MXPA97004050A - P-amidinobencilamidas of dipeptido novedosas with radicales sulfonilo or aminosulfonilo in ends - Google Patents
P-amidinobencilamidas of dipeptido novedosas with radicales sulfonilo or aminosulfonilo in endsInfo
- Publication number
- MXPA97004050A MXPA97004050A MXPA/A/1997/004050A MX9704050A MXPA97004050A MX PA97004050 A MXPA97004050 A MX PA97004050A MX 9704050 A MX9704050 A MX 9704050A MX PA97004050 A MXPA97004050 A MX PA97004050A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- hydrogen
- alkyl
- group
- ion
- Prior art date
Links
- 201000010099 disease Diseases 0.000 claims abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 150000002500 ions Chemical class 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 101710041643 ARIH1 Proteins 0.000 claims 2
- 101700027981 CCNC Proteins 0.000 claims 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 6
- -1 SULFONYL Chemical class 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- LCZDCKMQSBGXAH-AWEZNQCLSA-N 3-[[3-[(2S)-2-amino-2-carboxyethyl]-5-methyl-2,6-dioxopyrimidin-1-yl]methyl]-5-phenylthiophene-2-carboxylic acid Chemical compound O=C1C(C)=CN(C[C@H](N)C(O)=O)C(=O)N1CC1=C(C(O)=O)SC(C=2C=CC=CC=2)=C1 LCZDCKMQSBGXAH-AWEZNQCLSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241001520820 Joinvillea ascendens Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N Glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 241000152160 Ira Species 0.000 description 2
- 241000658540 Ora Species 0.000 description 2
- 241001367079 Una Species 0.000 description 2
- 230000036462 Unbound Effects 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 101700005055 ani-1 Proteins 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000005842 heteroatoms Chemical group 0.000 description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940094070 Ambien Drugs 0.000 description 1
- 241000331231 Amorphocerini gen. n. 1 DAD-2008 Species 0.000 description 1
- 240000002254 Ananas comosus Species 0.000 description 1
- 235000007119 Ananas comosus Nutrition 0.000 description 1
- 241001365682 Bouteloua juncea Species 0.000 description 1
- 241000566113 Branta sandvicensis Species 0.000 description 1
- OSXGJMLMULAVRO-RJMJUYIDSA-N C(C=1C(C(=O)O)=CC=CC1)(=O)O.OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO Chemical compound C(C=1C(C(=O)O)=CC=CC1)(=O)O.OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO OSXGJMLMULAVRO-RJMJUYIDSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 241000022805 Diopa Species 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 101700063252 ERO1 Proteins 0.000 description 1
- 241000083551 Ena Species 0.000 description 1
- 101700057417 FLI1 Proteins 0.000 description 1
- 101700047253 FLII Proteins 0.000 description 1
- 206010016256 Fatigue Diseases 0.000 description 1
- QHZQILHUJDRDAI-UHFFFAOYSA-N Febarbamate Chemical compound O=C1N(CC(COCCCC)OC(N)=O)C(=O)NC(=O)C1(CC)C1=CC=CC=C1 QHZQILHUJDRDAI-UHFFFAOYSA-N 0.000 description 1
- 101710017531 H4C15 Proteins 0.000 description 1
- 101700001236 INTU Proteins 0.000 description 1
- 241000089854 Iberus Species 0.000 description 1
- 241000575946 Ione Species 0.000 description 1
- 241001417512 Kyphosidae Species 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine zwitterion Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 210000000088 Lip Anatomy 0.000 description 1
- 241000090179 Lorio Species 0.000 description 1
- 241000286819 Malo Species 0.000 description 1
- 240000000233 Melia azedarach Species 0.000 description 1
- 206010027175 Memory impairment Diseases 0.000 description 1
- 208000010125 Myocardial Infarction Diseases 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 101700032742 PROC Proteins 0.000 description 1
- 241000282322 Panthera Species 0.000 description 1
- 229960005190 Phenylalanine Drugs 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 210000001747 Pupil Anatomy 0.000 description 1
- 206010038563 Reocclusion Diseases 0.000 description 1
- 240000003670 Sesamum indicum Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N Sulfuryl chloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N Triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 101700028444 USO1 Proteins 0.000 description 1
- 101700061199 WNT1 Proteins 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N Zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229920005549 butyl rubber Polymers 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001054 cortical Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol EtOH Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000000414 obstructive Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002758 oxo-lambda(3)-iodanyloxy group Chemical group *OI=O 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
Abstract
The present invention relates to compounds of the formula I wherein R 1; A and B have the meanings stated in the description, as well as the preparation thereof. The novel compounds are suitable for controlling disease
Description
P-AMTD? NOBENCT. DIPEPTIDE MIDAS NOVEDOSAS WITH PADIOAl IS SULFONYL OR AMINOSULFONI 1.0 IN TERMINAL N The p. This pivenpón refers to p-ami _ nobepc and lmidas de di ^ í'i > "'> i radiates ls sulfoni lo or bipp an? noíu] fopila in ii-? n n 1 f J, = •, *? reíit-rp also a ß? prep ra - ón and t] use the nuartii-' T. i mu t nh "t gone f.fi of the trintintuna. F] oojn.er.l-o FP 601 459 deíbbe i nh ib i hers hetero irl J oi of t p nih ir »? what They have an > group 3ul f onamide. I -) μt? .íHnt. nve r - ón _ .. * -? ef .ei'f Odt ivesto of -a formula 0
and: .n_, Pnlpi t? üi? ó? i? epoí and ísiis -, 3] > = - =, with ¿i > _ i os * ". i bic.1 o and i t- le dob, where the = sust.l uents in the fitijtusn is meanings: P1 6 alkyl C1-C2 <-, f luoroalquilo C1-C3, C3-C8alkyl, C1-RiO, C1-RiO, I1, I1, I1, or R1R2N where P2 and P3 are identical or different and are hydrogen, so that Cl-r-, .¡?], - C1-CO alkyl, or together they are a chain of alkyl.no r-07 to the> < a can be fused a i'idu "? lnn'i 1 > heter 1 or n can contain a hetero atom, S, NH or N substituted), A = - ?? an i-iidnn? > e «1 fa-ami uoß» c of formula II R < NH-C-CO I II R5 where P4 in hydrogen, alkyl 01-08, C1 to C1 to C3 to C7, to R1 or C1-C3 arylalkyl, P5 t > hydrogen, alkyl Ci-OP, alkyl alkyl 03-07, i. i c loa 1 i] o 03-07-a 1 qu 11 o 01 - 03, -tr. lo, ri 1 Iqu 11 or 01-0"* ,,? ¡j *> ul alquiln C3--07. -nn-d tío or di f? i. lnii-1> j 1 oo bien - - J Rl
- H - a r -., ._. Al - i 't l Cl - OP where n -. L m. |. »Ii? D? oijefií i S - ncue r l. , .a by 0R6 or rrn CO-ORo iR
-! n?!? ÓIJ IIII, at 01 01 CF; , _,. ) i P? = t t i lciliju_.li) 01- 0 -, P - - R3 together nn uni i a ti '. '"- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -.
You where you. e- ^ 2, 3 well 4, a h_ dróueno ^ n ^ l ani l l it can be replaced by a hydrophilic group or Lueu alkyl 01 - C "* y - si o? = 3 or bie - 3 - a ni'.ipu 0H2 in the, r¡? 1] r.ufede ed reem ao by o; -geno, adufr, NH- or bi n N - alkyl O1-0? And / or two * lo (t? nay cent s of the hid? geno can be
• '^ Pin ld.'. I-Joi for a double link.
