Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-10
2001-09-18
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06291485
ABSTRACT:
CROSS-REFERENCE
This application is a 371 of PCT/JP98/02758 filed Jun. 22, 1998, which is based on Japanese Application No. 199,128/97 filed Jul. 10, 1997.
TECHNICAL FIELD
This invention relates to novel 4,5-dihydro-[1H]-benz[g]-indazole-3-carboxylic acid derivatives. More particularly, it relates to 4,5-dihydro-[1H]-benz[g]-indazole-3-carboxylic acid derivatives represented the following formula, or salts thereof.
wherein Ar represents an optionally substituted aryl group, and R
1
represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group.
BACKGROUND ART
Endothelin is a vasoconstrictive peptide composed of 21 amino acid residues, which was isolated from the culture supernatant of porcine vascular endothelial cells in 1988. This is produced by the processing of an endothelin precursor with an endothelin converting enzyme. Although endothelin is known to be widely produced by the cells of the lungs, intestines, kidneys, pancreas, spleen, heart, eyes, placenta, central nervous system and the like, it is said that endothelin is also produced by many cells other than these cells, such as bronchial epithelial cells, vascular smooth muscle cells and macrophages. As to endothelin, three isopeptides (endohelin-1, endothelin-2 and endothelin-3) are known, and they have a transient vasodilative effect and a subsequent sustained vasoconstrictive effect. Moreover, in addition to their effects on the cardiovascular system, endothelins have a wide variety of effects such as contraction of the airway, intestinal tract and uterine smooth muscle, proliferation of cells, and promotion of aldosterone secretion. It is believed that these effects are achieved through the medium of two subtypes of endothelin receptors (i.e., the endothelin A receptor and the endothelin B receptor). Since an oversecretion of endothelins is considered to be associated with various diseases such as hypertension, ischemic heart diseases, cerebral ischemia, kidney diseases, hepatic dysfunction, arteriosclerosis, and restenosis after percutaneous transluminal coronary angioplasty (i.e., post-PTCA restenosis), compounds having antagonism to endothelin receptors are expected to be effective as remedies for diseases caused by an oversecretion of endothelins.
The conventionally known nonpeptide compounds having antagonism to endothelins include, for example, Bosentan (see EP-A-510526), SB-209670 (see the pamphlet of WO93/8799) and the like. However, these compounds may not be said to be satisfactory.
Moreover, as 4,5-dihydro-[1H]-benz[g]indazole-3-carboxylic acid derivatives, there are known certain 4,5-dihydro-1-phenyl-[1H]-benz[g]indazole-3-carboxylic acids which are substituted by a substituted phenyl group at the 1-position [see J. Heterocyclic Chem., 13, 545 (1976)]. However, neither statement nor suggestion about their antagonism to endothelins is found in this reference.
It has now been found that compounds comprising 4,5-dihydro-[1H]-benz[g]indazole-3-carboxylic acid which is substituted by a 5-pyrimidinylmethoxy group at the 7-position and by a substituted phenylmethyl group at the 1-position have excellent antagonism to endothelin receptors and, moreover, some of these compounds also have an excellent inhibitory effect on phosphodiesterase III.
Thus, the present invention provides 4,5-dihydro-[1H]-benz[g]indazole-3-carboxylic acid derivatives represented by the above formula (I), or their salts.
DISCLOSURE OF THE INVENTION
The term “lower” as used herein means that the radicals or compounds modified by this term have not more than 6 carbon atoms and preferably 1 to 4 carbon atoms.
Thus, examples of the “lower alkyl group” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-hexyl. Examples of the “lower cycloalkyl group” include cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl. Examples of the “aryl group” include aryl groups having 6 to 14 carbon atoms, such as phenyl, naphthyl and anthryl. Among others, phenyl and naphthyl are preferred.
The “heterocyclic group” may be a monocyclic or polycyclic heterocyclic group which contains 1 to 4 heteroatoms selected from among N, S and O and in which each ring is a four- to eight-membered ring. In such groups, the heterocyclic ring may be a saturated ring or an unsaturated ring (e.g., an aromatic ring), and may be formed by the condensation of a monocyclic hydrocarbon radical with a monocyclic heterocyclic ring. Thus, specific examples of the ring in such heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothienyl, benzofuranyl, indolyl, benzothiazolyl, quinolyl, isoquinolyl, pyridinothiazolyl, pyrrolidinyl and piperidinyl.
Among others, preferred examples of the “heterocyclic group” are monocyclic or bicyclic unsaturated heterocyclic groups which contain 1 to 4 heteroatoms selected from among N, S and O and in which each ring is a five- or six-membered ring. In particular, five- or six-membered monocyclic aromatic heterocyclic groups containing 1 or 2 nitrogen atoms are especially preferred.
The number of substituents in the “optionally substituted aryl group” which can be represented by Ar in the above formula (I) may generally be 0 or from 1 to 5, and preferably from 1 to 3. Preferred examples of the substituents include lower alkyl groups, lower alkoxy groups, halogen-substituted lower alkoxy groups, lower alkoxy-substituted lower alkoxy groups, carboxy-substituted lower alkoxy groups, lower alkylthio groups, lower alkylenedioxy groups, halogen atoms, the hydroxy group, the nitro group and the amino group. As used herein, the “lower alkoxy groups” include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and isopentyloxy. The “lower alkylthio groups” include, for example, methylthio, ethylthio and isopropylthio. The “lower alkylenedioxy groups” include, for example, methylenedioxy, ethylenedioxy and propylenedioxy. It is preferable that these group be attached to two adjacent carbon atoms constituting the ring of the aryl group. The “halogen-substituted lower alkoxy groups” include, for example, trifluoromethoxy and 2,2,2-trifluoroethoxy. The “lower alkoxy-substituted lower alkoxy groups” include, for example, methoxy-methoxy and 2-methoxyethoxy. The “carboxy-substituted lower alkoxy groups” include, for example, carboxymethoxy and 2-carboxy-ethoxy. On the other hand, the halogen atoms include fluorine, chlorine, bromine and like atoms.
The number of substituents in the “optionally substituted alkyl group” which can be represented by R
1
in the above formula (I) may generally be 0, 1 or 2, and preferably 1. Preferred examples of the substituents include lower alkoxyl groups, the hydroxy group, and the phenoxy group. Moreover, the number of substituents in the “optionally substituted aryl group” which can be represented by R
1
may generally be 0 or from 1 to 5, and preferably from 1 to 3. Preferred examples of the substituents include lower alkyl groups, halogen-substituted lower alkyl groups, lower alkoxy groups, halogen-substituted lower alkoxy groups, aralkyloxy groups, lower alkylene-dioxy groups, halogen atoms and the phenyl group. Moreover, the number of substituents in the “optionally substituted cycloalkyl group” which can be represented by R
1
may generally be 0, 1 or 2, and preferably 1. Examples of the substituents include lower alkyl groups and lower alkoxy groups. Furthermore, the number of substituents in the “optionally substituted heterocyclic group” which can be represented by R
1
may generally be 0 or from 1 to 3, and preferably 1 or 2. Preferred examples of the substituents include lower alkyl groups, lower alkoxy groups, halogen atoms and the
Azuma Hiroshi
Hamasaki Hidehisa
Keino Katsuyuki
Ota Shuji
Saito Takahisa
Ford John M.
Teikoku Hormone Mfg. Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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