JP2003530329A - Bile acid-containing prodrugs with increased bioavailability - Google Patents

Abstract

(57) SUMMARY The present invention relates to a method of increasing the bioavailability of a compound by binding or linking a bile acid to the compound and reducing the variability of the bioavailability of the compound. The invention also relates to novel compositions of matter obtained by binding a bile acid to another compound to form a prodrug. The invention further relates to the use of a bile acid transporter to actively move a prodrug out of the lumen of the small intestine. It is an object of the present invention to increase the bioavailability of a compound by binding the compound to bile acids to create a prodrug.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to methods of increasing the bioavailability of a compound and reducing the variability of the bioavailability of the compound by binding or linking bile acids to the compound. . The present invention also relates to novel compositions of matter obtained by coupling bile acid to another compound to produce a prodrug. The invention further relates to the use of bile acid transporters to actively move the prodrug from the lumen of the small intestine.

Description of the Related Art Inadequate or variable intestinal permeability is the reason for inadequate oral drug bioavailability. Many methods are available to improve the bioavailability of various drugs [1]. Some of these methods improve the bioavailability of some drugs, but not all compounds work.

Some compounds that exhibit poor bioavailability, suboptimal permeability, or variable bioavailability may have some or all of the following characteristics [2]: 1. Lower than full oral absorption.

2. Lower permeability than appropriate reference markers (eg, metoprolol tartrate [eg, 40 × 10 ⁻⁶ cm / sec permeability across Caco-2 monolayers]).

[0005]   3. Molecular weight greater than 500 Daltons.

[0006]   Hydrogen donor greater than 4.5.

[0007]   Hydrogen bond acceptors greater than 5.10.

[0008] 6. Being a substrate for P-glycoprotein efflux, multidrug resistance associated protein (MRP) efflux, or other efflux systems.

7. Not a substrate or ligand for a carrier or transporter.

1 for increasing the bioavailability of compounds with these characteristics
One possible way is to couple bile acids to this drug or compound to make a prodrug. Bile acid-binding prodrugs are intestinal bile acid transporters (I
Due to the active transporter of the prodrug by BAT), it allows for increased bioavailability and / or decreased variability of this compound.
Intestinal absorption of bile acids is a sodium-dependent process involved in the human intestinal bile acid transporter (hIBAT) and Na ⁺ / K ⁺ ATP-ase [3].

The bile acid transporter is an ideal candidate for drug targeting because human IBAT has a high transport capacity of 10 g per day [4,5], and bile acids are taken up by carrier-mediated systems. It is one of the largest molecules [6]. Given this biology, bile acid transporters appear to be a potential mechanism for improving oral drug absorption by incorporating a bile acid moiety into the active drug in a prodrug fashion. Bile acid prodrug approaches targeting bile acid transporters in various tissues have been studied with peptides [7,8,9], HMG-CoA reductase inhibitors [8], and chlorambucil [10]. This study
It concerns either very small molecules or targeted delivery of drugs to the liver. Other attempts at drug therapy include inhibiting bile acid transporters to reduce cholesterol synthesis in the liver [11].

One compound that can benefit from bile acid conjugates to improve uptake in the small intestine is acyclovir. Acyclovir is an antiviral compound used to inhibit herpes virus growth. Its target is all tissues in the body, not the liver. A typical treatment requires a 200 mg dose to be administered 5 times daily with a 20% bioavailability after oral administration [12].

Different prodrug strategies have been shown to succeed in improving the oral bioavailability of acyclovir [13,14]. Valacyclovir (va
lacyclovir) (L-valine ester prodrug of acyclovir)
It has an oral bioavailability of 54% [15]. This improved bioavailability of valacyclovir allows for a more convenient dosing regimen of 1000 mg twice daily with clinical efficacy similar to that previously found for the acyclovir parent compound [16]. Valacyclovir is a substrate of the human intestinal peptide transporter (PepT1), and Xenopus laevis
A _K i = _4.08mM in PepT1 expressing oocytes [17], and a _K i = 1.10 mm in a stable strain CHO / PepT1 [18].

Compared to PepT1, IBAT has the potential advantage of higher potency and micromolar affinity. Therefore, it is possible to further enhance the oral bioavailability of acyclovir by synthesizing cholate prodrugs to target IBAT. It is also possible to increase the bioavailability of other compounds by binding this compound to bile acids.

In addition, non-human animals have intestinal bile acid transporters. Intestinal bile acid transporters and bile acid-binding prodrugs can be used to increase the absorption of the prodrug and the bioavailability of this compound in animals.

BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention to increase the bioavailability of a compound by binding the compound to bile acids to make a prodrug. It is a further object of the invention that the prodrug is orally administered to an animal or human. It is a further object of the invention that the intestinal bile acid transporter binds to the prodrug and transfers the prodrug from the lumen of the small intestine to the brush border cells. It is a further object of the invention that the prodrug or compound moves from the inside of the brush border into the bloodstream.

It is an object of the present invention to increase the bioavailability of a compound by binding the compound to bile acids to make a prodrug. It is another object of the invention that there is a metabolically labile bond between the compound and bile acid. It is a further object of the invention that the prodrug is orally administered to an animal or human. It is a further object of the invention that the intestinal bile acid transporter binds to the prodrug and transfers the prodrug from the lumen of the small intestine to the brush border cells. It is a further object of the invention that the prodrug or compound moves from the inside of the brush border into the bloodstream.

It is an object of this invention to increase the bioavailability of a compound by linking the compound to a bile acid via a linker group to create a prodrug. It is a further object of the invention that the prodrug is orally administered to an animal or human. It is a further object of the invention that the intestinal bile acid transporter binds to the prodrug and transfers the prodrug from the lumen of the small intestine to the brush border cells. It is a further object of the invention that the prodrug or compound moves from the inside of the brush border into the bloodstream. It is another object of the invention that the linker group is any bifunctional chemical moiety that achieves one or more of the following four functions: (1) facilitating the synthesis of the prodrug, (2) Prodrug enteric bile acid transporter (IB
(3) facilitates the compound to dissociate from bile acids after the prodrug has passed through the lumen of the small intestinal stomach, (4) inside the body Enhances the solubility of the prodrug. It is another object of the invention that the linker groups are of any size, but preferably less than 200 daltons. It is a further object of the invention that there is a metabolically labile bond between the linker group and the compound, between the linker group and the bile acid, or within the linker group itself.

It is an object of the present invention to increase the bioavailability of biologically active compounds by linking the biologically active compounds to bile acids to make prodrugs. It is a further object of the present invention that there is a metabolically labile bond between the biologically active compound and bile acid. It is a further object that the prodrug is administered orally to the animal or human. It is a further object of the invention that the intestinal bile acid transporter binds to the prodrug and transfers the prodrug from the lumen of the small intestine to the brush border cells. It is a further object of the invention that the prodrug or compound moves from the inside of the brush border into the bloodstream.

It is an object of this invention to bind compounds to bile acids to form prodrugs.

It is an object of the present invention to have a pharmaceutical compound which comprises the compound and bile acid.

It is another object of the invention to have pharmaceutical compounds that include compounds, metabolically labile bonds, and bile acids.

It is an object of the invention to have a pharmaceutical compound that comprises a drug, a linker group, and a bile acid. It is another object of the invention to have a pharmaceutical compound that contains a drug, a linker group, a bile acid, and a metabolically labile bond.

Having a pharmaceutical compound that includes a biologically active agent and a bile acid,
It is an object of the present invention.

It is another object of the invention to have pharmaceutical compounds that include biologically active agents, metabolically labile bonds and bile acids.

