Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-27
2001-01-09
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S439000, C549S048000, C549S460000
Reexamination Certificate
active
06172099
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel tricyclic compounds having saturated rings and to medicinal compositions containing such tricyclic compounds.
PRIOR ARTS
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)]. Later, 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
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 was 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 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 Kokai is Sho 55-53262 and Sho 58-41860 and a compound exhibiting a vasodilating function having 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 the function.
Problems to be solved by the invention
There is a demand for novel and effective medicament which can be used for therapeutic treatment and preventive treatment of diseases correlating to &bgr;3, such as diabetes, obesity and hyperlipemia.
Means for solving the problems
The inventors of the present invention had been synthesized various compounds and studied on these activities and functions in order to solve the above problems and reached the discovery that novel tricyclic compounds having saturated rings represnted by the general formula (I) given below had &bgr;3-activities with functions for lowering blood glucose level and for lypolysis, thereby led to the completion of the present invention.
Thus, the present invention comprises in a compound represented by the general formula (I) or a salt thereof:
in which R represents hydrogen atom or methyl, R1 stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R2 stands for hydrogen atom, hydroxymethyl, NHR3, SO2NR4R4′ or nitro, wherein R3 is hydrogen atom, methyl, SO2R5, formyl or CONHR6′, with R5 being lower alkyl, benzyl or NR4R4′ and R4 and R4′ may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, and R6′ being hydrogen atom or lower alkyl, R6 represents hydrogen atom or lower alkyl, n is 1 or 2, X stands for a secondary nitrogen atom, oxygen atom or sulfur atom and, in case that n is 1, either one of R7 and R8 is hydrogen atom and the other one is hydrogen atom, amino, acetylamino or hydroxy, or, in case that n is 2, R8 is hydrogen atom, and R7 is hydrogen atom, amino, acetylamino or hydroxy, *1 indicates an asymmetric carbon atom and *2 and *3 indicate asymmetric carbon atom in case that R6 and R8 are not hydrogen atom.
According to the present invention, there fluorine atom, chlorine atom, bromine atom or iodine atom may be exemplified for the halogen atom, and 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, 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. R1 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 R1 denotes hydrogen atom. Also preferred example of the compound represented by the general formula (I) is one in which R1 denotes amino or hydroxymethyl group. A further preferred example of the compound represented by the general formula (I) is one in which R1 denotes halogen atom or hydroxy or benzyloxy group.
R2 stands for hydrogen atom, hydroxymethyl, NHR3, SO2NR4R4′ or nitro. A preferred example of the compound represented by the general formula (I) is one in which R1 denotes hydrogen atom. Also preferred example of the compound represented by the general formula (I) is one in which R2 is hydroxymethyl or nitro group. A further preferred example of the compound represented by the general formula (I) is one in which R2 stands for NHR3 or SO2NR4R′. R3 in the group NHR3 may be hydrogen atom, methyl, SO2R5, formyl or CONHR6′, wherein reference is given especially to NHR3 which is NH2, NHMe, NHSO2R5, NHCHO and NHCONHR6′ among which NHSO2R5 is more preferable. In the group NHSO2R5, R5 stands for lower alkyl, benzyl or NR4R4′. R4 and R4′ may be either be identical with or different from each other and may stand each for hydrogen atom, lower alkyl or benzyl, wherein either one of R4 and R4′ is preferably hydrogen.
Concrete examples of NR4R4′ 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 NHSO2R5 include NHSO2Me, NHSO2Et, NHSO2CH2Ph, NHSO2NH2, NHSO2NHMe, NHSO2NHEt, NHSO2NMe2, NHSO2NEt2, NHSO2NMeEt and NHSO2NMeCH2Ph. R6′ in the group NHCONHR6′ is hydrogen atom or lower alkyl, Concrete examples of NHCONHR6′ include NHCONH2, NHCONHMe, NHCONHEt and NHCONHPr. Concerning the group SO2NR4R4′ for the group R2,the groups R4 and R4′ have the same meanings as given above and may either be identical with or different from each other and may stand for hydrogen atom, lower alkyl or benzyl, wherein it is preferable that either one of R4 and R4′ is hydrogen atom. Therefore, concrete examples of the group SO2NR4R4′ include SO2NH2, SO2NHMe, SO2NHEt, SO2NMe2, SO2NEt2, SO2NHCH2Ph or SO2NMeCH2Ph.
R6 represents hydrogen atom or lower alkyl. Preferred examples include hydrogen atom, methyl and ethyl. Here, preference is given to the case where it stands for hydrogen atom.
Example of n is 1 or 2, and preferred example is that n is 1.
X stands for secondary nitrogen atom, oxygen atom or sulfur atom. A preferred example of the compound is one in which X is secondary nitro
Miyoshi Shiro
Ogawa Kohei
Asahi Kasei Kogyo Kabushiki Kaisha
Pennie & Edmonds LLP
Ramsuer Robert W.
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