What is claimed is:
1. A compound of formula I
20
wherein
R1 is hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2 is hydrogen, carboxy, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms or alkyl of one to six carbon atoms;
Z is NR3(CH2)nY,
21
wherein
Y is hydrogen, hydroxy, cycloalkyl of 3 to 15 carbon atoms, or phenyl, substituted phenyl, phenoxy, substituted phenoxy, naphthyl, substituted naphthyl, naphthyloxy, substituted naphthyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy or substituted heteroaryloxy, wherein the heteroaryl or the heteroaryl group of heteroaryloxy is selected from thiophene, furan, pyridine, indole, chroman, coumarin, carbostyril, and quinoline;
R3 is hydrogen or alkyl of 1 to 6 carbon atoms;
n is an integer from 0 to 6;
R4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, substituted phenyl, -phenylalkyl, substituted -phenylalkyl, -diphenylalkyl, substituted -diphenylalkyl, wherein the alkyl chain contains 1 to 4 carbon atoms, indole, substituted indole, indazole, substituted indazole, pyridine, substituted pyridine, pyrimidine, substituted pyrimidine, quinoline, substituted quinoline, benzoisothiazole, substituted benzoisothiazole, benzisoxazole, or substituted benzisoxazole;
R5 is hydrogen, hydroxy, cyano or carboxamido;
R6 is hydrogen, 1-benzimidazol-2-one, benzoisothiazole, or benzisoxazole, each optionally substituted, or QAr;
Q is CO, CHOH, or (CH2)m,
m is an integer from 0 to 4;
Ar is phenyl optionally substituted; or
R5 and R6, taken together with the carbon atom to which they are attached, form
22
R7 is hydrogen;
R8 is phenyl, naphthyl, thiophene, benzoisothiazole, or benzisoxazole, each optionally substituted; or
R7 and R8, taken together with the carbon atoms to which they are attached, form phenyl or substituted phenyl;
R9 is hydrogen or alkyl of 1 to 6 carbon atoms; and
R10, R11 and R12 are, independently hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein R1 is hydrogen, methoxy or halo, R2 is hydrogen, Z is NR3(CH2)nY and R3 is hydrogen.
3. A compound of claim 1 wherein R2 is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
23
and R4 is phenyl, indole, indazole, pyridine, pyrimidine, quinoline, benzoisothiazole, or benzisoxazole, each optionally substituted.
4. A compound of claim 3 wherein R1 is hydrogen, methoxy or halogen and R2 is hydrogen.
5. A compound of claim 1 wherein R2 is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
24
R5 is hydrogen or hydroxy and R6 is 1-benzimidazol-2-one, benzoisothiazole, or benzisoxazole, each optionally substituted.
6. A compound of claim 5 wherein R1 is hydrogen, methoxy or halogen, R2 is hydrogen and R5 is hydrogen.
7. A compound of claim 1 wherein R2 is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
25
R5 is hydrogen or hydroxy, R6 is QAr, Q is CO or (CH2)m, m is an integer from 0 to 4, and Ar is phenyl or indole, each optionally substituted.
8. A compound of claim 7 wherein R1 is hydrogen, methoxy or halogen, R2 is hydrogen, and R5 is hydrogen.
9. A compound of claim 1 wherein R2 is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
26
R7 is hydrogen and R8 is phenyl, indole, benzoisothiazole, or benzisoxazole, each optionally substituted.
10. A compound of claim 9 wherein R1 is hydrogen, methoxy or halogen and R2 is hydrogen.
11. A compound of claim 1 wherein R2 is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
27
and R7 and R8, taken together with the carbon atoms to which they are attached form phenyl or substituted phenyl.