It is an object of the invention to have a pharmaceutical compound that comprises a biologically active agent, a linker group and a bile acid. It is another object of the invention to have a pharmaceutical compound that comprises a biologically active agent, a linker group, a bile acid and a metabolically labile bond.

It is an object of the present invention to use the intestinal bile acid transporter to actively uptake and remove bile acid containing prodrugs from the lumen of the small intestine.

It is possible to have a method for increasing the bioavailability of a compound by using an intestinal bile acid transporter to actively uptake and remove bile acid containing prodrugs from the lumen of the small intestine. It is an object of the present invention.

It is another object of the invention to use a linker group to link a compound to a bile acid to create a prodrug. It is a further object of the present invention that the linker group is any bifunctional chemical moiety that achieves one or more of the following four functions: (
1) facilitates the synthesis of the prodrug, (2) assists or enhances the binding of the prodrug to the intestinal bile acid transporter (IBAT), (3) after the prodrug has passed through the lumen of the small intestine , (4) enhances solubility of the prodrug inside the body, which makes it easier for the compound to dissociate from bile acids. It is another object of the invention that the linker groups are of any size, but preferably less than 200 daltons. It is also an object of the present invention that the linker group, when attached to a compound or bile acid, results in the existing metabolically labile bond.

It is an object of this invention to reduce the variability of a compound's bioavailability by binding the compound to bile acids to make a prodrug. It is a further object that the prodrug is administered orally to the animal or human. It is a further object of the invention that the intestinal bile acid transporter binds to the prodrug and transfers the prodrug from the lumen of the small intestine to the brush border cells. It is a further object of the invention that the prodrug or compound moves from the inside of the brush border into the bloodstream.

It is an object of the present invention to reduce the variability of a compound's bioavailability by linking the compound to a bile acid to make a prodrug. It is another object of the invention that there is a metabolically labile bond between the compound and bile acid. It is a further object of the invention that the prodrug is orally administered to an animal or human. It is a further object of the invention that the intestinal bile acid transporter binds to the prodrug and transfers the prodrug from the lumen of the small intestine to the brush border cells. It is a further object of the invention that the prodrug or compound moves from the inside of the brush border into the bloodstream.

It is an object of the present invention to reduce the variability of bioavailability of a compound by linking the compound to a bile acid via a linker group to create a prodrug. It is a further object that the prodrug is administered orally to the animal or human. It is a further object of the invention that the intestinal bile acid transporter binds to the prodrug and transfers the prodrug from the lumen of the small intestine to the brush border cells. It is a further object of the invention that the prodrug or compound moves from the inside of the brush border into the bloodstream. It is another object of the invention that the linker group is a bifunctional chemical moiety. It is another object of the invention that the linker groups are of any size, but more preferably less than 200 daltons. It is a further object of the invention that there is a metabolically labile bond between the linker group and the compound, between the linker group and the bile acid, or within the linker group itself.

It is an object of the present invention to reduce the bioavailability variability of a biologically active compound by linking the biologically active compound to a bile acid to make a prodrug. . It is a further object of the present invention that there is a metabolically labile bond between the biologically active compound and bile acid. It is a further object that the prodrug is administered orally to the animal or human. It is a further object of the invention that the intestinal bile acid transporter binds to the prodrug and transfers the prodrug from the lumen of the small intestine to the brush border cells. It is a further object of the invention that the prodrug or compound moves from the inside of the brush border into the bloodstream.

To reduce a harmful drug-drug interaction by linking or linking a bile acid to at least one of the compounds involved in the harmful drug-drug interaction to make a prodrug. Or it is an object of the invention to prevent. Using the intestinal bile acid transporter to take up the prodrug, thereby
It is a further object of the invention to avoid transporters involved in deleterious drug-drug interactions.

It is possible to reduce or prevent harmful drug-nutrient interactions by linking or binding bile acids to compounds involved in the harmful drug-nutrient interaction to make a prodrug. It is an object of the present invention. Using an intestinal bile acid transporter to uptake a prodrug, thereby removing harmful drug-
It is a further object of the invention to avoid transporters involved in nutrient interactions.

It is an object of the present invention to increase the lipophilicity of a compound by linking or binding the bile acid to the compound. It is a further object of the present invention that increased lipophilicity increases bioavailability and reduces bioavailability variability of compounds.

It is an object of the present invention that the compound component of the prodrug is cleaved from this prodrug after it binds to the intestinal bile acid transporter.

It is an object of the invention to coat the prodrug with a substance that protects it from the acidic environment of the stomach and does not interfere with the absorption of the intestinal prodrug.

Acyclovirvalyl deoxycholate
It is an object of the present invention to have a pharmaceutical compound of

Acyclovir barykenodeoxycholate (valylchenodeoxyc)
It is an object of the present invention to have pharmaceutical compounds of

It is an object of the invention to have a pharmaceutical compound of atenolol cholic acid amide.

DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment, the invention is a prodrug containing a bile acid linked to a compound. In alternative embodiments, more than one bile acid may be attached to the compound. Alternatively, more than one compound can be bound to one bile acid. Alternatively, one or more bile acid complexes may be attached to more than one compound.

As used herein, the term “compound” refers to a pharmaceutical drug, a biologically active agent, a metabolic precursor to a pharmaceutical drug, a metabolic precursor to a biologically active agent, or It includes, but is not limited to, any other factor desired to be administered to an animal or human. The compound may be therapeutic or diagnostic in nature. The compounds may also provide nutritional benefits to animals or humans.

It is preferred that a metabolisable bond exists between the compound and the bile acid to which the compound is bound or conjugated. By way of example only, the metabolizable bond can be an ester, amide, carbamate, carbonate, ether, urea, acid anhydride, or sulfur-containing derivative such as thioamides, thioesters, thiocarbamates, and thioureas.

In an alternative embodiment, the linker group is between the compound and the bile acid to which the compound is attached. The linker group can be any bifunctional chemical moiety, but preferably has a molecular weight of less than 200 Daltons. There are four reasons for the use of linker groups; any bifunctional chemical moiety that achieves any one of these reasons is considered a linker group. First, the linker group may facilitate the synthesis of the prodrug. Second, the linker group is a bile acid intestinal transporter (in
testal bile acid transporter (IBAT
A) may assist or enhance the binding of the prodrug. Third, the linker group may facilitate the compound's dissociation from bile acids after the prodrug has passed through the lumen of the small intestine. Fourth, the linker group may enhance the solubility of the prodrug in the body.

Various types of linker groups can be used. Linker groups can be, for example, natural and unnatural amino acids, diacids, di-amines, di-alcohols, sulfates, phosphates, sulfur-containing moieties, amino alcohols, hydroxy acids, and polymers. Examples of amino acids are valine, glycine, taurine, alanine, leucine,
Tyrosine, aspartate, glutamate, lysine, arginine, asparagine, cysteine. Examples of diacids are oxalic acid, fumaric acid, succinic acid, maleic acid, and tartaric acid. Di-amines include ethylenediamine, propylenediamine, 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, piperazine, homopiperazine, and 3-aminopiperidine. Examples of di-alcohols are ethylene glycol, propylene glycol,
1,4-butanediol, polyethylene glycol, and 1,5-pentanediol. Examples of sulfur-containing moieties are mercaptoacetic acid, mercaptopropionic acid, mercaptobenzyl alcohol, 2-mercaptoethanol, 3-mercaptopropanol, and 4-mercaptobutanol. Examples of amino alcohols are 2-aminoethanol, 3-aminopropanol, 4-aminobutanol, 4-hydroxypiperidine, and 3-hydroxypiperidine. Examples of hydroxy acids include 3-hydroxypropionic acid, 4-hydroxybutanoic acid,
And 5-hydroxypentanoic acid. One example of a polymer is polyethylene glycol.

