EP0833845A1 - Compounds with growth hormone releasing properties - Google Patents
Compounds with growth hormone releasing propertiesInfo
- Publication number
- EP0833845A1 EP0833845A1 EP96920742A EP96920742A EP0833845A1 EP 0833845 A1 EP0833845 A1 EP 0833845A1 EP 96920742 A EP96920742 A EP 96920742A EP 96920742 A EP96920742 A EP 96920742A EP 0833845 A1 EP0833845 A1 EP 0833845A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phe
- 2nal
- aminomethylbenzoyl
- acid
- aib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 74
- 102000018997 Growth Hormone Human genes 0.000 title claims abstract description 44
- 108010051696 Growth Hormone Proteins 0.000 title claims abstract description 44
- 239000000122 growth hormone Substances 0.000 title claims abstract description 44
- 230000003578 releasing effect Effects 0.000 title description 5
- 230000001817 pituitary effect Effects 0.000 claims abstract description 18
- -1 guanidino, piperazino, morpholino, piperidino Chemical group 0.000 claims description 94
- 239000000203 mixture Substances 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 20
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- JPZXHKDZASGCLU-GFCCVEGCSA-N 3-(2-Naphthyl)-D-Alanine Chemical compound C1=CC=CC2=CC(C[C@@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-GFCCVEGCSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims description 7
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 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 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 6
- 230000012010 growth Effects 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000004936 stimulating effect Effects 0.000 claims description 6
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 claims description 5
- 150000008574 D-amino acids Chemical class 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- WVMBPWMAQDVZCM-UHFFFAOYSA-N N-methylanthranilic acid Chemical compound CNC1=CC=CC=C1C(O)=O WVMBPWMAQDVZCM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- GSWYUZQBLVUEPH-UHFFFAOYSA-N 3-(azaniumylmethyl)benzoate Chemical compound NCC1=CC=CC(C(O)=O)=C1 GSWYUZQBLVUEPH-UHFFFAOYSA-N 0.000 claims description 3
- 238000003691 Amadori rearrangement reaction Methods 0.000 claims description 3
- 108010077895 Sarcosine Proteins 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000000539 amino acid group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
- 235000013336 milk Nutrition 0.000 claims description 3
- 239000008267 milk Substances 0.000 claims description 3
- 210000004080 milk Anatomy 0.000 claims description 3
- 238000007911 parenteral administration Methods 0.000 claims description 3
- 230000002685 pulmonary effect Effects 0.000 claims description 3
- 229940043230 sarcosine Drugs 0.000 claims description 3
- 210000002268 wool Anatomy 0.000 claims description 3
- WTKYBFQVZPCGAO-LURJTMIESA-N (2s)-2-(pyridin-3-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CN=C1 WTKYBFQVZPCGAO-LURJTMIESA-N 0.000 claims description 2
- KGSVNOLLROCJQM-UHFFFAOYSA-N 2-(benzylamino)acetic acid Chemical compound OC(=O)CNCC1=CC=CC=C1 KGSVNOLLROCJQM-UHFFFAOYSA-N 0.000 claims description 2
- ATAFDSCDEDHMOK-UHFFFAOYSA-N 3,3-diaminopropanoic acid Chemical compound NC(N)CC(O)=O ATAFDSCDEDHMOK-UHFFFAOYSA-N 0.000 claims description 2
- NFQAIWOMJQWGSS-UHFFFAOYSA-N 3-amino-3-methylbutanoic acid Chemical compound CC(C)(N)CC(O)=O NFQAIWOMJQWGSS-UHFFFAOYSA-N 0.000 claims description 2
- OWSRLHPWDZOHCR-UHFFFAOYSA-N 4,4-diaminobutanoic acid Chemical compound NC(N)CCC(O)=O OWSRLHPWDZOHCR-UHFFFAOYSA-N 0.000 claims description 2
- CMUHFUGDYMFHEI-QMMMGPOBSA-N 4-amino-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N)C=C1 CMUHFUGDYMFHEI-QMMMGPOBSA-N 0.000 claims description 2
- 150000008575 L-amino acids Chemical class 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 241000024188 Andala Species 0.000 claims 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical compound CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 claims 1
- 239000001294 propane Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 136
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
- 229910001868 water Inorganic materials 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 230000014759 maintenance of location Effects 0.000 description 36
- 238000004007 reversed phase HPLC Methods 0.000 description 36
- 239000003921 oil Substances 0.000 description 35
- 235000019198 oils Nutrition 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
- 108090000765 processed proteins & peptides Proteins 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 23
- 235000017557 sodium bicarbonate Nutrition 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 238000010828 elution Methods 0.000 description 19
- 239000012467 final product Substances 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 238000004987 plasma desorption mass spectroscopy Methods 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 238000011894 semi-preparative HPLC Methods 0.000 description 9
- 238000004949 mass spectrometry Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000004108 freeze drying Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- 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 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 239000007821 HATU Substances 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- 102100022831 Somatoliberin Human genes 0.000 description 5
- 101710142969 Somatoliberin Proteins 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 5
- 229940080818 propionamide Drugs 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 5
- 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 4
- 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 4
- 102100033367 Appetite-regulating hormone Human genes 0.000 description 4
- 206010053759 Growth retardation Diseases 0.000 description 4
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 231100000001 growth retardation Toxicity 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 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
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 4
