MXPA00012489A - Compounds with growth hormone releasing properties - Google Patents
Compounds with growth hormone releasing propertiesInfo
- Publication number
- MXPA00012489A MXPA00012489A MXPA/A/2000/012489A MXPA00012489A MXPA00012489A MX PA00012489 A MXPA00012489 A MX PA00012489A MX PA00012489 A MXPA00012489 A MX PA00012489A MX PA00012489 A MXPA00012489 A MX PA00012489A
- Authority
- MX
- Mexico
- Prior art keywords
- ethyl
- methyl
- methylcarbamoyl
- naphthyl
- oxoethyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 151
- 239000000122 growth hormone Substances 0.000 title claims abstract description 62
- 108010051696 Growth Hormone Proteins 0.000 title claims abstract description 59
- 102000018997 Growth Hormone Human genes 0.000 title claims abstract description 59
- 230000003578 releasing Effects 0.000 title claims description 10
- 239000000203 mixture Substances 0.000 claims abstract description 21
- -1 (3S) -3- (dimethyl-aminomethyl) piperidin-1-yl Chemical group 0.000 claims description 170
- 229910052739 hydrogen Inorganic materials 0.000 claims description 89
- 239000001257 hydrogen Substances 0.000 claims description 89
- 239000002253 acid Substances 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 44
- 239000011780 sodium chloride Substances 0.000 claims description 42
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 206010053759 Growth retardation Diseases 0.000 claims description 24
- 231100000001 growth retardation Toxicity 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- BKMADDIPSQRZPU-ONEGZZNKSA-N (E)-5-amino-5-methylhex-2-enoic acid Chemical compound CC(C)(N)C\C=C\C(O)=O BKMADDIPSQRZPU-ONEGZZNKSA-N 0.000 claims description 19
- 150000002431 hydrogen Chemical group 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 230000001817 pituitary Effects 0.000 claims description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- 125000005418 aryl aryl group Chemical group 0.000 claims description 15
- 102100003313 GHRL Human genes 0.000 claims description 14
- 150000001412 amines Chemical group 0.000 claims description 14
- 239000003324 growth hormone secretagogue Substances 0.000 claims description 13
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 101700010630 GHRL Proteins 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- AOGUDKCUEZSLHY-GQCTYLIASA-N (E)-5-amino-3,5-dimethylhex-2-enoic acid Chemical compound CC(N)(C)CC(/C)=C/C(O)=O AOGUDKCUEZSLHY-GQCTYLIASA-N 0.000 claims description 10
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 201000003883 cystic fibrosis Diseases 0.000 claims description 8
- 230000000366 juvenile Effects 0.000 claims description 8
- 201000003068 rheumatic fever Diseases 0.000 claims description 8
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 7
- 125000000732 arylene group Chemical group 0.000 claims description 7
- 208000006673 Asthma Diseases 0.000 claims description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 230000004936 stimulating Effects 0.000 claims description 6
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- IZRYKPCDTFCCFL-HNQUOIGGSA-N (E)-4-(1-aminocyclobutyl)but-2-enoic acid Chemical compound OC(=O)/C=C/CC1(N)CCC1 IZRYKPCDTFCCFL-HNQUOIGGSA-N 0.000 claims description 4
- 101700054787 GHRP Proteins 0.000 claims description 4
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 3
- WQQUCHWQGNUJBR-ONEGZZNKSA-N NC(C/C=C/C(=O)N)(C)C Chemical compound NC(C/C=C/C(=O)N)(C)C WQQUCHWQGNUJBR-ONEGZZNKSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- DWLKMLKWKIBQPI-HEEVJTNBSA-N FC1=CC=C(C[C@H](C(=O)N2CCC(CC2)O)N(C(=O)[C@@H](CC2=CC3=CC=CC=C3C=C2)N(C(\C=C\CC2(CCC2)N)=O)C)C)C=C1 Chemical compound FC1=CC=C(C[C@H](C(=O)N2CCC(CC2)O)N(C(=O)[C@@H](CC2=CC3=CC=CC=C3C=C2)N(C(\C=C\CC2(CCC2)N)=O)C)C)C=C1 DWLKMLKWKIBQPI-HEEVJTNBSA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 176
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
- 239000000243 solution Substances 0.000 description 113
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 79
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 60
- 239000002904 solvent Substances 0.000 description 60
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 37
- 101700067048 CDC13 Proteins 0.000 description 36
- 239000000377 silicon dioxide Substances 0.000 description 35
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 34
- 239000012043 crude product Substances 0.000 description 32
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
- 235000019341 magnesium sulphate Nutrition 0.000 description 31
- 238000003818 flash chromatography Methods 0.000 description 30
- 239000007864 aqueous solution Substances 0.000 description 29
- 239000003480 eluent Substances 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000008346 aqueous phase Substances 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 21
- AJGJINVEYVTDNH-GFCCVEGCSA-N (2R)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N(C)[C@@H](C(O)=O)CC1=CC=CC=C1 AJGJINVEYVTDNH-GFCCVEGCSA-N 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 238000004949 mass spectrometry Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 15
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 14
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- VMWJCFLUSKZZDX-UHFFFAOYSA-N N,N-dimethylmethanamine Chemical group [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 230000001681 protective Effects 0.000 description 9
- 229940088597 Hormone Drugs 0.000 description 8
- 230000001808 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- 239000005556 hormone Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 230000000638 stimulation Effects 0.000 description 8
- NRPOEGFAIJAQIE-VOTSOKGWSA-N (E)-5-methyl-5-[(2-methylpropan-2-yl)oxycarbonylamino]hex-2-enoic acid Chemical compound CC(C)(C)OC(=O)NC(C)(C)C\C=C\C(O)=O NRPOEGFAIJAQIE-VOTSOKGWSA-N 0.000 description 7
- 229960000583 Acetic Acid Drugs 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 210000004027 cells Anatomy 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229940100996 SODIUM BISULFATE Drugs 0.000 description 6
- 210000002966 Serum Anatomy 0.000 description 6
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M Sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 6
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DSCBERFCMRPLAS-VQHVLOKHSA-N (E)-3,5-dimethyl-5-[(2-methylpropan-2-yl)oxycarbonylamino]hex-2-enoic acid Chemical compound OC(=O)\C=C(/C)CC(C)(C)NC(=O)OC(C)(C)C DSCBERFCMRPLAS-VQHVLOKHSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 230000000875 corresponding Effects 0.000 description 5
- 230000004059 degradation Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000000580 secretagogue Effects 0.000 description 5
- 210000001519 tissues Anatomy 0.000 description 5
- UPELCGTZMOPXQW-SNVBAGLBSA-N (2R)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-thiophen-2-ylpropanoic acid Chemical compound CC(C)(C)OC(=O)N(C)[C@@H](C(O)=O)CC1=CC=CS1 UPELCGTZMOPXQW-SNVBAGLBSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- 206010016256 Fatigue Diseases 0.000 description 4
- 229960004666 Glucagon Drugs 0.000 description 4
- 108060003199 Glucagon Proteins 0.000 description 4
- MASNOZXLGMXCHN-ZLPAWPGGSA-N Glucagonum Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 125000006630 butoxycarbonylamino group Chemical group 0.000 description 4
- 150000001793 charged compounds Chemical class 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000001151 peptidyl group Chemical group 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 230000002685 pulmonary Effects 0.000 description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- WTGCDTYRZPRKIL-MRXNPFEDSA-N (2R)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-naphthalen-2-ylpropanoic acid Chemical compound C1=CC=CC2=CC(C[C@@H](N(C)C(=O)OC(C)(C)C)C(O)=O)=CC=C21 WTGCDTYRZPRKIL-MRXNPFEDSA-N 0.000 description 3
- HRNLPPBUBKMZMT-SSSXJSFTSA-N (2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-aminopropanoyl]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](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](C)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(=O)[C@H](N)C)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 HRNLPPBUBKMZMT-SSSXJSFTSA-N 0.000 description 3
- HAAUASBAIUJHAN-LXOXETEGSA-N (4S)-4-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-(carboxymethylamino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol- Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(O)=O)C1=CN=CN1 HAAUASBAIUJHAN-LXOXETEGSA-N 0.000 description 3
- SXVNAOBGFOYCBT-GQCTYLIASA-N (E)-4-[1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclobutyl]but-2-enoic acid Chemical compound CC(C)(C)OC(=O)NC1(C\C=C\C(O)=O)CCC1 SXVNAOBGFOYCBT-GQCTYLIASA-N 0.000 description 3
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-Hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
- NGHWWOXFYMDOPV-UHFFFAOYSA-N 2-[1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclobutyl]acetic acid Chemical compound CC(C)(C)OC(=O)NC1(CC(O)=O)CCC1 NGHWWOXFYMDOPV-UHFFFAOYSA-N 0.000 description 3
- 102100016549 ANPEP Human genes 0.000 description 3
- 108010064733 Angiotensins Proteins 0.000 description 3
- 102000015427 Angiotensins Human genes 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 108010049990 CD13 Antigens Proteins 0.000 description 3
- LDHQCZJRKDOVOX-NSCUHMNNSA-N Crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 3
- 229940088598 Enzyme Drugs 0.000 description 3
- GMFUEDQBARLAIG-UHFFFAOYSA-N N,N'-di(propan-2-yl)methanediimine;hydrochloride Chemical compound Cl.CC(C)N=C=NC(C)C GMFUEDQBARLAIG-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229960000208 PRALMORELIN Drugs 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 159000000021 acetate salts Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000001684 chronic Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 201000010874 syndrome Diseases 0.000 description 3
- SRFKYSQSLHKPOK-UHFFFAOYSA-N tert-butyl 4-[(dimethylamino)methyl]piperidine-1-carboxylate Chemical compound CN(C)CC1CCN(C(=O)OC(C)(C)C)CC1 SRFKYSQSLHKPOK-UHFFFAOYSA-N 0.000 description 3
- VNOWIHHJPAJYHL-UHFFFAOYSA-N tert-butyl N-(2-methyl-4-oxobutan-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC(C)(C)CC=O VNOWIHHJPAJYHL-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 229960001322 trypsin Drugs 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- 229960003726 vasopressin Drugs 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- ZUSDIXVXKSYBLT-GOSISDBHSA-N (2R)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-(4-phenylphenyl)propanoic acid Chemical compound C1=CC(C[C@@H](N(C)C(=O)OC(C)(C)C)C(O)=O)=CC=C1C1=CC=CC=C1 ZUSDIXVXKSYBLT-GOSISDBHSA-N 0.000 description 2
- GDUBFXWWALXNPA-GFCCVEGCSA-N (2R)-3-(4-fluorophenyl)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound CC(C)(C)OC(=O)N(C)[C@@H](C(O)=O)CC1=CC=C(F)C=C1 GDUBFXWWALXNPA-GFCCVEGCSA-N 0.000 description 2
- WTGBIRGNNDATDA-ZCFIWIBFSA-N (3R)-3-formylpiperidine-1-carboxylic acid Chemical compound OC(=O)N1CCC[C@@H](C=O)C1 WTGBIRGNNDATDA-ZCFIWIBFSA-N 0.000 description 2
- RAMWDJGOOVFUPC-VOTSOKGWSA-N (E)-5-(butoxycarbonylamino)-5-methylhex-2-enoic acid Chemical compound CCCCOC(=O)NC(C)(C)C\C=C\C(O)=O RAMWDJGOOVFUPC-VOTSOKGWSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 2
- FTVFPPFZRRKJIH-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidin-4-amine Chemical compound CC1(C)CC(N)CC(C)(C)N1 FTVFPPFZRRKJIH-UHFFFAOYSA-N 0.000 description 2
- WTGCDTYRZPRKIL-UHFFFAOYSA-N 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-naphthalen-2-ylpropanoic acid Chemical compound C1=CC=CC2=CC(CC(N(C)C(=O)OC(C)(C)C)C(O)=O)=CC=C21 WTGCDTYRZPRKIL-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- MQNHKLMHRZYTBZ-UHFFFAOYSA-N 3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]benzoic acid Chemical compound CC(C)(C)OC(=O)NCC1=CC=CC(C(O)=O)=C1 MQNHKLMHRZYTBZ-UHFFFAOYSA-N 0.000 description 2
- LHJVMOIOTPJSLS-UHFFFAOYSA-N 3-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)NC(C)(C)CC(O)=O LHJVMOIOTPJSLS-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 229940035620 ACTH and synthetic analog preparations Drugs 0.000 description 2
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 2
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 2
- PRKQVKDSMLBJBJ-UHFFFAOYSA-N Ammonium carbonate Chemical compound N.N.OC(O)=O PRKQVKDSMLBJBJ-UHFFFAOYSA-N 0.000 description 2
- 230000036912 Bioavailability Effects 0.000 description 2
- 108090000087 Carboxypeptidase B Proteins 0.000 description 2
- 102000003670 Carboxypeptidase B Human genes 0.000 description 2
- 102000005572 Cathepsin A Human genes 0.000 description 2
- 108010059081 Cathepsin A Proteins 0.000 description 2
- 206010008874 Chronic fatigue syndrome Diseases 0.000 description 2
- 108090000317 Chymotrypsin Proteins 0.000 description 2
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 206010011652 Cushing's syndrome Diseases 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229940110715 ENZYMES FOR TREATMENT OF WOUNDS AND ULCERS Drugs 0.000 description 2
- 102100017551 GHSR Human genes 0.000 description 2
- 101700085209 GHSR Proteins 0.000 description 2
- 229960001031 Glucose Drugs 0.000 description 2
- WZHKXNSOCOQYQX-KAGZITNASA-N Growth hormone releasing hexapeptide 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-KAGZITNASA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 241001622557 Hesperia Species 0.000 description 2
- 210000003016 Hypothalamus Anatomy 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 210000000987 Immune System Anatomy 0.000 description 2
- 206010022489 Insulin resistance Diseases 0.000 description 2
- 210000004080 Milk Anatomy 0.000 description 2
- 210000003205 Muscles Anatomy 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N N,N'-Diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- SWQDHDJAIYSTRF-UHFFFAOYSA-N N,N-dimethyl-1-piperidin-4-ylmethanamine Chemical compound CN(C)CC1CCNCC1 SWQDHDJAIYSTRF-UHFFFAOYSA-N 0.000 description 2
- 101710008205 OXT Proteins 0.000 description 2
- 102100017240 OXT Human genes 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 229960001723 Oxytocin Drugs 0.000 description 2
- XNOPRXBHLZRZKH-DSZYJQQASA-N Oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 2
- 102100010734 PRL Human genes 0.000 description 2
- 108010067372 Pancreatic Elastase Proteins 0.000 description 2
- 102000016387 Pancreatic Elastase Human genes 0.000 description 2
- 210000002381 Plasma Anatomy 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 229940097325 Prolactin Drugs 0.000 description 2
- 108010057464 Prolactin Proteins 0.000 description 2
- 102000005765 Proto-Oncogene Proteins c-akt Human genes 0.000 description 2
- 108010045717 Proto-Oncogene Proteins c-akt Proteins 0.000 description 2
- DNXIASIHZYFFRO-UHFFFAOYSA-N Pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 102000005157 Somatostatin Human genes 0.000 description 2
- 108010056088 Somatostatin Proteins 0.000 description 2
- 229960000553 Somatostatin Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GGUBFICZYGKNTD-UHFFFAOYSA-N Triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 2
- 210000002268 Wool Anatomy 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 230000035514 bioavailability Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 2
- 230000001925 catabolic Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229960002376 chymotrypsin Drugs 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- FEMLEJLXNKJPFL-CMDGGOBGSA-N ethyl (E)-5-methyl-5-[(2-methylpropan-2-yl)oxycarbonylamino]hex-2-enoate Chemical compound CCOC(=O)\C=C\CC(C)(C)NC(=O)OC(C)(C)C FEMLEJLXNKJPFL-CMDGGOBGSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 108010015153 growth hormone releasing hexapeptide Proteins 0.000 description 2
- 229940020899 hematological Enzymes Drugs 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 230000001965 increased Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000002609 media Substances 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 231100000957 no side effect Toxicity 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000003287 optical Effects 0.000 description 2
- 101700057139 oxyT Proteins 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000816 peptidomimetic Substances 0.000 description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 2
- 238000004987 plasma desorption mass spectroscopy Methods 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 229910052761 rare earth metal Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- JGMMNOYMEULLTJ-NSHDSACASA-N tert-butyl (3S)-3-[(dimethylamino)methyl]piperidine-1-carboxylate Chemical compound CN(C)C[C@@H]1CCCN(C(=O)OC(C)(C)C)C1 JGMMNOYMEULLTJ-NSHDSACASA-N 0.000 description 2
- CDFOYUMGBSSYSV-UHFFFAOYSA-N tert-butyl 2-oxo-1-azaspiro[3.3]heptane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(=O)CC11CCC1 CDFOYUMGBSSYSV-UHFFFAOYSA-N 0.000 description 2
- VRVUOIHXJJWKIY-UHFFFAOYSA-N tert-butyl 4-(dimethylcarbamoyl)piperidine-1-carboxylate Chemical compound CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1 VRVUOIHXJJWKIY-UHFFFAOYSA-N 0.000 description 2
- 230000002992 thymic Effects 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- ZENPGVFRMNRSDE-UHFFFAOYSA-N (2-methyl-4-oxopentan-2-yl)carbamic acid Chemical compound CC(=O)CC(C)(C)NC(O)=O ZENPGVFRMNRSDE-UHFFFAOYSA-N 0.000 description 1
- PUSNGFYSTWMJSK-GSZQVNRLSA-N (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan- Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](OC)O[C@@H]1COC.CC(O)CO[C@@H]1[C@@H](OCC(C)O)[C@H](OCC(C)O)[C@@H](COCC(O)C)O[C@H]1O[C@H]1[C@H](OCC(C)O)[C@@H](OCC(C)O)[C@H](OCC(C)O)O[C@@H]1COCC(C)O PUSNGFYSTWMJSK-GSZQVNRLSA-N 0.000 description 1
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
- VIYKYVYAKVNDPS-HKGPVOKGSA-N (2S)-2-azanyl-3-[3,4-bis(oxidanyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 VIYKYVYAKVNDPS-HKGPVOKGSA-N 0.000 description 1
- NXILIHONWRXHFA-MRVPVSSYSA-N (3R)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](C(O)=O)C1 NXILIHONWRXHFA-MRVPVSSYSA-N 0.000 description 1
- VQPXWMYSKOQPPG-IVQLKPQISA-N (E)-5-amino-N-[(2R)-1-[[(2R)-1-(4-hydroxypiperidin-1-yl)-1-oxo-3-phenylpropan-2-yl]-methylamino]-3-naphthalen-2-yl-1-oxopropan-2-yl]-N,5-dimethylhex-2-enamide Chemical compound C([C@@H](N(C)C(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)N(C)C(=O)\C=C\CC(C)(C)N)C(=O)N1CCC(O)CC1)C1=CC=CC=C1 VQPXWMYSKOQPPG-IVQLKPQISA-N 0.000 description 1
- FKMGDDQSZCZCNU-SNAWJCMRSA-N (E)-5-methyl-5-(methylamino)hex-2-enoic acid Chemical compound CNC(C)(C)C\C=C\C(O)=O FKMGDDQSZCZCNU-SNAWJCMRSA-N 0.000 description 1
- 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 1
- ZQEBQGAAWMOMAI-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC1C(O)=O ZQEBQGAAWMOMAI-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical class OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 description 1
- ZUSDIXVXKSYBLT-UHFFFAOYSA-N 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-(4-phenylphenyl)propanoic acid Chemical compound C1=CC(CC(N(C)C(=O)OC(C)(C)C)C(O)=O)=CC=C1C1=CC=CC=C1 ZUSDIXVXKSYBLT-UHFFFAOYSA-N 0.000 description 1
- KMJRESLQULQGKI-UHFFFAOYSA-N 2-oxo-1-azaspiro[3.3]heptane-1-carboxylic acid Chemical compound OC(=O)N1C(=O)CC11CCC1 KMJRESLQULQGKI-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- WKBGXDWFIPYTBR-UHFFFAOYSA-N 3-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]benzoic acid Chemical compound CC(C)(C)OC(=O)N(C)C1=CC=CC(C(O)=O)=C1 WKBGXDWFIPYTBR-UHFFFAOYSA-N 0.000 description 1
- FSPJQCLZFGPHEF-UHFFFAOYSA-N 4-[(dimethylamino)methyl]piperidine-1-carboxylic acid Chemical compound CN(C)CC1CCN(C(O)=O)CC1 FSPJQCLZFGPHEF-UHFFFAOYSA-N 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical group OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 1
- FTHUQCQZQRXJLF-UHFFFAOYSA-N 5-methylhex-2-enoic acid Chemical compound CC(C)CC=CC(O)=O FTHUQCQZQRXJLF-UHFFFAOYSA-N 0.000 description 1
- 101710006356 ACTI Proteins 0.000 description 1
- 101710027066 ALB Proteins 0.000 description 1
- 102100001249 ALB Human genes 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 206010001897 Alzheimer's disease Diseases 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N Ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003549 Asthenia Diseases 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- QBOFHILPWODDAF-AATRIKPKSA-N C(C)OC(\C=C\CC(C)(C)N)=O Chemical compound C(C)OC(\C=C\CC(C)(C)N)=O QBOFHILPWODDAF-AATRIKPKSA-N 0.000 description 1
- SDXBRHDLTKRITC-JKSUJKDBSA-N C(C1=CC=CC=C1)[C@H](C(=O)N1[C@@H](CCC1)CN(C)C)N(C(O)=O)C Chemical compound C(C1=CC=CC=C1)[C@H](C(=O)N1[C@@H](CCC1)CN(C)C)N(C(O)=O)C SDXBRHDLTKRITC-JKSUJKDBSA-N 0.000 description 1
- 101700046715 CSTI Proteins 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 241001247986 Calotropis procera Species 0.000 description 1
- 229940077731 Carbohydrate nutrients Drugs 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 206010007554 Cardiac failure Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000005846 Cardiomyopathy Diseases 0.000 description 1
- 210000000845 Cartilage Anatomy 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N Chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N Cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 206010010149 Complicated fracture Diseases 0.000 description 1
- LMYWWPCAXXPJFF-UHFFFAOYSA-P Cornforth reagent Chemical compound C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O LMYWWPCAXXPJFF-UHFFFAOYSA-P 0.000 description 1
- 206010011401 Crohn's disease Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 101700020566 DEFA4 Proteins 0.000 description 1
- 206010061428 Decreased appetite Diseases 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 229960003957 Dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N Dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 102000019460 EC 4.6.1.1 Human genes 0.000 description 1