It is preferred that the linker group has a metabolizable linkage for easy cleavage of the prodrug to the compound and bile acid. By way of example only, the metabolizable bond can be an ester, amide, carbamate, carbonate, ether, urea, acid anhydride, or sulfur-containing derivative such as thioamides, thioesters, thiocarbamates, and thioureas.

These bile acid-containing prodrugs are orally administered and absorbed in the small intestine. The bile acid intestinal transporter actively transports this prodrug from the inner lumen of the small intestine to brush border cells. Once inside the brush border cells, the prodrug can either passively cross the cell membrane down the concentration gradient into the bloodstream or be actively transported from the brush border cells into the bloodstream. Good. This active transport of the prodrug from the lumen of the small intestine
It is caused by the affinity of the bile acid intestinal transporter for its ligand, bile acid.

Intracellular or extracellular enzymes cleave one of the bonds between bile acids and compounds with either: (1) after the prodrug enters inside the brush border cells, 2)
In a state of being bound to the outside of the brush border cells, (3) in the vicinity of the brush border cells, (4) in the bloodstream, or (5) elsewhere in the body (however, the cutting is performed in the stomach or Should not occur within the lumen of the small intestine).

Active transport of the prodrug by this bile acid intestinal transport results in enhanced bioavailability of this compound when compared to the unconjugated compound. It also reduces bioavailability variability and provides an alternative mechanism for compound permeability. These mechanisms include the avoidance of efflux pumps such as P-glycoprotein used by some drugs (eg, fexofenadine) and other drug and / or nutrient transporters. Is mentioned. By avoiding other drug transporters and / or nutrient transporters, drug-drug interactions and / or
Alternatively, drug-nutrient interactions can be reduced or eliminated.

Any bile acid may be conjugated or linked to the compound. More than one bile acid may be conjugated or linked to one compound. Also, more than one compound may be conjugated or linked to one bile acid. Bile acids include, by way of example, cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid,
Ursodeoxycholate, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and lithocholic acid. The general structure of bile acids is shown in Figure 1A.

The following structural requirements generally facilitate the recognition of bile acids by the bile acid intestinal transporter (IBAT): negatively charged side groups on bile acids; positions 3, 7 or of the steroid nucleus. At least one α-oriented hydroxyl group at the 12-position; and cis configuration of the A and B rings of the steroid nucleus [3].

By way of example, a compound that has improved bioavailability as a result of conjugation or ligation of the compound to bile acids is a compound containing: (Group 1) chemically coupled to bile acids. An alcohol functional group capable of being rendered an ester; or a (group 2) primary or secondary amine functional group capable of being chemically coupled with a bile acid to give an amide; or a (group 3) chemically acting with a bile acid. Acid functional groups that can be coupled to give acid anhydrides.

Compounds containing an alcohol functional group (Group 1) include antiviral agents (
For example, 6-deoxyacyclovir, ganciclovir, dihydroxybutylguanine, foscarnet, penciclovir, famciclovir, zidovudine, idoxuridine, 5-trifluorothymidine, vidarabine, cytarabine, ribavirin) can be mentioned. It is not limited to these. Compounds containing a primary or secondary amine functional group (Group 2) include, but are not limited to, H-2 antagonists (eg, cimetidine, ranitidine, nizatidine, famotidine, derivatives of roxatidine). . Compounds containing acid functional groups (Group 3)
Bisphosphonates (eg, alendrona)
te), etidronate, pamidronate, tiludronate, clonronate.
)) And ACE inhibitors (eg, enalapril, captopril, risonopril), but are not limited thereto. This list is not exhaustive and is not intended to limit the scope of the invention, but is provided for illustration only.

Any salt, solvate, isomeric composition, and physical form of these compounds and / or derivatives thereof may be conjugated or linked to bile acids to form prodrugs. Enteric coatings known in the art may be used to protect the prodrug from the acidity of the stomach.

FIG. 1A illustrates the general structure of bile acids. Bile acids include R ₁ , R ₂ and R ₃ (
That is, its substituents at the 12-position, 7-position, and 3-position, respectively) may vary. For example, for chenodeoxycholic acid, R ₁ is H and R ₂ is α-O.
H and R ₃ is α-OH. For deoxycholic acid, R ₁ is α-OH, R ₂ is H, and R ₃ is α-OH. For cholic acid, R ₁ , R ₂ and R ₃ are all α-OH. Many natural and synthetic bile acids exist and are well known in the art. Any of these natural or synthetic bile acids can be used to produce prodrugs. However, it may be preferable to have at least one α-oriented hydroxyl group in the bile acid, and the α-oriented hydroxyl group may be located at R ₁ , R ₂ or R ₃ .

FIG. 1B illustrates the general structure of the bile acid component of the prodrug. The compound, either directly or through a linker group, can be attached to any natural or synthetic bile acid at either R ₁ , R ₂ , R ₃ , or R ₄ . Although it is preferred that only one compound be conjugated or linked to one bile acid, more than one compound can be conjugated or linked to the same bile acid. Furthermore, although it may be preferable to link or conjugate the compound at R ₄ of the bile acid (due to the potential structural requirements necessary for recognition of the bile acid by the bile acid intestinal transporter), the compound is The bile acids can be linked or conjugated at R ₁ , R ₂ , or R ₃ . When the compound is linked or conjugated to either R ₁ , R ₂ or R ₃ , it is preferred that R ₄ is any chemical moiety. This chemical moiety may assist or enhance binding of the prodrug to IBAT and / or enhance solubility of the prodrug in the body. Examples of such chemical moieties include hydroxyl, any amino acid (eg, glycyl, valyl, alanyl,
Tauryl, and leucyl), any di-amino acid (eg, glycyl-valyl, glycyl-glycyl, valyl-glycyl, alanyl-glycyl, alanyl-valyl, and leucyl-valyl), any tri-amino acid (eg, glycyl-
Glycyl-glycyl, glycyl-valyl-glycyl, glycyl-glycyl-alanyl, valyl-glycyl-leucyl, alanyl-glycyl-glycyl, alanyl-valyl-glycyl, and leucyl-valyl-valyl). It is preferred that this chemical moiety has a molecular weight of less than 1500 daltons.

1C, 1D, and 1E outline the synthesis of three prodrugs: acyclovir valylchenodeoxycholic acid, acyclovir valyldeoxycholic acid, and atenolol cholic acid amide. These prodrugs are compound (
Acyclovir and atenolol) have increased bioavailability and decreased bioavailability variability as a result of conjugating or linking bile acids. For these three prodrugs, the compound is attached at R ₄ of the bile acid (chenodeoxycholic acid, deoxycholic acid, or cholic acid). For acyclovir valylchenodeoxycholic acid and acyclovir valyldeoxycholic acid, valine is utilized as the linker group. In addition, both acyclovir valylchenodeoxycholic acid and acyclovir valyldeoxycholic acid use an ester as a metabolizable bond that can be cleaved to release acyclovir. For atenolol cholic acid amide, no linker group is used and atenolol is directly conjugated to cholic acid. further,
Atenolol cholic acid uses an amide as a metabolizable bond that can be cleaved to release atenolol.

(Synthesis of Acyclovir Valylchenodeoxycholic Acid) As shown in FIG. 1C, isobutyl chloroformate (iBuOCOCl; 130 μL, 1 mmol) was used to synthesize acyclovir valylchenodeoxycholic acid (1).
) Was cooled (-15 ° C) N, of chenodeoxycholic acid (2) (1 mmol) and triethylamine (140 μL, 1 mmol) under nitrogen (N ₂ ) atmosphere.
Add dropwise to N-dimethylformamide (DMF) (10 mL) solution. After 1.5 minutes, then valacyclovir (3) (0.42 g,
1.3 mmol) and triethylamine (NEt ₃ ; 280 μL, 2 mmol
) Is added to the reaction mixture as a DMF (5 mL) solution. This reaction system is
Maintain at −15 ° C. for 5 hours, then warm to room temperature for 1 hour. The triethylammonium chloride formed during the reaction is filtered off and the filtrate is concentrated by rotary evaporation. The crude material was then loaded with MeOH / CHCl ₃ (1: 4, 250 m
Purify using silica gel flash chromatography with L) as the eluent.