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- BPWCSEZBKVGKQR-CQSZACIVSA-N (1r)-1-(methylamino)-3-naphthalen-2-ylpropan-1-ol Chemical compound C1=CC=CC2=CC(CC[C@@H](O)NC)=CC=C21 BPWCSEZBKVGKQR-CQSZACIVSA-N 0.000 description 3
- JYUTZJVERLGMQZ-AREMUKBSSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-naphthalen-2-ylpropanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@@H](C(=O)O)CC1=CC=C(C=CC=C2)C2=C1 JYUTZJVERLGMQZ-AREMUKBSSA-N 0.000 description 3
- GBROUWPNYVBLFO-HSZRJFAPSA-N (2r)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-phenylpropanoic acid Chemical compound C([C@@H](N(C)C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(O)=O)C1=CC=CC=C1 GBROUWPNYVBLFO-HSZRJFAPSA-N 0.000 description 3
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 3
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- 235000001014 amino acid Nutrition 0.000 description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
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- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
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- 239000005556 hormone Substances 0.000 description 3
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- AERJECVIDUOZNH-QGZVFWFLSA-N methyl (2r)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-naphthalen-2-ylpropanoate Chemical compound C1=CC=CC2=CC(C[C@H](C(=O)OC)N(C)C(=O)OC(C)(C)C)=CC=C21 AERJECVIDUOZNH-QGZVFWFLSA-N 0.000 description 3
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- BJNIQYOUHCEVAD-UHFFFAOYSA-N 1-hydroxytriazolo[4,5-b]pyridine;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=N1 BJNIQYOUHCEVAD-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-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 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- 208000014311 Cushing syndrome Diseases 0.000 description 2
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- 239000002858 neurotransmitter agent Substances 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
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- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/60—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to novel peptide derivatives, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.
- Growth hormone is a hormone which stimulates growth of all tissues capable of growing, ln addition, growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilization and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism.
- Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone
- GHRH somatostatin
- somatostatin somatostatin
- the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary.
- Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example arginine,
- L-Dopa L-3,4-dihydroxyphenylaIanine
- glucagon glucagon
- vasopressin PACAP (pituitary adenylyl cyclase activating peptide)
- muscarinic receptor agonists and a synthethic hexapeptide
- GHRP growth hormone releasing peptide
- growth hormone releasing peptides or peptide derivatives are important for their growth hormone releasing potency as well as their bioavailability. It is therefore the object of the present invention to provide novel peptides with growth hormone releasing properties which have improved properties relative to known peptides of this type.
- A is hydrogen or R 1 -(CH 2 )q-(X) r -(CH 2 ) s -CO-, wherein q is 0 or an integer selected from the group: 1 , 2, 3, 4, 5; r is O or l; s is 0 or an integer selected from the group: 1 , 2, 3, 4, 5;
- R ⁇ is hydrogen, imidazolyl, guanidino, piperazino, morpholino, piperidino or N(R ⁇ )- R3, wherein each of R ⁇ and R ⁇ is independently hydrogen or lower alkyl optionally substituted by one or more hydroxyl, pyridinyl or furanyl groups; and
- each of R 1 ⁇ and R ⁇ is independently hydrogen or lower alkyl;
- B is (G) t -(H) U wherein each of t and u independently is 0 or 1;
- G and H are amino acid residues selected from the group consisting of natural L- amino acids or their corresponding D-isomers, or non-natural amino acids such as 1 ,4-diaminobutyric acid, amino-isobutyric acid, 1,3-diaminopropionic acid, 4- aminophenylalanine, 3-pyridylalanine, 1 ⁇ .S ⁇ -tetrahydroisoquinoline-S-carboxylic acid, I ⁇ S ⁇ -tetrahydronorharman-S-carboxylic acid, N-methylanthranilic acid, anthranilic acid, N-benzylglycine, 3-aminomethylbenzoic acid, 3-amino-3-methyl butanoic acid, sarcosine, nipecotic acid or
- C is a D-amino acid of formula -NH-CH((CH 2 ) w -R )-CO- wherein w is 0, 1 or 2;
- R 4 is selected from the group consisting of
- D when p is 1, is a D-amino acid of formula -NR 20 -CH((CH 2 ) k -R 5 )-CO- or, when p is 0, D is -NR 20 -CH((CH 2 ) r R 5 )-CH 2 -R 6 or -NR 20 -CH((CH 2 ) m -R 5 )-CO-R 6 , wherein k is O, 1 or 2; l is O, 1 or 2; m is 0, 1 or 2; R 2 ⁇ is selected from the group consisting of lower alkyl or lower aralkyl;
- R5 is selected from the group consisting of
- R 6 is piperazino, mo ⁇ holino, piperidino, -OH or -N(R 7 )-R 8 , wherein each of R 7 and R 8 is independently hydrogen or lower alkyl;
- E when p is 1 , is -NH-CH(R 10 )-(CH 2 ) v -R 9 , wherein v is 0 or an integer selected from the group: 1 ⁇ 2, 3, 4, 5, 6, 7, 8;
- R is hydrogen, imidazolyl, guanidino, piperazino, mo ⁇ holino, piperidino, -N(R1 1 )-
- n 0, 1 or 2
- R-' ⁇ is hydrogen or lower alkyl
- o is an integer selected from the group: 1 , 2, 3, each of R 1 1 and R ⁇ 2 is independently hydrogen or lower alkyl, or
- R ⁇ is piperazino, mo ⁇ holino, piperidino, -OH or -N(R ⁇ )-R ⁇ , wherein each of R ⁇ 4 and R ⁇ is independently hydrogen or lower alkyl;
- I 8 is hydrogen, lower alkyl or lower aralkyl; or a pharmaceutically acceptable salt thereof;
- the peptide derivatives of formula I exhibit an improved resistance to proteolytic degradation by enzymes due to the presence of adjacent D-amino acids in the peptide sequence, optionally combined with the substitution of an amide bond (-
- the lower alkyl moities specified above are intended to include those alkyl moities, preferably with 1-6 carbon atoms, of the designated length in either a linear or branched or cyclic configuration.
