Claims
- 1. A compound of the general formula (I):
- 2. The compound according to claim 1, with the further proviso that when Ar is optionally substituted phenyl, pyridyl or quinoxalinyl, then A is a group -Het-CH(R6)—CH(R6)-Het-, where each Het independently is selected from O, S and N(R6), and R6 is as defined in claim 1.
- 3. The compound according to claim 1 or 2, wherein A is a C2-8-alkylene chain or a heteroalkylene chain having at least two chain atoms.
- 4. The compound according to claim 1, wherein A is a group of the general formula (II):
- 5. The compound according to claim 4, wherein A is a group -Het-CH(R6)—CH(R6)-Het-, where each Het independently is selected from O, S and N(R6), and R6 is as defined in claim 1.
- 6. The compound according to claim 5, wherein R6 is hydrogen or methyl, preferably hydrogen.
- 7. The compound according to claim 5 or 6, wherein A is selected from the groups —O—CH2—CH2—O—, —S—CH2—CH2—O—, —O—CH2—CH2—S—, and —O—CH2—CH2—CH2—, preferably —O—CH2—CH2—O.
- 8. The compound according to claim 7, wherein A is —O—CH2—and R is optionally substituted heteroaryl, e.g. 2,3-dihydro-1,4-benzodioxine, 3,4-dihydro-2H-1,4-benzoxazine, or 2,3-dihydro-1,4-benzoxathiine, quinoline, benzofuran, 3,4-dihydro-2H-pyrido(3,2-b)-1,4-oxazine.
- 9. The compound according to any one of claims 1 to 8, wherein R is optionally substituted aryl or heteroaryl.
- 10. The compound according to claim 9, wherein R is an optionally substituted phenyl, pyridine, isoquinoline, quinoline, quinoxaline, 2,3-dihydro-1,4-benzodioxine, benzoxazole, 2,1 ,3-benzothiadiazole, coumarin, 3,4-dihydro-2H-1,4-benzoxazine or quinazoline, preferably a substituted (especially meta-substituted) phenyl ring, or an unsubstituted or substituted pyridine ring
- 11. The compound according to any one of claims 1 to 10, wherein Ar is optionally substituted pyrazine, quinoxaline, 1,2,5-thiadiazole or phenyl.
- 12. The compound according to any one of claims 1 to 11, wherein Ar is unsubstituted or mono- or di-substituted.
- 13. The compound according to any one of claims 1 to 12, wherein Ar is unsubstituted or mono- or independently di-substituted by C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-alkylsulphonyl, cyano, hydroxy, C2-4-alkenyl, C2-4-alkynyl, trifluoromethyl, trifluoromethylthio, halogen, amino, methylamino, dimetylamino, acetamido, aryl, aryloxy, arylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, wherein any aryl and heterocyclyl residues in turn may be substituted in one or more positions independently of each other by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, trifluoromethyl, cyano, hydroxy, amino, methylamino and dimethylamino or acetamido.
- 14. The compound according to any one of claims 1 to 13, wherein B is —N(R6)—, —O—, —S— or —SO2—, where R6 is as defined in claim 1
- 15. The compound according to claim 1 which has the general formula (Ia)
- 16. The compound according to claim 15, wherein A is as defined in claim 4, preferably as defined in claim 5, and more preferably as defined in claim 6, especially as defined in claim 7.
- 17. The compound according to claim 15 or 16, wherein n is 0, or n is 1 and B is —N(R6)—, —O—, —S— or —SO2—, where R6 is as defined in claim 1.
- 18. The compound according to claim 15, 16 or 17, wherein R20 and R21 independently of each other are hydrogen, C1-4-alkyl (preferably methyl), C1-4-alkoxy (preferably methoxy), C1-4-alkylthio (preferably methylthio), halogen, amino, methylamino, dimethylamino, acetamido, phenyl, phenoxy or phenylthio, wherein phenyl, phenoxy and phenylthio optionally may be substituted in one or more positions (preferably mono- or disubstituted) independently of each other by halogen, methyl, methoxy, methylthio, cyano, hydroxy or trifluoromethyl, or R20 and R21 together with the carbon atoms to which they are bound form a 5- or 6-membered aromatic or heteroaromatic ring, which optionally is independently substituted in one or more positions by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino or acetamido
- 19. The compound according to claim 18, wherein R20 and R21 independently of each other are hydrogen, halogen or C1-4-alkyl.