Acyclovir valylchenodeoxycholic acid (1) prodrug synthesis
altech, Inc. (Newark, DE) silica gel GHLF-0.
Monitor using thin layer chromatography (TLC) plates coated with 25 mm plates (60 F ₂₅₄ ). Fast atom bombardment mass spectrometry (FAB-MS) and high resolution mass spectrometry (HRMS) spectra were obtained on a Jeol SX102 mass spectrometer in positive ion mode. Proton Nuclear Magnetic Resonance (NMR)
Spectroscopy, _{d 6} - dimethyl sulfoxide (DMSO), MacNMR v. 5
． 300 MHz General Electric controlled by Macintosh Power Mac® 7100 using O. software.
c Perform on an Aqueerius model spectrometer. The purity of bile acid conjugates was
126 solvent module, model 168 detector, and model 50
Determined by analysis on a Beckman System Gold High Performance Liquid Chromatography (HPLC) system consisting of a 7 autosampler. H to use
The PLC column is a Vydac analytical column (C ₁₈ , 300Å, 5 μm, 4.6 × 250 mm) equipped with a guard cartridge. Solvent A is an aqueous solution of 0.1% trifluoroacetic acid (TFA), and solvent B is acetonitrile containing 0.1% TFA. Conjugate 5 minutes at a flow rate of 1.0 mL / min for 5 minutes.
Elute using a linear gradient of ~ 75% B and detect at 214 nm.

The amount of purified acyclovir valylchenodeoxycholic acid (1) was 0.62.
g (89%). Furthermore, TLC R _f (MeOH / CHCl ₃ , 1: 4)
= 0.46; HPLC R _t = 32.1 min (purity 99.3%); and ESI-
MS [M + H] = 700.4. HRMS _(calcd for _{C 37 H 59 O 7 N 6} ): 699.4445. Found 699.4454. The NMR spectrum is
It contained peaks consistent with both the chenodeoxycholic acid and valacyclovir moieties. The amine-mediated coupling of amino acids (but not aniline) was confirmed by the presence of the NH ₂ signal at 5.3 ppm.

(Synthesis of Acyclovir Valyldeoxycholic Acid) As shown in FIG. 1D, isobutyl chloroformate (iBuOCOCl; 130 μL, 1 mmol) was mixed with nitrogen (N ₂ ) atmosphere to synthesize acyclovir valyldeoxycholic acid (4). Below, a solution of deoxycholic acid (5) (1 mmol) and triethylamine (140 μL, 1 mmol) was added dropwise to a cooled (-15 ° C.) N, N-dimethylformamide (DMF) (10 mL) solution. After 1.5 minutes, valacyclovir (3) (0.42 g, 1.3 mmol) and triethylamine (NEt ₃ ; 280 μL, 2 mmol) are then added to the reaction mixture as a solution in DMF (5 mL). The reaction system is maintained at -15 ° C for 0.5 hours and then allowed to warm to room temperature for 1 hour. The triethylammonium chloride formed during the reaction is filtered off and the filtrate is concentrated by rotary evaporation. The crude material is then added to M
Purify using silica gel flash chromatography using eOH / CHCl ₃ (1: 4, 250 mL) as eluent.

Acyclovir valyldeoxycholic acid (4) prodrug synthesis was analyzed by Anal
tech, Inc. Silica gel GHLF-0.25 manufactured by (Newark, DE)
Monitoring using thin layer chromatography (TLC) plates coated with mm plates (60 F ₂₅₄ ). Fast atom bombardment mass spectrometry (F
AB-MS) and high resolution mass spectroscopy (HRMS) spectra were obtained on a Jeol SX102 mass spectrometer in positive ion mode. Proton Nuclear Magnetic Resonance (NMR) spectroscopy was performed in d ₆ -dimethyl sulfoxide (DMSO) with MacNMR v. 5.0
Macintosh Power Mac (registered trademark) using software
300MHz General Electric controlled by 7100
Performed on an Aqueerius model spectrometer. The purity of the bile acid conjugate was measured by model 1
It is determined by analysis on a Beckman System Gold High Performance Liquid Chromatography (HPLC) system consisting of a 26 solvent module, a model 168 detector, and a model 507 autosampler. HPL to use
The C column is a Vydac analytical column (C ₁₈ , 3 equipped with a guard cartridge).
00Å, 5 μm, 4.6 × 250 mm). Solvent A is an aqueous solution of 0.1% trifluoroacetic acid (TFA), and solvent B is acetonitrile containing 0.1% TFA. The conjugate was applied at a flow rate of 1.0 mL / min for 50 minutes for 5-7
Elute using a linear gradient of 5% B and detect at 214 nm.

The amount of purified acyclovir valyldeoxycholic acid (4) was 0.59 g (
89%). Furthermore, TLC R _f (MeOH / CHCl ₃ , 1: 4) = 0
． 47; HPLC R _t = 33.0 min (purity 98.1%); and FAB-MS
^{[M + H] + = 699.54} ; ( calcd for _{C 37 H 59 O 6 N 7} ) HRMS: 699.4445. Found 699.4448. The NMR spectrum contained peaks consistent with both the deoxycholic acid and valacyclovir moieties. Amine-mediated coupling of amino acids (rather than aniline) at 5.3 p
Confirmed by the presence of NH ₂ signal in pm.

(Synthesis of Atenolol Choleamide) As shown in FIG. 1E, isobutyl chloroformate (iBuOCOCl; 130 μL, 1 mmol) was added to nitrogen (in order to synthesize atenolol choleamide (6).
Under a N ₂ atmosphere, cholic acid (7) (0.5 mmol) and triethylamine (
140 μL, 1 mmol) in a cooled (−15 ° C.) N, N-dimethylformamide (DMF) (10 mL) solution is added dropwise. After 1.5 minutes, then atenolol (8) (0.42 g, 1.3 mmol) and triethylamine (NEt ₃ ; 2
80 μL, 2 mmol) is added to the reaction mixture as a DMF (5 mL) solution. The reaction system is maintained at -15 ° C for 0.5 hours and then allowed to warm to room temperature for 1 hour. The triethylammonium chloride formed during the reaction is filtered off and the filtrate is concentrated by rotary evaporation. The crude material is then purified using silica gel flash chromatography with MeOH / CHCl ₃ (1: 4, 250 mL) as eluent.

The atenolol cholic acid amide (6) prodrug synthesis was synthesized according to Analtech,
Inc. Thin layer chromatography (TLC) coated with silica gel GHLF-0.25 mm plate (60 F ₂₅₄ ) from (Newark, DE).
Monitor using plate. Fast atom bombardment mass spectrometry (FAB-MS
) And high resolution mass spectrometry (HRMS) spectra in positive ion mode by Jeol
Obtained on SX102 mass spectrometer. Proton Nuclear Magnetic Resonance (NMR) spectroscopy was performed in d ₆ -dimethyl sulfoxide (DMSO) with MacNMR v. 300 MHz General Electric Aquer Controlled by Macintosh Power Mac® 7100 Using 5.0 Software
with an ius model spectrometer. Bile acid conjugate purity is determined by analysis on a Beckman System Gold High Performance Liquid Chromatography (HPLC) system consisting of a model 126 solvent module, a model 168 detector, and a model 507 autosampler. The HPLC column used was a Vydac analytical column equipped with a guard cartridge (C ₁₈ , 300Å, 5
μm, 4.6 × 250 mm). Solvent A is 0.1% trifluoroacetic acid (T
FA) aqueous solution, and solvent B is acetonitrile containing 0.1% TFA. The conjugate is eluted using a linear gradient of 5-75% B over 50 minutes at a flow rate of 1.0 mL / min and detected at 214 nm.

