Mass uptake study of the diffusion of water and SBF into poly(2-hydroxyethyl methacrylate-co-tetrahydrofurfuryI methacrylate) containing aspirin or vitamin B-12

The ingress of water and Kokubo simulated body fluid (SBF) into poly (2-hydroxyethyl methacrylate) (PHEMA), and its co-polymers with tetrahydrofurduryl methacrylate (THFMA), loaded with either one of two model drugs, vitamin 1312 or aspirin, was studied by mass uptake over the temperature range 298-318 K. The polymers were studied as cylinders and were loaded with either 5 wt% or 10 wt% of the drugs. From DSC studies it was observed that vitamin B-12 behaved as a physical cross-linker restricting chain segmental mobility, and so had a small anti-plasticisation effect on PHEMA and the co-polymers rich in HEMA, but almost no effect on the T-g of co-polymers rich in THFMA. On the other hand, aspirin exhibited a plasticising effect on PHEMA and the copolymers. All of the polymers were found to absorb water and SBF according to a Fickian diffusion mechanism. The polymers were all found to swell to a greater extent in SBF than in water, which was attributed to the presence of Tris buffer in the SBF. The sorptions of the two penetrants were found to follow Fickian kinetics in all cases and the diffusion coefficients at 310 K for SBF were found to be smaller than those for water, except for the polymers containing aspirin where the diffusion coefficients were higher than for the other systems. For example, for sorption into PHEMA the diffusion coefficient for water was 1.41 X 10(-11) m(2)/s and for SBF was 0.79 x 10-11 m(2)/s, but in the presence of 5 wt% aspirin the corresponding values were 1.27 x 10(-1)1 m(2)/s and 1.25 x 10(-11) m(2)/s, respectively. The corresponding values for PHEMA loaded with 5 wt% B-12 were 1.25 x 10(-11) m(2)/s and 0.74 x 10(-11) m(2)/s, respectively.

Diphenyltin(IV) complexes of the 2-quinolinecarboxaldehyde Schiff bases of S-methyl- and S-benzyldithiocarbazate (Hqaldsme and Hqaldsbz): X-ray crystal structures of Hqaldsme and two conformers of its diphenyltin(IV) complex

New organometallic tin(IV) complexes of the empirical formula Sn(NNS)Ph2Cl (NNS = anionic forms of the 2-quinolinecarboxaldehyde Schiff bases of S-methyl- and S-benzyldithiocarbazate) have been prepared and characterized by IR, electronic, I H NMR and ES mass spectroscopic techniques. The molecular structures of the 2-quinolinecarboxaldehyde Schiff base of S-methyldithiocarbazate (Hqaldsme) and its diphenyltin(IV) complex, Sn(qaldsme)Ph2Cl, have been determined by X-ray diffraction. In the solid state, the ligand remains as the thione tautomer in which the dithiocarbazate chain adopts an E,E configuration and is almost coplanar with the quinoline ring. The Sn(qaldsme)Ph2Cl complex crystallizes in two distinctly different conformationally isomeric forms, each having the same space group but different lattice parameters. X-ray analysis shows that in each polymorph, the tin atom adopts a distorted octahedral geometry with the Schiff base coordinated to it as a uninegatively charged tridentate chelating agent via the quinoline nitrogen atom, the azomethine nitrogen atom and the thiolate sulfur atom. The two phenyl groups occupy axial positions and the chloride ligand occupies the sixth coordination position of the tin atom. The deprotonated ligand adopts an E,E,Z configuration in the complex. (C) 2004 Elsevier Ltd. All rights reserved.

NMR imaging of the diffusion of water at 310 K into poly[(2-hydroxyethyl methacrylate)-co-(tetrahydrofurfuryl methacrylate)] containing vitamin B12 or aspirin

The ingress of water into copolymers of 2-hydroxyethyl methacrylate (HEMA) and tetrahydrofurfuryl methacrylate (THFMA) loaded with either one of two model drugs, ie vitamin B-12 or aspirin, was studied at 310 K using three-dimensional nuclear magnetic resonance (3D NMR) imaging. The poly(HEMA) was loaded with 5 wt% of the drugs. From the imaging profiles it was observed that incorporation of vitamin B-12 into the polymers rich in HEMA resulted in crack formation at the interface between the rubbery region and the glassy core on sorption of water, although these cracks were 'healed' behind the diffusion front. However, for the copolymers with low HEMA contents and for those containing aspirin, no evidence for similar crack formation was found. For the copolymers loaded with 5 wt% of aspirin or vitamin B-12 the values of the water diffusion coefficients, determined by curve-fitting the relative water concentration profiles from magnetic resonance imaging (MRI) measurements, were found to be smaller than those obtained from a mass uptake study. (C) 2004 Society of Chemical Industry.

