GILPIN MARTIN LEONARD (GB)
COULTON STEVEN (GB)
GILPIN MARTIN LEONARD (GB)
| WO2003055478A1 | 2003-07-10 |
| 1. | A compound of formula (I) : or a salt, solvate or a physiologically functional derivative thereof, wherein: (i) R'and R2 are independently: (a) a group (CR11R12) nA wherein R11 and R12 are independently hydrogen or C1 C6 alkyl, n is 0 or 1 and A is hydrogen, optionally substituted CiCe alkyl, optionally substituted aryl or optionally substituted arylC1C4 alkyl, wherein R'and R2are not both hydrogen; or (b) a group wherein m is 1,2, 3,4 or 5 and R13 is hydrogen or CiCe alkyl ; or (c) a group wherein p is 1,2, 3,4 or 5, R14 is hydrogen or ClC6 alkyl, and B is an optionally substituted aryl ; or (ii) R'and R2, together with the nitrogen atom to which they are attached, form a group: wherein Q is an optionally substituted 4, 5, 6or 7membered saturated ring, wherein one or more of the carbon atoms of the saturated ring is optionally replaced by a heteroatom independently selected from N, O and S, and R'5, R, R17 and R18 are independently hydrogen or CiCe alkyl ; R3 is wherein Y is CiC2 alkylen, C2 alkenylene or C2 alkynylene, qis0or1, and Z is a 5to 7membered optionally substituted monocyclic aromatic ring system or 6to 11membered optionally substituted bicyclic aromatic ring system; R4 and R5 are both hydrogen, or one of R4 and R5 is hydrogen and the other is: (a) SO2R19 wherein R19 is a 5to 7membered optionally substituted monocyclic aromatic ring system or a 6to 11membered optionally substituted bicyclic aromatic ring system; or (b) XR20 wherein X isCO (CH2) r (wherein r is 0,1, 2,3 or 4) orCONH wherein R20 is hydrogen, C1C6 alkyl or a 5to 7membered optionally substituted monocyclic aromatic ring system or a 6to 11membered optionally substituted bicyclic aromatic ring system; R6 is independently selected from hydrogen, C1C6alkyl, C3C6cycloalkyl, C3 C6cycloalkylC1C6alkyl, aryl and arylC1C4 alkyl ; and R7, R8, R9 and R10 are independently selected from hydrogen, CiCe alkyl, C3C6 cycloalkyl, aryl or arylC1C4 alkyl ; or R7 and R3 together form a C3C6 cycloalkyl group, and/or R9 and R10 together form a C3C6 cycloalkyl group. |
| 2. | A compound as claimed in claim 1, having the following stereochemical configuration:. |
| 3. | A compound as claimed in claim 1 or claim 2, wherein R'and R2 are independently selected from optionally substituted CiCe alkyl. |
| 4. | A compound as claimed in claim 3, wherein the C1C6 alkyl is substituted by one, two or three groups selected from: halogen, C16alkyl, C14alkoxy, haloC14alkyl, haloC14alkoxy, C14alkylsulfonamidoC14alkyl, C14alkylamidoC14alkyl, aryl, arylC1 4alkyl, a group R2'CON (R22) (CH2) r, R21R22NCO (CH2) r, R21R22NSO2 (CH2) r or R2'SO2NR22 (CH2) r (where each of R21 and R22 independently represents a hydrogen atom or a C14alkyl group or where appropriate R21R22 forms part of a Cgazacyioaikane or C36 (2oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4). |
| 5. | A compound as claimed in claim 1 or claim 2, wherein R1 and R2 together with the nitrogen atom to which they are attached are linked to form a 4, 5, 6or 7membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R'and R2 are attached, said ring being optionally substituted by one, two or three groups selected from the group consisting of: halogen, C16alkyl, C14alkoxy, haloC14alkyl, haloC14alkoxy, C14alkylsulfonamidoC14alkyl, C14alkylamidoC14alkyl, aryl, arylC14alkyl, a group R21CON(R22)(CH2)r. R21R22NCO(CH2)r, R21R22NSO2 (CH2) r or R21SO2NR22(CH2) r (where each of R21 and R22 independently represents a hydrogen atom or a C14alkyl group or where appropriate R21R22 forms part of a C3 6azacyloalkane or C36 (2 oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4), said ring being further optionally fused to a C5C7 alicyclic or 5or 6membered aromatic or heteroaromatic ring. |
| 6. | A compound as claimed in claim 1 or claim 2, wherein R'and R2 together with the nitrogen atom to which they are attached are linked to form a 5or 6membered ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said ring being optionally substituted by one, two or three groups selected from the group consisting of: halogen, C16alkyl, C14alkoxy, haloC14alkyl, haloC14alkoxy, C14alkylsulfonamidoC14alkyl, C14alkylamidoC1 4alkyl, aryl, arylC14alkyl, a group R2'CON (R22) (CH2) r, R21R22NCO(CH2)r, R2'RzzNS02 (CH2) r or R21SO2NR22(CH2)r (where each of R21 and R22 independently represents a hydrogen atom or a C14alkyl group or where appropriate R2'R22 forms part of a C3 gazacyloalkane or C36 (2oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4), said ring being further optionally fused to a C5C7 alicyclic or 5or 6 membered aromatic or heteroaromatic ring. |
| 7. | A compound as claimed in claim 1 or claim 2, wherein R'and R2 together with the nitrogen atom to which they are attached are linked to form a 5or 6membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R'and R2 are attached, said ring being optionally substituted by one or more groups independently selected from optionally substituted CiCe alkyl and optionally substituted C3C6 cycloalkyl, more preferably by one or more groups independently selected from CiC4 alkyl, most preferably methyl, ethyl or isopropyl. |
| 8. | A compound as claimed in claim 1, wherein R'and R2, together with the nitrogen atom to which they are linked, form: azetidine, azepine, pyrrolidine, imidazolidine, piperidine, morpholine, thiomorpholine or piperazine, all of which being optionally substituted by one, two or three groups selected from the group consisting of: halogen, C16alkyl, C14alkoxy, haloC14alkyl, haloC14alkoxy, C14alkylsulfonamidoC14alkyl, C1 4alkylamidoC1 4alkyl, aryl, arylC1 4alkyl, a group R2'CON (R22) (CH2) r, R21R22NCO (CH2) r, R21R22NSO2 (CH2) r or R2'SO2NR22 (CH2) r (where each of R21 and R22 independently represents a hydrogen atom or a Chalky) group or where appropriate R21R22 forms part of a C3 6azacyloalkane or C3 6 (2oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4). |
| 9. | A compound as claimed in claim 1, wherein R1 and R2 together with the nitrogen atom to which they are attached are linked to form a pyrrolidinyl ring, said ring being optionally substituted by one or more groups independently selected from optionally substituted C1C4 alkyl, preferably methyl, ethyl or isopropyl. |
| 10. | A compound as claimed in claim 9, wherein the pyrrolidinyl ring formed by R'and R2 together with the nitrogen atom to which they are attached is substituted by one or more C1C4 alkyl groups, preferably methyl, ethyl or isopropyl groups, preferably at the 2 and/or 5positions, more preferably at the 2position. |
| 11. | A compound as claimed in claim 1, wherein R'and R2, together with the nitrogen atom to which they are attached are linked to form a piperidinyl ring, said ring being optionally substituted by one or more groups independently selected from optionally substituted C1C4 alkyl, preferably methyl or ethyl. |
| 12. | A compound as claimed in claim 11 wherein the piperidinyl ring formed by R'and R2 together with the nitrogen atom to which they are attached is substituted by one or more methyl or ethyl groups, preferably at the 2and 6positions. |
| 13. | A compound as claimed in claim 11 wherein the piperidinyl ring formed by R'and R2 together with the nitrogen atom to which they are attached is substituted by two methyl groups, preferably at the 2and 6positions. |
| 14. | A compound as claimed in any of claims 113, wherein q is 0. |
| 15. | A compound as claimed in any of claims 114, wherein Z is substituted by 1,2 or 3 groups independently selected from :hal,R23,ORa4,C (O) OR25,CN,N02, NR C(O)NR28R29, NR30C(O)R31, C(O)R32, C(NR33)NR34R35, C(NOR36)R37, and C1 6alkylsulphonyl ; wherein R23 is CiCe alkyl, C3C6 cycloalkyl, C3C6 cycloalkylC1C4 alkyl, aryl, aryloxy or arylC1C4 alkyl, all of which being optionally substituted by one or more groups independently selected from hal, C1C6 alkyl, OR24. COOR25 CN, NO2 andNR R27, wherein R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 R36 and R37 are independently selected from hydrogen and CiCe alkyl. |
| 16. | A compound as claimed in any of claims 115, wherein Z is a 5to 7membered optionally substituted monocyclic aromatic ring system. |
| 17. | A compound as claimed in claim 16, wherein Z is phenyl, optionally substituted by one or more groups independently selected fromhal,R23,CF3,C1C6alkylsulphonyl, OR,COOR,CN,NO2 orNR26R27, wherein R 23, R 24, R25, R26 and R27 are as defined in claim 14. |
| 18. | A compound as claimed in any of claims 115, wherein Z is a 8to 10membered optionally substituted bicyclic aromatic ring system. |
| 19. | A compound as claimed in claim 18, wherein Z is naphthyl, naphthyridinyl, <BR> <BR> quinolinyl, isoquinolyl, benzothienyl, chromanyl, chromenyl, imidazoleisothiazolyl, benzothiadiazolyl or benzofuryl. |
| 20. | A compound as claimed in claim 19, wherein Z is quinolinyl (preferably 5 quinolinyl), optionally substituted by one or more groups independently selected from hal, R23, OR24, COOR25, CF3, C1C6alkylsulphonyl, CN, NO2, and NR26R27, wherein R23 R24 R25 R26and R27are as defined in claim 14. |
| 21. | A compound as claimed in claim 20, wherein Z is quinolinyl (preferably 5 quinolinyl), optionally substituted by one or more groups independently selected fromhal, R23, CF3, C1C6alkylsulphonyl, OR24, COOR25, CN, NO2 or NR26R27, wherein R23, R24, R25, R26 and R27 are independently selected from hydrogen and CiCe alkyl. |
| 22. | A compound as claimed in any of claims 121 wherein R3 is phenyl or 5quinolinyl. |
| 23. | A compound as claimed in any of claims 122, wherein one of R4 and R5 is hydrogen and the other is a groupCOCH2R38,COR38 orCONHR38 wherein R38 is a 5 to 7membered monocylic aromatic ring system or a 6to 11membered bicyclic aromatic ring system, said ring system being optionally substituted by one or two groups independently selected from hal, CF3, C1C6alkyl, C1C6alkoxy,CN, C1C6alkylamido, C1C6alkanoyl and C1C6alkylsulphonyl. |
| 24. | A compound as claimed in any of claims 123, wherein R6 is selected from hydrogen, CiCe alkyl, aryl and benzyl, optionally substituted by one or more groups independently selected from hal, C1C6 alkyl, hydroxy and ClC6 alkoxy. |
| 25. | A compound as claimed in any of claims 124, wherein R7, R8, R9 and R10 are hydrogen. |
| 26. | A compound of formula (la) : or a salt or solvate or a physiologically functional derivative thereof, wherein: R39 and R40 are independently selected from C3C6 alkyl, or R39 and R40, together with the nitrogen atom to which they are attached, are linked to form a 5, 6, or 7membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R39 and R40 are attached, said heterocyclic ring being optionally substituted by one or more groups independently selected from C1C4 alkyl and C3C6 cycloalkyl, and said heterocyclic ring being further optionally fused to a C6 alicyclic or aromatic ring, and said heterocyclic ring being further optionally bridged by a methylene group; R41 is wherein ais0or1, and Z1 is a 5or 6membered monocyclic aromatic ring system or a 6to 10membered bicyclic aromatic ring system, said ring system being optionally substituted by one or more groups independently selected fromhal,R44,OR45,COOR46,CN, NO2, NR47R48, wherein R44 is C1C4 alkyl or phenyl optionally substituted by one or more hal groups and R45, R46, R47 and R48 are independently selected from hydrogen and methyl, one of R42 and R43 is hydrogen and the other is a groupX1R49, wherein Xi is CONHor CO (CH2) b wherein b is 0,1 or 2, and R49 is a 5to 6membered monocylic aromatic ring system or a 6to 10membered bicyclic aromatic ring system, said ring system being optionally substituted by one, two or three groups independently selected fromhal,R50, OR51, C(O)OR52, CN, NO2, NR53R54, C(O)NR55R56, NR57C(O)R58, C(O)R59, C (NR60) NR61R62, C(NOR63)R64, or C16alkylsulphonyl, wherein R50 is CiCe alkyl, C3C6 cycloalkyl, C3Cg cycloalkylCC4 alkyl, aryl, aryloxy or arylC1C4 alkyl, all of which being optionally substituted by one or more groups independently selected from hal, CiCe alkyl, OR51, COOR52, CN, NO2 and NR53R54 ; wherein R51, R52, R53, R54, R55, R56, , R58, R, R, R61, R62, R63 and R64 are independently selected from hydrogen and Ci C6 alkyl. |
| 27. | A compound as claimed in claim 26, having the following stereochemical configuration:. |