- 108060000200 EC 4.6.1.1 Proteins 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000001362 Fetal Growth Retardation Diseases 0.000 description 1
- 206010070531 Foetal growth restriction Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229940065521 Glucocorticoid inhalants for obstructive airway disease Drugs 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- 229940074045 Glyceryl Distearate Drugs 0.000 description 1
- 206010056438 Growth hormone deficiency Diseases 0.000 description 1
- 206010019280 Heart failure Diseases 0.000 description 1
- 206010020100 Hip fracture Diseases 0.000 description 1
- 102000002265 Human Growth Hormone Human genes 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 239000000854 Human Growth Hormone Substances 0.000 description 1
- 206010020610 Hypercorticoidism Diseases 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010021113 Hypothermia Diseases 0.000 description 1
- 101710006353 IP3R Proteins 0.000 description 1
- 101700035656 ISOTI Proteins 0.000 description 1
- 101700035039 ITI Proteins 0.000 description 1
- 101700052013 ITR2 Proteins 0.000 description 1
- 101700068039 ITRP Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102400000022 Insulin-Like Growth Factor II Human genes 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 102000004218 Insulin-like growth factor I Human genes 0.000 description 1
- 108090000723 Insulin-like growth factor I Proteins 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N Isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 101700036939 MTI Proteins 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 230000036650 Metabolic stability Effects 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor family Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor family Proteins 0.000 description 1
- 206010048592 Musculoskeletal disease Diseases 0.000 description 1
- 208000010125 Myocardial Infarction Diseases 0.000 description 1
- FEKRFYZGYUTGRY-UHFFFAOYSA-N N'-ethylmethanediimine Chemical compound CCN=C=N FEKRFYZGYUTGRY-UHFFFAOYSA-N 0.000 description 1
- XRYGCVVVDCEPRL-UHFFFAOYSA-N N,1-dimethylpiperidin-4-amine Chemical compound CNC1CCN(C)CC1 XRYGCVVVDCEPRL-UHFFFAOYSA-N 0.000 description 1
- LFMTUFVYMCDPGY-UHFFFAOYSA-N N,N-diethylethanamine oxide Chemical compound CC[N+]([O-])(CC)CC LFMTUFVYMCDPGY-UHFFFAOYSA-N 0.000 description 1
- QOVQVKFKBHWTAA-MRVPVSSYSA-N N,N-dimethyl-1-[(3R)-piperidin-3-yl]methanamine Chemical compound CN(C)C[C@@H]1CCCNC1 QOVQVKFKBHWTAA-MRVPVSSYSA-N 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- YFJAIURZMRJPDB-UHFFFAOYSA-N N,N-dimethylpiperidin-4-amine Chemical compound CN(C)C1CCNCC1 YFJAIURZMRJPDB-UHFFFAOYSA-N 0.000 description 1
- 208000000713 Nesidioblastosis Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 206010029748 Noonan syndrome Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 230000035536 Oral bioavailability Effects 0.000 description 1
- 208000004286 Osteochondrodysplasias Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000035443 Peptidases Human genes 0.000 description 1
- 108091005771 Peptidases Proteins 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N Phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 210000003635 Pituitary Gland Anatomy 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 201000010769 Prader-Willi syndrome Diseases 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N Pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- LEHBURLTIWGHEM-UHFFFAOYSA-N Pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 1
- 206010038435 Renal failure Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 208000001076 Sarcopenia Diseases 0.000 description 1
- 206010072610 Skeletal dysplasia Diseases 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- 206010040984 Sleep disease Diseases 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N Sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 108010026080 Somatomedins Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 229940037128 Systemic Glucocorticoids Drugs 0.000 description 1
- 101700062451 TI Proteins 0.000 description 1
- 206010043554 Thrombocytopenia Diseases 0.000 description 1
- 206010045181 Turner's syndrome Diseases 0.000 description 1
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 description 1
- 208000009982 Ventricular Dysfunction Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical class [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 201000005255 adrenal gland hyperfunction Diseases 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-N calcium;sulfuric acid Chemical compound [Ca+2].OS(O)(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbamate Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 201000008031 cardiomyopathy Diseases 0.000 description 1
- 230000035569 catabolism Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 201000006233 congestive heart failure Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004980 cyclopropylene group Chemical group 0.000 description 1
- 230000002354 daily Effects 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 230000000994 depressed Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- QFWWKJJQZCWKPL-UHFFFAOYSA-N dithiazine Chemical compound S1SN=CC=C1 QFWWKJJQZCWKPL-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000002283 elective surgery Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- FFLYUXVZEPLMCL-UHFFFAOYSA-N ethylchloranuidyl formate Chemical compound CC[Cl-]OC=O FFLYUXVZEPLMCL-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000004129 fatty acid metabolism Effects 0.000 description 1
- 230000001605 fetal Effects 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000002238 fumaric acids Chemical class 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 108010085742 growth hormone-releasing peptide-2 Proteins 0.000 description 1
- 239000001963 growth media Substances 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000005842 heteroatoms Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- KLGZELKXQMTEMM-UHFFFAOYSA-N hydride Chemical compound [H-] KLGZELKXQMTEMM-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000003451 hyperinsulinaemic Effects 0.000 description 1
- 201000007088 hyperinsulinemic hypoglycemia Diseases 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000002631 hypothermal Effects 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001771 impaired Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- NZTNZPDOBQDOSO-UHFFFAOYSA-N lithium;boron(1-) Chemical compound [Li+].[B-] NZTNZPDOBQDOSO-UHFFFAOYSA-N 0.000 description 1
- 201000009673 liver disease Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- RPHFGEHBXPSYLK-UHFFFAOYSA-N methanamine;dihydrochloride Chemical compound Cl.Cl.NC RPHFGEHBXPSYLK-UHFFFAOYSA-N 0.000 description 1
- QIRVGKYPAOQVNP-UHFFFAOYSA-N methylidenecyclobutane Chemical compound C=C1CCC1 QIRVGKYPAOQVNP-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 125000004957 naphthylene group Chemical group 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 230000000790 osteoblast Effects 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000000541 pulsatile Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000026267 regulation of growth Effects 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000000268 renotropic Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 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
- 230000028327 secretion Effects 0.000 description 1
- 238000002098 selective ion monitoring Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000003860 sleep quality Effects 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CNVUYXYLHUYWKR-JTQLQIEISA-N tert-butyl (2S)-2-[(dimethylamino)methyl]pyrrolidine-1-carboxylate Chemical compound CN(C)C[C@@H]1CCCN1C(=O)OC(C)(C)C CNVUYXYLHUYWKR-JTQLQIEISA-N 0.000 description 1
- YDBPZCVWPFMBDH-QMMMGPOBSA-N tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C=O YDBPZCVWPFMBDH-QMMMGPOBSA-N 0.000 description 1
- CTVHINDANRPFIL-SECBINFHSA-N tert-butyl (3R)-3-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1 CTVHINDANRPFIL-SECBINFHSA-N 0.000 description 1
- RFIBKTPXDQMOPZ-VQTJNVASSA-N tert-butyl N-[(2R)-1-[(3S)-3-[(dimethylamino)methyl]piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-N-methylcarbamate Chemical compound C1[C@H](CN(C)C)CCCN1C(=O)[C@H](N(C)C(=O)OC(C)(C)C)CC1=CC=CC=C1 RFIBKTPXDQMOPZ-VQTJNVASSA-N 0.000 description 1
- ZYICIRQFYBWSJH-HXUWFJFHSA-N tert-butyl N-[(2R)-1-[4-[(dimethylamino)methyl]piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-N-methylcarbamate Chemical compound C1CC(CN(C)C)CCN1C(=O)[C@H](N(C)C(=O)OC(C)(C)C)CC1=CC=CC=C1 ZYICIRQFYBWSJH-HXUWFJFHSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- BSUNTQCMCCQSQH-UHFFFAOYSA-N triazine Chemical compound C1=CN=NN=C1.C1=CN=NN=C1 BSUNTQCMCCQSQH-UHFFFAOYSA-N 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Abstract
The invention relates to novel compounds, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.
Description
COMPOUNDS WITH GROWTH HORMONES RELEASE ISSUES
FIELD OF THE INVENTION
The present invention concerns new compounds, compositions thereof, and their use for the medical treatment of disorders that are a consequence of a deficiency in growth hormone.
BACKGROUND OF THE INVENTION
Growth hormone is a hormone that stimulates the growth of all tissues that can grow. In addition, it is known that growth hormone has a number of effects on metabolic processes, for example, the stimulation of protein synthesis and the mobilization of free fatty acids and cause an interruption in the energy metabolism of carbohydrates for fatty acid metabolism. Growth hormone deficiency can cause a number of severe medical disorders, such as dwarfism.
REF. 125646 Growth hormone is released from the pituitary. The release is under close control of a number of hormones and neurotransmitters either directly or indirectly. The release of growth hormone can be stimulated by the hormone of growth that releases the hormone (GHRH) and is inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily by specific receptors located in the pituitary. Other compounds that stimulate the release of growth hormone from the pituitary have also been described. For example, arginine, L-3,4-dihydroxyphenylalanine (L-dopa), glucagon, vasopressin, PACAP (peptide that activates adenylyl cyclase of the pituitary), muscarinic receptor agonists and a synthetic hexapeptide, GHRP (peptide-releasing growth hormone) release endogenous growth hormones either by a direct effect on the pituitary or by affecting the release of GR. and / or somatostatin from the hypothalamus.
In disorders or conditions where it is desired to increase the levels of growth hormone, the nature of the growth hormone protein does something but parenteral administration is not viable.
- .--- »- > for example, GR. and PACAP, are longer polypeptides for which parenteral administration is reasonably preferred.
The use of certain compounds to increase levels of growth hormone in mammals has been previously proposed, for example in EP 18 072, EP 83 864, WO 8302272, WO 8907110, WO 8901711, WO 8910933, WO 8809780, WO 9118016, WO 9201711, WO 9304081, WO 9413696, WO 9517423, WO 9514666, WO 9515148, WO 9622997, WO 9635713, WO 9700894, WO 9722620, WO 9723508, WO 9740023, and WO 9810653.
The composition of the compounds that release growth hormone is important because of its growth hormone release potency as well as its bioavailability, however, it is an object of the present invention to provide new compounds with hormone releasing properties. increase. Furthermore, it is an object to provide new compounds that release growth hormone (growth hormone secretagogues) that are specific and / or selective and have no or substantially no side effects, such as, for example, the release of LH, FSH. , TSH, ACTH, vasopressin, oxytocin, cortisol and / or prolactin. It is also an object to provide compounds that have good oral bioavailability.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention provide compounds that act directly on the pituitary cells under normal experimental conditions in vi tro to release the growth hormones thereof.
These compounds that release growth hormone can be used as the only research tool to understand, inter alia, how growth hormone secretion is regulated at the level of the pituitary.
In addition, the growth hormone releasing compounds of the present invention can also be administered in vivo to increase the release of endogenous growth hormone.
DESCRIPTION OF THE INVENTION Accordingly, the present invention concerns a compound of the general formula I
Formula I wherein R 1 is hydrogen or C 6 alkyl; R ~ is hydrogen or Ci-e alkyl; L is
wherein R 4 is hydrogen or C 6 alkyl; p is 0 or 1;
_ ^ __ ^ _ d_dl ^^ aui_ q, s, t, u, are independently of each other 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum of q + r + s + t + u is 0, 1, 2, 3, or 4;
R9, R10, R11, and R12 are independently of each other, hydrogen or C? -6 alkyl;
where o is 0 or 2;
T is -N (R15) (R16) or hydroxyl;
R13, R15 and R16 are each independently of the other hydrogen or C? -6 alkyl;
R is hydrogen, aryl or hetaryl;
• M rfüÉtait. ^ ÉMkÍkM.WM G is -O- (CHz '-R1
wherein R17, R18, R19, R20 and R21 independently of each other are hydrogen, halogen, aryl, hetaryl, Ci-e-alkyl or C6-6-alkoxy;
k is 0, 1 or 2;
j is -0- (CH2)? - R22,
wherein R22, R23, R24, R25 and R26 independently of each other are hydrogen, halogen, aryl, hetaryl, C6-6-alkyl or C6-alkoxy;
1 is O, 1 or 2;
a is 0, 1, or 2;
b is O, 1, or 2;
c is 0, 1, or 2;
d is O or 1;
e is O, 1, 2, or 3;
f is O or 1;
R5 is hydrogen or C6-6-alkyl optionally substituted with one or more hydroxyls, aryls or hetaryls;
R6 and R7 are independently each other hydrogen or C? -6-alkyl, optionally substituted with one or more halogens, hydroxyl, aryl, or hetaryl;
R8 is hydrogen or C6-alkyl-alkyl, optionally substituted with one or more halogens, amines, hydroxyl, aryl, or hetaryl;
R6 and R7 or R5 and R8 or R7 and R8 can optionally form
- (CH2) i-U- (CH2) 1 -, where i and j independently of each other are 1, 2 or 3 and U is -0-, -S-, or a valence bond;
M is arylene, hetherylene, -0-, -S-, or -CR2 = CR26-,
R27 and R28 are independently each other hydrogen or C6-alkyl, optionally substituted with one or more aryls or hetaryls; or a pharmaceutically acceptable salt thereof.
In addition, the compounds of formula I can comprise any optical isomer thereof, in the form of racemic mixtures or separate, pure or partially purified optical isomers thereof. Each time one or more chiral carbon atoms are present such a chiral center or center may be in the R- and / or S configuration, or a mixture of R and S.
Furthermore, the compounds of formula I may have one or more carbon-carbon double bonds with the possibility of geometric isomerism, and it is intended to include possible stereoisomers (E or Z isomers) within the scope of the invention, unless a geometric isomer is specified special.
In one embodiment of the compound of formula I, R "is Ci -? - alkyl, such as C? -4-alkyl, in particular methyl In a second embodiment R1 is hydrogen.
In a further embodiment of the compound of formula I, R2 is C1_6-alkyl, such as C1"4-alkyl, in particular methyl,
In yet a further embodiment of the compound of formula I, L is
wherein R is hydrogen or C? _4 alkyl;
p is 0 or 1;
. , i i, .. .. . .. .. .. ^. . . . .. .... »Q, s, t, u are independently of each other 0, 1, 2, 3 or 4;
r is 0 or 1;
The sum of q + r + s + t + u is O, 1, 2, 3, 6 4;
R9, R10, R11, and R12 are each independently of the other hydrogen or C? -alkyl;
, 14 / ^ "
where o is 0, 1 or 2; T is -N (R15) (R16) or hydroxyl; R13, R15, and R16 are independently of each other hydrogen or C6-alkyl; R14 is hydrogen, aryl or hetaryl. In an R4 mode it is hydrogen. In a second embodiment R4 is C? -6-alkyl, such as C? -4-alkyl, in particular methyl. In a third mode p is 0. In an additional mode q is 0. In still an additional mode q is 1. In an additional mode s is 0. In yet an additional mode s is 1. in
I? A ^ to ^ ita? U¿¿ta ^ _M_1_ ^ mH _ ^ __ ^^^^^^^^^^^^ atert an additional modality t is 0. In an additional modality t is 1. in a modality additional u is 0. In yet an additional mode u is 1. In an additional mode r is 0. In still an additional mode r is 1. In a further 5 mode R9 is hydrogen. In yet a further embodiment R9 is C? -6-alkyl, in particular methyl. In an additional mode Rio is hydrogen. In yet a further embodiment R10 is C? -e-alkyl, such as CL-4_alkyl, in particular methyl. In an additional mode R11 is
hydrogen. In still an additional embodiment R11 is C? _5-alkyl, such as C? -4-alkyl, in particular methyl. In an additional embodiment R12 is hydrogen. In still an additional embodiment R12 is Ci-β-alkyl, such as Ci-4-alkyl, in particular methyl. In an additional mode Q is > N-R13.
in still an additional embodiment R13 is hydrogen. In an additional embodiment R 13 is C 6 -alkyl, such as C 4 -alkyl, in particular methyl. In still an additional mode Q is,
In still an additional embodiment R14 is hetaryl, in particular triazolyl. In an additional mode R14 is
hydrogen. In still an additional modality or is 0. In a
"Saw. ???? > ? i-aiti I i li l 1- i I additional mode or is 1. In yet an additional mode T is hydroxyl. In an additional embodiment T is N (R15) (R16). In yet a further embodiment R 15 is C 4 -4 alkyl, such as C 4 -4 alkyl, in particular methyl. In a further embodiment Rld is C? -6-alkyl, such as C? -4-alkyl, in particular methyl.
In a further embodiment of the compound of formula I, L is
where q, s, t, u independently of each other are 0, 1, 2, 3 or 4; r is 0 or 1; the sum of q + r + s + t + u is 0, 1, 2, 3, or 4; R9, R10, R11, and R12 are each independently of the other hydrogen or C6-6 alkyl; Q is > N-R13 or
where o is 0, 1, or 2; T is -N (R15) (R16) or hydroxyl; R13, R15, and R16 are independently of each other hydrogen or C6-alkyl; R14 is hydrogen, aryl or hetaryl. In a modality q is 0. In a second modality q is 1. in a third modality s is 0. In an additional modality t is 1. In still an additional modality u is 0. In an additional modality u is 1. in still an additional modality r is 0. in an additional modality r is 1. In still an additional modality
R9 is hydrogen. In still an additional embodiment R '* is C? -6-alkyl, such as C? -alkyl, in particular methyl. In an additional embodiment R10 is hydrogen. In yet a further embodiment R 10 is C 6 -alkyl, such as C 4 -4 -alkyl, in particular methyl. In an additional embodiment R11 is hydrogen. In still an additional embodiment R 11 is C 6 -alkyl, such as C 4 -4 -alkyl, in particular methyl. In an additional embodiment R12 is hydrogen. In still an additional embodiment R12 is C? -6-alkyl, such as C? -4-alkyl, in particular methyl. In an additional mode Q is > N-R13.
In still an additional embodiment R 13 is hydrogen. In yet an additional embodiment R 13 is C 4 -4 alkyl, such as C 1-4 alkyl, in particular methyl. In an additional mode Q is
In an additional embodiment R14 is hetaryl, in particular thiazolyl. In an additional embodiment R14 is hydrogen. In still an additional mode or it is 0. in an additional mode or it is 1. In yet an additional mode Y is hydroxyl. In an additional embodiment T is N (R15) (R16). In yet a further embodiment R15 is C? -6-alkyl, such as C? _4-alkyl, in particular methyl. In a further embodiment Rld is C? _6 -alkyl, such as C? -alkyl, in particular methyl.
In the compound of formula I above, L is preferably 4-hydroxy-4- (2-thienyl) piperidino, (3-hydroxycyclohexy) amino, 4- (N, N-dimethylamino) piperidino, N-methyl-N- ( l-methylpiperidin-4-yl) amino), 4- ((N, N-dimethylamino) methyl) piperidino, 4-methylpiperazino, (2,2,6,6-tetra-methylpiperidin-4-yl) amino, 4- hydroxypiperidino, (3S) -3- ((N, N-dimethylamino) methyl) -piperidino, (2S) -2- ((N, N-dimethylamino) methyl) pyrrolidino.
In yet one embodiment of the compound of formula I, G is
wherein R17, R18, R19, R20 and R21 independently of each other are hydrogen, halogen, aryl, hetaryl, C? -6-alkyl or C? -6-alkoxy. In an R17 mode it is hydrogen. In a second embodiment R18 is hydrogen. In a third embodiment R19 is hydrogen. In an additional embodiment R19 is aryl, in particular phenyl. In still an additional embodiment R20 is hydrogen. In an additional embodiment R21 is hydrogen. In the compound of formula I above, G is preferably 2-naphthyl or biphenyl-4-yl. In a further embodiment of the compound of formula I, J is 1.
wherein R22, R23, R24, R25 and R26 independently of each other are hydrogen, halogen, aryl, hetaryl, C6-alkyl or C6-alkoxy. In an R22 mode it is hydrogen.
riH! MatMaÍiá¿IÉMIIA¿Í In a second modality R22 is hydrogen. In a third mode R24 is hydrogen. In a further embodiment R ~ "is halogen, in particular fluorine, In yet a further embodiment R25 is hydrogen In an additional embodiment R2" is hydrogen In the compound of formula I above, J is preferably phenyl, 4-fluoro- phenyl or 2-thienyl.
In yet a further embodiment of the compound of formula I, a is 1.
In a further embodiment of the compound of formula I, b is 1.
In yet a further embodiment of the compound of formula I, c is 0.
In a further embodiment of the compound of formula I, d is 0.
In yet a further embodiment of the compound of formula I, M is arylene or -CR27 = CR28, wherein R27 and R28 are independently each other hydrogen or C6-6alkyl, optionally substituted with aryl or hetaryl. In an M mode it is arylene, in particular phenylene. In another mode M is -CR27 = CR28-, where R27 and R28 are
. < . .....,. ,. *,. i. . ... .. ...... .. ^, ... ... - ir-rn1 > tr »MIT independently hydrogen or Ci-e-alkyl. In an additional embodiment R27 is hydrogen. In yet a further embodiment R 27 is C 6 -alkyl, in particular methyl. In an additional embodiment R28 is hydrogen. In a further embodiment M is the E-isomer of -CR "7 = CR28 In the compound of formula I above, M is preferably ethenylene, 1,3-phenylene or 1,2-propenylene.
