Tricyclic compounds and drug compositions containing same

Details Tricyclic compounds and drug compositions containing same Tricyclic compounds and drug compositions containing same

2000-11-16

2003-04-08

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S605000, C564S079000, C564S099000, C564S218000, C564S352000, C564S363000

Reexamination Certificate

active

06545053

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel tricyclic compounds and to drug compositions containing such tricyclic compounds.
BACKGROUND OF THE INVENTION
In the past, it was accepted that &bgr;-adrenaline receptors are classified into two groups &bgr;1 and &bgr;2, wherein the stimulation by &bgr;1 induces an increase in the cardiac rate and the stimulation by &bgr;2 brings about relaxation in the smooth muscle tissue and lowering of blood pressure. Arch et al discovered a compound which exhibits scarce activities to &bgr;1 and &bgr;2 but emphasizes lipolysis of fatty cells, wherefrom they have made clear the existence of a third receptor [Nature, 309, 163-165 (1984)]. Afterwards, the primary structure thereof was clarified [Emorine et al: Science, Vol. 245, 1118-1121 (1989)] and the receptor was named as &bgr;3.
Recently, it has been shown that compounds exhibiting a &bgr;3-activity are useful as a drug for preventive treatment of diabetes, obesity, hyperlipemia, digestive diseases and depression [Int. J. Obesity 8 (suppl. 1), 93-102 (1984); Nature, 309, 163-165(1984); U.S. Pat. No. 5,120,766; Brit. J. Pharmacol., 103, 1351-1356 (1991); Eur. J. Pharmacol., 219, 193-201 (1992)].
Various compounds with correlation to &bgr;3 have been reported in the literatures, for example, a compound (BRL 37344) having the following-molecular structure A
as disclosed in EP 023 385 and in Drugs of the Future, Vol. 16. 797-800 (1991); a compound (CL316, 243) having the following molecular structure
as disclosed in EP 0 455 006 and J. Med. Chem. Vol. 35, 3081-3084 (1992); a compound having the following molecular structure
as disclosed in WO9429290; and a compound having the following molecular structure
as disclosed in EP 0 659 737 in Example 1 thereof. All these compounds have molecular structures different clearly from that of the compound according to the present invention.
There vias known a compound exhibiting a function for increasing the myocardial contraction strength and for antagonizing obesity represented by the following structural formula
as disclosed in EP 171 702, which is distinguished from the compound according to the present invention in that it has a strong pharmacological activity onto the heart and has a molecular structure quite different from that of the compound according to the present invention.
Further, a compound exhibiting an &agr;, &bgr;-blocking activity, namely, a function of lowering the blood pressure, represented by the following structural formula
is disclosed in Japanese Patent Kokais Sho 55-53262 and Sho 58-41860 and a compound exhibiting a vasodilatoric function represented by the following structural formula
is disclosed in DE 2 651 572. They are different from the compound according to the present invention in the molecular structure and in function.
There is a demand for a novel and effective medicament or pharmaceutic composition which can be used for therapuetic treatment and preventive treatment of diseases correlating to &bgr;3, such as diabetes, obesity and hyperlipemia.
DISCLOSURE OF THE INVENTION
The inventors in sound research responding to the existing demand, by synthesizing various compounds and examining their functions reached the discovery that novel tricyclic compounds represented by the general formula (I) given below had &bgr;3-activities with functions for lowering blood sugar value and for lipolysis, which has led to the completion of the present invention.
Thus, the present invention consists in a compound represented by the general formula (I) or a salt thereof:
in which R represents hydrogen atom or methyl, R
1
stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R
2
