IL107836A - Spiro piperidines and homologues, their preparation and pharmaceutical preparations containing them - Google Patents

Spiro piperidines and homologues, their preparation and pharmaceutical preparations containing them

Info

Publication number: IL107836A
Authority: IL; Israel
Prior art keywords: amino; indene; alkyl; oxopropyl; methyl
Prior art date: 1992-12-11

Application number

IL107836A

Other languages

English (en)

Hebrew (he)

Other versions

IL107836A0 (en

Original Assignee

Merck & Co Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1992-12-11

Filing date

1993-12-02

Publication date

1998-01-04

1993-11-03 Priority claimed from US08/146,848 external-priority patent/US5578593A/en

1993-12-02 Application filed by Merck & Co Inc filed Critical Merck & Co Inc

1994-04-12 Publication of IL107836A0 publication Critical patent/IL107836A0/xx

1998-01-04 Publication of IL107836A publication Critical patent/IL107836A/en

Links

-1 Spiro piperidines Chemical class 0.000 title claims abstract description 194
238000002360 preparation method Methods 0.000 title claims description 28
239000008194 pharmaceutical composition Substances 0.000 title description 4
150000001875 compounds Chemical class 0.000 claims abstract description 390
239000000203 mixture Substances 0.000 claims abstract description 197
102000018997 Growth Hormone Human genes 0.000 claims abstract description 53
108010051696 Growth Hormone Proteins 0.000 claims abstract description 53
239000000122 growth hormone Substances 0.000 claims abstract description 53
241001465754 Metazoa Species 0.000 claims abstract description 13
238000004519 manufacturing process Methods 0.000 claims abstract description 7
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 254
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 171
238000000034 method Methods 0.000 claims description 141
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 133
125000003118 aryl group Chemical group 0.000 claims description 105
229910052739 hydrogen Inorganic materials 0.000 claims description 60
239000001257 hydrogen Substances 0.000 claims description 58
125000000217 alkyl group Chemical group 0.000 claims description 48
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 45
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 38
239000002253 acid Substances 0.000 claims description 28
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 27
238000011282 treatment Methods 0.000 claims description 27
125000006239 protecting group Chemical group 0.000 claims description 26
229910052736 halogen Inorganic materials 0.000 claims description 25
150000002367 halogens Chemical class 0.000 claims description 25
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
150000003839 salts Chemical class 0.000 claims description 19
229910052757 nitrogen Chemical group 0.000 claims description 18
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
239000003324 growth hormone secretagogue Substances 0.000 claims description 14
229910052760 oxygen Inorganic materials 0.000 claims description 13
FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 claims description 12
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
125000001424 substituent group Chemical group 0.000 claims description 12
229910052717 sulfur Inorganic materials 0.000 claims description 12
101710142969 Somatoliberin Proteins 0.000 claims description 10
239000000095 Growth Hormone-Releasing Hormone Substances 0.000 claims description 9
125000004429 atom Chemical group 0.000 claims description 9
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
239000001301 oxygen Substances 0.000 claims description 9
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
125000000753 cycloalkyl group Chemical group 0.000 claims description 8
125000001041 indolyl group Chemical group 0.000 claims description 8
239000011593 sulfur Substances 0.000 claims description 8
229940122361 Bisphosphonate Drugs 0.000 claims description 7
125000003545 alkoxy group Chemical group 0.000 claims description 7
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
241000282414 Homo sapiens Species 0.000 claims description 6
125000004122 cyclic group Chemical group 0.000 claims description 6
125000005842 heteroatom Chemical group 0.000 claims description 6
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
208000001132 Osteoporosis Diseases 0.000 claims description 5
229910052799 carbon Inorganic materials 0.000 claims description 5
239000000460 chlorine Substances 0.000 claims description 5
125000005843 halogen group Chemical group 0.000 claims description 5
125000004076 pyridyl group Chemical group 0.000 claims description 5
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
239000005977 Ethylene Substances 0.000 claims description 4
125000002883 imidazolyl group Chemical group 0.000 claims description 4
125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
125000001544 thienyl group Chemical group 0.000 claims description 4
108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 3
125000001153 fluoro group Chemical group F* 0.000 claims description 3
NWQWNCILOXTTHF-HLCSKTDOSA-N (2s)-6-amino-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-aminopropanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]hexanamide Chemical compound C([C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CNC=N1 NWQWNCILOXTTHF-HLCSKTDOSA-N 0.000 claims description 2