| 28. | A compound as claimed in claim 1 which is: Ex 1 Naphthalene1sulfonic acid [ (R)2amino3 ( (2S, 6R) 2, 6dimethylpiperidin1yl) propyl]amide Ex 2 N{(R)2((2S,6R)2,6Dimethylpioperidin1yl)1[(naphthalene1sulfonylamino) methyl]ethyl}acetamide EX 3 N{(R)2((2S, 6R)2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino) methyl]ethyl}benzamide Ex 4 N{(R)2((2S, 6R) 2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino) methyl]ethyl}butyramide Ex 5 N{(R)2((2S, 6R) 2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino) methyl]ethyl}2phenylacetamide Ex 6 Thiophene2carboxylic acid { (R)2 ( (2S, 6R) 2, 6dimethylpioperidin1yl)1 [(naphthalene1sulfonylamino)methyl]ethyl}amide Ex 7 N{(R)2((2S, 6R) 2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino) methyl]ethyl}4methanesulfonylbenzamide Ex 8 4bromoN{(R)2((2S, 6R)2, 6dimethylpiperidin1yl)1[(naphthalene1 sulfonylamino)methyl]ethyl}benzamide Ex 9 Naphthalene2carboxylic acid {(R)2((2S, 6R) 2, 6dimethylpiperidin1yl)1 [(naphthalene1sulfonylmaino)methyl]ethyl}amide Ex 10 Benzo [1,3] dioxole5carboxylic acid {(R)2((2S, 6R) 2, 6dimethylpiperidin1yl)1<BR> <BR> <BR> <BR> <BR> <BR> [(naphthalene1sulfonylamino)methyl]ethyl}amide Ex 11 N{(R)2((2S, 6R)2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino) <BR> <BR> <BR> methyl]ethyl}3methoxybenzamide<BR> <BR> <BR> <BR> <BR> <BR> Ex 12 3, 5DichloroN { (R)2 ( (2S, 6R) 2, 6dimethylpiperidin1yl)1[(naphthalene1 sulfonylamino)methyl]ethyl}benzamide Ex 13 N{(R)2((2S, 6R) 2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino) methyl]ethyl}3methanesulfonylbenzamide Ex 14 N{(R)2((2S, 6R)2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino) <BR> <BR> <BR> methyl]ethyl}2methanesulfonylbenzamide<BR> <BR> <BR> <BR> <BR> <BR> Ex 15 N{(R)2((2R, 6S) 2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino)<BR> <BR> <BR> <BR> <BR> <BR> methyl]ethyl}4methoxybenzamide<BR> <BR> <BR> <BR> <BR> <BR> Ex 16 N{(R)2((2R, 6S) 2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino) methyl]ethyl}terephthalamic acid methyl ester Ex 17 4AcetylN{(R)2((2R, 6S) 2, 6dimethylpiperidin1yl)1[(naphthalene1 <BR> <BR> <BR> sulfonylamino)methyl]ethyl}benzamide<BR> <BR> <BR> <BR> <BR> <BR> Ex 18 4cyano N{(R)2((2R, 6S) 2, 6dimethylpiperidin1yl)1[(naphthalene1<BR> <BR> <BR> <BR> <BR> <BR> sulfonylamino)methyl]ethyl}benzamide Ex 19 4Acetylamino N{(R)2((2R, 6S) 2, 6dimethylpiperidin1yl)1[(naphthalene1 sulfonylamino)methyl]ethyl}benzamide Ex 20 N { (R)2 ( (2R, 6S) 2, 6Dimethylpiperidin1yl)1[(naphthalene1sulfonylamino) methyl]ethyl}2(4methanesulfonylphenyl)acetamide <BR> <BR> <BR> Ex 21 N[(R)1(Benzenesulfonylaminomethyl)2((2S, 6R) 2, 6dimethylpiperidin1yl) ethyl]4methanesulfonylbenzamide <BR> <BR> <BR> Ex 22 N { (R)2 ( (2S, 6R) 2, 6Dimethylpiperidin1yl)1[(quinoline5sulfonylamino)<BR> <BR> <BR> <BR> <BR> <BR> methyl]ethyl}4methanesulfonylbenzamide Ex 23 N { (R)2 ( (2S, 6R) 2, 6Dimethylpiperidin1yl)1 [ (5fluoro2methyl benzenesulfonylamino)methyl]ethyl}4methanesulfonylbenzamide Ex 24 N { (R)2 ( (2S, 6R) 2, 6Dimethylpiperidin1yl)1[(4methoxy benzenesulfonylamino)methyl]ethyl}4methanesulfonylbenzamide Ex 25 M { (R)2 ( (2S, 6R) 2, 6Dimethylpiperidin1yl)1[(naphthalene2sulfonylamino) methyl]ethyl}4methanesulfonylbenzamide Ex 26 N[(R)1[(5Cyanonaphthalene1sulfonylamino)methyl]2((2S, 6R) 2, 6dimethyl piperidin1yl)ethyl]4methanesulfonylbenzamide Ex 27 N[(R)1(Benzenesulfonylaminomethyl)2((2S, 6R)2, 6dimethylpiperidin1yl) ethyl]4methoxybenzamide <BR> <BR> <BR> Ex 28 N{(R)2((2S, 6R) 2, 6Dimethylpiperidin1yl)1[(quinoline5sulfonylamino)<BR> <BR> <BR> <BR> <BR> <BR> methyl]ethyl}4methoxybenzamide Ex 29 N{(R)2((2S, 6R) 2, 6Dimethylpiperidin1yl)1 [ (5fluoro2methyl benzenesulfonylamino)methyl]ethyl}4methoxybenzamide Ex 30 N{(R)2((2S, 6R) 2, 6Dimethylpioperidin1yl)1[(4methoxy benzenesulfonylamino)methyl]ethyl}4methoxybenzamide Ex 31 N{(R)2((2S, 6R) 2, 6Dimethylpiperidin1yl)1[(naphthalene2sulfonylamino)<BR> methyl]ethyl}4methoxybenzamide Ex 32 N[(R)1[(5Cyanonaphthalene1sulfonylamino)methyl]2((2S, 6R) 2, 6dimethyl piperidin1yl)ethyl]4methoxybenzamide Ex 33 Naphthalene1sulfonic acid [(R)2benzenesulfonylamino3((2S, 6R) 2,6 dimethylpiperidin1yl)propyl]amide Ex 34 Naphthalene1sulfonic acid [ (R)3 ( (2S, 6R) 2, 6dimethylpiperidin1yl)2 (toluene4sulfonylamino)propyl]amide Ex 35 Naphthalene1sulfonic acid [ (R)3 ( (2S, 6R) 2, 6dimethylpiperidin1yl)2 (4 methoxybenzenesulfonylamino)propyl]amide Ex 36 Naphthalene1sulfonic acid [ (R)3 ( (2S, 6R) 2, 6dimethylpiperidin1yl)2(4 methanesulfonylbenzenesulfonylamino)propyl]amide Ex 37 Naphthalene1sulfonic acid [ (R)2 (3, 5dichlorobenzenesulfonylamino)3 ( (2S, 6R) 2, 6dimethylpiperidin1yl)propyl]amide<BR> Ex 38 Naphthalene1sulfonic acid [ (R)3 ( (2S, 6R) 2, 6dimethylpiperidin1yl)2 (3<BR> phenylureido)propyl]amide Ex 39 Naphthalene1sulfonic acid { (R)3 ( (2S, 6R) 2, 6dimethylpiperidin1yl)2 [3 (4 methoxyphenyl)ureido]propyl}amide Ex 40 Naphthalene1sulfonic acid { (R)3 ( (2S, 6R)2, 6dimethylpiperidin1yl)2 [3 (4 trifluoromethylphenyl)ureido]propyl}amide Ex 41 Naphthalene1sulfonic acid {(R)3((2S, 6R) 2, 6dimethylpiperidin1yl)2 [3 (3<BR> trifluoromethylphenyl)ureido]propyl}amide Ex 42 Naphthalene1sulfonic acid [ (R)2 [3 (2, 3dichlorophenyl)ureido]3 ( (2S, 6R) 2,6 dimethylpiperidin1yl)propyl]amide or a salt or solvate or a physiologically functional derivative thereof. |
| 29. | A process for the preparation of a compound as claimed in any of claims 128, comprising the steps of: (a) reacting a compound of formula (II) wherein R', R2, R4, R5, R6, R, R8, R10 and R9 are as hereinbefore defined, with a compound of formula (III) R3SO2L (111) wherein R3 is as hereinbefore defined and L is a suitable leaving group, such as, for example, a halogen, preferably chlorine; or (b) converting a compound of formula (IV) (IV) wherein R, R2, R3, R6, R7, R8, R9 and Rlo are as defined for formula (I) ; and thereafter optionally for process (a) or process (b): converting a compound of formula (I) into another compound of formula (I) ; or removing any protecting groups; or forming a pharmaceutical acceptable salt, solvate or a physiologically functional derivative thereof. |
| 30. | A compound as claimed in any of claims 128 for use in therapy. |
| 31. | A compound as claimed in any of claims 128 for use in treating a disorder mediated by GlyT1. |
| 32. | A compound as claimed in claim 31, wherein the disorder is a psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia. |
| 33. | A method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GlyT1, which comprises administering an effective amount of a compound as defined in any of claims 128. |
| 34. | A method as claimed in claim 33, wherein the disorder is psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia. |
| 35. | Use of a compound as defined in any of claims 128 in the preparation of a medicament for the treatment of a disorder mediated by GlyT1. |
| 36. | Use as claimed in claim 35, wherein the disorder is psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia. |
| 37. | A pharmaceutical composition comprising a compound as claimed in any of claims 128 and at least one pharmaceutically acceptable carrier, diluent or excipient. |
Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GlyT1 and GlyT2. GlyT1 is found predominantly in the forebrain and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8,1992 : 927-935). Molecular cloning has further revealed the existence of three variants of GlyT1, termed GlyT-la, GlyT-1b and GlyT-1c (Kim et al., Molecular Pharmacology, 45,1994 : 608-617), each of which displays a unique distribution in the brain and peripheral tissues. The variants arise by differential splicing and exon usage, and differ in their N-terminal regions. GlyT2, in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64,1995 : 1026-1033).
Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT1. These data are consistent with the view that, by regulating the synaptic levels of glycine, GlyT1 and GlyT2 selectively influence the activity of NMDA receptors and strychnine-sensitive glycine receptors, respectively.
NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev., 19 533-552 (1995); Danysz et al, Behavioral Pharmacol., 6 455-474 (1995) ) ; and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry, 52,998-1007 (1996). Thus, agents that inhibit GlyT1 and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes. Conversely, over-activation of NMDA receptors has been implicated in a number of disease states, in particular the neuronal death associated with stroke and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke or head trauma. Coyle & Putffarcken, Science, 262, 689-695 (1993); Lipton and Rosenberg, New Enal. J. of Medicine, 330, 613-622 (1993); Choi, Neuron, 1,623-634 (1988). Thus, pharmacological agents that increase the activity of GlyT1 will result in decreased glycine- activation of NMDA receptors, which activity can be used to treat these and related
disease states. Similarly, drugs that directly block the glycine site of the NMDA receptors can be used to treat these and related disease states.
Glycine transport inhibitors are already known in the art, for example as disclosed in published International Applications W097/45423 (Trophix Pharmaceuticals, Inc.), and W097/45115 (Trophix Pharmaceuticals Inc.). The classes of compounds disclosed in these applications inhibit glycine transport via the GlyT1 or GlyT2 transporters.
In published International Application W099/34790 (Alielix Neuroscience, Inc.), there is disclosed a class of compounds which also inhibits glycine transport via the GlyT1 or GlyT2 transporters, with preferred compounds showing selectivity for the inhibition of glycine transport via GlyT2 versus GlyT1.
Further publications disclosing glycine transport inhibitors include published International Applications W099/45011 (Janssen Pharmaceutica N. V.), WO00/07978 (Akzo Nobel N. V. ) and W001/87855 (Yamanouchi Pharmaceutical Co. Ltd. ). Published International Applications W001/32602 and W001/81308 (both NPS Allelix Corp. ) disclose classes of compounds which inhibit glycine transport (or reuptake) via the GlyT1 transporter.
Published International Applications W001/36423 (Akzo Nobel N. V. ) and W003/55478 (SmithKline Beecham pic) disclose compounds that inhibit glycine transport by the human GlyT1 transporter.
However, there still remains the need to identify further compounds that can inhibit GlyT1 transporters, including those that inhibit GlyT1 transporters selectively over GlyT2 transporters. Such compounds would thus be suitable for the treatment of certain neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes. Other neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS,"schizophrenia- spectrum"disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor- related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
It has now surprisingly been found that a class of compounds inhibit GlyT1 transporters and are useful in the treatment of certain neurological and neuropsychiatric disorders, including schizophrenia.
Thus, in the first aspect, there is provided a compound of formula (I) :
(I) or a salt, solvate or a physiologically functional derivative thereof, wherein: (i) R'and R2 are independently: (a) a group -(CR11R12)n-A wherein R11 and R12 are independently hydrogen or C1- C6 alkyl, n is 0 or 1 and A is hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted aryl or optionally substituted arylC1-C4 alkyl, wherein R'and R2are not both hydrogen; or (b) a group wherein m is 1,2, 3,4 or 5 and R13 is hydrogen or Ci-Ce alkyl ; or (c) a group wherein p is 1,2, 3,4 or 5, R14 is hydrogen or Ci-Ce alkyl, and B is an optionally substituted aryl ; or (ii) R'and R, together with the nitrogen atom to which they are attached, form a group:
wherein Q is an optionally substituted 4-, 5-, 6-or 7-membered saturated ring, wherein one or more of the carbon atoms of the saturated ring is optionally replaced by a heteroatom independently selected from N, O and S, and R, R, R 17 and R'8 are independently hydrogen or Ci-Ce alkyl ; R3 is wherein Y is C1-C2 alkylene, C2 alkenylene or C2 alkynylene, q is 0 or 1, and Z is a 5-to 7-membered optionally substituted monocyclic aromatic ring system or 6-to 11-membered optionally substituted bicyclic aromatic ring system; R4 and R5 are both hydrogen, or one of R4 and R5 is hydrogen and the other is: (a)-S02R'9 wherein R'9 is a 5-to 7-membered optionally substituted monocyclic aromatic ring system or a 6-to 11-membered optionally substituted bicyclic aromatic ring system; or (b) -XR20 wherein X is-CO (CH2) r- (wherein r is 0,1, 2,3 or 4) or-CONH- wherein R20 is hydrogen, Ci-Ce alkyl or a 5-to 7-membered optionally substituted monocyclic aromatic ring system or a 6-to 11-membered optionally substituted bicyclic aromatic ring system; R6 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3- C6cycloalkyl-C1-C6alkyl, aryl and arylC1-C4 alkyl ; and R7, R8, R9 and R10 are independently selected from hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl or arylC1-C4 alkyl ; or R7 and R8 together form a C3-C6 cycloalkyl group, and/or R9 and R10 together form a C3-C6 cycloalkyl group.
As used herein, the term "C1-C6 alkyl" refers to a straight or branched chain hydrocarbon which contains at least 1, and at most 6, carbon atoms. Examples of"C1-C6 alkyl"groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, t-butyl, n-pentyl and n-hexyl.
In a like manner, the term "C1-C4 alkyl" refers to a straight or branched chain hydrocarbon which contains at least 1, and at most 4, carbon atoms. Examples of "C1-c4 alkyl"groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-propyl and t-butyl.
As used herein, the term"C3C6 cycloalkyl"refers to a non-aromatic cyclic hydrocarbon ring having from three to six carbon atoms. Examples of"C3-C6 cycloalkyl"groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term"C3-C6 cycloalkylC,-C4 alkyl"refers to a C3 C6 cycloalkyl group, as hereinbefore defined, attached through a Ci-C4 alkylen linker, wherein Ci-C4 alkylen is as defined herein. Examples of"C3-C6 cycloalkylC1-C4 alkyl"include, but are not limited to, cyclohexylmethyl.
As used herein, the term"aryl"refers to a 5-to 7-membered aromatic or heteroaromatic ring system wherein the heteroatomic ring contains at least one heteroatom selected from nitrogen, oxygen and sulphur. Examples of aryl groups include phenyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxadiazolyl, isothiazolyl, thiazolyl, furyl, thienyl, pyridyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and azepinyl.
As used herein, the term"arylC1-C4 alkyl"refers to an aryl group, as hereinbefore defined, attached through a Ci-C4 alkylen linker, wherein Ci-C4 alkylen is as defined herein.
Examples of"arylC1-C4 alkyl"include, but are not limited to, benzyl, phenethyl, pyridylmethyl and phenylpropyl.