- linear alkyl are methyl, ethyl, propyl, butyl, pentyl, and hexyl.
- branched alkyl are isopropyl, sec-butyl, tert- butyl, isopentyl, and isohexyl.
- Examples of cyclic alkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- the lower alkoxy moities specified above are intended to include those alkoxy moities preferably with 1-6 carbon atoms, of the designated length in either a linear or branched or cyclic configuration.
- linear alkyloxy are methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.
- branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy.
- Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
- the lower alkylamino moities specified above are intended to include those alkylamino moities preferably with 1-6 carbon atoms, of the designated length in either a linear or branched or cyclic configuration.
- linear alkylamino are methylamino, ethylamino, propylamino, butylamino, pentylamino, and hexylamino.
- branched alkylamino are isopropylamino, sec-butylamino, tert-butylamino, isopentylamino, and isohexylamino.
- cyclic alkylamino examples include cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino.
- aryl is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected from the group consisting of phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrazinyl, or isothiazolyl, optionally substituted by one or more d-6-alkyl, halogen, amino or aryl.
- Aryl is preferably phenyl, thienyl, imidazolyl, pyridyl, indolyl, quinoline or naphthyl optionally substituted with halogen, amino, hydroxy, or C ⁇ - 6 -alkoxy.
- the lower aralkyl moities specified above are composed of a lower alkyl moity and a aryl moiety, wherein the lower alkyl moiety and aryl moiety are as defined above.
- halogen is intended to include Cl, F, Br and I.
- the common three-letter code is used for natural amino acids, e.g. Ala for alanine.
- A is hydrogen, 3-N-Me- AMB, -3-AMB or Aib.
- G in the compund of formula I is preferably Ala, Gly, sarcosine, 3-aminomethylbenzoyl, R-nipecotinyl, nipecotic acid or isonipecotic acid, more preferably 3-aminomethylbenzoyl, R-nipecotinyl, nipecotic acid or isonipecotic acid.
- H is preferably His, Phe, Tic, Phe(4-NH 2 ), 3-Pyal, Gly, Ala, Sar, Pro, Tyr, Arg, Orn, 3-aminomethylbenzoic acid or D-Phe, more preferably H is His, Phe or Ala, most preferably H is His or Ala.
- C in the compound of formula I is preferably D-2-naphthylalanine (D-2Nal), D-1-naphthylalanine (D- 1 Nal), D-Phe or D-T ⁇ , more preferably D-2Nal or D-Phe and most preferably N- Me-D-2Nal, D-2Nal, D-Phe, or N-Me-D-Phe.
- D in the compound of formula I is preferably -NR 20 -CH((CH 2 ) k -R 5 )-CO-, wherein k is preferably 1 and R 20 is lower alkyl, more preferably D is D-Phe or D-2Nal. Most preferably D is N-Me-D-Phe-ol, N-Me-D-Phe, N-Me-D-2Nal-ol, N-Me-D-Phe-NH 2 , N-Me-D-Phe-NH-Me, or N-Me-D- . (4-l)Phe-NH-Me.
- E is preferably Lys-NH , Ser-NH 2 , NH-
- R 4 in the compound of formula I is preferably 2-naphthyl.
- R 5 is preferably phenyl.
- v is preferably 2-6, and R is NH 2 ,2-mo ⁇ holinoethyl , 3-morpholinopropyl
- R 10 is preferably -COOH, -CH 2 -OH, -H, -CONH 2 or
- Examples of specific compounds of the present invention are (2R)-2-((3-Aminomethylbenzoyl))-N-Me-D-2Nal-N-Me)-3-(2-naphthyl) ⁇ ropanol:
- Solid phase synthesis may be carried out substantially as described by Stewart and Young, Solid Phase Peptide Svnthesis, 2nd. Ed., Rockford, Illinois, USA, 1976.
