LABRUZZO CARLA (IT)
| US20060270635A1 | 2006-11-30 |
GREENE, WUTS: "Protective Groups in Organic Synthesis", pages: 503 - 648
| Claims 1) Compound of formula (I): wherein: R = C4-Cg alkanoyl; and Χ = ΝΗ-Ρ where K\ = H, or an amine protecting group, preferably the tert-butyloxycarbonyl group (Boc); and/or the pharmaceutically acceptable salts thereof. 2) Compound according to claim 1, having formula (la): (la) wherein: R = C4-C8 alkanoyl; and/or the pharmaceutically acceptable salts thereof. 3) 5-amino-2-(butyryloxy)benzoic acid and/or pharmaceutically acceptable salts thereof, preferably hydrochloride salt. 4) A compound according to any one of claims 2 or 3, for use as a medicament. 5) A compound according to any one of claims 2 or 3, for use in the treatment of acute or chronic intestinal inflammatory diseases preferably selected from among IBD, IBS, ulcerative colitis, Crohn's disease, diverticular disease, more preferably IBD. 6) A compound according to any one of claims 2 or 3, characterised in that it is administered enterally, preferably orally and/or rectally. 7) Pharmaceutical composition containing a compound according to any one of claims 2 or 3, and at least one physiologically acceptable excipient 8) Pharmaceutical composition according to claim 7 selected from among tablet, capsule, granule, microgranule, suspension or aqueous solution, enema, suppository, gel and rectal foam. 9) Process for the preparation of the compound of formula (la) comprising the following steps: a') protection of 5-ASA with an amine protecting group to obtain the compound of formula (IF); (II') b') acylation of the hydroxyl group of the compound of formula (IF) to obtain the compound of formula (IIF); (III') c') deprotection of the amino group of the compound of formula (IIF); wherein: R = C4-Cg alkanoyl; And Ri is an amine protecting group, preferably the tert-butyloxycarbonyl group (Boc). 10) Process for the preparation of 5-arnino-2-(butyryloxy)benzoic acid hydrochloride comprising the following steps: a) protection of 5-ASA as a Boc-derivative to obtain the compound (II); b) butyrylation of the hydroxyl group of the compound (II) to obtain the compound (in); (ill) c) deprotection of the amino group of the compound (III). 11) Process according to any one of claims 9 or 10, characterised in that the step a) is conducted in an aprotic polar solvent and/or in a mixture of said solvent with H20 preferably in a molar ratio comprised between 1:1 and 3:1, more preferably 2:1. 12) Process according to any one of claims 9 or 10, characterised in that said mixture is constituted by dioxane and water, preferably in a 2:1 molar ratio. 13) Process according to any one of claims 9 or 10, characterised in that the step a) is conducted in presence of a base, preferably organic, more preferably triethylamine, in a molar ratio comprised between 1:1 and 3:1, preferably 1.5:1 with respect to the 5-ASA and/or in presence of di-tert-butyl dicarbonate in a molar ratio comprised between 1:1 and 2:1, preferably 1.5:1 with respect to 5-ASA. 14) Process according to any one of claims 9 or 10, characterised in that the step b) is conducted in presence of a butyryl halide, preferably butyryl chloride and/or butyric anhydride in a molar ratio comprised between 1:1 and 3:1, preferably 2:1 with respect to the compound (II). 15) Process according to any one of claims 9 or 10, characterised in that the step b) is conducted in an aprotic apolar solvent, preferably selected from among an aliphatic or aromatic hydrocarbon, halogenated aliphatic hydrocarbon, more preferably dichloromethane, in presence of a base, preferably organic, more preferably diisopropylemylamine, preferably in a 3:1 molar ratio with respect to the compound (II). 16) Process according to any one of claims 9 or 10, characterised in that the step c) is conducted in an acid environment preferably generated by HCl in an aprotic solvent, more preferably by HCl in dioxane or HCl in ethyl ether. 17) Process for the preparation of the compound of formula (la) comprising the following steps: d') acylation of the hydroxyl group of the compound of formula (V') (V) to obtain the compound of formula (VI'); (VI') e') hydrogenation of the nitro group of the compound of formula (VP); wherein: R = C4-C8 alkanoyl. 