* "» Ep efie in the following e-, group *. »E.-Umpuet o__: 1. Compounds of the f mul I where l -.-.» U_.l uents have the following meanings * Rl is OH or either R3R2N, where R2 and R3 are either denative or different __ • -.a hydrogen, some> > > C1-CU "', ari lo, C1-CIO aplalkyl or together in a na lquil «n
C2-C7 to l -? my can »-1 st r1 f» < - »? Ona.do a radical crilo?" I well l.e '.--. L •> u can e ou.e.ener a herer A tome (0, S, NH
O »I • - r 1; > US 1 i 1.1 I l > I), A i -'- a? -, | iln? c | fj - 3ti »i riuAr i r¡e 1 __ frtrfpiil a IT
R * I
NH - C CO II R5
where P4 is hydr-no, alkyl 01-08, > _ i cl o qu o 1 o 03-07, anlo o bi n - = > r 1 to lqtu 1 or 01 -03 ,, RT- is hydrouene, at 1 u t 3 or PJ ~ 08, r? > : 3 or 3 qui 1 or 03-07, c? > . loqui 3 C3-0"* - a 1 qui 1 o Ol -03, .ri lo, splalqutlo 01-03, di ff?: 1 or 1 qu i 03-C" 7) -met i lo odif ro.3 me »i lo o - - =? P-3 = H
- a rad? > -.- l? For example 01 -0B where one m of hydrogen is ie .-- l l -.l by ORA or 00-0F.A (R ^ = hydrogen, alkyl
01-C8 or .i ilalqnilo 01-03), or R.-1 and R1"* junt -, are ufid ca ena of pupil C2- 06, which can contain a r -,? ¡? > - To the uilo fusion-nio, P is a residue ea 1 f -ia i noAi. Gone r í> .J. Of J formula III
where?, - | e? - 3 bi n 4, and a hydrogen atom in the anil can be replaced by a hydrophilic group or ti i in -ilqui l ») 01-03 • _ - si m - 3 or bi n 4 - a group 0H2 in the ring can e.- »? ? reemp la, _a > J > ) by o, in, sulfur, NH- or CÍ 1 i | i 11111 O - 4 and O dos-tfcom n adyacent -.-- *;, of the nuedi- i e-, - -? i eenij »Id-'a ur Oüi a link of l, 2. G, IIII- | IIIH_ 1 ii- JH 1 -! f ¿MUJ 1 a I o e l s -.u =,. j .. i rd is also
1 i) - .. - I i j n i.? i e - -s i? j I o f i i 3 • _ -_ > íí Pl e-, dlijiidn 01 -C2, f 3 uoro-lq 3 or 01-03. > _ i l oal qu i 1 o 03-l * "! OR, -i Ítlalqui lo Cl-OK" -, -r.ri or else hetap lo, A e- > a . esiduo of 31 f - mi no ?. gone from 'la f r u a II
R «I
NH - C C0 II I R5
?? Je R μ4 _, 1 ri. > .1 or '"* 1 - 08, icloaloui lo 03-0"! r 11 o o b i er i
-ii'i lal'i 'lii 01-O ", P e_., on the 01-08, C ooaluui 3o 03-07,. -c3oa3qu? 03o 03 ~ 0" r- a 1 qu i 3 o 0 - -C3, -.v il, -ir 11 to 1 qu i 1 or 01-03, d > When the first or third of three weeks, either phenyl or P4 and P * 5 together have an alkylene chain 02-CS, which may contain a fused aryl radical. , B is one of the, - »radicals
/ - \ - N NH N N- C? _4-alqo? Lo »
coco -
- N 'O - N' - N 'NH - N' C? _4-alC | «o, _) 1 CO - CO- co-
3, Compounds of the formula I where the su - - j listeners have
K) -? next nt s i gni f a a; P f ^. alkyl 01-020, f 1 uoraa 1 qu 11 or 01-07, cu 3oalqu? te 03- 08, a 11 a Iqu? lo Ct-Cl, aplo, hetari lo or OH NO A is a residual of a 1 fa -aminoáe gone from 1 to formula
- NH - CH - C0 R5
, .or don e »P5 * • -. . Iq il 01-08, ft n e a Hydrogen atom Ì is found by ORA or bi n C00PA ÍRA = hydrogen, at 1 ppu 01 -08 or bi n i 1 a 1 qu 11 or 01 -03 > , B is one of the radi a
-
-3 _ C m ue of the formula I where the sust i tu n have the s guient si nified; Pl e_ < alkyl 01-C2, f} norcnlquilo 01-03, cio I a 3 qu i lo 03- 08, at? la3qu? 3o 01-010 arilo, he ^ arilo or OH, TÍ A is a re iduo wa 1 f í ~ am i no ^ o de the formula
NH - CH C0 I R5 where a hydrogen peroxide is found either by OPA or bi o COOPA IRA - hi. well al lo 01-08), B is a si uo de al f -aminoá gone c íe 1 ir or de 1 -i formula II T
li rtue ui -, ", 3 or 4, and a hydrogen? -n the arti l can,". PGI-; I I T et - m l < "_r? k? noc a prn uh? d? g? i i ii or alky Cl -
03. Fl t é I III t U? "<" 'ti l l "- ^ l- >,? _. >" i e | i--, -1? j, i ¡.II i - > ? ' ? 1 1 > > > S monoc i c 1 i > _ > "__"> l.? -? I? Ui? 1. i • o-> rn! IHH ^ H of A • < 1 O £ s i- - < i bof? HII lais at the end of the year, 5 items are not identical or differ- ent. The term is not "ht-i-rl io" srfi ra- a an? L lu = > ÜUJIIWUC S of? A? \? Ieb i'i-tn what ??? _ > ~ i cont ni 1 or 2 IIPI PI pl iiin s with example M ,, 0 or tu n 8 y sob? > - which can- merge Fu: lo: - > group- 1-4 > -e oo ue - Toa T, can iwñui fidf IH? 5- 11.?. 1 -ii melele. o., composed- »with lss iqu i entes
-ji? -, 1 i? f.i | t, is P 1, A and Tj. Group of > _ "; .mpuer,), or--, 1" "i Rl: is UH2, mono- or bi n di al qu 11 apu no 01-04 well iptid mi 1 o A: residual of the a - noric i two al i na, 1 & u > ~ nid,? -. ol u > ina, f eni Ig 1? o ma, c i c lohe: i lg 1 go. i na, feru la lam na, t. i c lohe: -, i la laní na, di f eni la lartia, d i c i c 1 ohe: i 1 a 1 ani na,
Ti where the pyrillin particles present in the waste can
Pi r = »ust you by up to 3 identical or different groups ilqu. 01-04, a 1 o: i 01-04, OH, F, 01 or CHOPA P 'resi uos de 1 > J. am i no? »I to A. idos acet? D? N-2- i i b? > i 31 • "'" I, prol i u -i, - < > i r | o p i pe, i, 1 j i. ct, deh l d ru i op i 1 -t u, 4- '"idni, ii" il itip, ?? H | i? ? i; , p-,) npro i, ai i do 4- ilqiii 1JII | J? l n n Ol -04, «c i • lo * ..» > r f o 1 i 11 - 2 - a F! ? . í '-? i _ HI.HJH U i f f i f i - 2 i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i 1 -04 - - Rr upo de > iiniμiie .lor 2 *. "Rl alkyl 01-04, femlo, nafti lo, ffruUlqiult.no 01-04 í ---? c). {icularmen e benzyl and phenethyl), na f 11 la iqu i 1 eno 01- 0-3 < s? C), pit'idilo, isi oqu i nol i lo £. T -ji u - »ls ani it? Aids <; - > 1 f - -met • 1 f ero 1 i lanirta, at íd- nel'Llcii lohei i lalanina -t 1 f a-met 11 f em 1 y 1 i c i na, alfa - 0 m t i] c j i- 1 ohe;. i 1 g 1 u ina BÍ r if u -. of the-- amiunAcido- deh i d > op rol - 1 ta, or api ol ina, t J ip i o 1 i na, < to. i or p i μ r or 1 i, a i 'io J- p? p í o lu ".or 01 -04 _ <? ido mrf ol í 2- i arbo M ico, t > ti tipera, ind 2- ai, f 1 u., ni io 4- to uil C1 - 04- i e «j? 1 na- 2--> ._c- rbu, f 1 ico * 5 Group eto í le-ito --- 3 o
Rt: alkyl 01-04, phenyl, naphthyl, m 1 to Iqu i 1 ene 01-04 (parcularly benzyl and feueti lo), na f 11 to 1 qu i loño 01-04, pyridi 1 o, ii qu i no 1 i lo A: residues of ls amino acids aspic acid, glutaric acid, serine, or osepna, threonine, where A ido c. r: .11 o or bi-in the unbound hydrophilic group can be e = d r} f j t. ado > > b i eri eterifi »a > -lo, respect. It is possible, by an alky radical 01 -0R, to specify t-but? 3epna ..- t.i.t. '< F.; r? - i > 'IJ-- lo, - o 11? O- »t i d 1-" »deh i> 1 rop > 1? A" o1 apt ol i u- <
I? -) i ul) u,? Ied mpi f ol i 11-?? A rbo; í l i o-n? an I IO i. ottiOU s »> s -i R1: a 1 qu 11 o 01 -C4, f n. . or, i,., f l i 1, fen 11 to I u i »-t t j 01 -04 i: - ,,. \ ípai t 1 i. u the roten t nene 11 o and feuetilu. , n * f 1 to 3 qu 11 ene 01 -C4 me), pin di lo, ts? oqt.11 nol 1 lo A. residues d the amino acids setinp, homoserin., treontp-, where the OH group can be etherified by 'alkyl 01-CR or Lien rid s ecto or, glutamate acid, where the unbound carbohydrate, or carbon, can be included in the formula: -two-by-1, -oe Ps • is i duos of the a inoá idos 4- hidro; - 1 prol 1113, s uio 4- a 1 qu 11 p 1 f 1 e > - or 11 •; or 01 - 04. Do you have the lines R1, A P estAo, as illustrated in the _ ..! ru? t 3 T, united together, and the residues of -a 1 noc 1 in A have preferably the configuration (D) and residues.