Drugs to treat inflammation: A historical introduction

Drugs to treat inflammation are discussed under the following headings: (1) random discoveries covering copper, salicylates, heterocyclic diones, ACTH, adrenal steroids and disease-modifying agents (DMARDs); these include Au(I)-thiolates, chloroquine, and hydroxychloroquine, minocycline, cyclosporin, salazopyrine, D-penicillamine and methotrexate; (2) programmed NSAID developments covering salicylates and fenamates, arylalkanoates, diones, non-acidic NSAIDs, clozic, lobenzarit and coxibs; (3) synthetic glucocorticosteroids; and (4) 'Biologicals' for neutralising pro-inflammatory cytokines. Clinical problems are highlighted, particularly unacceptable side-effects affecting the GI tract, skin, liver, etc. that caused many drugs to be withdrawn. Drug combinations may overcome some of these problems. The bibliography has selected reviews and monographs covering 50 years of publications.

Synthetic, EPR spectroscopic, magnetic and X-ray crystallographic structural studies on copper(II) complexes of the tridentate N2S donor ligand formed from 6-methyl-2-formylpyridine and S-methyldithiocarbazate (Hmpsme)

New copper(II) complexes of general empirical formula, Cu(mpsme)X center dot xCH(3)COCH(3) (mpsme = anionic form of the 6-methyl-2-formylpyridine Schiff base of S-methyldithiocarbazate; X = Cl, N-3, NCS, NO3; x = 0, 0.5) have been synthesized and characterized by IR, electronic, EPR and susceptibility measurements. Room temperature mu(eff) values for the complexes are in the range 1.75-2.1 mu(beta) typical of uncoupled or weakly coupled Cu(II) centres. The EPR spectra of the [Cu(mpsme)X] (X = Cl, N-3, NO3, NCS) complexes reveal a tetragonally distorted coordination sphere around the mononuclear Cu(II) centre. We have exploited second derivative EPR spectra in conjunction with Fourier filtering (sine bell and Hamming functions) to extract all of the nitrogen hyperfine coupling matrices. While the X-ray crystallography of [Cu(mpsme)NCS] reveals a linear polymer in which the thiocyanate anion bridges the two copper(II) ions, the EPR spectra in solution are typical of a magnetically isolated monomeric Cu(II) centres indicating dissociation of the polymeric chain in solution. The structures of the free ligand, Hmpsme and the {[Cu(mpsme)NO3] center dot 0.5CH(3)COCH(3)}(2) and [Cu(mpsme)NCS](n) complexes have been determined by X-ray diffraction. The {[Cu(mpsme)NO3]0.5CH(3)COCH(3)}(2) complex is a centrosymmetric dimer in which each copper atom adopts a five-coordinate distorted square-pyramidal geometry with an N2OS2 coordination environment, the Schiff base coordinating as a uninegatively charged tridentate ligand chelating through the pyridine and azomethine nitrogen atoms and the thiolate, an oxygen atom of a unidentate nitrato ligand and a bridging sulfur atom from the second ligand completing the coordination sphere. The [Cu(mpsme)(NCS)](n) complex has a novel staircase-like one dimensional polymeric structure in which the NCS- ligands bridge two adjacent copper(II) ions asymmetrically in an end-to-end fashion providing its nitrogen atom to one copper and the sulfur atom to the other. (c) 2005 Elsevier B.V. All rights reserved.

