ZA200502216B - Heterocyclic substituted piperazines for the treatment of schizophrenia. - Google Patents
Heterocyclic substituted piperazines for the treatment of schizophrenia. Download PDFInfo
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- ZA200502216B ZA200502216B ZA200502216A ZA200502216A ZA200502216B ZA 200502216 B ZA200502216 B ZA 200502216B ZA 200502216 A ZA200502216 A ZA 200502216A ZA 200502216 A ZA200502216 A ZA 200502216A ZA 200502216 B ZA200502216 B ZA 200502216B
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- South Africa
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- disorders
- disorder
- quinolin
- piperazin
- dihydro
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- 201000000980 schizophrenia Diseases 0.000 title claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 8
- 150000004885 piperazines Chemical class 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 32
- 125000001153 fluoro group Chemical group F* 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- -1 nitro, cyano, amino Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 27
- 208000028017 Psychotic disease Diseases 0.000 claims 26
- 208000035475 disorder Diseases 0.000 claims 26
- 208000019901 Anxiety disease Diseases 0.000 claims 17
- 206010012335 Dependence Diseases 0.000 claims 16
- 208000020401 Depressive disease Diseases 0.000 claims 16
- 206010012289 Dementia Diseases 0.000 claims 13
- 230000036506 anxiety Effects 0.000 claims 13
- 208000023105 Huntington disease Diseases 0.000 claims 12
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- 208000015238 neurotic disease Diseases 0.000 claims 12
- 208000020925 Bipolar disease Diseases 0.000 claims 11
- 239000003814 drug Substances 0.000 claims 10
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- 208000019022 Mood disease Diseases 0.000 claims 8
- 230000003542 behavioural effect Effects 0.000 claims 8
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims 8
- 238000000034 method Methods 0.000 claims 8
- 239000000203 mixture Substances 0.000 claims 8
- 208000019906 panic disease Diseases 0.000 claims 8
- 208000024827 Alzheimer disease Diseases 0.000 claims 7
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- 229940079593 drug Drugs 0.000 claims 6
- 208000021465 Brief psychotic disease Diseases 0.000 claims 5
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- 208000028683 bipolar I disease Diseases 0.000 claims 5
- 208000002851 paranoid schizophrenia Diseases 0.000 claims 5
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims 4
- 206010001541 Akinesia Diseases 0.000 claims 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
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- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 claims 4
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- 208000025748 atypical depressive disease Diseases 0.000 claims 4
- 229940049706 benzodiazepine Drugs 0.000 claims 4
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 4
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- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims 4
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 claims 4
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- SRAQFALNAGNAQE-UHFFFAOYSA-N 6-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-4,4,8-trimethyl-1,3-dihydroquinolin-2-one Chemical compound N1C(=O)CC(C)(C)C2=C1C(C)=CC(CCN1CCN(CC1)C=1C3=CC=CC=C3SN=1)=C2 SRAQFALNAGNAQE-UHFFFAOYSA-N 0.000 claims 2
