WO2004041923A2 - Composes actifs sur le plan biologique hydrolysables chimio-enzymatiquement - Google Patents

Composes actifs sur le plan biologique hydrolysables chimio-enzymatiquement Download PDF

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Publication number
WO2004041923A2
WO2004041923A2 PCT/IN2003/000354 IN0300354W WO2004041923A2 WO 2004041923 A2 WO2004041923 A2 WO 2004041923A2 IN 0300354 W IN0300354 W IN 0300354W WO 2004041923 A2 WO2004041923 A2 WO 2004041923A2
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WO
WIPO (PCT)
Prior art keywords
formula
biologically active
alkyl
aziridine
epoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/IN2003/000354
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English (en)
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WO2004041923A3 (fr
Inventor
Jayant Venkatesh Deshpande
Vaishali Madhukar Kadam
Vandana Sandeep Gupte
Kamlesh Jayantilal Ranbhan
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Kopran Research Laboratories Ltd
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Kopran Research Laboratories Ltd
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Priority to AU2003300696A priority Critical patent/AU2003300696A1/en
Publication of WO2004041923A2 publication Critical patent/WO2004041923A2/fr
Publication of WO2004041923A3 publication Critical patent/WO2004041923A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin

Definitions

  • This invention relates to chemoenzymatically hydrolysable biologically active compounds.
  • This invention also relates to process for the preparation of the chemoenzymatically hydrolysable biologically active compounds.
  • Biologically active agents substituted with polymers by covalent conjugation are reported to show therapeutic activity.
  • US Patent No. 5162307 describes polymeric inhibitors of the enzyme elastase having the Formula P -L - R, where P is a non-biodegradable polymer, L is a covalent bond or a linker group and R is a peptide.
  • Therapeutic peptides conjugated to polyethylene glycol chains are reported to show improved durability and reduced antigenicity (US Patent No. 5183660).
  • No. WO 99/63940 discusses low molecular weight polymeric derivatives of benzimidazoles as antiulcer agents.
  • the molecular weight of such polymers is generally in the range of 1000 - 10,000.
  • Such polymeric drugs get absorbed from the gastro intestinal tract and elicit systemic activity.
  • the above polymeric drugs are non-biodegradable in physiological fluid and are excreted from the body.
  • US Patent No. 5372807 describes an intravenous formulation comprising an antifibrotic agent linked to a cis-4-hydroyl-L-proline polymer.
  • US Patent No. 5622718 describes an alginate conjugated with antineoplastic agent such as daunomycin or doxorubicin via an acid labile biodegradable spacer linkage.
  • US Patent No. 6011008 describes water-soluble conjugates of a polysaccharide and an unoxidised, oxidation-sensitive substance, conjugated via amine or imine bonds.
  • US Patent No. 4587046 describes biologically active drug such as catecholamine hormones coupled to carrier molecules like monodisperse peptides.
  • US Patent Publication No. 20010031262 describes polylactide-CO-glycolide copolymers in the form of particles or a gel, lipid vesicles or liposomes, which are stabilized or targeted to enhance the delivery of antigens.
  • biodegradable porous particles incorporating a therapeutic agent which may be effectively aerosolized for administration to the respiratory tract to permit systemic or local delivery of the therapeutic agent.
  • biodegradable particles are formed of a functionalized polyester graft copolymer consisting of a linear ⁇ -hydroxy-acid polyester backbone having an amino acid group incorporated therein and polyamino acid side chain extending from an amino acid group in the polyester backbone. Chlorambucil i.e.
  • Daunomycin has also been attached to polymeric carriers to form amino sugar daunosamine. (Shih et. al, 1991, Cancer Res. 51: 4192). Polymers like poly[N-2 hydroxypropyl) methacrylamide] containing hydroxyl groups activated by BrCN have been used to bind insulin (Sung Wan Kim et al in Polymeric Drug Delivery Systems, Drug Design, Volume X, Academic Press, 1980). Activated 4-alkylthioderivatives of cyclophosphamide bound to DIVEMA (divinyl ether and maleic anhydride) copolymer via the anhydride groups are reported (Hirano et. al., Cancer Res. 40:2263, 1980).
  • Oligopeptide sequences can be incorporated into N-(2-hydroxypropyl) methacrylamide copolymers, which have been reported to serve as potential drug attachment/ release sites.
  • Progesterone has been conjugated with aliphatic polyesters such as poly-( ⁇ -Caprolactone), poly[ ⁇ -(+,-)-Calactone], polypivalolactone and poly -(+,-)- dilactide through an ester linkage [Biomed. Mater. Res., Pitt et al, 1979, 13, 491; "Polymer conjugates with Anticancer Activity", Advances in Polymer Science, D Putnam et al, 1995, Vol. 122, page 55 - 123, Springer Verlag Berlin].