18) Process for the synthesis of 5-amino-2-(butyryloxy)benzoic acid comprising the following steps: d) butyrylation of the compound of formula (V') (V') to obtain the compound (VI); (VI) e) hydrogenation of the compound (VI). 19) Process according to any one of claims 17 or 18, characterised in that the step d) is conducted in presence of butyric anhydride and/or a butyryl halide, preferably butyric anhydride in a molar ratio with respect to the compound (V') comprised between 1:1 and 5:1, preferably 3:1. 20) Process according to any one of claims 17 or 18, characterised in that the step d) is conducted in presence of an acid catalysis, preferably sulfuric acid and/or at a temperature comprised between 40°C and 70°C, preferably about 55°C. 21) Process according to any one of claims 17 or 18, characterised in that the step d) is conducted in a polar solvent, preferably in a C C4 alcohol, dioxane, tetrahydrofuran and/or mixtures thereof, more preferably ethanol. 22) Compound of formula (lb): (l b) 23) Use of a compound according to claim 22 as an intermediate in the preparation of 5- amino-2-(butyryloxy)benzoic acid. |
Description of the invention
The present invention refers to the compounds corresponding to the following general formula (I):
wherein:
R = C 4 -C8 alkanoyl; and where R \ = H, or protecting group for amines;
and/or the pharmaceutically acceptable salts thereof.
Preferred compounds according to the present invention are represented by the following formula (la):
wherein:
R = C 4 -C8 alkanoyl;
and/or the pharmaceutically acceptable salts thereof.
In a preferred embodiment, an object of the present invention is to provide 5-arnino-2- (butyryloxy)benzoic acid and/or the pharmaceutically acceptable salts thereof, preferably hydrochloride salt.
A further object of the present invention is represented by the use of the compounds of formula (la), in particular 5-amino-2-(butyryloxy)benzoic acid and/or pharmaceutically acceptable salts thereof, as a medicament and by the use thereof for the treatment of intestinal inflammatory diseases.
The present invention also regards the synthesis processes to obtain such compounds and some intermediate compounds of said synthesis processes. State of the art
5 -aminosalicylic acid (hereinafter also referred to as 5-ASA or mesalazine) represents one of the fundamental and historically used drugs in the therapy of both acute and chronic intestinal inflammatory diseases. Actually, it is preferably used for the treatment of IBD, ulcerative colitis, Crohn's disease and IBS. (Regueiro et al. Clinical Guidelines for the Medical Management of left-side ulcerative colitis and ulcerative proctitis: summary statement; Kormbluth A et al. Ulcerative colitis practice guidelines in adults: American college of gastroenterology, practice parameters committee). Such active ingredient has a topic anti-inflammatory action at the intestinal lumen level, with consequent inhibition of biosynthesis of the chemical mediators of the inflammatory process, derivatives of arachidonic acid such as prostaglandin E2, thromboxane B2 and leukotrienes.
Mesalazine does not react systemically but only topically at contact with the mucosa of the lower intestine, distal ileum and colon, selective sites of acute and chronic idiopathic flogosis. Administered orally, mesalazine should thus reach the sites of the disease through tablets or granulates with modified release, a formulation which goes through the stomach and the small intestine unaltered, releasing the active ingredient solely in the distal ileum and, above all, in the colon. Mesalazine is administered rectally preferably in aqueous suspension in form of retention enema, or in suppositories, rectal foam and anorectal gel.
Short Chain Fatty Acids (SCFA) are used for treating intestinal inflammatory diseases. They are used in topic formulations, especially in patients with rectal ulcerative colitis, and in oral formulations, in association with conventional therapy. This family of fatty acids, which comprises acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, caproic acid, lactic acid and succinic acid is considered the main source of energy for the cells of the colon mucosa and a fundamental factor for controlling the growth of the mucosa.
