HRP931484A2 - Spiro piperidines and homologs which promote the release of growth hormone - Google Patents

Spiro piperidines and homologs which promote the release of growth hormone Download PDF

Info

Publication number: HRP931484A2
Authority: HR; Croatia
Prior art keywords: amino; alkyl; oxopropyl; dihydrospiro; methyl
Prior art date: 1992-12-11

Application number

HR931484A

Other languages

English (en)

Croatian (hr)

Inventor

Meng-Hsin Chen

David B R Johnston

Ravi P Nargund

Arthur A Patchett

James R Tata

Lihu Yang

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

1993-12-10

Publication date

1996-04-30

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

1993-12-10 Application filed by Merck & Co Inc filed Critical Merck & Co Inc

1996-04-30 Publication of HRP931484A2 publication Critical patent/HRP931484A2/hr

Links

-1 Spiro piperidines Chemical class 0.000 title claims abstract description 256
239000000122 growth hormone Substances 0.000 title claims abstract description 60
102000018997 Growth Hormone Human genes 0.000 title claims abstract description 59
108010051696 Growth Hormone Proteins 0.000 title claims abstract description 59
150000001875 compounds Chemical class 0.000 claims abstract description 376
239000000203 mixture Substances 0.000 claims abstract description 212
230000028327 secretion Effects 0.000 claims abstract description 35
241001465754 Metazoa Species 0.000 claims abstract description 16
238000004519 manufacturing process Methods 0.000 claims abstract description 7
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 248
238000000034 method Methods 0.000 claims description 173
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 148
125000003118 aryl group Chemical group 0.000 claims description 96
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 90
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 81
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 72
229910052739 hydrogen Inorganic materials 0.000 claims description 57
239000001257 hydrogen Substances 0.000 claims description 55
238000006243 chemical reaction Methods 0.000 claims description 45
229910052757 nitrogen Chemical group 0.000 claims description 41
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 38
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 38
YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 35
125000000217 alkyl group Chemical group 0.000 claims description 33
150000002431 hydrogen Chemical class 0.000 claims description 32
229910052736 halogen Inorganic materials 0.000 claims description 30
150000002367 halogens Chemical class 0.000 claims description 30
125000006239 protecting group Chemical group 0.000 claims description 27
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 26
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
229910052760 oxygen Inorganic materials 0.000 claims description 19
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
150000003839 salts Chemical class 0.000 claims description 19
239000000021 stimulant Substances 0.000 claims description 19
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
125000000753 cycloalkyl group Chemical group 0.000 claims description 14
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
125000001424 substituent group Chemical group 0.000 claims description 12
229940122361 Bisphosphonate Drugs 0.000 claims description 9
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 9
101710142969 Somatoliberin Proteins 0.000 claims description 9
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
229910052717 sulfur Inorganic materials 0.000 claims description 9
239000011593 sulfur Substances 0.000 claims description 9
NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 9
239000000095 Growth Hormone-Releasing Hormone Substances 0.000 claims description 8
125000001041 indolyl group Chemical group 0.000 claims description 8
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
208000001132 Osteoporosis Diseases 0.000 claims description 7
229910052799 carbon Inorganic materials 0.000 claims description 7
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 6
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
125000004429 atom 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
125000003545 alkoxy group Chemical group 0.000 claims description 5
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 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
125000004432 carbon atom Chemical group C* 0.000 claims description 4
125000002883 imidazolyl group Chemical group 0.000 claims description 4
230000008569 process Effects 0.000 claims description 4
125000004076 pyridyl 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
OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 3
108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 3
229940062527 alendronate Drugs 0.000 claims description 3
125000001624 naphthyl group Chemical group 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
125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 2
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
