1. A compound of formula (1):
wherein:
R1 is a group chosen from phenyl, 2-indolyl, 3-indolyl, 3-indazolyl, and benzobthiophen-3-yl, wherein the group is optionally substituted with a halogen or C1-C3 alkyl;
R2 and R3, which may be the same or different, are chosen from a halogen, hydrogen, OCH3, CH3 and CF3;
Q is chosen from optionally substituted, aromatic or heteroaromatic five- or six-membered rings, connected by a carbon-carbon bond;
the pyrido1,2-apyrazine moiety optionally contains a double bond, wherein the double bond is between carbon atoms 6 and 7 or between carbon atoms 7 and 8; or
at least one stereoisomer or pharmacologically acceptable salt thereof.
2. The compound of claim 1, wherein Q is an optionally substituted, six-membered, nitrogen containing heteroaromatic ring.
3. The compound of claim 1, wherein R1 is 3-indolyl, R2 and R3 are CF3 groups in the 3- and 5-positions, and Q is an optionally substituted, six-membered, nitrogen containing heteroaromatic ring.
4. The compound of claim 1, wherein said compound of formula (1) is chosen from:
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyridin-4-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyridin-3-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyridin-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyrimidin-5-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyrazin-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyrimidin-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-thiazol-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone; and
stereoisomers or pharmacologically acceptable salts thereof.
5. A pharmaceutical composition, comprising a pharmacologically active amount of at least one compound of formula (1):
wherein:
R1 is a group chosen from phenyl, 2-indolyl, 3-indolyl, 3-indazolyl, and benzobthiophen-3-yl, wherein the group is optionally substituted with a halogen or C1-C3 alkyl;
R2 and R3, which may be the same or different, are chosen from a halogen, hydrogen, OCH3, CH3 and CF3;
Q is chosen from optionally substituted, aromatic or heteroaromatic five- or six-membered rings, connected by a carbon-carbon bond;
the pyrido1,2-apyrazine moiety optionally contains a double bond, wherein the double bond is between carbon atoms 6 and 7 or between carbon atoms 7 and 8; or
at least one stereoisomer or pharmacologically acceptable salt thereof.
6. The pharmaceutical composition of claim 5, wherein said compound of the general formula 1 is chosen from:
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyridin-4-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyridin-3-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyridin-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyrimidin-5-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyrazin-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyrimidin-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R,9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-thiazol-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone; and
stereoisomers or pharmacologically acceptable salts thereof.
7. A method for the treatment of at least one disorder involving neurokinins interacting with NK1 receptors in a patient in need thereof, comprising: administering an effective amount of a pharmaceutical composition, wherein said pharmaceutical composition comprises at least one compound of formula (1):
wherein:
R1 is a group chosen from phenyl, 2-indolyl, 3-indolyl, 3-indazolyl, and benzobthiophen-3-yl, wherein the group is optionally substituted with a halogen or C1-C3 alkyl;
R2 and R3, which may be the same or different, are chosen from a halogen, hydrogen, OCH3, CH3 and CF3;
Q is chosen from optionally substituted, aromatic or heteroaromatic five- or six-membered rings, connected by a carbon-carbon bond;
the pyrido1,2-apyrazine moiety optionally contains a double bond, wherein the double bond is between carbon atoms 6 and 7 or between carbon atoms 7 and 8; or
at least one stereoisomer or pharmacologically acceptable salt thereof, wherein the at least one disorder involving neurokinins interacting with NK1 receptors is selected from the group consisting of acute and chronic pain, emesis, asthma, unipolar depressive disorders, minor depression, seasonal affective disorder, postnatal depression, dysthymia, major depression and anxiety.
8. The method of claim 7, wherein said compound of formula (1) is chosen from:
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyridin-4-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyridin-3-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyridin-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyrimidin-5-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyrazin-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-pyrimidin-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone;
(3R, 9aR)-3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-ylmethyl)-7-thiazol-2-yl-1,3,4,8,9,9a-hexahydro-pyrido1,2-apyrazin-2-yl-methanone; and
stereoisomers or pharmacologically acceptable salts thereof.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An insulating glazed element comprising at least two glass sheets, separated from each other by a space and joined at their periphery by a seal, and at least one section, characterized in that said element has at least one heating border on at least one face of at least one glass sheet, and in that said border is covered by the section and is joined to the section by a heat-conducting seal.
2. The element as claimed in claim 1, characterized in that the heating border consists of an enamel or of a resin containing metal particles.
3. The element as claimed in claim 2, characterized in that the metal particles are chosen from particles of silver, nickel, zinc, copper, graphite or precious metals such as gold, platinum or palladium.
4. The element as claimed in one of claims 1 to 3, characterized in that the heating border is borne by the external face of the outer glass sheet.
5. The element as claimed in one of claims 1 to 3, characterized in that the border is borne by the internal face of the outer glass sheet.
6. The element as claimed in one of claims 1 to 3, characterized in that the border is borne by the external face of an intermediate or inner glass sheet.
7. The element as claimed in one of claims 1 to 6, characterized in that it comprises at least three glass sheets.
8. The element as claimed in either of claims 4 and 5, characterized in that it furthermore comprises an intermediate heat-conducting element combined with the heating border, which makes it possible to increase the contact area between the border and the heat-conducting seal.
9. The element as claimed in one of claims 1 to 8, characterized in that the outer sheet is a glass sheet having undergone thermal toughening.
10. A refrigerated enclosure comprising at least one glazed element according to one of claims 1 to 9.