- 20. The compound according to any one of claims 15 to 18, wherein R20 and R21 form a ring together with the ring carbons to which they are bound.
- 21. The compound according to claim 20, wherein R20 and R21 together with the carbon atoms to which they are bound form benzene to form a quinoxaline ring or thiophene to form a thieno[3,4-b]pyrazine ring, optionally mono- or di-substituted by halogen.
- 22. The compound according to any one of claims 15 to 21, wherein m is 0.
- 23. The compound according to any one of claims 1 to 22, wherein R1 is piperazine, optionally substituted (preferably at a carbon atom, especially in 2-position) by C1-4-alkyl, fluoromethyl, trifluoromethyl, hydroxymethyl or C1-4-alkoxymethyl, preferably C1-4-alkyl.
- 24. The compound according to any one of claims 1 to 23, wherein n is 0.
- 25. The compound according to any one of claims 4 to 24, wherein o is 2.
- 26. The compound according to any one of claims 4 to 25, wherein p is 1
- 27. The compound according to any one of claims 4 to 26, wherein q is 0
- 28. The compound according to any one of claims 4 to 27, wherein r is 0
- 29. The compound according to any one of claims 4 to 28, wherein at least one of X, Y and Z is oxygen.
- 30. The compound according to any one of claims 4 to 29, wherein R9 to R12 are hydrogen.
- 31. The compound according to claim 1 which has the general formula (II):
- 32. The compound according to claim 31, wherein R20 and R21 are as defined in any one of claims 18 to 21.
- 33. The compound according to claim 31 or 32, wherein X1 and Y1 both are —O—.
- 34. The compound according to claim 31 or 32, wherein X1 is —S—and Y1 is —O—.
- 35. The compound according to claim 31 or 32, wherein X1 is —O—and Y1 is —S—.
- 36. The compound according to claim 31 or 32, wherein X1 and Y1 both are —S—.
- 37. The compound according to any one of claims 31 to 36, wherein R22 is hydrogen.
- 38. The compound according to any one of claims 31 to 37, wherein R23 is methyl, z is 1 and R24 is hydrogen, preferably in (R)-configuration.
- 39. The compound according to any one of claims 31 to 38, wherein R25 is hydrogen and R26 is methyl.
- 40. The compound according to any one of claims 31 to 39, wherein R25 is hydrogen.
- 41. The compound according to claim 1, which is:
2-(2-Phenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 2-(2-Fluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 2-(3-Cyanophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 2-(3-Methoxyhenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 2-[3-(2-hydroxyethoxy)phenoxy]ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 2,3-Dihydro-1,4-benzodioxin-2-ylmethyl 3-(1-piperazinyl)-1-pyrazinyl ether 2-(2-Methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 2-(2,5-Difluorophenoxy)ethyl 3-( 1-piperazinyl)-2-pyrazinyl ether 2-(3,5-Dimethoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 2-(3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethoxy,)-3-(1-piperazinyl)pyrazine 2-Methyl-1-[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine, particularly the (R)-enantiomer thereof 2--Methyl-1-{3-(2-(3-phenoxyethoxy)ethoxy]-2-pyrazinyl}piperazine, particularly the (R)-enantiomer thereof 2-(Quinazolinyl-8-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 2-(Isoquinolinyl-5-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)-6,7-difluoroquinoxaline 2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)thieno[3,4-b]pyrazine 2-(3,4-Dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine 2-Methyl-1-{3-[2-(2-amino-8-quinolinyloxy)ethoxy]-2-pyrazinyl}piperazine, particularly the (R)-enantiomer thereof 1-{3-[2-(2-Methoxy-3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine 2-Methyl-1-{3-[2-(2-methoxy-3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, particularly the (R)-enantiomer thereof, 2-{2-[(2-Chloro-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, 2-{2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, 1-(3-{2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy }-2-pyrazinyl)-2-methylpiperazine, particularly the (R)-enantiomer thereof, 2-(2-{[2-(Methylsulfanyl)-3-pyridinyl]oxy}ethoxy)-3-(1-piperazinyl)pyrazine, 2-Methyl-1-[3-(2-{[2-(methylsulfanyl)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]piperazine, particularly the (R)-enantiomer thereof, 2-{2-[(2-Bromo-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, 1-(3-{2-[(2-Bromo-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, particularly the (R)-enantiomer thereof, 2-( 1-Piperazinyl)-3-(2-{3-[2-(2-pyridinyl)ethoxy]phenoxy}ethoxy)pyrazine, 2-(2-{3-[2-(4-Methyl-1,3-thiazol-5-yl)ethoxy]phenoxy}ethoxy)-3-(1-piperazinyl)pyrazine. 