JP2010229140A - Active agent delivery system and method for protecting and administering active agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide drug delivery systems and the like, enabling use of new molecular compositions improving active agent performance associated with absorption parameter and stability and decreasing risk of technological aspect, controlling aspect and financial aspect accompanied with the active agent. <P>SOLUTION: There are provided active agent delivery systems, and more specifically, compositions that comprise amino acids, as single amino acids or peptides, covalently attached to active agents, and conjugated active agent compositions. More specifically, a composition comprising a carrier peptide that comprises at least one active agent covalently attached to the carrier peptide at the C-terminus, interspersed, side-chain attached, or combination thereof, wherein the carrier peptide further comprises fewer than 50 amino acids, and wherein the composition is in a form suitable for release of the active agent into the bloodstream. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

Cross-reference of related applications
This application is a continuation-in-part of each of the following patents: US Patent Application Publication No. 10 / 156,527, filed May 29, 2002; US Patent Application, filed November 8, 2001; 09 / 986,426; U.S. patent application Ser. No. 09 / 411,238 filed Oct. 4, 1999 and now abandoned; U.S. patent application 09/265, now abandoned. 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(I) Field of the Invention The present invention relates to an active agent delivery system, and more particularly to a composition comprising a peptide covalently bound to an active agent and a method of administering a conjugated active agent composition.

(Ii) Background of the Invention Active substance delivery systems are often very important for the safe and effective administration of biologically active agents (active substances). Perhaps the importance of these systems is best realized when taking into account patient compliance and consistent dosing. For example, reducing the dosing requirement for one drug from four times a day (QID) to once a day would be of significant value in the sense of ensuring patient compliance. Increasing the stability of the active substance will ensure dose reproducibility and possibly reduce the required number of doses. Moreover, any benefit that can provide a modulated absorption to an existing drug will certainly improve the safety of the drug. Finally, improving drug absorption should have a significant impact on the safety and efficacy of the drug.

  Absorption of orally administered active substances is due to the severely acidic stomach environment, strong digestive enzymes in the gastrointestinal (GI) tract, lack of penetration and transport of agents across the lipid bilayer , Often cut off. These systems are partially responsive to the physicochemical properties of the drug molecule itself. The physical constants describing specific physicochemical properties such as lipophilicity (logP) and ionization power (pKa) depend on the molecular structure of the active substance. Some drugs are poorly absorbed because they are too hydrophilic and do not effectively cross the plasma membrane of cells. There are also drugs that are too hydrophilic and insoluble in the intestinal lumen and cannot migrate to the surface of the mucosa. The total digestion and absorption process is a complex series of events, including those that are closely interdependent. There should be optimal physicochemical properties that maximize the bioavailability of the active substance. However, it is often difficult to optimize these properties without losing therapeutic efficacy.

  Optimization of the bioavailability of a drug provides a number of potential benefits. It is generally accepted that low dosing frequency is desirable for patient convenience and enhanced compliance. By prolonging the period during which the drug is absorbed, the duration of action per dose is expected to increase. This in turn will lead to an overall improvement in dosing parameters such as taking the drug twice a day if previously required four times a day dosing. A number of drugs are currently administered at a dosing frequency of once a day. Still, not all of these drugs have pharmacokinetic properties that are suitable for a 24-hour dosing interval. It would be equally beneficial to extend the time period during which these drugs are absorbed.

  One basic consideration in drug therapy involves the relationship between blood levels and therapeutic activity. For most drugs, it is most important that serum levels remain between the lowest effective concentration and the potential toxicity level. In terms of pharmacokinetics, the peaks and valleys in the blood level of the drug are ideally well within the therapeutic range of serum concentration. For certain therapeutic substances, this area is very narrow and therefore dosage formulation is very important. This is true for digoxin, a drug used to treat cardiac dysfunction.

  The therapeutic blood levels of digoxin range between 0.8 ng / mL (below the desired effect may not be observed) and about 2 ng / mL (beyond this can cause toxicity) Is in. Two-thirds of adults with observed clinical toxicity have serum concentrations higher than 2 ng / mL. In addition, adverse reactions can increase dramatically with slight increases above this maximum level. For example, digoxin-induced arrhythmias occur at rates of 10%, 50%, and 90% at serum drug levels of 1.7, 2.5, and 3.3 ng / mL, respectively.

  After oral administration of digoxin, the effect is usually evident within 1-2 hours and the peak effect is seen between 4-6 hours. After sufficient time, plasma concentration and systemic reserves depend on a single daily maintenance dose. It is very important that this dose be individualized for each patient. Accordingly, it is useful to obtain a dosage form of dioxin that provides more consistent serum levels between doses.

  Another example of the benefits of a more consistent dosing is provided by β-blocker-atenolol. The duration of effect of this commonly used drug is usually assumed to be 24 hours. However, in the normal dose range of 25-100 mg administered once a day, the effect may disappear hours before the next dose begins to work. For patients undergoing treatment for angina pectoris, hypertension or for prevention of a heart attack, this can be extremely risky. One alternative is to give more dosage than is necessary to obtain the desired level of action when serum levels are minimized. However, this can cause side effects related to excessively high concentrations in the first hours of the dosing interval. At these higher levels, atenolol loses its potential advantages. The adverse reactions related to β-1 selectivity and β-2 receptor blockade are even more significant.

  In the case of anti-HIV nucleoside drugs, there is a substantial benefit in measuring the absorption of the drug into the bloodstream. Whether a drug such as AZT is effective depends on whether phosphorylation occurs after absorption and before ingestion into the virus. At regular dosing, drug levels rise rapidly after absorption and the phosphorylation pathway can become saturated. Furthermore, the phosphorylation rate depends on the serum concentration. The reaction occurs more rapidly at lower concentrations. Thus, nucleoside analogs that retain lower serum concentrations are converted to active drugs more efficiently than other rapidly absorbed antiviral drugs.

  While the toxicity of digoxin and atenolol can be considered as an extension of its desired activity, the toxicity associated with statins is apparently independent of the therapeutic effect of the drug. Among the toxic side effects of statins are liver problems and rhabdomyolysis. The exact cause of statin-induced rhabdomyolysis and liver toxicity is not well understood, but these have been linked to potent liver enzymes. The therapeutic effect of statins is the result of down-regulation of one of the key enzymes responsible for cholesterol production. However, statin overdose can cause a decrease in non-sterol product synthesis, which is important for cell growth, in addition to rhabdomyolysis. Thus, it can be argued that for statins, by modulating the absorption of the drug, therapeutic effects can be obtained at lower doses, thus minimizing the risk of producing toxic side effects.

  Finally, increasing the absorption of the active substance can have a significant impact on its safety. Taking the statin example again, the statin is absorbed at any rate between 10-30% and the dosage is based on the average of this range and thus absorbs 30% of the administered statin. For patients who do, adverse side effects can occur. The risk of presenting these side effects would be greatly reduced if the bioavailability of the drug was more predictable.

  In an effort to address the need for improved bioavailability, several drug release modulation techniques have been developed. Enteric coatings have been used as protectives of pharmaceuticals in the stomach, and microencapsulation of the active substance using proteinoid microspheres, liposomes or polysaccharides reduces the enzymatic degradation of the active substance It is effective in making it happen. Enzyme inhibitor additives have been used as well to prevent enzymatic degradation.

  A wide range of pharmaceutical formulations are said to provide sustained release through microencapsulation of the active substance in amides of dicarboxylic acids, modified amino acids or heat condensed amino acids. Additives that give sustained release can also be mixed with various active substances in tablet form. For example, when diazepam is formulated with a copolymer of glutamic acid and aspartic acid, sustained release of the active substance becomes possible. As another example, a copolymer of lactic acid and glutaric acid is used to provide timed release of human growth hormone. Microencapsulation of therapeutic and diagnostic agents is generally described, for example, in US Pat. No. 5,238,714 to Wallace et al.

  While microencapsulation and enteric coating techniques provide enhanced stability and timed release for active agents, these techniques have several drawbacks. Active agent uptake is often dependent on diffusion into the microencapsulation matrix, which may not be quantitative and may complicate dose reproducibility. Furthermore, the encapsulated drug relies on matrix out-diffusion or matrix degradation, which depends largely on the water solubility of the active substance. In other words, the water-soluble microspheres expand indefinitely and unfortunately can explode the active substance with only a few active substances available for sustained release. Moreover, in some technologies, the control of the degradation process required for active substance release is unreliable. For example, enteric-coated active substances are pH dependent to release the active substance, thus making it difficult to control the release rate.

The active substance has been covalently attached to the amino acid side chain of the polypeptide as a pendant group. These techniques typically require the use of a spacer group between the amino acid pendant group and the active substance. Examples of targeted timed-release pharmaceuticals administered intravenously, intraperitoneally or intraarterially include improved poly- [N ^5- (2-hydroxyl) when attached to carriers and stabilizing units. Linking nitrogen mustard via a stabilizing peptide spacer to a polymeric carrier such as (ethyl) -L-glutamine] (PHEG).

  Dexamethasone has been directly covalently attached to the beta-carboxylate of polyaspartic acid as a colon-specific drug delivery system that is released by bacterial hydrolases resident in the large intestine. Dexamethasone actives were targeted to treat colonic disease and were not intended to be absorbed into the bloodstream. Other examples include techniques for forming peptide-linked biotin, peptide-linked acridine, naphthylic acid bonds to LH-PH, and coumaric acid cyclic bonds to opioid peptides.

  Several implantable drug delivery systems have utilized polypeptide attachment to drugs. An example includes linking norethindrone via a hydroxypropyl spacer to gamma-carboxylates of a large polyglutamic acid polymer carrier designed to biodegrade over time following implantation or implantation via surgical procedures. . In addition, other large polymeric carriers that incorporate the drug within its matrix are used as implants for the gradual release of the drug. Examples of implantable delivery systems are generally described in US Pat. No. 4,356,166 to Peterson et al. And US Pat. No. 4,976,962 to Bichon et al. Has been. Yet another technique combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to a higher lipid film (known as HAR) via a peptide linker. Further descriptions can be found in US Pat. No. 5,851,536 and WO 97/36616 to Yager et al.

  Some systems are designed for the delivery of cytotoxic agents with specific amino acid sequences so that the drug is not cleaved until the conjugate contacts a specific enzyme or receptor. One such example is an oligopeptide directed against an enzymatically active prostate-specific antigen (PSA) against a cytotoxic agent that also contains a protecting group to prevent premature release of the conjugate in the blood. Is a combination of Another system designed for delivery via injection relies on a specific peptide linked directly to a polymeric carrier attached to a cytotoxic moiety to be internalized by the cell itself. Yes. In this case, the polymeric carrier, which is typically large, will not enter a cell lacking a receptor for the attached specific peptide. In another example, gastrin receptor specific tetragastrin and pentagastrin amide were attached to cytotoxic drugs for in vitro testing. These systems are described in US Pat. No. 5,948,750 to Garsky et al., US Pat. No. 5,087,616 to Myers et al .; and Schmidt et al., Peptides. Linked 1,3-dialkyl-3-acyltriazenes; gastrin receptor specific antineoplastic alkylating agents, Journal of Medical Chemistry, Vol. 37, No. 22, p3812-17 1994).

  Several systems have been directed to the treatment of tumor cells. In one case, daunorubicin-conjugated poly-L-aspartic acid delivered intravenously or intraperitoneally showed a lower cytotoxic effect. In another example, daunorubicin was covalently attached to both poly-L-aspartic acid and poly-L-lysine via the methyl ketone side chain of the drug. Conjugates were prepared for intravenous and intraperitoneal administration. While poly-L-lysine was found to be ineffective, poly-L-aspartate conjugates showed preferential tumor cell uptake. In another system, a highly substituted polypeptide conjugated to the active agent was designed for introduction into the blood vessels that further entered the tumor stroma through the length of the long chain. For further discussion of delivery systems targeted to tumor cells, see Zunino et al., Antitumor Effects of Daunorubicin Covalently Linked to Poly-L-Amino Acid Carrier, Eur. J, Cancer Clin. Oncol. 20, Vol. 3, p421-425 (1984); Zunino et al., Antitumor activity of daunorubicin linked to poly-L-aspartic acid, Int. J. et al. Cancer, 465-470 (1982); and US Pat. No. 5,762,909 to Uzgiris.

  Several examples are associated with the delivery of paclitaxel, an anticancer drug. One delivery system relies on drugs that remain attached to the conjugate for transport into the cell through the membrane transport system. In another example, paclitaxel was conjugated to high molecular weight polyglutamic acid and was delivered via injection. Paclitaxel conjugates have also been used in conjunction with implants, coatings and injectable materials. These systems are further described in US Pat. No. 6,306,993; Li et al., Complete regression of established tumors using a new water-soluble poly (L-glutamic acid) -paclitaxel conjugate, p2404-2409; and US Pat. No. 5,977,163 to Li et al.

  Delivery systems can be designed to take advantage of attachment to chemical moieties that are specifically recognized by specialized transporters or that have enhanced adsorption into target cells through specific polypeptide sequences. . There are seven known intestinal transport systems classified according to the physical properties of the substrate being transported. These include amino acids, oligopeptides, glucose, monocarboxylic acids, phosphates, bile acids and P-glycoprotein transport systems, each with its own associated transport mechanism. There is evidence to suggest that hydrophilic compounds are absorbed through the intestinal epithelium through these specialized transporters more efficiently than by passive diffusion. The active transport mechanism can depend on hydrogen ions, sodium ions, binding sites or other cofactors. The facilitation of these transporters also applies to certain specialized additives that can result in local delivery of the active agent, increased absorption of the active agent, or some combination of both. Can be influenced. Incorporation of additives such as resorcinol, surfactant, polyethylene glycol (PEG) or bile acid enhances the permeability of the cell membrane. Increased bioavailability was seen when the peptide was bound to the modified bile acid. Kramer et al., Intestinal Absorption of Peptides by Coupling to Bile Acids, The Journal of Biological Chemistry, Vol. 269, No. 14, p10621-627 (1994). The use of specific polypeptide sequences to increase absorption has been discussed in the literature showing that drug penetration into cells has been enhanced by attaching the drug to the polypeptide chain. For example, Paul Wender of Stanford University reported the use of polyarginine tags on cyclosporine to promote diffusion across the cell membrane. The penetratin system provides another example. Peptides of this class about 16 residues in length have been shown to enhance the absorption of oligonucleotides and polypeptides.

  It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weight has unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or slowly, as is the case for dextran linked to naproxen, which is almost entirely digested in the colon by bacterial enzymes. High molecular weight microspheres usually have a high moisture content, which poses a problem for water labile active ingredients. Due to the inherent instability of non-covalent bonds, the bond between the active agent and the microspheres usually cannot withstand the active conditions used to reduce the particle size of the composition.

  Thus, no pharmaceutical composition has ever been reported that encompasses the concept of attaching an active agent to a peptide or its pendant group with targeted delivery of the active agent into the general systemic circulation. . Furthermore, there were no pharmaceutical compositions that taught the release of active substances from peptides by enzymatic action in the gastrointestinal tract.

  There remains a need for an active agent delivery system that does not require the active agent to be released in specific cells (eg, in tumor promoting cells) but rather results in the release of the active agent for general systemic delivery. is doing.

  In addition, active substance delivery that allows oral delivery of active substances that can persist in the stomach and release the reference active substance by enzymes in the small intestine, brush border membrane, intestinal epithelial cells or in the bloodstream There is also a need for systems. The present invention also provides a need for an active agent delivery system that can deliver an active agent as an active agent peptide conjugate in such a way that the molecular mass and physicochemical properties of the conjugate can be easily manipulated to achieve a desired release rate. Also dealt with. There is still a need for an active agent delivery system that allows release of the active agent over a sustained time period that is convenient for patient dosing.

  There is also a generally recognized need for obtaining active agent delivery systems that reduce the daily dosage requirements and allow timed release or controlled release absorption of the composition. The present invention accomplishes this by extending the period of time during which the active substance is absorbed and further increasing the duration of action per dose than currently anticipated. This leads to an overall improvement in dosing parameters, for example, taking the active substance only twice a day even if it previously required four times a day dosing. Instead, many active substances currently given with a once-daily dosing frequency lack the pharmacokinetic properties suitable for exactly 12 or 24 hour dosing intervals. There is still an extended period of active substance absorption for current single dose active substances, which seems beneficial.

  Thus, it enables the use of new molecular compositions that can reduce the technical, regulatory and financial risks associated with active substances while improving the performance of the active substance with respect to its absorption parameters and stability as described above. There remains a need for drug delivery systems. Furthermore, the release of drugs from peptides can be caused by enzymatic action on peptide-drug conjugates in the bloodstream or by enzymatic action on peptide-drug conjugates in the gastrointestinal tract followed by absorption through the intestine or stomach. There is a need for active agent delivery systems targeted to the systemic circulation.

  The present invention provides for covalent attachment of active agents to peptides. The present invention is directed to the direct covalent attachment of active substances including, for example, pharmaceutical drugs and nutrients to the side chain or C-terminus, N-terminus of amino acids, oligopeptides or polypeptides, also referred to herein as carrier peptides. Thus, it can be distinguished from the above-described technique. In another embodiment, if the active agent itself is an amino acid active agent, the active agent may form part of the chain at either the C-terminus or N-terminus through the peptide bond, or active It may be interspersed within the polypeptide via peptide bonds on both sides of the substance.

  In another embodiment, the peptide stabilizes the active agent through conformational protection primarily in the stomach. In this field of application, active substance delivery is controlled in part by the unfolding kinetics of the carrier peptide. At the point of entry into the upper gastrointestinal tract, the endogenous enzyme releases active ingredients for absorption by the body by hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second stage of the sustained release mechanism.

  In another embodiment, the present invention provides a composition comprising a peptide and an active agent covalently linked to the peptide. Preferably the peptide is (i) an oligopeptide, (ii) one of the 20 naturally occurring amino acids (L or D isomer), or a homopolymer of its isomer, analog or derivative, (iii) Two or more naturally occurring amino acids (L or D isomers) or heteropolymers of isomers, analogs or derivatives thereof, (iv) homopolymers of synthetic amino acids, (v) of two or more synthetic amino acids A heteropolymer or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

  The present invention provides a composition comprising a carrier peptide and an active agent covalently attached to the carrier peptide. Preferably, the carrier peptide is (i) an amino acid, (ii) a dipeptide, (iii) a tripeptide, (iv) an oligopeptide or (v) a polypeptide. The carrier peptide is similarly (i) a homopolymer of naturally occurring amino acids, (ii) a heteropolymer of two or more naturally occurring amino acids, (iii) a homopolymer of synthetic amino acids, (iv) 2 It can also be a heteropolymer of one or more synthetic amino acids or (v) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.

  A further embodiment of the carrier and / or conjugate is that the unattached part of the carrier / conjugate is free and unprotected.

In another embodiment, the present invention further provides a composition comprising an amino acid, dipeptide or tripeptide, with the active agent covalently bound. Preferably, the amino acid, dipeptide or tripeptide is (i) one of the 20 naturally occurring amino acids (L or D isomer), or an isomer, analog or derivative thereof, (ii) two or more Naturally occurring amino acids (L or D isomers) or isomers, analogs or derivatives thereof, (iii) synthetic amino acids, (iv) two or more synthetic amino acids, or (v) one or more naturally occurring amino acids. Amino acids and one or more synthetic amino acids. Preferably, synthetic amino acids with alkyl side chains, the length _C 1 _{-C 17,} more preferably the length is selected from alkali _C 1 -C _6.

  In one embodiment, the active agent conjugate is attached to a single amino acid that is either naturally occurring or a synthetic amino acid. In another embodiment, the active agent conjugate is attached to a dipeptide or tripeptide that can be any combination of naturally occurring and synthetic amino acids. In another embodiment, the amino acid is selected from L-amino acids for digestion with proteases.

  In another embodiment, peptide carriers can be prepared using conventional techniques. A preferred technique is the copolymerization of a mixture of amino acid N-carboxyanhydrides. In another embodiment, the peptides can be prepared through a recombinant microorganism fermentation process followed by harvesting and purification of the appropriate peptide. Alternatively, if a specific sequence of amino acids is desired, an automated peptide synthesizer can be used to produce peptides with specific physicochemical properties for specific performance characteristics.

  In a preferred embodiment, the active substance is an inorganic or carboxylic acid and the carboxylate or acidic group is covalently attached to the N-terminus of the peptide. In another preferred embodiment, the active substance is a sulfonamide or an amine and the amino group is covalently attached to the C-terminus of the peptide. In another embodiment, the active agent is an alcohol and the alcohol group is covalently bound to the C-terminus of the peptide.

  In another embodiment, the active substance is itself an amino acid and is preferably covalently interspersed within the peptide in peptide-linked form or shared on the side chain, N-terminus or C-terminus of the peptide. Are connected. In this embodiment, if the amino acid active substance is attached to the C-terminal or N-terminal, the resulting active substance is a terminal amino acid and is considered to be C-capped or N-capped, respectively.

  The active agent may be covalently bound to the side chain of the polypeptide using conventional techniques. In a preferred embodiment, a carboxylic acid containing the active substance can be attached to the amine or alcohol group of the peptide side chain to form an amide or ester, respectively. In another preferred embodiment, an amine containing the active substance can be attached to the side chain carboxylate, carbamide or guanine group to form an amide or new guanine group. In yet another embodiment of the invention, the linker can be selected from among all chemical compound class groups so that virtually any side chain of the peptide can be attached.

  In a preferred embodiment of the side chain attachment of the active substance to the polypeptide, the amino acid used in either the homopolymer or heteropolymer is glutamic acid, aspartic acid, serine, lysine, cysteine, threonine, asparagine, arginine, tyrosine. And glutamine. Preferred examples of peptides include homopolymers of Leu-Ser, Leu-Glu, Glu and Leu and (Glu) n-Leu-Ser heteropolymers.

  In another embodiment, direct attachment of the active agent to the carrier peptide may not form a stable compound, thus requiring incorporation of a linker between the active agent and the peptide. The linker should have a functional pendant group such as a carboxylate, alcohol, thiol, oxime, hydraxone, hydrazide, or amine group to covalently attach to the carrier peptide. In one preferred embodiment, the active agent is an alcohol and the alcohol group is covalently attached to the N-terminus of the peptide via a linker. In another preferred embodiment, the active agent is a ketone or aldehyde attached to the linker through the formation of ketals or acetals, respectively, and the linker is a pendant group attached to the carrier peptide. In yet another preferred embodiment, the active substance is an amide, imide, imidazole or urea, where the nitrogen is attached to the linker and the pendant group of the linker is attached to the carrier peptide.

The present invention also provides a method for preparing a composition comprising a peptide and an active agent covalently linked to the peptide. The method comprises the following steps:
(A) attaching an active substance to the side chain (and / or N-terminal and / or C-terminal) of an amino acid to form an active substance / amino acid complex;
(B) forming an active substance / amino acid complex NCA from an active substance / amino acid complex or forming an amino acid complex N-carboxyanhydride (NCA); and (c) an active substance / amino acid complex N- Polymerizing carboxy anhydride (NCA);

  In a preferred embodiment, the active substance is a pharmaceutical agent or additive. In another preferred embodiment, steps (a) and (b) are repeated with a second active substance prior to step (c). When steps (a) and (b) are repeated with the second agent prior to step (c), the active agent and the second active agent are copolymerized in step (c). Step (b) can include amino acids (eg, glycine, alanine, etc.) without the active agent attached, thus the product in step (c) was interspersed in a peptide-linked form. Copolymer of amino acid and active substance / amino acid complex.

  In a further embodiment of the above method, the combination of the NCA of the bioactive amino acid NCA and the NCA of the other amino acid NCA results in the bioactive amino acids interspersed within the peptide with common amino acids in a peptide-linked form. The amino acid itself can be an active substance (eg thyroxine or DOPA) so that the product in (c) is produced.

  Alternatively, the active agent / amino acid complex can serve as a synthesis module for solid phase or solution phase peptide synthesis. Here, a drug can be attached to a selected amino acid by an α-amino group, an α-carboxylate or a side chain functional group. By using resin mount peptide synthesis, it is possible to better control peptide composition, dosage, and relative positioning of drugs. Thus, the use of these modules has become the only approach for incorporating drugs identified at specific locations within a peptide.

  Thus, a further embodiment of the present invention is to extend the scope of current peptide synthesis techniques to include new amino acids derived from side chain modified amino acids. Furthermore, the N-terminus of the amino acid can be modified for N-capped drug-peptide conjugates. Similarly, the C-terminus of an amino acid can be derivatized with a drug to produce an ultimate C-capped peptide-drug conjugate.

  The present invention provides a synthesis for coupling an active substance to an amino acid, dipeptide, tripeptide, oligopeptide or polypeptide. Another embodiment of the present invention is dosage form reliability and batch-to-batch reproducibility.

  In another embodiment, active agent delivery is targeted to general systemic circulation. Release of the active substance from the peptide is due to its enzymatic action on the peptide-active substance conjugate in the bloodstream or absorption through the intestine or stomach through the enzymatic action on the peptide-active substance conjugate in the gastrointestinal tract followed by a regular approach. Can happen.

  In another embodiment, the invention also relates to a method for delivering an active substance to a patient, wherein the patient is a human or non-human animal and the activity is covalently attached to peptides and peptides. There is also provided a method comprising the step of administering a composition comprising a substance to a patient. In a preferred embodiment, the active substance is released from the composition by enzyme catalysis. In another preferred embodiment, the active substance is released in a time dependent manner based on the pharmacokinetics of the enzyme catalyzed release.

  In another preferred embodiment, the common amino acid is glutamic acid, the side chain attached active substance / glutamic acid complex is released from the peptide at the time of peptide hydrolysis, and the active substance is then subjected to simultaneous intramolecular transamination. Is released from glutamic acid. In another preferred embodiment, glutamic acid is substituted with an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine and serine, wherein the active substance is in the side chain of the amino acid. Attached to form amides, thioesters, esters, ethers, thioethers, carbonates, anhydrides, orthoesters, hydroxamic acids, hydrazones, sulphonamides, sulphone esters, other derivatives of sulfur or carbamates. In yet another embodiment, glutamic acid is substituted with a synthetic amino acid with an amine, alcohol, sulfhydryl, amide, urine or pendant group containing an acid functional group.

  The compositions of the present invention may also include one or more microencapsulating agents, additives, and pharmaceutically acceptable excipients. The active agent can be bound to the microencapsulating agent, additive or pharmaceutically acceptable excipient through covalent bonds, ions, hydrophilic interactions or by some other non-covalent means. is there. The microencapsulating agent can be selected from polyethylene glycol (PEG), amino acids, carbohydrates or salts. If delayed peptide digestion is desired, microencapsulating agents can be used to delay protein unfolding. In another embodiment, if an additive is included in the composition, the additive is preferably better by enhancing the permeability of the intestinal or gastric membrane or activating the intestinal transporter. Gives absorption.

  The intestinal wall is coated with a mucosal surface layer mainly composed of mucin. A number of reagents that can bind to mucin have been identified. In another embodiment, the present invention provides the unique ability to bind mucin-binding additives to peptide / drug conjugates to bioattach the entire complex to the intestinal wall. The intestinal wall is impregnated with receptors for various reagents including numerous vitamins such as vitamin K. For example, binding vitamin K to a peptide-active substance conjugate will retain the entire complex in the intestine for a much longer time. It is this additive that bioadhesives adhere to the intestinal mucosal surface, thus extending the transit time of the drug-peptide conjugate in the intestine and maximizing peptide digestion and thus drug bioavailability. It is a further embodiment of the invention.

  In another preferred embodiment, the composition further comprises a microencapsulating agent and the active agent conjugate is swelled or dissolved in the microencapsulating agent followed by the action of the enzyme to release the active agent. It is then released from the composition by diffusion of the active substance conjugate that must be received. In yet another preferred embodiment, the composition further comprises an additive covalently attached to the peptide, and the release of the additive from the composition is controlled by enzymatic action on the peptide. The additive can be microencapsulated in a carrier peptide active agent conjugate for biphasic release of the active agent. In another preferred embodiment, the peptide-active agent conjugate can be microencapsulated, where the peptide-active agent is released in two phases, initially through physicochemical means such as solvation or swelling. Released, after which the active substance is released from the peptide carrier by enzymatic action. In yet another embodiment of the present invention, the active agent can be covalently attached to the microencapsulating agent via a peptide bond, wherein the active agent is first the peptidase action followed by the active agent from the microencapsulation medium. Released by the movement of.

  Another embodiment of the invention confers specific physicochemical properties to the conjugate, including molecular weight, size, functional group, pH sensitivity, solubility, three-dimensional structure and digestibility, to provide the desired performance characteristics. In order to do so, it is possible to combine peptides with various amino acid contents and active substances. Similarly, various active agents can be used with certain preferred peptides to confer certain performance characteristics. Significant advantages regarding the stability, release and / or adsorption properties of the active agent conferred by the use of one or more of the 20 naturally occurring amino acids are in the conjugate formed with the active agent It is evident in the physicochemical properties of the peptides that confer specific stability, digestibility and release properties.

  The amino acids that make up the carrier peptide are a set of tools that allow the carrier peptide to adapt to the pharmacological demands and chemical structure of the active agent so that maximum stability and optimal performance of the composition is achieved. The concept is another embodiment of the present invention.

  In another preferred embodiment, the length of the amino acid chain can be varied to meet different delivery criteria. For delivery with increased bioavailability, the active agent can be attached to a single to 8 amino acids, but a range of 2-5 amino acids is preferred. For modulation of active substance delivery or for increased bioavailability, preferred oligopeptide lengths are between 2 and 50 amino acids. For conformational protection, extended digestion time and sustained release, the preferred amino acid length is 8 to 400 amino acids. In another embodiment, the conjugates of the invention are also suitable for both large and small molecule actives. In another embodiment of the invention, the carrier peptide controls the solubility of the active agent-peptide conjugate and is independent of the solubility of the active agent. Thus, the sustained or zero order kinetic mechanism provided by the conjugate-drug composition avoids the cumbersome formulation and release irregularities found in standard dissolution controlled sustained release methods.

  In another preferred embodiment, the active agent conjugate incorporates the additive in such a way that the composition is designed to interact with a particular receptor so that targeted delivery can be achieved. I can't. These compositions provide targeted delivery within any region within the intestine and at specific sites along the intestinal wall. In another preferred embodiment, the active substance is released from the peptide conjugate as a reference active substance prior to entry into the target cell. In another preferred embodiment, the particular amino acid sequence used is not targeted to a particular cellular receptor and is not designed for recognition by a particular gene sequence. In a further preferred embodiment, the peptide carrier is designed for and / or not recognized by tumor promoting cells. In another preferred embodiment, the active agent delivery system does not require the active agent to be released within or within a particular cell. In preferred embodiments, the carrier and / or conjugate results in specific recognition within the body (eg, serum proteins (eg, kinin or to improve chemotactic activity by cancer cells, by primers) By sequence for specific binding sites for eicosanoids).

  In another embodiment, the active substance can be attached to an additive recognized and taken up by the active transporter. In a more preferred example, the active transporter is not a bile acid active transporter. In another embodiment, the present invention does not require attachment of the active agent to an additive recognized and taken up by the active transporter for delivery.

  Although microspheres / capsules can be used in combination with the compositions of the present invention, preferably the combination is not incorporated with the microspheres / capsules and does not require additional additives to improve sustained release.

  In another preferred embodiment, the active substance is a hormone, glutamine, methotrexate, daunorubicin, trypsin-kallikrein inhibitor, insulin, calmodulin, calcitonin, naltrexone, L-dopa, interleukin, gonadoberine, norethindrone, tolmethine, valacyclovir, taxol GABA analogs, L-aromatic amino acid decarboxylase inhibitors, catechol O-methyltransferase inhibitors, naturally occurring amino acids, bis- (2-chloroethyl) amine-containing nitrogen mustards, polypeptides, four or more amino acids Peptide mimetics derived from linear oligopeptides, oligonucleotides, cyclophane derivatives, diethylenetriaminopentaacetate derivatives, Glutamic, not a steroid or silver sulfadiazine. In preferred embodiments where the active agent is a peptide active agent, it is preferred that the active agent is not modified (eg, the amino acid structure is not substituted).

  In a preferred embodiment, the present invention provides carriers and actives that are bound to each other but otherwise unmodified in structure. This embodiment can be further described as a carrier having free carboxy and / or amine ends and / or side groups other than the attachment site for the active substance. In a more preferred embodiment, the carrier comprises only naturally occurring amino acids, whether single amino acids, dipeptides, tripeptides, oligopeptides or polypeptides.

  In preferred embodiments, the carrier is not a protein transporter (eg, histone, insulin, transferrin, IGF, albumin or prolactin), Ala, Gly, Phe-Gly or Phe-Phe. In preferred embodiments, the carrier is also preferably PVP, poly (alkylene oxide), amino acid copolymer or alkyloxycarbonyl (polyaspartate / polyglutamate) or aryloxycarbonylmethyl (polyaspartate / polyglutamate). It is not an amino acid copolymerized with a non-amino acid substitution product such as

  In preferred embodiments, neither carriers nor conjugates can be used for assay purification, binding studies or enzyme analysis.

  In another embodiment, the carrier peptide allows multiple active agents to be attached. Conjugates are not only active agents, but also in combination with other active agents or other modified molecules that can further modify delivery, enhance release, target delivery and / or enhance adsorption Provides the additional benefit of allowing the attachment of multiple active substances. In further embodiments, the conjugate can be combined with the additive as well as microencapsulated.

  In another embodiment, the conjugate provides a wide range of pharmaceutical applications including drug delivery, cellular targeting, and biological responsiveness.

  In another embodiment, the present invention can stabilize the active agent to prevent digestion in the stomach. Furthermore, the pharmacological effect can be prolonged by delaying or slow release of the active substance. Sustained release can occur through the additional covalent bonding of additives that adhere to the intestinal mucosa and / or by the covalent attachment of the active substance to the peptide. In addition, active substances can be combined to produce a synergistic effect. Similarly, absorption of active substances in the gastrointestinal tract can be enhanced through the synergistic effect of added additives or by being covalently attached to the peptide.

  In another preferred embodiment, the composition of the invention is an ingestible tablet or capsule, intravenous preparation, intramuscular preparation, subcutaneous preparation, depot-graft, transdermal preparation, oral suspension. It is in the form of a suspension, sublingual preparation, nasal preparation, inhaler or anal suppository. In another embodiment, the peptide has the ability to release the active agent from the composition in a pH dependent manner. In another preferred embodiment, the active agent is prepared and / or administered through means other than transplantation and / or infusion material. In a preferred embodiment, the active agent conjugate does not bind to the immobilized carrier, but rather is designed for transport and transition through the digestive system.

  Embodiments of the present invention are preferably not bound to additives recognized and / or taken up by active transporters. Preferably, the active agent conjugates of the invention are not attached to an antigenic agent such as an active transporter or a receptor that recognizes sequences found on cells and tumors. Preferably, the active agent conjugates of the invention are not linked to or constitute an implantable polymer that does not biodegrade in less than 48 hours, preferably between 12 and 24 hours. The active substance conjugates of the invention are preferably designed to release the active substance into the blood after absorption from the intestine as a reference active substance.

  In another embodiment, after administration of the active agent conjugate by a method other than oral, first pass metabolism is prevented by avoiding recognition of liver oxidase due to its peptide structure.

  In another preferred embodiment, the active agent is attached directly to the amino acid without the use of a linker.

  The invention also provides a method for protecting an active agent from degradation comprising the step of covalently binding the active agent to the peptide in such a way that the peptide will confer conformational protection to the active agent. Also provide.

  The present invention also provides a method for controlling the release of an active substance from a composition comprising a peptide comprising the step of covalently binding the active substance to the peptide. A further embodiment of the present invention is that enhanced performance of active agents from various chemical and therapeutic classes is achieved by prolonging sustained blood level synchronization within the therapeutic area. . For drugs where the standard formulation produces superior bioavailability, serum levels may peak too quickly and too quickly for optimal clinical effects, as illustrated below. Designing and synthesizing specific peptide conjugates that release the active substance upon digestion with intestinal enzymes mediates the release and absorption profile, thus facilitating absorption of the active substance over time and below the curve. Maintain comparable areas.

  Conjugate prodrugs can provide sustained or extended release to the parent compound. Sustained release typically means shifting the absorption towards a slow first order kinetic. Extended release typically means providing zero order kinetics for the absorption of the compound. Bioavailability can also be affected by factors other than absorption rates, such as first-pass metabolism by enterocytes and liver and clearance rate by the kidneys. The mechanism involving these factors requires that the drug-conjugate be intact after absorption. The mechanism for timed release may be due to any or all of a number of factors. These factors include 1) gradual enzymatic release of the parent drug by luminal digestive enzymes, 2) gradual release by intestinal mucosal surface-related enzymes, 3) gradual release of intestinal mucosal cells by intracellular enzymes, 4 ) Gradual release by serum enzymes, 5) Transition from passive uptake mechanism to active absorption mechanism, making drug absorption dependent on Km and receptor density for receptor binding, 6) More gradual Reducing the solubility of the parent drug resulting in dissolution, 7) increasing the amount of drug dissolved and thus increasing the solubility resulting in longer absorption due to the increase in available amount.

  The potential benefits of enzyme-mediated release technology extend beyond the examples described above. For active agents that can benefit from increased absorption, this effect is achieved by covalently attaching these active agents to one or more amino acids of the peptide and administering the drug to the patient as described above. This is an embodiment of the present invention. The present invention also allows targeting to the intestinal epithelial transport system to facilitate absorption of the active substance. Better bioavailability itself contributes to reducing the required dosage. Thus, it is a further embodiment of the invention that a reduction in the toxicity of the active substance can be achieved by modulating the release and improving the bioavailability of the active substance in the manner described above.

  The attachment of the amino acid, oligopeptide or polypeptide is a polymer-drug conjugate of the parent drug in such a way that the amino acid-prodrug can be taken up by the amino acid receptor and / or di- and tripeptide receptor (PEPT transporter) It is another embodiment of the present invention that the absorption / bioavailability of the parent drug can be enhanced by any number of mechanisms, including conversion to. This may also be true for polymeric drug conjugates, since by-products of intestinal enzyme activity can produce prodrugs with 1-3 amino acids attached. Moreover, it is possible that other receptors may be active in binding and ingesting the prodrug. Adding additional mechanism (s) for drug absorption may improve its bioavailability, especially if the additional mechanism is more efficient than the parent drug absorption mechanism. is there. Many drugs are absorbed by passive diffusion. Therefore, prodrugs can be progressively converted to the parent drug by enzymatic activity in the intestinal lumen, so by attaching amino acids to compounds, the absorption mechanism can be changed from passive to active. Or in some cases it is possible to switch to a combination of active and passive intake.

  It is another embodiment of the present invention that the efficiency of the active agent is enhanced by a lower active agent serum concentration. In addition, the conjugation of various active substances to the carrier peptide, thus sustaining the release and absorption of the active substance, helps to achieve true once-daily pharmacokinetics. It is another embodiment. In another embodiment of the invention, peaks and troughs can be improved, such as those that can be achieved at a more constant atenolol level after administration of the peptide-atenolol conjugate.

  In another embodiment of the invention, the amino acids used can make the conjugate more or less unstable at certain pH or temperature based on the required delivery. In yet another embodiment, the choice of amino acid will depend on the desired physical properties. For example, if an increase in bulk or lipophilicity is desired, the carrier polypeptide will include glycine, alanine, valine, leucine, isoleucine, phenylalanine and tyrosine. On the other hand, polar amino acids can be selected to increase the hydrophobicity of the peptide. In another embodiment, amino acids with reactive side chains (eg glutamine, asparagine, glutamic acid, lysine, aspartic acid, serine, threonine) due to attachment points with multiple actives or additives to the same carrier peptide And cysteine). This embodiment is particularly useful for providing a synergistic effect between two or more active substances.

  In another embodiment, the peptide is hydrolyzed by any one of several aminopeptidases that are found in the intestinal lumen or associated with the brush border membrane, and thus the active substance in the jejunum or ileum. Release and subsequent absorption can occur. In another embodiment, the molecular weight of the carrier molecule can be controlled to provide increased reliability, reproducibility and / or active agent input.

  In another embodiment, the present invention provides a method for testing conjugates using Caco-2 cells.

  It is to be understood that both the foregoing general description and the following detailed description are exemplary only and are not restrictive of the invention. These and other aspects and various advantages and utilities of the present invention will become more apparent by referring to the detailed description of the preferred embodiments and the accompanying drawings.

  The present invention also addresses the need for an unprotected active substance that facilitates manufacture and delivery. The present invention also provides an active substance capable of delivering an active substance through the stomach as an active substance peptide conjugate in such a way that the molecular mass and physicochemical properties of the conjugate can be easily manipulated to achieve a desired release rate. Address the need for delivery systems. The present invention also addresses the need for an active agent delivery system that allows release of the active agent over time, which is convenient for patient dosing. The present invention also addresses the need for an active agent delivery system that would provide protection through the stomach but does not require that the active agent be released within or within a particular cell.

  Embodiments of the invention preferably do not generate an antigenic response or otherwise stimulate the immune system within the host. In another preferred embodiment, the active agent conjugate attached to the carrier peptide is used to create an immune response when administered.

  The invention is best understood from the following detailed description when read in conjunction with the accompanying drawings. The following figures are included in the drawing.

It describes the transamination reaction in the molecule of glutamic acid. 1 illustrates in situ digestion of polytoroids in intestinal epithelial cell cultures. Illustrates improved adsorption of T4 from poly T4 compared to T4 alone. 6 illustrates a decrease in the amount of apical polytoroid over time (4 hours) in the absence of an intact polytoroid crossing a Caco-2 monolayer.

  Throughout this application, the use of the term “peptide” is intended to include single amino acids, dipeptides, tripeptides, oligopeptides, polypeptides or carrier peptides. The oligopeptide shall contain 2 to 70 amino acids. Furthermore, to illustrate specific embodiments for active agent conjugates, the present invention is described as being an active agent attached to an amino acid, dipeptide, tripeptide, oligopeptide or polypeptide. Sometimes. Preferred lengths of conjugates and other preferred embodiments are described herein.

  Modulation shall at least include affecting changes or otherwise altering total absorption, adsorption rate and / or target delivery. The term sustained release includes at least an increase in the amount of reference drug in the bloodstream over a period of up to 36 hours after delivery of the carrier peptide active agent composition compared to a reference drug delivered alone. And Sustained release can be further defined as the release of the active substance into the blood circulation over a longer period of time compared to the release of the active substance in conventional formulations through a similar delivery route.

  The active substance is released from the composition by pH-dependent unfolding of the carrier peptide or released from the composition by enzyme catalysis. In a preferred embodiment, the active substance is released from the composition by a combination of time-dependent enzyme catalysis and the pH-dependent unfolding of the carrier peptide. The active substance is released from the composition in a sustained release form. In another preferred embodiment, the sustained release of the active agent from the composition has zero order or near zero order pharmacokinetics.

  The present invention provides several advantages for active agent delivery. First of all, the present invention can stabilize the active substance and prevent digestion in the stomach. Furthermore, the pharmacological effect can be prolonged by delayed or sustained release of the active substance. Sustained release can occur by the active agent being covalently attached to the peptide and / or through additional covalent attachment of an additive that bioadheses to the intestinal mucosa. Moreover, the active substances can be combined to produce a synergistic effect. Similarly, the absorption of the active substance in the intestinal tract can be enhanced by being covalently attached to the peptide or through the synergistic effect of added additives. The present invention also allows for targeted delivery of active agents to specific sites of action.

  Most of the enhanced performance imparted to the active agent by the carrier peptide can be explained by the structure of the composition. Proteins, oligopeptides and polypeptides are polymers of amino acids having primary, secondary and tertiary structures. The secondary structure of the peptide is the local conformation of the peptide chain and consists of a helix, a pleated sheet and a turn. Structural constraints on the peptide amino acid sequence and chain conformation determine the spatial arrangement of the molecule. Secondary structure folding and spatial arrangement of side chains constitute tertiary structure.

  Peptides fold due to the associated dynamics between adjacent atoms and solvent molecules on them. Peptide folding and unfolding thermodynamics are defined by the free energy of a particular condition of the peptide depending on the particular model. The peptide folding process involves, among other things, the packing of amino acid residues into the hydrophobic core. The amino acid side chain inside the peptide core occupies the same volume as the amino acid crystal. Thus, the interior of the folded peptide appears to be a crystalline solid rather than an oil drop, and therefore the best model for determining the force contributing to peptide stability is the solid reference state.

  The main forces that contribute to the thermodynamics of peptide folding are van der Waals interactions, hydrogen bonding, electrostatic interactions, coordination entropy and hydrophobic effects. When considering peptide stability, the hydrophobic effect means the energy consequence of removing nonpolar groups from the interior of the peptide and exposing them to water. When comparing the energy of peptide unfolding and amino acid hydrolysis in the solid reference state, the hydrophobic effect is the dominant force. Hydrogen bonds are established during the peptide folding process, and intramolecular bonds are formed at the expense of hydrogen bonds with water. Water molecules are “pushed out” from the packed hydrophobic peptide core. All of these forces combine to contribute to the overall stability of the folded peptide, where the degree to which an ideal packing occurs determines the relative stability of the peptide. The result of maximum packing is to produce a residue or hydrophobic core center with the greatest shielding from the solvent.

  Since there is a high probability that the hydrophobic active substance will be resident in the hydrophobic core of the peptide, energy is required to unfold the peptide before the active substance can be released. The unfolding process requires overcoming the hydrophobic effect by hydrating amino acids or achieving the melting temperature of the peptide. Heat of hydration is peptide destabilization. Typically, the peptide folding state is advantageous by about 5-15 kcal / mol compared to the unfolding state. Nevertheless, chemical reagents are required for peptides that unfold at neutral pH and room temperature. In fact, partial unfolding of peptides is often observed before irreversible chemical or conformational processes begin. Moreover, peptide conformation generally controls the rate and extent of harmful chemical reactions.

  Conformational protection of the active agent by the peptide depends on the stability of the peptide's folded state and the thermodynamics associated with the degradation of the agent. The conditions necessary for agent degradation should be different from peptide unfolding.

  The choice of amino acid will depend on the desired physical properties. For example, if an increase in bulk or lipophilicity is desired, the carrier peptide will be enriched for amino acids with bulky lipophilic side chains. On the other hand, polar amino acids can be selected to increase the hydrophilicity of the peptide.

  Ionized amino acids can be selected for pH-controlled peptide unfolding. Aspartic acid, glutamic acid, and tyrosine carry a neutral charge in the stomach, but become ionized when they enter the intestine. In other words, basic amino acids such as histidine, lysine and arginine ionize in the stomach and are neutral in an alkaline environment.

  Other factors such as π-π interactions between aromatic residues, peptide chain twisting with proline addition, disulfide bridges, and hydrogen bonding all help to select the optimal amino acid sequence for the desired performance parameter. Can be used. The ordering of the linear sequences can affect how these interactions can be maximized and is important in deriving the secondary and tertiary structure of the polypeptide.

  The variable molecular weight of the carrier peptide can have a profound effect on the active agent release kinetics. As a result, low molecular weight active agent delivery systems are preferred. One advantage of the present invention is that peptide chain length and molecular weight can be optimized depending on the desired level of conformational protection. This property can be optimized for the first stage kinetics of the release mechanism. Thus, another advantage of the present invention is that long release times can be imparted by increasing the molecular weight of the carrier peptide.

  Another significant advantage of the present invention is that the kinetics of release of the active substance is controlled primarily by enzymatic hydrolysis of the main bond between the carrier peptide and the active substance. Enzymes found in the intestinal lumen, on the intestinal cell surface, and inside the cell surface of the intestine can completely remove the drug from the carrier peptide before reaching the bloodstream. Thus, there are no concerns about the safety of the new composition.

  Dextran has been explored as a polymeric carrier for the covalent attachment of drugs for colon-specific drug delivery. In general, it was only possible to dose the drug up to one-tenth of the total drug-dextran conjugate weight. As mentioned above, polysaccharides are mainly digested in the colon and drug absorption is mainly limited in the colon. Compared to dextran, the present invention has at least two important advantages. First of all, the peptide is found in the intestinal lumen and is hydrolyzed by any one of a plurality of aminopeptidases or associated with the brush border membrane, so that active substance release and subsequent absorption is taken up in the jejunum and ileum. Can occur within. Second, the molecular weight of the carrier molecule can be controlled, and thus the input amount of the active substance can also be controlled.

  As a practical example, Table 1 below lists the molecular weights of lipophilic amino acids (minus 1 water molecule) and selected analgesics and vitamins.

  Lipophilic amino acids are preferred because conformational protection through the stomach is important for active agents selected based on ease of covalent attachment to the oligopeptide. Eighteen was subtracted from the molecular weight of the amino acid so that its condensation into the peptide was taken into account. For example, a glycine decamer linked to aspirin (MW = 588) would have a total molecular weight of 750, aspirin being 24% of the total weight of the active agent delivery composition or maximum drug input for dextran Will account for more than twice as much. This is only for N- or C-terminal applications, for example for these active substances attached to the pendant group of decaglutamic acid, a drug with a molecular weight of 180 may have an input of probably 58%. But this may not be completely practical.

  In one embodiment, the active agent is attached to a peptide having a length range between a single amino acid and 450 amino acids. In another embodiment, 2-50 amino acids are preferred, a range of 1-12 amino acids is more preferred, and 1-8 amino acids is most preferred. In another embodiment, the number of amino acids is selected from among 1, 2, 3, 4, 5, 6 or 7 amino acids. In another embodiment of the invention, the molecular weight of the carrier portion of the conjugate is less than about 2,500, more preferably less than about 1000 and most preferably less than about 500.

  In another embodiment, the active agent conjugate is a dimer of the active agent and a single amino acid. In another embodiment, the active agent conjugate is attached to a dipeptide or tripeptide.

  The composition of the present invention comprises four basic types of deposition. These attachment types are called C-capping, N-capping, side chain attachment and scattered types. C-capping forms involve the covalent attachment of the active substance to the C-terminus of the peptide, either directly or through a linker. N-capping forms involve the covalent attachment of the active substance to the N-terminus of the peptide, either directly or through a linker. Side chain attachment involves the covalent attachment of the active agent to the functional side chain of the peptide, either directly or through a linker. The scattered form involves the attachment of an active substance which is itself an amino acid. In this case, the active substance constitutes a part of the amino acid chain. Scattered form is here intended to include that the amino acid active (drug) is at the C-terminus, N-terminus or is scattered throughout the peptide. If the amino acid active substance is attached to the C-terminus or N-terminus, the result is that the active substance is terminal amino and is considered C-capped or N-capped, respectively. In addition, amino acids with reactive side chains (eg, glutamic acid, lysine, aspartic acid, serine, threonine and cysteine) can be incorporated to attach multiple active substances or additives to the same carrier peptide. This is particularly useful when a synergistic effect between two or more active substances is desired. The present invention also contemplates the use of multiple active agent or multiple attachment sites of active agent along the peptide chain. Further embodiments of the invention will become apparent from the following disclosure.

  The alcohol, amine or carboxylic acid group of the active substance is covalently bound to the N-terminus, C-terminus or side chain of the peptide. The location of attachment depends somewhat on the choice of functional group. For example, when the active drug is a carboxylic acid (eg, aspirin), the N-terminus of the oligopeptide is a preferred attachment point. When the active agent is an amine (eg, ampicillin), the C-terminus is a preferred point of attachment to achieve a stable peptide-linked active agent. In both cases, the C-terminal and N-terminal examples, essentially one monomer unit that forms a new peptide bond adds one molecule to the end of the peptide.

  If the active substance is an amine, an alternative way of attaching the amine to the C-terminus of the peptide is to allow the amine to initiate the polymerization of the amino acid NCA. When the active substance is an alcohol, either the C-terminus or N-terminus is a preferred point of attachment to achieve a stable composition. For example, if the active substance is an alcohol, the alcohol can be converted to an alkyl chloroformate with phosgene or triphosgene. This intermediate is then reacted with the N-terminus of the peptide carrier to produce an active agent peptide composition linked via carbamate. The carbamate active ingredient can then be released from the peptide carrier by intestinal peptidase, amidase or esterase.

  Alternatively, the alcohol active can be selectively coupled to the gamma carboxylate of glutamic acid, which is then covalently bound to the C-terminus of the peptide carrier. Since the glutamic acid-drug conjugate can be considered a dimer, the product contains two monomer units for the C-terminus of the peptide carrier where the glutamic acid moiety serves as a spacer between the peptide and the drug. Append. Intestinal enzymatic hydrolysis of the major peptide bond releases the glutamate-drug moiety from the peptide carrier. At this time, the newly formed free amine of the glutamic acid residue undergoes an intramolecular transamination reaction, thus releasing the active substance while simultaneously forming pyroglutamic acid as shown in FIG.

  Alternatively, the glutamic acid-drug dimer can be converted to the gamma ester of glutamic acid N-carboxyanhydride. This intermediate can then be polymerized using any suitable initiator as described above. The product of this polymerization is polyglutamic acid with the active ingredient attached to a number of pendant groups. Therefore, the maximum drug input amount of the carrier peptide can be achieved. Furthermore, other amino acid-NCAs can be copolymerized with gamma ester glutamic acid NCA to impart specific properties to the drug delivery system.

  Alternatively, alcohol can be added to the side chain chloroformate of polyserine as shown in Section III of the Examples. The product is a carbonate, where intramolecular rearrangement occurs at the time of hydrolysis of the peptide bond, many of which release the drug as described above.

  When the active substance is a ketone or aldehyde, a ketal is formed with a linker having a pendant group suitable for attachment to the N-terminus, C-terminus or side chain of the peptide. For example, ketal can be formed by reaction of methylnaltrexone with glucose or methylribofuranoside as shown in the example of glucose reacting with methylnaltrexone. At this time, the residual free hydroxyl from the sugar moiety can be treated as an alcohol for attachment to the appropriate side chain or C-terminus of the carrier peptide.

  The present invention also provides a method of imparting the same mechanism of action for other peptides containing functional side chains. Examples include, but are not limited to, polylysine, polyasparagine, polyarginine, polyserine, polycysteine, polytyrosine, polythreonine, and polyglutamine. This mechanism can be translated to these peptides through a spacer or linker on the pendant group, preferably terminated by a glutamate-active substance dimer. The side chain attached carrier peptide active agent conjugate preferably releases the active agent moiety through the peptidase, not necessarily the esterase activity. Alternatively, the active agent can be attached directly to a pendant group where any other resident enzyme in the gastrointestinal tract can affect release.

  When the active substance is an amide or imide, the active substance nitrogen can be added in Michael form to the dihydropyrancarboxylic acid alkyl ester as shown in Example VII: D. The R group can be an electron withdrawing group such that transesterification with the side chain of the peptide occurs or can be part of the side chain of the peptide. Release of the active substance from the linker is conferred by hydrolysis of the peptide carboxylate bond followed by an associated decarboxylation / removal reaction.

  The active agent can be covalently attached to the N-terminus, C-terminus or side chain using known techniques. When the active substance is an amino acid (eg thyroxine, triiodothyronine, DOPA, etc.), in addition to covalently binding the active substance to the N-terminus, C-terminus or side chain as described above, in peptide-linked form It can be interspersed within the peptide chain. It is a preferred embodiment of the present invention that a dispersed copolymer of an amino acid active substance and a neutral amino acid can be produced by polymerization of a mixture of the respective amino acids NCA.

  The composition of the invention comprises a peptide and an active substance covalently attached to the peptide. Examples of active substances that can be used in the present invention include, but are not limited to, the active substances listed in Table 2, either alone or in combination with other agents included in Table 2. Do not mean. As one skilled in the art will readily appreciate, the active agents listed in Table 2 may exist in a form that has been modified to facilitate bioavailability and / or activity (eg, Table 1). Sodium salt, halide-containing derivative or HCl form of the active substance listed in 2). Accordingly, the present invention encompasses variants of the active substances listed in Table 2 (ie salts, halogenated derivatives, HCl form).

  The present invention allows the combination of different peptides and different active substances to confer specific properties according to the desired solubility, pH or folding. Similarly, various peptides can be used to confer specific physicochemical properties to produce specific performance characteristics. The present invention offers significant advantages with regard to the stability and release and / or adsorption properties of the active substance (s). The conjugates of the invention are also suitable for the delivery of both large and small molecules.

  In another embodiment, conjugation formed with an active agent by using, as individual amino acids, one or more of 20 naturally occurring amino acids within an oligopeptide or within a polypeptide. Gives the body specific stability, digestibility and release characteristics.

  In another embodiment, the active agent conjugate is designed to interact with a specific resident enzyme so that targeted delivery can be achieved. These conjugates provide targeted delivery within all regions of the intestine and at specific sites along the intestinal wall. In another preferred embodiment, the active agent conjugate can incorporate the additive in such a way that the composition is designed to interact with a specific receptor so that targeted delivery can be achieved. . These compositions provide targeted transmission in all regions of the intestine and at specific sites along the intestinal wall. In another preferred embodiment, the active agent is released from the peptide conjugate as a reference active agent prior to entry into the target cell. In another preferred embodiment, the specific amino acid sequence used is not targeted to a specific cellular receptor and is not designed for recognition by a specific gene sequence. In a more preferred embodiment, the peptide carrier is not designed for recognition and / or is not recognized by tumor promoting cells. In another preferred embodiment, the active agent delivery system does not require the active agent to be released within or within a specific cell.

  In another embodiment, the active agent conjugate allows multiple active agents to be attached. Conjugates are not only numerous attachments of active agents, but also other active agents or other modified molecules that can further modify delivery, enhance release, target delivery and / or enhance adsorption Provides the additional advantage of allowing the attachment of a large number of active substances in combination. As an example, conjugates can be combined with additives as well as microencapsulated.

  In another embodiment of the invention, the composition includes one or more additives to enhance the bioavailability of the active agent. Otherwise, the addition of additives is particularly preferred when using active substances with low absorption levels. For example, suitable additives include papain, a potent enzyme for releasing the catalytic domain of aminopeptidase-N in the lumen; a sugar recognition substance that activates the enzyme in the brush border membrane (BBM); and peptides The bile acids attached to the peptides to enhance the absorption of are included.

  In another embodiment, absorption can be improved by increasing the solubility of the parent drug through selective attachment of amino acids, oligopeptides or polypeptides. As a result of increasing solubility, the dissolution rate increases. There is therefore an increase in the total amount of drug available for absorption. Bioavailability is increased because the drug must be in solution for absorption to occur.

  In another embodiment, the composition provides a wide range of pharmaceutical applications, including active agent delivery, cell targeting, and enhanced biological responsiveness.

  The present invention provides several advantages for active agent delivery. First, the present invention can stabilize the active substance and prevent digestion in the stomach. Furthermore, delayed or sustained release of the active substance can prolong the pharmacological effect. Sustained release can occur by the covalent attachment of the active substance to the peptide and / or through the additional covalent attachment of additives that bioadhere to the intestinal mucosa. Furthermore, the active substances can also be combined to produce a synergistic effect.

  Absorption of the active substance in the intestinal tract can be enhanced by being covalently attached to the peptide or through the synergistic effect of added additives. In a preferred embodiment of the present invention, the absorption of the active substance is increased due to its covalent binding to a peptide, which is a specialized example of a carrier peptide, hereinafter referred to as a transport peptide. In further embodiments, the transporter peptide activates a specific peptide transporter. In yet another embodiment, the peptide transporter is either a PepT1 or PepT2 transporter. In a preferred embodiment, the transporter peptide contains 2 amino acids. In another preferred embodiment, the transporter dipeptide is AlaSer, CysSer, AspSer, GluSer, PheSer, GlySer, HisSer, IleSer, LysSer, LeuSer, MetSer, AsnSer, ProSer, GrSer, Ser, SerGer It is selected from the list of TrpSer and TyrSer.

  In another embodiment, the present invention does not require attachment of the active agent to an additive that recognizes or is taken up by the active transporter. The present invention also allows for targeted delivery of active agents to specific sites of action.

  In another preferred embodiment, the amino acid chain length can be varied to suit different delivery criteria. In one embodiment, the present invention allows for the delivery of the active agent in sustained release.

  The present invention is further characterized by the following embodiments in which the active substance is released from the amino acid conjugate as a reference active substance prior to entry into the target cell for the active substance. In another embodiment, the active agent is prepared and / or administered through means other than transplantation and / or infusion material. Embodiments of the present invention preferably do not generate an antigenic response or otherwise stimulate the immune system in the host.

  In another embodiment of the invention, for a composition administered by an extra-gastrointestinal method, the intact conjugate is biotransformed by cytochrome P450 (CYP) 3A4 and efflux by the transporter P-glycoprotein. May be less likely to undergo first-pass metabolism by enterocytes, including. Through the maintenance of the three-dimensional structure of the composition or some other means that maintains blood levels below a threshold for expression of these metabolic factors, immunogenicity and metabolic effects are avoided.

  In another preferred embodiment, the active agent is attached directly to the amino acid without the use of a linker.

  A monolayer of Caco-2 human intestinal epithelial cells is increasingly used to predict the absorption of orally delivered drugs. Caco-2 cells are grown on the surface of collagen-coated walls in a 24-well format to form a confluent monolayer that represents a small segment of the intestine. The wells are removable and contain an upper chamber (facing the intestinal lumen) representing the distal side and a lower chamber (serosa drug absorption site) representing the basolateral side. The integrity of the epithelial barrier is monitored by testing the electrical resistance across the monolayer. Drug absorption can be studied by adding a specimen to the apical side and assaying the concentration of drug in the basolateral chamber after incubation.

  The small intestine has a very large surface area covered with highly specialized epithelial cells that produce both extracellular and intracellular oxygen. Caco-2 cells also release enzymes similar to small intestinal epithelial cells. There is little precedent for using Caco-2 cells as a model for digesting synthetic peptides. However, it is possible to measure the drug release from the peptide at the tip side of the Caco-2 transwell monolayer. A copolymer of glutamic acid and thyroxine enhanced the absorption of thyroxine across the Caco-2 monolayer.