WZHKXNSOCOQYQX-FUAFALNISA-N (2s)-6-amino-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-amino-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]propanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]hexanamide Chemical compound C([C@H](N)C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CN=CN1 WZHKXNSOCOQYQX-FUAFALNISA-N 0.000 claims description 2
125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 claims description 2
125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
DHSSDEDRBUKTQY-UHFFFAOYSA-N 6-prop-2-enyl-4,5,7,8-tetrahydrothiazolo[4,5-d]azepin-2-amine Chemical compound C1CN(CC=C)CCC2=C1N=C(N)S2 DHSSDEDRBUKTQY-UHFFFAOYSA-N 0.000 claims description 2
OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 2
102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims description 2
108090001117 Insulin-Like Growth Factor II Proteins 0.000 claims description 2
102000048143 Insulin-Like Growth Factor II Human genes 0.000 claims description 2
125000004423 acyloxy group Chemical group 0.000 claims description 2
108010083553 alanyl-histidyl-(2-naphthyl)alanyl-tryptophyl-phenylalanyl-lysinamide Proteins 0.000 claims description 2
229940062527 alendronate Drugs 0.000 claims description 2
125000001931 aliphatic group Chemical group 0.000 claims description 2
125000004432 carbon atom Chemical group C* 0.000 claims description 2
125000004093 cyano group Chemical group *C#N 0.000 claims description 2
125000002541 furyl group Chemical group 0.000 claims description 2
108010015153 growth hormone releasing hexapeptide Proteins 0.000 claims description 2
125000005059 halophenyl group Chemical group 0.000 claims description 2
125000004430 oxygen atom Chemical group O* 0.000 claims description 2
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
125000000335 thiazolyl group Chemical group 0.000 claims description 2
150000002431 hydrogen Chemical group 0.000 claims 15
125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
102000038461 Growth Hormone-Releasing Hormone Human genes 0.000 claims 2
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
CXXGJFDTPWYQNM-HSZRJFAPSA-N 2-amino-2-methyl-n-[(2r)-1-oxo-1-(3-oxospiro[2h-indene-1,4'-piperidine]-1'-yl)-5-phenylpentan-2-yl]propanamide Chemical compound C([C@@H](NC(=O)C(C)(N)C)C(=O)N1CCC2(C3=CC=CC=C3C(=O)C2)CC1)CCC1=CC=CC=C1 CXXGJFDTPWYQNM-HSZRJFAPSA-N 0.000 claims 1
AWGBKZRMLNVLAF-UHFFFAOYSA-N 3,5-dibromo-n,2-dihydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=CC(Br)=C1O AWGBKZRMLNVLAF-UHFFFAOYSA-N 0.000 claims 1
MYQAPLQODBOKJG-JIPXPUAJSA-N ethyl 2-[(1s)-1'-[(2r)-2-[(2-amino-2-methylpropanoyl)amino]-3-(1h-indol-3-yl)propanoyl]spiro[1,2-dihydroindene-3,4'-piperidine]-1-yl]acetate Chemical compound C12=CC=CC=C2[C@H](CC(=O)OCC)CC11CCN(C(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)CC1 MYQAPLQODBOKJG-JIPXPUAJSA-N 0.000 claims 1
230000000707 stereoselective effect Effects 0.000 claims 1
230000012010 growth Effects 0.000 abstract description 9
230000028327 secretion Effects 0.000 abstract description 9
230000003578 releasing effect Effects 0.000 abstract description 5
150000003413 spiro compounds Chemical class 0.000 abstract description 5
239000004480 active ingredient Substances 0.000 abstract description 4
208000020221 Short stature Diseases 0.000 abstract description 3
230000007812 deficiency Effects 0.000 abstract description 3
230000002950 deficient Effects 0.000 abstract description 3
230000001195 anabolic effect Effects 0.000 abstract description 2
235000013305 food Nutrition 0.000 abstract description 2
235000013622 meat product Nutrition 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 334
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 306
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 237
239000000243 solution Substances 0.000 description 215
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 165
239000000543 intermediate Substances 0.000 description 153
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 148
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 123
235000019439 ethyl acetate Nutrition 0.000 description 120
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 106
238000005481 NMR spectroscopy Methods 0.000 description 99
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 98
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 95
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
229940093499 ethyl acetate Drugs 0.000 description 89
239000000047 product Substances 0.000 description 88
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 80
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 72
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
229910001868 water Inorganic materials 0.000 description 63
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
239000000741 silica gel Substances 0.000 description 62
229910002027 silica gel Inorganic materials 0.000 description 62
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 60
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 59
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 57
238000003818 flash chromatography Methods 0.000 description 55
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 53
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
238000006243 chemical reaction Methods 0.000 description 48