Nitrenes, diradicals, and ylides. Ring expansion and ring opening in 2-quinazolylnitrenes

Tetrazolo[1,5-a] quinazoline (9) is converted to 2-azidoquinazoline (10) on sublimation at 200 degrees C and above, and the azide-tetrazole equilibrium is governed by entropy. 2-Quinazolylnitrenes 11 and 27 and/ or their ring expansion products 14 and 29 can undergo type I (ylidic) and type II (diradicaloid) ring opening. Argon matrix photolysis of 9/10 affords 2-quinazolylnitrene (11), which has been characterized by ESR, UV, and IR spectroscopy. A minor amount of a second nitrene, formed by rearrangement or ring opening, is also observed. A diradical (19) is formed rapidly by type II ring opening and characterized by ESR spectroscopy; it decays thermally at 15 K with a half-life of ca. 47 min, in agreement with its calculated facile intersystem crossing (19T -> 19OSS) followed by facile cyclization/rearrangement to 1-cyanoindazole (21) (calculated activation barrier 1- 2 kcal/mol) and N-cyanoanthranilonitrile (22). 21 and 22 are the isolated end products of photolysis. 21 is also the end product of flash vacuum thermolysis. An excellent linear correlation between the zero-field splitting parameter D (cm(-1)) and the spin density F on the nitrene N calculated at the B3LYP/EPRIII level is reported (R-2 = 0.993 for over 100 nitrenes). Matrix photolysis of 3-phenyltetrazolo[1,5-a] quinazoline (25) affords the benzotriazacycloheptatetraene 29, which can be photochemically interconverted with the type I ring opening product 2-isocyano-alpha-diazo-alpha- phenyltoluene (33) as determined by IR and UV spectroscopy. The corresponding carbene 37, obtained by photolysis of 33, was detected by matrix ESR spectroscopy.

Oxoketene-oxoketene, imidoylketene-imidoylketene and oxoketenimine-imidoylketene rearrangements. 1,3-shifts of phenyl groups

Dibenzoylketene 5 undergoes degenerate 1,3-shifts of the phenyl group between acyl and ketene carbon atoms, thus interconverting it with 6 and 7. This 1,3-shift takes place in the gas phase under flash vacuum thermolysis (FVT) conditions, but not in solution at 110-145 degrees C. Imidoyl(benzoyl)ketene 13 undergoes degenerate 1,3-shift of the phenyl group on FVT, thus interconverting it with 14, but the ketenimine isomer 15 is not formed, and none of these shifts take place in the solid state at 250 degrees C. Imidoyl(p-toluoyl)ketene 21 undergoes a 1,3-p-tolyl shift, interconverting it with ketene 22 but not with ketenimine 23. The imidoyl(p-toluoyl)ketene rotamer 25 cyclizes to 4-toluoyloxyquinoline 28 and 4-quinolone 29. The cyclization of imidoyl(benzoyl)ketene 13 to 4-benzoyloxyquinoline 18, and of 25 to 28 involves 1,3-C-to-O shifts of benzoyl (toluoyl) groups. Calculations of the transition states for the transformations at the B3LYP/6-31G** level of theory are in agreement with the observed reaction preferences.

Organic reactions in ionic liquids: ionic liquid-promoted efficient synthesis of N-alkyl and N-arylphthalimides

Phthalic anhydride reacts rapidly with Aromatic and aliphatic amines in ionic liquid [Bmim][PF6] or [Bmim][BF4] at 130 °C to give N-aryl and N-alkylphthalimides in excellent yields.

Organic reactions in ionic liquids: N-alkylation of phthalimide and several nitrogen heterocycles

N-Alkylation of heterocyclic compounds bearing an acidic hydrogen atom attached to nitrogen with alkyl halides is accomplished in ionic liquids ([bmim]BF4 = 1-butyl-3-methylimidazolium tetrafluoroborate, [bmim]PF6 = 1-butyl-3-methylimida-zolium hexafluorophosphate, [buPy]BF4 = butylpyridinium tetra­fluoroborate) in the presence of potassium hydroxide as a base. In this manner, phthalimide, indole, benzimidazole, succinimide can be successfully alkylated. The procedure is convenient, efficient, and generally affords the N-alkylated product exclusively.

Hypervalent iodine in synthesis 93. A facile synthesis of 2-substituted imidazo[1,2-a]pyrimidines by cyclocondensation of alkynyl(phenyl)iodonium salts and 2-aminopyrimidine

Simple stirring of a mixture of the alkynyl(phenyl)iodonium salts 1 with 2-aminopyrimidine 2 in chloroform under reflux for two hours in the presence of K2CO3 gave, after workup, the 2-substituted imidazo[1,2-]pyrimidines 3 in moderate to good yields. A possible mechanism for the formation of 3 involves the intramolecular cyclization of the intermediate alkylidenecarbene 6.