As used herein, the terms "C1-C2 alkylene", "C1-C3 alkylene" and "C1-C4 alkylene" refer to a straight or branched chain divalent hydrocarbon radical, which contains at least 1, and at most 2,3 or 4, carbon atoms respectively. Examples of"C-C2 alkylene","C1 C3 alkylene" and"C1 C4 alkylene"groups useful in the present invention include methylene, ethylene, n- propylene and n-butylene.
As used herein, the term"C2 alkenylene"refers to a divalent hydrocarbon radical with a double bond, which contains 2 carbon atoms.
As used herein, the term"2 alkynylene"refers to a divalent hydrocarbon radical with a triple bond, which contains 2 carbon atoms.
As used herein, the terms"hal"and"halo"are abbreviations for"halogen"and refers to fluorine, chlorine, bromine, or iodine.
The term"5-to 7-membered monocyclic aromatic ring system"refers to a monocyclic aromatic ring system consisting of 5,6 or 7 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of such groups include: phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, furazanyl, oxazolyl, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, oxadiazolyl, triazolyl, thiadiazolyl, pyrazinyl, triazinyl, azepinyl and pyranyl.
The term"6-to 11-membered bicyclic aromatic ring system"refers to a bicyclic aromatic ring system consisting of 6,7, 8,9, 10 or 11 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur. The term includes bicyclic aromatic ring systems wherein both rings are aromatic, as well as bicyclic aromatic ring systems wherein one of the rings is partially or fully saturated. Examples of bicyclic aromatic ring systems in which both rings are aromatic include: naphthyl, indenyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, naphthridinyl, quinolyl, quinoxalinyl, quinazolinyl and isoquinolyl. Examples of bicyclic aryl groups in which one of the rings is partially or fully saturated includes dihydrobenzofuranyl, indanyl, tetrahydronaphthyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, benzoxazinyl and benzoazepinyl.
All of these ring systems may be attached to the rest of the molecule via any available atom on the ring system, such as carbon or nitrogen.
As used herein, the term"salt"refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation. Suitably physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Salts having a non-physiologically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
As used herein, the term"solvate"refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or formula (la), or a salt or physiologically functional derivative thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of
suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutical acceptable solvent. Examples of suitable pharmaceutical acceptable solvents include water, ethanol and acetic acid.
Most preferably the solvent used is water.
As used herein, the term"physiologically functional derivative"refers to any pharmaceutical acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.
Suitable substituents for groups in formula (I) which are optionally substituted include one or more groups selected from: halogen, hydroxy, oxo, cyano, nitro, C1-6alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, arylC1-4alkoxy, C1-4alkylthio, hydroxyC1-4alkyl, C1- 4alkoxyC1-4alkyl, C3-6cycloalkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkanoyl, C1- 4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkylsuflonyloxy, C1-4alkylsulfonylC1-4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC1-4alkyl, C1-4alkylsulfonamido, C1-4alkylamido, Cl-4a alkylsulfonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC1 4alkyl, arylcarboxamidoC1 4alkyl, aroyl, aroylC1 4alkyl, aryl1 alkanoyl, C1-4acyl, aryl, arylC1-4alkyl, C1-4alkylaminoC1-4alkyl, a group R21R22N-, R21OCO(CH2)r, R21CON(R22)(CH2) r, R"R"NCO (CH2) r, RNS02 (CH2) r or RS02NR (CH2) r (where each of R21 and R22 independently represents a hydrogen atom or a C1-4alkyl group or where appropriate R21R22 forms part of a C3-6azacyloalkane or C3-6(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), a group R21R22N (CH2) t-or R21R22N (CH2) tO- (wherein t represents an integer from 1 to 4); wherein when the substituent is R21R22N (CH2) t-or R21R22N (CH2) tO, R21 with at least one CH2 of the (CH2) t portion of the group may also form a Cgazacydoatkane and R22 may represent hydrogen, a Chalky ! group or with the nitrogen to which it is attached, may form a second C3 6azacycloalkane fused to the first Cgazacydoaikane ; furthermore, the optionally substituted 4-, 5-, 6-or 7-membered saturated ring formed by R'and R2 may be additionally optionally bridged by a C1-C3 alkylen group; and the optionally substituted 4-, 5-, 6-or 7-membered saturated ring formed by R1 and R2 may be additionally optionally fused to a C5-C7 alicyclic or 5-or 6-membered aromatic or heteroaromatic ring optionally substituted by one or more groups independently selected from Ci-Ce alkyl and C3-C6 cycloalkyl. Where there is more than one substituent, the substituents may be different or the same. If substituent (s) is/are present, preferably the number of substituent (s) is 1,2, 3 or 4.
Certain of the compounds described herein may exist in stereoisomeric forms (i. e. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism).
The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formulae (I) and (la) may exist in tautomeric forms other than that shown in the formulae and these are also included within the scope of the present invention.
As referred to above, individual enantiomers of compounds of formulae (I) and (la) may be prepared and an indication of the preferred stereochemistry for such enantiomers has been given. In a preferred embodiment, an optically pure enantiomer is desired. The term"optically pure enantiomer"means that the compound contains greater than about 90 % of the desired isomer by weight, preferably greater than about 95 % of the desired isomer by weight, and most preferably greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer (s) of the compound.
Preferably, the compound of formula (I) as hereinbefore described has the following stereochemical configuration: It will be understood by the skilled artisan that the stereochemical configuration at the chiral centre marked with a * will be assigned the Chan-Ingold-Prelog notation of (R).
In one embodiment of the present invention, R'and R2 are independently selected from optionally substituted Ci-Ce alkyl, preferably C3-C6 alkyl such as isopropyl. The optional substituents for the Ci-Ce alkyl may be one, two or three groups selected from: halogen, C1-6alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, C1-4alkylsulfonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, aryl, arylC1-4alkyl, a group R21CON(R22)(CH2)r, R21R22NCO (CH2) r, R"R"NS02 (CH2) r or R2'SO2NR22 (CH2) r (where each of R21 and R22 independently represents a hydrogen atom or a C1 4alkyl group or where appropriate R21R22 forms part of a C3 6azacyloalkane or C3 6 (2-oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4).
In another embodiment, R1 and R2 together with the nitrogen atom to which they are attached are linked to form a 4-, 5-, 6-or 7-membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R1 and R2 are attached, said ring being optionally substituted by one, two or three groups selected from: halogen, C1 6alkyl, C1
4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, C1-4alkylsulfonamidoC1-4alkyl, C1- 4alkylamidoC1-4alkyl, aryl, arylC1-4alkyl, a group R21CON (R22) (CH2) r, R 21 R22 NCO (CH2) r, R21R22NSO2 (CH2) r or R21SO2NR22(CH2)r (where each of R21 and R22 independently represents a hydrogen atom or a C1-4 alkyl group or where appropriate R21R22 forms part of a C3 6azacyloalkane or C3 6 (2-oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4), said ring being further optionally fused to a C5-C7 alicyclic or 5-or 6- membered aromatic or heteroaromatic ring as hereinbefore described.
In another embodiment, R'and R2 together with the nitrogen atom to which they are attached are linked to form a 5-or 6-membered ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said ring being optionally substituted by one, two or three groups selected from: halogen, C1-6alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, C1-4alkylsulfonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, aryl, arylC1-4alkyl, a group RCON (R) (CH2) r, R21R22NCO (CH2) r, R2'R2NS02 (CH2) r or Rz'S02NR22 (CH2) r (where each of R21 and R2 independently represents a hydrogen atom or a C1-4alkyl group or where appropriate R2'R22 forms part of a C3 6azacyloalkane or C3 6 (2-oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4), said ring being further optionally fused to a C5- C7 alicyclic or 5-or 6-membered aromatic or heteroaromatic ring as hereinbefore described.
In another embodiment, R1 and R2 together with the nitrogen atom to which they are attached are linked to form a 5-or 6-membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R'and R2 are attached, said ring being optionally substituted by one, two or three groups selected from: halogen, C1 6alkyl, C 4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, C1-4alkylsulfonamidoC1-4alkyl, C1- 4alkylamidoC1-4alkyl, aryl, arylC1-4alkyl, a group R21CON (R22) (CH2) r, R21R22NCO(CH2) r, R21R22NSO2 (CH2) r or R21SO2NR22(CH2) r (where each of R21 and R22 independently represents a hydrogen atom or a Chalky) group or where appropriate R2'R22 forms part of a C3-6azacyloalkane or C3 6 (2-oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4), preferably by one or more groups independently selected from optionally substituted Ci-Ce alkyl and optionally substituted C3-C6 cycloalkyl, more preferably by one or more groups independently selected from Ci-C4 alkyl, most preferably methyl, ethyl or isopropyl.
Suitably, the 4-, 5-, 6-or 7-membered saturated ring formed by R1 and R2 together with the nitrogen atom to which they are linked is selected from the group comprising: azetidine, azepine, pyrrolidine, imidazolidine, piperidine, morpholine, thiomorpholine, piperazine, all of which being optionally substituted by one, two or three groups selected from: halogen, C1-6alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, C1- 4alkylsulfonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, aryl, arylC1-4alkyl, a group R21CON(R22)(CH2)r, R21R22NCO(CH2)r, R21R22NSO2 (CH2) r or R21SO2NR22(CH2) r (where
each of R21 and R22 independently represents a hydrogen atom or a C1 4alkyl group or where appropriate R21R22 forms part of a C3 6azacyloalkane or Cgg (2- oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4).
In another embodiment, R'and R2 together with the nitrogen atom to which they are attached are linked to form a pyrrolidinyl ring, said ring being optionally substituted by one or more groups independently selected from optionally substituted Ci-C4 alkyl, preferably methyl, ethyl or isopropyl. Preferably, the pyrrolidinyl ring formed by R1 and R2 together with the nitrogen atom to which they are attached is substituted by one or more Ci-C4 alkyl groups, preferably methyl, ethyl or isopropyl groups, preferably at the 2-and/or 5- positions, more preferably at the 2-position.
In another embodiment, R1 and R2 together with the nitrogen atom to which they are attached are linked to form a piperidinyl ring, said ring being optionally substituted by one or more groups independently selected from optionally substituted Ci-C4 alkyl, preferably methyl or ethyl. Preferably, the piperidinyl ring formed by R1 and R2 together with the nitrogen atom to which they are attached is substituted by one or more methyl or ethyl groups, preferably at the 2-and 6-positions. More preferably, the piperidinyl ring formed by R'and R2 together with the nitrogen atom to which they are attached is substituted by two methyl groups, preferably at the 2-and 6-positions.
In one embodiment of the present invention, q is 0.
In one embodiment, Z is substituted by 1,2 or 3 groups independently selected from:- hal, -R23, -OR24, -C(O)OR25, -CN, -NO2, -NR26R27, -C(O)NR28R29, -NR30C(O)R31, - C (O) R32,-C (NR33) NR34R35,-C (NOR36) R3', or C1 6alkylsulphonyl ; wherein R23 is Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C4 alkyl, aryl, aryloxy or arylC1-C4 alkyl, all of which being optionally substituted by one or more groups independently selected from hal, Cl-C6 alkyl,-OR24,-COOR-CN,-N02 and-NR R, wherein R, R, R, R, R 28, R29, R30, R 31, R32, R33, R34, R35, R36 and R37 are independently selected from hydrogen and Ci-Ce alkyl.
In one embodiment, Z is a 5-to 7-membered optionally substituted monocyclic aromatic ring system as hereinbefore described. Suitably, Z is a 5-or 6-membered optionally substituted monocyclic ring system as hereinbefore described. Suitably, Z is phenyl optionally substituted as hereinbefore described, preferably by one or more groups independently selected from -hal, -R10, -CF3, -C1-C6alkylsulphonyl, -OR11, -COOR12, -CN, -NO2,-NR13R14 as hereinbefore defined, more preferably by one or more groups independently selected from-hal, C1-C6 alkyl, C1-C6 alkoxy, CF3,-CN and C3-C6 cycloalkyl.
In another embodiment, Z is a 6-to 11-membered optionally substituted bicyclic aromatic ring system as hereinbefore described. Suitably, Z is a 8-to 10-membered optionally substituted bicyclic aromatic ring system as hereinbefore described. Suitably, Z is selected from the group comprising: naphthyl, naphthyridinyl, quinolinyl, isoquinolyl, benzothienyl, chromanyl, chromenyl, imidazoleisothiazolyl, benzothiadiazolyl, benzofuryl, all of which being optionally substituted as hereinbefore described. Preferably, Z is quinolinyl (preferably 5-quinolinyl), optionally substituted as hereinbefore described, preferably by one or more groups independently selected from-hal,-R23,-OR24,- COOR25, -CF3, -C1-C6alkylsulphonyl, -CN, -NO2, and -NR26R27, wherein hal, R, R R25, Ra6 and R27 are as hereinbefore defined, preferably hal, Ci-Ce alkyl, Cl-C6 alkoxy, CF3,-CN and C3-C6 cycloalkyl. Most preferably, Z is 5-quinolinyl optionally substituted by one or more groups independently selected from-hal, Ci-Ce alkyl, Ci-Ce alkoxy,- CF3, -CN and C3-C6 cycloalkyl.
Preferably, R3 is phenyl or 5-quinolinyl.
In one embodiment, one of R4 and R5 is hydrogen and the other is a group -COCH2R38, - COR38 or-CONHR38 wherein R38 is a 5-to 7-membered monocylic aromatic ring system or a 6-to 11-membered bicyclic aromatic ring system, said ring system being optionally substituted by one or two groups independently selected from hal, CF3, C1-C6alkyl, C1- C6alkoxy,-CN, C1-C6alkylamido, C1-6alklanoyl and C1-C6alkylsulphonyl.
In another embodiment, R6 is selected from hydrogen, Ci-Ce alkyl, aryl and benzyl, wherein the Ci-Ce alkyl, aryl and benzyl are optionally substituted by one or more groups independently selected from hal, Ci-Ce alkyl, hydroxy and Ci-Ce alkoxy. Preferably, R6 is hydrogen.
In one embodiment, R7, R8, R9 and R10 are independently selected from hydrogen and C1- C6 alkyl, preferably hydrogen.