The food sources of short chain fatty acids are quite limited; they are produced especially during the fermentation of fibres carried out by the bacteria found in the colon. In particular, among these short chain fatty acids, butyric acid represents the largest source of energy for colonocytes to a point that deficiency thereof determines atrophy of the mucosa. In addition, it seems to have positive effects in the prevention of colon cancer given that in vitro, it has proven not only the capacity to inhibit the proliferation of carcinogenic cells but also to stimulate differentiation thereof.
Furthermore, short chain fatty acids perform an anti-inflammatory role on the colon mucosa.
Also regarding butyric acid and derivatives, which perform therapeutic activity thereof locally in acute or chronic intestinal diseases, there arises the need of oral administration through modified release tablets or in form of enema as specified above regarding mesalazine.
Novel derivatives of mesalazine which are particularly advantageous in the cure of both acute and chronic intestinal inflammatory diseases have now been discovered; in particular, a novel compound capable of combining the therapeutic effects of mesalazine and butyric acid, i.e. 5-amino-2-(butyryloxy)benzoic acid and/or the pharmaceutically acceptable salts thereof, such as hydrochloride have been surprisingly discovered.
Detailed description of the invention
An object of the present invention is represented by the compounds corresponding to the following general formula (I):
wherein:
R = C4-C8 alkanoyl; and
X = NH-R. !
where Ri = H, or protecting group for amines, preferably the tert-butyloxycarbonyl group (Boc);
and/or the pharmaceutically acceptable salts thereof.
The expression "protecting group for amines" refers to the text "Greene and Wuts, Protective Groups in Organic Synthesis, Third edition, pages. 503-648", incorporated herein for reference.
Preferred compounds according to the present invention are represented by the following formula (la):
wherein: (la)
R = C 4 -Cg alkanoyl;
and/or the pharmaceutically acceptable salts thereof.
In a preferred embodiment, an object of the present invention is to provide 5-amino-2- (butyryloxy)benzoic acid and/or the pharmaceutically acceptable salts thereof, preferably hydrochloride salt (compound (IV)).
(IV)
The compounds of formula (la), in particular 5-amino-2-(butyryloxy)benzoic acid and/or the pharmaceutically acceptable salts thereof, preferably hydrochloride salt, as a medicament form a further object of the present invention.
In particular, said 5-amino-2-(butyryloxy)benzoic acid and/or the pharmaceutically acceptable salts thereof intervene as prodrugs capable of releasing the two active ingredients, mesalazine and butyric acid, in the selective sites of the intestinal idiopathic flogosis, distal ileum and colon.
The compounds of formula (la), in particular 5-amino-2-(butyryloxy)benzoic acid and/or pharmacologically useable salts thereof, for use in the treatment of acute and chronic intestinal inflammatory diseases, among which IBD (Inflammatory Bowel Disease), ulcerative colitis, Crohn's disease, diverticular disease, IBS (Irritable Bowel Syndrome) form a further object of the present invention. Preferably, the compounds of formula (la) are specifically applied in the treatment of IBD
According to the present invention the aforementioned compounds of formula (la) and, in particular 5-amino-2-(butyryloxy)benzoic acid and/or the pharmaceutically useable salts thereof, can be administered to human beings, intended both as an adult subject and as "paediatric population", where the term "paediatric population" is used to indicate the part of population between birth and eighteen years of age. A pharmaceutical composition containing the compounds of formula (la), in particular 5-amino-2-(butyryloxy)benzoic acid and/or the pharmaceutically acceptable salts thereof, and at least one physiologically acceptable excipient form a further object of the present invention.
Actually, the compounds according to the present invention can be administered to patients affected by acute and chronic intestinal inflammatory diseases, in form of pharmaceutical preparations taking into account the local and non-systemic activity of these active ingredients. The expression "local activity" is used to indicate that the active ingredient should come to contact with the mucosa of the colon.