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- NPMULJKKBNCCDE-UHFFFAOYSA-N 6-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-8-chloro-4,4-dimethyl-1,3-dihydroquinolin-2-one;hydrochloride Chemical compound Cl.C1=CC=C2C(N3CCN(CC3)CCC3=CC(Cl)=C4NC(=O)CC(C4=C3)(C)C)=NSC2=C1 NPMULJKKBNCCDE-UHFFFAOYSA-N 0.000 claims 1
- PYLOOAAZCQAYIV-UHFFFAOYSA-N 6-[2-[4-(1,2-benzoxazol-3-yl)piperazin-1-yl]ethyl]-3,3,4-trimethyl-1,4-dihydroquinolin-2-one Chemical compound C1=CC=C2C(N3CCN(CC3)CCC=3C=C4C(C(C(=O)NC4=CC=3)(C)C)C)=NOC2=C1 PYLOOAAZCQAYIV-UHFFFAOYSA-N 0.000 claims 1
- HMMNBVXJFGFCOH-UHFFFAOYSA-N 6-[2-[4-(1,2-benzoxazol-3-yl)piperazin-1-yl]ethyl]-3,3-dimethyl-1,4-dihydroquinolin-2-one Chemical compound C1=CC=C2C(N3CCN(CC3)CCC=3C=C4CC(C(NC4=CC=3)=O)(C)C)=NOC2=C1 HMMNBVXJFGFCOH-UHFFFAOYSA-N 0.000 claims 1
- VUUTVDVGKRASMV-UHFFFAOYSA-N 6-[2-[4-(1,2-benzoxazol-3-yl)piperazin-1-yl]ethyl]-3-methyl-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2C(N3CCN(CC3)CCC=3C=C4CC(C(NC4=CC=3)=O)C)=NOC2=C1 VUUTVDVGKRASMV-UHFFFAOYSA-N 0.000 claims 1
- ICYAYJZMSZYRTH-UHFFFAOYSA-N 6-[2-[4-(1,2-benzoxazol-3-yl)piperazin-1-yl]ethyl]-4,4-dimethyl-1,3-dihydroquinolin-2-one Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=C4NC(=O)CC(C4=C3)(C)C)=NOC2=C1 ICYAYJZMSZYRTH-UHFFFAOYSA-N 0.000 claims 1
- ZGXRKIVHNAJFGW-UHFFFAOYSA-N 6-[2-[4-(1h-indazol-3-yl)piperazin-1-yl]ethyl]-3,4-dimethyl-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2C(N3CCN(CC3)CCC=3C=C4C(C)C(C(NC4=CC=3)=O)C)=NNC2=C1 ZGXRKIVHNAJFGW-UHFFFAOYSA-N 0.000 claims 1
- LZDIGLUPIQGJDJ-UHFFFAOYSA-N 6-[2-[4-(1h-indazol-3-yl)piperazin-1-yl]ethyl]-3-methyl-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2C(N3CCN(CC3)CCC=3C=C4CC(C(NC4=CC=3)=O)C)=NNC2=C1 LZDIGLUPIQGJDJ-UHFFFAOYSA-N 0.000 claims 1
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- JHBMJIYNOSDZEY-UHFFFAOYSA-N 6-[2-[4-(1h-indazol-3-yl)piperazin-1-yl]ethyl]-4-methyl-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=C4NC(=O)CC(C4=C3)C)=NNC2=C1 JHBMJIYNOSDZEY-UHFFFAOYSA-N 0.000 claims 1
- AKILNVRTEPFPLQ-UHFFFAOYSA-N 6-[3-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]propyl]-3,3-dimethyl-1,4-dihydroquinolin-2-one Chemical compound C1=CC=C2C(N3CCN(CC3)CCCC=3C=C4CC(C(NC4=CC=3)=O)(C)C)=NSC2=C1 AKILNVRTEPFPLQ-UHFFFAOYSA-N 0.000 claims 1
- BVHBZOKJMIKPOZ-UHFFFAOYSA-N 6-[3-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]propyl]-3-methyl-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2C(N3CCN(CC3)CCCC=3C=C4CC(C(NC4=CC=3)=O)C)=NSC2=C1 BVHBZOKJMIKPOZ-UHFFFAOYSA-N 0.000 claims 1
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Description
HETEROCYCLIC SUBSTITUTED PIPERAZINES FOR THE
TREATMENT OF SCHIZOPHRENIA
) 5
This invention relates to heterocyclic substituted piperazines, pharmaceutical compositions containing them and their use for the treatment of schizophrenia and other central nervous system (CNS).
The heterocyclic substituted piperazine derivatives of this invention exhibit activity as antagonists of dopamine D2 receptors and of serotonin 2A (BHT2A) receptors.
Other heterocyclic piperazine derivatives that are useful for the treatment of schizophrenia are referred to in United States patent 5,350,747, which issued on September 27, 1994, and in United States patent 6,127,357, which issued on October 3, 2000. These patents are incorporated herein by reference in their entireties.