In a further aspect of the present invention, there is provided a compound of formula (la) : or a salt or solvate or a physiologically functional derivative thereof, wherein: R39 and R40 are independently selected from C3-C6 alkyl, or R39 and R40, together with the nitrogen atom to which they are attached, are linked to form a 5-, 6-, or 7-membered heterocyclic ring, wherein the sole heteroatom is the nitrogen
atom to which R39 and R40 are attached, said heterocyclic ring being optionally substituted by one or more groups independently selected from C1-C4 alkyl and C3-C6 cycloalkyl, and said heterocyclic ring being further optionally fused to a Ce alicyclic or aromatic ring, and said heterocyclic ring being further optionally bridged by a methylene group; R41 is wherein ais0or1, and Z, is a 5-or 6-membered monocyclic aromatic ring system or a 6-to 10-membered bicyclic aromatic ring system, said ring system being optionally substituted by one or more groups independently selected from-hal,-R44,-OR45,-COOR46,-CN,- NO2,-NR47R48, wherein R44 is C1-C4 alkyl or phenyl optionally substituted by one or more hal groups and R45, R46, R47 and R43 are independently selected from hydrogen and methyl, one of R42 and R 43 is hydrogen and the other is a group-X1R49, wherein Xi is CONH-or- CO (CH2) b- wherein b is 0,1 or 2, and R49 is a 5-to 6-membered monocylic aromatic ring system or a 6-to 10-membered bicyclic aromatic ring system, said ring system being optionally substituted by one, two or three groups independently selected from-hal,-R50, -OR51, -C(O)OR52, -CN, -NO2, -NR53R54, -C(O)NR55R56, -NR57C(O)R58, -C(O)R59, - C (NR60) NR61R62, -C(NOR63)R64, or C1 6alkylsulphonyl, wherein R50 is C1-6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC3-C4 alkyl, aryl, aryloxy or ary alkyl, all of which being optionally substituted by one or more groups independently selected from ha !, Ci-Ce alkyl,-OR5',-COOR,-CN,-N02 and-NRR wherein, R, R R, R, R56, R57, R58, R59, R60, R61, R62, R63 and R64 are independently selected from hydrogen and C1- C6 alkyl When a is 1, the C2 alkenylene group may be in the cis or trans configuration, preferably the trans configuration. Preferably a is 0.
In a further embodiment, the compound of formula (la) as hereinbefore described has the following stereochemical configuration:
It will be understood by the skilled artisan that the stereochemical configuration at the chiral centre marked with a * will be assigned the Cahn-Ingold-Prelog notation of (R).
Preferred features of formula (I) apply to formula (1 a) mutatis mutandis.
Examples of preferred compounds of the invention include Examples 1 to 42 shown below, as well as salts, solvates and physiologically functional derivatives thereof: <BR> <BR> Ex 1 Naphthalene-1-sulfonic acid [ (R)-2-amino-3- ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)- propyl]-amide Ex 2 N- { (R)-2- ( (2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylamino)- methyl]-ethyl}-acetamide EX 3 N-{(R)-2-((2S, 6R)-2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylamino)- methyl]-ethyl}-benzamide Ex 4 N-{[(R)-2-((2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylamino)- methyl]-ethyl}-butyramide Ex 5 N-{(R)-2-((2S, 6R)-2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylamino)- methyl]-ethyl}-2-phenyl-acetamide Ex 6 Thiophene-2-carboxylic acid {(R)-2-((2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-1- [(naphthalene-1-sulfonylamino)-methyl]-ethyl}-amide Ex 7 N-{(R)-2-((2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(napthahalene-1-sulfonylamin- methyl]-ethyl}-4-methanesulfonyl-benzamide Ex 8 4-bromo-N-{(R)-2-((2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-1-[(naphthalene-1- sulfonylamino)-methyl]-ethyl}-benzamide Ex 9 Naphthalene-2-carboxylic acid { (R)-2- ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-1- [(naphthalene-1-sulfonylamino)-methyl]-ethyl}-amide Ex 10 Benzo [1,3] dioxole-5-carboxylic acid { (R)-2- ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-1-<BR> [ (naphthalene-1-sulfonylamino)-methyl]-ethyl}-amide<BR> Ex 11 N- (R)-2- ( (2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylamino)- methyl]-ethyl}-3-methoxy-benzamide Ex 12 3, 5-Dichloro-N-{(R)-2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-1- [(naphthalene-1- sulfonylamino)-methyl]-ethyl}-benzamide<BR> Ex 13 N-{(R)-2-((2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylamino)- <BR> methyl]-ethyl}-3-methanesulfonyl-benzamide<BR> Ex 14 N-{(R)-2-((2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylamino)- methyl]-ethyl}-2-methanesulfonyl-benzamide Ex 15 N- { (R)-2- ( (2R, 6S) -2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylmaino)- methyl]-ethyl}-4-methoxy-benzamide Ex 16 N-{(R)-2-((2R, 6S) -2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylamino)- methyl]-ethyl}-terephthalamic acid methyl ester Ex 17 4-Acetyl -N-{(R)-2-((2R, 6S) -2, 6-dimethyl-piperidin-1-yl)-1-[(naphthalene-1- sulfonylamino)-methyl]-ethyl}-benzamide
Ex 18 4-cyano -N-{(R)-2-((2R, 6S) -2, 6-dimethyl-piperidin-1-yl)-1-[(naphthalene-1-<BR> <BR> <BR> <BR> <BR> <BR> sulfonylamino)-methyl]-ethyl}-benzamide<BR> <BR> <BR> <BR> <BR> <BR> Ex 19 4-Acetylamino-N-{(R)-2-((2R, 6S) -2, 6-dimethyl-piperidin-1-yl)-1-[(naphthalene-1-<BR> <BR> <BR> <BR> <BR> <BR> sulfonylamino)-methyl]-ethyl}-benzamide Ex 20 N-{(R)-2-((2R, 6S)-2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-1-sulfonylamino)- methyl]-ethyl}-2- (4-methanesulfonyl-phenyl)-acetamide Ex 21 N-[(R)-1-(Benzenesulfonylamino-methyl)-2-((2S, 6R)-2, 6-dimethyl-piperidin-1-yl)- ethyl]-4-methanesulfonyl-benzamide Ex 22 N- { (R)-2- ( (2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(quinoline-5-sulfonylamino)- methyl]-ethyl}-4-methanesulfonyl-benzamide Ex 23 N-{(R)-2-((2S, 6R)-2, 6-Dimethyl-piperidin-1-yl)-1-[(5-fluoro-2-methyl- benzenesulfonylamino)-methyl]-ethyl}-4-methanesulfonyl-benza mide Ex 24 N-{(R)-2-((2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1- [ (4-methoxy- benzenesulfonylamino)-methyl]-ethyl}-4-methanesulfonyl-benza mide <BR> <BR> <BR> Ex 25 N-{[(R)-2-((2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-2-sulfonylamino)- methyl]-ethyl}-4-methanesulfonyl-benzamide Ex 26 N-[(R)-1-[(5-Cyano-naphthalene-1-sulfonylamino)-methyl]-2-(( 2S, 6R) -2, 6-dimethyl- piperidin-1-yl)-ethyl]-4-methanesulfonyl-benzamide Ex 27 N-[(R)-1-(Benzenesulfonylamino-methyl)-2-((2S, 6R)-2, 6-dimethyl-piperidin-1-yl)- ethyl]-4-methoxy-benzamide Ex 28 N-{(R)-2-((2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(quinoline-5-sulfonylamino)- methyl]-ethyl}-4-methoxy-benzamide Ex 29 N- {(R)-2- ( (2S, 6R)-2, 6-Dimethyl-piperidin-1-yl)-1- [ (5-fluoro-2-methyl- benzenesulfonylamino)-methyl]-ethyl}-4-methoxy-benzamide Ex 30 N-{(R)-2-((2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1- [ (4-methoxy- benzenesulfonylamino)-methyl]-ethyl}-4-methoxy-benzamide <BR> <BR> <BR> Ex 31 N-{(R)-2-((2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-1-[(naphthalene-2-sulfonylamino)- methyl]-ethyl}-4-methoxy-benzamide Ex 32 N-[(R)-1-[(5-Cyano-naphthalene-1-sulfonylamino)-methyl]-2-(( 2S, 6R) -2, 6-dimethyl- piperidin-1-yl)-ethyl]-4-methoxy-benzamide Ex 33 Naphthalene-1-sulfonic acid [(R)-2-benzenesulfonylamino-3-((2S, 6R) -2,6- dimethyl-piperidin-1-yl)-propyl]-amide Ex 34 Naphthalene-1-sulfonic acid [ (R)-3- ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-2- (toluene-4-sulfonylamino)-propyl]-amide Ex 35 Naphthalene-1-sulfonic acid [ (R)-3- ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-2- (4- methoxy-benzenesulfonylamino)-propyl]-amide Ex 36 Naphthalene-1-sulfonic acid [ (R)-3- ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-2- (4- methanesulfonyl-benzenesulfonylamino)-propyl]-amide Ex 37 Naphthalene-1-sulfonic acid [ (R)-2- (3, 5-dichloro-benzenesulfonylamino)-3- <BR> <BR> <BR> ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-propyl]-amide<BR> <BR> <BR> <BR> <BR> <BR> Ex 38 Naphthalene-1-sulfonic acid [ (R)-3- ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-2- (3- phenyl-ureido)-propyl]-amide
Ex 39 Naphthalene-1-sulfonic acid { (R)-3- ( (2S, 6R)-2, 6-dimethyl-piperidin-1-yl)-2- [3- (4- methoxy-phenyl)-ureido]-propyl}-amide<BR> Ex 40 Naphthalene-1-sulfonic acid {(R)-3-((2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-2- [3- (4-<BR> trifluoromethyl-phenyl)-ureido]-propyl}-amide<BR> Ex 41 Naphthalene-1-sulfonic acid { (R)-3- ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-2- [3- (3-<BR> trifluoromethyl-phenyl)-ureido]-propyl}-amide Ex 42 Naphthalene-1-sulfonic acid [ (R)-2- [3- (2, 3-dichloro-phenyl)-ureido]-3- ( (2S, 6R) -2,6- dimethyl-piperidin-1-yl)-propyl]-amide The compounds of formulae (I) and (la) have the ability to crystallise in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of formulae (I) and (la).
Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
It is to be understood that the following embodiments refer to compounds within the scope of both formula (I) and formula (la) as defined above unless specifically limited by the definition of each formula or specifically limited otherwise. It is also understood that the embodiments of the present invention described herein, including uses and compositions, are applicable to both formula (I) and formula (la).
The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
Compounds of general formula (I) or formula (la) may be prepared by methods disclosed in the documents hereinbefore referred to and by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. Generally, the following schemes are illustrated using compounds of formula (la), but it is recognised that such schemes are easily adaptable by the skilled artisan to prepare compounds of formula (I). It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991) Protecting Groups in Organic Svnthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I) or (la). Those skilled in the art will recognise if a stereocentre
exists in compounds of formula (I) or (la). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. Where the stereochemistry is indicated as being variable at certain positions, a mixture of stereoisomers may be obtained, this mixture having been separated where indicated. Stereoisomers may be separated by high-performance liquid chromatography or other appropriate means. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N.
Mander (Wiley-Interscience, 1994).
Typical reaction routes for the preparation of a compound of formula (I) as hereinbefore defined, wherein R4, R5, R6, R7, R8, R9 and R10 are hydrogen, are shown in Schemes 1 and 2.
Scheme 1 Scheme 2 0 0 N-O o o ici \/ O H O O HNRR2 HNRRz KH/THF 0°C-RT 0 V o \N NRR2 //. \ NNR R2 O H OH 0"OH LiN3, 20% aq/THF Et0 H N2H4'H20 N NR IR2 /OH OH H 1R2 H2, Pd (OH) 2 H2N MEOH OH OH | R3-SO2CI DCM s NR R 1°l NR. R2 t' 0 3 \ 1 2 O OH 0 OH (A) 1. Nitrobenzene sulphonyl chloride + triethylamine 2. Sodium azide + DMF 3. Hydrogenation o R3 $I I N NR'R 0 H NH2 (I) In Scheme 1, the compounds of formula (A) may be prepared using methodology similar to that described by Gutcait A. et a/., Tetrahedron Asymmetry, 1996,7 (6), 1641-1648.
Compounds of formula (A) may be converted to compounds of formula (I) above by displacement of the hydroxyl with azide, as shown above.
In Scheme 2, the reduction of the azide may be carried out using all methods known to those skilled in the art, for example, hydrogenation in the presence of catalyst such as palladium on carbon, Pd (OH) and those known in the art, see for example March, Advanced Organic Chemistry, 4th edition, Wiley Interscience. The reduction of the azide is preferably carried out by hydrogenation in the presence of a catalyst such as palladium on carbon.
As indicated above, Schemes 1 and 2 can be adapted to prepare compounds wherein R6, R7, R8, R9 and R10 are other than hydrogen.
Thus, in a further aspect of the invention, there is provided a process for the preparation of the compound of formula (I) as hereinbefore defined, by: (a) reacting a compound of formula (II) wherein R', R2, R4, R5, R6, R7, R8, R10 and R9 are as hereinbefore defined, with a compound of formula (III) R3SO2L (111) wherein R3 is as hereinbefore defined and L is a suitable leaving group, such as, for example, a halogen, preferably chlorine; or (b) converting a compound of formula (IV)
wherein R', R2, R3, R6, R7, R8, R9 and R10 are as defined for formula (I) ; and thereafter optionally for process (a) or process (b): converting a compound of formula (I) into another compound of formula (I) ; or 'removing any protecting groups; or forming a pharmaceutically acceptable salt, solvate or a physiologically functional derivative thereof.
Compounds of the present invention are useful for treating certain neurological and neuropsychiatric disorders. Thus, the present invention provides a compound of formula (I) or formula (1a) as hereinbefore described and salts, solvates and physiologically functional derivatives thereof, for use in therapy. In particular, the present invention provides a compound of formula (I) or formula (1a) as hereinbefore described and salts, solvates and physiologically functional derivatives thereof, for use in treating a disorder mediated by GlyT1.
In a further aspect of the invention, there is provided a method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GlyT1, which comprises administering an effective amount of a GlyT1 inhibiting compound of formula (I) or (la) as hereinbefore defined or a salt, solvate or a physiologically functional derivative thereof.
As used herein, the terms"therapy"and"treatment"refer to alleviation and/or cure of established symptoms as well as prophylaxis.
As used herein, the term"an effective amount"means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
The present invention also provides the use of a compound of formula (I) or formula (la) as hereinbefore defined or a salt, solvate or a physiologically functional derivative thereof in the preparation of a medicament for the treatment of a disorder mediated by GlyT1.
As used herein, the term"a disorder mediated by GlyT1"refers to a disorder that may be treated by the administration of a medicament that alters the activity of the GlyT1 transporter. As hereinbefore described, the action of GlyT1 transporters affects the local concentration of glycine around NMDA receptors. As a certain amount of glycine is needed for the efficient functioning of NMDA receptors, any change to that local concentration can affect NMDA-mediated neurotransmission. As hereinbefore described, changes in NMDA-mediated neurotransmission have been implicated in certain neuropsychiatric disorders such as dementia, depression and psychoses, for example schizophrenia, and learning and memory disorders, for example attention deficit disorders
and autism. Thus, alterations in the activity of the GlyT1 transporter are expected to influence such disorders.
The disorders mediated by GlyT1 referred to herein include neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes. Other neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS,"schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
Preferably, the disorders mediated by GlyT1 to be treated by the use or method as hereinbefore described are psychoses, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.
Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition comprising as active ingredient the compound of formula (I) or formula (la) as hereinbefore described, or a salt, solvate or a physiologically functional derivative thereof, and at least one pharmaceutical acceptable carrier, diluent or excipient.