- Solution peptide synthesis may for instance be carried out substantially as described by Bodansky et al., Peptide Synthesis. 2nd. Ed., New York, New York, USA, 1976.
- Aminomethylene as a substitution of an amide bond may be introduced according to the method described by Y. Sasaki and D.H. Coy, Peptides 8(1 ), 1987, pp. 119-
- Peptide derivatives containing a mono- or di-hexapyranose derivatised amino group may be prepared by an Amadori rearrangement substantially by the method described by R. Albert et al., Life Sciences 53, 1993, pp. 517-525.
- suitable mono- or di-hexapyranoses are glucose, galactose, maltose, lactose or cellobiose.
- Derivatives used as starting materials in the synthesis may either be obtained commercially and, when required, provided with suitable protecting groups, or starting materials used to prepare the "A" moiety in general formula I may be prepared by well-known methods and optionally protected in a manner known perse.
- Pharmaceutically acceptable acid addition salts of compounds of formula I include those prepared by reacting the peptide with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, oxalic, •toluenesulfonic, trifluoracetic, sulfamic and fumaric acid.
- an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, oxalic, •toluenesulfonic, trifluoracetic, sulfamic and fumaric acid.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising, as an active ingredient, a compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
- compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences. 1985.
- the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions, patches or topical applications.
- the pharmaceutical carrier or diluent employed may be a conventional solid or liquid carrier.
- solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
- liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
- 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.
- the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
- the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
- a typical tablet which may be prepared by conventional tabletting techniques may contain:
- Active compound (as free compound or salt thereof) 100 mg
- the preparation may be in. the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
- the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
- the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants such as bile acid salts polyethylene glycols, polypropylene glycols or polyoxyethylene higher alcohol ethers, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
- solubilizing agents e.g. propylene glycol
- surfactants such as bile acid salts polyethylene glycols, polypropylene glycols or polyoxyethylene higher alcohol ethers
- absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin
- preservatives such as parabenes.
- the preparation may be in a form suitable for patches or iontophoresis.
- the compounds of the present invention are dispensed in unit dosage form comprising 0.0001-100 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
- the dosage of the compounds according to this invention is suitably 1-500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
- the present invention relates to a pharmaceutical composition for stimulating the release of growth hormone from the pituitary, the composition comprising, as an active ingredient, a compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
- the present invention relates to 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 pharmaceutically acceptable salt thereof.
- the present invention relates to 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.
- the compounds of formula I have interesting pharmacological properties. Examples of such properties are the stimulation of release of growth hormone from the pituitary which has similar effects or uses as growth hormone itself.
- the uses of growth hormone may be summarized as follows: stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glucocorticoids, treatment of osteoporosis, stimulation of the immune system, acceleration of wound healing, accelerating bone fracture repair, treatment of growth retardation, treating renal failure or insufficiency resulting from growth retardation, treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness, treatment of obesity and growth retardation associated with obesity, treating growth retardation associated with the Prader-Willi syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of burn patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushing's syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients, treatment of osteochondrodysplasias, No
- the dosage may vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired. However, generally dosage levels between 0.0001 and 100 mg/kg body weight per day may be administered to patients and animals to obtain effective release of endogenous growth hormone.
- dosage forms suitable for oral or nasal administration comprise from about 0.0001 mg to about 100 mg, preferably from about 0.001 mg to about 50 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
- the compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a 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.
- the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more compounds exhibiting a different activity, e.g., an antibiotic or other pharmacologically active material.
- This might be another secretagogue, such as GHRP (1 or 6) or GHRH or an analogue thereof, growth hormone or an analogue thereof or a somatomedin such as IGF-1 or IGF-2.
- the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral, the oral route being preferred.
- the compounds of formula I may also be useful in vivo tools for evaluating the growth hormone releasing capability of the pituitary. For example, serum samples taken before and after administration of these compounds to humans can be assayed for growth hormone. Comparison of the growth hormone in each serum sample would directly determine the ability of the patients pituitary to release growth hormone.
- Compounds of formula I may be administered to commercially important animals to increase their rate and extent of growth, and to increase milk production.
- Compounds of formula I may be evaluated in vitro for their efficacy and potency to release growth hormone in primary rat somatotrophs.
- Rat primary somatotrophs may be prepared essentially as described previously (Chen et al., Endocrinology 1991 , 129, 3337-3342 and Chen et al., Endocrinology 1989, 124, 2791-2798). Briefly, rats are killed by decapitation. The pituitary is quickly removed. The pituitaries are digested with 0.2 % collagenase n 0.2 % hyalurinidase in Hanks balanced salt solution.