  In another embodiment, the present invention provides a method for testing conjugates using Caco-2 cells.

  Table 3 provides a list of active substances covalently attached to the peptides. This table also provides a standard use area list for active substance conjugates.

  The compositions of the present invention can be formulated into pharmaceutical compositions by combining the compound with pharmaceutically acceptable excipients known in the art. The conjugate can be utilized in powder or crystalline form, liquid solution or suspension. Conjugates of the invention include topical administration, oral administration, parenteral administration by injection (intravenous, intramuscular or subcutaneous), including depot grafts, intranasal preparations, as inhalers or as anal suppositories. Can be administered by various means. Injectable compositions can take the form of suspensions, solutions or oils or emulsions in aqueous vehicles and can contain a variety of pharmaceutical agents. Alternatively, the conjugate may be in the form of a powder for reconstitution with a suitable vehicle such as sterile water upon delivery. In injectable compositions, the carrier typically consists of sterile water, saline or another injectable liquid such as peanut oil for intramuscular injection. Similarly, various buffering agents, preservatives and the like can be included. For topical application, it can be formulated in carriers such as ointments, creams, hydrophobic or hydrophilic bases to form lotions, or in aqueous, oily or dry diluents to form powders. Oral compositions can take the form of tablets, capsules, oral suspensions and oral solutions. Oral compositions can utilize carriers such as conventional pharmaceutical agents and can include sustained release properties as well as fast delivery forms. The dose to be administered depends to a large extent on the physical condition and size of the subject to be treated, the route of administration and its frequency. One embodiment of the method of administering the conjugate includes oral and parenteral methods such as intravenous infusion, intravenous bolus and intramuscular injection. In a further embodiment of the invention, the composition incorporates a microencapsulating agent. Preferably, the compositions of the invention are ingestible tablets or capsules, implantable devices, skin patches, sublingual preparations, subcutaneous preparations, intravenous preparations, intraperitoneal preparations, intramuscular preparations. Or in the form of an oral suspension. Most preferably, the composition is formulated for oral delivery.

  Throughout the application, the figures are intended to depict a general scheme for attaching active agents through different functional groups to various peptide conjugates that result in different embodiments of the invention. One skilled in the art will recognize other reagents, conditions and properties necessary to conjugate other active agents to other peptides from the scheme, which are intended to be non-limiting examples. Would do. The drawing shows a book on the length of active substance conjugates in which amino acids, dipeptides, tripeptides, oligopeptides and peptide active substances can each be represented by n = 0 for amino acids and n ≧ 1 for other peptide embodiments. It further represents different embodiments of the invention.

I N-terminal attachment of the active substance to the peptide The N-terminal attachment of the active substance to the peptide can be formed through multiple active substance functional groups. Non-limiting examples of active substance functional groups include alcohol groups, carboxylic acid groups, amine groups or other reactive substituents. Preferred active agent attachment functional groups for N-terminal attachment to peptides include carboxylic acids, ketones and aldehydes. If attachment at the N-terminus is to be done with alcohol or its equivalent or amine or its equivalent, insertion of a linker between the functional group and the active substance is typically required.

  Any amino acid can be used as the N-terminus of the peptide / active agent conjugate. Preferred amino acids for attachment include glutamic acid, aspartic acid, serine and lysine.

  The following specific examples of active substances attached to the N-terminus are provided as examples only and are intended to limit the invention to any specific active substance, amino acid or combination thereof. It is not what was done. Preferred drugs for N-terminal attachment typically provide inorganic functional groups for carboxylic acid or conjugation. As an example, ibuprofen, furosemide, gemfibrozil, naproxen can be attached to the N-terminus.

The following scheme depicts a method for attaching an active substance to the N-terminus. These figures and procedures describe a general scheme for attaching active agents to the N-terminus of peptides.

As described, the acid-bioactive substance can be dissolved in DMF under nitrogen and cooled to 0 ° C. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by an amine peptide carrier. The reaction can then be stirred at room temperature for several hours, the urea byproduct can be removed by filtration, the product can be precipitated in ether and purified using gel permeation chromatography (GPC) or dialysis.

  As mentioned above, the combination of triphosgene and alcohol produces a chloroformate, which produces a carbamate when reacted with the N-terminus of the peptide. Accordingly, alcohol bioactive substances can be treated with triphosgene under nitrogen in dry DMF. Next, the appropriately protected peptide carrier is slowly added and the solution is stirred for several hours at room temperature. The product is then precipitated in ether. The crude product is deprotected as appropriate and purified using GPC.

Other solvents, activators, cocatalysts and bases can also be used. Examples of other solvents include dimethyl sulfoxide (DMSO), ethers such as tetrahydrofuran (THF), or chlorinated solvents such as chloroform (CHCl ₃ ). Examples of other activators include dicyclohexylcarbodiimide or thionyl chloride. Another example of a cocatalyst is N-hydroxysuccinimide (NHS). Examples of the base include pyrrolidinopyridine, dimethylaminopyridine, triethylamine (Et ₃ N) or tributylamine.

I: A-Example: Attachment of Furosemide via Carboxylic Acid to the N-terminus of Poly (Serine) The following example describes the attachment of an amino acid active substance to the N-terminus of a peptide. In the embodiment, poly Ser attached to furosemide is used.

  Furosemide-OSu and N-methylmorpholine (NMM) were added to a solution of pSer (OtBu) in N-methylpyrrolidinone (NMP). The reaction was stirred overnight at room temperature. The reaction was stirred overnight at 60 ° C. because solid material remained. After cooling, the reaction was taken up in water (50 mL), the solid was collected by filtration and the solid was dried (0.480 g, 86% yield).

The addition of 95% TFA / H ₂ O to the above material advanced the deprotection of pSer (OtBu). The resulting dark solution was stirred overnight. The solvent was then removed, NaHCO ₃ (saturated solution) was added and the crude product was purified using ultrafiltration (YM1) to give furosemide-pSer (0.101 g) as a dark green solid. .

I: B-Example: Attachment of Enalipril via Carboxylic Acid to the N-terminus of GluGlu Synthesis of Enalipril-Glu-Glu Enalipril maleate (0.200 g, 406 umol) hydroxybenzotriazole (0.164 g) in 7 ml dry DMF , 1217 umol), Glu (OtBu) Glu (OtBu) OtBu (0.560 g, 1217 umol) and diisopropylethylamine (0.210 ml, 1217 umol), O- (1H-benzotriazol-1-yl) N, N, N ', N' tetramethyluronium hexafluorophosphate (0.461 g, 1217 umol) was added. After stirring for 16 hours under argon, 40 ml of saturated NaCl (aq) was added to the black solution. The reaction was extracted with 2 × 10 ml of EtOAc (dark color remained in organic material). The organic material was dried over anhydrous MgSO ₄ , filtered and the solvent removed by rotary evaporation. The residue was purified by flash chromatography _{(SiO 2 1: 0-60: 1-40} : 1-30: 1-20: 1-10: 1) to give the as gum yellowish Enaripuriru -Glu (OtBu) Glu ( OtBu) OtBu was obtained (0.231 g, 54%): R _f 0.43 (9: 1 CHCl ₃ : MeOH + HOAc ¹ drop); ¹ H-NMR (DMSO / CDCl ₃ ) 7.13 (m, 5H), 4 .43-4.09 (m, 5H), 2.20 (m, 7H), 1.97-1.80 (m, 13H), 1.35 (m, 27H), 1.22 (m, 6H) ); ESMS803.

Enalipril-Glu (OtBu) Glu (OtBu) OtBu (0.172 g, 214 umol) was stirred with 9.5 ml trifluoroacetic acid and 0.5 ml H ₂ O for 7.5 hours. The solvent was removed by rotary evaporation and the residue was dried under vacuum. ¹ H-NMR (DMSO) 7.13 (m, 5H), 4.43-4.09 (m, 5H), 2.20 (m, 7H), 1.97-1.80 (m, 13H) , 1.42 (m, 3H), 1.22 (m, 3H); FABMScalc635.293, ob635.490.

II: C-terminal attachment of the active substance to the peptide The C-terminal attachment of the active substance to the peptide could be formed through multiple active substance functional groups. Functional groups include amines and their equivalents and alcohols and their equivalents. Although any amino acid can be used to link the active substance to the C-terminus, glutamic acid, aspartic acid, serine and lysine are preferred amino acids. Preferred active substances for C-terminal attachment are active substances with alcohol and amino functions. More preferred active substances include atenolol, metropolol, propanolol, methylphenidate and sertraline.

  The following scheme depicts a method for attaching an active substance to the C-terminus. Those skilled in the art will recognize other reagents, conditions and properties necessary to conjugate other active agents from the scheme, which are intended to be non-limiting.

This figure and procedure describe a general scheme for attachment of amine actives to the C-terminus of peptides. In the following scheme, the peptide carrier can be dissolved in DMF under nitrogen and cooled to 0 ° C.
The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by an amine bioactive substance. The reaction can then be stirred at room temperature for several hours, the urea byproduct can be removed by filtration, the product can be precipitated in ether and purified using GPC or dialysis.

  The following specific examples of active substances attached to the C-terminus are intended as examples only and are intended to limit the invention to any specific active substance, amino acid or combination thereof. It is not a thing.

II: A—Example: Amine-Initiated Polymerization of L-Glutamic Acid NCA This example can be used to comprehensively describe the process of amine active material that initiates the polymerization of amino acid NCA. The following procedure was successfully used to synthesize a polyglutamic acid conjugate of atenolol. Similarly, it should be noted that atenolol is also an alcohol active and can also initiate polymerization of the amino acid NCA. This procedure is readily applicable to the other amine drugs described herein.

  Table 24 describes the relative proportions that will be used in standard atenolol preparations. Other amine drugs that will be used to initiate the polymerization of the amino acid NCA are expected to utilize similar proportions.

  Although the procedure is further described below, one of ordinary skill in the art will recognize other solvents, proportions and reaction conditions that can be utilized to achieve the desired result. DMF is anhydrous dimethylformamide and was purchased from Aldrich. Glassware was oven dried prior to use. Glu-NCA (500 mg, 2.89 mmoles) was dissolved in 4 mL DMF and stirred under argon in a 15 mL round bottom flask equipped with a gas inlet tube. Atenolol dissolved in 1 mL of DMF was added to this Glu-NCA solution and allowed to stir at room temperature for 72 hours. In general, the reaction can be carried out by thin layer chromatography (TLC) until no free amine initiator is present. For this reason, TLC was performed using a silica plate eluting with 20% methanol in ethyl acetate. The reaction was quenched by pouring into 20 mL of 10% sodium bicarbonate (pH = 8) in water. The water was washed with 3 × 20 mL methylene chloride and 3 × 20 mL ethyl acetate. The combined aqueous layer was brought to pH 6 with 6N hydrochloric acid (HCl) and reduced to a volume of about 20 mL by rotary evaporation.

  The solution was then allowed to cool in the refrigerator for more than 3 hours. In order to precipitate the polymer product, the aqueous solution was then acidified with 6N HCl to about pH 2 and returned to the refrigerator for 1-2 hours. The suspension was poured little by little into a 10 mL test tube and centrifuged for 15 minutes until the precipitate formed a solid pack at the bottom of the tube, from which water could be decanted. (At this point in the general procedure, it is preferred that the solid is filtered through a filter funnel and washed with acidic water. Centrifugation was used for athenol because the solid was too thin to filter. ) The solid was then resuspended in acidic water (pH about 2) and subjected to vortex before being centrifuged again and the water decanted. This procedure was repeated once for a total of three washes. The solid was then dried by high vacuum overnight to give 262 mg (59%) of polymer. NMR analysis showed that the Glu / Athenol ratio was about 30/1.

II: B—Example: Preparation of (Glu) _n -cephalexin via an amine bond The following example describes the attachment of an amino acid active to the C-terminus of a peptide. In this example, glutamic acid NCA is used to produce poly-Glu attached to cephalexin. Cephalexin attached to a single amino acid can be generated via the following method when an excess of cephalexin is added to the procedure.

Glu (OtBu) NcA (1.000 g, 4.4 mmol) and cephalexin.HCl (0.106 g, 0.3 mmol) were dissolved in anhydrous DMF (5 mL). The reaction was then allowed to stir at room temperature under argon. After 3 days, the solvent was removed by rotary evaporation under vacuum. The resulting solid was then placed under argon and then dissolved in 4N HCl in dioxane (2 mL) and then allowed to stir at room temperature under a side of argon. After 1 hour, dioxane and HCl were removed by rotary evaporation under vacuum. The solid was then suspended in methanol (2 mL) and dried once more under rotary evaporation to remove residual HCl and dioxane. This material was then resuspended in methanol (2 mL) and precipitated by adding water (20 mL). The aqueous suspension was then stored for 4 hours at 4 ° C. and the solid was isolated by centrifugation. The pelletized material was then dried under vacuum overnight. This process resulted in a mixture of (Glu) _n and (Glu) _n -cephalexin (464 mg) as determined by MALDI. MALDI refers to a mixture of the polymers (Glu) _7-13 and (Glu) _5-14 -cephalexin. Other chain lengths may exist, but these are not clearly visible in the MALDI spectrum. Reverse phase HPLC (265 nm detection, C18 column, 16% MeOH / 4% THF / 80% water, mobile phase) showed no free cephalexin present in the isolated material. “Water” in HPLC actually means an aqueous buffer of 0.1% heptane sulfonic acid and 1.5% triethylamine.

II: C—Example: Synthesis of PolyGlu-Atenolol The following procedure was successfully used to synthesize a polyglutamic acid conjugate of atenolol.

ＤＭＦは無水ジメチルホルムアミドであり、アルドリッチから購入した。ガラス製品は使用前にオーブン乾燥させた。

DMF is anhydrous dimethylformamide and was purchased from Aldrich. Glassware was oven dried before use.

  Glu-NCA (2 g, 11.56 mmoles) was dissolved in 8 mL DMF and stirred under Ar in a 25 mL round bottom flask equipped with a gas inlet tube. Atenolol dissolved in 2 mL of DMF was added to the Glu-NCA solution and stirred for 93 hours at room temperature. Bubbles were observed at the start of the reaction. DMF was reduced by rotary evaporation, the oil was transferred into a 125 mL Erlenmeyer flask, and the round bottom well was rinsed with water. The pH of the solution was adjusted to 3 with 1N HCl. This solution (total volume 60 mL) was then supercooled in the refrigerator for 3 hours. The suspension was filtered through a sintered glass funnel and washed first with 3 × 30 mL of 1% AcOH in methanol and then with 3 × 30 mL of ethanol. The solid was then dried under high vacuum to give 892 mg (68%) of polymer. NMR analysis showed that the Glu / Atenolol ratio was about 15/1. This is based on the relative incorporation of methyl groups on the N-isopropyl substituent of atenolol (6 protons) and the β and γ protons of Glu (two each).

II: D-Example: Synthesis of [Glu] ₁₅ -carbadopa To 50 mg carbadopa (0.22 mmoles) dissolved in 4 mL dry dimethylformamide is added 573 mg (3.3 mmoles) GluNCA. Stir overnight under argon. After adding 12 mL of H ₂ O, pH = 2.0, the solution was ultrafiltered with an additional 100 mL of H ₂ O, pH = 2 (regenerated cellulose, millipore, YM1, NMWL = 1000). The resulting precipitate was collected by filtration, washed with 30 mL H ₂ O and dried in vacuo at room temperature to give 268 mg of light brown powder. The ratio of carbadopa to Glu was determined to be 1: 4 by ¹ HNMR. ¹ H NMR (500 MHz, DMSO) peak assignments were as follows: δ 6.61-6.58 (aromatic, carbadopa), 6.47-6.41 (aromatic, carbadopa), 4.25 ( α, Glu), 2.25 (γ , Glu), 2.00~1.65 (β, Glu), 1.11 (CH 3, Carbadopa).

II: E—Example: Preparation of Drug-Glu Conjugate as Starting Synthon for Polymerization The following example is a description of C-terminal attachment. This example describes how to attach a single amino acid to an active agent which is one of the preferred embodiments. This example also provides an active substance / amino acid conjugate that can be supplemented with additional amino acids, resulting in the desired peptide. A preferred embodiment of the peptide includes a copolymer of glutamic acid and N-acetylcysteine.

  For non-primary amine drug candidates, formation of the active substance-poly-Glu conjugate may require formation of the active substance / amino acid synthon prior to polymerization. The following scheme was used in which the active substance was first conjugated to Glu and then this synthon was used to initiate coupling. Examples of this protocol are further described as applied to sertraline, propranolol and metoprolol.

II: Protocol for coupling Boc-Glu (OtBu) -OH to F-sertraline Boc-Glu (OtBu) -OH (0.44 g, 1.46 mmol) in dry DMF (15 mL) with stirring ) And PyBOP (0.84 g, 1.60 mmol) were dissolved. DIEA (0.31 mL, 1.75 mmol) was added and the amino acid derivative was activated for 15 minutes. Sertraline hydrochloride (0.50 g, 1.46 mmol) was added to the stirred mixture followed by an additional 0.31 mL of DIEA. The mixture was allowed to stir for 16 hours. The solution was stripped to give a brown oil. The oil was dissolved in EtOAc (100 mL) and the resulting solution was washed with 10% HCl (3 × 30 mL), saturated NaHCO ₃ , 4M NaHSO ₄ and brine (2 × 30 mL each). The solution was dried over MgSO ₄ , filtered and the solvent removed by rotary evaporation under reduced pressure to give a light brown oil. The oil was dried on a vacuum manifold and the product was purified by column chromatography on silica gel using a solvent system of EtOAc / hexane 1: 5 to 1: 4. The product fractions were pooled and the solvent removed again by rotary evaporation to give 0.85 g (99%) of the final product sertraline-NH—C (O) -Glu-NH ₃₊ . The preparation was dried on a vacuum manifold.

II: Synthesis of G-polyGlu-propranolol (i) Protocol for coupling Boc-Glu (OtBu) -OH to propranolol Boc-Glu (OtBu)-in dry DMF (15 mL) with stirring OH (0.44 g, 1.46 mmol) and PyBOP (0.84 g, 1.60 mmol) were dissolved. DIEA (0.31 mL, 1.75 mmol) was added and the amino acid derivative was activated for 15 minutes. Propranolol hydrochloride (0.43 g, 1.46 mmol) was added to the stirring mixture followed by an additional 0.31 mL of DIEA. The mixture was allowed to stir for 16 hours. The solution was stripped to give a brown oil. The oil was dissolved in EtOAc (100 mL) and the resulting solution was washed with 10% HCl (3 × 30 mL), saturated NaHCO ₃ , 4M NaHSO ₄ and brine (2 × 30 mL each). The solution was dried over MgSO ₄ , filtered and the solvent removed by rotary evaporation under reduced pressure to give a light brown oil. The oil was dried on a vacuum manifold and the product was purified by column chromatography on silica gel using a solvent system of EtOAc / hexane 1: 5 to 1: 4. The product fractions were pooled and the solvent removed again by rotary evaporation to give the final product propranolol-NH-C (O) -Glu-NH ₃₊ . The preparation was dried on a vacuum manifold.

(Ii) Protocol for Initiating Glu-NCA Polymerization with Propranolol-Glu The synthons described above were used in a reaction similar to that provided for atenolol.

II: H—Example: Synthesis of PolyGlu-Metroprolol This synthesis was identical to that described for PolyGlu-Propranolol.

II: I—Example: Preparation of PolyGlu-Prednisone The following example describes an alcohol that initiates the polymerization of Glu-NCA to produce a C-terminal ester / drug conjugate.

Glu (21-prednisone) (0.045 g, 92 μmol) was added to GluNCA (0.128 g, 738 μmol) in 4 mL of dry DMF. After stirring for 68 h under Ar, 30 mL of H ₂ O was added. The reaction was acidified to pH 4 with 1N HCl and then concentrated in vacuo. ¹ HNMR (DMSO) analysis showed a Glu: prednisone ratio of 13: 1.

II: Preparation of J-Glu-Furosemide This is an example of a sulfonamide attached to the C-terminus of a peptide.

Glu-Furosemide To the furosemide solution in dioxane, NMM was added followed by Boc-Glu (OtBu) -OSu. The solution was stirred at ambient temperature for 18 hours. The reaction was quenched with saturated NaHCO ₃ (25 ml) and the solvent was removed. The crude material was purified by preparative HPLC (Phenomenex Luna C18, 30 × 250 mm, 5 μM, 100 μm; gradient; 70 0.1% TFA-water / 30 0.1% TFA-MeCN → 0 / 100 0-15 min; 30 ml / min). The solid was collected as a white powder (0.054 g, 9% yield). ¹ H NMR (DMSO-d6) δ 1.40 (m, 18H), 1.53 (m, 1H), 1.62 (m, 1H), 1.85 (m, 2H), 3.95 (m, 1H), 4.60 (d, 2H), 6.42 (d, 2H), 7.00 (d, 1H), 7.07 (s, 1H), 7.62 (s, 1H), 8. 47 (s, 1H), 8.83 (t, 1H), 12.31 (brs, 1H).

II: Preparation of Ala-Pro-hydrocodone via K-enolic acid hydrocodone

Ala-Pro-Hydrocodone NMM followed by Boc-Ala-OSu was added to the Pro-hydrocodone solution in DMF. The solution was stirred at ambient temperature for 18 hours. The solvent was removed. The crude material was used using preparative HPLC (Phenomenex Luna C18, 30 × 250 mm, 5 μM, 100 μm; gradient; 100 water / 0 0.1% TFA-MeCN → 0/100; 30 ml / min). Purified. The solid was collected as a slightly yellow powder (0.307 g, 85% yield). ¹ H NMR (DMSO-d ₆ ) δ 1.16 (d, 3H), 1.35 (s, 9H), 1.51 (m, 2H), 1.86-2.10 (m, 6H), 2 .50 (m, 1H), 2.54 (m, 1H), 2.69 (m, 1H), 2.88 (s, 3H), 3.02 (dd, 1H), 3.26 (d, 1H), 3.55 (m, 1H), 3.67 (m, 1H), 3.72 (s, 3H), 3.80 (s, 1H), 4.25 (m, 1H), 4. 43 (d, 1H), 5.01 (s, 1H), 5.59 (d, 1H), 6.75 (d, 1H), 6.88 (d, 1H), 6.99 (t, 1H) ), 9.91 (br s, 1H).

To Boc-Ala-Pro-hydrocodone (0.100 g), 10 ml of 4N HCl in dioxane was added. The resulting mixture was stirred at ambient temperature for 18 hours. The solvent was removed and the final product was dried under vacuum. The solid was collected as a slightly yellowish solid (0.56 g, 71% yield). ¹ H NMR (DMSO-d ₆ ) δ 1.38 (s, 3H), 1.48 (t, 1H), 1.80-2.29 (m, 8H), 2.65 (m, 1H), 2 .80 (s, 3H), 2.96 (m, 3H), 3.23 (m, 2H), 3.76 (s, 3H), 3.92 (s, 1H), 4.22 (s, 1H), 4.53 (s, 1H), 5.00 (s, 1H), 5.84 (d, 1H), 6.77 (d, 1H), 6.86 (d, 1H), 8. 25 (br s, 3H).

II: Preparation of L-Leu-hydrocodone

Leu-hydrocodone LiN (TMS) ₂ in THF was added via a syringe to the hydrocodone solution in THF. The solution was stirred for 5 minutes at ambient temperature, then Boc-Leu-OSu was added. The resulting reaction mixture was stirred for 18 hours at ambient temperature. The reaction was neutralized to pH 7 with 6M HCl. The solvent was removed. The crude material was taken up in CHCl ₃ (100 ml), washed with saturated NaHCO ₃ (3 × 100 ml), dried over MgSO ₄ , filtered and the solvent removed. The solid was collected as a yellow powder (1.98 g, 95% yield). ¹ H NMR (DMSO-d ₆ ) δ 0.86 (dd, 6H), 1.31 (s, 9H), 1.46 (s, 2H), 1.55 (m, 2H), 1.69 (m 1H), 1.87 (dt, 1H), 2.07 (dt, 2H), 2.29 (s, 3H), 2.43 (m, 2H), 2.93 (d, 1H), 3 .11 (s, 1H), 3.72 (s, 3H), 3.88 (dt, 1H), 4.03 (dt, 1H), 4.87 (s, 1H), 5.51 (d, 1H), 6.65 (d, 1H), 6.73 (d, 1H), 6.90 (s, 1H).

To Boc-Leu-hydrocodone, 25 ml of 4N HCl in dioxane was added. The resulting mixture was stirred at ambient temperature for 18 hours. The solvent was removed and the final product was dried under vacuum. The solid was collected as a slightly yellowish solid (1.96 g, 97% yield). ¹ H NMR (DMSO-d ₆ ) δ 0.94 (d, 6H), 1.52 (m, 1H), 1.75-1.90 (m, 4H), 2.22 (dt, 1H), 2 .34 (dt, 1H), 2.64 (q, 1H), 2.75 (s, 3H), 2.95-3.23 (m, 4H), 3.74 (s, 3H), 3. 91 (d, 1H), 4.07 (s, 1H), 5.10 (s, 1H), 5.72 (d, 1H), 6.76 (d, 1H), 6.86 (d, 1H) ), 8.73 br s, 3H).

II: Preparation of M-Gly-Gly-Leu-hydrocodone

Gly-Gly-Leu-hydrocodone To a solution of Leu-hydrocodone in DMF was added NMM followed by Boc-Gly-Gly-OSu. The solution was stirred at ambient temperature for 18 hours. The solvent was removed. The crude material was used using preparative HPLC (Phenomenex Luna C18, 30 × 250 mm, 5 μM, 100 μm; gradient; 90 water / 10 0.1% TFA-MeCN → 0/100; 30 ml / min). Purified. The solid was collected as a slightly yellow powder (2.08 g, 73% yield). ¹ H NMR (DMSO-d ₆ ) δ 0.88 (dd, 6H), 1.38 (s, 9H), 1.53-1.72 (m, 5H), 1.89 (d, 1H), 2 .15 (m, 1H), 2.67 (m, 2H), 2.94 (s, 3H), 3.05 (m, 2H), 3.25 (m, 2H), 3.56 (d, 3H), 3.76 (s, 6H), 3.98 (s, 1H), 4.35 (q, 1H), 5.04 (s, 1H), 5.59 (d, 1H), 6. 77 (d, 1H), 6.85 (d, 1H), 7.04 (t, 1H), 8.01 (t, 1H), 8.30 (d, 1H), 9.99 (brs, 1H).

To Boc-Gly-Gly-Leu-hydrocodone (2.08 g), 50 ml of 4N HCl in dioxane was added. The resulting mixture was stirred at ambient temperature for 18 hours. The solvent was removed and the final product was dried under vacuum. The solid was collected as a slightly yellow solid (1.72 g, 86% yield). ¹ H NMR (DMSO-d ₆ ) δ 0.89 (dd, 6H), 1.50-1.87 (m, 5H), 2.26 (m, 2H), 2.66 (m, 2H), 2 0.82-2.97 (m, 5H), 3.21 (m, 2H), 3.60 (m, 4H), 3.88 (m, 5H), 4.37 (m, 1H), 04 (s, 1H), 5.60 (s, 1H), 6.79 (d, 2H), 8.07 (brs, 3H), 8.54 (brs, 1H), 8.66 (br s, 1H), 11.29 (br s, 1H).

II: Preparation of N-Gly-Gly-Gly-Gly-Leu-hydrocodone

Gly-Gly-Gly-Gly-Leu-Hydrocodone NMM followed by Boc-Gly-Gly-OSu was added to the aqueous solution of Gly-Gly-Leu-hydrocodone in DMF. The solution was stirred at ambient temperature for 18 hours. The solvent was removed. The crude material was analyzed using preparative HPLC (Phenomenex Luna C18, 30 × 250 mm, 5 μM, 100 μm; gradient; 85 water / 15 0.1% TFA-MeCN → 50/50; 30 ml / min). Purified. The solid was collected as a slightly yellow powder (0.304 g, 37% yield).

To Boc-Gly-Gly-Gly-Gly-Leu-hydrocodone (0.304 g), 25 ml of 4N HCl in dioxane was added. The resulting mixture was stirred at ambient temperature for 18 hours. The solvent was removed and the final product was dried under vacuum. The solid was collected as a slightly yellow solid (0.247 g, 97% yield). ¹ H NMR (DMSO-d ₆ ) δ 0.87 (m, 6H), 1.23 (s, 1H), 1.51-1.86 (m, 4H), 2.18 (m, 1H), 2 .71 (m, 2H), 2.77 (s, 3H), 2.96 (m, 2H), 3.17 (m, 2H), 3.61 (s, 3H), 3.81-3. 84 (m, 10H), 4.22 (m, 1H), 4.36 (m, 1H), 5.09 (m, 1H), 5.59 (d, 1H), 6.74 (dd, 2H) ), 8.16 (br s, 4H), 8.38 (br s, 1H), 8.74 (br s, 1H), 11.42 (br s, 1H).

III. Drug side chain attachment to the peptide The active substance attachment to the peptide side chain can be formed through a plurality of functional group combinations that can be selected from among the amino acids or active substances used for conjugation. Unlike when the active substance is conjugated at the N-terminus or C-terminus, where the amino acid functional group is limited to either an amine or carboxylate group, respectively, side chain attachment is a specific amino acid side chain functional group. Allows variation in the choice of Furthermore, where applicable, the active agent functional group can be selected to be compatible with the amino acid side chain utilized for attachment. The functional group depends on the functional group on the side chain of the peptide utilized for conjugation. Because of the diversity of side chain attachment, any active substance can be attached directly to the amino acid side chain with an appropriate functional group. Active substances containing alcohols, amines and / or carboxylic acids are directly susceptible to attachment valleys and can determine the side chains of selected amino acids. For active substances lacking these functional groups, alcohol, amine or carboxyl groups are preferably included in the linker incorporation.

  More preferred amino acids used to create attachments and / or peptides are glutamic acid, aspartic acid, serine, lysine, cysteine, threonine and glutamine. Although homopolymers are often used, heteropolymers can also be utilized to provide specific performance parameters. These heteropolymers can be of various chain lengths and heterogeneities. Preferred examples include, but are not limited to, Leu-Ser, dipeptides including Leu-Glu, homopolymers of Glu and Leu, and heteropolymers of (Glu) n-Leu-Ser. Absent.

An example of side chain attachment conjugation to an acid drug is depicted in the following scheme:

The following example is a depiction of the side chain attachment conjugation of an acid drug. In this case, the depicted amino acid is lysine.

An example of side chain attachment to an amine drug is depicted in the following scheme:

An example of side chain attachment conjugation to an alcohol drug is depicted in the following scheme:

  The following examples describe general procedures for the attachment of amino acid actives to the side chains of peptides. Example III: A-III: G describes the attachment of an active substance to a peptide through an alcohol group. One of the examples describes the attachment of naltrexone to aspartic acid, while the other examples show different active substances attached to glutamic acid. Example III: H-III: I is converted from one of the naturally occurring amino acids, in this case Glu, to a glutamic acid derivative for subsequent incorporation into the peptide through the NCA method or through the use of a peptide synthesizer The conversion of is illustrated. Example III: J is also one of the naturally occurring amino acids, in this case Glu, to a glutamic acid derivative that can be further incorporated into linear or dendritic peptides through the NCA method or through the use of a peptide synthesizer. This is an example of conversion. Example III: K-III: N represents a carboxylic acid attached to the side chain of an amino acid. In this example, the active substance is attached to polylysine through an amino group. Example III: O describes a sulfonamide attached to the side chain of polyglutamic acid.

  The following specific examples of active agents attached to side chain attachments are intended as examples only and are intended to limit the invention to either specific active agents, amino acids, or combinations thereof. It was n’t. One skilled in the art will recognize from this disclosure other active agents that can be attached to the side chain of the peptide.

III: Attachment of active substance via alcohol group to the side chain of A-peptide

To a poly (glutamic acid) solution in DMF, N-methylmorpholine and bromo-tris-pyrrolidino-phosphonium foxafluorophosphate (PyBrOP) were added. The resulting mixture was allowed to stir at room temperature for 30-60 minutes. After this time, N-methylmorpholine and DMAP followed by drug were added. The resulting solution was stirred at room temperature or 60 ° C. for 24-48 hours. Thereafter, the solvent and excess base were removed using vacuum evaporation. Thereafter, water was added methanol or i- propanol, collect the resulting solid was dissolved in NaHCO 3 _(sat). The crude product was purified using ultrafiltration. The product was then collected from the ultrafiltration using acid precipitation, methanol precipitation, acetone precipitation or water removal under reduced pressure.

III: B-Example: Naltrexone derivative

(I) Boc-Glu (Nal) -OtBu:
The following examples describe the attachment of different alcohol actives to glutamic acid side chains to generate new ester bonds.

Solid Boc-Glu-OtBu (0.96 g, 3.18 mmol), naltrexone (1.00 g, 2.65 mmol) and PyBrop (1.73 g, 3.71 mmol) were dissolved in 5 mL anhydrous DMF and under argon. Stir at room temperature. Dry N-methylmorpholine (1.08 mL, 9.81 mmol) was added and the reaction was continued at room temperature under argon. Two days later, additional Boc-Glu-OtBu (0.096 g, 0.32 mmol), PyBrop (0.173 g, 0.37 mmol) and N-methylmorpholine (0.10 mL, 0.981 mmol) were added. Two more days later, the solvent was removed by rotary evaporation under high vacuum. The resulting residue was then dissolved in CHCl ₃ and the resulting organic solution was finally washed with 2 × 20 mL saturated NaCl, 3 × 20 mL 10% Na ₂ CO ₃ and 20 mL saturated NaCl water. Extracted. The organic solution was collected, dried over sodium sulfate and then adsorbed onto silica. The pure naltrexone conjugated amino acid (0.486 g, 0.78 mmol, 29%) was then isolated by flash chromatography and a gradient of 0-1.5% CH ₃ OH in CHCl ₃ . The purity of the isolated material was determined by TLC (6: 1 CH ₃ OH: CHCl ₃ ) and 1H NMR confirmed the presence of both the amino acid moiety and naltrexone.

¹ H NMR (360 MHz, CDCl ₃ ); δ 6.81 (d, 1H, aromatic naltrexone), 6.63 (d, 1H, aromatic naltrexone), 4.3 to 4.2 (m, 1H, glutamic acid α -Proton) 1.7-1.3 (base pairs, 18H, Boc and OtBu groups), 0.6-0.4 ppm (m, 2H, naltrexone cyclopropyl) and 0.2-0.0 ppm (m, 2H, naltrexone cyclopropyl).

(Ii) Boc-Asp (Nal) -OtBu
Using a protocol similar to that used to prepare Boc-Glu (Nal) -OtBu, Boc-Asp (Nal) -OtBu was obtained with a separation-like yield of 41%.

¹ H-NMR (360 MHz, CDCl ₃ ); δ 6.84 (d, 1H, aromatic naltrexone), 6.66 (d, 1H, aromatic naltrexone), 4.6 to 4.5 (m, 1H, asparagine) Acid α-proton), 1.6-1.3 (base pair, 18H, Boc and OtBu groups), 0.7-0.5 ppm (m, 2H, naltrexone cyclopropyl) and 0.4-0.1 ppm ( m, 2H, naltrexone cyclopropyl).

NMR characterization

  Although naltrexone has a complex NMR spectrum, there are multiple major protons that have completely different chemical shifts and are unique to naltrexone.

III: C-Example: Glu (AZT)

For a solution of zidovudine (1.00 g, 3.75 mmol) and Boc-Glu (OSuc) -OtBu (3.00 g, 7.49 mmol) in dioxane (75 mL), DMAP (0.137 g, 1.13 mmol) And N-methylmorpholine (0.82 mL, 7.49 mmol) was added. The solution was heated to reflux for 6 hours and heated at 70 ° C. for 12 hours. The solvent was then removed and the crude product was purified on silica gel (100%, CHCl ₃ ) to give Boc-Glu (AZT) -OtBu (1.09 g, 1.91 mmol, 51%) as a yellow foam. .

¹ H NMR (360 MHz, CDCl ₃ ): δ 1.40 (d, 32 H, t-Bu), 1.86 (s, 3 H, AZTCH ₃ ), 2.11 (m, 2 H, Glu-βH), 2. 38 (m, 4H, Glu-γH and AZT2′CH ₂ ), 4.00-4.31 (m, 4H, AZT4′CH, 5′CH ₂ and Glu-αH), 5.21 (d, 1H, AZT3′CH), 6.01 (t, 1H, AZT1′CH), 7.16 (s, 1H, AZT6CH).

  A solution of Boc-Glu (AZT) -OtBu (1.09 g, 1.91 mmol) in 4N HCl in dioxane (20 mL) was stirred for 4 hours to remove the solvent. The product Glu (AZT) (0.89 g, 1.99 mmol, quantitative) was obtained as a yellow glass.

¹ H NMR (360 MHz, D ₂ O): δ 1.89 (s, 3H, AZTCH ₃ ), 2.21 (m, 4H, Glu-βH and AZT2′CH ₂ ), 2.58 (m, 2H, Glu) -γH), 3.70 (t, 1H , Glu-αH), 4.05-4.41 (m, 4H, AZT4'CH, 3'CH and _{5'CH 2), 6.18 (t,} 1H , AZT1′CH), 7.51 (s, 1H, AZT6CH).

III: D-Example: Poly-Glu (Acyclovir)

To a solution of poly-glu ₁₅ (0.600 g, 0.310 mmol) in DMF (25 mL) was added EDCI (2.07 g, 10.8 mmol). The resulting mixture was stirred for 1 hour at ambient temperature. Next, N-methylmorpholine (0.51 mL, 4.7 mmol) was added, followed by acyclovir (1.74 g, 7.75 mmol), DMF (25 mL), and N-methylmorpholine (0.85 mL). ) Was added. The reaction mixture was stirred for 4 days at ambient temperature. After this time, water (50 mL) was added and all solvents were removed. To the dried mixture, water (100 mL) was added and a precipitate of unreacted acyclovir formed. The solid was centrifuged and the supernatant was purified using ultrafiltration (YM1 membrane). About 300 mL of water was passed through the membrane. NMR showed an unexpected alkylurea side chain attached impurity. Poly-glu (acyclovir) (0.970 g) was obtained as a light yellow solid.

¹ H NMR (360 MHz, D ₂ O): δ 1.11 (br m, 4H, urea), 2.01 (br m, 2H, Glu- ■ H), 2.39 (br m, 2H, Glu-γH) ), 2.72 (br m, 2H , urea), 3.32 (br m, 6H , acyclovir CH ₂ and urea), 3.83 (br m, 3H , urea), 4.38 (br d, 3H , Glu-αH), 5.47 (brs, 2H, acyclovir 1′CH2), 7.94 (brs, 1H, acyclovir 8CH).

III: E-Example: Poly-Glu (fexofenadine)

To a solution of poly-glu ₁₅ (0.078 g, 0.040 mmol) in DMF (5 mL) was added EDCI (0.035 g, 0.18 mmol). After stirring for 30 minutes, N-methylmorpholine was added (0.03 mL, 0.24 mmol). After stirring for 10 minutes, a solution of fexofenadine (0.100 g, 0.20 mmol), N-methylmorpholine (0.07 mL, 0.60 mmol) and DMF (5 mL) was added via syringe. After a stirring reaction at ambient temperature for 3 days, the specimen was dissolved in water (25 mL). A solid precipitate formed which was both a drug-conjugate and free fexofenadine. The water was acidified and all solids dissolved. Purification using ultrafiltration (YM1 followed by YM3) and size exclusion chromatography using Sephadex-25 at pH 7 gave poly-glu (fexofenadine (0.010 g) as a white solid. .

¹ H NMR (360 MHz, D ₂ O): δ 1.37 (s, 8H, fex. CH ₂ and CH ₃ ), 1.58 (br m, 5H, fex. CH and CH ₂ ), 1.99 (br m, 24H, Glu-βH) , 2.31 (br m, 24H, Glu-γH), 2.70 (br m, 10H, fex.CH and _{CH 2), 4.14 (br m} , 26H, Glu -[Alpha] H), 7.25 (brm, 14H, fex. Aromatic H).

III: F-Example: Poly-Glu (Zarcitabine)

To a solution of poly-glu ₁₅ (0.123 g, 0.060 mmol) in DMF (8 mL) was added EDCI (0.403 g, 2.10 mmol). After 30 minutes, N-methylmorpholine (0.13 mL, 1.2 mmol) was added. After 35 minutes, sarcinabine (0.200 g, 0.95 mmol), N-methylmorpholine (0.10 mL, 0.9 mmol) and DMF (2 mL) solution were added via syringe. The resulting mixture was stirred for 48 hours at ambient temperature. The solvent was removed and the residue was dissolved in water (15 mL). Poly-glu (Zalcitabine) (0.083 g) was obtained as a light yellow solid by ultrafiltration (YM1 followed by YM3) and size exclusion with Sephadex-25 at pH 7.

¹ H NMR (360 MHz, DMSO-d ₆ w / D ₂ O): δ 1.14 (br m, 20 H, urea), 1.90 (br m, 30 H, Glu-βH, Glu-γH and CH in sarcitabine _{2), 2.66 (br m,} 4H, urea), 3.24 (br m, 36H , urea in zalcitabine, CH and _{CH 2), 4.29 (br m} , 8H, Glu-αH), 5 .87 (br s, 1H, zalcitabine 1'CH), 7.18 (br s, 1.19H, zalcitabine _{NH 2), 8.52 (br s} , 1H, zalcitabine 6CH)

（ｉ） 方法Ａ

III: G-Example: Poly-Glu (Stavudine)

(I) Method A

  The preparation was similar to poly-Glu (zarcitabine). Purification using ultrafiltration (YM1) gave poly-Glu (stavudine) (0.089 g) as a white solid.

¹ H NMR (360 MHz, D ₂ O): δ 1.87 (s, 3H, stavudine 5CH ₃ ), 2.06 (br m, 38 H, Glu-βH and Glu-γH), 2.49 (br m, 12H , Glu-γH), 3.75 (brm, 12H, urea and stavudine 5′CH ₂ ), 3.96 (brm, 12H, urea), 4.45 (brd, 13H, Glu-αH), 5.98 (d, 1H, stavudine 1′CH), 6.48 (d, 1H, stavudine 3′CH), 6.96 (d, 1H, stavudine 2′CH), 7.63 (s, 1H, Stavudine 6CH).
(Ii) Method B

N-methylmorpholine (1.80 mL, 16.4 mmol), and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate against a solution of poly (glutamic acid) (1.00 g, 7.81 mmol) in DMF (50 mL) (PyBrOP) (2.91 g, 6.25 mmol) was added. The resulting mixture was allowed to stir at room temperature for 30 minutes. This was followed by N-methylmorpholine (1.11 mL, 10.2 mmol) and 4-dimethylaminopyridine (0.191 g, 1.56 mmol) (DMAP) followed by stavudine (1.57 g, 7.03 mmol). Added. The resulting solution was stirred for 24 hours at room temperature. The solvent and excess base were then removed using reduced pressure evaporation. Water was then added and the resulting solid was collected and dissolved in saturated NaHCO ₃ . The crude product was purified using ultrafiltration. The product was then collected from ultrafiltration using acid precipitation (1.15 g, 48%).

_{^{1 H NMR (360MHz, DMSO-}} d 6): δ1.73 (br s, 3H, stavudine _{5CH 3), 1.89 (br s} , 4H, Glu-βH), 2.27 (br s, 4H, Glu -γH), 4.16 (br m, 4H, Glu-αH and stavudine _{5'CH 2), 4.95 (br s} , 1H, stavudine 4'CH), 5.97 (br s, 1H, stavudine 1 'CH), 6.42 (brs, 1H, stavudine 3'CH), 6.80 (brs, 1H, stavudine 2'CH), 7.20 (brs, 1H, stavudine 6CH), 8.06 (Br s, 2H, Glu-NH), 11.37 (br s, 1H, stavudine NH), 12.14 (br s, 1H, Glu OH).

Stavudine UVλ _max (266 nm), poly-glu (stavudine) UVλ _max (266 nm), average mass% of stavudine in poly-glu (stavudine), 36%; MALDI: Glu _n (stavudine) + NAn = 6-8, Glu _{n (stavudine) 2 + NAn = 4-7, Glu} n ( _{stavudine) 3 + NAn = 2-8, Glu} n ( _{stavudine) 4 + NAn = 3-10, Glu} n ( _{stavudine) 5 + NAn = 5-13, Glu} n ( _{stavudine) 6 + NAn = 7-14, Glu} n ( stavudine) 7 + NAn = 9-14

III: H-Example: Poly-Glu (Metronidazole)

  The preparation was similar to poly-glu (zarcitabine). Purification using ultrafiltration (YM1) gave poly-Glu (metronidazole) (0.326 g) as a yellow solid.

1H NMR (360 MHz, DMSO-d ₆ ): δ 1.18 (br d, 13H, urea), 1.93 (br s, 17H, Glu-βH and Glu-γH), 2.71 (br s, 16H, urea), 4.01 (br m, 18H , Glu-αH and metronidazole _{CH 2), 4.58 (br s} , 2H, metronidazole _{CH 2), 8.05 (br s} , 1H, metronidazole 2CH).

III: I—Example: Attachment of quetiapine via alcohol to the side chain of poly (glutamic acid)

N-methylmorpholine (1.80 mL, 16.4 mmol) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate against a solution of poly (glutamic acid) (1.00 g, 7.81 mmol) in DMF (50 mL) (PyBrOP) (2.55 g, 5.47 mmol) was added. The resulting mixture was allowed to stir at room temperature for 30 minutes. This was followed by N-methylmorpholine (1.11 mL, 10.2 mmol) and 4-dimethylaminopyridine (0.191 g, 1.56 mmol) (DMAP) followed by quetiapine (1.79 g, 4.69 mmol). Added. The resulting solution was stirred for 24 hours at room temperature. The solvent and excess base were then removed using reduced pressure evaporation. Water was then added and the resulting solid was collected and dissolved in saturated NaHCO ₃ . The crude product was purified using ultrafiltration. The product was then collected from ultrafiltration using acid precipitation (0.965 g, 35%).

¹ H NMR (360 MHz, DMSO-d ₆ ): δ 1.87 (br d, 12 H, Glu-βH), 2.33 (br m, 12 H, Glu-γH), 2.78 (br m, 8 H, quetiapine ), 3.49 (brm, 6H, quetiapine), 4.13 (brs, 2H, quetiapine), 4.22 (brs, 6H, quetiapine), 6.91 (brs, 1H, quetiapine), 7.01 (brs, 1H, quetiapine), 7.19 (brs, 1H, quetiapine), 7.38 (brm, 4H, quetiapine), 7.54 (brs, 1H, quetiapine), 8. 07 (br s, 4H, Glu NH).

Quetiapine UVλ _max (250 nm), poly-glu (quetiapine) UVλ _max (250 nm), average mass% of quetiapine in poly-glu (quetiapine) 43%.

III: J-Example: 2-Amino-pentanedioic acid 5- (4-acetylamino-phenyl) ester or Glu (acetaminophen)

(I) Preparation of Boc-Glu (acetaminophen) -OtBu Boc-Glu (OSuc) -OtBu (0.500 g, 1.25 mmol) and acetaminophen (0.944 g, 6.25 mmol) in THF (15 mL). ) Was added N-methylmorpholine (1.40 mL, 12.5 mmol). The reaction was heated to reflux and stirred at reflux overnight. The solvent was then removed and the crude compound was purified on silica gel (50-75% ethyl acetate in hexanes) to give Boc-Glu (acetaminophen) -OtBu (0.432 g, 0.900 mmol, 72% )

¹ H NMR (360 MHz, CDCl ₃ ): δ1.43 (d, 18H, t-Bu), 1.97 (m, 1H, Glu-βH), 2.12 (s, 3H, acetaminophen CH ₃ ) 2.25 (m, 1H, Glu-βH), 2.60 (m, 2H, Glu-γH), 4.25 (m, 1H, Glu-αH), 7.04 (d, 2H, aromatic Acetaminophen), 7.48 (d, 2H, aromatic acetaminophen)

(Ii) Preparation of Glu (acetaminophen) A solution of Boc-Glu (acetaminophen) -OtBu (0.097 g, 0.20 mmol) in 4N HCl in dioxane (10 mL) was stirred at ambient temperature for 2 hours. . Removal of the solvent gave Glu (acetaminophen) (0.90 g) as the HCl salt.

¹ H NMR (360 MHz, D ₂ O): δ 2.19 (s, 3H, acetaminophen CH ₃ ), 2.41 (m, 2H, Glu-βH), 2.97 (t, 2H, Glu- γH), 4.18 (t, 1H, Glu-αH), 7.19 (d, 2H, aromatic acetaminophen), 7.51 (d, 2H, aromatic acetaminophen)

¹³ C NMR (360 MHz, DMSO-d ₆ ): δ 23.80, 29.25, 51.00, 66.24, 119.68, 121.69, 137.00, 145.35, 168.23, 170. 42, 170.79

(Iii) Preparation of Glu (acetaminophen) NCA To a mixture of 2-amino-pentanedioic acid 5- (4-acetylamino-phenyl) ester (1.54 g, 4.29 mmol) in THF (40 mL) Triphosgene (1.02 g, 3.43 mmol) was added. The resulting solution was stirred at reflux for 3 hours. During the reaction, the product precipitated and was filtered off to give Nlu (1.02 g, 2.64 mmol, 62%) of Glu (acetaminophen) as an off-white solid.

¹ H NMR (360 MHz, DMSO-d ₆ ): δ 2.01 (s, 3H, acetaminophen CH ₃ ), 2.15 (m, 2H, Glu-βH), 2.81 (m, 2H, Glu- γH), 3.76 (t, 1H, Glu-αH), 7.06 (d, 2H, aromatic acetaminophen), 7.63 (d, 2H, aromatic acetaminophen), 8.57 ( br s, 1H, amide), 10.19 (s, 1H, amide).

¹³ C NMR (360 MHz, DMSO-d ₆ ): δ 23.81, 29.25, 52.13, 54.62, 119.66, 121.71, 136.98, 145.35, 167.44, 168. 19, 170.46, 170.77.

III: K-Example: Preparation of PolyGlu Prednisone (i) BocGlu (21-Prednisone) O-tBu
To BocGlu-O-tBu (0.400 g, 1.32 mmol) in 20 mL of CHCl ₃ was added dicyclohexylcarbodiimide (0.544 g, 2.64 mmol). The reaction was stirred for 1 hour and filtered to remove insoluble dicyclohexylurea. N-dimethyl-4-aminopyridine (0.320 g, 2.64 mmol) and prednisone (0.472 g, 1.32 mmol) were added. The reaction was stirred for 60 hours and filtered. The solvent was removed by rotary evaporation and the residue was purified by flash chromatography (10: 1 to 0: 1 hexane: EtOAc) to give the target material as a clear film (0.256 g, 31%).

R _f = 0.54 (6: ¹ CHCl ₃ : MeOH; ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.68 (d, 1H, 1), 6.16 (d, 1H, 2), 6.04 ( s, 1H, 4), 5.15 (d, 1H, NH), 5.03 (d, 1H, 21), 4.71 (d, 1H, 21), 4.08 (t, 1H, α) , 1.40 (s, 18H, t-Bu)

(Ii) Glu (21-prednisone)
BocGlu (21-prednisone) O-tBu (0.060 g, 93 μmol) in 15 mL CH ₂ Cl ₂ was stirred with trifluoroacetic acid (1.5 mL) for 1 hour. The solvent was removed by rotary evaporation and the residue was purified by flash chromatography (8: 1 CHCl ₃ : MeOH) to give a clear film.

Rf = 0.13 (6: 1 CHCl ₃ : MeOH)

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.72 (d, 1H, 1), 6.25 (d, 1H, 2), 6.14 (s, 1H, 4), 5.14 (d, 1H) , 21), 4.75 (d, 1H, 21), 4.10 (t, 1H, α).

(Iii) Glu (21-prednisone) NCA
Triphosgene (0.021 g, 72 μmol) was added to Glu (21-prednisone) (0.044 g, 90 μmol) in 20 mL dry THF. After gently refluxing for 3 hours, the solvent was removed by rotary evaporation. The residue was washed 3 times with 15 mL hexane and dried under vacuum to give NCA as a white solid.

R _f = 0.98 (EtOAc)

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.72 (1H), 6.89 (1H), 6.25 (1H), 6.14 (s, 1H, 4), 5.14 (d, 1H, 21), 4.75 (d, 1H, 21), 4.49 (1H, α).

(Iv) PlyGlu (21-prednisone)
Glu (21-prednisone) NCA (0.037 g, 72 μmol) and Glu (21-prednisone) (0.004 g, 8 μmol) were dissolved in 5 mL of dry DMF. After stirring for 88 hours under argon, the reaction mixture was poured into 30 mL H ₂ O and extracted three times with 15 mL CHCl ₃ . The organic layer was concentrated and vacuum dried to obtain a drug-carrying polymer having a prednisone: glutamic acid ratio of 1: 1.

III: L-Example: Glu (dipyrimador)

(I) Preparation of Boc-Glu (dipyrimador) -OtBu To a solution of dipyrimador (0.500 g, 0.990 mmol) and Boc-Glu (OSuc) -OtBu (3.96 g, 9.91 mmol) in THF (35 mL). In contrast, DMAP (0.072 g, 0.60 mmol) and N-methylmorpholine (0.22 mL, 1.98 mmol) were added. The solution was then refluxed for 48 hours. The solvent was then removed and the crude product was purified on silica gel (25-50% ethyl acetate in hexane). Two major products as light yellow oils, one with Rf = 2-3, Boc-Glu (dipyrimador) -OtBu, (0.57 g) and the other with Rf = 3-4 (2. 80 g).

_{R f = 2-3,1H NMR (360MHz,} CDCl 3): δ1.41 (s, 42H, t-Bu), 1.64 (br s, 5H, Jipirimadoru), 1.85 (m, 2H, Glu -ΒH), 2.07 (m, 2H, Glu-βH), 2.37 (m, 4H, Glu-γH), 3.60-4.24 (m, 12H, Glu-αH and dipyrimador).

  (For Rf = 3-4, the same as above except for δ1.44 (s, 56H, t-Bu))

(Ii) Preparation of Glu (dipyrimador) A solution of Boc-Glu (dipyrimador) -OtBu (Rf = 2-3, 0.57 g) and 4N HCl in dioxane (20 mL) was stirred for 2.5 hours at ambient temperature. . The solvent was removed and the product (0.280 g) was a light yellow solid.

¹ H NMR (360 MHz, DMSO-d ₆ ): δ 1.65 (br m, 4H, Glu-βH and dipyrimador), 2.04 (br m, 2H, Glu-βH), 2.40 (br m, 4H , Glu-γH), 3.75 (br m, 8H, dipyrimador), 3.91 (br m, 2H, Glu-αH), 8.55 (br m, 2H, amide H).

ｎｄ：算定されていない；ＮＡ：適用されない

nd: not calculated; NA: not applicable

III: M-Example: Attachment of furosemide via sulfonamide to the side chain of poly (glutamic acid)

To a solution of poly (glutamic acid) (0.700 g, 5.47 mmol) in DMF (40 mL), N-methylmorpholine (1.26 mL, 11.5 mmol) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate ( PyBrOP) (2.04 g, 4.38 mmol) was added. The resulting mixture was stirred for 30 minutes at room temperature. This was followed by the addition of N-methylmorpholine (0.78 mL, 7.11 mmol) and 4-dimethylaminopyridine (0.133 g, 1.09 mmol) (DMAP) and furosemide (1.63 g, 4.92 mmol). The resulting solution was stirred for 24 hours at room temperature. Thereafter, the solvent and excess base were removed using vacuum evaporation. Water (100 mL) was then added and the resulting solid was collected and dissolved in saturated NaHCO ₃ . The crude product was purified using ultrafiltration. The product was then collected from ultrafiltration using acid precipitation as a green solid (0.678 g, 32%).

¹ H NMR (360 MHz. DMSO-d ₆ ): δ 1.84 (br d, 8H, Glu-βH), 2.273 (br m, 8H, Glu-γH), 4.21 (br s, 4H, Glu -ΑH), 4.57 (brs, 2H, furosemide), 6.37 (brd, 2H, furosemide), 7.04 (brs, 1H, furosemide), 7.61 (brs, 1H, furosemide) ), 8.06 (br m, 4H, Glu NH), 8.51 (br s, 2H, furosemide), 8.80 (br s, 1H, furosemide), 12.25 (br s, 1.5H, Glu and furosemide COOH).

  Average mass% of furosemide in poly-Glu (furosemide): 39%.

III: N-Examples: Synthesis of poly-lysine-ibuprofen (i) Preparation of ibuprofen-O-succinimide (RI-172) (Graf & Hoffman, Pharmazie 55: 286-292, 2000)

  To a stirred solution of ibuprofen (2.06 g, 10 mmol) in 5 mL dioxane at room temperature was added a solution of dichlorohexylcarbodiimide (DCC, 2.27 g, 11 mmol) in 25 mL dioxane. After 10 minutes, a solution of N-hydroxysuccinimide (NHS, 1.16 g, 10 mmol) in 15 mL dioxane was added. The reaction mixture was allowed to stir at room temperature for 5 hours and then filtered through a sintered glass funnel to remove dicyclohexylurea (DCU). After rotary evaporation, the product was crystallized from methylene chloride / hexane to give 2.36 g (78%) of a colorless solid.

¹ H NMR (500 MHz, DMSO-d6): δ 0.86 (d, 6, CH ₃ ), 1.49 (d, 3, α-CH ₃ ), 1.81 (m, 1, CH), 2 .43 (d, 2, CH ₂ ), 3.33 (m, 4, CH ₂ CH ₂ ), 4.22 (q, 1, CH), 7.16 (d, 2, ArH), 7.28 (D, s, ArH).

(Ii) Conjugation of ibuprofen-O-succinimide (RI-197) and poly-lysine

  Poly-lysine-HBr (Sigma, 100 mg, 34.5 nmol) was dissolved in 1 mL of water brought to pH 8 with sodium bicarbonate and stirred at room temperature. To this solution was added a solution of ibuprofen-O-succinimide (116 mg, 380 nmol) in 2 mL of dioxane. After stirring overnight, dioxane was removed by rotary evaporation and diluted with 10 mL of pH 8 sodium bicarbonate in water. The precipitated product was filtered through a sintered glass funnel and washed with 3 × 10 mL water and 4 × 10 mL diethyl ether. After drying in high vacuum overnight, the solid product was scraped to give 105 mg (62%).

¹ H NMR (500 MHz, DMSO-d6): δ 0.85 (br s, 6, CH ₃ ), 1.27 (br s, 3, α-CH ₃ ), 1.40-1.79 (m, 5 , Ibu CH and lysine γ and δCH ₂ CH ₂ ), 2.31 (d, 2, βCH ₂ ), 2.41-2.52, under dmso (m, 2, βCH ₂ ), 2.73-3 .01 (m, 2, εCH ₂ ), 3.51-3.85 (m, 1 ibuCH), 4.01-4.43 (m, 1, αCH), 7.14 (d, 2, ArH) 7.6 (d, 2, ArH), 7.90-8.06 (m, 2, NH).

III: O—Example—Synthesis of polylysine-naproxen (i) Synthesis of naproxen-succinimide N-hydroxysuccinimide dissolved in 15 mL dioxane to naproxen (2.303 g, 10 mmol) in 5 mL dioxane (1.16 g, 10 mmol) and dicyclohexylcarbodiimide (2.27 g, 11 mmol) in 25 mL dioxane were added. The reaction was stirred overnight and insoluble dicyclohexylurea was removed by filtration. The solvent was removed by rotary evaporation, the residue was dissolved in of _CH 2 Cl ₂ 30-40. About 10 mL of hexane was added and the mixture was cooled to 4 ° C. for 2 hours. Additional hexane was added dropwise until small flat white crystals began to form and the solution was refrigerated overnight. The activated ester was harvested, washed with hexane and dried under vacuum (2.30 g, 70.0%).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 1.70 (d, 3H, CH ₃ ) 2.9 (s, 4H, succinimide), 3.91 (s, 3H, OCH ₃ ), 4.18 ( q, 1H, methine) 7.75-7.12 (m, 6H, aromatic).