ZIOBGZDFMKCKGZ-UHFFFAOYSA-N 2-amino-2-methylpropanamide Chemical compound CC(C)(N)C(N)=O ZIOBGZDFMKCKGZ-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
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
125000001931 aliphatic group Chemical group 0.000 claims description 2
125000004093 cyano group Chemical group *C#N 0.000 claims description 2
125000004122 cyclic group Chemical group 0.000 claims description 2
125000001153 fluoro group Chemical group F* 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
102000038461 Growth Hormone-Releasing Hormone Human genes 0.000 claims 2
125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
241000282412 Homo Species 0.000 claims 1
230000000707 stereoselective effect Effects 0.000 claims 1
230000012010 growth Effects 0.000 abstract description 10
150000003413 spiro compounds Chemical class 0.000 abstract description 5
208000020221 Short stature Diseases 0.000 abstract description 3
230000001195 anabolic effect Effects 0.000 abstract description 2
230000002950 deficient Effects 0.000 abstract description 2
235000013305 food Nutrition 0.000 abstract description 2
239000004480 active ingredient Substances 0.000 abstract 1
230000007812 deficiency Effects 0.000 abstract 1
235000013622 meat product Nutrition 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 295
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 291
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 259
239000000243 solution Substances 0.000 description 230
239000000543 intermediate Substances 0.000 description 189
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 180
238000005160 1H NMR spectroscopy Methods 0.000 description 163
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 160
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 143
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 135
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 120
235000019439 ethyl acetate Nutrition 0.000 description 103
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 101
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 96
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 84
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 79
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 74
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 70
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 67
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 65
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 62
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 58
229910000041 hydrogen chloride Inorganic materials 0.000 description 58
239000000741 silica gel Substances 0.000 description 56
229910002027 silica gel Inorganic materials 0.000 description 56
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
239000011541 reaction mixture Substances 0.000 description 54
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
125000004494 ethyl ester group Chemical group 0.000 description 48
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 46
239000000047 product Substances 0.000 description 45
239000007787 solid Substances 0.000 description 44
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 43
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 41
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 41
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
239000000463 material Substances 0.000 description 38
238000004587 chromatography analysis Methods 0.000 description 37
239000012044 organic layer Substances 0.000 description 37
238000011282 treatment Methods 0.000 description 35
238000003818 flash chromatography Methods 0.000 description 34
239000012267 brine Substances 0.000 description 33
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 33
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
125000003003 spiro group Chemical group 0.000 description 33
238000000746 purification Methods 0.000 description 32
239000002253 acid Substances 0.000 description 29
150000001412 amines Chemical class 0.000 description 28
229910052943 magnesium sulfate Inorganic materials 0.000 description 28
235000019341 magnesium sulphate Nutrition 0.000 description 28
235000019441 ethanol Nutrition 0.000 description 27
MFNXWZGIFWJHMI-UHFFFAOYSA-N 2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C)(C)C(O)=O MFNXWZGIFWJHMI-UHFFFAOYSA-N 0.000 description 26
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
239000012442 inert solvent Substances 0.000 description 24
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 23
239000010410 layer Substances 0.000 description 23
238000003756 stirring Methods 0.000 description 23
239000002904 solvent Substances 0.000 description 22
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 21
230000002829 reductive effect Effects 0.000 description 21
229920006395 saturated elastomer Polymers 0.000 description 21
229910052938 sodium sulfate Inorganic materials 0.000 description 21
235000011152 sodium sulphate Nutrition 0.000 description 21
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 19