The amount of purified atenolol cholic acid amide (6) is 0.19 g (58%). Furthermore, TLC R _f (AcOH / MeOH / CHCl ₃ , 1: 1: 4)
= 0.47; HPLC R _t = 34.9 min (purity 98.3%); and FAB-
^{MS [M + H] + =} 657.6; ( calcd for _{C 38 H 61 N 2 O 7} ) HRMS: 657.4479. Found 657.4470. IR (CHCl ₃ ) 33
94, 2932, 2870, 1671, and 1610 cm- ¹ .

Atenolol (8) contains both a secondary alcohol and a secondary amine, and the coupling of cholic acid (7) via both of these nucleophiles occurs to yield the ester or amide, respectively. obtain. Only the amide was formed during the above reaction of cholic acid with atenolol, which is confirmed by the presence of the characteristic amide C = O stretching band at 1671 cm ^-1 and 1610 cm ^-1 in the IR spectrum. The NMR spectrum also shows the spectrum expected for the conjugate between cholic acid and atenolol (ie 4.92 p in NMR).
(absence of pm secondary amine proton signal). Coupling of atenolol via amines (rather than alcohols) is also confirmed by the negative chloranil test (test for secondary and primary amines). Atenolol is used as a positive control for the chloranil test.

Bioavailability Assay To test for increased bioavailability of acyclovir valyl chenodeoxycholic acid 1, acyclovir valyl deoxycholic acid 4 and atenolol cholic amide 6 human intestinal bile acid transporter (hIBAT) cD.
NA (specifically, pCMV5-hIBAT expression plasmid) was added to Life Te
chnpologies protocol (Grand Island, NY) according to LipofectAMINE 2000 transfection reagent (Lif.
eTechnologies, Grand Island, NY) are used to transduce competent DH5α cells. Cell dilutions are plated on nutrient agar plates containing 50 μg / ml ampicillin and incubated overnight at 37 ° C. Isolated colonies are selected objectively and used to inoculate 200 ml of nutrient broth culture containing 50 μg / ml ampicillin. The culture is incubated at 225 RPM for 24 hours at 37 ° C. Qui
gan maxi-prep kit (DNA plasmid maxi kit No. 12
162; Valencia, CA) is used to isolate cDNA from broth cultures. After isopropanol precipitation and ethanol washing, the DNA was
Reconstitute in μl sterile deionized water. The DNA concentration is 1.18 μg / μl. This is determined by a spectrophotometer at 260 nm. The 260/280 absorbance ratio was 1.50, indicating that this DNA is free of RNA contaminants. pC
MV5-hIBAT also contains the restriction endonucleases BAMH1 and N
When digested with DE and electrophoresed on a 1% agarose gel, it produces bands of the appropriate size (4238 bp and 1689 bp).

COS-7 cells are grown in T-75 flasks at 37 ° C., 5% CO ₂ and 95% RH using Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS. Cells are passaged at 80-90% confluence using 0.25% trypsin / 0.20% EDTA solution and plated at a density of 8 x 10 ⁴ cells / well (1.88 cm ² ). Cells are transfected 24 hours after seeding. 0.8 μg of hIB for each transfected well
AT cDNA is combined with LipofectAMINE 2000 reagent and incubated at room temperature for 20 minutes to allow complex formation. A volume of 100 μl of hIBAT-lipid complex is added to the cells in each well. Transfected cells were incubated at 37 ° C., 5% CO ₂ and 95 until ready for uptake assay.
Incubate at% RH for 24 hours.

Uptake studies are performed on COS-hIBAT cells 24 hours after transfection. The uptake buffer is Hank's containing 137 mM NaCl.
Balanced Salts Solution (HBSS) or modified Ha in which sodium chloride is replaced with 137 mM tetraethylammonium chloride
nk's Balanced Salts Solution (MHBSS) [19]. Since the bile acid transporter is sodium-dependent, this MHBSS procedure can simply modify the uptake buffer to eliminate all sources of sodium, thus allowing a control uptake assay under sodium-free conditions. .

For the K _m and V _max studies of taurocholate in COS-hIBAT cells, cell culture medium is removed from each well and replaced with 0.5 ml of uptake solution. 0.5 μM ³ H-taurocholic acid is investigated in HBSS.
Cells are incubated at 100 RPM for 10 minutes at 37 ° C. Uptake solution is removed and cells are washed 3 times with cold HBSS. Cells are lysed, neutralized, and relevant radioactivity is counted. Using the Lowry method [20],
Analyze for protein content. This uptake assay is performed 3 times, both in sodium and without sodium conditions.

The saturated uptake of ³ H-taurocholate is determined using the following equation (Equation 1):

[0074]

[Chemical 16] Where V _max and K _m represent the Michaelis-Menten constant, k _p is the passive uptake rate constant, S is the concentration of taurocholate, and dM / dt is taurocholate. Is the uptake ratio of COS-hIBAT cells. This approach involves the contribution of passive uptake to the saturation kinetics of taurocholate uptake into cells.

In the competition inhibition studies (see FIGS. 2, 3 and 4) the concentration of acyclovir valylchenodeoxycholic acid 1 varied between 10 μM and 400 μM; the concentration of acyclovir valyl deoxycholic acid 4 was 10 μM and 600 μM. The concentration of atenolol cholic acid amide 6 varies between 10 μM and 400 μM. An inhibition study of chenodeoxycholic acid 2, deoxycholic acid 5 and cholic acid is performed as a positive control. An inhibition study of valacyclovir and atenolol is performed as a negative control.

FIG. 2 shows valacyclovir 3 (white triangle), chenodeoxycholic acid (CDC).
2 (open circle), and acyclovir valyl chenodeoxycholic acid (acyclovir C
The inhibition study of DC) 1 (black circle) is illustrated. 6 in COS-hIBAT cells
There is no inhibition of bile acid transporters after application of valacyclovir up to 00 μM. This indicates that valacyclovir is not a substrate for hIBAT. A chenodeoxycholic acid inhibition study is performed as a positive control for this experiment, yielding a K _i = 5.4 (± 0.4) μM. This indicates that the COS-hIBAT model is suitable for inhibition studies. The calculated K _i for acyclovir valylkenodeoxycholic acid is K _i = 35.6 (± 4.4) μM, indicating a very strong interaction of acyclovir valylchenodeoxycholic acid with the hIBAT transporter.

Similar to acyclovir valyldeoxycholic acid (FIG. 3), valacyclovir 3
Inhibition studies of (open triangles), deoxycholic acid (DC) 5 (open circles), and acyclovir valyldeoxycholic acid (acyclovir vDC) 4 (filled circles) are performed. Acyclovirvalyl deoxycholic acid has a h of K _i = 401 (± 50) μM
Strongly interacts with IBAT.

Similarly, in FIG. 4, atenolol cholic acid amide 6 (black circle) has a K _i =
Strongly interacts with hIBAT at 160 (± 21) μM, but atenolol 8 (
White triangles) themselves do not interact. Natural bile acid cholic acid 7 (white circle) is also
Strongly interacts with hIBAT (K _i = 32.1 (± 2.4) μM).