In a further embodiment of the compound of formula I, e is 0.
In yet a further embodiment of the compound of formula I, e is 1.
In a further embodiment of the compound of formula I, f is 0.
In yet a further embodiment of the compound of formula I, f is 1.
In a further embodiment of the compound of formula I, R6 and R7 are each independently of the other hydrogen or C6-alkyl. In an R6 mode it is hydrogen. In a second embodiment R6 is C? _6-alkyl, in particular methyl.
In a third mode R is hydrogen. In a further embodiment R7 is C6-6-alkyl, in particular methyl.
In yet an additional form of the compound of
Formula I, RD and R7 or Rd and R8 or R7 and R8 can optionally form - (CH2) iU- (CH2) j-, where i and j independently of each other are 1 or 2 and U is -0-, - S- or a valence link.
In a further embodiment of the compound of formula I, R6 and R7 form - (CH2) iU- (CH2) j-, where i and j independently of each other are 1, 2 or 3 and U is -0-, -S -, or a valence link. In a modality the sum i + j is 3. In a second mode U is a link of
valencia. In a particular embodiment (CR6R7) it is cyclobutyl.
In yet one embodiment of the compound of formula I, R6 and R7 form - (CH2) ± -U- (CH2) j-, where i and j independently of each other are 1 and U is -0-, -S-, or a valence link. In one modality the sum i + j is 3. In a second mode U is a valence bond. In a particular embodiment (CR6R7Jes cyclobutyl.
* "- -" »- - * w *« w- In a further embodiment of the compound of formula I, R6 is hydrogen. In a second embodiment R8 is d-6-alkyl, in particular methyl.
In a special embodiment, the present invention concerns a compound of the general formula I
formula I
where
R1 is hydrogen or C6-alkyl-alkyl;
R is Ci-e-alkyl;
L is
wherein R4 is hydrogen or Ci-o-alkyl;
p is 0 or 1;
q, s, t, u are independently of each other 0, 1, 2, 3 or 4;
r is 0 or 1;
the sum q + r + s + t + u is O, 1, 2, 3, or 4;
R9, R10, R11, and R12 are each independently of the other hydrogen or C6-6-alkyl;
Q is > N-R13 or
£ 14"
where o is 0, 1 or 2;
T is -N (R15) (R16) or hydroxyl;
R13, R15, and R16 are independently each other hydrogen or C6-alkyl;
R14 is hydrogen, aryl or hetaryl;
G is
Wherein R17, R18, R19, R20 and R21 independently of each other are hydrogen, halogen, aryl, hetaryl, C? -6-alkyl or C? -6-alkoxy;
J is
Wherein R22, R23, R, R25 and R26 independently of each other are hydrogen, halogen, aryl, hetaryl, C? 6-alkyl or C? -6-alkoxy;
a is 0, 1, or 2; 25
- ** «* -" - - *** • ^^ kal ^ dtaÉl? Mte b is 0, 1, or 2;
c is 0, 1 or 2;
d is 0 or 1;
e is 0, 1, 2 or 3;
f is 0 or 1;
R5 is hydrogen or C? -6-alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl,
R6 and R7 are independently each other hydrogen or C6-6 alkyl, optionally substituted with one or more halogens, amines, hydroxyl, aryl, or hetaryl;
R8 is hydrogen or Ci-e-alkyl, optionally substituted with one or more halogens, amines, hydroxyl, aryl, or hetaryl;
R6 and R7 or R6 and R8 or R7 and R8 can optionally form - (CH2) iU- (CH2) -, -, where i and j independently of each other are 1, 2 or 3 and U is -O-, -S -, or a valence link;
"Aa? KkM ^ t M is arylene or -CR27 = CR28-;
R2 / and R28 are independently each other hydrogen or C? -e-alkyl, optionally substituted with one or more aryls or hetaryls; or a pharmaceutically acceptable salt thereof.
Preferred compounds of formula I of the invention 10 are:
N- ((lR) -l- {N - [(lR) -l-benzyl-2- (4- ((dimethylamino) -methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl ] -2- (2-A) -5-amino-5-methylhex-2-enoic acid (2-naphthyl) ethyl) -N-methylamide.
N- ((1R) -l- {N - [(1R) -l-benzyl-2- ((3S) -3- (di-ethyl-aminomethyl) piperidin-1-yl) -2-oxoethyl]] -N-methylcabamoyl.} -2-
ÜH ^ m¡ ^ m ^^^^^^^ ía ~ ^ - ^^^^^^^^^ - * -f * ^^ * á *? M (2-naphthyl) ethyl) -N-methylamide (2E) -5-amino-5-methylhex-2-enoic acid
N- ((IR) -1- {N - [(1R) -l-benzyl-2- ((3S) -3- (dimethyl-aminomethyl) piperidin-1-yl) 2-oxoethyl] -N- Methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methyl-amide of (2 E) -4- (the inociclobutyl) but-2-enoic acid
N- ((IR) -1- ( {N- [(IR) -l-benzyl-2- ((2S) -2- (dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] - N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-methylhex-2-enoic acid
N- ((1R) -l- {N - [(1R) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] - N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methyl-3- ((methylamino) methyl) benzamide
N- ((1R) -l- {N - [(1R) -l-benzyl-2- (4- (dimethyl-1-amino) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid
*
N-methyl-N - [(lR) -1- (N-methyl-N- { (IR) -l- [N-methyl-N- (1-methylpiperidin-4-yl) carbamoyl] -2- (2E) -5-amino-5-methylhex-2-enoic acid phenylethyl.}. carbamoyl) -2- (2-naphyl) ethyl] amide
3-aminomethyl-N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4-methyl-piperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl}. -2- (2-naphthyl) ethyl) -N-methylbenzamide
N- ((IR) -1- {N-- (IR) -l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- ( 2-naphthyl) ethyl) -N-methylamide
(2E) -5-amino-5-methylhex-2-enoic acid
N-methyl-N- ((1R) -1- (N-methyl-N- [(IR) -2-pheni Ll- ((2,2,6,6-tetramethylpiperidin-4-yl) carbamoyl) ethyl ] (2E) -5-amino-5-methylhex-2-enoic acid carbamoyl.) -2- (2-naphthyl) ethyl) amide
Hl riÉari i.Al ^
3-aminomethyl-N-methyl-N- ((IR) l- {N-methyl-N- [(IR) -2- phenyl-1- ((2,6,6,6-tetramethyl-piperidine) -4-yl) carbamoyl) ethyl] carbamoyl.} -2- (2-naphthyl) ethyl) benzamide
twenty
N-methyl-N- ((IR) -l- { N-methyl-N- [(IR) -2-phenyl-1- ((2,2,6,6-tetramethylpiperidin-4-yl) carbamoyl) ) ethyl] carbamoyl.} - (2E) -5-amino-25 3,5-dimethylhex-2-enoic acid 2- (2-naphthyl) ethylamide
lililí III llÉJ ililMi ll «lltll lll áÉEMIÍÍl > I
N- ((IR) 1- {N - [(1R) l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2- Naphthyl) ethyl) -Is-methylamide of (2E) -4- (1-aminocyclobutyl) but-2-enoic acid
N- ((IR) 1- {N - [(1R) l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2- Naphthyl) ethyl) -N-methylamide of (2E) -5-amino-3,5-dimethylhex-2-enoic acid
. ^^^^^ ?? ^? iMm ^
N- ((1R) -1-. {N - [(1 R) -l-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl}. 2- (Biphenyl-4-yl) ethyl) -N-methylamide of (2 E) -4- (1-aminocyclobutyl) but-2-enoic acid
0 N- ((IR) -l- {N- [(IR) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2E) -5-amino-5-methylhex-2-enoic acid (biphenyl-4-yl) ethyl-N-methylamide
.? uß im¿ ^
N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2E) -5-amino-3,5-dimethylhex-2-enoic acid (biphenyl-4-yl) ethyl) -N-methylamide
^ ^ Jjfe ^^ j ^^^^ N- ((IR) -1- { N-- (IR) -l-benzyl-2- (4-hydroxy.piperidin-1-yl) -2- oxoethyl] -methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid
N- ((1R) -l- {N - [(1R) -l-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl) -2- ( 2-Naphthyl) ethyl) -N-methylamide of (2E) -5-amino-3,5-dimethylhex-2-enoic acid
N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2 - (2-E) -4- (1-aminocyclobutyl) but-2-enoic acid (2-naphthyl) ethyl) -N-methylamide
N- ((IR) -l- { N- [(IR) -1- (4-f luorobenzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl 2 (2E) -5-amino-5-methylhex-2-enoic acid (2-naphthyl) ethyl) -N-methylamide
N- ((IR) -1- {N - [(1R) -1- (4-fluorobenzyl) -2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl) -2 (21) -5-amino-3,5-dimethylhex-2-enoic acid (2-naphthyl) ethyl) -N-methylamide
N- ((IR) -1- {N [(1R) -l-benzyl-2- (4-hydroxy-4- (2-thienyl) piperidin-1-yl) -2-oxoethyl] -N- Methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2 E) -5-amino-methylhex-2-enoic acid
i • taMüiikiiBAaÉ iii N- ((IR) -1- { N - [(1R) -1- (3-hydroxycyclohexyl-carbamoyl) -2-phenylethyl] -N-methylcarbamoyl.} -2- (2- naf til) ethyl) -N-methylamide of 2-e) -5-amino-5-methylhex-2-enoic acid
N- (IR) -l-. { N- [(IR) -l-Benzyl-2- (4- (dimethylamino) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-naphthyl-ethyl) -N-methylamide of L (2E) -4- (l-aminocyclobutyl) but-2-enoic acid
N- ((1R) -l- {N - [(2R) -2- (4-hydroxypiperidin-1-yl) -2-oxo-1- ((2-thienyl) methyl) ethyl] -N- Methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid
N- ((IR) -l- {N- [(2R) -2- (4-hydroxypiperidin-1-yl) -2-oxo-1- ((2-thienyl) methyl) ethyl] -N- Methylcarbamoyl] -2- (2- (2-naphthyl) ethyl-N-methylamide of (2 E) -5-amino-3,5-dimethylhex-2-enoic acid
N- ((IR) -2- (biphenyl-4-yl) -1- {N - [(2R) -2- (4-hydrox? -piperidin-1-yl) -2-oxo-l- ((2-thienyl) methyl) ethyl] | -N-methylcarbamoyl.} Ethyl) -N-methylamide of (2E) -5-ammo-5-methylhex-2-enoic acid
N- ((IR) -2- (biphenyl-4-yl) -1- { N - [(1R) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-l- (( 2-thienyl) methyl 1) ethyl] -N-methylcarbamoyl.} Ethyl) -N-methylamide of (2E) -5-amino-3,5-dimethylhex-2-enoic acid
^ g ^^^ jífe ^ N- ((1R9-1- { N - [(1R) -l-benzyl-2- (4-hydroxypiperidin-l-yl) -2-oxoethyl] -N-oxoethyl ] -N-methylcarbamoyl.} -2- (biphenyl-4-yl) ethyl) -N-methylamide of (2E) -5-methyl-5- (methylamino) ex-2-enoic acid
((IR) -l- {N- [(IR) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (biphenyl-) 4-yl) ethyl) (2E) -4- (1-aminocyclobutyl) ut-2-enoic acid amide
and pharmaceutically acceptable salts thereof General Methods
The methods illustrated in the following schemes I-III are not intended to limit the present invention in some aspect, but are only as a guide to how the present compounds were prepared.
Scheme I
ra 15
Amines of the type
can be synthesized from an amino acid protected by
BOC (see diagram I). The acid is converted to an ester by reaction with or without a reagent such as, for example, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, or 3-hydroxy-1,2,3-benzotriazole-4- (3H) -ketone. and a reagent such as for example N- (3-dimethylaminopropyl) -15 N'-ethylcarbodiimide or diisopropylcarbodiimide hydrochloride and a catalyst such as N, N-dimethylaminopyridine. The ester can be reproduced by a suitable reagent, such as diisobutyl aluminum hydride in an appropriate solvent such as for example toluene, dichloromethane, ether, or
tetrahydrofuran to give the alcohol or the aldehyde protected by BOC. If the alcohol is obtained, the alcohol can be oxidized to the corresponding aldehyde, by a suitable method, such as for example dimethylsulfoxide / oxalyl chloride / triethylamine or dimethylsulfoxide / sulfothioxide /
pyridine, pyridinium dichromate, or chlorochromate
pyridinium. A reductive amination with an appropriate amine (N (R15) (Rld) and a suitable reagent, such as sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent such as for example alcohols can result in the BOC-protected amine. at least one of R15 or Rxo is hydrogen, the amino group can be protected by a method known to those skilled in the art and described in the literature as for example TW Greene, PGM Wuts Protective Groups in Organic Synthesis, 2nd Ed., Wiley, New York, before carrying out the following steps The removal of the BOC protection group can be accomplished by a method known to those skilled in the art as described in TW Greene, PGM Wuts Protective Groups in Organic Synthesis, 2a. Ed. Wiley, New York, such as, for example, hydrogen chloride in ethyl acetate, or trifluoroacetic acid in dichloromethane.
Scheme II
group
c
coupling conditions 2-) undrotection
Compounds of the type of formula I can be synthesized by coupling an amine of type
and a suitable protected acid with or without an assembly reagent such as for example 1-hydroxy-benzotriazole, l-hydroxy-7-azabenzotriazole, or 3-hydroxy-1,2,3-benzotriazole-4- (3H) -ketone and a reagent such as for example N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide or diisopropylcarbodiimide hydrochloride in a suitable solvent, such as N, N-dimethylformamide or dichloromethane (see Scheme II). The product can be deprotected in the nitrogen of the acid by a method known to those skilled in the art and described in the literature for example in T. W. Greene, P.M. Wuts Protectives groups in organic synthesis, 2a. Ed. Wiley, New York. The product is coupled with a suitable protected acid with or without a tai coupling reagent such as for example 1-hydroxybenzotriazole, l-hydroxy-7-azabenzotriazole, or 3-hydroxy-1,2,3-benzotriazole-4 (3H) - ketone and a reagent such as N- (3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride in a suitable solvent, such as N, N-dimethylformamide or dichloromethane.) The product can be deprotected in the nitrogen of the acid by a method known to the skilled artisan. In the material described in the literature for example in TW Greene, PGM Wuts Protective groups in organic synthesis, 2nd Ed. Wiley, New York The product is coupled with a suitable protected acid with or without a coupling reagent such as for example
-hydroxybenzotriazole, l-hydroxy-7-azabenzotriazole, or 3-hydroxy-1,2,3-benzotriazole-4- (3H) -ketone and a reagent such as N- (3-dimethylaminopropyl) -N 'hydrochloride - ethylcarbodiimide or diisopropylcarbodiimide in a suitable solvent, such as N, N-dimethylformamide or dichloromethane.
All protection groups can be eliminated by methods known to those skilled in the art and described in the literature for example in T.W. Greene, P. G. M. Wuts Protective groups in organic synthesis, 2a. Ed., Wiley, New York. twenty
- "" iar '~ - * "- 1- Scheme III
coupling conditions 2.) deprotection
Compounds of the type of formula I can be synthesized by coupling an amine of type
and a suitable protected acid with or without a coupling reagent such as for example 1-hydroxy-benzotriazole, 1-hydroxy-7-azabenzotriazoi, or 3-hydroxy-1,2,3-benzotriazole-4 (3H) -ketone and a reagent such as N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide or diisopropylcarbodiimide hydrochloride in a suitable solvent, such as N, N-dimethylformamide or dichloromethane (see scheme III). The product can be deprotected in the nitrous oxide of the acid by a method known to those skilled in the art and described in the literature for example in T. W. Greene, P. G. M. Wuts Protective groups m organic synthesis, 2a. Ed. Wiley, New York. The product is coupled with a suitable protected acid with or without a coupling agent such as for example 1-hydroxybenzotriazole, l-hydroxy-7-azabenzotriazole, or 3-hydroxy-1,2,3-benzotriazole-4 (3H) - ketone and a reagent such as for example N- (3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride in a suitable solvent, such as N, N-dimethylformamide or dichloromethane.) The product can be deprotected in the nitrogen of the acid by a method known to those skilled in the art and described in the literature for example in TW Greene, PGM Wuts Protective groups in organic synthesis, 2nd Ed., Wiley, New York.The product is coupled with a suitable protected acid with or without reagent of tai coupling such as for example 1-hydroxybenzotriazole, l-hydroxy-7-azabenzotriazole, or 3-hydroxy-1,2,3-benzotriazole-4 (3H) -ketone and a reagent such as for example N- (3-hydrochloride) -dimethylaminopropyl) -N'-ethylcarbodiimide or diisopropylcarbodiimide in a suitable solvent, such as
N, N-dimethylformamide or dichloromethane. All protective groups can be eliminated by a method known to a person skilled in the art and described in the literature for example in T.W. Greene, P.G.M. Wuts Protective groups in organic synthesis, 2a. Ed. Wiley, New York.
The compounds of formula I exhibit enhanced proteolytic degradation by enzymes because they are not natural, in particular because the natural amide bonds are replaced by non-natural non-natural amide bonds. The increased resistance for proteolytic degradation of the compounds of the invention compared to hormone-releasing peptides is expected to improve in their bioavailability as compared to that of the peptides suggested in the prior literature.
In the above structural formulas and in the course of the present specification, the following terms have the meanings indicated:
The C? -S-alkyl, C? -6-alkylene, Ci-j-alkyl or C? -4-alkylene groups specified above are intended to include the alkyl or alkylene groups of the indicated length in either a linear configuration, branched or cyclical. Examples of linear alkyls are methyl, ethyl, propyl, butyl, pentyl, and hexyl and their corresponding divalent moieties, such as ethylene. Examples of branched alkyls are isopropyl, sec-butyl, tertbutyl, isopentyl, and isohexyl and their corresponding divalent moieties, such as isopropylene. Examples of cyclic alkyls are C-6-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their corresponding divalent moieties, such as cyclopropylene.
The C? _6-alkoxy groups specified above are intended to include alkoxy groups of the indicated length in either a straight, branched or cyclic configuration. Examples of linear alkoxies are methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy. Examples of branched alkoxies are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cyclic alkoxies are C3-6-cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
In the present context, the term "aryl" is intended to include monovalent carboxylic aromatic ring portions, which are either monocyclic, bicyclic or polycyclic, for example, selected from the group consisting of phenyl and naphthyl, optionally substituted with one or more C? 6-alkyl, C? _6-alkoxy, halogen, amino or aryl.
In the present context, the term "arylene" is intended to include divalent carboxylic aromatic ring moieties, which are either monocyclic, bicyclic or polycyclic, for example, selected from the group consisting of phenylene and naphthylene, optionally substituted with one or more C ? -6-alkyl, C? -6-alkoxy, halogen, amino or aryl.
In the present context, the term "hetaryl" is intended to include monovalent heterocyclic aromatic ring moieties, which are either monocyclic, bicyclic or polycyclic, selected from the group consisting of pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl, indolyl, pyrimidyl, thiadiazolyl, pyrazolyl, oxalyl, isoxazolyl, oxadiazolyl, thienyl, quinolinyl, pyrazinyl, or isothiazolyl, optionally substituted with one or more C? -s-alkyl, de-alkoxy, halogen, amino or aryl.
In the present context, the term "heteroarylene" is intended to include divalent heterocyclic aromatic ring moieties, either monocyclic, bicyclic or polycyclic, for example, selected from the group consisting of pyridienyl, 1-H-tetrazoldiyl, thiazoldiyl, imidazoldiyl, indoldiyl. , pyrimidindiyl, thiazoldiyl, pyrazoldiyl, oxazoldiyl, isoxazoldiyl, oxadiazoldiyl, thiofendiyl, quinolindiyl, pyrazindiyl, or isothiazoldiyl, optionally substituted with one or more C? _6-alkyl, C? _6-alkoxy, halogen, amino or aryl.
In the present context, the term "heterocyclic system" is intended to include aromatic as well as non-aromatic ring portions, which may be monocyclic, bicyclic or polycyclic, and
t,,.,.,.,., contain in their annular structure at least one, of which one, two, or three nitrogen atoms, and optionally one or more of which one or two, are different of heteroatoms, the heterocyclic siet is preferably selected from pyrazole, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine, pyrazoline, aziridine, dithiazine, pyrro !, imidazole, pyrazole, isoindole, indole, indazole, purine, pyrrolidine, imidazolidine, i idazoline, pyrazolidine, pyrazoline, piperidine, piperazine, indoline, isoindoline, or morpholine, optionally substituted with one or more C? -6-alkyl, C? -6-alkoxy, halogen, amino, oxy or aryl.
The term "halogen" is intended to include chlorine (Cl), fluorine (F), bromine (Br) and iodine (I).
In the context of the present application, the term "growth hormone secretagogue" is intended to include any compound that has the ability, directly or indirectly, to induce (e.g., stimulate or increase) the release of the hormone. of the growth of the pituitary gland. The term "growth hormone secretagogue" 1 includes peptides that release growth hormone, peptide mimetics that release the
Growth hormone, and compounds that release growth hormone of a non-peptidyl nature.
The compounds of the present invention can optionally be in a pharmaceutically acceptable salt form such as the pharmaceutically acceptable acid addition salts of compounds of formula I including those prepared by reacting the compound of formula I with an inorganic or organic acid such hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, malic, maleic, mandelic, phthalic, citric, glutamic, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, trifluoroacetic, sulphamic or fumaric acids and / or water
The compounds of formula I can be administered in the form of pharmaceutically acceptable acid addition salts or, where appropriate, as an alkali metal or alkaline earth metal or lower alkylammonium salt. Such salt forms are believed to exhibit approximately the same order of activity as the free base forms.
