CA1088520A - Process for the manufacture of dipeptide derivatives - Google Patents
Process for the manufacture of dipeptide derivativesInfo
- Publication number
- CA1088520A CA1088520A CA274,078A CA274078A CA1088520A CA 1088520 A CA1088520 A CA 1088520A CA 274078 A CA274078 A CA 274078A CA 1088520 A CA1088520 A CA 1088520A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- histidyl
- proline
- group
- carbon atoms
- 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.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 34
- 108010016626 Dipeptides Proteins 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- LNCFUHAPNTYMJB-IUCAKERBSA-N His-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CN=CN1 LNCFUHAPNTYMJB-IUCAKERBSA-N 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 22
- -1 p-nitrophenoxy Chemical group 0.000 claims description 20
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 229960005010 orotic acid Drugs 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 150000007513 acids Chemical class 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000005917 acylation reaction Methods 0.000 claims description 5
- 230000010933 acylation Effects 0.000 claims description 4
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims 1
- 108010085325 histidylproline Proteins 0.000 abstract description 3
- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 239000000935 antidepressant agent Substances 0.000 abstract description 2
- 239000003368 psychostimulant agent Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 150000008064 anhydrides Chemical class 0.000 description 9
- 229940093499 ethyl acetate Drugs 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000012362 glacial acetic acid Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- 125000002091 cationic group Chemical group 0.000 description 5
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- BVQMQRWLLWQCLL-UHFFFAOYSA-N 1-[2-amino-3-(1h-imidazol-5-yl)propanoyl]pyrrolidine-2-carboxamide Chemical compound C1CCC(C(N)=O)N1C(=O)C(N)CC1=CN=CN1 BVQMQRWLLWQCLL-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 101800004623 Thyrotropin-releasing hormone Proteins 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 108010006939 histidylprolineamide Proteins 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 229910000039 hydrogen halide Inorganic materials 0.000 description 3
- 239000012433 hydrogen halide Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 229940086542 triethylamine Drugs 0.000 description 3
- WOXWRWOEURENTO-NSHDSACASA-N (2s)-n-benzylpyrrolidine-2-carboxamide Chemical compound O=C([C@H]1NCCC1)NCC1=CC=CC=C1 WOXWRWOEURENTO-NSHDSACASA-N 0.000 description 2
- PRQAIVKHRVEJPG-JEDNCBNOSA-N (2s)-n-methylpyrrolidine-2-carboxamide;hydrochloride Chemical compound Cl.CNC(=O)[C@@H]1CCCN1 PRQAIVKHRVEJPG-JEDNCBNOSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000002252 acyl group Chemical class 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachlorophenol Chemical compound OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- JXGVXCZADZNAMJ-NSHDSACASA-N (2s)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-NSHDSACASA-N 0.000 description 1
- URHXQSTYLJNJMT-YFKPBYRVSA-N (2s)-n-methylpyrrolidine-2-carboxamide Chemical compound CNC(=O)[C@@H]1CCCN1 URHXQSTYLJNJMT-YFKPBYRVSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- HSQFVBWFPBKHEB-UHFFFAOYSA-N 2,3,4-trichlorophenol Chemical compound OC1=CC=C(Cl)C(Cl)=C1Cl HSQFVBWFPBKHEB-UHFFFAOYSA-N 0.000 description 1
- ITOKTMBSXWNASD-UHFFFAOYSA-N 2,4-dioxo-5-propyl-1h-pyrimidine-6-carboxylic acid Chemical compound CCCC1=C(C(O)=O)NC(=O)NC1=O ITOKTMBSXWNASD-UHFFFAOYSA-N 0.000 description 1
- CIOOTGUETLQXHS-UHFFFAOYSA-N 2,5,6-trimethylthiomorpholin-3-one Chemical compound CC1NC(=O)C(C)SC1C CIOOTGUETLQXHS-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- IRLLLHYGMMQKFU-UHFFFAOYSA-N 4,4-dimethylimidazolidin-2-one Chemical compound CC1(C)CNC(=O)N1 IRLLLHYGMMQKFU-UHFFFAOYSA-N 0.000 description 1
