AU2001298033B2 - A novel pharmaceutical compound containing abacavir sulfate and methods of making and using same - Google Patents

A novel pharmaceutical compound containing abacavir sulfate and methods of making and using same Download PDF

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AU2001298033B2
AU2001298033B2 AU2001298033A AU2001298033A AU2001298033B2 AU 2001298033 B2 AU2001298033 B2 AU 2001298033B2 AU 2001298033 A AU2001298033 A AU 2001298033A AU 2001298033 A AU2001298033 A AU 2001298033A AU 2001298033 B2 AU2001298033 B2 AU 2001298033B2
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covalently attached
polypeptide
active agent
present
treatment
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AU2001298033A1 (en
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Thomas Picariello
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Shire LLC
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Shire LLC
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A NOVEL PHARMACEUTICAL COMPOSITION AND METHODS OF MAKING AND USING SAME FIELD OF THE INVENTION The present invention relates to active agent delivery systems and, more specifically, to compositions that comprise polypeptides covalently attached to active agents and methods for protecting and administering active agents.
BACKGROUND OF THE INVENTION The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeabilityof cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and
I
aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone.
A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings.
Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptidedrug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate ofpolyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate ofpolyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a 26/07 2007 THU 12:30 FAX +61 2 8231 1099 PBRice Co 0007/019
O
O polypeptide pendant group with its targeted delivery into the bloodstream via oral Sadministration.
n It is also important to control the molecular weight, molecular size and particle IO size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight 0 microspheres usually have high moisture content which may present a problem with 00 water labile active ingredients. Particle size not only becomes a problem with 10 injectable drugs, as in the HAR application, but absorption through the brush-border 0 membrane of the intestines is limited to less than 5 microns.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.
SUMMARY OF THE INVENTION In a first aspect, the present invention provides a pharmaceutical composition comprising a polypeptide covalently attached to an active agent selected from hydromorphone, butorphanol, propoxyphene, dextroamphetamine, methylphenidate, noradrenalin and dopamine reuptake inhibitor, citalopram, fluoxetine, fluvoxamine maleate, ACE/neutral endopeptidase inhibitor, amoxicillin, amoxicillin and clavulanate, cefadroxil, ceftazidime, ceftibuten, cefuroxime, cephalexin, ciprofloxacin, quinolone antibiotic, cefuroxime axetil, azithromycin, caspofungin, clarithromycin, erythromycin, gentamicin isoton, cefdinir, lansoprazole, ketolide antibiotic, doxyrubicin, and cilastin and imipenem, and a pharmaceutically acceptable excipient, wherein said active agent is released in the bloodstream following oral administration of said pharmaceutical composition and wherein said polypeptide consists of naturally occurring amino acids.
In a second aspect, the present invention provides a method for protecting an active agent from degradation comprising covalently attaching an active agent selected from hydromorphone, butorphanol, propoxyphene, dextroamphetamine, methylphenidate, noradrenalin and dopamine reuptake inhibitor, citalopram, fluoxetine, fluvoxamine maleate, ACE/neutral endopeptidase inhibitor, 3 COMS ID No: ARCS-154462 Received by IP Australia: Time 12:42 Date 2007-07-26 26/07 2007 THU 12:31 FAX +61 2 8231 1099 FBRice Co o008/019 0 amoxicillin, amoxicillin and clavulanate, cefadroxil, ceftazidime, ceftibuten, Scefuroxime, cephalexin, ciprofloxacin, quinolone antibiotic, cefuroxime axetil, Z azithromycin, caspofungin, clarithromycin, erythromycin, gentamicin isoton, cefdinir, I lansoprazole, ketolide antibiotic, doxyrubicin, and cilastin and imipenem to a polypeptide wherein said active agent is released into the bloodstream following oral administration of said pharmaceutical composition and wherein said polypeptide C consists of naturally occurring amino acids.
In a third aspect, the present invention provides a method for controlling release of an active agent from a composition comprising covalently attaching said active agent to a polypeptide, wherein said active agent is selected from hydromorphone, butorphanol, propoxyphene, dextroamphetamine, methylphenidate, N noradrenalin and dopamine reuptake inhibitor, citalopram, fluoxetine, fluvoxamine maleate, ACE/neutral endopeptidase inhibitor, amoxicillin, amoxicillin and clavulanate, cefadroxil, ceftazidime, ceftibuten, cefuroxime, cephalexin, ciprofloxacin, quinolone antibiotic, cefuroxime axetil, azithromycin, caspofungin, clarithromycin, erythromycin, gentamicin isoton, cefdinir, lansoprazole, ketolide antibiotic, doxyrubicin, and cilastin and imipenem, and wherein said active agent is released in the bloodstream following oral administration of said composition and wherein said polypeptide consists of naturally occurring amino acids.
In a fourth aspect, the present invention provides a method for delivering an active agent to a patient comprising administering to said patient a composition comprising: a polypeptide-covalently attached to an active agent selected from hydromorphone, butorphanol, propoxyphene, dextroamphetamine, methylphenidate, noradrenalin and dopamine reuptake inhibitor, citalopram, fluoxetine, fluvoxamine maleate, ACE/neutral endopeptidase inhibitor, amoxicillin, amoxicillin and clavulanate, cefadroxil, ceftazidime, ceftibuten, cefuroxime, cephalexin, ciprofloxacin, quinolone antibiotic, cefuroxime axetil, azithromycin, caspofungin, clarithromycin, erythromycin, gentamicin isoton, cefdinir, lansoprazole, ketolide antibiotic, doxyrubicin, and cilastin and imipenem, wherein said active agent is released in the bloodstream following oral administration of said composition and wherein said polypeptide consists of naturally occurring amino acids.
Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
3A COMS ID No: ARCS-154462 Received by IP Australia: Time 12:42 Date 2007-07-26 26/07 2007 THU 12:32 FAX +61 2 8231 1099 FBRice Co 0009/019
O
O The present invention provides covalent attachment of active agents to a polymer of peptides or amino acids. The invention is distinguished from the above mentioned technologies by virtue of covalently attaching the active agent, which I\O includes, for example, pharmaceutical drugs and nutrients, to the N-terminus, the Cterminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will en stabilize the active agent, primarily in the stomach, through conformational 0 protection. In these applications, delivery of the active agent is controlled, in part, by 00 the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal 10 tract, indigenous enzymes release the active ingredient for absorption by the body by 0 selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action 0C introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising an active agent microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. Preferably, the polypeptide is an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids (L or D isomers), or an isomer, analogue, or derivative thereof, (iii) a heteropolymer of two or more naturally occurring amino acids (L or D isomers), or an isomer, analogue, or derivative thereof, (iv) a homopolymer of a synthetic amino acid, a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
An active agent preferably is covalently attached to a side chain, the Nterminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another 3B COMS ID No: ARCS-154462 Received by IP Australia: Time 12:42 Date 2007-07-26 preferred embodiment, the active agent is an amine and is covalently attached to the Cterminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting an active agent from degradation comprising covalently attaching the active agent to a polypeptide.
The invention also provides a method for controlling release of an active agent from a composition comprising covalently attaching the active agent to the polypeptide.
The invention also provides a method for delivering an active agent to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, an active agent is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, an active agent is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and an active agent is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, the active agent is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, the active agent is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: attaching an active agent to a side chain of an amino acid to form an active agent/amino acid complex; forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, the active agent is a pharmaceutical agent or an adjuvant.
In another preferred embodiment, steps and are repeated prior to step with a second active agent. When steps and are repeated prior to step with a second agent, the active agent and second active agent can be copolymerized in step In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting ofaspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incorporated herein by reference.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides several benefits for active agent delivery. First, the invention can stabilize the active agent and prevent digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of the active agent. Furthermore, active agents can be combined to produce synergistic effects. Also, absorption of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises a polypeptide and an active agent covalently attached to the polypeptide. Preferably, the polypeptide is an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Active agents may be selected from the below sections, either alone or in combination with other active agents. By way of example, active agents may be selected and covalently attached through the preferred means in each section.
Acarbose Acarbose is a known pharmaceutical agent that is used in the treatment of type II diabetes. Its chemical name is O-4,6-dideoxy-4-[[[1S-(lalpha,4alpha,5beta,6alpha)]-4,5,6trihydroxy-3-(hydroxymethyl)-2-cyclohexen- 1-yl]amino]-alpha-D-glucopyranosyl-(1-4)-0alpha-D-glucopyranosyl-(l-4)-D-glucose. Its structure is as follows: 0 O0N
O
Oo (4 0 0 0 In the present invention, acarbose is covalently attached to the polypeptide via any of the free hydroxyl groups. Acarbose is the subject of U.S. Patent Number 4,904,769, herein incorporated by reference, which describes how to make that drug.
Acyclovir Acyclovir is a known pharmaceutical agent that is an antiviral drug used in the treatment of herpes simplex viruses. Acyclovir is both commercially available and readily manufactured using public synthetic schemes by those of ordinary skill in the art. Its chemical name is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one. Its structure is: HN OH
H
2 N N KN In the present invention, acyclovir is covalently attached to the polypeptide via the hydroxyl group.
Adenosine Adenosine is a known pharmaceutical agent that is used as a coronary vasodilator. Its chemical name is 9-alpha-D-ribofuranosyl-9H-purin-6-amine. Its structure is:
N
N
O O Adenosine is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. In the present invention, adenosine is covalently attached to the polypeptide via the ribose hydroxyl group.
Albuterol Albuterol is a known pharmaceutical agent that is used for the symptomatic management ofbronchospasm in patients with reversible, obstructive airway disease. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
OH
N C H,
OH
3 HO I In the present invention, albuterol is covalently attached to the polypeptide via one of the hydroxyl groups.
Acetaminophen Acetaminophen is a known pharmaceutical agent that is used in the treatment of minor aches and pains. Its chemical name is N-acetyl-p-aminophenol. Acetaminophen is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
In the present invention, acetaminophen is covalently attached to the polypeptide via its hydroxyl group.
Acetaminophen with Codeine Acetaminophen is a known pharmaceutical agent that is used in the treatment of minor aches and pains. Its chemical name is N-acetyl-p-aminophenol; It is often used in combination with codeine, whose chemical name is 7,8-didehydro-4,5-a-epoxy-3-methoxy- 17-methylmephorinan-6a-ol. Both are commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
In the present invention, acetaminophen and codeine are covalently attached to the polypeptide via its hydroxyl group.
Acetylsalicylic acid Acetylsalicylic acid is a known pharmaceutical agent that is used in the treatment of minor aches and pains. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
In the present invention, acetylsalicylic acid is covalently attached to the polypeptide via the hydroxy group.
Amprenavir Amprenavir, a proteinase inhibitor, is a known pharmaceutical agent that is used in the treatment of HIV infection. Its chemical name is aminophenyl)sulfonyl](2-methylpropyl)amino] -2-hydroxy-l-(phenylmethyl)propyl]carbamic acid tetrahydro-3-furanyl ester. Its structure is: 0 i° oz "<U=q Amprenavir is the subject of U.S. Patent Numbers 5,585,397, 5,646,180, and 5,723,490, herein incorporated by reference, which describes how to make that drug. In the present invention, amprenavir is covalently attached to the polypeptide via the hydroxyl group.
Antisense Oligonucleotides Antisense oligonucleotides are a class of compounds made of RNA that is complementary to the mRNA that produces a protein of interest. Their usefulness is primarily for gene therapy. Individual uses include those for the treatment of inflammatory bowel diseases. They are made by chemical RNA synthesis or, alternatively, by using a gene construct containing the antisense orientation of the gene of interest and isolating the RNA of interest.
In the present invention, antisense oligonucleotides are covalently attached to the polypeptide via the ribose hydroxyl group.
Atenolol Atenolol is a known pharmaceutical agent that is used in the treatment of hypertension or chronic stable angina pectoris in patients with chronic obstructive pulmonary disease (COPD) or type 1 diabetes mellitus. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
OH
I
OCH CHCH 2
NHCH(CH
3 2
CH
2
CONH
2 In the present invention, atenolol is covalently attached to the polypeptide via the hydroxyl group.
Atorvastatin Atorvastatin is a known pharmaceutical agent that is used in the treatment of high cholesterol. Its chemical name is (betaR,deltaR)-2-(4-fluorophenyl)-beta,delta-dihydroxy-5- (1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- H-pyrrole-1-heptanoic acid. Its structure is: Atorvastatin is the subject of U.S. Patent Numbers 4,681,893, 5,273,995, 5,686,104, and 5,969,156, herein incorporated by reference, which describes how to make that drug. In the present invention, atorvastatin is covalently attached to the polypeptide via the hydroxyl group.
Atovaquone Atovaquone is a known pharmaceutical agent that is used in the prevention of Pneumocystis carinii pneumonia. Its chemical name is 2-[trans-4-(4chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Its structure is: C 1 o Atovaquone is the subject of U.S. Patent Numbers 4,981,874 and 5,053,432, herein incorporated by reference, which describes how to make that drug. In the present invention, atovaquone is covalently attached to the polypeptide via the hydroxyl group.
Azithromycin Azithromycin is a known pharmaceutical agent that is used in the treatment of bacterial infections. Its chemical name is (2R,3S,4R,5R,8R, 1 OR, 11R,12S,13S,14R)-13-[(2,6dideoxy-3-C-methyl-3-O-methyl-alpha- -ribohexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy- 3,5,6,8,10,12,heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)beta-D-xylohexopyranosyl]oxy]-1 -oxa-6-azacyclopentadecan- 15-one. Its structure is: Azithromycin is the subject of GB 2094293 B (1985), herein incorporated by reference, which describes how to make that drug. In the present invention, azithromycin is covalently attached to the polypeptide via the hydroxyl group.
Befloxatone Befloxatone is a known pharmaceutical agent that is used in smoking cessation treatment. Its chemical name is (R)-5-(methoxymethyl)-3-[4-[(R)-4,4,4-trifluoro-3hydroxybutoxy)phenyl]-2-oxazolidinone. Its structure is:
F
F
o00 Befloxatone is the subject of EP 424244 B (1995), herein incorporated by reference, which describes how to make that drug. In the present invention, befloxatone is covalently attached to the polypeptide via the hydroxyl group.
Benazepril Benazepril has the chemical name [S-(R*,R*)]-3-[[1-(ethoxycarbonyl)-3phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-l-benzazepine-l-acetic acid. It is available commercially or can be made by those of skill in the art. Its structure is as follows: 0<) 0 Benazepril is the subject of U.S. Patent Number 4,410,520, herein incorporated by reference, which describes how to make that drug. In the present invention, benazepril is covalently attached to the polypeptide via the hydroxyl group.
Bosentan Bosentan is a known pharmaceutical agent that is used in the treatment of pulmonary hypertension. Its chemical name is 4-(1,1-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide. Its structure is: 'N N N N S 0 00 Bosentan is the subject of EP 526708 A (1993), herein incorporated by reference, which describes how to make that drug. In the present invention, bosentan is covalently attached to the polypeptide via the hydroxyl group.
Butorphanol Butorphanol is a known pharmaceutical agent that is used in the treatment of pain. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: In the present invention, butorphanol is covalently attached to the polypeptide via the hydroxyl group.
Calcitriol Calcitriol is a known pharmaceutical agent that is used in the treatment of hypocalcemia. Its structure is:
SOH
H 0 EHC~jL C H 3 HO, CMi"' HOj j H
H
Calcitriol is the subject of U.S. Patent Numbers 4,308,264 and 6,051,567, herein incorporated by reference, which describes how to make that drug. In the present invention, calcitriol is covalently attached to the polypeptide via the hydroxyl group.
Capecitabine Capecitabine is a known pharmaceutical agent that is used in the treatment of colorectal cancer. Its chemical name is pentyl 1-(5-deoxy-.beta.-D-ribofuranosyl)-5-fluoro- 1,2-dihydro-2-oxo-4-pyrimidinecarbamate. Its structure is: 0
F
N
0 0 Capecitabine is the subject of U.S. Patent Numbers 4,966,891 and 5,472,949, herein incorporated by reference, which describes how to make that drug. In the present invention, capecitabine is covalently attached to the polypeptide via the hydroxyl groups.
Carvedilol Carvedilol is a known pharmaceutical agent that is 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: 0/ Carvedilol is the subject of U.S. Patent Numbers 4,503,067, 5,760,069, and 5,902,821, herein incorporated by reference, which describes how to make that drug. In the present invention, carvedilol is covalently attached to the polypeptide via the hydroxyl group.