FIG. 5 shows both sodium-dependent and ³ H-taurocholate uptake saturation. The uptake ratio is measured in HBSS with 137 mM NaCl and in MHBSS without sodium at a concentration of 0.1-125 μM ³ H-taurocholate. As expected, carrier-mediated ³ H-taurocholate uptake was
Not present in the absence of sodium ions. Thus, a permeability baseline is established due to the passive permeability of ³ H-taurocholate into cells. 0.12 (pmol
The passive uptake ratio constant (k _p ) of e / min mg protein) / μM is estimated using linear regression. Control uptake studies are also performed on untransfected COS-7 cells, COS-7 cells transfected with the antibiotic resistance vector pcDNA3. Passive uptake of ³ H-taurocholate in these cells is the same as that obtained under sodium-free conditions (data not shown). Kinetic parameters for carrier-mediated uptake were estimated using WinNonlin (version 1.0) and K _m = 1.
Obtain 2.0 (± 2.2) μM and V _max = 126.0 (± 5.9) pmol / min / mg protein. These Michaelis-Menten parameters are close to those previously obtained [21].

Competitive inhibition studies are performed in HBSS containing 0.25 μM ³ H-taurocholate and varying the concentration of unlabeled bile acid from 1-100 μM. Glycine, taurine, acyclovir and atenolol inhibition studies are performed as negative controls. The incubation conditions and analyzes are performed as described for the study of K _m and V _{ma x.} The following equation (Equation 2) is used to evaluate K _i for a series of naturally occurring bile acids:

[0081]

[Chemical 17] Where V _max and K _m represent the Michaelis-Menten parameter for taurocholic acid uptake, S is 0.25 μM ³ H-taurocholic acid, dM / dt is the taurocholic acid uptake rate, And I is the concentration of inhibitor applied to the cells.

For the uptake of ³ H-taurocholic acid into COS-hIBAT cells, various bile acids (cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, taurodeoxycholic acid, glycodeoxycholic acid, chenodeoxycholic acid, The effects of glycochenodeoxycholic acid, taurochenodeoxycholic acid, ursodeoxycholic acid, and lithocholic acid) are determined (see Figure 6). Inhibition studies using glycine, taurine, valacyclovir and atenolol are also performed as negative controls. FIG. 6 shows the K _i values (± SEM) for each compound tested. All bile acids are ³ H-on COS-hIBAT cells.
It inhibited the uptake of taurocholate. However, ³ H-taurocholate uptake is not reduced in the presence of glycine or taurine. ³ H-taurocholic acid uptake is reduced in the presence of lithocholic acid, but never reaches the 50% maximal rate at a concentration of 100 μM lithocholic acid. Lithocholic acid concentrations higher than 100 μM were not investigated. All bile acids are ³ H in COS-hIBAT cells.
-Inhibits the uptake of taurocholate. Valacyclovir and atenolol do not inhibit ³ H-taurocholate uptake. In these inhibition studies, ³ H-taurocholate concentrations remained constant at 0.25 μM and inhibitor concentrations varied between 1 μM and 100 μM (glycine and taurine in the concentration range 50-200 μM, 10 Excluding valacyclovir in the range of -600 μM and atenolol in the range of 10-200 μM). Inhibition studies are performed 3 times.
N / A indicates not applicable. Because there was no evidence of inhibition.

A compound may be conjugated or linked to a bile acid via a linker group to improve the compound's bioavailability and reduce the compound's bioavailability variability. It is preferred that a metabolically labile bond be present between the bile acid and the compound (with or without a linker group) for easy cleavage of the compound from the bile acid. The compound, or compound and linker group, is preferably attached to R ₄ of the bile acid, but the compound, or compound and linker group, is also
It may be attached at R ₁ , R ₂ or R ₃ . Also, different or identical compounds may be linked or complexed to multiple sites of bile acids. In addition, more than one bile acid may be attached to the compound.

The prodrug may be coated with various coating compounds known in the art to protect the prodrug from the acidic environment of the stomach. These coating compounds dissolve in the basic environment in the small intestine, which allows the prodrug to react with IBA.
Available for uptake by T.

The prodrugs may also be converted into pharmaceutically acceptable salts or pharmaceutically acceptable solvates or other physical forms (eg, polymorphs for exemplary purposes only and not for purposes of limitation). It can be converted via methods known in the art. A pharmaceutically acceptable carrier can be used with the prodrug. To make the compositions of the present invention, the prodrug can be mixed with an excipient, diluted with the excipient, or included in a carrier. It can be in the form of capsules, sachets, paper or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or vehicle for the prodrug. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, and other oral ingestions. It can be in the form of a formulation.

Some examples of suitable excipients include: lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose. , Polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. Formulations further include: lubricants (eg, talc, magnesium stearate, and mineral oil); wetting agents; emulsifying and suspending agents; protecting agents (eg, methyl hydroxybenzoate and propyl hydroxybenzoate).
Sweeteners; and flavors. The compositions of the present invention may also be formulated to provide a patient with a rapid, sustained or delayed release prodrug after administration by using procedures known in the art.

The composition is preferably formulated in a single dosage form. Each dosage is about 0.00
It contains from 5 mg to 100 mg, more usually from about 1.0 mg to about 300 mg of prodrug. A unit dosage form generally refers to physically discrete units suitable as unit dosages for human and animal patients, each unit having the desired therapeutic effect according to a suitable pharmaceutical excipient. It contains a predetermined amount of prodrug calculated to produce.

The prodrug is used for the treatment of human or animal patients in need of treatment with the compounds contained in the prodrug. The particular purpose of treatment, and the range of doses to be administered, depends on the individuality of the compound and the circumstances for the patient to be treated.

Although the list of compounds on which this prodrug means acts is too large to be included herein, the following is a short list of compounds and their "drug" class: Foscanet, valacyclovir, acyclovir. , Ganciclovir, penciclovir, famciclovir (antiviral agent); alendronate, etidronate disodium, pamidronate, risedronate, tiludronate, clodronic acid (bisphosphonate); cimetidine, ranitidine (H-2 antagonist);
Enalaprilate, captopril, lisonopril (ACE inhibitor); losartan, E-3171
(Angiotensin II antagonist); Levofloxacin, Norfloxacin (quinalone antibiotic with reduced absorption with antacids); Formycin B; acetobutanol, pindolol, alprenolol, atenolol, nadolol (β) Adrenergic blocker); bretylium tosylate (antiarrhythmic); cefuroxime sodium (cephalosporin); chlorothiazide, hydrochlorothiazide, furosemide (diuretic); gabapentin, lamotrigine (anticonvulsant); didanosine (nucleoside reversal) Nephriapine (Transcriptase inhibitor);
Non-nucleoside reverse transcriptase inhibitor); ritinavir
, Saquinavir, amplinavir (HIV protease inhibitor); tacrolimus, cyclosporine (immunosuppressive agent); zafirlukast (leukotriene receptor antagonist); leuprorelin actateate
(LHRH analog); dDAVP (1-deamino-8-D-arginine-vasopressin; desmopressin), calcitonin, thyrotropin-releasing hormone (
Polypeptide hormones); loratidine, cetirizine (
Non-sedating antihistamine); penicillin V, amoxicillin, cefacol (cefa)
cor), cefixime, cefuroxime axetil, cefuroxime sodium,
Ampicillin (antibiotic); hemi terbutaline sulfate (adrenergic agonist); metformin (anti-diabetes); celecoxib, refecoxib (COX-2 inhibitor); sumatriptan, naratriptan, araztriptan, zolmi Triptan (anti-migraine); 6-
Mercaptopurine; ziprasidone; RGD mimetic (αIIβ3-antagonist); leuenkephalin analog; α-methyldopa; 5-fluorouracil (fluoropoyrimidine); tacrine (acetylcholinesterase inhibitor); DZ-2640 (active parent compound D)
Oral carbapenems and other carbapenems of U-6681); vitamin B12 (nutrients and minerals); 7-chlorokynurenic acid; oseltamivir or its active portion; RGD (Arg-Gly-Asp) analogs (glycoprotein (G
P) IIb / IIIa agonists and antagonists; platelet aggregation inhibitors; sibrafiban (oral platelet aggregation inhibitors); nelarabine (nela)
rabine), 9-β-D-arabinofuranosylguanine (ara-G), and ara-G; mycophenolate mofetil (MMF) and its active immunosuppressive minophenolic acid (MPA); nabumetone and its active metabolism. The products 6-methoxy-2-naphthylacetic acid (an anti-osteoarthritis agent); adefovir (9- [2-phosphonylmethoxyethyl] -adenine (PMEA)) and adefovir dipivoxil [bis- (POM) -PMEA], and Cidofovir (antiviral nucleotide); lysethyl cromoglycate and cromoglycic acid (antiarthritic agent); oseltamivir or active portion thereof; its parent Ro64-0802 (inhibitor of influenza virus neuraminidase); peptidomimetics; nucleic acids; Is only Not meant to be exhaustive in. Other compounds increase bioavailability and / or decrease bioavailability variability by bile acid conjugation.