Other piperazine and piperidine derivatives that have been stated to be useful as antipsychotic agents are those referred to in PCT patent publication WO 93/04684, which published on March 18, 1983, and
European patent application EP 402644A, which was published on
December 19, 1990. These patent applications are incorporated herein by reference in their entireties.
The present invention relates to compounds of the formula 1 i
Rr’ wW2—W! «A =o . ~N
RY —— TN _A as : F 7 wi Rr? = R! ood R® 1 wherein X is sulfur, oxygen, SO, SO, CH, or NR;
Y is nitrogen or CH;
Z is nitrogen or CH;
A is ~(CH2)mCHz-, -(CH2)mO-, -(CH2)mNR''-, or ~(CH2)mC(R"R™)-, wherein R' and R™ are independently selected from (C4-C,) alkyl optionally substituted with from one to three fluorine atoms, (C1-C4) alkoxy optionally substituted with from one to three fluorine atoms, hydroxy, and aminoalkyl; or R'2 and R™, together with the carbon to which they are attached, form a carbonyl group; m is an integer from one to four;
R* and R® are independently selected from hydrogen, (C+-Ca) alkyl optionally substituted with from one to three fluorine atoms, (C4-C4) alkoxy optionally substituted with from one to three fluorine atoms, halogen, nitro, cyano, amino, (C4-Cy) alkylamino and di-(C+-C4) alkylamino; or, when X is NR', one of R* and R® can form, together with the carbon to which it is attached, and together with R'® and the nitrogen to . 20 which it is attached, a heterocyclic ring containing from 4 to 7 ring members of which from 1 to 3 ring members are heteroatoms selected . from nitrogen, oxygen and sulfur, and of which the remaining ring members are carbon, with the proviso that when R" forms a ring with one of R* and R®, the other of R* and R® is absent;
R'® and R" are independently selected from hydrogen, (C-Cy) alkyl optionally substituted with from one to three fluorine atoms and (C4- : C,) alkoxy optionally substituted with from one to three fluorine atoms.
R' is hydrogen, (C4-C4) alkyl optionally substituted with from one to ’ 5 three fluorine atoms, aryl, -C(O)R™ wherein R' is aryl, (C;-Cy) alkyl, aryl- (C4-Cy4) alkyl-, or heteroaryl-(C+-C,)alkyl-, wherein the alkyl moieties of the aryl-(C-C4) alkyl- groups and the heteroaryl-(C+-Ca) alkyl- groups can be optionally substituted with from one to three fluoro atoms, and wherein the aryl and heteroaryl moieties of these groups can optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from halo, nitro, amino, cyano, (Cs-
Ce) alkyl optionally substituted with from one to three fluorine atoms and (C4-Cs) alkoxy optionally substituted with from one to three fluorine atoms;
R? and R® are independently selected from hydrogen, halo, (C1-Cy) alkyl, (C1-C4) alkoxy, aryl, aryl-(C4+-C,4) alkyl-, heteroaryl and heteroaryl- (C4-Cy) alkyl-, wherein the alkyl moieties of the (C1-C,) alkyl and (C4-Cy) alkoxy groups can be optionally substituted with from one to three fluoro atoms and can also be independently optionally substituted with an amino or hydroxy substituent, and wherein alkyl moieties of the aryi-(C4-C,) alkyl- and heteroaryl-(C4-C,) alkyl groups can be optionally substituted with from one to three fluoro atoms, and wherein the aryl and heteroaryl moieties of these groups can optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from halo, nitro, amino, cyano, (C4-Cg) alkyl optionally substituted with from one to three fluorine atoms and (C-Cs) alkoxy optionally substituted with from one to three fluorine atoms; or one of R? and R® can form, together with the carbon to which it is ’ attached, and together with the quinolinone ring carbon of W', a saturated or unsaturated heterocyclic ring containing from 4 to 7 ring members of which from 1 to 3 ring members can be heteroatoms selected from nitrogen, oxygen and sulfur, and of which the remaining ring members are carbon, with the proviso that when W' forms a ring with one of R? and R®, the other of R? and R® is absent; :