Caspofungin Caspofungin is a known pharmaceutical agent that is used in the treatment of bacterial and fungal infections. Its chemical name is 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12dimethyl-1 -oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-Lornithine]pneumocandin BO. Its structure is: N
N--
0 0 0 N
N
0 NH0 O- H N 0
N
H 0 0 o Caspofungin is the subject of WO 94/21677 (1994), based on U.S. Patent Application Number 32847 (1993), herein incorporated by reference, which describes how to make that drug. In the present invention, caspofungin is covalently attached to the polypeptide via the hydroxyl group.
Ciclesonide Ciclesonide is a known pharmaceutical agent that is used in the treatment of asthma.
Its chemical name is [11 beta,16alfa (R)]-16,17-[(cyclohexylmethylene)bis(oxy)]- 1 -hydroxy- 21-(2-methyl-1 -oxopropoxy)-pregna-1,4-diene-3,20-dione. Its structure is: 0 H
H
Ciclesonide is the subject of GB 2247680 B (1994), based on US Application Number 578942 (1990), herein incorporated by reference, which describes how to make that drug. In the present invention, ciclesonide is covalently attached to the polypeptide via the hydroxyl group.
Clarithromycin Clarithromycin is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is 6-O-methylerythromycin. Its structure is: 0
II
0 0 0 N I o-
\N-
0 0 oJJ^o Clarithromycin is the subject of EP 41355 B (1983) and EP 293885 B (1993), and US application number 58499 (1987), herein incorporated by reference, which describes how to make that drug. In the present invention, clarithromycin is covalently attached to the polypeptide via the hydroxyl group.
Dapitant Dapitant is a known pharmaceutical agent that is used in the treatment of asthma. Its chemical name is [3aS-[2(R*),3aalpha,4beta,7aalpha]]-octahydro-4-(2-methoxyphenyl)-2-[2- (2-methoxyphenyl)-l-oxopropyl]-7,7-diphenyl-1H-isoindol-4-ol. Its structure is: Dapitant is the subject of WO 93/21155 (1993), herein incorporated by reference, which describes how to make that drug. In the present invention, dapitant is covalently attached to the polypeptide via the hydroxyl group.
Desogestrel and Ethinyl Estradiol Desogestrel and ethinyl estradiol are known pharmaceutical agents used together as a contraceptive.
Desogestrel's chemical name is (17alpha)-13-ethyl-11 -methylene-18,19-dinorpregn- 4-en-20-yn-17-ol. Its structure is: 0 Ethinyl estradiol's chemical name is (17alpha)-19-norpregna-1,2,5(10)-trien-20-yne- 3,17-diol. Its structure is: 0 Desogestrel are the subject of GB 1455270 (1976), herein incorporated by reference, which describes how to make that drug. In the present invention, desogestrel and ethinyl estradiol are covalently attached to the polypeptide via their hydroxyl groups.
Digoxin Digoxin is a known pharmaceutical agent that is used in the treatment of digitalization and maintenance therapy. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: In the present invention, digoxin is covalently attached to the polypeptide via the hydroxyl group.
Dipyridamole Dipyridamole is a known pharmaceutical agent that is used as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: In the present invention, dipyridamole is covalently attached to the polypeptide via the hydroxyl group.
Ecopipam Ecopipam is a known pharmaceutical agent that is 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 ]naphth[2,1-b]azepin-12-ol. Its structure is:
N-
Ecopipam is the subject of EP 254737 A (1990), priority U.S. application 820471 (1986), herein incorporated by reference, which describes how to make that drug. In the present invention, ecopipam is covalently attached to the polypeptide via the hydroxyl group.
Erythromycin Erythromycin is a known pharmaceutical agent that is used in the treatment of bacterial infections. Its chemical name is 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*, 14R *)-4-((2,6-Dideoxy-3-C-methyl-3-O-methyl-a-L- ribo- hexopyranosyl) -oxy) -14- ethyl- 7,12,13- trihydroxy 3,5,7,9,11,13-hexa methyl-6- ((3,4,6-trideoxy-3-(dimethylamino)-b-Dxylo- hexopyran osyl)oxy)oxacyclotetradecane-2,10-dione. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
In the present invention, erythromycin is covalently attached to the polypeptide via a hydroxyl group.
Esterified Estrogens and Methyltestosterone Esterified estrogens and methyltestosterone are known pharmaceutical agents that are used together in hormone replacement therapy. Esterified estrogens is a mixture of the sodium salts of the sulfate esters of the estrogenic substances, principally estrone, that are of the type excreted in the urine of pregnant mares. Estrone sodium sulfate is the principal active ingredient in esterified estrogens. Esterified estrogens may be derived from natural sources and/or prepared synthetically. The structure of estrone is:
HHO
H H
HO
The structure of methyltestosterone is:
OH
CH!
0 In the present invention, esterified estrogens and methyltestosterone are covalently attached to the polypeptide via their hydroxy groups.
Conjugated Estrogens In women, oral conjugated estrogens USP and synthetic conjugated estrogens A are used for the management of moderate to severe vasomotor symptoms associated with menopause. Conjugated estrogens USP is a mixture containing the sodium salts of the watersoluble sulfate esters of estrone and equilin derived wholly or in part from equine urine or may be prepared synthetically from estrone and equilin. Conjugated estrogens USP also contains conjugated estrogenic substances of the type excreted by pregnant mares including 17alpha-dihydroequilin, 17alpha-estradiol, 17beta-dihydroequilin, equilenin, 17alphadihydroequilenin, 17beta-dihydroequilenin, Delta 8 9 -dehydroestrone, and 17beta-estradiol.
Conjugated estrogens USP contains 52.5-61.5% sodium estrone sulfate and 22.5-30.5% sodium equilin sulfate. Conjugated estrogens contains, as sodium sulfate conjugates, 13.5- 19.5% 17alpha-dihydroequilin, 2.5-9.5% 17alpha-estradiol, and 0.5-4% 17betadihydroequilin. They are available from natural sources. The structure of estrone is: 0 H H
HO
In the present invention, conjugated estrogens are covalently attached to the polypeptide via the hydroxyl groups.
Conjugated Estrogens and Medroxyprogesterone Acetate Conjugated estrogens and medroxyprogesterone acetate are known pharmaceutical agents used in hormone replacement therapy.
In women, oral conjugated estrogens USP and synthetic conjugated estrogens A are used for the management of moderate to severe vasomotor symptoms associated with menopause. Conjugated estrogens USP is a mixture containing the sodium salts of the watersoluble sulfate esters of estrone and equilin derived wholly or in part from equine urine or may be prepared synthetically from estrone and equilin. Conjugated estrogens USP also contains conjugated estrogenic substances of the type excreted by pregnant mares including 1 7alpha-dihydroequilin, 17alpha-estradiol, 17beta-dihydroequilin, equilenin, 17alphadihydroequilenin, 17beta-dihydroequilenin, Delta 8 9 -dehydroestrone, and 17beta-estradiol.
Conjugated estrogens USP contains 52.5--61.5% sodium estrone sulfate and 22.5-30.5% sodium equilin sulfate. Conjugated estrogens contains, as sodium sulfate conjugates, 13.5- 19.5% 17alpha-dihydroequilin, 2.5-9.5% 17alpha-estradiol, and 0.5-4% 17betadihydroequilin. They are available from natural sources. The structure of estrone is: HO Medroxyprogesterone acetate is a synthetic progestin. Medroxyprogesterone acetate is a derivative of 17 alpha-hydroxyprogesterone that differs structurally by the addition of a 6 alpha-methyl group and a 17 alpha-acetate group. Its structure is: H CHC In the present invention, conjugated estrogens and medroxyprogesterone acetate are covalently attached to the polypeptide via the hydroxyl groups.
Estropipate Estropipate is a known pharmaceutical agent that is used in hormone replacement therapy. Estropipate is estrone solubilized as the sulfate and stabilized with piperazine.
Conjugation of estrone with sulfate at the 3-hydroxy position on ring A of the steroid nucleus results in the formation of a water-soluble derivative; the pharmacologically inert piperazine moiety acts as a buffer to increase the stability and uniform potency of estrone sulfate. The structure of estrone is:
U,
HO
In the present invention, estropipate is covalently attached to the polypeptide via the hydroxyl group.
Ethinyl Estradiol and Norethindrone Ethinyl estradiol and norethindrone are known pharmaceutical agents that are used together as a contraceptive. The structure of ethinylestradiol is: 0 The structure of norethindrone is:
CH
In the present invention, ethinyl estradiol and norethindrone are covalently attached to the polypeptide via the hydroxyl groups.
Ethinyl Estradiol and Ethynodiol Diacetate Ethinyl estradiol and ethynodiol diacetate are known pharmaceutical agents that are used together as a contraceptive. Each is isolatable from natural sources, or alternatively synthesized, by those of skill in the art.
In the present invention, ethinyl estradiol and ethynodiol diacetate are covalently attached to the polypeptide via the hydroxyl groups.
Ethinyl Estradiol and Levonorgestrel Ethinyl estradiol and levonorgestrel are known pharmaceutical agents that are used together as a contraceptive. Each is isolatable from natural sources, or alternatively synthesized, by those of skill in the art.
In the present invention, ethinyl estradiol and levonorgestrel are covalently attached to the polypeptide via the hydroxyl groups.
Ethinyl Estradiol and Norethindrone Ethinyl estradiol and norethindrone 28 are known pharmaceutical agents that are used together as a contraceptive. Each is isolatable from natural sources, or alternatively synthesized, by those of skill in the art.
In the present invention, ethinyl estradiol and norethindrone 28 are covalently attached to the polypeptide via the hydroxyl groups.
Ethinyl Estradiol and Norethindrone Acetate Ethinyl estradiol and norethindrone acetate are known pharmaceutical agents that are used together as a contraceptive. Each is isolatable from natural sources, or alternatively synthesized, by those of skill in the art.
In the present invention, ethinyl estradiol and norethindrone acetate are covalently attached to the polypeptide via the hydroxyl group.
Ethinyl Estradiol and Norgestimate Ethinyl estradiol and norgestimate are known pharmaceutical agents that are used together as a contraceptive. Each is isolatable from natural sources, or alternatively synthesized, by those of skill in the art.
In the present invention, ethinyl estradiol and norgestimate are covalently attached to the polypeptide via the hydroxyl groups.
Ethinyl Estradiol and Norgestrel Ethinyl estradiol and norgestrel are known pharmaceutical agents that are used together as a contraceptive. Each is isolatable from natural sources, or alternatively synthesized, by those of skill in the art.
In the present invention, ethinyl estradiol and norgestrel are covalently attached to the polypeptide via the hydroxyl groups.
Fenretinide Fenretinide is a known pharmaceutical agent that is used in the treatment of cancer.
Its chemical name is N-(4-hydroxyphenyl)retinamide. Its structure is: 0O Fenretinide is the subject of GB 1543824 (1979) based on priority US application 628177 (1975), US 4,323,581 (1982), and US 4,665,098 (1987),, herein incorporated by reference, which describes how to make that drug. In the present invention, fenretinide is covalently attached to the polypeptide via the hydroxyl.
Fluconazole Fluconazole is a known pharmaceutical agent that is used in the treatment of fungal infections. Its chemical name is alpha-(2,4-difluorophenyl)-alpha-(lH-1,2,4-triazol-lylmethyl)-1H-1,2,4-triazole-1-ethanol. Its structure is: 0 N N N NL
F
Fluconazole is the subject of U.S. Patent Numbers 4,404,216 and 4,416,682, herein incorporated by reference, which describes how to make that drug. In the present invention, fluconazole is covalently attached to the polypeptide via the hydroxyl group.
Formoterol Formoterol is a known pharmaceutical agent that is used in the treatment of asthma.
Its chemical name is rel-N-[2-hydroxy-5-[(1R)-l-hydroxy-2-[[(1R)-2-(4-methoxypheny)-lmethylethyl]amino]ethyl]phenyl]formamide. Its structure is:
N
0 0 Formoterol is the subject of GB 1415256 (1975), herein incorporated by reference, which describes how to make that drug. In the present invention, formoterol is covalently attached to the polypeptide via the hydroxyl group.
Ganaxolone Ganaxolone is a known pharmaceutical agent that is used in the treatment of epilepsy and migraine. Its chemical name is (3alpha,5alpha)-3-hydroxy-3-methyl-pregnan-20-one. Its structure is: 0 H H
H
Ganaxolone is the subject of DE 2162555 A (1972), WO 93/3732 (1993) based on priority US application 745216 (1991), WO 93/5786 1993 based on priority US application 759512 (1991), and WO 94/27608 (1994) based on priority US application 68378 (1993), herein incorporated by reference, which describes how to make that drug. In the present invention, ganaxolone is covalently attached to the polypeptide via the hydroxyl group.
Ganciclovir Ganciclovir is a known pharmaceutical agent that is used in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: Na N N
H
2 N N N
CH
2 0
H
I
CH
2
OCH
CH
2 0H Ganciclovir is the subject of U.S. Patent Numbers 4,355,032; 4,423,050; 4,507,305 and 4,642,346, herein incorporated by reference, which describes how to make that drug. In the present invention, ganciclovir is covalently attached to the polypeptide via the hydroxyl group.
Gentamicin Isoton Gentamicin isoton is a known pharmaceutical agent that is used in the treatment of bacterial infections and muscular dystrophy. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
N-
NN N 0 0 0N
N
N N O 0 1 0 0N N 0
N
I o In the present invention, gentamicin isoton is covalently attached to the polypeptide via the hydroxyl group.
Haloperidal Haloperidal is a known pharmaceutical agent that is used in the treatment of psychotic disorders. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
HO
N
In the present invention, haloperidal is covalently attached to the polypeptide via the hydroxyl group.
Hydromorphone Hydromorphone is a known pharmaceutical agent that is used in the treatment of cough and pain. Its structure is:
H
;N-CH,
HH
HO 0' O In the present invention, hydromorphone is covalently attached to the polypeptide via the hydroxyl group.
Hydroxychloroquinone Hydroxychloroquinone is a known pharmaceutical agent that is used in the treatment of malaria. Its structure is:
H
C1 OH In the present invention, hydroxychloroquinone is covalently attached to the polypeptide via the hydroxyl group.
Idarubicin Idarubicin is a known pharmaceutical agent that is used in the treatment of cancer.
Its chemical name is (7S,9S)-9-acetyl-7-[(3-amino-2,3,6-trideoxy-alfa-L-lyxohexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenedioone. Its structure is: o O fy Idarubicin is the subject of GB 1467383 (1977), herein incorporated by reference, which describes how to make that drug. In the present invention, idarubicin is covalently attached to the polypeptide via the hydroxyl group.
Ilomastat Ilomastat is a known pharmaceutical agent that is used in the treatment of retinopathy, diabetes and cancer. Its chemical name is (2R)-N4-hydroxy-N1-[(1S)-(1H-indol-3ylmethyl)-2-(methylamino)-2-oxoethyl]-2-(2-methylpropyl)butanediamide. Its structure is: 0 NN 0 N N Ilomastat is the subject of WO 92/9556 (1992), priority application US 615798 (1990), and US Patent 5,114,953, herein incorporated by reference, which describes how to make that drug. In the present invention, ilomastat is covalently attached to the polypeptide via the amine or hydroxyl group.
lodixanol lodixanol is a known pharmaceutical agent that is used as a contrast medium for medical imaging. Its chemical name is 5,5'-[(2-hydroxy-1,3propanediyl)bis(acetylamino)]bis[N,N'-bis(2,3-dih ydroxypropyl)-2,4,6-triodo-1,3benzenedicarboxamide]. Its structure is: Iodixanol is the subject of U.S. Patent Number 5,349,085, herein incorporated by reference, which describes how to make that drug. In the present invention, iodixanol is covalently attached to the polypeptide via the hydroxyl group.
Iopromide lopromide is a known pharmaceutical agent that is used as an X-ray contrast medium.
Its chemical name is N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(2methoxyacetyl)amino]-N-methyl-1,3-benzenedicarboxamide. Its structure is: *0 o
I
f I 0 o 0 lopromide is the subject of U.S. Patent Number 4,364,921, herein incorporated by reference, which describes how to make that drug. In the present invention, iopromide is covalently attached to the polypeptide via the hydroxyl group.