- the cells are resuspended in Dulbecco's Modified Eagle's medium containing 0.37 % NaHCO3, 10 % horse serum, 2.5 % fetal calf serum, 1 % nonessential amino acids, 1 % glutamine and 1 % penicillin/streptomycin and adjusted to 1.5 x 105 cells/ml.
- Dulbecco's Modified Eagle's medium containing 0.37 % NaHCO3, 10 % horse serum, 2.5 % fetal calf serum, 1 % nonessential amino acids, 1 % glutamine and 1 % penicillin/streptomycin and adjusted to 1.5 x 105 cells/ml.
- One ml of this suspension is placed in each well of 24-well trays and left for 2-3 days before release experiments are performed.
- the peptide was eluted from the Sep-Pak ® cartridge with 70% CH 3 CN 0.1% TFA and isolated from the eluate by lyophilisation after dilution with water.
- the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma deso ⁇ tion mass spectrometry (molecular mass). Mass spectrometry agreed with the expected structure within the experimental error of the method (mass spectrometry ⁇ 0.9 amu).
- the RP-HPLC analysis was performed using UV detection at 214 nm and a Vydac 218TP54 4.6mm x 250mm 5 ⁇ C-18 silica column (The Separations Group, Hesperia) which was eluted at 1 ml/min at 42 °C. Two different elution conditions were used: A1: The column was equilibrated with 5% CH 3 CN in a buffer consisting of 0JM
- the retention time using elution conditions A1 and B1 was found to be 29.90 min and 31.52 min, respectively.
- the aqueous phase was concentrated to dryness and redissolved in 400 ml THF and 343 ml 1 M NaOH. A solution of 30g Boc-anhydride in 100 ml THF was added and the mixture was stirred overnight. Then the reaction mixture was acidified to pH 3 with 1 N HCl and extracted with 3 x 300 ml of EtOAc. The organic phase was evaporated to a foam. The yield was 22 g.
- N-Me-D-2Nal N-methyl-D-2-naphtylalanine
- DCM dichloromethane
- DIEA diisopropylethyl amine
- Boc-N-Me-D-Phe-OH (279 mg) was dissolved in DMF (4 ml) and stirred 10 min with HOBt (168 mg) and EDAC (230 mg ). 3-Dimethylamino-1 -propylamine (188 ⁇ l) was added and the mixture was stirred 18h at r.t. Then 5% aqueous sodium hydrogen carbonate (50 ml) was added and the resulting mixture was extracted with EtOAc (50 ml) and the organic phase was dried over Na 2 SO and concentrated in vacuum to an oil.
- reaction mixture was concentrated to an oil with a stream of nitrogen and stirred for 15 min with 5% aqueous sodium hydrogen carbonate (100 ml).
- the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass).
- the molecular mass found (MH + :608.2 amu) agreed with the expected structure (teor. MH +: 608.8 amu) within the experimental error of the method.
- the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 25.23 min and 26.58 min, respectively.
- the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass).
- the molecular mass found (MH + : 586.3 amu) agreed with the expected structure (teor. MH +: 585.8 amu) within the experimental error of the method.
- the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1 was found to be 25.33 min and 26.35 min, respectively.
- Boc-N-Me-D-Phe-OH (279 mg) was dissolved in DMF (10 ml) and stirred 10 min with HOBt (168 mg) and EDAC (384 mg ).
- 2-(Aminoethyl)-1-methyl-pyrrolidine (290 ⁇ l) and DIEA (171 ⁇ l) were added and the mixture was stirred for 20 h at r.t. Then the mixture was concentrated to an oil which was dissolved in 50 ml water and lyophilized. The product was redissolved in 25 ml water and then applied to a Sep-Pak® C18 cartridge (Waters part. #:43345 ) which was equilibrated with 0.03 N hydrochloric acid .
- the product was eluted from the Sep-Pak® cartridge with 70% CH 3 CN in 0.03 N hydrochloric acid and isolated from the eluate by lyophilisation after dilution with water.
- the resulting material is stirred 10 min at r.t. with TFA / DCM 1 : 1 (6 ml). After this the TFA / DCM was evaporated by a stream of nitrogen and the resulting oil was dissolved in 70% CH 3 CN (10 ml) and 1 N hydrochloric acid (2 ml) was added.
- the product was isolated by lyophilisation after dilution with water (50 ml).
- the resulting material was dissolved in DMF (3 ml) and stirred 18h at r.t.
- the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass).
- the molecular mass found (MH + : 612.2 amu) agreed with the expected structure (teor. MH +: 612.39 amu) within the experimental error of the method.
- the RP-HPLC retention time using elution condition A1 as defined in example 1. was found to be 25.80 min.
- N- ⁇ (1 R)-1 -(N-[(1 R)-2-hydroxy-1 -((2-naphthyl)methyl)ethyl)-N-methylcarbamoyl]-2- (2-naphthyl)ethyl ⁇ -N-methylcarbamic acid tert-butyl ester (0,25 g; 0,475 mmol) was dissolved in DCM (3 ml). Triflouroacetic acid (1 ml) was added and the reaction mixture was stirred for 20 min. The solvent was removed in vacuo. DCM (5 ml) was added and removed in vacuo and repeated. The residue was dissolved in methanol (5 ml).