These pharmaceutical compositions may be used in the treatment of clinical conditions for which a GlyT1 inhibitor is indicated such as, for example, schizophrenia. The carrier must be pharmaceutical acceptable to the recipient and must be compatible with, i. e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or (la) as hereinbefore described as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
Within the context of the present invention, the terms used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). The various subtypes of the disorders mentioned herein
are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.
In particular, the compounds of formula (I) are of use in the treatment of schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60) ; Schizophreniform Disorder (295.40) ; Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298. 8) ; Shared Psychotic Disorder (297.3) ; Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations ; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81) and With Hallucinations (293. 82) ; and Psychotic Disorder Not Otherwise Specified (298.9).
The compounds of formula (I) are also of use in the treatment of mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80) ; Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90).
The compounds of formula (I) are also of use in the treatment of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type, Natural Environment Type, Blood-Injection-Injury Type, Situational Type and Other Type), Social Phobia (300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified (300.00).
The compounds of formula (I) are also of use in the treatment of substance-related disorders including Substance Use Disorders such as Substance Dependence and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced
Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-induced Sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-induced Mood Disorder, Alcohol- Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9) ; Amphetamine (or Amphetamine-Like)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9) ; Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9) ; Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-Induced Psychotic Disorder, Cannabis-Induced Anxiety Disorder and Cannabis- Related Disorder Not Otherwise Specified (292.9) ; Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-induced Anxiety Disorder, Cocaine- Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9) ; Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9) ; Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9) ; Nicotine-Related Disorders such as Nicotine Dependence (305.1), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9) ; Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-Induced Psychotic Disorder, Opioid-Induced Mood Disorder, Opioid-Induced Sexual Dysfunction, Opioid-induced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9) ; Phencyclidine (or Phencyclidine-Like)-Related Disorders
such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292. 89), Phencyclidine Intoxication Delirium, Phencyclidine- Induced Psychotic Disorder, Phencyclidine-Induced Mood Disorder, Phencyclidine- Induced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9) ; Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304. 10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic- Induced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-induced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-induced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9) ; Polysubstance-Related Disorder such as Polysubstance Dependence (304.80) ; and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide.
The compounds of formula (I) are also of use in the treatment of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47) ; primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47) ; Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44) ; Sleep Disorder Due to a General Medical Condition; and Substance-induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type.
The compounds of formula (I) are also of use in the treatment of eating disorders such as Anorexia Nervosa (307.1) including the subtypes Restricting Type and Binge- Eating/Purging Type; Bulimia Nervosa (307.51) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
The compounds of formula (I) are also of use in the treatment of Autistic Disorder (299.00) ; Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01), Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit/Hyperactivity Disorder Hyperactive-impulse Type (314.01) and Attention-Deficit/Hyperactivity Disorder Not Otherwise Specified (314.9) ; Hyperkinetic Disorder; Disruptive Behaviour Disorders such
as Conduct Disorder including the subtypes childhood-onset type (321.81), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).
The compounds of formula (I) are also of use in the treatment of Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301,81), Avoidant Personality Disorder (301. 82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9).
The compounds of Formula (I) are also of use in the enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment. Within the context of the present invention, the term cognitive impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i. e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebella atrophy and amyotropic lateral sclerosis ; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post-electroconvulsive treatment related cognitive disorders; and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.
The compounds of formula (I) are also of use in the treatment of sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79) ; sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72) ; orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75) ; sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51) ; Sexual Dysfunction Not Otherwise Specified (302.70) ; paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3),
Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9) ; gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85) ; and Sexual Disorder Not Otherwise Specified (302.9).
The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive- compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders.
The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
In another aspect of the invention, there is provided a method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by G lytl, which comprises administering an effective amount of a compound of formula ( !) as hereinbefore defined or a salt or solvate thereof.
The invention also provides a method of treating schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.
The invention also provides a method of treating psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia,
aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutical acceptable salt or solvate thereof.
In another aspect of the invention, there is provided use of a compound of formula (I) as hereinbefore defined or a salt or solvate thereof in the preparation of a medicament for the treatment of a disorder mediated by GlyT1.
Preferably, the disorder mediated by GlyT1 to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
The invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutical acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders.
The invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutical acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
As used herein, the term"effective amount"means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.
Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt or solvate thereof, and at least one pharmaceutical acceptable carrier, diluent or excipient.
These pharmaceutical compositions may be used in the treatment of clinical conditions for which a GlyT1 inhibitor is indicated such as, for example, schizophrenia. The carrier must be pharmaceutical acceptable to the recipient and must be compatible with, i. e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or a salt or solvate thereof as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.
Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
Suitable SNRts which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.
It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
The compounds of formula (I) and their pharmaceutical acceptable salts and solvates thereof are also suitable for combination with other typical and atypical antipsychotics to provide improved treatment of psychotic disorders. Particular advantages associated with the combinations, uses and methods of treatment of compounds of formula (I) and their pharmaceutical acceptable salts and solvates thereof include equivalent or improved efficacy at doses of administration which are lower than those commonly used for the individual components. Improved treatments of positive symptoms and/or negative symptoms and/or cognitive symptoms of the psychotic disorder may also be observed.
The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to treatment with certain neuroleptic agents.
The combination therapies of the invention are preferably administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilised on a therapeutic administration of one or more of the of the components for a period of time and then receives administration of another component. Within the scope of this invention, it is preferred that the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one neuroleptic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one neuroleptic agent to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
In a further aspect therefore, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient receiving therapeutic administration of at least one neuroleptic agent. In a further aspect, the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one neuroleptic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In a further aspect, the invention provides the use of at least one neuroleptic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The invention further provides at least one neuroleptic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with at least one neuroleptic agent. The invention further provides the use of a combination of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of compounds of formula (I) or a pharmaceutical acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder. The invention further provides the use of at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
In further aspects, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutical acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutical acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
In a further aspect, the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more further dosage forms each comprising a neuroleptic agent for simultaneous therapeutic administration.
Within the context of the present invention, the term psychotic disorder includes those disorders mentioned above, such as schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, dyskinetic disorders, depression, bipolar disorder, cognitive impairment and obsessive-compulsive disorders and all the various forms of the disorders as mentioned herein. which are contemplated as part of the present invention.
Examples of neuroleptic/antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol ; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene ; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles ; dibenzothiazepines; imidazolidinones ; benzisothiazolyl-piperazines ; triazine such as lamotrigine ; dibenzoxazepines, such as loxapine ; dihydroindolones, such as molindone ; aripiprazole ; and derivatives thereof that have antipsychotic activity.
Examples of neuroleptic drugs that are preferred for use in the present invention are shown in Table 1.
Table 1 Neuroleptic drugs Common Trade Name Route of Form Name Administration Dosage Range and (Median) a Clozapine CLOZARIL oral tablets 12.5-900 mg/day (300-900 mg/day) Olanzapine ZYPREXA oral tablets 5-25 mg/day (10-25 mg/day) Ziprasidone GEODON oral capsules 20-80mg/twice a day (80-160 mg/day) Risperidone RISPERDAL oral solution tablets 2-16 mg/day tablets (4-12 mg/day) Quetiapine SEROQUEL oral tablets fumarate 50-900 mg/day (300-900 mg/day) Sertindole SERLECT (4-24 mg/day) Amisulpride Haloperidol HALDOL oral tablets 1-100 mg/day (1-15 mg/day) Haloperidol HALDOL parenteral injection Decanoate Decanoate Haloperidollactate HALDOL oral solution INTENSOL parenteral injection Chlorpromazine THORAZINE rectal suppositories 30-800 mg/dåy Common Trade Name Route of Form Name Administration Dosage Range and (Median) a oral capsules (200-500 mg/day) solution tablets parenteral injection Fluphenazine PROLIXIN 0.5-40 mg/day (1-5 mg/day) Fluphenazine PROLIXIN parenteral injection decanoate Decanoate (about one-half the dosage shown for oral) Fluphenazine PROLIXIN parenteral injection enanthate (same as above Fluphenazine PROLIXIN oral elixer hydrochloride solution parenteral injection Thiothixene NAVANE oral capsules 6-60 mg/day (8-30 mg/day) Thiothixene NAVANE oral solution hydrochloride parenteral injection Trifluoperazine STELAZINE (2-40 mg/day) Perphenazine TRILAFON oral solution 12-64 mg/day tablets (16-64 mg/day) parenteral injection Perpehazine and ETRAFON oral tablets Amitriptyline TRIAVIL hydrochloride Thioridazine MELLARIL oral suspension solution 150-800 mg/day tablets (100-300 mg/day) Mesoridazine (30-400 mg/day) Common Trade Name Route of Form Name Administration Dosage Range and (Median) a Molindone MOBAN 50-225 mg/day (15-150 mg/day) Molindone MOBAN oral solution hydrochloride Loxapine LOXITANE 20-250 mg/day (60-100 mg/dav) Loxapine LOXITANE oral solution hydrochloride parenteral injection Loxapine LOXITANE oral capsules succinate Pimozide (1-10 mg/day) Flupenthixol Promazine SPARINE Triflupromazine VESPRIN Chlorprothixene TARACTAN Droperidol INAPSINE Acetophenazine TINDAL Prochlorperazine COMPAZINE Methotrimeprazine NOZINAN Pipotiazine PIPOTRIL Aripiprazole Hoperidone
Examples of tradenames and suppliers of selected neuroleptic drugs are as follows : clozapine (available under the tradename CLOZARIL@, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREX@, from Lilly ; ziprasidone (available under the tradename GEODONO, from Pfizer); risperidone (available under the tradename RISPERDAL@, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL@, from AstraZeneca); haloperidol (available under the tradename HALDOL@, from Ortho-McNeil) ; chlorpromazine (available under the tradename THORAZINE@, from SmithKline Beecham (GSK); fluphenazine (available under the tradename PROLIXINO, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); thiothixene (available under the tradename NAVANE@ ;, from Pfizer); trifluoperazine (10- [3- (4-methyl-1-piperazinyl) propyl]- 2- (trifluoromethyl) phenothiazine dihydrochloride, available under the tradename STELAZINEO, from Smith Klein Beckman; perphenazine (available under the tradename TRILAFON@ ; from Schering); thioridazine (available under the tradename MELLARIL@ ; from Novartis, Roxane, HiTech, Teva, and Alpharma) ; molindone (available under the tradename MOBAN@, from Endo); and loxapine (available under the tradename LOXITANEO ; from Watson). Furthermore, benperidol (Glianimon@), perazine (Taxilan@) or melperone (Eunerpan@)) may be used.
Other preferred neuroleptic drugs include promazine (available under the tradename SPARINE@), triflurpromazine (available under the tradename VESPRIN@), chlorprothixene (available under the tradename TARACTAN@), droperidol (available under the tradename NAPS) NE@), acetophenazine (available under the tradename TINDAL@ ; ), prochlorperazine (available under the tradename COMPAZINE@), methotrimeprazine (available under the tradename NOZINAN@), pipotiazine (available under the tradename PIPOTRIL@), ziprasidone, and hoperidone.
Particularly preferred neuroleptic agents for use in the invention are olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
Possible formulations include those suitable for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose). The most suitable means of administration for a particular patient will depend on the nature and severity of the conditions being treated and on the nature of the active compound, but, where possible, oral administration is preferred.
Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules ; as solutions or suspensions in aqueous or non-aqueous liquids ; or as oil-in-water or water-in-oil emulsions.
Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intraveneously, they may also be administered by subcutaneous or intramuscular injection.
Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
The formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound (s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
For example, a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
It will be appreciated that the precise dose administered will depend on the age and condition of the patient and the frequency and route of administration and will be at the ultimate discretion of the attendant physician. The compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.
A proposed dose of the active ingredient for use according to the invention for oral, sub- lingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a GlyT1 inhibitor, including schizophrenia, may be about 1 to about 1000 mg, preferably about 5 to about 500 mg, more preferably about 10 to about 100 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
The invention is further illustrated by the following non-limiting examples.
Examples As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams) ; L (litres); ml (millilitres) ; , uL (microlitres) ; psi (pounds per square inch); M (molar) ; mM (millimolar) ; i. v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles) ; mmol (millimoles) ; RT (room temperature); min (minutes); h (hours); mp (melting point) ; TLC (thin layer chromatography); Tr (retention time); RP (reverse phase); MeOH (methanol) ;/-PrOH (isopropanol) ; TEA (triethylamine) ; TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide) ; EtOAc (ethyl acetate); DME (1,2-dimethoxyethane) ; DCM (dichloromethane) ; DCE (dichloroethane) ; DMF (N, N-dimethylformamide) ; DMPU (N, N'dimethylpropyleneurea) ; (CDI (1, 1-carbonyldiimidazole) ; IBCF (isobutyl chloroformate) ; HOAc (acetic acid); HOSu (N-hydroxysuccinimide) ; HOBT (1-hydroxybenzotriazole) ; mCPBA (meta-chloroperbenzoic acid; EDC (ethylcarbodiimide hydrochloride) ; BOC (tert-butyloxycarbonyl) ; FMOC (9-fluorenylmethoxycarbonyl) ; DCC (dicyclohexylcarbodiimide) ; CBZ (benzyloxycarbonyl) ; Ac (acetyl) ; atm (atmosphere); TMSE (2- (trimethylsilyl) ethyl) ; TMS (trimethylsilyl) ; TIPS (triisopropylsilyl) ; TBS (t-butyidimethylsilyl) ;
Me (methyl) ; HPLC (high pressure liquid chromatography); Et (ethyl) ; tBu (tert-butyl).
All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCI. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions conducted under an inert atmosphere at room temperature unless otherwise noted.
'H NMR spectra were recorded on a Bruker B-ACS 60 400MHz, Bruker DPX 400 or a Bruker DPX 250. Chemical shifts are expressed in parts per million (ppm, 6 units).
Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).
Low-resolution mass spectra (MS) were recorded on a HP1100 series spectrometer; MS and liquid chromatography MS were recorded on a Micromass MS2 Plafform LC spectrometer. All mass spectra were taken under electrospray ionisation (ESI), chemical ionisation (CI), electron impact (EI) or by fast atom bombardment (FAB) methods. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualised with UV light, 5% ethanolic phosphomolybdic acid or p- anisaldehyde solution. Flash column chromatography was performed on silica gel (230- 400 mesh, Merck).
The following descriptions set out the syntheses of intermediates particularly useful in the synthesis of compounds of formulae (I) and (la).
Description 1 General description exemplified for (R)-1 sazido-3-pyrrolidin-1-ylpropan-2-ol (D1).
The title compound was prepared using the method of Dhanoa et al, Tet. Lett., 33 (13) p. 1725-8, (1992). Pyrrolidine (0. 41 ml ; 5mmol) was added to a suspension of potassium hydride (35% in mineral oil) (630mg; 5. 5mmol) in anhydrous tetrahydrofuran (THF) (20ml) under argon. After stirring for 2h, a solution of (S)- (+)-glycidyl nosylate (1. 19g ; 4. 6mmol) in anhydrous THF (5ml) was added over 2 minutes. The mixture was stirred overnight at ambient temperature, then filtered through kieselguhr and washed with THF. Finally, the mixture was concentrated under reduced pressure to approximately a quarter of the original volume (n. b. use cold water bath-volatile product). The resulting THF solution of crude epoxide was treated with lithium azide (20% solution in water) (5 eq; 6. 2ml) then
heated at 70° overnight. The cooled solution was evaporated under reduced pressure and the residue treated with saturated aqueous NaHCO3 solution and extracted into ethyl acetate (x 2). The organic phase was dried (Na2SO4) and evaporated under reduced pressure to a light brown oil. Purified by column chromatography, eluting with methanol/dichloromethane (2.5%, 4%) to afford the pure hydroxy azide as a pale orange oil (168mg, 21 % over two steps). MH+ 171.
