hydroxyl. For example, R
7
may be C
1
-C
4
-alkyl at position 5, 6 or 7, such as 5- or 7-methyl or 5- or 6-t-butyl or C
1
-C
4
-alkoxy at position 6, such as 6-methoxy, or 6-hydroxy.
More preferably R
7
is hydrogen or 6-hydroxy or 6-t-butyl.
R
8
is preferably at position 6 or 7.
R
8
is preferably hydrogen, hydroxy, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, such as methyl or methoxy, for example C
1
-C
4
-alkyl at position 7, such as 7-methyl or 7-t-butyl or C
1
-C
4
-alkoxy at position 6, such as 6-methoxy or 6-hydroxy.
When n=m=1
R
1
, R
2
, R
3
, R
5
, R
8
, R
9
and R
10
are preferably hydrogen.
R
4
is preferably hydrogen or C
1
-C
4
-alkyl, such as, for example, methyl.
R
6
is preferably at position 5, 6 or 7.
R
6
is preferably hydrogen, C
1
-C
4
-alkoxy or hydroxy, for example methoxy. For example, R
6
may be 5-, 6- or 7-methoxy, or 6- or 7-hydroxy.
R
7
is preferably hydrogen or C
1
-C
4
-alkyl, such as, for example, t-butyl.
When n=0 and m=1
R
3
, R
4
, R
5
, R
7
, R
8
, R
9
and R
10
are preferably hydrogen.
R
6
is preferably hydrogen or halogeN, for example chlorine. R
6
may be a halogen at position 5, such as, for example 5-chloro.
The invention includes within its scope all the possible isomers and stereoisomers, in particular Z and E (cis and trans isomers) and enantiomers.
The compounds of the formula (I) form acid addition salts with both organic and inorganic acids. Typical acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates. Furthermore, compounds wherein one or more of R
4
to R
8
is a hydroxy group form esters and salts with alkali metals and alkaline earth metals. Typical esters include the lower alkyl esters, such as the methyl, ethyl and propyl esters.
The compounds of the invention may be prepared using the following methods. (It is to be noted that in the formulae below, when the imidazole group is protected, the protecting group R′ (benzyl or trityl) may be attached to either of the two nitrogen atoms of the imidazole ring. Accordingly, the use of 1-benzyl-5-imidazolecarbaldehyde as starting material leads to 1.5 substituted derivatives whereas when trityl is used the substitution is mainly 1.4.)
Synthesis of 4(5)-(1-indanyl)imidazoles and the corresponding 4(5)-[1-(1,2,3,4-tetrahydronaphthyl)]imidazoles
Method a
Compounds of formula I wherein n=0 and m=0 or 1 may be prepared by an acid catalyzed cyclization of protected or unprotected 4(5)-(1-hydroxy-3-phenylpropyl or 1-hydroxy4-phenylbutyl)imidazoles of formulae II and II′, respectively.
Accordingly, the 4(5)-(1-indanyl)imidazoles may be prepared by cyclization of the compound of formula II
wherein R
3
to R
9
are as defined above and R′ is a protecting group, in the presence of an acid to form the compounds of formula III
wherein the substituents are as defined above, and removing the protecting group R′ to form the compounds of formula Ia
The corresponding 4(5)-[1-(1,2,3,4-tetrahydronaphthyl)]imidazoles may be prepared by cyclization of the compound of II′
wherein R
3
to R
10
are as defined above I and R′ is a protecting group in the presence of an acid to form the compounds of formula III′
wherein the substituents are as defined above, and removing the protecting group R′ to form the compounds of formula Ia′
wherein the substituents are as defined above.
The protecting group R′ may be, for example, benzyl or trityl. When R′ is trityl it may be removed using an acid and, when it is benzyl, by catalytic hydrogenation. The acid used in the cyclization reacti

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