12. A compound of claim 11 wherein R1 is hydrogen, methoxy or halogen and R2 is hydrogen.
13. The compound of claim 1 which is benzyl-(-7,8-dihydro-2,6,9-trioxa-3-aza-cyclopentaanaphthalen-8-ylmethyl)-amine or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 which is 8-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-7,8-dihydro-2,6,9-trioxa-3-aza-cyclopentaanaphthalene or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 which is 8-4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl-7,8-dihydro-2,6,9-trioxa-3-aza-cyclopentaanaphthalene or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 which is 8-4-(5-fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl-7,8-dihydro-2,6,9-trioxa-3-aza-cyclopentaanaphthalene or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 which is 1-(7,8-dihydro-2,6,9-trioxa-3-aza-cyclopentaanaphthalen-8-ylmethyl)-piperidin-4-yl-(4-fluoro-phenyl)-methanone or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 which is 2,3-dihydro-N-3-(1H-indol-3-yl)propyl-1,4-dioxino2,3-e2,1benzisoxazole-2-methanamine or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 which is (7,8-dihydro-2,6,9-trioxa-3-aza-cyclopentaanaphthalen-8-ylmethyl)-(4-phenyl-butyl)-amine or a pharmaceutically acceptable salt thereof.
20. A compound of formula (II)
28
wherein
R1 is hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2 is hydrogen, carboxy, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms or alkyl of one to six carbon atoms; and
X is halogen, hydroxy, alkylsulfonate of 1 to 6 carbon atoms, trifluoro-methanesulfonate or benzenesulfonate, in which the benzene ring is optionally substituted with halogen, nitro, trifluoromethyl, cyano, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.
21. A compound of claim 20 which is 2,3-dihydro1,4dioxino2,3-e-2,1-benzisoxazol-2-ylmethyl 4-methylbenzenesulfonate.
22. A method of treating a subject suffering from a condition selected from schizophrenia, schizoaffective disorder, bipolar disorder, Parkinson’s disease, L-DOPA induced psychoses or dyskinesias, Tourette’s syndrome or hyperprolactinemia which comprises providing to the subject suffering from said condition, a therapeutically effective amount of a compound of formula I
29
wherein
R1 is hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2 is hydrogen, carboxy, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms or alkyl of one to six carbon atoms;
Z is NR3(CH2)nY,
30
wherein,
Y is hydrogen, hydroxy, cycloalkyl of 3 to 15 carbon atoms, or phenyl, substituted phenyl, phenoxy, substituted phenoxy, naphthyl, substituted naphthyl, naphthyloxy, substituted naphthyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy or substituted heteroaryloxy, wherein the heteroaryl or the heteroaryl group of heteroaryloxy is selected from thiophene, furan, pyridine, indole, chroman, coumarin, carbostyril, and quinoline;
R3 is hydrogen or alkyl of 1 to 6 carbon atoms;
n is an integer from 0 to 6;
R4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, substituted phenyl, -phenylalkyl, substituted -phenylalkyl, -diphenylalkyl, substituted -diphenylalkyl, wherein the alkyl chain contains 1 to 4 carbon atoms, indole, substituted indole, indazole, substituted indazole, pyridine, substituted pyridine, pyrimidine, substituted pyrimidine, quinoline, substituted quinoline, benzoisothiazole, substituted benzoisothiazole, benzisoxazole, or substituted benzisoxazole;
R5 is hydrogen, hydroxy, cyano or carboxamido;
R6 is hydrogen, 1-benzimidazol-2-one, benzoisothiazole, or benzisoxazole, each optionally substituted, or QAr;
Q is CO, CHOH, or (CH2)m,
m is an integer from 0 to 4;
Ar is phenyl optionally substituted; or
R5 and R6, taken together with the carbon atom to which they are attached, form
31
R7 is hydrogen;
R8 is phenyl, naphthyl, thiophene, benzoisothiazole, or benzisoxazole, each optionally substituted; or
R7 and R8, taken together with the carbon atoms to which they are attached, form phenyl or substituted phenyl;
R9 is hydrogen or alkyl of 1 to 6 carbon atoms; and
R10, R11 and R12 are, independently hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.