  • US Patent No. 5976527 describes conjugates of proteins such as albumin, immunoglobulms, blood clotting factors and peptide hormones with polymethylmethacrylate or polymethacrylamide comprising reactive oxirane groups, which after immobilisation are used for interaction with biological systems. These conjugates on administration, under physiological pH and influence of enzymes, are cleaved/ hydrolysed at the point of attachment of the polymer to the biologically active agent to release the drug in the original chemical form.
  • R 6 H or CH 3
  • X -OCOCH 2 COO-, — ⁇ — or - CONHCH 2 NHCO-
  • R 7 H
  • each of R 1 , R 2 , R 3 , R 4 , R 5 H, C ⁇ - ⁇ 2 alkyl, C 6 - ⁇ 2 (un) substituted aryl, Cj. 8 alkoxy, C 6 . n aryloxy, C1.5 alkoxy carbonyl, C 6 - ⁇ 2 aryloxy carbonyl, C 1 . 5 alkoxy alkyl, C 6 - ⁇ 2 alkoxyaryl, Ci.
  • polymeric benzimidazoles of the Formula I are formed by condensing an antiulcer benzimidazole and a biocompatible partially orally biodegradable synthetic crosslinked polymer of the Formula III:
  • cleavage of the polymeric benzimidazole takes place in the gastrointestinal fluid under the influence of enzymes/ chemicals, at the hydrolysable group "E” to release N-substituted benzimidazole derivatives (the benzimidazole along with a part of the polymer), which are acid stable.
  • Another object of the invention is to provide chemoenzymatically hydrolysable biologically active compounds capable of undergoing rapid chemoenzymatic hydrolysis to release hydroxy alkyl derivatives thereof showing high polarity.
  • Another object of the invention is to provide chemoenzymatically hydrolysable biologically active compounds capable of undergoing rapid chemoenzymatic hydrolysis to release hydroxy alkyl derivatives thereof showing high optical purity.
  • Another object of the invention is to provide chemoenzymatically hydrolysable biologically active compounds capable of undergoing rapid chemoenzymatic hydrolysis to release hydroxy alkyl derivatives thereof showing improved bioavailability and bio-efficacy and reduced side effects.
  • Another object of the invention is to provide a process for the preparation of chemoenzymatically hydrolysable biologically active compounds capable of undergoing rapid chemoenzymatic hydrolysis to release hydroxy alkyl derivatives thereof.
  • Another object of the invention is to provide a process for the preparation of chemoenzymatically hydrolysable biologically active compounds capable of undergoing rapid chemoenzymatic hydrolysis to release hydroxy alkyl derivatives thereof showing improved lipophilicity.
  • Another object of the invention is to provide a process for the preparation of chemoenzymatically hydrolysable biologically active compounds capable of undergoing rapid chemoenzymatic hydrolysis to release hydroxy alkyl derivatives thereof showing high polarity.
  • Another object of the invention is to provide a process for the preparation of chemoenzymatically hydrolysable biologically active compounds capable of undergoing rapid chemoenzymatic hydrolysis to release hydroxy alkyl derivatives thereof showing high optical purity.
  • Another object of the invention is to provide a process for the preparation of chemoenzymatically hydrolysable biologically active compounds capable of undergoing rapid chemoenzymatic hydrolysis to release hydroxy alkyl derivatives thereof showing improved bioavailability and bioefficacy and reduced side effects.
  • R 1 H or CH 3
  • R 2 H, C ⁇ _ 8 alkyl or C 6 - ⁇ 2 aryl
  • D Biologically active agent having functional groups such as
  • X represents a cross linking group such as C— O— CH 2 CH 2 -0— C , H 4 — or CONHCH 2 NHCC which is optional o o
  • R 3 epoxy or aziridine
  • R ! H or CH 3
  • R 2 H, C ⁇ _ 8 alkyl or C 6 - ⁇ 2 aryl
  • D Biologically active agent having functional groups such as
  • X represents a cross linking group such as which is optional C— O— CH 2 CH 2 -0— C j C 6 H 4 — or CONHCH 2 NHCC
  • R 1 H or CH 3
  • R 2 H, d. 8 alkyl or C 6 _ ⁇ 2 aryl
  • X represents a cross linking group such as C— O— CH 2 CH 2 -0— C , C 6 H 4 — or CONHCH 2 NHCO which is optional
  • R 3 CI, Br, I, F, OTs, OMs, p-nitrobenzene sulphonate, OSO 2 CF 3 , OH, NH 2 , NHR 5
  • R 1 is CH 3
  • R 2 is H and R 3 is I or OT s and R 4 is COOH
  • R 1 is CH 3 and R 2 is H and R 4 is COOH.