(Ii) Synthesis of polylysine-naproxen 2 mL dioxane for [Lys] ₁₄ · 14 · HBr (0.100 g, 35 mmol) in 1 mL H ₂ O (containing 10 mg / mL Na ₂ CO ₃ ) Naproxen-succinimide (0.124 g, 379 mmol) in was added. A precipitate formed after stirring overnight. Adding 30-40 mL H ₂ O (containing 10 mg / mL Na ₃ CO ₃ ) formed more precipitate, which was isolated by filtration and washed with 50 mL Et ₂ O . A fine white powder was dried (0.095 g, 53%).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.1 (m, 1H, lysine; amide), 7.8-7.0 (m, 6H, aromatic), 4.4-4.1 (m 2H, α, methine), 3.3 (s, 3H, OCH ₃ ), 2.8 (m, 2H, ε), 1.7-1.0 (m, 9H, β, γ, δ, CH ₃ )

III: P-Example: Synthesis of polylysine-gemfibrozil (i) Synthesis of gemfibrozil-succinimide Gemfibrozil (GEM) (5.0 g, 20.0 mmol) in 30 mL dioxane vs. N-hydroxy in 20 mL dioxane Succinimide (2.3 g, 20.0 mmol) and dicyclohexylcarbodiimide (4.5 g, 22.0 mmol) in 50 mL dioxane were added. The reaction was stirred overnight and insoluble dicyclohexylurea was removed by filtration. The solvent was removed by rotary evaporation, the residue was dissolved in _CH 2 Cl ₂ in 15-20 mL. Hexane was added dropwise until crystal formation was visible and the mixture was cooled to 4 ° C. overnight. About 3 mL of additional n-hexane was added and the mixture was cooled to −20 ° C. overnight. The activated ester formed small, flat crystals that were harvested, washed with hexane and dried in vacuo (5.8 g, 80%).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 1.2, 1.3 (s, 6H, CH ₃ ), 1.8-1.5 (m, 6H, GEMCH ₂ ), 2.3-2. 1 (s, 6H, aromatic _{CH 3), 2.85-2.7 (d,} 4H, succinimide _{CH 2), 7.0-6.6 (m,} 3H, aromatic)

(Ii) Synthesis of polylysine-gemfibrozil ₂ mL against [Lys] ₁₁ · 11 · HBr (0.100 g, 43.5 μmol) in 1 mL H ₂ O (containing 10 mg / mL Na ₂ CO ₃ ) Of gemfibrozil succinimide (0.094 g, 261.1 μmol) in dioxane was added. After stirring overnight, a precipitate formed. By adding (10 mg / mL Na ₂ CO ₃ ), more precipitate formed, which was isolated and washed with 50 mL Et ₂ O. A fine white powder was dried (0.019 g, 1%).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 1.5-1.0 (m, 12H, β, γ, δ,... CH ₃ ), 1.85-1.5 (m, 4H, CH ₂ ), 2.3, 2.1 (s, 6H, aromatic CH ₃ ), 3.35 (s, 2H, ε), 3.85 (s, 2H, OCH ₂ ), 4.05 (s, 1H) , Α), 5.6 (d, 1H, carbamate), 7.0-6.7 (m, 3H, aromatic), 8.0 (d, 1H, amide).

III: Q-Example: Polylysine depacoat (valproic acid)
(I) Synthesis of parproic acid-succinimide N-hydroxysuccinimide (0.8 g, 6) against valproic acid (1.0 g, 6.9 mmol) in 14 mL of 6: 1 CH ₂ Cl ₂ : DMF 0.9 mmol), dicyclohexylcarbodiimide (1.6 g, 7.6 mmol) and triethylamine (0.9 g, 8.9 mmol) were added. The reaction was stirred for 60 hours at which time the solution was filtered to remove the white precipitate and the solvent was removed by rotary evaporation. The residue was purified by flash chromatography (10: 1-2: 1, hexane: EtOAc) to give the succinimidyl ester as a clear oil (1.0 g, 59%).

_Rf = 0.43 (3: 1, hexane: EtOAc).

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.76 (s, 4H, succinimide), 2.61 (m, 1H, methine), 1.65 to 1.19 (m, 8H, methylene), 0.88 (T, 6H, methyl)

(Ii) Synthesis of polylysine-valproic acid Lys ₁₄ HBr (0.106 g, 37 μmol) in 0.8 mL of H ₂ OpH 8 to valprosuccinimidyl ester (0.104 g) dissolved in 0.4 mL of THF 431 μmol). The reaction was stirred overnight, at which time the mixture was acidified with 6M HCl to pH 3 and extracted twice with 2 mL CH ₂ Cl ₂ . The aqueous layer was dried and the residue was dissolved in 1 mL H ₂ O. The solution was purified by SEC (G-15, 10 mL dry volume) and eluted with water. These fractions containing the conjugate were combined and dried to give a white solid (0.176 mg) which showed 28 lysine for all 1 drug molecule by ¹ HNMR.

¹ H NMR (300 MHz, D ₂ O): d 4.29 (m, 1H, α), 3.00 (m, 2H, ε), 1.87-1.68 (m, 4H, β, δ) 1.43 (m, γ, methylene), 0.85 (t, methyl)

III: R—Example: Attachment of Pravastatin to Side Chain of Peptide The following example shows the attachment of pravastatin to the side chain so that the peptide forms a medium-linked drug / peptide conjugate [Lys (pravastatin) ] The preparation of ₁₅ is described.

To pravastatin sodium (0.994 g, 2226 μmol) in 10 mL dry DMF, dicyclohexylcarbodiimide (0.458 g, 2226 μmol) was added. After stirring for 3 hours under argon, the solution was filtered through glass wool into a solution of polylysine pH 8 (0.288 g, 148 μmol) dissolved in 1 mL H ₂ O (to remove insoluble dicyclohexylurea). After stirring overnight, the milky white reaction was filtered through glass wool and the solvent was removed by rotary evaporation. The resulting syrup was dissolved in 5 mL 2-propanol and then diluted with 60 mL H ₂ O. The mixture was acidified with 1N HCl to pH 6 and extracted three times with 30 mL CHCl ₃ . The organic solvent was removed by rotary evaporation and replaced with 45 mL H ₂ O and 5 mL 2-propanol. This solution was ultrafiltered with 100 mL H ₂ O (Amicon YM1, 1000 MW) and the retentate was dried under vacuum to give a white solid (130 mg).

_{R f = 0.77 (6: 1} , CHCl 3: CH 3 OH).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 5.97 (1H, 5 ′), 5.85 (1H, 3 ′), 5.50 (1H, 4 ′), 5.19 (1H, 8 ′) ), 4.78 (1H, 6 ′), 4.40 (1H, α), 4.15 and 4.01 (2H, 3, 5), 3.45 (2H, ε), 2.30 (4H) , 2,2,2 ', 2 "), 1.04 (3H, 2" -CH 3), 0.83 (6H, 4 ", 2'-CH 3)

III: Preparation of S-Boc-Leu-Ser (Boc-Ciprofloxacin) -OCH ₃ Solid Boc-Leu-Ser-OCH ₃ (500 mg, 1.5 mmol), Boc-Cipro ( 970 mg, 2.25 mmol), PyBrop (1.05 g, 2.25 mmol) and DMAP (183 mg, 1.5 mmol) were dissolved. To this solution / suspension, N-methylmorpholine (414 μl, 3.75 mmol) was added. The reaction mixture was then stirred overnight at room temperature under argon. Most of the solvent was then removed by rotary distillation under vacuum. The remaining oil was dissolved in CHCl ₃ (20 ml) and the organic solution was extracted first with saturated NaHCO ₃ (3.20 ml) and then with acidic water (pH 3 HCl, 3.20 ml). The organic layer was collected and dried over MgSO ₄ . At this time, the suspension was filtered and the CHCl ₃ solution was collected. Thereafter, the solvent was removed by rotary distillation under vacuum to obtain a yellow oil. This was redissolved in CHCl ₃ (20 ml) and the organic solution was extracted again with saturated NaHCO ₃ (3 × 20 ml) and then with 0.1 N NaOH (3.20 ml). The organic solution was then dried over MgSO ₄ , the CHCl ₃ solution was collected, and the suspension was filtered. The solvent was then removed by rotary distillation under vacuum to give a yellow oil. This oil was dissolved in a minimum volume of CHCl ₃ and the solution was deposited on a preparative TLC plate. The plate was developed with 19: 1 CHCl ₃ / MeOH. A second band was collected and characterized by ¹ H-NMR; (500 MHz, (CD ₃ ) ₂ SO) _δ 0.868 (d, 6 H, Leu _δ ), 1.285-1.096 (m, 2 H, Cip), 1.4-1.2 (m, 11H , Boc and Cip), 1.5-1.4 (m, 11H , Boc and Leu), 1.7-1.6 (m, 1HLeu β) 3.3-3.1 (m, 4H, Cip), 3.6-3.5 (m, 4H, Cip), 3.660 (bs, 4H, -OCH ₃ and Cip), 4.05- _{4.15 (m1H, Leu α),} 4.35-4.5 (m, 2H, Ser β), 4.7-4.8 (m, 1HSer α), 6.885 (d, 1H, amide) 7.47.4 (d, 1H, Cip), 7.79 (d, 1H, Cip) and 8.48 (d, 1H, Cip).

III: Preparation of T-Leu-Glu (AZT) (i) Preparation of Boc-Leu-Glu-OtBu

Boc-Leu-Glu-OtBu
NMM and DMAP were added to a solution of Boc-Leu-OSu and Glu-OtBu in DMF. The solution was stirred at ambient temperature for 18 hours and then the solvent was removed. The crude product was taken up in 100 ml CHCl ₃ and washed three times with pH 3 water (100 ml), once with water (100 ml) and once with brine (100 ml). The organic layer was dried with MgSO ₄ and filtered. The solvent was removed and the solid was dried on vacuum. The solid was collected as a white powder (8.78 g, quantitative, yield, ˜80%, purity TLC). The product was used directly without further characterization.

(Ii) Preparation of Leu-Glu (AZT) .TFA

Boc-Leu-Glu-OtBu
NMM and PyBrOP were added to a solution of Boc-Leu-Glu-OtBu in DMF. The solution was stirred for 0.5 hours at ambient temperature, then AZT and DMAP were added. The reaction mixture was then stirred at ambient temperature for 18 hours. The solvent was removed and the crude product was taken up in 400 ml CHCl ₃ and washed three times with pH 3 water (250 ml), once with water (250 ml) and once with brine (250 ml). The organic layer was dried with MgSO ₄ and filtered. The solvent was removed and the solid was dried on vacuum. The product was preparative HPLC [Phenomenex Luna C18, 30 × 250 mm, 5 μM, 100 μm; gradient; (100 0.1% TFA-water / 0.01% TFA-MeCN → 80 / 20) 0-10 min, (80/20 → 50/50) 10-25 min, 30 ml / min]. The product was deprotected with 100 ml 95% TFA / water. The product was dried on vacuum to give a slightly yellow solid (2.45 g, 4.04 mmoles, 38% yield). ¹ H NMR (DMSO-d ₆ ) δ 0.90 (m, 6H), 1.58 (m, 2H), 1.69 (m, 2H), 1.80 (s, 3H), 1.87 (m 1H), 2.07 (m, 1H), 2.35 (m, 1H), 2.45 (m, 2H), 3.78 (m, 1H), 3.97 (t, 1H), 4 .28 (m, 3H), 4.45 (t, 1H), 6.14 (t, 1H), 7.46 (s, 1H), 8.14 (brs, 3H), 8.75 (d 1H), 11.32 (br s, 1H).

IV Amino Acid Active Substances and Their Attachment to Peptides Amino acid active substances allow one completely different embodiment of the present invention. This embodiment occurs when the active substance itself is an amino acid and thus has the ability to bind both amines and carboxylates, allowing the active substance to be interspersed into the peptide chain. Amino acid drugs can be C-capped, N-capped and side chain attached according to the procedures and mechanisms described above. As a unique embodiment of an amino acid drug, the active substance may be interspersed within the peptide chain through peptide bonds at both ends.

  Most preferred conjugates for scattered attachment of amino acid actives include amoxiline; amoxiline and clavulanate; baclofen; benazepril hydrochloride; candoxatril; captopril; carbidopa / levodapa; cefaclor; Diclofenac sodium; diclofenac sodium and misoprostol; enalapril; enapril maleate; gabapentin; levothyroxine; lizinopril; lizinopril and hydrochlorothiazide; Drapril; and trovafloxacin mesylate.

An example of a scattered attachment to an amino acid drug is described in the following scheme.

IV: Preparation of A-active substance conjugate (N-terminal)
In the following examples, an amino acid active substance is attached to the N-terminus of different amino acids. These examples not only describe N-terminal attachment, but also represent peptide linkages of amino acid actives as amino acids to form either dipeptides or peptide conjugates.

  T4 conjugated to an amino acid polymer is either prepared by (protected) coupling to a commercially available amino acid homopolymer or incorporated by adding T4-NCA to the corresponding polypeptide in situ.

(I) T4 conjugation to commercially available polyglycine To N-TeocT4 (0.017 g, 17 μmol) in 1 mL dry DMF, dicyclohexylcarbodiimide (0.004 g, 18 μmol) was added. After stirring for 30 minutes, N-dimethyl-4-aminopyridine (0.004 g, 36 μmol) and Gly ₁₈ (0.017 g, 17 μmol) were added and the reaction was stirred overnight. The cloudy solution was poured into 20 mL H ₂ O and extracted twice with 10 mL CH ₂ Cl ₂ . The aqueous component was acidified to pH 3 with 1N HCl and cooled to 4 ° C. The material was isolated by centrifugation and the pellet was washed 3 times with 8 mL H ₂ O. Drying the pellets in vacuo to give the dicyclohexylurea and _{N-TeocT4-Gly 18.}

¹ H NMR (500 MHz, DMSO-d ₆ ): δ7.8 (T4 aromatic), 7.1 (T4 aromatic), 4.1 (α).

  2 mL of trifluoroacetic acid was added to the impure protected polymer. The reaction was stirred at room temperature for 2 hours and the solvent was removed by rotary distillation. The residue was dissolved in 1 mL DMF and the insoluble material was removed by filtration. DMF was removed by rotary distillation and dried under vacuum to give a white material (0.012 g, 40%).

¹ H NMP (500 MHz, DMSO-d ₆ ): δ 7.75 (T4 aromatic), 7.08 (T4 aromatic), 4.11 (bs, α).

(Ii) Preparation of Amino Acid-NCA N-carboxyanhydrides (NCA) of the amino acids listed below were prepared using a protocol similar to that reported for glutamic acid. The slight variations in the final work-up are noted below.

  To a mixture of Thr-OtBu (0.500 g, 2.85 mmol) in THF (25 mL) was added triphosgene (0.677 g, 2.28 mmol). The resulting solution was stirred at reflux for 3 hours. The solution was evaporated to dryness to give Thr-NCA (0.500 g, 2.48 mmol, 87%) as a white solid. Thr-NCA was used without further characterization.

Triphosgene (0.8 eq) was added to L-amino acid (1.5 g) in 100 mL dry THF. The reaction vessel was equipped with a reflux condenser and NaOH trap, which was heated to reflux for 3 hours. The solvent was removed by rotary distillation and the residue was washed with hexane to give the amino acid NCA as a white residue.
Leu-NCA: ¹ H NMR (500 MHz, CDCl ₃ ): δ 6.65 (s, 1H, NH), 4.33 (dd, 1H, α), 1.82 (m, 2H, β), 1.68 (M, 1H, γ), 0.98 (dd, 6H, δ).
Phe-NCA: ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.36-7.18 (m, 5H), 5.84 (s, 1H, NH), 4.53 (dd, 1H), 3.28 (Dd, 1H, α), 2.98 (dd, 1H, β).
Trp (Boc) -NCA: ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.14 (d, 1H), 7.49 (d, 2H), 7.36 (t, 1H), 7.27 (m, 1H), 5.90 (s, 1H, NH), 4.59 (dd, 1H, α), 3.41 (dd, 1H, β), 3.07 (dd, 1H, β), 1.67 (S, 9H, t-Bu).
Ile-NCA: ¹ H NMR (300 MHz, CDCl ₃ ): δ 6.65 (s, 1H, NH), 4.25 (d, 1H, α), 1.94 (m, 1H, β), 1.43 (Dm, 2H, γ-CH ₂ ), 1.03 (d, 3H, γ-CH ₃ ), 0.94 (t, 3H, δ).
Lys (Boc) -NCA: ¹ H NMR (500 MHz, CDCl ₃ ): 6.65 (bs, 1H, NtH), 4.64 (s, 1H, carbamate NH), 4.31 (t, 1H, α) 3.13 (s, 2H, ε), 2.04 (m, 2H, β), 1.84 (m, 2H, δ), 1.48 (m, 11H, γ, t-Bu).
Met-NCA: ¹ H NMR (500 MHz, CDCl ₃ ): δ 6.89 (s, 1H, NH), 4.50 (dd, 1H, α), 2.69 (t, 2H, γ), 2.10 (M, 1H, β), 2.08 (m, 4H, β, δ).

(Iii) Examples of other amino acids-NCA

(Iv) T4 conjugated T4-Asp _n for preformed homopolymer in situ
The following example depicts the attachment of T4 to the N-terminus of the peptide conjugate polyAsp in situ. Polyserine and polythreonine were also prepared using this protocol. The serine reaction mixture contained N-methylmorpholine (1.1 eq).

  Polyaspartic acid: Asp (OtBu) (13 mg, 0.07 mmol) and Asp (OtBu) -NCA (200 mg, 0.93 mmol) were dissolved in anhydrous DMF (5 mL) and the solution was stirred at room temperature under argon overnight. I let you. The next morning, 2.5 mL of the reaction mixture was transferred to another flask (Flask B). To the original flask (Flask A) was added T4-NCA (27 mg, 0.03 mmol) and both solutions were allowed to continue stirring under argon for an additional 24 hours. Then, the polymer was precipitated by adding water (50 mL) to each flask. The resulting solid was collected by filtration and dried overnight under vacuum.

The dried Asp (OtBu) _n (Flask B) and T4-Asp (OtBu) _n (Flask A) were then dissolved in 95% trifluoroacetic acid in water (3 mL) and allowed to stir at room temperature for 2 hours. The deprotected polymer was then precipitated by the addition of ethyl ether (10 mL) and then the suspension was stored at 4 ° C. for 2 hours. Each polymer was then collected by filtration and the solid was dried under vacuum overnight. 48 mg Asp _n (flask B) and 12 mg T4Asp _n (flask A) were thus obtained. MALDI showed that T4-Asp _n (Flask A) consisted of a polymer mixture T4-Asp _3-12 of varying length.

Other examples of T4 conjugation for preformed homopolymers in situ are listed below:
T4-Leu ₁₅
Isoleucine (0.012 g, 0.1 μmol) was added to IleNCA (0.200 g, 1.3 μmol) in 2.5 mL DMF. After stirring overnight under Ar, T4-NCA (0.037 g, 0.050 μmol) was added and the reaction was stirred for a further 72 hours. The white solution was added to 8 mL H ₂ O. The heterogeneous solution was cooled to 4 ° C., centrifuged, the supernatant discarded, and the pellet washed with 8 mL H ₂ O. The dried residue was washed with 50 mL of ethanol warmed to 50 ° C. and dried to give a white powder (0.124 g, 55%).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.75 (s, T4 aromatic), 7.08 (s, T4 aromatic), 4.11 (dd, α), 1.77 (m, β ), 1.38 (m, β, γ-CH), 0.91 (m, γ-CH, γ-CH ₃ , δ).

T4-Phe ₁₅
White powder (58%).
¹ H NMR (360 MHz, DMSO-d ₆ ): δ 7.0-8.1 (NH, aromatic), 4.5 (α), 3.0 (β); MALDI-MS indicates T4-Phe ₁₅ ing.

T4-Met ₁₅
White powder (10%).
¹ H NMR (500 MHz, DMSO-d6): δ 8.0-8.5 (amide NH), 4.4 (α) 2.5 (γ), 2.05 (ε), 2.0-1.7 (Β).

T4-Val ₁₅
White powder (14%).
¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.75 (T4 aromatic), 7.08 (T4 aromatic), 4.35 (α), 3.45 (β), 1.05 (γ) .

For these conjugates with protected NCA, an additional separate deprotection step was required:
T4-Lys _4-11
T4- [Lys (Boc)] _4-11 (0.256 g, 61 μmol) in 10 mL CH ₂ Cl ₂ was stirred with trifluoroacetic acid (10 mL) for 2 hours. The solvent was removed by rotary distillation and the residue was dissolved in 3 mL H ₂ O and ultrafiltered (Amicon regenerated cellulose, YM1, NMWL 1000, washed with 30 mL pH 5 H ₂ O). The retentate was dried under vacuum to give a light brown residue.

¹ H NMP (500 MHz, D ₂ O): δ 7.82 (s, T4 aromatic), 7.41 (s, T4 aromatic), 4.29 (bs, α), 3.00 (bs, ε) 2.13-1.70 (m, β, δ, γ); MALDI-MS gives the T4-Lys _4-11 range.

T4-Trp ₁₅
¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.25-6.80 (m, aromatic), 4.50 (bs, α), 3.40 (bs, β), 3.00 (bs, β).

IV: B- active agent conjugate (C-terminus) Preparation of (i) T4C- capping type homopolymer standard preparation _Trp 15 of -T4
Trp (Boc) -NCA (0.500 g, 1.514 mmol) was added to T4 (0.078 g, 100 μmol) in 10 mL dry DMF. After stirring for 64 hours under argon, the reaction was quenched by adding 30 mL of H ₂ O. The cloudy white solution was cooled to 4 ° C., centrifuged, and the pellet was washed 3 times with 25 mL H ₂ O. The residue was dried under vacuum to give Trp (Boc) ₁₅ -T4 as a brown solid. This material was further purified by ultrafiltration (Amicon regenerated cellulose, YM1, NMWL1000, washed with 30 mL of pH 5 H ₂ O) to give [Trp (Boc)] ₁₅ -T4 as a golden brown solid ( 0.400 g, 79%).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.25-6.80 (m, aromatic), 4.50 (bs, α), 3.40 (bs, β), 3.00 (bs, β), 1.50 (bs, t-Bu).

[Trp (Boc)] ₁₅ -T4 (0.509 g) in 8 mL of 1: 1 CH ₂ Cl ₂ : trifluoroacetic acid was stirred for 1.5 hours. The solvent was removed by rotary distillation and the residue was dried under vacuum to give a brown solid (0.347 g, 97%).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.25-6.80 (m, aromatic), 4.50 (bs, β), 3.40 (bs, α), 3.00 (bs, β).

Lys ₁₅ T4
Tys ₁₅ -T4 was prepared using a protocol similar to that used for Trp ₁₅ -T4.
[Lys (Boc)] ₁₅ -T4:
¹ H NMR (500 MHz, D ₂ O): δ 7.82 (s, T4 aromatic), 7.41 (s, T4 aromatic), 4.29 (bs, α), 3.00 (bs, ε) 2.13-1.70 (m, β, δ, γ).
Lys ₁₅ -T4:
¹ H NMR (500 MHz, D ₂ O): δ 7.82 (s, T4 aromatic), 7.41 (s, T4 aromatic), 4.29 (bs, α), 3.00 (bs, ε) 2.13-1.70 (m, β, δ, γ).

The (ii) _[Glu] 15 -L- dihydroxyphenylalanine or _[Glu] in DMF Synthesis 6mL of 15 -L-DOPA L-DOPA ( 0.050g, 254μmol) and GluNCA (0.666g, 3.85mmol) Dissolved. After stirring overnight under argon, the reaction was examined by thin layer chromatography (9: 1 H ₂ O: HOAc) and more than expected to be some free drug (Rf = 0.70) and polymer. A highly polar spot (Rf = 0.27) was shown. The reaction was quenched by adding 12 mL of H ₂ O. The pH was adjusted to pH 1-2 using 1N HCl. The solvent was removed by rotary distillation and the viscous residue was dried under vacuum. The resulting syrup was transferred to a new container in H ₂ O and lyophilized. The resulting crystals were off-white or light brown. Yield: 0.470 g, 62%. ¹ H NMR showed pyroglutamic acid contamination; therefore, the material was suspended in H ₂ O, ultrafiltered (Millipore, regenerated cellulose, YM1, NMWL = 1000) and the retentate was vacuum dried. Yield: 0.298 grams.

¹ H NMR (500 MHz, DMSO-d ₆ ) shows a relative ratio of Glu: L-DOPA of 30: 1: δ6.6 (L-DOPA aromatic), 6.4 (L-DOPA aroma) Group), 4.1 (Glu, α), 1.85 (Glu, β), 2.25 (Glu, γ, L-DOPA), 2.3 (L-DOPA, benzyl type), 12.4- 11.5 (Glu, CO ₂ H), 8.0 (Glu, amide).

(Iii) Synthesis of [Glu] ₁₀ -L-DOPA As in the synthesis of [Glu] ₁₅ -L-DOPA, except that 0.439 grams of GluNCA was used. The final yield of purified material was 0.007 grams.

¹ H NMR (500 MHz, DMSO-d ₆ ) shows 8: 1 Glu: L-DOPA.

IV: Preparation of C-dispersed active substance / peptide conjugate (i) Synthesis of random copolymerization of T4 and Trp T4-NCA (0.065 g, 0.1 mmol) and Trp (Boc) in 4 mL dry DMF -NCA (0.400 g, 1.2 mmol) was combined. Triethylamine (11 μl, 0.1 mmol) was added and the reaction was stirred for 44 h under argon. After adding 10 mL of H ₂ O and quenching, the heterogeneous mixture was cooled to 4 ° C. and centrifuged. The pellet was isolated, washed 3 times with 10 mL H ₂ O and dried under vacuum.

To a random T4 / [Trp (Boc)] ₁₅ polymer, 10 mL of 1: 1, CH ₂ Cl ₂ : trifluoroacetic acid was added and the reaction was stirred for 1 hour. Removal of the solvent by rotary distillation gave a deprotected polymer as a brown solid (0.262 g, 91%), which was further purified by ultrafiltration (Amicon regenerated cellulose, YM1, NMWL1000, 30 mL pH 5). Wash with H ₂ O).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.25-6.80 (m, aromatic), 4.50 (bs, α), 3.40 (bs, β), 3.00 (bs, β).

(Ii) Synthesis of random copolymer of T4 and Lys Random T4 / Lys ₁₅ was prepared using a protocol similar to that used to prepare random T4 / Trp.

¹ H NMR (500 MHz, D ₂ O): δ 7.82 (s, T4 aromatic), 7.41 (s, T4 aromatic), 4.29 (bs, α), 3.00 (bs, ε) 2.13-1.70 (m, β, δ, γ)

IV: D-fatty acid acylation (i) Preparation of N-palmitoyl-L-triiodothyronine (C16T3) DCC against palmitic acid (0.500 g, 2.0 mmol) in 5 mL of dichloromethane CH ₂ Cl ₂ (0.201 g, 1.0 mmol) was added. The solution was allowed to stir for 45 minutes, at which time it was added 3 mL of L-triiodothyronine (0.578 g, 0.9 mmol) and N-dimethyl-4-aminopyridine (0.119 g, 1.0 mmol). Insoluble 1,3-dicyclohexylurea and DCU were removed by filtration through glass wool into DMF. After stirring for 18 hours, the solvent was removed by rotary distillation and the residue was purified by flash chromatography (30: 1-8: 1 CHCl ₃ : CH ₃ OH using 1 drop of HOAc / 100 mL eluent) to give a white The target material was obtained as a solid (0.242 g, 31%): R _f (6: 1, CHCl ₃ : CH ₃ OH) 0.27; ¹ H NMR (CDCl ₃ 500 MHz) 8.10 (d, 2H) 7.63 (s, 1H, NH), 7.06 to 6.48 (m, 3H), 4.64 (bs, 1H, α), 3.12 (m, 2H, β), 2.16 (M, 2H), 1.55 (m, 2H), 1.33-1.10 (bs, 24H), 0.83 (t, 3H).

(Ii) Preparation of N-octanoyl-L-triiodothyronine (O-octanoyl) (C8T3 (C8)) DCC against octanoic acid (0.30 ml, 1.9 mmol) in 5 mL of CH ₂ Cl ₂ (0.201 g, 1.0 mmol) was added. The solution was allowed to stir for 30 minutes at which time it was added to 3 mL of L-triiodothyronine (0.578 g, 0.9 mmol) and N-dimethyl-4-aminopyridine (0.217 g, 1.8 mmol). Insoluble DCU was removed by filtration through glass wool into DMF. After stirring for 16 hours, the solvent was removed by rotary distillation and the residue was purified by flash chromatography (30: 1-8: 1 CHCl ₃ : CH ₃ OH using 1 drop of HOAc / 100 mL eluent) to give a white The target material was obtained as a solid (0.473 g, 64%): R _f (6: 1 CHCl ₃ : CH ₃ OH) 0.16; ¹ H NMR (CDCl ₃ 500 MHz) 8.16 (d, 2H), 7 .65 (s, 1H, NH), 7.11-6.52 (m, 3H), 4.68 (dd, 1H, α), 3.17 (dd, 1H, β), 3.08 (dd 1H, β), 2.28 (m, 4H), 1.61 (m, 4H), 1.29-1.20 (bs, 16H), 0.85 (m, 6H).

(Iii) Preparation of triiodothyronine octoate TFA (T3C8) To TeocT3 (0.300 g, 0.38 mmol) in 3 mL dry DMF, DCC (0.086 g, 0.42 mmol), 1-octanol ( 0.2 mL, 1.2 mmol) and N-dimethyl-4-aminopyridine (0.051 g, 0.42 mmol) were added. After stirring for 21 hours, the solvent was removed by rotary distillation and the residue was purified by flash chromatography (12: 1-0: 1, hexane: EtOAc) to give the target material as a white solid (0.187 g, 55% ): R _f (1: 1, hexane: EtOAc) 0.95; ¹ H NMR (CDCl ₃ 500 MHz) 7.62 (s, 2H), 7.11-6.57 (m, 3H), 5.29 (D, 1H, NH), 4.57 (m, 1H, α), 4.08 (m, 4H, C (O) OCH ₂ alkyl, CH ₂ OC (O) N), 2.88 (m, 2H, β), 2.28 (m, 4H), 1.57 (m, 2H, OCH ₂ CH ₂ alkyl), 1.30-1.24 (m, 10H), 0.96 (m, 2H, _{SiCH 2), 0.84 (m,} 3H, CH 3).

TeocT3C8 material (0.187 g, 0.21 mmol) was dissolved in 10 mL CH ₂ Cl ₂ and 5 mL trifluoroacetic acid TFA. After stirring for 1 hour, the solvent was removed by rotary distillation to give the target material as a white solid (0.177 _g , 100%): R _f (1: 1, hexane: EtOAc) 0.78; ¹ H NMR ( DMSO 500 MHz) 7.83 (s, 2H), 6.95-6.66 (m, 3H), 4.45 (m, 1H, α), 4.13 (m, 2H, C (O) OCH ₂ alkyl ), 3.30 (m, 1H, β), 3.06 (m, 1H, β), 2.00 (m, 2H), 1.52 (m, 2H), 1.30-1.25 ( m, 10), 0.86 (m , 3H, CH 3).

(Iv) Preparation of triiodothyronine hexadeconoate TFA (T3C16) a) For TeocT3 (0.300 g, 0.38 mmol) in 3 mL dry DMF, DCC (0.086 g, 0.42 mmol), 1-Hexadecanol (0.274 g, 1.13 mmol) and N-dimethyl-4-aminopyridine (0.051 g, 0.42 mmol) were added. After stirring for 18.5 hours, remove the solvent by rotary distillation and purify the residue by flash chromatography (12: 1-0: 1, hexane: EtOAc) to target as a white solid contaminated with 1-hexadecanol The material was obtained (0.348 g, 90%): R _f (3: 1, hexane: EtOAc) 0.46; ¹ H NMR (CDCl ₃ 500 MHz) 7.63 (s, 2H), 7.08-6 .62 (m, 3H), 5.29 (d, 1H, NH), 4.56 (m, 1H, α), 4.11 (m, 4H, C (O) OCH ₂ alkyl, CH ₂ OC ( O) N), 2.99 (m, 2H, β), 2.28 (m, 4H), 1.55 (m, 2H, OCH ₂ CH ₂ alkyl), 1.31-1.24 (m, 26H), 0.96 (m, 2H, SiCH ₂ ), 0.86 (m , 3H, _CH 3).

b) Impure TeocT3C16 material (0.348 g) was dissolved in 10 mL CH ₂ Cl ₂ and 5 mL TFA. After stirring for 1 hour, the solvent was removed by rotary distillation to give the target material as a white solid: R _f (1: 1, hexane: EtOAc) 0.85; ¹ H NMR (DMSO 500 MHz) 7.84 (s, 2H), 6.95-6.64 (m, 3H), 4.45 (m, 1H, α), 4.10 (m, 2H, C (O) OCH ₂ alkali), 3.30 (m, 1H, β), 3.06 (m, 1H, β), 2.00 (m, 2H), 1.52 (m, 2H), 1.30-1.25 (m, 10), 0.86 _{(m, 3H, CH 3)} .

IV: Synthesis of E-mPEG-amine-triiodothyronine (i) Synthesis of mPEG-Teoc-T3 To a stirred solution of Teoc-T3 (88 mg, 0.11 mmol) in 3 mL dry DMF under Ar, DCC (25 mg, 1.20 mmol) was added. After stirring overnight, the insoluble DCU was filtered and the solid byproduct was washed with 2 mL DMF. To the combined clear filtrate was added mPEG-amine (534 mg, 0.10 mmol, average MW (molecular weight) = 5336) and 3 mL of additional DMF. The solution was heated briefly with a heat gun until all the amine was dissolved. The reaction was stirred overnight at room temperature. The reaction solution was poured into 50 mL of diethyl ether and the product was crushed as a filtered white solid. The solid product was then dissolved in 10 mL DMF and poured back into 50 mL ether. This process was repeated once more and the filtered solid was dried overnight under high vacuum to give 340 mg (56%) of hygroscopic product.

(Ii) Deprotection of mPEG-Teoc-T3 The dried product from Part A was stirred in 3 mL of TFA for 1 hour at room temperature. TFA was removed by rotary distillation of the azeotrope with hexane. The residue was dissolved in 3 mL DMF and the solution was poured into 50 mL ether. The suspension was cooled to 4 ° C., filtered and dried under high vacuum for 5 hours. This material was further purified by ultrafiltration (3000 MW) filter using saturated sodium bicarbonate as diluent. The product was dissolved in 10 mL of diluent, passed through the filter at 40 psi and rinsed 4 times in a similar manner. The residue was taken up in 3 mL of water and the filter was washed twice more with 3 mL of water. The combined solution was frozen and lyophilized, resulting in 162 mg (55%) of a fluffy white powder. The amount of T3 present in the conjugate by UV potency (λ ₃₂₀ , 1M NaOH) was determined to 5.3% of the total mass.

IV: Preparation of F-triiodothyronine cyclodextrin ester DCC (0.237 g, 1.15 mmol) was added to TeocT3 (0.457 g, 0.57 mmol) in 5 mL dry DMF. After stirring for 40 minutes under Ar, β-cyclodextrin (0.652 g, 0.57 mmol) and N-dimethyl-4-aminopyridine (0.070 g, 0.57 mmol) were added. After stirring the suspension for 26 hours under Ar, 20 mL of H ₂ O was added. The cloudy white solution was filtered through glass wool and washed with 20 mL EtOAc. Water was removed by lyophilization and the off-white residue was purified by flash chromatography (C18, CH ₃ OH) to give TeocT3-β-CD (Rf7: 7: 5: ₄ EtOAc: 2-propanol: NH ₄ OH: H _2. An approximately 1: 1 mixture of O) 0.64) and unmodified β-CD (Rf 0.28) was obtained as an off-white solid (0.098 g).

V. General Preparation of Peptide Additives Specific examples of active agents describe how different embodiments of the invention should be performed, but in the following, the general preparation of amino acid conjugates is described, which It can be used in combination with any number of active substances or alone. The formation of the peptide moiety of the present invention is essentially the formation of an amide from an acid and an amine and can be prepared by the following examples or by other known techniques.

V: A-side chain carrier peptide additive attachment (i) Preparation of γ-alkyl glutamate With reference to the above scheme, over 30 different γ-alkyl glutamates have been prepared, any one of which is selected It may be suitable for a given drug alcohol. For example, a suspension of glutamic acid, alcohol and concentrated hydrochloric acid can be prepared and heated for several hours. The γ-alkyl glutamate product can be precipitated in acetone, filtered, dried and recrystallized from hot water.

(Ii) Preparation of γ-alkyl glutamate-NCA The γ-alkyl glutamate can be suspended in dry THF, to which triphosgene is added and the mixture is refluxed under a nitrogen atmosphere until homogeneous. The solution can be poured into heptane to precipitate the NCA product, which can be filtered, dried and recrystallized from a suitable solvent.

(Iii) Preparation of poly [γ-alkylglutamate] γ-alkylglutamate-NCA can be dissolved in dry DMF, where a catalytic amount of primary amine is made viscous (typically overnight). Can be added to the solution. The product can be isolated from the solution by pouring into water and filtering. The product can be purified using GPC or dialysis.

(Iv) γ-alkyl glutamate / C-terminal conjugation Referring again to the above scheme, the peptide carrier can be dissolved in DMF under nitrogen and cooled to 0 ° C. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by γ-alkyl glutamate bioactive agent. The reaction can then be stirred at room temperature for several hours, the urea byproduct can be filtered, the product precipitated in ether and purified using GPC or dialysis.

V: Specific example of preparation of B-poly-γ-benzylglutamic acid (i) Preparation of benzylglutamic acid-NCA (additive) Benzylglutamic acid (25 grams) was suspended in 400 mL of anhydrous ethyl acetate under nitrogen. The mixture was heated to reflux where 30 grams of triphosgene was added in 6 equal portions. The reaction was refluxed for 3 hours until homogeneous. The solution was cooled to room temperature, filtered and concentrated in vacuo. The white powder was recrystallized from 50 mL of hot anhydrous ethyl acetate to give 17.4 grams (63%) of white powder.

(Ii) Preparation of polybenzylglutamic acid Benzylglutamic acid (17.4 grams) was dissolved in anhydrous tetrahydrofuran (THF) under nitrogen to which 238 mg of sodium methoxide was added in portions. The solution was allowed to stir for 2 days and the viscosity increased significantly. The solution was poured into 1.5 L petroleum ether with stirring. Petroleum ether was decanted and 1 L of petroleum ether was added back. The mixture was stirred by hand, the petroleum ether was decanted and the process was repeated with 500 mL of petroleum ether. The white solid was air dried and then vacuum dried to give 14.7 (95%) white fluffy paper-like solid.

V: C-Preparation of various peptides (i) Preparation of polyglutamic acid 1.96 g of polybenzylglutamic acid added by hand was stirred in 10 mL of 30 wt% hydrogen bromide (HBr) in acetic acid. The mixture was stirred at room temperature for 1 day and then added to 50 mL ether. The white precipitant was filtered, washed with 4 × 30 mL of ether and dried under high vacuum to give 1.11 grams (97%) of white powder.

(Ii) Preparation of polyarginine All reagents were used as received. ¹ H NMR was performed on a Bruker 300 MHz (300) or JEOL 500 MHz (500) NMR spectrophotometer using tetramethylsilane as an internal standard. Thin layer chromatography was performed using flat plates pre-coated with silica gel 60F ₂₅₄ . Flash chromatography was performed using silica gel 60 (230-400 mesh).

(A) Method 1
To H-Arg (Z) _2- OH (0.300 g, 0.68 mmol) in 3.0 mL dry DMSO, diphenylphosphoryl azide (219 [mu] l, 1.02 mmol) and triethylamine (236 [mu] l, 1.69 mmol) were added. Added. The reaction was allowed to stir under argon for 48 hours, at which time the solution was poured into 100 mL H ₂ O. The resulting heterogeneous solution is centrifuged to isolate a white precipitate, which is washed with 3 × 100 mL H ₂ O, 3 × 100 mL CH ₂ OH and 100 mL Et ₂ O, and then vacuum dried to give 172 mg off-white. A solid was obtained.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.31 (m, 10H), 5.21 (m, 1H, benzyl type), 5.01 (m, 1H, benzyl type), 3.83 (m 1H, α), 3.34 (m, 2H, δ) 1.54 (m, 4H, β, γ).

This material is dissolved in 1.5 mL of dry anisole and stirred with 0.3 mL of methanesulfonic anhydride for 3 hours, at which time an additional 0.3 mL of methanesulfonic anhydride is added and the solution is stirred for 1 hour. did. The reaction mixture was poured into 6 mL Et ₂ O and refrigerated for 15 minutes. The heterogeneous two-phase mixture was concentrated to 0.5 mL by rotary distillation. An additional 8 mL of Et ₂ O was added twice and the biphasic mixture was centrifuged and the supernatant removed to leave a yellowish viscous material. This residue was washed twice with 6 mL of acetone, centrifuged, and the supernatant was discarded to leave a pale yellow residue. The residue was dissolved in _{H 2} O in 0.3 mL, it was shaken with Amberlite (Amberlite) IRA-400. The resin was removed by filtration and washed with 3 mL H ₂ O. The combined eluent and wash were vacuum dried to give 0.063 g (90% yield) of a yellow film.

¹ H NMR (500 MHz, D ₂ O): δ 4.37 (m, 1H, α), 3.22 (m, 2H, δ) 1.94-1.66 (m, 4H, β, γ); MALDI-MS shows a degree of polymerization that varies between 6 and 14 residues.

(B) Method 2
Diphenyl for Boc-Arg (Z) _2- OH (0.025 g, 0.05 mmol) and H-Arg (Z) _2- OH (0.280 g, 0.63 mmol) in 3.0 mL dry DMSO. Phosphoryl azide (219 μl, 1.02 mmol) and triethylamine (236 μl, 1.69 mmol) were added. The reaction was stirred for 48 hours and then poured into 100 mL of H ₂ O. The heterogeneous solution was centrifuged and the precipitate was washed with 3 × 100 mL H ₂ O, 3 × 100 mL CH ₃ OH and 100 Et ₂ O and then dried in vacuo to give 132 mg of solid.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.31 (m, 10H), 5.21 (m, 1H, benzyl type), 5.01 (m, 1H, benzyl type), 3.83 (m 1H, α), 3.34 (m, 2H, δ) 1.54 (m, 4H, β, γ)

The protected polymer was dissolved in 1.5 mL dry anisole and stirred with 1.3 mL methanesulfonic anhydride for 4 hours. The solution was concentrated to 0.5 mL by rotary distillation. Et ₂ O (8 mL) was added, the two phase system was centrifuged and the supernatant was discarded. 10 mL of acetone was added twice, the solution was centrifuged, and the supernatant was discarded. The pellet was dried in vacuo overnight, then dissolved in _{H 2} O in 0.3 mL, was shaken with Amberlite (Amberlite) IRA-400. The resin was removed by filtration and washed with 3 mL H ₂ O. The combined eluent and wash were vacuum dried to give 0.019 g (24% yield) of a yellow film.

¹ H NMR (500 MHz, D ₂ O): δ 4.37 (m, 1H, α), 3.22 (m, 2H, δ) 1.94-1.66 (m, 4H, β, γ); MALDI-MS shows a degree of polymerization that varies between 5 and 11 residues.

VI. Multiple attachments of active agents to peptides In another preferred embodiment of the invention, multiple active agents can be attached to peptides. In the case of oligopeptides and polypeptides, active substances are distributed randomly or at set intervals along the chain through side chain attachment and terminated with either C-capping and / or N-capping type active substances. Can be made. Furthermore, in the case of an amino acid active substance, the amino acid active substance may be interspersed in a manner similar to the side chain distribution. The distribution may further be a cluster of active substances at the chain ends or throughout the peptide.

  The following examples provide a description of active agent attachment to the C-terminus and side chains of peptides. In the following examples, the peptide chain comprises PolyGlu. Furthermore, in the following examples, the active substance is attached through a carboxylate group.

  One skilled in the art will recognize that other peptides can be substituted depending on the active agent selected. Similarly, those skilled in the art will recognize that the attachment of the active agent can be from different functional groups.

  A general scheme for attaching active agents to the side chain and N-terminus of amino acids is further exemplified below through the preparation of furosemide conjugated to serine.

VI: Preparation of furosemide conjugated to A-serine The following example describes the attachment of furosemide to the N-terminus and side chain of polyserine.

  Furosemide-OSu and N-methylmorpholine (NMM) were added to a solution of pSer in NMP. The reaction was stirred at 70 ° C. overnight. After cooling, the reaction was placed in ether and the solid was collected by filtration. The solid was suspended in pH 8 water and purified using ultrafiltration. The product was filtered and dried.

  In the following examples, active agent peptide conjugates are produced that result in attachment of mevastatin, prednisone and pravastatin to the carboxylate side chain and C-terminus of the peptide. In these examples, the amino acid peptide is a polyGlu peptide.

  Using protection / deprotection techniques, one skilled in the art will recognize that the drug can be attached only to the C-terminus of the amino acid or only to the side chain. Furthermore, those skilled in the art will also recognize that an amino acid can be attached to a single amino acid at both the C-terminus and side chain, provided that it has the required functional groups as in Glu. Let's go.

VI: Preparation of B-PolyGlu Mevastatin (i) AcNGlu ₁₅ (3-Mevastatin) ₂
To polyGlu ₁₅ (0.116 g, 69 μmol) in 3 mL dry DMF, 1 mL of pyridine and acetic anhydride (20 μl, 207 μmol) was added. After stirring for 21 hours, the mixture was acidified with 6N HCl to pH 1 and then cooled to 4 ° C. The white precipitate was collected by centrifugation, washed 3 times with H ₂ O, and then vacuum dried to give 11 mg of N-acetylated polyGlu ₁₅ .

To N-acetylated polyGlu ₁₅ (0.011 g, 7α mol) in 4.8 mL dry DMF, dicyclohexylcarbodiimide (0.022 g, 108 μmol) was added. After stirring for 20 minutes, the heterogeneous solution is filtered to remove insoluble dicyclohexylurea and combined with mevastatin (0.042 g, 108 μmol) and N-dimethyl-4-aminopyridine (0.013 g, 108 μmol). The mixture was stirred for 23 hours, at which time the reaction was quenched by the addition of 20 mL of H ₂ O. Extract the solution twice with 10 mL CHCl ₃ . The aqueous component was adjusted to pH 3 with 1N HCl and cooled to 4 ° C. The resulting white precipitate was isolated by centrifugation and washed 3 times with 8 mL H ₂ O. The solid was dissolved in 1 mL H ₂ O and washed once with 1 mL CH ₂ Cl ₂ and twice with 2 mL EtOAc. The aqueous layer was acidified to pH 3 with 1N HCl, cooled to 4 ° C., the precipitate was isolated by centrifugation and washed twice with 2 mL H ₂ O. The dried conjugate (2 mg) was shown by ¹ H NMR to contain 15 Glu per 2 mevastatin molecules.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 5.92 (5 ′ mevastatin), 5.72 (3 ′ mevastatin), 5.19 (4 ′ mevastatin), 5.17 (8 ′ mevastatin), 5. 12 (3 mevastatin), 4.41 (5 mevastatin), 4.03 (α, Glu), 2.25 (γ, Glu), 1.88 (β, Glu), 0.82 (4 ″, 2 ′ Allyl methylmevastatin), 1.17 (2 "mevastatin).

(Ii) Glu ₁₅ (3-mevastatin) (160)
Dicyclohexylcarbodiimide (0.239 g, 1.159 mmol) was added to Glu ₁₅ (0.151 g, 77 μmol) in 3 mL dry DMF and the reaction was stirred under argon for 4 h. The white precipitate was removed and N-dimethyl-4-aminopyridine (0.141 g, 1.159 mmol) and mevastatin (0.222 g, 0.569 mmol) were added dissolved in 10 mL CHCl ₃ . The reaction was stirred under argon for 21 hours, at which point the precipitate was removed. The solution was concentrated by rotary distillation and added to 40 mL of saturated NaCl (aqueous) adjusted to pH 8. The homogeneous solution was extracted three times with 20 mL CHCl ₃ and then ultrafiltered (Amicon regenerated cellulose, YM1, NMWL, 1000). The retentate to give a white residue of 8mg dried under vacuum, which showed a ratio of 15 glutamate to 1 mevastatin by ^{1 H} NMR.

¹ H NMR (500 MHz, D ₂ O): δ 5.92 (5 ′ mevastatin), 5.72 (3 ′ mevastatin), 5.19 (4 ′ mevastatin), 5.17 (8 ′ mevastatin), 5.12 (3 mevastatin), 4.41 (5 mevastatin), 4.03 (α, Glu), 2.25 (γ, Glu), 1.88 (β, Glu), 0.82 (4 ″, 2 ′ allyl) Type methyl mevastatin), 1.17 (2 "mevastatin).

(Iii) BocGlu (3-mevastatin) O-tBu
N-dimethyl-4-aminopyridine (0.055 g, 453 μmol) was added to BocGlu (OSu) O-tBu (0.181 g, 453 μmol) and mevastatin (0.177 g, 453 μmol) in 40 mL of CHCl ₃ . . The reaction was heated to reflux under argon for 7 hours and then allowed to stir at 20 ° C. for 8 hours. The solvent was removed by rotary distillation and the residue was purified by flash chromatography (8: 1 to 1: 1 hexane: EtOAc) to give the conjugate as a clear film (0.038 g, 11%).

R _f (3: 1, hexane: EtOAc): 0.22; ¹ H NMR (500 MHz, CDCl ₃ ): δ 5.97 (d, 1H, 5 ′), 5.73 (dd, 1H, 3 ′), 5.55 (s, 1H, 4 ′), 5.32 (s, 1H, 8 ′), 5.24 (dd, 1H, 3), 5.09 (d, 1H, NH), 4.48 ( m, 1H, 5), 4.20 (m, 1H, α), 2.78 (m, 2H, 2), 2.37 (m, 4H, 2 ′, 2 ″, γ), 1.45 ( s, 18H, t-Bu) , 1.12 (d, 3H, 2 "-CH 3), 0.88 (m, 6H, 4", 2'-CH 3).

VI: Preparation of C-PolyGlu Prednisone Bromo-tris-pyrrolindinophosphonium hexane fluorophosphate (0.510 g, 1.1 mmol) and N-methylmorpholine (1 mL) against Glu ₁₅ (0.350 g) in 30 mL DMF 9.3 mmol). The mixture was stirred for 30 minutes under Ar, at which time N-dimethyl-4-aminopyridine (0.067 g, 0.5 mmol) and prednisone (0.489 g, 1.4 mmol) were added. After stirring for 14 hours, the solvent was removed under reduced pressure. The residue was dissolved in 50 mL H ₂ O and acidified to pH 3 with 6N HCl. The precipitate was filtered and washed with 30 mL CHCl ₃ . The solid was then dissolved in 70 mL H ₂ O, pH 8, and extracted twice with 40 mL CHCl ₃ . The aqueous layer was ultrafiltered with 150 mL of H ₂ O (Amicon regenerated cellulose, YM1, NMWL, 1000) and the retentate was vacuum dried to give a white residue. ¹ HNMR (DMSO) analysis showed a Glu: prednisone ratio of 4: 1.

Preparation of VI: D-Glu ₁₅ (Gly-pravastatin) This example describes the C-terminal attachment of alcohol to a single amino acid (glycine) along with subsequent attachment to the side chain and C-terminus of polyglutamic acid.

To N-Boc-glycine (0.247 g, 1.41 mmol) in 5 mL of dry DMF was added dicyclohexylcarbodiimide (0.138 g, 0.67 mmol). After stirring for 1 hour under Ar, the solution was filtered through glass wool to remove insoluble urea. Pravastatin sodium (0.300 g, 0.67 mmol) followed by N-methylmorpholine (147 μl, 1.34 mmol) was stirred. The mixture was stirred for a further 23 hours under argon, at which time the solution was filtered through glass wool and the solvent was removed by rotary distillation. The residue was purified by flash chromatography (30: 1 to 8: 1, CHCl ₃ : (CH ₃ OH) to give the peracylated statin as a white solid (0.118 g).

R _f = 0.23 (6: 1 CHCl ₃ : CH ₃ OH); ¹ H NMR (500 MHz, CDCl ₃ ): δ 5.97 (m, 1H, 5 ′), 5.89 (m, 1H, 3 ′) ), 5.58 (bs, 1H, 6 ′), 5.40 (bs, 1H, 4 ′), 5.16 (bs, 1H, 8 ′), 3.92 (m, 6H, α), 2 .69-2.34 (4H, 2, 2, 2 ′, 2 ″), 1.43 (s, 18H, t-Bu), 1.09 (d, 3H), 0.87 (m, 6H) .
VII. General description of linkers for attachment to peptides

  For drugs that do not react sensitively to attachment through the C-terminus, N-terminus or side chain, a linker is required for stable covalent bonding. For example, a direct covalent bond of an amino acid to a ketone does not appear to produce a stable entity. However, insertion of a carbonyl between the active agent and the carrier peptide should provide increased stability of the active agent / peptide conjugate. Moreover, the formation of ketals using reagents with appropriate functional groups in the agent provides the link between the active agent and the amino acid conjugate with the desired stability. Another example of this type of linker is a DHP linker. Ideally, these linkers should be removable in vivo. From the following examples, those skilled in the art will recognize how other linkers and attachment functionality should be derived.

VII: Preparation of Naltrexone Polymer Conjugate Linked with A-Carbamate

Naltrexone hydrochloride (520 mg, 1.37 mmol) and 1,1′-carbonyl-diimidazole (CDI) (202 mg, 1.25 mmol) were dissolved in anhydrous DMF (5 mL). The reaction was then allowed to stir at room temperature under argon for 1 hour. Glutamate - lysine copolymer _(Glu n Lys _m, free lysine side chains 2.5 mmol ^*) was added into DMF in 15mL then as suspension, the reaction under argon was allowed to continue stirring at room temperature for 2 days . The solvent, DMF, was then removed by rotary distillation under high vacuum, leaving a green solid. The solid was dissolved in water (20 mL), and the aqueous solution was filtered and concentrated using ultrafiltration (molecular weight cut-off 1000). Two aliquots of water (10 mL each) were added and the solution was filtered and concentrated with each addition to a final volume of ˜2 mL. The solvent was removed from the remaining solution by rotary distillation and the resulting solid was dried overnight in a vacuum chamber at room temperature. Thus, the carbamate conjugate (642 mg, 43% yield assuming saturation of available lysine side chain) was estimated to be approximately 1: 4 (naltrexone / amino acid residue) as estimated by ¹ H-NMR. Was obtained with the input amount.

¹ H NMR (360 MHz, DMSO-d ₆ ): δ 6.78 and 6.61 (bs, each 1H, naltrexone-aromatic); 2.74 (bs, ˜8H, γ-Glu); 2.20 (bs) -8H, β-Glu), 0.50 (bs, 2H, naltrexone-cyclopropyl) and 0.16 (bs, 2H, naltrexone-cyclopropyl).

( ^* The mmol of the resin side chain is estimated based on a 1: 1 Glu / Lys ratio as previously determined by NMR. This copolymer can be lysed using standard NCA polymerization methods using the Lys ( Prepared from Boc) -NCA and Glu (OtBu) -NCA The resulting polymer (1.00 g, 2.5 mmol Lys) was deprotected using 4N HCl in dioxane.

VII: Preparation of B-carbonate linked naltrexone polymer conjugate (i) Reaction of naltrexone (free radical) with CDI

CDI (0.522 g, 3.2 mmol) was dissolved in 20 mL of dry methylene chloride at room temperature in a flask filled with argon. Naltrexone (1.00 g, 2.9 mmol) dissolved in methylene chloride (20 mL) was then added dropwise to the CDI solution. An additional 10 mL of methylene chloride was used to wash away the container containing naltrexone, and the wash was added to the reaction mixture. The reaction was heated to 50 ° C. and allowed to stir overnight at a temperature between 40-50 ° C. under argon. The solvent was then removed by rotary distillation under high vacuum. ¹ H-NMR showed that the sticky solid contained a mixture of imidazole, adduct 1 and unreacted starting material. Imidazole and Compound 1 were the dominant components.

¹ H NMR (360 MHz, d ₆ -DMSO): δ 8.27 (bm, 1H, 1); 7.74 (bs, 2H, imidazole); 7.53 (t, 1H, 1); 7.24 (bs) 1H, imidazole); 7.14 (bm, 1H, 1); 6.95 (d, 1H, 1) and 6.73 (d, 1H, 1).

(Ii) reaction of naltrexone -CDI adduct with Ser _n

The solid from Step 1 was dissolved in anhydrous N-methylpyrrolidinone (NMP) and solid Ser _n (0.51 g, 5.9 mmol) was added to the solution. The reaction mixture was then heated to 60 ° C. under argon and allowed to stir under argon overnight at a temperature between 50-60 ° C. The organic solution was then diluted in 100 mL of water. A precipitate immediately formed and the solid (A) was collected by a centrifuge and then the pellet was dried overnight in a vacuum chamber. Water in the supernatant was removed by rotary distillation and the remaining NMP solution was diluted in ether (100 mL). Again, a precipitate formed immediately. This solid (B) was collected by filtration and then dried overnight in a vacuum chamber. Both solids were hygroscopic and appeared to be similar in composition by TLC (3: 1 CHCl ₃ / CH ₃ OH). Therefore, solids A and B were combined and dissolved / suspended in ~ 50 mL of water. Ultrafiltration (cut-off molecular weight 1000) was used to remove impurities such as unreacted naltrexone and imidazole, leaving Ser _n and the naltrexone conjugate, Ser _n-m [Ser (Nal)] _m . The suspended material was washed with 5 aliquots of water (10 mL each) and then pelleted by centrifugation. The polymer conjugate was then dried in a vacuum chamber overnight. This gave 80 mg (~ 50% yield) with an estimated input of 1:19 naltrexone / serine (based on ¹ H-NMR).

¹ H NMR (360 MHz, DMSO-d ₆ ): δ 5.03 (bs, ˜19 H, α-Ser); 0.59 (bs, 2 H, naltrexone-cyclopropyl) and 0.34 (bs, 2 H, naltrexone-cyclopropyl) )

VII: Preparation of C-methylnaltrexone-glucose ketal conjugate

(I) Preparation of 3-methylnaltrexone Naltrexone (6.0 g, 16.5 mmol) was dissolved in 100 mL of distilled water. The solution was added dropwise with 1N NaOH to a final pH of 11.8. During the titration, neutral naltrexone precipitated from the solution and then returned into the solution. When pH 11.8 was reached, the solvent was removed by rotary distillation under high vacuum and the resulting solid was stored under vacuum overnight at room temperature. The solid was then suspended / dissolved in anhydrous tetrahydrofuran (200 mL) and allowed to stir at room temperature under argon. A solution of iodomethane (2.1 mg, 33 mmol) in 50 mL of tetrahydrofuran was added dropwise over 30 minutes. The reaction was then stirred at room temperature under argon for an additional 3 hours. Thereafter, the solvent was removed by rotary distillation under reduced pressure. The residual solid was then dissolved in 40 mL CHCl ₃ and the organic solution was washed twice with 30 mL saturated NaCl, 3 × 30 mL 1N NaOH and 30 mL saturated aqueous NaCl. The organic solution was collected and dried over sodium sulfate. Removal of the solvent by rotary distillation and drying under vacuum overnight gave pure 3-methylnaltrexone (5.6 g, 15.8 mmol, 96% yield) as a brown residue, the composition of which was determined by TLC and ¹ H-NMR. Were determined.

¹ H NMR (360 MHz, CDCl ₃ ): δ6.677 (d, 1H, aromatic naltrexone), 6.591 (d, 1H, aromatic naltrexone), 3.874 (s, 3H, methoxy group), 0. 6-0.5 (m, 2H, naltrexone cyclopropyl) and 0.2-0.1 (m, 2H, naltrexone cyclopropyl).

(Ii) Preparation of methylnaltrexone-glucose ketal conjugate D-α-glucose (2.02 g, 11.2 mmol) against a solution of methylnaltrexone (0.200 g, 0.56 mmol) in dioxane (20 mL), Trifluoromethanesulfonic acid (0.05 mL, 0.62 mmol) and CuSO ₄ (1.00 g) were added. The reaction mixture was stirred at ambient temperature for 4 days. The reaction was then filtered, neutralized with saturated NaHCO ₃ and filtered again. Dioxane and water were removed and the residue was taken up in CHCl ₃ and extracted with water (3 × 100 mL). The organic layer was dried over MgSO ₄ and the solvent was removed under reduced pressure. The crude product was purified on silica gel (0-10% MeOH in CHCl ₃ ) to give the ketal conjugate (0.010 g) in a 1: 1 mixture with free methylnaltrexone.

¹ H NMR (360 MHz, CDCl ₃ ): δ 0.14 (brs, 4H, naltrexone cyclopropyl), 0.53 (br m, 4H, naltrexone cyclopropyl), 0.90 (m, 2H, naltrexone cyclopropyl) ), 1.48 (m, 6H, naltrexone), 2.19-2.78 (m, 12H, naltrexone), 3.03 (m, 2H, naltrexone), 3.75 (q, 2H, glucose), 3.87 (m, 8H, naltrexone CH ₃ and glucose), 3.97 (q, 2H, glucose), 4.14 (q, IH, glucose), 4.33 (t, IH, glucose), 4. 66 (s, 1H, naltrexone), 6.65 (m, 4H, naltrexone).

VII: D-DHP linker chemistry

All reagents were used as received. ¹ H NMR was performed on a JEOL 500 MHz (500) NMR spectrophotometer (Spectrophotomer) using tetramethylsilane as an internal standard. Thin layer chromatography was performed using flat plates pre-coated with silica gel 60F ₂₅₄ . Flash chromatography was performed using silica gel 60 (230-400 mesh).

(I) Method (a)
3,4-Dihydro-2H-pyran-5-carboxylic acid in 2 mL of CHCl ₃ [M. Hojo, R.H. Masuda, S .; Sakaguchi, M .; Takagawa, 1986, convenient synthetic method for B-alkoxy- and B-phenoxyacrylic acid and 3,4-dihydro-2H-pyran-5- and 2,3-dihydrofuran-4-carboxylic acid ( A Convenient Synthetic Method for B-Alkoxy-and B-Phenoxyacrylic Acids and 3,4-Dihydro-2H-pyran-5-and 2,3-Dyhydrofuran-4-carboxylic). Phosphorus pentachloride (0.143 g, 687 μmol) was added to Synthesis, 1016-17] (0.044 g, 343 μmol). After general stirring, Fmoc-Ser (0.101 g, 309 μmol) was added. After stirring for an additional 72 hours, 5 mL of CH ₂ Cl ₂ was added and the mixture was washed with 5 mL of saturated NaCl. The solvent was removed by rotary distillation and the residue was purified by flash chromatography (15: 1: 0 to 10: 1: 0 to 100: 10: 1, CHCl ₃ : MeOH: HOAc) to give the target material as a white solid. (23%).