239000011541 reaction mixture Substances 0.000 description 48
229940073584 methylene chloride Drugs 0.000 description 47
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 45
239000012267 brine Substances 0.000 description 44
239000000463 material Substances 0.000 description 44
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 44
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 40
239000007787 solid Substances 0.000 description 40
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 39
239000012044 organic layer Substances 0.000 description 35
238000000746 purification Methods 0.000 description 35
YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 34
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
230000002829 reductive effect Effects 0.000 description 31
239000002904 solvent Substances 0.000 description 31
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
239000010410 layer Substances 0.000 description 30
150000002148 esters Chemical class 0.000 description 28
125000003003 spiro group Chemical group 0.000 description 28
150000001412 amines Chemical class 0.000 description 27
229910052938 sodium sulfate Inorganic materials 0.000 description 27
235000011152 sodium sulphate Nutrition 0.000 description 27
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
229910052943 magnesium sulfate Inorganic materials 0.000 description 25
235000019341 magnesium sulphate Nutrition 0.000 description 25
238000003756 stirring Methods 0.000 description 25
239000012442 inert solvent Substances 0.000 description 24
235000019441 ethanol Nutrition 0.000 description 23
229920006395 saturated elastomer Polymers 0.000 description 22
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 20
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 20
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 20
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 19
238000005859 coupling reaction Methods 0.000 description 19
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
229910000041 hydrogen chloride Inorganic materials 0.000 description 19
238000003820 Medium-pressure liquid chromatography Methods 0.000 description 18
230000008878 coupling Effects 0.000 description 18
238000010168 coupling process Methods 0.000 description 18
230000000580 secretagogue effect Effects 0.000 description 18
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 17
239000003054 catalyst Substances 0.000 description 17
239000003921 oil Substances 0.000 description 17
235000019198 oils Nutrition 0.000 description 17
229940086542 triethylamine Drugs 0.000 description 17
238000004809 thin layer chromatography Methods 0.000 description 16
238000005160 1H NMR spectroscopy Methods 0.000 description 15
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 15
235000011114 ammonium hydroxide Nutrition 0.000 description 15
239000012043 crude product Substances 0.000 description 15
239000012074 organic phase Substances 0.000 description 15
235000001014 amino acid Nutrition 0.000 description 14
150000001413 amino acids Chemical class 0.000 description 14
238000003786 synthesis reaction Methods 0.000 description 14
NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 13
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 13
239000000908 ammonium hydroxide Substances 0.000 description 13
238000001704 evaporation Methods 0.000 description 13
230000008020 evaporation Effects 0.000 description 13
238000012746 preparative thin layer chromatography Methods 0.000 description 13
239000007858 starting material Substances 0.000 description 13
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
230000015572 biosynthetic process Effects 0.000 description 12
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
238000004458 analytical method Methods 0.000 description 11
239000003153 chemical reaction reagent Substances 0.000 description 11
235000017557 sodium bicarbonate Nutrition 0.000 description 11
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
101150041968 CDC13 gene Proteins 0.000 description 10
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 10
239000012230 colorless oil Substances 0.000 description 10
238000001035 drying Methods 0.000 description 10
150000002576 ketones Chemical class 0.000 description 10
229910052763 palladium Inorganic materials 0.000 description 10
150000003462 sulfoxides Chemical class 0.000 description 10
239000000725 suspension Substances 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
238000000605 extraction Methods 0.000 description 9
229910000342 sodium bisulfate Inorganic materials 0.000 description 9
229910000104 sodium hydride Inorganic materials 0.000 description 9
YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 8
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
102100022831 Somatoliberin Human genes 0.000 description 8
150000007513 acids Chemical class 0.000 description 8
230000029936 alkylation Effects 0.000 description 8
238000005804 alkylation reaction Methods 0.000 description 8
239000002585 base Substances 0.000 description 8
230000000694 effects Effects 0.000 description 8
125000004494 ethyl ester group Chemical group 0.000 description 8
238000001914 filtration Methods 0.000 description 8
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
239000012279 sodium borohydride Substances 0.000 description 8
229910000033 sodium borohydride Inorganic materials 0.000 description 8