Said pharmaceutical composition may contain the aforementioned compounds in solid form, preferably selected from among tablet, capsule, granule, microgranule or in liquid form, preferably selected from among suspension or aqueous solution for oral administration or for rectal administration preferably through enema, suppository, gel or rectal foam.
Oral administration may use modified-release preparations which go through the stomach or small intestine unaltered and then release the active ingredient in the colon. Administration of the pharmaceutical composition according to the present invention is particularly advantageous in that it allows administering the anti-inflammatory 5-ASA and the intestinal trophic factor, butyric acid, in a single administration, thus improving the patient compliance with respect to a combined administration of the two active ingredients separate.
The in vitro and in vivo tests, indicated below in the experimental part, reveal some considerable characteristics of 5-amino-2-(butyryloxy)benzoic acid in form of hydrochloride salt, the compound (IV).
It is stable in storage both in the normal (25°C, 60% RH) and accelerated conditions (40°C, 75% RH) as well as in the gastric and in the simulated intestinal fluids; it has a high hydrolysis percentage in both human and murine plasma; it has low permeability through the basolateral membrane of the Caco2 cell line, hence guaranteeing maintaining the topic action of 5-ASA to be released; furthermore, it is quickly metabolised in the rat intestine.
In vivo pharmacokinetic studies in rats wherein the compound (IV) is administered p.o. and i.v. revealed good pharmacokinetic parameters thereof. The same in vitro and in vivo studies carried out on another conjugated derivative of mesalazine with butyric acid, in particular the derivative of formula (Illb):
on the contrary did not reveal positive results.
This shows that not all conjugates of mesalazine with butyric acid are suitable for the treatment of intestinal disease.
A further object of the present invention is the process of synthesis of the compounds of formula (la) characterised by the following steps:
a') protection of 5 -ASA with an amine protecting group to obtain the compounds of formula (IF);
(II·)
b') acylation of the hydroxyl group of the compounds of formula (IF) to obtain the compounds of formula (IIF);
(III')
c') deprotection of the amino group,
wherein:
R = C 4 -C 8 alkanoyl;
and R \ is an amine protecting group, preferably the tert-butyloxycarbonyl group (Boc). In particular, Scheme A reported below, shows the preferred synthesis for obtaining 5- amino-2-(butyryloxy)benzoic acid, in forma of hydrochloride (compound IV), starting from 5-ASA:
Schema A
Such process is characterised by the following steps:
a) protection of 5-ASA as a Boc-derivative to obtain the compound (II);
(II)
b) butyrylation of the hydroxyl group of the compound (II) to obtain the compound
c) deprotection of the amino group of the compound (III) to obtain 5-amino-2- (butyryloxy)benzoic acid as hydrochloride, compound (IV).
(IV)
The step a) is conducted in an aprotic polar solvent and/or in a mixture of said solvent with H 2 0, preferably in a molar ratio comprised between 1 :1 and 3:1, more preferably 2:1. Said mixture is preferably constituted by dioxane and water, preferably in a 2:1 molar ratio. Such step is conducted in presence of a base, preferably organic, more preferably triethylamine in a molar ratio comprised between 1:1 and 3:1, preferably 1.5:1 with respect to the 5-ASA. Di-tert-butyl dicarbonate (Boc 2 0) is used in a molar ratio comprised between 1:1 and 2:1, preferably 1.5:1 with respect to the 5-ASA. The step b) is conducted in presence of a butyryl halide, preferably butyryl chloride and/or butyric anhydride in a molar ratio comprised between 1:1 and 3:1, preferably 2:1 with respect to the compound (II).
The step b) is conducted in an aprotic apolar solvent, preferably selected from among an aliphatic or aromatic hydrocarbon, halogenated aliphatic hydrocarbon, more preferably dichloromethane, in presence of a base, preferably organic, more preferably diisopropylemylamine, preferably in a 3:1 molar ratio with respect to the compound
(II).