W' is CR°R® and W? is CR’R®, and the broken line extending from
W’ to W2 represents an optional double bond, with the proviso that when : the there is a double bond between W' and W?, R® and R’ are absent;
R°, R®, R’, and R® selected, independently, from hydrogen, halogen, ’ 5 nitro, cyano, amino, (C4-C,) alkylamino, di-(C4-C,) alkylamino, (C-C4) alkyl optionally substituted with from one to three fluorine atoms, and (Cs-Cs) alkoxy optionally substituted with from one to three fluorine atoms; or any two of R°, R®, R’, and R® that are attached to carbon atoms, taken together with the carbon or carbons to which they are attached, form a (Cs-C7) saturated or unsaturated carbocyclic ring or a (Cs-C,) saturated or unsaturated heterocyclic ring wherein one or two of the ring members are selected from nitrogen, oxygen and sulfur, with the proviso that the quinolinone ring carbon of W' can not form a ring with two of R®, R®, R’, and R® and also form a ring with R2 or R®; and the pharmaceutically acceptable salts of such compounds. ~ Another more specific embodiment of this invention relates to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein A is -(CHy),O-.
Another more specific embodiment of this invention relates to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein Ais -(CHz)mNR!'-.
Another more specific embodiment of this invention relates to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein A is -(CHz)mC(R'2R"3)-.
Another more specific embodiment of this invention relates to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein A is -(CHz)mCHo-. » Another more specific embodiment of this invention relates to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein X is sulfur.
Another more specific embodiment of this invention relates to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein X is SO or SO,
Claims (25)
1. A compound of the formula 1 & W2—w' A =o oF TA Nad Hn SF 7 N 3. | NE J RBoEn OR X—Y R” 1 wherein X is sulfur, oxygen, SO, SOz, CH; or NR"; Y is nitrogen or CH, Z is nitrogen or CH; A is (CHo)mCHz-, ~(CH2)mO-, -(CHz)mNR'™-, or ~(CH2)mC(R™*R™)-, wherein R'2 and R' are independently selected from (C4-Cs) alkyl optionally substituted with from one to three fluorine atoms, (C1-C4) alkoxy optionally substituted with from one to three fluorine atoms, hydroxy, and aminoalkyl; or R'2 and R™, together with the carbon to which they are attached, form a carbonyl group; m is an integer from one to four; R* and R® are independently selected from hydrogen, (C+-Cy) alkyl optionally substituted with from one to three fluorine atoms, (C1-Cs) alkoxy optionally substituted with from one to three fluorine atoms, halogen, nitro, cyano, amino, (C-Ca) atkylamino and di-(C+-C,) alkylamino; or, when X is NR'™, one of R* and R® can form, together with the carbon to which it is attached, and together with R' and the nitrogen to which it is attached, a heterocyclic ring containing from 4 to 7 ring members of which from 1 to 3 ring members are heteroatoms selected