Reactions of directly related tellurium and selenium heterocycic compunds with triiron dodecacarbonyl

The reactions of directly related tellurium and selenium heterocyclic compounds with triiron dodecacarbonyl are described. The reaction of 2-telluraphthalide, C8H8OTe with [Fe3(CO)12 gave [Fe{C6H4(CH2)Te}(CO)3]2, (1). An iron atom has inserted into the telluracyclic ring, and it is probable that one co-ordinated CO ligand arises from the initially organic carbonyl group. X-ray analysis of compound (1) showed that the compound has a Fe2Te2 core, which is achieved by dimerisation. The reaction of telluraphthalic anhydride, C8H402Te with [Fe3(CO)12] gave a known, but unexpected, organic phthalide product, C8H602, which was confirmed by X-ray crystallography. Selenaphthalic anhydride,  C8H4O2Se gave intractable products on reaction with [Fe3(CO)12], 2-selenaphthalide, C8H6OSe, on reaction with [Fe3(CO)12] gave a major product [Fe2{C6H4(CH2)Se}(CO)6], (2) and a minor product [Fe3{C6H4(CH2)Se}(CO)8], (3) which is an intermediate in the formation of (2). X-ray analysis of (2) shows that compound (2) is very similar to (1) except that the 18 electron rule is satisfied by co-ordination of a Fe(CO)3 moiety, rather than dimerisation. Compound (3), also studied by X-ray crystallography, differs from (2) mainly in the addition of an Fe(CO)2 moiety. Telluraphtbalic anhydride, C8H402Te, and selenaphthalic anhydride, C8H402Se, are both monoclinic and crystallise in space group P21/n. 2-Selenaphthalide, C8H402Se, is also monoclinic, space group P21/C. The reactions of the following compounds (l,3-dihydrobenzo[c]selenophene, 1,3,7,9-tetrahydrobenzo[1,2c; 4,5c'] ditellurophene, dibenzoselenophene, phenoxselenine, 3, 5-naphtho-1-telluracyclohexane and 3,5-naphtho-1-selenacyclohexane) with [Fe3lCO)12] are reported. It is unfortunate that the above compounds do not react under the conditions employed; this may be due to differing degrees of ring strain. 1,8-bis(bromomethyl)naphthalene, C12H10Br2 is monoclinic and crystallises in space group C2/c. 1,1-diiodo-3,5-naphthotelluracyclohexane, C12H10TeI2 and 3,5-naphtho-l-telluracyclohexane, C12H10Te are monoclinic and crystallise in space group P21/c. 3,5-naphtho-l-selenacyclohexane, C12H10Se and 2,2,8,8-tetraiodo-1,3,7,9-tetrahydrobenzo[1,2c;4,5c']ditellurophene are also monoclinic, space group P21/a. The syntheses of intramolecular stabilised organo-tellurium and selenium compounds are reported, having a general formula of REX (where R = phenylazophenyl; E = Se, Te; X = electronegative group, for example C1, Br or I). The crystal structures of R'TeBr, RTeI, RSeCI, RSeCI/I and RSeI (where R = phenylazophenyl) are reported. The tellurium containing X-ray structures are triclinic and have a space group P-1. The selenium containing X-ray structures are monoclinic with space group P21/n. The inclusion of nitrogen in selenium heterocycles provides access to an entirely new area of organometallic chemistry. The reaction of 2-methylbenzoselenazole with [Fe3(CO)12] gave [Fe2{C6H4(NCH2CH3)Se}(CO)6]. The reactions of 2-(methyltelluro)benzanilide or 2-(methylseleno)benzanilide with [Fe3(CO)12] gave reaction products [Fe2(μTeMe)2(CO)6] and [Fe2 (μ-SeMe)2(CO)6] respectively, which were confmned by X-ray crystallography. The use of Mossbauer spectroscopy on the products obtained from the reactions of heterocyclic compounds with [Fe3(CO)12] can give useful information, for example the number of iron sites and the environments of these iron sites within the products.