de aiTiinoA »; In B they have the pref * -renc i to the ortf i juru. ion (L). F, e can mention the following substances - as substances pr ferida-- "; 5 CF3-CH2-S02- i) Fe-P ro-NH-pAmb C4H9-S02- (D. Fe-P ro-NH-p Amb CRH 17-S02- (D> Fe-P r -NH-p Amb 01 H33 -002- < D Fe-P ro-NH-p A.ith i -prop i 1 -9.02-JD) FP-P? .- H- A f in 1 -S? 2- Fe-Pro- Hp Amb ", -iidft i 1 -R02- v'D) Fe-P? O -NH-pAmb 3-p indi 1 -R02- (. Fe ~ Pc > -NH-- pAmb 2- 1 int 1 -902-. "Fe-P r».? - Hp Aml t N- pi peí i din »1-502- < D > Fe-P ro ~ NH-p Amb 5 H2 -502- < D "Fe-P ro-NH-p mb &Me2N -S02 ~ < n 'i Fe-P r o -NH-p Amb F. HN-R02- <) Fe-P ro- NH-p mb Me-S02- (D) FHÍ 4-OMe. -P. I -NH- Amb Me-502 - í D Fe (3-OMe? -P ro-NH-p Amb 0 Me-R02- < D) Fe f 2-01) -P ro-NH-p Amb M S02- (D) Dp a -P ro-NH-p mb Me-902- (l) Dp -F ro-NH- Amb Me -B02- < D) p (4, '-OMe. ~ P ro-NH- Amb Me - R02 ~ < L. • Dp to < 4, 4' -OMe) -p ro- NH- pA b ^ Me-F »02- íD 's Í4,' -01) -P ro-NH-pA b 1 l
Me-S02-d) Dp- < »', 4' -01) -P ro-NH-p Amb Me- B02- f D, l"> Phg »'3, 4- 01. -P ro-NH-p Amb Me-S02- () Aso C OH) -P r -NH -p Amb Me- S02- (L. < Asp 'OH' < -Pn > -NH-pAmb Me-S02- íDl'Asp í0Me) -Pro-r4H ~ pAmb Me- 02- (I.> Asp <OMe) -P o-NH-pA b Me-S02- <D) Asp (QtBu) -P ro-NH-p Amb Me- 02 - (I-) A-> p < GtBu. ~ P ro-NH- Aml > -c:; 02-. D) P | -, eA- .-- NH- pA b 1 ri > --- B02- íD ' iFe-F íp-NH-pAmb 1 -, -? - f I-. 1 -R02-R1 i -F ro -NH-pA b L -i -th - evi. ii * ra - wii.p 1 ec. d - < - en - ,. 1 ii 1Ü.
.- »1 g U i e u e e -, -, t. ? j f t i f j r, 5 -,: F e = - ífiu l-il. pina, p mb - p - am i d 1 nob > in > - j lo, Fr - p. or ma, tc? Opa di íñj l - ldinfH, Phg - feni lyl o ma, A- »= i gone A,? E - _ -» > gone acet i > i i rt- - a rbo, .13 i co, F ?? - Acido l os conipi? n Those from l to f or t mu 1 to T can e; I s go as such or b. in in? rr ?. > -. n--. -, they are given the correct or tolerated conditions- Example - »do tale =» á > _ are they? To gone c lorhíd ico,
Ai. • • • • • • • • • • • • • •. > r 11. > i. - ?? gone titel. a snl fón? ». or, -iciclo se ético, Ac i or formic, A? _ i o malo. or, A > r? »Jo fnmArico, to i o _5U.cc í ni o,
-.i j > »? _. hoii o! i i t t Juico, A i o stfl f f't i > , ai i do ylutArico, 5 A ,; gone - »i? i o, -trillo p i r? v i c o, Af ido heni-oic, Acid »n 1 uc i n o n o, A •. i do Al i s orbíco, a > ..e 111 g 1 i > . i r? a "The invention also refers to the intermediate products of the TV formula
where P1, A and P ie in the established meanings,, .u > - u d n etu¡ > 1 - - * i s n-a r-re -jr-ar i '- ues s I - [> i -,? ? )? »? ? i. '•' 1 o- i-'U'i r-, i = > e e? i i-; Tu It pa: -t l r
a 1 f a - -t t.t i? "? > I--" I '"-OH, JA l d l a a i i no i i r i.
1? 1 i L (l> o, P- OH L r.f> o?,., I? J- »d • ou > -j 1« -schema
.t u t n - -iin.ieitt *. i i "t I i,
Scheme T T
Eri the schema-, of reaction iridíf 1 ore- > , P7 e--. Either alkyl 01-04, P8 alkyl 01-04, preferably methyl or t-butyl, P *? is CN or you in
^ H ^ © v X © - C (X - Cl, Br, I, CH3COO) H;
v P is a protective group, preferably t-bu t ca b bo 3 o (Bac) or b n 13o- »ic rbom lo i" 0b "». Al lerna! 1 j merd, the two protected P-A-0H H-P-0R8 can be used to form the dipeptide P -A-P-ORR and r'í? C. c i LUt-t 1 -ubsec ut-r? Lieutenant after r-tcr ioo e P > ou R1002C1 or PS with p-cyano- or else? amid inobsnc i lamina, being any »sequence of passive reaction. R1-S02-A-0H can also be directly coupled with para-H-B-NHCH2C2-, H4PC? To propose proposing the final product I or the intermediate product IV. t aa required coupling reactions are performed under i ione ^ e- = d, Peptide chemistry gauges (see M. Bodanst and A »1 < .nal" Tt > e Fraclice of Feptide Synthesis ", Sps i rtger See 1 -tg, 1¡ ".R4 (if c) .. Orupos pr? -? tec! or -.-- B &rt? - are eliminated -» HCl 'gave: year well 0E30000H C lot nt 11 d> -! Ll n, yui -tp-i r le »Lores Cb» r »e eliminate by hidi ogenó 1 go &i> = -> > .m Hl7. Ia • - > Fuu: 1-Ester ester hydrolymeric ester has OH or L i OH in an alcoholic solvent such as methanol or ethanol.T-Butyl esters are hydrolyzed with acids, for example 0F3C00H. 13 IPII with the sulfonyl chlorides P1-SO201 in the presence of an organic base, for example tri et i1 tiirii na, pipdine or N, Nd i isopt op 11 et i lami, is carried out in solvent- »Organic, such as CH2C12,
THF or DMF. In the case of fun > _ canvas 1 idade-r- free > of Ai gone i < When the reaction was complete, the reaction was carried out in the presence of hydroxide ions or liquids in metal carbonate at 1 ° Celsius. Amyclins are prepared from rutplo precursors by the classical Pinrter synthesis (P. Poger and D.G. Neilson, Cltem, Rev. 61, 1961, 179) or, preferably, by modifying 1? P inner synthesis which is carried out by means of phosphate salts as an intermediate product (H. Vietxeg et al., Pharma -? e ~ *, 1994, 226). The hydrogenated catalytic ion of N-hydr-o: - i ami d i ñas, which can be obtained by adding eleh? D? OM 1 amine in the cyano group, with Ni Paney or Pd C in -olvenl alcohol i or »- > resu t - also in ami.cl.ina- íP. J. Prougtiton et al., 1. Me . 01 tem. 10, 1 7, 111"" *. The novel compounds can be used for 1.-therapy and 1-t prof-la: is of all the erif i ages where - »tromhin. t?; t. involved tra¡ < I hope This is mainly due to rhombic factors such as, for example, myocardial infarction, * 5 peripheral arterial obstruction disease, deep vein thrombosis, pulmonary embolism, apoplexy. In addition, they can be used to avoid a reocclusion after the opening of the Artepanos vessels by method. ecAmco- »o
? Their particular case is that they are also effective after oral administration. The compounds according to the present invention can be administered orally or parenterally in a conventional manner, subcutaneously, intravenously, intramuscularly, intravenously, rectally. The administration can also be carried out with vapors or sprays through the nasolabial space. The dosage depends on the dose, condition and weight of the patient and the mode of administration. In general terms, the diopa dose of active substance per person is approximately 5 -, OOO mg in case of 3dm? no oral ration and you appropriately 1-200 mg in the case of administering it, ton pa rentera 1. These doses can be extended in 1 a • * • do - »? s ? ucas or else one see >; Jía in the form of depot, the compuedos novedi td > They can be used in solitary farm forms > onventional liquidations,? o? example ,. to t blf-tís uo r j - t i tJ s > t well reves i - »., (per film), capsules, pol 'tía, granules, supposi ions, solu ciones tions, ung, ies, or b roc io ns. They are produced in a conventional way. In these, the active substances can p? to deal with au: liare-, farmecéu 1 convention them as for example aglomera te- ar tablet, reí lumberjacks, conservatives, de =,? nt s ns of tablets, flow regulators, plast i f i ra ntes, wetting agents, ispersants, e ú 1 f o. ntes, -_. ol fc.nt.es, prolonged-release agents, ni or »i d < __rties / or gassers sulfuctores í.er H. Sucl er ei al. Pha > d r e 1 - »r he Technologie, Thie e- Verlag, tulty-srt, 1C? 7R '.