Ioxaglate loxaglate is a known pharmaceutical agent that is used as a radiopaque contrast aide.
It is usually used as a combination of Ioxaglate meglumine and Ioxaglate sodium. Both units can be attached to a polypeptide carrier.
In the present invention, ioxaglate is covalently attached to the polypeptide via the hydroxyl group.
Ipratropium Ipratropium is used as a bronchodilator for the long-term symptomatic treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD). Its structure is: HC \CHCCHA N~ H
H
CH
2
OH
In the present invention, ipratropium is covalently attached to the polypeptide via the hydroxyl group.
Irinotecan Irinotecan is a known pharmaceutical agent that is used in the treatment of cancer. Its chemical name is [1,4'-bipiperidine]- '-carboxylic acid (S)-4,11-diethyl-3,4,12,14-tetrahydro- 4-hydroxy-3,14-dioxo-lH-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl ester. Its structure is: 0 Irinotecan is the subject of U.S. Patent Number 4,604,463, herein incorporated by reference, which describes how to make that drug. In the present invention, irinotecan is covalently attached to the polypeptide via the hydroxyl group.
Labetalol Labetalol is a known pharmaceutical agent that is used in the treatment of hypertension. Its structure is: OH3OH U 1
OH
In the present invention, labetalol is covalently attached to the polypeptide via the hydroxyl group.
Lamivudine Lamivudine is a known pharmaceutical agent that is used in the treatment of hepatitis, viral infection and HIV infection. Its chemical name is (2R-cis)-4-amino-l-[2- (hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone. Its structure is:
N
O Lamivudine is the subject of U.S. Patent Numbers 5,047,407 and 5,905,082, herein incorporated by reference, which describes how to make that drug. In the present invention, lamivudine is covalently attached to the polypeptide via the hydroxyl group.
Lamivudine and Zidovudine Lamivudine is a known pharmaceutical agent that is used in the treatment of hepatitis, viral infection and HIV infection. Its chemical name is (2R-cis)-4-amino-l-[2- (hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone. Its structure is:
N
Zidovudine has the chemical name 3'-azido-3'-deoxythymidine. Its structure is O0
N
0/
N
N
N
The two drugs together are used as a fixed-dose combination tablet comprising the reverse transcriptase inhibitors lamivudine and zidovudine for the treatment of HIV infection.
Lamivudine is the subject of U.S. Patent Numbers 5,047,407 and 5,905,082, herein incorporated by reference, which describes how to make that drug. Zidovudine is covered by EP 196185 B (1989). The combination is covered by the following U.S. patents, which are hereby incorporated by reference: 4,724,232; 4,818,538; 4,828,838; 4,833,130; 4,837,208 and 6,113,920. In the present invention, lamivudine and zidovudine are covalently attached to the polypeptide via the hydroxyl group on each.
Noradrenalin and Dopamine Reuptake Inhibitor The noradrenalin and dopamine reuptake inhibitor of the present invention is used in the treatment of attention deficit hyperactivity disorder (ADHA). Its chemical name is [2S- (2alpha,3alpha,5alpha)]-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol hydrochloride.
Its structure is: N
F
F
The noradrenalin and dopamine reuptake inhibitor of the present invention is the subject of EP 426416 B (1994), herein incorporated by reference, which describes how to make that drug. In the present invention, the noradrenalin and dopamine reuptake inhibitor is covalently attached to the polypeptide via the hydroxyl.
ACE/neutral endopeptidase inhibitor ACE/neutral endopeptidase inhibitor is a known pharmaceutical agent that is used in the treatment of hypertension and heart failure. Its chemical name is [S-(R*,R*)]-hexahydro- 6-[(2-mercapto-l-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo- 1H-azepine. Its structure is: 0 0 In the present invention, ACE/neutral endopeptidase inhibitor is covalently attached to the polypeptide via the carboxylic acid group.
ACE /neutral endopeptidase inhibitor is the subject of EP 599444 B (1998), priority based on US application 884664 (1992), herein incorporated by reference, which describes how to make that drug.
Alprostadil Alprostadil is a known pharmaceutical agent that is used in the treatment of male erectile dysfunction. Its chemical name is (1 lalpha,13E,15S)- 1,15-dihydroxy-9-oxoprost- 13-en-l-oic acid. Its structure is: 0 0 0 0 In the present invention, alprostadil is covalently attached to the polypeptide via the carboxylic acid.
Alprostadil is the subject of U.S. Patent Number 5,741,523, herein incorporated by reference, which describes how to make that drug.
Acitretin Acitretin is a known pharmaceutical agent that is used in the treatment of psoriasis.
Its chemical name is (all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8nonatetraenoic acid. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: In the present invention, acitretin is covalently attached to the polypeptide via the carboxylic acid group.
Amoxicillin Amoxicillin is a known pharmaceutical agent that is used in the treatment of bacterial infection. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: N N' -N H H H In the present invention, amoxicillin is covalently attached to the polypeptide via the carboxylic acid.
Amoxicillin and Clavulanate Amoxicillin and clavulanate are known pharmaceutical agents used in the treatment of bacterial infections. Each is available commercially and can be made by those of ordinary skill in the art. The structure of amoxicillin is:
HO
HO H
H
N C H 3 gN H H H The structure of clavulanate is(Z)-(2R, 5R )-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1azabicyclo[3.2.0]-heptane-2-carboxylate.
In the present invention, amoxicillin and clavulanate are each covalently attached to the polypeptide via the carboxylic acid group.
Betamethasone Betamethasone is a known pharmaceutical agent that is used principally as an antiinflammatory or immunosuppressant agent. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: 0
HO
H Ha
OH
HO
I
H
H,3 H
CH
F H In the present invention, betamethasone is covalently attached to the polypeptide via the carboxylic acid group.
Candoxatril Candoxatril is a known pharmaceutical agent that is 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: 0 OO N 0 0 Candoxatril is the subject of EP 274234 B (1991), herein incorporated by reference, which describes how to make that drug. In the present invention, candoxatril is covalently attached to the polypeptide via the carboxylic acid.
Captopril Captopril is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is 1-(3-mercapto-2-methyl-l-oxopropyl)-L-proline. Its structure is: Captopril is the subject of U.S. Patent Number 5,238,924, herein incorporated by reference, which describes how to make that drug. In the present invention, captopril is covalently attached to the polypeptide via the carboxylic acid.
Carbidopa and Levodopa Carbidopa and levodopa are known pharmaceutical agents that are used together in the treatment of Parkinson's disease. Each is commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
Carbidopa's structure is: NH2
I
HO CHe---C----COOH
H
HO
Levodopa's structure is:
CH
3 HO CH -C--COOH H
NHNH
g In the present invention, carbidopa and levodopa are each covalently attached to the polypeptide via the carboxylic acid group.
Cefaclor Cefaclor is a known pharmaceutical agent that is used in the treatment of bronchitis.
It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: HO 0 0\ C N H2N H H H In the present invention, cefaclor is covalently attached to the polypeptide via the carboxylic acid.
Cefadroxil Cefadroxil is a known pharmaceutical agent that is used in the treatment of bacterial infections. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: In the present invention, cefadroxil is covalently attached to the polypeptide via the carboxylic acid group.
Cefazolin Cefazolin is a known pharmaceutical agent that is used in the treatment of respiratory tract infections, urinary tract infections, skin and skin structure infections, biliary tract infections, bone and joint infections, genital infections, septicemia, and endocarditis caused by susceptible bacteria. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
N-N
COONG 3'j -CH C.NH- N=N H H In the present invention, cefazolin is covalently attached to the polypeptide via the carboxylic acid group.
Cefdinir Cefdinir is a known pharmaceutical agent that is used in the treatment of acute maxillary sinusitis, acute exacerbations of chronic bronchitis, pharyngitis, tonsilitis, community-acquired pneumonia and bacterial skin infections. Its chemical name is [6R- [6alpha,7beta(Z)] ]-7-[[(2-amino-4-thiazolyl)(hydroxyimino) acetyl]amino]-3-ethenyl-8-oxo- 5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Its structure is:
N
S^ 0 I Is 0 -0 Cefdinir is the subject of EP 105459 B (1989), based on US Application Serial Number 428,970 (1982) and EP 304019 B (1995), herein incorporated by reference, which describes how to make that drug. In the present invention, cefdinir is covalently attached to the polypeptide via the carboxylic acid group.
Cefixime Cefixime is a known pharmaceutical agent that is used in the treatment of respiratory tract infections, gonorrhea, biliary tract infection and pediatric otitis media. Its chemical name is [6R-[6alpha,7beta(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:
N
S.
N N 0 0 Cefixime is the subject of EP 30360 B (1987), herein incorporated by reference, which describes how to make that drug. In the present invention, cefixime is covalently attached to the polypeptide via the carboxylic acid group.
Cefotaxime Cefotaxime is a known pharmaceutical agent that is used in the treatment of serious bone and joint infections, serious intra-abdominal and gynecologic infections (including peritonitis, endometritis, pelvic inflammatory disease, pelvic cellulitis), meningitis and other CNS infections, serious lower respiratory tract infections (including pneumonia), bacteremia/septicemia, serious skin and skin structure infections, and serious urinary tract infections caused by susceptible bacteria. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its chemical name is (6R,7R)-7-[2-(2-Amino-4-thiazolyl) glyoxylamido]-8-oxo-3-vinyl-5-thia-1azabicyclo[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 polypeptide via the carboxylic acid group.
Cefotetan Cefotetan is a known pharmaceutical agent that is used in the treatment of septicemia, genitourinary, biliary and respiratory tract infections, and in postoperativewound infection prophylaxis. Its chemical name is [6R-(6alpha,7alpha)]-7-[[[4-(2-amino-l-carboxy-2oxoethylidene)-1,3-dithietan-2-yl]carbonyl]amino]-7-methoxy-3-[[(1-methyl- yl)thio] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid. Its structure is: 0 N 0 0 N-N O S o.
0 H Cefotetan is the subject of GB 1604739 (1981), herein incorporated by reference, which describes how to make that drug. In the present invention, cefotetan is covalently attached to the polypeptide via the carboxylic acid group.
Cefoxitin Cefoxitin is a known pharmaceutical agent that is used in the treatment of serious infections of the lower respiratory tract, skin and skin structure, bone and joint, and urinary tract; septicemia; gynecologic infections (including endometritis, pelvic cellulitis, and pelvic inflammatory disease); and intra-abdominal infections (including peritonitis and intraabdominal abscess) caused by susceptible bacteria. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
Its structure is:
COOH
0 N, .CHeOCONHz S CH CONH- r OCHi .H In the present invention, cefoxitin is covalently attached to the polypeptide via the carboxylic acid group.
Cefprozil Cefprozil is a known pharmaceutical agent that is used in the treatment of upper respiratory tract infections, otitis media, acute exacerbation of chronic bronchitis, and skin infections. Its chemical name is [6R-[6alpha,7beta(R*)]]-7-[[amino(4hydroxyphenyl)acetyl]amino-8-oxo-3-(1-propenyl)-5-thia- -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid. Its structure is:
N
N S o o Cefprozil is the subject of GB 2135305 B (1987), based on US Patent Application Serial Number 461833 (1983), herein incorporated by reference, which describes how to make that drug. In the present invention, cefprozil is covalently attached to the polypeptide via the carboxylic acid group.
Ceftazidime Ceftazidime is a known pharmaceutical agent that is used in the treatment of bacterial infections. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: o o N, H H o In the present invention, ceftazidime is covalently attached to the polypeptide via the carboxylic acid group.
Ceftibuten Ceftibuten is a known pharmaceutical agent that is used in the treatment of bacterial infections. Its chemical name is [6R-[6alpha,7beta(Z)]]-7-[[2-(2-amino-4-thiazolyl)-4carboxy- 1-oxo-2-butenyl]amino]-8-oxo 5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid. Its structure is:
S
N O 0 H N S HH 0 0 Ceftibuten is the subject of EP 136721 B (1993), herein incorporated by reference, which describes how to make that drug. In the present invention, ceftibuten is covalently attached to the polypeptide via the carboxylic acid group.
Cefuroxime Cefuroxime is a known pharmaceutical agent that is used in the treatment of bacterial infection. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: OCNM
COOH
I 0 CHOCONHg \NjI -4.
U I H In the present invention, cefuroxime is covalently attached to the polypeptide via the carboxylic acid group.
Cephalexin Cephalexin is a known pharmaceutical agent that is used in the treatment of bacterial infection. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: HO 0 SH
S
HZN H H H In the present invention, cephalexin is covalently attached to the polypeptide via the carboxylic acid group.
Cerivastatin Cerivastatin is a known pharmaceutical agent that is 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-heptenoic acid. Its structure is:
F
000 -oo Cerivastatin is the subject of U.S. Patent Number 5,177,080, herein incorporated by reference, which describes how to make that drug. In the present invention, cerivastatin is covalently attached to the polypeptide via the carboxylic acid group.
Cetirizine Cetirizine is a known pharmaceutical agent that is used in the treatment of allergic rhinitis. Its chemical name is [2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl] ethoxy]acetic acid. Its structure is: Cl N N O O Cetirizine is the subject of U.S. Patent Number 4,525,358, herein incorporated by reference, which describes how to make that drug. In the present invention, cetirizine is covalently attached to the polypeptide via the carboxylic acid group.
Chlorazepate Depot Chlorazepate depot is a known pharmaceutical agent that is used in the treatment of anxiety disorders. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: H ,0 CI -N
OK
In the present invention, chlorazepate depot is covalently attached to the polypeptide via the carboxylic acid group.
Cilomilast Cilomilast is a known pharmaceutical agent that is used in the treatment of asthma.
Its chemical name is cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl] cyclohexanecarboxylic acid. Its structure is: 0
N-X
0 oCr- Cilomilast is the subject of WO 93/19749 (1993), based on priority US application 862030 (1992), herein incorporated by reference, which describes how to make that drug. In the present invention, cilomilast is covalently attached to the polypeptide via the carboxylic acid group.
Ciprofloxacin Ciprofloxacin is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-3-quinolinecarboxylic acid. Its structure is: 0 0 Ciprofloxacin is the subject of U.S. Patent Numbers 4,670,444 and 5,286,754, herein incorporated by reference, which describes how to make that drug. In the present invention, ciprofloxacin is covalently attached to the polypeptide via the carboxylic acid.
Diclofenac Diclofenac is a known pharmaceutical agent that is used in the treatment of acute and chronic rheumatoid arthritis. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its chemical name is potassium (o-(2,6-dichloroanilino)-phenyl)acetate. Its structure is: 0 Ii -I OCCH 2 C1
NH
C1 In the present invention, diclofenac is covalently attached to the polypeptide via the carboxylic acid group.
Divalproex Divalproex is a known pharmaceutical agent that is used in the treatment of epilepsy, migraine, schizophrenia and depression. Its chemical name is 2-propylpentanoic acid. Its structure is: HO 0 Divalproex is the subject of U.S. Patent Numbers 4,988,731 and 5,212,326, herein incorporated by reference, which describes how to make that drug. In the present invention, divalproex is covalently attached to the polypeptide via the carboxylic acid group.
Enalapril Enalapril is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is (S)-l-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]- L-proline. Its structure is: O N 0 O NS Enalapril is the subject of EP 12401 (1984), priority US application 968249 (1978), herein incorporated by reference, which describes how to make that drug. In the present invention, enalapril is covalently attached to the polypeptide via the carboxylic acid group.
Eptifibatide Eptifibatide is a known pharmaceutical agent that is used in the treatment of thrombosis, angina, myocardial infarction and restenosis. Its chemical name is N6- (aminoiminomethyl)-N2-(3-mercapto-1 -oxopropyl)-L-lysylglycyl-L-alph a-aspartyl-Ltryptophyl-L-prolyl-L-cysteinamide cyclic (1-6)-disulfide. Its structure is:
N
o o N 0 0 0 NN
N
Eptifibatide is the subject of U.S. Patent Numbers 5,686,570; 5,756,451 and 5,807,825, herein incorporated by reference, which describes how to make that drug. In the present invention, eptifibatide is covalently attached to the polypeptide via the carboxylic acid group.
Etodolac Etodolac is a known pharmaceutical agent that is used in the treatment of inflammation. Its chemical name is 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1acetic acid. Its structure is: 0 0 Etodolac is the subject of U.S. Patent Number 4,966,768, herein incorporated by reference, which describes how to make that drug. In the present invention, etodolac is covalently attached to the polypeptide via the carboxylic acid group.