- the resulting organic phase was dried with Na 2 SO 4 and concentrated in vacuum on a rotary evaporator to an oil.
- the oil was then dissolved in DCM / TFA 1 :1 (6 ml) and stirred. After 10 min the mixture was concentrated by a stream of nitrogen and the resulting oil was redissolved in 70% CH 3 CN / 0J % TFA (5 ml) and diluted with water to a volume of 100 ml.
- the peptide was synthesized according to the Fmoc strategy on an Applied Biosystems 431 A peptide synthesizer in 0.22 mmol scale using the manufacturer supplied FastMoc UV protocols which employ HBTU mediated couplings in NMP and UV monitoring of the deprotection of the Fmoc protection group.
- the starting resin used for the synthesis was cat. #: D-1675 from Bachem Feinchemikalien AG, Bubendorf, Switzerland (427) mg which is a Fmoc-2,4-dimethoxy-4'- (carboxymethyloxy)-benzhydryl-amine linked to amino methyl polystyrene resin through an amide bond.
- the substitution capacity was 0.55 mmol / g .
- the protected amino acid derivatives used were Fmoc-N-Me-D-Phe-OH, Fmoc-D-2Nal- OH, Fmoc-His(Trt) and Fmoc-Aib-OH.
- the coupling of Fmoc-N-Me-D-Phe-OH was carried out as a double coupling.
- the peptide was cleaved from 750 mg of the peptide resin by stirring for 180 min at room temperature with a mixture of 8 ml TFA , 600 mg phenol, 200 ⁇ l ethanedithiol, 400 ⁇ l thioanisole and 400 ⁇ l H 2 O.
- the cleavage mixture was filtered and the filtrate was concentrated to approximately 2 ml by a stream of nitrogen.
- the crude peptide was precipitated from this oil with 50 ml diethyl ether and washed 2 times with 50 ml diethyl ether.
- the crude peptide was dried and purified by semipreparative HPLC in one run and lyophilized using similar procedures as described in example 1.
- the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass).
- the molecular mass found (MH + :598.5 amu) agreed with the expected structure (teor. MH +: 598.73 amu) within the experimental error of the method.
- the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1 was found to be 24.68 min and 25.58 min, respectively.
- This compound was synthesized using similar procedures as described in example 6. The only exception was that the coupling of Fmoc-D-2Nal-OH was performed using HATU as the activating reagent. H-N-Me-D-Phe-resin (0.23 mmol) was coupled for 150 min with 1 mmol Fmoc-D-2Nal-OH using 1 mmol HATU in the presence of DIEA (2 mmol).
- the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma deso ⁇ tion mass spectrometry (molecular mass).
- the molecular mass found (MH + :511.2 amu) agreed with the expected structure (teor. MH +: 509.6 amu) within the experimental error of the method.
- the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 30.73 min and 32.47 min, respectively.
- the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 21.13 min and 22.60 min, respectively.
- the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 15.71 min and 17.82 min, respectively.
- This compound was synthesized using similar procedures as described in example 11. using Fmoc-N-Me-D-Phe-OH, Fmoc-N-Me-D-2Nal-OH and Boc-(R)-Nipecotic acid, where both Fmoc-N-Me-D-2Nal-OH and Boc-(R)-Nipecotic acid were coupled using HATU.
- the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass). The molecular mass found (MH + :500.7 amu) agreed with the expected structure (teor. MH +: 501.7 amu) within the experimental error of the method.
- the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 28J 8 min and 29.55 min, respectively.
- Boc-3AMB-OH 115 mg, 0.458 mmol
- 1 -hydroxy-7-azabenzotriazole 62 mg, 0.458 mmol
- 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride 97 mg, 0.504 mmol
- N-methyl-2-methylamino-N-((1R)-1-(methylcarbamoyI)-2-phenylethyl)-3-(2- naphthyl)propionamide (185 mg, 0.458 mmol) dissolved in DCM (5 ml) was added followed by addition of diisopropylethylamine (80 ml, 0.458 mmol) and the mixture was stirred for 20 hours.
- Fmoc-L-His(Trityl)-OH (1,54 g, 2.48 mmol) (BACHEM B-1570) and 1-hydroxyaza- benzotriazol (338 mg, 2.48 mmol) were dissolved in 9 ml of DMF, cooled to 0-4°C and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (475 mg, 2.48 mmol) was added. The reaction mixture was stirred for 15 min. at 0-4° C.
- N-Methyl-2-methylamino-N-((1 R)-1-(Methylcarbamoyl)-2-phenylethyl)-3-(2- naphthyl)propionamid 500 mg, 1.24 mmol
- methylen chloride (18 ml) was cooled to 0-4° C and added and stirred for 1 hour at 0-4° C followed by addition of diisopropylethylamine (0.425 ml, 2.48 mmol). The temperature of the mixture was slowly raised to room temperature and the mixture was stirred for 72 hours.