Description 2 General description exemplified for (S)-1-amino-3-pyrrolidin-1-ylpropan-2-ol (D2) A solution of (R)-1-azido-3-pyrrolidin-1-ylpropan-2-ol (D1) (168mg; 0. 988mmol) in methanol (10ml) was hydrogenated at atmospheric pressure and ambient temperature over Pearlmans'catalyst (130mg) overnight. The catalyst was removed by filtration through kieselguhr, and the filtrate evaporated under reduced pressure, to yield the title compound as a clear colourless oil (130mg ; 91 %).
Description 3 (R)-1-Azido-3-(2-methylpyrrolidin-1-yl) propan-2-ol (D3) The title compound was prepared from 2-methylpyrrolidine (430mg; 5.06mmol) using the method outlined in Description 1 (119mg; 14% over 2 steps). MH+ 185.'H NMR (400MHz, CDCts) 6 : 3.86-3. 78 (m, 1H), 3.4-3. 31 (m, 1H), 3.29-3. 13 (m, 2H), 3.03-2. 57 (m, 2H), 2.53-2. 42 (m, 1H), 2.2-2. 11 (m, 1H), 1.98-1. 89 (m, 1H), 1.83-1. 67 (m, 2H), 1.45-1. 35 (m, 1 H), 1.09 (t, 3H).
Description 4 (S)-1-Amino-3-(2-methylpyrrolidin-1-yl) propan-2-ol (D4).
The title compound was obtained from (R)-1-azido-3-(2-methylpyrrolidin-1-yl) propan-2-ol (D3) (119mg; 0. 646mmol) using the method outlined in Description 2 (80mg; 78%) MH+ 159.
Description 5 2, 4-Dimethylpyrrolidine (D5)
The title compound was prepared by the method of DeJong and Wibaut, Recl. Trav.
Chim. Pays-Bas. , 49 p. 237-46 (1930). A solution of 2, 4-dimethylpyrrole (10g; 0. 105mol) in glacial acetic acid (500moi) was hydrogenated at atmospheric pressure and ambient temperature over platinum oxide (2g). After 4h, a further 2g platinum oxide was added and the reaction continued overnight. The catalyst was removed by filtration, and the resulting filtrate was basified strongly with potassium hydroxide pellets (with addition of ice and external card-ice/acetone cooling). The product was obtained by steam distillation of the basic solution, followed by extraction with diethyl ether. The organic phase was dried (Na2SO4) and evaporated under reduced pressure (n. b. use cold water bath-volatile product) to leave the crude product which was further purified by bulb-to-bulb distillation as a clear, colourless oil. (5g; 48%). 1H NMR (400MHz, CDCI3) 6 : 3.2-3. 1 (m, 1H), 3.05- 2.99 (m, 1H), 2.56-2. 5 (m, 1H), 2.22-2. 13 (m, 1H), 2.11-2. 03 (m, 1H), 1.15 (d, 3H), 1.00 (d, 3H), 0. 88-0. 79 (m, 1H).
Description 6: (R)-1-Azido-3-(2, 4-dimethylpyrrolidin-1-yl) propan-2-ol (D6)
The title compound was prepared from 2, 4-dimethylpyrrolidine (D5) (193mg; 1. 94mmol) using the method outlined in Description 1 (91 mg; 26% over 2 steps) MH 199.
Description 7: (S)-1-Amino-3-(2, 4-dimethylpyrrolidin-1-yl) propan-2-ol (D7)
The title compound was prepared from (R)-1-azido-3-(2, 4-dimethylpyrrolidin-1-yl) propan- 2-ol (D6) (91mg, 0. 459mmol) using the method outlined in Description 2 (69mg; 87%).
MH+ 173.
Description 8 (R)-1-Azido-3-(2-isopropylpyrrolidin-1-yl) propan-2-ol (D8) The title compound was prepared from 2-isopropylpyrrolidine (565mg; 5mmol) using the method outlined in Description 1 (379mg; 39% over 2 steps). MH+ 213.
Description 9 (S)-1-Amino-3-(2-isopropylpyrrolidin-1-yl) propan-2-ol (D9) The title compound was prepared from (R)-1-azido-3-(2-isopropylpyrrolidin-1-yl) propan-2- ol (D8) (379mg; 1. 78mmol) using the method outlined in Description 2 (303mg; 91%).
Description 10 (R)-1-Azido-3-(2,5-dimethylpyrrolidin-1-yl)-propan-2-ol(D10) The title compound was prepared from 2, 5-dimethylpyrrolidine (495mg; 5mmol) using the method outlined in Description 1 (185mg; 20% over 2 steps). MH+ 199.
Description 11 (S)-1-Amino-3- (2, 5-dimethylpyrrolidin-1-yl)-propan-2-ol (D11)
The title compound was prepared from (R)-1-azido-3-(2, 5-dimethylpyrrolidin-1-yl)-propan- 2-ol (D10) (185mg; 0. 93mmol) using the method outlined in Description 2 (145mg; 90%).
Description 12 (R)-1-Azido-3-(2-cyclohexylpyrrolidin-1-yl) propan-2-ol (D12) The title compound was prepared from 2-cyclohexylpyrrolidine (1. 0g ; 6. 54mmol) using the method outlined in Description 1 (220mg; 15% over 2 steps). MH+ 253.
Description 13 (S)-1-Amino-3-(2-cyclohexylpyrrolidin-1-yl) propan-2-ol (D13) The title compound was prepared from (R)-1-azido-3-(2-cyclohexylpyrrolidin-1-yl) propan- 2-ol (D12) (220mg; 0. 873mmol) using the method outlined in Description 2 (177mg; 90%).
MH+ 227.
Description 14 (R)-1-Azido-3-(2-isobutylpyrrolidin-1-yl) propan-2-ol (D14)
The title compound was prepared from 2-isobutylpyrrolidine (700mg; 5. 5mmol) using the method outlined in Description 1 (369mg; 33% over 2 steps). MH+ 227.
Description 15 (S)-1-Amino-3-(2-isobutylpyrrolidin-1-yl) propan-2-ol (D15) The title compound was prepared from (R)-1-azido-3-(2-isobutylpyrrolidin-1-yl)propan-2-ol (D14) (369mg; 1. 6mmol) using the method outlined in Description 2 (302mg; 92%). MH+ 201.
Description 16 2-Ethylpyrrolidine (D16) The title compound was prepared from 2-ethyl pyrrole (2. 0g ; 0. 021mol) using the method outlined in Description 5 (525mg; 25%). Mu+ 100.
Description 17 (R)-1-Azido-3- (2-ethylpyrrolidin-1-yl) propan-2-ol (D17)
The title compound was prepared from 2-ethylpyrrolidine (D16) (525mg; 5. 3mmol) using the method outlined in Description 1 (82mg; 8% over 2 steps).
Description 18 (S)-1-Amino-3-(2-ethylpyrrolidin-1-yl) propan-2-ol (D18) The title compound was prepared from (R)-1-azido-3-(2-ethylpyrrolidin-1-yl) propan-2-ol (D17) (82mg; 0. 414mmol) using the method outlined in Description 2 (65mg; 91%).
Description 19 2-tert-Butylpyrrolidine hydrochloride (D19) To a solution of 5-tert-butyl-3, 4-dihydro-2H-pyrrole (prepared from 2-pyrrolidone using the method of Mundy et al, J. Org. Chem. , 39, (13) p. 1963,1974) (200mg; 1. 6mmol) in methanol (10m1) was added sodium borohydride portionwise (121mg; 3. 2mmol) and the solution was stirred at ambient temperature for 2h. 1. OM ethereal HCI (5ml) was added portionwise, and the mixture was stirred for 1hr. The white precipitate was removed by filtration and the organic phase was evaporated under reduced pressure, to afford the title compound as a white powder (128mg; 49%). MH+ 128.'H NMR (400MHz, d4-MeOH) 6 : 3.35-3. 2 (m, 3H), 2.12-1. 95 (m, 3H), 1.83-1. 72 (m, 1H), 1.04 (s, 9H).
Description 20 (R)-1-Azido-3-(2-tert-butylpyrrolidin-1-yl) propan-2-ol (D20)
The title compound was prepared from 2-tert-butylpyrrolidine hydrochloride (D19) (817mg, 5mmol) using the method outlined in Description 1, (n. b. 2.6 equivalents of potassium hydride used) (282mg; 27% over 2 steps). MH+ 227.
Description 21 (S)-1-Amino-3-(2-tert-butylpyrrolidin-1-yl) propan-2-ol (D21) The title compound was prepared from (R)-1-azido-3-(2-tert-butylpyrrolidin-1-yl) propan-2- ol (D20) (282mg; 1. 25mmol) using the method outlined in description 2 (112mg; 45%).
MH+ 201.
Description 22 2-cyclopropylpyrrolidine hydrochloride (D22) The title compound was prepared from 5-cyclopropyl-3, 4-dihydro-2H-pyrrole (prepared from 2-pyrrolidone using the method of Mundy et al, J. Org. Chem. , 39, (13) p. 1963,1974) (1.4g ; 12. 8mmol) using the method outlined in Description 19 (1.54g ; 81%). MH+ 112.
Description 23 (R)-1-Azido-3-(2-cyclopropylpyrrolidin-1-yl) propan-2-ol (D23)
The title compound was prepared from 2-cyclopropylpyrrolidine hydrochloride (D22) (1.54g ; 0. 01mol) using the method outlined in Description 1 (n. b. 2.6 equivalents of potassium hydride used) (420mg; 21 % over 2 steps). MH+ 211.
Description 24 (S)-1-Amino-3-(2-cyclopropylpyrrolidin-1-yl) propan-2-ol (D24) The title compound was prepared from (R)-1-azido-3-(2-cyclopropylpyrrolidin-1-yl) propan- 2-ol (D23) (420mg; 20mmol) using the method outlined in Description 2 (336mg; 91%).
MH+ 185.
Description 25 (R)-1-Azido-3- (3-methylpiperidin-1-yl) propan-2-ol (D25) The title compound was prepared from 3-methylpiperidine (0.5g ; 5mmol) using the method outlined in Description 1 (404mg; 44% over 2 steps). MH+ 199.
Description 26 (S)-1-Amino-3- (3-methylpiperidin-1-yl) propan-2-ol (D26) The title compound was prepared from (R)-1-azido-3- (3-methylpiperidin-1-yl) propan-2-ol (D25) (404mg; 2. 04mmol) using the method outlined in Description 2 (310mg; 88%). MH+ 173.
Description 27 (R)-1-Azido-3- (5-ethyl-2-methylpiperidin-1-yl) propan-2-ol (D27)
The title compound was prepared from 5-ethyl-2-methylpiperidine (635mg; 5mmol) using the method outlined in Description 1 (244mg; 23% over 2 steps). MH+ 227.
Description 28 (S)-1-Amino-3- (5-ethyl-2-methylpiperidin-1-yl) propan-2-ol (D28) The title compound was prepared from (R)-l-azido-3- (5-ethyl-2-methylpiperidin-l- yl) propan-2-ol (D27) (244mg; 0. 108mol) using the method outlined in Description 2 (140mg; 65%).
Description 29 (R)-1-Azido-3-(2-ethylpiperidin-1-yl)propan-2-ol (D29) The title compound was prepared from 2-ethylpiperidine (0. 67ml ; 5. 05mmol) using the method outlined in Description 1 (255mg; 26% over 2 steps). MH+ 213.
Description 30 (S)-1-Amino-3-(2-ethylpiperidin-1-yl) propan-2-ol (D30)
The title compound was prepared from (R)-1-azido-3-(2-ethylpiperidin-1-yl) propan-2-ol (D29) (255mg; 1. 2mmol) using the method outlined in Description 2 (188mg; 84%). MH+ 187.
Description 31 2-Isopropylpiperidine (D31) The title compound was prepared from 2-isopropylpyridine (10g; 0. 083mol) using the method outlined in Description 5 (7.3g ; 70%). Mu+ 128.
Description 32 (R)-1-Azido-3-(2-isopropylpiperidin-1-yl) propan-2-ol (D32) The title compound was prepared from 2-Isopropylpiperidine (D31) (641 mg ; 5. 05mmol) using the method outlined in Description 1 (80mg ; 8% over 2 steps). MH+ 227.
Description 33 (S)-1-Amino-3-(2-isopropylpiperidin-1-yl) propan-2-ol (D33) The title compound was prepared from (R)-1-azido-3-(2-isopropylpiperidin-1-yl) propan-2- ol (D32) (80mg; 0. 353mmol) using the method outlined in Description 2 (50mg; 71 %).
Description 34 (R)-Azido-(sec-butylpropylamino) propan-2-ol (D34)
The title compound was prepared from N-n-propyl-N-sec-butylamine (575mg; 5mmol) using the method outlined in Description 1 (133mg ; 14% over 2 steps). MH+ 215.
Description 35 (S)-Amino- (sec-butylpropylamino) propan-2-ol (D35) The title compound was prepared from (R)-azido- (sec-butylpropylamino) propan-2-ol (D34) (133mg; 0. 62mmol) using the method outlined in Description 2 (79mg; 68%). MH+ 189.
Description 36 tert-butylpropylamine (D36) A solution of tert-butylamine 12.28g ; 0. 168mol) and n-propyl bromide (10.34g ; 0. 084mol) in N, N-dimethylformamide (30ml) was heated at gentle reflux overnight. On cooling, the crude product crystallised as the hydrobromide salt, and was was triturated with diethyl ether and filtered, to give a white crystalline solid. (11. 45g; 70%). The salt was free-based by dissolving in 15% aq. sodium hydroxide solution, and removing the upper oily layer.
Bulb-to-bulb distillation gave the pure product as a colourless oil.'H NMR (400MHz, d4- MeOH) 8 : 2.49 (t, 2H), 1.53-1. 42 (m, 2H), 1.1 (s, 9H), 0.95 (t, 3H).
Description 37 (R)-Azido- (tert-butylpropylamino) propan-2-ol (D37)
The title compound was prepared from tert-butylpropylamine (D36) (632mg; 5. 5mmol) using the method outlined in Description 1 (40mg; 4% over 2 steps).
Description 38 (S)-Amino- (tert-butylpropylamino) propan-2-ol (D38) The title compound was prepared from (R)-azido-(tert-butylpropylamino)propan-2-ol (D37) (40mg; 0. 187mmol) using the method outlined in Description 2 (32mg; 91%). MH+ 189.