PCT/IB2003/003902 3 -143- from nitrogen, oxygen and sulfur, and of which the remaining ring members are carbon, with the proviso that when R'® forms a ring with one of R* and RS, the other of R* and R® is absent; : R' and R'' are independently selected from hydrogen, (C1-Cs) alkyl optionally substituted with from one to three fluorine atoms and (C- C,) alkoxy optionally substituted with from one to three fluorine atoms; R' is hydrogen, (C1-Cs) alkyl! optionally substituted with from one to three fluorine atoms, aryl, -C(O)R' wherein R'is aryl, (C1-Ca4) alkyl, aryl- (C1-Ca)-alkyl-, or heteroaryl-(C;-C4)alkyl-, and wherein the alkyl moieties of the aryl-(C1-Ca) alkyl- groups and the heteroaryl-(C4-C4) alkyl- groups can be optionally substituted with from one to three fluoro atoms, and wherein the aryl and heteroaryl moieties of these groups can optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from halo, nitro, amino, cyano, (C;- Ce) alkyl optionally substituted with from one to three fluorine atoms and (C+-Ce) alkoxy optionally substituted with from one to three fluorine atoms; R? and R?® are independently selected from hydrogen, (C+-C4) alkyl, (C4-C4) alkoxy, halo, aryl, aryl-(C4-C.) alkyl-, heteroaryl and heteroaryl- (C4-C4) alkyl-, wherein the alkyl moieties of the (C4-C4) alkyl and (C4-Cy) alkoxy groups can be optionally substituted with from one to three fluoro atoms and can also be independently optionally substituted with an amino or hydroxy substituent, and wherein alkyl moieties of the aryl-(C4-C,) alkyl- and heteroaryl-(C:-C4) alkyl groups can be optionally substituted with from one to three fluoro atoms, and wherein the aryl and heteroaryl moieties of these groups can optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from halo, nitro, amino, cyano, (C;-Cg) alkyl optionally substituted with from one to three fluorine atoms and (C1-Ce) alkoxy optionally substituted with from one to three fluorine atoms; or one of R? and R® can form, together with the carbon to which it is attached, and together with the quinolinone ring carbon of W', a saturateq or unsaturated heterocyclic ring containing from 4 to 7 ring members of which from 1 to 3 ring members can be heteroatoms selected from AMENDED SHEET nitrogen, oxygen and sulfur, and of which the remaining ring members are carbon, with the proviso that when W' forms a ring with one of R? and R?®, the other of R? and R® is absent; : W' is CR°R® and W? is CR’R®, and the broken line extending from W' to W? represents an optional double bond, with the proviso that when the there is a double bond between W' and W?, R® and R are absent; RS, R% R’, and R®selected, independently, from hydrogen, halogen, nitro, cyano, amino, (C1-C4) alkylamino, di-(C4-C4) alkylamino, (C+-Ca) alkyl optionally substituted with from one to three fluorine atoms, and (C4-Ca) - alkoxy optionally substituted with from one to three fluorine atoms; ~ or any two of R®, R®, R’, and R® that are attached to carbon atoms, taken together with the carbon or carbons to which they are attached, form a (Cs-Cy) saturated or unsaturated carbocyclic ring, with the proviso that the quinolinone ring carbon of W' can not form a ring with two of R®, R®, R’, and R® and also form a ring with R? or R%; or a pharmaceutically acceptable salt of such compound.
2. A compound or salt according to claim 1, wherein A is -(CHz)mCHz-.