- DCM was evaporated in a stream of N 2 and to the mixture was added 100 ml ethyl acetate and washed with sodium hydrogen carbonate (2 x 100 ml, 5%) and potassium hydrogen sulfate (100 ml, 5%). The phases were separated and the organic phase was dried with sodium sulfate and evaporated in vacuo. The residue was dissolved in DMF (8 ml) and treated with piperidine for 15 min., diluted with H 2 O (100 ml) and quenched with acetic acid (1 ,5 ml). Acetonitrile was added and the mixture was diluted with H 2 O to 250 ml.
- Boc- ⁇ aminoisobutyric acid (756 mg, 3.72 mmol), 1-hydroxyazabenzotriazole hydrate (506 mg, 3.72 mmol) and 1-ethyI-3(3-dimethylaminopropyl)carbodiimide hydrochloride (713 mg, 3.72 mmol) were dissolved in DMF (6 ml) and after 15 min. was added H-L- His(trityl)-NMeD2Nal-NMeDPhe-NHCH 3 , 2 HCL dissolved in DCM (12 ml) followed by addition of diisopropylethylamine (0.637 ml) and stirred for 72 hours.
- DCM was evaporated in a stream of N 2 and the mixture was added 100 ml ethyl acetate and washed with sodium hydrogen carbonate (2 x 50 ml, 5%) and potassium hydrogen sulfate (50 ml, 5%). The phase were separated and the organic phase was dried with sodium sulfate and evaporated in vacuo. The residue was dissolved in DCM (6 ml), cooled to 0 ⁇ ° C and treated with TFA (6 ml) for 10 min. at 0-4° C. With a stream of N 2 the volatiles was removed.
- Boc-NMe3AMB-OH (658 mg, 2.48 mmol), 1-hydroxyazabenzotriazole hydrate (338 mg, 2.48 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (475 mg, 2.48 mmol) were dissolved in 6 ml of DMF and stirred for 15 min.
- N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2- naphthyl)propionamid 500 mg, 1.24 mmol
- methylene chloride (12 ml) was added, followed by addition of diisopropylethylamine (0,425 ml, 2.48 mmol). The mixture was stirred for 20 hours.
- N-((1 R)-2-(4-lodophenyl)-1 -(methylcarbamoyl)ethyl)-N-methylcarbamic acid tert-butylester (1.7 g; 4.0 mmol) was dissolved in methylene chloride (10 ml) and trifluoroacetic acid (5 ml) was added. The mixture was stirred for 1 h. Methylene chloride (30 ml) and water (30 ml) was added. Solid sodium hydrogen carbonate was added to pH 8. The organic phase was separated, dried (MgSO 4 ) and evaporated in vacuo to afford 1.22 g of (2R)-3-(4-iodo ⁇ henyl)-N-methyl-2-(methylamino)propionamide.
- N-Methyl-N-((1 R)-1 -(N-methyl-N-((1 R)-1 -(methylcarbamoyl)-2-(4- iodophenyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester was dissolved in a mixture of methylene chloride and trifluoroacetic acid and stirred for 15 min.
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PCT/DK1996/000266 WO1997000894A1 (en) | 1995-06-22 | 1996-06-19 | Compounds with growth hormone releasing properties |
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AU3938797A (en) * | 1996-08-29 | 1998-03-19 | Novo Nordisk A/S | Transdermal delivery of peptides |
US6127341A (en) * | 1997-06-20 | 2000-10-03 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
AU7906998A (en) | 1997-06-20 | 1999-01-04 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
WO1999009991A1 (en) | 1997-08-22 | 1999-03-04 | Kaken Pharmaceutical Co., Ltd. | Novel amide derivatives |
ATE470671T1 (de) | 1998-01-16 | 2010-06-15 | Helsinn Therapeutics Us Inc | Verbindungen mit wachstumshormon-freisetzender eigenschaft |
US6528529B1 (en) | 1998-03-31 | 2003-03-04 | Acadia Pharmaceuticals Inc. | Compounds with activity on muscarinic receptors |
EP1077949A2 (en) * | 1998-05-12 | 2001-02-28 | Warner-Lambert Company | Combinations of protein farnesyltransferase and hmg coa reductase inhibitors and their use to treat cancer |
CA2334315C (en) * | 1998-06-30 | 2011-07-26 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
US6919315B1 (en) | 1998-06-30 | 2005-07-19 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
JP2002525265A (ja) | 1998-08-14 | 2002-08-13 | アドミニストレイターズ オブ ザ トゥレーン エジュケーショナル ファウンド | 成長ホルモン放出活性を有する化合物 |
EP1930021A3 (en) | 1999-02-18 | 2008-06-18 | Kaken Pharmaceutical Co., Ltd. | Novel amide derivatives as growth hormone secretagogues |