  • the biologically active agents may be antibacterial such as, Ciprofloxacin; antiamoebic such as secnidazole; antifungal such as fluconazole or 2-mercaptobenzothiazole; antithelmintic such as albendazole; antitubercular such as ethambutol; anti-inflammatory such as mefenamic acid; anti-ulcer such as omeprazole; antiosteoporotic such as alendronate; respiratory drugs such as albuterol, astemizole, ephedrine, Montelukast, pseudoephedrine, terbutaline, fenoterol, salmeterol; antidiabetic such as metformin, Pioglitazone, rosiglitazone, troglitazone, glipizide, glimepiride, tolbutamide, gliclazide; anticoagulant such as warfarin, antimigraine such as sumatriptane, CNS drugs such as amphetamine
  • the compounds of the Formula VI may be isolated by solvent extraction and identified by LCMS (Liquid Chromatography Mass Spectra) analysis.
  • the condensation may be preferably carried out at 40 - 80°C and pH 4 to 9.
  • the biologically active compound may be dried at 25 - 50°C.
  • the polar solvent may be water, alcohol such as methanol, isopropyl alcohol or mixtures thereof preferably water or water : methanol or water : isopropyl alcohol.
  • the reactive polymers of the Formula IV have been described in our Patent Application No. 962/MUM/2002.
  • the biologically active compounds i.e. the conjugates of the invention are unreported and novel. They comprise a side chain having a hydrolysable ester group viz., -COO- attached to the polymeric backbone thereof through a spacer or linkage L. Because of the spacer the compounds of the invention have reduced steric hinderance and are capable of undergoing rapid enzymatic hydrolysis. On being chemoenzymatically hydrolysed/ cleaved at the hydrolysable group viz. -COO- group, the compounds of the invention release hydroxyalkyl derivatives thereof i.e. chemically modified biologically active compounds represented by the Formula VII.
  • the hydroxyalkyl derivatives of the biologically active compounds are capable of stereo selective hydrolysis to form optically pure isomers thereof. Because the hydroxyalkyl derivatives of the biologically active compounds are optically pure and highly lipophilic, their bioavailability and bioefficacy are improved. Due to the improved bioavailability and bioefficacy, the hydroxyalkyl derivatives of the biologically active compounds are effective at low doses thereby correspondingly reducing the side effects.
  • Step 1 45 gm of 2-(paratoluenesulphonyl) ethyl Methacrylate (prepared as per methods known in the art), 5 gm of acrylic acid and 0.6 gm of benzoyl peroxide were mixed together and added to 200 ml of ethyl acetate + Acetone (1 :1) mixture. The reaction mass was agitated at 80 rpm and refluxed for 4 hours under inert conditions. The material obtained was cooled and stirred in 200 ml of ethyl acetate + acetone (1:1) mixture for one hour. The product was filtered and dried at 50°C for 12 hours (Yield : 51 gm) to obtain polymer of the Formula VIII :
  • Step 2 Preparation of substituted pseudoephedrine 10 gm of the above reactive polymer of Formula VIII was mixed with 5 gm of pseudoephedrine hydrochloride dissolved in a solvent system of methanol + water ( 1: 1) at pH 9.5. The reaction mixture was refluxed for 36 hours. The product was washed with water (100 ml x 5) till free from pseudoephedrine and then dried under vacuum at 50°C for 12 hours to obtain 16.0 gm of polymer-substituted pseudoephedrine of the Formula IX.
  • Step 1 The copolymer was prepared in the same way as in example 1 (Step 1), except that 45 gm of 2-chloro ethyl acrylate was used in place of 2-(paratoluenesulphonyl) ethyl methacrylate and 1 g of ethylene glycol dimethacrylate was also added. 35 g of polymer of Formula X was obtained.
  • Step 1 The copolymer was prepared in the same way as in example 1 (Step 1), except that 45 gm of 3-iodopropyl Methacrylate was used in place of 2-(paratoluenesulphonyl) ethyl methacrylate and 1 g of ethylene glycol dimethacrylate was also added. 37 g of polymer of Formula XII was obtained
  • Step 1 (a) The copolymer was prepared in the same way as Example 1 (step 1), except that 45 g of 3-[Epoxy-(2-methacrylate)]-l-[n-butoxy-(4-glycidylether)]-2-propanol (prepared as per methods known in the art) was used in place of 2-(paratoluenesulphonyl) ethyl methacrylate. 46 g polymer of Formula XIV was obtained.