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
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230000008439 repair process Effects 0.000 description 1
230000004044 response Effects 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
238000012552 review Methods 0.000 description 1
238000006049 ring expansion reaction Methods 0.000 description 1
229940089617 risedronate Drugs 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
229960002101 secretin Drugs 0.000 description 1
OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
238000000926 separation method Methods 0.000 description 1
229940076279 serotonin Drugs 0.000 description 1
210000002966 serum Anatomy 0.000 description 1
208000019116 sleep disease Diseases 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
239000008247 solid mixture Substances 0.000 description 1
FAHNQCZLQAFESR-UHFFFAOYSA-N spiro[1,2-dihydroindene-3,4'-piperidine]-1,1'-dicarboxylic acid Chemical compound C12=CC=CC=C2C(C(=O)O)CC21CCN(C(O)=O)CC2 FAHNQCZLQAFESR-UHFFFAOYSA-N 0.000 description 1
DZYGNYHYAOMISO-UHFFFAOYSA-N spiro[1,2-dihydroindene-3,4'-piperidine]-1-ol Chemical compound C12=CC=CC=C2C(O)CC21CCNCC2 DZYGNYHYAOMISO-UHFFFAOYSA-N 0.000 description 1
HOKAPAAIDOZSQP-UHFFFAOYSA-N spiro[1,3-dihydroindene-2,4'-piperidine]-1'-carboxylic acid Chemical compound C1CN(C(=O)O)CCC11CC2=CC=CC=C2C1 HOKAPAAIDOZSQP-UHFFFAOYSA-N 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
239000003206 sterilizing agent Substances 0.000 description 1
238000010254 subcutaneous injection Methods 0.000 description 1
239000007929 subcutaneous injection Substances 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
229950007447 sulbenox Drugs 0.000 description 1
230000006103 sulfonylation Effects 0.000 description 1
238000005694 sulfonylation reaction Methods 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
208000011580 syndromic disease Diseases 0.000 description 1
230000002195 synergetic effect Effects 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
229940037128 systemic glucocorticoids Drugs 0.000 description 1
FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
229910052714 tellurium Inorganic materials 0.000 description 1
PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 1
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
XHTRZVGYPZUGDA-UHFFFAOYSA-N tert-butyl 3-pyridin-2-ylspiro[indene-1,4'-piperidine]-1'-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC21C1=CC=CC=C1C(C=1N=CC=CC=1)=C2 XHTRZVGYPZUGDA-UHFFFAOYSA-N 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
DAYKVICQLDRGJD-XMMPIXPASA-N tert-butyl n-[(2s)-3-benzylsulfanyl-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]carbamate Chemical group C([C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)SCC1=CC=CC=C1 DAYKVICQLDRGJD-XMMPIXPASA-N 0.000 description 1
229960003604 testosterone Drugs 0.000 description 1
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
229960000278 theophylline Drugs 0.000 description 1
VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
229930192474 thiophene Natural products 0.000 description 1
239000005495 thyroid hormone Substances 0.000 description 1
229940036555 thyroid hormone Drugs 0.000 description 1
229940034208 thyroxine Drugs 0.000 description 1
XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
229940019375 tiludronate Drugs 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
230000009466 transformation Effects 0.000 description 1
230000014616 translation Effects 0.000 description 1
GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
150000008648 triflates Chemical class 0.000 description 1
229940035722 triiodothyronine Drugs 0.000 description 1
CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
150000003673 urethanes Chemical class 0.000 description 1
238000002255 vaccination Methods 0.000 description 1
230000002227 vasoactive effect Effects 0.000 description 1
229960003726 vasopressin Drugs 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
235000019786 weight gain Nutrition 0.000 description 1
230000004584 weight gain Effects 0.000 description 1
238000009736 wetting Methods 0.000 description 1
210000002268 wool Anatomy 0.000 description 1
229960002300 zeranol Drugs 0.000 description 1
150000003952 β-lactams Chemical class 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06147—Dipeptides with the first amino acid being heterocyclic and His-amino acid; Derivatives thereof
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Veterinary Medicine (AREA)
Biochemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
General Chemical & Material Sciences (AREA)
Animal Behavior & Ethology (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
Molecular Biology (AREA)
Genetics & Genomics (AREA)
Biophysics (AREA)
Engineering & Computer Science (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Physical Education & Sports Medicine (AREA)
Rheumatology (AREA)
Diabetes (AREA)
Orthopedic Medicine & Surgery (AREA)
Obesity (AREA)
Endocrinology (AREA)
Hematology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Peptides Or Proteins (AREA)
Steroid Compounds (AREA)
Fodder In General (AREA)
Other In-Based Heterocyclic Compounds (AREA)
Feed For Specific Animals (AREA)
Plural Heterocyclic Compounds (AREA)
Hydrogenated Pyridines (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