3. A compound or salt according to claim 1, wherein X is sulfur and Y is nitrogen.
4, A compound or salt that is selected from the following compounds and their pharmaceutically acceptable salts: 6-[2-(4-benzo|d]isoxazol-3-yl-piperazin-1-yl)-ethyl]-4-methyl-3,4- dihydro-1H-quinolin-2-one; 6-[2-(4-benzold]isoxazol-3-yl-piperazin-1-yl)-ethyi]-4S-methyl-3,4~ dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[d]isoxazol-3-yi-piperazin-1-yl)-ethyl]-4R-methyl-3,4- dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl}-1,4-dimethyl-3,4- dihydro-1H-quinolin-2-one;
6-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl]-4,4-dimethyl-3,4- dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[d]isoxazol-3-yl-piperazin-~1-yl}-ethyl]-1,4,4-trimethyl- 3,4-dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-4,4,8-trimethyl- 3,4-dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl]-3-methyl-3,4- dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl]-3,3-dimethyl-3,4- dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyi]-3,4-dimethyl-3,4- dihydro-1H-quinolin-2-one; 8-[2-(4-benzo[dlisoxazol-3-yl-piperazin-1-yl)-ethyl]-1,3,3,4,4- pentamethyl-3,4-dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl}-3,3,4-trimethyl- - 3,4-dihydro-1H-quinolin-2-one; : 6-{2-[4-(1H-indazol-3-yl)-piperazin-1-yl}-ethyl}-4-methyl-3,4-dihydro- 1H-quinolin-2-one; 6-{2-[4-(1H-indazol-3-yl)-piperazin-1-yl]-ethyl}-4,4-dimethyl-3,4- dihydro-1H-quinolin-2-one; 6-{2-[4-(1H-indazol-3-yl)-piperazin-1-yl}-ethyl}-3-methyl-3,4-dihydro- 1H-quinolin-2-one; 6-{2-[4-(1H-indazol-3-yl)-piperazin-1-yl}-ethyl}-3,3-dimethyl-3,4- dihydro-1H-quinolin-2-one; 6-{2-[4-(1 H-indazol-3-yl)-piperazin-1 -yl}-ethyl}-3,4-dimethyl-3,4- dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyi]-1,3,3,4,4- pentamethyl-3,4-dihydro-1H-quinolin-2-one; 6-[2-(4-benzo[djisothiazol-3-yl-piperazin-1-yl)-ethyl]-3,3,4-trimethyl- 3,4-dihydro-1H-quinolin-2-one; 6-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-4,4,8-trimethyl- 3,4-dihydro-1H-quinolin-2-one, mesylate salt;
-14B- 6-[2-(4-Benzo[dlisothiazol-3-yl-piperazin-1-yl)-ethyl]-7-chloro-4,4,8- trimethyl-3,4-dihydro-1H-quinolin-2-one methanesulfonate;, 6-[2-(4-Benzo[dlisothiazol-3-yl-piperazin-1-yl)-ethyl]-7-fluoro- 4,4,8-trimethyi-3,4-dihydro-1H-quinolin-2-one hydrochloride; 6-{3-[4-(1H-indazol-3-yl)-piperazin-1-yl}-propyl}-4,4-dimethyl-3,4- dihydro-1H-quinolin-2-one; 7-chloro-6-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-4,4- dimethyl-3,4-dihydro-1H-quinolin-2-one; 7-chloro-6-[3-(4-1,2-benzisoxazol-3-yl-piperazin-1-yl)-propyl]-4,4- dimethyl-3,4-dihydro-1H-quinolin-2-one; 6-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-4-methyl-3,4- dihydro-1H-quinolin-2-one; 6-[3-(4-1,2-benzisoxazol-3-yl-piperazin-1-yl)-propyl}-4-methyi-3,4- dihydro-1H-quinolin-2 one; 6-{3-[4-(1H-indazol-3-yl)-piperazin-1-yl}-propyl}-4-methyl-3,4- dihydro-1H-quinolin-2-one; 6-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl}-3,3-dimethyl- 3,4-dihydro-1H-quinolin-2-one; 6-[3-(4-1,2-benzisoxazol-3-yl-piperazin-1-yl)-propyl]-3,3-dimethyi- 3,4-dihydro-1H-quinolin-2 one; + 6~{3-[4-(1H-indazol-3-yl)-piperazin-1-yl]-propyl}-3,3-dimethyl-3,4- dihydro-1H-quinolin-2-one; 6-{3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-3-methyl-3,4- dihydro-1H-quinolin-2-one; : 6-[3-(4-1,2-benzisoxazol-3-yl-piperazin-1-yl)-propyl]-3-methyl-3,4- dihydro-1H-quinolin-2 one; and 6-{3-[4-(1H-indazol-3-yl)-piperazin-1-yl]-propyl}-3-methyl-3,4- dihydro-1H-quinolin-2-one.