23. The method of claim 22 wherein the subject is a human.
24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
32
wherein
R1 is hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2 is hydrogen, carboxy, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms or alkyl of one to six carbon atoms;
Z is NR3(CH2)nY,
33
wherein,
Y is hydrogen, hydroxy, cycloalkyl of 3 to 15 carbon atoms, or phenyl, substituted phenyl, phenoxy, substituted phenoxy, naphthyl, substituted naphthyl, naphthyloxy, substituted naphthyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy or substituted heteroaryloxy, wherein the heteroaryl or the heteroaryl group of heteroaryloxy is selected from thiophene, furan, pyridine, indole, chroman, coumarin, carbostyril, and quinoline;
R3 is hydrogen or alkyl of 1 to 6 carbon atoms;
n is an integer from 0 to 6;
R4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, substituted phenyl, -phenylalkyl, substituted -phenylalkyl, -diphenylalkyl, substituted -diphenylalkyl, wherein the alkyl chain contains 1 to 4 carbon atoms, indole, substituted indole, indazole, substituted indazole, pyridine, substituted pyridine, pyrimidine, substituted pyrimidine, quinoline, substituted quinoline, benzoisothiazole, substituted benzoisothiazole, benzisoxazole, or substituted benzisoxazole;
R5 is hydrogen, hydroxy, cyano or carboxamido;
R6 is hydrogen, 1-benzimidazol-2-one, benzoisothiazole, or benzisoxazole, each optionally substituted, or QAr;
Q is CO, CHOH, or (CH2)m,
m is an integer from 0 to 4;
Ar is phenyl optionally substituted; or
R5 and R6, taken together with the carbon atom to which they are attached, form
34
R7 is hydrogen;
R8 is phenyl, naphthyl, thiophene, benzoisothiazole, or benzisoxazole, each optionally substituted; or
R7 and R8, taken together with the carbon atoms to which they are attached, form phenyl or substituted phenyl;
R9 is hydrogen or alkyl of 1 to 6 carbon atoms; and
R10, R11 and R12 are, independently hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
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. A method of producing a movable tensioning element (1) of a tensioning device for tensioning flexible drive means, in particular for timing chain drives of internal combustion engines, the tensioning element (1) having at least a tensioning piston (3) and a tensioning rail (2) made of a plastic material, and the tensioning rail (2) being arranged on a tensioning end of the tensioning piston (3), comprising the steps of:
i. placing the tensioning piston (3) into an injection mold suitable for producing the tensioning rail (2);
ii. injecting the plastic material into the injection mold;
iii. encompassing the tensioning piston (3) by the plastic material in certain areas thereof; and
iv. letting the plastic material solidify under formation of a positive connection between the tensioning piston (3) and the tensioning rail (2).
2. A method according to claim 1, and in the area enclosed by the tensioning rail (2), providing the tensioning piston (3) with formed elements, and encompassing or filling the formed elements with the plastic material, whereby the tensioning rail (2) is connected to the tensioning piston (3) in a non-releasable manner.
3. A tensioning element for a tensioning device for tensioning flexible drive means, in particular for timing chain drives of internal combustion engines, comprising at least a tensioning piston (3) and a tensioning rail (2) made of a plastic material, the tensioning rail (2) being arranged on a tensioning end of the tensioning piston (3), and the tensioning rail (2) being applied by injection molding to the tensioning piston (3) such that it is positively connected thereto.
4. A tensioning element according to claim 3, wherein the tensioning rail (2) is connected to the tensioning piston (3) in a non-releasable manner.
5. A tensioning element according to claim 3, wherein the tensioning piston (3) comprises formed elements in the area of the tensioning rail (2).
6. A tensioning element according to claim 3, wherein the tensioning rail (2) has a vent hole (12) which extends preferably coaxially with the tensioning piston (3) and which communicates with a vent means of the tensioning piston (3).
7. A tensioning element according to claim 3, wherein the tensioning rail (2) comprises an upper slide section (4) and a lower rear section (6), and the upper slide section (4) and lower rear section (6) are interconnected by webs (7).
8. A tensioning element according to claim 3, wherein the tensioning rail (2) comprises at least one guide arm (13) which is arranged essentially axially parallel to the tensioning piston (3) and which is formed integrally with said tensioning rail (2).
9. A tensioning element according to claim 8, wherein the guide arm (13) comprises at least one end stop (14).
10. A tensioning element according to claim 8, wherein the guide arm (13) comprises at least one arresting element (15).
11. A tensioning device for tensioning flexible drive means, in particular for timing chain drives of internal combustion engines, comprising a housing (16) and a tensioning element according to claim 3, the tensioning piston (3) being guided in said housing (16) in a longitudinally displaceable manner, and the tensioning rail (2) is applied by injection molding to the tensioning piston (3) such that it is positively connected thereto.
12. A method according to claim 2, wherein the formed elements are one of circumferentially extending grooves (10) and flanges.
13. A tensioning element according to claim 5, wherein the formed elements are one of circumferentially extending grooves (10) and flanges.