IL107836A 1992-12-11 1993-12-02 Spiro piperidines and homologues, their preparation and pharmaceutical preparations containing them IL107836A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US98932292A	1992-12-11	1992-12-11
US08/146,848 US5578593A (en)	1992-12-11	1993-11-03	Spiro piperidines and homologs promote release of growth hormone

Publications (2)

Publication Number	Publication Date
IL107836A0 IL107836A0 (en)	1994-04-12
IL107836A true IL107836A (en)	1998-01-04

Family

ID=26844355

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL107836A IL107836A (en)	1992-12-11	1993-12-02	Spiro piperidines and homologues, their preparation and pharmaceutical preparations containing them

Country Status (14)

Country	Link
EP (1)	EP0662481B1 (fr)
JP (1)	JP2509147B2 (fr)
CN (1)	CN1040432C (fr)
AT (1)	ATE178070T1 (fr)
AU (1)	AU673017B2 (fr)
CA (1)	CA2110672A1 (fr)
DE (1)	DE69324148T2 (fr)
DZ (1)	DZ1735A1 (fr)
ES (1)	ES2129072T3 (fr)
HR (1)	HRP931484A2 (fr)
IL (1)	IL107836A (fr)
MX (1)	MX9307851A (fr)
PH (1)	PH31168A (fr)
SI (1)	SI9300647A (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DK78692D0 (da) *	1992-06-12	1992-06-12	Lundbeck & Co As H	Dimere piperidin- og piperazinderivater
TW432073B (en)	1995-12-28	2001-05-01	Pfizer	Pyrazolopyridine compounds
EP0900086A4 (fr) *	1996-05-07	2000-01-12	Merck & Co Inc	Stimulation du sommeil avec un secretagogue d'hormone de croissance
WO1998016527A1 (fr) *	1996-10-15	1998-04-23	Fujisawa Pharmaceutical Co., Ltd.	Derives de benzoxepine promoteurs de la liberation d'hormone de croissance
US6639076B1 (en)	1998-08-18	2003-10-28	Eli Lilly And Company	Growth hormone secretagogues
US6828331B1 (en)	1999-02-19	2004-12-07	Eli Lilly And Company	Growth hormone secretagogues
CO5160260A1 (es) *	1999-02-19	2002-05-30	Lilly Co Eli	Secretagogos de la hormona del crecimiento derivados de imi- dazol 1,4- substituido
EP1200432B1 (fr) *	1999-07-13	2004-05-12	Merck & Co., Inc.	Amido-spiropiperidines favorisant la liberation de l'hormone de croissance
US7125840B2 (en)	2001-10-09	2006-10-24	Eli Lilly And Company	Substituted dipeptides as growth hormone secretagogues
US7396846B2 (en)	2002-04-09	2008-07-08	Eli Lilly And Company	Growth hormone secretagogues
DE10317878A1 (de) *	2003-04-17	2004-11-11	Consortium für elektrochemische Industrie GmbH	Verfahren zur Herstellung von alpha-methylierten Cystein und Serin-Derivaten
CA2581415C (fr) *	2004-10-28	2011-10-04	Sankyo Company Limited	Derives optiquement actifs de l'oxazolidine disubstituee en position 4,4 et procedures de preparation connexes
CN101081835B (zh) *	2006-05-30	2011-09-21	上海药明康德新药开发有限公司	一种螺[苯并环-3-酮-1-(4′-哌啶)]模板化合物的合成方法
AU2008205642B2 (en) *	2007-01-12	2013-06-06	Msd K.K.	Spirochromanon derivatives
JP5585822B2 (ja) *	2010-05-11	2014-09-10	東レ・ファインケミカル株式会社	光学活性ニペコチン酸誘導体の製造方法
EP4282867A1 (fr) *	2021-04-25	2023-11-29	Changchun Genescience Pharmaceutical Co., Ltd.	Dérivé spiro contenant de l'indoline, son procédé de préparation et son utilisation en médecine
CN119968381A (zh) *	2022-10-21	2025-05-09	长春金赛药业有限责任公司	吲哚啉螺环类化合物的晶型、无定形物及二者的制备方法和应用
TW202423413A (zh) *	2022-10-21	2024-06-16	大陸商長春金賽藥業有限責任公司	吲哚啉螺環類化合物的溶劑化物及其晶型、製備方法和用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB8332704D0 (en) *	1983-12-07	1984-01-11	Pfizer Ltd	Growth promotants for animals
US5206235A (en) *	1991-03-20	1993-04-27	Merck & Co., Inc.	Benzo-fused lactams that promote the release of growth hormone