- FEVSXQMJLWVHDA-UHFFFAOYSA-N 4,5-dimethylimidazolidin-2-one Chemical compound CC1NC(=O)NC1C FEVSXQMJLWVHDA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- AXBVSRMHOPMXBA-UHFFFAOYSA-N 4-nitrothiophenol Chemical compound [O-][N+](=O)C1=CC=C(S)C=C1 AXBVSRMHOPMXBA-UHFFFAOYSA-N 0.000 description 1
- HJRAYYQPWDYEAD-GQKFXUNGSA-N 5-ethyl-N-[(2S)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-2-oxoimidazolidine-4-carboxamide Chemical compound C(C)NC([C@H]1N(CCC1)C([C@@H](NC(=O)C1NC(NC1CC)=O)CC1=CNC=N1)=O)=O HJRAYYQPWDYEAD-GQKFXUNGSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- DLDZDJKHBWTGNX-FVGYRXGTSA-N Cl.N1[C@H](C(=O)N2CCCCC2)CCC1 Chemical compound Cl.N1[C@H](C(=O)N2CCCCC2)CCC1 DLDZDJKHBWTGNX-FVGYRXGTSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- VRVMYKPBIXYBSK-KBPBESRZSA-N N-[(2S)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-2,4-dioxo-5-propan-2-yl-1H-pyrimidine-6-carboxamide Chemical compound C(C)NC([C@H]1N(CCC1)C([C@@H](NC(C1=C(C(=O)NC(=O)N1)C(C)C)=O)CC1=CNC=N1)=O)=O VRVMYKPBIXYBSK-KBPBESRZSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-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
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 108700020496 deamido- thyrotropin-releasing hormone Proteins 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- LTYRAPJYLUPLCI-UHFFFAOYSA-N glycolonitrile Chemical compound OCC#N LTYRAPJYLUPLCI-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical group COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940053544 other antidepressants in atc Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2615455A DE2615455C2 (de) | 1976-04-09 | 1976-04-09 | N-Acyl-L-histidyl-L-prolin (N-substituierte)-amide, Verfahren zu deren Herstellung und diese Verbindungen enthaltende pharmazeutische Zubereitungen |
DEP2615455.2 | 1976-04-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1088520A true CA1088520A (en) | 1980-10-28 |
Family
ID=5974903
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA274,078A Expired CA1088520A (en) | 1976-04-09 | 1977-03-16 | Process for the manufacture of dipeptide derivatives |
Country Status (17)
Country | Link |
---|---|
JP (1) | JPS52125166A (xx) |
AT (1) | AT352921B (xx) |
AU (1) | AU2322677A (xx) |
BE (1) | BE853444A (xx) |
CA (1) | CA1088520A (xx) |
CH (1) | CH632737A5 (xx) |
DE (1) | DE2615455C2 (xx) |
DK (1) | DK148902C (xx) |
ES (1) | ES457563A1 (xx) |
FR (1) | FR2347338A1 (xx) |
GB (1) | GB1564078A (xx) |
IE (1) | IE44485B1 (xx) |
NL (1) | NL7703789A (xx) |
PT (1) | PT66283B (xx) |
SE (1) | SE427835B (xx) |
YU (1) | YU85977A (xx) |
ZA (1) | ZA771097B (xx) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE58849B1 (en) * | 1984-12-18 | 1993-11-17 | Gruenenthal Chemie | Use of dipeptide derivatives for the manufacture of medicaments for the treatment of patients with amyotrophic lateral sclerosis |
DE3502041A1 (de) | 1985-01-23 | 1986-07-24 | Grünenthal GmbH, 5190 Stolberg | Verwendung von dipeptidderivaten zur behandlung posttraumatischer nervenschaeden |
JPS63316724A (ja) * | 1987-06-19 | 1988-12-26 | Nippon Shinyaku Co Ltd | 抗けいれん剤 |
US5151497A (en) * | 1989-02-21 | 1992-09-29 | Japan Tobacco Inc. | Histidyl peptide derivatives |
WO1996008265A1 (en) * | 1994-09-12 | 1996-03-21 | The Trustees Of The University Of Pennsylvania | Corticotropin release inhibiting factor and methods of using same |
US6039956A (en) * | 1994-09-12 | 2000-03-21 | Pennsylvania, Trustees Of The University Of, The | Corticotropin release inhibiting factor and methods of using same for treating behavioral symptoms in an anxiety disorder |
-
1976
- 1976-04-09 DE DE2615455A patent/DE2615455C2/de not_active Expired
-
1977
- 1977-02-21 AT AT113977A patent/AT352921B/de not_active IP Right Cessation
- 1977-02-23 ZA ZA00771097A patent/ZA771097B/xx unknown