In another aspect, the present invention concerns a pharmaceutical composition comprising, as an ingredient
^^ > t aÉ | aj ^^ kArifedM || aak active, a compound of the general formula] or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
Pharmaceutical compositions containing a compound of the present invention can be prepared by conventional techniques, for example as described in Remington's Pharmaceutical Sciences, 1985 or in Remmton: The Sciences and Practice of Pharmacy, 19ava. Ed. (1995). The compositions may appear in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or topical applications.
The vehicles or diluents employed can be a solid carrier or conventional liquid. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, acacia pectin, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
If a solid carrier is used for oral administration, the preparation may be in tablet form, placed in a rigid gelatin capsule in powder or tablet form or may be in the form of a lozenge or diamond. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 gram. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsules or sterile injectable liquid such as a suspension or aqueous or non-aqueous liquid solution.
A typical tablet that can be prepared by conventional rattling techniques may contain:
Core: Active compound (as free compound or salt thereof) 10.0 mg Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcrystalline (Avicel) 70.0 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Coating: HPMC approx. 9.0 mg * Mywacett 9-40 T approx. 0.9 mg
* Acylated monoglyceride used as a plasticizer for film coating.
For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid vehicle, in particular an aqueous vehicle, for aerosol application. The vehicle may contain additives such as solubilizing agents, for example propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
It has been shown that compounds of general formula I possess the ability to release endogenous growth hormone in vivo. The compounds can however be used in the treatment of conditions that require increasing the levels of growth hormone in the plasma such as deficiencies of growth hormone in humans or in geriatric or livestock patients.
Thus, in a particular aspect, the present invention concerns a pharmaceutical composition for stimulating the release of growth hormone from the pituitary, the composition comprising, as an active ingredient, a compound of general formula I or a salt thereof. pharmaceutically acceptable together with a pharmaceutically acceptable carrier or diluent.
In a further aspect, the present invention concerns a method of stimulating the release of growth hormone from the pituitary, the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula I or a salt thereof pharmaceutically acceptable.
In yet a further aspect, the present invention concerns a method of treating growth retardation in connection with asthma, the method comprising administering to a subject in need thereof, an effective amount of a growth hormone secretagogue or a salt thereof acceptable pharmaceutically. In a particular embodiment, the present invention concerns a method of treating growth retardation in connection with asthma, the method comprising administering to a subject in need thereof, an effective amount of a compound of the general formula I or
< ^^^^ a pharmaceutically acceptable salt thereof.
In yet a further aspect, the present invention concerns a method of treating growth retardation in connection with juvenile rheumatic arthritis or cystic fibrosis, the method comprising administering to a subject in need thereof, an effective amount of a secretagogue of growth hormone or a pharmaceutically acceptable salt thereof. In one modality, the present
The invention relates to a method of treating growth retardation in connection with juvenile rheumatic arthritis, the method comprising administering to a subject in need thereof an effective amount of a secretagogue of growth hormone or a salt thereof.
pharmaceutically acceptable. In a second embodiment, the present invention concerns a method of treating growth retardation in connection with cystic fibrosis, the method comprising administering to a subject in need thereof an effective amount of a secretagogue.
of the growth hormone or a pharmaceutically acceptable salt thereof. In a particular embodiment, the present invention concerns a method of treating growth retardation in connection with juvenile rheumatic arthritis, the method comprising administering to
a subject in need of it, an effective amount of a
composed of the general formula I or a pharmaceutically acceptable salt thereof. In another particular embodiment, the present invention concerns a method of treating growth retardation in connection with cystic fibrosis, the method comprising administering to a subject in need thereof, an effective amount of a compound of the general formula I or a salt thereof acceptable pharmaceutically.
In yet a further aspect, the present invention concerns the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for stimulating the release of growth hormone from the pituitary.
It is well known to those skilled in the art that the potential and current uses of human growth hormone are varied and multiple. Accordingly, compounds of formula I can be administered for purposes stimulating the release of growth hormone from the pituitary and would then have similar effects or uses such as growth hormone itself. Compounds of formula I are useful for, stimulation of the release of growth hormone in geriatrics, prevention of collateral catabolic effects of
• '~ "" ^ - glucocorticoids, prevention and treatment of osteoporosis, treatment of chronic fatigue syndrome (CFS), treatment of acute fatigue syndrome and elective surgery that follows muscle loss, stimulation of the immune system, acceleration of wound healing , acceleration of the repair of bone fractures, acceleration of complicated fractures, for example disc osteogenesis, treatment of secondary depletion in fractures, treatment of growth retardation, treatment of growth retardation resulting from failure or renal failure, treatment of cardiomyopathies, treatment of exhaustion in connection with chronic liver disease, treatment of thrombocytopenia, treatment of growth retardation in connection with Crohn's disease, treatment of small bowel syndrome, treatment of exhaustion in connection with chronic obstructive pulmonary disease (COPD) , complicated treatment ions associated with transplants, physiological treatment of short stature that includes children deficient in growth hormone and short stature associated with chronic disease, treatment of obesity and growth retardation associated with obesity, treatment of anorexia, treatment of growth retardation associated with the Prader-Willi syndrome and Turner syndrome; which increases the growth rate of a patient who has partial insensible growth hormone syndrome, accelerated recovery and reduced hospitalization of burned patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushing's syndrome; induction of the release of pulsatile growth hormone; replacement of growth hormone in fatigued patients, treatment of osteochondrodysplasia, Noonan's syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of catabolism in connection with pulmonary dysfunction and ventilator dependence; treatment of heart failure or related vascular dysfunction, treatment of impaired cardiac function, treatment or prevention of myocardial infarction, lowering of blood pressure, protection against ventricular dysfunction or prevention of reperfusion events; treatment of adults on chronic dialysis; attenuation of protein catabolic responses after major surgery; reduce cachexia and loss of proteins due to chronic diseases such as cancer or AIDS; treatment of hyperinsulinemia that includes nesidioblastosis, adjuvant in the treatment of induction of ovulation; stimulation of thymic development and prevention of the decline of thymic function related to age, treatment of immunosuppressed patients, treatment of sarcopenia, treatment of exhaustion in connection with AIDS; improvement of muscle strength, mobility, maintenance of skin thickness, treatment of metabolic homeostasis and renal homeostasis in geriatric fragility, stimulation of osteoblasts, remodeling of cartilage and bone growth; regulation of dietary intake; stimulation of the immune system in associated animals and treatment of age disorders in associated animals, promotion of growth in cattle and stimulation of wool growth in sheep, increase in milk production in cattle, treatment of metabolic syndrome (syndrome X) , treatment of insulin resistance, including NIDDM, in mammals, for example humans, treatment of insulin resistance in the heart, improvement of sleep quality and correction of the relative to the hyposomatotropism of old age due to high increase in REM sleep and a decrease in REM latency, treatment of hypothermia, treatment of frailty associated with old age, treatment of congestive heart failure, treatment of hip fractures, treatment of immune deficiency in individuals with a cellular T4 / T8 depressed, treatment of muscular atrophy, treatment of musculoskeletal disorders in geriatrics, improvement of the activity of protein kinase B (PKB), improvement of the integral pulmonary function, and treatment of sleep disorders.
In the context of the present application, the term
"Treatment" is also intended to include prophylactic treatment.
In a further aspect the present invention concerns the use of a growth hormone secretagogue or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of growth retardation in connection with asthma. In a particular embodiment, the invention concerns the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof for the treatment of growth retardation in connection with asthma. In a second particular embodiment the invention concerns the use of peptides releasing growth hormone, peptidomimetics releasing growth hormone, or compounds releasing growth hormone of a non-peptidyl nature or a pharmaceutically acceptable salt thereof for treatment of growth retardation in connection with asthma.
In still a further aspect the present invention concerns the use of a growth hormone secretagogue or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of growth retardation in connection with juvenile rheumatic arthritis or cystic fibrosis. . In one embodiment, the invention concerns the use of a growth hormone secretagogue or a pharmaceutically acceptable salt thereof for the preparation of a medicament.
for the treatment of growth retardation in connection with juvenile rheumatic arthritis. In a second embodiment, the invention concerns the use of a growth hormone secretagogue or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the
treatment of growth retardation in connection with cystic fibrosis. In a particular embodiment the invention concerns the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof for the treatment of growth retardation in connection with
juvenile rheumatic arthritis. In another particular embodiment, the invention concerns the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof for the treatment of growth retardation in connection with cystic fibrosis. In an additional mode
The invention concerns the use of peptides that release the
^^^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^ growth hormone, peptidomimetics that release growth hormone, or compounds that release growth hormone of a non-peptidyl nature or a pharmaceutically acceptable salt thereof for the treatment of growth retardation in connection with juvenile rheumatic arthritis. In still a particular additional embodiment the invention concerns the use of peptides releasing growth hormone, peptides that release growth hormone, or compounds that release growth hormone of a non-peptidyl nature or a pharmaceutically acceptable salt thereof. the treatment of growth retardation in connection with cystic fibrosis.
For the above indications the dosage will vary depending on the secretagogue of the growth hormone employed, for example, in the compound of formula I employed, in the mode of administration and in the desired therapy. However, they are usually administered
doses in levels between 0.0001 and 100 mg / Kg of body weight daily to patients and animals to obtain effective release of endogenous growth hormone. In addition, the compounds of formula I have no or substantially no side effects, when administered at the levels of
previous dosages, such side effects that are
For example, release of LH, FSH, TSH, ACTH, vasopressin, oxytocin, cortisol and / or prolactin. Usually, dosage forms suitable for oral, nasal, pulmonary or transdermal administration comprise from about 0.001 mg to about 100 mg, preferably from about 0.001 mg to about 50 mg of the compounds of formula I mixed with a pharmaceutically acceptable carrier or diluent.
The dosage of the compounds according to this invention is suitably 0.01-500 mg / day, for example from about 5 to about 50 mg, such as about 10 mg per dose, when administered to patients, for example humans, as a drug . Optionally, the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more compounds that exhibit a different activity, for example, an antibiotic or other
pharmacologically active material.
The route of administration can be any route that effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary,
transdermal or parenteral, the preferred route being
& .. "- *" • oral.
Apart from the pharmaceutical use of the compounds of formula I, they may be useful in vi tro as instruments to investigate the regulation of growth hormone release.
Compounds of formula I may also be useful as in vivo instruments to evaluate the pituitary's ability to release growth hormone. For example, serum samples taken before and after administration of these compounds to humans can be assayed for growth hormone. The comparison of the growth hormone in each of the serum samples would directly determine the ability of the patient's pituitary to release growth hormone.
Compounds of formula I can be administered to commercially important animals to increase their growth rate and extent, and to increase milk and wool production.
An additional use of growth hormone secretagogue compounds of formula I is in combination with other secretagogues such as GHRP (2 or 6), GR. and its analogues, growth hormone and its analogues or somatomedins including IGF-1 and IGF-2.
Pharmacological Methods
Compounds of formula I can be evaluated in vi tro for their efficiency and potency to release growth hormone in rat pituitary primary cultures, and such evaluation can be carried out as described below.
The isolation of rat pituitary cells is a modification of O. Sartor et al., Endocrinology 116, 1985, pp 952-957. Spargue-Dawley male albino rats (250 ± 25 grams) were purchased from Mollegaard, Lille Skensved, Denmark. The rats were housed in group cages (four animals / cage) and stained in rooms with 12 light cycles of 12 hours. Room temperature varied from 19 - 24 ° C and humidity from 30 - 60%.
The rats were decapitated and the pituitary dissected. The neurointermediate lobes were removed and the remaining tissue was immediately placed in ice-cold isolation buffer (Gey's medium (Gibco 041-04030) supplemented with 0.25% D-glucose, 2% non-essential amino acids (Gibco 043-01140) and albumin of 1% bovine serum (BSA) (Sigma A-4503)). The tissue was cut into small pieces and transferred to the isolation buffer supplemented with 3.8 mg / ml trypsin (Worthington # 3707 TRL-3) and 330 mg / ml DNase (Sigma D-4527). This mixture was incubated at 70 rotations for 35 minutes at 37 ° C in a 95/5% atmosphere of 0 / CO;. The fabric was then washed three times in the previous regulator. Using a standard pasteur pipette, the tissue was aspirated into individual cells. After dispersion the cells were filtered through a nylon filter (160 mm) to remove undigested tissue. The cell suspension was washed 3 times with an isolation buffer supplemented with trypsin inhibitor (0.75 mg / ml, Worthington # 2829) and finally resuspended in culture medium; DMEM (Gibco 041-01965) supplemented with 25 mM HEPES (Sigma H-3375), 4 mM glutamine (Gibco 043-05030H), 0.075% sodium bicarbonate (Sigma S-8875), 0.1% non-essential amino acid , 2.5% fetal calf serum (FCS, Gibco 011-06290), 3% horse serum (Gibco 034-06050), 10% rat serum 1 nM T3 (Sigma T-2752) and 40 mg / l of dexamethasone (Sigma D-4902) pH 7.3, at a density of 2 X 10d cells / ml. Cells were seeded in microtiter plates (Nunc. Denmark), 200 ml / well, and cultured for 3 days at 37 ° C and 8% C02.
Verification of compounds
After culture, the cells were washed twice
on stimulus regulator (Hanks Balanced Salt Solution (Gibco 041-04020) supplemented with 1% BSA (Sigma A-4503), 25% D-glucose (Sigma G-5250) and 25 mM HEPES (Sigma H- 3375) pH 7.3) and preincubated for 1 hour at 37 ° C. The regulator was exchanged with 90 ml of regulator
stimulus (37 ° C). 10 ml of test compound solution was added and the plates were incubated for 15 minutes at 37 ° C and 5% C02. The medium was decanted and analyzed for GH content in a rGH SPA test system.
All the compounds were examined in doses ranging from 10 pM to 100 mM. A dose-response relationship was constructed using the Hill equation (Fig. P, Biosoft). The efficiency (maximum GH released, Ema) was expressed in% Emax of GHRP-6. Potency (EC50) was determined as the concentration that induces the maximum mean stimulation of GH release.
Compounds of formula I can be evaluated for their metabolic stability using the procedure described 5 below:
•• "-" - .Ha ^ UbaÉ - ^ - ^ i * - The compounds are dissolved at a concentration of 1 mg / ml in water, 25 ml of this solution is added to 175 ml of the respective enzyme solution (which results in an enzyme: substrate (weight / weight) ratio of approximately 1: 5). The solution is set aside at 37 ° C all night. 10 ml of the various degradation solutions are analyzed against a corresponding zero sample using electrospray flow injection mass spectrometry (ESMS) with selected ion monitoring of the molecular ion. If the signal has decreased more than 20% compared to the zero sample, the rest of the solution is analyzed by HPLC and mass spectrometry in order to identify the extent and sites of degradation precisely.
Several standard peptides (ACTH 4-10, Angiotensin 1-14 and Glucagon) were included in the stability tests in order to verify the ability of the various solutions to degrade peptides.
Standard peptides (angiotensin 1-14, ACTH 4-10 and glucagon) were purchased from Sigma, MO, USA).
Enzymes (trypsin, chymotrypsin, elastase aminopeptidase M and carboxypeptidase Y and B) were purchased from Boehringer Mannheim GmbH (Mannheim, Germany).
The pancreatic enzyme mixture: trypsin, chymotrypsin and elastase in 100 mM ammonium bicarbonate pH 8 (all concentrations of 0.025 mg / ml).
The carboxypeptidase mixture: carboxypeptidase Y and B in 50 mM ammonium acetate pH 4.5 (all concentrations of 0.025 mg / ml).
The solution aminopeptidase M: aminopeptidase M (0.025 mg / ml) in 100 mM of ammonium bicarbonate pH 8.0
The mass spectrometry analysis was performed using two different mass spectrometers. A Sciex API III quadrupole LC-MS instrument (Sciex Instruments, Thomhill, Notary) equipped with an electrospray ion source and a Bio-Ion Plasma Desorption instrument 20 times of discharge (Bio-Ion Nordic AB, Uppsala, Sweden) .
The quantification of the compounds (before and after degradation) occurred in the API III instrument using the simple ion monitoring of the molecular ions in question with low analyte injection. The liquid flow (MeOH: water 1: 1) of 100 ml / min was controlled by an ABI 140B HPLC unit (Perkin-Elmer Applied Biosystems Divisions, Foster City, CA). Instrument parameters 5 were set for standard operating conditions, and SIM monitoring was performed using the most intense molecular ions (in most cases these corresponded to twice the charged molecular ion).
The identification of degradation products also involved the use of plasma desorption mass spectrometry (PDMS) with application of the sample on nitrocellulose coated targets and standard instrument fixation. Accuracy of masses
determined in this way is generally better than 0.1%.
The separation and isolation of the degradation products was done using a 4.6 × 105 mm reverse phase HY-TACH C-18 HPLC column (Hewlett-Packard Company, 20 palo alto, CA) with a standard separation gradient of acetonitrile: TFA The HPLC system used was HP1090M (Hewlett-Packard Company, Palo Alto, CA).
"- *» --- • Derived from ion MW / SIM Mixture Mixture
Peptide (amu) carboxy-Pan. Peptidase enzyme
Standards
ACTH 4-10 1124.5 / 562
Glucagon 3483 / 871.8
Insulin (B23-29) 859.1 / 430.6
Angiotensin 1-14 1760.1 / 881.0
GHRP-2 817.4 / 409.6
GHRP-6 872.6 / 437.4
+: stable (less than 20% decrease in signal after 24 hours in degradation solution) -: Unstable (more than 20% decrease in signal? IM after 24 hours in degradation solution)
Any new feature or combination of features described herein is considered essential to this invention.
EXAMPLES:
The process for preparing compounds of formula I and preparations containing them is further illustrated in the following examples, which, however, were not constructed as limiting.
The structures of the compounds were confirmed either by elemental analysis (MA) of nuclear magnetic resonance (NMR) or by mass spectrometry (MS). The NMR shifts (d) are given in parts per million (ppm) and only the selected peaks were given. P.F. it is the melting point and it is given in degrees centigrade (° C). Column chromatography was carried out using the technique described by W.C. Still and collaborators J. Org. Chem. 1978, 43, 2923-2925 on silica gel 60. The compounds used as starting materials are either known compounds or compounds that can be easily prepared by methods known per se.
HPLC analysis
Method Al
The RP analysis was carried out using UV detections at 214, 254, 276, and 301 nm on a C-18 218TP54 4.6 mm x 5 cm silica column (The Seperations Group, Hesperia),
which eluted at 1 ml / min at 42 ° C. the column was equilibrated with 5% acetonitrile in a regulator consisting of 0.1 M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuric acid, after injection the sample was eluted by a gradient of 5% to 60% acetonitrile in the
same regulator for 50 min.
Method Bl.
The RP analysis was carried out using UV detections at 20 214, 254, 276, and 301 nm on a C-18 218TP54 silica column of 4.6 mm x 250 mm 5 m (The Seperations Group, Hesperia), which eluted at 1 ml / min at 42 ° C. The column was equilibrated with 5% (acetonitrile + 0.1% TFA) in an aqueous solution of TEA in water (0.1%). After 25 injection the sample was eluted by a gradient of 5% to 60
% (acetonitrile + 0.1% TFA) in the same aqueous buffer for 50 min.
Abbreviations
TLC: Thin layer chromatography DMSO: dimethylsulfoxide min: minutes h: hours Boc: tert butyloxycarbonyl DMF: dimethylformamide THF: tetrahydrofuran EDAC: N-ethyl-N '-dimethylamino propylcarbodiimide hydrochloride HOAt: 1-hydroxy-7-azabenzotriazole DIEA: diisopropylethylamine TFA: trifluoroacetic acid
Modules:
The N-methylated amino acids used in the following examples were prepared as in Can. J. Chem. 1977, 55, 906.
Ester of tert-butyl 3-hydroxy-l, 1-dimethylpropylcarbamic acid
_ * adi ^ __ ^ _ a > j > tel_l U
Ethyl chloroformate was added dropwise at 0 ° C.
(1.10 mL, 11.5 mmol) to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran.
(10 ml). The solution was stirred for 40 minutes at 0 ° C. HE
The precipitate formed was filtered off and washed with tetrahydrofuran (20 ml). The liquid was immediately cooled to 0 ° C. A 2M solution of lithium borohydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 ° C for 2 h, and
Then it was heated to room temperature, for a period of 4 h. It was cooled to 0 ° C. Methanol (5 ml) was carefully added. IN hydrochloric acid (100 ml) was added. The solution was extracted with ethyl acetate (2 X 100 ml, 3 X 50 ml). The combined organic layers were washed with
Saturated sodium bicarbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate / heptane 1: 2 to give 1.84 g of tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamic acid ester.
^ uuá ^ i? msastm ^ -NMR (CDCI3): d 1.33 (s, 6H); 1.44 (s, 9H); 1.88 (t, 2H); 1.9 (br, 1H); 3.75 (q, 2H); 4.98 (br, 1H). 3- (tert-butoxycarbonylamino) -3-methylbutanal:
DMSO (1.22 ml, 17.2 mmol) was added to a solution of oxalyl chloride 81.1 ml, 12.9 mmol) at -78 ° C in dichloromethane (15 ml). the mixture was stirred for 15 minutes at -78 ° C. a solution of tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamic acid ester (1.75 g, 8.6 mmol) in dichloromethane (10 ml) was added dropwise over a period of 15 min. The solution was stirred at -78 ° C for another 15 min. Triethylamine (6.0 ml, 43 mmol) was added. The solution was stirred at -78 ° C for 5 minutes and then warmed to room temperature. The solution was diluted with dichloromethane (100 ml) and extracted with IN hydrochloric acid (100 ml). The aqueous phase was extracted with dichloromethane (50 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (140 g) with ethyl acetate / heptane (1: 3) to give 1.10 g of 3- (tert-butoxycarbonylamino) -3-methylbutanal.
MHz - ^ - H-NMRÍCDCls): d 1.39 (s, 6H); 1.45 (s, 8H); 2.85 (d, 2H); 4.73 (br.H); 9.80 (t, 1H).