stands for hydrogen atom, hydroxymethyl, NHR
3
, SO
2
NR
4
R
4′
or nitro. wherein R
3
is hydrogen atom, methyl, SO
2
R
5
, formyl or CONHR
6′
, with R
5
being a lower alkyl, benzyl or NR
4
R
4′
and R
6′
being hydrogen atom or lower alkyl, and R
4
and R
4′
may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R
6
represents hydrogen atom or lower alkyl, X stands for a secondary nitrogen atom, oxygen atom, sulfur atom or methylene and, in case X is secondary nitrogen atom, oxygen atom or sulfur atom, R
9
stands for hydrogen atom and either one of R
7
and R
8
is hydrogen atom and the other one is hydrogen atom, amino, acetylamino or hydroxy, or, in case X is methylene, both R
7
and R
8
are hydrogen atom and R
9
stands for hydrogen atom, amino, acetylamino or hydroxy, *1 indicates an asymmetric carbon atom and *2 indicates that the carbon atom is asymmetric provided that R
6
is lower alkyl.
According to the present invention, there may be exemplified for the halogen atom fluorine atom, chlorine atom, bromine atom or iodine atom, among them, fluorine atom and chlorine atom are preferred. In the context of the present invention, “lower alkyl” means a straight or branched chain saturated hydrocarbon having 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
In the formula (I), R may preferably be hydrogen atom, while R may favorably be also methyl for reason of providing more higher selectivity.
R
1
stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl. A preferred example of the compound represented by the general formula (I) is one in which R
1
denotes hydrogen atom. Also preferred example of the compound represented by the general formula (I) is one in which R
1
denotes amino or hydroxymethyl group. A further preferred example of the compound represented by the general formula (I) is one in which R
1
denotes halogen atom or hydroxyl or benzyloxy group.
R
2
stands for hydrogen atom, hydroxymethyl, NHR
3
, SO
2
NR
4
R
4′
or nitro. A preferred example of the compound represented by the general formula (I) is one in which R
2
is hydrogen atom. Also preferred example of the compound represented by the general formula (I) is one in which R
2
is hydroxymethyl or nitro group. A further preferred example of the compound represented by the general formula (I) is one in which R
2
stands for NHR
3
or SO
2
NR
4
R′. R
3
in the group NHR
3
may be hydrogen atom, methyl, SO
2
R
5
, formyl or CONHR
6′
, wherein preference is given especially to NHR
3
which is NH
2
, NHMe, NHSO
2
R
5
and NHCONHR
6′
, among which NHSO
2
R
5
is more preferable. In the group NHSO
2
′R
5
, R
5
stands for lower alkyl, benzyl or NR
4
R
4′
, R
4
and R
4′
may either be identical with or different from each other and may stand each for hydrogen atom, lower alkyl or benzyl, wherein either one of R
4
and R
4′
is preferably hydrogen.
Concrete examples of NR
4
R
4′
include amino, methylamino, ethylamino, propylamino, benzylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino and methylbenzylamino, among which preference is given to methylamino and dimethylamino. Therefore, preferred concrete examples of NHSO
2
R
5
include NHSO
2
Me, NHSO
2
Et, NHSO
2
CH
2
Ph, NHSO
2
NH
2
, NHSO
2
NHMe, NHSO
2
NHEt, NHSO
2
NMe
2
, NHSO
2
NEt
2
, NHSO
2
NMeEt and NHSO
2
NMeCH
2
Ph. R
6′
in the group NHCONHR
6′
is hydrogen atom or lower alkyl. Concrete examples of NHCONHR
6′
include NHCONH
2
. NHCONHMe, NHCONHEt and NHCONHPr. Concerning the group SONR
4
R
4′
for the group R
2
, the groups R
4
and R
4′
have the same meanings as given above and may either be identical with or different from each other and may stand each for hydrogen atom, lower alkyl or benzyl, wherein it is preferable that either one of R
4
and R
4′
is hydrogen atom. Therefore, concrete examples of the group SO
2
NR
4
R
4′
include SO
2
NH
2
, SO
2
NHMe, SO
2
NHEt, SO
2
NMe
2
, SO
2
NEt
2
, SO
2
NHCH
2
Ph and SO
2
NMeCH
2
Ph.
R
6
represents hydrogen atom or lower alkyl. Preferred examples include hydrogen atom. methyl and ethyl. Here, preference is given t

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