- 1977-03-09 PT PT66283A patent/PT66283B/pt unknown
- 1977-03-15 AU AU23226/77A patent/AU2322677A/en not_active Expired
- 1977-03-15 GB GB10831/77A patent/GB1564078A/en not_active Expired
- 1977-03-16 CA CA274,078A patent/CA1088520A/en not_active Expired
- 1977-03-21 IE IE593/77A patent/IE44485B1/en unknown
- 1977-03-31 YU YU00859/77A patent/YU85977A/xx unknown
- 1977-04-05 ES ES457563A patent/ES457563A1/es not_active Expired
- 1977-04-06 DK DK157077A patent/DK148902C/da not_active IP Right Cessation
- 1977-04-06 NL NL7703789A patent/NL7703789A/xx not_active Application Discontinuation
- 1977-04-06 SE SE7704088A patent/SE427835B/xx not_active IP Right Cessation
- 1977-04-06 CH CH437277A patent/CH632737A5/de not_active IP Right Cessation
- 1977-04-08 BE BE176590A patent/BE853444A/xx not_active IP Right Cessation
- 1977-04-08 JP JP3962977A patent/JPS52125166A/ja active Granted
- 1977-04-08 FR FR7710825A patent/FR2347338A1/fr active Granted
Also Published As
Publication number | Publication date |
---|---|
BE853444A (fr) | 1977-08-01 |
ES457563A1 (es) | 1978-03-16 |
IE44485B1 (en) | 1981-12-16 |
YU85977A (en) | 1982-10-31 |
ATA113977A (de) | 1979-03-15 |
FR2347338B1 (xx) | 1980-07-11 |
SE427835B (sv) | 1983-05-09 |
DK148902B (da) | 1985-11-11 |
NL7703789A (nl) | 1977-10-11 |
CH632737A5 (en) | 1982-10-29 |
SE7704088L (sv) | 1977-10-10 |
PT66283B (de) | 1978-08-09 |
IE44485L (en) | 1977-10-09 |
JPS52125166A (en) | 1977-10-20 |
DK148902C (da) | 1986-06-09 |
PT66283A (de) | 1977-04-01 |
AT352921B (de) | 1979-10-10 |
DE2615455C2 (de) | 1985-06-20 |
DK157077A (da) | 1977-10-10 |
JPS6110479B2 (xx) | 1986-03-29 |
DE2615455A1 (de) | 1977-10-20 |
GB1564078A (en) | 1980-04-02 |
ZA771097B (en) | 1978-01-25 |
FR2347338A1 (fr) | 1977-11-04 |
AU2322677A (en) | 1978-09-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0462884B1 (fr) | Dérivés de TRH, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent | |
US4100152A (en) | Peptides | |
KR850001269B1 (ko) | 아미노산 유도체의 제조방범 | |
US4386073A (en) | Tripeptides acting on the central nervous system and a process for the preparation thereof | |
CA2115221A1 (en) | Aminomethylene-peptides as immunosuppressants | |
HU209413B (en) | Method for producing 2-azabicyclo [3.1.0] hexane-3-carboxylic acid derivatives as well as their physiologically acceptable salts | |
US4045556A (en) | Dipeptide derivatives, process for manufacture and pharmaceutical preparations | |
CA1088520A (en) | Process for the manufacture of dipeptide derivatives | |
EP1220852B1 (en) | Substituted diazepans | |
GB2095252A (en) | N-(substituted aminoalkanoyl)heterocyclic compounds | |
GB2203740A (en) | Novel peptides, their preparation & use | |
US4060603A (en) | Histidine derivatives | |
CA1158236A (en) | Process for the preparation of novel substituted phenylacetic acid amide compounds | |
US3850908A (en) | Aminoacyloxymethyl esters of penicillins | |
US6399599B1 (en) | Substituted 2-oxo-1,4-diazacycloalkanes | |
HU180925B (en) | Process for producing tripeptide-amides trh-analogues,effectives on the central nerve systhem | |
KR890002085B1 (ko) | 디히드로오로트산 유도체의 제조방법 | |
US4711878A (en) | Novel peptides and processes for preparing the same | |
US4450155A (en) | Analgesic dipeptide amides and method of use and compositions thereof | |
US4678800A (en) | Gamma-r-glutamoyl derivatives | |
CA1257748A (en) | N-acyl derivatives of peptides, their preparation and their use in the treatment of disorders, and agents for this purpose | |
WO1987004348A1 (en) | Acylated cyanamide composition | |
US4503043A (en) | Substituted acyl derivatives of octahydro-1H-isoindole-1-carboxylic acids | |
US3705887A (en) | Cyclic decapeptides and methods of synthesizing the same | |
GB2196958A (en) | Halo-homostatin peptide derivatives, their preparation and pharmaceutical compositions containing them |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEX | Expiry |