5. A compound according to claim 1 wherein R* is hydrogen and one or both of RZ and R® are hydrogen.
PCT/IB2003/003902 PS 147-
6. A compound according to claim 1 wherein R', R, R®, R and R® are : selected, independently, from hydrogen and (C4-Cs)alkyl. a
7. A pharmaceutical composition for use in a method for 5: treating a disorder or condition selected from single episodic or : recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and : pediatric depression; bipolar disorders or manic depression, for example, bipolar | disorder, bipolar {I disorder and cyclothymic disorder; conduct oo disorder; disruptive behavior disorder; attention deficit hyperactivity + 15 disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history oo of panic disorder, specific phobias, for example, specific animal phobias, oo social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders brief psychotic disorders, shared psychotic disorders, psychotic disorders N with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe : major depressive disorder; mood disorders associated with psychotic . disorders such as acute mania and depression associated with bipolar : disorder; mood disorders associated with schizophrenia; delirium, ~ dementia, and amnestic and other cognitive or neurodegenerative } disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory disorders, loss of executive function, vascular dementia, and other dementias, for example, due to HiV disease, head trauma, AMENDED SHEET
PCT/1B2003/003902 o -148- Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt- Jakob disease, or due to multiple etiologies; movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, oo oo spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic- -rigid syndrome; extra-pyramidal movement disorders such as medication- induced movement disorders, for example, neuroleptic-induced : Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; chemical dependencies and addictions (e.g., dependencies on, or addictions to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol) and : behavioral addictions such as an addiction to gambling; and ocular : disorders such as glaucoma and ischemic retinopathy in a mammal, including a human, said composition comprising a compound according to ~ any of clams 1 - 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and said method comprising administering an effective amount of said composition that is effective in treating such disorder or condition.
8. Use of a compound according to any of claims 1 - 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder or condition selected from Ny single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking | : or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar | disorder, bipolar i - disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity disorder (ADHD); behavioral disturbances associated -with mental retardation, autistic disorder, and conduct disorder; anxiety disorders such as panic disorder with or without AMENDED SHEET
PCT/IB2003/003902 ® -149- agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post- traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychatic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; mood disorders associated with schizophrenia; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory disorders, loss of executive function, vascular dementia, and other dementias, for example, : due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple etiologies; movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; chemical dependencies and addictions (e.g., dependencies on, or addictions to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol) and behavioral addictions such as an addiction to gambling; and ocular disorders such as glaucoma and ischemic retinopathy in a mammal, including a human.
AMENDED SHEET
PCT/IB2003/003902 ® | -150-
9. Use according to claim 8, wherein the disorder or condition that is being treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to general "medical condition, and schizophreniform disorder.
10. Use according to claim 8, wherein said medicament is administrable to a human for the treatment of any two or more comorbid disorders or conditions selected from those disorders and conditions referred to in claim
8.
11. Use according to claim 10, wherein the disorder or condition to be treated is schizophrenia with concomitant depression.
12. Use according to claim 10, wherein the disorder or condition to be treated is schizophrenia with concomitant anxiety.
13. Use of a compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and another pharmaceutically active compound that is an antidepressant or an anti-anxiety agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder or condition selected from single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking or psychomotor retardation, atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar | disorder, bipolar II disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders such as panic disorder with or without AMENDED SHEET
PCT/IB2003/003902 agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post- traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for | example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, : shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; mood disorders associated with schizophrenia; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile ~ dementia, dementia of the Alzheimer's type, memory disorders, loss of executive function, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple etiologies; movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette’s syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute - akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour, chemical dependencies and addictions (e.g, dependencies on, or addictions to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol) and behavioral addictions : such as an addiction to gambling; and ocular disorders such as glaucoma and ischemic retinopathy in a mammal, including a human. i AMENDED SHEET
PCT/IB2003/003902 ® -152-
14. Use of a compound according to any one of claims 1 - 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use with another pharmaceutically active compound that is an antidepressant or an anti-anxiety agent, or a pharmaceutically acceptable salt thereof, for treating a disorder or condition selected from those listed in claim 13.