Etoposide Etoposide is a known pharmaceutical agent that is used in the treatment of inflammation. Its chemical name is 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1acetic acid. Its structure is: 0 0 Etoposide is the subject of GB 1391005 (1975), based on priority US application 148895 (1971), herein incorporated by reference, which describes how to make that drug. In the present invention, etoposide is covalently attached to the polypeptide via the carboxylic acid group.
Fexofenadine Fexofenadine is a known pharmaceutical agent that is used in the treatment of seasonal allergic rhinitis. Its chemical name is 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)- 1-piperidinyl]butyl]-alpha,alpha-dimethylbenzeneacetic acid. Its structure is: Fexofenadine is the subject of U.S. Patent Numbers 4,254,129; 5,578,610; 5,855,912; 5,932,247; and 6,037,353, herein incorporated by reference, which describes how to make that drug. In the present invention, fexofenadine is covalently attached to the polypeptide via the carboxylic acid group.
Fluvastatin Fluvastatin is a known pharmaceutical agent that is used in the treatment of hyperlipidemia. Its chemical name is (3R,5S,6E)-rel-7-[3-(4-fluorophenyl)-1-(1methylethyl)-lH-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid. Its structure is:
F
=o 0 Fluvastatin is the subject of U.S. Patent Number 5,354,772, herein incorporated by reference, which describes how to make that drug. In the present invention, fluvastatin is covalently attached to the polypeptide via the carboxylic acid group.
Fosinopril Fosinopril is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is [1[S*(R*)],2alpha.,4beta]-4-cyclohexyl- 1 -[[[2-methyl- (1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline. Its structure is:
O
Fosinopril is the subject of U.S. Patent Number 4,337,201; 4,384,123 and 5,006,344, herein incorporated by reference, which describes how to make that drug. In the present invention, fosinopril is covalently attached to the polypeptide via the carboxylic acid group.
Furosemide Furosemide is a known pharmaceutical agent that is used in the treatment of edema and hypertension. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
HO
0 II
H
2 N-S NH O
CI
In the present invention, furosemide is covalently attached to the polypeptide via the carboxylic acid group.
Gabapentin Gabapentin is a known pharmaceutical agent that is used in the treatment of epilepsy and depression. Its chemical name is 1-(aminomethyl)cyclohexaneacetic acid. Its structure is: 00 Gabapentin is the subject of U.S. Patent Numbers 4,087,544; 4,894,476; 5,084,479; and 6,054,482, herein incorporated by reference, which describes how to make that drug. In the present invention, gabapentin is covalently attached to the polypeptide via the carboxylic acid group.
Gemfibrozil Gemfibrozil is a known pharmaceutical agent that is used in the treatment of hyperlipidemia. Its chemical name is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid.
Its structure is: 0 Gemfibrozil is the subject of GB 1225575 (1971), priority based on US application 73046 (1968), herein incorporated by reference, which describes how to make that drug. In the present invention, gemfibrozil is covalently attached to the polypeptide via the carboxylic acid group.
Ibuprofen Ibuprofen is a known pharmaceutical agent that is used in the treatment of pain and arthritis. Its structure is:
CH
3 CH CH 2
CHCOOH
CH CH I In the present invention, ibuprofen is covalently attached to the polypeptide via the carboxylic acid group.
Isotretinoin Isotretinoin is a known pharmaceutical agent that is used in the treatment of acne. Its structure is:
H
3 C CH3 CH 3 CH3
SCOOH
CH3 In the present invention, isotretinoin is covalently attached to the polypeptide via the carboxylic acid group.
Ketoprofen Ketoprofen is a known pharmaceutical agent that is used in the treatment of arthritis and pain. Its structure is: 0 If C CHCOOH
CH
3 In the present invention, ketoprofen is covalently attached to the polypeptide via the carboxylic acid group.
Ketorolac Ketorolac is a known pharmaceutical agent that is used in the treatment of pain. Its chemical name is (+,-)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-l-carboxylic acid. Its structure is: 0 0 Ketorolac is the subject of GB 1554057 (1979), based on priority application US 704909 (1976), herein incorporated by reference, which describes how to make that drug. In the present invention, ketorolac is covalently attached to the polypeptide via the carboxylic acid group.
Adefovir Dipivoxil Adefovir dipivoxil is a known pharmaceutical agent that is 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:
N
N
0^ N 0 0 O O0 0O Adefovir dipivoxil is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. In the present invention, adefovir dipivoxil is covalently attached to the polypeptide via the amino group.
Amlodipine Besylate Amlodipine besylate is a known pharmaceutical agent that is used in the treatment and prevention of myocardial infarction and stroke. Its chemical name is aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid, 3-ethyl 5-methyl ester monobenzenesulfonate. Its structure is: 0 0 N ON Amlodipine besylate is the subject of U.S. Patent Numbers 4,572,909 and 4,879,303, herein incorporated by reference, which describe how to make that drug. In the present invention, amlodipine besylate is covalently attached to the polypeptide via the amino group.
Anagrelide Anagrelide is a known pharmaceutical agent that is used as a platelet reducing drug.
Its chemical name is 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one. Its structure is:
H
Cl Anagrelide is the subject of GB patent 1418822 (1975), (based on U.S. Patent Application Serial Number 223,723, filed in 1972, herein incorporated by reference, which describes how to make that drug. In the present invention, anagrelide is covalently attached to the polypeptide via the amino group.
Benzatropine Mesylate Benzatropine mesylate is a known pharmaceutical agent that is used in the treatment of Parkinsoniajn syndrome. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: o n
H
8 C CHKSO n In the present invention, benzatropine mesylate is covalently attached to the polypeptide via the amino group.
Cefpodoxime Proxetil Cefpodoxime proxetil is a known pharmaceutical agent that is used in the treatment of mild to moderate infections of the upper and lower respiratory tract, skin and urinary tract and sexually transmitted diseases. Its chemical name is [6R-[6alfa,7beta(Z)]]-7-[[(2-amino- 4-thiazolyl)(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1-[[(1-methylethoxy)carbonyl]oxy]ethyl ester.
Its structure is: 0 oo
NO
Cefpodoxime proxetil is the subject of EP 49118 B (1986), herein incorporated by reference, which describes how to make that drug. In the present invention, cefpodoxime proxetil is covalently attached to the polypeptide via the amino group.
Chlordiazepoxide Chlordiazepoxide is a known pharmaceutical agent that is used in the treatment of anxiety and tension. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
NHCH
3
N-
C1
C
In the present invention, chlordiazepoxide is covalently attached to the polypeptide via the amino group.
Cimetidine Cimetidine is a known pharmaceutical agent that is used in the treatment of duodenal ulcer. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
N-CN
HC S N H
N-CH
H
In the present invention, cimetidine is covalently attached to the polypeptide via the amino group.
Cisapride Cisapride is a known pharmaceutical agent that is used in the treatment of gastrointestinal motility disease. Its chemical name is cis-4-amino-5-chloro-N-[l-[3-(4fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide. Its structure is: F N -o Cl 0
N
Cisapride is the subject of U.S. Patent Number 4,962,115, herein incorporated by reference, which describes how to make that drug. In the present invention, cisapride is covalently attached to the polypeptide via the amino group.
Cisplatin Cisplatin is a known pharmaceutical agent that is used in the treatment of bladder and ovarian carcinoma. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: CI
NH
3 Pt 1CI
NH
3 Cisplatin is the subject of U.S. Patent Number 5,562,925, herein incorporated by reference, which describes how to make that drug. In the present invention, cisplatin is covalently attached to the polypeptide via the amino group.
Clonidine Clonidine is a known pharmaceutical agent that is used in the treatment of hypertension. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: In the present invention, clonidine is covalently attached to the polypeptide via the amino group.
Clozapine Clozapine is a known pharmaceutical agent that is used in the treatment of psychotic disorders. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: N NCH 3 C1 N-
N
H
In the present invention, clozapine is covalently attached to the polypeptide via the amino group.
Colestipol Colestipol is a known pharmaceutical agent that is used in the treatment of hypercholesterolemia. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Colestipol hydrochloride is a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane that contains secondary and tertiary amines with approximately 1 out of 5 amine nitrogens protonated with chloride.
In the present invention, colestipol is covalently attached to the polypeptide via one of its amino groups.
Cyclophosphamide Cyclophosphamide is a known pharmaceutical agent that is used in the treatment of myeloproliferative and lymphoproliferative disorders and solid malignancies. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: 0 P-N CI
CI
In the present invention, cyclophosphamide is covalently attached to the polypeptide via the amino group.
Desmopressin Desmopressin is a known pharmaceutical agent that is used in the treatment of urinary incontinence. Its chemical name is 1-(3-mercaptopropanic acid)-8-D-arginine-vasopressin.
Its structure is: SChfC C--'yr PLt- 4-t- P.
9 -t-Arg-61y-?Hn CH.COOk Desmopressin is the subject of U.S. Patent Numbers 5,047,398; 5,500,413; 5,674,850; and 5,763,407, herein incorporated by reference, which describes how to make that drug. In the present invention, desmopressin is covalently attached to the polypeptide via an amide linkage with the amino group.
Dextroamphetamine Dextroamphetamine is a known pharmaceutical agent that is used in the treatment of narcolepsy and attention deficit hyperactivity disorder. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
Its structure is:
H
CH
2
-C-NH
2
I
CH
3 In the present invention, dextroamphetamine is covalently attached to the polypeptide via the amino group.
D-Methylphenidate D-methylphenidate is a known pharmaceutical agent that is used in the treatment of attention deficit disorder. Its chemical name is (alphaR,2R)-alpha-phenyl-2-piperidineacetic acid methyl ester. Its structure is: N 0
H
D-methylphenidate is the subject of U.S. Patent Number 2,507,631 (1950) and WO 99/16439 (1999), based on US application Number 937684 (1997), each of which is herein incorporated by reference, which describes how to make that drug. In the present invention, D-methylphenidate is covalently attached to the polypeptide via the amino group.
Dopamine Dopamine is a known pharmaceutical agent that is used used to increase cardiac output, blood pressure, and urine flow as an adjunct in the treatment of shock that persists after adequate fluid volume replacement. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: HO
NH
2
HO
In the present invention, dopamine is covalently attached to the polypeptide via the amino group.
Doxazosin Doxazosin is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3dihydro- 1,4-benzodioxin-2-yl)carbonyl]piperizine. Its structure is: 0
N
IN
Doxazosin is the subject of U.S. Patent Number GB 2007656 B (1982), herein incorporated by reference, which describes how to make that drug. In the present invention, doxazosin is covalently attached to the polypeptide via the amino group.
Duloxetine Duloxetine is a known pharmaceutical agent that is used in the treatment of depression. Its chemical name is (S)-N-methyl-gamma-(1-naphthalenyloxy)-2thiophenepropanamine. Its structure is: 0 Duloxetine is the subject of 273658 B (1990), priority US 945122 (1986), herein incorporated by reference, which describes how to make that drug. In the present invention, duloxetine is covalently attached to the polypeptide via the amino group.
Dutasteride Dutasteride is a known pharmaceutical agent that is used in the treatment of benign prostate 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, 10,11,11 a-tetradecahydro-4a,6adimethyl-2-oxo-1H- indeno[5,4-f]quinoline-7-carboxamide. Its structure is:
F
Dutasteride is the subject of WO 95/7927 (1995), priority US 123280 (1993), herein incorporated by reference, which describes how to make that drug. In the present invention, dutasteride is covalently attached to the polypeptide via the amino groups.
Ecadotril Ecadotril is a known pharmaceutical agent that is used in the treatment of hypertension, heart failure and cirrhosis. Its chemical name is (S)-N-[2-[(acetylthio)methyl]- 1-oxo-3-phenylpropyl]glycine phenyl methyl ester. Its structure is: I41 Ecadotril is the subject of EP 318377 B (1993), herein incorporated by reference, which describes how to make that drug. In the present invention, ecadotril is covalently attached to the polypeptide via the amino group.
Eniluracil Eniluracil is a known pharmaceutical agent that is used in the treatment of pancreatic and colorectal cancer. Its chemical name is 5-ethynyl-2,4(1H,3H)-pyrimidinedione. Its structure is:
O
Eniluracil is the subject of WO 92/1452 (1992), herein incorporated by reference, which describes how to make that drug. In the present invention, eniluracil is covalently attached to the polypeptide via the amino groups.
Esatenolol Esatenolol is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is (S)-4-[2-hydroxy-3-[(1-methylethyl)amino] propoxy]benzeneacetamide. Its structure is: 0
O
Esatenolol is the subject of GB 1285035 (1972), herein incorporated by reference, which describes how to make that drug. In the present invention, esatenolol is covalently attached to the polypeptide via the amido group.
Famciclovir Famciclovir is a known pharmaceutical agent that is used in the treatment of viral infection. Its chemical name is 2-[2-(2-amino-9H-purin-9-yl)ethyl]-l,3-propanediol diacetate. Its structure is:
N
O
0 Famciclovir is the subject of EP 182024 B (1991) and U.S. Patent Number 5,246,937, herein incorporated by reference, which describes how to make that drug. In the present invention, famciclovir is covalently attached to the polypeptide via the amino group.
Famotidine Famotidine is a known pharmaceutical agent that is used in the treatment of ulcers and heartburn. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: HPN N ,N, ,S
NH
2
H
2
NSO
2
NMH
In the present invention, famotidine is covalently attached to the polypeptide via the amino groups.
Finasteride Finasteride is a known pharmaceutical agent that is used in the treatment of cancer, benign prostate hypertrophy, alopecia and acne. Its chemical name is (5alpha,17beta)-N- (1,1 -dimethylethyl)-3-oxo-4-azaandrost-1 -ene-17-carb oxamide. Its structure is:
N
0
H
H
Finasteride is the subject of U.S. Patent Numbers 5,377,584; 4,760,071; 5,547,957; 5,571,817; and 5,886,184, herein incorporated by reference, which describes how to make that drug. In the present invention, finasteride is covalently attached to the polypeptide via an amino group.
Flecainide acetate Flecainide acetate is a known pharmaceutical agent that is used in the treatment of arrythmia. Its chemical name is N-(2-piperidinylmethyl)-2,5-bis(2,2,2trifluoroethoxy)benzamide. Its structure is:
N
F N F F 0 F Flecainide acetate is the subject of U.S. Patent Number 4,642,384, herein incorporated by reference, which describes how to make that drug. In the present invention, flecainide acetate is covalently attached to the polypeptide via the amino group.
Fluoxetine Fluoxetine is a known pharmaceutical agent that is used in the treatment of depression. Its chemical name is (N-methyl 3-(p-trifluoromethylphenoxy)-3phenylpropylamine. Its structure is: F3C y0-CHCH2CHgNHCH3 Fluoxetine is the subject of U.S. Patent Number 4,329,356, herein incorporated by reference, which describes how to make that drug. In the present invention, fluoxetine is covalently attached to the polypeptide via the amino group.
Flutamide Flutamide is a known pharmaceutical agent that is used in the treatment of prostate cancer. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
F
3 C N ON HC CH3 2 N CH 3 In the present invention, flutamide is covalently attached to the polypeptide via the amino group.
Fluvoxamine maleate Fluvoxamine maleate is a known pharmaceutical agent that is used in the treatment of depression and anxiety. Its chemical name is 5-methoxy-l-[4-(trifluoromethyl)phenyl]-1pentanone (E)-O-(2-aminoethyl)oxime. Its structure is: 0-
F
F N-0
N
Fluvoxamine maleate is the subject of GB 1535226 (1978), herein incorporated by reference, which describes how to make that drug. In the present invention, fluvoxamine maleate is covalently attached to the polypeptide via the amino group.
Gantofiban Gantofiban is a known pharmaceutical agent that is used in the treatment of thrombosis and angina. Its chemical name is 4-[[(5R)-3-[4-[imino[(methoxycarbonyl) acid ethyl ester 2hydroxy-1,2,3-propanetricarboxylate Its structure is: I I
OIN
0 N 0 Gantofiban is the subject of EP 741133 A (1996), herein incorporated by reference, which describes how to make that drug. In the present invention, gantofiban is covalently attached to the polypeptide via the amino group.
Lamotrigine Lamotrigine is a known pharmaceutical agent that is used in the treatment of epilepsy, psychosis and depression. Its chemical name is 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5diamine. Its structure is:
N
Lamotrigine is the subject of U.S. Patent Numbers 4,602,017 and 5,698,226, herein incorporated by reference, which describes how to make that drug. In the present invention, lamotrigine is covalently attached to the polypeptide via the amino group.