Description 39 (R)-l-Azido-3- (1, 3-dihydroisoindol-2-yl) propan-2-ol (D39) The title compound was prepared from 2, 3-dihydro-1H-isoindole (595mg; 5mmol) using the method outlined in Description 1 (484mg; 48% over 2 steps). MH+ 219.
Description 40 (S)-l-Amino-3- (1, 3-dihydroisoindol-2-yl) propan-2-ol (D40) The title compound was prepared from (R)-l-azido-3- (1, 3-dihydroisoindol-2-yl) propan-2-ol (D39) (484mg; 2. 2mmol) using the method outlined in Description 2 (396mg; 93%). MH+ 193.
Description 41 (R)-1-Azido-3-(octahydroisoquinolin-1-yl) propan-2-ol (D41)
The title compound was prepared from decahydroisoquinoline (695mg; 5mmol) using the method outlined in Description 1 (336mg; 31 % over 2 steps). MH+ 239.
Description 42 (S)-1-Amino-3-(octahydroisoquinolin-1-yl) propan-2-ol (D42) The title compound was prepared from (R)-1-azido-3-(octahydroisoquinolin-1-yl) propan-2- ol (D41) (336mg; 1. 41mmol) using the method outlined in Description 2 (267mg; 89%).
MH+ 213.
Description 43 (R)-1-Azido-3-(octahydroquinolin-1-yl)propan-2-ol (D43) The title compound was prepared from decahydroquinoline (910mg; 6. 54mmol) using the method outlined in Description 1 (346mg; 25% over 2 steps). MH+ 239.
Description 44 (S)-1-Amino-3-(octahydroquinolin-1-yl) propan-2-ol (D44)
The title compound was prepared from (R)-1-azido-3-(octahydroquinolin-1-yl) propan-2-ol (D43) (346mg; 1. 45mmol) using the method outlined in Description 2 (288mg ; 93%). MH+ 213.
Description 45 (R)-1-Azido-3- ( (1S, 5R) -1,3, 3-trimethyl-6-azabicyclo [3.2. 1] oct-6-yl) propan-2-ol (D45) The title compound was prepared from (1S, 5R) -1,3, 3-trimethyl-6-azabicyclo [3.2. 1] octane (0. 857moi ; 5. 05mmol) using the method outlined in Description 1 (213mg; 18% over 2 steps). MH+ 253.
Description 46 (S)-1-Amino-3-((1S, 5R) -1,3, 3-trimethyl-6-azabicyclo [3.2. 1] oct-6-yl) propan-2-ol (D46) The title compound was prepared from (R)-1-azido-3-((1S, 5R) -1,3, 3-trimethyl-6- . azabicyclo [3. 2.1] oct-6-yl) propan-2-ol (D45) (213mg; 0. 845mmol) using the method outlined in Description 2 (153mg; 80%). MH+ 227.
Description 47 (R)-1-Amino-3-(2, 4-dimethylpyrrolidin-1-yl) propan-2-ol (D47)
The title compound was prepared from 2, 4-dimethylpyrrolidine (193mg; 1. 94mmol) and (R)- (-)-glycidyl nosylate (460mg; 1. 77mmol) using the methods outlined in Descriptions 1 and 2 (71 mg ; 23% over three steps). MH+ 173.
Description 48 1-(R)-1-Oxiranylmethyl-piperidine (D48)
Potassium hydride (527mg; 30% in oil) was weighed into an oven-dried 3-necked flask and THF (5ml) was added under an atmosphere of argon. A solution of piperidine (0. 44moi) in THF (5ml) was added to the stirred suspension. The reagents were stirred together at room temperature for 2 hrs, under an atmosphere of argon. S- (-)-Glycidyl nosylate (904mg) was then added dropwise as a solution in THF (5ml) and the reaction mixture stirred at room temperature overnight. The reaction mixture was filtered under an inert atmosphere through CeliteT" and the liquor reduced to half volume in vacuo, m/z (API+) 142 [MH+].
Description 49 (R)-1-Azido-3-piperidin-1-yl-propan-2-ol (D49) 0
To the product solution from Description 48 was added lithium azide (5. 34ml ; 20% solution in water) and the reaction mixture heated at 70°C overnight. The THF was then removed in vacuo and the solution partitioned between EtOAc and NaHCO3 solution.
Organics were collected, dried (MgS04), and evaporated. The residual oil was chromatographed over silica gel, eluting with a gradient of 0-10% [9: 1 MeOH: NH3] in dichloromethane. The title compound was obtained as a colourless oil (348mg), m/z (API+) 185 [MH+].
Description 50 (S)-1-Amino-3-piperidin-1-yl-propan-2-ol (D50)
(R)-1-Azido-3-piperidin-1-yl-propan-2-ol (340mg) was dissolved in ethanol (25ml) and hydrogenated at 50 psi and room temperature in the presence of 10% Pd/C catalyst (350mg). After 2hrs the reaction mixture was filtered and evaporated. The title compound was obtained as a colourless oil (117mg), m/z (API+) 159 [MH+].
Description 51 (2R, S)-Methyl-1-[(R)-oxiranylmethyl] piperidine (D51)
Potassium hydride (527mg; 30% in oil) was weighed into an oven dried 3-necked flask and stirred in THF (5ml) under an inert atmosphere during the addition of a solution of (2R, S)-methylpiperidine (0. 52ml) in THF (5ml). The reaction solution was stirred at room temperature for 2 hrs. S- (-)-Glycidyl nosylate (904mg) was then added dropwise as a solution in THF (5ml) and the reaction mixture stirred at room temperature for 16 hours.
The reaction mixture was filtered under an inert atmosphere through CeliteT" and the organic solution reduced to half volume at reduced pressure, m/z 156 (API+) [MH+].
Description 52 1-Azido-3-[(2R, S)-methylpiperidin-1-yl]-propan-(2R)-ol (D52)
To the product solution from Description 51 was added lithium azide (5. 34moi, 20% solution in water) and the reaction mixture heated at 70°C for 16 hours. The solvent was then removed at reduced pressure and the residue was partitioned between EtOAc and NaHCO3 solution. The organic solution was dried (MgSO4), and evaporated. The
residual oil was chromatographed over silica gel, eluting with a gradient of 0-10% [9: 1 MeOH: NH3] in dichloromethane. The title compound was obtained as a colourless oil (326mg), m/z 199 (API+) [MH+].
Description 53 1-Amino-3-[(2R, S)-methylpiperidin-1-yl)-propan-(2S)-ol (D53)
1-Azido-3-[(2R, S)-methylpiperidin-1-yl]-propan-(2R)-ol (320mg) was dissolved in EtOH (25moi) and hydrogenated at 50 psi and room temperature in the presence of 10% Pd/C catalyst (350mg). After 2hrs the reaction mixture was filtered and evaporated. Title compound was obtained as a colourless oil (215mg), m/z 173 (API+) [MH+].
Description 54 (2R, 6S)-Dimethyl-l- [ (R)-oxiranylmethyl] piperidine (D54)
Potassium hydride (860mg; 30% in oil) was weighed into an oven dried 3-necked flask and stirred in THF (5ml) under an inert atmosphere during the addition of (2R, 6S)- dimethylpiperidine (0. 75ml) as a solution in THF (5ml). The suspension was stirred at room temperature for 2 hrs. S- (-)-Glycidyl nosylate (1. 13g) was then added dropwise as a solution in THF (5ml) and the reaction mixture stirred at room temperature overnight. The reaction mixture was filtered under an inert atmosphere through CeliteT" and the organic solution evaporated to half volume at reduced pressure, m/z 170 (API+) [MH+].
Description 55 (R)-1-Azido-3-[(2R, 6S) dimethylpiperidin-1-yl] propan-2-ol (D55)
To the product solution from Description 54 was added lithium azide (5. 63ml, 20% solution in water) and the reaction mixture heated at 70°C overnight. The solvent was then evaporated in vacuo and the solution partitioned between EtOAc and NaHCO3 solution. The organic solution was dried (MgS04), and evaporated. The residual oil was chromatographed over silica gel, eluting with a gradient of 0-10% [9: 1 MeOH: NH3] in dichloromethane. The title compound was obtained as a colourless oil (80mg), m/z 213 (API+) [MH+].
Description 56 (S)-1-Amino-3-[(2R, 6S) dimethylpiperidin-1-yl)-propan-2-ol (D56)
(R)-1-Azido-3-[(2R, 6S) dimethylpiperidin-1-yl] propan-2-ol (80mg) was dissolved in ethanol (25ml) and hydrogenated at 50 psi and room temperature in the presence of 10% Pd/C catalyst (80mg). After 2hrs the reaction mixture was filtered and evaporated. Title compound was obtained as a colourless oil (80mg).
Description 57 (2S)-Ethyl-1-[(R)-oxiranylmethyl] piperidine (D57)
(S)- (+)-2-ethylpiperidine hydrochloride (1. 00g, 6.69 mmol) (prepared by the method of J.
Cymerman Craig and A. R. Pinder, J. Org. Chem., 1971,36 (23), 3648) was added portionwise to a stirred suspension of potassium hydride (2.05g, 30% in oil, 15. 39mmol) in dry THF (45 ml) under argon at room temperature. The suspension was stirred for a further two hours. A solution of the (S)-glycidyl nosylate (1.73g, 6.69 mmol) in dry THF (10 mi) was then added dropwise and the resulting mixture stirred overnight. The suspension was filtered through CeliteT" and the filtrate evaporated to half-volume under reduced pressure to yield a solution of the title compound.
Description 58 1-Azido-3-[(2S)-ethylpiperidin-1-yl]-propan-(2R)-ol (D58)
A 20% solution of lithium azide in water (8. 2moi, 33.4 mmol) was added to the solution of the product from Description 57 and the mixture stirred at 70° overnight. The cooled solution was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was washed with further saturated sodium hydrogen carbonate solution and dried over MgSO4. Removal of the solvent gave an oil which was chromatographed on silica gel.
Elution with CHCI3 followed by 10% MeOH in CHC13 afforded the title product as a yellow oil (500mg, 35%). 1H NMR 8 (CDCI3) 0.89 (3H, t, J=7 Hz), 1.34-1. 69 (9H, overlapping m), 2.1-2. 25 (2H, overlapping m), 2.71 (1H, dd, J=12.4 and 10.4 Hz), 2.93 (1H, m), 3.19 (1H, dd, J=12. 8 and 5.6 Hz), 3.37 (1 H, dd, J=12. 8 and 4. 0Hz), 3.85 (1 H, m) ppm.
Description 59 1-Amino-3-[(2S)-ethylpiperidin-1-yl)-propan-(2S)-ol (D59)
Hydrogenation of the azide from Description 58 (500mg, 2.36 mmol) over 10% palladium on charcoal (100mg) in methanol (25ml) at ambient temperature and pressure for 3 hours and subsequent removal of the catalyst by filtration through celite gave, after removal of the solvent under reduced pressure, the crude amine (2.36 mmol) which was used without further purification.
Description 60 (S)-1-Azido-3-(2-methylpyrrolidin-1-yl) propan-2-ol (D60)
The title compound was prepared from 2-methylpyrrolidine (155mg ; 1. 82mmol) and (R)- (-)- glycidyl nosylate (429mg; 1. 6mmol) using the method outlined in Description 1 (76mg; 25% over two steps). MH+ 185.
Description 61 (R)-1-Amino-3-(2-methylpyrrolidin-1-yl) propan-2-ol (D61)
The title compound was prepared from (S)-1-azido-3-(2-methylpyrrolidin-1-yl) propan-2-ol (D60) (63mg; 0. 34mmol) using the method outlined in Description 2 (50mg; 92%). MH+ 159.
Description 62 (S)-1-Azido-3- (3-methylpiperidin-1-yl) propan-2-ol (D62) The title compound was prepared from 3-methylpiperidine (366mg; 3. 7mmol) and (R)- (-)- glycidyl nosylate (871 mg ; 3. 4mmol) using the methods outlined in Description 1 (220mg; 33% over two steps).
Description 63 (R)-1-Amino-3- (3-methylpiperidin-1-yl) propan-2-ol (D63) The title compound was prepared from (S)-1-azido-3- (3-methylpiperidin-1-yl) propan-2-ol (D62) (160mg; 0. 81mmol) using the method outlined in Description 2 (130mg; 94%).
Description 64.
2-Oxiranylmethyl-isoindole-1, 3-dione (D64)
To a stirred solution of phthalimide (735mg) in THF (30MI) was added triphenylphosphine (1.310g) and (S)-glycidol (0. 38ml). This solution was cooled using an external ice bath for the dropwise addition of diethylazodicarboxyate (0. 8mi). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated, and stirred in diethyl ether for 2h. White precipitate was filtered and liquor was evaporated. The residual yellow oil was chromatographed over silica gel, eluting with ethyl acetate/hexane (1: 1).
Title compound was obtained as a white solid (815mg), m/z 204 [MH+].
Description 65.
2, 6-Diethylpyridine (D65)
2, 6-Diacetylpyridine (2g) was dissolved in diethyleneglycol (50mut) with hydrazine monohydrate (3. 6ml). The reaction mixture was heated at 170°C for 30 min. The reaction mixture was then cooled to room temperature for the addition of potassium hydroxide (3.1g), then heated at 200°C for 2h when the reaction mixtue lost all colour. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted with ether, organics combined, washed with brine, dried (MgS04) and concentrated to give desired product (1.5g, 93%), AH (CDCI3) 1.29 (6H, t, J 7. 6Hz), 2.76- 2.82 (4H, q, J 7.6Hz), 6.96 (2H, d, J 7.6Hz), 7.50 (1 H, t, J 7.6Hz).
Description 66.
2,6-Diethylpiperidine (D66)
2, 6-Diethylpyridine (D65) was hydrogenated in acetic acid with platinum oxide overnight.
The reaction mixture was filtered through celite, washed with a small amount of AcOH and basified with KOH and K2CO3 to pH 9. The emulsion was extracted with diethyl ether, dried (MgS04) and concentrated to give the desired product (1g, 70%), AH (CDCI3) 0. 91 (6H, m), 1.06 (2H, m), 1.41 (1H, m), 1.44 (4H, m), 1.68 (2H, m), 1.70 (1H, m), 2.44 (2H, m).
Description 67.
2-[(R)-3-(2, 6-Diethylpiperidin-1-yl)-2-hydroxy-propyl]-isoindole-1, 3-dione (D67)
2, 6-Diethylpiperidine (D66) (1g) and 2-oxiranylmethylisoindole-1, 3-dione (D64) (1.4g) were heated together at 70°C overnight. After cooling to room temperature the crude mixture was chromatographed over silica gel, eluting with a gradient of 0-10% [9 : 1 MeOH: NH3] in dichloromethane. Title compound was obtained as an oil (90mg), m/z 345 [MH+] Description 68.
(S)-1-Amino-3-(2, 6-diethylpiperidin-1-yl)-propan-2-ol (D68)
2-[(R)-3-(2, 6-Diethylpiperidin-1-yl)-2-hydroxypropyl]-isoindole-1, 3-dione (D67) (90 mg) was stirred in ethanol (2ml) with hydrazine monohydrate (0. 06moi) overnight. White precipitate was removed by filtration and liquor concentrated. The crude mixture (70mg) containing the title compound was progressed without purification.