R _f = 0.23 (6: 1 CHCl ₃ : MeOH); ¹ H NMR (360 MHz, CDCl ₃ ): δ 7.81-7.25 (m, 9H, aromatic and vinyl), 5.63 (s, 1H, carbamate), 4.64 (t, 1H, a), 4.47 (m, 2H, serine _{CH 2), 4.23 (m,} 3H, Fmoc CH 2 and CH), 4.04 (m, 2H, _OCH 2) of DHP, 2.24 (m, 2H, allylic), 1.86 (m, 2H, homoallyl type).

(Ii) Method (b)
To 3,4-dihydro-2H-pyran-5-carboxylic acid (0.527 g, 4.1 mmol) in 30 mL CHCl ₃ was added diisopropylcarbodiimide (0.260 g, 2.1 μmol). After stirring for 2 hours, Fmoc-Ser (0.673 g, 2.1 mmol) and N-dimethyl-4-aminopyridine (0.502 g, 4.1 mmol) were added and the reaction was stirred for an additional 14 hours. More diisopropylcarbodiimide (0.260 g) was added and the reaction was mixed for an additional 24 hours, at which point additional diisopropylcarbodiimide (0.130 g) was added and the reaction was allowed to stir for an additional 24 hours. The solvent was removed by rotary distillation and the residue was repeatedly purified by flash chromatography to give the target material as a white solid (7%).

VIII. In Vitro Performance Study of Various Active Substances and Amino Acid Conjugates VIII: Materials and Methods for In Vitro Performance Studies for A-Peptide Conjugated Active Substance Tests Esterase (EC 3.1.1.1: from porcine liver), lipase (EC 3.1.1.3: derived from porcine pancreas), amidase (EC 3.5.1.4; derived from Pseudomonas aeruginosa), protease (EC 3.4.24.31; type XIV, streptomy Derived from Streptomyces grieseus; also known as pronase), pancreatin (EC232-468-9; derived from porcine pancreas), pepsin (derived from EC 3.4.23.1: porcine gastric mucosa), Tris-HCl and methimazole are all It was purchased from Sigma (Sigma). The buffer used in the digestion assay was prepared as follows: reducing buffer [110 mM sodium chloride, NaCl, 50 mM methimazole, 40 mM Tris-HCl, 1N sodium hydroxide NaOH, pH 8. 4), intestinal simulator (IS) buffer [pH adjusted to 7.5 with 100 mM potassium dihydrogen phosphate, 1N NaOH], gastric simulator (GS) buffer [with 69 mM NaCl, HCl pH adjusted to 1.2], esterase buffer [10 mM borate buffer, pH adjusted to 8 with NaOH], lipase and amidase buffer [100 mM potassium dihydrogen phosphate, pH 7 with NaOH. Adjust to 5.]

Proteolytic release of the active substance from the peptide conjugate was determined in various assays. Peptide conjugates were shaken at 37 ° C. for 24 hours in the presence of pronase, pancreatin, esterase, lipase or amylase or 4 hours in the presence of pepsin. Each conjugate (0.5-2.0 mg / mL) and enzyme (protease, reducing buffer, 6 mg / mL; pancreatin, IS buffer, 20 mg / mL; pepsin, GS buffer, 6.40 mg / mL Esterase, esterase buffer, 1.02 mg / mL; lipase, lipase buffer, 0.10 mg / mL; amidase, amidase buffer, 0.10 μl / mL). For protease, pancreatin and pepsin digestion, conjugate and enzyme were diluted 2-fold in the assay with a final volume of 2 mL. After the indicated incubation time for each assay, 2 mL of acetonitrile MeCN containing 1% phosphoric acid, H ₃ PO ₄ is added to each sample to stop digestion, and the sample is subjected to centrifugation to increase Particulate matter was removed. The remaining particulate material was filtered through a 0.2 μm nylon syringe filter (Whatman) prior to HPLC analysis.

Enzyme digested conjugates were analyzed for the presence of unconjugated active agent by reverse phase HPLC (C18, 4.6 × 250 mm, 5 μm, 300 A) using the following conditions: Mobile phase-Lotus buffer (4 of _H 3 _PO 4 .5ML, triethylamine 8.8mL, pH = 3.5) / THF / MeCN [68.6 / 4.5 / 26.9] or TBA- phosphate buffer (10 mM hydrochloric acid tetrabutyl Ammonium, 10 mM monobasic sodium phosphate, pH = 6.0) / MeCN [65/35]: injection volume—20 μl; flow rate—1 mL / min; UV—230 nm. The retention time of the active substance was determined from the standard in the calibration curve used to calculate the concentration of active substance released enzyme.

VIII: B-In Vitro Performance Study Results Table 8 below describes active substance conjugates tested in the stomach, intestine and pronase simulators.

VIII: C-Caco-2 human intestinal epithelial cell studies A monolayer of Caco-2 human intestinal epithelial cells is increasingly used to predict absorption of orally delivered drugs. Caco-2 transwell system and other in vitro assays were used to evaluate the performance of polytoroids. Findings have shown that polytoroids enhance the oral delivery of thyroid hormone for the treatment of hypothyroid disorders.

(I) Caco-2 human intestinal epithelial cell assay Caco-2 cells are grown on the surface of collagen-coated wells in a 24-well format to form a confluent monolayer representing small segments of the intestine. I let you. The wells were removable and included an upper chamber representing the distal side (facing the intestinal lumen) and a lower chamber representing the basolateral side (site of serosal drug absorption). The integrity of the epithelial barrier was monitored by testing the electrical resistance across the monolayer. Drug absorption was studied by adding the specimen to the apical side and assaying the concentration of drug in the basolateral chamber after incubation.

(Ii) Intestinal epithelial cell protease digests polytoroids.
A polytoroid is a synthetic glutamic acid polymer in which T4 and T3 are covalently linked by peptide bond linkage. The polymer is a delivery vehicle for thyroid hormones and is not designed to cross the intestinal barrier itself. Rather, it was designed to release T4 and T3 in a time-dependent manner. The release of thyroid hormone depends on the enzymatic resolution of the glutamic acid polymer. Theoretically, this would be the result of one polytoroid encountering a proteolytic enzyme as it descends the intestine. Proteins are digested into small peptides by gastric pepsin and pancreatic enzymes secreted into the small intestine. At this time, intestinal epithelial cells function to further disrupt small peptides. These cells accomplish this using a proteolytic enzyme called a brush border protease that is attached to the cell surface.

  In order to monitor the effect of brush border peptidases on polytoroids, it was necessary to develop an assay to specifically distinguish polytoroids from polyglutamic acid and thyroid hormones. Accordingly, the present inventors have developed an enzyme immunoassay (ELISA) that specifically recognizes polytoroids. The assay utilizes antibodies against glutamic acid polymers to capture polytoroids and antibodies against T4 or T3 to detect the presence of polytoroids. The assay does not have any cross-reactivity with polyglutamic acid or thyroid hormone itself. Thus, proteolysis of polytoroids results in T4 and T3 release from the polymer and a corresponding decrease in ELISA reactivity. Thus, a polytoroid specific ELISA can be used to monitor polytoroid decay.

  A polytoroid specific assay was used to analyze in situ digestion of polytoroids in Caco-2 cell culture. Different concentrations of polytoroids were added to the apical side of Caco-2 cells and incubated in PBS for 4 hours at 37 ° C. (n = 4). The apical polytoroid concentration was measured by polytoroid specific ELISA before and after the 4 hour incubation (FIG. 2). At a relatively high concentration of 100 micrograms, 26% of the polytoroids were degraded, while at a low concentration of 1/10, 84% of the polytoroids were isolated. The amount of polytoroid remaining after 4 hours of incubation at the time the 0.5 microgram concentration (closer to that which would be encountered by the intestine at normal human doses) is the detection limit of the ELISA. (10 ng), which basically represented complete digestion. The loss of polymer in the apical chamber was not due to absorption of the polytoroid across the monolayer, as the basolateral chamber contained no detectable polytoroid in any experiment (see below). However, the inventors of the present application cannot extrapolate the cellular uptake of polytoroids, and enzyme digestion may explain most if not all of the decrease in polytoroid concentration at the tip side. Is expensive. At higher concentrations, cell uptake may be difficult to account for this large difference in residual polytoroids.

(Iii) PolyT4 enhances the absorption of T4 across the Caco-2 monolayer.
Absorption of T4 was monitored in a Caco-2 transwell system (n = 4). PolyT4 (10 micrograms) was added to the tip side of the transwell. T4 was added to the tip side at a concentration equal to the T4 content of PolyT4. A commercial ELISA for T4 was used to determine the level of T4 in the basolateral chamber after 4 hours incubation at 37 ° C. (FIG. 3). A much larger amount of T4 was absorbed from PolyT4 compared to Caco-2 cells incubated with an amount of T4 equivalent to that containing the polymer.

(Iv) Polytoroids do not cross the Caco-2 monolayer.
In order to determine whether the polytoroid itself crosses the Caco-2 monolayer, we have determined to determine the amount of polymer in the basolateral side after incubation with the polytoroid at a high concentration (100 micrograms). A specific ELISA was used. After 4 hours of incubation, specimens from the basolateral side (n = 4) did not show any reactivity in the ELISA (Figure 4). The detection limit for polytoroid was 10 ng, thus 1 / 10,000 of polytoroid was absorbed. In conclusion, within the limits of ELISA detection, polytoroids do not cross the Caco-2 monolayer.

(V) Conclusion and Summary The following discussion lists in vitro performance studies performed on specific embodiments of the present invention. Although these performance studies have described specific embodiments of the invention, the invention is not limited to these embodiments. Alternative embodiments and modifications that the invention will further encompass, particularly in light of the above teachings, can be made by those skilled in the art. Accordingly, the present invention is intended to embrace all such alternative embodiments, modifications or equivalents that may fall within the spirit and scope thereof.

  In vitro performance assays provide the following conclusions: The active substance is released from the peptide conjugate by cellular proteases in the pancreas and intestine. T4 and T3 released from the polytoroid are absorbed across the intestinal monolayer. PolyT4 enhances T4 absorption across intestinal epithelial tissue in vitro. The polytoroid itself does not cross the intestinal epithelial barrier in vitro. The kinetics of timed release can be controlled by the polytoroid synthesis method.

  Data from an in vitro intestinal epithelial model show that T4 attachment to glutamic acid polymers can enhance thyroid hormone absorption, possibly by providing a second uptake mechanism and / or enhancing hormone solubility , Suggests that. The polytoroid itself does not cross the intestinal epithelial barrier within the in vitro Caco-2 model. Thus, any concern about the systemic effect of the polymer is minimized because it cannot be absorbed into the bloodstream.

IX: In Vivo Performance Study of Various Active Substances and Amino Acid Conjugates IX: In Vivo Performance Study of A-Polymer-Drug Conjugates Pharmacokinetics of amino acid polymer drug conjugates containing various parent drugs and equivalent doses Sprague Dawley rats were tested in vivo by oral gavage. The dose (mg / kg) was given as a solution in water or sodium bicarbonate buffer. Serum was collected under anesthesia by jugular vein puncture for the first bleeding and cardiac puncture for the second bleeding. Collection is 1 set before administration (jugular vein) and 6 hours (heart); 1 hour (jugular vein) and 9 hours (heart); and 3 hours (jugular vein) and 12 hours (heart) Per 5 animals. Serum drug levels were determined by LC / MS / MS or ELISA.

IX: In vivo performance of B-furosemide (side chain)

  Study 6856-120 shows the relationship between PolySer (furosemide) conjugate containing an equivalent amount of furosemide and the serum concentration level of furosemide. Furosemide had an (AUC) of 21,174 compared to a conjugate with an AUC of 8,269 (39.1% in relation to the parent drug). The above figure shows a serum concentration curve representing the relationship between the parent drug and the PolySer (furosemide) conjugate. The 9 hour serum level of PolySer (furosemide) conjugate was 95.5% of its 3 hour level, while the 9 hour serum level of the parent drug was only 59.8% of its 3 hour level. This and relative flatness of the PolySer (Furosemide) conjugate serum concentration curve between 3 and 9 hours compared to that of the curve for the parent drug indicates the sustained release by the PolySer (Furosemide) conjugate. Illustrated.

IX: In vivo performance of C-quetiapine

  The results of study 6856-117 are shown in the table and figure above.

  Summary of in vivo performance studies of IX: D-various polymer-drug conjugates

  The relative percentage of the area under the serum concentration curve (AUC) for various amino acid polymer drug conjugates compared to the parent drug AUC is shown in Table 9. The relative percentage was in the range of 9.4% to 42.6% and varied depending on the amino acid content of the polymer drug conjugate. These examples covalently link various drugs to various amino acid polymers and affect the release and absorption of the bound drug into serum when given as an oral dose to animals. Illustrates ability.

IX. In vitro and in vivo performance of polyserine-naltrexone conjugate (carbonate linked) X: In vivo performance of A-polyserine-naltrexone conjugate (rat model) (Naltrexone: serine ratio of lot number BB-272, 1: 6) .
Polyserine-naltrexone conjugates were tested in male Sprague Dawley rats (˜250 g). Confirmed doses were delivered orally in the form of gelatin capsules containing purified dry powder polyserine-naltrexone conjugates or naltrexone. No excipients were added to the capsule.

  The naltrexone content in the polyserine-naltrexone conjugate was estimated to be 30% based on a 1: 6 ratio of naltrexone: serine determined by NMR. Polyserine-naltrexone conjugate was administered to 4 rats at a dose of 12 mg containing 3.6 mg of naltrexone. A dose of naltrexone (3.6 mg) equal to the naltrexone content of the conjugate was also given to 4 rats. Capsules were delivered orally to rats at 0:00 using a capsule weighing syringe. Serum was collected from the rats at 2, 4, 6, 9 and 12 hours after capsule delivery. Serum naltrexone concentrations were determined by ELISA using a commercially available kit (Nalbuphine, product number # 102819, Neogen Corporation, Lansing, Michigan).

  Serum levels for individual animals are shown in Table 10. Average serum levels are shown in Table 11. As shown in the above figure, serum levels showed a rapid rise in the case of naltrexone (2 hours) compared to the drug administered as a polyserine-naltrexone conjugate (4 hours). Serum levels of naltrexone for the polyserine-naltrexone conjugate remained elevated much longer than with naltrexone. Furthermore, the peak level was significantly lower with the polyserine-naltrexone conjugate. It should be noted that the 2 hour time point was the first measurement of naltrexone serum levels. Since this was the peak level measured for naltrexone, it cannot be determined whether the level reached the peak earlier at higher concentrations. Therefore, in this experiment, it was impossible to accurately determine the area under the serum concentration curve (AUC) or Cmax for naltrexone.

In vivo performance of X: B-polyserine-naltrexone conjugate (lot number BB-301, 1:10 naltrexone: serine ratio)
Polyserine-naltrexone conjugates were tested in Sprague-Dawley rats (˜250 g). Confirmed doses were delivered orally in the form of gelatin capsules containing purified dry powder polyserine-naltrexone conjugates or naltrexone. No excipients were added to the capsule.

  The naltrexone content in the polyserine-naltrexone conjugate BB-272 was estimated to be 30% based on a 1: 6 ratio of naltrexone: serine determined by NMR. Polyserine-naltrexone conjugate was administered to 5 rats at a dose of 12.9 mg containing 3.6 mg of naltrexone. A dose equivalent to naltrexone contained in a polyserine-naltrexone batch (BB-301) was also given to 5 rats. In addition, half of the equivalent dose (1.8 mg) was given at zero, and then 5 rats were given a second half dose at 6.5 hours.

  Capsules were delivered orally to rats at 0 o'clock using a capsule weighing syringe. Serum was collected 0.5, 1.5, 3, 5, 8, 12, 15, and 24 hours after capsule delivery for rats administered with polyserine-naltrexone (BB-301) and equivalent naltrexone. Serum 0.5, 1.5, 3, 5, 8, 11.5, 14.5, and 24 hours after capsule delivery for rats that received half of the equivalent dose after 0 and 6.5 hours Collected. Serum naltrexone concentrations were determined by ELISA using a commercially available kit (Nalbuphine, product number # 102819, Neogen Corporation, Lansing, Michigan).

  Serum levels for individual animals are shown in Table 12. Average serum levels are shown in Table 13. As shown in the above figure, naltrexone serum levels rose earlier (0.5 hours) with naltrexone than with drugs administered as polyserine-naltrexone conjugates (5 hours). Serum levels of naltrexone for the polyserine-naltrexone conjugate remained elevated much longer (> 12 hours) than the monomeric naltrexone control (<8 hours). Serum concentration curves crossed at about 7 hours. Furthermore, the average peak level concentration (Cmax) was significantly lower for conjugated naltrexone (Table 14). Furthermore, the average time for peak concentration (Tmax) was significantly longer for polyserine-naltrexone conjugates (Table 14). The average AUC of the polyserine-naltrexone conjugate was approximately 75% of the naltrexone average AUC (Table 5). Statistically, the average AUC was not significantly different (P <0.05). Serum levels of rats fed half dose (1.8 mg) at time zero and at 6.5 hours were compared to those of rats fed polyserine-naltrexone conjugate. Concentration levels remained high for the conjugate beyond that for the second naltrexone dose, and the curve crossed at about 2.5 hours and again at about 11 hours (serum concentration curve Double crossover).

X: In situ performance of C-polyserine-naltrexone-Caco-2 cell digestion Polyserine-naltrexone conjugates BB-272 and BB-301 were incubated with Caco-2 cell monolayers in phosphate buffer solution for 4 hours. The buffer was removed from the monolayer and concentrated on a SP-18 column. Concentrated specimens were analyzed for the presence of naltrexone by reverse phase HPLC. Each polyserine-naltrexone conjugate showed significant release of free naltrexone from the polymer conjugate in three separate specimens. In conclusion, Caco-2 cellular enzymes affected the release of naltrexone from the polyserine-naltrexone conjugates BB-272 and BB-301. Release of carbonate-linked drugs from conjugates by intestinal cell enzymes provides a mechanism for drug absorption after oral administration.

X: Treatment of polyserine-naltrexone conjugates using D-intestinal enzymes Polyserine-naltrexone (BB-272 and BB-301) were treated with enzymes found in the lumen of the stomach and small intestine. Enzymes to be tested, including pepsin, pancreatic lipase and pancreatin, were ineffective in releasing naltrexone from the polyserine-naltrexone conjugate. Other enzymes, including protease and amidase, also did not affect drug release. These results suggest that polyserine-naltrexone is resistant to enzymes found in the stomach and intestinal lumen.

X: E-Conclusion In conclusion, conjugation of naltrexone to a serine polymer via carbonate linkages constituted a pharmaceutical composition that provided extended release when administered orally. The conjugate was resistant to a certain number of enzymes found in the luminal fluid of the intestinal tract. In contrast, incubation of the composition with Caco-2 human intestinal epithelial cells affected naltrexone release. In certain embodiments of the invention, a pharmaceutical composition comprising a drug that is resistant to luminal enzymes and covalently attached to a carrier that relies on intestinal cell-related enzymes for drug release comprises: Provides extended release characteristics to the bound drug.

XI. In vivo performance of polyglutamic acid-azidothymidine (AZT) conjugate (ester-linked) XI: In vivo performance of A-polyglutamic acid-azidothymidine (AZT) conjugate (Lot No. TM-113, 41% AZT content)
Polyglutamic acid-AZT conjugates were tested in male Sprague-Dawley rats (˜250 g). Orally established doses were delivered in sodium bicarbonate solution containing polyglutamic acid-AZT conjugate or AZT.

  The content of AZT in conjugate TM-113 was estimated to be 41% based on the UV spectrophotometric test. Polyglutamic acid-AZT conjugate was given to 5 rats at a dose containing 15 mg / kg AZT. A dose of AZT equivalent to AZT contained in polyglutamic acid-AZT (TM-113) was also given to five rats.

  The dose was delivered orally to rats at zero time using an intragastric delivery syringe. Plasma was collected 0.5, 1.5, 3, 5, 8, 12, and 24 hours after delivery to rats administered polyglutamic acid-AZT (TM-113) and equivalent AZT. Plasma AZT concentrations were determined by ELISA using a commercially available kit (AZT ELISA, product number 400110, Neogen Corporation, Lexington, Kentucky).

  The plasma levels of individual animals are shown in Table 15. Average plasma levels are shown in Table 16. As shown in the above figure, AZT plasma levels rise rapidly at 0.5 hours and drop by 1.5 hours, while the level of AZT for polyglutamic acid-AZT is 0. It was quite low at 5 hours and did not drop rapidly until 0.5 hours. Plasma levels of AZT for the polyglutamic acid-AZT conjugate remained longer (> 3 hours) and higher than for the monomeric AZT control (<3 hours). Plasma concentration curves crossed at about 1.5 hours. Pharmacokinetic parameters are summarized in Table 17. The average peak concentration level (Cmax) was significantly lower for the polyglutamic acid-AZT conjugate. Furthermore, the average time to peak concentration (Tmax) was significantly longer for the polyglutamic acid-AZT conjugate. The average AUC of the polyglutamic acid-AZT (TN-113) conjugate was about 124% of the AZT average AUC.

XI: In vivo performance of B-polyglutamic acid-azidothymidine (AZT) conjugate (rat model) (lot number, TM-248, 43% AZT content)
Polyglutamic acid-AZT conjugates were tested in male Sprague-Dawley rats (˜250 g). Established doses were delivered orally in sodium bicarbonate solution containing polyglutamic acid-AZT conjugate or AZT.

  The content of AZT in conjugate TM-248 was estimated to be 43% based on the UV spectrophotometric assay. Polyglutamic acid-AZT conjugate was given to 5 rats at a dose containing 7.5 mg / kg AZT. A dose of AZT equivalent to AZT contained in polyglutamic acid-AZT (TM-248) was also given to 5 rats.

  The dose was delivered orally to rats at zero time using an oral gavage syringe. Plasma was collected 0.5, 1, 2, 3, 4, 6 and 9 hours after delivery of rats administered polyglutamic acid-AZT (TM-248) and equivalent AZT. Plasma AZT concentrations were determined by ELISA using a commercially available kit (AZT ELISA, product number 400110, Neogen Corporation, Lexington, Kentucky).

  The plasma levels for individual animals are shown in Table 18. Average plasma levels are shown in Table 19. As shown in the above figure, AZT plasma levels rise sharply at 0.5 hours and drop sharply by 1 hour, while levels of AZT for polyglutamic acid-AZT are up to 4 hours Stayed high. Pharmacokinetic parameters are summarized in Table 20. The Cmax of polyglutamic acid-AZT (TM-248) was increased by 149% compared to AZT. The average AUC of polyglutamic acid-AZT (TM-248) increased by 598% compared to AZT. Furthermore, the average time to peak concentration (Tmax) was significantly longer for the polyglutamic acid-AZT conjugate. This example clearly illustrates that both enhanced absorption and sustained release can be imparted to AZT by covalent bonds to glutamic acid polymers.

XII: Active substance list The active substance attached to the carrier peptide can have one or more different functional groups. Functional groups include amines, carboxylic acids, alcohols, ketones, amides (or their chemical equivalents), thiols, or sulfates. Examples of attachment sites for these active substances, their functional groups and carrier peptides are provided in the following sections.

アデフォビルジピボキシルは、市販されていると同時に、公開済の合成スキームを用いて当業者によって容易に製造されるものでもある。本発明においては、アデフォビルジピボキシルは、アミノ基を介してペプチドに対し共有結合している。 XII: Adefovir dipivoxil via an A-amine or amino group Adefovir dipivoxil is a known drug used in the treatment of AIDS. Its chemical name is [[[2- (6-Amino-9H-purin-9-yl) ethoxy] methyl] phosphinylidene] bis (oxymethylene) -2,2-dimethylpropanoic acid. Its structure is as follows:

Adefovir dipivoxil is not only commercially available but also easily produced by those skilled in the art using published synthetic schemes. In the present invention, adefovir dipivoxil is covalently attached to the peptide via the amino group.

アレンドロン酸塩は、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６２１，０７７；５，３５８，９４１；５，６８１，９５０；５，８０４，５７０；５，８４９，７２６；６，００８，２０７；及び６，０９０，４１０号明細書の主題である。本発明においては、アレンドロン酸塩は、アミノ基を介してペプチドに対し共有結合している。 Alendronate Alendronate is a known drug that has been used to control human osteoporosis. Its chemical name is (4-amino-1-hydroxybutylidene) bisphosphonic acid. Its structure is as follows:

Alendronate describes US Pat. Nos. 4,621,077; 5,358,941; 5,681,950; 5,804,570; incorporated herein by reference, which describe how to make the drug. 5,849,726; 6,008,207; and 6,090,410. In the present invention, alendronate is covalently attached to the peptide via the amino group.

アミフォスチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，４２４，４７１；５，５９１，７３１；及び５，９９４，４０９号明細書の主題である。本発明においては、アミフォスチンは、アミン基を介してペプチドに対し共有結合している。 Amifostine Amifostine is a known drug used in the treatment of head and neck cancer undergoing postoperative radiation therapy. This pharmaceutical is a cytoprotective agent. It is used as an adjunct to chemotherapy and radiation therapy in cancer treatment. Its chemical name is 2-[(3-aminopropyl) amino] ethanethiol dihydrogen phosphate. Its structure is as follows:

Amifostine is the subject of US Pat. Nos. 5,424,471; 5,591,731; and 5,994,409, incorporated herein by reference, which describe how to make the drug. In the present invention, amifostine is covalently attached to the peptide via the amine group.

ベシル酸アムロジピンは、該薬物の作り方を記載する、本書中に参考として内含された、米国特許第４，５７２，９０９及び４，８７９，３０３号明細書の主題である。本発明においては、ベシル酸アムロジピンは、アミノ基を介してペプチドに対し共有結合している。 Amlodipine besylate Amlodipine besylate is a known drug used for the treatment and prevention of myocardial infarction and stroke. Its chemical name is 2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid, 3-ethyl 5-methyl ester mono Benzene sulfonate. Its structure is as follows:

Amlodipine besylate is the subject of US Pat. Nos. 4,572,909 and 4,879,303, incorporated herein by reference, which describes how to make the drug. In the present invention, amlodipine besylate is covalently attached to the peptide via the amino group.

本発明においては、アステミゾールは、アミン基を介してペプチドに対し共有結合している。 Astemizole Astemizole is a known drug used in the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria. Its chemical name is 1-[(4-fluorophenyl) methyl] -N- [1- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl] -1H-benzimidazol-2-amine. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, astemizole is covalently attached to the peptide via the amine group.

本発明においては、アザチオプレンは、アミン基を介してペプチドに対し共有結合している。 Azathioprene Azathioprene is a known drug used in the treatment of transplant rejection. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes.
Its structure is as follows:

In the present invention, azathioprene is covalently attached to the peptide via the amine group.

本発明の胆汁酸輸送阻害剤は、該薬物の作り方を記載する、本書中に参考として内含された米国特許出願公開第２８８５２７号明細書（１９９４）基づく国際公開第９６／５１８８号パンフレット（１９９６）の主題である。本発明においては、、胆汁酸輸送阻害剤は、アミノ基を介してペプチドに対し共有結合している。 Bile acid transport inhibitor The bile acid transport inhibitor of the present invention is a known drug used in the treatment of hypercholesterolemia. Its chemical name is (3R, 5R) -1-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1- Dioxide. Its structure is as follows:

The bile acid transport inhibitor of the present invention describes WO 96/5188 (1996) based on US Patent Application Publication No. 288527 (1994), which is incorporated herein by reference, which describes how to make the drug. ). In the present invention, the bile acid transport inhibitor is covalently attached to the peptide via the amino group.

ビュープロピオンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，３５８，９７０；５，４２７，７９８；５，７３１，０００；５，７６３，４９３；及びＲｅ．３３，９９４号明細書の主題である。本発明においては、、ビュープロピオンは、アミノ基を介してペプチドに対し共有結合している。 Viewpropion Viewpropion is a known drug used in smoking cessation therapy and depression treatment. Its chemical name is 1- (3-chlorophenyl) -2-[(1,1-dimethylethyl) amino] -1-propanone. Its structure is as follows:

Viewpropion describes US Pat. Nos. 5,358,970; 5,427,798; 5,731,000; 5,763,493; and Re, which are incorporated herein by reference, which describe how to make the drug. . 33,994. In the present invention, view propion is covalently attached to the peptide via the amino group.

カベルゴリンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５２６，８９２号の主題である。本発明においては、、カベルゴリンは、アミノ基を介してペプチドに対し共有結合している。 Cabergoline Cabergoline is a known drug used in the treatment of Parkinson's disease. Its chemical name is (8β) -N- [3- (dimethylamino) propyl] -N-[(ethylamino) carbonyl] -6- (2-propenyl) ergoline-8-carboxamide. Its structure is as follows:

Cabergoline is the subject of US Pat. No. 4,526,892, incorporated herein by reference, which describes how to make that drug. In the present invention, cabergoline is covalently attached to the peptide via the amino group.

本発明においては、カルボプラチンは、アミン基を介してペプチドに対し共有結合している。 Carboplatin Carboplatin is a known drug used in the treatment of ovarian cancer. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, carboplatin is covalently attached to the peptide via the amine group.

セフポドキシムプロキセチルは、該薬物の作り方を記載する本書中に参考として内含された、欧州特許第４９１１８Ｂ号明細書（１９８６）の主題である。本発明においては、セフポドキシムプロキセチルは、アミノ基を介してペプチドに対し共有結合している。 Cefpodoxime proxetil Cefpodoxime proxetil is a known drug used in the treatment of mild to moderate upper and lower respiratory tract, skin and urethral infections and sexually transmitted diseases. Its chemical name is [6R- [6α, 7β (Z)]]-7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3- (methoxymethyl) -8-oxo- 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 1-[[(1-methylethoxy) carbonyl] oxy] ethyl ester. Its structure is as follows:

Cefpodoxime proxetil is the subject of EP 49118B (1986), incorporated herein by reference, which describes how to make the drug. In the present invention, cefpodoxime proxetyl is covalently attached to the peptide via the amino group.

セフプロジルは、該薬物の作り方を記載する、本書中に参考として内含された、米国特許出願第４６１８３３号（１９８３）に基づく英国特許第２１３５３０５Ｂ号明細書（１９８７）の主題である。本発明においては、セフプロジルは、カルボン酸又は、アミノ基を介してペプチドに対し共有結合している。 Cefprodil Cefprodil is a known drug used in the treatment of upper respiratory tract infections, otitis media, acute exacerbations of chronic bronchitis and skin infections. Its chemical name is [6R- [6α, 7β (R ^* )]]-7-[[amino (4-hydroxyphenyl) acetyl] amino-8-oxo-3- (1-propenyl) -5-thia-1 -Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. Its structure is as follows:

Cefprozil is the subject of British Patent No. 2135305B (1987) based on US Patent Application No. 461833 (1983), which is incorporated herein by reference, which describes how to make that drug. In the present invention, cefprozil is covalently attached to the peptide via a carboxylic acid or amino group.

本発明においては、クロロヂアゼポキシドは、アミノ基を介してペプチドに対し共有結合している。 Chlorodiazepoxide Chlorodiazepoxide is a known drug used in the treatment of anxiety and tension. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, chlorodiazepoxide is covalently attached to the peptide via the amino group.

コリン作動性チャンネルモジュレータは、該薬物の作り方を記載する、本書中に参考として内含された、優先権米国特許出願公開第４７４８７３号明細書に基づく国際公開第９６／４０６８２号パンフレット（１９９６）の主題である。本発明においては、コリン作動性チャンネルモジュレータは、アミン基を介してペプチドに対し共有結合している。 Cholinergic channel modulators Cholinergic channel modulators are known drugs used in the treatment of pain. Its chemical name is (R) -2-chloro-5- (2-azetidinylmethoxy) pyridine. Its structure is as follows:

Cholinergic channel modulators are described in WO 96/40682 (1996), which is hereby incorporated by reference, which describes how to make the drug, based on priority US Patent Application Publication No. 474873. It is the subject. In the present invention, the cholinergic channel modulator is covalently attached to the peptide via the amine group.

シサプリドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９６２，１１５号明細書の主題である。本発明においては、シサプリドは、アミノ基を介してペプチドに対し共有結合している。 Cisapride Cisapride is a known drug used in the treatment of gastrointestinal motility disorders. Its chemical name is cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide. Its structure is as follows:

Cisapride is the subject of US Pat. No. 4,962,115, herein incorporated by reference, which describes how to make that drug. In the present invention, cisapride is covalently attached to the peptide via the amino group.

シスプラチンは、該薬物の作り方を記載する、本書中に参考として内含された、米国特許第５，５６２，９２５号明細書の主題である。本発明においては、シスプラチンは、アミノ基を介してペプチドに対し共有結合している。 Cisplatin Cisplatin is a known drug used in the treatment of bladder and uterine carcinomas. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

Cisplatin is the subject of US Pat. No. 5,562,925, herein incorporated by reference, which describes how to make that drug. In the present invention, cisplatin is covalently attached to the peptide via the amino group.

本発明においては、クロザピンは、アミノ基を介してペプチドに対し共有結合している。 Clozapine Clozapine is a known drug used in the treatment of mental disorders. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, clozapine is covalently attached to the peptide via the amino group.

Colestipol Colestipol is a known drug used in the treatment of hypercholesterolemia. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Colestipol hydrochloride is a copolymer of 1-chloro-2,3-epoxypropane and diethylenetriamine containing secondary and tertiary amines in which approximately one of the five amino nitrogens is protonated by chloride. is there. In the present invention, colestipol is covalently attached to the peptide via one of its amino groups.

本発明においては、クロロホスファミドは、アミノ基を介してペプチドに対し共有結合している。 Chlorophosphamide Chlorophosphamide is a known drug used in the treatment of myeloproliferative and lymphoproliferative diseases and solid malignancies. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, chlorophosphamide is covalently attached to the peptide via the amino group.

デスモプレシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，０４７，３９８；５，５００，４１３；５，６７４，８５０；及び５，７６３，４０７号明細書の主題である。本発明においては、デスモプレシンはアミノ基とのアミドリンケージを介してペプチドに対し共有結合している。 Desmopressin Desmopressin is a known drug used in the treatment of urinary incontinence. Its chemical name is 1- (3-mercaptopropanoic acid) -8-D-arginine-vasopressin. Its structure is as follows:

Desmopressin describes US Pat. Nos. 5,047,398; 5,500,413; 5,674,850; and 5,763,407, incorporated herein by reference, which describe how to make the drug. The theme of In the present invention, desmopressin is covalently attached to the peptide via an amide linkage with the amino group.

本発明においては、デキストロアンフェタミンは、アミノ基を介してペプチドに対し共有結合している。 Dextroamphetamine Dextroamphetamine is a known drug used in the treatment of narcolepsy and attention deficit hyperactivity disorder. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, dextroamphetamine is covalently attached to the peptide via the amino group.

メシル酸ドラセトロンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９０６，７７５号明細書の主題である。本発明においては、メシル酸ドラセトロンは、アミノ基を介してペプチドに対し共有結合している。 Dorasetron mesylate dolasetron mesylate is a known drug used in the treatment of nausea and vomiting associated with chemotherapy. Its chemical name is 1H-indole-3-carboxylic acid trans-octahydro-3-oxo-2,6-methano-2H-quinolidin-8-yl ester. Its structure is as follows:

Dorasetron mesylate is the subject of U.S. Pat. No. 4,906,775, incorporated herein by reference, which describes how to make the drug. In the present invention, dolasetron mesylate is covalently attached to the peptide via the amino group.

ドキサゾシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第ＧＢ２００７６５６Ｂ号明細書（１９８２）の主題である。本発明においては、ドキサゾシンは、アミノ基を介してペプチドに対し共有結合している。 Doxazosin Doxazosin is a known drug used in the treatment of hypertension. Its chemical name is 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4-[(2,3-dihydro-1,4-benzodioxin-2-yl) carbonyl] piperidine. Its structure is as follows:

Doxazosin is the subject of US Pat. No. GB2007656B (1982), incorporated herein by reference, which describes how to make that drug. In the present invention, doxazosin is covalently attached to the peptide via the amino group.

ジュロキセチンは、該薬物の作り方を記載する、本書中に参考として内含された、特許第２７３６５８Ｂ号明細書（１９９０）、優先権米国特許第９４５１２２号（１９８６）の主題である。本発明においては、ジュロキセチンは、アミノ基を介してペプチドに対し共有結合している。 Duloxetine Duloxetine is a known drug used in the treatment of depression. Its chemical name is (S) -N-methyl-γ- (1-naphthalenyloxy) -2-thiophenepropanamine. Its structure is as follows:

Duloxetine is the subject of patent 273658B (1990), priority US Pat. No. 945122 (1986), incorporated herein by reference, which describes how to make that drug. In the present invention, duloxetine is covalently attached to the peptide via the amino group.

ファムシクロビルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１８２０２４Ｂ号明細書（１９９１）及び米国特許第５，２４６，９３７号明細書の主題である。本発明においては、ファムシクロビルは、アミノ基を介してペプチドに対し共有結合している。 Famciclovir Famciclovir is a known drug used in the treatment of viral infections. Its chemical name is 2- [2- (2-amino-9H-purin-9-yl) ethyl] -1,3-propanediol diacetate. Its structure is as follows:

Famciclovir is the subject of EP 182024B (1991) and US Pat. No. 5,246,937, herein incorporated by reference, which describes how to make the drug. In the present invention, famciclovir is covalently attached to the peptide via the amino group.

本発明においては、ファモチジンはアミノ基を介してペプチドに対し共有結合している。 Famotidine Famotidine is a known drug used in the treatment of ulcers and heartburn. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, famotidine is covalently attached to the peptide via the amino group.

フェロジピンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，２６４，６１１及び４，８０３，０８１号明細書の主題である。本発明においては、フェロジピンは、アミン基を介してペプチドに対し共有結合している。 Felodipine Felodipine is a known drug used in the treatment of hypertension. Its chemical name is 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ethyl methyl ester. Its structure is as follows:

Felodipine is the subject of US Pat. Nos. 4,264,611 and 4,803,081, incorporated herein by reference, which describe how to make that drug. In the present invention, felodipine is covalently attached to the peptide via the amine group.

酢酸フルカイニドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６４２，３８４号明細書の主題である。本発明においては、酢酸フルカイニドは、アミノ基を介してペプチドに対し共有結合している。 Flucainide acetate Flucainide acetate is a known drug used in the treatment of arrhythmias. Its chemical name is N- (2-piperidinylmethyl) -2,5-bis (2,2,2-trifluoroethoxy) benzamide. Its structure is as follows:

Flucainide acetate is the subject of US Pat. No. 4,642,384, incorporated herein by reference, which describes how to make the drug. In the present invention, flucainide acetate is covalently attached to the peptide via the amino group.

フルオキセチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３２９，３５６号明細書の主題である。本発明においては、フルオキセチンは、アミノ基を介してペプチドに対し共有結合している。 Fluoxetine Fluoxetine is a known drug used in the treatment of depression. Its chemical name is (N-methyl 3- (p-trifluoromethylphenoxy) -3-phenylpropylamine. Its structure is as follows:

Fluoxetine is the subject of US Pat. No. 4,329,356, herein incorporated by reference, which describes how to make that drug. In the present invention, fluoxetine is covalently attached to the peptide via the amino group.

マレイン酸フルボキサミンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１５３５２２６号明細書（１９７８）の主題である。本発明においては、マレイン酸フルボキサミンは、アミノ基を介してペプチドに対し共有結合している。 Fluvoxamine maleate Fluvoxamine maleate is a known drug used in the treatment of depression and anxiety. Its chemical name is 5-methoxy-1- [4- (trifluoromethyl) phenyl] -1-pentanone (E) -O- (2-aminoethyl) oxime. Its structure is as follows:

Fluvoxamine maleate is the subject of British Patent No. 1535226 (1978), incorporated herein by reference, which describes how to make the drug. In the present invention, fluvoxamine maleate is covalently attached to the peptide via the amino group.

ヒドロクロロチアジドの化学構造は以下の通りである：

本発明においては、トリアムテレンは、アミン基を介してペプチドに対し共有結合している。 Hydrochlorothiazide and triamterene Hydrochlorothiazide and triamterene are known drugs that have been combined in the treatment of edema and hypertension. The chemical structure of triamterene is as follows:

The chemical structure of hydrochlorothiazide is as follows:

In the present invention, triamterene is covalently attached to the peptide via the amine group.

本発明においては、イスラジピンは、アミン基を介してペプチドに対し共有結合している。 Isradipine Isradipine is a known drug used in the treatment of hypertension. Its chemical name is 4- (4-benzofurananyl) -1,4-dihydro-2,6-dimethyl 3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester. Its structure is as follows:

In the present invention, isradipine is covalently attached to the peptide via the amine group.

ラモトリジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６０２，０１７及び５，６９８，２２６号明細書の主題である。本発明においては、ラモトリジンは、アミノ基を介してペプチドに対し共有結合している。 Lamotrigine Lamotrigine is a known drug used in the treatment of epilepsy, psychosis and depression. Its chemical name is 6- (2,3-dichlorophenyl) -1,2,4-triazine-3,5-diamine. Its structure is as follows:

Lamotrigine is the subject of US Pat. Nos. 4,602,017 and 5,698,226, herein incorporated by reference, which describes how to make the drug. In the present invention, lamotrigine is covalently attached to the peptide via the amino group.

Ｄ−メチルフェニデートは、該薬物の作り方を記載する、各々本書中に参考として内含された米国特許出願公開第９３７６８４号明細書（１９９７）に基づく米国特許第２，５０７，６３１号明細書（１９５０）及び国際公開第９９／１６４３９号パンフレット（１９９９）の主題である。本発明においては、Ｄ−メチルフェニデートは、アミノ基を介してペプチドに対し共有結合している。 D-methylphenidate D-methylphenidate is a known drug used in the treatment of attention deficit disorder. Its chemical name is (αR, 2R) -α-phenyl-2-piperidineacetic acid methyl ester. Its structure is as follows:

D-methylphenidate describes how to make the drug, U.S. Pat. No. 2,507,631, based on U.S. Published Application No. 937684 (1997), each incorporated herein by reference. (1950) and WO 99/16439 (1999). In the present invention, D-methylphenidate is covalently attached to the peptide via the amino group.

本発明の組成物は、ペプチドに対し電子対供給により付着するメチルフェニデートを含んでなる。本発明においては、メチルフェニデートは、アミノ基を介してペプチドに対し共有結合している。 Methylphenidate Methylphenidate is a known drug used in the treatment of attention deficit disorder. Its structure is as follows:

The composition of the invention comprises methylphenidate attached to a peptide by electron pair supply. In the present invention, methylphenidate is covalently attached to the peptide via the amino group.

本発明の組成物は、ペプチドに対し電子対供給により付着するメトラゾンを含んでなる。本発明においては、メトラゾンは、アミン基を介してペプチドに対し共有結合している。 Metrazone Metrazone is a known drug used in the treatment of edema and hypertension. Its structure is as follows:

The composition of the invention comprises metolazone attached to a peptide by electron pair supply. In the present invention, metolazone is covalently attached to the peptide via the amine group.

ナラトリプタンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４９９７８４１号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているナラトリプタンを含んでなる。本発明においては、ナラトリプタンはアミノ基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、ジヒドロピラン−３−カルボン酸が適切であると思われる。 Naratriptan Naratriptan is a known drug used in the treatment of migraine. Its chemical name is N-methyl-3- (1-methyl-4-piperidinyl) -1H-indole-5-ethanesulfonamide. Its structure is as follows:

Naratriptan is the subject of US Pat. No. 4,997,841, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises naratriptan covalently attached to a peptide. In the present invention, naratriptan is covalently attached to the peptide via the amino group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ニフェジピンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４３２７７２５；４６１２００８；４７６５９８９；４７８３３３７；及び５２６４４４６号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているニフェジピンを含んでなる。本発明においては、ニフェジピンは、アミン基を介してペプチドに対し共有結合している。 Nifedipine Nifedipine is a known drug used in the treatment of hypertension and angina. Its structure is as follows:

Nifedipine is the subject of U.S. Pat. Nos. 4,327,725; 4612008; 4765989; 4783337; and 5264446, which are incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises nifedipine covalently attached to a peptide. In the present invention, nifedipine is covalently attached to the peptide via the amine group.

ニモジピンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４４０６９０６号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているニモジピンを含んでなる。本発明においては、ニモジピンは、アミン基を介してペプチドに対し共有結合している。 Nimodipine Nimodipine is a known drug used in the treatment of migraine, cognitive impairment, Alzheimer's disease and cerebral ischemia. Its chemical name is 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester. Its structure is as follows:

Nimodipine is the subject of US Pat. No. 4,406,906, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises nimodipine covalently attached to a peptide. In the present invention, nimodipine is covalently attached to the peptide via the amine group.

ニソルジピンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８９２，７４１号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているニソルジピンを含んでなる。本発明においては、ニソルジピンは、アミン基を介してペプチドに対し共有結合している。 Nisoldipine Nisoldipine is a known drug used in the treatment of angina and hypertension. Its chemical name is 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester. Its structure is as follows:

Nisoldipine is the subject of US Pat. No. 4,892,741, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises nisoldipine covalently attached to a peptide. In the present invention, nisoldipine is covalently attached to the peptide via the amine group.

本発明のノルアドレナリン及びドーパミン再摂取阻害剤は、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第４２６４１６Ｂ号明細書（１９９４）の主題である。本発明においては、ノルアドレナリン及びドーパミン再摂取阻害剤は、アミノ基を介してペプチドに対し共有結合している。 Noradrenaline and dopamine reuptake inhibitors The noradrenaline and dopamine reuptake inhibitors of the present invention are used to treat attention deficit hyperactivity disorder (ADHA). Its chemical name is [2S- (2α, 3α, 5α)]-2- (3,5-difluorophenyl) -3,5-dimethyl-2-morpholino hydrochloride. Its structure is as follows:

The noradrenaline and dopamine reuptake inhibitors of the present invention are the subject of EP 426416B (1994), incorporated herein by reference, which describes how to make that drug. In the present invention, noradrenaline and dopamine reuptake inhibitors are covalently attached to the peptide via the amino group.

ノルアステミゾールは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５３１８Ｂ号明細書１９８２、優先権米国特許第８９２５３４号明細書１９７８、国際公開第９４／７４９５号パンフレット１９９４、優先権米国特許第９４００５４号明細書１９９２の主題である。本発明の組成物は、ペプチドに対し共有結合しているノルアステミゾールを含んでなる。本発明においては、ノルアステミゾールは、いずれかのアミノ基を介してペプチドに対し共有結合している。 Norastemizole Norastemisol is a known drug used in the treatment of allergies. Its chemical name is 1-[(4-fluorophenyl) methyl] -N-4-piperidinyl-1H-benzimidazol-2-amine. Its structure is as follows:

Norastemisole describes how to make the drug, EP 5318B 1982, Priority US Pat. No. 892,534 1978, WO 94/7495, incorporated herein by reference. 1994, the subject of priority US 940054 1992. The composition of the invention comprises norastemisol covalently attached to a peptide. In the present invention, norastemizole is covalently attached to the peptide via any amino group.

本発明の組成物は、ペプチドに対し共有結合しているノルトリプチリンを含んでなる。本発明においては、ノルトリプチリンは、いずれかのアミノ基を介してペプチドに対し共有結合している。 Nortriptyline Nortriptyline is a known drug used in the treatment of depression. Its structure is as follows:

The composition of the invention comprises nortriptyline covalently attached to a peptide. In the present invention, nortriptyline is covalently attached to the peptide via any amino group.

酢酸オクトレオチドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３９５，４０３；５，５３８，７３９；５，６３９，４８０；５，６８８，５３０；５，９２２，３３８；及び５９２２６８２号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合している酢酸オクトレオチドを含んでなる。本発明においては、酢酸オクトレオチドは、アミノ基を介してペプチドに対し共有結合している。 Octreotide acetate Octreotide acetate is a known drug used in the treatment of Alzheimer's disease, cancer, viral infections, psoriasis, diarrhea, diabetes, pain and acromegaly. Its chemical name is [R- (R *, R *)]-D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyll-L-lysyl-L-threonyl-N- [2-hydroxy. -1- (hydroxymethyl) propyl] -L-cyclic cysteine amide (2-7) -disulfide. Its structure is as follows:

Octreotide acetate describes US Pat. Nos. 4,395,403; 5,538,739; 5,639,480; 5,688,530; 5, incorporated herein by reference, which describes how to make the drug. 922, 338; and 5922682. The composition of the invention comprises octreotide acetate covalently attached to a peptide. In the present invention, octreotide acetate is covalently attached to the peptide via the amino group.

オランザピンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，２２９，３８２；５，６０５，８９７；５，７３６，５４１；及び５，９１９，４８５号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているオランザピンを含んでなる。本発明においては、オランザピンはアミン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、ジヒドロピラン−３−カルボン酸は適切であると思われる。 Olanzapine Olanzapine is a known drug used in the treatment of schizophrenia and psychosis. Its chemical name is 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine. Its structure is as follows:

Olanzapine describes US Pat. Nos. 5,229,382; 5,605,897; 5,736,541; and 5,919,485, incorporated herein by reference, which describe how to make the drug. The theme of The composition of the invention comprises olanzapine covalently attached to a peptide. In the present invention, olanzapine is covalently attached to the peptide via an amine group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

パミドロネートは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，７１１，８８０号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているパミドロネートを含んでなる。本発明においては、パミドロネートは、アミノ基を介してペプチドに対し共有結合している。 Pamidronate Pamidronate is a known drug used in the treatment of osteoporosis and cancer. Its chemical name is (3-amino-1-hydroxypropylidene) bisphosphonic acid. Its structure is as follows:

Pamidronate is the subject of US Pat. No. 4,711,880, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises pamidronate covalently attached to a peptide. In the present invention, pamidronate is covalently attached to the peptide via the amino group.

パロキセチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，７２１，７２３；４，８３９，１７７；５，４２２，１２３；５，７８９，４４９；５，８７２，１３２；５，９００，４２３；６，０６３，９２７；及び６，０８０，７５９号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているパロキセチンを含んでなる。本発明においては、パロキセチンは、アミノ基を介してペプチドに対し共有結合している。 Paroxetine Paroxetine is a known drug used in the treatment of depression, obsessive compulsive disorder, anxiety and panic disorder. Its chemical name is (3S, 4R) -3-[(1,3-benzodioxol-5-yloxy) methyl] -4- (4-fluorophenyl) piperidine hydrochloride. Its structure is as follows:

Paroxetine describes how to make the drug, US Pat. Nos. 4,721,723; 4,839,177; 5,422,123; 5,789,449; 5,872 incorporated herein by reference. 132; 5,900,423; 6,063,927; and 6,080,759. The composition of the invention comprises paroxetine covalently attached to a peptide. In the present invention, paroxetine is covalently attached to the peptide via the amino group.

本発明の組成物は、ペプチドに対し共有結合しているペモリンを含んでなる。本発明においては、ペモリンは、アミノ基を介してペプチドに対し共有結合している。 Pemoline Pemoline is a known drug used in the treatment of attention deficit hyperactivity disorder. Its structure is as follows:

The composition of the invention comprises pemoline covalently attached to a peptide. In the present invention, pemoline is covalently attached to the peptide via the amino group.

ペルゴリドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，１６６，１８２；４，７９７，４０５；及び５，１１４，９４８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているペルゴリドを含んでなる。本発明においては、活性物質は、アミノ基及びリンカーを介してペプチドに対し共有結合している。 Pergolide Pergolide is a known drug used in the treatment of Parkinson's disease and depression. Its chemical name is (8β) -8-[(methylthio) methyl] -6-propylergoline. Its structure is as follows:

Pergolide is the subject of US Pat. Nos. 4,166,182; 4,797,405; and 5,114,948, herein incorporated by reference, which describes how to make the drug. The composition of the invention comprises pergolide covalently attached to a peptide. In the present invention, the active substance is covalently attached to the peptide via the amino group and a linker.

プラミペキソールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８４３，０８６及び４，８８６，８１２号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているプラミペキソールを含んでなる。本発明においては、プラミペキソールは、アミノ基を介してペプチドに対し共有結合している。 Pramipexole Pramipexole is a known drug used in the treatment of Parkinson's disease and depression. Its chemical name is (S) -2-amino-4,5,6,7-tetrahydro-6- (propylamino) -benzothiazole. Its structure is as follows:

Pramipexole is the subject of US Pat. Nos. 4,843,086 and 4,886,812, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises pramipexole covalently attached to a peptide. In the present invention, pramipexole is covalently attached to the peptide via the amino group.

レマセミデは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２７９９３７Ｂ号明細書１９９１、優先権米国特許第１１９８２号明細書１９８７及び国際公開第９３／２１９１０号パンフレット１９９３の主題である。本発明の組成物は、ペプチドに対し共有結合しているレマセミドを含んでなる。本発明においては、レマセミドは、アミノ基を介してペプチドに対し共有結合している。 Remasemide Remasemide is a known drug used in the treatment of epilepsy, Parkinson's disease and neurodegeneration. Its chemical name is 2-amino-N- (1-methyl-1,2-diphenylethyl) acetamide. Its structure is as follows:

Remasemide describes the methods of making the drug in European Patent No. 279937B 1991, priority US Patent No. 11982 1987 and WO 93/21910, 1993, which are incorporated herein by reference. The subject. The composition of the invention comprises remasemide covalently attached to a peptide. In the present invention, remasemide is covalently attached to the peptide via the amino group.

レピノタンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，１３７，９０１号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているレピノタンを含んでなる。本発明においては、レピノタンは、アミノ基を介してペプチドに対し共有結合している。 Repinotan Repinotan is a known drug used in the treatment of stroke and trauma. Its chemical name is (R) -2- [4-[[(3,4-dihydro-2H-1-benzopyran-2-yl) methyl] amino] butyl] -1,2-benzisothiazole-3 ( 2H) ■ On 1,1-dioxide. Its structure is as follows:

Repinotan is the subject of US Pat. No. 5,137,901, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises repinotan covalently attached to a peptide. In the present invention, repinotan is covalently attached to the peptide via the amino group.

リルゾールは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５０５５１Ｂ号明細書１９８４、欧州特許第２８２９７１Ａ号明細書１９８８（優先権米国特許第２６４２８号明細書１９８７）及び欧州特許第３０５２７７Ａ号明細書１９８９の主題である。本発明の組成物は、ペプチドに対し共有結合しているリルゾールを含んでなる。本発明においては、リルゾールは、アミノ基を介してペプチドに対し共有結合している。 Riluzole Riluzole is a known drug used in the treatment of amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. Its chemical name is 6- (trifluoromethoxy) -2-benzothiazolamine. Its structure is as follows:

Riluzole is described in EP 50551B 1984, EP 282971A 1988 (priority US Pat. No. 26428 1987), which is incorporated herein by reference, and describes how to make the drug. This is the subject of EP 305277A 1989. The composition of the invention comprises riluzole covalently attached to a peptide. In the present invention, riluzole is covalently attached to the peptide via the amino group.

リマンタジンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１０６９５６３号明細書１９６７、優先権米国特許第２９７２３３号明細書１９６３、欧州特許第１６２４４４Ｂ号明細書１９９０、優先権米国特許第６１３３７４号明細書１９８４の主題である本発明の組成物は、ペプチドに対し共有結合しているリマンタジンを含んでなる。本発明においては、リマンタジンは、アミノ基を介してペプチドに対し共有結合している。 Rimanadine Rimantazine is a known drug used in the treatment of viral infections and trypanosomiasis. Its chemical name is α-methyl-1-adamantanemethylamine. Its structure is as follows:

Rimantazine is described in British Patent No. 1069563 1967, priority US Pat. No. 2,297,233 1963, European Patent No. 162444B 1990, which is incorporated herein by reference, describing how to make the drug. The composition of the present invention, the subject of US Patent No. 613374, 1984, comprises rimantadine covalently attached to a peptide. In the present invention, rimantadine is covalently attached to the peptide via the amino group.

安息香酸リザトリプタンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３７１，５１６；５，２９８，５２０；５，４５７，８９５；及び５，６０２，１６２号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合している安息香酸リザトリプタンを含んでなる。本発明においては、安息香酸リザトリプタンはアミノ基及びリンカーを介してペプチドに対し共有結合している。 Rizatriptan benzoate Rizatriptan benzoate is a known drug used in the treatment of migraine. Its chemical name is N, N-dimethyl-5- (1H-1,2,4-triazol-1-ylmethyl) -1H-indole-3-ethanamine. Its structure is as follows:

Rizatriptan benzoate describes US Pat. Nos. 4,371,516; 5,298,520; 5,457,895; and 5,602,162, incorporated herein by reference, which describe how to make the drug. The subject of the specification. The composition of the invention comprises Rizatriptan benzoate covalently attached to a peptide. In the present invention, Rizatriptan benzoate is covalently attached to the peptide via the amino group and a linker.

サトラプラチンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第３２８２７４Ｂ号明細書１９９４、優先権米国特許第１５１６７４号明細書１９８８の主題である。本発明の組成物は、ペプチドに対し共有結合しているサトラプラチンを含んでなる。本発明においては、サトラプラチンは、アミノ基を介してペプチドに対し共有結合している。 Satraplatin Satraplatin is a known drug used in the treatment of cancer. Its chemical name is satraplatin. Its structure is as follows:

Satraplatin is the subject of European Patent No. 328274B 1994, priority US Pat. No. 151,647, 1988, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises satraplatin covalently attached to a peptide. In the present invention, satraplatin is covalently attached to the peptide via the amino group.

セルトラリンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５３６，５１８；４，９６２，１２８；及び５，２４８，６９９号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているセルトラリンを含んでなる。本発明においては、セルトラリンは、アミン基を介してペプチドに対し共有結合している。 Sertraline Sertraline is a known drug used in the treatment of depression, obsessive compulsive disorder, anxiety, panic disorder, sexual dysfunction and obesity. Its chemical name is (1S, 4S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine. Its structure is as follows:

Sertraline is the subject of US Pat. Nos. 4,536,518; 4,962,128; and 5,248,699, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises sertraline covalently attached to a peptide. In the present invention, sertraline is covalently attached to the peptide via the amine group.

セベラマーは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，４９６，５４５及び５，６６７，７７５号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているセベラマーを含んでなる。本発明においては、セベラマーは、いずれかのアミノ基を介してペプチドに対し共有結合している。 Sevelamer Sevelamer is a known drug used in the treatment of kidney disease. Its chemical name is 2-propen-1-amine which is a polymer with (chloromethyl) oxirane. Its structure is as follows:

Sevelamer is the subject of US Pat. Nos. 5,496,545 and 5,667,775, herein incorporated by reference, which describe how to make the drug. The composition of the invention comprises sevelamer covalently attached to a peptide. In the present invention, sevelamer is covalently attached to the peptide via any amino group.

ナトリウムチャンネル阻害剤は、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９７／９３１７号パンフレット（１９９７）の主題である。本発明においては、ナトリウムチャンネル阻害剤は、いずれかのアミノ基を介してペプチドに対し共有結合している。 Sodium Channel Inhibitor The sodium channel inhibitor of the present invention is a known drug used in the treatment of pain. Its chemical name is (5R) -5- (2,3-dichlorophenyl) -6- (fluoromethyl) -2,4-pyrimidinediamine. Its structure is as follows:

Sodium channel inhibitors are the subject of WO 97/9317 (1997), incorporated herein by reference, which describes how to make the drug. In the present invention, the sodium channel inhibitor is covalently attached to the peptide via any amino group.

スマトリプタンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４８１６４７０及び５０３７８４５号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているスマトリプタンを含んでなる。本発明においては、スマトリプタンはアミン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、ジヒドロピラン−３−カルボン酸が適切であると思われる。 Sumatriptan Sumatriptan is a known drug used in the treatment of migraine. Its chemical name is 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide. Its structure is as follows:

Sumatriptan is the subject of US Pat. Nos. 4,816,470 and 5,037,845, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises sumatriptan covalently attached to a peptide. In the present invention, sumatriptan is covalently attached to the peptide via the amine group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

タビモレリンは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９７／２３５０８号パンフレット１９９７の主題である。本発明の組成物は、ペプチドに対し共有結合しているタビモレリンを含んでなる。本発明においては、タビモレリンは、アミン基を介してペプチドに対し共有結合している。 Tabimorelin Tabimorelin is a known drug used in the treatment of hormone deficiencies. Its chemical name is N-[(2E) -5-amino-5-methyl-1-oxo-2-hexenyl] -N-methyl-3- (2-naphthalenyl) -D-alanyl-N, N-α. -Dimethyl-D-phenylalaninamide. Its structure is as follows:

Tabimorelin is the subject of WO 97/23508, 1997, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises tabimorelin covalently attached to a peptide. In the present invention, tabimorelin is covalently attached to the peptide via the amine group.

タムスロシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，７３１，４７８；４，７０３，０６３；４，７７２，４７５；及び４，８６８，２１６号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているタムスロシンを含んでなる。本発明においては、タムスロシンは、アミノ基を介してペプチドに対し共有結合している。 Tamsulosin Tamsulosin is a known drug used in the treatment of benign prostatic hypertrophy. Its chemical name is R-(-)-5- [2-[[2- (2-ethoxyphenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide. Its structure is as follows:

Tamsulosin describes US Pat. Nos. 4,731,478; 4,703,063; 4,772,475; and 4,868,216, incorporated herein by reference, which describe how to make the drug. The theme of The composition of the invention comprises tamsulosin covalently attached to a peptide. In the present invention, tamsulosin is covalently attached to the peptide via the amino group.

テノフォビル・ジソプロキシルは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９４／３４６７号パンフレット１９９４、優先権米国特許第９２５６１０号明細書１９９２の主題である。本発明の組成物は、ペプチドに対し共有結合しているテノフォビル・ジソプロキシルを含んでなる。本発明においては、テノフォビル・ジソプロキシルは、アミノ基を介してペプチドに対し共有結合している。 Tenofovir Tenofovir Disoproxil is a known drug used in the treatment of HIV infection. Its chemical name is [[(1R) -2- (6-amino-9H-purin-9-yl) -L-methylethoxy] methyl] phosphonic acid. Its structure is as follows:

Tenofovir disoproxil is the subject of WO 94/3467, 1994, priority US Pat. No. 925610, 1992, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises tenofovir disoproxil covalently attached to a peptide. In the present invention, tenofovir disoproxil is covalently attached to the peptide via the amino group.

テラゾシンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１５１７４０３号明細書１９７８、優先権米国特許第６２１９８０号明細書１９７５、英国特許第１５９１４９０号明細書１９８１、優先権米国特許第８２１６７５号明細書１９７７、国際公開第９２／７３号パンフレット１９９２、優先権米国特許第５４６３４９号明細書１９９０、及び米国特許第５２９４６１５号明細書１９９４の主題である。本発明の組成物は、ペプチドに対し共有結合しているテラゾシンを含んでなる。本発明においては、テラゾシンは、アミノ基を介してペプチドに対し共有結合している。 Terazosin Terazosin is a known drug used in the treatment of benign prostatic hypertrophy and hypertension. Its chemical name is 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4-[(tetrahydro-2-furanyl) carbonyl] piperazine. Its structure is as follows:

Terazosin describes how to make the drug, including British Patent No. 1517403, 1978, priority US Pat. No. 621,980, 1975, British Patent No. 1591490, 1981, which is incorporated herein by reference. US Pat. No. 821,675, 1977, WO 92/73, 1992, priority US Pat. No. 546,349, 1990, and US Pat. No. 5,294,615, 1994. The composition of the invention comprises terazosin covalently attached to a peptide. In the present invention, terazosin is covalently attached to the peptide via the amino group.

チラパザミンは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９１／４０２８号パンフレット１９９１、優先権ＰＣＴ／ＵＳ／４１１２，１９８９の主題である。本発明の組成物は、ペプチドに対し共有結合しているチラパザミンを含んでなる。本発明においては、チラパザミンは、アミン基を介してペプチドに対し共有結合している。 Tilapazamine Tilapazamine is a known drug used in the treatment of cancer. Its chemical name is 3-amino-1,2,4-benzotriazine-1,4 dioxide. Its structure is as follows:

Tilapazamine is the subject of WO 91/4028 1991, priority PCT / US / 4112, 1989, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises tirapazamine covalently attached to a peptide. In the present invention, tirapazamine is covalently attached to the peptide via the amine group.

チザニジンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１４２９９２６号明細書１９７６及び英国特許第１５５９８１１号明細書１９８０の主題である。本発明の組成物は、ペプチドに対し共有結合しているチザニジンを含んでなる。本発明においては、チザニジンは、アミン基を介してペプチドに対し共有結合している。 Tizanidine Tizanidine is a known drug used in the treatment of muscle spasm. Its chemical name is 5-chloro-N- (4,5-dihydro-1H-imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine. Its structure is as follows:

Tizanidine is the subject of British Patent 1429926 1976 and British Patent 1559811 1980, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises tizanidine covalently attached to a peptide. In the present invention, tizanidine is covalently attached to the peptide via the amine group.

トモキセチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４３１４０８１号明細書１９８０及び欧州特許第５２４９２Ｂ号明細書１９８４、優先権米国特許第２０６４９８ １９８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているトモキセチンを含んでなる。本発明においては、トモキセチンは、アミン基を介してペプチドに対し共有結合している。 Tomoxetine Tomoxetine is a known drug used in the treatment of attention deficit disorder. Its chemical name is (γR) -N-methyl-γ- (2-methylphenoxy) benzenepropanamide. Its structure is as follows:

Tomoxetine is the subject of U.S. Pat. No. 4,314,081 1980 and EP 52492B 1984, priority U.S. Pat. No. 206498 198, herein incorporated by reference, which describes how to make that drug. It is. The composition of the invention comprises tomoxetine covalently attached to a peptide. In the present invention, tomoxetine is covalently attached to the peptide via the amine group.

トピラメートは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５１３，００６号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているトピラメートを含んでなる。本発明においては、トピラメートは、アミノ基を介してペプチドに対し共有結合している。 Topiramate Topiramate is a known drug used in the treatment of epilepsy, psychosis and depression. Its chemical name is 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate. Its structure is as follows:

Topiramate is the subject of US Pat. No. 4,513,006, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises topiramate covalently attached to a peptide. In the present invention, topiramate is covalently attached to the peptide via the amino group.

トレセミドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８６１，７８６号明細書及びＲＥ３４６７２の主題である。本発明の組成物は、ペプチドに対し共有結合しているトレセミドを含んでなる。本発明においては、トレセミドは、アミン基を介してペプチドに対し共有結合している。 Toresemide Toresemide is a known drug used in the treatment of hypertension and heart failure. Its chemical name is N-[[(1-methylethyl) amino] carbonyl] -4-[(3-methylphenyl) amino] -3-pyridinesulfonamide. Its structure is as follows:

Toresemide is the subject of U.S. Pat. No. 4,861,786 and RE 34672, incorporated herein by reference, which describe how to make that drug. The composition of the invention comprises toresemide covalently attached to a peptide. In the present invention, tolsemide is covalently attached to the peptide via the amine group.

本発明の組成物は、ペプチドに対し共有結合しているトリアムテレン含んでなる。本発明においては、トリアムテレンは、アミノ基を介してペプチドに対し共有結合している。 Triamterene Triamterene is a known drug used in the treatment of edema. Its structure is as follows:

The composition of the invention comprises triamterene covalently attached to a peptide. In the present invention, triamterene is covalently attached to the peptide via the amino group.

バラシクロビルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９５７，９２４号明細書の主題である。本発明においては、バラシクロビルは、アミノ基を介してペプチドに対し共有結合している。 Valaciclovir Valacyclovir is a known drug used in the treatment of viral infections. Its chemical name is 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] -L-valine ethyl ester. Its structure is as follows:

Valacyclovir is the subject of US Pat. No. 4,957,924, incorporated herein by reference, which describes how to make that drug. In the present invention, valacyclovir is covalently attached to the peptide via the amino group.

バルデコキシブは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９６／２５４０５号パンフレット１９９６、優先権米国特許第３８７６８０号明細書１９９５の主題である。本発明の組成物は、ペプチドに対し共有結合しているバルデコキシブを含んでなる。本発明においては、バルデコキシブは、アミノ基を介してペプチドに対し共有結合している。 Valdecoxib Valdecoxib is a known drug used in the treatment of arthritis and pain. Its chemical name is 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide. Its structure is as follows:

Valdecoxib is the subject of WO 96/25405 1996, priority US Pat. No. 387,680, which is incorporated herein by reference, describing how to make the drug. The composition of the invention comprises valdecoxib covalently attached to a peptide. In the present invention, valdecoxib is covalently attached to the peptide via the amino group.

ゾルミトリプタンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，４６６，６９９及び５，８６３，９３５号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているゾルミトリプタンを含んでなる。本発明においては、ゾルミトリプタンはアミン基及びリンカーを介してペプチドに対し共有結合している。 Zolmitriptan Zolmitriptan is a known drug used in the treatment of migraine. Its chemical name is (4S) -4-[[3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] methyl] -2-oxazolidinone. Its structure is as follows:

Zolmitriptan is the subject of US Pat. Nos. 5,466,699 and 5,863,935, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises zolmitriptan covalently attached to a peptide. In the present invention, zolmitriptan is covalently attached to the peptide via an amine group and a linker.

XII: Via the B-carboxylic acid group Acetylsalicylic acid Acetylsalicylic acid is a known drug used in the treatment of mild pain and pain. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. In the present invention, acetylsalicylic acid is covalently attached to the peptide via the carboxylic acid group.

本発明においては、アシトレチンは、カルボン酸基を介してペプチドに対し共有結合している。 Acitretin Acitretin is a known drug used in the treatment of psoriasis. Its chemical name is (all-E) -9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, acitretin is covalently attached to the peptide via the carboxylic acid group.

カンドキサトリルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２７４２３４Ｂ号明細書（１９９１）の主題である。本発明においては、カンドキサトリルは、カルボン酸基を介してペプチドに対し共有結合している。 Candoxatril Candoxatril is a known drug used in the treatment of heart failure and hypertension. Its chemical name is 4-[[[1- [3-[(2,3-dihydro-1H-inden-5-yl) oxy] -2-[(2-methoxyethoxy) methyl] -3-oxopropyl]. Cyclopentyl] carbonyl] amino] -cyclohexanecarboxylic acid. Its structure is as follows:

Candoxatril is the subject of EP 274234B (1991), incorporated herein by reference, which describes how to make the drug. In the present invention, candoxatril is covalently attached to the peptide via the carboxylic acid group.

本発明においては、セファゾリンは、カルボン酸基を介してペプチドに対し共有結合している。 Cefazolin is used in the treatment of respiratory tract infections, urinary tract infections, skin and skin tissue infections, biliary tract infections, bone and joint infections, genital infections, sepsis and endocarditis caused by susceptible bacteria Known drug. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, cefazolin is covalently attached to the peptide via the carboxylic acid group.

セフジニルは、該薬物の作り方を記載する、本書中に参考として内含された特許出願公開第４２８，９７０号明細書（１９８２）に基づく欧州特許第１０５４５９Ｂ号明細書（１９８９）、及び欧州特許第３０４０１９Ｂ号明細書（１９９５）の主題である。本発明においては、セフジニルは、カルボン酸基を介してペプチドに対し共有結合している。 Cefdinir Cefdinir is a known drug used in the treatment of acute maxillary sinusitis, chronic bronchitis, pharyngitis, tonsillitis, community-acquired pneumonia and acute exacerbations of bacterial skin infections. Its chemical name is [6R- [6α, 7β (Z)]]-7-[[(2-amino-4-thiazolyl) (hydroxyimino) acetyl] amino] -3-ethenyl-8-oxo-5-thia. -1-Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. Its structure is as follows:

Cefdinir describes how to make the drug, EP105459B (1989), based on patent application 428,970 (1982), which is incorporated herein by reference, and EP 304019B specification (1995). In the present invention, cefdinir is covalently attached to the peptide via the carboxylic acid group.

セフィキシムは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第３０３６０Ｂ号明細書（１９８７）の主題である。本発明においては、セフィキシムは、カルボン酸基を介してペプチドに対し共有結合している。 Cefixime Cefixime is a known drug used in the treatment of respiratory tract infections, gonorrhea, biliary tract infections and otitis media in children. Its chemical name is [6R- [6α, 7β (Z)]]-7-[[(2-amino-4-thiazolyl) [(carboxymethoxy) imino] acetyl] amino] -3-ethenyl-8-oxo- 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. Its structure is as follows:

Cefixime is the subject of EP 30360B (1987), incorporated herein by reference, which describes how to make the drug. In the present invention, cefixime is covalently attached to the peptide via the carboxylic acid group.

Cefotaxime Cefotaxime is caused by susceptible bone and joint infections, severe intraperitoneal and gynecological infections (including peritonitis, endometritis, pelvic inflammatory disease), meningitis and others CNS infections, severe lower respiratory tract infections (including pneumonia), bacteremia / sepsis, severe skin and skin tissue infections, and known urinary tract infections. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its chemical name is (6R, 7R) -7- [2- (2-amino-4-thiazolyl) glyoxylamido] -8-oxo-3-vinyl-5-thia-1-azabicyclo [4.2.0. ] Oct-2-ene-2-carboxylic acid, 7 ² (Z)-[O- (carboxymethyl) oxime]. In the present invention, cefotaxime is covalently attached to the peptide via the carboxylic acid group.

セフォテタンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１６０４７３９号明細書（１９８１）の主題である。本発明においては、セフォテタンは、カルボン酸基を介してペプチドに対し共有結合している。 Cefotetan Cefotetan is a known drug used in the treatment of sepsis, genitourinary, biliary and respiratory tract infections and prevention of postoperative wound infections. Its chemical name is [6R- (6α, 7α)]-7-[[[4- (2-amino-1-carboxy-2-oxoethylidene) -1,3-dithietan-2-yl] carbonyl] amino] -7-Methoxy-3-[[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid. Its structure is as follows:

Cefotetan is the subject of GB 1604739 (1981), incorporated herein by reference, which describes how to make the drug. In the present invention, cefotetan is covalently attached to the peptide via the carboxylic acid group.

本発明においては、セフォキシチンは、カルボン酸基を介してペプチドに対し共有結合している。 Cefoxitin Cefoxitin is a serious lower respiratory tract, skin and skin tissue, bone and joint, and urethral infection caused by susceptible bacteria; sepsis; gynecological infections (including endometritis, pelvic inflammatory diseases, And pelvic inflammatory diseases); and known drugs used in the treatment of intraperitoneal infections (including peritonitis and intraabdominal abscesses). This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, cefoxitin is covalently attached to the peptide via the carboxylic acid group.

本発明においては、セフタジジムは、カルボン酸基を介してペプチドに対し共有結合している。 Ceftazidime Ceftazidime is a known drug used in the treatment of bacterial infections. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, ceftazidime is covalently attached to the peptide via the carboxylic acid group.

セフチブテンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１３６７２１Ｂ号明細書（１９９３）の主題である。本発明においては、セフチブテンは、カルボン酸基を介してペプチドに対し共有結合している。 Ceftibutene Ceftibutene is a known drug used in the treatment of bacterial infections. Its chemical name is [6R- [6α, 7β (Z)]]-7-[[2- (2-amino-4-thiazolyl) -4-carboxy-1-oxo-2-butenyl] amino] -8- Oxo 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. Its structure is as follows:

Ceftibbutene is the subject of EP 136721B (1993), incorporated herein by reference, which describes how to make the drug. In the present invention, ceftibbutene is covalently attached to the peptide via the carboxylic acid group.

本発明においては、セフロキシムは、カルボン酸基を介してペプチドに対し共有結合している。 Cefuroxime Cefuroxime is a known drug used in the treatment of bacterial infections. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, cefuroxime is covalently attached to the peptide via the carboxylic acid group.

セチリジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５２５，３５８号明細書の主題である。本発明においては、セチリジンは、カルボン酸基を介してペプチドに対し共有結合している。 Cetirizine Cetirizine is a known drug used in the treatment of allergic rhinitis. Its chemical name is [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid. Its structure is as follows:

Cetirizine is the subject of US Pat. No. 4,525,358, incorporated herein by reference, which describes how to make that drug. In the present invention, cetirizine is covalently attached to the peptide via the carboxylic acid group.

本発明においては、クロラゼペート・デポーは、カルボン酸基を介してペプチドに対し共有結合している。 Chlorazepate depot Chlorazepate depot is a known drug used in the treatment of anxiety disorders. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, chlorazepate depot is covalently attached to the peptide via the carboxylic acid group.

コレシストキニン拮抗薬は、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９３／８９７号パンフレット１９９３、優先権米国特許第７２９２７１号明細書１９９１の主題である。本発明の組成物は、ペプチドに対し共有結合しているコレシストキニン拮抗薬を含んでなる。本発明においては、コレシストキニン拮抗薬の成分は、カルボン酸基を介してペプチドに対し共有結合している。 Cholecystokinin Antagonist The cholecystokinin antagonist of the present invention is a known drug used in the treatment of anxiety. This is the result of [1S- [1α, 2β [S * (S *)], 4α]]-4-[[2-[[3- (1H-indol-3-yl) -2-methyl-1-oxo. 2-[[[[(1,7,7-trimethylbicyclo [2.2.1] hept-2-yl) oxy] carbonyl] amino] propyl] amino] -1-phenylethyl] amino] -4-oxobutane It is a combination (1: 1) of an acid compound and meglumine. Its structure is as follows:

Cholecystokinin antagonists are the subject of WO 93/897 1993, priority US Pat. No. 729271, which is incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises a cholecystokinin antagonist covalently attached to a peptide. In the present invention, the component of the cholecystokinin antagonist is covalently attached to the peptide via the carboxylic acid group.

シロミラストは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９３／１９７４９号パンフレット（１９９３）、優先権米国特許出願公開第８６２０３０号明細書（１９９２）の主題である。本発明においては、シロミラストは、カルボン酸基を介してペプチドに対し共有結合している。 Silomilast Silomilast is a known drug used in the treatment of asthma. Its chemical name is cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexanecarboxylic acid. Its structure is as follows:

Siromilast is the subject of WO 93/19749 (1993), priority US Patent Application No. 862030 (1992), incorporated herein by reference, which describes how to make the drug. . In the present invention, cilomilast is covalently attached to the peptide via the carboxylic acid group.

ジバルプロックスは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９８８，７３１及び５，２１２，３２６号明細書の主題である。本発明においては、ジバルプロックスは、カルボン酸基を介してペプチドに対し共有結合している。 Divalprox Divalprox is a known drug used in the treatment of epilepsy, migraine, schizophrenia and depression. Its chemical name is 2-propylpentanoic acid. Its structure is as follows:

Divalprox is the subject of US Pat. Nos. 4,988,731 and 5,212,326, incorporated herein by reference, which describes how to make the drug. In the present invention, divalprox is covalently attached to the peptide via the carboxylic acid group.

エプチフィバチドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，６８６，５７０；５，７５６，４５１；及び５，８０７，８２５号明細書の主題である。本発明においては、エプチフィバチドは、カルボン酸基を介してペプチドに対し共有結合している。 Eptifibatide eptifibatide is a known drug used in the treatment of thrombosis, angina pectoris, myocardial infarction and restenosis. Its chemical name is N6- (aminoiminomethyl) -N2- (3-mercapto-1-oxopropyl) -L-lysylglycyl-L-α-aspartyl-L-tryptophyll-L-prolyl-L-cysteine amide cyclic ( 1-6) -Disulfide. Its structure is as follows:

Eptifibatide is the subject of US Pat. Nos. 5,686,570; 5,756,451; and 5,807,825, incorporated herein by reference, which describe how to make that drug. In the present invention, eptifibatide is covalently attached to the peptide via the carboxylic acid group.

エトドラクは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９６６，７６８号明細書の主題である。本発明においては、エトドラクは、カルボン酸基を介してペプチドに対し共有結合している。 Etodolac Etodolac is a known drug used in the treatment of inflammation. Its chemical name is 1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid. Its structure is as follows:

Etodolac is the subject of US Pat. No. 4,966,768, herein incorporated by reference, which describes how to make that drug. In the present invention, etodolac is covalently attached to the peptide via the carboxylic acid group.

エトポシドは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１３９１００５号明細書（１９７５）、優先権米国特許出願公開第１４８８９５号明細書（１９７１）の主題である。本発明においては、エトポシドは、カルボン酸基を介してペプチドに対し共有結合している。 Etoposide Etoposide is a known drug used in the treatment of inflammation. Its chemical name is 1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid. Its structure is as follows:

Etoposide is the subject of British Patent No. 1391005 (1975), priority US Patent Application No. 148895 (1971), incorporated herein by reference, which describes how to make that drug. In the present invention, etoposide is covalently attached to the peptide via the carboxylic acid group.

フェキソフェナジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，２５４，１２９；５，５７８，６１０；５，８５５，９１２；５，９３２，２４７；及び６，０３７，３５３の主題である。本発明においては、フェキソフェナジンは、カルボン酸基を介してペプチドに対し共有結合している。 Fexofenadine Fexofenadine is a known drug used in the treatment of seasonal allergic rhinitis. Its chemical name is 4- [1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] butyl] -α, α-dimethylbenzeneacetic acid. Its structure is as follows:

Fexofenadine describes US Pat. Nos. 4,254,129; 5,578,610; 5,855,912; 5,932,247; incorporated herein by reference, which describes how to make the drug. This is the subject of 6,037,353. In the present invention, fexofenadine is covalently attached to the peptide via the carboxylic acid group.

フォシノプリルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３３７，２０１；４，３８４，１２３；及び５，００６，３４４号明細書の主題である。本発明においては、フォシノプリルは、カルボン酸基を介してペプチドに対し共有結合している。 Fosinopril Fosinopril is a known drug used in the treatment of hypertension. Its chemical name is [1 [S * (R *)], 2α, 4β] -4-cyclohexyl-1-[[[2-methyl-1- (1-oxopropoxy) propoxy] (4-phenylbutyl) phosphinyl. Acetyl] -L-proline. Its structure is as follows:

Fosinopril is the subject of US Pat. Nos. 4,337,201; 4,384,123; and 5,006,344, incorporated herein by reference, which describe how to make the drug. In the present invention, fosinopril is covalently attached to the peptide via the carboxylic acid group.

本発明においては、フロセミドは、カルボン酸基を介してペプチドに対し共有結合している。 Furosemide Furosemide is a known drug used in the treatment of edema and hypertension. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, furosemide is covalently attached to the peptide via the carboxylic acid group.

ゲムフィブロジルは、該薬物の作り方を記載する、本書中に参考として内含された優先権米国特許出願公開第７３０４６号明細書（１９６８）に基づく英国特許第１２２５５７５号明細書（１９７１）、の主題である。本発明においては、ゲムフィブロジルは、カルボン酸基を介してペプチドに対し共有結合している。 Gemfibrozil Gemfibrozil is a known drug used in the treatment of hyperlipidemia. Its chemical name is 5- (2,5-dimethylphenoxy) -2,2-dimethylpentanoic acid. Its structure is as follows:

Gemfibrozil is the subject matter of British Patent No. 1225575 (1971), based on priority US Patent Application Publication No. 73046 (1968), incorporated herein by reference, which describes how to make that drug. is there. In the present invention, gemfibrozil is covalently attached to the peptide via the carboxylic acid group.

本発明においては、イブプロフェンは、カルボン酸基を介してペプチドに対し共有結合している。 Ibuprofen Ibuprofen is a known drug used in the treatment of pain and arthritis. Its structure is as follows:

In the present invention, ibuprofen is covalently attached to the peptide via the carboxylic acid group.

イスラジピンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１５０Ｂ号明細書（１９８１）及び英国特許第２０３７７６６Ｂ号明細書（１９８３）の主題である。本発明においては、イソトレチノインは、カルボン酸基を介してペプチドに対し共有結合している。 Isotretinoin isotretinoin is a known drug used in the treatment of acne. Its structure is as follows:

Isradipine is the subject of EP 150B (1981) and GB 2037766 B (1983), incorporated herein by reference, which describes how to make the drug. In the present invention, isotretinoin is covalently attached to the peptide via the carboxylic acid group.

本発明においては、ケトプロフェンは、カルボン酸基を介してペプチドに対し共有結合している。 Ketoprofen Ketoprofen is a known drug used in the treatment of arthritis and pain. Its structure is as follows:

In the present invention, ketoprofen is covalently attached to the peptide via the carboxylic acid group.

ケトロラックは、該薬物の作り方を記載する、本書中に参考として内含された優先権出願米国特許第７０４９０９号明細書（１９７６）に基づく英国特許第１５５４０５７号明細書（１９７９）の主題である。本発明においては、ケトロラックは、カルボン酸基を介してペプチドに対し共有結合している。 Ketorolac Ketrolac is a known drug used in the treatment of pain. Its chemical name is (+,-)-5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid. Its structure is as follows:

Ketorolac is the subject of British Patent No. 1554057 (1979) based on priority application US Pat. No. 6,704,909 (1976), incorporated herein by reference, which describes how to make that drug. In the present invention, ketorolac is covalently attached to the peptide via the carboxylic acid group.

本発明の組成物は、ペプチドに対し共有結合しているレボカルニチンを含んでなる。本発明においては、レボカルニチンは、カルボン酸基を介してペプチドに対し共有結合している。 Levocarnitine Levocarnitine is a known drug used in the treatment of cardiovascular disease and septic shock. Its chemical name is (R) -3-carboxy-2-hydroxy-N, N, N-trimethyl-1-propanaminium hydroxide. Its structure is as follows:

The composition of the invention comprises levocarnitine covalently attached to a peptide. In the present invention, levocarnitine is covalently attached to the peptide via the carboxylic acid group.

レボセチリジンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５８１４６Ｂ号明細書（１９８４）の主題である。本発明の組成物は、ペプチドに対し共有結合しているレボセチリジンを含んでなる。本発明においては、レボセチリジンは、カルボン酸基を介してペプチドに対し共有結合している。 Levocetirizine Levocetirizine is a known drug used in the treatment of rhinitis. Its chemical name is [2- [4-[(R)-(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid. Its structure is as follows:

Levocetirizine is the subject of EP 58146B (1984), herein incorporated by reference, which describes how to make the drug. The composition of the invention comprises levocetirizine covalently attached to a peptide. In the present invention, levocetirizine is covalently attached to the peptide via the carboxylic acid group.

レボフロキサシンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２０６２８３Ｂ号明細書（１９９３）の主題である。本発明の組成物は、ペプチドに対し共有結合しているレボフロキサシンを含んでなる。本発明においては、レボフロキサシンは、カルボン酸基を介してペプチドに対し共有結合している。 Levofloxacin Levofloxacin is a known drug used in the treatment of bacterial infections. Its chemical name is (S) -9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de]. -1,4-benzoxazine-6-carboxylic acid. Its structure is as follows:

Levofloxacin is the subject of EP 206283B (1993), incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises levofloxacin covalently attached to a peptide. In the present invention, levofloxacin is covalently attached to the peptide via the carboxylic acid group.

メロペネムは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１２６５８７Ｂ号明細書１９９５及び欧州特許第２５６３７７Ｂ号明細書１９９２の主題である。本発明の組成物は、ペプチドに対し共有結合しているメロペネムを含んでなる。本発明においては、メロペネムは、カルボン酸基を介してペプチドに対し共有結合している。 Meropenem Meropenem is a known drug used in the treatment of bacterial infections. Its chemical name is (4R, 5S, 6S) -3-[[(3S, 5S) -5-[(dimethylamino) carbonyl] -3-pyrrolidinyl] thio] -6-[(1R) -1-hydroxyethyl. ) -4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid. Its structure is as follows:

Meropenem is the subject of European Patent Nos. 126587B 1995 and 256377B 1992, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises meropenem covalently attached to a peptide. In the present invention, meropenem is covalently attached to the peptide via the carboxylic acid group.

ミチグリニドは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５０７５３４Ｂ号明細書１９９２の主題である。本発明の組成物は、ペプチドに対し共有結合しているミチグリニドを含んでなる。本発明においては、ミチグリニドは、カルボン酸基を介してペプチドに対し共有結合している。 Mitiglinide Mitiglinide is a known drug used in the treatment of diabetes. Its chemical name is [2 (S) -cis] -octahydro-gamma-oxo-α- (phenylmethyl) -2H-isoindole-2-butanoic acid. Its structure is as follows:

Mitiglinide is the subject of EP 507534B 1992, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises mitiglinide covalently attached to a peptide. In the present invention, mitiglinide is covalently attached to the peptide via the carboxylic acid group.

モンテルカストは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，５６５，４７３号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているモンテルカストを含んでなる。本発明においては、モンテルカストは、カルボン酸基を介してペプチドに対し共有結合している。 Montelukast Montelukast is a known drug used in the treatment of asthma. Its chemical name is [R- (E)]-1-[[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2- (1-hydroxy-1 -Methylethyl) phenyl] propyl] thio] methyl] -cyclopropaneacetic acid. Its structure is as follows:

Montelukast is the subject of US Pat. No. 5,565,473, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises montelukast covalently attached to a peptide. In the present invention, montelukast is covalently attached to the peptide via the carboxylic acid group.

Montelukast and fexofenadine Montelukast is a known drug used in the treatment of asthma. Its chemical name is [R- (E)]-1-[[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2- (1-hydroxy-1 -Methylethyl) phenyl] propyl] thio] methyl] -cyclopropaneacetic acid. Its structure is as follows:

本発明の組成物は、ペプチドに対し共有結合しているモンテルカスト及びフェキソフェナジンを含んでなる。本発明においてはモンテルカスト及びフェキソフェナジンは、各々のカルボン酸基を介してペプチドに対し共有結合している。 Fexofenadine is a known drug used in the treatment of seasonal allergic rhinitis. Its chemical name is 4- [1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] butyl] -α, α-dimethylbenzeneacetic acid. Its structure is as follows:

The composition of the invention comprises montelukast and fexofenadine covalently attached to a peptide. In the present invention, montelukast and fexofenadine are covalently attached to the peptide via their respective carboxylic acid groups.

本発明の組成物は、ペプチドに対し共有結合しているナプロキセンを含んでなる。本発明においては、ナプロキセンは、カルボン酸基を介してペプチドに対し共有結合している。 Naproxen Naproxen is a known drug used in the treatment of pain and arthritis. Its structure is as follows:

The composition of the invention comprises naproxen covalently attached to a peptide. In the present invention, naproxen is covalently attached to the peptide via the carboxylic acid group.

オフロキサシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４３８２８９２号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているオフロキサシンを含んでなる。本発明においては、オフロキサシンは、カルボン酸基を介してペプチドに対し共有結合している。 Ofloxacin Ofloxacin is a known drug used in the treatment of bacterial infections. Its chemical name is 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] -1,4. -Benzoxazine-6-carboxylic acid. Its structure is as follows:

Ofloxacin is the subject of US Pat. No. 4,382,892, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises ofloxacin covalently attached to a peptide. In the present invention, ofloxacin is covalently attached to the peptide via the carboxylic acid group.

オキサプロジンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１２０６４０３号明細書１９７０の主題である。本発明の組成物は、ペプチドに対し共有結合しているオキサプロジンを含んでなる。本発明においては、オキサプロジンは、カルボン酸基を介してペプチドに対し共有結合している。 Oxaprozin Oxaprozin is a known drug used in the treatment of inflammation. Its chemical name is 4,5-diphenyl-2-oxazolepropanoic acid. Its structure is as follows:

Oxaprozin is the subject of GB 1206403 1970, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises oxaprozin covalently attached to a peptide. In the present invention, oxaprozin is covalently attached to the peptide via the carboxylic acid group.

ペメトレキセドは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第４３２６７７Ｂ号明細書（１９９６）、優先権米国特許第４４８７４２号明細書（１９８９）の主題である。本発明の組成物は、ペプチドに対し共有結合しているペメトレキセドを含んでなる。本発明においては、ペメトレキセドは、カルボン酸基を介してペプチドに対し共有結合している。 Pemetrexed Pemetrexed is a known drug used in the treatment of cancer. Its chemical name is N- [4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L- It is glutamic acid. Its structure is as follows:

Pemetrexed is the subject of EP 432677B (1996), priority US Pat. No. 4,487,742 (1989), incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises pemetrexed covalently attached to a peptide. In the present invention, pemetrexed is covalently attached to the peptide via the carboxylic acid group.

本発明の組成物は、ペプチドに対し共有結合しているペニシリンＶを含んでなる。本発明においては、ペニシリンＶは、カルボン酸基を介してペプチドに対し共有結合している。 Penicillin V
Penicillin V is a known drug used in the treatment of bacterial infections. Its structure is as follows:

The composition of the invention comprises penicillin V covalently attached to a peptide. In the present invention, penicillin V is covalently attached to the peptide via the carboxylic acid group.

本発明の組成物は、ペプチドに対し共有結合しているピペラシリンを含んでなる。本発明においては、ピペラシリンは、カルボン酸基を介してペプチドに対し共有結合している。 Piperacillin Piperacillin is a known drug used in the treatment of bacterial infections. Its structure is as follows:

The composition of the invention comprises piperacillin covalently attached to a peptide. In the present invention, piperacillin is covalently attached to the peptide via the carboxylic acid group.

レパグリニドは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５８９８７４Ｂ号明細書１９９９の主題である。本発明の組成物は、ペプチドに対し共有結合しているレパグリニドを含んでなる。本発明においては、レパグリニドは、カルボン酸基を介してペプチドに対し共有結合している。 Repaglinide Repaglinide is a known drug used in the treatment of diabetes. Its chemical name is (S) -2-ethoxy-4- [2-[[3-methyl-1- [2- (1-piperidinyl) phenyl] butyl] amino] -2-oxoethyl] benzoic acid. Its structure is as follows:

Repaglinide is the subject of EP 589874B 1999, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises repaglinide covalently attached to a peptide. In the present invention, repaglinide is covalently attached to the peptide via the carboxylic acid group.

チアガビンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，０１０，０９０及び５，３５４，７６０号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているチアガビンを含んでなる。本発明においては、チアガビンは、カルボン酸基又はその水酸基のいずれかを介してペプチドに対し共有結合している。 Tiagabine Tiagabine is a known drug used in the treatment of epilepsy. Its chemical name is (R) -1- [4,4-bis (3-methyl-2-thienyl) -3-butenyl] -3-piperidinecarboxylic acid. Its structure is as follows:

Tiagabine is the subject of US Pat. Nos. 5,010,090 and 5,354,760, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises tiagabine covalently attached to a peptide. In the present invention, tiagabine is covalently attached to the peptide via either the carboxylic acid group or its hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているバルプロン酸を含んでなる。本発明においては、バルプロン酸は、カルボン酸基を介してペプチドに対し共有結合している。 Valproic acid Valproic acid is a known drug used in the treatment of epilepsy. Its structure is as follows:

The composition of the invention comprises valproic acid covalently attached to a peptide. In the present invention, valproic acid is covalently attached to the peptide via the carboxylic acid group.

バルサルタンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，３９９，５７８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているバルサルタンを含んでなる。本発明においては、バルサルタンは、カルボン酸基を介してペプチドに対し共有結合している。 Valsartan Valsartan is used in combination in the treatment of hypertension. Its chemical name is N- (1-oxopentyl) -N-[[2 ′-(1H-tetrazol-5-yl) [1,1-biphenyl] -4-yl] methyl] -L-valine. Its structure is as follows:

Valsartan is the subject of US Pat. No. 5,399,578, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises valsartan covalently attached to a peptide. In the present invention, valsartan is covalently attached to the peptide via the carboxylic acid group.

ゼナレスタットは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２１８９９９Ｂ号明細書１９９１の主題である。本発明の組成物は、ペプチドに対し共有結合しているゼナレスタットを含んでなる。本発明においては、ゼナレスタットは、カルボン酸基を介してペプチドに対し共有結合している。 Zenarestat Zenarestat is a known drug used in the treatment of diabetes, retinopathy and neuropathy. Its chemical name is 3-[(4-bromo-2-fluorophenyl) methyl] -7-chloro-3,4-dihydro-2,4-dioxo-1 (2H) -quinazoline acetic acid. Its structure is as follows:

Xenarestat is the subject of EP 218999B 1991, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises zenarestat covalently attached to a peptide. In the present invention, zenarestat is covalently attached to the peptide via the carboxylic acid group.

XII. Via the C-hydroxyl group The following compounds are preferably attached via the hydroxyl group.

本発明においては、アカルボースはいずれかの遊離水酸基を介してペプチドに対し共有結合している。アカルボースは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９０４，７６９号明細書の主題である。 Acarbose Acarbose is a known drug used in the treatment of type II diabetes. Its chemical name is O-4,6-dideoxy-4-[[[1S- (1α, 4α, 5β, 6α)]-4,5,6-trihydroxy-3- (hydroxymethyl) -2-cyclohexene- 1-yl] amino] -α-D-glucopyranosyl- (1-4) -O-α-D-glucopyranosyl- (1-4) -D-glucose. Its structure is as follows:

In the present invention, acarbose is covalently attached to the peptide via any free hydroxyl group. Acarbose is the subject of US Pat. No. 4,904,769, herein incorporated by reference, which describes how to make that drug.

Acetaminophen Acetaminophen is a known drug used in the treatment of mild pain and pain. Its chemical name is N-acetyl-P-aminophenol. Acetaminophen is not only commercially available but also easily produced by those skilled in the art using published synthetic schemes. In the present invention, acetaminophen is covalently attached to the peptide via its hydroxyl group.

Acetaminophen with codeine Acetaminophen is a known drug used in the treatment of mild pain and pain. Its chemical name is N-acetyl-P-aminophenol. This is often used in combination with codeine (chemical name 7,8-didehydro-4,5-α-epoxy-3-methoxy-17-methylmethorninan-6α-ol). While both are commercially available, they are also easily manufactured by those skilled in the art using published synthetic schemes. In the present invention, both acetaminophen and codeine are covalently attached to the peptide via their hydroxyl groups.

本発明においては、アシクロビアは、水酸基を介してペプチドに対し共有結合している。 Acyclovir Acyclovir is a known drug that is an antiviral used to treat herpes simplex virus. Acyclovir is not only commercially available, but also easily produced by those skilled in the art using published synthetic schemes. Its chemical name is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy) methyl] -6H-purin-6-one. Its structure is as follows:

In the present invention, acyclovir is covalently attached to the peptide via the hydroxyl group.

アデノシンは、市販されていると同時に、公開済の合成スキームを用いて当業者によって容易に製造されるものでもある。本発明においては、アデノシンは、リボースの水酸基を介してペプチドに対し共有結合している。 Adenosine Adenosine is a known drug used as a coronary dilator. Its chemical name is 9-α-D-ribofuranosyl-9H-purin-6-amine. Its structure is as follows:

Adenosine is not only commercially available but also easily produced by those skilled in the art using published synthetic schemes. In the present invention, adenosine is covalently attached to the peptide via the hydroxyl group of ribose.

アンプレナビルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，５８５，３９７；５，６４６，１８０；及び５，７２３，４９０号明細書の主題である。本発明においては、アンプレナビルは、水酸基を介してペプチドに対し共有結合している。 Amprenavir, an amprenavir proteinase inhibitor, is a known drug used in the treatment of HIV infection. Its chemical name is [3S-3R * (1R *, 2S *)]]-[3-[[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl ) Propyl] carbamic acid tetrahydro-3-furanyl ester. Its structure is as follows:

Amprenavir is the subject of US Pat. Nos. 5,585,397; 5,646,180; and 5,723,490, incorporated herein by reference, which describe how to make the drug. . In the present invention, amprenavir is covalently attached to the peptide via the hydroxyl group.

一つの抗真菌薬は、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９６／１１２１０号パンフレット１９９６、の主題である。本発明の組成物は、ペプチドに対し共有結合している抗真菌薬を含んでなる。本発明においては、抗真菌薬は、いずれかの水酸基を介してペプチドに対し共有結合している。 Antifungal Agents The antifungal agents of the present invention are known agents used in the treatment of fungal infections. Its chemical name is 4,5-dihydroxy-N-2- [4- [5- [4- (pentyloxy) phenyl] -3-isoxazolyl] benzoyl] ornithylleonyl-4-hydroxyprolyl-4-hydroxy 4- [4-Hydroxy-3- (sulfoxy) phenylthreonyl-3-hydroxyglutaminyl-3-hydroxy-4-methylproline cyclic (6-1) -peptide monosodium salt. Its structure is as follows:

One antifungal agent is the subject of WO 96/11210, 1996, which is incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises an antifungal agent covalently attached to a peptide. In the present invention, the antifungal agent is covalently attached to the peptide via any hydroxyl group.

Antisense oligonucleotides Antisense oligonucleotides are a class of compounds consisting of RNA complementary to the mRNA that produces the protein of interest. Its utility is primarily in gene therapy. Individual uses include applications for inflammatory bowel disease. These are made by chemical RNA synthesis or alternatively by isolating the RNA of interest using a gene construct that contains the antisense orientation of the gene of interest. In the present invention, the antisense oligonucleotide is covalently attached to the peptide via the hydroxyl group of ribose.

本発明においては、アバレリクスは遊離水酸基を介してペプチドに対し共有結合している。 Abarelix Abarelix is a known drug that is used in the treatment of prostate cancer and acts as a gonadotropin releasing hormone antagonist. Its chemical name is N-acetyl-3- (2-naphthalenyl) -D-alanyl-4-chloro-D-phenylalanyl-3- (3-pyridinyl) -D-alanyl-L-seryl-N-methyl- L-tyrosyl-D-asparaginyl-LN-6- (1-methylethyl) -L-lysyl-L-prolyl-D-alaninamide. Abarelix is commercially available and at the same time is easily produced by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, abarelix is covalently attached to the peptide via the free hydroxyl group.

アトルバスタチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６８１，８９３；５，２７３，９９５；５，６８６，１０４；及び５，９６９，１５６号明細書の主題である。本発明においては、アトルバスタチンは、水酸基を介してペプチドに対し共有結合している。 Atorvastatin Atorvastatin is a known drug used in the treatment of hypercholesterolemia. Its chemical name is (βR, δR) -2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H. -Pyrrol-1-heptanoic acid. Its structure is as follows:

Atorvastatin describes how to make the drug, US Pat. Nos. 4,681,893; 5,273,995; 5,686,104; and 5,969,156, incorporated herein by reference. Is the theme. In the present invention, atorvastatin is covalently attached to the peptide via the hydroxyl group.

アトバクオンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９８１，８７４及び５，０５３，４３２号明細書の主題である。本発明においては、アトバクオンは、水酸基を介してペプチドに対し共有結合している。 Atovaquon Atovaquon is a known drug used to prevent carini pneumonia. Its chemical name is 2- [trans-4- (4-chlorophenyl) cyclohexyl] -3-hydroxy-1,4-naphthalenedione. Its structure is as follows:

Atovaquon is the subject of US Pat. Nos. 4,981,874 and 5,053,432, incorporated herein by reference, which describe how to make the drug. In the present invention, atovaquone is covalently attached to the peptide via the hydroxyl group.

アジトロマイシンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第２０９４２９３ Ｂ号明細書（１９８５）の主題である。本発明においては、アジトロマイシンは、いずれかの水酸基を介してペプチドに対し共有結合している。 Azithromycin Azithromycin is a known drug used in the treatment of bacterial infections. Its chemical name is (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R) -13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α- 1-ribohexopyranosyl) oxy] -2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12-heptamethyl-11-[[3,4,6-trideoxy- 3- (dimethylamino) β-D-xylo-hexopyranosyl] oxy] -1-oxa-6-azacyclopentadecan-15-one. Its structure is as follows:

Azithromycin is the subject of GB 2094293 B (1985), incorporated herein by reference, which describes how to make the drug. In the present invention, azithromycin is covalently attached to the peptide via any hydroxyl group.

ベフロキサトンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第４２４２４４Ｂ号明細書（１９９５）の主題である。本発明においては、ベフロキサトンは、水酸基を介してペプチドに対し共有結合している。 Befloxatone Befloxatone is a known drug that has been used to treat smoking cessation. Its chemical name is (R) -5- (methoxymethyl) -3- [4-[(R) -4,4,4-trifluoro-3-hydroxybutoxy] phenyl] -2-oxazolidinone. Its structure is as follows:

Befloxatone is the subject of EP 424244B (1995), incorporated herein by reference, which describes how to make the drug. In the present invention, befloxatone is covalently attached to the peptide via the hydroxyl group.

本発明においては、ベタメタゾンは、いずれかの水酸基を介してペプチドに対し共有結合している。 Betamethasone Betamethasone is a known drug that is mainly used as an anti-inflammatory or immunosuppressant. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, betamethasone is covalently attached to the peptide via any hydroxyl group.

ビカルタミドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，４７２，３８２；４，６３６，５０５；及び５，３８９，６１３号明細書の主題である。本発明においては、ビカルタミドは、水酸基を介してペプチドに対し共有結合している。ＬＨＲＨを、同一のペプチドに付着させて２つの薬剤を組み合わせて提供することもできる。 Bicalutamide Bicalutamide is a known drug used in the treatment of non-metastatic prostate cancer that has progressed locally in combination with LHRH. Its chemical name is (+,-)-N- [4-cyano-3- (trifluoromethyl) phenyl] -3-[(4-fluorophenyl) sulfonyl] -2-hydroxy-2-methylpropanamide. is there. Its structure is as follows:

Bicalutamide is the subject of US Pat. Nos. 4,472,382; 4,636,505; and 5,389,613, incorporated herein by reference, which describe how to make the drug. In the present invention, bicalutamide is covalently attached to the peptide via the hydroxyl group. LHRH can also be provided in combination with two agents attached to the same peptide.

本発明においては、ビソプロロールは、水酸基を介してペプチドに付着している。 Bisoprolol Bisoprolol is a known drug used for the treatment of angina, arrhythmia and hypertension. Its structure is as follows:

In the present invention, bisoprolol is attached to the peptide via the hydroxyl group.

ボセンタンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５２６７０８Ａ号明細書（１９９３）の主題である。本発明においては、ボセンタンは、水酸基を介してペプチドに対し共有結合している。 Bosentan Bosentan is a known drug used in the treatment of pulmonary hypertension. Its chemical name is 4- (1,1-dimethylethyl) -N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy)-[2,2′-bipyrimidin] -4-yl]. Benzenesulfonamide. Its structure is as follows:

Bosentan is the subject of EP 526708A (1993), incorporated herein by reference, which describes how to make that drug. In the present invention, bosentan is covalently attached to the peptide via the hydroxyl group.

本発明においては、ブトルファノールは、フェニルヒドロキシル基を介してペプチドに対し共有結合している。 Butorphanol Butorphanol is a known drug used in the treatment of pain. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, butorphanol is covalently attached to the peptide via the phenyl hydroxyl group.

カルシトリオールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３０８，２６４及び６，０５１，５６７号明細書の主題である。本発明においては、カルシトリオールは、水酸基のいずれかを介してペプチドに対し共有結合している。 Calcitriol Calcitriol is a known drug used in the treatment of hypocalcemia. Its structure is as follows:

Calcitriol is the subject of US Pat. Nos. 4,308,264 and 6,051,567, incorporated herein by reference, which describe how to make the drug. In the present invention, calcitriol is covalently attached to the peptide via any of the hydroxyl groups.

カペシタビンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９６６，８９１及び５，４７２，９４９号明細書の主題である。本発明においては、カペシタビンは、水酸基のいずれかを介してペプチドに対し共有結合している。 Capecitabine Capecitabine is a known drug used in the treatment of colorectal cancer. Its chemical name is pentyl 1- (5-deoxy-β-D-ribofuranosyl) -5-fluoro-1,2-dihydro-2-oxo-4-pyrimidinecarbamate. Its structure is as follows:

Capecitabine is the subject of US Pat. Nos. 4,966,891 and 5,472,949, herein incorporated by reference, which describes how to make the drug. In the present invention, capecitabine is covalently attached to the peptide via any of the hydroxyl groups.

カルバペネム系抗生物質は、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５９９５１２Ａ号明細書（１９９４）の主題である。本発明の組成物は、ペプチドに対し共有結合しているカルバペネム系抗生物質を含んでなる。本発明においては、カルバペネム系抗生物質は、水酸基を介してペプチドに対し共有結合している。 Carbapenem antibiotics Carbapenem antibiotics of the present invention are known drugs used in the treatment of bacterial infections. Its chemical name is [4R- [3 (R ^* ), 4α, 5β, 6β (R ^* )]]-6- (1-hydroxyethyl) -4-methyl-7-oxo-3-[(5-oxo -3-pyrosinyl) thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy) methyl ester. Its structure is as follows:

Carbapenem antibiotics are the subject of EP 599512A (1994), incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises a carbapenem antibiotic covalently attached to a peptide. In the present invention, the carbapenem antibiotic is covalently bonded to the peptide via the hydroxyl group.

シクレゾニドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許出願公開第５７８９４２号明細書（１９９０）に基づく英国特許第２２４７６８０Ｂ号明細書（１９９４）の主題である。本発明においては、シクレゾニドは、水酸基を介してペプチドに対し共有結合している。 Ciclesonide Ciclezonide is a known drug used in the treatment of asthma. Its chemical name is [11β, 16α (R)]-16,17-[(cyclohexylmethylene) bis (oxy)]-11-hydroxy-21- (2-methyl-1-oxopropoxy) -pregna-1,4 -Diene-3,20-dione. Its structure is as follows:

Ciclezonide is the subject of British Patent No. 2247680B (1994) based on US Pat. No. 5,789,942 (1990), incorporated herein by reference, which describes how to make that drug. In the present invention, ciclezonide is covalently attached to the peptide via the hydroxyl group.

クラリトロマイシンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第４１３５５Ｂ号明細書（１９８３）及び欧州特許第２９３８８５Ｂ号明細書（１９９３）、及び米国特許出願公開第５８４９９号明細書（１９８７）の主題である。本発明においては、クラリトロマイシンは、水酸基のいずれかを介してペプチドに対し共有結合している。 Clarithromycin Clarithromycin is a known drug used in the treatment of bacterial infections. Its chemical name is 6-O-methylerythromycin. Its structure is as follows:

Clarithromycin describes EP 41355B (1983) and EP 293885B (1993), which are incorporated herein by reference, and US Patent Application Publication No. 58499 (1987). In the present invention, clarithromycin is covalently attached to the peptide via any of the hydroxyl groups.

Codeine Codeine is a known drug used in the treatment of pain. The composition of the invention comprises codeine covalently attached to a peptide. In the present invention, codeine is covalently attached to the peptide via the hydroxyl group.

本発明においては、共役エストロゲンは、水酸基を介してペプチドに対し共有結合している。 Conjugated estrogens In women, oral conjugated estrogens USP and synthetic conjugated estrogens A are used to manage moderate to severe vasomotor symptoms associated with menopause. Conjugated estrogen USP is a formulation that contains, in whole or in part, equine urine derived from urine and sodium salt of water-soluble sulfate ester of estrone, or it can be prepared synthetically from estrone and echrin. it can. Conjugated estrogens USP likewise, 17 [alpha dihydro et giraffe, 17 [alpha-estradiol, 17.beta.-dihydro et giraffe, equilenin, 17 [alpha dihydro equi renin, 17.beta.-dihydro equi renin, [delta] ⁸⁹ - Pregnant comprising dehydroepiandrosterone estrone, and 17.beta. estradiol It also contains conjugated estrogens of the type excreted by horses. Conjugated estrogen USP contains 52.5-61.5% sodium estrone sulfate and 22.5-30.5% sodium equinate sulfate. Conjugated estrogens are sodium sulfate conjugates as follows: 13.5-19.5% 17α-dihydroeline, 2.5-9.5% 17α-estradiol, and 0.5-4% 17β-dihydroequilin. Containing. These can be obtained from natural sources. The structure of estrone is as follows:

In the present invention, conjugated estrogens are covalently attached to the peptide via the hydroxyl group.

Conjugated estrogens and medroxyprogesterone acetate Conjugated estrogens and medroxyprogesterone acetate are known drugs used in hormone replacement therapy. In women, oral conjugated estrogens USP and synthetic conjugated estrogens A are used to manage moderate to severe vasomotor symptoms associated with menopause. Conjugated estrogen USP is a formulation that contains, in whole or in part, equine urine derived from urine and sodium salt of water-soluble sulfate ester of estrone, or it can be prepared synthetically from estrone and echrin. it can. Conjugated estrogens USP similarly comprises 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, echilenin, 17α-dihydroequilenin, 17β-dihydroequilenin, δ ^8,9 -dehydroestrone, and 17β-estradiol. It also contains conjugated estrogens of the type excreted by pregnant mares. Conjugated estrogen USP contains 52.5-61.5% sodium estrone sulfate and 22.5-30.5% sodium equinate sulfate. Conjugated estrogens are sodium sulfate conjugates as follows: 13.5-19.5% 17α-dihydroeline, 2.5-9.5% 17α-estradiol, and 0.5-4% 17β-dihydroequilin. Containing. These can be obtained from natural sources. The structure of estrone is as follows:

本発明においては、共役エストロゲン及び酢酸メドロキシプロゲステロンは、水酸基を介してペプチドに対し共有結合している。 Medroxyprogesterone acetate is a synthetic progestin. Medroxyprogesterone acetate is a structurally different derivative of 17α-hydroxyprogesterone with the addition of 6α-methyl and 17α-acetate groups. Its structure is as follows:

In the present invention, conjugated estrogens and medroxyprogesterone acetate are covalently attached to the peptide via the hydroxyl group.

本発明においては、シクロスポリンは、水酸基を介してペプチドに対し共有結合している。 Cyclosporine Cyclosporine is a known drug used in the prevention and treatment of renal, liver or heart allograft rejection. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, cyclosporine is covalently attached to the peptide via the hydroxyl group.

ダピタントは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９３／２１１５５号パンフレット（１９９３）の主題である。本発明においては、ダピタントは、水酸基を介してペプチドに対し共有結合している。 Dapitant Dapitant is a known drug used in the treatment of asthma. Its chemical name is [3aS- [2 (R ^* ), 3α, 4β, 7α]]-octahydro-4- (2-methoxyphenyl) -2- [2- (2-methoxyphenyl) -1-oxopropyl] -7,7-diphenyl-1H-isoindol-4-ol. Its structure is as follows:

Dapitant is the subject of WO 93/21155 (1993), incorporated herein by reference, which describes how to make the drug. In the present invention, dapitant is covalently attached to the peptide via the hydroxyl group.

Desogestrel and ethinyl estradiol Desogestrel and ethinyl estradiol are known drugs used in combination as contraceptives. The chemical name of desogestrel is (17α) -13-ethyl-11-methylene-18,19-dinorpregn-4-en-20-in-17-ol. Its structure is as follows:

デソゲストレルは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１４５５２７０号明細書（１９７６）の主題である。本発明においては、デソゲストレル及びエチニルエストラジオールは、それらの水酸基を介してペプチドに対し共有結合している。 The chemical name of ethinyl estradiol is (17α) -19-norpregna-1,2,5 (10) -triene-20-in-3,17-diol. Its structure is as follows:

Desogestrel is the subject of British Patent 1455270 (1976), incorporated herein by reference, which describes how to make the drug. In the present invention, desogestrel and ethinyl estradiol are covalently attached to the peptide via their hydroxyl groups.

ジダノシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８６１，７５９及び５，６１６，５６６号明細書の主題である。本発明においては、ジダノシンは、リボースのヒドロキシル基を介してペプチドに対し共有結合している。 Didanosine didanosine is a known drug used in the treatment of HIV. Its chemical name is 2 ', 3'-dideoxyinosine. Its structure is as follows:

Didanosine is the subject of US Pat. Nos. 4,861,759 and 5,616,566, incorporated herein by reference, which describe how to make the drug. In the present invention, didanosine is covalently attached to the peptide via the hydroxyl group of ribose.

Dihydrocodeine Dihydrocodeine is a known drug used in the treatment of pain. The composition of the invention comprises dihydrocodeine covalently attached to a peptide. In the present invention, dihydrocodeine is covalently attached to the peptide via the hydroxyl group.

Dihydromorphine Dihydromorphine is a known drug used in the treatment of pain. The composition of the invention comprises dihydromorphine covalently attached to a peptide. In the present invention, dihydromorphine is covalently attached to the peptide via the hydroxyl group.

本発明においては、ジゴキシンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Digoxin Digoxin is a known drug used in the treatment of digitalis drug administration and maintenance therapy. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, digoxin is covalently attached to the peptide via any of the hydroxyl groups.

本発明においては、ジプリダモールは、ヒドロキシル基を介してペプチドに対し共有結合している。 Dipyridamole Dipyridamole is a known drug used as an adjunct to coumarin anticoagulants in the prevention of thromboembolic complications after heart valve replacement. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, dipridamole is covalently attached to the peptide via the hydroxyl group.

ドセタキセルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２５３７３８Ｂ号明細書１９９０及び欧州特許第５９３６５６Ｂ号明細書１９９７の主題である。本発明の組成物は、ペプチドに対し共有結合しているドセタキセルを含んでなる。本発明においては、ドセタキセルは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Docetaxel Docetaxel is a known drug used in the treatment of cancer and malaria. Its chemical name is β-[[(1,1-dimethylethoxy) carbonyl] amino] -α-hydroxybenzenepropanoic acid [2aR- [2α, 4β, 4aβ, 6β, 9α (αR ^* , βS ^* )-11α, 12α, 12aα, 12bα]]-12b- (acetyloxy) -12- (benzoyloxy) -2a, 3,4,4a, 5,6,9,10,11,12,12a, 12b-dodecahydro-4, 6,11-Trihydroxy-4a, 8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca [3,4] benz [1,2-b] oct-9-yl ester It is. Its structure is as follows:

Docetaxel is the subject of EP 253738B 1990 and EP 593656B 1997, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises docetaxel covalently attached to a peptide. In the present invention, docetaxel is covalently attached to the peptide via any of the hydroxyl groups.

エコピパムは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２５４７３７Ａ号明細書（１９９０）、優先権米国特許出願公開第８２０４７１号明細書（１９８６）の主題である。本発明においては、エコピパムは、ヒドロキシル基を介してペプチドに対し共有結合している。 Ecopipam Ecopipam is a known drug used in the treatment of obesity. Its chemical name is (6aS, 13bR) -11-chloro-6,6a, 7,8,9,13b-hexahydro-7-methyl-5H-benzo [d] naphtho [2,1-b] azepine-12 -All. Its structure is as follows:

Ecopipam is the subject of EP 254737A (1990), priority US patent application 820471 (1986), incorporated herein by reference, which describes how to make the drug. In the present invention, ecopipam is covalently attached to the peptide via the hydroxyl group.

Erythromycin Erythromycin is a known drug used in the treatment of bacterial infections. Its chemical name is (3R ^* , 4S ^* , 5S ^* , 6R ^* , 7R ^* , 9R ^* , 11R ^* , 12R ^* , 13S ^* , 14R ^* )-4-((2,6-dideoxy-3-C -Methyl-3-O-methyl-aL-ribo-hexopyranosyl) -oxy) -14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-6 ((3,4,6-trideoxy-3- (dimethylamino) -bD-xylo-hexopyranosyl) oxy) oxacyclotetradecane-2,10-dione. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. In the present invention, erythromycin is covalently attached to the peptide via the hydroxyl group.

エサテノロールは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１２８５０３５号明細書（１９７２）の主題である。本発明においては、エサテノロールは、ヒドロキシル基を介してペプチドに対し共有結合している。 Esatenolol Esatenolol is a known drug used in the treatment of hypertension. Its chemical name is (S) -4- [2-hydroxy-3-[(1-methylethyl) amino] propoxy] benzeneacetamide. Its structure is as follows:

Esatenolol is the subject of GB 1285035 (1972), incorporated herein by reference, which describes how to make the drug. In the present invention, esatenolol is covalently attached to the peptide via the hydroxyl group.

Esterified estrogens and methyltestosterone Esterified estrogens and methyltestosterone are known drugs used in combination with hormone replacement therapy. Esterified estrogens are a mixture of sodium salts of sulfate esters of estrogenic substances such as estrone, which are of the type secreted in the urine of pregnant horses. Esterone sodium sulfate is the main active ingredient in esterified estrogens. Esterified estrogens can be derived from natural sources and / or prepared synthetically. The structure of estrone is as follows:

本発明においては、エステル化エストロゲン及びメチルテストステロンは、それらのヒドロキシル基を介してペプチドに対し共有結合している。 The structure of methyltestosterone is as follows:

In the present invention, esterified estrogens and methyltestosterone are covalently attached to the peptide via their hydroxyl groups.

本発明においては、エストロピペートは、ヒドロキシル基を介してペプチドに対し共有結合している。 Estropipate Estropipeate is a known drug used for hormone replacement therapy. Estropipate is estrone solubilized as sulfate and stabilized with piperazine. As a result of the conjugation of sulfate and estrone at the 3-hydroxy position on ring A of the steroid nucleus, a water-soluble derivative is formed. The pharmaceutically inert perazine half acts as a buffer to enhance the stability and homogeneity of estrone sulfate. The structure of estrone is as follows:

In the present invention, estropipete is covalently attached to the peptide via the hydroxyl group.

Ethinylestradiol and dogestrel Ethinylestradiol and dogestrel are used in combination as contraceptives. The chemical name of ethinyl estradiol is (17α) -19-norpregna-1,2,5 (10) -triene-20-in-3,17-diol. Its structure is as follows:

本発明の組成物は、ペプチドに対し共有結合しているエチニルエストラジオール及びドジステレルを含んでなる。本発明においては、エチニルエストラジオール及びドジステレルは、ヒドロキシル基を介してペプチドに対し共有結合している。 The chemical name of desogesterel is (17α) -13-ethyl-11-methylene-18,19-dinorpregn-4-en-20-in-17-ol. Its structure is as follows:

The composition of the invention comprises ethinylestradiol and dodisterel covalently attached to a peptide. In the present invention, ethinyl estradiol and dodisterer are covalently attached to the peptide via the hydroxyl group.

Ethinylestradiol and norethindrone Ethinylestradiol and norethindrone are known drugs that are used in combination as contraceptives. The structure of ethinyl estradiol is:

本発明においては、エチニルエストラジオール及びノルエチンドロンは、ヒドロキシル基を介してペプチドに対し共有結合している。 The structure of norethindrone is as follows:

In the present invention, ethinyl estradiol and norethindrone are covalently attached to the peptide via the hydroxyl group.

Ethinyl estradiol and levonorgestrel Ethinyl estradiol and levonorgestrel are known drugs that are used in combination as contraceptives. Each can be isolated from a natural source or alternatively synthesized by one skilled in the art. In the present invention, ethinyl estradiol and levonorgestrel are covalently attached to the peptide via the hydroxyl group.

Ethinylestradiol and norethindrone Ethinylestradiol and norethindrone 28 are known drugs that are used in combination as contraceptives. Each can be isolated from a natural source or alternatively synthesized by one skilled in the art. In the present invention, ethinyl estradiol and norethindrone 28 are covalently attached to the peptide via the hydroxyl group.

Ethinylestradiol and norgestimate Ethinylestradiol and norgestimate are known drugs used in combination as contraceptives. Each can be isolated from a natural source or alternatively synthesized by one skilled in the art. In the present invention, ethinyl estradiol and norgestimate are covalently attached to the peptide via the hydroxyl group.

Ethinylestradiol and norgestrel Ethinylestradiol and norgestrel are known drugs that are used in combination as contraceptives. Each can be isolated from a natural source or alternatively synthesized by one skilled in the art. In the present invention, ethinyl estradiol and norgesterel are covalently attached to the peptide via the hydroxyl group.