The chemistry of British bituminous coals : an assessment of phase transfer catalysed reactions in the determination of coal structure

Three British bituminous coals, (Gedling, Cresswell, and Cortonwood Silkstone) were selected for study. Procedures were developed, using phase transfer catalysts (PTC's), to degrade the solvent insoluble fractions of the coals. PTC's are of interest because they have the potential to bring about selective high conversion reactions, under mild conditions, (often in the past, severe reaction conditions have had to be used to degrade the coals, this in turn resulted in the loss of much of the structural information). We have applied a variety of physical and chemical techniques to maximise the amount of structural information, these include, elemental analysis, 1H-NMR, 13C-CPMAS-NMR, GPC, GC-MS, FTIR spectroscopy, DRIFT spectroscopy, and gas adsorption measurements. The main conclusions from the work are listed below:- ( 1 ) PTC O-methylation; This reaction removes hydrogen bonds within the coal matrix by 'capping' the phenolic groups. It was found that the polymer-like matrix could be made more flexible, but not significantly more soluble, by O-methylation. I.E. the trapped or 'mobile' phase of the coals could be removed at a faster rate after this reaction had been carried out. ( 2 ) PTC Reductive and Acidic Ether Cleavage; The three coals were found to contain insignificant amounts of dialkyl and alkyl aryl ethers. The number of diaryl ethers could not be estimated, by reductive ether cleavage, (even though a high proportion of all three coals was solublised). The majority of the ethers present in the coals were inert to both cleavage methods, and are therefore assumed to be heterocyclic ethers. ( 3 ) Trif!uoroperacetic Acid Oxidation; This oxidant was used to study the aliphatic portions of the polymer-like macromolecular matrix of the coals. Normally this reagent will only solublise low rank coals, we however have developed a method whereby trifluoroperacetic acid can be used to degrade high rank bituminous coals. ( 4 ) PTC/Permanganate Oxidation; This reagent has been found to be much more selective than the traditional alkaline permanganate oxidation, with a lot more structural information being retained within the various fractions. This degradative method therefore has the potential of yielding new information about the molecular structure of coals.

Synthesis and characterization of triazolotriazines

The Dimroth rearrangement in ring-fused 1,2,4-triazoles has been reviewed in detail in Part I and the synthesis of all known triazolo-triazines is described in Part II. Experimental investigations concerned the establishinent of the skeletal arrangement of a variety of triazolotriazines formed by several synthetic routes. Interaction of 3-amino-5-hydrazino-12,4-triazole and benzilafforded 2-amino-6, 7-diphenyl-1, 2,4-triazolo[ 5, 1-c-]-1,2,4-triazine,whereas cyclization of 5,6-diphenyl-3-hydrazino-1,2,4-triazine withcyanogen bromide resulted in the isomeric 3-amino-6,7-diphenyl,-1,2,4-triazolo [4, 3-b]-1,2,4-triazine: both amines were deaminated with amyl nitrite in boiling tetrahydrofuran without rearrangement of the heterocyclic skeleton. 6,7-Diphenyl-1,2,4-triazolo[5,1-cJ-1,2.4-triazine, synthesized from 3-hydrazino-1,2,4-triazole and benzil, formed a covalent hydrate which could be detected spectroscopically in solution, and a covalemt methanolate and ethanolate which could be isolated. A new route to 3-amino-5-hydrazino-pyrazole is described and cyclization to 7-amino-3,4-diphenyl-pyrazolo[ 5,1-.c]-1,2,4-triazine was achieved with benzil. The diazonium nitrate of 3-amino-1,2,4-triazole coupled with ethyl cyanoacetate to yield a mixture of two geometrical isomers of ethyl 2-(2H-1,2,4-triazol-3-ylhydrazono) cyanoacetate.Recrystallization of the crude coupling mixture from aqueous ethanol gave a single hydra-zone which cyclized predominantly to ethyl 7-amino-1,2,4-triazolo[5,1-c]-1,2,4-triazine-6-carboxylate in acid conditions and 6-cyano-1,2,4-triazolo[ 5,1-c]-1,2,4~triazin-7(4H)-one under basic conditions. The nature of the cyclizing medium also controlled the cyclization of .the (pyrazol-ylhydrazono) cyanoacetate hut the corresponding (tetrazol- ylhydrazono) cyanoacetate gave only ethyl 7-aminotetrazolo[ 5,1-cJ-1,2,4- -triazine-6-carboxylate. 2-( 2H-1,2,4-Triazol-3-:ylhydrazono) malonitrile cyclized unambiguously to 7-amino-6-cyano-1,2,4-triazolo-[ 5,1-c]-1,2,4- triazine. Drastic hydrolysis of ethyl 2-(2H-1,2,4-triazol-3-yllhydrazono)-cyanoacetate, ethyl 7-amino-1, 2,4-triazolo[ 5,1-c]-1,2,4-triazine-6-carboxylate, 6-cyano-1,2,4-triazolo[ 5,1-c]-1,2,4-triazin-7{ 4H)-one and 7-amino-6- cyano-1,2,4-triazolo[5,1-c]-1,2,4-triazine gave a hydrate of 1,2,4-triazo1o[5,1-c ]-1,2,4-triazin-7(4H)-one. Mass spectral fragmentations of 7-aminoazolo-[5,1-c]-1,2,4-triazinesconfirm that the azole ring is more stable than the 1,2,4-triazine ring on electron impact.