Lansoprazole Lansoprazole is a known pharmaceutical agent that is used in the treatment of ulcer and bacterial infection. Its chemical name is 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2pyridinyl]methyl]sulfinyl]-1H-benzimidazole. Its structure is: N S
F
OF
Lansoprazole is the subject of U.S. Patent Number 4,628,098; 4,689,333; 5,026,560; 5,045,321; 5,093,132 and 5,433,959, herein incorporated by reference, which describes how to make that drug. In the present invention, lansoprazole is covalently attached to the polypeptide via the amino group.
Sodium Channel Blocker The sodium channel blocker of the present invention is a known pharmaceutical agent that is used in the treatment of pain. Its chemical name is (5R)-5-(2,3-dichlorophenyl)-6- (fluoromethyl)-2,4-pyrimidinediamine. Its structure is: N N N
F
A sodium channel blocker is the subject of WO 97/9317 (1997), herein incorporated by reference, which describes how to make that drug. In the present invention, a sodium channel blocker is covalently attached to the polypeptide via the amino group.
Allopurinal Allopurinal is a known pharmaceutical agent that is is a xanthine oxidase inhibitor used in the treatment of gout and selected hyperuricemias. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: H N
HN.
I
N
II
0 In the present invention, allopurinal is covalently attached to the polypeptide via its NH group.
Carboplatin Carboplatin is a known pharmaceutical agent that is used in the treatment of ovarian cancer. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
O
0 NH 3 Pt
NH
0 NH 3 In the present invention, carboplatin is covalently attached to the polypeptide via the amine groups.
Cholinergic Channel Modulator Cholinergic channel modulator is a known pharmaceutical agent that is used in the treatment of pain. Its chemical name is (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine. Its structure is: N Cl Cholinergic channel modulator is the subject of WO 96/40682 (1996), based on priority US application 474873, herein incorporated by reference, which describes how to make that drug. In the present invention, cholinergic channel modulator is covalently attached to the polypeptide via the amine group.
Glimepiride Glimepiride is a known pharmaceutical agent that is used in the treatment of diabetes.
Its chemical name is trans-3-ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(4methylcyclohexyl)ami no]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo- 1H-pyrrole-1carboxamide. Its structure is: Glimepiride is the subject of U.S. Patent Number 4,379,785, herein incorporated by reference, which describes how to make that drug. In the present invention, glimepiride is covalently attached to the polypeptide via the amine group.
Glipizide Glipizide is a known pharmaceutical agent that is used in the treatment of diabetes. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: 0 a0 14H NH In the present invention, glipizide is covalently attached to the polypeptide via the amine group.
Glyburide Glyburide is a sulfonylurea antidiabetic agent used in the treatment of diabetes. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: S0 0 CI XNH NH OCH O N In the present invention, glyburide is covalently attached to the polypeptide via the amine group.
Granisetron Granisetron is a known pharmaceutical agent that is used in the treatment of nausea and vomiting in cancer patients Its chemical name is endo-1-methyl-N-(9-methyl-9azabicyclo[3,3,1]non-3-yl)-1H-indazole-3-carboxamide. Its structure is:
N/
Granisetron is the subject of U.S. Patent Number 4,886,808, herein incorporated by reference, which describes how to make that drug. In the present invention, granisetron is covalently attached to the polypeptide via the amine group.
Hydrochlorothiazide Hydrochlorothiazide is a known pharmaceutical agent that is used in the treatment of hypertension. The chemical structure ofhydrochlorothiazide is: N, a 'N c "N In the present invention, hydrochlorothiazide is covalently attached to the polypeptide via the amine group.
Hydrochlorothiazide and Triamterene Hydrochlorothiazide and triamterene are known pharmaceutical agents that are used together in the treatment of edema and hypertension. The chemical structure of triamterene is: HzN N N NH2
ON
NH
2 Its chemical name is The chemical structure ofhydrochlorothiazide is: N' )a 0N o In the present invention, hydrochlorothiazide and triamterene are covalently attached to the polypeptide via the amine group on each.
Indinavir Indinavir is a known pharmaceutical agent that is 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: N 0 0
I
NN
Indinavir is the subject of EP 541168 B (1998), based on priority application US 789508 (1991), and U.S. Patent Number 5,413,999, herein incorporated by reference, which describes how to make that drug. In the present invention, indinavir is covalently attached to the polypeptide via the amine groups.
Itasetron Itasetron is a known pharmaceutical agent that is used in the treatment of emesis and anxiety. Its chemical name is endo-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2oxo-lH-benzimidazole-1-carboxamide. Its structure is:
N
N 0 Itasetron is the subject of EP 309423 B (1994), herein incorporated by reference, which describes how to make that drug. In the present invention, itasetron is covalently attached to the polypeptide via the amine group.
Quinolone Antibiotic The quinolone antibiotic of the present invention is a known pharmaceutical agent that is 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-3quinolinecarboxylic acid monomethanesulfonate. Its structure is:
F
N N O O A quinolone antibiotic is the subject of EP 882725 Al (1998), herein incorporated by reference, which describes how to make that drug. In the present invention, a quinolone antibiotic is covalently attached to the polypeptide via the amine group.
Adrenocorticotropic hormone Adrenocorticotropic hormone is a known pharmaceutical agent that is useful for the diagnosis ofAddison's disease and other conditions in which the functionality of the adrenal cortex is to be determined. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
In the present invention, adrenocorticotropic hormone is covalently attached to the polypeptide via an amide bond.
Carbamazepine Carbamazepine is a known pharmaceutical agent that is used in the treatment of epilepsy. Its structure is: 0 NH 2
N
Carbamazepine is the subject of U.S. Patent Numbers 5,284,662 and Re. 34,990, herein incorporated by reference, which describes how to make that drug. In the present invention, carbamazepine is covalently attached to the polypeptide via the amido group.
Carisoprodol Carisoprodol is a known pharmaceutical agent that is used in the treatment of skeletal muscle spasm. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: CH, 0 0
H
3 C H3
CH
3 In the present invention, carisoprodol is covalently attached to the polypeptide via the amido group.
Cefuroxime Axetil Cefuroxime axetil is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is [6R-[6alpha,7beta(Z)]]-3-[[(aminocarbonyl) oxy]methyl]-7-[[2-furan yl (methoxyimino)acetyl]amino]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1-(acetyloxy)ethyl ester. Its structure is: I o o Cefuroxime axetil is the subject of GB 1571683 (1980), herein incorporatedby reference, which describes how to make that drug. In the present invention, cefuroxime axetil is covalently attached to the polypeptide via the amido group.
AGE Crosslink Breaker The AGE crosslink breaker of the present invention is a known pharmaceutical agent that is used in the treatment of diabetes and cardiovascular disease. Its chemical name is dimethyl-3-(2-oxo-2-phenylethyl)thiazolium. Its structure is: 0 In the present invention, the AGE crosslink breaker is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
AGE crosslink breaker is the subject of WO 96/22095 (1996), priority US application 375155 (1995), herein incorporated by reference, which describes how to make that drug.
Alprazalom Alprazalom is a known pharmaceutical agent that is used in the treatment of anxiety disorders. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
H
3 C N Cl N In the present invention, alprazalom is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Altinicline Altinicline is a known pharmaceutical agent that is used in the treatment of Parkinson's disease. Its chemical name is 3-ethynyl-5-[(2S)-l-methyl-2pyrrolidinyl]pyridine. Its structure is: N \N In the present invention, altinicline is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Altinicline is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
Amiodarone Amiodarone is a known pharmaceutical agent that is used in the treatment of cardiac arrhythmia. Its chemical name is (2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5diiodophenyl]methanone. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: 0 In the present invention, amiodarone is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Amitriptyline Amitriptyline is a known pharmaceutical agent that is used in the treatment of depression. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
CH
3
I
N
H3C In the present invention, amitriptyline is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Azelastine Azelastine is a known pharmaceutical agent that is used in the treatment of itching of the eye associated with allergic conjunctivitis. Its chemical name is chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)- 1(2H)-phthalazinone. Its structure is: 0 II N- C 1 Azelastine is the subject of U.S. Patent Number 5,164,194, herein incorporated by reference, which describes how to make that drug. In the present invention, the azelastine is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Bile Acid Transport Inhibitor The bile acid transport inhibitor of the present invention is a known pharmaceutical agent that is used in the treatment of hypercholesterolemia. Its chemical name is 3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide.
Its structure is: The bile acid transport inhibitor of the present invention is the subject of WO 96/5188 (1996), based on US application 288527 (1994), herein incorporated by reference, which describes how to make that drug. In the present invention, the bile acid transport inhibitor is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Bromocriptine Bromocriptine is a known pharmaceutical agent that is used in the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea, with or without galactorrhea; hypogonadism; and infertility. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: (CH .CH. f N No 0 H C-IACH(CH3 QNH H
'CHCCHH
3
HN
HN-
In the present invention, bromocriptine is covalently attached to the polypeptide via the hydroxyl group. Alternatively, it is covalently attached to the polypeptide via a linker.
This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Bupropion Bupropion is a known pharmaceutical agent that is used in smoking cessation therapy and in the treatment of depression. Its chemical name is 1-(3-chlorophenyl)-2-[(1,1dimethylethyl)amino]- 1-propanone. Its structure is: c Cl Bupropion is the subject of U.S. Patent Numbers 5,358,970; 5,427,798; 5,731,000; 5,763,493; and Re. 33,994, herein incorporated by reference, which describes how to make that drug. In the present invention, bupropion is covalently attached to the polypeptide via the amino group. Alternatively, it is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Buspirone Buspirone is a known pharmaceutical agent that is used in the treatment of atopic dermatitis. Its chemical name is 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8azaspiro[4,5]decane-7,9-dione hydrochloride. Its structure is: N N 0 ,-NN
O
Buspirone is the subject of U.S. Patent Number 4,182,763 and 5,015,646, herein incorporated by reference, which describes how to make that drug. In the present invention, the buspirone is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Cabergoline Cabergoline is a known pharmaceutical agent that is used in the treatment of Parkinson's disease. Its chemical name is (8beta)-N-[3-(dimethylamino)propyl]-N- [(ethylamino)carbonyl]-6-(2-prop enyl)ergoline-8-carboxamide. Its structure is: Cabergoline is the subject of U.S. Patent Number 4,526,892, herein incorporated by reference, which describes how to make that drug. In the present invention, cabergoline is covalently attached to the polypeptide via the amino group. Alternatively, it can be covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Caffeine Caffeine is a known pharmaceutical agent that is used in the treatment of neonatal apnea. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: 0
CH
3 Candesartan Cilexitil
CH
3 In the present invention, the caffeine is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Candesartan Cilexitil Candesartan cilexitil is a known pharmaceutical agent that is used in the treatment of heart failure. Its chemical name is 2-ethoxy-l-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-l-H-benzimidazole-7-carboxylic acid 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester. Its structure is:
N..
Candesartan cilexitil is the subject of U.S. Patent Numbers 5,196,444; 5,534,534; 5,703,110 and 5,705,517, herein incorporated by reference, which describes how to make that drug. In the present invention, the candesartan cilexitil is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Celecoxib Celecoxib is a known pharmaceutical agent that is used in the treatment of osteo- and rheumatoid arthritis. Its chemical name is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lHpyrazol-l-yl]benzenesulfonamide. Its structure is:
I
O=S-O
NI
F
F
Celecoxib is the subject of U.S. Patent Numbers 5,466,823, 5,563,165, 5,760,068 and 5,972,986, herein incorporated by reference, which describes how to make that drug. In the present invention, the celecoxib is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Cilansetron Cilansetron is a known pharmaceutical agent that is used in the treatment of irritable bowel syndrome. Its chemical name is (R)-5,6,9,10-tetrahydro-10-[(2-methyl-lH-imidazol- 1-yl)methyl]-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one. Its structure is:
N
Cilansetron is the subject of EP 297651 (1989), herein incorporated by reference, which describes how to make that drug. In the present invention, the cilansetron is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Cisatracurium Besylate Cisatracurium besylate is a known pharmaceutical agent that is used as a neuromuscular blocker in surgery. Its chemical name is [1R-[1alpha,2alpha(1'R*,2'R*)]] 2,2'-[1,5-pentanediylbis[oxy(3-oxoo-3,1-propanediyl)]]bis[l-[(3,4-dimethoxyphenyl) methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-isoquinolinium. Its structure is: 0 0 N O-N-0 Cisatracurium besylate is the subject of U.S. Patent Number 5,453,510 and WO 92/965 (1992), herein incorporated by reference, which describes how to make that drug. In the present invention, the cisatracurium is covalently attached to the polypeptide via a linker.
This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Citalopram Citalopram is a known pharmaceutical agent that is used in the treatment of depression. Its chemical name is 1-[3-(dimethylamino)propyl]-l-(4-fluorophenyl)-l,3dihydro-5-isobenzofurancarbonitrile. Its structure is:
N
IN-
Citalopram is the subject of GB 1526331 (1978), GB 1486 (1976), and EP 171943 B (1988), herein incorporated by reference, which describes how to make that drug. In the present invention, the citalopram is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Clomipramine Clomipramine is a known pharmaceutical agent that is used in the treatment of obsessive-compulsive disorder. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: 00 N C1
I
CHCH
2 CH, N(CH In the present invention, the clomipramine is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Clopidogrel Clopidogrel is a known pharmaceutical agent that is used in the treatment of thrombosis and stroke. Its chemical name is (S)-alfa-(2-chlorophenyl)-6,7dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester sulfate Its structure is: 0 o
II
I I 0 1 Clopidogrel is the subject of U.S. Patent Numbers 4,529,596; 4,847,265; and 5,576,328, herein incorporated by reference, which describes how to make that drug. In the present invention, the clopidogrel is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Chlorpheniramine Chlorpheniramine is a known pharmaceutical agent that is used in the treatment of nasal congestion. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: .L OHL In the present invention, the chlorpheniramine is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Conivaptan Conivaptan is a known pharmaceutical agent that is 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 ]benzazepin-6(1H)-yl)carbonyl]-benzamide. Its structure is:
N
Conivaptan is the subject of EP 709386 A (1996), herein incorporated by reference, which describes how to make that drug. In the present invention, the conivaptan is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Cyclobenzaprine Cyclobenzaprine is a known pharmaceutical agent that is used in the treatment of muscle spasm. Its chemical name is 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,Ndimethyl-1-propanamine. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: In the present invention, the cyclobenzaprine is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Dextromethorphan Dextromethorphan is a known pharmaceutical agent that is used in the treatment of coughs. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
CHH
I
H N CH2 H O CHZ CH3O In the present invention, the dextromethorphan is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Diazepam Diazepam is a known pharmaceutical agent that is used in the treatment of anxiety. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
H
3
C
1 O r^-r^ Ci c N 7 In the present invention, the diazepam is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Dicyclomine Dicyclomine is a known pharmaceutical agent that is used in the treatment of functional disturbances of GI motility such as irritable bowel syndrome. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: 0 C Ha In the present invention, the dicyclomine is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Diltiazem Diltiazem is a known pharmaceutical agent that is used in the treatment of hypertension and angina. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: 0
SO
0
N
Diltiazem is the subject of U.S. Patent Number 5,529,791, herein incorporated by reference, which describes how to make that drug. In the present invention, the diltiazem is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Dolasetrom Mesylate Dolasetrom mesylate is a known pharmaceutical agent that is used in the treatment of nausea and vomiting associated with chemotherapy. Its chemical name is 1H-indole-3carboxylic acid trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester. Its structure is:
N
N H 0 0 Dolasetrom mesylate is the subject of U.S. Patent Number 4,906,775, herein incorporated by reference, which describes how to make that drug. In the present invention, the dolasetrom mesylate is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Donepezil Donepezil is a known pharmaceutical agent that is used in the treatment of Alzheimer's and attention deficit disorder. Its chemical name is 2,3-dihydro-5,6-dimethoxy- 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1 H-inden-1-one. Its structure is: 0 0 Donepezil is the subject of U.S. Patent Number 4,895,841, herein incorporated by reference, which describes how to make that drug. In the present invention, the donepezil is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Emivirine Emivirine is a known pharmaceutical agent that is 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: 0
N
O
Emivirine is the subject of EP 420763 B (1999), herein incorporated by reference, which describes how to make that drug. In the present invention, the emivirine is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Felodipine Felodipine is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5pyridinedicarboxylic acid ethyl methyl ester. Its structure is: Cl 0 0 I I1
N
Felodipine is the subject of U.S. Patent Numbers 4,264,611 and 4,803,081, herein incorporated by reference, which describes how to make that drug. In the present invention, the felodipine is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Fenofibrate Fenofibrate is a known pharmaceutical agent that is used in the treatment of hyperlipiemia. Its chemical name is 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid 1-methylethyl ester. Its structure is: Cl Fenofibrate is the subject of U.S. Patent Number 4,895,726, herein incorporated by reference, which describes how to make that drug. In the present invention, the fenofibrate is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Fentanyl Fentanyl is a known pharmaceutical agent that is used in the treatment of pain. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
N
0 N In the present invention, the fentanyl is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Flumazenil Flumazenil is a known pharmaceutical agent that is used in the treatment of depression and liver disease. Its chemical name is 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4Himidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester. Its structure is: 0 N 0 o Flumazenil is the subject of U.S. Patent Number 4,316,839, herein incorporated by reference, which describes how to make that drug. In the present invention, the flumazenil is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Gepirone Gepirone is a known pharmaceutical agent that is used in the treatment of anxiety and depression. Its chemical name is 4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]- 2,6-piperidinedione. Its structure is: 0 oN N Gepirone is the subject of GB 2114122 B (1985), based on priority US application 334688 (1981), herein incorporated by reference, which describes how to make that drug. In the present invention, the gepirone is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Imipramine Imipramine is a known pharmaceutical agent that is used in the treatment of depression. Its structure is:
CH
3 It
H
3
CN
N
In the present invention, the imipramine is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Irbesartan Irbesartan is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is 2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1, '-biphenyl]-4yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one. Its structure is: N N
N
Irbesartan is the subject of U.S. Patent Number 5,270,317, herein incorporated by reference, which describes how to make that drug. In the present invention, the irbesartan is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Isradipine Isradipine is a known pharmaceutical agent that is used in the treatment of hypertension. Its chemical name is 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester. Its structure is:
N
oo0
N
N
Isradipine is the subject of EP 150 B (1981) and UK 2037766 B (1983), herein incorporated by reference, which describes how to make that drug. In the present invention, the isradipine is Scovalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2- 6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Itraconazole Itraconazole is a known pharmaceutical agent that is used in the treatment of mycosis. Its chemical name is 4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-1,2,4-triazol-l-yl)methyl]-1,3-dioxolan- 4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-( -methylpropyl)-3H- 1,2,4-triazol-3-one.