2-(1-Piperazinyl)-3-{2-[3-(tetrahydro-3-furanylmethoxy)phenoxy]ethoxy}pyrazine, 2-(1-Piperazinyl)-3-{2-[3-(tetrahydro-3-furanyloxy)phenoxy]ethoxy}pyrazine, 1-{2-[3-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenoxy]ethyl}-2-pyrrolidinone, 2-{2-[3-(2-Methoxyethoxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine, 2-{[3-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenoxy]methyl}-benzonitrile, 2-(1-Piperazinyl)-3-{2-[3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]ethoxy}-pyrazine, N,N-Dimethyl-N-{2-[3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-phenoxy]-ethyl}amine, 7-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2H-chromen-2-one, 1-(3-{2-[(2-Chloro-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, particularly the (R)-enantiomer thereof, 7-Isoquinolinyl 2-{[3-(1-piperazinyl)]-2-pyrazinyl}oxy)ethyl ether, 2-(2-Chloro-4-methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, 4-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine,
or a pharmacologically acceptable salt or solvate thereof.
- 42. A compound according to any one of claims 1 to 41 for use in therapy of a human being or an animal.
- 43. The compound according to claim 42, wherein the therapy is directed towards prophylaxis or treatment of a serotonin-related disease, particularly 5-HT2 receptor-related.
- 44. The compound according to claim 43, wherein the serotonin-related disease is related to the 5-HT2c receptor.
- 45. The compound according to claim 44, wherein the serotonin-related disease is selected from eating disorders, especially obesity.
- 46. The compound according to claim 44, wherein the serotonin-related disease is selected from memory disorders
- 47. The compound according to claim 44, wherein the serotonin-related disease is selected from mood disorders, comprising major depression and bipolar depression including both mild and bipolar disorder, and seasonal affective disorder (SAD)
- 48. The compound according to claim 44, wherein the serotonin-related disease is selected from anxiety disorders, including situational anxiety, generalized anxiety disorder, primary anxiety disorders and secondary anxiety disorders.
- 49. The compound according to claim 44, wherein the serotonin-related disease is selected from sexual dysfunctions and urinary disorders.
- 50. The compound according to claim 44, wherein the serotonin-related disease is pain.
- 51. The compound according to claim 44, wherein the serotonin-related disease is schizophrenia.
- 52. Use of a compound according to any one of claims 1 to 41 for the manufacture of a medicament for treating or preventing a serotonin-related disease, particularly 5-HT2 receptor-related, especially 5-HT2c receptor-related.
- 53. The use according to claim 52, wherein the serotonin-relateded disease is selected from eating disorders, especially obesity, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctions, and urinary disorders.
- 54. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier
- 55. A method for the prophylaxis or treatment of a serotonin-related, especially 5-HT2 receptor-related, disease in a human being or in an animal, particularly a disease related to the 5-HT2c receptor, especially selected from eating disorders, especially obesity, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctions, and urinary disorders, which method comprises administering an effective amount of a compound according to any one of claims 1 to 41 to a subject suffering from said disease.
- 56. A method for modulating 5HT2 receptor function, especially 5HT2c receptor function, comprising contacting the receptor with an effective inhibitory amount of a compound according to any of claims 1 to 41.