The step of deprotection c) is conducted in an acidic environment preferably generated by HC1 in an aprotic solvent, more preferably by HC1 in dioxane or HC1 in ethyl ether. Alternatively, the compounds of formula (la) can be synthesised according to the following steps:
d') acylation of the hydroxyl group of the nitro derivative (V') available in the market
(V)
to obtain the compounds of formula (VP);
(VI')
e') hydrogenation of the nitro group of the compounds of formula (VI')
wherein:
R = C 4 -C 8 alkanoyl.
In particular, Scheme B reported below shows the synthesis for obtaining the 5- 2-(butyryloxy)benzoic acid starting from (V):
Such process is characterised by the following steps:
d) butyrylation of the nitro derivative (V')
to obtain the compound (VI);
(VI)
e) hydrogenation of the compound (VI) to obtain 5-amino-2-(butyryloxy)benzoic acid.
The step d) is conducted in presence of butyric anhydride and/or a butyryl halide, preferably butyric anhydride, preferably in presence of an acid catalysis, preferably sulfuric acid. Said butyric anhydride is used in a molar ratio with respect to the compound (V') comprised between 1:1 and 5:1, preferably 3:1. Said step d) is conducted at a temperature comprised between 40°C and 70°C, preferably about 55°C. The step d) is conducted in a polar solvent, preferably in a C1-C4 alcohol, dioxane, tetrahydrofuran and/or mixtures thereof. Said C C 4 alcohol is preferably ethanol.
The compound corresponding to the formula (lb) indicated below BocHN
(lb) and the use thereof as an intermediate in the synthesis processes indicated above is also an object of the present invention.
The examples below are intended to be illustrative and not limiting of the present invention.
Example 1: Synthesis of the 5-(tert-bntoxycarbonylamino)-2 hydroxy benzoic acid OB
(II)
Triemylamine (1.5 eq) (complete dissolution) followed by di-tert-butyl dicarbonate (1.5 eq) are added to a suspension of about 0.27 M of 5-ASA in a 2:1 dioxane/water mixture, cooled to 0°C. It is stirred for 30 min at 0°C and at ambient temperature for 16 hours. Dioxane is evaporated, the aqueous resulting solution is cooled in an ice bath and acidified with HC1 3N. The product (II) precipitates as white solid. It is filtered, it is washed with water, it is dried under vacuum at 50°C. Quantitative yield.
Example 2: Synthesis of S-(tert-bntoxycarbonylamino ' >-2-(bntyryloxy)benzoic acid (III)
Diisopropylethylamine (3 eq) (complete dissolution) followed by butyryl chloride (2 eq) is added to a suspension of about 0.4 M of the compound (II) in dichloromethane, cooled to 0°C and in inert atmosphere. It is stirred at ambient temperature for 16 hours. HCl IN (cooled in an ice bath) up to acid pH is added. The organic phase is washed with water, anhydrified and evaporated. At this stage a mixture of the desired product (III) and deacylated product (probably the corresponding anhydride) is obtained as a whitish solid. The mixture is dissolved in ethyl ether (concentration of about 0.1 M), a 2N solution of HCl in ethyl ether (0.2 eq) is added and it is stirred at ambient temperature for 25 days, during which 2N hydrochloride ether is added other 2 times (0.4 eq HCl totally) up to obtaining complete conversion in the product (III). The solvent is evaporated, the resulting solid is triturated with hexane (2 times), it is filtered and it is dried, obtaining the product (III) as white solid. 88% yield, LC-MS 99% purity.
Example 3; Synthesis of the hydrochloride of the 5-amino-2-(butvryloxv)benzoic acid (TV)
(III) (IV)
A 4N solution of HCl in dioxane (5 eq HCl) is added to a solution of about 0.07 M of the compound (III) in ethyl ether; it is stirred at ambient temperature for 20 days, during which hydrochloride dioxane is added periodically and hence 2N HCl in ethyl ether (10 eq HCl totally) and there is a gradual precipitation of the product. It is filtered by washing abundantly with ethyl ether, it is dried at ambient temperature, obtaining (IV) as a light beige solid. 65% yield, LC-MS 98% purity.