- L -.-» forms of administration obtained d est :. form r nrd leueu normly the substance - < c ti goes in an amount of O.l to 997, in peao, EXAMPLE 1 Acetate (p-amid i uobenc 11) am? N-i oprop i lsul foni 1-D-phenylalanyl-pyrolone a) O-i-c lanobenz i 1) Boc-D-phenylene amide lam lprol ina 2.0 g (14.6 mmol) > .ie isobutyl chloroformate for 2 minutes at a solution of .1 g M4.2 mmol) of Poc-D-Phe-Pr-o-OH and 1.53 g (15.2 mmol) of N-met il mor fo 1 ina in 15 ml of DMF at a temperature of -15 * 0. The first time that it lasted for the first time was a solifer in 1, * ">" j (14.2 mmol) ce -ci. * N. "Beno 11 ami n-_ (i - Wa 11 er e ~ 1,, Ann-660, 1962, 6 '"• 1.53 g of N-met i 1 mor-Ol i ,, -. in 3 ml of DMF. .-. - 15ß? During 3 u?,, -, - a <-revision by TLC (0H2012 / Me0H, 9/1) or os.ró tiuuún initial compound tabl e. In the isolation, the reaction was drained in 200 ml of a > gu, when an oil separated and, after a short time, solidified and broke and was removed by suction filtration. The residue, still wet, was dissolved in a mixture of 250 ml of ethyl acetate: 50 ml of ether and washed successively with a 3 - or aqueous acid, V,, b, > "3 rbon. and solutions for the solution of c 3 »-> -> -> sodium.> After drying Na2SO4, the solvent was recovered by means of a reduced pressure ation, and the "H,], J, J, J was m. *? side with n-he \ ano and then temovida medíanle filtration with his ci n. L-i recr esta 1 i -ra i ón «_ from 5, n] l ethyl acetate propor». lorio 5.6 g d (n product pur TIC, point of fi.i-.iott 15? -l 57 ° 0. b) hydrochloride of 0_ > The amount of D- The above compound was dissolved in 100 ml of 5N HCl in dioxane and stirred at room temperature for 3 hours, during which time the temperature was determined. ocl orur. E = »to was later removed me. filtering > on suc > "i n, washing with étet hast ue -.e l iberó" -.ie HCl and s c n 1 OH under pressure
1-f.d? .i? "I da. S oh iiv i erou. Ó tj f ° 5" of the level t ri de c? ? = »Tale_-, bl r» > > s (fusion pin 22. "'- ^ 2" "C.'"> qi - c l nob it i 1) an? The first one was dissolved in 2.0 ml of 0.05 mmol) of the former 1-fluoride in 50 ml of 0H2-012. The addition of 1.35 and (13.5 mmol) of t = 1-one resulted in a solution to which drop a and ci were added, at a temperature of < "> -i 5ßC, > "-, 9 g < o.l mmol) of? Ro? An-2-sulphthalide chloride or dissolved in CH.sub.2-012 ttl.The elast e reaction was agitated at room temperature. ambien e during 5 hours and then extracted medium agi-ion »-.ort water, A citred to the 5. and a lucid &nt; f NaH003 to 5 i. After >After drying in Na 2 SO 4 of the mixture in the sun, after the dissolution, the oily VISLOSO residue was redissolved in a liquid or ethyl acetate, 11 o / e er < 1; 1). D) (p-11 or id i nobenc i 1) am? Da) of N-isoprop and Isul f oni 1-D-phen? Lln? Lprol? Na 4.1 g of the above compound and 4 ml t riet i lamí na were dissolved in 4 ml of pipdine, saturated with H2S at ßC and left to stand at room temperature overnight A review by Tt O.0H20 2 / MeOH, 9/1) showed that the conversion into I The first step was to move to isolation, it was removed, and it was moved to the first place. to μre ».. nín reduced, and the residue fu collected n 250 i from a i and I. -i tt > ue et i lo * wash c ou > .3 > 11 i u o sodlo. J ?. j rl, -,? f I r i? or il 5t- and - »?) 3 '. > "Nu-iC03. Fl -t.? ao, -.? - n ?? ??. -., -. u of the sun comes med ient from,», i 1 a- ~ i ou t eslul tó n 4.1, "Ii" i? t? i da p ^ '-l ifa pu i - .. e) ac talo Or-ami di nobenc i 1) anda da e N- i soμrop i 1 his 1 'orn 1 - D-- feni l? laiu I li na Id iam ida was clisuel ta in 150 ml of acetone and, after the addition of my induro de meti lo, was allowed to stand atmea ur environment during On the night the residue was removed after the sun removal was carried out with dry ether and then dried, and the hydroiodide was poured, and the imide was added to the methyl ester in ethanol. a solution of ammonium acetate at 10 μg and 15 μl was added to a solution of ammonium acetate at 10 μg, and it was cal to at -i ≤ 0 ... 0 during 3 tictra. When the residue was removed in 100 ml of CH2012, the insoluble constituents were removed by filtration and then CH2012 was distilled, digested. n with an er! a > The ethyl acetate / diethyl ether was made to remove the soluble pures. The remaining slurry of the precipitate / solution was dissolved in acetone (3/2) and converted by a bi-ionic IPA acetate ionizer into the pure cao, which after 1 ntami ent in ace tom tr 11 o, it was in form? Ie a forget tti st a 1 i not white, fusion point 14S-152 '* C wjes > .-ou! pn._n i n). FAB-.1 (| + H) to - 500. E TEMPLE 2 o. e a o de O; .- are d i notierti. i 1 antid i d > - ti-. i, in i 1 -2- -n 1 fnil '-u - fnil l-ini 1 u ua' 'p- am idi notierii- i 1). «ii da de Poc-D- em 1 a am Ipt ol i na P convi rt i or »'p- > Anobenzene 11) amide of Foc ~ r. ~ fent l-.lt.ni Iprulipa (see example 13 for prep ra in ^ by method 1. 'using H29 er »1-thioamide and then with Id. The diina was obtained in the form of cr > s ta 1 • = .- •. whites, melting point 2"t -" - 239o0 FAP-l?, íM-Ht = • 34 , b 'ih id or 1 oruro > le f p-ami di nobenc i 3) am ida of t -? "er? i la 1 an 11 p rol i na The iuo pt ci Bot was selected as part i] i »m-oue» -, previously with 5N HCl in uto, »« not as the first 1 or 1, the Iihi roi. lorur o went to isla.lt > n form e, &pol; v very h .yi '., .. opo., melting point 30-140 0, FAB-MB ..? - iT. -re' < acetate (p- aidi nobenc 11) amide you N- »11 in i 1 -2- aul foru 1) -Df ni lal ni 1 rol i na A solution of 3.9 (J .12. Or, mmol) of N- f in i I nl f om lD-5 phenylalanine (Egypt T. Obem. 23, 1981, 273) in 40 μl of THP was added to: 1, addition of 1. Q g (12. or mmol of 1-hydro).; - 1 hen- "ol, t I -»,? 1 and 3.3, j .25 mmol i of ij o. I cl ohe;, il -t rbod ii mi da, at room temperature for 4 hours. pret ipi l ada was renrtov? c? -? me? -.me. " i 11 r ac l ion (", -or? suc ction ylat ou a little" le TH * - »- f? llfa» 1 »? = _e le .IJI jy /? -i 5 * 0, a ni? r ,,, ..e .1?