Description 69.
2-[(R)-3-[(2R, 6S)-Dimethylpiperidin-1-yl]-2-hydroxy-propyl]-isoindole-1, 3-dione (D69)
2, 6-Dimethylpiperidine was reacted with 2-oxiranylmethylisoindole-1, 3-dione (D64) by the procedure of Description 67. The title compound was obtained as a colourless oil.
Description 70.
(S)-1-Amino-3-[(2R, 6S)-dimethylpiperidin-1-yl]-propan-2-ol (D70)
2-[(R)-3-[(2R,6S)-Dimethylpiperidion-1-yl]-2-hydroxy-propyl] -isoindole-1, 3-dione (D69) was treated with hydrazine hydrate according to the procedure of Description 68 to yield the title compound as a colourless oil, which was identical to the product of Description 56.
Description 71.
Quinoline-5-sulfonyl chloride (D71)
(a) Thionyl chloride (2. 1ml) was added dropwise to water (12. 5ml) at 5°C. This mixture was allowed to warm to room temperature and stirred for 16h. Copper I chloride (10mg) was then added and the resulting yellow solution coofed to 0°C.
(b) Concentrated hydrochloric acid (6. 75mut) was cooled to 0°C for the portionwise addition of 5-amino quinoline (1g). This was allowed to warm slightly between additions, when the reaction mixture turned red/orange. After complete addition, the reaction mixture was cooled to-5°C for the dropwise addition of a solution of NaN02 (0.5g) in water (2ml). After complete addition and at-5°C, the resulting mixture was added slowly to the cooled thionyl chloride/CuCI mixture from part (a).. A solid precipitated and the mixture was stirred at 0°C for 1.5h. The brick red solid was filtered and washed with water (300mg), 8H (CDCI3) 7.71 (1H, m), 7.88 (1H, m), 8.44 (1H, m), 8.52 (1H, m), 9.1-9. 2 (2H, m).
Description 72.
5-Methoxynaphthalen-1-ylamine (D72)
5-Amino-1-naphthol (3. 0g) was dissolved in dry DMF (75mut) and cooled to 5°C under an atmosphere of argon. Sodium hydride (0. 828g, 60% dispersion in oil) was added portionwise to the stirred, cooled sollution over a period of 15 minutes. A solution of methyl iodide (1.17 ml) in dry DMF (5ml) was then added dropwise to the stirred, cooled suspension. The resulting suspension was then stirred at room temperature for 16 hours.
The reaction solution was then partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic solution was washed with brine, dried (MgSO4) and evaporated. Crystallisation from ethyl acetate/hexane provided the pure title compound as black needles (1.34g), AH (dg-DMSO) 3.92 (3H, s), 5.61 (2H, broad s), 6.69 (1H, d), 6.88 (1H, d), 7.17 (1H, t), 7.29 (1H, t), 7.37 (1H, d), 7.6 (1H, d).
Description 73.
5-Methoxynaphthalene-1-sulfonyl chloride (D73) 5-Methoxynaphthalen-1-ylamine (D72) was converted to the title compound by the procedure of R. V. Hoffman, Organic Syntheses, 60,121. Silica gel column chromatography, eluting with a gradient of 0 to 30% ethyl acetate in hexane gave the title compound as a pale yellow solid, 8H (CDCI3) 4.09 (3H, s) 7.0 (1 H, d), 7.59 (1H, t), 7.72 (1H, t), 8.35 (1H, d), 8.4 (1H, d), 8.72 (1H, d).
Description 74.
5-Cyanonaphthalene-1-sulfonyl chloride (D74)
5-Cyanonaphthalen-1-ylamine was converted to the title compound by the procedure of R. V. Hoffman, Organic Syntheses, 60,121. Silica gel column chromatography, eluting with a gradient of 0 to 30% ethyl acetate in hexane gave the title compound as a pale yellow solid, 8H (d6-DMSO) 7.67-7. 78 2H, 2 x t), 8.10 (2H, d), 8.18 (1H, d), 9.21 (1H, d) Description 75.
4-Cyanonaphthalene-1-sulfonyl chloride (D75) 4-Cyanonaphthalen-1-ylamine was converted to the title compound by the procedure of R.
V. Hoffman, Organic Syntheses, 60,121. Silica gel column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexane gave the title compound as a white solid, AH (d6-DMSO) 7.70 (1H, t), 7.78 (1 H, t), 8.06 (1H, d), 8.11 (2H, d), 9.0 (1H, d).
Description 76.
4-Bromonaphthalene-1-sulfonyl chloride (D76) 4-Bromonaphthalen-1-ylamine was converted to the title compound by the procedure of R. V. Hoffman, Organic Syntheses, 60,121. Silica gel column chromatography, eluting with a gradient of 0 to 30% ethyl acetate in hexane gave the title compound as a pale orange solid, AH (d6-CDCI3) 7. 80 (1 H, t), 7. 88 (1H, t), 7.96 (1 H, d), 8.20 (1 H, d), 8.48 (1H, d), 8.83 (1 H, d).
Description 77.
4-Fluoronaphthalene-1-sulfonyl chloride (D77)
1-Fluoronaphthalene (1.262 ml) was added dropwise over a period of 20 min to an ice- cooled, stirred solution of chlorosulphonic acid (2. 3mi). The mixture was stirred for an additional 30min at 5°C and 3h at room temperature. The mixture was then poured onto ice and extracted twice with ethyl acetate. The organic solution was washed with water, brine, dried (MgS04) and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 30% ethyl acetate in hexane. The title compound was obtained as a pale yellow solid (0.86g), SH (dg-CDCI3) 7.27 (1 H, dd, J 8.6, 9.1 Hz), ), 7.77 (1H, ddd, J 0. 8,7. 2,8. 2Hz), 7.89 (1H, ddd, J 1. 3,7. 1,8. 6Hz), 8. 29 (1H, d, J 8. 4Hz), 8.39 (1H, dd, J 8. 4,5. 1 Hz), 8.80, (1H, ddd, J 0. 9,0. 9,8. 7Hz).
Example 1 Naphthalene-1-sulfonic acid f (R)-2-amino-3- ( (2S. 6R)-2, 6-dimethyl-piperidin-1-vl)-propvll- amide Naphthalene-1-sulfonic acid [ (R)-3- ( (2S, 6R) -2, 6-dimethyl-piperidin-1-yl)-2-hydroxy- propyl]-amide was prepared by the following procedure: (S)-1-Amino-3-piperidin-1- ylpropan-2-ol (D50; 117mg) was dissolved in dichloromethane (6ml) and 1- naphthylsulfonylchloride (185mg) and triethylamine (0. 11ml) were added. The reaction mixture was stirred overnight, diluted with dichloromethane and washed with NaHCO3 solution and brine. The organic solution was dried (MgS04), and evaporated. The residual oil was chromatographed over silica gel, eluting with a gradient of 0-10% [9: 1 MeOH: NH3] in dichloromethane. The compound was obtained as a colourless oil (143mg), m/z (API+) 349 [MH+]- A stirred solution of naphthalene-1-sulfonic acid [ (R)-3- ( (2S, 6R) -2, 6-dimethyl-piperidin-1- yl)-2-hydroxy-propyl]-amide (2.26g, 6. 01mmol) in dry DCM (100ml) under argon was treated with 4-nitrobenzenesulphonyl chloride (2. 00g, 9. 02mmol) and triethylamine (1. 68mi, 12. 02mmol) and stirred for 2 hours. The solvent was removed by evaporation.
The crude intermediate was then dissolved in dry DMF (24ml) and treated with sodium azide (0. 78g, 12. 02mol). The mixture was stirred at room temperature for 24 hours and then diluted with EtOAc, washed with water (6X), dried and evaporated to afford crude
product. Chromatography on silica gel, eluting with 2% (10% NH3 in MeOH) in DCM, gave the azide as a yellow oil (0.88g, 37%). MS APCI (+ve ion) 402 (MH+).
This azide in MeOH (30ml) was hydrogenated over 10% palladium on charcoal at atmospheric pressure and temperature for 18 hours. The mixture was filtered through celite and the filtrate evaporated to afford the title compound as a pale foam (0.92g).
Example 2 N-{ (R)-2- ( (2S, 6R)-2, 6-Dimethvl-piperidin-1-vl)-1-f (naphthalene-1-sulfonvlamino)-methyll- ethyt}-acetamide The amine from example 1 (50mg, 0. 13mmol) in DCM (1. 5moi) was treated with 1- hydroxybenzotriazole hydrate (7mg), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg) and acetic acid (8mg, 0. 13mmol) and shaken overnight. The reaction mixture was shaken with sat. sodium hydrogen carbonate solution (1 ml) and the organic layer applied to a silica gel column. Gradient elution with 5%-10% (10% NH3 in MeOH) in DCM gave the title compound as a foam (40mg, 74%). MS electrospray (+ve ion) 418 (MH+) ; (-ve ion) 416 (M-H).'H NMR (CDCI3) 6 0.95 (6H, overlapping d), 1.1-1. 7 (6H, overlapping m), 1.84 (3H, s), 2.40 (2H, br m), 2.47 (2H, d, J = 7.6Hz), 2.94 (1 H, dd, J = 12. 4 and 6. OHz), 3.12 (1H, dd, J = 12.4 and 4.8Hz), 3.67 (1H, m), 5.98 (1H, br), 7.53 (1H, dd, J = 8.0 and 8. 0Hz), 7.61 (1H, dd, J = 8.0 and 8. 0Hz), 7.69 (1H, dt, J = 7.2, 7.2 and 1.6Hz), 7.93 (1H, d, 8. 0Hz), 8.05 (1H, d, J = 8.4Hz), 8.23 (1H, dd, 7.2 and 1.2Hz), 8. 69 (1 H, d, 8.8Hz) ppm.
The following compounds were prepared by the same method:- Table 1 Example no. R MH+ riz 3 480 4 446 Example 21 N-r (R)-1-(Benzenesulfonylamino-methyl)-2-((2sb6R)-2s6-dimethyl- piperidin-1-vl)-ethyll-4-<BR> <BR> methanesulfonyl-benzamide
A solution of 2- [ (R)-3- ( (2S, 6R) -2, 6-Dimethyl-piperidin-1-yl)-2-hydroxy-propyl]-isoindole- 1,3-dione (2.45g, 7. 75mmol) (D69) in ethanol (150moi) was treated with hydrazine hydrate (1. 88moi, 38. 8mmol) and stirred overnight at room temperature under argon. The white precipitate was filtered off and the filtrate evaporated to afford a gum which was dissolved in DCM (50moi) and treated with di-t-butyl dicarbonate (2.39g, 10. 97mmol) and dimethylaminopyridine (50mg). Stirred at room temperature for 3 days, washed with water (1X), dried over MgS04 and the solvent removed by evaporation to afford a crude product.
Chromatography on silica gel, eluting with 5% (10% NH3 in MeOH) in DCM, gave the N- BOC derivative as a white solid (1.35g, 65%). MS electrospray (+ve ion) 287 (MH+), 231 (MH+-butene).
The alcohol was converted to the azide by treatment with 4-nitrobenzenesulphonyl chloride and sodium azide as outlined in example 1. Hydrogenation as described in example 1 gave the amine as a yellow gum which was used without further purification.
A solution of the amine (1. 25mmol) in DCM was acylated with 4- methanesulphonylbenzoic acid as described in example 2. Chromatography on silica gel afforded the amide as a white solid. MS electrospray (+ve ion) 468 (MH+), 412 (MH+- butene).
A solution of the t-butyl ester (47mg, 0. 1mmol) in trifluoroacetic acid (1. 9mi) and water (0. 1ml) was stirred for 2 hours and the volatile components removed under reduced pressure. The residue was re-evaporated from toluene (2X) and dissolved in DCM (1. 5ml) and treated with triethylamine (70ul, 0. 5mmol) followed by benzenesuphonyl chloride (26mg, 0. 15mmol). Stirring was continued overnight and saturated sodium hydrogen carbonate solution (1ml) added. The organic layer was chromatographed on silica gel eluting with 5%-10% (10% NH3 in MeOH) to afford the title compound as a colourless gum (50mg). MS electrospray (+ve ion) 508 (MH+) ; (-ve ion) 506 (M-H).'H NMR (CDCI3) 6 1.04 (3H, br d), 1.10 (3H, br d), 1.2-1. 8 (6H, overlapping br m), 2.56 (2H, br m), 2.73 (2H, br m), 3.08 (3H, s), 3.16 (1H, br m), 3.33 (1H, br d, J = 13Hz), 3.87 (1H, br m), ca.
7.55 (3H, overlapping m), 7.87 (2H, d, J = 7.6Hz), ca. 8.0 (4H, overlapping m) ppm.
The following compounds were prepared by the same method:-
Table 2 Example no. R Ar MH+ I "'SOzMe 22 S02Me 559 NEZ Me 23 aSOzMe f 540 F F 24-aSO2Me 538 MeO"v 25 S02Me 558 a A 26 -aSO2Me 583 CM CN 27 vOMe ¢ 460 s f' 28 511 N Me 29 nOMe ß 492 F F 30 OMe MeO 490 MeO"- 31 *aOMe 510
Example 33 Naphthalene-1-sulfonic acid r (R)-2-benzenesulfonvlamino-3- ( (2S, 6R)-2, 6-dimethyl- piperidin-1-vl)-propvll-amide
The amine from example 1 (70mg, 0. 18mmol) in DCM (5ml) was treated with benzenesulphonyl chloride (106mg, 0. 60mmol) and triethylamine (30ul, 0. 21mmol) and stirred overnight. The reaction mixture was washed with water, sat. sodium hydrogen carbonate solution (1ml) and brine and the organic layer applied to a silica gel column.
Gradient elution with 1%-5% (10% NH3 in MeOH) in DCM gave the title compound (44mg, 46%). MS APCI (+ve ion) 516 (MH+) ; (-ve ion) 514 (M-H).
The following compounds were prepared by the same method:- Table 3 Example no. Ar MH+ 34 530 I 35 neo 546 36 I/594 MeSO- CI 37 k 584 ci
Example 38 Naphthalene-1-sulfonic acid [(R)-3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-2-(3-phenyl- ureido)-propyll-amide
The amine from example 1 (70mg, 0. 19mmol) in DMF (5ml) was treated with phenylisocyanate (21ul, 0. 19mmol) and stirred overnight. The reaction mixture was washed with water, sat. sodium hydrogen carbonate solution (1ml) and brine and the organic layer applied to a silica gel column. Gradient elution with 1%-5% (10% NH3 in MeOH) in DCM gave the title compound (46mg, 50%). MS APCI (+ve ion) 495 (MH+) ; (- ve ion) 493 (M-H).
The following compounds were prepared by the same method:-
Table 4 Example no. Ar MH+ fizz mye0 40 cl/563 C ; F3 Caf3 41 563 w 42 c) 563 o
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