 new compound with effects of thrombolysis, free radical elimination and thrombus targeting as well a
专利摘要:
Abstract "New compound with thrombolysis, free radical elimination and thrombus targeting effects as well as method of preparation and use thereof" The present invention discloses a new compound with thrombolysis, free radical elimination and thrombus targeting effects as well as a method of preparation and use thereof. The compound is a ternary conjugate formed by conjugation to a thrombolytic peptide, a free radical scavenger, and a thrombus / antithrombotic targeting peptide joined via a linker arm. The present invention also discloses a pharmaceutical composition containing the compounds, wherein the compounds form a nanospheric structure. 公开号:BR112015004854A2 申请号:R112015004854 申请日:2013-03-15 公开日:2020-04-22 发明作者:Zhao Ming；Peng Shiqi；Jiang Xueyun 申请人:Shanghai Lumosa Therapeutics Co Ltd； IPC主号:
专利说明:
"NEW COMPOUND WITH EFFECTS OF THROMBOLYSIS, ELIMINATION OF FREE RADICAL AND DIRECTION TO THE THROMBO WELL AS A METHOD OF PREPARATION AND USE OF THE SAME" Technical Field [001] The present invention relates to a new compound simultaneously having effects of thrombolysis, elimination of free radical and targeting the thrombus, as well as a method of preparation and use thereof. The present invention also relates to a new ternary conjugate of a peptide comprising a PAK / imidazoline sequence / a peptide comprising an RGD sequence formed by binding together with a thrombolytic oligopeptide comprising a PAK (Pro-Ala-Lys) 1- ( 4-oxyacetyl-phenyl) -3,3,4,4-tetramethylimidazoline and an anti-thrombus thrombus / oligopetide targeting peptide comprising an RGD (Arg-Gly-Asp) sequence through a linker arm containing carboxyl and amino groups. The present invention further relates to a pharmaceutical composition comprising the above compound for use in the elimination of free radical NO, thrombolysis, thrombus targeting / anti-thrombus therapy, and treatment of stroke / cerebral infarction. The present invention also relates to a method for preparing the compound. Background to the Technique [002] Thrombotic diseases rank first in global morbidity and mortality. Coronary artery thrombosis results in myocardial infarction. Cerebral vascular thrombosis leads to cerebral infarction, that is, clinical ischemic stroke. Patients with myocardial infarction can be injected intravenously with thrombolytic agents or have bypass surgery. It should be noted that the positive result of intravenous injection of thrombolytic agents for patients with myocardial infarction is ischemia / reperfusion. Since a large amount of NO free radicals are generated during the ischemia / reperfusion process, the 2/95 thrombolysis is associated with myocardial damage and death of the patient. This is a serious problem in the current treatment of myocardial infarction thrombolysis. At present, the treatment of cerebral infarction is faced with even more complicated problems. For example, current thrombolytic agents not all capable of crossing the blood-brain barrier, and thus the effectiveness of intravenous injection of thrombolytic agents in patients with cerebral infarction is very limited. Also, for example, no surgical procedure that can save patients with cerebral infarction is currently available. Similarly, even if there is a positive result from intravenous injection thrombolytic agents in patients with cerebral infarction, a tremendous amount of NO free radicals can still be generated in the ischemia / reperfusion process such that the thrombolysis process is associated with damage from brain tissues and patient death. This is a serious problem in the treatment of current cerebral infarction thrombolysis. In addition, four serious problems are present in clinical treatment for patients with stroke: 1) no medication other than tPA (tissue-type plasminogen activator) shows efficacy in patients with stroke; 2) tPA treatment is only effective within 3 hours from the start of the stroke, that is, there is only a 3 hour window for tPA treatment; 3) tPA treatment always results in systemic bleeding; 4) brain tissue damage in patients and patient death associated with the tremendous amount of NO free radicals produced in the ischemia / reperfusion process cannot be prevented by tPA treatment. It is therefore imperative to address these four problems in order to achieve a substantial advance in the clinical treatment of stroke patients. [003] Two compounds, N a - (1,3-dioxo-4,4,5,5-tetramethylimidazoline-2-phenyl-4'oxiacetyl) -n w -acylgraxo-Lys-Arg-Gly-Asp-Val and N a - (1,3-dioxo-4,4,5,5tetramethylimidazoline-2-phenyl-4'-oxyacetyl) -n w -acylgraxo-Lys-Arg-Gly-Asp-Phe, are disclosed in the Chinese Patent Application CN102807604 and CN102807605. Both with 3/95 ranks are derived from a conjugation of an imidazoline having NO free radical scavenging activity with an anti-thrombus oligopeptide comprising an RGD (Arg-Gly-Asp) sequence through lysine. Unlike the compound of the present invention, these two compounds do not have a thrombolytic peptide attached to it. These two compounds have no role in thrombolysis, and thus are not suitable for the manufacture of thrombolytic drugs and are not suitable for the treatment of patients with ischemic stroke. [004] To solve the above problems, there is a need for a new compound to simultaneously have thrombolysis, free radical elimination and thrombus targeting effects. In addition, it is required that such a new compound be able to be effective even if administered after 3 hours from the start of the stroke in patients, that is, not restricted by a 3-hour window as in the treatment using tPA; it does not cause systemic bleeding as in tPA treatment; and can clean up the tremendous amount of NO free radicals generated during ischemic / reperfusion. Summary of the Invention [005] The present invention provides a ternary conjugate simultaneously having activities of crossing the blood-brain barrier, thrombolysis, anti-thrombus and elimination of free radical NO, in which the three in the ternary conjugate refer to an imidazoline having NO free radical scavenging activity, a peptide having thrombolytic activity, and a thrombus targeting peptide, in which the three members are linked together through an appropriate ligating arm. [006] Specifically, the ternary conjugate of the present invention can be represented by the compound of formula I: -YY 2 NN — AAj aA 3 (D [007] where, NN represents an imidazoline having 4/95 free radical NO; AAi represents a connecting arm having at least three groups for connecting; AA 2 represents a peptide having thrombolytic activity; and AA 3 represents a peptide targeting the thrombus. [008] The imidazoline used in the present invention may include imidazole nitroxyl nitroxide (NN) radicals that can eliminate NO and work to eliminate oxygen free radicals, providing strong protection for cells damaged by oxygen free radicals. The imidazoline having NO free radical scavenging activity according to the present invention is preferably 1,3-dioxo-2 - [(4-oxyacetoxy) phenyl] -4,4,5,5tetramethylimidazoline, which has excellent chemical and physical stability , and is not only suitable for any chemical reaction of conjugation of a peptide having thrombolytic activity with a peptide directed to the thrombus, but also not susceptible to decomposition during storage, thus satisfying the requirements for formulations. [009] The linking arm used in the present invention can comprise at least three linking groups, for example, carboxyl and amino groups, which are used to bind to imidazoline, the peptide having thrombolytic activity, and the peptide directed to the thrombus together. The linking arm according to the present invention can be a natural amino acid, for example, L-Lys, L-Asp and L-Glu. When the connection arm (AA-i) used in the present invention has three or more groups for connection, one or more NN, AA 2 or AA 3 can be connected to it, where two or more NN AA 2 or AA 3 can be connected to it be the same or different. For example, when AAi has four groups for binding, an NN, two AA 2 and an AA 3 can be linked, so while the two AA 2 can be the same or different peptides having thrombolytic activity. [010] The peptide having thrombolytic activity used in the present invention can be an oligopeptide comprising a PAK sequence (Pro-Ala-Lys), an AKP sequence (Ala-Lys-Pro) or a KAP sequence (Lys-Ala-Pro), or a peptide 5/95 having repeating units of the PAK sequence, the AKP sequence or the KAP sequence. An oligonucleotide refers to a small molecule peptide having a molecular weight of 1000 Dalton (D) or less, which is generally composed of 3 to 8 amino acids. The oligopeptide having thrombolytic activity according to the present invention can be an octopeptide tripeptide comprising a PAK sequence, an AKP sequence, or a KAP sequence, preferably a pentapeptide tripeptide comprising a PAK sequence, an AKP sequence, or a sequence KAP. For example, the oligopeptide used for the present invention comprising a PAK sequence, an AKP sequence, or a KAP sequence can be PAK, RPAK (Arg-Pro-Ala-Lys), ARPAK (Ala-Arg-Pro-Ala-Lys ), GRPAK (GlyArg-Pro-Ala-Lys), QRPAK (Gln-Arg-Pro-Ala-Lys), AKP, KAP, KPAK (Lys-Pro-AlaLys), PAKP (Pro-Ala-Lys-Pro), AKPAK (Ala-Lys-Pro-Ala-Lys) or PAKPA (Pro-AlaLys-Pro-Ala). For example, the peptide having repeated units of the PAK sequence, the AKP sequence or the KAP sequence used in the present invention can be any of those peptides being described in Chinese patent publication CN101190941 as a peptide having thrombolytic activity, including a peptide having repeated units of the PAK sequence, such as (PAK) 2 , (PAK) 3 , (PAK) 4 , (PAK) 5 and (PAK) 6 ; a peptide having repeated units of the AKP sequence, such as (AKP) 2 , (AKP) 3 , (AKP) 4 , (AKP) 5 and (AKP) 6 ; and a peptide having repeated units of the KPA sequence, such as (KPA) 2 , (KPA) 3 , (KPA) 4 , (KPA) 5 and (KPA) 6 . [011] The thrombus / anti-thrombus directed peptide used in the present invention can be an oligopeptide containing an RGD sequence (Arg-Gly-Asp). The oligopeptide containing an RGD sequence can be an RGD-based tetrapeptide, such as RGDS (Arg-Gly-Asp-Ser), RGDV (Arg-Gly-Asp-Val) and RGDF (ArgGly-Asp-Phe). Specific fibrinogen (Fg) binding to the activated platelet membrane (GP) glycoprotein receptor llb / llla is a common end pathway leading to platelet aggregation initiated by various physiological inducers, and develops a 6/95 important role in thrombus formation. In addition, RGD sequences serve as active sites for the binding of activated Fg ligands and GPIIb / llla receptors and have an activated platelet targeting property. Structures comprising an RGD sequence can competitively inhibit and block the binding of Fg and GPIIb / llla receptors, thus preventing platelet aggregation and thrombus formation, in order to allow an RGD containing oligopeptide to become a molecule targeting the effective thrombus and agent anti-thrombus. [012] Furthermore, the thrombus-directed peptide used in the present invention can be any of the polypeptides being described in Chinese patent publication CN101190940 as a polypeptide having target and anti-thrombus activity, including the polypeptides obtained from the modification of the conjugation of an RGD peptide with a YIGS peptide (Tyr-lle-Gly-Ser). The polypeptides obtained by modifying YIGSRRGDS include, YIGSRRGDV, YIGSRRGDF, YIGSRYIGSK, YIGSRYIGSR, YIGSKRGDS, YIGSKRGDF, YIGSKRGDV, YIGSKYIGSK, YIGSKYIGSR, RGDSRGDS, RGDVRGDV, RGDFRGDF, RGDSYIGSR, RGDSYIGSK, RGDVYIGSR, RGDVYIGSK, RGDFYIGSR or RGDFYIGSK. [013] In a preferred embodiment, in the compound according to the present invention, imidazoline having NO free radical scavenging activity is 1,3-dioxo- 2 - [(4-oxyacetoxy) phenyl] -4,4,5,5-tetramethylimidazoline, the peptide having thrombolytic activity is an oligopeptide comprising a PAK (Pro-Ala-Lys) sequence, and the thrombus-directed peptide is a oligopeptide comprising an RGD sequence (Arg-Gly-Asp). Therefore, the present invention provides a ternary conjugate of a peptide comprising a PAK / imidazoline sequence / a peptide comprising an RGD sequence simultaneously having activities in crossing the blood-brain barrier, thrombolysis, anti-thrombus and elimination of free radical NO. [014] In an embodiment, in the compound according to the present invention, the 7/95 imidazoline having free radical scavenging activity NO is 1,3-dioxo-2 - [(4oxyacetoxy) phenyl] -4,4,5,5-tetramethylimidazoline, the linking arm is L-Lys, the peptide having thrombolytic activity is an oligopeptide comprising a PAK sequence (Pro-Ala-Lys), and the thrombus-directed peptide is an oligopeptide comprising an RGD sequence (Arg-Gly-Asp). In this case, the oligopeptide comprising a PAK sequence can be an ARPAK pentapeptide, a GRPAK pentapeptide, an RPAK tetrapeptide, or a PAK tripeptide; the oligopeptide comprising an RGD (Arg-Gly-Asp) sequence can be an RGD-based tetrapeptide, such as RGDS, RGDV or RGDF. When L-Lys is used as the connecting arm, the compound according to the present invention can be of the following general formula 1-1 or I-2: [015] where, aai and aa 2 can be both present or both absent, or aai is present but aa 2 is absent; when both of aai and aa 2 are present, aa1 is R (Arg), and aa 2 is G (Gly), A (Ala) or Q (Gin); when aai is present but aa 2 is absent, aai is R (Arg); aa 3 can be S (Ser), V (Vai), or F (Phe). [016] For examples related to the compound of general formula 1-1, in a preferred example, the compound according to the present invention can be a tertiary conjugate of ARPAK / imidazoline / RGD represented by the following formula 1-1-1; in another preferred example, the compound according to the present invention can be a ternary GRPAK / imidazoline / RGD conjugate represented by the following formula 1-1-2; in yet another preferred example, the compound according to the present invention can be a ternary RPAK / imidazoline / RGD conjugate 8/95 presented by the following formula 1-1-3; and yet another preferred example, the compound according to the present invention can be a ternary PAK / imidazoline / RGD conjugate represented by the following formula 1-1-4; [017] where aa 3 can be S (Ser), V (Vai) or F (Phe), preferably V (Vai). [018] For examples related to the compound of general formula I-2, the compound according to the present invention can preferably be of the following general formula 1-2-1, I-2-2, I-2-3 or I- 2-4: RPAK PAK 9/95 [019] where aa 3 can be S (Ser), V (Val) or F (Phe), preferably V (Val). [020] In another embodiment, in the compound according to the present invention, the imidazoline having NO free radical scavenging activity is 1,3-dioxo-2 - [(4oxyacetoxy-phenyl] -4,4,5,5- tetramethylimidazoline, the binding arm is L-Asp, the peptide having thrombolytic activity is an oligopeptide comprising a PAK sequence (Pro-Ala-Lys), and the thrombus-directed peptide is an oligopeptide comprising an RGD sequence (Arg-Gly- When L-Asp is used as the binding arm, the compound according to the present invention can be of the following general formula I-3 or I-4; [021] where, aai and aa2 can either be present or both absent, or aa1 is present but aa2 is absent; when both of aai and aa2 are present, aai is R (Arg), and aa2 is G (Gly), A (Ala) or Q (Gin); when aai is present but aa2 is absent, aai is R (Arg); aa 3 can be S (Ser), V (Vai), or F (Phe). Aai is preferably R (Arg), aa2 is preferably G (Gly), and aa 3 is preferably V (Val). [022] For examples related to the compound of general formula I-3, the compound according to the present invention can preferably be of the following general formula 1-3-1, I-3-2, I-3-3 or I- 3-4: 10/95 [023] where aa 3 can be S (Ser), V (Vai) or F (Phe), preferably V (Vai). [024] For examples related to the compound of general formula I-4, the compound according to the present invention can preferably be of the following general formula 1-4-1, I-4-2, I-4-3 or I- 4-4: [025] where aa 3 can be S (Ser), V (Val) or F (Phe), preferably V (Val). [026] In yet another embodiment, in the compound according to the present invention, imidazoline having NO free radical scavenging activity is 1,3-dioxo-2 [(4-oxyacetoxy) phenyl] -4,4,5, 5-tetramethylimidazoline, the binding arm is L-Glu, the peptide 11/95 deo having thrombolytic activity is an oligopeptide comprising a sequence PAK (Pro-Ala-Lys), and the thrombus-directed peptide is an oligopeptide comprising an RGD (Arg-Gly-Asp) sequence, When L-Glu is used as the linker, the compound according to the present invention can be of the following general formula I-5 or I-6: Q Q · [027] where, aai and aa 2 can be both present or both absent, or aai is present but aa 2 is absent; when both of aai and aa 2 are present, aai is R (Arg), and aa2 is G (Gly), A (Ala) or Q (Gin); when aai is present but aa2 is absent, aai is R (Arg); aa 3 can be S (Ser), V (Vai), or F (Phe). Aai is preferably R (Arg), aa 2 is preferably G (Gly), and aa 3 is preferably V (Val). [028] For examples related to the compound of general formula I-5, the compound according to the present invention can preferably be of the following general formula 1-5-1, I-5-2, I-5-3 or I- 5-4: 12/95 [029] where aa 3 can be S (Ser), V (Vai) or F (Phe), preferably V (Vai). [030] For examples related to the compound of general formula I-6, the compound according to the present invention can preferably be of the following general formula 1-6-1, I-6-2, I-6-3 or I- 6-4: [031] where aa 2 can be S (Ser), V (Vai) or F (Phe), preferably V (Vai). [032] In another aspect, the present invention relates to a pharmaceutical composition comprising the above compound according to the present invention and a pharmaceutically acceptable carrier. Preferably, the composition The pharmaceutical 13/95 according to the present invention comprises the compound of the above general formula 1-1, I-2, I-3, I-4, I-5 or I-6. More preferably, the pharmaceutical composition according to the present invention comprises the compound of the above general formula 1-1-1, 1-1-2, 1-1-3 or 1-1-4. When the pharmaceutical composition according to the present invention comprises the compound of the general formula 1-1-1, 1-1-2, 1-1-3 or 1-1-4, the compound can be in the form of a dimer structure , tri-camera or t-camera in the pharmaceutical composition, and can be in the form of a nanosphere having a diameter of 2 to 300 nm. In the pharmaceutical composition according to the present invention, the nanospherical structure can preferably have a diameter of 2 to 100 nm. It is a well-known fact in nanopharmacology that nanospheres having a diameter of less than 100 nm are likely to be engulfed by macrophages during transport in the blood and can easily cross the blood capillary wall. These properties allow the compound according to the present invention to cross the blood-brain barrier. The pharmaceutical composition according to the present invention can be used as a thrombolytic drug in the treatment of diseases such as myocardial infarction, ischemic stroke, deep vein thrombosis, pulmonary embolism, peripheral artery occlusive disease, occluded central vascular access devices, coagulated arteriovenous fistula and shunt, and carotid stenosis. The pharmaceutical composition according to the present invention can also be used as a NO free radical scavenging drug in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, motor neuron diseases, amyotrophic lateral sclerosis, hearing loss noise-induced, Lou Gehring's disease or Huntington's disease; in the treatment of cardiovascular diseases, such as atherosclerosis, coronary heart disease or myocardial infarction; in the treatment of mental illnesses, such as bipolar disorder, schizophrenia or autism; and in the treatment of diseases including altitude sickness, diabetes, rheumatoid arthritis, traumatic brain injury, cancer, 14/95 fragile X syndrome, sickle cell disease, lichen planus, vitiligo, chronic fatigue syndrome and the like. The pharmaceutical composition according to the present invention can also be used as a thrombus / anti-thrombus drug in the treatment of diseases such as thrombocytosis, myeloproliferative disease, polyethemia vera or Budd-Chiari syndrome. The pharmaceutical composition according to the present invention can also be used as a drug in the treatment of stroke or cerebral infarction, preferably in the treatment of stroke or cerebral infarction after 3, 4, 6 and 24 hours from the onset of symptoms with administration successive. The pharmaceutical composition / compound according to the present invention simultaneously has NO free radical scavenging, thrombolysis, and anti-thrombus / thrombus targeting functions, and then shows efficacy even when administered 3 hours after the onset of stroke to patients; namely, it is not restricted by the 3 hour window as in the treatment using tPA, it does not cause a systemic hemorrhage response such as tPA, and it can clean the tremendous amount of NO free radicals generated during ischemia / reperfusion, preventing damage to the cranial nerve tissues in patients during treatment. In the pharmaceutical composition according to the present invention, the nanospheric structures of the compounds are capable of maximizing the effects of crossing the blood-brain barrier, thrombolysis, targeting the thrombus / anti-thrombus, as well as the effect of cleaning NO free radicals during ischemia / reperfusion. [033] The pharmaceutical composition according to the present invention can be any clinically acceptable formulation, for example, an injectable formulation (powder for injection, lyophilized powder for injection, liquid for injection, infusion etc.), a tablet, oral liquid, an granule, capsule, soft capsule, dripping pill and the like, wherein the pharmaceutically acceptable carriers can be one or more of xylitol, mannitol, lactose, fructose, dextran, glucose, polyvinylpyrrolidone, low molecular weight dextran, sodium chloride , calcium gluconate, or phosphate 15/95 calcium. In addition, the pharmaceutical composition according to the present invention can further comprise an excipient which can be an antioxidant complexing agent, a filler, a structural material and the like. [034] In another aspect, the present invention relates to a method of preparing the aforementioned compound of formula I, comprising the steps of: [035] (1) providing an imidazoline having NO free radical scavenging activity (NN), a binding