DE60140285D1 (de) | 2000-05-31 | 2009-12-10 | Pfizer Prod Inc | Verwendung von Wachstumshormonsekretagoga zur Förderung der Beweglichkeit des Verdauungstrakts |
HUP0303652A2 (hu) | 2000-12-20 | 2004-03-01 | Bristol-Myers Squibb Company | Ciklikus származékok, mint kemokin receptor aktivitás modulátorai és ezeket tartalmazó gyógyszerkészítmények |
WO2002050019A2 (en) | 2000-12-20 | 2002-06-27 | Bristol-Myers Squibb Pharma Co. | Diamines as modulators of chemokine receptor activity |
TWI331922B (en) | 2002-08-09 | 2010-10-21 | Ipsen Pharma Sas | Growth hormone releasing peptides |
US7476653B2 (en) | 2003-06-18 | 2009-01-13 | Tranzyme Pharma, Inc. | Macrocyclic modulators of the ghrelin receptor |
WO2007025177A2 (en) | 2005-08-26 | 2007-03-01 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
CU23558A1 (es) | 2006-02-28 | 2010-07-20 | Ct Ingenieria Genetica Biotech | Compuestos análogos a los secretagogos peptidicos de la hormona de crecimiento |
US8138191B2 (en) | 2007-01-11 | 2012-03-20 | Critical Outcome Technologies Inc. | Inhibitor compounds and cancer treatment methods |
EP2644618B1 (en) | 2007-02-09 | 2016-08-17 | Ocera Therapeutics, Inc. | tether intermediates for the synthesis of macrocyclic ghrelin receptor modulators |
WO2009079797A1 (en) | 2007-12-26 | 2009-07-02 | Critical Outcome Technologies, Inc. | Compounds and method for treatment of cancer |
WO2011120153A1 (en) | 2010-04-01 | 2011-10-06 | Critical Outcome Technologies Inc. | Compounds and method for treatment of hiv |
WO2013190520A2 (en) | 2012-06-22 | 2013-12-27 | The General Hospital Corporation | Gh-releasing agents in the treatment of vascular stenosis and associated conditions |
US9119832B2 (en) | 2014-02-05 | 2015-09-01 | The Regents Of The University Of California | Methods of treating mild brain injury |
US20170121385A1 (en) | 2015-10-28 | 2017-05-04 | Oxeia Biopharmaceuticals, Inc. | Methods of treating neurodegenerative conditions |
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US5663146A (en) * | 1991-08-22 | 1997-09-02 | Administrators Of The Tulane Educational Fund | Polypeptide analogues having growth hormone releasing activity |
CA2179597A1 (en) * | 1993-12-23 | 1995-06-29 | Nils Langeland Johansen | Compounds with growth hormone releasing properties |
US5798337A (en) * | 1994-11-16 | 1998-08-25 | Genentech, Inc. | Low molecular weight peptidomimetic growth hormone secretagogues |
-
1996
- 1996-06-19 PL PL96324200A patent/PL186520B1/pl unknown
- 1996-06-19 CZ CZ19974081A patent/CZ287948B6/cs not_active IP Right Cessation
- 1996-06-19 CA CA002224434A patent/CA2224434A1/en not_active Abandoned
- 1996-06-19 HU HU9802821A patent/HUP9802821A3/hu unknown
- 1996-06-19 KR KR1019970709617A patent/KR19990028303A/ko not_active Application Discontinuation
- 1996-06-19 IL IL12237196A patent/IL122371A0/xx not_active IP Right Cessation
- 1996-06-19 WO PCT/DK1996/000266 patent/WO1997000894A1/en not_active Application Discontinuation
- 1996-06-19 EP EP96920742A patent/EP0833845A1/en not_active Withdrawn
- 1996-06-19 AU AU61882/96A patent/AU711104B2/en not_active Ceased
- 1996-06-19 BR BR9608909A patent/BR9608909A/pt not_active Application Discontinuation
- 1996-06-28 TW TW085107813A patent/TW458958B/zh not_active IP Right Cessation
-
1997
- 1997-12-19 NO NO975992A patent/NO975992L/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO9700894A1 * |
Also Published As
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KR19990028303A (ko) | 1999-04-15 |
IL122371A0 (en) | 1998-06-15 |
AU6188296A (en) | 1997-01-22 |
CZ287948B6 (cs) | 2001-03-14 |
CA2224434A1 (en) | 1997-01-09 |
WO1997000894A1 (en) | 1997-01-09 |
PL324200A1 (en) | 1998-05-11 |
JP4173541B2 (ja) | 2008-10-29 |
BR9608909A (pt) | 1999-03-02 |
HUP9802821A3 (en) | 2000-03-28 |
TW458958B (en) | 2001-10-11 |
NO975992D0 (no) | 1997-12-19 |
AU711104B2 (en) | 1999-10-07 |
CZ408197A3 (cs) | 1998-05-13 |
HUP9802821A2 (hu) | 1999-03-29 |
PL186520B1 (pl) | 2004-01-30 |
NO975992L (no) | 1998-02-20 |
MX9710377A (es) | 1998-03-29 |
JPH11507928A (ja) | 1999-07-13 |
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