Its structure is: C1 N N N N Itraconazole is the subject of U.S. Patent Numbers 4,267,179; 4,727,064; and 5,707,975, herein incorporated by reference, which describes how to make that drug. In the present invention, the itraconazole is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Ketoconazole Ketoconazole is used in the treatment ofblastomycosis, candidal infections oropharyngeal and/or esophageal candidiasis, vulvovaginal candidiasis, candiduria, chronic mucocutaneous candidiasis), chromomycosis (chromoblastomycosis), coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. Its structure is: In the present invention, the ketoconazole is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Ketolide Antibiotic The ketolide antibiotic of the present invention is a known pharmaceutical agent that is used in the treatment of bacterial infection. Its chemical name is (3aS,4R,7R,9R, 1 R, 11 R,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)-beta-D-xylohexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetrone. Its structure is:
\N
oo 0 0 0 0 A ketolide antibiotic is the subject of WO 98/9978 (1998), priority US 707776 (1996), herein incorporated by reference, which describes how to make that drug. In the present invention, the ketolide antibiotic is covalently attached to the polypeptide via a linker.
This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Leflunomide Leflunomide is a known pharmaceutical agent that is used in the treatment of rheumatoid arthritis. Its chemical name is 5-methyl-N-[4-(trifluoromethyl)phenyl]-4isoxazolecarboxamide. Its structure is: 0
F
Leflunomide is the subject of U.S. Patent Number 5679709, herein incorporated by reference, which describes how to make that drug. In the present invention, the leflunomide is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Lesopitron Lesopitron is a known pharmaceutical agent that is used in the treatment of anxiety.
Its chemical name is 2-[4-[4-(4-chloro-1H-pyrazol-l-yl)butyl]-l-piperazinyl]pyrimidine dihydrochloride. Its structure is: E N N
N
N
Lesopitron is the subject of EP 382637 A (1990), herein incorporated by reference, which describes how to make that drug. In the present invention, the lesopitron is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Propoxyphene Propoxyphene is a known pharmaceutical agent that is used in the treatment of pain.
It is a mild narcotic analgesic. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is as follows:
CH
HaC oH CM CH3 In the present invention, propoxyphene is covalently attached to the polypeptide via a linker.
This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Activated Protein C Activated protein C is a known pharmaceutical agent that is used in the treatment of blood clots. Its structure is well known and it is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
In the present invention, activated protein C is covalently attached to the polypeptide via a peptide bond.
Anaritide Anaritide is a known pharmaceutical agent that is used in the treatment of oliguric acute renal failure. Its chemical name is N-L-arginyl-8-L-methionine-21 a-L-phenylalanine- 21b-L-arginine-21 c-L-tyrosine-atriopeptin-21. Its structure is: 0 er rl Gly. et Gly Asp I 9rg In the present invention, anaritide is covalently attached to the polypeptide via a peptide bond.
Epoetin Epoetin is a known pharmaceutical agent that is used in the treatment of anemia. Its chemical name is 1-165-erythropoietin (human clone lambdaHEPOFL13 protein moiety) glycoform alpha.
Epoetin is the subject of EP 148605 B (1990), priority US application 561024 (1983), herein incorporated by reference, which describes how to make that drug. In the present invention, epoetin is covalently attached to the polypeptide via a peptide linkage.
Etanercept Etanercept is a known pharmaceutical agent that is 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 gamma 1-chain Fc fragment) Etanercept is the subject of EP 418014 B (1995), priority based on US application 403241 (1989), herein incorporated by reference, which describes how to make that drug. In the present invention, etanercept is covalently attached to the polypeptide via a peptide bond.
Exendin Exendin-4 is a known pharmaceutical agent that is used in the treatment of diabetes.
It is a synthetic form of a peptide isolated from the salivary secretions of the Gila monster lizard. In the present invention, exendin-4 is covalently attached to the polypeptide via a peptide bond.
Filgrastim Filgrastim is a known pharmaceutical agent that is used in the treatment of cancer, HIV infection, pneumonia, leukopenia and skin ulcer. Its chemical name is N-L-methionylcolony-stimulating factor (human clone 1034).
Filgrastim is the subject of EP 237545 B (1991), based on priority application US 768959 (1985), herein incorporated by reference, which describes how to make that drug. In the present invention, filgrastim is covalently attached to the polypeptide via a peptide bond.
Follitropin Follitropin is a known pharmaceutical agent that is used in the treatment of infertility.
Its chemical name is follicle-stimulating hormone (human alpha-subunit reduced), complex with follicle-stimulating hormone (human beta-subunit reduced).
Follitropin is the subject of WO 95/19991 (1995) and U.S. Patent Numbers 4,589,402; 5,270,057; and 5,767,251, herein incorporated by reference, which describes how to make that drug. In the present invention, follitropin is covalently attached to the polypeptide via a peptide bond.
Gastrin Immunogen GASTRIMMUNE is an immunogenic form of gastrin-17 (G17), a growth factor for colorectal, stomach and pancreatic cancers. It has use as a vaccine for cancer and gastrointestinal ulcer.
Gastrin 17 immunogen is the subject of U.S. Patent Numbers 5,622,702; 5,785,970; 5,607,676 and 5609870, herein incorporated by reference, which describes how to make that drug. In the present invention, gastrin 17 immunogen is covalently attached to the polypeptide via a peptide bond.
Glatiramer Acetate Glatiramer acetate is a known pharmaceutical agent that is 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 U.S. Patent Number 6,054,430 and 5,981,589, herein incorporated by reference, which describes how to make that drug. In the present invention, glatiramer acetate is covalently attached to the polypeptide via a peptide bond.
Glucagon Glucagon is a known pharmaceutical agent that is used in the treatment of diabetes It is a naturally occurring peptide that can either be isolated or synthesized, preferably using recombinant DNA technology.
In the present invention, glucagon is covalently attached to the polypeptide via a peptide linkage.
Ilodecakin Ilodecakin is a known pharmaceutical agent that is used in the treatment of hepatitis, autoimmune disorders and HIV infections. Its chemical name is interleukin 10, and it is both isolatable from natural sources and capable of being synthesized by those of skill in the art.
In the present invention, ilodecakin is covalently attached to the polypeptide via a peptide bond.
Imiglucerase Imiglucerase is a known pharmaceutical agent that is used in the treatment of Gaucher disease. Its chemical name is glucosyl-(human placenta isoenzyme protein moiety) 495-Lhistidine-ceramidase. It is a recombinant glucocerebrosidase enzyme.
Imiglucerase is the subject of EP 401362 B (1996), based on priority application US 289589 (1988), herein incorporated by reference, which describes how to make that drug. In the present invention, imiglucerase is covalently attached to the polypeptide via a peptide bond.
Infliximab Infliximab is a known pharmaceutical agent that is used in the treatment of arthritis and HIV infection. It is a monoclonal antibody targeting tumor necrosis factor alpha. Its chemical name is immunoglobulin G, anti-(human tumour necrosis factor) (human-mouse monoclonal cA2 heavy chain), disulfide with human-mouse monoclonal cA2 light chain, dimer.
In the present invention, infliximab is covalently attached to the polypeptide via a peptide bond.
Insulin Human insulin is a known pharmaceutical agent that is used in the treatment of diabetes. Insulin human is a biosynthetic or semisynthetic protein that is structurally identical to endogenous insulin secreted by the beta cells of the human pancreas. Although structurally identical to endogenous human insulin, commercially available insulin human is not extracted from the human pancreas, but is prepared biosynthetically from cultures of genetically modified Escherichia coli or Saccharomyces cerevisiae or semisynthetically by transpeptidation of pork insulin. Its structure is: G0 Cr- T -1 S I -Str- l B-r in- LVJ-4 -A -W W P-O H 1P 1\ ia is S r p Ld"i[ -pIWH Choi" a HO -Il. -n.Lp -1b-Tyr. I Rk4P N Arg- Human insulin is the subject of U.S. Patent Numbers 5,474,978 and 5,514,646, herein incorporated by reference, which describes how to make that drug. In the present invention, human insulin is covalently attached to the polypeptide via a peptide bond.
Interferon Alfacon-1 Interferon alfacon-1 is a known pharmaceutical agent that is used in the treatment of viral infection and cancer. Its chemical name is interferon alpha 1 (human lymphoblast reduced), N-L-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 the subject of EP 422697 B (1994), based on priority US application 375494 (1982), herein incorporated by reference, which describes how to make that drug. In the present invention, interferon alfacon-1 is covalently attached to the polypeptide via a peptide bond.
Interferon Beta-la Interferon beta-1 a is a known pharmaceutical agent that is used in the treatment of multiple sclerosis, viral infection and cancer. It is 145258-61-3 human fibroblast protein moiety 74899-73-3 pre-(human fibroblast protein moiety reduced) 74899-71-1 human fibroblast protein moiety reduced. Biogen was awarded European patent number 41313 for the production of interferon beta through recombinant technology. The patent covered recombinant DNA molecules, transformed hosts and methods for producing recombinant interferon beta proteins.
In the present invention, interferon beta-1 a is covalently attached to the polypeptide via a peptide bond.
Interleukin-2 Interleukin-2 is a known pharmaceutical agent that is used in the treatment of renal cell carcinoma. IL-2 promotes proliferation, differentiation, and recruitment ofT and B cells, natural killer (NK) cells, and thymocytes; IL-2 also causes cytolytic activity in a subset of lymphocytes and subsequent interactions between the immune system and malignant cells; IL-2 can stimulate lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL) cells. LAK cells (which are derived from lymphocytes from a patient and incubated in IL-2) have the ability to lyse cells which are resistant to NK cells.
In the present invention, interleukin-2 is covalently attached to the polypeptide via a peptide bond.
Avasimibe Avasimibe is a known pharmaceutical agent that is used in the treatment of hyperlipidemia. Its chemical name is N-[[2,6-bis(1-methylethyl)phenoxy]sulfonyl]-2,4,6tris(1-methylethyl)benzeneacetamide. Its structure is: Avasimibe is the subject of WO 94/26702 1994 (priority US 62515 (1993)), herein incorporated by reference, which describes how to make that drug. In the present invention, avasimibe is covalently attached to the polypeptide via the sulfate group.
Didanosine Didanosine is a known pharmaceutical agent that is used in the treatment of HIV. Its chemical name is 2',3'-dideoxyinosine. Its structure is: 0
N
Didanosine is the subject of U.S. Patent Numbers 4,861,759 and 5,616,566, herein incorporated by reference, which describes how to make that drug. In the present invention, didanosine is covalently attached to the polypeptide via the ribose alcohol group.
Doxorubicin Doxorubicin is a known pharmaceutical agent that is used in the treatment of bacterial infection. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: O O O 0 0 0 0 0 0 0 0
N
Doxorubicin is the subject of U.S. Patent Number 4,837,028, herein incorporated by reference, which describes how to make that drug. In the present invention, doxorubicin is covalently attached to the polypeptide via the alcohol group.
Isosorbide Dinitrate Isosorbide dinitrate is a known pharmaceutical agent that is used in the treatment of angina. It is made up of the organic nitrates and nitrites are esters of nitrous or nitric acid, primarily amyl nitrite.
In the present invention, isosorbide dinitrate is covalently attached to the polypeptide via the nitrite group.
Amifostine Amifostine is a known pharmaceutical agent that is used in the treatment of moderate to severe xerostomia in patients with head and neck cancer undergoing postoperative radiotherapy. Its chemical name is 2-[(3-aminopropyl)amino]ethanethiol dihydrogen phosphate. Its structure is: 0 N N S p I N' 0 0 Amifostine is the subject of U.S. Patent Numbers 5,424,471; 5,591,731; and 5,994,409, herein incorporated by reference, which describes how to make that drug. In the present invention, amifostine is covalently attached to the polypeptide via the phosphate group.
Etidronate Etidronate is a known pharmaceutical agent that is used in the treatment of moderate to severe symptomatic Paget's disease of bone (osteitis deformans). It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: 0 II OH
P
ONa
CH
3
C-OH
.ONa
P
II OH 0 O In the present invention, etidronate is covalently attached to the polypeptide via the phosphate group.
Fludrocortisone Fludrocortisone is a known pharmaceutical agent that is used in the treatment of epilepsy. Its chemical name is 5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4imidazolidinedion. Its structure is: 0 0 o 0P\O Fludrocortisone is the subject of U.S. Patent Number 4,260,769 (1981), and EP 473687 B (1996), based on priority application US 356948 (1989), herein incorporated by reference, which describes how to make that drug. In the present invention, fludrocortisone is covalently attached to the polypeptide via the phosphate group.
Alpha 1 Proteinase Inhibitor Alpha 1 proteinase inhibitor is a known pharmaceutical agent that is used in the treatment of emphysema. It is a natural product isolated from human blood, using methods known to those of ordinary skill in the art.
Anastrozole Anastrozole is a known pharmaceutical agent that is used in the treatment of breast cancer. Its chemical name is alpha,alpha,alpha',alpha'-tetramethyl-5-(1H-1,2,4-triazol-1ylmethyl)- 1,3-benzenediacetonitrile. Its structure is:
N
Anastrozole is the subject of EP 296749 B (1994), priority GB 14013 (1987), herein incorporated by reference, which describes how to make that drug. In the present invention, the anastrozole is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Aripiprazole Aripiprazole is a known pharmaceutical agent that is used in reducing both the positive and negative symptoms of acutely psychotic patients. Its chemical name is (2,3-dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydro-2(lH)-quinolinone. Its structure is: C1
N
Aripiprazole is the subject of EP 367141 B (1996)(priority Japan 276953 (1988)), herein incorporated by reference, which describes how to make that drug. In the present invention, the aripiprazole is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Astemizole Astemizole is a known pharmaceutical agent that is used in the treatment of seasonal allergic rhinitis and chronic idiopathic urticara. Its chemical name is fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-1H-benzimidazol-2amine. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: In the present invention, the astemizole is covalently attached to the polypeptide via a linker. This linker may be a small molecule containing 2-6 carbons and one or more functional groups (such as amines, amides, alcohols, or acids) or may be made up of a short chain of either amino acids or carbohydrates.
