Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-07
2002-06-04
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06399639
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an apoptosis inhibitor which is useful as an agent for prophylaxis and treatment of a disease mediated by promotion of apoptosis.
BACKGROUND ART
Apoptosis means a physiological and active death of cells, abnormality of which is known to be closely related with occurrence of various diseases [Rinshou Byouri, vol.45, No.7, pp.603-605 (1997); Igaku no Ayumi, vol.178, No.10, pp.712-716 (1996)].
As compounds having an apoptosis inhibitory activity, there are known, for instance, (1-heteroazolyl-1-heterocyclyl)alkane derivatives (JP-A H8(1996)-512312), (3S,4aR,6R,8aR)-6-[2-(1H-tetrazol-5-yl)-ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (European Journal of Pharmacology, vol.314, pp.249-254 (1996)) and the like.
Saishin igaku, vol.52, No.6, pp.95-102 (1997), especially at page 100 describes “thiazolidines will, probably via PPAR&ggr; activities, promote differentiation from preadipocytes to adipocytes, remarkably increase the number of small adipocytes, and decrease the number of large adipocytes (apoptosis ??)”, “thiazolidine derivatives affecting fatty tissues show remarkable effects to this types of insulin resistance”, and shows “a mechanism of thiazolidine derivatives in changes of fatty tissues and improvement of insulin resistance (hypothesis)”. However, these do not relate to an apoptosis inhibitory activity.
Drugs showing an apoptosis inhibitory activity can be used as an agent for prophylaxis and treatment of diseases which are thought to be mediated by promotion of apoptosis, such as viral diseases, neurodegenerative diseases, myelodysplasis, ischemic diseases and hepatic diseases. Therefore, development of such new types of drug is desired.
DISCLOSURE OF INVENTION
The inventors of the present invention, after various research about compounds having an apoptosis inhibitory activity, found, for the first time, that compounds having an insulin sensitivity enhancing activity, especially the compound of the formula:
wherein R represents a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted; Y represents a group of the formula: —CO—, —CH(OH)— or —NR
3
— where R
3
represents an alkyl group that may be substituted; m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms; Q represents oxygen or sulfur; R
1
represents hydrogen or an alkyl group; ring E may have further 1 to 4 substituents, which may form a ring in combination with R
1
; L and M respectively represent hydrogen or may be combined with each other to form a chemical bond; or a salt thereof; which are characterized by azolidine and a particular side chain thereto, unexpectedly showed an excellent apoptosis inhibitory activity based on the characteristic chemical structure, and that it was useful as an agent for prophylaxis and treatment of diseases which are thought to be mediated by promotion of apoptosis. Based on this finding, the present invention has been completed.
The present invention relates to
(1) An apoptosis inhibitor which comprises a compound represented by the formula (I);
(2) An apoptosis inhibitor according to the above (1), wherein the heterocyclic group represented by R is a 5- to 7-membered monocyclic and heterocyclic group containing 1 to 4 hetero-atoms selected from oxygen, sulfur and nitrogen in addition to carbon as ring members or its condensed heterocyclic group;
(3) An apoptosis inhibitor according to the above (1), wherein R represents a heterocyclic group that may be substituted;
(4) An apoptosis inhibitor according to the above (3), wherein the heterocyclic group is pyridyl, oxazolyl, thiazolyl or triazolyl;
(5) An apoptosis inhibitor according to the above (1), wherein the partial structural formula:
(6) An apoptosis inhibitor according to the above (1), wherein X represents CH;
(7) An apoptosis inhibitor according to the above (1), wherein R
1
represents hydrogen;
(8) An apoptosis inhibitor according to the above (1), wherein L and M respectively represent hydrogen;
(9) An apoptosis inhibitor which comprises a compound having an insulin sensitivity enhancing activity;
(10) An apoptosis inhibitor according to the above (1), which is an agent for prophylaxis or treatment of a neurodegenerative disease;
(11) An apoptosis inhibitor according to the above (1), which comprises pioglitazone or its salt;
(12) An apoptosis inhibitor according to the above (1), which comprises troglitazone or its salt;
(13) An apoptosis inhibitor according to the above (1), which comprises rosiglitazone or its salt;
(14) Method for inhibiting apoptosis in a mammal, which comprises administering to said mammal an effective amount of a compound or a salt as defined in the above (1);
(15) Method for treating or preventing a disease mediated by promotion of apoptosis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound or a salt as defined in the above (1);
(16) Use of a compound or a salt as defined in the above (1) for the manufacture of an agent for prophylaxis or treatment of a disease mediated by promotion of apoptosis;
(17) Method for inhibiting apoptosis in a mammal, which comprises administering to said mammal an effective amount of a compound having an insulin sensitivity enhancing activity;
(18) Method for treating or preventing a disease mediated by promotion of apoptosis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound having an insulin sensitivity enhancing activity; and
(19) Use of a compound having an insulin sensitivity enhancing activity for the manufacture of an agent for prophylaxis or treatment of a disease mediated by promotion of apoptosis.
The compound used in the present invention is not limited as long as it is a compound having an insulin sensitivity enhancing activity. Especially preferred is the compound represented by the formula (I) or salt thereof. Substituents in the formula (I) are explained below.
Referring to the hydrocarbon group that may be substituted for R, the hydrocarbon group includes aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, alicyclic-aliphatic hydrocarbon groups, aromatic-aliphatic hydrocarbon groups, and aromatic hydrocarbon groups. The number of carbon atoms constituting such hydrocarbon groups is preferably 1 to 14.
The aliphatic hydrocarbon group is preferably a C
1-8
aliphatic hydrocarbon group. The aliphatic hydrocarbon group includes saturated C
1-8
aliphatic hydrocarbon groups (e.g. alkyl groups) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, heptyl, and octyl; and unsaturated C
2-8
aliphatic hydrocarbon groups (e.g. alkenyl, alkadienyl, alkynyl, and alkadiynyl groups) such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, and 1-octynyl.
The alicyclic hydrocarbon group is preferably a C
3-7
alicyclic hydrocarbon group. The alicyclic hydrocarbon group includes saturated C
3-7
alicyclic hydrocarbon groups (e.g. cycloalkyl groups) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. And unsaturated C
5-7
alicyclic hydrocarbon groups (e.g. cycloalkenyl groups and cycloalkadienyl groups) such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, and 2,4-cycloheptadienyl.
The alicyclic-aliphatic hydrocarbon group is a group consisting of the above-described alicyclic hydrocarbon group and aliphatic hydrocarbon group (e.g. cycloalkyl-alkyl and cycloalke
Matsui Junji
Momose Yu
Naruo Ken-ichi
Tarui Naoki
Chao Mark
Gerstl Robert
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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