arm having at least three binding groups (AA-i), a peptide having thrombolytic activity (AA 2 ) and a targeted peptide to the thrombus (AA 3 ), in which the connecting arm has a first group for connection, a second group for connection, and a third group for connection; [036] (2) under appropriate reaction conditions, attach the imidazoline having NO free radical scavenging activity (NN) to the first group for binding on the binding arm (AA-i), to form a compound of the general formula IM- 1: NN-AAi (IM-1); [037] (3) under appropriate reaction conditions, binding of the peptide having thrombolytic activity (AA 2 ) to the compound of the general formula IM-1, in which one end of the peptide having thrombolytic activity is linked to the second group for binding in the bond, to form a compound of general formula IM-2: NN-AA1-AA2 (IM-2); and [038] (4) under appropriate reaction conditions, link the peptide targeting the thrombus (AA 3 ) to the compound of general formula IM-2, in which a peptide termination targeting the thrombus is linked to the third group for ligation in the connecting arm, to form the compound of formula I; [039] in which step (3) and (4) are subject to change in their order. [040] In the preparation method according to the present invention, step (1) still comprises protection of the second and third groups for connection in the 16/95 binding (AA-ι) with protecting groups, and active protecting groups of the peptide having thrombolytic activity (AA 2 ) and of the peptide targeting the thrombus (AA 3 ), other than the termination to be used for binding with groups protectors; step (3) further comprises deprotection of the second protected group for first binding, and then binding to the peptide having thrombolytic activity to the second unprotected group for binding; step (4) further comprises deprotection of the third protected group for first binding, and then binding to the peptide targeting the thrombus to the third unprotected group for binding; and after step (4), there is still a step of deprotection of the active groups protected from the peptide having thrombolytic activity (AA 2 ), and from the peptide targeting the thrombus (AA 3 ). By applying techniques for adding and removing protective groups, the order in which NN, AA 2 and AA 3 are connected to the connecting arm and their connecting position are controllable. Protective groups in the active groups are then removed after termination of the coupling. Appropriate reaction conditions refer to conventional conditions employed in peptide synthesis. Imidazoline having NO free radical scavenging activity (NN), the binding arm having at least three binding groups (ΑΑ-ι), the peptide having thrombolytic activity (AA 2 ), and the thrombus directed peptide (AA 3 ) are the same as defined above for the compound of formula I according to the present invention. [041] The method of preparing the present invention can be further understood from the more detailed description as follows. [042] In one embodiment, the first group for attachment to the attachment arm in the preparation method according to the present invention is an amino group, while the second and third groups for attachment are selected from the group consisting of a carboxyl group. and an amino group. [043] In a preferred embodiment of the preparation method according to the present invention, imidazoline having NO free radical scavenging activity is 17/95 1,3-dioxo-2 - [(4-oxyacetoxy) phenyl] -4,4,5,5-tetramethylimidazoline, the linking arm is LLys, the peptide having thrombolytic activity is an oligopeptide comprising a PAK (Pro-Ala -Lys), and the thrombus-directed peptide is an oligopeptide comprising an RGD sequence (Arg-Gly-Asp). When the connecting arm is L-Lys, the following two forms for conjugation can occur: [044] (1) 1,3-dioxo-2 - [(4-oxyacethoxy) phenyl] -4,4,5,5-tetramethylimidazoline is attached to an amino group on the L-Lys binding arm, a carboxyl group on the an oligopeptide comprising a PAK sequence is linked to another amino group on the L-Lys linker, and an amino group on the oligopeptide comprising an RGD sequence is linked to a carboxyl group on the L-Lys linker (as shown in the above compound of formula 1 -1); or [045] (2) 1,3-dioxo-2 - [(4-oxyacethoxy) phenyl] -4,4,5,5-tetramethylimidazoline is attached to an amino group on the L-Lys linker, an amino group of the oligopeptide, comprising a PAK sequence is attached to a carboxyl group on the L-Lys linker, and a carboxyl group on the oligopeptide comprising an RGD sequence is linked to another amino group on the L-Lys linker (as shown in the above compound of formula I-2). [046] For examples related to the compound of formula 1-1, when the compound of general formula 1-1-1, 1-1-2, 1-1-3 or 1-1-4 is prepared, the method of preparation of the present invention can be carried out according to the synthesis schemes shown in Figs. 1 to 4. Fig. 1 shows a synthetic scheme for the compound of general formula 1-1-1. Fig. 2 shows a synthetic scheme for the compound of general formula 1-1-2. Fig. 3 shows a synthetic scheme for the compound of general formula I- 1-3. Fig. 4 shows a synthetic scheme for the compound of general formula 1-1-4. In Figs. 1 to 4, aa3 can be S (Ser), V (Val), or F (Phe), as described herein. For examples related to the compound of general formula 1-1-2, the method of preparation according to the present invention is described as follows: 18/95 [047] (1) prepare 1,3-dioxo-2- (4-oxyacethoxy-phenyl) -4,4,5,5-tetramethylimidazoline; [048] (2) prepare 1,3-dioxo-2 - [(4'-oxyacetyl-Lys-OMe) phenyl] -4,4,5,5tetramethylimidazoline (the carboxyl group on the Lys binding arm is protected with a group of protection); [049] (3) prepare HCI-Arg (NO2) -Gly-Asp (OBzl) -Ser (Bzl) -Obzl, HCI-Arg (NO2) -GlyAsp (OBzl) -Val-Obzl or HCI-Arg (NO2) -Gly-Asp (OBzl) -Phe-Obzl; [050] (4) prepare Boc-Gly-Arg (N0 2) -Pro-Ala-Lys (Z); [051] (5) attachment of Boc-Gly-Arg (N0 2) -Pro-Ala-Lys (Z) lysine 1,3-dioxo-2 - [(4'oxiacetil-Lys-OMe) phenyl] - 4,4,5,5-tetramethylimidazoline to provide 1,3-dioxo-2- {4'oxyacetyl- {N w - [Boc-Gly-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys } -4,4,5,5-tetramethylimidazoline; [052] (6) respectively, conjugate HCI-Arg (NO2) -Gly-Asp (OBzl) -Ser (Bzl) -Obzl, HCI-Arg (NO 2 ) -Gly-Asp (OBzl) -Val-Obzl, or HCI-Arg (NO 2 ) -Gly-Asp (OBzl) -Phe-Obzl to 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Gly-Arg (N02) -Pro-Ala -Lys (Z)] - Lys} phenyl} - 4,4,5,5tetramethylimidazoline to provide 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Gly-Arg (N02) Pro- Ala-Lys (Z)] - Lys-Arg (NG 2 ) -Gly-Asp (OBzl) -Ser (Bzl) -OBzl} phenyl} -4,4,5,5tetramethylimidazoline, 1,3-dioxo-2- {{ 4'-oxyacetyl- {N w - [Boc-Gly-Arg (N02) -Pro-AlaLys (Z)] - Lys-Arg- (N02) -Gly-Asp- (OBzl) -Val-OBzl} phenyl} - 4,4,5,5-tetramethylimidazoline, or 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Gly-Arg (N02) -Pro-Ala-Lys (Z)] - Lys -Arg (NO 2 ) Gly-Asp (OBzl) -Phe-OBzl} phenyl} -4,4,5,5-tetramethylimidazoline, respectively; [053] (7) deprotection of the resulting compounds from step (6) to provide 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Gly-Arg-Pro-Ala-Lys] -Lys -Arg-Gly-Asp-Ser} phenyl} - 4,4,5,5-tetramethylimidazoline, 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Gly-Arg-Pro-Ala-Lys] -LysArg-Gly-Asp-Val} phenyl} -4,4,5,5-tetramethylimidazoline or 1,3-dioxo-2- {4'-oxyacetyl- {N w [Gly-Arg-Pro-Ala-Lys] -Lys-Arg-Gly-Asp-Phe} phenyl} -4,4,5,5-tetramethylimidazoline. [054] In the case that compounds of general formula -1-1, 1-1-3 and 1-1-4 are prepared, the above manufacturing process is repeated but replacing “Boc-Gly-Arg (N0 2 ) Pro -Ala-Lys (Z) ”in step (4) with“ Boc-Ala-Arg (N0 2 ) -Pro-Ala-Lys (Z) ”,“ Boc19 / 95 Arg (NQ 2 ) -Pro-Ala-Lys (Z) ”and“ Boc-Pro-Ala-Lys (Z) ”. [055] Active groups at the appropriate positions on the oligopeptide comprising a PAK sequence and the oligopeptide comprising an RGD sequence can be protected by the need for conjugation design, so that the termination of the selected sequences (comprising an active group to be attached to the arm of link) is used to couple an active group on the link arm. The oligopeptide coupling step comprising a PAK sequence and the oligopeptide coupling step comprising an RGD sequence are subject to change in order. For example, the oligonucleotide comprising an RGD sequence is coupled to the first linker, and then the oligopeptide comprising a PAK sequence is coupled to it. [056] Active groups include groups that can be subjected to the condensation reaction, such as an amino group or a carboxyl group. Amino protecting groups can be carboxybenzyl (CBz), t-butoxy carbonyl (Boc), 9-florenyl methoxy carbonyl (Fmoc), benzyl (Bn) or p-methoxyphenyl (PMP). Carboxyl protecting groups can be methyl ester (OMe), benzyl ester (OBn), benzyl methyl ester (Obzl), t-butyl ester (OBUT), or silyl ester (OSi (CH 3 ) 3 ). [057] For examples related to the compound of formula I-2, when the compound of general formula 1-2-1, I-2-2, I-2-3 or I-2-4 is prepared, the method of preparation of the present invention can be carried out according to the synthetic schemes in Figs. 5 to 8. Fig. 5 show a synthetic scheme for the compound of general formula 1-2-1. Fig. 6 shows a synthetic scheme for the compound of general formula I-2-2. Fig. 7 shows a synthetic scheme for the compound of general formula I-2-3. Fig. 8 shows a synthetic scheme for the compound of general formula I-2-4. In Figs. 5 to 8, aa 3 can be S (Ser), V (Val) or F (Phe), as described above. When the compound of the general formula 1-2-1, I-2-2, I-2-3 or I-2-4 is prepared, 1,3-dioxo-2 - [(4'-oxyacetylLys-OMe) phenyl ] -4,4,5,5-tetramethylimidazoline can be prepared first, and then the 20/95 The terminal of the oligopeptide comprising an RGD sequence is attached to the amino group on the Lys binding arm; and finally, the N-terminus of the oligopeptide comprising a PAK sequence is attached to the unprotected carboxyl group on the linking arm. [058] In another embodiment, in the preparation method according to the present invention, imidazoline having NO free radical scavenging activity is 1,3dioxo-2 - [(4-oxyacetoxy) phenyl] -4,4,5, 5-tetramethylimidazoline, the binding arm is L-Asp, the peptide having thrombolytic activity is an oligopeptide comprising a PAK sequence (Pro-Ala-Lys), and the thrombus targeting peptide is an oligopeptide comprising an RGD sequence (Arg- Gly-Asp), where 1,3-dioxo- 2 - [(4-oxyacethoxy) phenyl] -4,4,5,5-tetramethylimidazoline is attached to the amino group on the L-Asp binding arm, the amino group on the oligopeptide comprising a PAK sequence is attached to a carboxyl group on the arm L-Asp linker, and the amino group on the oligopeptide comprising an RGD sequence is linked to another carboxyl group on the L-Asp linker (as shown in the above compound of formula I-3 or I4). [059] For examples related to the compound of formula I-3, when the compound of general formula 1-3-1, I-3-2, I-3-3 or I-3-4 is prepared, the method of preparation of the present invention can be carried out according to the synthetic schemes shown in Figs. 9 to 12. Fig. 9 shows a synthetic scheme for the compound of general formula 1-3-1. Fig. 10 shows a synthetic scheme for the compound of general formula I-3-2. Fig. 11 shows a synthetic scheme for the compound of general formula I-3-3. Fig. 12 shows a synthetic scheme for the compound of general formula I-3-4. In Figures 9 to 12, aa 3 can be S (Ser), V (Val), or F (Phe), as described above. When the compound of the general formula 1-3-1, I-3-2, I-3-3 or I-3-4 is prepared, 1,3dioxo-2 - [(4'-oxyacetyl-Asp-OMe) phenyl ] -4,4,5,5-tetramethylimidazoline can be prepared first, and then the N-terminal of the oligopeptide comprising a PAK sequence 21/95 is attached to a carboxyl group on the Asp binding arm; and finally, the terminal N of the oligopeptide comprising an RGD sequence is linked to another unprotected carboxyl group on the Asp binding arm. [060] For examples related to the compound of formula I-4, when the compound of general formula 1-4-1, I-4-2, I-4-3 or I-4-4 is prepared, the method of preparation of the present invention can be carried out according to the synthetic schemes shown in Figs. 13 to 16. Fig. 13 shows a synthetic scheme for the compound of general formula 1-4-1. Fig. 14 shows a synthetic scheme for the compound of general formula I-4-2. Fig. 15 shows a synthetic scheme for the compound of general formula I-4-3. Fig. 16 shows a synthetic scheme for the compound of general formula I-4-4. In Figs. 13 to 16, aa 3 can be S (Ser), V (Val), or F (Phe), as described above. When the compound of general formula 1-4-1, I-4-2, I-4-3 or I-4-4 is prepared, 1.3- dioxo-2 - [(4'-oxyacetyl-Asp-OMe) phenyl] -4,4,5,5-tetramethylimidazoline can be prepared first, and then the N-terminal of the olipeptide comprising an RGD sequence is attached to a group carboxyl in the Asp connecting arm; and finally, the terminal N of the oligopeptide comprising a PAK sequence is linked to another unprotected carboxyl group on the Asp binding arm. [061] In yet another embodiment, in the preparation method according to the present invention, imidazoline having NO free radical scavenging activity is 1.3- dioxo-2 - [(4-oxyacetoxy) phenyl] -4,4,5,5-tetramethylimidazoline, the binding arm is LGlu, the peptide having thrombolytic activity is an oligopeptide comprising a PAK (Pro-Ala-Lys) sequence ) and the thrombus-directed peptide is an oligopeptide comprising an RGD (Arg-Gly-Asp) sequence, where 1,3dioxo-2 - [(4-oxyacetoxy) phenyl] -4,4,5,5-tetramethylimidazoline is attached to the amino group on the L-Glu binding arm, the amino group on the oligopeptide comprising a PAK sequence is attached to a carboxyl group on the L-Glu binding arm, and the amino group on the oligopeptide comprising a RGD sequence is attached to another group 22/95 carboxyl in the L-Glu binding arm (as shown in the above compound of formula 1-5 or 1-6). [062] For examples related to the compound of formula 1-5, when the compound of general formula 1-5-1, I-5-2, I-5-3 or I-5-4 is prepared, the method of preparation of the present invention can be carried out according to the synthetic schemes shown in Figs. 17 to 20. Fig. 17 shows a synthetic scheme for the compound of general formula 1-5-1. Fig. 18 shows a synthetic scheme for the compound of general formula I-5-2. Fig. 19 shows a synthetic scheme for the compound of general formula I-5-3. Fig. 20 shows a synthetic scheme for the compound of general formula I-5-4. In Figs. 17 to 20, aa 3 can be S (Ser), V (Val), or F (Phe), as described above. When the compound of general formula 1-5-1, I-5-2, I-5-3 or I-5-4 is prepared, 1,3-dioxo-2 - [(4'-oxyacetyl-Glu-OMe) phenyl] -4,4,5,5-tetramethylimidazoline can be prepared first, and then the N-terminal of the oligopeptide comprising an RGD sequence is linked to a carboxyl group on the Glu connecting arm; and finally, the N-terminus of the oligopeptide comprising a PAK sequence is linked to another unprotected carboxyl group on the Glu binding arm. [063] For examples related to the compound of formula I-6, when the compound of general formula 1-6-1, I-6-2, I-6-3 or I-6-4 is prepared, the method of preparation of the present invention can be carried out according to the synthetic schemes in Figs. 21 to 24. Fig. 21 shows a synthetic scheme for the compound of general formula 1-6-1. Fig. 22 shows a synthetic scheme for the compound of general formula I-6- 2. Fig. 23 shows a synthetic scheme for the compound of general formula I-6-3. Fig. 24 shows a synthetic scheme for the compound of general formula I-6-4. In Figs. 21 to 24, aa 3 can be S (Ser), V (Val), or F (Phe), as described above. When the compound of the general formula 1-6-1, I-6-2, I-6-3 or I-6-4 is prepared, 1,3-dioxo-2- [4'oxyacetyl-Glu-OMe) phenyl ] -4,4,5,5-tetramethylimidazoline can be prepared first, and then the N-terminus of the oligopeptide comprising a PAK sequence is linked to 23/95 a carboxyl group on the Glu binding arm; and finally, the N-terminal of the oligopeptide comprising an RGD sequence is linked to another unprotected carboxyl group on the Glu binding arm. [064] In the preparation method previously described, the oligopeptide comprising a PAK sequence can be ARPAK (Ala-Arg-Pro-Ala-Lys), GRPAK (Gly-ArgPro-Ala-Lys), QRPAK (Gln-Arg-Pro- Ala-Lys), RPAK (Arg-Pro-Ala-Lys) or PAK (ProAla-Lys), and the oligopeptide comprising an RGD sequence can be RGDS (Arg-Gly-Asp-Ser), RGDV (Arg-Gly-Asp -Val) or RGDF (Arg-Gly-Asp-Phe). [065] For the compound or pharmaceutical composition according to the present invention, high NO free radical scavenging activity is demonstrated by in vivo mouse models of NO free radical scavenging; upper thrombolysis and anti-thrombus activities are demonstrated by in vivo and in vitro thrombolysis and anti-thrombus experiments; neuroprotective efficacy and superior anti-stroke activity are demonstrated by in vivo rat stroke models; and effectiveness in decreasing the volume of infarction is demonstrated by models of rat effusion. Description of Drawings [066] Fig. 1 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of formula 1-1-1); [067] Fig. 2 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula 1-1-2); [068] Fig. 3 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula 1-1-3); [069] Fig. 4 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula 1-1-4); [070] Fig. 5 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula 1-2-1); [071] Fig. 6 shows a synthetic scheme for an embodiment of the 24/95 according to the present invention (the compound of general formula 1-2-2); [072] Fig. 7 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula 1-2-3); [073] Fig. 8 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of formula 1-2-4); [074] Fig. 9 shows a synthetic scheme of an embodiment of the compound according to the present invention (the compound of general formula 1-3-1); [075] Fig. 10 shows a synthetic scheme of an embodiment of the compound according to the present invention (the compound of general formula I-3-2); [076] Fig. 11 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-3-3); [077] Fig. 12 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-3-4); [078] Fig. 13 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula 1-4-1); [079] Fig. 14 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-4-2); [080] Fig. 15 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-4-3); [081] Fig. 16 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-4-4); [082] Fig. 17 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula 1-5-1); [083] Fig. 18 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-5-2); [084] Fig. 19 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-5-3); 25/95 [085] Fig. 20 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula 1-5-4); [086] Fig. 21 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula 1-6-1); [087] Fig. 22 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-6-2); [088] Fig. 23 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-6-3); [089] Fig. 24 shows a synthetic scheme for an embodiment of the compound according to the present invention (the compound of general formula I-6-4); [090] Fig. 25 shows the nanostructures of compound Ia according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [091] Fig. 26 shows the nanostructures of compound Ib according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [092] Fig. 27 shows the nanostructures of compound Ic according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [093] Fig. 28 shows the nanostructures of the compound Id according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [094] Fig. 29 shows the nanostructures of compound l according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [095] Fig. 30 shows the nanostructures of the If compound according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [096] Fig. 31 shows the nanostructures of the Ig compound according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [097] Fig. 32 shows the nanostructures of compound Ih according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [098] Fig. 33 shows the nanostructures of compound li according to the present 26/95 invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [099] Fig. 34 shows the nanostructures of compound Ij according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [01 OO] Fig. 35 shows the nanostructures of the compound Ik according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [0101] Fig. 36 shows the nanostructures of compound II according to the present invention in aqueous solutions 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M; [0102] Fig. 37 shows the high resolution FT-MS spectrum of compound le according to the present invention at a concentration of 0.01 μΜ; [0103] Fig. 38 shows the high resolution FT-MS spectrum of compound le according to the present invention at a concentration of 0.1 μΜ; [0104] Fig. 39 shows the high resolution FT-MS spectrum of compound le according to the present invention at a concentration of 1 μΜ; [0105] Fig. 40 shows the high resolution FT-MS spectrum of compound le according to the present invention at a concentration of 10 μΜ. Detailed Description of the Modalities [0106] The present invention will now be described in connection with the following specific examples, and the advantages and characteristics of the same will become apparent in the view of the description. These examples are merely illustrative and in no way limit the scope of the present invention. One skilled in the art can understand that modification or substitution can be made in details and formality of technical solutions of the present invention without departing from the spirit and purpose of the present invention, and such modifications or substitutions are intended to be within the protection objective of the present invention. [0107] Preparation of imdazolines having NO free radical scavenging activity: 1,3-dioxo-2 - [(4-oxyacethoxy) phenyl] -4,4,5,5-tetramethylimidazoline Example 1. Preparation of 2,3-dimethyl-2,3-dinitrobutane 27/95 [0108] 69 g (0.78 mol) 2-nitropropane were added to 130 ml of aqueous NaOH solution (6N). 