Bisoprolol and Hydrochlorothiazide Etoricoxib Etoricoxib is a known pharmaceutical agent that is used as a cox-2 inhibitor. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
The polypeptide carrier can be prepared using conventional techniques. A preferred technique is copolymerization of mixtures of amino acid N-carboxyanhydrides.
Alternatively, if a specific sequence is desired, a solid state automated peptide synthesizer can be used.
Gadopentetate dimeglumine Gadopentetate dimeglumine is a known pharmaceutical agent that is used for imaging in brain scans.
The polypeptide carrier can be prepared using conventional techniques. A preferred technique is copolymerization of mixtures of amino acid N-carboxyanhydrides.
Alternatively, if a specific sequence is desired, a solid state automated peptide synthesizer can be used.
Gemcitabine Abacavir Sulfate Abacavir sulfate is a known pharmaceutical agent a carbocyclic 2'-deoxyguanosine nucleoside analogue that is a reverse 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: $1 Abacavir sulfate is the subject of U.S. Patent Numbers 5,034,394 and 5,089,500, herein incorporated by reference, which describes how to make that drug. In the present invention, abacavir sulfate is covalently attached to the polypeptide via its alcohol group or, alternatively, its amino group.
Abarelix Abarelix is a known pharmaceutical agent that is used in the treatment of prostate cancer, acting as a gonadotropin-releasing hormone antagonist. Its chemical name is Nacetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-Lseryl-N-methyl-L-tyrosyl-D-asparagynyl-L-N6-(1 -methylethyl)-L-lysyl-L-prolyl-Dalaninamide. Abarelix is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is as follows:
N
0l 0 0 0 N 0 lNY N I
N
N N N N N N N 0 0 0 0
N
In the present invention, abarelix is covalently attached to the polypeptide via the free alcohol group or, alternatively, through one of its amino groups.
Alendronate Alendronate is a known pharmaceutical agent that is used for controlling osteoporosis in men. Its chemical name is (4-amino-1-hydroxybutylidene)bisphosphonic acid. Its structure is: 0 0 0 N \O P-0 Alendronate is the subject of U.S. Patent Numbers 4,621,077; 5,358,941; 5,681,950; 5,804,570; 5,849,726; 6,008,207; and 6,090,410, herein incorporated by reference, which describe how to make that drug. In the present invention, alendronate is covalently attached to the polypeptide via the hydroxyl or phosphate groups.
Amlodipine Besylate and Benazepril Amlodipine besylate is a known pharmaceutical agent that is used in the treatment and prevention of myocardial infarction and stroke. Its chemical name is aminoethoxy)methyl]-4-(2-chlorophenyl)- 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid, 3-ethyl 5-methyl ester monobenzenesulfonate. Its structure is: Benazepril has the chemical name [S-(R*,R*)]-3-[[1-(ethoxycarbonyl)-3phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo- 1H- -benzazepine-1-acetic acid. It is available commercially or can be made by those of skill in the art. Its structure is as follows: 0 Amlodipine besylate is the subject of U.S. Patent Numbers 4,572,909 and 4,879,303, herein incorporated by reference, which describe how to make that drug. In the present invention, amlodipine besylate is covalently attached to the polypeptide via the amino group.
Benazepril is attached via its carboxylic acid.
Azathioprene Azathioprene is a known pharmaceutical agent that is used in the treatment of transplant organ rejection. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
/_N
H
3
C-N
SNO
S
In the present invention, azathioprene is covalently attached to the polypeptide via the nitrate group, or alternatively though a linker.
Baclofen Baclofen is a known pharmaceutical agent that is used in the treatment of spasticity.
It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is:
HJN
OH
i OH
CI
In the present invention, baclofen is covalently attached to the polypeptide via the carboxylic acid group or the amine group.
Bicalutamide Bicalutamide is a known pharmaceutical agent that is used in the treatment of locally advanced, non-metastatic prostate cancer, in combination with LHRH. Its chemical name is (+,-)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy- 2 methylpropanamide. Its structure is: N N 0 Bicalutamide is the subject of U.S. Patent Numbers 4,472,382; 4,636,505; and 5,389,613, herein incorporated by reference, which describes how to make that drug. In the present invention, bicalutamide is covalently attached to the polypeptide via the hydroxyl group.
LHRH may also be attached to the same polypeptide to provide the two drugs in combination.
Cilastatin and Imipenem Cilastatin and imipenem are known pharmaceutical agents that are used together in the treatment of bacterial infections. Cilastatin has no antibacterial activity, but increases the effectiveness of imipenem. Each is commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. The structure of imipenem is:
H
2 0 In the present invention, imipenem is covalently attached to the polypeptide via the carboxylic acid. Ciliastatin can be attached via any free alcohol, acid, or amine group, or can be attached via a linker.
Clonazepam Clonazepam is a known pharmaceutical agent that is used in the treatment of epilepsy.
It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: O2
N
Ci In the present invention, clonazepam is covalently attached to the polypeptide via the amino or nitro group.
Cyclosporine Cyclosporine is a known pharmaceutical agent that is used in the treatment of prevention of rejection of kidney, liver or heart allografts. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: In the present invention, cyclosporine is covalently attached to the polypeptide via the hydroxyl group or, alternatively, via an artificial linker.
Dalteparin Dalteparin (also known as heparin) is a known pharmaceutical agent that is used in the treatment of prevention of ischemic complications, due to blood clot formation in patients with unstable angina and non-Q-wave myocardial infarction receiving concurrent aspirin therapy. It is a natural product that is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
Dalteparin is the subject of EP 14184 B (1989), herein incorporated by reference, which describes how to make that drug. In the present invention, dalteparin is covalently attached to the polypeptide via any free hydroxyl, amino, or carboxyl group or, alternatively, via an artificial linker.
Diclofenac and Misoprostol Diclofenac and misoprostol are known pharmaceutical agents that are used together in the treatment of pain and inflammation. Each is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art.
The chemical name of diclofenac is potassium (o-(2,6-dichloroanilino)phenyl)acetate. Its structure is: 0
II
.HOCCH
2 C1
NH
C1 The structure ofmisoprostol is: -0 In the present invention, diclofenac and misoprostol are covalently attached to the polypeptide via the carboxylic acid and alcohol groups, respectively.
Efavirenz Efavirenz is a known pharmaceutical agent that is 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: F F C1 N O Efavirenz is the subject of U.S. Patent Numbers 5,519,021; 5,663,169 and 5,811,423, herein incorporated by reference, which describes how to make that drug. In the present invention, efavirenz is covalently attached to the polypeptide via the amino group or alternately through an artificial linker.
Elanapril and Hydrochlorothiazide Elanapril and hydrochlorothiazide are known pharmaceutical agents used together in the treatment of hypertension.
The chemical name of elanapril is (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-Lalanyl]-L-proline. Its structure is: 0 N 0 The chemical structure of hydrochlorothiazide is: 0 o Elanapril is the subject ofofEP 12401 (1984), priority US application 968249 (1978), and U.S. patent numbers 4,374,829 and 4,472,380, herein incorporated by reference, which describes how to make that drug. In the present invention, elanapril is covalently attached to the polypeptide via the carboxylic acid group; hydrochlorothiazide is attached via its amino group.
Enoxaparin Enoxaparin is a known pharmaceutical agent that is used in the treatment of thrombosis and myocardial infarction. It is a low molecular weight heparin, and is described in U.S. Patent Numbers 4,486,420; 4,692,435 and 5,389,619, incorporated herein by reference.
In the present invention, enoxaparin is covalently attached to the polypeptide via any free alcohol, amine or acid groups, or alternatively via artificial linkers.
Ergotamine Ergotamine is a known pharmaceutical agent that is used in the treatment of migraines. It is both commercially available and readily manufactured using published synthetic schemes by those of ordinary skill in the art. Its structure is: r- A- WA", ~ow- 110 In the present invention, ergotamine is covalently attached to the polypeptide via the alcohol or amine groups.
Fosphenytoin Fosphenytoin is a known pharmaceutical agent that is used in the treatment of epilepsy. Its chemical name is 5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4imidazolidinedione. Its structure is: 0 0 0 oN 0 O
O
Fosphenytoin is the subject of U.S. Patent Numbers 4,260,769 and 4,925,860, herein incorporated by reference, which describes how to make that drug. In the present invention, fosphenytoin is covalently attached to the polypeptide via the phosphate or amino group.
Gadodiamide Gadodiamide is a known pharmaceutical agent that is used as a diagnostic agent in MRI. Its chemical name is [5,8-bis(carboxymethyl)-l l-[2-(methylamino)-2-oxoethyl]-3-oxo- 2,5,8,11-tetraazatridecan-13-oato(3-)]gadolinium. Its structure is: H H O Gadodiamide is the subject of U.S. Patent Number 4,687,659, herein incorporated by reference, which describes how to make that drug. In the present invention, gadodiamide is covalently attached to the polypeptide via the amino or hydroxy group.
Gadoteridol Gadoteridol is a known pharmaceutical agent that is used as a contrast reagent in diagnostic imaging. Its chemical name is (+,-)-[10-(2-hydroxypropyl)-1,4,7,10tetraazacyclododecane-1,4,7- triacetato(3-)]gadolinium. Its structure is: Gadoteridol is the subject of U.S. Patent Number 4,885,363, herein incorporated by reference, which describes how to make that drug. In the present invention, gadoteridol is covalently attached to the polypeptide via a hydroxyl or amino group, or alternatively through an artificial linker.
Interleukin-12 Interleukin-12 is a heterodimeric cytokine produced by phagocytic cells, professional antigen-presenting cells such as dendritic cells and skin Langerhans cells, and B cells.
Interleukin-12 production is induced by bacteria, intracellular pathogens, fungi, viruses, or their products in a T-cell-independent pathway or a T-cell-dependent pathway, the latter mediated through CD40 ligand-CD40 interaction. Interleukin-12 is produced rapidly after infection and acts as a proinflammatory cytokine eliciting production of interferon gamma, by T and natural killer cells, which activates phagocytic cells. The production of interleukin- 12 is strictly regulated by positive and negative feedback mechanisms. If interleukin-12 and interleukin-12-induced interferon gamma are present during early T-cell expansion in response to antigen, T-helper type-1 cell generation is favored and generation of T-helper type-2 cells is inhibited. Thus interleukin-12 is also a potent immunoregulatory cytokine that promotes T-helper type-1 differentiation and is instrumental in the T-helper type-1-dependent resistance to infections by bacteria, intracellular parasites, fungi, and certain viruses. By inhibiting T-helper type-2 cell response, interleukin-12 has a suppressive effect on allergic reactions; by promoting T-helper type-1 responses it participates in the immunopathology responsible for several organ-specific autoimmune diseases. Viruses inducing a permanent or transient immunodepression, such as HIV and measles, may act, in part, by suppressing interleukin-12 production. Because of its ability to enhance resistance to several infectious diseases and to act as an adjuvant in vaccination, and because of its powerful antitumor effect in vivo, interleukin-12 is currently in clinical trials in cancer patients and HIV-infected patients, and it is being considered for therapeutic use in other diseases.
In the present invention, edodekin alfa is covalently attached to the polypeptide via any free alcohol, amine or acid groups, or alternatively via an artificial linker.
Ketotifen Ketotifen is a known pharmaceutical agent that is used in the treatment of allergic conjunctivitis.
In the present invention, ketotifen is covalently attached to the polypeptide via a hydroxyl, amine or carboxylic acid group or, alternatively, via an artificial linker..
Lansoprazole, Amoxicillin and Clarithromicin Lansoprazole, amoxicillin and clarithromicin are used together in the treatment of duodenal ulcer. Lansoprazole's chemical name is 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2pyridinyl]methyl]sulfinyl]-1H-benzimidazole. Its structure is: 0 N N S N F
FF
0 The structure of amoxicillin is RN H H H 0 HO OCHa
H
3 OM
-CMH
HCC
OOHN
0 HO
CH,
The structure of clarithromicin is H3' In the present invention, lansoprazole, amoxicillin and clarithromicin are covalently attached to the polypeptide via the hydroxyl and or amino groups.
Discussion Proteins, oligopeptides and polypeptides are polymers of amino acids that have primary, secondary and tertiary structures. The secondary structure of the protein is the local conformation of the polypeptide chain and consists of helices, pleated sheets and turns. The protein's amino acid sequence and the structural constraints on the conformations of the chain determine the spatial arrangement of the molecule. The folding of the secondary structure and the spatial arrangement of the side chains constitute the tertiary structure.
Proteins fold because of the dynamics associated between neighboring atoms on the protein and solvent molecules. The thermodynamics of protein folding and unfolding are defined by the free energy of a particular condition of the protein that relies on a particular model. The process of protein folding involves, amongst other things, amino acid residues packing into a hydrophobic core. The amino acid side chains inside the protein core occupy the same volume as they do in amino acid crystals. The folded protein interior is therefore more like a crystalline solid than an oil drop and so the best model for determining forces contributing to protein stability is the solid reference state.
The major forces contributing to the thermodynamics of protein folding are Van der Waals interactions, hydrogen bonds, electrostatic interactions, configurational entropy and the hydrophobic effect. Considering protein stability, the hydrophobic effect refers to the energetic consequences of removing apolar groups from the protein interior and exposing them to water. Comparing the energy of amino acid hydrolysis with protein unfolding in the solid reference state, the hydrophobic effect is the dominant force. Hydrogen bonds are established during the protein fold process and intramolecular bonds are formed at the expense of hydrogen bonds with water. Water molecules are "pushed out" of the packed, hydrophobic protein core. All of these forces combine and contribute to the overall stability of the folded protein where the degree to which ideal packing occurs determines the degree of relative stability of the protein. The result of maximum packing is to produce a center of residues or hydrophobic core that has maximum shielding from solvent.
Since it is likely that lipophilic drugs would reside in the hydrophobic core of a peptide, it would require energy to unfold the peptide before the drug can be released. The unfolding process requires overcoming the hydrophobic effect by hydrating the amino acids or achieving the melting temperature of the protein. The heat of hydration is a destabilization of a protein. Typically, the folded state of a protein is favored by only 5-15 kcal/mole over the unfolded state. Nonetheless, protein unfolding at neutral pH and at room temperature requires chemical reagents. In fact, partial unfolding of a protein is often observed prior to the onset of irreversible chemical or conformation processes. Moreover, protein conformation generally controls the rate and extent of deleterious chemical reactions.
Conformational protection of active agents by proteins depends on the stability of the protein's folded state and the thermodynamics associated with the agent's decomposition.
Conditions necessary for the agent's decomposition should be different than for protein unfolding.
Selection of the amino acids will depend on the physical properties desired. For instance, if increase in bulk or lipophilicity is desired, then the carrier polypeptide will be enriched in the amino acids in the table provided below. Polar amino acids, on the other hand, can be selected to increase the hydrophilicity of the polypeptide.
Ionizing amino acids can be selected for pH controlled peptide unfolding. Aspartic acid, glutamic acid and tyrosine carry a neutral charge in the stomach, but will ionize upon entry into the intestine. Conversely, basic amino acids, such as histidine, lysine and arginine, ionize in the stomach and are neutral in an alkaline environment.
Other factors such as nt-7r interactions between aromatic residues, kinking of the peptide chain by addition ofproline, disulfide crosslinking and hydrogen bonding can all be used to select the optimum amino acid sequence for a given application. Ordering of the linear sequence can influence how these interactions can be maximized and is important in directing the secondary and tertiary structures of the polypeptide.
Furthermore, amino acids with reactive side chains glutamic acid, lysine, aspartic acid, serine, threonine and cysteine) can be incorporated for attaching multiple active agents or adjuvants to the same carrier peptide. This is particularly useful if a synergistic effect between two or more active agents is desired.
As stated above, variable molecular weights of the carrier compound can have profound effects on the active agent release kinetics. As a result, low molecular weight active agent delivery systems are preferred. An advantage of this invention is that chain length and molecular weight of the polypeptide can be optimized depending on the level of conformational protection desired. This property can be optimized in concert with the kinetics of the first order release mechanism. Thus, another advantage of this invention is that prolonged release time can be imparted by increasing the molecular weight of the carrier polypeptide. Another, significant advantage of the invention is that the kinetics of active Sagent release is primarily controlled by the enzymatic hydrolysis of the key bond between the carrier peptide and the active agent.