All references listed herein are incorporated by reference in their entireties.

[0091]   (References)

[0092]

[Chemical 18] Although the present invention has been described in detail and with reference to particular embodiments thereof, it is understood that various changes and modifications may be made herein without departing from the spirit and scope of the invention. It will be apparent to those skilled in the art. One of ordinary skill in the art will further appreciate that the examples listed herein are illustrative only and are not meant to be limiting.

[Brief description of drawings]

FIG. 1A   FIG. 1A shows the general structure of bile acids.

FIG. 1B   FIG. 1B shows the general structure of prodrugs.

[FIG. 1C]   FIG. 1C generalizes the synthesis of acyclovir barychenodeoxycholate.

[Figure 1D]   FIG. 1D generalizes the synthesis of acyclovirvalyl deoxycholate.

[FIG. 1E]   FIG. 1E generalizes the synthesis of atenolol cholic acid amide.

FIG. 2 shows acyclovir barrykenodeoxycholate (acyclovir vCDC) (
Figure 4 shows competitive inhibition of < ³ > H-taurocholate uptake by (black circles), chenodeoxycholate (CDC) (open circles), and valacyclovir (open triangles).

FIG. 3 shows competitive inhibition of ³ H-taurocholate uptake by acyclovir valyl deoxycholate (acyclovir vDC) (filled circles), deoxycholate (DC) (open circles), and valacyclovir (open triangles).

FIG. 4 shows competitive inhibition of ³ H-taurocholate uptake by atenolol cholic acid amide (filled circles), cholate (open circles), and atenolol (open triangles).

FIG. 5 shows the concentration dependence of ³ H-taurocholate uptake in COS-hIBAT (hIBAT-transfected COS cells) HBSS (solid diamonds), MHBSS (without sodium) (filled squares).

FIG. 6 shows the inhibition constants (K _i ) of various bile acids and other agents by inhibiting ³ H-taurocholate uptake in hIBAT-transfected COS cells.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/04 A61P 9/04 31/12 31/12 43/00 123 43/00 123 C07J 43/00 C07J 43/00 // A61K 47/48 A61K 47/48 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC , NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD , GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG , US, UZ, VN, YU, ZA, ZW (71) Applicant Coup, Andrew United States Maryland 21244, Baltimore, Flaxton Coat 17 (71) Applicant Maeda, Dean Wye. United States Washington 98012, Bothell, Bothell-Everett Highway 19811, No. 826 (71) Applicant Lenz, Kimberley A. United States Connecticut 06422, Durham, Pine Ledge Trail 56 (72) Inventor Polly, James E. United States Maryland 21403, Ellicott City, Bucks County Court 3524 (72) Inventor Coup, Andrew United States Maryland 21244, Baltimore, Flaxton Court 17 (72) Inventor Maeda, Dean Wye. United States Washington 98012, Bothell, Bothell-Everett Highway 19811, Number 826 (72) Inventor Lenz, Kimberley A .. United States Connecticut 06422, Durham, Pine Ledge Trail 56 F Term (Reference) 4C076 BB01 CC12 CC35 DD70 EE59 FF02 4C086 AA01 CB07 DA11 DA12 MA01 MA04 NA13 NA15 ZB33 4C091 AA01 BB01 Q01 Q01 Q01 Q01 Q01 HQ01H0101 4C206 AA01 GA09 GA22 MA01 MA04 NA13 NA15 ZA36 ZA37 ZC43

Claims (50)