235000001014 amino acid Nutrition 0.000 description 19
150000001413 amino acids Chemical class 0.000 description 19
150000002148 esters Chemical class 0.000 description 19
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
238000005859 coupling reaction Methods 0.000 description 18
229940086542 triethylamine Drugs 0.000 description 18
239000003054 catalyst Substances 0.000 description 17
230000008878 coupling Effects 0.000 description 17
238000010168 coupling process Methods 0.000 description 17
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 16
239000003921 oil Substances 0.000 description 16
235000019198 oils Nutrition 0.000 description 16
235000017557 sodium bicarbonate Nutrition 0.000 description 16
229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
239000007858 starting material Substances 0.000 description 16
238000004809 thin layer chromatography Methods 0.000 description 16
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
238000003820 Medium-pressure liquid chromatography Methods 0.000 description 14
239000000460 chlorine Substances 0.000 description 14
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
238000003786 synthesis reaction Methods 0.000 description 14
239000004202 carbamide Substances 0.000 description 13
238000002360 preparation method Methods 0.000 description 13
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
238000004458 analytical method Methods 0.000 description 12
230000015572 biosynthetic process Effects 0.000 description 12
235000013877 carbamide Nutrition 0.000 description 12
KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 11
239000012043 crude product Substances 0.000 description 11
239000012074 organic phase Substances 0.000 description 11
238000012746 preparative thin layer chromatography Methods 0.000 description 11
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
235000011114 ammonium hydroxide Nutrition 0.000 description 10
239000000284 extract Substances 0.000 description 10
150000002576 ketones Chemical class 0.000 description 10
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
239000012279 sodium borohydride Substances 0.000 description 10
229910000033 sodium borohydride Inorganic materials 0.000 description 10
KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 10
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
150000007513 acids Chemical class 0.000 description 9
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
239000003153 chemical reaction reagent Substances 0.000 description 9
230000000694 effects Effects 0.000 description 9
238000001704 evaporation Methods 0.000 description 9
108090000765 processed proteins & peptides Proteins 0.000 description 9
239000000725 suspension Substances 0.000 description 9
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
239000000908 ammonium hydroxide Substances 0.000 description 8
239000002585 base Substances 0.000 description 8
230000008020 evaporation Effects 0.000 description 8
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
229910052763 palladium Inorganic materials 0.000 description 8
230000009467 reduction Effects 0.000 description 8
238000006722 reduction reaction Methods 0.000 description 8
150000003462 sulfoxides Chemical class 0.000 description 8
102100022831 Somatoliberin Human genes 0.000 description 7
150000001299 aldehydes Chemical class 0.000 description 7
238000001914 filtration Methods 0.000 description 7
239000012299 nitrogen atmosphere Substances 0.000 description 7
238000000926 separation method Methods 0.000 description 7
229910000104 sodium hydride Inorganic materials 0.000 description 7
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
206010062767 Hypophysitis Diseases 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
230000029936 alkylation Effects 0.000 description 6
238000005804 alkylation reaction Methods 0.000 description 6
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
239000007864 aqueous solution Substances 0.000 description 6
239000012298 atmosphere Substances 0.000 description 6
238000009903 catalytic hydrogenation reaction Methods 0.000 description 6
239000003324 growth hormone secretagogue Substances 0.000 description 6
QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 6
230000014759 maintenance of location Effects 0.000 description 6
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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
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- 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
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- 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
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- 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
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Medicinal Chemistry (AREA)
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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)
Other In-Based Heterocyclic Compounds (AREA)
Fodder In General (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Feed For Specific Animals (AREA)
Hydrogenated Pyridines (AREA)