Dextran is the only polysaccharide known that has been explored as a macromolecular carrier for the covalent binding of drug for colon specific drug delivery. Generally, it was only possible to load up to 1/10 of the total drug-dextran conjugate weight with drug. As stated earlier, polysaccharides are digested mainly in the colon and drug absorption is mainly limited to the colon. As compared to dextran, this invention has two major advantages. First, peptides are hydrolyzed by any one of several aminopeptidases found in the intestinal lumen or associated with the brush-border membrane and so active agent release and subsequent absorption can occur in the jejunum or the ileum. Second, the molecular weight of the carrier molecule can be controlled and, thus, active agent loading can also be controlled.
As a practical example, the following table lists the molecular weights of lipophilic amino acids (less one water molecule) and selected analgesics and vitamins.
TABLE 1 Amino acid MW Active agent MW Glycine 57 Acetaminophen 151 Alanine 71 Vitamin B 6 (Pyroxidine) 169 Valine 99 Vitamin C (Ascorbic acid) 176 Leucine 113 Aspirin 180 Isoleucine 113 Ibuprofen 206 Phenylalanine 147 Retinoic acid 300 Tyrosine 163 Vitamin B 2 (Riboflavin) 376 Vitamin D 2 397 Vitamin E (Tocopherol) 431 Lipophilic amino acids are preferred because conformational protection through the stomach is important for the selected active agents, which were selected based on ease of covalent attachment to an oligopeptide. Eighteen was subtracted from the amino acid's molecular weight so that their condensation into a polypeptide is considered. For example, a decamer of glycine (MW=588) linked to aspirin would have a total molecular weight of 750 and aspirin would represent 24% of the total weight of the active agent delivery composition or over two times the maximum drug loading for dextran. This is only for an N- or Cterminus application, for those active agents attached to pendant groups ofdecaglutamic acid, for instance, a drug with a molecular weight of 180 could conceivably have a loading of 58%, although this may not be entirely practical.
The alcohol, amine or carboxylic acid group of the active agent is covalently attached to the N-terminus, the C-terminus or the side chain of the oligopeptide or polypeptide. The location of attachment depends somewhat on the functional group selection. For instance, if the active drug is a carboxylic acid aspirin) then the N-terminus of the oligopeptide is the preferred point of attachment. If the active agent is an amine ampicillin), then the C-terminus is the preferred point of attachment in order to achieve a stable peptide linked active agent. In both, the C- and N-terminus examples, the peptide is, in essence, extended by one monomeric unit forming a new peptide bond. If the active agent is an alcohol, then either the C-terminus or the N-terminus is the preferred point of attachment in order to achieve a stable composition. As in the example above where the alcohol, norethindrone, was covalently attached to poly(hydroxypropylglutamine), an alcohol can be converted into an alkylchloroformate with phosgene. This invention, then, pertains to the reaction of this key intermediate with the N-terminus of the peptide carrier. The active ingredient can be released from the peptide carrier by intestinal peptidases.
The ilcohol can be selectively bound to the gamma carboxylate of glutamic acid and then this conjugate covalently attached to the C-terminus of the peptide carrier. Because the glutamic acid-drug conjugate can be considered a dimer, this product adds two monomeric units to the C-terminus of the peptide carrier where the glutamic acid moiety serves as a spacer between the peptide and the drug as shown in Fig. 4. Intestinal enzymatic hydrolysis of the key peptide bond releases the glutamic acid-drug moiety from the peptide carrier. The newly formed free amine of the glutamic acid residue will then undergo an intramolecular transamination reaction, thereby, releasing the active agent with coincident formation of pyroglutamic acid as shown in Fig. 5. Alternatively, the glutamic acid-drug dimer can be converted into the gamma ester of glutamic acid N-carboxyanhydride. This intermediate can then be polymerized, as described above, using any suitable initiator as shown in Fig. 4. The product of this polymerization is polyglutamic acid with active ingredients attached to multiple pendant groups. Hence, maximum drug loading of the carrier peptide can be achieved. In addition, other amino acid-NCA's can be copolymerized with the gamma ester glutamic acid NCA to impart specific properties to the drug delivery system.
The invention also provides a method of imparting the same mechanism of action for other polypeptides containing functional side chains. Examples include, but are not limited to, polylysine, polyasparagine, polyarginine, polyserine, polycysteine, polytyrosine, polythreonine and polyglutamine. The mechanism can translate to these polypeptides through a spacer or linker on the pendant group, which is terminated, preferably, by the glutamic acid-drug dimer. This carrier peptide-drug conjugate is distinguished from the prior art by virtue of the fact that the primary release of the drug moiety relies on peptidases and not on esterases. Alternatively, the active agent can be attached directly to the pendant group where some other indigenous enzymes in the alimentary tract can affect release.
The active agent can be covalently attached to the N-terminus, the C-terminus or the side chain of the polypeptide using known techniques. Examples of linking organic compounds to the N-terminus type of a peptide include, but are not limited to, the attachment of naphthylacetic acid to LH-RH, coumarinic acid to opioid peptides and 1,3-dialkyl-3acyltriazenes to tetragastrin and pentagastrin. As another example, there are known techniques for forming peptide linked biotin and peptide linked acridine.
The polypeptide carrier can be prepared using conventional techniques. A preferred technique is copolymerization of mixtures of amino acid N-carboxyanhydrides.
Alternatively, if a specific sequence is desired, a solid state automated peptide synthesizer can be used.
The addition of stabilizers to the composition has the potential of stabilizing the polypeptide further. Stabilizers such as sugar, amino acids, polyethylene glycol (PEG) and salts have been shown to prevent protein unfolding. In another embodiment of the invention, a pre-first order release of the active agent is imparted by microencapsulating the carrier polypeptide-active agent conjugate in a polysaccharide, amino acid complex, PEG or salts.
There is evidence that hydrophilic compounds are absorbed through the intestinal epithelia efficiently via specialized transporters. The entire membrane transport system is intrinsically asymmetric and responds asymmetrically to cofactors. Thus, one can expect that excitation of the membrane transport system will involve some sort of specialized adjuvant resulting in localized delivery of active agents. There are seven known intestinal transport systems classified according to the physical properties of the transported substrate. They include the amino acid, oligopeptide, glucose, monocarboxic acid, phosphate, bile acid and the P-glycoprotein transport systems and each has its own associated mechanism of transport.
The mechanisms can depend on hydrogen ions, sodium ions, binding sites or other cofactors.
The invention also allows targeting the mechanisms for intestinal epithelial transport systems to facilitate absorption of active agents.
In another embodiment of the invention, the composition includes one or more adjuvants to enhance the bioavailability of the active agent. Addition of an adjuvant is particularly preferred when using an otherwise poorly absorbed active agent. Suitable adjuvants, for example, include: papain, which is a potent enzyme for releasing the catalytic domain of aminopeptidase-N into the lumen; glycorecognizers, which activate enzymes in the BBM; and bile acids, which have been attached to peptides to enhance absorption of the peptides.
Preferably, the resultant peptide-active agent conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
EXAMPLES
Compositions of the invention are, in essence, the formation of amides from acids and amines and can be prepared by the following examples.
Acid/N-terminus conjugation An acid bioactive agent can be dissolved in DMF under nitrogen and cooled to 0 OC.
The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the amine peptide carrier. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, the product precipitated out in ether and purified using gel permeation chromatography (GPC) or dialysis.
Amine/C-terminus conjugation The peptide carrier can be dissolved in DMF under nitrogen and cooled to 0 OC. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the amine bioactive agent. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, the product precipitated out in ether and purified using GPC or dialysis.
Alcohol/N-Terminus Conjugation In the following example the combination of the alcohol with triphosgene produces a chloroformate, which when reacted with the N-terminus of the peptide produces a carbamate.
Pursuant to this, an alcohol bioactive agent can be treated with triphosgene in dry DMF under nitrogen. The suitably protected peptide carrier is then added slowly and the solution stirred at room temperature for several hours. The product is then precipitated out in ether The crude product is suitably deprotected and purified using GPC.
Other solvents, activating agents, cocatalysts and bases can be used. Examples of other solvents include dimethylsulfoxide, ethers such as tetrahydrofuran or chlorinated solvents such as chloroform. Examples of other activating agents include dicyclohexylcarbodiimide or thionyl chloride. An example of another cocatalyst is Nhydroxysuccinimide. Examples of bases include pyrrolidinopyridine, dimethylaminopyridine, triethylamine or tributylamine.
Preparation of y-Alkyl Glutamate There have been over 30 different y-alkyl glutamates prepared any one of which may be suitable for the drug alcohol of choice. For example, a suspension of glutamic acid, the alcohol and concentrated hydrochloric acid can be prepared and heated for several hours.
The y-alkyl glutamate product can be precipitated out in acetone, filtered, dried and recrystallized from hot water.
y-Alkyl Glutamate/C-Terminus Conjugation The peptide carrier can be dissolved in DMF under nitrogen and cooled to 0 OC. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the y-alkyl glutamate bioactive agent. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, the product precipitated out in ether and purified using GPC or dialysis.
Preparation of y-Alkyl Glutamate-NCA y-Alkyl glutamate can be suspended in dry THF where triphosgene is added and the mixture refluxed under a nitrogen atmosphere until the mixture becomes homogenous. The solution can be poured into heptane to precipitate the NCA product, which is filtered, dried and recrystallized from a suitable solvent.
Preparation of Poly[y-Alkyl Glutamate] y-Alkyl glutamate-NCA can be dissolved in dry DMF where a catalytic amount of a primary amine can be added to the solution until it becomes viscous (typically overnight).
The product can be isolated from the solution by pouring it into water and filtering. The product can be purified using GPC or dialysis.
120

Claims (21)

1. A pharmaceutical composition comprising a polypeptide covalently attached to an active agent selected from hydromorphone, butorphanol, propoxyphene, dextroamphetamine, methylphenidate, noradrenalin and dopamine reuptake cc inhibitor, citalopram, fluoxetine, fluvoxamine maleate, ACE/neutral o endopeptidase inhibitor, amoxicillin, amoxicillin and clavulanate, cefadroxil, Sceftazidime, ceftibuten, cefuroxime, cephalexin, ciprofloxacin, quinolone antibiotic, cefuroxime axetil, azithromycin, caspofungin, clarithromycin, Serythromycin, gentamicin isoton, cefdinir, lansoprazole, ketolide antibiotic, Ci doxyrubicin, and cilastin and imipenem, and a pharmaceutically acceptable excipient, wherein said active agent is released in the bloodstream following oral administration of said pharmaceutical composition and wherein said polypeptide consists of naturally occurring amino acids.
2. The composition according to claim 1 wherein the polypeptide is an oligopeptide.
3. The composition according to claim I wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition according to claim I wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
The composition according to claim I wherein said active agent is covalently attached to a side chain or the N-terminus of said polypeptide.
6. The composition according to claim 1 wherein said active agent is covalently attached to a side chain or the C-terminus of said polypeptide.
7. The composition according to any one of claims 1 or 2 to 6 further comprising a microencapsulating agent.
8. The composition according to claim 7 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
9. The composition according to any one of claims 1 or 2 to 8 further comprising an adjuvant.
The composition according to claim 8 wherein said adjuvant activates an intestinal transporter.
11. The composition according to any one of claims 1 or 2 to 9 wherein said composition is in the form of an ingestable tablet. 121 COMS ID No: ARCS-154462 Received by IP Australia: Time 12:42 Date 2007-07-26 26/07 2007 THU 12:34 FAX +61 2 8231 1099 FBRice Co 0011/019 0 0 3
12. The composition according to any one of claims 1 or 2 to 9 wherein said composition is in the form of an oral suspension. C
13. The composition according to any one of claims 1 or 2 to 9 wherein said active agent is conformationally protected by folding of said polypeptide about said active agent. C
14. The composition according to any one of claims 1 or 2 to 9 wherein said O 00 polypeptide is capable of releasing said active agent from said composition O in a pH-dependent manner.
A method for protecting an active agent from degradation comprising Scovalently attaching an active agent selected from hydromorphone, C butorphanol, propoxyphene, dextroamphetamine, methylphenidate, noradrenalin and dopamine reuptake inhibitor, citalopram, fluoxetine, fluvoxamine maleate, ACE/neutral endopeptidase inhibitor, amoxicillin, amoxicillin and clavulanate, cefadroxil, ceftazidime, ceftibuten, cefuroxime, cephalexin, ciprofloxacin, quinolone antibiotic, cefuroxime axetil, azithromycin, caspofungin, clarithromycin, erythromycin, gentamicin isoton, cefdinir, lansoprazole, ketolide antibiotic, doxyrubicin, and cilastin and imipenem to a polypeptide wherein said active agent is released into the bloodstream following oral administration of said pharmaceutical composition and wherein said polypeptide consists of naturally occurring amino acids.
16. A method for controlling release of an active agent from a composition comprising covalently attaching said active agent to a polypeptide, wherein said active agent is selected from hydromorphone, butorphanol, propoxyphene, dextroamphetamine, methylphenidate, noradrenalin and dopamine reuptake inhibitor, citalopram, fluoxetine, fluvoxamine maleate, ACE/neutral endopeptidase inhibitor, amoxicillin, amoxicillin and clavulanate, cefadroxil, ceftazidime, ceftibuten, cefuroxime, cephalexin, ciprofloxacin, quinolone antibiotic, cefuroxime axetil, azithromycin, caspofungin, clarithromycin, erythromycin, gentamicin isoton, cefdinir, lansoprazole, ketolide antibiotic, doxyrubicin, and cilastin and imipenem, and wherein said active agent is released in the bloodstream following oral administration of said composition and wherein said polypeptide consists of naturally occurring amino acids.
17. A method for delivering an active agent to a patient comprising administering to said patient a composition comprising: a polypeptide 122 COMS ID No: ARCS-154462 Received by IP Australia: Time 12:42 Date 2007-07-26 26/07 2007 THU 12:35 FAX +61 2 8231 1099 FBRice Co 0012/019 O S covalently attached to an active agent selected from hydromorphone, n butorphanol, propoxyphene, dextroamphetamine, methylphenidate, C noradrenalin and dopamine reuptake inhibitor, citalopram, fluoxetine, fluvoxamine maleate, ACE/neutral endopeptidase inhibitor, amoxicillin, C-n amoxicillin and clavulanate, cefadroxil, ceftazidime, ceftibuten, cefuroxime, o Zcephalexin, ciprofloxacin, quinolone antibiotic, cefuroxime axetil, 00 azithromycin, caspofungin, clarithromycin, erythromycin, gentamicin isoton, ON cefdinir, lansoprazole, ketolide antibiotic, doxyrubicin, and cilastin and imipenem, wherein said active agent is released in the bloodstream following Soral administration of said composition and wherein said polypeptide consists of naturally occurring amino acids.
18. The method according to any one of claims 15 to 17 wherein said active agent is released from said composition by an enzyme-catalyzed release mechanism.
19. The method according to any one of claims 15 to 17 wherein said active agent is released from said composition by a pH-dependent unfolding of said polypeptide.
The method according to any one of claims 15 to 17 wherein said active agent is released from said composition in a sustained release.
21. The method according to any one of claims 15 to 17 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide. DATED this 26th day of July 2007 New River Pharmaceuticals Inc. Patent Attorneys for the Applicant: F.B. RICE CO. 123 COMS ID No: ARCS-154462 Received by IP Australia: Time 12:42 Date 2007-07-26
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5534496A (en) * 1992-07-07 1996-07-09 University Of Southern California Methods and compositions to enhance epithelial drug transport
WO1999049901A1 (en) * 1998-03-30 1999-10-07 Pg-Txl Company, L.P. Water soluble paclitaxel derivatives
US6030941A (en) * 1996-05-01 2000-02-29 Avi Biopharma, Inc. Polymer composition for delivering substances in living organisms

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5534496A (en) * 1992-07-07 1996-07-09 University Of Southern California Methods and compositions to enhance epithelial drug transport
US6030941A (en) * 1996-05-01 2000-02-29 Avi Biopharma, Inc. Polymer composition for delivering substances in living organisms
WO1999049901A1 (en) * 1998-03-30 1999-10-07 Pg-Txl Company, L.P. Water soluble paclitaxel derivatives

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