15. A pharmaceutical composition for use in a method for ‘treating a disorder or condition selected from single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar | disorder, bipolar Il disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity : disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders "brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; mood disorders associated with schizophrenia; delirium, : AMENDED SHEET
PCT/1B2003/003902 C -153- dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile-dementia, dementia of the Alzheimer's type, memory disorders, loss of executive function, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, : Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt- Jakob disease, or due to multiple etiologies; movement disorders such as . akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette’s syndrome, Scott syndrome, PALSYS and akinetic- rigid syndrome; extra-pyramidal movement disorders such as medication- induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; chemical dependencies and addictions (e.g., dependencies on, or addictions to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol) and behavioral addictions such as an addiction to gambling; and ocular disorders such as glaucoma and ischemic retinopathy in a mammal, said composition comprising a compound according to any of claims 1 -6 or a pharmaceutically acceptable salt thereof, and another pharmaceutically active agent that is an antidepressant or an anti-anxiety agent, and said method comprising administering said composition.
Co
16. A pharmaceutical composition for use with another pharmaceutically active agent that is an antidepressant or an anti-anxiety agent; in a method for treating a disorder or condition selected from those listed in claim 15, said composition comprising a compound according to any one of claims 1 - 6 or a pharmaceutically acceptable salt thereof, and said method comprising administering said composition and said another active agent.
AMENDED SHEET
. PCT/IB2003/003902
17. Use according to claim 13, wherein the disorder or condition being treated is schizophrenia.
18. A compound or salt which is 6-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1- yl)-ethyl}-7-chioro-4,4,8-trimethyl-3,4-dihydro-1H-quinolin-2-one.
19. A compound which is 6-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)- ethyl]-7-chloro-4,4,8-trimethyi-3,4-dihydro-1H-quinolin-2-one methanesulfonate.
20. A compound or salt which is 6-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1- yh-ethyl}-8-chloro-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one.
21. A compound which is 6-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)- ethyl]-8-chloro-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one hydrochloride.
22. A compound according to any one of claims 1 to 6, substantially as herein described and illustrated.
23. A composition for use in a method of treatment according to claim 7, claim 15 or claim 16, substantially as herein described and illustrated.
24. Use according to any one of claims 8 to 14 or 17, substantially as herein described and illustrated.
25. A new compound, a composition for a new use in a method of treatment, a new use of a compound as claimed in any one of claims 1 to 6 or 18 to 21, or a new use of a compound as claimed in any one of claims 1 to 6 and another pharmaceutically active agent, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41147502P | 2002-09-17 | 2002-09-17 |
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|---|---|
| CN (1) | CN1701072A (en) |
| CR (1) | CR7735A (en) |
| TN (1) | TNSN05074A1 (en) |
| ZA (1) | ZA200502216B (en) |
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|---|---|---|---|---|
| WO2010012121A1 (en) * | 2008-07-28 | 2010-02-04 | 江苏国华投资有限公司 | Aralkyl substituted piperidine or piperazine derivatives and their use for treating schizophrenia |
| AU2009294695B2 (en) * | 2008-09-22 | 2012-09-13 | F. Hoffmann-La Roche Ag | Piperazine D3 and 5-HT2a receptor modulators |
| CN102718758A (en) * | 2011-03-31 | 2012-10-10 | 江苏恒谊药业有限公司 | Quinolinone derivative and application thereof as anti-schizophrenic drug |
| CN103130737B (en) * | 2011-12-05 | 2015-12-02 | 江苏恒谊药业有限公司 | Hexanaphthene aminated compounds and the application as antipsychotic drug thereof |
| CN113727968A (en) * | 2019-05-14 | 2021-11-30 | 杏林制药株式会社 | Process for preparing 4-oxopyrrolidine-3-carboxamide derivatives |
| CN112142737B (en) * | 2019-06-29 | 2022-03-18 | 武汉珈瑜科技有限公司 | Solid form of hydrochloride of medicine for treating schizophrenia |
-
2003
- 2003-09-05 CN CN 03825236 patent/CN1701072A/en active Pending
-
2005
- 2005-03-11 CR CR7735A patent/CR7735A/en not_active Application Discontinuation
- 2005-03-16 ZA ZA200502216A patent/ZA200502216B/en unknown
- 2005-03-17 TN TNP2005000074A patent/TNSN05074A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1701072A (en) | 2005-11-23 |
| TNSN05074A1 (en) | 2007-05-14 |
| CR7735A (en) | 2005-06-15 |
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