(2E) -5- (tert-butoxycarbonylamino) -5-methyl-2-ene-enoate ethyl;
Triethylphosphonoacetate (1.96 ml, 9.8 mmol) was dissolved in tetrahydrofuran (30 ml). Potassium tert-butoxide (1.10 g, 9.8 mmol) was added. The solution was stirred for 40 minutes at room temperature. A solution of 3- (tert-butoxycarbonylamino) -3-methylbutanal (1.10 g, 5.5 mmol) in tetrahydrofuran (6 mL) was added. The solution was stirred at room temperature for 75 minutes. It was diluted with ethyl acetate (8100 ml) and 1 N hydrochloric acid (100 ml) The phases were separated The aqueous phase was extracted with ethyl acetate (2 x 50 ml) The combined organic phases were washed with saturated sodium bicarbonate solution. sodium (60 ml) and dried over magnesium sulfate The solvent was removed in vacuo The crude product was purified by column chromatography on silica (90 g) with ethyl acetate / heptane (1: 4) to give 1.27 g of ethyl (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoate.
^ - MR (CDC13): d 1.30 (s, 6H); 1.30 (t, 3H); 1.46 (s, 8H); 2.62 (d, 2H); 4.27 (q, 2H); 4.42 (br, 1H); 5.88 (d, 1H); 6.94 (td, 1H).
Acid (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoic:
Ethyl (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoate (1.233 g, 4.54 mmol) was dissolved in dioxane (20 ml). Lithium hydroxide (0.120 g, 5.00 mmol) was added as a solid. Water (10 ml) was added until a clear solution was achieved. The solution was stirred 16 h at room temperature. The solution was diluted with water (70 ml) and extracted with tert-butyl methyl ether (2 x 100 ml).
^ m? t ᐠthe aqueous phase was acidified with sodium bisulfate solution IN (pH = 1) and extracted with tert-butyl methyl ether (3 x 70 ml). The organic phases were combined and dried over magnesium sulfate. The solvent was removed under vacuum to give 1.05 g of (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoic acid. The crude product was used for further synthesis.
1 H-MR (DMSO d6): d 1.15 (s, 6H); 1.35 (s, 9H); 2.53 10 (d, 2H); 5.75 (d, 1H); 6.57 (br, 1H); 6.75 (td, 1H); 12.15 (s, 1H).
l-aza-spiro [3, 3] heptan-2-ketone;
Methylenecyclobutane (40.0 g, 0.587 mol) was dissolved in diethyl ether (250 ml). to -40 a a gota
chlorosulfonyl isocyanate 826 ml, 0.294 moles). The reaction mixture was heated to 10 ° C. An exothermic reaction was observed, and a precipitate formed. The reaction mixture was cooled to -20 ° C. It was stirred for 16 hours, while heating to room temperature. HE
added dropwise a saturated aqueous solution of sulfite
Hh ^ lÉßllÉkHfitWtßÍlBMk ^. * D ^ > b < l > > ^ Sodium (100 ml). The reaction mixture was stirred vigorously for 1 hour. Another saturated aqueous solution of sodium sulfite (100 ml) was added dropwise. Solid sodium bicarbonate was added until pH 7. dichloromethane (500 ml) was added. The phases were separated. The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo to give 23.59 g of 1-aza-spiro [3, 3] heptan-2-ketone.
^ -NMRÍCDCl3): d 1.75 (m, 2H); 2.26 (m, 2H); 2.39 (m,
2H); 2.96 (s, 2H); 6.55 (br, 1H).
2-Oxo-l-azaspiro [3, 3] heptane-1-carboxylic acid tert-butyl ester
A solution of di-tert-butyl dicarbonate (55.7 g, 0.211 mol) in dichloromethane was added dropwise to a solution of l-aza-spiro [3, 3] heptan-2-ketone, triethylamine (36 ml, 0.255 moles), and 4-dimethylaminopyridiene (2.6 g,
0.01 mole) in dichloromethane (100 ml). The reaction mixture was stirred for 16 h at room temperature. It was washed with an aqueous solution of ammonium chloride (100 ml), water (100 ml) and a saturated aqueous solution of sodium bicarbonate (100 ml). The organic layer was dried over magnesium sulfate. The solvent was removed under vacuum to give 48.24 g of crude tert-butyl ester of crude 2-oxo-l-azaspiro [3, 3] heptane-1-carboxylic acid, which was used for the next step without purification.
1H-MR (CDC13): d 1.55 (s, 9H); 1.78 (m, 1H); 1.92 (m, 1H); 2.18 (, 2H); 2.90 (m, 2H); 3.04 (s, 1H).
Acid (1- (tert-butoxycarbonylamino) cyclobutyl) acetic acid
An aqueous solution of lithium hydroxide IN (227 ml, 227 mmol) was added to a solution of 2-oxo-l-azaspiro [3, 3] heptane-1-carboxylic acid tert-butyl ester (48 g, 0.227 mmol) ) in tetrahydrofuran (200 ml). The reaction mixture was stirred for 2 hours. Diethyl ether (200 ml) and water (200 ml) were added. The mixture was stirred for 16 hours.
The organic layer was isolated. The aqueous phase was extracted with diethyl ether (200 ml). The aqueous phase was acidified with a 10% aqueous solution of sodium bisulfate until pH 3. The above-formed one was separated by filtration, washed with water, and dried under vacuum, to give 38.84 g of acid (1- (tert-butoxycarbonylamino) cyclobutyl) acetic acid.
^ -NMR (CDC13): d 1.45 (s, 9H); 1.85 (m, 1H); 1.95 (m, 1H); 2.25 (m, 4H); 2.87 (m, 2H); 5.15 and 6.20 (both br, along with 1H).
Acid (2E) -4- (1- (tert-butoxycarbonylamino) cyclobutyl) but-2-enoic
(2E) -4- (1- (tert-butoxycarbonylamino) cyclobutyl) but-2-enoic acid was synthesized starting from (1- (tert-butoxycarbonylamino) cyclobutyl) acetic acid analogously to the synthesis of (2E) -5 acid - (tert-butoxycarbonylamino) -5-methylhex-2-enoic which started with 3-tert-butoxycarbonyl-amino-3-methylbutanoic acid.
^ -NMR (CDCl 3): d 1.43 (s, 9H); 1.84 (m, 1H); 1.95 (m, 1H); 2.10 (m, 2H); 2.20 (m, 2H); 2.70 (m, 2H); 4.75 (br, 0.5H); 5.90 (m, 1H); 6.35 (br, 0.5H); 6.95 (m, 1H).
Ethyl ester of (2E) -5-tert-butoxycarboni lamino-3,5-dimethylhex-2-enoic acid
Hydrogenated oxalate of diacetoneamine (30.0 g, 146 mmol) in tetrahydrofuran (400 ml) was suspended. An aqueous solution of sodium hydroxide (IN, 146 ml) was added. Di-tert-butyl dicarbonate (38.3 g, 1.75 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to the reaction mixture. The reaction mixture was stirred for 2 hours at room temperature. Sodium hydroxide (IN = 146 ml) was added and the reaction mixture was stirred for 12 hours at room temperature. Water (200 ml) and ethyl acetate (200 ml) were added. The aqueous phase was extracted with ethyl acetate (4 x 200 ml). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica (200 g), using ethyl acetate / heptane (1: 3) as eluent, to give 28.4 g of tert-butyl ester of (1,1-dimethyl-3-butyl ester) -oxobutil) carbamic.
Triethyl phosphonoacetate (4.7 g, 20.9 mmol) was dissolved in tetrahydrofuran (36 mL). potassium tert-butoxide (2.3 g, 20.9 mmol) was added and the reaction mixture was stirred for 40 minutes at room temperature. Tert-butyl ester of (1,1-dimethyl-3-oxobutyl) carbamic acid (2.5 g, 11.6 mmol) was dissolved in tetrahydrofuran (15 ml) and added dropwise to the reaction mixture which was heated to reflux for 12 hours. Ethyl acetate (100 ml) and hydrochloric acid (IN, 100 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic phases were washed with an aqueous solution of sodium bicarbonate (saturated, 100 ml), dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by flash chromatography on silica (120 g) using ethyl acetate / heptane (1: 2) as eluent to give 2.0 g of (2E) -5-tert-butoxycarbonylamino-3-ethyl ester. -dimethylhex-2-enoic.
-NMR (CDC13) d 125 (t, 3H); 1.30 (s, 6H); 1.44 (s, 9H); 2.21 (s, 3H); 2.58 (s, 2H); 4.14 (q, 2H); 4.48 (s,
JkSESiiBdat- 1H); 5.65 (s, 1H).
(2E) -5-tert-Butoxycarbonylamino-3, 5-dimethylhex-2-enoic acid 5
(2E) -5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ester (1.95 g, 6.83 mmol) was dissolved in 1,4-dioxane (25 ml) and water (15 ml). Lithium hydroxide (0.18 g, 7.52 mmol) was added and the reaction mixture was stirred for 12 hours at room temperature. Water (150 ml) and tert-butyl methyl ether 8150 ml were added. The aqueous phase was diluted with a 10% aqueous solution of sodium bisulfate to pH 2.5 and extracted with tert-butyl methyl ether (3 x 100 ml). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from heptane (20 ml) to yield 0.6 g of (2E) -5-tert-butoxycarbonylamino-3,5-dimethylhex-2-enoic acid.
XH-NMR (CDC13) d 1.29 (s, 6H); 1.44 (s, 9H); 2.23 (s, 25 3H); 2.62 (s, 2H); 4.45 (s, 1H); 5.66 (s, 1H).
g ^ UJUgH ^^^^^^ gH ^ - "" --- "• - Acid (2E) -5- (N- (tert-butoxycarbonyl) -N-methylamino) -5-methylhex-2-enoic
The (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoic acid (5.00 g, 20.6 mmol) was dissolved in tetrahydrofuran (70 mL). Methyloduro (10.3 ml, 164 mmol) was added and the solution was cooled to 0 ° C. Sodium hydride (60% in oil) (2.07 g, 61.6 mmol) was added in portions and the solution was stirred at room temperature for four days. Ethyl acetate (70 ml) and water (60 ml) were added dropwise and the solvent was removed in vacuo. The crude product was dissolved in water (40 ml) and ether (40 ml). The organic phase was washed with a saturated aqueous solution of sodium bicarbonate (30 ml). The aqueous phases were mixed and 5% aqueous solution of citric acid was added until pH 3. The aqueous phase was extracted with ethyl acetate (4 x 50 ml). The organic phase was washed with water (2 x 40 ml), an aqueous solution of sodium thiosulfate (5%, 40 ml), water (40 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The residue was dissolved in
a¡¡fcaiflji? aiLj JLiiL ± ^ j? _ L- _? _ _? _? _ - - - - • ~~ "- - - - -» - - ^ ---linden acetate (45 ml) and washed with an aqueous solution of sodium bicarbonate (10%, 3 x 30 ml), dried over magnesium sulfate and concentrated in vacuo to give 4.00 g of acid (2E) -5- (N- ( ter-butoxy-carbonyl) -N-methylamino) -5-methylhex-2-enoic.
-NMR (CDC13) d 1.38 (s, 6H), 1.45 (s, 9H); 2.80 (d, 2H); 2.85 (s, 3H); 5.88 (d, 1H); 7.01 (q, 1H).
Example 1
N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid
4- [dimethylcarbamoyl) piperidine-1-carboxylic acid tert-butyl ester
1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (8.0 g) was dissolved, 35 mmol) in dichloromethane (70 ml) and N, N-dimethylformamide (35 ml). L-hydroxy-7-azabenzotriazole (4.75 g, 35 mmol) was added. The solution was cooled to 0 ° C. N- (3-dimet laminopropyl) -N'-ethylcarbodiimide hydrochloride (6.69 g, 35 mmol) was added. The reaction mixture was stirred for 20 minutes at 0 ° C. A 5.6 M solution of dimethylamine in ethanol (37 mL, 209 mmol) was added. The reaction mixture was stirred for 3 days, while warming to room temperature. It was diluted with ethyl acetate (400 ml) and washed with a 10% aqueous solution of sodium bisulfate (400 ml). The aqueous solution was extracted with ethyl acetate (2 x 200 ml). The organic layers were washed with saturated aqueous sodium bicarbonate solution (300 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using dichloromethane / methanol 20: 1 as eluent, to give 4.56 g of 4- (dimethyl-carbamoyl) piperidine-1-carboxylic acid tert-butyl ester.
XH-NMR (CDC13): d 1.47 (s, 9H); 1.70 (m, 4H); 2.80-2.90 (m, 3H); 2.96 (s, 3H); 3.08 (s, 3H); 4.17 (m, 2H).
4- ((Dimethylamino) methyl) piperidine-1-carboxylic acid tert-butyl ester
At 0 ° C, a solution of 4- ((dimethylamino) methyl) piperidine-1-carboxylic acid tert-butyl ester (4.56 g, 18 mmol) in tetrahydrofuran (80 ml) was added dropwise to a suspension of Sodium borohydride (1.61 g, 43 mmol) in tetrahydrofuran (80 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. A solution of iodide (4.51 g, 18 mmol) in tetrahydrofuran (80 ml) at 0 ° C was added dropwise. The reaction mixture was heated to reflux for 16 hours, cooled to 4 ° C. methanol (200 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in a 20% solution of sodium hydroxide (200 ml) and tert-butyl methyl ether (150 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3 x 100 ml). The combined aqueous layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using dichloromethane / methanol / 25% aqueous ammonia (100: 10: 1) as eluent, to give 4.07 g of 4- (( dimethylamino) methyl) piperidine-1-carboxylic acid.
4. -NMR (CDC13): d 1.22 (m, 2H); 1.44 (s, 9H); 1.85 (d, 2H); 2.09 (m, 1H); 2.61 (s, 6H); 2.65 (m, 2H); 2.78 (t, 2H); 4.05 (d, 2H).
N, N-dimethyl-N- ((piperidin-4-yl) methyl) amine
A 3M solution of hydrogen chloride in ethyl acetate (120 ml, 360 mmol) was added to a solution of 4- ((dimethylamino) methyl) piperidine-1-carboxylic acid tert -butyl ester (2.0 g, 14 mmol) in ethyl acetate (50 ml). The reaction mixture was stirred for 30 minutes at room temperature. The solvent was removed under vacuum to give 2.3 g of the crude di, N-N-dimethyl-N- ((piperidin-4-yl) methyl) amine dihydrochloride salt, which was used without purification for the next step.
^ -NMR (CDC13, selected values): d 1.48 (m, 2H); 1.92 (s, 6H); 3.22 (d, 2H).
N- [(IR) -l-Benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamic acid tert-butyl ester
At 0 ° C, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (1158 g, 6.04 mmol) was added to a solution of (2R) -2- (N- (tert-butoxycarbonyl) -N- methylamino) -3-phenylpropionic acid (1.69 g,
? it ^^^^^ aßm 6.04 mmoles) and l-hydroxy-7-azabenzotriazole (0.822 g, 6.04 mmoles9 in dichloromethane (25 ml) and N, N '-dimethylformamide (12 ml) The reaction mixture was stirred for 20 minutes at 0 ° C. A solution of the crude N, N-dimethyl-N- ((piperidin-4-yl) methyl) amine dihydrochloride salt (1.3 g, 6.04 mmole) in N, N was added successively. dimethylformamide (10 ml) and dichloromethane (5 ml) and ethyldiisopropylamine (6.2 ml, 36.25 mmol) The reaction mixture was stirred for 16 hours while it was warmed to room temperature and diluted with ethyl acetate.
(100 ml) and washed with a saturated aqueous sodium bicarbonate solution (100 ml). The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo.
The crude product was purified by flash chromatography on silica (100 g), using dichloromethane / methanol / 25% aqueous ammonia solution (200: 10: 1) as eluent, to give 1.22 g of N- [(3-tert-butyl ester. IR) -l-benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamic acid.
^ -NMR (CDC13, selected values): or 1.28, 1.11, 1.37, and 1.38 (all s, along with 9H); 4.00 (m, 1H); 4.57 (m, 1H); 4.97 and 5.28 (both t, together with 1H); 7.10-7.40 (m, 5H).
MS: 404 [M + l] t
(2R) -1- (4- ((dimethylamino) methyl) piperidin-1-yl) -2- (methylamino) -3-phenylpropan-1-ketone
At 0 ° C, trifluoroacetic acid (820 ml) was added to a solution of N- [(IR) -1-benzyl-2- (4- ((di-methylamino) methyl) piperidin-yl) butyl ester. -2-oxoethyl] -methylcarbamic acid (1.22 g, 3.02 mmol) in dichloromethane (20 ml). The reaction mixture was stirred for 1 h at 0 ° C.
The solvents were removed in vacuo. The residue was dissolved in dichloromethane (70 ml) and the solvent was removed in vacuo. The subsequent procedure was repeated twice. The crude product was purified by flash chromatography on silica (100 g), using dichloromethane / methanol / 25% aqueous ammonia solution (100: 10: 1), to give 659 mg of (2R) -l- (4- ( (dimethylamino) methyl) piperidin-1-yl) -2-methylamino) -3-phenylpropan-1-ketone.
1 H-NMR (CDCl 3, selected values): d 0.91 and 1.47 (m and d, together with 1 H); 1.27 (m, 1H); 4.62 (t, 1H).
N- ((IR) -l- {N- [(IR) -1-benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl tert-butyl ester ] -N-methylcarbamoyl] -2- (2-naphthyl) ethyl) -N-methylcarbamic
At 0 ° C, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (416 mg, 2.17 mmol) was added to a solution of (2R) -2- (N- (tert-butoxycarbonyl) -N- methylamino) -3- (2-naphthyl) -propionic (715 mg, 2.17 mmol) and l-hydroxy-7-azabenzotriazole (296 mg, 2.17 mmol) in dichloromethane (20 ml) and N, N-dimethylformamide (10 ml) . The reaction mixture was stirred for 20 minutes at 0 ° C. a solution of (2R) -1- (4- ((dimethylamino) methyDpiperidin-1-yl) -2 - (methylamino) -3-phenylpropan-1-ketone (659 mg, 2.17 mmol) in dichloromethane was added successively. ml) and N, N-dimethylformamide (5 ml) and ethyldiisopropylamine (0.56 ml, 3.26 mmol) The reaction mixture was stirred for 16 hours, while warming to room temperature, diluted with ethyl acetate (100 ml). ) and washed with a saturated aqueous solution of sodium bicarbonate (100 ml), the aqueous solution was extracted with ethyl acetate (3 x 50 ml) The combined organic layers were dried over magnesium sulfate. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate / hexane / triethylamine (1: 1: 0.08) as eluent, to give 1.05 g of N- (( IR) -1- {N - [(1R) -l-benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl. - (2-naphthyl) ethyl) -N-methylcarbamic.
1H-NMR (CDC13, selected values): d 1.24 and 1.42 (both s, together with 9H); 5.04, 5.28, 5.44, 5.54, 5.73 (m, dd, dd, dd, and m, together with 3H);
(2R) -N - [(LR) -l-benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methyl-2- (methylamino) -3- (2-naphthyl) propionamide
At 0 ° C, trifluoroacetic acid (18 ml) was added to a solution of N- ((IR) -1-. {N - [(1 R) -l-benzyl-2- (4-butyl) -butyl ester. - ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2- (2-naphthyl) -ethyl) -N-methylcarbamic acid (1.05 g, 1.71 mmol) in dichloromethane (18 ml) The reaction mixture was stirred for 50 minutes at 0 ° C. The solvents were removed in vacuo, the residue was dissolved in dichloromethane (50 ml) and the solvent was removed in vacuo. repeated twice.
The crude product was purified by flash chromatography on silica (80 g), using dichloromethane / methanol / 25% aqueous ammonia solution as eluent, to give 846 mg of (2R) -N- [(IR) -l-benzyl- 2- (4- ((dimethylamino) methypiperidin-1-yl) -2-oxoethyl] -N-methyl-2- (methylamino) -3- (2-naphthyl) propionamide.
^ -NMR (CDC13), selected values): d 0.60 (m, 1H);
4. 38 (t, 1H); 5.72 and 5.79 (both t, together with 1H).
Ter-butyl ester of acid. { (3E) -4- [N- ((IR) -1- { N- (1R) -1-benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl ] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] -1,2-dimethylbut-3-enyl} carbamic
At 0 ° C, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride 8112 mg, 0.5 μm) is added to a solution of (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2 acid. -enoic acid (142 mg, 0.5 mmoles) and l-hydroxy-7-azabenzotriazole (79 mg, 0.58 mmoles) in dichloromethane (10 ml) and N, N-dimethylformamide (5 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. a solution of (2R) -N- [(IR) -1-benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methyl-2- was successively added. (methylamino) -3- (2-naphthyl) propionamide (300 mg, 0.58 mmole) in dichloromethane (5 ml) and N-N-dimethylformamide (5 ml) and ethyldiisopropylamine (0.10 ml, 0.58 mmole). The reaction mixture was stirred for 3 days, while heating to room temperature. It was diluted with ethyl acetate (70 ml) and washed with a saturated aqueous sodium bicarbonate solution (70 ml). extracted the aqueous phase with ethyl acetate (3 x 50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (70 g), using dichloromethane / methanol / 25% aqueous ammonia solution (200: 10: 1) as eluent, to give 313 g of tert-butyl ester of the acid. { (3E) -4- [N- ((IR) -1- {N - [(IR) -l-benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2- oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-carbamoyl] -1, 1-dimethylbut-3-enyl} carbártico.
XN-NMR (CDC13), selected values): d 1.28 and 1.30 (both s, together with 6H); 1.42 (s, 9H); 2.23, 2.27, 2.38, 2.43, 2.51, 2.52, 2.81, and 2.82 (all s, along with 12H); 5.56, 5.76, and 5.90 (m, m, and dd, together with 1H); 6.94
( , 1 HOUR) .