HR931484A 1992-12-11 1993-12-10 Spiro piperidines and homologs which promote the release of growth hormone HRP931484A2 (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 (1)

Publication Number	Publication Date
HRP931484A2 true HRP931484A2 (en)	1996-04-30

Family

ID=26844355

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HR931484A HRP931484A2 (en)	1992-12-11	1993-12-10	Spiro piperidines and homologs which promote the release of growth hormone

Country Status (14)

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

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
CA2253390A1 (en) *	1996-05-07	1997-11-13	Merck & Co., Inc.	Enhancement of sleep with a growth hormone secretagogue
WO1998016527A1 (en) *	1996-10-15	1998-04-23	Fujisawa Pharmaceutical Co., Ltd.	Benzoxepine derivatives which promote release of growth hormone
US6639076B1 (en)	1998-08-18	2003-10-28	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
US6828331B1 (en)	1999-02-19	2004-12-07	Eli Lilly And Company	Growth hormone secretagogues
CA2379282C (en) *	1999-07-13	2010-03-09	Merck & Co., Inc.	Amido spiropiperidines promote the release of growth hormone
US7125840B2 (en)	2001-10-09	2006-10-24	Eli Lilly And Company	Substituted dipeptides as growth hormone secretagogues
AU2003218337A1 (en)	2002-04-09	2003-10-27	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
EP1806344A4 (de) *	2004-10-28	2012-02-01	Sankyo Co	Optisch aktiviertes 4,4-disubstituiertes oxazolidinderivat und herstellungsverfahren dafür
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
US8138197B2 (en) *	2007-01-12	2012-03-20	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
US20240190875A1 (en) *	2021-04-25	2024-06-13	Changchun Genescience Pharmaceutical Co., Ltd.	Spiroindoline derivative, and preparation method and medical use thereof
WO2024083160A1 (zh) *	2022-10-21	2024-04-25	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/en not_active Abandoned
- 1993-12-08 ES ES93309868T patent/ES2129072T3/es not_active Expired - Lifetime
- 1993-12-08 EP EP93309868A patent/EP0662481B1/de not_active Expired - Lifetime
- 1993-12-08 AT AT93309868T patent/ATE178070T1/de not_active IP Right Cessation
- 1993-12-08 DZ DZ930130A patent/DZ1735A1/fr active
- 1993-12-08 DE DE69324148T patent/DE69324148T2/de not_active Expired - Fee Related
- 1993-12-10 SI SI9300647A patent/SI9300647A/sl unknown
- 1993-12-10 HR HR931484A patent/HRP931484A2/hr not_active Application Discontinuation
- 1993-12-10 MX MX9307851A patent/MX9307851A/es not_active IP Right Cessation
- 1993-12-10 AU AU52321/93A patent/AU673017B2/en not_active Ceased
- 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
AU673017B2 (en)	1996-10-24
CN1040432C (zh)	1998-10-28
SI9300647A (en)	1994-09-30
ES2129072T3 (es)	1999-06-01
DE69324148T2 (de)	1999-10-28
ATE178070T1 (de)	1999-04-15
MX9307851A (es)	1994-06-30
PH31168A (en)	1998-03-20
CN1092767A (zh)	1994-09-28
CA2110672A1 (en)	1994-06-12
DE69324148D1 (de)	1999-04-29
JP2509147B2 (ja)	1996-06-19
EP0662481B1 (de)	1999-03-24
IL107836A (en)	1998-01-04
IL107836A0 (en)	1994-04-12
AU5232193A (en)	1994-06-23
DZ1735A1 (fr)	2002-02-17
EP0662481A1 (de)	1995-07-12
JPH0797367A (ja)	1995-04-11

Publication	Publication Date	Title
US5578593A (en)	1996-11-26	Spiro piperidines and homologs promote release of growth hormone
RU2168512C2 (ru)	2001-06-10	Спиропиперидины, способы их получения (варианты)
HRP931484A2 (en)	1996-04-30	Spiro piperidines and homologs which promote the release of growth hormone
US5559128A (en)	1996-09-24	3-substituted piperidines promote release of growth hormone
WO1998010653A1 (en)	1998-03-19	Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
WO1997036873A1 (en)	1997-10-09	Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
US5965565A (en)	1999-10-12	Piperidines promote release of growth hormone
WO1997011697A1 (en)	1997-04-03	3-spirolactam, 3-spiroamino, 3-spirolactone and 3-spirobenzopyran piperidines and pyrrolidines promote release of growth hormone
WO1998025897A1 (en)	1998-06-18	Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
AU767433B2 (en)	2003-11-13	Amido spiropiperidines promote the release of growth hormone

Legal Events

Date	Code	Title
1996-04-30	A1OB	Publication of a patent application
1996-10-25	AIPI	Request for the grant of a patent on the basis of a substantive examination of a patent application
2000-05-19	OBST	Application withdrawn