Non-classical inhibitors of dihydrofolate reductase

This thesis comprises two main objectives. The first objective involved the stereochemical studies of chiral 4,6-diamino-1-aryl-1,2-dihydro-s-triazines and an investigation on how the different conformations of these stereoisomers may affect their binding affinity to the enzyme dihydrofolate reductase (DHFR). The ortho-substituted 1-aryl-1,2-dihydro-s-triazines were synthesised by the three component method. An ortho-substitution at the C6' position was observed when meta-azidocycloguanil was decomposed in acid. The ortho-substituent restricts free rotation and this gives rise to atropisomerism. Ortho-substituted 4,6-diamino-1-aryl-2-ethyl-1,2-dihydro-2-methyl-s-triazine contains two elements of chirality and therefore exists as four stereoisomers: (S,aR), (R,aS), (R,aR) and (S,aS). The energy barriers to rotation of these compounds were calculated by a semi-empirical molecular orbital program called MOPAC and they were found to be in excess of 23 kcal/mol. The diastereoisomers were resolved and enriched by C18 reversed phase h.p.l.c. Nuclear overhauser effect experiments revealed that (S,aR) and (R,aS) were the more stable pair of stereoisomers and therefore existed as the major component. The minor diastereoisomers showed greater binding affinity for the rat liver DHFR in in vitro assay. The second objective entailed the investigation into the possibility of retaining DHFR inhibitory activity by replacing the classical diamino heterocyclic moiety with an amidinyl group. 4-Benzylamino-3-nitro-N,N-dimethyl-phenylamidine was synthesised in two steps. One of the two phenylamidines indicated weak inhibition against the rat liver DHFR. This weak activity may be due to the failure of the inhibitor molecule to form strong hydrogen bonds with residue Glu-30 at the active site of the enzyme.

Design, synthesis and development of PDE5 inhibitors

This research project is concerned with the design, synthesis and development of new phosphodiesterase 5 (PDE5) inhibitors with improved selectivities and lower toxicities. Two series of a 5 member and a 6 member ring fused heterocyclic compounds were designed, and synthesized. By alteration of starting materials and fragments, two virtual libraries, each is consisted of close to hundred compounds, were obtained successfully. The screening of sexual stimulation activity with rabbits demonstrated both groups of compounds were able to stimulate rabbit penile erection significantly. The following toxicity studies revealed 2-(substituted-sulfonylphenyl)-imidazo [1,5-a]-1,3,5-triazine-4-(3H)-one group possessed an unacceptable toxicity with oral LD50 about 200mg/kg; while 2-(substituted-sulfonylphenyl)-pyrrolo[2,3-d]pyrimidin-4-one group showed an acceptable toxicity with oral LD50 over 2000mg/kg. The continued bioactivity studies showed yonkenafil, the representative of 2-(substituted-sulfonylphenyl)-pyrrolo[2,3-d]pyrimidin-4-one group, has a better selectivity towards PDE5 and PDE6 than sildenafil and a better overall profile of sexual stimulation on animals than sildenafil. Chronic toxicity studies of yonkenafil further confirmed yonkenafil did not cause any serious side effect and damage on animal models and most actions were explainable. Based on evidences of the above studies, yonkenafil were recommended to enter clinical trials by the regulation authority of China, SFDA. Currently yonkenafil has been through the Phase I clinical trials and ready to progress into Phase II. Hopefully, yonkenafil will provide an alternative to the ED patients in the future.