20 mL (0.38 mol) of Br 2 was added dropwise with stirring in an ice-salt bath within 1 h. After the completion of the addition of Br 2 , 240 ml of ethanol were added to it and left at reflux at 90 ° C for 3 h. The reaction solution, while still hot, was instantly poured into 800 ml of ice water, and then filtered to provide 55 g of the title compound (81%) as a colorless, scaly crystal, Mp 110-112 ° C. Example 2. Preparation of 2,3-dimethyl-2,3-dihydroxyminobutane [0109] 7 g (40 mmol) of 2,3-dimethyl-2,3-dinitrobutane and 4 g of NH 4 CI were mixed and suspended in 80 mL of aqueous ethanol solution (50%) and stirred in an ice bath, in which 16 g of zinc powder were added within 3 h. After the addition of zinc powder was completed, the ice bath was removed, and a reaction continued for 3 h at room temperature (RT) with stirring, and then the reaction mixture was vacuum filtered. The filtered mass was washed repeatedly with aqueous ethanol solution (50%). The filtrate and the washing liquid were combined, adjusted to pH = 2 with conc. HCI, and then distilled under reduced pressure in a mixture. After adding an appropriate amount of potassium carbonate, the mixture was uniformly mixed and extracted for 6 h using a Soxhlet extractor with chloroform as the extractor. The extract was concentrated under reduced pressure in a small amount, to which the petroleum ether was added to precipitate 2.60 g of the title compound (44%) as a colorless crystal, Mp 157-159 ° C. Example 3. Preparation of 1,3-dihydroxy-2- (4-hydroxyphenyl 1) -4,4,5,5-tetramethylimidizolidine [0110] 1.22 g (10 mmol) p-hydroxy benzaldehyde and 1.48 g (10 mmol) 2,3-dimethyl-2,3dihydroxyminobutane were dissolved in 10 mL of methanol and stirred at RT for 8 h until the starting material disappeared as shown by TLC. Upon vacuum 28/95 filtration, 1.29 g (51%) title compound was obtained as a colorless crystal. EI-MS (m / z) 252 [M] + . 1 H-NMR (DMSO-d 6 ) õ (ppm) = 1.03 (s, 6H), 1.05 (s, 6H), 4.39 (s, 1H), 6.70 (d, J = 6.9 Hz, 2H), 7.23 ( d, J = 6.9 Hz, 2H), 7.63 (s, 1H), 7.85 (s, 2H). Example 4. Preparation of 1,3-dihydroxy-2- (4'-hydroxyphenyl) -4,4,5,5tetramethylimidazoline [0111] 504 mg (2 mmol) 1,3-dihydroxy-2- (4'-hydroxyphenyl) -4,4,5,5-imidizolidine was dissolved in 30 ml methanol followed by the addition of 3 g PbO 2 , and stirred in RT for 40 min until the spot starting material disappeared as shown by TLC. After removal of the solids by vacuum filtration, the filtrate was distilled to dry under reduced pressure in RT, and the residue was purified by column chromatography (with chloroform as the eluent) to provide 260 mg (52%) of the title compound as a blue solid. Mp 134-135 ° C, EI-MS (m / z) 249 [M] + . IR (KBr) 3250,1610,1500,1490, 840. Example 5. Preparation of 1,3-dioxo-2- (4 '- (ethyl ester oxyacetate) -phenyl) - 4,4,5,5-tetramethylimidazoline [0112] 250 mg (1 mmol) 1,3-dihydroxy-2- (4'-hydroxyphenyl) -4,4,5,5-tetramethylimidazoline, 0.32 mL ethyl bromoacetate and 32 mg of NaH were dissolved in 5 ml anhydrous THF. The mixture was stirred at 60 ° C for 5 h until the point of the starting material disappeared as shown by TLC After filtration under reduced pressure at RT, the filtrate was concentrated under reduced pressure until dry, and the residue was purified by column chromatography. (ethyl acetate: petroleum ether = 1: 5) to give 300 mg (90%) of the target compound, MP 107-109 ° C. Example 6. Preparation of 1,3-dioxo-2- (4'-oxyacethoxy-phenyl) -4,4,5,5-tetramethylimidazoline (TMMZ) [0113] 7 drops of an aqueous solution of NaOH (2N) were added in a solution of 33 mg (0.1 mmol) 1,3-dioxo-2- (4 '- (oxyacetate ethyl ester) -phenyl) -4,4,5,5 tetramethylimidazoline in 3 ml of methanol, followed by stirring in TA for 30 min 29/95 until the starting material point disappears as shown by CCF. The reaction mixture was concentrated under reduced pressure, and the residue was diluted by adding 2 ml of saturated saline, adjusted to pH 6 with 2N HCI, and then extracted 3 times with ethyl acetate (3 ml χ 3). The ethyl acetate layer was combined and dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure at RT until dry to provide 30 mg (99%) of the title compound as a blue crystal. Mp 155-157 ° C. EI-MS (m / z) 307 [M] + . [0114] Alcohol imidazolines having NO free radical scavenging activity with a binding arm: 1,3-dioxo-2 - [(4'-oxyacetyl-Lys-OMe) phenill-4,4,5,5tetramethylimidazoline Example 7. Preparation of 1,3-dioxo-2 - [(4'-oxyacetyl-N w -Boc-Lys-OMe) phenyl] - 4,4,5,5- tetramethylimidazoline [0115] The 307 mg (1 mmol) 1,3-dioxo-2- (4'-oxyacetyl-phenyl) -4,4,5,5tetramethylimidazoline solution in 30 ml of THF anhydrous was stirred in an ice bath, in which 250 mg (1.2 mmol) DCC and 135 mg (1 mmol) HOBt were added and stirred in an ice bath for 10 min. Then the solution prepared with 300 mg (1 mmol) HCI Lys (Boc) -Ome, 122 mg (1 mmol) N-methylmorpholine and 6 mL of anhydrous THF was added, and the reaction mixture was reacted at RT for 24 h. TLC (ethyl acetate: petroleum ether = 2: 1) showed disappearance of HCI Lys (Boc) -Ome. The reaction mixture was concentrated under reduced pressure until dry, the residue was dissolved in ethyl acetate and insoluble material was removed by filtration. The filtrate was sequentially washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of NaCl, the separated ethyl acetate phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was then concentrated under reduced pressure at 37 ° C. ° C (these operations were later referred to here as a generic routine procedure). The residue was purified by column chromatography (ethyl acetate: petroleum ether = 2: 1) to give 433 mg (65%) of the compound 30/95 title as blue solid. ESI-MS (m / z) 550 [M + H] + . Example 8. Preparation of 1,3-dioxo-2 - [(4'-oxyacetyl-Lys-OMe) phenyl] -4,4,5,5tetramethylimidazoline [0116] 625 mg (1 mmol) 1,3-dioxo-2 - [(4'-oxyacetyl-N w -Boc-Lys-OMe) phenyl] -4,4,5,5tetramethylimidazoline was dissolved in 15 ml of anhydrous hydrogen chloride-ethyl acetate (4N) and stirred at RT for 3 h until the point of the starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was then subjected to the routine procedure. The residue was crystallized from anhydrous ethyl ether to provide the title compound. [0117] Peptide preparation having thrombolytic activity: properly protected ARPAK Example 9. Preparation of Boc-Ala-Lys (Z) -OBzl [0118] 473 mg (2.5 mmol) Boc-Ala was dissolved in 10 ml of anhydrous THF. The solution prepared with 338 mg (2.5 mmol) HOBt, 619 mg (3 mmol) DCC and 10 mL of anhydrous THF was added to it in an ice bath. The reaction mixture was stirred in an ice bath for 20 min before a solution prepared with 936 mg (2.3 mmol) HCI Lys (Z) -Obzl, 232 mg (2.3 mmol) N-methyl morpholine and 6 mL of Anhydrous THF were added to it. The resulting reaction mixture was reacted at RT for 24 h until HCI Lys (Z) -Obzl disappeared as shown by TLC (CHCI 3 : MeOH = 30: 1). The reaction mixture was subjected to the routine procedure to give 1.204 g (97%) of the title compound as a colorless solid. Mp 88-90 ° C. [The]; = -29.2 (c = 0.1, MeOH). ESI-MS (m / z) 565 [M + Na] + . Example 10. Preparation of HCI AIa-Lys (Z) -Obzl [0119] 1.354 g (2.5 mmol) Boc-Ala-Lys (Z) -Obzl was dissolved in approximately 10 ml of anhydrous hydrogen chloride solution in acetate of ethyl (4N) and stirred at RT for 3 h until the point of starting material disappears as shown by TLC (CHCI 3 : MeOH, 30: 1). The reaction mixture solution was concentrated under pressure 31/95 are reduced to TA, and the residue was dissolved in ethyl acetate and then concentrated to TA; the above process was repeated several times until all free hydrogen chloride was removed (these operations are hereinafter referred to as a routine procedure). The residue was crystallized from anhydrous ethyl ether to provide the title compound that was directly used in the next step reaction. Example 11. Preparation of Boc-Pro-Ala-Lys (Z) -OBzl [0120] 538 mg (2.5 mmol) Boc-Pro were dissolved in an appropriate amount of anhydrous THF followed by the addition of 338 mg (2.5 mmol) HOBt and 619 mg (3 mmol) DCC in anhydrous THF in an ice bath, and then reacted for 20 min. To this solution, the solution prepared with 1.099 g (2.3 mmol) HCI AIa-Lys (Z) -Obzl and 232 mg (2.3 mmol) N-methyl morpholine in 10 mL of anhydrous THF was added, and the reaction was performed in TA for 24 h. TLC (CHCI 3 : MeOH, 20: 1) showed disappearance of the starting material point. The reaction compounds were subjected to the routine procedure to provide 2.847 g (98%) title compound, Mp 82-83 ° C. [a] 2 D ° = -46.4 (c = 0.11, MeOH). ESI-MS (m / z) 661 [M + Na] + . Example 12. Preparation of HCI Pro-Ala-Lys (Z) -Obzl [0121] 1.596 g (2.5 mmol) Boc-Pro-Ala-Lys (Z) -Obzl were dissolved in 15 ml of solution of hydrogen chloride anhydrous in ethyl acetate (4N) and stirred at RT for 3 h until the point of starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the residue was crystallized from anhydrous ethyl ether to give the title compound which was directly used in the next step reaction. Example 13. Preparation of Boc-Arg (N0 2 ) -Pro-Ala-Lys (Z) -OBzl [0122] In an ice bath, the 798 mg (2.5 mmol) solution Boc-Arg (N0 2 ) , 338 mg (2.5 mmol) HOBt, 619 mg (3 mmol) DCC in 10 mL anhydrous THF were stirred for 20 min, in which the solution prepared with 1.322 g (2.3 mmol) HCI Pro-AlaLys (Z) -Obzl and 232 mg (2.3 mmol) of N-methylmorpholine in 5 ml of anhydrous THF were 32/95 added and the reaction was carried out at RT for 24 hours until the point of the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The routine procedure was carried out to give 1.642 g (85%) of the title compound. Mp 84-85 ° C. [a] 2 D ° = -65.0 (c = 0.13, MeOH). ESI-MS (m / z) 864 [M + Na] + . Example 14. Preparation of HCl · Arg (N0 2 ) -Pro-Ala-Lys (Z) -OBzl [0123] 2.099 g (2.5 mmol) Boc-Arg (N0 2 ) -Pro-Ala-Lys (Z) -OBzl were dissolved in 20 mL of anhydrous hydrogen chloride solution in ethyl acetate (4N) and stirred at RT for 3 h until the starting material point disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the residue was crystallized from anhydrous ethyl ether to give the title compound which was directly used in the next step reaction. Example 15. Preparation of Boc-Ala-Arg (N0 2) -Pro-Ala-Lys (Z) -OBzl [0124] In an ice bath, a solution of 473 mg (2.5 mmol) , Boc-Ala, 338 mg (2.5 mmol) HOBt, 619 mg (3 mmol) DCC in 10 mL of anhydrous THF was stirred for 20 min, in which the solution prepared with 1.785 g (2.3 mmol) HCI Arg (N0 2 ) -Pro -AlaLys (Z) -Obzl, 232 mg (2.3 mmol) N-methylmorpholine in 5 ml of anhydrous THF was added and the reaction was carried out for 24 hours to give 1.802 g (86%) of the title compound. Mp 87 - 89 ° C. fa] 2 D ° = -63.9 (c = 0.12, MeOH). ESI-MS (m / e) 934 [M + Na] + . Example 16. Preparation of Boc-Ala-Arg (N0 2) -Pro-Ala-Lys (Z) [0125] 921 mg (1 mmol) of Boc-Ala-Arg (N0 2) -Pro-Ala-Lys (Z) -OBzl were dissolved in 3 ml methanol, in which the aqueous solution of NaOH (2N) was added in an ice bath and stirred at RT for 30 min. With pH maintained at 12, the reaction was stirred in an ice bath for 10 min until the point of the starting material disappeared as shown by TLC. pH was adjusted to 7 with 2N HCl, and the reaction liquid was concentrated under reduced pressure. The residue was diluted with 2 ml saturated saline and adjusted to pH 2 with 2N HCl, and then extracted 3 times with ethyl acetate (5 ml x 3). The layers of the ethyl acetate phase were combined and dried over sulfate 33/95 anhydrous sodium, and concentrated under reduced pressure at RT to provide 767 mg (80%) of the title compound as a colorless solid. EI-MS (m / z) 830 [M - H] _ . [0126] Oeotide preparation directed to the thrombus / anti-thrombus: properly protected RGDS, RGDV, RGDF Example 17. Preparation of Boc-Asp (OBzl) -Ser (Bzl) -OBzl [0127] In an ice bath, the 808 mg (2.5 mmol) Boc-Asp (OBzl) solution, 338 mg (2, 5 mmol) HOBt, 619 mg (3 mmol) DCC rm 10 mL of anhydrous THF was stirred and reacted for 20 min, and then the solution prepared with 740 mg (2.3 mmol) HCI Ser (Bzl) -Obzl, 232 mg (2.3 mmol) N-methylmorpholine in 5 mL of anhydrous THF was added thereto and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction compounds were subjected to the routine procedure to provide 1.29 g (95%) of the title compound as a colorless oily matter. ESI-MS (m / z) 591 [M + H] + . Example 18. Preparation of HCI-Asp (OBzl) -Ser (Bzl) -OBzl [0128] 1.477 g (2.5 mmol) Boc-Asp (OBzl) -Ser (Bzl) -Obzl were dissolved in 15 ml of anhydrous hydrogen chloride in ethyl acetate (4N) and stirred at RT for 3 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the residue was crystallized from anhydrous ethyl ether to give the title compound which was directly used in the next step reaction. Example 19. Preparation of Boc-Gly-Asp (OBzl) -Ser (Bzl) -OBzl [0129] In an ice bath, the solution of 438 mg (2.5 mmol) Boc-Gly, 338 mg (2.5 mmol) HOBt, 619 mg (3 mmol) DCC in 10 mL anhydrous THF was stirred for 20 min, and then the solution prepared with 1.212 g (2.3 mmol) HCI Asp (OBzl) -Ser (Bzl) Obzl and 232 mg (2.3 mmol) N-methylmorpholine in 5 mL of anhydrous THF was added thereto and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the procedure 34/95 routine to provide 1,461 g (98%) of the title compound as a colorless solid. Mp 53 - 55 ° C. [a] 2 D ° = -23.7 (c = 0.13, MeOH). ESI-MS (m / z) 649 [M + H] + . Example 20. Preparation of HCl · Gly-Asp (OBzl) -Ser (Bzl) -OBzl [0130] 1.619 g (2.5 mmol) Boc-Gly-Asp (OBzl) -Ser (Bzl) -Obzl were dissolved in 15 mL of anhydrous hydrogen chloride solution in ethyl acetate (4N) and stirred at RT for 3 h until the point of starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the residue was crystallized from anhydrous ethyl ether to give the title compound which was directly used in the next step reaction. Example 21. Preparation of Boc-Arg (N0 2) -Gly-Asp (OBzl) -Ser (Bzl) -OBzl [0131] In an ice bath, a solution of 798 mg (2.5 mmol) , Boc-Arg ( NO 2 ), 338 mg (2.5 mmol) HOBt, 619 mg (3 mmol) DCC in 10 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 1.343 g (2.3 mmol) HCI GIy-Asp (OBzl) Ser (Bzl) -Obzl and 232 mg (2.3 mmol) N-methylmorpholine in 5 ml of anhydrous THF was added and reacted in RT for 24 h until the starting material disappeared as shown by CCF (CHCI 3 : MeOH, 20: 1). After the routine procedure, 1.66 g (85%) of the title compound was obtained as a colorless solid. Mp 74 - 75 ° C. [a] 2 D ° = -26.2 (c = 0.12, MeOH). ESI-MS (m / z) 872 [M + Na] + . Example 22. Preparation of HCI Arg (NO 2 ) -Gly-Asp (OBzl) -Ser (Bzl) -OBzl [0132] A mixture of 2.122 g (2.5 mmol) Boc-Arg (N0 2 ) -Gly-Asp (OBzl) -Ser (Bzl) Obzl and 20 mL of hydrogen chloride solution in ethyl acetate (4N) was stirred at RT for 3 h until the starting material disappear as shown by CCF (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, the residue was crystallized from anhydrous ethyl ether to provide the title compound. Example 23. Preparation of Boc-Asp (OBzl) -Val-OBzl [0133] In an ice bath, a solution of 808 mg (2.5 mmol) Boc-Asp (OBzl), 338 mg (2.5 mmol) HOBt, 619 mg (3 mmol) DCC in 10 mL of anhydrous THF was stirred 35/95 da for 20 min, and then the solution prepared with 558 mg (2.3 mmol) of HCI Val-Obzl and 232 mg (2.3 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added the same and reacted at RT for 24 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 1.129 g (96%) of the title compound as an oily liquid oncolor. ESI-MS (m / z) 512 [M + H] + . Example 24. Preparation of HCI Asp (OBzl) -Val-OBzl [0134] 1.258 g (2.5 mmol) Boc-Asp (OBzl) -Val-OBzl were dissolved in 15 ml of anhydrous hydrogen chloride solution in ethyl acetate ( 4N) and stirred at RT for 3 h until the point of starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the residue was crystallized from anhydrous ethyl ether to give the title compound which was directly used in the next step reaction. Example 25. Preparation of Boc-Gly-Asp (OBzl) -Val-OBzl [0135] In an ice bath, the solution of 438 mg (2.5 mmol) Boc-Gly, 338 mg (2.5 mmol) HOBt , 619 mg (3 mmol) DCC in 10 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 1.03 g (2.3 mmol) HCI Asp (OBzl) -Val-Obzl and 232 mg (2 , 3 mmol) N-methylmorpholine in 5 mL of anhydrous THF was added thereto and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 1.242 g (95%) of the title compound as a colorless solid. Mp 66 - 68 ° C. [a] 2 D ° = -43.8 (c = 0.11, MeOH). ESI-MS (m / z) 592 [M + Na] + . Example 26. Preparation of HCI GIy-Asp (OBzl) -Val-OBzl [0136] 1.421 g (2.5 mmol) Boc-Gly-Asp (OBzl) -Val-OBzl was dissolved in 15 ml of hydrogen chloride solution anhydrous in ethyl acetate (4N) and stirred at RT for 3 h until the point of starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the 36/95 The residue was crystallized from anhydrous ethyl ether to give the title compound which was directly used in the next step reaction. Example 27. Preparation of Boc-Arg (N0 2 ) -Gly-Asp (OBzl) -Val-OBzl [0137] In an ice bath, the 798 mg (2.5 mmol) solution Boc-Arg (N0 2 ) , 338 mg (2.5 mmol) HOBt, 619 mg (3 mmol) DCC in 10 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 1.162 g (2.3 mmol) HCI GIy-Asp (OBzl) -ValObzl and 232 mg (2.3 mmol) N-methylmorpholine in 5 ml of anhydrous THF was added and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1 ). The reaction mixture was subjected to the routine procedure to provide 1.523 g (86%) of the title compound as a colorless solid. Mp 107 - 109 ° C. fa] 2 D ° = -38.0 (c = 0.12, MeOH). ESI-MS (m / z) 793 [M + Na] + . Example 28. Preparation of HCl-Gly - Asp (OBzl) -Val-OBzl [0138] 1.925 g (2.5 mmol) , Boc-Arg (N0 2) -Gly-Asp (OBzl) -Val-OBzl was dissolved in 20 ml of anhydrous hydrogen chloride solution in ethyl acetate (4N) and stirred at RT for 3 h until the starting material point disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the residue was crystallized from anhydrous ethyl ether to give the title compound. Example 29. Preparation of Boc-Asp (OBzl) -Phe-OBzl [0139] In an ice bath, the solution of 808 mg (2.5 mmol) Boc-Asp (OBzl), 338 mg (2.5 mmol) HOBt, 619 mg (3 mmol) DCC in 10 mL anhydrous THF was stirred for 20 min, and then the solution prepared with 668 mg (2.3 mmol) of HCI Phe-Obzl and 232 mg (2.3 mmol) of N -methylmorpholine in 5 mL of anhydrous THF was added thereto and reacted in RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). After the routine procedure, 1.222 g (95%) of the title compound was obtained as a colorless solid. Mp 79 - 80 °°. [a |; j = -24.2 (c = 0.13, MeOH), ESI-MS (m / z) 561 [M + H] + . Example 30. Preparation of HCI Asp (OBzl) -Phe-OBzl 37/95 [0140] 1.398 g (2.5 mmol) Boc-Asp (OBzl) -Phe-OBzl were dissolved in 15 ml of anhydrous hydrogen chloride solution in ethyl acetate (4N) and stirred at RT for 3 h until the starting material point disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the residue was crystallized from anhydrous ethyl ether to give the title compound which was directly used in the next step reaction. Example 31. Preparation of Boc-Gly-Asp (OBzl) -Phe-OBzl [0141] In an ice bath, the 438 mg (2.5 mmol) solution of Boc-Gly, 338 mg (2.5 mmol) HOBt, 619 mg (3 mmol) of DCC in anhydrous THF was stirred for 20 min, and then the solution prepared with 1.141 g (2.3 mmol) of HCI Asp (OBzl) -PheObzl and 232 mg (2.3 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 1.29 g (91%) of the title compound as a colorless solid. Mp 70 71 ° C. [The]; = -22.5 (c = 0.14, MeOH). ESI-MS (m / z) 640 [M + Na] + . Example 32. Preparation of HCI GIy-Asp (OBzl) -Phe-OBzl [0142] 1.541 g (2.5 mmol) of Boc-Gly-Asp (OBzl) -Phe-OBzl were dissolved in 15 ml of hydrogen chloride solution anhydrous in ethyl acetate (4N) and stirred at RT for 3 h until the point of starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the residue was crystallized from anhydrous ethyl ether to give the title compound which was directly used in the next step reaction. Example 33. Boc-Arg (N0 2 ) -Gly-Asp (OBzl) -Phe-OBzl [0143] In an ice bath, the 798 mg (2.5 mmol) solution of Boc-Arg (N0 2 ), 338 mg (2.5 mmol) of HOBt, 619 mg (3 mmol) of DCC in 10 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 1.272 g (2.3 mmol) of HCI GIy-Asp (OBzl) -Phe-Obzl and 232 mg (2.3 mmol) of N-methylmorpholine in 5 mL THF Anhydrous 38/95 was added and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 1.637g (87%) of the title compound as a colorless solid. Mp 77 - 79 ° C. [cr] |> 0 = -22.6 (c = 0.09, MeOH). ESI-MS (m / z) 841 [M + Na] + . Example 34. Preparation of HCIArg (NO2) -Gly-Asp (OBzl) -Phe-OBzl [0144] 2.045 g (2.5 mmol) of Boc-Arg (N0 2) -Gly-Asp (OBzl) -Phe OBzl were dissolved in 15 mL solution of anhydrous hydrogen chloride in ethyl acetate (4N) and stirred at RT for 3 h until the starting material disappear as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure, and the residue was crystallized from anhydrous ethyl ether to give the title compound. [0145] Preparation of ARPAK / imidazoline / RGD ternary conjugates (compounds of general formula 1-1-1): Ia, Ib, Ic Example 35. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Ala-Arg (N0 2 ) Pro-Ala- Lys (Z)] - Lys-OMe} phenyl} - 4,4,5,5-tetramethylimidazoline [0146] In an ice bath, the 821 mg (1 mmol) solution of Boc-Ala-Arg (NG 2 ) Pro-Ala-Lys (Z), 135 mg (1 mmol) of HOBt and 250 mg (1 mmol) of DCC in 10 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 480 mg (1 mmol) of 1,3-dioxo-2 - [(4'- oxyacetyl-Lys-OMe) phenyl] -4,4,5,5-tetramethylimidazoline and 100 mg (1 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted in RT for 24 h until the match disappear as shown by CCF (CHCI 3 : MeOH, 40: 1). The reaction mixture was subjected to the routine procedure to provide 925 mg (83%) of the title compound as a blue solid. Mp 179 182 ° C. [The]; = -34.3 (c = 0.14, MeOH), ESI-MS (m / z) 1275 [M + Na] + . IR (KBr) 3319, 2935, 1658, 1531, 1448, 1363, 1254, 1168, 1053, 835, 749, 540 cm -1 . Example 36. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Ala-Arg (N0 2 ) 39/95 Pro-Ala- Lys (Z)] - Lys} phenyl} - 4,4,5,5-tetramethylimidazoline [0147] In an ice bath, 1260 mg (1 mmol) of 1,3-dioxo-2- {4 '-oxyacetyl- {N w [Boc-Ala-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys-OMe} phenyl} -4,4,5,5-tetramethylimidazoline were dissolved in 3 mL of methanol followed by addition of an aqueous solution of NaOH (2N), and then stirred at RT for 30 min. With pH maintained at 12, the reaction was stirred in an ice bath for 10 min until the starting material disappeared as shown by TLC. With pH adjusted to 7 with 2N HCI, the reaction liquid was concentrated under reduced pressure, and the residue was diluted in 2 mL of saturated saline, adjusted to pH 2 with 2N HCI, and then extracted 3 times with ethyl acetate (5 mLx 3). The combined ethyl acetate phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure at RT to provide 945 mg (82%) of the title compound as a blue solid. EI-MS (m / z) 1238 [M - H] _ . Example 37. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Ala-Arg (N0 2 ) Pro-Ala-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Ber (Bzl) -OBzl} phenyl} -4,4,5,5-tetramethylimidazoline [0148] In an ice bath, the 618 mg (0.5 mmol) solution of 1 , 3-dioxo-2- {4'oxyacetyl- {N w - [Boc-Ala-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys} phenyl} -4,4,5,5tetramethylimidazoline, 69 mg (0.5 mmol) of HOBt and 126 mg (0.6 mmol) of DCC in 20 ml of anhydrous THF was stirred for 20 min, and then the solution prepared with 442 mg (0.5 mmol) of HCI Arg (NO 2 ) -Gly-Asp (OBzl) - Ser (Bzl) -Obzl and 50 mg (0.5 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted in RT for 24 h until starting material disappear as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 300 mg (31%) of the title compound as a blue solid. Mp 138 - 140 ° C. [a] ;, = -39.4 (c = 0.13, MeOH). ESI-MS (m / z) 1991 [M + H] + . IR (KBr) 3309, 2936, 1656, 1531, 1449, 1363, 1256, 836, 743, 697, 601 cm -1 . Example 38. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Ala-Arg (N0 2 ) 40/95 Pro-Ala-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Val-OBzl} phenyl} -4,4,5,5tetramethylimidazoline [0149] In an ice bath, the 618 mg (0.5 mmol) solution of 1,3-dioxo-2- {4'oxyacetyl- {N w - [Boc-Ala-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys } phenyl} -4,4,5,5tetramethylimidazoline, 69 mg (0.5 mmol) of HOBt and 126 mg (0.6 mmol) of DCC in 20 ml of anhydrous THF was stirred for 20 min, and then the solution prepared with 421 mg (0.5 mmol) of HCI Arg (NO 2 ) -Gly-Asp (OBzl) -Val-Obzl and 50 mg (0.5 mmol) of Nmethylmorpholine in 5 ml of anhydrous THF was added and reacted at RT for 24 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 389 mg (36%) of the title compound as a blue solid. Mp117 - 120 ° C. [a] ™ = -14.8 (c = 0.01, MeOH). ESI-MS (m / z) 1913 [M + H] + . IR (KBr) 3312, 2937, 1655, 1530, 1448, 1362, 1257, 835, 744, 697, 592 cm -1 . Example 39. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Ala-Arg (N0 2 ) Pro-Ala-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Phe-OBzl} phenyl} -4,4,5,5tetramethylimidazoline [0150] In an ice bath, the 618 mg (0.5 mmol) solution of 1,3-dioxo- 2- {4'oxyacetyl- {N w - [Boc-Ala-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys} phenyl} -4,4,5,5tetramethylimidazoline, 69 mg (0, 5 mmol) HOBt and 126 mg (0.6 mmol) DCC in 20 mL anhydrous THF was stirred for 20 min, and then the solution prepared with 445 mg (0.5 mmol) HCI Arg (NO 2 ) - Gly-Asp (OBzl) -Phe-Obzl and 50 mg (0.5 mmol) of Nmethylmorpholine in 5 ml of anhydrous THF was added and reacted in RT for 24 h until the starting material disappeared as shown by CCF (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 320 mg (36%) of the title compound as a blue solid. Mp115 - 118 ° C. [a] ™ = -21.5 (c = 0.16, MeOH). ESI-MS (m / z) 1961 [M + H] + . IR (KBr) 3316, 2936, 1654, 1529, 1448, 1362, 1256, 1169, 742, 698, 593 cm -1 . 41/95 Example 40. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Ala-Arg-Pro-AlaLys) -Lys-Arg-Gly-Asp-Ser] phenyl} -4,4, 5,5-tetramethylimidazoline (Ia) [0151] In an ice bath, 199 mg (0.1 mmol) 1,3-dioxo-2- {4'-oxyacetyl- {N w - [BocAla-Arg (N0 2 ) -Pro-Wing-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Be (Bzl) -OBzl} phenyl} - 4.4.5.5- tetramethylimidazoline were mixed with 6 mL of trifluoroacetic acid and 1.5 mL of trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH = 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 109 mg (85%) of the title compound as a blue solid. Mp 134 - 135 ° C. [a] „= -39.7 (c = 0.12, MeOH). FT-MS (m / z) 1374.7290 [M + H] + , 2748.4580 [2M + H] + , 4122.1870 [3M + H] + , 5495.9160 [4M + H] + . g = 2.00779. IR (KBr) 3346, 3180, 2920, 1665, 1537, 1449, 1252, 1179, 1030, 837, 801,720, 639, 518 cm -1 . Example 41. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Ala-Arg-Pro-AlaLys) -Lys-Arg- Gly-Asp-Val] phenyl} -4,4, 5,5-tetramethylimidazoline (Ib) [0152] In an ice bath, 190 mg (0.1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Ala-Arg ( N0 2 ) -Pro-Wing-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Val-OBzl} phenyl} - 4.4.5.5- tetramethylimidazoline were mixed with 6 mL of trifluoroacetic acid and 1.5 mL of trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 96 mg (82%) of the title compound as a blue solid. Mp 143 - 144 ° C. [a] „= 42/95 -31.8 (c = 0.01, MeOH). FT-MS (m / z) 1386.7654 [M + H] + , 2772.5308, [2M + H] + , 4158.2962 [3M + H] + , 5544.0616 [4M + H] + . g = 2.00779. IR (KBr) 3349, 2942, 1659, 1539, 1394, 1250, 1030, 639 cm -1 . Example 42. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Ala-Arg-Pro-AlaLys) -Lys-Arg- Gly-Asp-Phe] phenyl} -4,4, 5,5-tetramethylimidazoline (Ic) [0153] In an ice bath, 194 mg (0.1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Ala-Arg ( N0 2 ) -Pro-Wing-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Phe-OBzl} phenyl} - 4,4,5,5-tetramethylimidazoline were mixed with 6 mL of trifluoroacetic acid and 1.5 mL of trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 106 mg (81%) of the title compound as a blue solid. Mp 96 - 97 ° C. [a] „= 44.4 (c = 0.15, MeOH). FT-MS (m / z) ESI-MS (m / z) 1444.7654 [M + H] + , ESI-MS (m / z) 2888.5308 [2M + H] + , 4332.2962 [3M + H] + , 5776.0616 [ 4M + H] + . g = 2.00789. IR (KBr) 3363, 1665, 1538, 1448, 1256, 1173, 1031,640, 577, 518 cm -1 . [0154] Preparation of the peptide having thrombolytic activity: properly protected GRPAK Example 43. Preparation of Boc-Gly-Arg (N0 2) -Pro-Ala-Lys (Z) -OBzl [0155] In an ice bath, a solution of 438 mg (2.5 mmol) of Boc-Gly, 338 mg (2.5 mmol) of HOBt, 619 mg (3 mmol) of DCC in 10 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 1.785 g (2.3 mmol) of HCI Arg (NO 2 ) Pro-Ala-Lys (Z) -Obzl and 232 mg (2.3 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted in RT for 24 h to give 1.857 g (90%) of the title compound. Mp 85 - 87 ° C. [a] 2 , = -38.5 (c = 0.11, MeOH). ESI-MS (m / e) 920 [M 43/95 + Na] + . Example 44. Preparation of Boc-Gly-Arg (N0 2) -Pro-Ala-Lys (Z) [0156] 907 mg (1 mmol) of Boc-Gly-Arg (N0 2) -Pro-Ala-Lys (Z ) -OBzl were dissolved in 3 ml of methanol followed by addition of an aqueous solution of NaOH (2N) in an ice bath, and then stirred in RT for 30 min. With pH maintained at 12, the reaction was stirred in an ice bath for 10 min until the starting material disappeared as shown by TLC. With pH adjusted to 7 with 2N HCI, the reaction liquid was concentrated under reduced pressure, and the residue was diluted in 2 mL of saturated saline, adjusted to pH 2 with 2N HCI, and then extracted 3 times with ethyl acetate (5 mLx 3). The combined ethyl acetate phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure at RT to provide 785 mg (82%) of the title compound as a colorless solid. EI-MS (m / z) 816 [M - H] _ . [0157] Preparation of ternary GRPAK / imidazoline / RGD conjugates (compounds of general formula 1-1-2): Id, le, If Example 45. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Gly-Arg (N0 2 ) Pro-Ala- Lys (Z)] - Lys-OMe} phenyl} - 4,4,5,5-tetramethylimidazoline [0158] In an ice bath, the 817 mg (1 mmol) solution of Boc-Gly-Arg (N0 2 ) Pro-Ala-Lys (Z), 135 mg (1 mmol) of HOBt and 250 mg (1 mmol) of DCC in 10 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 480 mg (1 mmol) of 1,3-dioxo-2 - [(4'- oxyacetyl-Lys-OMe) phenyl] -4,4,5,5-tetramethylimidazoline and 100 mg (1 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted in RT for 24 h until the match disappear as shown by CCF (CHCI 3 : MeOH, 40: 1). The reaction mixture was subjected to the routine procedure to provide 680 mg (52%) of the title compound as a blue solid. Mp 79 - 82 ° C. [a] 2 D ° = -12.3 (c = 0.14, MeOH), ESI-MS (m / z) 1261 [M + Na] + . IR (KBr) 3319, 2935, 1658, 1531, 1448, 1363, 1254, 1168, 1053, 835, 749, 540 cm -1 . Example 46. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Gly-Arg (N0 2 ) 44/95 Pro-Ala- Lys (Z)] - Lys} phenyl} -4,4,5,5-tetramethylimidazoline [0159] In an ice bath, 1260 mg (1 mmol) of 1,3-dioxo-2- {4 '-oxyacetyl- {N w [Boc-Gly-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys-OMe} phenyl} -4,4,5,5-tetramethylimidazoline were dissolved in 3 ml of methanol followed by addition of an aqueous solution of NaOH (2N), and then stirred at RT for 30 min. With pH maintained at 12, the reaction was stirred in an ice bath for 10 min until the starting material disappeared as shown by TLC. With pH adjusted to 7 with 2N HCI, the reaction liquid was concentrated under reduced pressure, and the residue was diluted in 2 mL of saturated saline, adjusted to pH 2 with 2N HCI, and then extracted 3 times with ethyl acetate (5 mLx 3). The combined ethyl acetate phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure at RT to provide 945 mg (82%) of the title compound as a colorless solid. EI-MS (m / z) 1223 [M - H] _ . Example 47. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Gly-Arg (N0 2 ) Pro-Ala- Lys (Z)] - Lys-Arg- (NO 2 ) -Gly-Asp (OBzl) -Ser (Bzl) -OBzl} phenyl} -4,4,5,5-tetramethylimidazoline [0160] In an ice bath, the 611 mg (0.5 mmol) solution of 1 , 3-dioxo-2- {4'oxyacetyl- {N w - [Boc-Gly-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys} phenyl} -4,4,5,5tetramethylimidazoline, 69 mg (0.5 mmol) of HOBt and 126 mg (0.6 mmol) of DCC in 20 ml of anhydrous THF was stirred for 20 min, and then the solution prepared with 442 mg (0.5 mmol) of HCI Arg (NO 2 ) -Gly-Asp (OBzl) -Ser (Bzl) -Obzl and 50 mg (0.5 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted in RT for 24 h until starting material disappear as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 500 mg (48%) of the title compound as a blue solid. Mp 127 - 129 ° C. [ap = -49.4 (c = 0.13, MeOH). ESI-MS (m / z) 1956 [M + H] + . IR (KBr) 3306, 2936, 1652, 1531, 1449, 1362, 1255, 1166, 742, 697, 592 cm -1 . Example 48. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Gly-Arg (N0 2 ) 45/95 Pro-Ala-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Val-OBzl} phenyl} -4,4,5,5tetramethylimidazoline [0161] In an ice bath, the 611 mg (0.5 mmol) solution of 1,3-dioxo-2- {4'oxyacetyl- {N w - [Boc-Gly-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys } phenyl} -4,4,5,5tetramethylimidazoline, 69 mg (0.5 mmol) of HOBt and 126 mg (0.6 mmol) of DCC in 20 ml of anhydrous THF was stirred for 20 min, and then the solution prepared with 421 mg (0.5 mmol) of HCI Arg (NO 2 ) -Gly-Asp (OBzl) -Val-Obzl, 50 mg (0.5 mmol) of Nmethylmorpholine in 5 ml of anhydrous THF was added and reacted at RT for 24 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 392 mg (35%) of the title compound as a blue solid. Mp 147 - 150 ° C. [a] ™ = -34.6 (c = 0.16, MeOH). ESI-MS (m / z) 1899 [M + Na] + . IR (KBr) 3311, 3068, 2937, 1661, 1531, 1451, 1395, 1254, 1163, 839, 743, 697, 596 cm -1 . Example 49. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Gly-Arg (N0 2 ) Pro-Ala-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Phe-OBzl} phenyl} -4,4,5,5tetramethylimidazoline [0162] In an ice bath, a solution of 611 mg (0.5 mmol) of 1,3-dioxo- 2 {4'-oxyacetyl- {N w - [Boc-Gly-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys} phenyl} -4,4,5,5tetramethylimidazoline, 69 mg (0, 5 mmol) HOBt and 126 mg (0.6 mmol) DCC in 20 mL anhydrous THF was stirred for 20 min, and then the solution prepared with 445 mg (0.5 mmol) HCI Arg (NO 2 ) - Gly-Asp (OBzl) -Phe-Obzl and 50 mg (0.5 mmol) of Nmethylmorpholine in 5 ml of anhydrous THF was added and reacted in RT for 24 h until the starting material disappeared as shown by CCF (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 336 mg (31%) of the title compound as a blue solid. Mp 125 - 128 ° C. [a] ™ = -31.3 (c = 0.18, MeOH). ESI-MS (m / z) 1925 [M + H] + . IR (KBr) 3315, 2935, 1657, 1529, 1448, 1361, 1257, 1173, 834, 742, 698, 541 cm -1 . 46/95 Example 50. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Gly-Arg-Pro-AlaLys) - Lys-Arg-Gly-Asp-Ser] phenyl} -4,4, 5,5-tetramethylimidazoline (Id) [0163] In an ice bath, 195 mg (0.1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Gly-Arg ( N02) -Pro-Ala-Lys (Z)] - Lys-Arg- (N02) -Gly-Asp (OBzl) -Ser (Bzl) OBzl} phenyl} -4,4,5,5-tetramethylimidazoline were mixed with 6 ml of trifluoroacetic acid and 1.5 ml of trifluorethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI3: MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 102 mg (82%) of the title compound as a blue solid. Mp 142 - 145 ° C. fa] 2 D ° = -29.7 (c = 0.14, MeOH). FT-MS (m / z) 1360.7133 [M + H] + , 2720.4266 [2M + H] + , 4080.1399 [3M + H] + , 5439.8532 [4M + H] + . g = 2.00779. IR (KBr) 3348, 3180, 2940, 1670, 1539, 1447, 1199, 1134, 1034, 836, 801, 721, 638 cm -1 . Example 51. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Gly-Arg-Pro-AlaLys) -Lys-Arg- Gly-Asp-Val] phenyl} -4,4, 5,5-tetramethylimidazoline (le) [0164] In an ice bath, 190 mg (0.1 mmol) 1,3-dioxo-2- {4'-oxyacetyl- {N w - [BocGly-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Val-GBzl} phenyl} -4,4,5,5tetramethyl-imidazoline were mixed with 6 mL of trifluoroacetic acid and 1.5 mL of trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then 47/95 purified on a C18 column. The collected fractions were lyophilized to provide 99 mg (84%) of the title compound as a blue solid. Mp 147 - 149 ° C. [α] „= -31.1 (c = 0.17, MeOH). FT-MS (m / z) 1372.7497 [M + H] + , 2744.4994 [2M + H] + , 4116.2491 [3M + H] + , 5487.9988 [4M + H] + . g = 2.00779. IR (KBr) 3338, 2960, 1662, 1539, 1451, 1392, 1251.1170, 1030, 639, 519 cm -1 . Example 52. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Gly-Arg-Pro-AlaLys) -Lys- Arg-Gly-Asp-Phe] phenyl} -4,4, 5,5-tetramethylimidazoline (If) [0165] In an ice bath, 192 mg (0.1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Gly-Arg ( N0 2 ) -Pro-Wing-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Phe-OBzl} phenyl} - 4,4,5,5-tetramethylimidazoline were mixed with 6 mL of trifluoroacetic acid and 1.5 mL of trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 106 mg (81%) of the title compound as a blue solid. Mp 84 - 85 ° C. [a] „= 54.1 (c = 0.15, MeOH). FT-MS (m / z) 1420.7497 [M + H] + , 2840.4994 [2M + H] + , ESIMS FT-MS (m / z) 1420.7497 [M + H] + , 2840.4994 [2M + H] + , 4260.2491 [3M + H] + , 5679.9976 [4M + H] + . g = 2.00789. IR (KBr) 3344, 3080, 2930, 1666, 1535, 1392, 1250, 1181, 1030, 835, 800, 719, 638 cm -1 . [0166] Peptide preparation with thrombolytic activity: properly protected RPAK Example 53. Preparation of Boc-Arg (N0 2) -Pro-Ala-Lys (Z) [0167] In an ice bath, 850 mg (1 mmol) of Boc-Arg (N0 2) -Pro-Ala-Lys (Z) OBzl were dissolved in 3 ml of methanol followed by the addition of an aqueous solution of NaOH (2N), and then stirred at RT for 30 min. With pH maintained at 12, the The reaction was stirred in an ice bath for 10 min until the starting material disappeared as shown by TLC. With pH adjusted to 7 with 2N HCI, the reaction liquid was concentrated under reduced pressure, and the residue was diluted in 2 mL of saturated saline, adjusted to pH 2 with 2N HCI, and then extracted 3 times with ethyl acetate (5 mLx 3). The combined ethyl acetate phase was dried over anhydrous sodium sulfate, and filtered, then the filtrate is concentrated under reduced pressure at RT to provide 742 mg (92%) of the title compound as a colorless solid. EI-MS (m / z) 849 [M H] -. [0168] Preparation of ternary RPAK / imidazoline / RGD conjugates (compounds of general formula 1-1-3): lg, Ih, li Example 54. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Arg (N0 2 ) -ProAla- Lys (Z)] - Lys-OMe} phenyl} -4,4 , 5,5-tetramethylimidazoline [0169] In an ice bath, the solution of 760 mg (1 mmol) of Boc-Arg (NO 2 ) -ProAla-Lys (Z), 135 mg (1 mmol) of HOBt and 250 mg (1 mmol) of DCC in 10 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 480 mg (1 mmol) of 1,3-dioxo-2 - [(4'-oxyacetyl-Lys-OMe) phenyl] - 4,4,5,5-tetramethylimidazoline and 100 mg (1 mmol) of N-methylmorpholine in 5 ml of anhydrous THF it is reacted at RT for 24 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 40: 1). The reaction mixture was subjected to the routine procedure to provide 920 mg (83%) of the title compound as a blue solid. Mp 72 - 76 ° C. [The]; = 32.7 (c = 0.13, MeOH), ESI-MS (m / z) 1204 [M + Na] + . IR (KBr) 3317, 2937, 1658, 1531, 1447, 1362, 1254, 1168, 1055, 835, 746, 697, 541,460 cm -1 . Example 55. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Arg (N02) -ProAla- Lys (Z)] - Lys} phenyl} -4,4,5, 5-tetramethylimidazoline [0170] In an ice bath, 1200 mg (1 mmol) 1,3-dioxo-2- {4'-oxyacetyl- {N w - [BocArg (N02) -Pro-Ala-Lys (Z) ] -Lys-OMe} phenyl} -4,4,5,5-tetramethylimidazoline were dissolved in 3 ml of methanol followed by the addition of an aqueous solution of 49/95 NaOH (2N), and then stirred at RT for 30 min. With pH maintained at 12, the reaction was stirred in an ice bath for 10 min until the starting material disappeared as shown by TLC. With pH adjusted to 7 with 2N HCI, the reaction liquid was concentrated under reduced pressure, and the residue was diluted in 2 ml of saturated saline, adjusted to pH 2 with 2N HCI, and then extracted 3 times with ethyl acetate (5 mlx 3). The combined ethyl acetate phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure at RT to provide 899 mg (80%) of the title compound as a blue solid. EI-MS (m / z) 1116 [Μ - H] _ . Example 56. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Arg (N0 2 ) -ProAla- Lys (Z)] - Lys-Arg- (NO 2 ) -Gly -Asp (OBzl) -Ser (Bzl) -OBzl} phenyl} -4,4,5,5-tetramethylimidazoline [0171] In an ice bath, the 583 mg (0.5 mmol) solution of 1,3- dioxo-2- {4'oxiacetyl- {N w - [Boc-Arg (N02) -Pro-Ala-Lys (Z)] - Lys} phenyl} -4,4,5,5-tetramethylimidazoline, 69 mg (0 , 5 mmol) of HOBt and 126 mg (0.6 mmol) of DCC in 20 mL of anhydrous THF were stirred for 20 min, and then the solution prepared with 442 mg (0.5 mmol) of HCI Arg (NO2) - Gly-Asp (OBzl) -Ser (Bzl) -Obzl and 50 mg (0.5 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted in RT for 24 h until the starting material disappeared as shown by TLC (CHCl3: MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 421 mg (40%) of the title compound as a blue solid. Mp 77 - 79 ° C. [a] 2 D ° = -45.4 (c = 0.15, MeOH). ESIMS (m / z) 1897 [M + H] + . IR (KBr) 3319, 2934, 1658, 1530, 1449, 1361, 1256, 834, 741,698, 542 cm -1 . Example 57. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Arg (N02) -ProAla-Lys (Z)] - Lys-Arg- (N02) -Gly-Asp (OBzl) -Val-OBzl} phenyl} -4,4,5,5-tetramethylimidazoline [0172] In an ice bath, the 583 mg (0.5 mmol) solution of 1,3-dioxo-2- { 4'oxiacetyl- {N w - [Boc-Arg (N02) -Pro-Ala-Lys (Z)] - Lys} phenyl} -4,4,5,5-tetramethylimidazoline, 69 mg (0.5 mmol) HOBt and 126 mg (0.6 mmol) of DCC in 20 mL of anhydrous THF 50/95 was stirred for 20 min, and then the solution prepared with 421 mg (0.5 mmol) of HCIArg (NO 2 ) -Gly-Asp (OBzl) -Val-Obzl and 50 mg (0.5 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 472 mg (42%) of the title compound as a blue solid. Mp 107 - 109 ° C. [The]; = -28.8 (c = 0.11, MeOH). ESIMS (m / z) 1820 [M + H] + . IR (KBr) 3314, 2938, 1658, 1531, 1448, 1362, 1258, 742, 698, 594 cm -1 . Example 58. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Arg (N0 2 ) -ProAla-Lys (Z)] - Lys-Arg- (NO 2 ) -Gly -Asp (OBzl) -Phe-OBzl} phenyl} -4,4,5,5tetramethylimidazoline [0173] In an ice bath, the 583 mg (0.5 mmol) solution of 1,3-dioxo-2- { 4'oxiacetyl- {N w - [Boc-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys} phenyl} -4,4,5,5-tetramethylimidazoline, 69 mg (0.5 mmol) HOBt and 126 mg (0.6 mmol) of DCC in 20 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 445 mg (0.5 mmol) of HCI Arg (NO 2 ) -Gly-Asp (OBzl) -Phe-Obzl and 50 mg (0.5 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted at RT for 24 h until the starting material disappeared as shown by CCF (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 420 mg (47%) of the title compound as a blue solid. Mp 141 - 144 ° C. [a] 21 '= -35.7 (c = 0.12, MeOH). ESIMS (m / z) 1867 [M + H] + . IR (KBr) 3319, 2936, 1656, 1529, 1448, 1362, 1257, 1169, 834, 743, 698, 541 cm -1 . Example 59. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Arg-Pro-Ala-Lys) Lys-Arg-Gly- Asp-Ser] phenyl} -4,4,5 , 5-tetramethylimidazoline (Ig) [0174] In an ice bath, 170 mg (0.1 mmol) 1,3-dioxo-2- {4'-oxyacetyl- {N w - [BocArg (N0 2 ) -Pro -Ala-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Ser (Bzl) -OBzl} phenyl} -4,4,5,5tetramethylimidazoline were mixed with 6 ml of trifluoroacetic acid and 1.5 mL of 51/95 trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 102 mg (82%) of the title compound as a blue solid. Mp 148 - 150 ° C. [a] ™ = -22.4 (c = 0.14, MeOH). FT-MS (m / z) 1303.6919 [M + H] + , 2606.3838, [2M + H] + , 3909.0757 [3M + H] + , 5211.7676 [4M + H] + . g = 2.00779. IR (KBr) 3344, 3080, 2930, 1666, 1535, 1392, 1250, 1181,1030, 835, 800, 719, 638. Example 60. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Arg-Pro-Ala-Lys) Lys-Arg-Gly- Asp-Val] phenyl} -4,4,5 , 5-tetramethylimidazoline (Ih) [0175] In an ice bath, 182 mg (0.1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Arg (N0 2 ) -Pro-Ala-Lys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Val-OBzl} phenyl} -4,4,5,5tetramethylimidazoline were mixed with 6 ml of trifluoroacetic acid and 1.5 ml of trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 99 mg (84%) of the title compound as a blue solid. Mp 137 - 139 ° C. [α] „= -34.3 (c = 0.18, MeOH). FT-MS (m / z) ESI-MS (m / z) 1315.7282 [M + H] + , 2630.4564 [2M + H] + , 3945.1846 [3M + H] + , 5259.9128 [4M + H] + . g = 2.00779. IR (KBr) 3329, 2953, 1665, 1533, 1391,1198, 1134, 834, 801,720, 599 cm -1 . Example 61. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Arg-Pro-Ala-Lys) Lys-Arg-Gly- Asp-Phe] phenyl} -4,4,5 , 5-tetramethylimidazoline (li) 52/95 [0176] In an ice bath, 187 mg (0.1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Arg (N0 2 ) -Pro-Ala -Lys (Z)] - Lys-Arg- (NO 2 ) -Gly-Asp (OBzl) -Phe-OBzl} phenyl} -4,4,5,5tetramethylimidazoline were mixed with 6 ml of trifluoroacetic acid and 1.5 ml trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 96 mg (81%) of the title compound as a blue solid. Mp 99 - 100 ° C. [α] „= -24.7 (c = 0.14, MeOH). FT-MS (m / z) 1363.7282 [M + H] + , 2726.4564 [2M + H] + , 4089.1846 [3M + H] + , 5451.9128 [4M + H] + . g = 2.00789. IR (KBr) 3322, 3060, 2928, 1661, 1530, 1391, 1303, 1247, 641 cm -1 . [01771Preparation of the peptide having thrombolytic activity: properly protected PAK Example 62. Preparation of Boc-Pro-Ala-Lys (Z) [0178] In an ice bath, 638 mg (1 mmol) of Boc-Pro-Ala-Lys (Z) -OBzl were dissolved in 3 ml of methanol followed by the addition of an aqueous NaOH solution (2N), and then stirred at RT for 30 min. With pH maintained at 12, the reaction was stirred in an ice bath for 10 min until the starting material disappeared as shown by TLC. With pH adjusted to 7 with 2N HCI, the reaction liquid was concentrated under reduced pressure, and the residue was diluted in 2 ml of saturated saline, adjusted to pH 2 with 2N HCI, and then extracted 3 times with ethyl acetate (5 mlx 3). the combined ethyl acetate phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was then concentrated under reduced pressure at RT to provide 509 mg (91.6%) of the title compound as a colorless solid. EI-MS (m / z) 547 [M - H] _ . [0179] Preparation of ternary PAK / imidazoline / RGD conjugates (compounds 53/95 of general formula 1-1-4): li, Ik, II Example 63. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Pro-AlaLys (Z)] - Lys-OMe} phenyl} -4,4,5,5-tetramethylimidazoline [0180] In an ice bath, the solution of 548 mg (1 mmol) of Boc-Pro-AlaLys (Z), 135 mg (1 mmol) of HOBt and 250 mg (1 mmol) of DCC in 10 mL of THF anhydrous solution was stirred for 20 min, and then the solution prepared with 480 mg (1 mmol) of 1,3-dioxo-2 - [(4'-oxyacetyl-Lys-OMe) phenyl] -4,4,5,5-tetramethylimidazoline and 100 mg (1 mmol) of N-methylmorpholine in 5 ml of anhydrous THF it is reacted at RT for 24 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 40: 1). The reaction mixture was subjected to the routine procedure to provide 876 mg (87%) of the title compound as a blue solid. Mp 77 - 80 ° C. = - 12.6 (c = 0.16, MeOH). ESI-MS (m / z) 1003 [M + Na] + . IR (KBr): 3315, 3069, 2937, 1671, 1531, 1449, 1394, 1364, 1302, 1167, 1132, 1054, 836, 743, 698, 596, 541,458 cm -1 . Example 64. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Pro-AlaLys (Z)] - Lys} phenyl} -4,4,5,5-tetramethylimidazoline [0181 ] In an ice bath, 980 mg (1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Pro-Ala-Lys (Z)] - Lys- OMe} phenyl} -4,4,5,5-tetramethylimidazoline were dissolved in 3 ml of methanol followed by the addition of an aqueous solution of NaOH (2N), and then stirred at RT for 30 min. With pH maintained at 12, the reaction was stirred in an ice bath for 10 min until the starting material disappeared as shown by TLC With pH adjusted to 7 with 2N HCI, the reaction liquid was concentrated under reduced pressure, and the residue was diluted in 2 mL of saturated saline, adjusted to pH 2 with 2N HCI, and then extracted 3 times with ethyl acetate (5 mL x 3). The combined ethyl acetate phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure at RT to provide 867 mg (80%) of the title compound as a blue solid. EI-MS (m / z) 965 [M - H] _ . 54/95 Example 65. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Pro-AlaLys (Z)] - Lys-Arg- (NO 2 ) -Gly-Asp (OBzl) - Ser (Bzl) -OBzl} phenyl} -4,4,5,5tetramethylimidazoline [0182] In an ice bath, the 483 mg (0.5 mmol) solution of 1,3-dioxo-2- {4'oxiacetyl - {N w - [Boc-Pro- Ala-Lys (Z)] - Lys} phenyl} -4,4,5,5-tetramethylimidazoline, 69 mg (0.5 mmol) of HOBt and 126 mg (0.6 mmol) DCC in 20 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 442 mg (0.5 mmol) of HCI Arg (NO 2 ) -GlyAsp (OBzl) -Ser (Bzl) -Obzl and 50 mg (0.5 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added thereto and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 421 mg (42%) of the title compound as a blue solid. Mp 97 - 100 ° C. [a] 2 , = -42.5 (c = 0.14, MeOH). ESI-MS (m / z) 1697 [M + H] + . IR (KBr) 3298, 3070, 2935, 2869, 1642, 1534, 1450, 1369, 1253, 741, 697, 596 cm -1 . Example 66. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Pro-AlaLys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) - Val-OBzl} phenyl} -4,4,5,5-tetramethylimidazoline [0183] In an ice bath, the 483 mg (0.5 mmol) solution of 1,3-dioxo-2- {4'oxyacetyl- {N w - [Boc- Pro-Ala-Lys (Z)] - Lys} phenyl} -4,4,5,5-tetramethylimidazoline, 69 mg (0.5 mmol) HOBt and 126 mg (0.6 mmol ) of DCC in 20 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 432 mg (0.5 mmol) of HCI Arg (NO 2 ) Gly-Asp (OBzl) -Val-Obzl and 50 mg ( 0.5 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 357 mg (37%) of the title compound as a blue solid. Mp 117 - 120 ° C. [a] 2 ^ = -22.3 (c = 0.17, MeOH). ESI-MS (m / z) 1620 [M + H] + . IR (KBr) 3303, 3072, 2935, 1644, 1533, 1451, 1394, 1364, 1255, 1167, 745, 697, 597 cm -1 . 55/95 Example 67. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- {N w - [Boc-Pro-AlaLys (Z)] - Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) - Phe-OBzl} phenyl} -4,4,5,5-tetramethylimidazoline [0184] In an ice bath, the 483 mg (0.5 mmol) solution of 1,3-dioxo-2- {4'oxyacetyl- {N w - [Boc-Pro-Ala- Lys (Z)] - Lys} phenyl} -4,4,5,5-tetramethylimidazoline, 69 mg (0.5 mmol) HOBt and 126 mg (0.6 mmol ) of DCC in 20 mL of anhydrous THF was stirred for 20 min, and then the solution prepared with 439 mg (0.5 mmol) of HCI Arg (NO 2 ) Gly-Asp (OBzl) -Phe-Obzl and 50 mg ( 0.5 mmol) of N-methylmorpholine in 5 ml of anhydrous THF was added and reacted at RT for 24 h until the starting material disappeared as shown by TLC (CHCI 3 : MeOH, 20: 1). The reaction mixture was subjected to the routine procedure to provide 472 mg (48%) of the title compound as a blue solid. Mp 111 - 114 ° C. [cr] |> 0 = -15.3 (c = 0.13, MeOH). ESI-MS (m / z) 1667 [M + H] + . IR (KBr) 3296, 3071, 2935, 1641, 1534, 1394, 1253, 1170, 834, 745, 697, 594 cm -1 . Example 68. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Pro-Ala-Lys) -LysArg-Gly-Asp- Ser] phenyl} -4,4,5,5- tetramethylimidazoline (Ij) [0185] In an ice bath, 169 mg (0.1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Pro-Ala-Lys (Z) ] -Lys- Arg- (NO 2 ) -Gly-Asp (OBzl) -Ser (Bzl) -OBzl} phenyl} -4,4,5,5tetramethylimidazoline were mixed with 6 ml of trifluoroacetic acid and 1.5 ml of acid trifluoromethanesulfonic, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 98 mg (80%) of the title compound as a blue solid. Mp 127 - 128 ° C. [α] „= -22.4 (c = 0.13, MeOH). FT-MS (m / z) 1147.5907 [M + H] + , 2294.1814 [2M + H] + , 3440.7721 [3M + H] + , 4587.3628 [4M + H] + . g = 2.00779. IR (KBr) 3204, 1672, 1543, 1436,1199, 56/95 1133, 837, 801.722, 598 cm -1 . Example 69. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Pro-Ala-Lys) -LysArg-Gly-Asp-Val] phenyl} -4,4,5,5- tetramethylimidazoline (Ik) [0186] In an ice bath, 162 mg (0.1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Pro-Ala-Lys (Z) ] -Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Val-OBzl} phenyl} -4,4,5,5tetramethylimidazoline were mixed with 6 ml of trifluoroacetic acid and 1.5 ml of trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 96 mg (81%) of the title compound as a blue solid. Mp 123 - 124 ° C. [α] „= -24.6 (c = 0.13, MeOH). FT-MS (m / z) 1159.6271 [M + H] + , 2318.2542 [2M + H] + , 3476.8813 [3M + H] + , 4635.5084 [4M + H] + . g = 2.00779. IR (KBr) 3388, 2959, 1666, 1540, 1494, 1198, 1134, 835, 801,720, 598 cm -1 . Example 70. Preparation of 1,3-dioxo-2- {4'-oxyacetyl- [N w - (Pro-Ala-Lys) -LysArg-Gly-Asp- Phe] phenyl} -4,4,5,5- tetramethylimidazoline (II) [0187] In an ice bath, 169 mg (0.1 mmol) of 1,3-dioxo-2- {4'-oxyacetyl- {N w [Boc-Pro-Ala-Lys (Z) ] -Lys-Arg- (N0 2 ) -Gly-Asp (OBzl) -Phe-OBzl} phenyl} -4,4,5,5tetramethylimidazoline were mixed with 6 ml of trifluoroacetic acid and 1.5 ml of trifluoromethanesulfonic acid, and stirred for 1 h until the starting material disappears as shown by TLC (CHCI 3 : MeOH, 1: 1). The reaction mixture was concentrated under reduced pressure, and the residue was repeatedly washed with anhydrous ethyl ether and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 8 with 25% aqueous ammonia, desalted with Sephadex G10, and then purified on a C18 column. The collected fractions were lyophilized to provide 57/95 mg (81%) of the title compound as a blue solid. Mp 153 - 154 ° C. [afâ = -12.6 (c = 0.16, MeOH). FT-MS (m / z) 1207.6271 [M + H] + , 2414.2542 [2M + H] + , 3620.8813 [3M + H] + , 4827.5084 [4M + H] + . g = 2.00789. IR (KBr) 3385, 2938, 1659, 1541, 1450, 1391, 1251,1126, 963, 841,599, 456 cm -1 . Experimental example 1. Experiments in eliminating the NO radical by compounds 1 to 2 of the present invention [0188] Male Wistar rats weighing 250 to 300 g were fasted for 12 h before the operation with free access to water, and sacrificed by cervical dislocation . Thoracotomy was performed immediately and the thoracic aorta was removed, connective tissues attached to it were dissected, and vessels were cut into 3 to 5 mm aortic rings and placed in a perfusion bath. The bath contained 15 mL of Krebs-Henseleit solution and was maintained at a constant temperature of 37 ° C, where 95% O 2 - 5% CO 2 was charged. The anchor to which the aortic rings were immobilized was connected and a tension transducer, and vasomotion curves were recorded on a double trace recorder on paper at a speed of 1 mm / min. With the static tension adjusted to 1.0 g and 30 min of equilibrium, norepinephrine at a final concentration of 10 ' 8 M was measured to allow the aorta to contract for pre-excitation. Norepinephrine was washed, followed by 30 min of equilibrium, and norepinephrine was added to the bath at a final concentration of 10 ' 8 M. When the contraction tension was constant at a plateau level, 20 pL of normal saline (white), a 20 pL solution of any of the compounds Ia to II in normal saline (at a final concentration of 5χ10 ' 6 M), or 20 pL of NO free radical elimination solution (1,3-dioxo-2- (4' -oxyacetoxy-phenyl) -4,4,5,5tetramethylimidazoline, TMMZ) in normal saline (in a final concentration of 5x10 ' 6 M) were added (in a final concentration of 10' 6 Μ). The ability to eliminate NO from the drugs was expressed as a percentage of acetylcholine inhibition induced vasodilation. The experimental results are shown in Table 1. 58/95 [0189] As shown in the experimental results, la to II were able to inhibit the vasodilation effect of acetylcholine in pieces of vessels by eliminating NO. Such as by binding an ARPAK, GRPAK, RPAK or PAK thrombolytic peptide and a RGDS, RGDV or RGDF target peptide to a free radical scavenger (1,3-dioxo-2 (4'-oxyacetoxy-phenyl) -4, 4,5,5-tetramethylimidazoline, TMMZ) through Lys, 9 compounds had substantially greater activity in inhibiting acetylcholine-induced vasodilation than TMMZ, 2 compounds had the same activity in inhibiting acetylcholine-induced vasodilation as TMMZ, and one compound was less active in inhibiting vasodilation induced by acetylcholine than TMMZ. Among the 12 compounds under evaluation, 4 compounds had a percentage of inhibition greater than 30%, and these 4 compounds were positioned by activity in inhibiting vasodilation induced by acetylcholine as le> Ih> lb> If. This demonstrated that the activity of the TMMZ fraction in eliminating free NO radicals was generally improved by binding the thrombolytic peptide ARPAK, GRPAK, RPAK or PAK and the target peptide RGDS, RGDV or RGDF to the free radical scavenger TMMZ via Lys. Table 1. Percentage of inhibition from 1 to 2 of acetylacoline-induced vasodilation Compounds Inhibition percentage (Mean ± SD%) TMMZ 15.47 ± 2.20 Ia 22.82 ± 3.27 a Ib 35.32 ± 4.74 a Ic 21.78 ± 3.11 a Id 17.60 ± 2.75 D le 41.28 ± 3.27 a If 32.55 ± 2.55 a IG 24.40 ± 3.60 a Ih 37.54 ± 1.84 a li 13.75 ± 2.07 D 1 27.22 ± 2.68 a Ik 11.13 ± 2.92 c II 22.62 ± 3.60 a n = 6; a) p <0.01 vs. TMMZ; b) p> 0.05 vs. TMMZ; c) p <0.05 vs. TMMZ 59/95 Experimental example 2. Experiments in the lysis of the euglobin clot by Compounds 1 to 2 of the present invention [0190] Pig blood was taken and mixed with 3.8% sodium citrate in a volume ratio of 9: 1, immediately centrifuged at 3000 r / min for 10 min, and low platelet plasma was separated. 2 mL of platelet-poor pig plasma and 36 mL of ultrapure water were added to a 50 mL centrifuge tube. In each tube, 0.4 mL of acetic acid (1%) was added and completely mixed, and the tube was placed in a refrigerator at 4 o C for 10 min and then centrifuged at 3000 r / min for 10 min. The centrifuge tubes were inverted, and then the inner wall of the tubes was dried using filter paper after the liquid was drained. The euglobuine concentrates resulting from centrifugation were lyophilized for about 40 min and scraped. About 35 mg of euglobuine was taken and dissolved in 7 ml of borax buffer (pH 9.28). Most of the euglobuine was dissolved after 1 h, in which 0.7 ml of CaCI 2 solution (25 mM) were added and immediately placed on a 10 x 10 cm glass plate with a thickness of about 1 mm. After clot formation, 10 pL of normal saline, or 10 pL of a solution of one of the compounds from 1 to II in normal saline (1 mM) or 10 pL of a solution of urokinase in normal saline (0.8 mg / mL) were pipetted and placed in the clot plate, with an interval between each two drops more than 1.5 cm, and each sample was placed 3 times. The diameter of the clot lysis circle was measured after 4 h, and the readings are listed in Table 2. [0191] As shown in the experimental results, by binding an ARPAK, GRPAK, RPAK or PAK thrombolytic peptide and an RGDS, RGDV or RGDF target peptide to a TMMZ free radical scavenger via Lys, all compounds exhibited lysis activity of euglobulin clot. Table 2. The diameter of euglobulin clot lysis after 4 h of la-ll treatment Compounds Diameter (Mean ± SD mm) 60/95 Normal Saline 2.9 ± 0.6 a urokinase 10.7 ± 0.4 a over there 4.0 ± 0.0 Ib 5.2 ± 0.3 Ic 3.8 ± 0.3 Id 5.2 ± 0.3 le 5.5 ± 0.3 If 4.5 ± 0.5 IG 5.2 ± 0.3 Ih 4.2 ± 0.3 li 4.0 ± 0.0 1 4.0 ± 0.0 Ik 4.5 ± 0.5 II 4.2 ± 0.3 n = 3; a) p <0.01, vs. la-l Experimental example 3. In vitro thrombolysis experiments for compounds 1 to 2 of the present invention [0192] SD rats (male, 350 to 400 g) were anesthetized by intraperitoneal injection of a urethane solution at a dose of 1200 mg / kg. The anesthetized rats were fixed in a supine position, and the right common carotid artery was dissected, stapled to the proximal terminal with an arterial clamp, and sutured through the proximal and distal ends, respectively. The suture at the distal end is clamped tightly by a hemostatic clamp on the skin. Cannulation was performed at the distal end, the arterial clamp was removed, and the whole arterial blood was refilled in a 50 mL container previously treated with silicone oil. 0.8 mL of rat arterial blood was injected into a vertically fixed glass tube (20 mm in length, with an internal diameter of 4 mm and an external diameter of 5 mm, sealed with a rubber stopper at the bottom), in that a stainless steel thrombus immobilization screw was immediately inserted. The thrombus immobilization screw, formed by winding a stainless steel wire having a diameter of 0.2 mm, had a spiral part of 18 mm in length, 15 coils each having a diameter of 1.8 mm, and a rod 7.0 mm in length that was connected to the spiral part and had a question mark shape 61/95 tion. 40 min after the blood was clotted, the rubber cap at the bottom of the glass tube was removed, the stem of the thrombus immobilization screw was cut by forceps, and the thrombus immobilization screw involved in the thrombus was carefully removed from the glass. The screw was then suspended and dipped in triple distilled water to remove excess blood, and accurately weighed after 1 h. The thrombus was suspended in 8 mL of normal saline, or a solution of compounds la-ll in normal saline (at a concentration of 100 nM), or a solution of ARPAK, GRPAK, RPAK or PAK in normal saline (at a concentration of 100 nM), or a solution of urokinase in normal saline (100 lU / mL), then stirred at 37 ° C in a thermostatic shaker (53 r / min), and removed after 2 h and accurately weighed to determine the weight of the thrombus. The difference in thrombus mass before and after administration was calculated, and the results are listed in Table 3. [0193] As shown in the experimental results, by binding a thrombolytic peptide ARPAK, GRPAK, RPAK to PAK and a target peptide RGDS, RGDV or RGDF to a free radical scavenger TMMZ via Lys, all compounds exhibited thrombolytic activity in vitro substantial. Since the activity of Ia to Ic was comparable to that of ARPAK, the activity of Id a If was comparable to that of GRPAK, the activity of Ig a li was comparable to that of RPAK, and the activity of Ij a li was comparable to that of PAK , on the one hand the in vitro thrombolytic activity from 1 to II can be attributed to the activity of the thrombolytic peptide and on the other hand the binding of the ARPAK, GRPAK, RPAK or PAK thrombolytic peptide and the target peptide RGDS, RGDV or RGDF to the free radical eliminator TMMZ through Lys does not kill the activity of the thrombolytic peptide. Table 3. In vitro thrombolytic activity for 2 h of la-11 treatment Compounds Thrombus reduction weight (Mean ± SD mg) Normal Saline 16.67 ± 1.86 a urokinase 58.33 ± 4.08 a ARPAK 26.35 ± 3.10 Ia 28.50 ± 2.59 Ib 28.17 ± 2.31 62/95 Ic 27.33 ± 2.07 GR PAK 15.47 ± 2.61 Id 14.17 ± 3.55 le 14.00 ± 1.41 If 15.29 ± 3.36 RPAK 26.01 ± 3.11 IG 27.83 ± 2.56 Ih 29.33 ± 3.01 li 24.83 ± 1.17 PAK 26.67 ± 3.20 1 26.16 ± 3.15 Ik 25.00 ± 1.54 II 25.83 ± 2.31 n = 6; a) p <0.01, vs. la-ll Experimental example 4. In vivo thrombolysis experiments for compounds 1 to 2 of the present invention [0194] SD rats (male, 220 to 230 g) were anesthetized by intraperitoneal injection of a urethane solution at a dose of 1200 mg / kg. Anesthetized rats were fixed in a supine position, and the right common carotid artery was dissected, stapled and the proximal terminal with an arterial clip, and penetrated with a suture at the proximal and distal ends, respectively. The suture at the distal end is stapled tightly by a hemostatic clamp to the skin. Cannulation was performed at the distal end, the arterial clamp was removed, and about 1 mL of arterial blood was placed in a 1 mL eppendorf. 0.1 ml of rat arterial blood was injected into a vertically fixed glass tube (15 mm in length, with an internal diameter of 2.5 mm and an external diameter of 5.0 mm, sealed with a rubber stopper on the bottom), in which a thrombus immobilization screw made of stainless steel was immediately inserted. The thrombus immobilization screw, formed by winding a stainless steel wire having a diameter of 0.2 mm, had a spiral part of 12 mm in length, 15 rolls each having a diameter of 1.8 mm, and a rod 1.0 mm in length that was connected to the spiral part and had a question mark shape. 15 min after the blood was clotted, the rubber cap on the bottom of the glass tube was removed, the stem of the 63/95 thrombus immobilization screw was cut by forceps, and the thrombus immobilization screw wrapped in thrombus was carefully removed from the glass tube and then accurately weighed. [0195] A bypass cannula was made up of 3 segments. The middle segment was a polyethylene tube having a length of 60.0 mm and an internal diameter of 3.5 mm. The segments and both ends were similar to polyethylene tubes having a length of 100.0 mm, an internal diameter of 1.0 mm and an external diameter of 2.0 mm, a terminal from which it was pulled to form a tip, with an outer diameter of 1.0 mm, which can be inserted into the rat's carotid artery or vein, and the other end of which was covered by a polyethylene tube having a length of 7.0 mm and an outer diameter of 3.5 mm (thickness in order to be inserted in the polyethylene tube of the middle segment). The inner wall of the segment 3 cannula was completely silylated (with 1% silicone oil in ethyl ether). The thrombus immobilization screw involved in the thrombus was placed in the middle segment polyethylene tube, and both ends of the tube covered the thickened ends of the polyethylene tubes. The cannula was filled with a heparin solution in normal saline (50 lU / kg) through the final tip using an injector and was ready for use. The anesthetized rat's trachea was then dissected and tracheal cannulation was performed. The left external carotid vein of the rat was dissected, and sutured through the proximal and distal ends, respectively. An irregular open incision was carefully made in the exposed left external carotid vein, and the tip of the bypass cannula prepared as described above was inserted into a proximal end of the open incision in the left external carotid vein, outside the stem of the thrombus immobilization screw in the segment bypass cannula (which accommodated the accurately heavy thrombus immobolization screw). An amount of heparin in saline (50 lU / kg) was injected through the tip into the other end using an injector. At this point, without removing the injector from the tube 64/95 ethylene, the tube between the injector and the polyethylene tube was clipped with forceps. The blood flow was stopped by stapling the proximal end of the right common carotid artery with an arterial clip, and an irregular open incision was carefully cut through the common carotid artery near the clamp. The injector was removed from the tip of the polyethylene tube, and the tip of the polyethylene tube was then inserted into the proximal end of the open incision in the artery. Both ends of the bypass cannula were fixed to the artery or vein with # 4 sutures. [0196] Normal saline (3 mL / kg), or a urokinase solution in normal saline (at a dose of 20000 lU / kg), or a solution of one of the compounds la-ll in normal saline (at a dose of 0, 1 pmol / kg), or an ARPAK, GRPAK, RPAK or PAK solution in normal saline (at a dose of 0.1 pmol / kg), or an ARPAK, GRPAK, RPAK or PAK solution in normal saline (and a dose of 1 pmol / kg), was connected to a position close to the vein outside the thrombus immobilization screw by using a scalp needle to puncture the bypass cannula (which accommodated the accurately heavy thrombus immobilization screw). The artery clamp was then removed to allow blood to flow from the artery to the vein through the bypass cannula. A rat arteriovenous bypass thrombolysis model was then stabilized. The injector solution was slowly injected into the