. t 2. or, mmol) of d l uldt i lüi ili'il de < J- t'μ- -. iiud i tiób ni- i l) fi rr i n-uii í r¡- »j 1,? g of I • icarbou- »to -, hatred in or t? t3 water. Pe-pué • »de agí i a» inri a lentpe, a ur -t -. tt »r» ¡»-r > t »r
dur ant e 4R hora- », l _, o > The waste was collected in ethanol, filtered to remove insoluble parts, and another concentrate was concentrated. The residue was purified on a gel column of ice. -.- > A CH2C12 (mixture of acetic acid 50% W / 45 5 / 1.3). Distilled the elution of pure fractions, adding toluene to the fi lter, and the If there were 50% acetone with a 1% water content, then one was able to remove 50 ml of acetone. level of the earthquake level, and the cs, merger unit ^ .-- oe "'"'. FATó-HF, (MH) + - 540.5, EJFMFI .O 2 acet or of ip-a idi nobenc i 1) ida of N- (2-naf ti 1 sul f on i 1) ~ Df in i 1 to 1 ani 1 p ro 1 i na 3) (p - 1 - 1 to nobertc 11) < - < J da de Boc-prol ina Be introduced 27 > tj of Bor-Prs-OBu (0.88 mol) in 2 1 of chloriu of the lno at 0 ° C. To this solution were added - - light.- 1, 163.9, - of h id ro e loruro e 4-? l nobenc 13 ami na í "9" i * m l) 25; "'mi' 3e di isopropí l í 11 anona (1, .34 mol). l;, = 11? s -? I order > it was jyi tada n Uh bath of i it of > retido dur -in e
48 h l i -. -.e f .1 tr after- f f I 1 '. .-. do fi.ie .-.; ... Ti eye i.iiu i, f »_j Saddle, i n. | e HBH4 si 2 i < '- • ert S1 -? In S ».) 1. > . I ófi d > - '
NaHC03 -, - (I 1, r i r!, '5 .IJI.-IJW,) ^ una - li-i 1 ou d 1 I cure > -je sodium -.a ten da (2 --- e »e-, * re»?) or and - »evapot or in an evaporator yi i'atur 10. The ¡an? .sta31 The remainder = part of the tertiary system resulted in the isolation of 261 g (90 V) of white crystals, melting point 24 ° C to 24 ° C. 1 oruro d »-.- N- 4 - and ianotien»:. 13) pro3 inamide Be d? -> forgetfulness (0.70 mol 'of the above compound protected by Boc in 1 liter of ether diet ll _c >: & , after that
S 3 addition An e1 i-, 0 solliCloll lt.if.ri-H of HC3, stirred IJUI tnit '1"1101 tit, El h'dr clorut pt i 1 pi ao was resto vido >Ned? - »? il-e f? li 1 ain, the ether diet '1> &jt; ~ t.-that the H01 of ethanol rradn to split ethanol Ele _.b 1 u 'ie? A 2i ~ t »u (c;" 5 * i)?. | E ci lt-i whites, fusion cur r 209-211. i. The amount of N-T-naph 1 -sulfonyl-1-sulfuric acid (1-sulfuric acid) was 0.19 g (21.3 mmol of the hydrochloride or amide of proline). previously in 1 OO my DMF and they were added
- »nces? vamenf e 7.8 -q (21.3 rumo l) of N- (2-na f 1 3 sul foni l) - D-phenylalanine (A. Berrtat et al., FP 2593812), 2.15 g (21.3 mmol) ) of I peti lami na and 3.25 g (21.5 rumo l) of 1-hi cl oi i ben. "ot ri, ol (HOPT), Ba jojd -? i? .- ? a 0-5ß0. s -ujl íyi;. rt s Solution of 3. uí "^ 1 .3 miTi 1 'i de d? > - i »l he. 11 c - ri'od ii mi ri in 5. "mi d-- df '. Tp e HÍ, ,,,,?, M. T 1 ¡fu e è rg it«? < a l ... - i ur-t .mu ipni e dui nt 4R
It is necessary to remove, remove, filter, and dispose of 1. Remove all the solvent by distillation Liaison. In this case, the residue was received in 20% of the washed-out acetate, and it was deposited in a vacuum. Water and water After the removal and removal of the acetate by distillation, the oily residue was digested at 30 ° of 0H2012 and after that. -! i. I am getting the -. ilici ne 5o? n] »to» er 5 »-. -ii -. l n n 9.1» j
< 7 £, '/,) of the compound r ^ ei'? Jo. d) Actato de ín-_ ?? di rn ibene i 1) ditti d of N- (2- na f. il sul fon il) - Df in i 1 «1 ent i lp ili 11-, With e, trusion of humidity, 8 mi., methane 1 fu ro ura a •. on a g- »F >; H01, 5.I, and (10 mm) of the above compound were dissolved there, and the solution was left to stand at T for 4 hours. Be removed the solvent at a temperature of 2 < "0 °, and the residue was dissolved n 2 μm of the nol and added at a temperature of 0-5 * 0 to BO i of methanol solution met = NH3 The solution or so?". aa e reflux before 3 hjor -and then cooled down. "fili rad-i, e-, ilveni -fu i emol i medi -trd e desti ation,. ríi el-l? _) de atn &nt; n naido a intet > blado e ion - > t • < t. _, Í.-Ítr Í sa 1 i - <? - r? ap 3 ¡tj, d <? t-iiTu 1 1") 11 -i 1111" 1 f, n of a iiiμ 11 1 Je ,, nu-a 1 e-ii 11 I o en 5.1 'B', '' d] i »-) ¡?? ne-, t > t! (i, u 1 o »- shape of < ~ \? t -riles white-, side of fu-» or? T1--22r ".T. FAB-" IB (M + H) + = 5R4 .5 EXAMPLE 4 acetate (p --- tm? D? Nobenc 11) am- da of N- (piri el il- 3- uif opi 1) - D ~ f in 11 < -.1 ani 1 pro 1 i na - »" (pL i -i nobenc i 1 / amide> ie N-pj nd 1-3- ul foni "I-iin i 1 • = .1 an 11 p ro li na hie chlorchloride (pc i anobene i 1) amide of D- fen i li larti 1 prol it? a
(similar reparation the and b 'n .-. u i on? as in the
1? i on i lorur de μj i i i i > ~ 3 - su 1 f ou i 1. PF = ¡"-.57
(CH2C1 'MeOH, 9' 1).;,. 3cei -. What of (p- ludi o, i aiti idi ni ibern .: 11) ai da de N- (pir id i 1 - - i 13 fni 1 '< -D- fnt 1 a 1 - >No 1 cu l or solium of the hydrocarbon hydrochloride and 2.2 g of troetilla in 30 ml of ethanol and nitrogen was added. At a temp ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The reaction was affected and the pH was affected to 3-4 with the glacial ethic, the phase of the various phases of CH2C12, rad. of 0H2C12 combined for a number of years and the first of which was I + 1, - IO, I, I, I, I, I, I, I. fijni iar > . > rd eni endo - »? j do A ré! i i o, it was | .1 d 11 w i, a tile n i in 1 -i i e, t? ? i n if uiente.
RG - o. (OH20! 2 < 'Mer »H, ° i' •. I '• - iiat' idf ¡j -a td idi itribt -'i'H .1 'a ic' ^ of U- ip. R? Di 1 -3-.? 11 f?? N? 1) - - fen i 1 a 1 a • o 1 p fo j. > * Be hydrogenated a so ni. ¡N of 2.4 and '5 3) of the foreground IOI in 40 rt methanol in the presence of 0.4 of Pd c. i go to 10 to 50T for 7 hours: < - .. The catalyst was displaced by means of the traction with its i, -1
_-L.I1 was removed from you by distillation, and the residi - -) futi-O irte- > It is heated with eti ato and heated. Be produced a solution I'.I-J I by the addition of acetone from < > u o
U e - | g n .. to 1 erif r t se, the aceta or of a i ei ^. t -. ' Be a? -.l - »rc? n 1 .3 g (49.57.) of pol or target, point e fu-i i 2" "<1 ~ 2C2T, PP 0.2R (0H20 2 / MeOH / -'- .. : o.lo aético al c,
0-'2-'¡ ". -1-. '..
FJFMPLO 5 ac tato de íp- mi di nobenc ill ida de N- (2- na f 111 its fon il) 1 ii 1p rol i na a) í pia nia nobenc i 1) da da Boc ~ u 1 ici 1 p ro l ina 5 Se agev garon suc sivament, _t a solution? -le 7.0 g (40 mmol '' of BUL - li ina in 240 mi • of m ore of wood to O 3? mi? .ie lii soprop i 3 et i 1 ai na, ÍO.A ._. .40 mmol) of N - (? - L i -i noben > 11 < pr ol 11 amide and ~ "^ mi (44 mmo) of anhydride hydrochloride pr >) -n? í > > - »f orn fo (u pf? jón -.3 50 *. n acetate e el? ', r-esputí of _LJ i tac? ou -». " T di.i art 3 hours, 3 -t -.se orglani a was 1 .. on -iOI-i Hi, an,. N n. Ñ. Ii't iiJ '.. rí .4a C 1, - »e?« Li j de - iila 11 ap 11 -t • emc »see c 1 -, ol eu.'e. Bt. -. Alaron 1 .0> j '9, -J.; ije pol o | j] .n?, RF - .5"'.' 0H2C 12 -'ft nH, 9 1 .. 5 ÍH-IMMR ínilBO-dov), del I * ef, pp,., -" 1.4 (s, 9H, (0H3) 3), 1.7-2.2
Í.II, 4H, 0H2-0H2), 3.3-3. or. (m, 2H, M-CH2 of prol i na), 3.8 (,
2H, -OHO of ul tpna), 4.3-45, 'm- 2H, and U ~ CH2-Ar), 6.8
OH, l'H. & 0 »0- > 7.4-7.5 r, n (!, Apparent i>: ieh to second
, nt, '., - t, er, ..'. , 21 !, Ar-H), 7.P í.J, 2H, Ar-H) 0.5 and 0.8 (each m, ¡'' H'U'o K (two rotSmeroá), NH) b) itidroi lomro de íp - r lauobeni rl the going> .ie H-g 1 lpial HH Pl rnpii F-ii.ic was the i i i na e e rtle rtle rtle rtle rtle rtle rtle Ib Ib Ib Ib B to i-, 1-, rn 0 g of 4 *. 'Of illanco powder, 1H-W11R (PrlSO-dA), of a in ppm! 1. ^ - 2.2 Ott, 4M, 0H2-0H2), 5 3.4-4 ..- (or, 4H, N-CII2 - of |)? ',) L? Ni.} Yl ti na -), •' ¡2-4.
3H, OH -0H3-Ar), 7.5 (, _ |, 2t-i, Ar), 7.0 id, 2H, Ar ', B.3 (- =, br, 3H, NH3 +), 8.9 and Q "2 d da m, junlu 1H (do- iote me rs), NH) c '• í? -ci 3 nobenc 11 lick of N- (2- na f 1 i 1 su! f om 1) gl iei lprol- rr- i p], rniiiiu - »to interior rea. »- on horsehair with 1-� - ���������������� � � � � in 3.3 g of powder, PP - 0.39 (CH2012 MeOH, 9 - '1 1 H-MMP (PMBO-d), from ta to pm: 1. A-2. (, 4H, CH2-OH2 <, > j 1 í c 4.- OH N-PH2 ~ t, -! ,. ip -. i c nt i dobei? t 1 '.::,? tii -, IS 1 c iwP il .u 1 fon 11) g 1 ici 1 p ro l ina Fl Lom u Lo artteriL > rf? ¡ooiveí i 3 > 1 r »in the tho ioamicia oit.o in Id, Rendi i nt; 3.0 g (B3 * C) of po o anta r 11 lent.e IH-NMR .DMBO-d ?,), from a in ppm: 1.5-2.0 (m, 4H, CH2-CI-T), 3.3-3.5 (m, 2H, M-CH2 (f »ro 1 na '•), 3.7 μm, 2K, --OK2
(gl o- i ?? -) > , 4.1-4.4 μm, 3H, CH and M M-CH2-Ar), 9.5 =, 'l.., Am ida., ,8 ida ida 9 9 9, ,8 ,8,, 9 9 H -aitud i nobe til) _tm? > 1st of - (2-
- .-. r. i i su 1 f o¡ 113) »• • i i i i i i i i i i i i i i i "You've saved it, you've been able to isolate 2-5 g
CAO h i rlro indu o RP ¡i, 09 rCH2012-'rieOH, i i, < i S i i í i le ~ .pi? • on. «I r i eron e i i? ?.? tít-tt C »í" iu- i - i Ui, d er -i? '? bi ad "n of iniiiii-i (Ambei liti *, pui e.'a» | e] 99 * / - according to I-IPI.C, PAB-MB (rl-H) -? - - 1"3.5, 1H-NMP (pMSO-d, dlta in ppm? L .A-2.0, 4H, CH2-OH2 '' μi ro'- lutadamente 3.5 (t '??, 2H, N- OH2 íprol ina' 1 - p i iibierl Rcial entity or l 'H2n lev "" "" 7 (i. < , 2H, N-0H2 (glycoma)) 4.1-4.4 Oft, 3H, OH. »N-0H2- ?? '•, 7.3-B.5 (13H, aromatic H and NH'», i L>. J m-tdament B.4- c;, .2 <4H-amidine) G-'TPMPI n í [- -. no i 1 I f | ii! ")! -., IL I t '< -nit 1 i I t de - í 1 -? T-1 fi I 1 I f i 1'. »J 1 ~ I 1 OIO 1 I tt =? P] i >iiln.il le- i .. I l 1 t (1 hi O - »? - oti ii. it i o.7 |? in ei eiltl» 1 i 3 .in o > lot ro u 1 -, »- fli 1,? I" '. Il i- FAP- M- .¡ "ii-, a- - I -'- F Ft-.Fi or"' "the -, tit lie (- -t? T1 -1 I UObfcr-lli I 1 '-1111 O i - < le ..!' nh »-" ME "i i 1 - u 1 f JI. t 1. D- f e >? I 1 t i no 1 p. Í n- < L - r p-i t -i »i ón 1 j,. , '. • < As in example i, pol or target, fusion point 194-201 T, FAB-MB, fi-H.a- =. A95, ppripi n p, - r .- i - < _¡. ? _. d íp- i LÍ i r? »: tfc? ertc i 1 a aJJ of N-íu-b? ti 3 = nlf 3? ir-p- -i p? pra i on 11 t-n l e r mu 1 • i "i 1.1 ¡v o
> 1 -u IL o, ?? intu d »-" i US l r-, »"? FAP-MB -H '> -Go Iriil iuja »et ilo d IP- nti idim ici nc" i 1) am »J3 d ti- i ni i 3 ai pron s not your 1f on i 1 '- -p- faith >? t1 - 1. 'or > 1 f' ut 1 '• -T- f i 1 to 1 ring Iprol i ni Hi di or 1 oruro I - >.? ia i nubene 1) mu da Df in 11.3 Ani lprol i na rea ned i nd i nd i nd i n t i n t i t i n f i n t i ng th e e rm e r 3 o 1 .b 5 i-h i rl T i i oprop i 1 ami no-iii lf oni 1) -Df in i la 1 or Iprol itc.This was prepared in the example 4L by means of the reaction d 9 ^ in ti idroc luror ti idrcr llamnt,, 3 »e. _?! o of > 'p- am idi nober n il' iiii d. cic fj- < is »? p rop i 1..nii i no i 11 O»? o 1"• - D- fen i! a 1 a i 1 pr i > 1 i n- Be lililí Oijenó 9! i e »-. ijtia ilte-n-l-. rj? - l ^ o '> . i o - < i he i? .. o »jl - ?? - i« 1 's l veitt 6- THF "i rí Pd /?:: rbort» i - > 4. " "O (15 h > - > ~ '-, _, r > t o.1 i,....? - i - | jr fu- t emovidu mdi an efil trac i ron -. ? .H.1 '? R », 1 -i solni ir'-ii was cut by the b yo pt esi n redui oi-i \, c tide-jt, i 1 ada ethanol podinas vei es, l re ? - > i Juo was rec Gido in water, the aqueous phase was e ra eed ti is v ^ c cor 'acetate eti it, and clespuéc the aqueous phase qu .-- containing pr odu to required <.. [> liofili -.adu (solid bl anco, melting point 1 9 - 5 * O, FAP-MB; M + H: 1) E TEMPLE 10 Aceta to de ap - apti di nobenc i 1) am ? -i ele fi- (dimeti l? > ni jsul foiiil '-D-fufal 13 a nd 1 prol i na l prepares »in l lished an example in the example"' ONLY ILLINO, point from fu ind sc sic in < -oi it to FAP-MB: f1 + H: 1).
E TEMPLE 11 (p - art? Id i nobenc t 1) a? i.la of fJ-hydro I iuj ÍOIII 1 -GI- f R n 1-1 I 1 prl ina 0. 8 g (0.33 mi, 5 mmol) do you do c i 1 f ont orosul my co iO of DOM was added drop by drop at a temperature of 20 * 0 with cooling to a soln > -? 1, 8 g, 4.36 mmol) of hydro- iodide of iodide to ibebenc 1 of D-f eni 1 to lam Iprol i na and 1, o R g (13.0 trimril) of di i sop. op i 1 e t i 1,? i na in 20 mi of FOM • > is ués? ie a > _ > " the. i i -i t e r e, you -. a b -enl e tlu -mlf 30 »t nui?.? -». l -, n »e, i. I. Ote di li tla -i 100 d r oí, r < ? ri, e, tr aid-t
11I11 the utente > 'Ti HOl 311 j df'-ifliiL' :, di.i- e? e -,. jr. ? 1 rd
-i ULI a. v I -, f -.- -e?. "i 11 -i 1111 - < was sei '-ni'- < írt -i > 3 f -_ > - > de a • • sioa pi 3 iid < n? - ?? - 3 po i - »a i? jii 'a to io _ Be rs! > i 11, i > i i i 2. g? -. (p- > l art iberu ii. -.nucí-, e -hi ci.'cr »sul f om 1 - Df eti i 133 ar¡j 1 p col i n_ > tn f or ní a pro uc. What was the use of the next reaction if purification?
Be sCjl h "? T'Of? 2.0 g of said produc l '.) C ru JUftto CC» ft 0. »
(13 titol) from it i droc lui ui oh idrui, i 1 amr na and 2.5 mi di di soprop 11 ami na in 5 '"' my ethanol -i temper ura atmosphere during 1 .. uitcb ye ué se con», enti, the con-- »! i ti.iyen 1 e -, vnl?! i 3 s ii ru rowing. ' Do you know what is going on at 1 h'ii't, Fl pr oducto bastant *.? n = .uluble en agu ^? iiiiie hai urifi'jsible its preparation?: t? e: t racc ión ,, Fl p. odu., i mclo. ', R g) It was used d I f er i int ne? -. |' -.] .. < hi drog nar i on aiui in "Fl p?» ~. »lucl oc udd was hi >? tgenado under the H?.