Ethylmorphine Ethylmorphine is a known drug used in the treatment of pain. The composition of the invention comprises ethylmorphine covalently attached to a peptide. In the invention, ethylmorphine is covalently attached to the peptide via the hydroxyl group.

本発明においては、エイチドロネートは、アルコール基を介してペプチドに対し共有結合している。 Ethidronate Ethidronate is a known drug used in the treatment of moderate to severe bone symptomatic Paget's disease (degenerative osteoarthritis). This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, etidronate is covalently attached to the peptide via the alcohol group.

フェンレチニドは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１５４３８２４号明細書（１９７９）［−優先権米国特許出願公開第６２８１７７号明細書（１９７５）、米国特許第４，３２３，５８１号明細書（１９８２）及び米国特許第４，６６５，０９８号明細書（１９８７）に基づく］の主題である。本発明においては、フェンレチニドは、ヒドロキシル基を介してペプチドに対し共有結合している。 Fenretinide Fenretinide is a known drug used in the treatment of cancer. Its chemical name is N- (4-hydroxyphenyl) retinamide. Its structure is as follows:

Fenretinide is described in British Patent No. 1543824 (1979) [-priority U.S. Patent Publication No. 628177 (1975), U.S. Pat. 4,323,581 (1982) and US Pat. No. 4,665,098 (1987)]. In the present invention, fenretinide is covalently attached to the peptide via the hydroxyl group.

フルコナゾールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，４０４，２１６及び４，４１６，６８２号明細書の主題である。本発明においては、フルコナゾールは、ヒドロキシル基を介してペプチドに対し共有結合している。 Fluconazole Fluconazole is a known drug used in the treatment of fungal infections. Its chemical name is alpha- (2,4-difluorophenyl) -α- (1H-1,2,4-triazol-1-ylmethyl) -1H-1,2,4-triazole-1-ethanol. Its structure is as follows:

Fluconazole is the subject of U.S. Pat. Nos. 4,404,216 and 4,416,682, incorporated herein by reference, which describe how to make the drug. In the present invention, fluconazole is covalently attached to the peptide via the hydroxyl group.

フルチカゾンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第２０８８８７７Ｂ号明細書１９８４の主題である。本発明の組成物は、ペプチドに対し共有結合しているフルチカゾンを含んでなる。本発明においては、フルチカゾンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Fluticasone Fluticasone is a known drug used in the treatment of dermatitis, rhinitis, asthma, pulmonary obstructive disease and skin disease. Its chemical name is (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-1 7- (1-oxopropoxy) -androsta-1,4- Diene-17-carbothioic acid, S- (fluoromethyl) ester. Its structure is as follows:

Fluticasone is the subject of GB 20888877B 1984, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises fluticasone covalently attached to a peptide. In the present invention, fluticasone is covalently attached to the peptide via the hydroxyl group.

フォルモテロールは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１４１５２５６号明細書（１９７５）の主題である。本発明においては、フォルモテロールは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Formoterol Formoterol is a known drug used in the treatment of asthma. Its chemical name is 1-N- [2-hydroxy-5-[(1R) -1-hydroxy-2-[[(1R) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl]. Phenyl] formamide. Its structure is as follows:

Formoterol is the subject of GB 145256 (1975), incorporated herein by reference, which describes how to make the drug. In the present invention, formoterol is covalently attached to the peptide via any of the hydroxyl groups.

ガナクソロンは、該薬物の作り方を記載する、本書中に参考として内含された独国特許第２１６２５５５Ａ号明細書（１９７２）、国際公開第９３／３７３２号パンフレット（１９９３）［優先権米国特許出願公開第７４５２１６号明細書（１９９１）に基づく］、国際公開第９３／５７８６号パンフレット１９９３［優先権米国特許出願公開第７５９５１２号明細書（１９９１）に基づく］及び国際公開第９４／２７６０８（１９９４）号パンフレット［優先権米国特許出願公開第６８３７８号明細書（１９９３）に基づく］の主題である。本発明においては、ガナクソロンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Ganaxolone Ganaxolone is a known drug used in the treatment of epilepsy and migraine. Its chemical name is (3α, 5α) -3-hydroxy-3-methyl-pregnan-20-one. Its structure is as follows:

Ganaxolone is described in German Patent No. 2162555A (1972), International Publication No. 93/3732 (1993), which describes how to make the drug, and the publication of priority US patent applications. No. 745216 (1991)], WO 93/5786 pamphlet 1993 [based on priority US Pat. No. 7,595,512 (1991)] and WO 94/27608 (1994). It is the subject of a pamphlet [based on priority US Pat. Application Publication No. 68378 (1993)]. In the present invention, ganaxolone is covalently attached to the peptide via the hydroxyl group.

ガンシクロビルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３５５，０３２；４，４２３，０５０；４，５０７，３０５；及び４，６４２，３４６号明細書の主題である。本発明においては、ガンシクロビルは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Ganciclovir Ganciclovir is a known drug used in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients, including acquired immune deficiency syndrome (AIDS) patients. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

Ganciclovir describes US Pat. Nos. 4,355,032; 4,423,050; 4,507,305; and 4,642,346, incorporated herein by reference, which describe how to make the drug. Is the theme. In the present invention, ganciclovir is covalently attached to the peptide via any of the hydroxyl groups.

胃運動促進性化合物は、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第６４３０６８Ａ号明細書１９９５の主題である。本発明の組成物は、ペプチドに対し共有結合している胃運動促進性化合物を含んでなる。本発明においては、胃運動促進性化合物は、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Gastric Motility Promoting Compound The gastric motility promoting compound of the present invention is a known drug used in the treatment of gastrointestinal motility disorders. Its chemical name is 8,9-didehydro-N-demethyl-9-deoxo-6,11-dideoxy-6,9-epoxy-12-0-methyl-N- (1-methylethyl) -11-oxoerythromycin ( E) -2-butenedioate (2: 1). Its structure is as follows:

A gastric motility promoting compound is the subject of EP 634068A 1995, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises a gastric motility promoting compound covalently attached to a peptide. In the present invention, the gastric motility promoting compound is covalently attached to the peptide via any of the hydroxyl groups.

本発明においては、ハロペリダルは、ヒドロキシル基を介してペプチドに対し共有結合している。 Haloperidal Haloperidal is a known drug used in the treatment of mental disorders. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, haloperidal is covalently attached to the peptide via the hydroxyl group.

Heparin Heparin is a known drug used in the treatment of clots. Heparin is a heterogeneous group of linear anionic mucopolysaccharides called glycosaminoglycans with anticoagulant properties. The main sugars that appear in heparin, although others may be present, are:
(1) aL-iduronic acid 2-sulfate,
(2) 2-deoxy-2-sulfoamino-aD-glucose 6-sulfate,
(3) b-D-glucuronic acid,
(4) 2-acetamido-2-deoxy-aD-glucose, and (5) aL-iduronic acid.
The composition of the invention comprises heparin covalently attached to a peptide. In the present invention, heparin is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているヒドロモルフォンを含んでなる。発明においては、ヒドロモルフォンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Hydromorphone Hydromorphone is a known drug used in the treatment of cough and pain. Its structure is as follows:

The composition of the invention comprises hydromorphone covalently attached to a peptide. In the invention, hydromorphone is covalently attached to the peptide via the hydroxyl group.

本発明においては、硫酸ヒドロキシクロロキンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Hydroxychloroquine sulfate Hydroxychloroquine sulfate is a known drug used in the treatment of malaria. Its structure is as follows:

In the present invention, hydroxychloroquine sulfate is covalently attached to the peptide via the hydroxyl group.

インジナビルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５４１１６８Ｂ号明細書（１９９８）、優先権米国特許出願第７８９５０８号明細書（１９９１）及び米国特許第５，４１３，９９９号明細書の主題である。本発明においては、インジナビルは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Indinavir Indinavir is a known drug used in the treatment of HIV infection. Its chemical name is 2,3,5-trideoxy-N-[(1S, 2R) -2,3-dihydro-2-hydroxy-1H-inden-1-yl] -5-[(2S) -2- [ [(1,1-dimethylethyl) amino] carbonyl] -4- (3-pyridinylmethyl) -1-piperazinyl] -2- (phenylmethyl) -D-erythro-pentonamide. Its structure is as follows:

Indinavir is described in European Patent No. 541168B (1998), priority US Patent Application No. 789508 (1991) and US Pat. 413,999. In the present invention, indinavir is covalently attached to the peptide via any of the hydroxyl groups.

本発明においては、イノシトール又はＤ−チロイノシトールは、ヒドロキシル基のいずれかを介してペプチドに付着されている。 Inositol and D-Tyroinositol Inositol and D-Tyroinositol are nutritional supplements. Both are commercially available. Its structure is as follows:

In the present invention, inositol or D-tyrosinositol is attached to the peptide via any of the hydroxyl groups.

イオジキサノールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，３４９，０８５号明細書の主題である。本発明においては、イオジキサノールは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Iodixanol Iodixanol is a known agent used as a contrast agent for medical imaging. Its chemical name is 5,5 ′-[(2-hydroxy-1,3-propanediyl) bis (acetylamino)] bis [N, N′-bis (2,3-dihydroxypropyl) -2,4,6. -Triiodo-1,3-benzenedicarboxamide]. Its structure is as follows:

Iodixanol is the subject of US Pat. No. 5,349,085, herein incorporated by reference, which describes how to make that drug. In the present invention, iodixanol is covalently attached to the peptide via any of the hydroxyl groups.

イオプロミドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３６４，９２１号明細書の主題である。本発明においては、イオプロミドは、ヒドロキシル基を介してペプチドに対し共有結合している。 Iopromide Iopromide is a known drug used as an X-ray contrast agent. Its chemical name is N, N′-bis (2,3-dihydroxypropyl) -2,4,6-triiodo-5-[(2-methoxyacetyl) amino] -N-methyl-1,3-benzenedicarboxamide. It is. Its structure is as follows:

Iopromide is the subject of US Pat. No. 4,364,921, incorporated herein by reference, which describes how to make that drug. In the present invention, iopromide is covalently attached to the peptide via the hydroxyl group.

Ioxagrate Ioxagrate is a known drug used as an X-ray contrast aid. This is usually used as a combination of oxagrate meglumine and oxagrate sodium. Both building blocks can be attached to the peptide carrier. In the present invention, oxagrate is covalently attached to the peptide via the hydroxyl group.

本発明においては、イプラトロピウムは、ヒドロキシル基を介してペプチドに対し共有結合している。 Ipratropium Ipratropium has been used as a bronchodilator for long-term symptomatic treatment of reversible bronchospasm with chronic obstructive pulmonary disease (COPD). Its structure is as follows:

In the present invention, ipratropium is covalently attached to the peptide via the hydroxyl group.

イリノテカンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６０４，４６３号明細書の主題である。本発明においては、イリノテカンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Irinotecan Irinotecan is a known drug used in the treatment of cancer. Its chemical name is [1,4′-bipiperidine] -1′-carboxylic acid (S) -4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H -Pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinolin-9-yl ester. Its structure is as follows:

Irinotecan is the subject of US Pat. No. 4,604,463, herein incorporated by reference, which describes how to make that drug. In the present invention, irinotecan is covalently attached to the peptide via the hydroxyl group.

ケトライド系抗生物質は、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９８／９９７８号パンフレット（１９９８）、優先権米国特許第７０７７７６号明細書（１９９６）の主題である。本発明においては、ケトライド系抗生物質は、ヒドロキシル基を介してペプチドに対し共有結合している。 Ketolide antibiotics The ketolide antibiotics of the present invention are known drugs used in the treatment of bacterial infections. Its chemical name is (3aS, 4R, 7R, 9R, 10R, 11R, 13R, 15R, 15aR) -4-ethyloctahydro-3a, 7,9,11,13,15-hexamethyl-11-[[3- (3-Quinolinyl) -2-propenyl] oxy] -10-[[3,4,6-trideoxy-3- (dimethylamino)-(β-D-xylo-hexopyranosyl] oxy] -2H-oxacyclotetradec [4,3-d] oxazole-2,6,8,14 (1H, 7H, 9H) -tetron, whose structure is as follows:

Ketolide antibiotics are the subject matter of WO 98/9978 (1998), priority US Pat. No. 7070776 (1996), incorporated herein by reference, which describes how to make the drug. is there. In the present invention, the ketolide antibiotic is covalently attached to the peptide via the hydroxyl group.

ラミブジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，０４７，４０７及び５，９０５，０８２号明細書の主題である。本発明においては、ラミブジンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Lamivudine Lamivudine is a known drug used in the treatment of hepatitis, viral infections and HIV infections. Its chemical name is (2R-cis) -4-amino-1- [2- (hydroxymethyl) -1,3-oxathiolan-5-yl] -2 (1H) -pyrimidinone. Its structure is as follows:

Lamivudine is the subject of US Pat. Nos. 5,047,407 and 5,905,082, incorporated herein by reference, which describe how to make that drug. In the present invention, lamivudine is covalently attached to the peptide via the hydroxyl group.

Lamivudine and zidovudine Lamivudine is a known drug used in the treatment of hepatitis, viral infections and HIV infections. Its chemical name is (2R-cis) -4-amino-1- [2- (hydroxymethyl) -1,3-oxathiolan-5-yl] -2 (1H) -pyrimidinone. Its structure is as follows:

２つの薬物は、ＨＩＶ感染症の治療のために、逆転写酵素阻害剤ラミブジン及びジドブジンを含有する固定投与量の組み合わせ錠剤として併用されている。ラミブジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，０４７，４０７及び５，９０５，０８２号明細書の主題である。ジドブジンは、欧州特許第１９６１８５Ｂ号明細書（１９８９）により網羅されている。この組み合わせは、本書に参考として内含されている、以下の米国特許第４，７２４，２３２、４，８１８，５３８、４，８２８，８３８、４，８３３，１３０、４，８３７，２０８及び６，１１３，９２０号明細書により網羅されている。本発明においては、ラミブジン及びジドブジンは、各々の上のヒドロキシル基を介してペプチドに対し共有結合している。 Zidovudine has the chemical name 3'-azido-3'-deoxythymidine. Its structure is as follows

The two drugs are used together as fixed dose combination tablets containing the reverse transcriptase inhibitors lamivudine and zidovudine for the treatment of HIV infection. Lamivudine is the subject of US Pat. Nos. 5,047,407 and 5,905,082, incorporated herein by reference, which describe how to make that drug. Zidovudine is covered by EP 196185B (1989). This combination is incorporated herein by reference as in US Pat. Nos. 4,724,232, 4,818,538, 4,828,838, 4,833,130, 4,837,208 and 6 below. , 113,920. In the present invention, lamivudine and zidovudine are covalently attached to the peptide via the hydroxyl group on each.

酢酸リュープロライドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５７１６６４０、５６４３６０７及び５６３１０２１号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合している酢酸リュープロライドを含んでなる。本発明においては、酢酸リュープロライドは、ヒドロキシル基を介してペプチドに対し共有結合している。 Leuprolide acetate Leuprolide acetate is a known drug used in the treatment of cancer and endometriosis. Its chemical name is 6-D-leucine-9- (N-ethyl-L-prolinamide) -10-deglycinamide luteinizing hormone releasing factor (pig). Its structure is as follows:

Leuprolide acetate is the subject of US Pat. Nos. 5,716,640, 5,643,607 and 5,631,021, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises leuprolide acetate covalently attached to a peptide. In the present invention, leuprolide acetate is covalently attached to the peptide via the hydroxyl group.

ロペラミドは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１３１９０４０号明細書（１９７３）、優先権米国特許第４２５３０号明細書（１９７０）、欧州特許第５２３８４７Ｂ号明細書（１９９６）、優先権米国特許第７１５９４９号明細書（１９９１）の主題である。本発明の組成物は、ペプチドに対し共有結合しているロペラミドを含んでなる。本発明においては、ロペラミドは、ヒドロキシル基を介してペプチドに対し共有結合している。 Loperamide Loperamide is a known drug used in the treatment of diarrhea and ocular pain. Its chemical name is 4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide. Its structure is as follows:

Loperamide describes how to make the drug, British Patent No. 13119040 (1973), priority US Pat. No. 42530 (1970), European Patent No. 523847B, incorporated herein by reference. (1996), priority US Pat. No. 7,159,949 (1991). The composition of the invention comprises loperamide covalently attached to a peptide. In the present invention, loperamide is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているロラゼパムを含んでなる。本発明においては、ロラゼパムは、ヒドロキシル基を介してペプチドに対し共有結合している。 Lorazepam Lorazepam is a known drug used in the treatment of bacterial infections. Its structure is as follows:

The composition of the invention comprises lorazepam covalently attached to a peptide. In the present invention, lorazepam is covalently attached to the peptide via the hydroxyl group.

ロサルタンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，１３８，０６９及び５，１５３，１９７号明細書の主題である。本発明においては、ロサルタンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Losartan Losartan is a known drug used in the treatment of hypertension. Its chemical name is 2-butyl-4-chloro-1-[[2 ′-(1H-tetrazol-5-yl) [1, l′-biphenyl] -4-yl] methyl] -1H-imidazole-5. -Methanol. Its structure is as follows:

Losartan is the subject of US Pat. Nos. 5,138,069 and 5,153,197, incorporated herein by reference, which describe how to make the drug. In the present invention, losartan is covalently attached to the peptide via the hydroxyl group.

ロバスタチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，２３１，９３８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているロバスタチンを含んでなる。本発明においては、ロバスタチンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Lovastatin Lovastatin is a known drug used in the treatment of hyperlipidemia and cancer. Its chemical name is (4R, 6R) -6- [2-[(1S, 2S, 6R, 8S, 8aR) -1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6 -(Dimethyl-1-naphthyl] ethyl] tetrahydro-4-hydroxy-2H-pyran-2-one (S) -2-methylbutyric acid 8-ester. Its structure is as follows:

Lovastatin is the subject of US Pat. No. 4,231,938, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises lovastatin covalently attached to a peptide. In the present invention, lovastatin is covalently attached to the peptide via the hydroxyl group.

マリマスタットは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９４／２４４７号パンフレット１９９４及び国際公開第９６／２５１５６号パンフレット１９９６の主題である。本発明の組成物は、ペプチドに対し共有結合しているマリマスタットを含んでなる。本発明においては、マリマスタットは、ヒドロキシル基を介してペプチドに対し共有結合している。 Marimastat Marimastat is a known drug used in the treatment of cancer. Its chemical name is (2S, 3R) -N4-[(1R) -2,2-dimethyl-1-[(methylamino) carbonyl] propyl] -N1,, 2-dihydroxy-3- (2-methylpropyl) ) Butanediamide. Its structure is as follows:

Marimastat is the subject of WO 94/2447 pamphlet 1994 and WO 96/25156 pamphlet 1996, which is incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises marimastat covalently attached to a peptide. In the present invention, marimastat is covalently attached to the peptide via the hydroxyl group.

Methyldihydromorphinone Methyldihydromorphinone is a known drug used in the treatment of pain. The composition of the invention comprises methyldihydromorphinone covalently attached to a peptide. In the present invention, methyldihydromorphinone is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているメチルプレドニゾンを含んでなる。本発明においては、メチルプレドニゾンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Methylprednisolone Methylprednisolone and its derivatives are mainly used as anti-inflammatory agents or immunosuppressants. Since methylprednisolone has minimal electrolyte corticoid properties, the drug alone is insufficient to manage adrenal cortex failure. When methylprednisolone is used to treat this condition, combination therapy with electrolyte corticoids is also required. The steroid drug methylprednisolone is a known drug that is also used in the treatment of spinal cord injury. Its chemical name is 11,17,21-trihydroxy-6-methyl-, (6α, 11β) -pregna-1,4-diene-3,20-dione. Its structure is as follows:

The composition of the invention comprises methylprednisone covalently attached to a peptide. In the present invention, methylprednisone is covalently attached to the peptide via any of the hydroxyl groups.

本発明の組成物は、ペプチドに対し共有結合しているメトロニダゾールを含んでなる。本発明においては、メトロニダゾールは、ヒドロキシル基を介してペプチドに対し共有結合している。 Metronidazole Metronidazole is used orally for the treatment of symptomatic and asymptomatic trichomoniasis. Its structure is as follows:

The composition of the invention comprises metronidazole covalently attached to a peptide. In the present invention, metronidazole is covalently attached to the peptide via the hydroxyl group.

ミノサイクリンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１００３４７４号明細書、優先権米国特許第１４７１３７号明細書１９６１の主題である。本発明の組成物は、ペプチドに対し共有結合しているミノサイクリンを含んでなる。本発明においては、ミノサイクリンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Minocycline Minocycline is a known drug used in the treatment of bacterial infections. Its chemical name is 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a tetrahydroxy-1,11-dioxo-2 -Naphthacene carboxamide. Its structure is as follows:

Minocycline is the subject of British Patent No. 1003474, priority US Pat. No. 1,147,137, 1961, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises minocycline covalently attached to a peptide. In the present invention, minocycline is covalently attached to the peptide via any of the hydroxyl groups.

ミソプロストールは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１４９２４２６号明細書１９７４、優先権米国特許第４５４９１３号明細書１９７４、米国特許第５２５２６０２号明細書１９９３、米国特許第４３０１１４６号明細書及び欧州特許第５２７８８７Ｂ号明細書１９９５、優先権米国特許第５１８３５３号明細書１９９０の主題である。本発明の組成物は、ペプチドに対し共有結合しているミソプロストールを含んでなる。本発明においては、ミソプロストールは、ヒドロキシル基を介してペプチドに対し共有結合している。 Misoprostol Misoprostol is a known drug used in digestive ulcers, allergy treatment and labor inducers. Its chemical name is (11α, 13E)-(+, −)-11,16-dihydroxy-16-methyl-9-oxoprost-13-en-1-acid methyl ester. Its structure is as follows:

Misoprostol describes British Patent No. 1492426 1974, priority US Pat. No. 4,549,913 1974, US Pat. No. 5,252,602, which is incorporated herein by reference, describing how to make the drug. US Pat. No. 4,301,146 and European Patent No. 5,278,87B 1995, priority US Pat. No. 5,138,353, 1990. The composition of the invention comprises misoprostol covalently attached to a peptide. In the present invention, misoprostol is covalently attached to the peptide via the hydroxyl group.

ミトキサントロンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，２７８，６８９及び４，８２０，７３８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているミトキサトロンを含んでなる。本発明においては、ミトキサトロンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Mitoxantrone Mitoxantrone is a known drug used in the treatment of cancer and multiple sclerosis. Its chemical name is 1,4-dihydroxy-5,8-bis [[2-[(2-hydroxyethyl) amino] ethyl] amino] -9,10-anthracenedione. Its structure is as follows:

Mitoxantrone is the subject of US Pat. Nos. 4,278,689 and 4,820,738, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises mitoxatron covalently attached to a peptide. In the present invention, mitoxatron is covalently attached to the peptide via any of the hydroxyl groups.

本発明の組成物は、ペプチドに対し共有結合しているモルヒネを含んでなる。本発明においては、モルヒネは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Morphine Morphine is a known drug used in the treatment of pain. Its structure is as follows:

The composition of the invention comprises morphine covalently attached to a peptide. In the present invention, morphine is covalently attached to the peptide via any of the hydroxyl groups.

マイコフェニレートモフェチルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２８１７１３Ｂ号明細書１９９１、優先権米国特許第８７１７号明細書１９８７の主題である。本発明の組成物は、ペプチドに対し共有結合しているマイコフェニレートモフェチルを含んでなる。本発明においては、マイコフェニレートモフェチルは、ヒドロキシル基を介してペプチドに対し共有結合している。 Mycophenylate mofetil Mycophenylate mofetil is a known drug used in the treatment of graft rejection, rheumatoid arthritis, asthma, restenosis, kidney disease, systemic lupus and erythematosus. Its chemical name is (4E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl) -4-methyl-4-hexanoic acid 2 -(4-Morpholinyl) ethyl ester. Its structure is as follows:

Mycophenylate mofetil is the subject of EP 281713B 1991, priority US 8717 1987, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises mycophenylate mofetil covalently attached to a peptide. In the present invention, mycophenylate mofetil is covalently attached to the peptide via the hydroxyl group.

Naltrexone Naltrexone is a known drug used in the treatment of pain. The composition of the invention comprises naltrexone covalently attached to a peptide. In the present invention, naltrexone is covalently attached to the peptide via the hydroxyl group.

メシル酸ネルフィナビルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，４８４，９２６及び５，９５２，３４３号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているメシル酸ネルフィナビルを含んでなる。発明においては、メシル酸ネルフィナビルは、ヒドロキシル基を介してペプチドに対し共有結合している。 Nelfinavir mesylate Nelfinavir mesylate is a known drug used in the treatment of HIV infection. Its chemical name is [3S- [2 (2S ^* , 3S ^* ), 3α, 4aβ, 8aβ]]-N- (1,1-dimethylethyl) decahydro-2- [2-hydroxy-3-[(3 -Hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] -3-isoquinolinecarboxamide. Its structure is as follows:

Nelfinavir mesylate is the subject of US Pat. Nos. 5,484,926 and 5,952,343, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises nelfinavir mesylate covalently attached to a peptide. In the invention, nelfinavir mesylate is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているノルエチンドロンを含んでなる。本発明においては、ノルエチンドロンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Norethindrone acetate Norethindrone acetate has been used to treat irregular uterine bleeding due to hormonal ataxia and secondary amenorrhea in patients without intrinsic organic lesions such as uterine fibroids or uterine cancer. The drug is similarly used in the treatment of endometriosis. Its structure is as follows:

The composition of the invention comprises norethindrone covalently attached to a peptide. In the present invention, norethindrone is covalently attached to the peptide via the hydroxyl group.

Orally active carbohydrates Orally active carbohydrates of the present invention are known drugs used in the treatment of digestive ulcers. This is a natural product isolated from human breast milk, as disclosed in US Pat. No. 5,514,660, incorporated herein by reference. The composition of the invention comprises an orally active carbohydrate covalently attached to a peptide. In the present invention, the orally active carbohydrate is covalently attached to the peptide via any of the hydroxyl groups.

本発明の組成物は、ペプチドに対し共有結合しているオキサゼパムを含んでなる。本発明においては、オキサゼパムは、ヒドロキシル基を介してペプチドに対し共有結合している。 Oxazepam Oxazepam is a known drug used in the treatment of anxiety. Its structure is as follows:

The composition of the invention comprises oxazepam covalently attached to a peptide. In the present invention, oxazepam is covalently attached to the peptide via the hydroxyl group.

塩化オキシブチニンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５１９，８０１；４，６１２，００８；４，７８３，３３７；５，０８２，６６８；５，６７４，８９５；５，８４０，７５４；及び５，９１２，２６８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合している塩化オキシブチニンを含んでなる。本発明においては、塩化オキシブチニンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Oxybutynin Chloride Oxybutynin chloride is used in patients with uninhibited neurogenic bladder or reflex nerve bladder for the purpose of reducing symptoms associated with urination such as urgency, urge incontinence, frequent urination, nocturia and incontinence. Used as an antispasmodic. Its structure is as follows:

Oxybutynin chloride describes how to make the drug, U.S. Pat. Nos. 4,519,801; 4,612,008; 4,783,337; 5,082,668; 674,895; 5,840,754; and 5,912,268. The composition of the invention comprises oxybutynin chloride covalently attached to a peptide. In the present invention, oxybutynin chloride is covalently attached to the peptide via the hydroxyl group.

Oxymorphone Oxymorphone is a known drug used in the treatment of pain. The composition of the invention comprises oxymorphone covalently attached to a peptide. In the present invention, oxymorphone is covalently attached to the peptide via the hydroxyl group.

パクリタキセルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５８４００１Ｂ号明細書１９９７（優先権米国特許第９２３６２８号明細書１９９２）、欧州特許第６４５１４５Ｂ号明細書１９９７（優先権米国特許第１２８０２６号明細書１９９３）及び欧州特許第７１７０４１Ａ号明細書１９９６（優先権米国特許第３５５１２５号明細書１９９４）の主題である。本発明の組成物は、ペプチドに対し共有結合しているパクリタキセルを含んでなる。本発明においては、パクリタキセルは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Paclitaxel Paclitaxel is a known drug used in the treatment of cancer. Its chemical name is [2aR [2aα, 4β, 4aβ, 6β, 9α (αR ^* , βS ^* ), 11β, 12α, 12aα, 12bα]]-β- (benzoylamino) -α-hydroxybenzenepropanoic acid 6, 12b-bis (acetyloxy) -12- (benzoyloxy) -2a, 3,4,4a, 5,6,9,10,11,12,12a, 12b-dodecahydro-4,11-dihydroxy-4a, 8 , 13,13-Tetramethyl-5-oxo-7,11-methano-1H-cyclodeca [3,4] benz [1,2-b] ox-9-yl ester. Its structure is as follows:

Paclitaxel describes how to make the drug, EP 584001B 1997 (priority US 923628 1992), EP 645145B 1997 (incorporated herein by reference). Priority US Pat. No. 128026 1993) and European Patent No. 717041A 1996 (Priority US Pat. No. 355125 1994). The composition of the invention comprises paclitaxel covalently attached to a peptide. In the present invention, paclitaxel is covalently attached to the peptide via any of the hydroxyl groups.

パリカルシトロールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，２４６，９２５及び５，５８７，４９７号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているパリカルシトロールを含んでなる。本発明においては、パリカルシトロールは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Paricalcitrol is a known drug used in the treatment of hyperparathyroidism. Its chemical name is (1α, 3β, 7E, 22E) -19-nor-9,10-secoergost-5,7,22-triene-1,3,25-triol. Its structure is as follows:

Paricalcitrol is the subject of US Pat. Nos. 5,246,925 and 5,587,497, herein incorporated by reference, which describe how to make that drug. The composition of the invention comprises paricalcitrol covalently attached to a peptide. In the present invention, paricalcitrol is covalently attached to the peptide via any of the hydroxyl groups.

Phytoceterol Phytoceterol is a plant-derived product that has the potential to treat and prevent hypercholesterolemia. The product comprises a mixture of four phytosterols and is believed to work by competing with dietary cholesterol for absorption in the intestine. The composition of the invention comprises phytoceterol covalently attached to a peptide. In the present invention, the active substance is covalently attached to the peptide via the hydroxyl group.

Poloxamer 188
Poloxamer 188 is a known drug used in the treatment of thrombosis, sickle cell anemia and respiratory distress syndrome. Its chemical name is methyloxirane, a block polymer with oxirane. Poloxamer 188 is the subject of US Pat. No. 5,523,492, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises poloxamer 188 covalently attached to a peptide. In the present invention, poloxamer 188 is covalently attached to the peptide via the hydroxyl group.

ポサコナゾールは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９５／１７４０７号パンフレット１９９５、優先権米国特許第１７１０８３号明細書１９９３の主題である。本発明の組成物は、ペプチドに対し共有結合しているポサコナゾールを含んでなる。本発明においては、ポサコナゾールは、ヒドロキシル基を介してペプチドに対し共有結合している。 Posaconazole Posaconazole is a known drug used in the treatment of mycosis. Its chemical name is 2,5-anhydro-1,3,4-trideoxy-2-C- (2,4-difluorophenyl) -4-[[4- [4- [4- [1-[(1S, 2S) -1-ethyl-2-hydroxypropyl] -1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl] phenyl] -1-piperazinyl] phenoxy] methyl] -1 -(1H-1,2,4-triazol-1-yl) -D-threo-pentitol. Its structure is as follows:

Posaconazole is the subject of WO 95/17407 1995, priority US Pat. No. 1,710,833, which is incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises posaconazole covalently attached to a peptide. In the present invention, posaconazole is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているプレドニゾンを含んでなる。本発明においては、プレドニゾンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Prednisone Prednisone is usually considered to be an oral glucocorticoid selected for anti-inflammatory or or immunosuppressive effects. Its structure is as follows:

The composition of the invention comprises prednisone covalently attached to a peptide. In the present invention, prednisone is covalently attached to the peptide via any of the hydroxyl groups.

プリノマスタットは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，７５３，６５３号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているプリノマスタットを含んでなる。本発明においては、プリノマスタットは、ヒドロキシル基を介してペプチドに対し共有結合している。 Prinomastert Prinomastert is a known drug used in the treatment of cancer and retinopathy. Its chemical name is (3S) -N-hydroxy-2,2-dimethyl-4-[[4- (4-pyridinyloxy) phenyl] sulfonyl] -3-thiomorpholinecarboxamide. Its structure is as follows:

Prinomastert is the subject of US Pat. No. 5,753,653, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises purinomastert covalently attached to a peptide. In the present invention, purinomastert is covalently attached to the peptide via the hydroxyl group.

Propofol Propofol is a known drug used as an anesthetic. Its chemical name is 2,6-diisopropylphenol. As part of the present invention, it is provided as a sustained release oral version with low toxicity and high patient compliance. The composition of the invention comprises propofol covalently attached to a peptide. In the invention, propofol is covalently attached to the peptide via the hydroxyl group.

フマル酸クエチアピンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２４０２２８Ｂ号明細書１９９０及び４８７９２８８の主題である。本発明の組成物は、ペプチドに対し共有結合しているフマル酸クエチアピンを含んでなる。本発明においては、フマル酸クエチアピンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Quetiapine fumarate Quetiapine fumarate is a known drug used in the treatment of schizophrenia. Its chemical name is 2- [2- (4-dibenzo [b, f] [1,4] thiazepin-11-yl-1-piperazinyl) ethoxy] ethanol. Its structure is as follows:

Quetiapine fumarate is the subject of EP 240228B 1990 and 4879288, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises quetiapine fumarate covalently attached to a peptide. In the present invention, quetiapine fumarate is covalently attached to the peptide via the hydroxyl group.

ラロキシフェンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，４１８，０６８；５，３９３，７６３；５，４５７，１１７；５，４６６，８１０；５，４７８，８４７；５，５１４，８２６；５，５６９，７７２；５，６２９，４２５；５，６４１，７９０；５，６５９，０８７；５，７１０，２８５；５，７３１，３２７；５，７３１，３４２；５，７４７，５１０；５，８０８，０６１；５，８１１，１２０；５，８４３，９８４；及び５，９７２，３８３号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているラロキシフェンを含んでなる。本発明においては、ラロキシフェンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Raloxifene Raloxifene is a known drug used in the treatment of osteoporosis and cancer. Its chemical name is [6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methanone. Its structure is as follows:

Raloxifene describes how to make the drug, US Pat. Nos. 4,418,068; 5,393,763; 5,457,117; 5,466,810; 5,466, incorporated herein by reference. , 847; 5,514,826; 5,569,772; 5,629,425; 5,641,790; 5,659,087; 5,710,285; 5,731,327; 5,731,342 5,747,510; 5,808,061; 5,811,120; 5,843,984; and 5,972,383. The composition of the invention comprises raloxifene covalently attached to a peptide. In the present invention, raloxifene is covalently attached to the peptide via any of the hydroxyl groups.

ラノラジンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１２６４４９Ｂ号明細書１９８７、優先権米国特許第４９５９０４号明細書１９８３の主題である。本発明の組成物は、ペプチドに対し共有結合しているラノラジンを含んでなる。本発明においては、ラノラジンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Ranolazine Ranolazine is a known drug used in the treatment of angina and peripheral vascular disease. Its chemical name is (+,-)-N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- (2-methoxyphenoxy) propyl] -1-piperazineacetamide. Its structure is as follows:

Ranolazine is the subject of European Patent No. 126449B 1987, priority US Pat. No. 495904, 1983, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises ranolazine covalently attached to a peptide. In the present invention, ranolazine is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているリバビリンを含んでなる。本発明においては、リバビリンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Ribavirin Ribavirin is used via the nasal cavity and oral cavity for the treatment of severe lower respiratory tract infections (eg bronchiolitis, pneumonia) caused by respiratory syncytial virus (RSV) in hospitalized infants and children. Its structure is as follows:

The composition of the invention comprises ribavirin covalently attached to a peptide. In the present invention, ribavirin is covalently attached to the peptide via any of the hydroxyl groups.

リトナビルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，４８４，８０１；５，５４１，２０６；５，６３５，５２３；５，６４８，４９７；５，６７４，８８２；５，８４６，９８７；５，８８６，０３６；及び６，０３７，１５７号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているリトナビルを含んでなる。本発明においては、リトナビルは、ヒドロキシル基を介してペプチドに対し共有結合している。 Ritonavir Ritonavir is a known drug used in the treatment of HIV infection. Its chemical name is [5S- (5R ^* , 8R ^* , 10R ^* , 11R ^* )]-10-hydroxy-2-methyl-5- (1-methylethyl) -1- [2- (1-methylethyl) -4-thiazolyl] -3,6-dioxo-8,11-bis (phenylmethyl) -2,4,7.12-tetraazatridecan-13-acid, 5-thiazolylmethyl ester. Its structure is as follows:

Ritonavir describes how to make the drug, US Pat. Nos. 5,484,801; 5,541,206; 5,635,523; 5,648,497; 5,674, incorporated herein by reference. 882; 5,846,987; 5,886,036; and 6,037,157. The composition of the invention comprises ritonavir covalently attached to a peptide. In the present invention, ritonavir is covalently attached to the peptide via the hydroxyl group.

ロクロニウムは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８９４，３６９号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているロクロニウムを含んでなる。本発明においては、ロクロニウムは、ヒドロキシル基を介してペプチドに対し共有結合している。 Rocuronium Rocuronium is a known drug used as a muscle relaxant and neuromuscular blocking agent. Its chemical name is 1-[(2β, 3α, 5α, 16β, 17β) -17- (acetyloxy) -3-hydroxy-2- (4-morpholinyl) androstan-16-yl] -1- (2- Propenyl) pyrrolidinium bromide. Its structure is as follows:

Rocuronium is the subject of US Pat. No. 4,894,369, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises rocuronium covalently attached to a peptide. In the present invention, rocuronium is covalently attached to the peptide via the hydroxyl group.

ルビテカンは、該薬物の作り方を記載する、本書中に参考として内含された日本国特許出願第９１／１２０６９号明細書１９９１、米国特許第５，９２２，８７７号明細書１９９９及び国際公開第９９／３０６８４号パンフレット１９９９（優先権米国特許第９８９２８１号明細書１９９７）の主題である。本発明の組成物は、ペプチドに対し共有結合しているルビテカンを含んでなる。本発明においては、ルビテカンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Rubitecan rubitecan is a known drug used in the treatment of cancer. Its chemical name is (4S) -4-ethyl-4-hydroxy-10-nitro-1H-pyrano [3 ′, 4 ′: 6,7] indolizino [1,2-b] quinoline-3,14 (4H, 12H) -dione. Its structure is as follows:

Rubitecan describes how to make the drug, Japanese Patent Application No. 91/12069 1991, US Pat. No. 5,922,877 Specification 1999 and International Publication No. 99, which are incorporated herein by reference. / 30684 pamphlet 1999 (priority US Pat. No. 9,898,281, 1997). The composition of the invention comprises rubitecan covalently attached to a peptide. In the present invention, rubitecan is covalently attached to the peptide via the hydroxyl group.

サキナビルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，１９６，４３８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているサキナビルを含んでなる。本発明においては、サキナビルは、ヒドロキシル基を介してペプチドに対し共有結合している。 Saquinavir Saquinavir is a known drug used in the treatment of HIV infection. Its chemical name is [3S- [2 [1R ^* (R ^* ), 2S ^* ], 3α, 4aβ, 8aβ]]-N1- [3- [3-[[(1,1-dimethylethyl) amino] Carbonyl] octahydro-2 (1H) -isoquinolinyl] -2-hydroxy-1- (phenylmethyl) propyl] -2-[(2-quinolinylcarbonyl) amino] butanediamide. Its structure is as follows:

Saquinavir is the subject of US Pat. No. 5,196,438, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises saquinavir covalently attached to a peptide. In the present invention, saquinavir is covalently attached to the peptide via the hydroxyl group.

シンバスタチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，４４４，７８４号明細書、再発行米国特許第Ｒｅ．３６４８１号明細書及び再発行米国特許第Ｒｅ３６５２０号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているシンバスタチンを含んでなる。本発明においては、シンバスタチンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Simvastatin Simvastatin is a known drug used in the treatment of hyperlipidemia and osteoporosis. Its chemical name is 2,2-dimethylbutanoic acid [1S- [1α, 3α, 7β, 8β (2S ^* , 4S ^* ) 8aβ]]-1,2,3,7,8,8a-hexahydro-3,7 -Dimethyl-8- [2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl] -1-naphthalenyl ester. Its structure is as follows:

Simvastatin is described in US Pat. No. 4,444,784, which is incorporated herein by reference, reissued US Pat. No. Re. 36481 and reissued US Pat. No. Re36520. The composition of the invention comprises simvastatin covalently attached to a peptide. In the present invention, simvastatin is covalently attached to the peptide via the hydroxyl group.

ソタロールは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第９９３５８４号明細書１９６５、優先権米国特許第１６８４９８号明細書１９６２及び欧州特許第１２７４３５Ｂ号明細書１９９１、優先権米国特許第４９７３６８号明細書１９８３の主題である。本発明の組成物は、ペプチドに対し共有結合しているソタロールを含んでなる。本発明においては、ソタロールは、ヒドロキシル基を介してペプチドに対し共有結合している。 Sotalol Sotalol is a known drug used in the treatment of arrhythmias. Its chemical name is N- [4- [1-hydroxy-2-[(1-methylethyl) amino] ethyl] phenyl] methanesulfonamide. Its structure is as follows:

Sotalol is described in British Patent No. 993584, 1965, priority US Pat. No. 168498, 1962 and European Patent No. 127435B, 1991, which is incorporated herein by reference. This is the subject of U.S. Pat. No. 4,977,368. The composition of the invention comprises sotalol covalently attached to a peptide. In the present invention, sotalol is covalently attached to the peptide via the hydroxyl group.

スタブジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９７８，６５５号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているスタブジンを含んでなる。本発明においては、スタブジンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Stavudine Stavudine is a known drug used in the treatment of HIV infection. Its chemical name is 2 ', 3'-didehydro-3'-deoxythymidine. Its structure is as follows:

Stavudine is the subject of US Pat. No. 4,978,655, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises stavudine covalently attached to a peptide. In the present invention, stavudine is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているテマゼパムを含んでなる。本発明においては、テマゼパムは、ヒドロキシル基を介してペプチドに対し共有結合している。 Temazepam Temazepam is a known drug used in the treatment of insomnia. Its structure is as follows:

The composition of the invention comprises temazepam covalently attached to a peptide. In the present invention, temazepam is covalently attached to the peptide via the hydroxyl group.

テポキサリンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２４８５９４Ｂ号明細書１９８７、優先権米国特許第８６７９９６号明細書１９８６の主題である。本発明の組成物は、ペプチドに対し共有結合しているテポキサリンを含んでなる。発明においては、テポキサリンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Tepoxaline Tepoxaline is a known drug used in the treatment of asthma, inflammation and inflammatory bowel disease. Its chemical name is 5- (4-chlorophenyl) -N-hydroxyl-1- (4-methoxyphenyl) -N-methyl-1H-pyrazol-3-propanamide. Its structure is as follows:

Tepoxaline is the subject of EP 248594B 1987, priority US 867996 1986, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises tepoxaline covalently attached to a peptide. In the invention, tepoxaline is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合している硫酸テルブタリンを含んでなる。本発明においては、硫酸テルブタリンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Terbutaline sulfate Terbutaline sulfate is a known drug used in the treatment of asthma and bronchitis. Its structure is as follows:

The composition of the invention comprises terbutaline sulfate covalently attached to a peptide. In the present invention, terbutaline sulfate is covalently attached to the peptide via any of the hydroxyl groups.

本発明の組成物は、ペプチドに対し共有結合しているテトラサイクリンを含んでなる。本発明においては、テトラサイクリンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Tetracycline Tetracycline is a known drug used in the treatment of bacterial infections. Its structure is as follows:

The composition of the invention comprises tetracycline covalently attached to a peptide. In the present invention, tetracycline is covalently attached to the peptide via any of the hydroxyl groups.

トルテロジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，３８２，６００及び５，５５９，２６９号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているトルテロジンを含んでなる。本発明においては、トルテロジンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Tolterodine Tolterodine is a known drug used in the treatment of urinary incontinence. Its chemical name is (R) -2- [3- [bis (1-methylethyl) amino] -1-phenylpropyl] -4-methyl-phenol. Its structure is as follows:

Tolterodine is the subject of US Pat. Nos. 5,382,600 and 5,559,269, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises tolterodine covalently attached to a peptide. In the present invention, tolterodine is covalently attached to the peptide via the hydroxyl group.

トポテカンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第３２１１２２Ａ号明細書１９８９、優先権米国特許第１２７１４８号明細書１９８７の主題である。本発明の組成物は、ペプチドに対し共有結合しているトポテカンを含んでなる。本発明においては、トポテカンは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Topotecan Topotecan is a known drug used in the treatment of cancer. Its chemical name is (S) -10-[(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1H-pyrano [3 ′, 4 ′: 6,7] indolidino [1,2-b]. Quinoline-3,14 (4H, 12H) -dione. Its structure is as follows:

Topotecan is the subject of European Patent No. 321122A 1989, priority US Pat. No. 127,148, 1987, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises topotecan covalently attached to a peptide. In the present invention, topotecan is covalently attached to the peptide via any of the hydroxyl groups.

本発明の組成物は、ペプチドに対し共有結合しているトラマドールを含んでなる。本発明においては、トラマドールは、ヒドロキシル基を介してペプチドに対し共有結合している。 Tramadol Tramadol is a known drug used in the treatment of pain. Its structure is as follows:

The composition of the invention comprises tramadol covalently attached to a peptide. In the present invention, tramadol is covalently attached to the peptide via the hydroxyl group.

トログリタゾンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１３９４２１Ｂ号明細書１９８８の主題である。本発明の組成物は、ペプチドに対し共有結合しているトログリタゾンを含んでなる。本発明においては、トログリタゾンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Troglitazone Trotrotazone is a known drug used in the treatment of diabetes. Its chemical name is 5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl]- 2,4-thiazolidinedione. Its structure is as follows:

Troglitazone is the subject of EP 139421B 1988, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises troglitazone covalently attached to a peptide. In the present invention, troglitazone is covalently attached to the peptide via the hydroxyl group.

ベンラファキシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５３５，１８６号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているベンラファキシンを含んでなる。本発明においては、ベンラファキシンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Venlafaxine Venlafaxine is a known drug used in the treatment of anxiety and depression. Its chemical name is (+,-)-1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol. Its structure is as follows:

Venlafaxine is the subject of US Pat. No. 4,535,186, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises venlafaxine covalently attached to a peptide. In the present invention, venlafaxine is covalently attached to the peptide via the hydroxyl group.

酒石酸ビノレルビンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３０７，１００号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合している酒石酸ビノレルビンを含んでなる。本発明においては、酒石酸ビノレルビンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Vinorelbine tartrate Vinorelbine tartrate is a known drug used in the treatment of cancer. Its chemical name is 3 ', 4'-didehydro-4'-deoxy-C'-norvin caleucoblastin. Its structure is as follows:

Vinorelbine tartrate is the subject of US Pat. No. 4,307,100, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises vinorelbine tartrate covalently attached to a peptide. In the present invention, vinorelbine tartrate is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているビタミンＣを含んでなる。本発明においては、ビタミンＣは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Vitamin C
Vitamin C is a known drug used in the treatment of vitamin C deficiency. Its structure is as follows:

The composition of the invention comprises vitamin C covalently attached to a peptide. In the present invention, vitamin C is covalently attached to the peptide via any of the hydroxyl groups.

ボリコナゾールは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許４４０３７２Ｂ第号明細書１９９３の主題である。本発明の組成物は、ペプチドに対し共有結合しているボリコナゾールを含んでなる。本発明においては、ボリコナゾールは、ヒドロキシル基を介してペプチドに対し共有結合している。 Voriconazole Voriconazole is a known drug used in the treatment of mycosis. Its chemical name is α- (2,4-difluorophenyl) -5-fluoro-β-methyl-α- (1H-1,2,4-triazol-1-ylmethyl) -4-pyrimidineethanol [R- (R ^* , S ^* )]. Its structure is as follows:

Voriconazole is the subject of EP 440372B No. 1993, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises voriconazole covalently attached to a peptide. In the present invention, voriconazole is covalently attached to the peptide via the hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているワルファリンを含んでなる。本発明においては、ワルファリンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Warfarin Warfarin is a known drug used in the treatment of thrombosis and myocardial infarction. Its structure is as follows:

The composition of the invention comprises warfarin covalently attached to a peptide. In the present invention, warfarin is covalently attached to the peptide via the hydroxyl group.

ジドブジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，７２４，２３２；４，８１８，５３８；４，８２８，８３８；及び４８３３１３０号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているジドブジンを含んでなる。本発明においては、ジドブジンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Zidovudine Zidovudine is a known drug used in the treatment of HIV infection. Its chemical name is 3'-azido-3'-deoxythymidine. Its structure is as follows:

Zidovudine is the subject of US Pat. Nos. 4,724,232; 4,818,538; 4,828,838; and 4833130, incorporated herein by reference, which describe how to make the drug. . The composition of the invention comprises zidovudine covalently attached to a peptide. In the present invention, zidovudine is covalently attached to the peptide via the hydroxyl group.

XII. D—Active substances that fall into this category via multiple attachment sites are either active substances or combinations of active substances that have multiple attachment sites. Preferred attachment sites for active agents (such as acetaminophen and hydrocodone) that are part of a combination drug product can be found in the form listed in the active agent's own category (hydroxyl, amine, etc.).

アルプロスタジルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，７４１，５２３号明細書の主題である。本発明においては、アルプロスタジルは、カルボン酸基又は、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Alprostadil Alprostadil is a known drug used in the treatment of erectile dysfunction in men. Its chemical name is (11α, 13E, 15S) -11,15-dihydroxy-9-oxoprost-13-en-1-acid. Its structure is as follows:

Alprostadil is the subject of US Pat. No. 5,741,523, incorporated herein by reference, which describes how to make the drug. In the present invention, alprostadil is covalently attached to the peptide via either a carboxylic acid group or a hydroxyl group.

ＡＣＥ／中性エンドペプチダーゼ阻害剤は、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第５９９４４４Ｂ号明細書（１９９８）、優先権米国特許出願第８８４６６４号明細書（１９９２）の主題である。本発明においては、ＡＣＥ／中性エンドペプチダーゼ阻害剤は、カルボン酸又はチオール基を介してペプチドに対し共有結合している。 ACE / neutral endopeptidase inhibitors ACE / neutral endopeptidase inhibitors are known drugs used in the treatment of hypertension and heart failure. Its chemical name is [S- (R ^* , R ^* ]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl) amino] -2,2-dimethyl-7-oxo-1H- Azepine, whose structure is as follows:

ACE / neutral endopeptidase inhibitors are described in European Patent No. 594444B (1998), priority US Patent Application No. 844664 (1992), incorporated herein by reference, which describes how to make the drug. ). In the present invention, the ACE / neutral endopeptidase inhibitor is covalently attached to the peptide via the carboxylic acid or thiol group.

硫酸アバカビルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，０３４，３９４及び５，０８９，５００号明細書の主題である。本発明においては、硫酸アバカビルは、そのアルコール基又は代替的にはそのアミノ基を介してペプチドに対し共有結合している。 Abacavir sulfate Abacavir sulfate is a known drug-carbocycle 2'-deoxyguanosine nucleoside analog that is a reverse transcription transcriptase inhibitor used in the treatment of HIV. Its chemical name is (1S, 4R) -4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol. Its structure is as follows:

Abacavir sulfate is the subject of US Pat. Nos. 5,034,394 and 5,089,500, incorporated herein by reference, which describe how to make the drug. In the present invention, abacavir sulfate is covalently attached to the peptide via its alcohol group or alternatively its amino group.

Acetaminophen and hydrocodone Acetaminophen and hydrocodone are known drugs used in the treatment of pain. The chemical name for acetaminophen is N-acetyl-p-aminophenol. The structure of hydrocodone is shown in FIG. The composition of the invention comprises acetaminophen and hydrocodone covalently attached to a peptide.

AGI1067
The composite vasoprotective agent of the present invention is a known agent used in the treatment of atherosclerosis and restenosis. Compound AGI1067 is a complex vasoprotective agent and blocks the production of inflammatory genes VCAM-1 and MCP-1 that are involved in the pathogenesis and progression of disease states. The composition of the invention comprises a composite vascular protective agent covalently attached to a peptide.

本発明においては、アルブテロールは、ヒドロキシル基の一つを介してペプチドに対し共有結合している。代替的には、アルブテロールは、アミノ基を介してペプチドに対し電子対共有により付着していても良い。 Albuterol Albuterol is a known drug used for symptomatic management of bronchospasm in patients with reversible, obstructive airway disease. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, albuterol is covalently attached to the peptide via one of the hydroxyl groups. Alternatively, albuterol may be attached by electron pair sharing to the peptide via the amino group.

ベシル酸アムロジピンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５７２，９０９及び４，８７９，３０３号明細書の主題である。本発明においては、ベナゼプリルは、分散型薬物ペプチド共役体の一例を提供するべく、カルボン酸基又はアミノ基或いはその両方を介してペプチドに対し共有結合している。ベシル酸アムロジピンは、分散型薬物ペプチド共役体のさらなる例を提供するべく、アミノ基を介してぺプチドに対して付着されている。 Amlodipine besylate and benazepril Amlodipine besylate is a known drug used for the treatment and prevention of myocardial infarction and stroke. Its chemical name is 2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid, 3-ethyl-5-methyl. Ester monobenzene sulfonate. Its structure is as follows:

Amlodipine besylate is the subject of US Pat. Nos. 4,572,909 and 4,879,303, incorporated herein by reference, which describe how to make the drug. In the present invention, benazepril is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate. Amlodipine besylate is attached to the peptide via the amino group to provide a further example of a dispersed drug peptide conjugate.

本発明においては、アモキシシリンは、分散型薬物ペプチド共役体のさらなる例を提供するべくカルボン酸基又はアミノ基或いはその両方を介してペプチドに対し共有結合している。 Amoxicillin Amoxicillin is a known drug used in the treatment of bacterial infections. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, amoxicillin is covalently attached to the peptide via a carboxylic acid group and / or amino group to provide further examples of dispersed drug peptide conjugates.

クラリスロマイシンの構造は以下の通りである：

本発明においては、アモキシシリン及びクラリスロマイシンは、ヒドロキシル及び／又は、アミノ基を介してペプチドに対し共有結合している。 Amoxicillin and clarithromycin Amoxicillin and clarithromycin are used in combination to treat duodenal ulcers. The structure of amoxicillin is as follows:

The structure of clarithromycin is as follows:

In the present invention, amoxicillin and clarithromycin are covalently attached to the peptide via the hydroxyl and / or amino group.

クラブラネートの構造は次の通りである：（Ｚ）−（２Ｒ，５Ｒ）−３−（２−ヒドロキシエチリデン）−７−オキソ−４−オキサ−１−アザビシクロ［３．２．０］−ヘプタン−２−カルボキシレート。本発明においては、アモキシシリン及びクラブラネートは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Amoxicillin and clavulanate Amoxicillin and clavulanate are known drugs used to treat bacterial infections. Each is commercially available and can be manufactured by one skilled in the art. The structure of amoxicillin is as follows:

The structure of clavulanate is as follows: (Z)-(2R, 5R) -3- (2-hydroxyethylidene) -7-oxo-4-oxa-1-azabicyclo [3.2.0]- Heptane-2-carboxylate. In the present invention, amoxicillin and clavulanate are covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

Arginine Arginine is a known drug used as a nutritional supplement and nitrogen source. The composition of the invention comprises arginine covalently attached to a peptide. In the present invention, arginine is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明においては、アテノロールは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的には、アテノロールは、アミノ基を介してペプチドに対し電子対共有により付着していても良い。 Atenolol Atenolol is a known drug used in the treatment of chronic obstructive pulmonary disease (COPD) or hypertension with type 1 diabetes or chronic stable angina. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, atenolol is covalently attached to the peptide via the hydroxyl group. Alternatively, atenolol may be attached to the peptide via an amino group by electron pair sharing.

本発明においては、バクロフェンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Baclofen Baclofen is a known drug used in the treatment of spasticity. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, baclofen is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

ベナゼプリルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，４１０，５２０号明細書の主題である。本発明においては、ベナゼプリルは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Benazepril Benazepril is produced from [S- (R ^* , R ^* )]-3-[[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -2,3,4,5-tetrahydro-2-oxo-1H. It has the chemical name -1-benazepine-1-acetic acid. This is commercially available or can be produced by one skilled in the art. Its structure is as follows:

Benazepril is the subject of US Pat. No. 4,410,520, herein incorporated by reference, which describes how to make that drug. In the present invention, benazepril is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明の組成物は、ペプチドに対し共有結合しているブレオマイシンを含んでなる。本発明においては、ブレオマイシンは、アミノ基又は、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Bleomycin Bleomycin is a known drug used in the treatment of cancer. Its structure is as follows:

The composition of the invention comprises bleomycin covalently attached to a peptide. In the present invention, bleomycin is covalently attached to the peptide via either an amino group or a hydroxyl group.

本発明においては、ブロモクリプチンは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的にはそれは、リンカーを介してペプチドに対し共有結合している。このリンカーは、２〜６個の炭素原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸）を含む小さい分子であるか、又はアミノ酸又は炭水化物のいずれか短い鎖から成っていても良い。 Bromocriptine Bromocriptine is a known drug used in the treatment of dysfunction and infertility; dysfunction associated with hyperprolactinemia, including amenorrhea, with or without milk leakage. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, bromocriptine is covalently attached to the peptide via the hydroxyl group. Alternatively, it is covalently attached to the peptide via a linker. This linker may be a small molecule containing 2-6 carbon atoms and one or more functional groups (amine, amide, alcohol or acid), or may consist of either a short chain of amino acids or carbohydrates. .

カルバペネム系抗生物質は、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９３／１５０７８号パンフレット１９９３の主題である。本発明の組成物は、ペプチドに対し共有結合しているカルバペネム系抗生物質を含んでなる。本発明においては、カルバペネム系抗生物質は、カルボン酸叉はアルコール基を介してペプチドに対し共有結合している。 Carbapenem antibiotics Carbapenem antibiotics of the present invention are known drugs used in the treatment of bacterial infections. Its chemical name is [4R- [3 (3S ^* , 5S ^* ), 4α, 5β, 6β (R ^* )]]-3-[[5-[[(3-carboxyphenyl) amino] carbonyl] -3- Pyrodinyl] thio] -6- (1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid. Its structure is as follows:

Carbapenem antibiotics are the subject of WO 93/15078, 1993, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises a carbapenem antibiotic covalently attached to a peptide. In the present invention, the carbapenem antibiotic is covalently attached to the peptide via a carboxylic acid or alcohol group.

カルビドパの構造は以下の通りである：

本発明においては、カルビドパ及びレボドパは各々、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Carbidopa and levodopa Carbidopa and levodopa are known drugs that have been used in combination to treat Parkinson's disease. Each is commercially available and can also be readily produced by those skilled in the art using published synthetic schemes. The structure of levadopa is as follows:

The structure of carbidopa is as follows:

In the present invention, carbidopa and levodopa are each covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

カルベジロールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５０３，０６７；５，７６０，０６９；及び５，９０２，８２１号明細書の主題である。本発明においては、カルベジロールは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的に、カルベジロールは、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Carvedilol Carvedilol is a known drug used in the treatment of heart failure. Its chemical name is 1- (9H-carbazol-4-yloxy) -3-[[2- (2-methoxyphenoxy) ethyl] amino] -2-propanol. Its structure is as follows:

Carvedilol is the subject of US Pat. Nos. 4,503,067; 5,760,069; and 5,902,821, incorporated herein by reference, which describe how to make the drug. In the present invention, carvedilol is covalently attached to the peptide via the hydroxyl group. Alternatively, carvedilol may be attached by electron pair sharing to the peptide via the amino group.

カスポファンギンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許出願第３２８４７号明細書（１９９３）に基づく国際公開第９４／２１６７７号パンフレット（１９９４）の主題である。本発明においては、カスポファンギンは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的には、カスポファンギンは、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Caspofungin Caspofungin is a known drug used in the treatment of bacterial and fungal infections. Its chemical name is 1-[(4R, 5S) -5-[(2-aminoethyl) amino] -N-2- (10,12-dimethyl-1-oxotetradecyl) -4-hydroxyl-L- Ornithine] -5-[(3R) -3-hydroxy-L-ornithine] pneumocandin B0. Its structure is as follows:

Caspofungin is the subject of WO 94/21677 (1994), based on US Patent Application No. 32847 (1993), incorporated herein by reference, which describes how to make that drug. In the present invention, caspofungin is covalently attached to the peptide via the hydroxyl group. Alternatively, caspofungin may be attached by electron pair sharing to the peptide via the amino group.

カプトプリルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，２３８，９２４号明細書の主題である。本発明においては、カプトプリルは、カルボン酸又はチオール基を介してペプチドに対し共有結合している。 Captopril Captopril is a known drug used in the treatment of hypertension. Its chemical name is 1- (3-mercapto-2-methyl-1-oxopropyl) -L-proline. Its structure is as follows:

Captopril is the subject of US Pat. No. 5,238,924, herein incorporated by reference, which describes how to make that drug. In the present invention, captopril is covalently attached to the peptide via the carboxylic acid or thiol group.

CEB925
This lipid lowering agent is a known drug used in the treatment of hyperlipidemia. It is called CEB925 and is a cholesterol ester hydrolase inhibitor manufactured by American Home Products. The composition of the invention comprises a lipid lowering agent covalently attached to a peptide.