blood, allowing normal saline (white control), urokinase (positive control), ARPAK, GRPAK, RPAK or PAK (component control), or la-ll to act on the thrombus through the blood circulation in the vein-heart-artery order. The process had the time measured at the beginning of the injection, and the thrombus immobilization screw was removed from the bypass cannula after 1 h and accurately weighed. The difference in mass of the thrombus immobilization screw in the rat bypass cannula before and after administration was determined, and the experimental results are shown in Table 4. [0197] As shown in the experimental results, not only did the compounds la-lc, obtained by binding an ARPAK, GRPAK, RPAK or thrombolytic peptide 65/95 PAK and a target peptide RGDS, RGDV or RGDF to a free radical scavenger TMMZ through Lys, exhibit thrombolytic activity at a dose of 0.1 pmol / kg, the potency of its activity was also comparable to that of the corresponding thrombolytic peptide ARPAK, GRPAK, RPAK or PAK in a dose of 1 pmol / kg. Like, by binding the thrombolytic peptide ARPAK, GRPAK, RPAK or PAK and the target peptide RGDS, RGDV or RGDF to the free radical scavenger TMMZ via Lys, the effective dose can be decreased by 10 times. Table 4. In vivo thrombolytic activity of la-ll Compounds Weight reduction in the thrombus (Mean ± SD mg) Normal Saline 11.05 ± 1.51 a urokinase 18.02 ± 2.32 a ARPAK 15.20 ± 2.55 Ia 15.39 ± 3.19 Ib 14.35 ± 2.95 Ic 15.79 ± 3.07 GRPAK 15.47 ± 2.61 Id 14.17 ± 3.55 le 14.00 ± 1.41 If 15.29 ± 3.36 RPAK 15.67 ± 2.61 IG 16.35 ± 2.42 Ih 15.37 ± 1.82 li 15.73 ± 2.95 PAK 15.00 ± 2.61 1 14.89 ± 1.84 Ik 15.47 ± 2.61 II 16.21 ± 2.84 n = 10; a) p <0.01 vs. la-ll Experimental example 5. In vivo anti-thrombus experiments for compounds 1 to 2 of the present invention [0198] SD rats (male, 220 to 230 g) were randomly divided with 11 rats in each group. The rats were fed in a resting state for 1 day and fasted for one night. Rats were given normal saline (at a dose of 3 mL / kg), a solution of one of the compounds la-ll in normal saline (at a dose of 0.1 pmol / kg), a solution of the RGDS targeting peptide, 66/95 RGDV or RGDF in normal saline (in a dose of 10 pmol / kg), or aspirin (in a dose of 33 mg / kg) per gavage. After 30 min, the rats were anesthetized with a 20% urethane solution, and the right carotid artery and left carotid vein were dissected. One cannula was filled with sodium heparin in normal saline, and one end was inserted into the left vein, while the other end was injected with a certain amount of sodium heparin for anticoagulation with an injector and then inserted into the right artery. Blood flowed from the right artery to the left vein through the polyethylene tube, and the thread connected with a thrombus was taken after 15 min and the weight of it was recorded. The weight of the wet thrombus was determined by subtracting the weight of the thread from the total weight. The results are shown in Table 5. [0199] As shown in the experimental results, not only did compounds la-lc, obtained by binding an ARPAK, GRPAK, RPAK or PAK thrombolytic peptide and an RGDS, RGDV or RGDF targeting peptide to a TMMZ free radical scavenger Lys, exhibit anti-thrombus activity at an oral dose of 0.1 pmol / kg, the potency of their activity was also comparable to that of the target peptide RGDS, RGDV or RGDF at a dose of 10 pmol / kg. As, by binding the thrombolytic peptide ARPAK, GRPAK, RPAK or PAK and the targeting peptide RGDS, RGDV, or RGDF to the free radical eliminator TMMZ via Lys, the effective dose can be decreased by 100 times. [0200] Table 5. In vivo anti-thrombus activity of la-ll _________ Compounds Wet thrombus weight (Mean ± SD mg) normal saline 27.38 ± 2.62 a aspirin 12.85 ± 2.49 a RGDS 20.02 ± 2.35 RGDV 21.26 ± 2.07 RGDF 19.55 ± 2.21 Ia 24.32 ± 2.10 Ib 20.14 ± 2.45 Ic 20.50 ± 2.26 Id 19.46 ± 1.84 67/95 le 16.92 ± 1.53 If 17.99 ± 2.47 IG 17.89 ± 2.05 Ih 18.24 ± 1.89 li 17.79 ± 2.02 1 19.45 ± 1.79 Ik 22.25 ± 2.25 II 19.32 ± 2.56 n = 11; a) p <0.01 vs. la-ll [0201] Establishment of animal models for evaluating the efficacy of compounds according to the present invention in the treatment of patients with stroke [0202] (1) The experimental rat protocol described here was according to the Geneva guide in the experiments animals and approved by the university ethical committee. Clean healthy male SD rats, weighing 280 to 305 g, were purchased from Vital River Laboratories of Experimental Animals. These rats were randomly used to prepare a thrombus or establish stroke models. [0203] (2) A 10% chloral hydrate solution was injected intraperitoneally into the SD rats at a dose of 400 mg / kg body weight for anesthesia. The carotid artery was dissected, 15 mL of fresh arterial blood was removed, and 10 μL aliquots were then added in 1.5 mL EP flasks. The formed thrombus was kept at RT for 2 h and then in a -20 ° C refrigerator for 22 h. When used, 0.5 mL of saline was added to the thrombus that was broken by using a glass rod, in order to prepare a suspension solution of thrombus homogenate, with a volume of about 0.1 mm 3 for each piece of thrombus. [0204] (3) A 10% chloral hydrate solution was injected intraperitoneally into SD rats at a dose of 400 mg / kg body weight for anesthesia. The carotid artery was dissected, 15 ml of fresh arterial blood was removed and aliquots of 10 pL each were then added in 1.5 ml EP flasks. The formed thrombus was first maintained at RT for 24 h. When used, 1.5 mL of saline was added to the thrombus which was broken by the use of a glass stem, in order to prepare 68/95 to produce a thrombus homogenate suspension solution, with a volume of about 0.1 mm 3 for each piece of thrombus. [0205] (4) A 10% chloral hydrate solution was injected intraperitoneally into male SD rats at a dose of 400 mg / kg body weight for anesthesia. A longitudinal open incision was made in the center of the neck, and the trunk of the right common carotid artery was dissected (about 3 cm in length). Branches of the external carotid artery were each dissected and ligated at the hyode level, and the internal carotid artery was dissected in the swollen part of the neck. The open incisions in the internal carotid artery and the proximal end of the common carotid artery were occluded respectively with non-invasive arterial clamps, and the distal end of the external carotid artery was ligated. A catheter containing 0.5 mL of thrombus suspension in normal saline was inserted into the trunk of the external carotid artery. At the same time when the clamp on the internal carotid artery was released, 0.5 mL of the thrombus suspension in normal saline in the catheter slowly flowed from the external carotid artery to its proximal termination, and then injected into the arteries in the brain through the carotid artery internal. Subsequently, the proximal termination of the internal carotid artery was ligated, arterial clamps on the internal carotid artery and the common carotid artery were released, and the blood flow was restored. The main external jugular vein was dissected, and normal saline (white control) or a solution of the compounds of the present invention in normal saline was infused through the external jugular vein. After the wound was sewn, 20,000 IU of penicility was injected intramuscularly to prevent infection. The model of immediate treatment after the onset of the stroke was then established. [0206] (5) A 10% chloral hydrate solution was injected intraperitoneally into male SD rats at a dose of 400 mg / kg body weight for anesthesia. An open longitudinal incision was made in the center of the neck, and the trunk of the right common carotid artery was dissected (about 3 cm in length). Ramifications 69/95 of the external carotid artery were each dissected and connected at the hyoid level, and the internal carotid artery was dissected in the swollen part of the neck. The open incision in the internal carotid artery and the proximal end of the common carotid artery were occluded with non-invasive arterial clamps, respectively, and the distal end of the external carotid artery was ligated. A catheter containing 0.5 mL of thrombus suspension in normal saline was inserted into the trunk of the external carotid artery. At the same time, when the clamp on the internal carotid artery was released, 0.5 mL of the thrombus suspension in normal saline in the catheter slowly flowed from the external carotid artery to its proximal terminal, and then was injected into the arteries in the brain through the internal carotid artery. Subsequently, the proximal termination of the carotid artery was ligated, arterial clamps on the internal carotid artery and the common carotid artery were released, and blood flow was restored. After the wound was stitched, 20,000 IU of penicillin was injected intramuscularly to prevent infection. After 4 h, 6 h or 24 h, normal saline (white control) or a solution of the compounds of the present invention in normal saline was infused through the tail vein. The 4 h, 6 h and 24 h rat models after the start of the stroke treatment were then established. [02071 Establishment of animal models for evaluating the effectiveness of the compounds according to the present invention after 4 h, 6 h, and 24 h from the start of the stroke [0208] (1) Efficacy after immediate treatment, 4 h after the start of the treatment, and 6 h after start of treatment of the stroke of rats with the compounds according to the present invention means the result of the classification of the rats' behavior 24 h after the rats regain consciousness. Behaviors include how to walk, the degree of tilting the eyelid of the right eye, the degree of tightness to the tail, muscle tension, the degree of inclination of the head, the supporting strength of the limbs, and the state of death. 70/95 [0209] (2) The efficacy at 24 h after initiation of the stroke treatment in rats with the compounds according to the present invention means the result of observing the behavior of the rats 24 h after the rats regain consciousness. Behaviors include how to walk, the degree of tilting the eyelid of the right eye, the degree of tightness to the tail, muscle tension, the degree of inclination of the head, the supporting strength of the limbs, and the state of death. [0210] (3) The efficacy in rats with stroke treatments once with the compound of the present invention was compared to the effectiveness in rats with stroke treatments once with saline. [0211] (4) Rats with stroke with continuous treatment were injected with the compounds of the present invention in normal saline every 24 h through the tail vein. The next day, the videos were recorded, and a comparison was made between the recorded results. [0212] Test results for compounds 1 to 2 according to the present invention in the above animal models are as follows: Experimental example 6. Experiments in rats that received immediate treatment after stroke initiated with compounds 1 to 2 of the present invention [0213] The in vivo anti-stroke activity of the present invention was represented by a classification of neural function, with a lower classification indicating more activity high. A 10% chloral hydrate solution (400 mg / kg) was injected intraperitoneally into male SD rats (250-300 g) for anesthesia. An open incision of 2 cm in length was longitudinally made slightly in the right to the center of the neck, and the trunk of the right common carotid artery, external carotid artery and internal carotid artery were dissected along with the margin of the internal lateral sternocleidomastoid muscles. The open incisions in the internal carotid artery and the proximal end of the common carotid artery were occluded with non-invasive arterial clamps, respectively. A small open incision was made through the 71/95 external carotid artery, and the distal end of the external carotid artery was ligated. The arterial clamp at the proximal end of the external carotid artery was released, and 10 pL of blood was removed before the proximal end of the common carotid artery was again occluded with the noninvasive arterial clamp. The 10 pL of blood removed was placed in a 1 mL EP flask and held in RT for 30 min blood clotting, and then transferred to a -20 ° C refrigerator for 1 h to allow clotting. After 1 h, blood clots were removed, in which 1 mL of saline was added, and then broken into uniform microthrombi using a steel spatula. The suspension with microthrombi was then transferred to a 1 ml injector until use. At the same time when the clamp in the rat's internal carotid artery was released, 1 ml of thrombus suspension in the injector was slowly injected from the rat's external carotid artery to its proximal termination, and the suspension was injected into the rat's brain through the internal carotid artery. Subsequently, the proximal termination of the external carotid artery was ligated, arterial clamps on the internal carotid artery and the common carotid artery were released, and blood flow was restored. The rats' common jugular vein was dissected. The vein was immediately ligated, 3 drops of penicillin were dripped at the wound site, the wound was stitched, and the animals were the sham operation group. Or injection of urokinase in normal saline (positive control group, in a dose of 20000 lU / kg), normal saline (white control group, in a dose of 3 mL / kg), TMMZ in normal saline (component control group, in a dose of 1 pmol / kg), an ARPAK, GRPAK, RPAK or PAK thrombolytic peptide in normal saline (component control group, in a dose of 1 pmol / kg), or one of the compounds la-ll in normal saline (in a dose 0.1 pmol / kg) be performed. 24 h after the rats were awake, the degree of damage to neural function was assessed by the Zealonga method. A rating of 0 indicates no sign of loss in neural function, 1 indicated the front limbs on the undamaged side may not be able to stretch, 2 indicated the direction of walking in the 72/95 undamaged side, 3 indicated walking behind the tail in circles to the undamaged side, 4 indicated non-voluntary walking with disturbance of consciousness, and 5 indicated death. The experimental results are shown in Table 6. [0214] As shown in the experimental results, the la-lc compounds, obtained by binding an ARPAK, GRPAK, RPAK or PAK thrombolytic peptide and a targeting RGDS, RGDV or RGDF peptide to a TMMZ free radical scavenger via Lys, exhibited activity anti-stroke at a dose of 0.1 pmol / kg, although urokinase does not exhibit anti-stroke activity at a dose of 20000 lU / kg. Similarly, the thrombolytic peptide ARPAK, GRPAK, RPAK or PAK do not exhibit anti-spill activity at a dose of 1 pmol / kg. As, by binding the thrombolytic peptide ARPAK, GRPAK, RPAK or PAK and the peptide with targeting RGDS, RGDV or EGDF to the free radical scavenger TMMZ via Lys, the compounds were provided with an anti-spill function. Especially, at a dose of 1 pmol / kg, 4 compounds had anti-stroke activity comparable to those of urokinase at a dose of 20000 lU / kg, and 8 compounds had anti-stroke activity notably greater than urokinase at a dose of 20000 lU / kg. Table 6. La-lc in vivo anti-spill activity Compound Classification of neural function(Mean ± SD) normal saline 3.07 ± 1.04 urokinase 1.90 ± 1.37 a TMMZ 2.83 ± 0.75 a ARPAK 2.21 ± 0.94 a Ia 1.00 ± 1.01 ° Ib 0.56 ± 1.01 c Ic 0.89 ± 1.36 c GRPAK 2.38 ± 0.92 a Id 1.22 ± 1.32 0 le 0.44 ± 1.01 c If 0.60 ± 0.84 c RPAK 2.38 ± 0.97 a IG 1.00 ± 1.19 0 Ih 1.33 ± 1.22 D li 0.87 ± 1.05 c 73/95 PAK 2.42 ± 0.95 a 1 0.90 ± 1.10 c Ik 0.56 ± 0.53 c II 0.50 ± 0.53 c n = 10; a) p> 0.05 vs. normal saline; b) p> 0.05 vs. urokinase; p <0.01 vs. normal saline; c) p <0.01 vs. normal saline or urokinase Experimental example 7. Experiments on the volume of cerebral infarction in rats that received immediate treatment with compounds a to II of the present invention after the onset of stroke [0215] After the rats were awake for 24 h and evaluated for their degree of damage to neural function in the Experimental example 6, they were anesthetized with urethane followed by immediate decapitation and removal of the brain. Brain tissues were kept in a -20 ° C refrigerator for 2 h, and coronal sections of about 2 mm were successively cut from the prefrontal termination for a total of 6 sections, and then placed in a TTC 2 solution % to incubate in the dark at 37 ° C for 30 min. The color change in the brain sections was observed: normal brain tissues were stained red by TTC, while ischemic brain tissues, that is, brain tissue with infractions, appeared to be a white color. Photographs were taken using a digital camera and processed using the SPSS statistical program, and the volume of infarction in brain tissues and the volume of normal brain tissues in the coronal sections were calculated. The experimental results are shown in Table 7. [0216] As shown in the experimental results, not only do the compounds la-lc, obtained by binding a thrombolytic peptide ASPAK, GRPAK, RPAK or PAK and a peptide targeting RGDS, RGDV or RGDF to a TMMZ free radical scavenger through Lys, exhibited an effect in reducing the volume of cerebral infarction in rats with stroke at a dose of 0.1 pmol / kg, such an effect was substantially more potent than that of urokinase at a dose of 20000 74/95 lU / kg. Table 7. Volume of cerebral infarction in rats with stroke treated with Compounds Percentage of infarction volume (Mean ± SD%) normal saline 22.92 ± 2.74 urokinase 11.00 ± 2.42 0 TMMZ 22.96 ± 2.43 a ARPAK 22.00 ± 2.20 a Ia 7.21 ± 0.82 Ib 7.13 ± 0.83 Ic 7.40 ± 1.65 GRPAK 21.77 ± 2.46 a Id 8.21 ± 1.91 le 6.44 ± 1.51 If 7.47 ± 1.31 RPAK 22.11 ± 2.25 a IG 6.40 ± 0.28 Ih 7.35 ± 1.14 li 7.06 ± 1.08 PAK 22.07 ± 2.40 a 1 6.84 ± 0.82 Ik 7.86 ± 1.02 II 6.56 ± 0.41 n = 10; a) p> 0.05, vs. normal saline; b) p <0.01 vs. normal saline and la-lc Experimental example 8: Experiments in rats that received immediate treatment with different doses of compound l and of the present invention after the start of the stroke [0217] Any analysis and comparison of all results in the present invention, compound l and was used as the representative, in order to demonstrate the dose-dependent therapeutic effect exhibited by compounds 1 to 2 in the above experiments. It should be noted that other compounds from la to II may achieve similar dose-dependent therapeutic effect as compound le, provided that other compounds from la to II achieve the same effect as compound le in free radical elimination NO, euglobulin clot lysis, thrombolysis , anti-thrombus action, and treatment of strokes in rats. 75/95 [0218] A 10% chloral hydrate solution (400 mg / kg) was injected intraperitoneally into male SD rats (250 to 300 g) for anesthesia. An incision of about 2 cm in length was made longitudinally slightly on the right to the center of the neck, and the common right carotid artery, external carotid artery and internal carotid artery were dissected along with the internal lateral margin of sternocleidomastoid muscles. The open incision in the carotid artery and the proximal end of the common carotid artery were occluded with non-invasive arterial clamps, respectively. A small incision was made in the external carotid artery, and the distal end of the external carotid artery was ligated. The arterial clamp at the proximal end of the external carotid artery was released, and 10 pL of blood was removed before the proximal end of the common external carotid artery was occluded with a non-invasive arterial clamp. The 10 pL blood draw was placed in a 1 ml EP vial and held at RT for 30 min until blood clotting, and then transferred to a refrigerator at -20 ° C for 1 h to allow solid clotting. After 1 h, blood clots were removed, added in 1 mL of saline, and then broken into relatively uniform microthrombi using a steel spatula. The suspension of microthrombi was then transferred in a 1 mL injector until use. At the same time when the clamp on the rat's internal carotid artery was released, 1 ml of thrombus suspension in the injector was slowly injected from the rat's external carotid artery to its proximal termination, and then it was injected into the rat's brain through the artery internal carotid artery. Subsequently, the proximal termination of the external carotid artery was ligated, arterial clamps on the internal carotid artery and the common carotid artery were released, and blood flow was restored. Injection of urokinase in normal saline (positive control group, in a dose of 20000 lU / kg), tPA in normal saline (positive control group, in a dose of 3 mg / kg), normal saline (white control group, in one dose 3 mL / kg), or compound 1 in normal saline (in a dose of 1 pmol / kg, 0.1 pmol / kg or 0.1 pmol / kg) 76/95 was carried out. 24 h after the rats were awake, the degree of damage to neural function was assessed by the Zealonga method. A rating of 0 indicated no signs of loss in neural function, 1 indicated that the frontal limbs on the undamaged side may not stretch, 2 indicated the direction of walking on the undamaged side, 3 indicated walking behind the tail itself in circles to the side undamaged, 4 indicated non-voluntary walking with a consciousness disorder, and 5 indicated death. The experimental results are shown in Table 8. As shown in the results, in rats receiving immediate treatment after the start of the spill with 1 µmol / kg, 0.1 µmol / kg and 0.01 µmol / kg of compound 1, the percentage of rats with a neural classification of 0 were 60%, 30%, and 0%, respectively; and the percentage of rats with a neural function rating of 1 was 20%, 30%, and 10%, respectively. So, this shows that the anti-spill activity of compound 1 was dependent. In addition, in stroke mice treated with 20,000 lU / kg urokinase and 3 mg / kg tPA, the percentage of mice with a neural function rating of 0 was 10% and 40%, respectively, and the percentage of mice with a rating of neural function neural function of 1 was 50% and 10%, respectively; in comparison, the effectiveness of 1 µmol / kg and 0.1 µmol / kg of compound 1 was obviously higher. Table 8. In vivo anti-spill activity of compound l and of the present invention at different doses Compounds Classifications of daily neural function (Mean ± SD) and number of rats classified Rating 0 Classification 1 Classification 2 Classification 3 Classification 4 Rating 5 normal saline 0 2 3 5 1 0 urokinase 1 5 0 3 1 0 tPA 4 1 1 3 1 0 I and 1 pnmol / kg 6 2 0 2 0 0 100 nmol / k g 3 3 0 3 1 0 77/95 10 nmol / k g 0 1 6 1 1 0 η = 10; a) ρ <0.01 vs. normal saline Experimental example 9. Experiments in rats receiving 6 successive treatments with 1 pmol / kg of compound l of the present invention 4 hours after the start of the stroke [0219] Efficacy was represented by neural function classifications, and a lower index indicates greater efficacy. A 10% chloral hydrate solution was injected intraperitoneally into male SD rats at a dose of 400 mg / kg by body weight for anesthesia. A longitudinal incision was made in the center of the neck, and the trunk of the right common carotid artery was dissected (about 3 cm in length). Branches of the external carotid artery were each dissected and connected at the hyoid level, and the internal carotid artery was dissected in the swollen neck. The open incision in the internal carotid artery and the proximal end of the common carotid artery were occluded with non-invasive arterial clamps, respectively, and the distal end of the external carotid artery was ligated. A catheter containing 0.5 mL of the thrombus suspension in normal saline was inserted into the trunk of the external carotid artery. At the same time when the clamp on the internal carotid artery was released, 0.5 ml of the thrombus suspension in normal saline slowly flowed into the catheter from the external carotid artery to its proximal termination and was then injected into the arteries in the brain through the carotid artery internal. Subsequently, the proximal termination of the carotid artery was ligated, arterial clamps on the internal carotid artery and the common carotid artery were released, and blood flow was restored. After the wound was sewn, 20,000 IU of penicillin was injected intramuscularly to prevent infection. After 4 h, compound le in normal saline (in a dose of 1 pmol / kg, n = 11), urokinase in normal saline (in a dose of 20000 lU / kg, n = 6) or tPA in normal saline (in a dose of 3 mg / kg, n = 6) was infused through the tail vein. Infusion of compound le in saline 78/95 normal through the rat's tail vein was performed once a day for 6 consecutive days, observed for 7 days. The rats were compared to themselves each day, and assessed for degree of damage to neural function by the Zealonga method. Alternatively, urokinase infusion in normal saline through the rat's tail vein was performed once a day for two consecutive days, the rats were compared to themselves each day, and assessed for the degree of damage to neural function by the Zealonga method . Alternatively, infusion of tPA in normal saline through the rat's tail vein was performed once a day for two consecutive days, the rats were compared to themselves each day, and assessed for the degree of damage to neural function by the Zealonga method . A rating of 0 indicated no signs of loss in neural function, 1 indicated that the frontal limbs on the undamaged side may not stretch, 2 indicated the direction of walking on the undamaged side, 3 indicated walking behind the tail itself in circles to the side undamaged, 4 indicated non-voluntary walking with a consciousness disorder, and 5 indicated death. The experimental results are shown in Tables 9-1,9-2 and 9-3. [0220] The data in Table 9-1 demonstrated that in rats that received treatment 4 h from the start of the stroke with a dose of 11 pmol / kg of compound le every day for 6 consecutive days, excluding one that accidentally died in the day 2, 8 out of 10 remaining rats recovered had no sign of loss of neural function while the rest of the 2 rats had only the sign of slight loss in neural function. Therefore, compound 1 exhibited a therapeutic effect at a dose of 1 pmol / kg in stroke beyond the gold treatment window. Table 9-1. Efficacy in rats receiving treatment with 1 pmol / kg of compound of the present invention 4 h after the start of the stroke__________________________ Sorting Time Classification of daily neural function (Mean ± SD) and number of rats classified Rating 0 Classification 1 Classification 2 Classification 3 Classification 4 Rating 5 Day 1 1 mouse 4 mice 4 mice 1 mouse 1 mouse 0 Day 2 3 mice 5 mice 1 mouse 1 mouse 0 1 mouse 79/95 Day 3 5 mice 5 mice 0 0 0 0 Day 4 7 mice 3 mice 0 0 0 0 Day 5 8 mice 2 mice 0 0 0 0 6th 8 mice 2 mice 0 0 0 0 Day 7 8 mice 2 mice 0 0 0 0 [0221] The data in Table 9-2 demonstrated that, in rats that received treatment for 4 h after the onset of stroke with a dose of 20000 lU / kg of urokinase each day, 2 out of 6 rats died within 48 h. Under autopsy on the dead rats, both showed hemorrhage in internal organs, particularly severe bleeding in the lungs. Then, the dose regimen was discontinued after the two doses. No rat recovered after receiving two doses showed a sign of loss in neural function or had only a sign of slight loss in neural function. Table 9-2. Effective in rats receiving treatment with 20,000 lU / kg of uroquinse 4 h after onset of stroke Sorting time Classification of daily neural function (Mean ± SD) and number of rats classified Rating 0 Classification 1 Classification 2 Classification 3 Classification 4 Rating 5 Day 1 2 mice 3 mice1 mouse Day 2 3 mice 1 mouse1 mouse [0222] The data in Table 9-3 demonstrated that, in rats that received treatment 4 h after the start of the stroke with a dose of 3 mg / kg of tPA each day, 1 of 6 rats died within 24 h. At autopsy on the dead rat, bleeding in internal organs was demonstrated, particularly severe bleeding in the lungs. Then, the dose regimen was discontinued after two doses. No rat recovered after receiving two doses had a sign of loss of neural function, and 2 recovered rats had only the sign of slight loss in neural function. Table 9-3. Efficacy in rats receiving treatment with 3 mg / kg tPA 4 h after onset of stroke Sorting time Classification of daily neural function (Mean ± SD) and number of rats classified Classified Classified Classified Classified Classified Classified 80/95 cation 0 cation 1 cation 2 cation 3 cation 4 cation 5 Day 1 2 mice 3 mice1 mouse Day 22 mice 2 mice 1 mouse [0223] In summary of the data in Table 9-1, 9-2 and 9-3, even for rats that received treatment 4 h after the start of the stroke for two consecutive days, compound l at a dose of 1 pmol / kg showed much higher efficacy than urokinase at a dose of 20000 lU / kg and tPA at a dose of 3 mg / kg. [0224] Experimental example 10. Experiments in rats receiving 6 successive treatments with 1 pmol / kg of compound l of the present invention 6 h after the onset of stroke [0225] Efficacy was represented by neural function ratings, and a lower rating indicates greater effectiveness. A 10% chloral hydrate solution was injected intraperitoneally into male SD rats at a dose of 400 mg / kg of body weight for anesthesia. A longitudinal opening incision was made in the center of the neck, and the trunk of the right common carotid artery was dissected (about 3 in length). Branches of the external carotid artery were dissected and connected at the hoide level, and the internal carotid artery was dissected in the edemacinated part of the neck. The open incision in the internal carotid artery and the proximal end of the common carotid artery were occluded with non-invasive arterial clamps, respectively, and the distal end of the external carotid artery was ligated. A catheter containing 0.5 mL of thrombus suspension in normal saline was inserted into the trunk of the external carotid artery. At the same time when the clamp on the internal carotid artery was released, 0.5 ml of thrombus suspension in normal saline slowly flowed into the catheter from the external carotid artery to its proximal terminal, and then was injected into arteries in the brain through the artery internal carotid. Subsequently, the proximal end of the carotid artery was ligated, arterial clamps on the internal carotid artery and the common carotid artery were released, and the blood flow was 81/95 restored. After the wound was sewn, 20,000 IU of penicillin was injected intramuscularly to prevent infection. After 6 h compound le in normal saline (in a dose of 1 pmol / kg, n = 11), urokinase in normal saline (in a dose of 20000 lU / kg, n = 6) or tPA in normal saline (in a dose 3 mg / kg, n = 6) was infused through the tail vein. Infusion of compound le in normal saline through the tail vein was performed once a day for 6 consecutive days, observed for 7 days. The rats were compared to them each day, and assessed for the degree of damage to neural function by the Zealonga method. Alternatively, infusion of urokinase in normal saline through the tail vein was performed once a day for two consecutive days, the rats were compared to them each day, and assessed for the degree of damage to neural function by the Zealonga method. Alternatively, infusion of tPA in normal saline through the rat's tail vein was performed once a day for two consecutive days, the rats were compared to them each day, and assessed for the degree of damage to neural function by the Zealonga method. A rating of 0 indicated no signs of loss in neural function, 1 indicated that the frontal limbs on the undamaged side may not stretch, 2 indicated the direction of walking on the undamaged side, 3 indicated walking behind the tail itself in circles to the side undamaged, 4 indicated non-voluntary walking with a consciousness disorder, and 5 indicated death. The experimental results are shown in Tables 10-1, 10-2 and 10-3. [0226] The data in Table 10-1 demonstrated that in rats that received treatment 6 h after the start of the stroke with a dose of 1 1 pmol / kg of compound l each day for 6 consecutive days, excluding two that accidentally die in the day 2, 2 of the 9 remaining rats recovered had no sign of loss of neural function, one recovered rat had only the sign of slight loss of neural function, and 6 showed the sign of walking behind the tail in circles towards the side not damaged. So compound 1 exhibited a therapeutic effect at a dose of 1 pmol / kg 82/95 in a spill beyond the gold treatment window. Table 10-1. Efficacy in rats receiving treatment with 11 pmol / kg of post le d this invention 6 h after the start of the spill Sorting Time Classification of daily neural function (Mean ± SD) and number of rats classified Rating 0 Classification 1 Classification 2 Classification 3 Classification 4 Rating 5 Day 1 0 3 mice 5 mice 2 mice 1 mouse 0 Day 2 0 2 mice 2 mice 4 mice 1 mouse 2 mice Day 3 0 2 mice 4 mice 2 mice 1 mouse 0 Day 4 1 mouse 1 mouse 2 mice 4 mice 0 0 Day 5 1 mouse 1 mouse 2 mice 4 mice 0 0 6th 2 mice 1 mouse 1 mouse 4 mice 1 mouse 0 Day 7 2 mice 1 mouse 0 6 mice 0 0 [0227] The data in Table 10-2 demonstrated that, in rats that received treatment 6 h after the start of the stroke with a dose of 20000 lU / kg of urokinase each day, 4 out of 6 rats died within 24 h. At autopsy on the dead rats, all showed hemorrhage in the internal organs, particularly severe bleeding in the lungs. Then, the dose regimen was discontinued after two doses. A rat recovered after receiving the doses had no sign of loss of neural function, and a rat showed an end of involuntary walking with disturbed consciousness. Table 10-2. Efficacy in rats receiving treatment with 20,000 lU / kg of uroquinse 6 h after onset of stroke Time of scoring Classification of daily neural function (Mean ± SD) and number of rats classified Rating 0 Classification 1 Classification 2 Classification 3 Classification 4 Rating 5 Day 11 mouse 1 mouse 4 mice Day 2 1 mouse 1 mouse [0228] The data in Table 10-3 demonstrated that, in rats that received treatment 6 h after the start of the stroke with a dose of 3 mg / kg of tPA each day, 2 of 6 rats died within 24 h. At autopsy on the dead rats, all showed hemorrhage in the internal organs, particularly severe bleeding in the lungs. Then, the dose regimen was discontinued after two doses. No mouse 83/95 recovered after receiving two doses had a sign of loss of neural function, 2 recovered rats had only the sign of slight loss of neural function, one rat showed the sign of walking behind his tail in circles towards the undamaged side, and a rat showed the sign of involuntary walking with disturbed consciousness. Table 10-3. Efficacy in rats receiving treatment with 3 mg / kg tPA 6 h after onset of stroke Sorting Time Classification of daily neural function (Mean ± SD) and number of rats classifiedRating 0 Classification 1 Classification 2 Classification 3 Classification 4 Rating 5 Day 11 mouse 1 mouse 1 mouse 1 mouse 2 mice Day 22 mice1 mouse 1 mouse [0229] In summary of the data in Table 10-1, 10-2 and 10-3, even for rats that received treatment 6 h after the start of the stroke for two consecutive days, compound l at a dose of 1 pmol / kg showed much more effective than urokinase at a dose of 20000 lU / kg and tPA at a dose of 3 mg / kg. Experimental example 11. Experiments in rats receiving treatments 6 h after the start of the spillage with compound l of the present invention at an initial dose of 5 pmol / kg and 5 subsequent doses of 2 pmol / kg each [0230] Efficacy was represented by classifications neural function, and a lower rating indicates greater efficacy. A 10% chloral hydrate solution was injected intraperitoneally into male SD rats at a dose of 400 mg / kg body weight for anesthesia. A longitudinal open incision was made in the center of the neck, and the trunk of the right common carotid artery was dissected (about 3 cm in length). Branches of the external carotid artery were each dissected and connected at the hyoid level, and the internal carotid artery was dissected in the swollen part of the neck. The open incision in the internal carotid artery and the proximal end of the common carotid artery were occluded with arterial clamps, respectively 84/95 non-invasive, and the distal termination of the external carotid artery was ligated. A catheter containing 0.5 mL of thrombus suspension in normal saline was inserted into the trunk of the external carotid artery. At the same time when the clamp on the internal carotid artery was released, 0.5 mL of the thrombus suspension in normal saline slowly flowed into the catheter from the external carotid artery to its proximal terminal, and was then injected into arteries in the brain through the artery internal carotid artery. Subsequently, the proximal end of the carotid artery was ligated, arterial clamps on the internal carotid artery and the common carotid artery were released, and blood flow was restored. After the wound was sewn, 20,000 IU of penicillin was injected intramuscularly for prevention from the injection. After 6 h, compound 1 in normal saline (at an initial dose of 5 pmol / kg, n = 12) was infused through the tail vein. Then, infusion of compound le in normal saline (at a dose of 2 pmol / kg, n = 12) through the rat's tail vein was performed once a day for 6 consecutive days, observed for 7 days. The rats were compared to themselves each day, and assessed for the degree of damage to neural function by the Zealonga method. A rating of 0 indicated no signs of loss in neural function, 1 indicated that the frontal limbs on the undamaged side may not stretch, 2 indicated the direction of walking on the undamaged side, 3 indicated walking behind the tail itself in circles to the side undamaged, 4 indicated non-voluntary walking with a consciousness disorder, and 5 indicated death. The experimental results are shown in Table 11. [0231] The data in Table 11 demonstrated that efficacy was shown in rats that received treatment 6 h after the start of the stroke with a dose of 5 pmol / kg of compound l and on day 1 and a dose of 2 pmol / kg of compound le per day for the following 5 days. Among the 12 rats that received the treatment, two were killed, while 6 of the 10 recovered remaining rats had no sign of loss of neural function, two had only the sign of slight loss of neural function, one showed the 85/95 sign walks towards the undamaged side, and one showed the sign to walk behind the tail itself in circles towards the undamaged side. Therefore, continuous treatment with compound I showed a therapeutic effect on stroke beyond the gold treatment window. Table 11. Efficacy in rats receiving treatment with compound l and of the present invention 6 h after the start of the stroke______________________________ Mouse No. Classil tion of daily neural function (Mean ± SD) Day 1 Day 2 Day 3 Day 4 Day 5 6th Day 7 1 1 1 0 0 0 0 0 2 1 0 0 0 0 0 0 3 3 1 5 4 2 1 1 0 0 0 0 5 0 0 0 0 0 0 0 6 2 2 1 0 0 0 0 7 5 8 2 1 1 1 1 1 1 9 0 0 0 0 0 0 0 10 4 3 3 2 2 2 2 11 3 3 3 2 1 1 1 12 1 1 4 3 3 3 3 Experimental example 12: Experiment on rats receiving treatments 24 h after the start of the spillage with compound l of the present invention at an initial dosage of 5 pmol / kg and 5 subsequent doses of 2 pmol / kg each [0232] Efficacy was represented by classifications neural function, and a lower rating indicates greater efficacy. A 10% chloral hydrate solution was injected intraperitoneally into male SD rats at a dose of 400 mg / kg of body weight for anesthesia. A longitudinal open incision was made in the center of the neck, and the trunk of the right common carotid artery was dissected (about 3 cm in length). Branches of the external carotid artery were each dissected and connected at the hoide level, and the internal carotid artery was dissected in the swollen part of the neck. The open incisions in the internal carotid artery and the proximal end of the common carotid artery were occluded with non-invasive arterial clamps, respectively, and the distal end of the external carotid artery was ligated. A catheter 86/95 containing 0.5 mL of thrombus suspension in normal saline was inserted into the trunk of the external carotid artery. At the same time when the clamp on the internal carotid artery was released, 0.5 mL of the thrombus suspension in normal saline slowly flowed into the catheter from the external carotid artery to its proxinal termination, and then was injected into arteries in the brain through the artery internal carotid artery. Subsequently, the proximal end of the carotid artery was ligated, arterial clamps on the internal carotid artery and the common carotid artery were released, and blood flow was restored. After the wound was stitched, 20,000 IU of penicillide was injected intramuscularly to prevent infection. After 24 h, compound 1 in normal saline (at an initial dose of 5 pmol / kg, n = 12) was infused through the tail vein. Then, infusion of compound le in normal saline (at a dose of 2 pmol / kg, n = 12) through the rat's tail vein was performed once a day for 6 consecutive days, observed for 7 days. The rats were compared to themselves each day, and assessed for the degree of damage to neural function by the Zealonga method. A rating of 0 indicated no signs of loss in neural function, 1 indicated that the frontal limbs on the undamaged side may not stretch, 2 indicated the direction of walking on the undamaged side, 3 indicated walking behind the tail itself in circles to the side undamaged, 4 indicated non-voluntary walking with a consciousness disorder, and 5 indicated death. The experimental results are shown in Table 12. [0233] The data in Table 12 demonstrated that efficacy was shown in rats that received treatment 24 h after the start of the stroke with a dose of 5 pmol / kg of compound le on day 1 and a dose of 2 pmol / kg of compound le per day for the following 5 days. Among the 12 rats that received the treatment, three were killed, while 8 of the 9 recovered remaining rats had no sign of loss of neural function, and one had only the sign of slight loss in neural function. So, continuous treatment with compound l showed a therapeutic effect on the stroke in addition to 87/95 of the gold treatment window treatment. Table 12. Efficacy in rats received treatment with compound l of the present invention 24 h after the start of the stroke______________________________ Mouse No. Function ratings daily neural action (Mean ± SD) Day 1 Day 2 Day 3 Day 4 Day 5 6th Day 7 1 3 2 2 1 0 0 0 2 3 2 1 1 1 0 0 3 2 1 1 0 0 0 0 4 3 2 2 1 1 0 0 5 5 6 2 1 1 1 1 0 0 7 3 3 3 2 1 1 1 8 3 4 2 1 1 0 0 9 5 10 3 3 1 1 1 1 1 11 5 0 0 0 0 0 0 12 2 1 1 1 0 0 0 [0234] Experimental example 13. Experiments in rats receiving treatments with 6 successive administrations of 2 pmol / kg of compound l of the present invention 6 h after the onset of stroke [0235] Efficacy was represented by classifications of neural function, and a classification bottom indicates greater effectiveness. A 10% chloral hydrate solution was injected intraperitoneally into male SD rats at a dose of 400 mg / kg of body weight for anesthesia. A longitudinal opening incision was made in the center of the neck, and the trunk of the right common carotid artery was dissected (about 3 cm in length). Branches of the external carotid artery were dissected and ligated at the hyoid level, and the internal carotid artery was dissected in the swollen part of the neck. The open incisions in the internal carotid artery and the proximal end of the common carotid artery were occluded with non-invasive arterial clamps, respectively, and the distal end of the external carotid artery was ligated. A catheter containing 0.5 mL of thrombus suspension in normal saline was inserted into the trunk of the external carotid artery. At the same time when the clamp on the internal carotid artery was released, 0.5 mL of the thrombus suspension in normal saline flows slowly 88/95 into the catheter from the external carotid artery to its proximal terminal, and was then injected into the arteries in the brain through the internal carotid artery. Different from the previous experimental examples, the thrombus used in this experimental example was remarkably suspension of solid thrombus in normal saline prepared by using older thrombus having been stored in RT for 24 h, instead of the thrombus suspension in normal saline prepared by using thrombus stored at -24 ° C. Subsequently, the proximal end of the carotid artery was ligated, arterial clamps on the internal carotid artery and the common carotid artery were released, and blood flow was restored. After the wound was sewn, 20,000 IU of penicillin was injected intramuscularly to prevent infection. After 6 h, compound 1 in normal saline (at an initial dose of 5 pmol / kg, n = 12) was infused through the tail vein. Then, infusion of compound le in normal saline (at a dose of 2 pmol / kg, n = 12) through the rat's tail vein was performed once a day for 6 consecutive days, observed for 7 days. The rats were compared to them each day, and assessed for the degree of damage to neural function by the Zealonga method. A rating of 0 indicated no signs of loss in neural function, 1 indicated that the frontal limbs on the undamaged side may not stretch, 2 indicated the direction of walking on the undamaged side, 3 indicated walking behind the tail itself in circles to the side undamaged, 4 indicated non-voluntary walking with a consciousness disorder, and 5 indicated death. The experimental results are shown in Table 13. Table 13. Efficacy in rats receiving treatment with 2 pmol / kg of compound l of the present invention 6 h after the onset of the stroke_______________ Mouse No. Function ratings daily neural action (Mean ± SD) Day 1 Day 2 Day 3 Day 4 Day 5 6th Day 7 1 4 3 2 1 1 1 1 2 3 2 1 1 0 0 0 3 3 3 3 3 1 1 1 4 3 3 1 1 1 1 1 5 5 6 3 3 1 1 1 1 1 89/95 7 5 8 3 3 1 1 1 1 1 9 5 10 5 11 5 12 3 5 [0236] The data in Table 13 demonstrated that, in rat models 6 h after ο the beginning of the stroke induced by the aged thrombus, efficacy was shown after 6 successive treatments with a dose of 2 pmol / kg of compound le per day for 6 days consecutive. Among the 12 rats that received treatment, theirs were killed, while 1 of the 6 remaining rats recovered had no sign of loss in neural function, and five had only the sign of slight loss in neural function. Then, continuous treatment with compound 1 showed a therapeutic effect in old stroke. [0237] It should be noted that, because compounds 1 to 2, except 1, in Experimental Examples 1 to 7 achieved the effects on the elimination of the free radical NO, clot lysis by euglobulin, thrombolysis, anti-thrombus action, and treatment in rats with a stroke similar to those of compound le, the other compounds from a to II can achieve the same effects in the old stroke as a compound le had. Experimental example 14. Experiments in nanostructures of compounds la to II of the present invention in a concentration of 1 χ10 ' 6 M, 1 χ10' 9 M and 1 χ10 '12 M [0238] Compounds la to II according to the present invention were prepared in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M solutions, respectively. 