[Claims] 1. A pharmaceutical compound, comprising: a biologically active factor or a metabolic precursor of a biologically active factor bound to bile acid via a metabolically labile bond; A pharmaceutical compound comprising: 2. The pharmaceutical compound according to claim 1, wherein the biologically active agent or a metabolic precursor of the biologically active agent is bound to the bile acid via a linker group. . 3. The linker group has a molecular weight of less than 200 Daltons,
The pharmaceutical compound according to claim 2. 4. The pharmaceutical compound according to claim 1, wherein the metabolically labile bond is an amide, ester, carbamate, carbonate, ether, thio, urea, acid anhydride, thioamide, thioester, A pharmaceutical compound selected from the group consisting of thiocarbamates and thioureas. 5. The pharmaceutical compound according to claim 1, wherein the bile acid is cholate, glycocholate, taurocholate, deoxycholate, glycodeoxycholate, taurodeoxycholate, chenodeoxycholate, glycochenodeoxycholate, A pharmaceutical compound selected from the group consisting of taurochenodeoxycholate, ursodeoxycholate and litcholate. 6. A compound represented by Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein: Where R ₁ , R ₂ and R ₃ independently of the group consisting of hydrogen, α-hydroxyl, β-hydroxyl, a biologically active agent, and a metabolic precursor of the biologically active agent. R ₄ is a biologically active agent, a metabolic precursor of the biologically active agent, a moiety that increases binding of the compound to the intestinal bile acid transporter or a solubility-enhancing moiety, Provided that _one of R ₁ , R ₂ , R ₃ and R ₄ is a factor having the biological activity or a metabolic precursor of the factor having the biological activity, and each X is a single bond. Or three of X are single bonds and the fourth X is a moiety containing a metabolically labile bond, where X comprises a metabolically labile bond If it is a moiety, X is a factor that has the biological activity. Or it is coupled to a metabolic precursor of factors with biological activity, drug compound. 7. The compound according to claim 6, wherein each X is a single bond. 8. A compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, which compound is represented by formula II: Wherein R ₁ , R ₂ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl and β-hydroxyl; R ₄ is a biologically active agent and a biologically active agent. A compound selected from the group consisting of metabolic precursors of factors having. 9. A compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is represented by formula III: embedded image Wherein R ₂ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₁ is of a biologically active agent and a biologically active agent. A compound selected from the group consisting of metabolic precursors; R ₄ is a moiety that increases the binding of the compound to the intestinal bile acid transporter. 10. A compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is represented by formula IV: embedded image Wherein R ₁ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₂ is a biologically active agent and a biologically active agent. A compound selected from the group consisting of metabolic precursors; R ₄ is a moiety that increases the binding of the compound to the intestinal bile acid transporter. 11. A compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is represented by formula V below: Where R ₁ and R ₂ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₃ is of a biologically active agent and a biologically active agent. A compound selected from the group consisting of metabolic precursors; R ₄ is a moiety that increases the binding of the compound to the intestinal bile acid transporter. 12. A compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, which compound is represented by the following formula VI: embedded image Wherein R ₂ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₁ is of a biologically active agent and a biologically active agent. A compound selected from the group consisting of metabolic precursors; R ₄ is a solubility-enhancing moiety. 13. A compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is represented by formula VII: embedded image Wherein R ₁ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₂ is a biologically active agent and a biologically active agent. A compound selected from the group consisting of metabolic precursors; R ₄ is a solubility-enhancing moiety. 14. A compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, which compound is represented by formula VIII below: Where R ₁ and R ₂ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₃ is of a biologically active agent and a biologically active agent. A compound selected from the group consisting of metabolic precursors; R ₄ is a solubility-enhancing moiety. 15. The compound of claim 6, wherein 3 of said X are:
A single bond and the fourth X is a moiety containing a metabolically labile bond,
Compound. 16. The compound according to claim 15, wherein the metabolically labile bond is an amide, ester, carbamate, carbonate, ether, thio,
A compound selected from the group consisting of urea, acid anhydride, thioamide, thioester, thiocarbamate and thiourea. 17. A compound according to claim 15, or a pharmaceutically acceptable salt or solvate thereof, which compound is represented by the following formula IX: Where R ₁ , R ₂ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl and β-hydroxyl; X is a moiety containing a metabolically labile bond; and R ₄ is a compound selected from the group consisting of biologically active agents and metabolic precursors of biologically active agents. 18. A compound according to claim 15, or a pharmaceutically acceptable salt or solvate thereof, which compound is represented by formula X below: Wherein R ₂ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₄ is a moiety that increases the binding of the compound to the intestinal bile acid transporter. X is a moiety containing a metabolically labile bond; and R ₁ is selected from the group consisting of biologically active factors and metabolic precursors of biologically active factors. ,Compound. 19. A compound according to claim 15, or a pharmaceutically acceptable salt or solvate thereof, which compound is represented by the following formula XI: Wherein R ₁ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₄ is a moiety that increases the binding of the compound to the intestinal bile acid transporter. X is a moiety containing a metabolically labile bond; and R ₂ is selected from the group consisting of biologically active factors and metabolic precursors of biologically active factors. ,Compound. 20. A compound according to claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is represented by formula XII: embedded image Wherein R ₁ and R ₂ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₄ is a moiety that increases the binding of the compound to the intestinal bile acid transporter. X is a moiety containing a metabolically labile bond; and R ₃ is selected from the group consisting of biologically active factors and metabolic precursors of biologically active factors. ,Compound. 21. The compound of claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is represented by formula XIII: Where R ₂ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₄ is a solubility-enhancing moiety; X is a metabolically labile bond R ₁ is a moiety comprising; and R ₁ is selected from the group consisting of biologically active agents and metabolic precursors of biologically active agents. 22. The compound of claim 15 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is represented by formula XIV: Where R ₁ and R ₃ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₄ is a solubility-enhancing moiety; X is a metabolically labile bond And R ₂ is selected from the group consisting of biologically active agents and metabolic precursors of biologically active agents. 23. The compound of claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is represented by formula XV: Where R ₁ and R ₂ are independently selected from the group consisting of hydrogen, α-hydroxyl, and β-hydroxyl; R ₄ is a solubility-enhancing moiety; X is a metabolically labile bond And R ₃ is selected from the group consisting of biologically active agents and metabolic precursors of biologically active agents. 24. The compound of claim 6, wherein the compound is acyclovirvalyl deoxycholate. 25. The compound of claim 6, wherein the compound is acyclovirvalyl chenodeoxycholate. 26. The compound of claim 6, wherein the compound is atenolol bile acid amide. 27. A method of increasing the bioavailability of a biologically active agent or a metabolic precursor of a biologically active agent or reducing the variability of said availability, the method comprising: The following: binding bile acid to the biologically active agent or a metabolic precursor of the biologically active agent to form a prodrug, and requiring the prodrug Orally administering to the subject. 28. The method of claim 27, wherein the bile acid is bound directly to the biologically active agent or a metabolic precursor of the biologically active agent. 29. The method of claim 27, wherein the bile acid is attached to the biologically active agent or a metabolic precursor of the biologically active agent via a linker group. 30. The method of claim 27, wherein the linker group has a molecular weight of less than 200 Daltons. 31. The method of claim 27, further comprising coating the prodrug with a coating agent prior to oral administration of the prodrug. 32. The prodrug comprises a metabolically labile bond between the bile acid and the biologically active agent or a metabolic precursor of the biologically active agent. Item 27. The method according to Item 27. 33. The metabolically labile bond is selected from the group consisting of amides, esters, carbamates, carbonates, ethers, thios, ureas, anhydrides, thioamides, thioesters, thiocarbamates and thioureas. Item 32. The method according to Item 32. 34. A method of eliminating a detrimental interaction between a compound having a biologically active factor or a metabolic precursor of a biologically active factor and the compound, wherein said detrimental interaction is Results from intestinal absorption of said biologically active agent or a metabolic precursor of said biologically active agent, and at least one of said compounds, the method comprising: bile acid, said organism Binding to a biologically active factor or a metabolic precursor of said biologically active factor to form a prodrug, and orally administering said prodrug to a subject in need thereof. Including the method. 35. The method of claim 34, wherein the bile acid is bound directly to the biologically active agent or a metabolic precursor of the biologically active agent. 36. The method of claim 34, wherein the bile acid is attached to the biologically active agent or a metabolic precursor of the biologically active agent via a linker group. 37. The method of claim 36, wherein the linker group has a molecular weight of less than 200 Daltons. 38. The method of claim 34, further comprising the step of coating the prodrug with a coating agent prior to oral administration of the prodrug. 39. The method of claim 34, wherein the prodrug comprises a metabolically labile bond. 40. The metabolically labile bond is selected from the group consisting of amides, esters, carbamates, carbonates, ethers, thios, ureas, anhydrides, thioamides, thioesters, thiocarbamates and thioureas. Item 39. The method according to Item 39. 41. A method of eliminating a detrimental interaction between a biologically active agent or a metabolic precursor of a biologically active agent and a compound, wherein the detrimental interaction comprises: Results from intestinal absorption of the compound, or a biologically active factor or a metabolic precursor of the biologically active factor, the method comprising the following: bile acid, the biologically active agent. Binding to a factor or a metabolic precursor of said biologically active factor to form a prodrug, and orally administering said prodrug to a subject in need thereof. . 42. The method of claim 41, wherein the bile acid is directly bound to the biologically active agent or a metabolic precursor of the biologically active agent. 43. The method of claim 41, wherein the bile acid is attached to the biologically active agent or a metabolic precursor of the biologically active agent via a linker group. 44. The method of claim 42, wherein the linker group has a molecular weight of less than 200 Daltons. 45. The method of claim 41, further comprising the step of coating the prodrug with a coating prior to oral administration of the prodrug. 46. The linker group is attached to the biologically active agent or a metabolic precursor of the biologically active agent, and then the bile acid is attached to the linker group, 44. The method of claim 43, wherein the prodrug is formed. 47. The linker group is attached to the bile acid, and then the biologically active agent or a metabolic precursor of the biologically active agent is attached to the linker group, 44. The method of claim 43, wherein the prodrug is formed. 48. The prodrug comprises a metabolically labile bond between the biologically active agent or a metabolic precursor of the biologically active agent and the bile acid. Item 41. The method according to Item 41. 49. The metabolically labile bond is selected from the group consisting of amides, esters, carbamates, carbonates, ethers, thios, ureas, anhydrides, thioamides, thioesters, thiocarbamates and thioureas. Item 48. The method according to Item 48. 50. The method of claim 41, wherein the compound is a nutrient.