At 0 ° C, trifluoroacetic acid (6 ml) was added to a solution of / (3E) -4- [N- ((IR) -1- {N- [(IR) -) -butyl ester. l-Benzyl-2- (4- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) - N -methylcarbamoyl] -l , l-dimethylbut-3-enyl} Carbamic acid (212 mg, 0.29 mmol) in dichloromethane (6 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. It was diluted with dichloromethane
(30 ml). A saturated aqueous solution of sodium bicarbonate (30 ml) was added dropwise. Solid sodium bicarbonate was added until pH 7. The phases were separated. The aqueous phase was extracted with dichloromethane (3 x 50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (20 g.), Using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 5 mg of the title compound.
H-NMR (CDC13), selected values): d 1.20 (s, 6H); 2.28, 2.32, 2.41, 2.49, 2.56, 2.57, 2.82, and 2.83 (all s, along with 12H); 5.58, 5.78, and 5.92 (m, m, and dd, together with 2H); 6.16 and 6.19 (both d, together with 1H); 7.00 (n, 1H).
HPLC: 39.23 min (Al) 41.55 min (Bl)
MS: 640.4 [M + l] *
For biological verification, the title compound was transferred to its acetate salt by lyophilization with 0.5 M acetic acid (40 ml).
Example 2
N- ((IR) -1- {N- • (IR) -l-benzyl-2- ((3S) -3- (dimethyl amino methyl) piperidin-1-yl) -2-oxoethyl] -N -methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid
3-ethyl ester of (3R) -piperidine-1,3-dicarboxylic acid 1-tert-butyl ester
(R) -ethyl nipepcotate tartrate (10.0 g, 32.5 mmol) was suspended in tetrahydrofuran (90 mL). an aqueous solution of IN sodium hydroxide (98 ml, 98 mmol) was added. A solution of di-tert-butyl dicarbonate (7.10 g, 32.5 mmol) in tetrahydrofuran (90 ml) was added. The reaction mixture was stirred for 16 hours at room temperature. Ethyl acetate (400 ml) was added. The reaction mixture was washed with 10% aqueous sodium bisulfate solution (400 ml). The aqueous solution was extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g) using ethyl acetate / heptane 1: 4 as eluant to give 4.13 g of ester 3-ethyl ester 1-tert-butyl (3R) -piperidin -1, 3-dicarboxylic.
1 H-NMR (CDC13): d 1.27 (t, 3H); 1.48 (s, 9H); 1.54 (m, 1H) (m,; 1.62 (m, 1H), 1.73 (, 2H), 2.05 (m, 1H), 2.45 (m, 1H), 2.81 (m, 1H), 2.98 (br, 1H) 3.93 (m, 1H); 4.14 (q, 1H).
Termitic acid ester of (3R) -3-formylpiperidine-l-carboxylic acid
one 1.2 M disiobutilaluminio hydride in toluene (30.8 ml, 36.9 mmol) solution at -78 ° C to a solution of ester 3-ethyl ester 1-tert-butyl (3R) -piperidine-1, 3 is added -dicarboxylic (4.13 g, 16.1 mmol) in diethyl ether (30 ml). The reaction mixture was stirred for 2.5 hours at -78 ° C. Water (9.6 ml) was added dropwise. The reaction mixture was heated to room temperature. The precipitate is removed by filtration through a celite layer. The celite was washed with methyl tertiary butyl ether (3 x 100 ml). The liquids were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 1.94 g of ethyl ester (3R) -3-formylpiperidine-l-carboxylic acid, which was used in the next step without further purification.
I - 1 i, 1 > Lllll I 1-1 1 II _ _ ^^^^^^^ ^^^^ _ ^ _ ^ ^ --.---. ^^^^^^^^^^^^^^^. ^^ ^^. ^^^^. ^. ^^. ^ j ^ Jtjjj ^^^^ - 'H-NMR (CDCI3): d 1.45 (s, 9H); 1.67 (m, 2H); 1.95 (m, 1H); 2.43 (m, 1H); 3.10 (m, 1H); 3.32 (dd, 1H); 3.52 (d, 1H); 3.65 (m, 1H); 3.95 (m, 1H); 9.69 (5, 1H).
(3S) -3- (dimethylaminomethyl) piperidine-1-carboxylic acid tert-butyl ester
A solution of (3R) -3-formylpiperidine-1-carboxylic acid tert-butyl ester (1.94 g, 9.1 mmol) in dichloromethane (80 ml) was prepared. A 5.6 M solution of dimethylamine in ethanol (3.2 ml, 18.2 mmol) and molecular sieves were successively added. Sodium triacetoxyborohydride (5.78 g, 27.3 mmol) was added to this mixture. Acetic acid (1.04 ml, 18.2 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. An aqueous IN solution of sodium hydroxide (70 ml) and methyl tert-butyl ether (70 ml) was added. the phases were separated. The aqueous solution was extracted with methyl-tert-butyl ether (3 x 70 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 866 mg of tert-butyl ester of (3S) acid -3- (dimethylaminomethyl) piperidine-1-carboxylic acid.
^ • H-NMR (CDC13): d 1.10 (m, 1H); 1.45 (s, 9H), 1.45 (m, 1H); 1.64 (m, 2H); 1.85 (m, 1H); 2.10 (m, 2H); 2.20 (s, 6H); 2.50 (br, 1H); 2.79 (m, 1H); 3.95 (m, 2H).
N,. dimethyl-N- (((3R) -piperidin-3-yl) methyl) amine
(3S) -3- (dimethylaminomethyl) piperidine-l-carboxylic acid tert -butyl ester (1.25 g, 5.15 mmol) was dissolved in ethyl acetate (30 ml). A solution was added
2. 7 M hydrogen chloride in ethyl acetate (75 ml,
203 mmoles). The reaction mixture was stirred for 45 min. At room temperature. The solvent was removed in vacuo to give 976 mg of the crude N, N-dimethyl-N- (((3R) -piperidin-3-yl) methylamine dihydrochloride salt, which was used for the next step without further purification.
1 H-NMR (CD 3 OD): d 1.42 (m, 1H); 1.86 (m, 1H); 2.00 (m, 2H); 2.38 (m, 1H); 2.85 (t, 1H); 2.95 (s, 6H); 2.98 (m, 1H); 3.16 (m, 2H); 3.42 (, 1H); 3.53 (m, 1H).
N- [(IR) -l-benzyl-2- ((3S) -3- (dimethylaminomethyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamic acid tert-butyl ester
At 0 ° C, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (870 mg, 4.54 mmol) was added to a solution of (2R) -2- (N- (tert-butoxycarbonyl) -N- methylamino) -3-phenylpropionic acid (1.27 g, 4.54 mmole) and l-hydroxy-7-azabenzotriazole (617 mg, 4.54 mmole) in dichloromethane 820 ml) and N, N-dimethylformamide 810 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. a crude N, N-dimethyl-N- (((3R) -piperidin-3-yl) methyl) amine dihydrochloride salt (976 mg, 4.54 mmol) in dichloromethane (20 ml) and N, N-dimethyl were added successively. -formamide (10 ml) and ethyldiisopropylamine (3.9 ml, 22.7 mmol). The reaction mixture was stirred for 3 days, while heating to room temperature. Ethyl acetate (300 ml) was added. The solution was washed with saturated aqueous sodium bicarbonate solution (300 ml). The aqueous phase was extracted with ethyl acetate (2 x 200 ml). The combined aqueous layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 1.69 g of N- [-] -butyl butyl ester. (2R) -1-Benzyl- ((3S) -3- (dimethylaminomethyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamic acid.
^ -NMR (CDC13), selected values): d 1.20, 1.24, 1.31, and 1.32 (all s, along with 9H); 2.12, 2.13, and 2.18 (all s, along with 6H); 2.81 (m, 3H); 4.97 and 5.30 (both m, together with 1H); 7.05-7.35 (m, 5H).
(2R) -1- ((3S) -3- ((dimethylamino) methyl) piperidin-1-yl) -2-methylamino-3-phenylpropan-1-ketone
At 0 ° C, trifluoroacetic acid (25 ml) was added to a solution of N- [(IR) -1-benzyl-2- ((3S) -3- (dimethylaminomethyl) piperidin-1-tert-butyl ester. il) -2-oxoethyl] -N-methylcarbamic (1.69 g4.2 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 30 minutes at 0 ° C. the solvent was removed in vacuo. The residue was dissolved in dichloromethane (100 ml) and the solvent removed in vacuo. The following procedure was repeated twice. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane / methanol / 25% aqueous ammonia solution (100: 10: 1) as eluent, to give 1.15 g of (2R) -1- (( 3S) -3- ((dimethylamino) methyl) piperidin-1-yl) -2-methylamino-3-phenylpropan-1-ketone.
1 H-NMR (CDCl 3, selected va): d 0.38, 1.11, 1.37, and 1.65 (all m, together with 4H); '2.11, 2.19, 2.25, and 2.31 (all s, along with 9H); 4.37 and 4.53 (both m, together with 1H); 7.10-7.35 (m, 5H).
N- ((IR) -l- {N- [(IR) -1-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin-1-yl) tert-butyl ester -2-oxoethyl-N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamic
At 0 ° C N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (379 mg, 1.98 mmol) was added to a solution of (2R) -2- (N- (ter-
^ M ^ A ^ AHmaüÉ butoxicarbonil) -N-metilamino) -3- (2-naphthyl) -propionic (651 mg, 1.98 mmol) and l-hydroxy-7-azabenzotriazole (269 mg, 1.98 mmol) in dichloromethane (10 ml ) and N, N-dimethylformamide (85 ml). The reaction mixture was stirred for 20 min at 0 ° C. A solution of (2R) -1- ((3S) -3- ((dimethylamino) methyl) piperidin-1-yl) -2-methylamino-3-phenylpropan-1-ketone (600 mg, 1.98 mmol) was successively added. in dichloromethane (10 ml) and ethyldiisopropylamine (0.51 ml, 2.97 mmol). The reaction mixture was stirred for 3 days, while heating to room temperature. Ethyl acetate (100 ml) was added The solution was washed with a saturated aqueous solution of sodium bicarbonate
(lOOml) The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as et, to give 1.18 g of N-3-tert-butyl ester ((IR) -l- {N- [(IR) -l-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] - N- methylcarbamoyl.) -2- (2-naphthyl) ethyl) -N-methylcarbamic acid.
^ -NMR (CDC13), selected va): d 0.45 and 0.71 (both m, together with 1H); 1.03, 1.05, 1.15,1.20, 1.28, 1.36,
"- ^ - • a • and 1.42 (all s, along with 9H), 2.12, 2.15, 2.21, 2.26, 2.29, 2.85 (all s, along with 6H), 5.05, 5.44, 5.58, 5.85, and 6.00 (all s, along with 2H); 7.10- 7.80 (m, 12H).
(2R) -N - [(LR) -l-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methyl-2- (methylamino) ) -3- (2-naphthyl) propionamide
At 0 ° C, trifluoroacetic acid was added to a solution of N- ((IR) -l-. {N- [(IR) -1-benzyl-2- ((3S) -3-tert-butyl ester - ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylcarbamic acid (1.18 g, 1.92 mmol) in dichloromethane ml). The reaction mixture was stirred for 50 minutes at 0 ° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (80 ml) and the solvent was removed in vacuo. The following procedure was repeated twice. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as et, to give 788 mg of (2R) -N- [(IR ) -l-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoet? l] -N-methyl-2- (methylamino) -3- (2- naphthyl) -propione ida.
1H-NMR (CDC13), selected va): d 2.01 and 2.25
(both s, along with 9H); 3.72 (m, 2H); 3.95 and 4.27 (both m, together with 1H); 5.77, 5.86, and 6.03 (t, m, and dd, together with 1H); 7.10 and 7.85 (m, 12H).
Ter-butyl ester of acid. { (3E) -4- [N- ((IR) -1- {N- [N- [(1R) -l-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin- 1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl-1, l-dimethylbut-3-enyl} carbamic
At 0 ° C, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (105 mg, 0.55 mol) was added to a solution of (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2- enoic (136 mg, 0.55 mmol) and l-hydroxy-7-azabenzotriazole (74 mg, 0.55 mmol) in dichloromethane (5 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. A solution of (2R) -N- [(IR) -1-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N- was successively added. methyl-2- (methylamino) -3- (2-naphthyl) propionamide (281 mg, 0.55 mmole) in dichloromethane (5 ml) and N, N-dimethylformamide (5 ml) and ethyldiisopropylamine (0.094 ml, 0.55 mmole). The reaction mixture was stirred for 16 hours, while heating to room temperature. It was diluted with ethyl acetate (70 ml) and washed with a saturated aqueous solution of sodium bicarbonate (70 ml).
The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 398 g of tert-butyl ester of the acid. { (3E) -4- [N- ((IR) -1- {N- [ { (IR) -l-benzyl-2- ((3S) -3- ((dimethylamino) methyl) -piperidine -1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] -l, l-dimethylbut-3-enyl} carbamic
^ -H-NMR (CDC13, selected values): d 1.44 (s, 9H); 5.58, 5.75, and 5.86 (all m, 2H); 6.09 and 6.17 (both d, together with 1H); 6.84 (m, 1H); 7.10-7.80 (m, 12H).
At 0 ° C, trifluoroacetic acid (7 ml) is added to a solution of tert-butyl ester of the acid. { (3E) -4- [N- ((IR) -1- {N - [[(lR) -l-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin-1- il) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] -l, l-dimethylbut-3-enyl} Carbamic acid (398 mg, 0.54 mmol) in dichloromethane (7 ml). The reaction mixture was stirred for 40 minutes at 0 ° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (20 ml) and the solvent was removed in vacuo. The following procedure was repeated twice. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 150 mg of the title compound.
1H-NMR (CDC13) selected values): d 1.08, 1.12, 1.14, and 1.15 (all s, along with 6H), 5.46, 5.59, 5.75, and 5.94 (all m, together with 2H); 6.15 (m, 1H); 6.93 (m,
1 HOUR) .
HPLC: 27.55 min (Al) 30.23 min (Bl)
LC-MS: 640.4 [M + 1] + at 8.54 min.
To verify biologically, the title compound was transferred to its acetate salt, by lyophilization from 0.5 M acetic acid (40 ml).
Example 3
N- ((IR) -l-. {N- [(IR) -l-benzyl-2- ((3S) -3- (dimethylaminomethyl) piperidin-1-yl) -2-oxoethyl] -N- acid methylcarbamoyl.) -2- (2-naphthyl) ethyl) -N-methylamide.
- - •• - • * - - aMlj aaaMjMll
Ter-butyl acid ester (L- { (2E) -3- [N- ((IR) -1- { N- [(IR) -l-benzyl-2- ((3S) -3 - ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] allyl} cyclobutyl) carbamic
HkriEitiMtate AO ° C, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (85 mg, 0.44 mmol) was added to a solution of (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2 acid. -enoic acid (113 mg, 0.44 mmol) and l-hydroxy-7-azabenzotriazole (60 mg, 0.44 mmol) in dichloromethane 85 ml) and N, N-dimethylformamide (5 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. A solution of (2R) -N- [(IR) -1-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N- was successively added. methyl-2- (methylamino) -3- (2-naphthyl) propionamide
(228 mg, 0.44 mmol) in dichloromethane (10 ml) and ethyldiisopropylamine (0.07 ml, 0.44 mmol). The reaction mixture was stirred for 16 hours, while heating to room temperature. It was diluted with ethyl acetate (70 ml) and washed with a saturated aqueous solution of sodium bicarbonate (70 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 314 mg of tert-butyl ester of the acid (l- . {(2E) -3- [N- ((IR) -l- {N- [(IR) -1-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin- 1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] allylcyclobutyl) carbamic
1 H-NMR (CDCl 3), selected values): d 1.40 (, 9H); 4.22 and 4.67 (both m, together with 2H); 5.660, 5.75, 5.85, and 5.90 (dd, dd, m, y, together with 2H); 6.10 and 6.19 (both d, together with 1H); 6.73 and 6.87 (you loved m, along with 1H); 7.22, 7.42, and 7.76 (all m, along with 12 H).
At 0 ° C, trifluoroacetic acid (7 ml) was added to a solution of tert-butyl ester of the acid (l- { (2E) -3- [N- ((lR) -l- { N- [(1 R) -l-benzyl-2- ((3S) -3- ((dimethylamino) methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] allyl] cyclobutyl) carbamic acid (314 mg, 0.42 mmol) in dichloromethane (7 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. The solvent was removed under vacuum without heating. The residue was dissolved in dichloromethane
(20 ml) and the solvent was removed in vacuo. The following procedure was repeated twice. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane / methanol / ammonia (100: 10: 1) as eluent, to give 180 mg of the title compound.
1H-NMR (CDCI3), selected values): d 0.40 and 0.74 (amabas m, together with 2H); 3.73 and 4.22 (both m, together with 2H); 5.57, 5.77, and 5.91 (all m, along with 2H); 6.15 and 6.24 (both d, together with 1H); 6.85 and 6.96 (both m, together with 1H); 7.22, 7.92, and 7.74 (all m, along with 12H).
HPLC: 28.03 min. (Ai, 29.92 min. (Bl '
MS: 652.4 [M + l] +
To verify biologically, the title compound was transferred to its acetate salt, by lyophilization from 0.5 M acetic acid (40 ml).
Example 4
N- ((1 R) -l- [N - [(1 R) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] -N- Methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid
2-ethyl ester of (2S! Pyrrolidin-1,2-dicarboxylic acid 1-tert-butyl ester)
N-tert-butoxycarbonylproline (24.38 g, 113 mmol) was dissolved in dichloromethane (60 ml). methanol (7.9 ml, 135 mmol) and 4-dimethylaminopyridine (1.52 g, 12.5 mmol) were added. The solution was cooled to 0 ° C. N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (23.88 g, 125 mmol) was added. The reaction mixture was stirred for 16 hours, while heating to room temperature. Ethyl acetate (400 ml) was added. It was washed with a 10% aqueous solution of sodium bisulfate (300 ml). The aqueous phase was extracted with ethyl acetate (3 x 200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (300 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate (1: 4) as eluent, to give 17.11 g of 2-ethyl ester of (2S) -pyrrolidine-1-tert-butyl ester. -1, 2- dicarboxylic
1 H-NMR (CDCl 3): d 1.28 (, 3H); 1.43 and 1.46 (both s, along with 9H); 2.95 (m, 3H); 2.22 (m, 1H); 3.50 (m, 2H); 4.18 and 4.30 (m and dd, along with 3H).
N-t-butyloxycarbonyl- (S) -prolinal
At -78 ° C, a solution of 1.2 M diisobutylaluminum hydride (31.7 ml, 38 mmol) in toluene was added dropwise to a solution of 2-ethyl ester of 1-tert-butyl ester of (2S) acid - pyrrolidin-1,2-dicarboxylic acid (4.02 g, 16.5 min) in diethyl ether (15 ml). The reaction mixture was stirred for 3 hours at -78 ° C. Water (9.9 ml) was added dropwise. The reaction mixture was heated to room temperature. The mixture was filtered through a celite layer. The celite was washed with methyl tertiary butyl ether (3 x 100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed
Tur - * --- * * - "", - "- ~ • • - * - - ^ --- - J.-.- 1 .. - < ^^ J ^ J ^ JJ _j ^ ^ Then, the vacuum was added to give 2.34 g of Nt-butyloxy-carbonyl- (S) -prolinal, which was used to the next stage without further purification.
1H-NMR (CDC13): d 1.42 and 1.47 (both s, together with 9H);
1. 70-2.20 (m, 4H); 3.20 -4.30 (m, 3H); 9.45 and 9.55 (both s, together with 1H).
(2S) -2- ((dimethylamino) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
N-t-Butoxycarbonyl- (S) -prolinal (2.34 g, 11.7 mmol) was dissolved in dichloromethane (90 ml). A 5.6 M solution of dimethylamine in ethanol (4.19 mL, 23.5 mmol) was added. 0.4 nm molecular sieve (10.0 g) was added. Sodium triacetoxyborohydride (7.47 g, 35.2 mmol) and glacial acetic acid (1.34 ml, 23.5 mmol) were successively added. The reaction mixture was stirred for 3 days. It was filtered through a layer of celite. The celite was washed with methanol (150 ml). An aqueous IN solution of sodium hydroxide (150 ml) and tert-butyl methyl ether were added.
(150 ml). The phases were separated. The aqueous phase was extracted with methyl-tert-butyl ether (83 x 100 ml). The organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 1.29 g of (2S) -butyl tert-butyl ester. -2- ((dimethylamino) methyl) pyrrolidine-1-carboxylic acid.
XH-NMR (CDC13): d 1.48 (s, 9H); 1.90 (m, 4H); 2.15 and 2.23 (AB, 2H); 2.26 (s, 6H); 3.31 (br, 2H); 3.85 (br, 1H).
N-dimethyl-N- (((2S) -pyrrolidin-2-yl) methyl) amine
A 2.7 M solution of hydrogen chloride in ethyl acetate (75 ml, 202 mmol) was added to a solution of (2S) -2- ((dimethylamino) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.29 g, 5.65 mmol) in ethyl acetate (30 ml). the reaction mixture was stirred for 30 min at room temperature. The solvent was removed in vacuo to give 1.36 g of the crude N-dimethyl-N- (((2S) -pyrrolidin-2-yl) methyl) amine dihydrochloride salt, which was used in the next step without further purification.
XH-NMR (CDC13): d 1.90 (m, 2H); 2.17 (m, 1H); 2.40 (m, 1H); 2.90 (m, 2H); 3.14 (s, 6H); 3.55 (m, 2H); 4.35 (, 1H).