本発明においては、セファクロールは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Cefaclor Cefaclor is a known drug used in the treatment of bronchitis. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, cefaclor is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明においては、セファドロキシルは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Cefadroxyl Cefadroxyl is a known drug used in the treatment of bacterial infections. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, cefadroxyl is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明においては、セファレキシンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Cephalexin Cephalexin is a known drug used in the treatment of bacterial infections. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, cephalexin is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

セリバスタチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，１７７，０８０号明細書の主題である。本発明においては、セリバスタチンは、カルボン酸基又はヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Cerivastatin Cerivastatin is a known drug used in the treatment of cholesterolemia. Its chemical name is [S- [R ^* , S ^* -(E)]]-7- [4- (4-fluorophenyl) -5- (methoxymethyl) -2,6-bis (1-methylethyl) -3-pyridinyl] -3,5-dihydroxy-6-heptanoic acid. Its structure is as follows:

Cerivastatin is the subject of US Pat. No. 5,177,080, incorporated herein by reference, which describes how to make that drug. In the present invention, cerivastatin is covalently attached to the peptide via either a carboxylic acid group or a hydroxyl group.

Chlorophenylamine and hydrocodone Chlorophenylamine and hydrocodone are known drugs used in the treatment of pain. The composition of the invention comprises chlorophenylamine and hydrocodone covalently attached to a peptide.

Chondroitin Chondroitin is a nutritional supplement or nutritional supplement used to treat osteoarthritis. Chondroitin is commercially available. In the present invention, chondroitin is covalently attached to the peptide via the alcohol or amino group or both to provide an example of a dispersed drug peptide conjugate.

本発明においては、イミペネムは、カルボン酸を介してペプチドに対し共有結合している。シラスタチンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Cirastatin and imipenem Cilastatin and imipenem are known drugs that are used in combination in the treatment of bacterial infections. Cilastatin has no antibacterial activity, but enhances the efficacy of imipenem. Each is commercially available and easily manufactured by those skilled in the art using published synthetic schemes. The structure of imipenem is as follows:

In the present invention, imipenem is covalently attached to the peptide via the carboxylic acid. Cilastatin is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

シプロフロキサシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６７０，４４４及び５，２８６，７５４号明細書の主題である。本発明においては、シプロフロキサシンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Ciprofloxacin Ciprofloxacin is a known drug used in the treatment of bacterial infections. Its chemical name is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid. Its structure is as follows:

Ciprofloxacin is the subject of US Pat. Nos. 4,670,444 and 5,286,754, incorporated herein by reference, which describe how to make that drug. In the present invention, ciprofloxacin is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

Codeine and guaifenesin Codeine and guaifenesin are known drugs used in the treatment of cough. The composition of the invention comprises codeine and guaifenesin covalently attached to the peptide via the hydroxyl group of any active agent.

Codeine and promethazine Codeine and promethazine are known drugs used to treat cough. The composition of the invention comprises codeine and promethazine covalently attached to the peptide via the functional group specified in each category of active substance.

Codeine, guaifenesin and pseudoephedrine Codeine, guaifenesin and pseudoephedrine are used to treat cough and cold. The composition of the invention comprises codeine, guaifenesin and pseudoephedrine covalently attached to the peptide peptide via functional groups identified in each category of active agent.

Codeine, phenylephrine and promethazine Codeine, phenylephrine and promethazine are known drugs used in the treatment of cough and cold. The composition of the invention comprises codeine, phenylephrine and promethazine covalently attached to the peptide via the functional group specified in each category of active agent.

Dalteparin Dalteparin (also known as heparin) is used in the prevention and treatment of ischemic complications due to clot formation in patients with unstable angina and non-Q-wave myocardial infarction receiving daily aspirin therapy Known drug. This is a natural product that is not only commercially available, but also easily produced by those skilled in the art using published synthetic schemes. Dalteparin is the subject of EP 14184B (1989), incorporated herein by reference, which describes how to make the drug. In the present invention, dalteparin is covalently attached to the peptide via any free hydroxyl, amino or carboxy group or alternatively via a synthetic linker.

本発明においては、ジクロフェナクは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Diclofenac Diclofenac is a known drug used in the treatment of acute and chronic rheumatoid arthritis. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its chemical name is potassium acetate (o- (2,6-dichloroanilino) -phenyl). Its structure is as follows:

In the present invention, diclofenac is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明においては、ジクロフェナクは、酸又はアミノ基或いはその両方を介してペプチドに対し共有結合している。 Diclofenac Diclofenac is a known drug used in the treatment of pain and inflammation. Diclofenac is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its chemical name is potassium acetate (o- (2,6-dichloroanilino) -phenyl). Its structure is as follows:

In the present invention, diclofenac is covalently attached to the peptide via the acid or amino group or both.

本発明においては、ドーパミンは、アミノ基又はヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Dopamine Dopamine is a known drug used to increase cardiac output, blood pressure, and urine flow as an adjunct for the treatment of shock symptoms that persist after proper fluid replacement. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, dopamine is covalently attached to the peptide via either the amino group or the hydroxyl group.

ドキソルビシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８３７，０２８号明細書の主題である。本発明においては、ドキソルビシンは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的には、ドキソルビシンは、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Doxorubicin Doxorubicin is a known drug used in the treatment of bacterial infections. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

Doxorubicin is the subject of US Pat. No. 4,837,028, herein incorporated by reference, which describes how to make that drug. In the present invention, doxorubicin is covalently attached to the peptide via the hydroxyl group. Alternatively, doxorubicin may be attached to the peptide via an amino group by electron pair sharing.

エナラプリルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１２４０１号明細書（１９８４）、優先権米国特許出願公開第９６８２４９号明細書（１９７８）の主題である。本発明においては、エナラプリルは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Enalapril Enalapril is a known drug used in the treatment of hypertension. Its chemical name is (S) -1- [N- [1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl] -L-proline. Its structure is as follows:

Enalapril is the subject of EP 12401 (1984), priority US 968249 (1978), incorporated herein by reference, which describes how to make that drug. In the present invention, enalapril is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

Elanapril and hydrochlorothiazide Elanapril and hydrochlorothiazide are known drugs used in conjunction with the treatment of hypertension. Elanapril describes how to make the drug, EP 12401 (1984), Priority US 968249 (1978), and US Pat. 4,374,829 and 4,472,380. In the present invention, elanapril is covalently attached to the peptide via the carboxylic acid group; hydrochlorothiazide is attached via its amide group.

Enoxaparin Enoxaparin is a known drug used in the treatment of thrombosis and myocardial infarction. This is a low molecular weight heparin and is described in US Pat. Nos. 4,486,420; 4,692,435; and 5,389,619, which are incorporated herein by reference. In the present invention, enoxaparin is covalently attached to the peptide via any free alcohol, amine or amide group or alternatively via a linker.

本発明においては、エルゴタミンは、アルコール又はアミン基を介してペプチドに対し共有結合している。 Ergotamine Ergotamine is a known drug used in the treatment of migraine. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, ergotamine is covalently attached to the peptide via the alcohol or amine group.

Erythromycin and sulfax (sulfx)
Together, erythromycin and sulfax constitute a known drug used to treat bacterial infections. The chemical name of erythromycin is (3R ^* , 4S ^* , 5S ^* , 6R ^* , 7R ^* , 9R ^* , 11R ^* , 12R ^* , 13S ^* , 14R ^* )-4-((2,6-dideoxy-3- C-methyl-3-O-methyl-aL-ribo-hexopyranosyl) -oxy) -14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-6 -((3,4,6-trideoxy-3- (dimethylamino) -bD-xylo-hexopyranosyl) oxy) oxacyclotetradecane-2,10-dione. The composition of the invention comprises erythromycin and sulfax covalently attached to a peptide.

フルバスタチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，３５４，７７２号明細書の主題である。本発明では、フルバスタチンは、カルボン酸基又はヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Fluvastatin Fluvastatin is a known drug used in the treatment of hyperlipidemia. Its chemical name is (3R, 5S, 6E) -1-7- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -3,5-dihydroxy -6-heptaenoic acid. Its structure is as follows:

Fluvastatin is the subject of US Pat. No. 5,354,772, incorporated herein by reference, which describes how to make that drug. In the present invention, fluvastatin is covalently attached to the peptide via either the carboxylic acid group or the hydroxyl group.

ガバペンチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，０８７，５４４、４，８９４，４７６、５，０８４，４７９及び６，０５４，４８２号明細書の主題である。本発明においては、ガバペンチンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Gabapentin Gabapentin is a known drug used in the treatment of epilepsy and depression. Its chemical name is 1- (aminomethyl) cyclohexaneacetic acid. Its structure is as follows:

Gabapentin is described in US Pat. Nos. 4,087,544, 4,894,476, 5,084,479 and 6,054,482, incorporated herein by reference, which describe how to make the drug. The subject. In the present invention, gabapentin is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明においては、ゲムシタビンは、ヒドロキシル又はアミノ基又はその両方を介してペプチドに対し共有結合している。 Gemcitabine hydrochloride Gemcitabine HCl is a known drug used for the treatment of lung and pancreatic cancer. Its structure is as follows:

In the present invention, gemcitabine is covalently attached to the peptide via the hydroxyl or amino group or both.

本発明においては、ゲンタマイシンアイソトンは、ヒドロキシル基を介してペプチドに対し共有結合している。 Gentamicin isotones Gentamicin isotones are known drugs used in the treatment of bacterial infections and muscular dystrophy. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, gentamicin isotone is covalently attached to the peptide via the hydroxyl group.

Glucosamine Glucosamine is a nutritional supplement. It is commercially available or is easily synthesized. In the present invention, glucosamine is attached to the peptide via one or both of an amino group and a hydroxyl group.

Guaifenesin and hydrocodone Guaifenesin and hydrocodone are known drugs used in the treatment of cough. The compositions of the present invention comprise guaifenesin and hydrocodone covalently attached to the peptide using functional groups specifically described in each category of active agent.

Himatropine and hydrocodone Himatropin and hydrocodone are known drugs used in the treatment of pain. The composition of the invention comprises himatropin and hydrocodone covalently attached to the peptide using functional groups specifically described in each category of active agent.

本発明においては、ヒューペルジンはケトン又はアミノ基或いはその両方を介してペプチドに対し共有結合している。 Huperzine A
Huperzine A is an acetylcholinesterase inhibitor that has been used to treat Alzheimer's disease and other forms of dementia. This is commercially available. Its structure is as follows:

In the present invention, huperzine is covalently attached to the peptide via the ketone or amino group or both.

Hydrocodone and phenylpropanolamine Hydrocodone and phenylpropanolamine are used to treat cough and colds. The composition of the invention comprises hydrocodone and phenylpropanolamine covalently attached to a peptide. In the present invention, hydrocodone and phenylpropanolamine are covalently attached to the peptide via one of the hydroxyl groups. Alternatively, phenylpropanolamine may be attached by electron pair sharing to the peptide via the amino group.

本発明の組成物は、活性物質のそれぞれのカテゴリー中に特定的に記載されている官能基を用いてペプチドに対し共有結合しているイブプロフェン及びヒドロコドンを含んでなる。 Ibuprofen and hydrocodone Ibuprofen and hydrocodone have been used to treat pain. The structure of hydrocodone is shown in FIG. The structure of ibuprofen is as follows:

The composition of the invention comprises ibuprofen and hydrocodone covalently attached to the peptide using functional groups specifically described in each category of active agent.

イダルビシンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１４６７３８３号明細書（１９７７）の主題である。本発明においては、イダルビシンは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的には、イダルビシンは、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Idarubicin Idarubicin is a known drug used in the treatment of cancer. Its chemical name is (7S, 9S) -9-acetyl-7-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy] -7,8,9,10- Tetrahydro-6,9,11-trihydroxy-5,12-naphthacenedione. Its structure is as follows:

Idarubicin is the subject of British Patent No. 1467383 (1977), incorporated herein by reference, which describes how to make that drug. In the present invention, idarubicin is covalently attached to the peptide via the hydroxyl group. Alternatively, idarubicin may be attached by electron pair sharing to the peptide via the amino group.

アイロマスタットは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９２／９５５６号パンフレット（１９９２）、優先権米国特許出願第６１５７９８号明細書（１９９０）及び米国特許第５，１１４，９５３号明細書の主題である。本発明においては、アイロマスタットは、アミン又はヒドロキシル基を介してペプチドに対し共有結合している。 Iromasterat Iromastert is a known drug used in the treatment of retinopathy, diabetes and cancer. Its chemical name is (2R) -N4-hydroxy-N1-[(1S)-(1H-indol-3-ylmethyl) -2- (methylamino) -2-oxoethyl] -2- (2-methylpropyl) Butanediamide. Its structure is as follows:

Ironomat describes WO 92/9556 (1992), priority US Patent Application No. 615798 (1990) and US Patents, which are incorporated herein by reference, describing how to make the drug. No. 5,114,953. In the present invention, ilomastert is covalently attached to the peptide via an amine or hydroxyl group.

Iodothyronine Iodothyronine is a known drug used in the treatment of hypothyroidism. The composition of the invention comprises iodothyronine covalently attached to a peptide. In the present invention, iodothyronine is covalently attached to the peptide via a peptide bond. Iodothyronine and thyroxine are known drugs used to treat hypothyroidism. The composition of the invention comprises iodothyronine and roxin covalently attached to a peptide. In the present invention, iodothyronine and thyroxine are covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

Ketotifen Ketotifen is a known drug used in the treatment of allergic conjunctivitis. In the present invention, ketotifen is covalently attached to the peptide via a hydroxyl, amine or carboxylic acid group or alternatively a linker.

本発明においては、ラベタロールは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的に、ラベタロールは、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Labetalol Labetalol is a known drug used in the treatment of hypertension. Its structure is as follows:

In the present invention, labetalol is covalently attached to the peptide via the hydroxyl group. Alternatively, labetalol may be attached via electron pair sharing to the peptide via the amino group.

本発明の組成物は、ペプチドに対し共有結合しているレボチロキシンを含んでなる。本発明においては、レボチロキシンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Levothyroxine Levothyroxine is a known drug used in the treatment of hypothyroidism. Its structure is as follows:

The composition of the invention comprises levothyroxine covalently attached to a peptide. In the present invention, levothyroxine is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

リシノプリルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１２４０１Ｂ号明細書（１９８４）、優先権米国特許第９６８２４９号明細書（１９７８）の主題である。本発明の組成物は、ペプチドに対し共有結合しているリシノプリルを含んでなる。本発明においては、リシノプリルは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基或いはその両方を介してペプチドに対し共有結合している。 Lisinopril Lisinopril is a known drug used in the treatment of hypertension, heart failure, myocardial infarction, retinopathy, diabetes and kidney disease. Its chemical name is (S) -1- [N2- (1-carboxy-3-phenylpropyl) -L-lysyl] -L-proline. Its structure is as follows:

Lisinopril is the subject of EP 12401B (1984), priority US Pat. No. 968249 (1978), incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises lisinopril covalently attached to a peptide. In the present invention, lisinopril is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

Lisinopril and hydrochlorothiazide Lisinopril and hydrochlorothiazide are used in combination for the treatment of hypertension. The composition of the invention comprises lisinopril and hydrochlorothiazide covalently attached to a peptide.

ロラカルベルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１４４７６Ｂ号明細書１９８３、優先権日本特許第１４５３４号明細書１９７９、欧州特許第３１１３６６Ｂ号明細書１９９４、優先権米国特許第１０５７７６号明細書１９８７の主題である。本発明の組成物は、ペプチドに対し共有結合しているロラカルベルを含んでなる。本発明においては、ロラカルベルは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Loracarbeve Loracarbeve is a known drug used in the treatment of bacterial infections. Its chemical name is 7-[(aminophenylacetyl) amino] -3-chloro-8-oxo-1-azabicyclo- [4,2,0] oct-2-ene-2-carboxylic acid. Its structure is as follows:

Loracarbel describes how to make the drug, European Patent No. 14476B 1983, Priority Japanese Patent No. 14534 1979, European Patent No. 311366B 1994, which is incorporated herein by reference. This is the subject of U.S. Patent No. 1057776 1987. The composition of the invention comprises Loracarbel covalently attached to a peptide. In the present invention, Loracarbel is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

Losartan and hydrochlorothiazide Losartan and hydrochlorothiazide are used in combination to treat hypertension. Losartan and hydrochlorothiazide are the subject of US Pat. Nos. 5,138,069 and 5,153,197, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises losartan and hydrochlorothiazide covalently attached to a peptide.

メフロキンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５７９，８５５号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているメフロキンを含んでなる。本発明においては、メフロキンは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的には、メフロキンは、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Mefloquine Mefloquine is a known drug that is used in the treatment and prevention of malaria. Its structure is as follows:

Mefloquine is the subject of US Pat. No. 4,579,855, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises mefloquine covalently attached to a peptide. In the present invention, mefloquine is covalently attached to the peptide via the hydroxyl group. Alternatively, mefloquine may be attached to the peptide via an amino group by electron pair sharing.

メサラミンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，５４１，１７０及び５，５４１，１７１号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているメサラミンを含んでなる。本発明においては、メサラミンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基又はアミノ基又はその両方を介してペプチドに対し共有結合している。 Mesalamine Mesalamine is a known drug used in the treatment of inflammatory bowel disease. Its chemical name is 5-amino-2-hydroxybenzoic acid. Its structure is as follows:

Mesalamine is the subject of US Pat. Nos. 5,541,170 and 5,541,171, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises mesalamine covalently attached to a peptide. In the present invention, mesalamine is covalently attached to the peptide via a carboxylic acid group or an amino group or both to provide an example of a dispersed drug peptide conjugate.

本発明の組成物は、ペプチドに対し共有結合しているメトプロロールを含んでなる。本発明においては、メトプロロールは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的には、メトプロロールは、アミノ基を介してペプチドに付着されていても良い。 Metoprolol Metoprolol is a known drug used in the treatment of angina and hypertension. This is disclosed in US Pat. Nos. 4,957,745 and 5,001,161, which are incorporated herein by reference. Its structure is as follows:

The composition of the invention comprises metoprolol covalently attached to a peptide. In the present invention, metoprolol is covalently attached to the peptide via the hydroxyl group. Alternatively, metoprolol may be attached to the peptide via an amino group.

モエキシプリルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３４４，９４９及び４，７４３，４５０号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているモエキシプリルを含んでなる。本発明においては、モエキシプリルは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Moexipril Moexipril is a known drug used in the treatment of hypertension. Its chemical name is [3S- [2 [R ^* (R ^* ), 3R ^* ]]-2- [2-[[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl]. -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid. Its structure is as follows:

Moexipril is the subject of US Pat. Nos. 4,344,949 and 4,743,450, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises moexipril covalently attached to a peptide. In the present invention, moexipril is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明の組成物は、ペプチドに対し共有結合しているナドロールを含んでなる。本発明においては、ナドロールは、ヒドロキシル基のいずれかを介してペプチドに対し共有結合している。代替的には、ナドロールは、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Nadolol Nadolol is a known drug used in the treatment of hypertension and angina. Its structure is as follows:

The composition of the invention comprises nadolol covalently attached to a peptide. In the present invention, nadolol is covalently attached to the peptide via any of the hydroxyl groups. Alternatively, nadolol may be attached by electron pair sharing to the peptide via the amino group.

ネララビンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第号２９４１１４Ｂ明細書１９９６の主題である。本発明の組成物は、ペプチドに対し共有結合しているネララビンを含んでなる。本発明においては、ネララビンは、ヒドロキシル又はアミノ基を介してペプチドに対し共有結合している。 Nelarabine Nelarabine is a known drug used in the treatment of cancer. Its chemical name is 9-β-D-arabinofuranosyl-6-methoxy-9H-purin-2-amine. Its structure is as follows:

Nelarabine is the subject of EP 294114B 1996, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises nelarabine covalently attached to a peptide. In the present invention, nelarabine is covalently attached to the peptide via the hydroxyl or amino group.

Neuraminidase Inhibitor The oral neuraminidase inhibitor of the present invention is a known drug used in the treatment of viral infections. This is called the chemical name BCX1812. The composition of the invention comprises an oral neuraminidase inhibitor covalently attached to a peptide.

ノルフロキサシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，１４６，７１９及び４，６３９，４５８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているノルフロキサシンを含んでなる。本発明においては、ノルフロキサシンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Norfloxacin Norfloxacin is a known drug used in the treatment of mania and urinary tract infections. Its structure is as follows:

Norfloxacin is the subject of US Pat. Nos. 4,146,719 and 4,639,458, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises norfloxacin covalently attached to a peptide. In the present invention, norfloxacin is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

Oxycodone and acetaminophen Oxycodone and acetaminophen have been used in the treatment of pain. The composition of the invention comprises oxycodone and acetaminophen attached to a peptide by electron pair sharing.

Potassium channel modulators Potassium channel modulators are known drugs used in the treatment of stroke. This is called BMS204352. The composition of the invention comprises a potassium channel modulator covalently attached to a peptide.

プラバスタチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３４６，２２７；５，０３０，４４７及び５，１８０，５８９号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているプラバスタチンを含んでなる。本発明においては、プラバスタチンは、カルボン酸基又はヒドロキシル基のいずれかを介してペプチドに対し共有結合している。 Pravastatin Pravastatin is a known drug used in the treatment of hyperlipidemia and myocardial infarction. Its chemical name is [1S- [1α (βS ^* , δS ^* ), 2α, 6α, 8β (R ^* ), 8aα]]-1,2,6,7,8,8a-hexahydro-β, δ, 6-trihydroxy-2-methyl-8- (2-methyl-1-oxobutoxy) -1-naphthaleneheptanoic acid. Its structure is as follows:

Pravastatin is the subject of US Pat. Nos. 4,346,227; 5,030,447 and 5,180,589, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises pravastatin covalently attached to a peptide. In the present invention, pravastatin is covalently attached to the peptide via either the carboxylic acid group or the hydroxyl group.

プレガバリンは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９３／２３３８３号パンフレット１９９３、優先権米国特許第８８６０８０号明細書１９９２の主題である。本発明の組成物は、ペプチドに対し共有結合しているプレガバリンを含んでなる。本発明においては、プレガバリンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Pregabalin Pregabalin is a known drug used in the treatment of epilepsy and pain. Its chemical name is (S) -3- (aminomethyl) -5-methyl-hexanoic acid. Its structure is as follows:

Pregabalin is the subject of WO 93/23383, 1993, priority US Pat. No. 8,860,080, which is incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises pregabalin covalently attached to a peptide. In the present invention, pregabalin is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明の組成物は、ペプチドに対し共有結合しているプロプラノロールを含んでなる。本発明においては、プロプラノロールは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的には、プロプラノロールは、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Propranolol Propranolol is a known drug used in the treatment of hypertension and angina. Its structure is as follows:

The composition of the invention comprises propranolol covalently attached to a peptide. In the present invention, propranolol is covalently attached to the peptide via the hydroxyl group. Alternatively, propranolol may be attached by electron pair sharing to the peptide via the amino group.

本発明の組成物は、ペプチドに対し共有結合しているシュードエフェドリンを含んでなる。本発明においては、シュードエフェドリンは、ヒドロキシル基を介してペプチドに対し共有結合している。代替的には、シュードエフェドリンは、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Pseudoephedrine Pseudoephedrine is a known drug used in the treatment of allergies. Its structure is as follows:

The composition of the invention comprises pseudoephedrine covalently attached to a peptide. In the present invention, pseudoephedrine is covalently attached to the peptide via the hydroxyl group. Alternatively, pseudoephedrine may be attached by electron pair sharing to the peptide via the amino group.

キナプリルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３４４，９４９；４，７４３，４５０；５，６８４，０１６及び５，７４７，５０４号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているキナプリルを含んでなる。本発明においては、キナプリルは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Quinapril Quinapril is a known drug used in the treatment of hypertension. Its chemical name is [3S- [2 [R ^* (R ^* )], 3R ^* ]]-2- [2-[[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl. ] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid. Its structure is as follows:

Quinapril is described in US Pat. Nos. 4,344,949; 4,743,450; 5,684,016 and 5,747,504, incorporated herein by reference, which describe how to make the drug. The subject. The composition of the invention comprises quinapril covalently attached to a peptide. In the present invention, quinapril is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

キノロン系抗生物質は、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第８８２７２５Ａｌ号明細書（１９９８）の主題である。本発明においては、キノロン系抗生物質は、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Quinolone Antibiotics The quinolone antibiotics of the present invention are known drugs used in the treatment of bacterial infections. Its chemical name is 1-cyclopropyl-8- (difluoromethoxy) -7-[(1R) -2,3-dihydro-1-methyl-1H-isoindol-5-yl] -1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid monomethanesulfonate. Its structure is as follows:

Quinolone antibiotics are the subject of EP 882725 Al (1998), incorporated herein by reference, which describes how to make the drug. In the present invention, the quinolone antibiotic is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

ラミプリルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５８７，２５８及び５，０６１，７２２号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているラミプリルを含んでなる。本発明においては、ラミプリルは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Ramipril Ramipril is a known drug used in the treatment of hypertension and heart failure. Its chemical name is (2S, 3aS, 6aS) -1-[(S) -N-[(S) -1-carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b] pyrrole-2-carboxylic acid 1-ethyl ester. Its structure is as follows:

Ramipril is the subject of US Pat. Nos. 4,587,258 and 5,061,722, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises ramipril covalently attached to a peptide. In the present invention, ramipril is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

シタフロキサシンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第３４１４９３Ａ号明細書１９８９の主題である。本発明の組成物は、ペプチドに対し共有結合しているシタフロキサシンを含んでなる。本発明においては、シタフロキサシンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Sitafloxacin Sitafloxacin is a known drug used in the treatment of bacterial infections. Its chemical name is [1R- [1α (S ^* ), 2α]]-7- (7-amino-5-azaspiro [2,4] hept-5-yl) -8-chloro-6-fluoro-1- (2-Fluorocyclopropyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. Its structure is as follows:

Sitafloxacin is the subject of EP 341493A 1989, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises sitafloxacin covalently attached to a peptide. In the present invention, sitafloxacin is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

Sparfosic acid
Sparfos acid is a known drug used in the treatment of cancer. The composition of the present invention comprises spurfosic acid covalently attached to a peptide. In the present invention, spurfos acid is covalently attached to the peptide via the hydroxyl or carboxylic acid group.

ティロフィバンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，２９２，７５６；５，６５８，９２９；５，７３３，９１９；５，８８０，１３６；５，９６５，５８１；５，９７２，９６７及び５，９７８，６９８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているティロフィバンを含んでなる。本発明においては、ティロフィバンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Tirofiban Tirofiban is a known drug used in the treatment of thrombosis and angina. Its chemical name is N- (butylsulfonyl) -O- [4- (4-piperidinyl) butyl] -L-tyrosine. Its structure is as follows:

Tirofiban describes US Pat. Nos. 5,292,756; 5,658,929; 5,733,919; 5,880,136; 5,965, incorporated herein by reference, which describe how to make the drug. , 581; 5,972,967 and 5,978,698. The composition of the invention comprises tirofiban covalently attached to a peptide. In the present invention, tirofiban is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明の組成物は、ペプチドに対し共有結合している硫酸トブラマイシンを含んでなる。本発明においては、硫酸トブラマイシンは、ヒドロキシル又はアミノ基を介してペプチドに対し共有結合している。 Tobramycin sulfate Tobramycin sulfate is a known drug used in the treatment of bacterial infections. Its structure is as follows:

The composition of the invention comprises tobramycin sulfate covalently attached to a peptide. In the present invention, tobramycin sulfate is covalently attached to the peptide via the hydroxyl or amino group.

トランドラプリルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，２３３，３６１及び５，７４４，４９６号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているトランドラプリルを含んでなる。本発明においては、トランドラプリルは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Trandolapril Trandolapril is a known drug used in the treatment of hypertension, heart failure, and myocardial infarction. Its chemical name is [2S- [1 [R ^* (R ^* )], 2α, 3aα, 7aβ]]-1- [2-[[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1- Oxopropyl] octahydro-1H-indole-2-carboxylic acid. Its structure is as follows:

Trandolapril is the subject of U.S. Pat. Nos. 4,233,361 and 5,744,496, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises trandolapril covalently attached to a peptide. In the present invention, trandolapril is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

メシル酸トロバフロキサシンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，１６４，４０２；５，７６３，４５４；及び６，０８０，７５６号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているメシル酸トロバフロキサシンを含んでなる。本発明においては、メシル酸トロバフロキサシンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Trobafloxacin mesylate Trobafloxacin mesylate is a known drug used in the treatment of bacterial infections. Its chemical name is (1α, 5α, 6α) -7- (6-amino-3-azabicyclo [3.1.0] hex-3-yl) -1- (2,4-difluorophenyl) -6-fluoro. -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Its structure is as follows:

Trovafloxacin mesylate is described in US Pat. Nos. 5,164,402; 5,763,454; and 6,080,756, incorporated herein by reference, which describes how to make the drug. The subject. The composition of the invention comprises trovafloxacin mesylate covalently attached to a peptide. In the present invention, trovafloxacin mesylate is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

Ursodiol Ursodiol is a known drug used in the treatment of gallstones. Its chemical name is 3α, 7β-dihydroxy-5β-cholan-24-acid. The composition of the invention comprises ursodiol covalently attached to a peptide. In the invention, ursodiol is covalently attached to the peptide via either the carboxylic acid group or its hydroxyl group.

本発明の組成物は、ペプチドに対し共有結合しているバンコマイシンを含んでなる。本発明においては、バンコマイシンは、分散型薬物ペプチド共役体の一例を提供するべくカルボン酸基、アミノ基又はその両方を介してペプチドに対し共有結合している。 Vancomycin Vancomycin is a known drug used in the treatment of bacterial infections. Its structure is as follows:

The composition of the invention comprises vancomycin covalently attached to a peptide. In the present invention, vancomycin is covalently attached to the peptide via a carboxylic acid group, an amino group, or both to provide an example of a dispersed drug peptide conjugate.

本発明の組成物は、ペプチドに対し共有結合しているビタミンＢ１２を含んでなる。本発明においては、活性物質は、ヒドロキシル基の一つを介してペプチドに対し共有結合している。代替的には、ビタミンＢ１２は、アミノ基を介してペプチドに対し電子対共有により付着していて良い。 Vitamin B12
Vitamin B12 is a known drug used in the treatment of vitamin B12 deficiency. Its structure is as follows:

The composition of the invention comprises vitamin B12 covalently attached to a peptide. In the present invention, the active substance is covalently attached to the peptide via one of the hydroxyl groups. Alternatively, vitamin B12 may be attached by electron pair sharing to the peptide via the amino group.

本発明においては、ＡＧＥ架橋分離剤は、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。ＡＧＥ架橋分離剤は、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９６／２２０９５号パンフレット（１９９６）、優先権米国特許出願第３７５１５５号明細書（１９９５）の主題である。 XII. AGE cross-linking agent via E-ketone group The AGE cross-linking agent of the present invention is a known drug used in the treatment of diabetes and cardiovascular disease. Its chemical name is 4,5-dimethyl-3- (2-oxo-2-phenylethyl) thiazolium. Its structure is as follows:

In the present invention, the AGE cross-linking agent is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker. AGE cross-linking agents are the subject of WO 96/22095 (1996), priority US Patent Application No. 375155 (1995), incorporated herein by reference, which describes how to make the drug. It is.

本発明においては、アミオダロンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Amiodarone Amiodarone is a known drug used in the treatment of cardiac arrhythmias. Its chemical name is (2-butyl-3-benzofuranyl) [4- [2- (diethylamino) ethoxy] -3,5-diiodophenyl] methanone. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, amiodarone is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

シランセトロンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２９７６５１号明細書（１９８９）の主題である。本発明においては、シランセトロンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Silanestron Silanestron is a known drug used in the treatment of irritable bowel syndrome. Its chemical name is (R) -5,6,9,10-tetrahydro-10-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-pyrido [3,2,1-jk]. Carbazol-11 (8H) -one. Its structure is as follows:

Silanestron is the subject of EP 297651 (1989), incorporated herein by reference, which describes how to make the drug. In the present invention, silane setron is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

ドネペジルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８９５，８４１号明細書の主題である。本発明においては、ドネペジルは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Donepezil Donepezil is a known drug used in the treatment of Alzheimer's disease and attention deficit disorder. Its chemical name is 2,3-dihydro-5,6-dimethoxy 2-[[1- (phenylmethyl) -4-piperidinyl] methyl] -1H-inden-1-one. Its structure is as follows:

Donepezil is the subject of US Pat. No. 4,895,841, incorporated herein by reference, which describes how to make that drug. In the present invention, donepezil is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

フェノフィブレートは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８９５，７２６号明細書の主題である。本発明においては、フェノフィブレートは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Fenofibrate Fenofibrate is a known drug used in the treatment of hyperlipidemia. Its chemical name is 2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropanoic acid 1-methylethyl ester. Its structure is as follows:

Fenofibrate is the subject of US Pat. No. 4,895,726, herein incorporated by reference, which describes how to make that drug. In the present invention, fenofibrate is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

Hydrocodone Hydrocodone is a known drug used in the treatment of pain. The composition of the invention comprises hydrocodone covalently attached to a peptide. In the present invention, hydrocodone is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker. Alternatively, the hydrocon may be attached directly through the enolate.

本発明の組成物は、ペプチドに対し共有結合しているカバラクトンを含んでなる。本発明においては、カバラクトンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。 Kavalactone Kavalactone is taken orally to treat anxiety and sleep disorders. The structure is as follows:

The composition of the invention comprises kavalactone covalently attached to a peptide. In the present invention, kavalactone is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids).

本発明の組成物は、ペプチドに対し共有結合している酢酸メドロキシプロゲステロンを含んでなる。本発明においては、酢酸メドロキシプロゲステロンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Medroxyprogesterone acetate Medroxyprogesterone acetate is used orally to reduce the incidence of endometrial hyperplasia and the associated risk of endometrial cancer in postmenopausal women undergoing estrogen replacement therapy. Its structure is as follows:

The composition of the invention comprises medroxyprogesterone acetate covalently attached to a peptide. In the present invention, medroxyprogesterone acetate is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

酢酸メゲステロールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，３３８，７３２号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合している酢酸メゲステロールを含んでなる。本発明においては、酢酸メゲステロールは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Megesterol acetate Megesterol acetate is used for palliative treatment of recurrent, inoperable or metastatic endometrial cancer or breast cancer. This drug is also used as an adjunct to surgery or radiation therapy. Its structure is as follows:

Megesterol acetate is the subject of US Pat. No. 5,338,732, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises megesterol acetate covalently attached to a peptide. In the present invention, megestrol acetate is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

本発明においては、メラトニンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。 Melatonin Melatonin is a nutritional supplement. This is commercially available. Its structure is as follows:

In the present invention, melatonin is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids).

ナブメトンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，４２０，６３９号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているナブメトンを含んでなる。本発明においては、ナブメトンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Nabumetone Nabumetone is a known drug used in the treatment of pain and inflammation. Its chemical name is 4- (6-methoxy-2-naphthyl) -2-butanone. Its structure is as follows:

Nabumetone is the subject of US Pat. No. 4,420,639, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises nabumetone covalently attached to a peptide. In the present invention, nabumetone is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

オンダセトロンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４６９５５７８、４７５３７８９、５３４４６５８及び５５７８６２８号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているオンダセトロンを含んでなる。本発明においては、オンダセトロンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Ondacetron Ondasetron is a known drug used in the treatment of vomiting, cognitive dysfunction and eating disorders. Its chemical name is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one. Its structure is as follows:

Ondacetron is the subject of U.S. Pat. Nos. 4,695,578, 4753789, 5344658, and 5,578,628, incorporated herein by reference, which describe how to make that drug. The composition of the invention comprises ondasetron covalently attached to a peptide. In the present invention, ondasetron is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

本発明の組成物は、ペプチドに対し共有結合しているオキシコドンを含んでなる。本発明においては、オキシコドンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。代替的には、オキシコドンは、エノレートを通して直接付着していても良い。 Oxycodone Oxycodone is a known drug used in the treatment of pain. Its structure is as follows:

The composition of the invention comprises oxycodone covalently attached to a peptide. In the present invention, oxycodone is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker. Alternatively, oxycodone may be attached directly through the enolate.

パゴクロンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２７４９３０Ｂ号明細書１９９１の主題である。本発明の組成物は、ペプチドに対し共有結合しているパゴクロンを含んでなる。本発明においては、パゴクロンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Pagoclone Pagoclone is a known drug used in the treatment of anxiety and panic disorders. Its chemical name is (+)-2- (7-chloro-1,8-naphthyridin-2-yl) -2,3-dihydro-3- (5-methyl-2-oxohexyl) -1H-isoindole -1-one. Its structure is as follows:

Pagoclone is the subject of EP 274930B 1991, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises pagoclone covalently attached to a peptide. In the present invention, Pagoclone is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

本発明の組成物は、ペプチドに対し共有結合しているペントキシフィリンを含んでなる。本発明においては、ペントキシフィリンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Pentoxifylline Pentoxifylline is a known drug used in the treatment of peripheral vascular disease, stroke, atherosclerosis and rheumatoid arthritis. Its chemical name is 3,7-dimethyl-1- (5-oxo-hexyl) xanthine. Its structure is as follows:

The composition of the invention comprises pentoxifylline covalently attached to a peptide. In the present invention, pentoxifylline is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

本発明の組成物は、ペプチドに対し共有結合しているスピロノラクトンを含んでなる。本発明においては、スピロノラクトンは、ケトン基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えば、リンカーとしては、グルコースが適切であると思われる。 Spironolactone Spironolactone is a known drug used in the treatment of edema. Its structure is as follows:

The composition of the invention comprises spironolactone covalently attached to a peptide. In the present invention, spironolactone is covalently attached to the peptide via a ketone group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, glucose may be suitable as a linker.

アデノシンＡ１受容体拮抗薬は、この薬物の製造方法を記載する、本書に参考として内含された国際公開第９５／１１９０４号パンフレット１９９５、優先権米国特許第１４４４５９号明細書１９９３の主題である。本発明の組成物は、ペプチドに電子対共有により付着されたアデノシンＡ１受容体拮抗薬を含んでなる。本発明においては、アデノシンＡ１受容体拮抗薬は、イミダゾ基又はリンカーを介してペプチドに電子対共有により付着されている。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 XII. Adenosine A1 receptor antagonists via F-amide, imide, imidazo, pyrazolo or ureido groups and linkers Adenosine A1 receptor antagonists of the present invention are known drugs used in the treatment of hypertension and heart failure. Its chemical name is 3,7-dihydro-8- (3-oxatricyclo [3,2,1,0,2,4] oct-6-yl) -1,3-dipropyl-1H-purine-2 , 6-dione. Its structure is as follows:

Adenosine A1 receptor antagonist is the subject of WO 95/11904 1995, priority US 14444459, 1993, herein incorporated by reference, which describes how to make this drug. The composition of the invention comprises an adenosine A1 receptor antagonist attached to a peptide by electron pair sharing. In the present invention, an adenosine A1 receptor antagonist is attached to a peptide by electron pair sharing via an imidazo group or a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

Adrenocorticotropic hormone Adrenocorticotropic hormone is a known drug useful in the diagnosis of Addison's disease and other physical conditions that must determine the functionality of the adrenal cortex. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. In the present invention, adrenocorticotropic hormone is covalently attached to the peptide via an amide bond and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明においては、アロプリナルは、ピラゾロ基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Allopurinal Allopurinal is a known drug that is a xanthine oxidase inhibitor used in the treatment of gout and selective hyperuricemia. Its structure is as follows:

In the present invention, allopurinal is covalently attached to the peptide via a pyrazolo group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

アナグレリドは、該薬物の作り方を記載する、本書中に参考として内含された、１９７２年に出願された米国特許出願第２２３，７２３号明細書に基づく、英国特許第１４１８８２２号明細書（１９７５）の主題である。本発明においては、アナグレリドは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Anagrelide Anagrelide is a known drug used as a thrombocytopenic drug. Its chemical name is 6,7-dichloro-1,5-dihydroimidazo [2,1-b] quinazolin-2 (3H) -one. Its structure is as follows:

Anagrelide is described in British Patent No. 14188822 (1975), based on US Patent Application No. 223,723, filed in 1972, which is incorporated herein by reference, which describes how to make that drug. Is the theme. In the present invention, anagrelide is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

Angiotensin II antagonists Angiotensin II antagonists of the present invention are known drugs used in the treatment of hypertension. Its chemical name is N-[[4 ′-[(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] [1,1′-biphenyl]. -2-yl] sulfonyl] -benzamide. The composition of the invention comprises an angiotensin II antagonist covalently attached to a peptide. In the present invention, the active substance is covalently attached to the peptide via the linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

カルバマゼピンは、該薬物の作り方を記載する、本書中に参考として内含された、米国特許第５，２８４，６６２号明細書及び再発行米国特許第Ｒｅ．３４，９９０号明細書の主題である。本発明においては、カルバマゼピンは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Carbamazepine Carbamazepine is a known drug used in the treatment of epilepsy. Its structure is as follows:

Carbamazepine is described in US Pat. No. 5,284,662 and reissued US Pat. No. Re., Which are incorporated herein by reference, which describes how to make the drug. 34,990. In the present invention, carbamazepine is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明においては、カリソプロドールは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Carisoprodol Carisoprodol is a known drug used in skeletal muscle spasms. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, carisoprodol is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

セフロキシムアキセチルは、該薬物の作り方を記載する、本書中に参考として内含された、英国特許第１５７１６８３号明細書（１９８０）の主題である。本発明においては、セフロキシムアキセチルは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Cefuroxime axetil Cefuroxime axetil is a known drug used in the treatment of bacterial infections. Its chemical name is [6R- [6α, 7β (Z)]]-3-[[(aminocarbonyl) oxy] methyl] -7-[[2-furanyl (methoxyimino) acetyl] amino] -8-oxo -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, 1- (acetyloxy) ethyl ester. Its structure is as follows:

Cefuroxime axetil is the subject of GB 1571683 (1980), herein incorporated by reference, which describes how to make the drug. In the present invention, cefuroxime axetil is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明においては、シメチジンは、イミダゾ基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Cimetidine Cimetidine is a known drug used in the treatment of duodenal ulcers. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, cimetidine is covalently attached to the peptide via an imidazo group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明においては、クロナゼパムは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Clonazepam Clonazepam is a known drug used in the treatment of epilepsy. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, clonazepam is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明においては、クロニジンは、アミノ基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Clonidine Clonidine is a known drug used in the treatment of hypertension. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, clonidine is covalently attached to the peptide via the amino group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

コニバプタンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許出願公開第７０９３８６Ａ号明細書（１９９６）の主題である。本発明においては、コニバプタンは、窒素含有基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Conivaptan Conivaptan is a known drug used in the treatment of congestive heart failure and hyponatremia. Its chemical name is N- [1,1′-biphenyl] -2-yl-4-[(4,5-dihydro-2-methylimidazo [4,5-d] [1] benzazepine-6 (1H) -Yl) carbonyl] -benzamide. Its structure is as follows:

Conivaptan is the subject of EP 709386A (1996), incorporated herein by reference, which describes how to make the drug. In the present invention, conivaptan is covalently attached to the peptide via a nitrogen-containing group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

デュタステリドは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９５／７９２７号パンフレット（１９９５）、優先権米国特許第１２３２８０号明細書（１９９３）の主題である。本発明においては、デュタステリドは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Dutasteride Dutasteride is a known drug used in the treatment of benign prostatic hypertrophy and alopecia. Its chemical name is (4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR) -N- [2,5-bis (trifluoromethyl) phenyl] -2,4a, 4b, 5,6,6a, 7 , 8,9,9a, 9b, 10,11,11a-tetradecahydro-4a, 6a-dimethyl-2-oxo-1H-indeno [5,4-f] quinoline-7-carboxamide. Its structure is as follows:

Dutasteride is the subject of WO 95/7927 (1995), priority US Pat. No. 123280 (1993), incorporated herein by reference, which describes how to make the drug. In the present invention, dutasteride is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

エカドトリルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第３１８３７７Ｂ号明細書の主題である。本発明においては、エカドトリルは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Ecadotril Ecadotril is a known drug used in the treatment of hypertension, heart failure and cirrhosis. Its chemical name is (S) -N- [2-[(acetylthio) methyl] -1-oxo-3-phenylpropyl] glycine phenylmethyl ester. Its structure is as follows:

Ecadotril is the subject of EP 318377B, incorporated herein by reference, which describes how to make the drug. In the present invention, ecadotolyl is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

エファビレンツは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，５１９，０２１；５，６６３，１６９及び５，８１１，４２３号明細書の主題である。本発明においては、エファビレンツは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Efavirenz Efavirenz is a known drug used in the treatment of HIV infection. Its chemical name is (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one. Its structure is as follows:

Efavirenz is the subject of US Pat. Nos. 5,519,021; 5,663,169 and 5,811,423, incorporated herein by reference, which describe how to make the drug. In the present invention, efavirenz is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

エミビリンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第４２０７６３Ｂ号明細書（１９９９）の主題である。本発明においては、エミビリンは、イミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Emivirin Emivirin is a known drug used in the treatment of HIV infection. Its chemical name is 1- (ethoxymethyl) -5- (1-methylethyl) -6- (phenylmethyl) -2,4 (1H, 3H) -pyrimidinedione. Its structure is as follows:

Emivirin is the subject of EP 42063B (1999), incorporated herein by reference, which describes how to make the drug. In the present invention, emivirin is covalently attached to the peptide via an imide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

エニルウラシルは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９２／１４５２号パンフレット（１９９２）の主題である。本発明においては、エニルウラシルは、ウレイド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Eniluracil Eniluracil is a known drug used in the treatment of pancreatic cancer and colorectal cancer. Its chemical name is 5-ethynyl-2,4 (1H, 3H) -pyrimidinedione. Its structure is as follows.

Eniluracil is the subject of WO 92/1452 (1992), incorporated herein by reference, which describes how to make the drug. In the present invention, eniluracil is covalently attached to the peptide via the ureido group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

フィナステリドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，３７７，５８４；４，７６０，０７１；５，５４７，９５７；５，５７１，８１７及び５，８８６，１８４号明細書の主題である。本発明においては、フィナステリドはアミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Finasteride Finasteride is a known drug used in the treatment of cancer, benign prostatic hypertrophy, alopecia and acne. Its chemical name is (5α, 17β) -N- (1,1-dimethylethyl) -3-oxo-4-azaandrost-1-en-17-carboxamide. Its structure is as follows:

Finasteride describes US Pat. Nos. 5,377,584; 4,760,071; 5,547,957; 5,571,817 and 5,886, incorporated herein by reference, which describe how to make the drug. , 184 specification. In the present invention, finasteride is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

フルドロコルチゾンは、該薬物の作り方を記載する、本書中に参考として内含された優先権出願米国特許第３５６９４８号明細書（１９８９）に基づいた欧州特許第４７３６８７Ｂ号明細書（１９９６）及び米国特許第４，２６０，７６９号明細書（１９８１）の主題である。本発明においては、フルドロコルチゾンは、ウレイド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。例えば、リンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Fludrocortisone Fludrocortisone is a known drug used in the treatment of epilepsy. Its chemical name is 5,5-diphenyl-3-[(phosphonooxy) methyl] -2,4-imidazolidinedione. Its structure is as follows:

Fludrocortisone describes EP 473687B (1996) based on priority application US Pat. No. 356948 (1989), which is incorporated herein by reference, and describes how to make the drug. This is the subject of Japanese Patent No. 4,260,769 (1981). In the present invention, fludrocortisone is covalently attached to the peptide via a ureido group and a linker. The linker may be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids), Alternatively, it may consist of short chains of either amino acids or carbohydrates. For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明の組成物は、ペプチドに対して共有結合しているフルロウラシルを含んでいる。本発明においてはフルロウラシルは、ウレイド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アルコール又は酸といったような）１つ以上の官能基及び１つ以上のヘテロ原子を伴う２〜６個の原子を含んだ小さな線状又は環状分子でありうる。例えば、リンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Flurouracil Flurouracil is a known drug used in the treatment of actinic keratosis. Its structure is as follows:

The composition of the invention includes flurouracil covalently attached to a peptide. In the present invention, flurouracil is covalently attached to the peptide via a ureido group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more functional groups (such as amines, alcohols or acids) and one or more heteroatoms. For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明においては、フルタミドは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Flutamide Flutamide is a known drug used in the treatment of prostate cancer. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, flutamide is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ホスフェニトインは、該薬物の作り方を記載する、本書中に参考として内含された、米国特許第４，２６０，７６９及び４，９２５，８６０号明細書の主題である。本発明においては、ホスフェニトインは、ウレイド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。例えば、リンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Phosphenytoin Phosphenytoin is a known drug used in the treatment of epilepsy. Its chemical name is 5,5-diphenyl-3-[(phosphonooxy) methyl] -2,4-imidazolidinedione. Its structure is as follows:

Phosphenytoin is the subject of US Pat. Nos. 4,260,769 and 4,925,860, incorporated herein by reference, which describes how to make the drug. In the present invention, phosphenytoin is covalently attached to the peptide via a ureido group and a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains. For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ガントフィバンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許出願公開第７４１１３３Ａ号明細書（１９９６）の主題である。本発明においては、ガントフィバンは、イミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Gantofiban Gantofiban is a known drug used in the treatment of thrombosis and angina. Its chemical name is 4-[[(5R) -3- [4- [imino [(methoxycarbonyl) amino] methyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -1-piperazine acetic acid ethyl ester 2 -Hydroxy-1,2,3-propanetricarboxylate (1: 1). Its structure is as follows:

Gantofiban is the subject of EP-A-741133A (1996), incorporated herein by reference, which describes how to make the drug. In the present invention, gantofiban is covalently attached to the peptide via an imide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

グリメピリドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３７９，７８５号明細書の主題である。本発明においては、グリメピリドは、ウレイド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Glimepiride Glimepiride is a known drug used in the treatment of diabetes. Its chemical name is trans-3-ethyl-2,5-dihydro-4-methyl-N- [2- [4-[[[[(4-methylcyclohexyl) amino] carbonyl] amino] sulfonyl] phenyl] ethyl. ] -2-oxo-1H-pyrrole-1-carboxamide. Its structure is as follows:

Glimepiride is the subject of US Pat. No. 4,379,785, herein incorporated by reference, which describes how to make that drug. In the present invention, glimepiride is covalently attached to the peptide via the ureido group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明においては、グリピジドは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Glipizide Glipizide is a known drug used in the treatment of diabetes. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, glipizide is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明においては、グリブリドは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Glyburide Glyburide is a known drug used in the treatment of diabetes. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, glyburide is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ゴセレリンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１５２４７４７号明細書１９７８の主題である。本発明の組成物は、ペプチドに対して共有結合しているゴセレリンを含んでなる。本発明においては、ゴセレリンはアミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Goserelin Goserelin is a known drug used in the treatment of cancer, endometriosis and infertility. Its chemical name is 6- [O- (1,1-dimethylethyl) -D-serine] -1-9-luteinizing hormone releasing factor (porcine) 2- (aminocarbonyl) hydrazide. Its structure is as follows:

Goserelin is the subject of British Patent No. 1524747, 1978, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises goserelin covalently attached to a peptide. In the present invention, goserelin is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

グラニセトロンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８８６，８０８号明細書の主題である。本発明においては、グラニセトロンは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Granisetron Granisetron is a known drug used in the treatment of nausea and vomiting in cancer patients. Its chemical name is endo-1-methyl-N- (9-methyl-9-azabicyclo [3,3,1] non-3-yl) -1H-indazole-3-carboxamide. Its structure is as follows:

Granisetron is the subject of US Pat. No. 4,886,808, incorporated herein by reference, which describes how to make the drug. In the present invention, granisetron is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明においては、ハイドロクロロチアジドはアミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Hydrochlorothiazide Hydrochlorothiazide is a known drug used in the treatment of hypertension. The chemical structure of hydrochlorothiazide is as follows:

In the present invention, hydrochlorothiazide is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

イタセトロンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第３０９４２３Ｂ号明細書（１９９４）の主題である。本発明においては、イタセトロンは、ウレイド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Itasetron Itasetron is a known drug used in the treatment of vomiting and anxiety. Its chemical name is endo-2,3-dihydro-N- (8-methyl-8-azabicyclo [3,2,1] oct-3-yl) -2-oxo-1H-benzimidazole-1-carboxamide. is there. Its structure is as follows:

Itasetron is the subject of EP 309423B (1994), incorporated herein by reference, which describes how to make the drug. In the present invention, itasetron is covalently attached to the peptide via a ureido group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ランソプラゾールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６２８，０９８；４，６８９，３３３；５，０２６，５６０；５，０４５，３２１；５，０９３，１３２及び５，４３３，９５９号明細書の主題である。本発明においては、ランソプラゾールは、イミダゾ基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Lansoprazole Lansoprazole is a known drug used in the treatment of ulcers and bacterial infections. Its chemical name is 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole. Its structure is as follows:

Lansoprazole describes US Pat. Nos. 4,628,098; 4,689,333; 5,026,560; 5,045,321; 5,093, incorporated herein by reference, which describes how to make that drug. 132 and 5,433,959. In the present invention, lansoprazole is covalently attached to the peptide via an imidazo group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明の組成物は、ペプチドに対して共有結合しているメルカプトプリンを含んでなる。本発明においては、メルカプトプリンは、イミダゾ基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Mercaptopurine Mercaptopurine is a known drug used in the treatment of leukemia. Its structure is as follows:

The composition of the invention comprises mercaptopurine covalently attached to a peptide. In the present invention, mercaptopurine is covalently attached to the peptide via an imidazo group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明の組成物は、ペプチドに対して共有結合しているメトフォルミンを含んでなる。本発明においては、メトフォルミンは、グアニド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Metaformin Metformin is a known drug used in the treatment of diabetes. Its chemical name is N, N-dimethylimide dicarbonimide diamide. Its structure is as follows:

The composition of the invention comprises metformin covalently attached to a peptide. In the present invention, metformin is covalently attached to the peptide via a guanide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明の組成物は、ペプチドに対して電子対共有により付着するメタキサロンを含んでなる。本発明においては、メタキサロンは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Metaxalone Metaxalone is a known drug used in the treatment of skeletal muscle spasms. Its structure is as follows:

The composition of the present invention comprises metaxalone attached to a peptide by electron pair sharing. In the present invention, metaxalone is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

乳酸ミルリノンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３１３，９５１号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合している乳酸ミルリノンを含んでなる。本発明においては、乳酸ミルリノン又は修飾乳酸ミルリノンは、アミド基及びリンカーを介してペプチドに共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Milrinone lactate Milrinone lactate is a known drug used in the treatment of heart failure. Its chemical name is 1,6-dihydro-2-methyl-6-oxo- [3,4'-bipyridine] -5-carbonitrile. Its structure is as follows:

Milrinone lactate is the subject of US Pat. No. 4,313,951, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises milrinone lactate covalently attached to a peptide. In the present invention, lactic acid milrinone or modified lactic acid milrinone is covalently bonded to the peptide via an amide group and a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

モダフィニルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，９２７，８５５及び５，６１８，８４５号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているモダフィニルを含んでなる。本発明においては、モダフィニルはアミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Modafinil Modafinil is a known drug used in the treatment of neurological depression. Its chemical name is 2-[(diphenylmethyl) sulfinyl] acetamide. Its structure is as follows:

Modafinil is the subject of US Pat. Nos. 4,927,855 and 5,618,845, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises modafinil covalently attached to a peptide. In the present invention, modafinil is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ネビラピンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，３６６，９７２号の主題である。本発明の組成物は、ペプチドに対して共有結合しているネビラピンを含んでなる。本発明においては、ネビラピンは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Nevirapine Nevirapine is a known drug used in the treatment of HIV infection. Its chemical name is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2 ′, 3′-e] [1,4] diazepin-6-one. . Its structure is as follows:

Nevirapine is the subject of US Pat. No. 5,366,972, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises nevirapine covalently attached to a peptide. In the present invention, nevirapine is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明の組成物は、ペプチドに対して共有結合しているニトロフラントインを含んでなる。本発明においては、ニトロフラントインは、イミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Nitrofurantoin Nitrofurantoin is a known drug used in the treatment of urinary tract infections. Its structure is as follows:

The composition of the invention comprises nitrofurantoin covalently attached to a peptide. In the present invention, nitrofurantoin is covalently attached to the peptide via an imide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ニザチジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３７５，５４７；４，３８２，０９０及び４，７６０，７７５号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているニザチジンを含んでなる。本発明においては、ニザチジンは、ペプチドに対して共有結合している。本発明においては、ニザチジン又は修飾ニザチジンは、シュードウレイド基及びリンカーを介してペプチドに対し共有結合している。例えば、ジヒドロプラン−３−カルボン酸が適切なリンカーであると思われる。 Nizatidine Nizatidine is a known drug used in the treatment of gastrointestinal ulcers. Its chemical name is N- [2-[[[2-[(dimethylamino) methyl] -4-thiazolyl] methyl] thio] ethyl] -N′-methyl-2-nitro-1,1-ethenediamine. is there. Its structure is as follows:

Nizatidine is the subject of US Pat. Nos. 4,375,547; 4,382,090 and 4,760,775, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises nizatidine covalently attached to a peptide. In the present invention, nizatidine is covalently attached to the peptide. In the present invention, nizatidine or modified nizatidine is covalently attached to the peptide via a pseudoureido group and a linker. For example, dihydroplan-3-carboxylic acid appears to be a suitable linker.

オメプレゾールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，２５５，４３１；４，６３６，４９９；４，７８６，５０５及び４，８５３，２３０号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているオメプレゾールを含んでなる。本発明においては、オメプレゾールは、イミダゾ基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Omeprezole Omeprezole is a known drug used in the treatment of gastrointestinal ulcers and bacterial infections. Its chemical name is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole. Its structure is as follows:

Omeprezol is described in US Pat. Nos. 4,255,431; 4,636,499; 4,786,505 and 4,853,230, incorporated herein by reference, which describe how to make the drug. It is the subject. The composition of the invention comprises omeprezole covalently attached to a peptide. In the present invention, omeprezole is covalently attached to the peptide via an imidazo group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

オルリスタットは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５９８，０８９及び６，００４，９９６号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているオルリスタットを含んでなる。本発明においては、オルリスタットは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Orlistat Orlistat is a known drug used in the treatment of obesity, diabetes and hyperlipidemia. Its chemical name is N-formyl-L-leucine [2S- [2α (R ^* ), 3β]]-1-[(3-hexyl-4-oxo-2-oxetanyl) methyl] dodecyl ester. Its structure is as follows:

Orlistat is the subject of US Pat. Nos. 4,598,089 and 6,004,996, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises orlistat covalently attached to a peptide. In the present invention, orlistat is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明の組成物は、ペプチドに対して共有結合しているフェノバルビタルを含んでなる。本発明においては、フェノバルビタルは、イミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Phenobarbital Fenobarbital is a known drug used in the treatment of anxiety, epilepsy and insomnia. Its structure is as follows:

The composition of the invention comprises phenobarbital covalently attached to a peptide. In the present invention, phenobarbital is covalently attached to the peptide via an imide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明の組成物は、ペプチドに対して共有結合しているフェニトインを含んでなる。本発明においては、フェニトインは、ウレイド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Phenytoin Phenytoin is a known drug used in the treatment of epilepsy. Its structure is as follows:

The composition of the invention comprises phenytoin covalently attached to a peptide. In the present invention, phenytoin is covalently attached to the peptide via a ureido group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ピオグリタゾンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６８７，７７７号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているピオグリタゾンを含んでなる。本発明においては、ピオグリタゾンは、イミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Pioglitazone Pioglitazone is a known drug used in the treatment of diabetes. Its chemical name is 5-[[4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl] methyl] -2,4-thiazolidinedione. Its structure is as follows:

Pioglitazone is the subject of US Pat. No. 4,687,777, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises pioglitazone covalently attached to a peptide. In the present invention, pioglitazone is covalently attached to the peptide via an imide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明の組成物は、ペプチドに対して共有結合しているプリミドンを含んでなる。本発明においては、プリミドンは、アミド基の１つ及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Primidone Primidone is a known drug used in the treatment of epilepsy. Its structure is as follows:

The composition of the invention comprises primidone covalently attached to a peptide. In the present invention, primidone is covalently attached to the peptide via one of the amide groups and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ラベプラゾールは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２６８９５６Ｂ号明細書１９９４の主題である。本発明の組成物は、ペプチドに対して共有結合しているラベプラゾールを含んでなる。本発明においては、ラベプラゾールは、イミダゾ基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Rabeprazole Rabeprazole is a known drug used in the treatment of gastrointestinal ulcers and bacterial infections. Its chemical name is 2-[[[4- (3-methoxypropoxy) -3-methyl-2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole. Its structure is as follows:

Rabeprazole is the subject of European Patent No. 268,956B 1994, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises rabeprazole covalently attached to a peptide. In the present invention, rabeprazole is covalently attached to the peptide via an imidazo group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ラニチジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第英国特許第２２２０９３７Ｂ号明細書１９９１の主題である。本発明の組成物は、ペプチドに対して共有結合しているラニチジンを含んでなる。本発明においては、ラニチジン又は修飾ラニチジンはシュードウレイド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Ranitidine Ranitidine is a known drug used in the treatment of gastrointestinal ulcers. Its chemical name is N- [2-[[[5-[(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N′-methyl-2-nitro-1,1-ethylenediamine. . Its structure is as follows:

Ranitidine is the subject of U.S. Pat. No. 2,220,937 B, 1991, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises ranitidine covalently attached to a peptide. In the present invention, ranitidine or modified ranitidine is covalently attached to the peptide via a pseudoureido group and a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ロピニロールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，４５２，８０８及び４，８２４，８６０号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているロピニロールを含んでなる。本発明においては、ロピニロールは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Ropinirole Ropinirole is a known drug used in the treatment of Parkinson's disease. Its chemical name is (4-2 (-dipropylamino) ethyl) -1,3-dihydro-2H-indol-2-one-monohydrochloride. Its structure is as follows:

Ropinirole is the subject of US Pat. Nos. 4,452,808 and 4,824,860, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises ropinirole covalently attached to a peptide. In the present invention, ropinirole is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

マレイン酸ロジグリタゾンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，００２，９５３及び５，７４１，８０３号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているマレイン酸ロジグリタゾンを含んでなる。本発明においては、マレイン酸ロジグリタゾンは、イミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アルコール又は酸といったような）１つ以上の官能基及び１つ以上のヘテロ原子を伴う２〜６個の原子を含んだ小さな線状又は環状分子でありうる。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Roziglitazone rosiglitazone maleate is a known drug used in the treatment of diabetes. Its chemical name is 5-[[4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazolidinedione. Its structure is as follows:

Roziglitazone maleate is the subject of US Pat. Nos. 5,002,953 and 5,741,803, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises rosiglitazone maleate covalently attached to a peptide. In the present invention, rosiglitazone maleate is covalently attached to the peptide via an imide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more functional groups (such as amines, alcohols or acids) and one or more heteroatoms. For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

クエン酸シルデナフィルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，２５０，５３４号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているクエン酸シルデナフィルを含んでなる。本発明においては、クエン酸シルデナフィルは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アルコール又は酸といったような）１つ以上の官能基及び１つ以上のヘテロ原子を伴う２−６個の原子を含んだ小さな線状又は環状分子でありうる。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Sildenafil Sildenafil citrate is a known drug used in the treatment of sexual dysfunction. Its chemical name is 1-[[3- (4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxy. Phenyl] sulfonyl] -4-methyl-piperazine. Its structure is as follows:

Sildenafil citrate is the subject of US Pat. No. 5,250,534, herein incorporated by reference, which describes how to make the drug. The composition of the invention comprises sildenafil citrate covalently attached to a peptide. In the present invention, sildenafil citrate is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more functional groups (such as amines, alcohols or acids) and one or more heteroatoms. For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

タリドミドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，４６３，０６３号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているタリドミドを含んでなる。本発明においては、タリドミドは、イミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Talidimide Talidimide is a known drug used in the treatment of cachexia, diarrhea, Hansen's disease, rheumatoid arthritis, graft rejection, cancer and Crohn's disease. Its chemical name is N- (2,6-dioxo-3-piperidyl) phthalimide. Its structure is as follows:

Talidimide is the subject of US Pat. No. 5,463,063, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises thalidomide covalently attached to a peptide. In the present invention, thalidomide is covalently attached to the peptide via an imide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

本発明の組成物は、ペプチドに対して共有結合しているテオフィリンを含んでなる。本発明においては、テオフィリンは、イミダゾ基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Theophylline Theophylline is a known drug used in the treatment of asthma. Its structure is as follows:

The composition of the invention comprises theophylline covalently attached to a peptide. In the present invention, theophylline is covalently attached to the peptide via an imidazo group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ヴァルスポダルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２９６１２２Ｂ号明細書１９９３の主題である。本発明の組成物は、ペプチドに対して共有結合しているヴァルスポダルを含んでなる。本発明においては、ヴァルスポダルは、アミド基の１つ及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Valspodal Valspodal is a known drug used in the treatment of cancer. Its chemical name is 6-[[R- (E)]-6,7-didehydro-N, 4-dimethyl-3-oxo-L-2-aminooctanoic acid] -7-L-valine-cyclosporin A. is there. Its structure is as follows:

Valspodal is the subject of EP 296122B 1993, hereby incorporated by reference, which describes how to make the drug. The composition of the invention comprises a Valspodal covalently attached to a peptide. In the present invention, Valspodal is covalently attached to the peptide via one of the amide groups and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

ザフィルルカストは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１９９５４３Ｂ号明細書１９９１、欧州特許第４９０６４８Ｂ号明細書１９９５、欧州特許出願第４９０６４９Ａ号明細書１９９２及び米国特許第４，８５９，６９２；５，２９４，６３６；５，３１９，０９７；５，４８２，９６３；５，５８３，１５２及び５，６１２，３６７号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているザフィルルカストを含んでなる。本発明においては、ザフィルルカストは、アミド基及びリンカーを介してペプチドに対し共有結合している。このリンカーは、１つ以上のヘテロ原子及び１つ以上の官能基（アミン、アミド、アルコール又は酸など）を伴う２〜６個の原子を含む小さい線状又は環状分子であり得る。例えばリンカーとして、ジヒドロピラン−３−カルボン酸が適していると思われる。 Zafirlukast Zafirlukast is a known drug used in the treatment of asthma and rhinitis. Its chemical name is [3-[[2-methoxy-4-[[[2-methylphenyl] sulfonyl] amino] carbonyl] phenyl] methyl] -1-methyl-1H-indol-5-yl] carbamate cyclopentyl. Ester. Its structure is as follows:

Zafirlukast describes European Patent Application No. 1995543B 1991, European Patent No. 490648B 1995, European Patent Application No. 490649A 1992 and US Patents, which are incorporated herein by reference. 4,859,692; 5,294,636; 5,319,097; 5,482,963; 5,583,152 and 5,612,367. The composition of the invention comprises zafirlukast covalently attached to a peptide. In the present invention, zafirlukast is covalently attached to the peptide via the amide group and a linker. The linker can be a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups (such as amines, amides, alcohols or acids). For example, dihydropyran-3-carboxylic acid may be suitable as a linker.

XII. Mesna through the G-thiol group Mesna is used prophylactically as a urinary protective agent to reduce the prevalence of hemorrhagic cystitis in patients receiving ifosfamide. Its structure is as follows:
_{HS-CH 2} -CH ₂ -SO ₃
Mesna is the subject of US Pat. Nos. 4,220,660 and 5,696,172, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises mesna covalently attached to a peptide. In the present invention, mesna is covalently attached to the peptide via the thiol group.

本発明の組成物は、ペプチドに対して共有結合しているエトリコキシブである。本発明においては、エトリコキシブは、サルフェート基を介してペプチドに対し共有結合している。 XII. Etoroxib via H-sulfate group Etoroxib is a second generation cyclooxygenase II inhibitor. Its structure is as follows:

The composition of the invention is etoroxixib covalently attached to a peptide. In the present invention, etoroxib is covalently attached to the peptide via the sulfate group.

ポリ硫酸ペントサンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，１８０，７１５号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているポリ硫酸ペントサンを含んでなる。本発明においては、ポリ硫酸ペントサンは、サルフェート基を介してペプチドに対し共有結合している。 Polysulfate Pentosan Polysulfate pentosan is a known drug used in the treatment of arthritis, angina pectoris, hyperlipidemia, rheumatoid arthritis, cancer and cystitis. Its chemical name is (1-4) -β-D-xylan 2,3-bis (hydrogen sulfate). Its structure is as follows:

Polysulfate pentosan is the subject of US Pat. No. 5,180,715, herein incorporated by reference, which describes how to make the drug. The composition of the invention comprises polysulfate pentosan covalently attached to a peptide. In the present invention, polysulfate pentosan is covalently attached to the peptide via the sulfate group.

XII. I-activated protein C via protein binding
Activated protein C is a known drug used in the treatment of thrombi. Its structure is well known and commercially available, and at the same time is easily manufactured by those skilled in the art using published synthetic schemes. Carrier peptides attached to proteins are usually formed using standard chemical reactions.

Alpha 1 proteinase inhibitors Alpha 1 proteinase inhibitors are known drugs used in the treatment of emphysema. This is a natural product isolated from human blood using methods known to those skilled in the art. The carrier peptide attached to the protein is usually attached to the peptide using standard chemical reactions.

タンパク質に付着したキャリアペプチドは、通常は、標準的な化学反応を用いて形成される。 Analitide Analitide is a known drug used in the treatment of oliguric acute renal failure. Its chemical name is NL-arginyl-8-L-methionine-21a-L-phenylalanine-21b-L-arginine-21c-L-tyrosine-atriopeptin-21. Its structure is as follows:

Carrier peptides attached to proteins are usually formed using standard chemical reactions.

Atrial Natriuretic Peptide Atrial natriuretic peptide is a vasodilator and diuretic. Its structure is ArgSerSerCysPheGlyGlyArgMetAspArgIleGlyAlaGlnSerGlyLeuGlyCysAsnSerPheArgTyr. The carrier peptide is attached to the peptide using standard peptide chemistry

Bactericidal / Permeability Increased (BPI) Protein The bactericidal / increased permeability (BPI) protein derivatives of the present invention, in particular the BPI-21 derivatives, are known agents used in the treatment of septic shock. BPI was isolated from human blood cells. The composition of the invention comprises a bactericidal / permeability increasing protein derivative covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Endothelin A Receptor Antagonists The selective endothelin A receptor antagonists of the present invention are a known drug used in the treatment of heart failure (known as BMS193388). The composition of the invention comprises a selective endothelin A receptor antagonist covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Epoetin Epoetin is a known drug used in the treatment of anemia. Its chemical name is 1-165-erythropoietin (human clone lambda HEPOFL13 protein portion) glycoform alpha. Epoetin is the subject of European Patent No. 148605B (1990), priority US Patent Application No. 561024 (1983), incorporated herein by reference, which describes how to make that drug. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Ethanercept Ethanercept is a known drug used in the treatment of arthritis. Its chemical name is 1-235-tumor necrosis factor receptor (human) fusion protein with 236-467-immunoglobulin G1 (human γ1-chain FC fragment). Etanercept is the subject of European Patent No. 4180414B (1995), based on priority US patent application No. 403241 (1989), incorporated herein by reference, which describes how to make that drug. . A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Exendin Exendin-4 is a known drug used in the treatment of diabetes. This is a synthetic form of a peptide isolated from salivary secretions of the American lizard. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Filgrastim Filgrastim is a known drug used in the treatment of cancer, HIV infection, pneumonia, leukopenia and skin ulcers. Its chemical name is NL-methionyl-colony stimulating factor (human clone 1034). Filgrastin is the subject of European Patent No. 237545B (1991) based on priority application US Pat. No. 768,959 (1985), which is incorporated herein by reference, which describes how to make that drug. is there. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Follitropin Follitropin is a known drug used in the treatment of infertility. Its chemical name is follicle stimulating hormone (from human alpha-subunit) complex with follicle stimulating hormone (from human beta-subunit).
Follitropin is described in WO 95/19991 (1995) and US Pat. No. 4,589,402; 5,270,057 and 5, which are incorporated herein by reference, which describe how to make the drug. No. 767,251. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Gastrin Immunogen Gastrimin is an immunogenic form of gastrin-17 (G17), a growth factor for colorectal, gastric and pancreatic cancer. Its use is as a vaccine for cancer and gastrointestinal ulcers.
Gastrin 17 immunogen describes US Pat. Nos. 5,622,702; 5,785,970; 5,607,676 and 5,609,870, incorporated herein by reference, which describe how to make the drug. The subject of the description. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Glatiramer acetate is a known drug used in the treatment of multiple sclerosis. Its chemical name is L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine acetate.
Glatiramer acetate is the subject of US Pat. Nos. 6,054,430 and 5,981,589, incorporated herein by reference, which describe how to make the drug. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Glucagon Glucagon is a known drug used in the treatment of diabetes. This is a naturally occurring peptide that can be isolated or synthesized, preferably using recombinant DNA technology. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Humanized monoclonal antibody hu1124
Humanized monoclonal antibody hu1124 directed against CD11a is a known drug used in the treatment of dryness and graft rejection.
Humanized monoclonal antibody hu1124 directed against CD11a is the subject of US Pat. No. 5,622,700, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises a humanized monoclonal antibody hu1124 directed against CD11a covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Irodecaquin Irodecaquin is a known drug used in the treatment of pneumonia, autoimmune diseases and HIV infection. Its chemical name is interleukin 10, which can be isolated from natural sources or synthesized by one skilled in the art. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Imiglucerase Imiglucerase is a known drug used in the treatment of Gaucher disease. Its chemical name is glucosyl- (human placental isoenzyme protein portion) 495-L-histidine-ceramidase. This is a recombinant glucocerebrosidase enzyme. Imiglucerase is the subject of EP 401362B (1996) based on priority application US Pat. No. 2,289,589 (1988), which is incorporated herein by reference, which describes how to make the drug. . A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Infliximab Infliximab is a known drug used in the treatment of arthritis and HIV infection. It is a monoclonal antibody that targets tumor necrosis factor alpha. Its chemical name is immunoglobulin G with human-mouse monoclonal cA2 light chain dimer, anti- (human tumor necrosis factor) (human-mouse monoclonal cA2 heavy chain), disulfide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

ヒトインシュリンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，４７４，９７８及び５，５１４，６４６号明細書の主題である。タンパク質に付着したキャリアペプチドは、通常、典型的なペプチド化学反応を用いて形成される。 Insulin Human insulin is a known drug used in the treatment of diabetes. Human insulin is a biosynthetic or semisynthetic protein that is structurally identical to endogenous insulin secreted by human pancreatic beta cells. Although structurally identical to endogenous human insulin, commercially available human insulin is not extracted from human pancreas and is derived from a genetically modified Escherichia coli or Saccharomyces cerevisiae culture. Prepared synthetically or semi-synthetically by peptide transfer of porcine insulin. Its structure is as follows:

Human insulin is the subject of US Pat. Nos. 5,474,978 and 5,514,646, incorporated herein by reference, which describe how to make that drug. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Insulin Analogs The insulin analogs of the present invention are known drugs used in the treatment of diabetes. Its chemical name is human 29B- [N6- (1-oxotetradecyl) -L-lysine]-(1A-21A), (1B-29B) -insulin. The composition of the invention comprises an insulin analogue covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Interferon Alphacon-1
Interferon alphacon-1 is a known drug used in the treatment of viral infections and cancer. Its chemical name is interferon α1 (derived from human lymphoblasts), NL-methionyl-22-L-arg-76-L-ala-78-L-asp-79-L-glu-86-L-tyr. -90-L-tyr-156-L-thr-157-L-asn-158-L-leu.
Interferon alfacon-1 is described in European Patent No. 422697B (1994) based on priority US Patent Application No. 375494 (1982), which is incorporated herein by reference, which describes how to make that drug. ). A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Interferon beta-1a
Interferon β-1a is a known drug used in the treatment of multiple sclerosis, viral infections and cancer. This is derived from 145258-61-3 human fibroblast protein portion 74899-73-3 pre- (derived from human fibroblast protein portion) 74899-71-1 human fibroblasts. Biogen was awarded European Patent No. 41313 for the production of interferon β through recombinant technology. This patent covered recombinant DNA molecules, transformed hosts, and methods for producing recombinant interferon beta protein. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Interleukin-2
Interleukin-2 is a known drug used in the treatment of renal cell carcinoma. IL-2 promotes proliferation, differentiation and recruitment of T and B cells, natural killer (NK) cells, and thymocytes. IL-2 also causes cytolytic activity within the lymphocyte subset and subsequent interaction between the immune system and malignant cells. IL-2 can stimulate rack (LAK) cells and tumor infiltrating lymphocytes (TIL) cells. LAK cells (derived from patient-derived lymphocytes and incubated in IL-2) have the ability to lyse cells that are resistant to NK cells. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Interleukin-12
Interleukin-12 is a heterodimeric cytokine produced by native antigen presenting cells and B cells, such as phagocytic dendritic cells and skin Langerhans cells. The production of interleukin-12 is triggered by bacteria, intracellular pathogens, fungi, viruses, or their products in T cell independent or T cell dependent pathways, the latter through CD40 ligand-CD40 interaction Be mediated. Interleukin-12 is produced rapidly after infection and acts as a pro-inflammatory cytokine that triggers the production of interferon gamma by T and natural killer cells that activate phagocytic cells. The production of interleukin-12 is strictly regulated by positive and negative feedback mechanisms. When interleukin 12 and interleukin 12-induced interferon gamma are present during early T cell expansion in response to antigen, it favors T-helper type 1 cell generation and T-helper type 2 cell generation is Be inhibited. Thus, interleukin-12 is also a potent immunoregulatory cytokine that promotes T-helper type 1 differentiation, and T-helper type 1 against infection by bacteria, intracellular parasites, fungi and certain viruses. Useful in dependency tolerance. By inhibiting the T-helper type 2 cell response, interleukin-12 has a suppressive effect on the allergic response; by promoting the T-helper type 1 response it is Participate in causative immunopathology. Viruses that induce permanent or transient immunosuppression, such as HIV and measles, can act in part by suppressing interleukin-12 production. Due to its ability to enhance resistance to multiple infectious diseases and act as an additive in vaccination, and because of its potent anti-tumor effect in vivo, interleukin-12 is currently present in cancer patients and HIV-infected patients. It is in clinical trials and is being considered for therapeutic use in other diseases. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

LFA3TIP immunosuppressive protein The immunosuppressive protein of the present invention is a known drug used in dry therapy. It is a recombinant fusion protein, LFA3TIP. Immunosuppressive proteins are the subject of US Pat. No. 5,547,853, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises an immunosuppressive protein covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Lintuzumab Lintuzumab is a known drug used in the treatment of cancer. Its chemical name is immunoglobulin G1 with human monoclonal HuM195κ-chain, dimer (human-mouse monoclonal HuM195γ1-chain anti-human antigen CD33), disulfide. Lintuzumab is the subject of US Pat. No. 5,585,089 (1996), incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises lintuzumab covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

LYM1
LYM1 is an antibody used in cancer treatment. The novel pharmaceutical compounds of the present invention are useful in achieving one or more of the following end objectives: namely, enhancing the chemical stability of the original compound; Modification of release profile; enhanced digestion or absorption; targeted delivery to specific tissues / cell types; and provision of oral dosage forms when none are present. The novel pharmaceutical compound may contain one or more of the following: another active agent, additive or inhibitor. The composition of the invention comprises LYM1 covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Macrophage Colony Stimulating Factor The macrophage colony stimulating factor of the present invention is a known drug used in the treatment of mycosis, hyperlipidemia, wounds and bacterial infections. It is the human clone pcCSF-17 precursor protein that is the subject of European Patent No. 209601B (1993) based on US Patent Application No. 698359 (1985), incorporated herein by reference. The composition of the invention comprises a macrophage colony stimulating factor covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Mecasermin Mecasermin is a known drug used in the treatment of hormonal disorders, amyotrophic lateral sclerosis, neuropathy, kidney disease and osteoarthritis. Its chemical name is insulin-like growth factor I (human). Mecasermin is described in European Patent No. 476044B 1997, priority US Pat. No. 3,615,959, and European Patent No. 219814B, 1991, incorporated herein by reference, which describes how to make the drug. The subject. The composition of the invention comprises mecasermin covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Nesitide Nesitide is a known drug used in the treatment of hypertension and heart failure. Its chemical name is brain natriuretic peptide-32, a natural product. Nejitide is the subject of European Patent No. 418308B 1995, priority US Patent No. 2003033 1988, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises a tilitide that is covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Oprelbekin Oprelbekin is a known drug used in the treatment of cancer, HIV infection, mucositis and Crohn's disease. It is recombinant interleukin-11. Oprelbequin is the subject of EP 504177A 1992, priority US 441100 1989, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises oprelbequin covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Palivizumab A monoclonal antibody, palivizumab, is a known drug used in the treatment of respiratory and viral infections. Its chemical name is immunoglobulin G1, anti- (respiratory syncytium virus protein F) (human-mouse monoclonal MEDI-493γ1-chain), disulfide, with human-mouse monoclonal MEDI-493κ-chain, dimer. .
It is the subject of US Pat. No. 5,585,089, incorporated herein by reference. The composition of the invention comprises palivizumab covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Prourokinase Prourokinase is a known drug used in the treatment of thrombosis. Prourokinase is the subject of US Pat. No. 5,741,682, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises prourokinase covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Recombinant Hepatitis B Vaccine The recombinant hepatitis B vaccine of the present invention is used for immunization against hepatitis B virus infection. The composition of the invention comprises a recombinant hepatitis B vaccine covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Relaxin Relaxin is a known drug used in the treatment of scleroderma, scarring, infertility and peripheral vascular disorders. This is a recombinant natural protein. Relaxin is the subject of EP 112149B 1991, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises relaxin covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Rotavirus vaccine Rotavirus vaccine is a known drug used in the prevention of viral infections. The composition of the invention comprises a rotavirus vaccine covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Zagramostin Zagramostin is a known drug that is a granulocyte macrophage-colony stimulating factor used for the treatment of cancer and HIV infection. Its chemical name is 23-L-leucine colony stimulating factor 2 (human clone pHG25 protein portion). Sagramostin is described in European Patent No. 183350B 1992, priority US Pat. No. 6,660,041 1984 and European Patent No. 219914B 1992, which is incorporated herein by reference, which describes how to make the drug. This is the subject of U.S. Patent No. 763130 1985. The composition of the invention comprises sagramostin covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Sevirumab Sevirumab is a known drug used in the treatment of giant cell inclusion body disease. Its chemical name is human monoclonal EV2-7, kappa-chain, dimer, immunoglobulin G1, anti- (cytomegalovirus) (human monoclonal EV2-7γ1-chain), disulfide. Sevirumab is the subject of US Pat. No. 5,750,106, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises sevirumab covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Sinapultide is a known drug used in the treatment of respiratory distress syndrome. It is a mimic of human surfactant B protein for the treatment of meconium aspiration syndrome. Its structure is as follows: Lys-Leu-Leu-Leu-Leu-Lys-Leu-Leu-Leu-Leu-Lys-Leu-Leu-Leu-Leu-Lys-Leu-Leu-Leu-Leu-Leu-Lys . Sinapultide is the subject of WO 92/22315 1992, priority US Pat. No. 7,153,597, which is incorporated herein by reference, describing how to make the drug. The composition of the invention comprises cinapultide covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Soluble chimeric protein CTLA4Ig
The soluble chimeric protein CTLA4Ig is a known drug used in the treatment of psoriasis and graft rejection. The soluble chimeric protein CTLA4Ig is the subject of EP 606217B 1998, priority US Pat. No. 723617 1991, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises the soluble chimeric protein CTLA4Ig covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Teriparatide Teriparatide is a known drug used in the treatment of thyroid deficiency. It is a parathyroid hormone. The composition of the invention comprises teriparatide covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Thrombopoietin Thrombopoietin is a human protein used in the treatment of thrombocytopenia. The composition of the invention comprises thrombopoietin covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Thymosin alpha Thymosin alpha is a known drug used in the treatment of hepatitis B. Thymosin alpha is the subject of US Pat. No. 4,079,127, herein incorporated by reference, which describes how to make that drug. The composition of the invention comprises thymosin alpha covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Tifacodin Tifacodin, a tissue factor pathway inhibitor, is a known drug used in thrombosis and septic shock. Its structure is NL-alanyl-blood clotting factor LACI (human clone lambda P9, derived from protein portion). Tifacodine is the subject of Canadian Patent Application No. 2196296, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises tifacodin covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

TPA analogs TPA analogs are known drugs used in the treatment of acute myocardial infarction. It relates to naturally occurring tissue plasminogen activator and is disclosed in European Patent No. 293934B 1994, priority US Pat. No. 58217 1987, which is incorporated herein by reference. . The composition of the invention comprises a TPA analog covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Trastuzumab Trastuzumab is a monoclonal antibody used in the treatment of metastatic breast cancer. Trastuzumab is the subject of US Pat. No. 5,677,171, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises trastuzumab covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

Urokinase Urokinase is a lytic and unstable hemodynamic (ie, assisted) of acute widespread pulmonary embolism (occlusion or substantial shadow defect involving two or more lobar pulmonary arteries or other intravascular equivalent embolism) in adults It is used for embolization with blood pressure that cannot be maintained without measures. This drug is generally most effective at dissolving recently formed thrombi. Urokinase is an enzyme produced by the kidneys and excreted in the urine. Commercial urokinase is isolated from human renal tissue culture and contains both high molecular weight of 55,000 daltons and low molecular weight form of 34,000 daltons. The drug is water soluble. Urokinase is commercially available as a lyophilized white powder that also contains human albumin, mannitol, sodium chloride or gelatin, mannitol, sodium chloride and anhydrous sodium monophosphate. The composition of the invention comprises urokinase covalently attached to a peptide. A carrier peptide attached to a protein is usually formed using typical peptide chemistry.

XII. For drugs lacking a functional group that is adaptable to the formation of a stable bond with a peptide via a J-tertiary amine, the prodrug is re-established as the reference drug upon release of the prodrug from the carrier peptide. It may be necessary to modify the drug to form a prodrug in such a way that it is deployed. The following categories of drugs, tertiary amines, fall into this category.

本発明においてはアルプラザロム又は修飾アルプラザロムはリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Alprasalom Alprasalom is a known drug used in the treatment of anxiety disorders. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, Alprazarom or modified Alprazarom is covalently attached to the peptide via a linker. This linker may be a small molecule containing one or more functional groups (such as amines, alcohols or acids) and 2-6 carbons, or alternatively a short chain of either amino acids or carbohydrates May consist of:

本発明においては、アルチニクリン又は修飾アルチニクリンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。アルチニクリンは、市販されていると同時に、公開済の合成スキームを用いて当業者によって容易に製造されるものでもある。 Artiniclin Artiniclin is a known drug used in the treatment of Parkinson's disease. Its chemical name is 3-ethynyl-5-[(2S) -1-methyl-2-pyrrolidinyl] pyridine. Its structure is as follows:

In the present invention, artinicline or modified articularin is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains. Artiniclin is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes.

アナストロゾールは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第２９６７４９Ｂ明細書（１９９４）、優先権英国特許第１４０１３号明細書（１９８７）の主題である。本発明においては、アナストロゾール又は修飾アナストロゾールは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Anastrozole Anastrozole is a known drug used in the treatment of breast cancer. Its chemical name is α, α, α ′, α′-tetramethyl-5- (1H-1,2,4-triazol-1-ylmethyl) -1,3-benzenediacetonitrile. Its structure is as follows:

Anastrozole is the subject of EP 296749B (1994), priority British Patent 14013 (1987), incorporated herein by reference, which describes how to make the drug. In the present invention, anastrozole or modified anastrozole is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、アミトリプチリン又は修飾アミトリプチリンはリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Amitriptyline Amitriptyline is a known drug used in the treatment of depression. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, amitriptyline or modified amitriptyline is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

アリピプラゾールは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第３６７１４１Ｂ号明細書（１９９６）（優先権日本特許第２７６９５３号明細書（１９８８））の主題である。本発明においては、アリピプラゾール又は修飾アリピプラゾールは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Aripiprazole Aripiprazole is a known drug used to reduce both positive and negative symptoms in patients with acute psychiatric disorders. Its chemical name is 7- [4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy] -3,4-dihydro-2 (1H) -quinolinone. Its structure is as follows

Aripiprazole is the subject of EP 367141B (1996) (priority Japanese Patent No. 76953 (1988)), incorporated herein by reference, which describes how to make the drug. In the present invention, aripiprazole or modified aripiprazole is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

アバジミブは、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９４／２６７０２号パンフレット１９９４（優先権米国特許第６２５１５（１９９３））の主題である。本発明においては、アバジミブ又は修飾アバジミブは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Avadimib Avadimib is a known drug used in the treatment of hyperlipidemia. Its chemical name is N-[[2,6-bis (1-methylethyl) phenoxy] sulfonyl] -2,4,6-tris (1-methylethyl) benzeneacetamide. Its structure is as follows:

Avadimib is the subject of WO 94/26702 1994 (priority US Pat. No. 62,515 (1993)), incorporated herein by reference, which describes how to make the drug. In the present invention, avadimib or modified avadimib is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

アゼラスチンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，１６４，１９４号明細書の主題である。本発明においては、アゼラスチン又は修飾アゼラスチンはリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Azelastine Azelastine is a known drug used in the treatment of eye itch associated with allergic conjunctivitis. Its chemical name is 4-[(4-chlorophenyl) methyl] -2- (hexahydro-1-methyl-1H-azepin-4-yl) -1 (2H) -phthalazinone. Its structure is as follows:

Azelastine is the subject of US Pat. No. 5,164,194, herein incorporated by reference, which describes how to make that drug. In the present invention, azelastine or modified azelastine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、メシル酸ベンザトロピン及び修飾メシル酸ベンザトロピンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Benzatropine mesylate Benzatropine mesylate is a known drug used in the treatment of Parkinson's disease-like symptoms. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, benzatropine mesylate and modified benzatropine mesylate are covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ブスピロンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，１８２，７６３及び５，０１５，６４６号明細書の主題である。本発明においては、ブスピロン又は修飾ブスピロンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Buspirone Buspirone is a known drug used in the treatment of atopic dermatitis. Its chemical name is 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4,5] decane-7,9-dione hydrochloride. Its structure is as follows:

Buspirone is the subject of US Pat. Nos. 4,182,763 and 5,015,646, herein incorporated by reference, which describes how to make the drug. In the present invention, buspirone or modified buspirone is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、カフェイン又は修飾カフェインは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Caffeine Caffeine is a known drug used in the treatment of neonatal anemia. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, caffeine or modified caffeine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

カンデサルタン・シレキシチルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，１９６，４４４；５，５３４，５３４；５，７０３，１１０及び５，７０５，５１７号明細書の主題である。本発明においては、カンデサルタン・シレキシチル又は修飾カンデサルタン・シレキシチルはリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Candesartan cilexetil Candesartan cilexetil is a known drug used in the treatment of heart failure. Its chemical name is 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) [1,1′-biphenyl] -4-yl] methyl] -1-H-benzimidazole-7- Carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxy] ethyl ester. Its structure is as follows:

Candesartan cilexetil describes US Pat. Nos. 5,196,444; 5,534,534; 5,703,110 and 5,705,517, incorporated herein by reference, which describe how to make the drug. The subject of the book. In the present invention, candesartan cilexetil or modified candesartan cilexetil is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

セレコキシブは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，４６６，８２３；５，５６３，１６５；５，７６０，０６８及び５，９７２，９８６号明細書の主題である。本発明においては、セレコキシブ又は修飾セレコキシブは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Celecoxib Celecoxib is a known drug used in the treatment of osteoarthritis and rheumatoid arthritis. Its chemical name is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide. Its structure is as follows:

Celecoxib is described in US Pat. Nos. 5,466,823; 5,563,165; 5,760,068 and 5,972,986, incorporated herein by reference, which describe how to make the drug. It is the subject. In the present invention, celecoxib or modified celecoxib is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、クロルフェニラミン又は修正クロルフェニラミンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Chlorpheniramine Chlorpheniramine is a known drug used in the treatment of nasal congestion. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, chlorpheniramine or modified chlorpheniramine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ベシル酸シスアトラキュリウムは、該薬物の作り方を記載する、本書中に参考として内含された米国特許５，４５３，５１０及び国際公開第９２／９６５号パンフレット（１９９２）の主題である。本発明においては、シスアトラキュリウム又は修飾シスアトラキュリウムは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Cisatracurium besylate Cisatracurium besylate is a known drug used as a neuromuscular blocking agent in surgery. Its chemical name is [1R- [1a, 2a (1′R ^* , 2′R ^* )]]-2,2 ′-[1,5-pentanediylbis [oxy (3-oxoo-3,1- Propanediyl)]] bis [1-[(3,4-dimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-isoquinolinium. Its structure is as follows:

Cisatracurium besylate is the subject of US Pat. No. 5,453,510 and WO 92/965 (1992), herein incorporated by reference, which describes how to make the drug. In the present invention, cisatracurium or modified cisatracurium is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

シタロプラムは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１５２６３３１号明細書（１９７８）、英国特許第１４８６号明細書（１９７６）及び欧州特許第１７１９４３Ｂ号明細書（１９８８）の主題である。本発明においては、シタロプラム又は修飾シタロプラムは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Citalopram Citalopram is a known drug used in the treatment of depression. Its chemical name is 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile. Its structure is as follows:

Citalopram describes British Patent No. 1526331 (1978), British Patent No. 1486 (1976) and European Patent No. 171943B, which are incorporated herein by reference, describing how to make the drug. 1988). In the present invention, citalopram or modified citalopram is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、クロミプラミン又は修正クロミプラミンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Clomipramine Clomipramine is a known drug used in the treatment of threatening neurosis. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, clomipramine or modified clomipramine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

クロピドグレルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５２９，５９６；４，８４７，２６５及び５，５７６，３２８号明細書の主題である。本発明においては、クロピドグレル又は修飾クロピドグレルは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Clopidogrel Clopidogrel is a known drug used in the treatment of thrombosis and stroke. Its chemical name is (S) -a- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetic acid methyl ester sulfate (1: 1). Its structure is as follows:

Clopidogrel is the subject of US Pat. Nos. 4,529,596; 4,847,265 and 5,576,328, incorporated herein by reference, which describe how to make the drug. In the present invention, clopidogrel or modified clopidogrel is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、シクロベンザプリン又は修飾シクロベンザプリンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Cyclobenzaprine Cyclobenzaprine is a known drug used in the treatment of muscle spasms. Its chemical name is 3- (5H-dibenzo [a, d] cyclopentene-5-ylidene) -N, N-dimethyl-1-propanamine. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, cyclobenzaprine or modified cyclobenzaprine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、デキストロメトルファン又は修正デキストロメトルファンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Dextromethorphan Dextromethorphan is a known drug used in the treatment of cough. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, dextromethorphan or modified dextromethorphan is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

Diacetylmorphine Diacetylmorphine is a known drug used in the treatment of pain. The composition of the invention comprises diacetylmorphine covalently attached to a peptide. In the present invention, diacetylmorphine or modified diacetylmorphine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、ジアゼパム又は修飾ジアゼパムは、リンカーを介してを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Diazepam Diazepam is a known drug used in the treatment of anxiety. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, diazepam or modified diazepam is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、ジシクロミン又は修飾ジシクロミンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Dicyclomine Dicyclomine is a known drug used in the treatment of dysfunction of gastrointestinal motility such as irritable bowel syndrome. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, dicyclomine or modified dicyclomine is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ジルチアゼムは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，５２９，７９１号明細書の主題である。本発明においては、ジルチアゼム又は修飾ジルチアゼムは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Diltiazem Diltiazem is a known drug used in the treatment of hypertension and angina. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

Diltiazem is the subject of US Pat. No. 5,529,791, incorporated herein by reference, which describes how to make that drug. In the present invention, diltiazem or modified diltiazem is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、フェンタニル又は修飾フェンタニルは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Fentanyl Fentanyl is a known drug used in the treatment of pain. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. Its structure is as follows:

In the present invention, fentanyl or modified fentanyl is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

フルマゼニルは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３１６，８３９号明細書の主題である。本発明においては、フルマゼニル又は修飾フルマゼニルは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Flumazenil Flumazenil is a known drug used in the treatment of depression and liver disease. Its chemical name is 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl ester. Its structure is as follows:

Flumazenil is the subject of US Pat. No. 4,316,839, herein incorporated by reference, which describes how to make that drug. In the present invention, flumazenil or modified flumazenil is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ゼピロンは、該薬物の作り方を記載する、本書中に参考として内含された優先権米国特許出願第３３４６８８号明細書（１９８１）に基づく英国特許第２１１４１２２Ｂ号明細書（１９８５）の主題である。本発明においては、ゼピロン又は修飾ゼピロンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Zepirone Zepirone is a known drug used in the treatment of anxiety and depression. Its chemical name is 4,4-dimethyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperidinedione. Its structure is as follows:

Zepirone is the subject of British Patent No. 2114122B (1985), based on priority US Patent Application No. 334688 (1981), incorporated herein by reference, which describes how to make that drug. In the present invention, zepilone or modified zepilone is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、イミプラミン又は修飾イミプラミンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Imipramine Imipramine is a known drug used in the treatment of depression. Its structure is as follows:

In the present invention, imipramine or modified imipramine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

Isosorbide dinitrate Isosorbide dinitrate is a known drug used in the treatment of angina. It consists of organic nitrates and nitrites which are esters of nitrous acid or nitric acid, mainly amyl nitrite. In the present invention, isosorbide dinitrate is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

イルベサルタンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，２７０，３１７号明細書の主題である。本発明においては、イルベサルタン又は修飾イルベサルタンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Irbesartan Irbesartan is a known drug used in the treatment of hypertension. Its chemical name is 2-butyl-3-[[2 ′-(1H-tetrazol-5-yl) [1,1′-biphenyl] -4-yl] methyl] -1,3-diazaspiro [4.4. ] Non-1-en-4-one. Its structure is as follows:

Irbesartan is the subject of US Pat. No. 5,270,317, herein incorporated by reference, which describes how to make that drug. In the present invention, irbesartan or modified irbesartan is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

イトラコナゾールは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，２６７，１７９；４，７２７，０６４及び５，７０７，９７５号明細書の主題である。本発明においては、イトラコナゾール又は修飾イトラコナゾールは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Itraconazole Itraconazole is a known drug used in the treatment of mycosis. Its chemical name is 4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2-[(1H-1,2,4-triazol-1-yl) methyl] -1). , 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one is there. Its structure is as follows:

Itraconazole is the subject of US Pat. Nos. 4,267,179; 4,727,064 and 5,707,975, incorporated herein by reference, which describe how to make the drug. In the present invention, itraconazole or modified itraconazole is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明においては、ケトコナゾール又は修飾ケトコナゾールは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Ketoconazole Ketoconazole is blastomises, candida infections (ie, oropharyngeal and / or esophageal candidiasis, vulvovaginal candidiasis, candidauria, chronic mucocutaneous candidiasis), chromomicosis (chromoblastosmosis), coccidioidomycosis , Used in the treatment of histoplasmosis and paracoccidioidomycosis. Its structure is as follows:

In the present invention, ketoconazole or modified ketoconazole is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

レフルノミドは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，６７９，７０９号明細書である。本発明においては、レフルノミド又は修飾レフルノミドは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Leflunomide Leflunomide is a known drug used in the treatment of rheumatoid arthritis. Its chemical name is 5-methyl-N- [4- (trifluoromethyl) phenyl] -4-isoxazolecarboxamide. Its structure is as follows:

Leflunomide is US Pat. No. 5,679,709, incorporated herein by reference, which describes how to make the drug. In the present invention, leflunomide or modified leflunomide is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

レソピトロンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許出願公開第３８２６３７Ａ号明細書（１９９０）の主題である。本発明においては、レソピトロン又は修飾レソピトロンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Resopitron Resopitron is a known drug used in the treatment of anxiety. Its chemical name is 2- [4- [4- (4-chloro-1H-piperazol-1-yl) butyl] -1-piperazinyl] pyrimidine dihydrochloride. Its structure is as follows:

Resopitron is the subject of EP-A-382637A (1990), incorporated herein by reference, which describes how to make the drug. In the present invention, resopitron or modified resopitron is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

Lipoxygenase inhibitor The lipoxygenase inhibitor of the present invention is a known drug having the chemical name (R) -2-chloro-5- (2-azetidinylmethoxy) pyridine. The composition of the invention comprises a lipoxygenase inhibitor covalently attached to a peptide. In the present invention, the lipoxygenase inhibitor or the modified lipoxygenase inhibitor is covalently bound to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ロラチジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，２８２，２３３；４，６５９，７１６及び４，８６３，９３１号明細書の主題である。本発明の組成物は、ペプチドに対し共有結合しているロラチゾン又は修飾ロラチジンを含んでなる。本発明においては活性物質は、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Loratidine Loratidine is a known drug used in the treatment of allergies and rhinitis. Its chemical name is ethyl 4- (8-chloro-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridine-11-ylidene-1-piperidinecarboxylate. The structure is as follows:

Loratidine is the subject of U.S. Pat. Nos. 4,282,233; 4,659,716 and 4,863,931, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises loratizone or modified loratidine covalently attached to a peptide. In the present invention, the active substance is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ミルタザピンは、該薬物の作り方を記載する、本書中に参考として内含された英国特許第１５４３１７１号明細書１９７９の主題である。本発明の組成物は、ペプチドに対して共有結合しているミルタザピンを含んでなる。本発明においては、ミルタザピン又は修飾ミルタザピンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Mirtazapine Mirtazapine is a known drug used in the treatment of depression. Its chemical name is 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] [2] benzazepine. Its structure is as follows:

Mirtazapine is the subject of GB 1543171 1979, hereby incorporated by reference, which describes how to make the drug. The composition of the invention comprises mirtazapine covalently attached to a peptide. In the present invention, mirtazapine or modified mirtazapine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ミバクリウムは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，７６１，４１８号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているミバクリウムを含んでなる。本発明においては、ミバクリウム又は修飾ミバクリウムは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Mibacurium Mivacurium is a known drug used as a neuromuscular blocking agent and muscle relaxant. Its chemical name is [R- [R ^* , R ^* -(E)]]-2,2 '-[(1,8-dioxo-4-octene-1,8-diyl) bis (oxy-3, 1-propanediyl)] bis [1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl) methyl] -isoquinolinium chloride It is. Its structure is as follows:

Mibacurium is the subject of US Pat. No. 4,761,418, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises mibacurium covalently attached to a peptide. In the present invention, mivacurium or modified mibacurium is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ネファゾドンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３３８，３１７及び５，２５６，６６４号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているネファゾドンを含んでなる。本発明においては、ネファゾドン又は修飾ネファゾドンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Nefazodone Nefazodone is a known drug used in the treatment of depression. Its chemical name is 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-2,4-dihydro-4- (2-phenoxyethyl) -3H-1,2, , 4-triazol-3-one. Its structure is as follows:

Nefazodone is the subject of US Pat. Nos. 4,338,317 and 5,256,664, incorporated herein by reference, which describe how to make that drug. The composition of the invention comprises nefazodone covalently attached to a peptide. In the present invention, nefazodone or modified nefazodone is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

経口非ステロイド抗エストロゲン化合物は、該薬物の作り方を記載する、本書中に参考として内含された国際公開第９６／２６２０１号パンフレット１９９６、優先権米国特許第３８８２０７号明細書１９９５の主題である。本発明の組成物は、ペプチドに対して共有結合している経口非ステロイド抗エストロゲン化合物を含んでなる。本発明においては、経口非ステロイド抗エストロゲン化合物、又は修飾経口非ステロイド抗エストロゲン化合物はリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Oral Nonsteroidal Antiestrogens The oral nonsteroidal antiestrogenic compounds of the present invention are known drugs used in the treatment of cancer. Its chemical name is 2,2-dimethylpropanoic acid (S) -4- [7- (2,2-dimethyl-1-oxopropoxy) -4-methyl-2- [4- [2- (1-piperidinyl) ) Ethoxy] phenyl] -2H-1-benzopyran-3-yl] phenyl ester.

Oral non-steroidal anti-estrogen compounds are the subject of WO 96/26201 1996, priority US Pat. No. 388,207, 1995, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises an oral non-steroidal anti-estrogen compound covalently attached to a peptide. In the present invention, the oral non-steroidal anti-estrogen compound or the modified oral non-steroidal anti-estrogen compound is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明の組成物は、ペプチドに対して共有結合しているクエン酸オルフェナドリン又は修飾クエン酸オルフェナドリンを含んでなる。本発明においては、クエン酸オルフェナドリンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Orphenadrine citrate Orphenadrine citrate is a known drug used in the treatment of skeletal muscle spasms. Its structure is as follows:

The composition of the invention comprises orphenadrine citrate or modified orphenadrine citrate covalently attached to a peptide. In the present invention, orphenadrine citrate is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

プレコナリルは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許出願公開第５６６１９９Ａ号明細書１９９３、優先権米国特許第８６９２８７号明細書１９９２の主題である。本発明の組成物は、ペプチドに対して共有結合しているプレコナリル又は修飾プレコナリルを含んでなる。本発明においては、プレコナリルは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Preconaril Preconaril is a known drug used in the treatment of viral infections. Its chemical name is 3- [3,5-dimethyl-4- [3- (3-methyl-5-isoxazolyl) propoxy] phenyl] -5- (trifluoromethyl) -1,2,4-oxadiazole It is. Its structure is as follows:

Pleconaril is the subject of European Patent Application No. 565199A 1993, priority US Pat. No. 869287, 1992, incorporated herein by reference, which describes how to make that drug. The composition of the invention comprises pleconaril or modified pleconaril covalently attached to a peptide. In the present invention, pleconaril is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明の組成物は、ペプチドに対して共有結合しているマレイン酸プロクロルペラジンを含んでなる。本発明においては、マレイン酸プロクロルペラジン又は修飾マレイン酸プロクロルペラジンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Prochlorperazine maleate Prochlorperazine maleate is a known drug used in the treatment of nausea and mental disorders. Its structure is as follows:

The composition of the invention comprises prochlorperazine maleate covalently attached to a peptide. In the present invention, prochlorperazine maleate or modified prochlorperazine maleate is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明の組成物は、ペプチドに対して共有結合しているプロメタジンを含んでなる。本発明においては、プロメタジン又は修飾プロメタジンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Promethazine Promethazine is used for its sedative and antiemetic effects in surgery and obstetrics (at the time of labor). The drug reduces tension and anxiety before surgery, facilitates sleep, and reduces nausea and vomiting after surgery. As anesthetic premedication, promethazine is used in conjunction with narcotic analgesics and reduced doses of belladonna alkaloids. Promethazine can also be used as an adjunct to daily sedatives and pain control analgesics. Its structure is as follows:

The composition of the invention comprises promethazine covalently attached to a peptide. In the present invention, promethazine or modified promethazine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明の組成物は、ペプチドに対して共有結合しているプロポキシフェンを含んでなる。本発明においては、プロポキシフェン又は修飾プロポキシフェンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Propoxyphene Propoxyfen is a known drug used in the treatment of pain. It is a mild narcotic analgesic. This is not only commercially available but also easily manufactured by those skilled in the art using published synthetic schemes. The structure of propoxyphene is as follows:

The composition of the invention comprises propoxyphene covalently attached to a peptide. In the present invention, propoxyphene or modified propoxyphene is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

リスペリドンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，８０４，６６３及び５，１５８，９５２号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているリスペリドンを含んでなる。本発明においては、リスペリドン又は修飾リスペリドンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Risperidone Risperidone is a known drug used in the treatment of schizophrenia. Its chemical name is 3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl- 4H-pyrido [1,2-a] pyrimidin-4-one. Its structure is as follows:

Risperidone is the subject of US Pat. Nos. 4,804,663 and 5,158,952, incorporated herein by reference, which describe how to make that drug. The composition of the invention comprises risperidone covalently attached to a peptide. In the present invention, risperidone or modified risperidone is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ロフェコキシブは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，４７４，９９５；５，６９１，３７４及び６０６３８１１号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているロフェコキシブを含んでなる。本発明においては、ロフェコキシブ又は修飾ロフェコキシブは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Rofecoxib Rofecoxib is a known drug used in the treatment of inflammation, rheumatoid arthritis, osteoarthritis, pain, and Alzheimer's disease. Its chemical name is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. Its structure is as follows:

Rofecoxib is the subject of US Pat. Nos. 5,474,995; 5,691,374 and 6063811, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises rofecoxib covalently attached to a peptide. In the present invention, rofecoxib or modified rofecoxib is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明の組成物は、ペプチドに対して共有結合しているセレジリンを含んでなる。本発明においては、セレジリン又は修飾セレジリンはリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Seresillin Seresillin is a known drug used in the treatment of Parkinson's disease. Its chemical name is (R) -N, a-dimethyl-N-2-propynylbenzeneethanamine. Its structure is as follows:

The composition of the invention comprises selegiline covalently attached to a peptide. In the present invention, selegiline or modified selegiline is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

シブトラミンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，７４６，６８０及び４，９２９，６２９号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているシブトラミンを含んでなる。本発明においては、シブトラミン又は修飾シブトラミンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Sibutramine Sibutramine is a known drug used in the treatment of obesity. Its chemical name is 1- (4-chlorophenyl) -N, N-dimethyl-a- (2-methylpropyl) cyclobutanemethanamine hydrochloride monohydrate. Its structure is as follows:

Sibutramine is the subject of US Pat. Nos. 4,746,680 and 4,929,629, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises sibutramine covalently attached to a peptide. In the present invention, sibutramine or modified sibutramine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

タモキシフェンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，５３６，５１６号明細書の主題である。本発明においては、タモキシフェン又は修飾タモキシフェンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Tamoxifen Tamoxifen is a known drug used in the treatment of breast cancer. Its structure is as follows:

Tamoxifen is the subject of US Pat. No. 4,536,516, incorporated herein by reference, which describes how to make that drug. In the present invention, tamoxifen or modified tamoxifen is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

テルビナフィンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６８０，２９１及び４，７５５，５３４号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているテルビナフィンを含んでなる。本発明においては、テルビナフィン又は修飾テルビナフィンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Terbinafine Terbinafine is a known drug used in the treatment of mycosis. Its chemical name is (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethanamine. Its structure is as follows:

Terbinafine is the subject of US Pat. Nos. 4,680,291 and 4,755,534, incorporated herein by reference, which describe how to make the drug. The composition of the invention comprises terbinafine covalently attached to a peptide. In the present invention, terbinafine or modified terbinafine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明の組成物は、ペプチドに対して共有結合しているチオテパを含んでなる。本発明においては、活性物質は、ペプチドに対する付着のために構造的に修飾されている。修飾されたチオテパがペプチドから放出された時点で、チオチパのもとの構造が再生される。 Thiotepa Thiotepa is a known drug used in cancer treatment. Its structure is as follows:

The composition of the invention comprises thiotepa covalently attached to a peptide. In the present invention, the active substance is structurally modified for attachment to the peptide. When the modified thiotepa is released from the peptide, the original structure of thiotipa is regenerated.

チクロピジンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第５，５２９，７９１号明細書である。本発明の組成物はペプチドに対して共有結合しているチクロピジンを含んで成る。本発明においては、チクロピジン又は修飾チクロピジンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Ticlopidine Ticlopidine is a known drug used in the treatment of stroke and thrombosis. Its chemical name is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine. Its structure is as follows:

Ticlopidine is US Pat. No. 5,529,791, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises ticlopidine covalently attached to a peptide. In the present invention, ticlopidine or modified ticlopidine is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明の組成物は、ペプチドに対して共有結合しているトラザドンを含んでなる。本発明においては、トラザドン又は修飾トラザドンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Trazadone Trazadone is a known drug used in the treatment of depression.

The composition of the invention comprises trazadone covalently attached to a peptide. In the present invention, trazadone or modified trazadone is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明の組成物は、ペプチドに対して共有結合しているベクロニウムを含んでなる。本発明においては、ベクロニウム又は修飾ベクロニウムはリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Vecuronium Vecuronium is a known drug used for skeletal muscle relaxation. Its structure is as follows:

The composition of the invention comprises vecuronium covalently attached to a peptide. In the present invention, vecuronium or modified vecuronium is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

本発明の組成物は、ペプチドに対して共有結合しているベラパミルを含んでなる。本発明においては、ベラパミル及び修飾ベラパミルは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Verapamil Verapamil is a known drug used in the treatment of hypertension. Its structure is as follows:

The composition of the invention comprises verapamil covalently attached to a peptide. In the present invention, verapamil and modified verapamil are covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

キサリプロデンは、該薬物の作り方を記載する、本書中に参考として内含された欧州特許第１０１３８１Ｂ号明細書１９８５の主題である。本発明の組成物は、ペプチドに対して共有結合しているキサリプロデンを含んでなる。本発明においては、キサリプロデン又は修飾キサリプロデンは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Xaliproden Xaliproden is a known drug used in the treatment of Alzheimer's disease and amyotrophic lateral sclerosis. Its chemical name is 1,2,3,6-tetrahydro-1- [2- (1-naphthalenyl) ethyl] -4- [3- (trifluoromethyl) phenyl] pyridine. Its structure is as follows:

Xaliproden is the subject of EP 101381B 1985, herein incorporated by reference, which describes how to make the drug. The composition of the invention comprises xaliproden covalently attached to a peptide. In the present invention, xaliproden or modified xaliproden is covalently attached to the peptide via the linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ザレプロンは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，６２６，５３８号明細書の主題である。本発明の組成物は、ペプチドに対して共有結合しているザレプロンを含んでなる。本発明においては、ザレプロン又は修飾ザレプロンはリンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Zaleplon Zaleplon is a known drug used in the treatment of insomnia. Its chemical name is N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylacetamide. Its structure is as follows:

Zaleplon is the subject of US Pat. No. 4,626,538, incorporated herein by reference, which describes how to make the drug. The composition of the invention comprises zaleplon covalently attached to a peptide. In the present invention, zaleplon or modified zaleplon is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

ゾルピデムは、該薬物の作り方を記載する、本書中に参考として内含された米国特許第４，３８２，９３８号明細書、欧州特許第５０５６３Ｂ号明細書１９８４及び欧州特許第２５１８５９Ｂ号明細書１９９０の主題である。本発明の組成物は、ペプチドに対して共有結合しているゾルピデムを含んでなる。本発明においては、ゾルピデム又は修飾ゾルピデムは、リンカーを介してペプチドに対し共有結合している。このリンカーは、（アミン、アミド、アルコール又は酸といったような）１つ以上の官能基及び２〜６個の炭素を含む小さな分子であってもよいし、或いは又、アミノ酸又は炭水化物のいずれかの短鎖から成っていてもよい。 Zolpidem Zolpidem is a known drug used in the treatment of insomnia. Its chemical name is N, N, 6-trimethyl-2- (4-methylphenyl) -imidazole [1,2-a] pyridine-3-acetamide. Its structure is as follows:

Zolpidem is described in US Pat. No. 4,382,938, EP 50563B 1984 and EP 251859B 1990, which are incorporated herein by reference, describing how to make the drug. It is the subject. The composition of the invention comprises zolpidem covalently attached to a peptide. In the present invention, zolpidem or modified zolpidem is covalently attached to the peptide via a linker. The linker may be a small molecule containing one or more functional groups (such as amines, amides, alcohols or acids) and 2-6 carbons, or alternatively either an amino acid or a carbohydrate It may consist of short chains.

Claims (56)

A composition comprising a carrier peptide comprising at least one active agent that is covalently attached to the carrier peptide at the C-terminus, interspersed, side chain attached, or a combination thereof,
A composition wherein the carrier peptide further comprises less than 50 amino acids and is in a form suitable for release of the active agent into the bloodstream.   The composition of claim 1, wherein the carrier peptide is a single amino acid.   The composition of claim 1, wherein the carrier peptide is a dipeptide.   The composition according to claim 3, wherein the dipeptide further comprises at least one of glutamine, glutamic acid, aspartic acid, serine, lysine, cysteine, threonine, tyrosine, asparagine or arginine.   The composition of claim 1, wherein the carrier peptide is a tripeptide.   6. The composition of claim 5, wherein the tripeptide further comprises at least one of glutamine, aspartic acid, glutamic acid, serine, lysine, cysteine, threonine, tyrosine, asparagine, or arginine.   The composition of claim 1, wherein the carrier peptide has a length of 4-8 amino acids.   The composition according to claim 1, wherein the carrier peptide has a length of 4 to 15 amino acids.   The composition of claim 1, wherein the carrier peptide has a length of 9-50 amino acids.   The composition according to claim 1, wherein the active substance is selected from Table 2.   2. A composition according to claim 1 comprising a number of active substances.   The carrier peptide active substance composition is -Ser-Ser, -PolySer, -Lys, -Glu-Glu, Asp-Asp, Asp-Asp-Asp, Asp-Asp-Glu, Asp-Asp-Ser, Asp-Asp -Lys, Asp-Asp-Cys, Ala-Glu, Ala-Ser, Ala-Asp, Ala-Asn, Ala-Thr, Ala-Arg, Ala-Cys, Ala-Gln, Ala-Tyr, LeuGlu, Leu-Ser , Leu-Asp, Leu-Asn, Leu-Thr, Leu-Arg, Leu-Cys, Leu-Gln, Leu-Tyr, PheGlu, Phe-Ser, Phe-Asp, Phe-Asn, Phe-Thr, Phe-Arg , Phe-Cys, Phe-Gln, Phe-Tyr, selected from the group of active substances bound to al-Glu, Val-Ser, Val-Asp, Val-Asn, Val-Thr, Val-Arg, Val-Cys, Val-Gln, Val-Tyr, The composition of claim 1.   The composition of claim 1, wherein the active substance is an amino acid active substance and is interspersed by covalent bonds within the carrier peptide.   2. The composition of claim 1, further comprising the carrier peptide covalently attached to a fatty acid.   The composition of claim 1, wherein the carrier peptide is covalently attached to PEG.   The composition of claim 1, wherein the carrier peptide is covalently attached to cyclodextrin.   The composition of claim 1, wherein the carrier peptide is non-covalently associated with the cyclodextrin.   The composition of claim 1, wherein the polymer formulation provides sustained release of the active agent.   The composition of claim 1, wherein the carrier peptide enhances absorption.   The composition according to claim 1, wherein the carrier peptide is a homopolymer or a heteropolymer.   24. The composition of claim 23, wherein the carrier peptide is a homopolymer containing natural amino acids.   24. The composition of claim 23, wherein the carrier peptide is a homopolymer comprising a synthetic amino acid.   24. The composition of claim 23, wherein the carrier peptide is a heteropolymer comprising two or more natural amino acids.   24. The composition of claim 23, wherein the carrier peptide is a heteropolymer comprising two or more synthetic amino acids.   24. The composition of claim 23, wherein the carrier peptide is a heteropolymer comprising one or more natural amino acids and one or more synthetic amino acids.   The composition of claim 1 further comprising at least one additive attached to the carrier peptide.   30. The composition of claim 29, wherein the additive enhances absorption.   30. The composition of claim 29, wherein the additive enhances bioadhesion.   32. The composition of claim 31, wherein the bioadhesiveness of the additive imparts sustained release pharmacokinetics of the active substance in the gastrointestinal tract.   30. The composition of claim 29, wherein the additive targets delivery of the carrier peptide to a specific location within the gastrointestinal tract, a specific cell within the systemic circulation, or a specific enzyme within the intestinal lumen or brush border membrane. .   30. The composition of claim 29, wherein the additive is the peptide itself.   The composition of claim 1, wherein the carrier peptide is in a form that enhances the solubility of the active substance in an aqueous or organic solvent.   36. The composition of claim 35, wherein the solubility allows for uniform dispersion in the polymer formulation.   The composition of claim 1, wherein the carrier peptide is in a form that provides sustained release kinetics of absorption relative to the parent drug.   The composition of claim 1 in a form designed to allow release of the active agent according to zero order kinetics.   Reduce the toxicity of the active substance, reduce the clearance rate of the active substance, increase the steady state concentration of the active substance, maintain a long-term therapeutic level of the active substance, or effective level of the active substance The composition according to claim 1, wherein the composition is in a form that enhances the therapeutic efficacy of the active substance by avoiding a decrease in or by a combination thereof.   The composition of claim 1 in a form that enhances the in vivo stability of the active agent.   The composition of claim 1 in a form that enhances the in vitro stability of the active agent. A composition comprising a carrier peptide comprising at least one active substance covalently bound to the carrier peptide at the N-terminus, comprising:
A composition wherein the carrier peptide is not individually Glu, Tyr, Ala, Met or Gly-Gly but has a length of less than 50 amino acids and is in a form suitable for release of the active substance into the bloodstream. A composition comprising a carrier peptide comprising at least one active substance covalently bound to the carrier peptide comprising:
The carrier peptide has a length of 1 to 500 amino acids and is in a form suitable for releasing the active substance from the digestive tract into the bloodstream. A carrier peptide having a length of 1 to 50 amino acids;
At least one active substance covalently bound to the carrier peptide;
And a composition suitable for modulating the pharmacological effect of the composition in the small intestine. A carrier peptide having a length of 3-9 amino acids;
At least one active substance covalently bound to the carrier peptide;
A composition comprising   A composition comprising a carrier peptide comprising at least one active substance covalently bound to the carrier peptide, wherein the carrier peptide is a single amino acid, provided that the amino acid is not alanine, glutamine, tyrosine or methionine. A composition.   A composition comprising a carrier peptide and at least one active substance covalently bound thereto, wherein the carrier peptide is a dipeptide, provided that the dipeptide is not gly-gly.   A composition comprising a carrier peptide comprising at least one active substance covalently bound to a carrier peptide provided that the active substance is not salicylic acid, wherein the carrier peptide releases the active substance into the bloodstream A composition that is in a suitable form. A carrier peptide having a length of 1-50 amino acids and being in a form suitable for pharmacological effects in the small intestine of a subject
At least one active substance covalently attached to the carrier peptide and released into the bloodstream;
A composition comprising A carrier peptide having a length of 1 to 50 amino acids and in a form suitable for release of the active substance into the bloodstream;
At least two active agents covalently attached to the carrier peptide;
A composition comprising A carrier peptide having a length of 1-50 amino acids in a form wherein the active agent is delivered into the systemic circulation;
An active substance covalently bound to the carrier peptide;
A composition comprising A carrier peptide having a length of 1 to 50 amino acids in a form that converts the drug adsorption mechanism from passive to active intake;
A composition comprising an active substance covalently bound to the carrier peptide.   A method for the treatment of a disease or disorder comprising the step of administering a composition according to claim 1. A carrier peptide;
And at least one active agent covalently bound to the carrier peptide,
A method for treating a disorder comprising administering to a subject a composition wherein the carrier peptide has a length of less than 50 amino acids and the carrier peptide is in a form suitable for delivery into the bloodstream. .   A composition comprising at least one active substance covalently attached to PEG in a form suitable for modulation in the gastrointestinal tract.   A composition comprising at least one active substance covalently bound to a cyclodextrin in a form suitable for modulation in the gastrointestinal tract.   A composition comprising at least one active substance covalently bound to a fatty acid in a form suitable for modulation in the gastrointestinal tract.   49. The composition of claim 48, further comprising an additive that is non-covalently bound to the carrier peptide.   49. The composition of claim 48, wherein the parent drug reaches the systemic circulation rather than the conjugate-drug composition.

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