10 pL of solution was removed and dripped onto a copper grid with a paper filter placed underneath, dried, and then observed under a transmission electron microscope (MET) (JEOL, JEM-1230). Photographs were taken to record the particle size and morphology. [0239] 1. Test compound: compounds 1 to II of the present invention [0240] 2. Test method: the test compound (la to II) was prepared in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M solutions with triple distilled water, respectively. A small amount (about 10 pL) was removed and dripped onto the surface of 90/95 a copper grid with a paper filter, dried with air, and then observed under MET (JEOL, JEM-1230) for the morphology and particle size that were recorded in the photographs. [0241] 3. Test results: results are shown in Figs. 25 to 36. Fig. 25 shows the nanostructures of compound la according to the present invention in aqueous solutions of 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M, and the nanostructures of la in aqueous solutions are nanospheres having a diameter from 3.1 to 86.1 nm; Fig. 26 shows the nanostructures of compound Ib according to the present invention in aqueous solutions of 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M, and the nanostructures of Ib in aqueous solutions are nanospheres having a diameter of 4, 3 to 297.9 nm; Fig. 27 shows the nanostructures of compound Ic according to the present invention in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M aqueous solutions, and Ic nanostructures in aqueous solutions are nanospheres having a diameter of 2.2 to 165.7 nm; Fig. 28 shows the nanostructures of the Id compound according to the present invention in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M aqueous solutions, and Id nanostructures in aqueous solutions are nanospheres having a diameter of 16.2 at 201.2 nm; Fig. 29 shows the nanostructures of compound le according to the present invention in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M aqueous solutions, and le nanostructures in aqueous solutions are nanospheres having a diameter of 3.3 at 138.9 nm; Fig. 30 shows the nanostructures of the If compound according to the present invention in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M aqueous solutions, and If's nanostructures in aqueous solutions are nanospheres having a diameter of 3, 6 at 82.4 nm; Fig. 31 shows the nanostructures of the Ig compound according to the present invention in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M aqueous solutions, and Ig nanostructures in aqueous solutions are nanospheres having a diameter of 6, 3 at 264.5 nm; Fig. 32 shows the nanostructures of compound Ih according to the present invention in aqueous solutions at 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M, and the nanostructures of Ih at 91/95 aqueous solutions are nanospheres having a diameter of 5.1 to 149.8 nm; Fig. 33 shows the nanostructures of compound li according to the present invention in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M aqueous solutions, and the nanostructures in aqueous solutions are nanospheres having a diameter of 4, 7 to 107.7 nm; Fig. 34 shows the nanostructures of compound Ij according to the present invention in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M aqueous solutions, and Ij nanostructures in aqueous solutions are nanospheres having a diameter of 9.1 at 73.7 nm; Fig. 35 shows the nanostructures of compound Ik according to the present invention in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M aqueous solutions, and Ik nanostructures in aqueous solutions are nanospheres having a diameter of 10, 1 at 66.7 nm; Fig. 36 shows the nanostructures of compound II according to the present invention in 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M aqueous solutions, and II nanostructures in aqueous solutions are nanospheres having a diameter of 6, 1 at 153.3 nm. Experimental examples 15. FT-MS and high resolution experiments of compounds 1 to 2 of the present invention in concentrations of 1x10 ' 6 M, 1x10' 9 M and 1x10 '12 M [0242] Compounds 1 to II were prepared in a solution 12 , 5 μΜ with triple distilled water, and 10 pL of the sample were loaded onto an FT-ICR solariX mass spectroscope (Bruker Daltonik). Intermolecular association status was observed and data were acquired. The results are listed in Table 14 to 16. Table 14. High-resolution FT-MS data of phimers formed by la-ll compounds of the present invention in three different concentrations______ Compounds Concentration 1 x10 ' tí M / dimer 1 x 10 ' 9 M / dimer 1 x 10 '12 M / dimer Ia 2748,445 2748,445 2748,445 Ib 2772.5308 2772.5308 2772.5308 Ic 2888.5308 2888.5308 2888.5308 Id 2720.4266 2720.4266 2720.4266 le 2744.4994 2744.4994 2744.4994 If 2840.4994 2840.4994 2840.4994 IG 2606.3838 2606.3838 2606.3838 Ih 2630.4564 2630.4564 2630.4564 92/95 li 2726.4564 2726.4564 2726.4564 1 2294.1814 2294.1814 2294.1814 Ik 2318.2542 2318.2542 2318.2542 II 2414.2542 2414.2542 2414.2542 Table 15. FT-MS data of high resolution of trimers formed by compounds la-ll of the present invention in the three different concentrations __________ Compounds Concentration 1x10 ' 6 M / trimer 1 χ10 ' 9 M / trimer 1 x 10 '12 M / trimer Ia 4122.1870 4122.1870 4122.1870 Ib 4158.2962 4158.2962 4158.2962 Ic 4332.2962 4332.2962 4332.2962 Id 4080.1399 4080.1399 4080.1399 le 4116.2491 4116.2491 4116.2491 If 4260.2491 4260.2491 4260.2491 IG 3909.0757 3909.0757 3909.0757 Ih 3945.1846 3945.1846 3945.1846 li 4089.1846 4089.1846 4089.1846 lj 3440.7721 3440.7721 3440.7721 Ik 3476.8813 3476.8813 3476.8813 II 3620.8813 3620.8813 3620.8813 Table 16. High-resolution FT-MS data of tetramers formed by la-ll compounds of the present invention in three different concentrations_________ Compounds Concentration 1 x 10 'M ti / tetramer 1 x 10 ' 9 M / tetramer 1 x 10 '12 M / tetramer Ia 5495,9160 5495,9160 5495,9160 Ib 5544.0616 5544.0616 5544.0616 Ic 5776.0616 5776.0616 5776.0616 Id 5439.8532 5439.8532 5439.8532 le 5487,9988 5487,9988 5487,9988 If 5679,9976 5679,9976 5679,9976 93/95 IG 5211.7676 5211.7676 5211.7676 lh 5259.9128 5259.9128 5259.9128 li 5451.9128 5451.9128 5451.9128 1 4587.3628 4587.3628 4587.3628 Ik 4635,5084 4635,5084 4635,5084 II 4827,5084 4827,5084 4827,5084 [0243] Tables 14 to 16 show the precise mass numbers measured by high resolution FT MS. These mass numbers indicate that dimers, trimers and tetramers have all been detected in three different concentrations of the la-11 compounds of the present invention. Then, the compounds according to the present invention can form dimers, trimers and tetramers in an aqueous solution at the same time. Experimental example 16. High-resolution FT-MS experiments of compound l of the present invention in concentrations of 10.0 μΜ, 1.0 μΜ, 0.1 μΜ and 0.01 μΜ [0244] For MS visualization, Compounds and outside prepared in 10.0 μΜ, 1.0 μΜ, 0.1 μΜ and 0.01 μΜ solutions with triple distilled water, and a 10 pL sample was loaded on an FT-ICR solariX mass spectroscopy (Bruker Daltonik). Intermolecular association status was observed and data were acquired. The results are shown in Figs 37 to 40. Fig. 37 is the high resolution FT-MS spectrum of compound l according to the present invention at a concentration of 0.01 μΜ: 915.84146 is a triple charged ion of the dimer, 1030.32114 it is a quadruple charged ion of the trimer, and 1099.00914 is a quintuple charged ion of the tetramer; Fig. 38 is the high resolution FT-MS spectrum of compound le according to the present invention at a concentration of 0.1 μΜ: 915.84124 is a triple charged ion of the dimer, 1030.32208 is the quadruple charged ion in the trimer, and 1099.00829 it is the quintuple charged ion of the tetramer; Fig. 39 is the high-resolution FT-MS spectrum of compound l according to the present invention at a concentration of 1 μΜ: 915.84095 is the triple charged ion of the dimer, 1030.32067 is a quadruple charged ion of the trimer, and 94/95 1099.00914 is the quintuple charged ion of the tetramer; Fig. 40 is a high resolution FT-MS spectrum of the compost le according to the present invention at a concentration of 10 μΜ: 915.84163 is the triple charged ion of the dimer, 1030.32067 is ο ίοη quadruple charged of the trimer, and 1099.00914 is the quintuple charged ion of the tetramer. [0245] The dimers, trimers and tetramers formed by the compounds of the present invention are still joined in nanospheres having a diameter of 2 to 300 nm. Among nanospheres of such sizes, nanospheres having a diameter less than 100 nm went beyond 99%. It is well known in nanopharmacology that nanospheres having a diameter of less than 100 nm are unlikely to be encompassed by macrophages during transport in the blood and can easily pass through the capillary wall. These properties allow the compounds according to the present invention to cross the blood-brain barrier. It is the property of crossing the blood-brain barrier of the compounds according to the present invention that allows the metabolic products of the compounds according to the present invention to be detectable in brain tissues in rats receiving the stroke treatment. Experimental example 17. Experiments in high-resolution FT-MS monitoring of metabolic products in brain tissues treated with compound l according to the present invention [0246] The entire brain of the rat was taken and placed in a 50 mL centrifuge tube, in which 10 mL of 0.9% NaCI were added, and homogenized to obtain a uniform suspension which was then centrifuged at 3000 rom for 10 min. 5 ml of supernatant was added in 10 ml of methanol and eventually mixed by stirring, and centrifuged at 3000 rpm for 10 min. The supernatant was concentrated under reduced pressure until dry, followed by the addition of 1 ml of methanol, and again centrifuged at 12000 rpm for 10 min. The resulting supernatant was used 95/95 for monitoring the content of metabolic products in brain tissues in rats treated with compound le. [0247] Experimental results of high-resolution FT-MS showed two metabolic products M1 and M2 in the brain. Among them, M1 had a [M + 1] + of 291.06971 and a molecular formula of C15H-19O5N2; and M2 had a [M + 1] + of 307.04350 and a molecular formula of Ci5H 19 O 4 N2. (MS conditions: charging: 10 pL; ionization mode: ES +; cone voltage: 30 V; mobile phase flow rate: 0.2 mL / min). According to the data above, the metabolic products M1 and M2 were assumed to be the following compounds: M1 M2 Theoretical PM 291.1345 307,1249 Theoretical PM 291.0697 307.0435 [0248] This demonstrated that the compound 1 and 1 of the present invention did in fact cross the blood-brain barrier, allowing the free radical scavenging effect NO, thrombolysis and the anti-thrombus effect on the brain.
权利要求:
Claims (3) [1] 1. Compound of formula I: NN — AAj ^ AAs / 1X CHARACTERIZED by the fact that NN represents an imidazoline having NO free radical scavenging activity; AAi represents a linking arm having at least three linking groups; AA 2 represents a peptide having thrombolytic activity; and AA 3 represents a peptide targeting the thrombus. 2. Compound according to claim 1, CHARACTERIZED by the fact that imidazoline having NO free radical scavenging activity is 1,3-dioxo-2 [(4-oxyacetoxy) phenyl] -4,4,5,5 -tetramethylimidazoline. 3. Compound according to claim 1, CHARACTERIZED by the fact that the groups for attachment are selected from the group consisting of a carboxyl group and an amino group. 4. Compound according to claim 3, CHARACTERIZED by the fact that the linking arm is a natural amino acid, particularly L-Lys, L-Asp or L-Glu. 5. Compound according to claim 1, CHARACTERIZED by the fact that the peptide having thrombolytic activity is an oligonucleotide comprising a PAK sequence (Pro-Ala-Lys), an AKP sequence (Ala-Lys-Pro) or a sequence KAP (Lys-Ala-Pro), or a peptide having repeating units of the PAK sequence, the AKP sequence or the KAP sequence. 6. Compound according to claim 1, CHARACTERIZED by the fact that the thrombus-targeted peptide is an oligonucleotide comprising an RGD (Arg-Gly-Asp) sequence. 7. Compound according to claim 1, CHARACTERIZED by the fact that the peptide directed to the thrombus is a polypeptide obtained from conjugates 2/5 guarantee the modification of an RGD peptide (Arg-Gly-Asp) with a YIGS peptide (Tyrlle-Gly-Ser). 8. Compound according to claim 1, CHARACTERIZED by the fact that the imidazoline having NO free radical scavenging activity is 1,3-dioxo-2 [(4-oxyacetoxy) phenyl] -4,4,5,5 -tetramethylimidazoline, the binding arm is L-Lys, L-Asp or L-Glu, the peptide having thrombolytic activity is an oligopeptide comprising a PAK sequence (Pro-Ala-Lys), and the peptide targeting the thrombus is an oligopeptide comprising an RGD sequence (Arg-Gly-Asp). 9. Pharmaceutical composition CHARACTERIZED by the fact that it comprises the compound as described in any of claims 1 to 8 and a pharmaceutically acceptable carrier. 10. Pharmaceutical composition, according to claim 9, CHARACTERIZED by the fact that the compound is in the form of a nanospheric structure. 11. Pharmaceutical composition according to claim 9, CHARACTERIZED by the fact that it is for use as a thrombolytic drug, a NO free radical scavenger or an anti-thrombus drug. 12. Pharmaceutical composition according to claim 9, CHARACTERIZED by the fact that it is for use as a drug in the treatment of stroke or cerebral infarction. Pharmaceutical composition according to claim 12, CHARACTERIZED by the fact that it is for use in the treatment of stroke or cerebral infarction more than 3 hours after the onset of symptoms. 14. Method for preparing the compound of formula I, according to vindication 1, NN — AAi (D 3/5 CHARACTERIZED by the fact that NN represents an imidazoline having NO free radical scavenging activity; AAi represents a connecting arm having at least three groups for connecting; AA 2 represents a peptide having thrombolytic activity; and AA 3 represents a thrombus-targeted peptide; said method comprising the steps of: (1) providing imidazoline having NO free radical scavenging activity (NN), the linking arm having at least three binding groups (ΑΑ-ι), the peptide having thrombolytic activity (AA 2 ) and the peptide targeting the thrombus (AA 3 ), wherein the connecting arm has a first group for connection, a second group for connection, and a third group for connection; [2] (2) under appropriate reaction conditions, linking the imidazoline having the free radical scavenging activity NO (NN) to the first group for binding in the binding arm (AA1), to form a compound of the general formula IM-1: NN-AAi (IM-1); [3] (3) under appropriate reaction conditions, binding of the peptide having thrombolytic activity (AA 2 ) to the compound of the general formula IM-1, in which one end of the peptide having thrombolytic activity is linked to the second group to bind to the binding arm, to form a compound of general formula IM-2: NN-AA1-AA2 (IM-2); and (4) under appropriate reaction conditions, linking the peptide targeting the thrombus (AA3) to the compound of general formula IM-2, in which a termination of the peptide targeting the thrombus is linked to the third group for ligation in the ligation arm, to form the compound of formula I; in which steps (3) and (4) are interchangeable in their order. 15. Method, according to claim 14, CHARACTERIZED by the fact that step (1) still comprises protection of the second and third groups for 4/5 binding to the linking arm (AA-i) with protecting groups, and active protecting groups of the peptide having thrombolytic activity (AA 2 ) and of the peptide targeting the thrombus (AA 3 ), other than the termination to be used for binding , with protective groups; step (3) further comprises deprotection of the protected secondary group for first binding, and then linking the peptide having thrombolytic activity to the second unprotected group for binding; step (4) further comprises deprotecting the third protected group for first binding, and then binding the peptide to the thrombus to the third unprotected group for binding; and after step (4), there is still a step of deprotection of the active groups protected from the peptide having thrombolytic activity (AA 2 ) and the thrombus targeting peptide (AA 3 ). 16. Method, according to claim 14 or 15, CHARACTERIZED by the fact that the first group for attachment is an amino group, and the second and third groups for attachment are selected from the group consisting of a carboxyl group and a group amino. 17. Method according to claim 16, CHARACTERIZED by the fact that the linking arm is a natural amino acid, particularly L-Lys, L-Asp or L-Glu. 18. Method according to claim 16, CHARACTERIZED by the fact that the peptide having thrombolytic activity is an oligopeptide comprising a PAK sequence (Pro-Ala-Lys), an AKP sequence (Ala-Lys-Pro) or a KAP sequence (Lys-Ala-Pro), or a peptide having repeating units of the PAK sequence, the AKP sequence or the KAP sequence. 19. Method according to claim 16, CHARACTERIZED by the fact that the thrombus directed peptide is an oligonucleotide comprising an RGD (Arg-Gly-Asp) sequence. 20. Method according to claim 14 or 15, CHARACTERIZED by the fact that imidazoline having NO free radical scavenging activity is 5/5 1,3-dioxo-2 - [(4-oxyacetoxy) phenyl] -4,4,5,5-tetramethylimidazoline, the binding arm is LLys, L-Asp or L-Glu, the peptide having thrombolytic activity is an oligopeptide comprising a PAK sequence (Pro-Ala-Lys), and the thrombus-directed peptide is an oligopeptide comprising an RGD sequence (Arg-GlyAsp).
类似技术:
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同族专利:
公开号 | 公开日 RU2604193C2|2016-12-10| EP2894160A4|2016-04-13| PH12015500465B1|2015-04-20| JP2017206540A|2017-11-24| JP6212123B2|2017-10-11| WO2014036821A1|2014-03-13| TW201410708A|2014-03-16| US20180264126A1|2018-09-20| CN103665107B|2017-07-14| MX2015002848A|2015-05-15| CN103665107A|2014-03-26| JP2015529209A|2015-10-05| KR20150048871A|2015-05-07| PH12015500465A1|2015-04-20| US20150290339A1|2015-10-15| TWI568747B|2017-02-01| ZA201500316B|2017-09-27| CN105884905A|2016-08-24| CA2884057A1|2014-03-13| EP2894160B1|2019-03-13| US10806798B2|2020-10-20| EP2894160A1|2015-07-15| AU2013312689B2|2017-03-30| AU2013312689A1|2015-03-19| RU2015112025A|2016-10-27|
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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]| 2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]| 2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI | 2020-04-28| B15I| Others concerning applications: loss of priority|Free format text: PERDA DAS PRIORIDADES CN 201210323849.3, CN 201210323848.9, CN 201210323850.6, CN 201210323951.3 E CN 201310068532.4 REIVINDICADAS NO PCT/CN2013/072731, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9.279 DE 14/05/1996 (LPI) ART. 162O. ESTA PERDA SE DEU PELO FATO DE O REQUERENTE NAO APRESENTAR TRADUCAO SIMPLES DA CERTIDAO DE DEPOSITO OU DOCUMENTO EQUIVALENTE DA PRIORIDADE DENTRO DO PRAZO DE 60 DIAS A CONTAR DA DATA DA PUBLICACAO DA EXIGENCIA, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9.279 DE 14/05/1996 (LPI) ART. 167O. | 2020-06-23| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements| 2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|
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申请号 | 申请日 | 专利标题 CN2012103238493A|CN102875644A|2012-09-05|2012-09-05|GRPAK/tetrahydroglyoxaline/RGD ternary conjugate as well as preparation method and application thereof| CN2012103238489A|CN102887941A|2012-09-05|2012-09-05|PAK / imidazoline/RGDternary conjugate and preparation method and use thereof| CN2012103238506A|CN102898505A|2012-09-05|2012-09-05|ARPAK/imidazolidine/RGD ternary conjugate, preparation method and uses thereof| CN 201210323951|CN102898506A|2012-09-05|2012-09-05|RPAK/imidazolidine/RGD ternary conjugate, preparation method and uses thereof| CN201310068532.4A|CN103665107B|2012-09-05|2013-03-05|Have thrombus dissolving simultaneously, remove free radical and the compounds of thrombus target function and its production and use| PCT/CN2013/072731|WO2014036821A1|2012-09-05|2013-03-15|Novel compound with effects of thrombolysis, free radical scavenging and thrombus-targeting as well as preparation method and use thereof| 相关专利
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