N- [(IR) -l-benzyl-2- ((2S) -2- (. (Dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] -N-methylcarbamic acid tert-butyl ester
At 0 ° C, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride 81.30 g, 6.76 mmol) was added to a solution of (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino) ) -3-phenyl-propionic acid (1.89 g, 6.76 mmol) and l-hydroxy-7-azabenzotriazole (0.92 g, 6.76 mmol) endichloro ethane (10 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. a solution of the N-dimethyl-N- (((2S) -pyrrolidin-2-yl) methyl) amine dihydrochloride salt (1.36 g, 6.76 mmol) in dichloromethane (10 ml) and N, N- was added successively. dimethylformamide (10 ml) and ethyldiisopropylamine (5.75 ml, 33.8 mmol). The reaction mixture was stirred for 16 hours, while heating to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a saturated aqueous solution of sodium bicarbonate (100 ml). The aqueous phase was extracted with ethyl acetate (3 x 80 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 2.26 g of N- [(IR ) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] -N-methylcarbamic acid.
1H-NMR (CDC13), selected values): d 1.20, 1.33, and 1.37 (all s, together with 9H); 2.22 and 2.28 (both s, along with 6H); 2.82 and 2.84 (both s, together with 3H); 4.25 (m, 1H); 4.80, 5.11, and 5.30 (dd, t, and m, together with 1H); 7.10 - 7.30 (m, 5H).
C22H35N3O3 [389. 5] Cale. C, 67 83; H, 9 06; N, 10 79 Found C, 67.39; H, 9.13; N, 10.73
(2R) -1- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) 2-methylamino-3-phenylpropan-1-ketone
At 0 ° C, trifluoroacetic acid (8 ml) was added to a solution of N- [(IR) -1-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-tert-butyl ester. -1-yl) -2-oxoethyl] -N-methylcarbamic acid (2.26 g, 5.80 mmol) in dichloromethane (8 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. The solvent was removed in vacuo. Dichloromethane was added
(70 ml), and the solvent was removed in vacuo. The following procedure was repeated twice. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane / methanol / aqueous 27% ammonia solution (100: 10: 1) as eluent to give 1.24 g of (2R) -1- ((2S ) -2- ((dimethylanyl) methyl) pyrrolidin-1-yl) -2-methylamino-3-phenylpropan-1-ketone.
1H-NR (CDC13), selected values): d 2.33 (s, 3H); 2.43 (s, 6H); 3.25 (m, 3H); 4.17 (m, 1H); 7.25 (, 5H).
N- ((IR) -l- { N- [(IR) -1-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) tert-butyl ester -2-oxoethyl] -N-methylcarbamoyl] -2- (2-naphthyl) ethyl) -N-methylcarbamic
At 0 ° C, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (530 mg, 2.76 mmol) was added to a solution of (2R) -2- (N- (tert-butoxycarbonyl) -N- methylamino) -3- (2-naphthyl) -propionic acid (911 mg, 2.76 mmol) and l-hydroxy-7-azabenzotriazole (376 mg,
-á ^ dMMéwanaiii 2.76 mmoles) in dichloromethane (5 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. A solution of (2R) -1- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-methylamino-3-phenylpropan-1-ketone (800 mg, 2.76 mmol) was successively added. in dichloromethane
(5 ml) and N, N-dimethylformamide (5 ml) and ethyldiisopropylamine (0.71 ml, 4.15 mmoles). The reaction mixture was stirred for 3 days, while heating to room temperature. It was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate solution (100 ml). The aqueous solution was extracted with ethyl acetate (3 x 70 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane / methanol / 25% aqueous ammonia solution (200: 10: 1) as eluent, to give 1.37 g of N- (-butyl) -butyl ester ( (IR) -l- {N- [(IR) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] -N-methyl -carbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamic acid.
^ -NMR (CDC13, selected values): d 0.64 (m, 1H); 1.10, 1.29, 1.36, and 1.47 (all s, along with 9H); 4.99, 5.09, 5.45, and 5.53 (t, t, m, and t, together with 2H); 7.10 -7.90 (m, 12H).
(2R) -N - [(LR) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl: pyrrolidin-1-yl) -2-oxoethyl] -N-methyl-2- (methylamino) ) -3- (2-naphthyl) propionamide
At 0 ° C, trifluoroacetic acid (10 ml) is added to a solution of N- ((IR) -1- { N - [(IR) -l-benzyl-2- (( 2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylcarbamic acid (1.37 g, 2.28 mmol) in dichloromethane (10 ml). The reaction mixture was stirred for 75 minutes at 0 ° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (70 ml) and the solvent was removed in vacuo. The following procedure was repeated twice. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 692 mg of (2R) -N- [(IR ) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] -N-methyl-2- (methylamino) -3- (2-naphthyl) propionamide
XH-NMR (CDCI3, selected values): d 1.85 and 2.01 (both s, together with 3H); 2.20 and 2.31 (both s, together with
6H); 3.65 and 3.80 (both t, 1H); 4.04 and 4.45 (both m, together with 1H); 5.60 and 5.91 (t and dd, together with 1H); 7.10- 7.90 (m,
12H).
Ter-butyl ester of acid. { (3E) -4- [N- ((IR) -1- (. {N- [(1R) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1- il) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] -! -, 1-dimethylbut-3-enyl} -carbamic
At 0 ° C, N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (132 mg, 0.69 mmol) was added to a solution of (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2 acid. -noic acid (168 mg, 0.69 mmol) and l-hydroxy-7-azabenzotriazole (94 mg, 0.69 mmol) in dichloromethane (5 ml) The reaction mixture was stirred for 20 minutes at 0 ° C. A solution was successively added. of (2R) -N- [(IR) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] -N-methyl-2- ( methyl-amino) -3- (2-naphthyl) propionamide (345 mg, 0.69 mmol) in dichloromethane (10 ml) and N, N, dimethylformamide (5 ml) and ethyldiisopropylamine.The reaction mixture was stirred for 16 hours while The mixture was heated to room temperature, dissolved in ethyl acetate (70 ml) and washed with saturated aqueous sodium bicarbonate solution (70 ml), and the aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried over magnesium sulfate. The product was purified by flash chromatography on silica (40 mg)., using dichloromethane / methanol / 25% aqueous ammoniacal solut(100: 10: 1) as eluent, to give 491 mg of tert-butyl ester of the acid. { (3E) -4- [N- ((IR) -l- {N- [(IR) -l-benzyl-2- ((2S) -2- ((2S) -2- (8-dimethylamino) methyl ) pyrrolidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] -1, 1-dimethylbut-3-enyl} carbamic
^ -NMR (CDCI3, selected values): d 1.30 and 1.32
(both s, along with 6H); 1.45 (s, 9H); 1.60 (m, 2H); 4.00
(m, 1H); 4.48 (m, 1H); 5.48 (dd, 1H); 5.92 (dd, 1H); 6.11 and
6. 20 (both d, together with 1H); 6.82 and 6.9 (a, mbas m, together with 1H); 7.10 - 7.90 (, 12H).
At 0 ° C, trifluoroacetic acid (7 ml) was added to a solution of the tert-butyl ester of the acid. { (3E) -4- [N- ((IR) -1- {N - [(lR) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl. ) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] -l, l-dimethylbut-3-enyl} Carbamic acid (491 mg, 0.68 mmol) in dichloromethane (7 ml). The reaction mixture was stirred for 60 minutes at 0 ° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. The following procedure was repeated twice. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane / methanol / 25% ammonia solution (100: 10: 1) as eluent, to give 285 mg of the title compound.
4. -NMR (CDCI3, selected values): d 0.55 (m, 1H); 1.11, 1.12, and 1.17 (all s, along with 6H); 2.25 (s, 3H); 2.85 (s, 3H); 4.02 (m, 1H); 5.48 (dd, 1H); 5.80 and 5.93 (m, and dd, together with 1H); 6.10 and 6.18 (both d, together with
- «• HBkÁHiitltMai.
1 HOUR); 6.87 and 7.00 (both m, together with 1H); 7.10 - 7.90 (m, 12H).
HPLC: 27.97 min (Al) 27.80 min (Bl)
MS: 626.4 [M + 1] +
To verify biologically, the title compound was transferred to its diacetate salt by lyophilization from 0.5 M acetic acid (40 ml).
Example 5
N- ((1R) -l- {N - [(1R) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] - N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methyl-3- ((methylamino) methyl) benzamide
taa ^^^^^^ ^^^^^^^^^^^^^^^^^^? Yes, tm? Ter-butyl ester of N- acid. { 3- [N- ((IR) -l- {N- [(IR) l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl ] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] benzyl} -N-methyl-carbamic
At 0 ° C, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (132 mg, 0.69 mmol) was added to a solution of 3- (N- (tert-butoxycarbonyl) -N-methylamino) benzoic acid ( 183 mg, 0.69 mmole) and l-hydroxy-7-azabenzotriazole (94 mg, 0.69 mmole) in dichloromethane (5 ml). The reaction mixture was stirred for 20 minutes at 0 ° C. a solution of (2R) -N- [(IR) -1-benzyl-2- ((2S) -2- (dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] -N-methyl was added successively. -2- (dimethylamino) -3- (2-naphthyl) propionamide (345 mg, 0.69 mmol) in dichloromethane (10 ml) and N, N-dimethylformamide (5 ml) and ethyldiisopropylamine (0.118 ml). The reaction mixture was stirred for 16 hours, while
.á ^ li ^ l ^ iMai .MMM.MMMMÉÍÍ heated up to room temperature. It was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution (70 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 524 mg of N- -butyl tert-butyl ester. { 3- [N- (81R) -l-. { N- [(IR) -l-Benzyl-2- (2-naphthyl) ethyl) -N-methylcarbamoyl] benzyl} -N-methylcarbamic.
^ -NMR (CDC13, selected values): d 0.72 (m, 1H);
1. 45 (br, 9H); 3.18 (br, 6H); 4.05 (m, 1H); 4.32 and 4.40 (both br, together with 2H); 5.60 (dd, 1H); 5.95 (m, 1H); 6.80-6.90 (m, 16H).
At 0 ° C, trifluoroacetic acid (7 ml) was added to a solution of N- -butyl butyl ester. { 3- [N- ((IR) -1- {N - [(lR) -l-benzyl-2- ((2S) -2- ((dimethylamino) ethyl) pyrrolidin-1-yl) -2- oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylcarbamoyl] benzyl} -N-methylcarbamic acid (523 mg, 0.70 mmol) in dichloromethane (7 ml). The reaction mixture was stirred for 25 minutes at 0 ° C. the solvent was removed in vacuo. The residue was dissolved in dichloromethane (90 ml), and the solvent was removed in vacuo. The following procedure was repeated twice. The crude product was purified by flash chromatography on silica 840 g), using dichloromethane / methanol / 25% aqueous ammoniacal solution (100: 10: 1) as eluent, to give 436 mg of the title compound.
1 H-NMR (CDC13, selected values): d 0.87 (m, 1H); 1.22 (m, 1H); 1.45 (m, 1H); 1.67 (m, 1H); 4.09 (m, 1H); 5.53 and 5.90 (dd and m, together with 2H); 6.80-7.90 (m, 16H).
HPLC 28.43 min (Al) 30.63 min (Bl)
MS: 648.4 [M + l] +
To verify biologically, the title compound was transferred to its diacetate salt by lyophilization from 0.5 M acetic acid (40 ml).
Example 6
N- ((IR) -1- {N- [(1R) -l-benzyl-2- (4- (dimethyl-amino) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl] - 2- (2-E) -5-amino-5-methylhex-2-enoic acid 2- (2-naphthyl) ethyl) -N-methylamide
The title compound was prepared as in Example 1 using the hydrochloride salt of 4- (dimethylamino) piperidine, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino) -3-phenylpropionic acid,
(2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl)) propionic, and (2E) -5- (butoxycarbonylamino) -5-methylhex-2-enoic acid.
1H-NMR: (CDC13, selected values): d 1.40 (s, 6H); 2.00 (s, 6H); 4.42-4.85 (2H); 5.45 - 5.90 (m, 2H); 6.28 (dd, 1H); 6.85 (m, 1H); 7.10-7.85 (m, 12H).
MS (ES): m / z 626.2 (M + H) Example 7
N-methyl-N [(IR) -1- (N-methyl-N- { (IR) -1 - [N-methyl-N- (1-methylpiperidin-4-yl) carbamoyl] -2-f (2E) -5-amino-5-methylhex-2-enoic acid (2-naphthyl) ethyl] -aminoethyl) carbamoyl) -2- (2-naphthyl) ethyl] amide
The title compound was prepared as in Example 1 using 1-methyl-4- (methylamino) piperidine, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino) -3-phenylpropionic acid, ( 2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl) propionic, and (2E) -5- (butoxycarbonylamino) -5-methylhex-2-enoic acid.
• ui ^. ^. ^ Ít > a? .t 1 H-NMR (CDC13; selected values), d 5.50 - 6.08 (m, 2H); 6.20-6.70 (m, 2H); 7.10-7.85 (m, 12H).
Example 8
3-aminomethyl-N- ((IR) -l- [N- [(IR) -l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbarrol.oil. -2- (2-naphthyl) ethyl) -N-methylbenzamide
The title compound was prepared as in Example 1, using N-methyl piperazine, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino) -3-phenylpropionic acid, (2R) -2- ( N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl)) propionic, and 3- ((tert-butoxycarbonylamino) methyl) benzoic acid.
! Mi..M * k i • UÉ * ....!. ^ 1 H-NMR (CDC13, selected values): d 3.30 (m, 1H); 3.50 (dd, 1H); 3.75 (m, 1H); 3.95 (s, 2H); 5.78 (t, 1H); 3.88 (m, 1H); 7.00 - 7.80 (16H).
HPLC: 24.55 (A1). 26.52 (B1). MS (ES): m / z = 606.4 [M + H] +
Example 9
N- (IR) -1-. { N - [(1 R) -l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid
^^^^^^^^^^^^^ a ^ ^ The title compound was prepared as in Example 1 using N-methyl piperazine, (2R) -2- (N- (tert-butoxycarbonyl) -N- acid methylamino) -3-phenylpropionic acid, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl) propionic acid, and (2E) -5- (butoxycarbonylamino) -5- acid) methylhex-2-enoic.
^ - MR (CDC13, selected values): d 1.24 (s, 6H); 1.65 (s, 3H); 2.35 (s, 3H); 2.80 (s, 3H); 5.68 (dd, 1H); 6.18 (dd, 1H); 6.95 (m, 1H); 7.15-7.80 (m, 12H).
HPLC: 25.03 min (Al). 27.50 min (Bl).
MS (ES): m / z = 598.4 [M + H] +.
Example 10
N-methyl-N- ((IR) -l- { N-methyl-N- [(IR) -2-phenyl-1 - ((2,2,6,6-tetramethylpiperidin-4-yl) carbamoyl) ethyl) carbamoyl.} -2- (2-naphthyl) ethyl) (2E) -5-amino-5-methylhex-2-enoic acid amide
The title compound was prepared as in Example 1, using 4-amino-2,2,6,6-tetramethyl-piperidine, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino) - 3-phenylpropionic, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl)) propionic acid, and (2E) -5- (butoxycarbonylamino) -5-methylhex- 2-enoic.
^ -NMR (CDCl3: selected values): d 1.25 (s, 6H);
1. 40 (two s, 6H); 1.52 (two s, 6H); 2.92 (s, 3H); 3.02 (two s, 3H); 5.10 (dd, 1H); 5.50 (dd, 1H); 6.15 (d, 1H); 6.75 (m, 1H); 7.00-8.00 (m, 12H).
HPLC: 29.27 min (Al) 31.67 min (Bl) MS (ES): m / z = 654.8 [M + H] +.
Example 11
3-aminomethyl-N-methyl-N- ((IR) - {N-methyl-N- [(IR) -2-phenyl-1- ((2,6,6,6-tetramethylpiperidin-4-yl) ) carbamoyl) ethyl] carbamoyl.}. -2- (2-naphthyl) ethyl) benzamide
The title compound was prepared as in Example 1, using 4-amino-2,2,6,6-tetramethyl-piperidine, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino) - 3-phenylpropionic acid (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl)) propionic acid and 3- ((tert-butoxycarbonylamino) methyl) benzoic acid.
1 H-NMR (CDCl 3); selected values): d 3.60 - 3.85 (m, 2H); 3.90 - 4.30 (m, 1H); 5.25-5.95 (m, 2H); 6.70 - .90 (m, 16H).
HPLC: 29.27 min (Al) 31.55 min (Bl) MS (ES): m / z = 662.4 [M + H] 4
Example 12
N-methyl-N- ((1R) -l- {N-methyl-N - [(1R) -2-phenyl-1 - ((2,2,, 6-tetramethylpiperidin-4-yl) carbamoyl) ethyl] carbamoyl.} -2- (2-naphthyl) ethyl) (2E) -5-amino-3,5-dimethylhex- -enoic acid amide
• The title compound was prepared as in Example 1, using 4-amino, 2, 26, 6-tetramethyl-piperidine, (2R) -2- (N- (tert-butoxycarbonyl) -N- methylamino) -3-phenylpropionic acid, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl)) propionic acid, and (2E) -5- (butoxycarbonylamino) -3 acid , 5-methylhex-2-enoic.
1 H-NMR (CDC 13, selected values): d 3.92-4.30 (m, 1H); 5.05-5.88 (m, 3H); 7.00 - 7.80 (m, 12 H).
HPLC: 29.80 min (Al) 32. 43 min (Bl). MS (ES): m / z = 668. 4 [M + H] +.
Example 13
N- ((IR) 1- {N - [(1R) l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2- Naphthyl) (2E) -4- (1-aminocyclobutyl) but-2-enoic acid ethyl-N-methylamide
-llitltaAAatitiiiaitMl.
The title compound was prepared as in Example 1, using N-methylpiperazine, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino) -3-phenylpropionic acid, (2R) -2- ( N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl) propionic, and (2E) -4- (l-butoxycarbonylamino) cyclobutyl) but-2-enoic acid.
^ -NMR (CDC13, selected peaks): d 1.62 (s, 3H); 2.35 (s, 3H); 2.80 (s, 3H); 55.70 (dd, 1H); 5.80 (dd, 1H); 6.22 (d, 1H); 6.98 (m, 1H); 7.15-7.80 (m, 12H).
HPLC: 25.88 min (Ai, 28.65 min (Bi; MS (ES): m / z = 610.4 [M + H] +.
^ b ^^ M ^^ i || ^ ritwU¡aa? tti | Éj | flUfeÍBMafi | jhd ^ ^^^^^^ j mm? ik Example 14
N- ((IR) 1- {N - [(1R) l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2- (2E) -5-amino-3,5-dimethylhex-2-enoic acid) naphthyl) ethyl) -N-methylamide
The title compound was prepared as in Example 1, using N-methylpiperazine, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino) -3-phenylpropionic acid, (2R) -2- ( N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl)) propionic, and (2E) -5- (butoxycarbonylamino) -3,5-methyl-hex-2-enoic acid.
^ i-NMR (CDC13; selected values): d 1.18 (s, 6H); 1.68 (s, 3H); 1.95 (ss, 3H); 2.30 (s, 3H); 2.85 (s, 3H);
3. 40 (dd, 1H); 3.54-3.75 (m, 2H); 5.68-5.85 (m, 3H); 7.15-7.80 (m, 12H).
HPLC; 25.70 min (Al) 28.27 min (Bl) MS (ES): m / z = 612.4 [M + H] +.
Example 15
N- ((1R) -1- { N - [(1R) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -oxoethyl] -N-methylcarbamoyl.} - 2- (Biphenyl-4-yl) ethyl) -N-methylamide of (2 E) -4- (l-aminocyclobutyl) but-2-enoic acid
This compound was prepared as in Example 1 but using 4-hydroxypiperidine, (2R) - (N-tert-butoxycarbonyl-N-methylamino) -3-phenylpropionic acid and (2R) -2- (N-tert-butoxycarbonyl-) acid. N-methylamino) -3- (biphenyl-4-yl) propionic, and (2E) -4- (1- (tert-butoxycarbonylamino) cyclobutyl) but-2-enoic acid as starting materials.
ESMS: 637.4 (M + H) + HPLC: rt = 33.58 min (Al). HPLC: rt = 34.95 min (Bl).
Example 16
N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- ( bifenyl-4-yl) ethyl) -N-methylamide of the acid (2E) -5-amino-5-methylhex-2-enoic acid
This compound was prepared as in Example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3-phenylpropionic acid and (2R) -2- (N-tertiary) acid. butoxycarbonyl-N-methylamino) -3- (biphenyl-4-yl) propionic acid and (2E) -5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid as starting materials.
ESMS: 625.4 (M + H) + HPLC: rt = 32.65 min. (H) HPLC: rt = 34.02 min. (Bl).
Example 17
N- ((1R) -l-. {N - [(1 R) -l-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2 - (2E) -5-amino-3,5-dimethylhex-2-enoic acid (biphenyl-4-yl) ethyl-N-methylamide
? ^ ^ _ ^ i - ^ _ ^ _ -É-_ _ __ ^ _ ^^ _ ^^^^^^^^ - i ^ _ ^ -jÉa? B¡tÉjfc? iiál This compound was prepared as in Example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3-phenylpropionic acid and (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) acid) -3- (biphenyl-4-5-yl) propionic acid and (2E) -5-tert-butoxycarbonylamino-3,5-dimethylhex-2-enoic acid as starting materials.
ESMS: 639.4 (M + H) + HPLC: rt = 33.29 min. (H) HPLC: rt = 36.40 min. (Bl)
Example 18
N- ((1R) -l-. {N - [(1 R) -l-benzyl-2- (4-hydroxy-pperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-N-methyl-5-methylhex-2-enoic acid (2-naphthyl) ethyl) -N-methylamide
? «A-í -». TMI «r 'i» it - - iimm ^ íáM¡. ^ - ^^ *? * ^^^^^^^^^ a ^^ - ^ * u ^^^^^^ ? á ^ m ^ ** la ^ - ^^ ** li tttmmá¡? ^^ gíí¡m you? This compound was prepared as in Example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3-phenylpropionic acid and (2R) -2- (N-tertiary) acid. butoxycarbonyl-N-methylamino) -3- (2-naphthyl) propionic acid and (2E) -5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid as starting materials.