1 slightly exceeds hydrogen phase in a cl
40 ml methanol and 5 ml of < glacial activity. punt.i ile spatula of 1 *; of pa l adío in c. rborm to 5 < < t "
Or -spuíá-, ije 5.5 hor a- ,, the > -t i a 1 '' was re i by means of f i ltration, the solution was c nreni-id. in an evaporadoi i r ttji to and codest i l ade v - r i a - »rece- = > ethanol ethanol toluene- Fl [iriiiim i ii i e > t 11 I a n I r 111 - »i i t-ido i on non, -? i i - > - * ec; "]», niie pi nucn i Minó 1.5 g ("r" f, ", ijej 111.» -] I? -? r K Q in 3 e »3 n a -. '' d» - '
> 'f? --- t 111 I 1 i 1 (tobe 1 to 1 1 To my d -t of N -I 1 i 1 I r 11 < t -, 11.} f on 11 - u - feni l 11 -Ipi'ol i rta pi.ira, '"' '-'e- - yi' i fi P,» m uiitrih? In f »t? Al una Ijeí ajn. - Fuid o de fus i n. 2 ~ O-2 '", 4''0, ol
Lian, or, F AP-B c 474 i M- H '»i. l o. »following L orttpue = .t ~ o = -e i eiMi - in r-rmín in the, - t mpl o
ETEMPI 0 12 Acetate and í p - rto d 1 ub ni "11) -ami Ía d ..- i'i f 1 non it LI ul f oni 1 - D-fem 1 - 1 la ni Ipr l 1 ? A White crutches, melting puni 240-2 2"O
(from a ».ompos i» in, FAB-MB; r "> 2ó > (M-H1- +. ETFMPLO 13 Acet ti de (p-atttj di ne? l lmida e fj-!) e! e .jb i -Í, beta, i 1 (f 1 uoi ot 11 sul f ott 11) - D-feni nilprol uto
0? - 1 »- I, a 1 s itl -.n.-OS, pijrd d I - 'IIR" 7 - QQ? R; {, I -, »Ompos 1 r I or ii' 'FAP - MB: 540 y MH) +. FTF? PIO 1- ie The I oe (p - aidi nobenc il) am i da de M - r > - oc t 1 u 1 fni 1) - P- ent 1 tl -not l pr l l i C ists amorphous whites (su), FAE-MS; 570 (M- H) - »-. ETFMPI 15 Ai etatr &e (? - a? di nobenc i 1 lamiLla de U- iil ul fm l- (T), l '' - Ci -nili> rf > > -? I i 1 P.-MB: 54p (M-H'ia-.
Ai ei - < i »- i l. ' .-ij,? t i u t i toben »- 1 '!. \ - - ut i r 1 your 1 forum 1 •
, you go i i faith u I 1,, < 1-t i lllf o! l u. 0? l -i ¡- I e -, -i, r? o > f i? =. bl 'ii i- (s (i,' tP-M 'or, 1 ÍM-H FTFMP: O -i Tab i tr-s d 3 t • => i gn j ent e, n nsii ion L - I a pren-- < pa tablets of anet.convention l. JOñ mg ..le your tte i -idl example 2 2 0 (inj? | Ei! My gift d--? F? -i 1. ruu de 1 -, c tosa 4.5 tm.j de Acero-- »il í >» tt,, í - 1 I ire chemical enter ent in an ispr - t '- < riubmicr os or pi • - a I niefia) (?, 5 IIIIJ d a tio de magriesi FTFMPi 3 h Tabl i -. ij of substance from example 5 300 m of • omposieiórt ele tv. 'leo 5 35 u of composition of coating of airair The composition of cortical number = "e of 9 parts of starch of mal-", 3 lactose phthalate and 1 ¼ of _ u u .. .. .. lu lu lu lu lu JA JA JA JA JA JA (((((((((((((((((((((((. 40. see Fh '», nor. 111!, (1 A.) r? RA) .1 - .. 1 oiitp» t- irj / -. CÍ »I i- -, t I in '!'? -t or ai .. or 1? n-? - »i e» e 5 p ri ^? .e SI CI > a - 2 p «. r i • -.'- > , j li? io | u fu j 1,; , 2 pa 1 I e = > clt-. 1 a piitrw i; o ci c c i o j. i-r a p- "! e
1 I »-1 L a] O - I a - 1.1 b i e - i i r O. ii? > ~ or i -, -. d and i »f or rui-l t e ?. i í t t e, i > | »
-, lip i.U n e? |? | - | Í e an I e '- e ~ > ., J.? || j e || II l I t he 'ii "i. FTFMPIO, 3 lOO g ci r., I of the example 1 dissolve eu 5 - f.ijf.,.,., Ay aym with act 1 of N 01 and I was just in pH at 6.0 1 on? M-.GH 0, 1 1 »! What (result, in H ?, solin- i? N isotónit 5 • ou l-, -.artgre .B - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -. zar.1, - ', n. 0
Claims (2)
- RFT'JTNDTOACIGNFB Un -o pue de 1 a f r u 1 a T US e tpect 1 sótttero--, -u sa í s c »- > ! I uo_ f i s i t ical t e n t io n. dolide 1 OS iU i 1. I ent? i? e, | ei? what igui ns -, t gn lfl C a do--, i ni e-- 'I uj lo Ol -0", f luoro, lui U) C1- C3, ci .. 1 a 1 q .. i 3 o 0: 11 i 3.tluui lo 01-01"", -ii,], - ,, hel -ni lr, OH t »iei» p 'Oftj ij », filio P'1'« 'P -'- on idet l? o-, i, j | fet e t. :-or? • • »> > I > Genus, .111. i t 1 01-01. i i i lo. -i i 1 -. -] u i 1 or 0 '- 01 i ". i.> good, 11> d r t, li an li t i.atl f t il u Iflnp 02-0" - * 3] ¡. rii -, 1 nede 3.1 -, ona i t-1 a sdir ^ l. it or hetart it or a pi.iede, or 11 i ne i a hi PGOA i mi II I (0, B, NH or bi nf J su -_ ti 1 i .11 lo, -3 uri isi duo of a 3 f - m? No < ac to 3 to formula II I NH - C CO II I R5 R-3 e- hydrogen, i Iqu i 3 o C1-0B, cir loa 3 qu i 1 o C ".- r ~ 7, I o o liten -4 ri 1 a luu i o O. -03, ^ "i- -. h i d i i'.ijHfu.! . l -ju i 1. i 01 -OS, ricl il eiu i 1 J c 11 loalqu i l.- 03-07 lum ln 01-03, ari lo, i 11 qu, | Cl-03, di (cic 1 to 1 ui 1 or 03- C l-me i 1 oo i feni 3 m 1 ob ien - I P4 - H ~ an alkylo radical 01-CB t_n where a Hydrogen Atom Oxygen replaced by ORÓ n either 0 -0P? (F6 hydrogene., * 1 ». | ui 1 or 01--00 or ari 1? IJ II 3 or C C3., or P4 and P5 together are my A chain of aluine contains an alkaline ally, merged, a re. 1 of 1 < 1 f -. - •!? l? 1 ll? '- ic 1 cl? "li . {i. i. of]. formula III , -lfld »u U 1 l-'t I a dT -cannot r ee |||| j ¡. For a group ludi, lio or ln ..- u ¡lqni lu 01 - C. i m - 3 r? well 4 - an OH2 group in e] - .. o]] or μL, from t ee p 1 to a »Jo? o? oxig no, a. ufre, H- bi n M- C1-C4 alkyl _ ". 'O rlr s to dyacent s d < _ > Hydrogen can be displaced by 'nu nl c doí.-ile.