If necessary, the product can be triturated in an ethyl ether/dioxane mixture (3:1 respectively) to increase the titre thereof.
1H NMR (300 MHz, DMSO-£¾ δ ppm 7.64 (d, 1H), 7.33 (dd, 1H), 7.14 (d, 1H), 2.52- 2.55 (m, 2H), 1.65 (sxt, 2H), 0.97 (t, 3H).
Example 4; Evaluation of the stability of the compound (IV) at 25°C and at 40°C
The object of such study is the evaluation of the stability of the compound (IV) kept at a temperature equivalent to 25°C (60% RH) and at 40°C (75% RH). In particular, such study aims at evaluating the litre of the compound (IV) in the stability test at 25°C (60% RH) at 3, 6, 9, 12, 18, 24, 36, 48, 60 months and in the stability test accelerated at 40°C (75% RH) at 3, 6, 9, 12 months.
The compound (IV) is divided into 10 Eppendorfs numbered from 1 to 10, containing about 50 mg of product and stored in a cellar at 25°C 60% RH.
Other 4 Eppendorfs numbered from 11 to 14, containing about 50 mg of product are introduced into an oven at a temperature equivalent to 40°C 75% RH.
The titre at time t=0 is equivalent to 99.3%.
Currently there data are available at 3 months, indicated in the Tables 1 and 2.
Table 1. Compound (IV) at 25°C 60% RH
Table 2. Compound (W at 40°C 75% RH
From the experimental results obtained up to date, the compound (IV) does not seem to be subjected to considerable modifications in the two storage conditions.
Example 5: Evaluation of the stability of the compound (TV) in simulated gastric and simulated intestinal fluids
Such study is conducted with the aim of evaluating the stability of the compound (IV) at 1.1 pH (SIF) and 7.4 pH (SGF) in absence of enzymes of the intestinal bacterial flora. The stability of the compound (IV) is compared to that of known reference standards. Table 3 shows experimental results indicating that the molecule is stable in both media (SIF and SGF) both after 30 and 90 minutes from incubation.
Table 3. Residual percentage of the compound (IV) after 30 and 60 minutes of
incubation in SIF and SGF
SGF= Simulated Gastric Fluid
SIF= Simulated Intestinal Fluid
The values are expressed as mean ± SD (n
Example 6: Evaluation of the stability of the compound (TV) in human and rat plasma
Such study is conducted with the aim of evaluating possible hydrolysis of the compound (IV) by the plasma esterases.
The percentage of hydrolysis of the compound (IV) is compared to that of known reference standards.
The obtained experimental results, indicated in Table 4, indicate that in the human plasma the compound (IV) is 67.3% hydrolysed while in murine plasma it is 91.5% hydrolysed, after 1 hour of incubation.
Table 4. Results of the stability in human and murine plasma of the compound (IV)
The results are expressed as mean ± SD (n=2)
Values exceeding 100% are possibly due to the matrix effect Example 7; Evaluation of the permeability of the compound (TV) on the Caco2 cellular line
Such study is conducted with the aim of evaluating the capacity of the molecule to permeate the intestinal epithelium and be absorbed thereby evaluating the Papp (apparent permeability coefficient).
The Papp of the compound (IV) is compared to that of the known reference standards. Table 5 shows the obtained experimental results. They indicate that the molecule has poor permeability and that there are no apparent reflux phenomena (BA/AB<1 ratio). Hence, the product does not seem to be a substrate of P-gp (glycoprotein P), hence guaranteeing maintaining the topic action of the active ingredient, 5-ASA, to be released.
Table 5. Permeability data
The results are expressed as mean ± SD (n=2)
Apical (pH 6.5)→ Basolateral (pH 7.4)
Classification of absorption: Papp>50: High; Papp 10-50: Medium; Papp<10: Low
Example 8; Evaluation of the stability of the compound (TV) in murine intestinal homogenate
Such study is conducted with the aim of evaluating the stability of the compound (IV) in intestinal homogenate. The stability of the compound (IV) is compared to that of known reference standards. The obtained experimental results, indicated in Table 6 below, indicated that the compound (IV) is very unstable in the rat intestine, i.e. it is metabolized very quickly. In particular, the compound (IV) tested at two concentrations (25 and 50 μΜ) shows a hydrolysis concentration exceeding 90-95%.