ESMS: 599.4 (M + H) t HPLC: rt = 29.88 min. (To the).
Example 19
N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- ( 2-Naphthyl) ethyl) -N-methylamide of (2E) -5-amino-3,5-dimethylhex-2-enoic acid
.M ^^ - ^ a ^^ u ^ H-Et, This compound was prepared as in Example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) - 3-phenylpropionic acid and (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (2-naphthyl) propionic acid and (2E) -5-tert-butoxycarbonylammo-3,5-dimethylhex-2 acid -enoic as initial materials.
ESMS: 613.4 (M + H) + HPLC: rt = 30.58 min. (To the).
Example 20
N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2 - (2-E) -4- (1-aminocyclobutyl) but-2-enoic acid (2-naphthyl) ethyl) -N-methylamide
This compound was prepared as in example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3-phenylpropionic acid and (2R) -2- (N-tert-) butoxycarbonyl-N-methylamino) -3- (2-naphthyl) propionic acid and (2E) -4- (1- (tert-butoxycarbonylamino) cyclobutyl) but-2-enoic acid.
ESMS: 611.4 (M + H) + HPLC: rt = 30.82 min (Al). 10 Example 21
N- ((IR) -l- { N- [(IR) -1- (4-f luorobenzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl 2 (2E) -5-amino-5-methylhex-2-enoic acid (2-naphthyl) -5-ethyl) -N-methylamide
^^^ ¡* ^^ w This compound was prepared as in Example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (4-fluorophenyl) propionic acid and (2R) -2- (N-tert-butoxy-carbonyl-N-methylamino) -3- (2-naphthyl) ropionic acid and (2E) -5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid as initial materials.
ESMS: 617.4 (M + H) t HPLC: rt = 30.27 min. (Al) HPLC: rt = 31.60 min. (Bl)
Example 22
N- ((IR) -1- {N - [(1R) -1- (4-fluorobenzyl) -2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl] -2 - (2-E) -5-amino-3,5-dimethylhex-2-enoic acid (2-naphthyl) ethyl) -N-methylamide
This compound was prepared as in example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (4-fluorophenyl) propionic acid and (2R) -2- acid (N-tert-butoxy-carbonyl-N-methylamino) -3- (2-naphthyl) propionic acid and (2E) -5-tert-butoxycarbonylamino-3,5-dimethylhe-2-enoic acid as starting materials.
ESMS: 631.4 (M + H) + HPLC: rt = 30.98 min. (To the). HPLC: rt = 32.38 min. (Bl)
Example 23
N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4- (dimethylamino) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-Naphthyl) ethyl) -N-methylamide of (2E) 4- (1-aminocyclobutyl) but-2-enoic acid
The title compound was prepared as in Example 1 using 4-N, N-dimethylpiperazine, (2R) -2- (N- (tert-butoxycarbonyl) -N-methylamino) -3-phenylpropionic acid, (2R) - 2- (N- (tert-butoxycarbonyl) -N-methylamino-3- (2-naphthyl)) propionic, and (2E) -4- (1-butoxycarbonylamino) cyclobutyl) but-2-enoic acid.
^ -NMR (CDC13, selected peaks): d 1.90 (s, 3H); 2.38 (s, 3H); 2.45 and 2.47 (two s, 3H) 2.78 2.80 (two s, 3H); 6.32 (dd, 1H); 6.90 (m, 1H); 7.15-7.84 (m, 12H).
HPLC: 26.72 min (Al). MS (ES): m / z = 638.4 [M + H] +.
Example 24
N- ((IR) -l- {N- [(2R) -2- (4-hydroxypiperidin-1-yl) -2-oxo-1- (f 2-thienyl) methyl) ethyl] -N- methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid
This compound was prepared as in Example 1 but using 4-hydrox-piperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (2-thienyl) propionic acid and acid
(2R) -2- (N-tert-butoxy-carbonyl-N-methylamino) -3- (2-naphthyl) propionic and (2E) -5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid as starting materials .
ESMS: 605. 4 (M + H) + HPLC: rt = 29. 07 min. (Al)
Example 25
N- ((1R) -1- {N - [(2R) -2- (4-hydroxypiperidin-1-yl) -2-oxo-1- ((2-thienyl) methyl] ethyl-N-methylcarbamoyl 2 (2E) -5-amino-3,5-dimethylhex-2-enoic acid (2-naphthyl) ethyl) -N-methylamide
This compound was prepared as in example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (2-thienyl) propionic acid and acid
(2R9-2- (N-tert-butoxycarbonyl-N-methylamino) -3- (2-naphthyl) propionic acid and (2E) -5-tert-butoxycarbonylamino-3, 5-dimethylhex-2-enoic acid as starting materials.
ESMS: 619.4 (M + H) + HPLC: rt = 29.76 min. (To the).
Example 26
N- ((IR) -2- (biphenyl-4-yl) -1- { N - [(2R) -2- (4-hydroxypiperidin-1-yl) -2-oxo-l- ((2 methyl) ethyl] -N-methylcarbamoyl.} ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid
This compound was prepared as in example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (2-thienyl) propionic acid and acid
(2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (biphenyl-4-yl) propionic acid and (2E) -5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid as starting materials .
ESMS: 631. 2 (M + H) + HPLC: rt = 32. 20 min. (Al)
Example 27
N- ((1 R) -2- (biphenyl-4-yl) -l- { N - [(1 R) -2- (4-hydroxypiperidin-1-yl) -2-oxo-1 - ((2 thienyl) methyl) ethyl] -N-methylcarbamoyljetyl) -N-methylamide (2E) -5-amino-3,5-dimethylhex-2-enoic acid
This compound was prepared as in example 1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (2-thienyl) propionic acid and (2R) -2- acid (N-tert-butoxycarbonyl-N-methylamino) -3- (biphenyl-4-yl) propionic acid and (2E) -5-tert-butoxycarbonyl-amino-3,5-dimethylhex-2-enoic acid as starting materials ..
ESMS: 465.4 (M + H) + HPLC: rt = 32.89 min. (To the)
Example 28
N- ((1R) -l-. {N - [(1 R) -l-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- ( (2E) -5-Methyl-5- (methylamino) hex-2-enoic acid bifenyl-4-yl) ethyl) -N-methylamide
The title compound was prepared as in the example
1 but using 4-hydroxypiperidine, (2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3-phenylpropionic acid and acid
(2R) -2- (N-tert-butoxycarbonyl-N-methylamino) -3- (biphenyl-4-yl) propionic acid and (2E) -5- (N- (tert-butoxycarbonyl) -N-methylamino) - 5-methylhex-2-enoic as starting materials.
MS: m / z: 639.4 (M + H) + HPLC: Method Al: R t = 32.94 min.
Example 29
((IR) -1- {N - [(1R) -1-benzyl-2- (4-hydroxy-pperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (biphenyl-) (2 E) -4- (1-aminocyclobutyl) but-2-enoic acid (4-yl) ethyl) amide
HPLC 10: Rt = 31.55 min. (Al) Rt = 33.11 min. (Bl)
LC-MS: 623.6 [M + l] + 15 It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. Having described the invention as above, it is claimed as property in the following:
ala-auaaBBaifUÍÍ * JB_lÍaaM aUaaMÉi
Claims (19)
1. A compound of the general formula I 10 formula I which is characterized because, R1 is hydrogen or C ± s alkyl; R, 2 ~ is hydrogen or C? _6 alkyl; L is Wherein R 4 is hydrogen or C 6 alkyl; •• lládlattalfeaaaaurtHiaa ^ rfai HB ^ _ ^^ aBaBIBk __ ^^ BB ^ Ba p is 0 or 1; q, s, t, u, are independently of each other 5 0, 1, 2, 3, or 4; r is 0 or 1; the sum of q + r + s + t + u is O, 1, 2, 3, 6 4; R9, R10, R11, and R12 are each independently of the other, hydrogen or Ci-e alkyl; Q is > N-R1 or 15 where o is 0, 1 or 2; 20 T is -N (R15) (R16) or hydroxyl; R13, R15 and R15 are each independently of the other hydrogen or C? -6 alkyl; 25 --A * A- R is hydrogen, aryl or hetaryl; G is -O- (CH2) k -R17, wherein R17, R18, R19, R20 and R21 independently of each other are hydrogen, halogen, aryl, hetaryl, C? -6-alkyl or Ci-e-alkoxy; k is 0, 1 or 2; wherein R22, R23, R24, R25 and R26 independently of each other are hydrogen, halogen, aryl, hetaryl, Ci-e-alkyl or C? _d-alkoxy; 1 is 0, 1 or 2; a is 0, 1, or 2; b is 0, 1, or 2; c is 0, 1, or 2; d is 0 or 1; e is 0, 1, 2, or 3; f is 0 or 1; R5 is hydrogen or C6-6-alkyl optionally substituted with one or more hydroxyls, aryls or hetaryls; R6 and R7 are independently each other hydrogen or C6-6-alkyl, optionally substituted with one or more halogens, hydroxyl, aryl, or hetaryl; R "is hydrogen or Ci-e-alkyl, optionally substituted with one or more halogens, amines, hydroxyls, aryls, or hetaryls; R6 and R7 or R6 and R8 or R 'and R8 can optionally form - (CH2) iU- (CH2) -, -, where i and j independently of each other are 1, 2 or 3 and U is -0-, - S-, or a valence link; M is arylene, hetherylene, -0-, -S-, or -CR27 = CR28- R27 and R28 are independently each other hydrogen or C ± -β-alkyl, optionally substituted with one or more aryls or hetaryls; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 which is characterized in that R1 is Cj.-6-alkyl.
3. The compound according to any of the preceding claims which is characterized in that R2 is C? -6-alkyl.
4. The compound according to any of the preceding claims which is characterized in that L is wherein R4 is hydrogen or C6-6-alkyl; p is 0 or 1; q, s, t, u are independently of each other 0, 1, 2, 3 or 4; r is 0 or 1; the sum q + r + s + t + u is 0, 1, 2, 3, or 4; R9, R10, and R11 are each independently of the other hydrogen or C6-6-alkyl; Q is > N-R 13 or where o is 0, 1 or 2; T is -N (R15) (R16) or hydroxyl; R ± 3, R15, and Rld are independently each other hydrogen or C? -6-alkyl; Y R .14 is hydrogen, aryl or hetaryl,
5. The compound according to any of claims 1-3 which is characterized in that L is wherein q, s, t, u are independently of each other 0, 1, 2, 3 or 4; r is 0 or 1; the sum q + r + s + t + u is 0, 1, 2, 3, or 4; R9, R10, R11, and R12 are independently each other hydrogen or C6-alkyl; where o is 0, 1 or 2; T is -N (R15) (Rld) or hydroxyl; R, R, and R are each independently of the other hydrogen or C? -6-alkyl; Y R14 is hydrogen, aryl or hetaryl.
6. The compound according to any of the preceding claims which is characterized in that G is wherein R17, R18, R19, R20 and R21 independently of each other are hydrogen, halogen, aryl, hetaryl, C? -6-alkyl or C? -5-alkoxy.
7. The compound according to any of the preceding claims which is characterized in that J is wherein R, R23, R24, R25 and R26 are each independently of the other hydrogen, halogen, aryl, hetaryl, Ci-6-alkyl or C6-6-alkoxy.
8. The compound according to any of the preceding claims which is characterized in that M is arylene or -CR27 = CR28-, wherein R27 and R28 are independently each other hydrogen or Ci-alkyl-, optionally substituted with aryl or hetaryl.
9. The compound according to any of the preceding claims which is characterized in that R6 and R7 independently from each other are hydrogen or C6-6-alkyl.
10. The compound according to any of claims 1-8 which is characterized in that R6 and R 'of - (CH2) iU- (CH2) -, -, where i and J independently of each other are 1.2 or 3 and U is -O-, -S- or a valence bond.
11. The compound according to any of the preceding claims which is characterized in that R8 is hydrogen or C6-alkyl.
12. The compound according to any of the preceding claims which is characterized in that it is selected from: N- ((IR) -l- {N- [(IR) -l-benzyl-2- (4- ((dimethylamino) -methyl) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl 2 (2E) -5-am? No-5-methylhex-2-enoic acid (2-naphthyl) ethyl) -N-methylamide. 10 N- ((1R) -l- {N - [(1R) -l-benzyl-2- ((3S) -3- (dimethyl-aminomethyl) piperidin-1-yl) -2-oxoethyl]] -N-methylcabamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid N- ((IR) -l- {N- [(IR) -l-benzyl-2- ((3S) -3- (dimethyl-aminomethyl) piperidin-1-yl) 2-oxoethyl] -N- methylcarbamoyl.} -2- (2- Naphthyl) ethyl) -N-methylamide: 2E) -4- (1-aminocyclobutyl) but-2-enoic N- ((1R) -l- {N - [(1R) -l-benzyl-2- ((2S) -2- (dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] -N -methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid N- ((1R) -l- {N - [(1R) -l-benzyl-2- ((2S) -2- ((dimethylamino) methyl) pyrrolidin-1-yl) -2-oxoethyl] - N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methyl-3- ((methylamino) methyl) benzamide N- ((1R) -l- {N - [(1R) -l-benzyl-2- (4- (dimethyl-amino) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl. -2 (2E) -5-amino-5-methylhex-2-enoic acid (2-naphthyl) ethyl) -N-methylamide N-methyl-N - [(lR) -1- (N-methyl-N- { (IR) -l- [N-methyl-N- (1-methylpiperidin-4-yl) carbamoyl] -2- (2E) -5-amino-5-methylhex-2-enoic acid phenylethylcarbamoyl) -2- (2-naphthyl) ethyl] amide] HBaÜhi 3-aminomethyl-N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4-methyl-piperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl}. -2- (2-naphthyl) ethyl) -N-methylbenzamide N- ((IR) -1- {N-- (IR) -l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- ( 2-Naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid N-methyl-N- ((1R) -1- (N-methyl-N- [(IR) -2-f-enyl-1- ((2,2,6,6-tetramethylpiperidin-4-yl) carbamoyl) ethyl] carbamoyl.} -2- (2-naphthyl) ethyl) (2E) -5-amino-5-methylhex-2-enoic acid amide 3-aminomethyl-N-methyl-N ((IR) -l. {N-methyl-N- [(IR) -2-phenyl-1- ((2, 2, 6, 6, tetramethylpiperidin-4-yl) ) carbamoyl) ethyl] carbamoyl.}. -2- (2-naphyl) ethyl) benzamide N-methyl-N- ((lR) -l { N-methyl-N - [(lR) -2-phenyl-1 - ((2,2,6,6-tetramethylpiperidin-4-yl) carbamoyl) ethyl] carbamoyl.} -2- (2-naphthyl) ethyl) (2E) -5-amino-3,5-dimethylhex-2-enoic acid amide N- ((IR) 1- {N - [(1R) l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2- Naphthyl) ethyl) -N-methylamide of (2E) -4- (1-aminocyclobutyl) but-2-enoic acid N- ((IR) l-. {N - [(1R) l-benzyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2- Naphthyl) ethyl) -N-methylamide of (2E) -5-amino-3,5-dimethylhex-2-enoic acid N- ((IR) -1- {N- [(IR) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- ( (2E) -4- (1-aminocyclobutyl) ut-2-enoic acid biphenyl-4-yl) ethyl) -N-methylamide N- ((1R) -l-. {N - [(1 R) -l-benzyl-2- (4-hydroxy-pperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2E) -5-amino-5-methylhex-2-enoic acid (biphenyl-4-yl) ethyl-N-methylamide 25 i lniiiiirirriiii 'i' - 'N- ((IR) -l- { N- [(IR) -l-benzyl-2- (4-hydroxypiperidin-l-yl) -2-oxoethyl] -N- Methylcarbamoyl.} -2- (biphenyl-4-yl) ethyl) -N-methylamide of (2E) -5-amino-3,5-dimethylhex-2-enoic acid N- ((? R) -I- (N-- (lR) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2 -nafyl) (2E) -5-amino-5-methylhex-2-enoic acid) -N-methylamide N- ((IR) 1- {N - [(1R) l-benzyl-2- (4-hydroxypiperidin 1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-3,5-dimethylhex-2-enoic acid N- ((1R) -l-. {N - [(1 R) -l-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- ( 2-Naphthyl) ethyl) -N-methylamide of (2E) -4- (1-aminocyclobutyl) but-2-enoic acid N- ((1R) -1- { N - [(1R) -1- (4-fluorobenzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid N- ((IR) -1- {N - [(1R) -1- (4-fluorobenzyl) -2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl) -2 - (2-E) -5-amino-3,5-dimethylhex-2-enoic acid (2-naphthyl) ethyl) -N-methylamide N- ((1R) -l-. {N ((R) -l-benzyl-2- (4-hydroxy-4- (2-thienyl) piperidin-1-yl) -2-oxoethyl] -N- Methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid N- ((IR) -l-. {N- [(IR) -1- (3-hydroxy-cyclohexy-carbamoyl) -2-phenylethyl] -N-methylcarbamoyl} -2- (2-naphthyl) ethyl) - N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid N- (IR) -1-. { N - [(1R) -l-benzyl-2- (4- (dimethylamino) piperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl} -2- (2-Naphthyl) ethyl) -N-methylamide of (2 E) -4- (1-aminocyclobutyl) but-2-enoic acid 15 N- ((1R) -l- {N - [(2R) -2- (4-hydroxypiperidin-1-yl) -2-oxo-1- ((2-thienyl) methyl) ethyl] -N -methylcarbamoyl.} -2- (2-naphthyl) ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid 25 ^^^ U ^^^^ M N- ((IR) -1- { N - [(2R) -2- (4-hydroxypiperidin-1-yl) -2-oxo- 1- ((2 thienyl) methyl) ethyl] -N-methylcarbamoyl] -2- (2-naphthyl) ethyl-N-methylamide of (2E) -5-amino-3,5-dimethylhex-2-enoic acid N- ((IR) -2- (biphenyl-4-yl) -l- { N- [(2R) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-l- ( (2-Thienyl) methyl) ethyl] -N-methylcarbamoyl.} Ethyl) -N-methylamide of (2E) -5-amino-5-methylhex-2-enoic acid ^^^ üdüMa N- ((IR) -2- (biphenyl-4-yl) -1- { N - [(1R) -2- (4-hydroxypiperidin-1-yl) -2-oxo-l ((2-thienyl) methyl) ethyl] -N-methylcarbamoyl.} Ethyl) -N-methylamide of (2E) -5-amino-3,5-dimethylhex-2-enoic acid N- ((IR) -l-. {N- [(IR) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-oxoethyl] -N-methylcarbamoyl} 2 (2E) -5-Methyl-5- (methylamino) hex-2-enoic acid (2-biphenyl-4-yl) ethyl) -N-methylamide ((IR) -1- {N - [(1R) -l-benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -N-methylcarbamoyl.} -2- (biphenyl-) (2 E) -4- (1-aminocyclobutyl) but-2-enoic acid (4-yl) ethyl) amide and pharmaceutically acceptable salts thereof.
13. Use of a growth hormone secretagogue or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of growth retardation in connection with asthma.
14. The use according to claim 13 which is characterized in that the growth hormone secretagogue is a compound according to any of the compounds of the preceding claims or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition which is characterized in that it comprises, as an active ingredient, a compound according to any of the compounds of the preceding claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable vehicle or diluent.
16. A method of stimulating the release of growth hormone from the pituitary of a mammal, the method which is characterized in that it comprises administering 10 to said mammal an effective amount of a compound according to any of the compounds of the preceding claims or a pharmaceutically acceptable salt thereof or of a composition according to any of the compositions of the claims 15 preceding.
17. Use of a compound according to any of the compounds of the preceding claims or a pharmaceutically acceptable salt thereof for the preparation 20 of a medicament for stimulating the release of growth hormone from the pituitary of a mammal.
18. Use of a growth hormone secretagogue or a pharmaceutically acceptable salt thereof 25 for the preparation of a medication for the treatment t m &t¡ás¡¡. of growth retardation in connection with juvenile rheumatic arthritis or cystic fibrosis.
19. The use according to claims 13 or 18 which is characterized in that the growth hormone secretagogue is selected from among growth hormone releasing peptides, growth hormone releasing peptides, and growth hormone releasing compounds of a nature non-peptidic ^^^^^^^^^^^^^^^^^^ g ^^^^^^^
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PAPA199800857 | 1998-06-30 | ||
PAPA199801440 | 1998-11-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00012489A true MXPA00012489A (en) | 2002-07-25 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4938708B2 (en) | Compounds with growth hormone releasing properties | |
US6576648B2 (en) | Compound with growth hormone releasing properties | |
US6303620B1 (en) | Compounds with growth hormone releasing properties | |
JP2003527338A5 (en) | ||
US7576062B2 (en) | Compounds with growth hormone releasing properties | |
RU2298547C2 (en) | Compounds and pharmaceutical composition possessing property for growth hormone releasing, method for stimulation of secretion of growth hormone from mammal hypophysis | |
US6566337B1 (en) | Compounds with growth hormone releasing properties | |
MXPA00012489A (en) | Compounds with growth hormone releasing properties | |
ES2361606T3 (en) | COMPOSITIONS WITH GROWTH HORMONE RELEASE PROPERTIES. | |
MXPA00010585A (en) | Compounds with growth hormone releasing properties | |
IL149049A (en) | 2 - amino - n - [(1r) - 2 - [(3r) - 3 benzyl - 3 - (benzyl - 3 - (n', n', n - trimethylhydrazinocarbonyl) piperidin - 1 - yl] - 1 - (1h - indol - 3 - ylmethyl) - 2 oxoethyl] - 2 - methylpropionamide, pharmaceutical composition comprising it and its use for the manufacturing of medicaments for releasing growth hormone |