- 2. A L umpí? -l, l of the formula 7 of corri d i-d-d r 1 or reivin icated in l rei vin ica 1 for its use with the •• disease * .-. 5A FFBclMFtN PE THE TNUFNTION describe common s 3rd formula I where P1, A and have the .. --igm f i c í the -d able "- idci en 1 -. d s i i? Ion,, s. { »Or» ??? i the epara ion of lo-, HU HII Í. 1 i i ii'upi t s i o- »i? .-) See? losi i- - ttn d c i? ado _._, pa i - ».out» ni. enf f-? fuedsde -. ,
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4443390.5 | 1994-12-06 | ||
| DE4443390A DE4443390A1 (en) | 1994-12-06 | 1994-12-06 | New dipeptidic p-amidinobenzylamides with N-terminal sulfonyl or aminosulfonyl residues |
| PCT/EP1995/004646 WO1996017860A1 (en) | 1994-12-06 | 1995-11-25 | New dipeptide p-amidinobenzylamides with n-terminal sulfonyl or aminosulfonyl radicals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MXPA97004050A true MXPA97004050A (en) | 1997-08-01 |
| MX9704050A MX9704050A (en) | 1997-08-30 |
Family
ID=6535046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX9704050A MX9704050A (en) | 1994-12-06 | 1995-11-25 | New dipeptide p-amidinobenzylamides with n-terminal sulfonyl or aminosulfonyl radicals. |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5852051A (en) |
| EP (1) | EP0796271B1 (en) |
| JP (1) | JPH10509727A (en) |
| CN (1) | CN1168673A (en) |
| AT (1) | ATE189458T1 (en) |
| AU (1) | AU699579B2 (en) |
| BR (1) | BR9509970A (en) |
| CA (1) | CA2207874A1 (en) |
| CZ (1) | CZ153797A3 (en) |
| DE (2) | DE4443390A1 (en) |
| ES (1) | ES2143666T3 (en) |
| FI (1) | FI972384A0 (en) |
| HU (1) | HU222353B1 (en) |
| IL (1) | IL116231A (en) |
| MX (1) | MX9704050A (en) |
| NO (1) | NO972559L (en) |
| RU (1) | RU2152953C1 (en) |
| TW (1) | TW336222B (en) |
| WO (1) | WO1996017860A1 (en) |
| ZA (1) | ZA9510295B (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9900043D0 (en) * | 1999-01-11 | 1999-01-11 | Astra Ab | New use |
| US5726159A (en) * | 1994-03-04 | 1998-03-10 | Eli Lilly And Company | Antithrombotic agents |
| US5705487A (en) * | 1994-03-04 | 1998-01-06 | Eli Lilly And Company | Antithrombotic agents |
| US5707966A (en) * | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
| US5710130A (en) * | 1995-02-27 | 1998-01-20 | Eli Lilly And Company | Antithrombotic agents |
| US5914319A (en) * | 1995-02-27 | 1999-06-22 | Eli Lilly And Company | Antithrombotic agents |
| SE9602263D0 (en) | 1996-06-07 | 1996-06-07 | Astra Ab | New amino acid derivatives |
| US6200967B1 (en) | 1996-06-25 | 2001-03-13 | Eli Lilly And Company | Anticoagulant agents |
| US5863929A (en) | 1996-06-25 | 1999-01-26 | Eli Lilly And Company | Anticoagulant agents |
| AR013084A1 (en) | 1997-06-19 | 2000-12-13 | Astrazeneca Ab | USEFUL AMIDINE DERIVATIVES AS THROMBIN INHIBITORS, PHARMACEUTICAL COMPOSITION, USE OF SUCH COMPOUNDS FOR THE PREPARATION OF MEDICINES AND THE PROCESS FOR THE PREPARATION OF THE MENTIONED COMPOUNDS |
| SE9704543D0 (en) | 1997-12-05 | 1997-12-05 | Astra Ab | New compounds |
| TR200102913T2 (en) | 1999-04-09 | 2002-01-21 | Basf Aktiengesellschaft | Low molecular weight inhibitors of complete proteases. |
| CA2387002A1 (en) * | 2000-08-11 | 2002-02-21 | Corvas International, Inc. | Non-covalent inhibitors of urokinase and blood vessel formation |
| ES2285989T3 (en) | 2000-08-11 | 2007-12-01 | Wilex Ag | NON-COVALENT INHIBITORS OF THE UROQUINASE AND THE FORMATION OF BLOOD VESSELS. |
| DE10049937A1 (en) * | 2000-10-06 | 2002-04-11 | Knoll Ag | New sugar-modified amidine and guanidine compounds, useful as competitive inhibitors of serine protease, e.g. for treating thrombosis |
| CH695999A5 (en) | 2002-02-28 | 2006-11-15 | Wilex Ag | A process for preparing 3-amidinophenylalanine derivatives. |
| DE102004029812A1 (en) * | 2004-06-19 | 2006-05-24 | Clariant Gmbh | Process for the preparation of nitriles from aldehyde oximes by reaction with alkylphosphonic anhydrides |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9103612D0 (en) * | 1991-12-04 | 1991-12-04 | Astra Ab | NEW PEPTIDE DERIVATIVES |
| AU675981B2 (en) * | 1992-12-02 | 1997-02-27 | Bristol-Myers Squibb Company | Guanidinyl-substituted heterocyclic thrombin inhibitors |
| SE9301916D0 (en) * | 1993-06-03 | 1993-06-03 | Ab Astra | NEW PEPTIDES DERIVATIVES |
| AU1025795A (en) * | 1994-01-27 | 1995-08-03 | Mitsubishi Chemical Corporation | Prolineamide derivatives |
| ZA951617B (en) * | 1994-03-04 | 1997-02-27 | Lilly Co Eli | Antithrombotic agents. |
-
1994
- 1994-12-06 DE DE4443390A patent/DE4443390A1/en not_active Withdrawn
-
1995
- 1995-11-25 CZ CZ971537A patent/CZ153797A3/en unknown
- 1995-11-25 US US08/849,364 patent/US5852051A/en not_active Expired - Fee Related
- 1995-11-25 CN CN95196669A patent/CN1168673A/en active Pending
- 1995-11-25 BR BR9509970A patent/BR9509970A/en not_active Application Discontinuation
- 1995-11-25 ES ES95941015T patent/ES2143666T3/en not_active Expired - Lifetime
- 1995-11-25 EP EP95941015A patent/EP0796271B1/en not_active Expired - Lifetime
- 1995-11-25 HU HU9702107A patent/HU222353B1/en not_active IP Right Cessation
- 1995-11-25 MX MX9704050A patent/MX9704050A/en not_active IP Right Cessation
- 1995-11-25 RU RU97112398/04A patent/RU2152953C1/en active
- 1995-11-25 CA CA002207874A patent/CA2207874A1/en not_active Abandoned
- 1995-11-25 AT AT95941015T patent/ATE189458T1/en not_active IP Right Cessation
- 1995-11-25 JP JP8517287A patent/JPH10509727A/en active Pending
- 1995-11-25 AU AU42559/96A patent/AU699579B2/en not_active Ceased
- 1995-11-25 DE DE59507755T patent/DE59507755D1/en not_active Expired - Fee Related
- 1995-11-25 WO PCT/EP1995/004646 patent/WO1996017860A1/en not_active Application Discontinuation
- 1995-12-01 IL IL11623195A patent/IL116231A/en not_active IP Right Cessation
- 1995-12-05 ZA ZA9510295A patent/ZA9510295B/en unknown
- 1995-12-09 TW TW084113131A patent/TW336222B/en active
-
1997
- 1997-06-05 FI FI972384A patent/FI972384A0/en unknown
- 1997-06-05 NO NO972559A patent/NO972559L/en not_active Application Discontinuation
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| MXPA97004050A (en) | P-amidinobencilamidas of dipeptido novedosas with radicales sulfonilo or aminosulfonilo in ends | |
| SU1364238A3 (en) | Method of obtaining derivatives of pyrimido /4,5-d/quinoline or their optically active isomers or their pharmaceutically acceptable additive salts of acid | |
| PT91165B (en) | PROCESS FOR THE PREPARATION OF DERIVATIVES FROM 7- (1-PYRROLIDINYL) -3-QUINOLONO-ETHYDROBIDONOCARBOXYLS AND ANTIBACTERIAL AGENTS AND FOOD ADDITIVES CONTAINING THEM | |
| EP2204387B1 (en) | Novel chondroitin sulfate having decreased molecular weight and use thereof | |
| BR0310106A (en) | Compound, process for producing a compound, pharmaceutical composition, use of the compound and method for treating a subject suffering from a pathological condition or disease | |
| MY133479A (en) | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions | |
| NO984084L (en) | 4-Amino-pyrimidine derivatives, medicaments containing these compounds, their use and method of preparation thereof | |
| MXPA05013904A (en) | Pyrido` 2, 1-a - isoquinoline derivatives as dpp-iv inhibitors. | |
| PT1689751E (en) | 5,7-diaminopyrazolo[4,3-d]pyrimidines with pde-5 inhibiting activity | |
| MY144322A (en) | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions | |
| CN101595094A (en) | The isoquinolone derivatives that Cycloalkyl amine replaces | |
| CA2654244A1 (en) | Phenyl substituted pyrazinoylguanidine sodium channel blockers possessing beta agonist activity | |
| EP0960106A1 (en) | 1-phenyl-4-benzylpiperazines: dopamine receptor subtype specific ligands (d4) | |
| ATE133165T1 (en) | AZA MACROCYCLES AND METHOD FOR THE PRODUCTION THEREOF | |
| NO20023161L (en) | Substituted piperidines, drugs containing these compounds and processes for their preparation | |
| NO20052222L (en) | A pharmaceutical composition comprising crystalline sibutramine methanesulfonate hemihydrate | |
| EP0508220B1 (en) | Derivatives of amindinophenylalanine, procedure for their preparation, their utilisation and compositions comprising them | |
| KR100761099B1 (en) | An apparatus and method for manufacturing reducing hydrogen water using brown's gas, and an apparatus and method for manufacturing for reducing hydrogen drinking water using brown's gas | |
| EP2573071A1 (en) | Preparation method of (s)-4-hydroxy-2-oxo-1-pyrrolidine acetamide | |
| CA2149044C (en) | Use of dimethylbenzofurans and dimethylbenzopyrans as 5-ht3 antagonists | |
| DE2822528A1 (en) | METHOD FOR PRODUCING PROTEASE | |
| EP1840119A2 (en) | Process for producing methionine | |
| CN105440088B (en) | Glucosamine mixes strontium salt and its preparation method and application | |
| EP0811624A1 (en) | Purine compounds and xanthine oxidase inhibitors | |
| EP1083177B1 (en) | Compounds capable of cleaving double-stranded dna and method of utilization of the same |