- 57. A process for the preparation of a compound of the formula (I) in claim 1, which process comprises:
a) for the preparation of a compound of formula (I) above in which A is bound to Ar via an O, S or N atom in A, and (i) n=0 and R1 is a saturated aminoazacyclic, aminodiazacyclic, diazacyclic or diazabicyclic residue, or (ii) n=1, B is —N(R6)— or —N(R6)C(R4)(R5)—, wherein R4, R5 and R6 are as defined in claim 1, and R1 is a saturated or unsaturated azacyclic, or a saturated azabicyclic, residue, reacting a compound of the structural formula (III): 17 wherein Ar is as defined in claim 1 and Hal is halogen, with a compound R—A′—X′—H or its corresponding anion where X′ is —O—, —S— or —N(R15)—, A′ is C1-8-alkylene wherein the carbon chain may be interrupted by one or more heteroatoms and which may have a terminal heteroatom binding to R, said heteroatoms being selected from N, O and S, and R is as defined in claim 1 and R15 is as defined in claim 4, to produce a compound of the formula (IV): 18 wherein Ar, X′, A′, R and Hal are as defined above, and subsequently reacting the compound of formula (IV) with an appropriate amine to produce the compound of formula (I); or b) for the preparation of a compound of formula (I) in which n=1, B is oxygen or sulphur and R1 is a saturated azacyclic or azabicyclic residue, or a group —[C(P4)(R5)]xN(R2a)(R3a), wherein R2, R3, R4, R5 and x are as defined in claim 1, reacting a compound of formula (IV) above with a corresponding hydroxy- or mercapto-substituted azacyclic or azabicyclic compound, or with a compound HO—R1 or, HS—R1, where R1 is —[C(R4)(R5)]xN(R2a)(R3a), wherein R2, R3, R4, R5 and x are as defined above, to produce the compound of formula (I); or c) for the preparation of a compound of formula (I), wherein A is bound to R via an oxygen or sulphur atom in A, reacting a compound of formula (V): 19 wherein Ar, R1, B and n are as defined above, A″ is C1-8-alkylene wherein the carbon chain may be interrupted by one or more heteroatoms and which may have a terminal heteroatom bound to Ar, said heteroatoms being selected from N, O and S, and L is a hydroxy, thiol or a leaving group with a compound R—OH or R—SH, where R is as defined in claim 1, to produce the compound of formula (I); or d) for the preparation of a compound of formula (I), in which A is bound to Ar via an O, S or N atom in A, and wherein n=0, or n=1 and B is oxygen, nitrogen, sulphur or —N(R6)C(R4)(R5)—, wherein R4, R5 and R7 are as defined in claim 1, reacting a compound of formula (III) above with an appropriate amine, or an appropriate hydroxy- or mercapto-substituted compound to produce a compound of formula (VI). 20 wherein Ar, B, R1, Hal and n are as defined in claim 1, and subsequently reacting the compound of formula (VI) with a compound R—A′—X′—H or its corresponding anion, where X′ is —O—, —S— or —N(R15)—, A′ is C1-8-alkylene wherein the carbon chain may be interrupted by one or more heteroatoms and which may have a terminal heteroatom binding to R, said heteroatoms being selected from N, O and S, and R is as defined in claim 1 and R15 is as defined in claim 4, to produce the compound of the formula (I);
optionally converting a resulting compound of formula (I) to another compound of formula (I); and, if desired, separating a racemate obtained into optical isomers and/or forming an acid addition salt with an organic or inorganic acid.
Priority Claims (1)
Number |
Date |
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Kind |
9901884-8 |
May 1999 |
SE |
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Parent Case Info
[0001] The present application is a continuation-in-part application of app. Ser. No. 09/5/73,348, “Novel Compounds, Their Use and Preparation”, Attorney Docket No. 1614-233P, filed on May 19, 2000, which claims priority to provisional App. No. 60/137,527, filed on Jun. 3, 1999; the entire contents of which are hereby incorporated by reference.
Provisional Applications (1)
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Number |
Date |
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60137527 |
Jun 1999 |
US |
Divisions (1)
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Number |
Date |
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Parent |
09589282 |
Jun 2000 |
US |
Child |
10269670 |
Oct 2002 |
US |
Continuation in Parts (1)
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Number |
Date |
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Parent |
09573348 |
May 2000 |
US |
Child |
09589282 |
Jun 2000 |
US |