Table 6. Residue percentage of the compound (TV) in rat intestinal homogenate after 30 min, 1, 2 and 4 hours of incubation.
The results are expressed as mean ± SD (n=2)
(*) The increase detected at this last point could be due to injection problems.
Example 9; Evaluation of the hydrolysis of the compound (IV) in rat intestine preserved in different conditions
Such study is conducted with the aim of surveying the stability of the compound (TV) in rat intestine homogenate preserved in different conditions: frozen at 4°C and at -80°C. The stability of the compound (IV) is compared to that of known reference standards. The obtained experimental results, indicated in Table 7 below, indicated that the compound (IV) in the fresh rat intestine homogenate is metabolised quickly. The same enzymatic activity is observed in the homogenate preserved at 4°C and at -80°C after three weeks. Table 7. Residual percentage of the compound (IV) in rat intestine after 15, 30 and 60 min of incubation
The results are expressed as mean ± SD (n=2)
Example 10: Evaluation of the in vivo pharmacokinetic of the compound (TV)
The objectives of such study are the evaluation of the most relevant pharmacokinetic parameters (Cmax, Tmax, AUC, clearance, half-life and bioavailability after i.v. and p.o. administration) of the compound (IV) in the rat and the quantification of the product 5-ASA (metabolite of the compound (IV)) after administration of the compound (IV).
Tables 8 and 9 indicate the obtained experimental data.
They indicate that the compound (IV) is metabolised quickly after i.v. and p.o. treatment. An abundant amount of the metabolite thereof, 5-ASA, is observed in the plasma. After i.v. administration the amount of 5-ASA in the plasma is ten times greater than that of the compound (IV) with a range of concentration in the plasma comprised between 659 and 2.1 ng/ml.
After p.o. administration, the compound (IV) reveals a Cmax between 5 and 30 min. equivalent to 95 ng/ml and reduces up to 1 ng/ml after 4 hours. The levels of metabolite 5 -ASA are 50 times greater than those of the compound (IV).
Table 8. Pharmacokinetic parameters of the compound (TV) after i.v. administration (5 mg/kg) and oral gavage (50 mg/kg) in the rat
AUCinf= area below the lower curve; AUClast= area below the last curve; Cmax= maximum concentration; Tmax= time corresponding to the Cmax; Clast= last concentration; Tlast= time corresponding to the Clast; Tl/2=time of half-life; MRT= mean residence time; Cl= Clearance; Vdss= volume of distribution at stationary state; Mean Fpo= mean p.o. bioavailability. Table 9. Pharmacokinetic parameters of 5-ASA after i.v. and oral gavage administration of the compound (IV) respectively at 5 and 50 mg/Kg.
Parameters calculated on the mean concentrations of 5-ASA
Figures 1 to 7 respectively indicate:
Figure 1. Kinetic profile of the compound (IV) after i.v. administration, 5 mg/kg.
Figure 2. Kinetic profile of the metabolite 5-ASA after p.o. administration of the compound (IV), 50 mg/kg.
Figure 3. Comparison of the kinetic profiles of the compound (IV) and the 5-ASA metabolite thereof after i.v. administration of the compound (IV).
Figure 4. Kinetic profiles of the compound (IV) after oral administration 50 mg/kg. Figure 5. Kinetic profiles of the 5-ASA metabolite after oral administration of the compound (IV), 50 mg/kg.
Figure 6. Comparison of the kinetic profiles of the compound (TV) and of the 5-ASA metabolite thereof after oral adniinistration of the compound (IV).
Figure 7. Comparison of the kinetic profiles of the compound (IV) and of the 5-ASA metabolite thereof after A) i.v. administration mg/Kg and B) oral administration 50 mg/Kg of the compound (IV).