1993
- 1993-12-02 IL IL107836A patent/IL107836A/en active IP Right Grant
- 1993-12-03 CA CA002110672A patent/CA2110672A1/fr not_active Abandoned
- 1993-12-08 DE DE69324148T patent/DE69324148T2/de not_active Expired - Fee Related
- 1993-12-08 ES ES93309868T patent/ES2129072T3/es not_active Expired - Lifetime
- 1993-12-08 EP EP93309868A patent/EP0662481B1/fr not_active Expired - Lifetime
- 1993-12-08 DZ DZ930130A patent/DZ1735A1/fr active
- 1993-12-08 AT AT93309868T patent/ATE178070T1/de not_active IP Right Cessation
- 1993-12-10 SI SI9300647A patent/SI9300647A/sl unknown
- 1993-12-10 HR HR931484A patent/HRP931484A2/hr not_active Application Discontinuation
- 1993-12-10 AU AU52321/93A patent/AU673017B2/en not_active Ceased
- 1993-12-10 MX MX9307851A patent/MX9307851A/es not_active IP Right Cessation
- 1993-12-10 JP JP5341449A patent/JP2509147B2/ja not_active Expired - Lifetime
- 1993-12-10 PH PH47421A patent/PH31168A/en unknown
- 1993-12-11 CN CN93112857A patent/CN1040432C/zh not_active Expired - Fee Related

Also Published As

Publication number	Publication date
DE69324148D1 (de)	1999-04-29
IL107836A0 (en)	1994-04-12
AU673017B2 (en)	1996-10-24
SI9300647A (en)	1994-09-30
AU5232193A (en)	1994-06-23
CA2110672A1 (fr)	1994-06-12
CN1092767A (zh)	1994-09-28
ES2129072T3 (es)	1999-06-01
JPH0797367A (ja)	1995-04-11
EP0662481A1 (fr)	1995-07-12
DE69324148T2 (de)	1999-10-28
MX9307851A (es)	1994-06-30
JP2509147B2 (ja)	1996-06-19
PH31168A (en)	1998-03-20
HRP931484A2 (en)	1996-04-30
EP0662481B1 (fr)	1999-03-24
CN1040432C (zh)	1998-10-28
DZ1735A1 (fr)	2002-02-17
ATE178070T1 (de)	1999-04-15

Legal Events

Date	Code	Title
1998-06-15	FF	Patent granted
1998-11-26	KB	Patent renewed
2000-06-29	KB	Patent renewed

Publication	Publication Date	Title
US5578593A (en)	1996-11-26	Spiro piperidines and homologs promote release of growth hormone
EP0662481B1 (fr)	1999-03-24	Spiro piperidines et ses homologues favorisants la libération de l'hormone de croissance.
EP0615977B1 (fr)	2002-07-03	Spiro piperidines et ses homologues favorisants la libération de l'hormone de croissance
EP0730578A1 (fr)	1996-09-11	Composes contenant un groupe indolyle et leur utilisation pour favoriser la liberation d'hormones(s) de croissance
LV11525B (en)	1997-02-20	Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
WO1998010653A1 (fr)	1998-03-19	Piperidines, pyrrolidines et hexahydro-1h-azepines favorisant la secretion d'hormone de croissance
WO1997036873A1 (fr)	1997-10-09	Piperidines, pyrrolidines et hexahydro-1h-azepines declenchant la liberation de l'hormone de croissance
US5965565A (en)	1999-10-12	Piperidines promote release of growth hormone
GB2298647A (en)	1996-09-11	Bridged piperidines promoting release of growth hormone
WO1997011697A1 (fr)	1997-04-03	Piperidines et pyrroolidines de 3-spirolactame, 3-spiroamino, 3-spirolactone et 3-spirobenzopyran permettant de promouvoir la liberation de l'hormone de croissance
WO1998025897A1 (fr)	1998-06-18	Piperidines, pyrrolidines et hexahydro-1h azepines favorisent la liberation de l'hormone de croissance
AU767433B2 (en)	2003-11-13	Amido spiropiperidines promote the release of growth hormone
HK1009276A (en)	1999-05-28	Spiro piperidines and homologs which promote release of growth hormone