  • Step 1 The copolymer was prepared in the same way as in Example 1 (Step 1), except that 45 gm of 2-(methanesulphonyl) ethyl methacrylate (prepared as per methods known in the art) was used in place of 2-(paratoluenesulphonyl) ethyl methacrylate. 43 gm of the polymer of the Formula XVI was obtained.
  • mice or rats forced to swim in a restricted space from which they cannot escape are induced to characteristic behaviour of immobility. This behaviour reflects a state of despair, which can be reduced by several agents, which are therapeutically effective in human depression.
  • mice Swiss albino mice of either sex weighing about 30 - 40 g were used. They were brought to the laboratory and acclimatized for 7 days. Mice were individually forced to swim inside a vertical Plexiglas cylinder; mice placed in cylinders for the first time were initially highly active, after 2 - 3 min activity began to subside and phases of immobility or floating increased. Mice were immobilized approximately for 80% of the time. They were again placed in the cylinder 24 hr later and total duration of immobility was measured during a 5 min test. Floating behaviour during this 5 min period has been found to be reproducible in different groups of mice. An animal was judged to be immobile whenever it remains floating passively in water. The drugs were administered one hour prior to testing. Evaluation
  • N 6 *P ⁇ 0.05 significant as compared to control
  • Standard drug fluoxetine and test drug Compound of formula XIII showed less immobility time (sec) when compared to control group.
  • Standard drug fluoxetine and test compound Compound of formula XIII showed significant antidepressant activity when compared to control group.
  • Weight of animals 300 to 350gms.
  • Aerosol chamber with 2 compartments and with a central spout for introduction of atomized histamine.
  • Drugs Histamine, Test and standard drug.
  • Ischemia of kidneys causes elevation of blood pressure by activation of renin-angiotensin system.
  • This principle can be used for inducing acute renal hypertension by clamping the left renal artery.
  • the protease renin catalyses the first and rate limiting step in the formation of angiotensin-II leading to acute hypertension. This test was used to evaluate antihypertensive activities of drugs.
  • the skin incisions were closed by wound clips. Four to five weeks after clipping, the blood pressure was measured and rats with higher than 150 mm Hg selected for the experiments.
  • Blood pressure reading was taken at 1, 2, 3 and 4 hrs after drug treatment.
  • Group I received 25mg/kg of compound of Formula XV
  • Group II received 0.9 mg/kg of Amlodipine (Manufactured by Kopran Ltd.)
  • Group III were the hypertensive controls
  • Inhibition of microbial growth under standardized conditions may be utilized for demonstrating the therapeutic efficacy of antibiotics.
  • the microbiological assay is based upon the comparison of inhibition of growth of microorganisms by measured concentration of antibiotics to be examined with that produced by known concentration of the antibiotic having known activity. For such screening cylinder plate (or cup-plate) method and turbidimetric (or tube assay) methods are used.
  • 0.1 ml of standardized inoculum of Asp. niger was plated on to muller hinter agar plate, using surface spread method. Cups upto 8 mm in diameter were bored in the inoculated agar with a sterile borer. In one plate 3 cups were made for application of standard solution of 2- mercaptobenzothiazole, compound of Formula XI and DMF as a control respectively, of the same concentration. After application of above mentioned solution to the plate, plates were kept in a refrigerator for prediffusion of compound, for 1 hr. Plates were removed from the refrigerator after an hour and incubated for 3 days at 30°C. Results were noted after 24 hrs, 48 hrs and 72 hrs.
  • Parathyroid Hormone increases plasma calcium by stimulating bone reso ⁇ tion mediated through osteoclastic activity and reabsorption of calcium by the kidney. Hypercalcemia induced by PTH were reduced by drug like alendronate, so this model is used to test the antiosteoporotic activity of the test compound.
  • PTH was administered (30 ⁇ g/kg) orally to 7 weeks old male rats. At 5 th day, first dose of standard and test drug was administered. Blood was collected from fundus oculi at 1, 2, 3, 4, 6 and 9 days after the single dose of drugs. The results were analysed statistically using student's c t' test.
  • Plasma calcium was significantly increased above normal by intravenous injection of bPTH.
  • Animals Adult guinea pigs of either sex.
  • Weight of animals 300 to 350gms.
  • Aerosol chamber with 2 compartments and with a central spout for introduction of atomized Histamine.
  • Drugs Histamine, Test and standard drug.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés actifs sur le plan biologique hydrolysables chimio-enzymatiquement représentés par la formule (VI). L'invention concerne également des sels d'addition acide acceptables sur le plan pharmaceutique, ainsi que des énantiomères de ces composés. L'invention concerne enfin un procédé de préparation de composés représentés par la formule (VI) consistant à condenser un agent actif sur le plan biologique possédant des groupes fonctionnels tels que (1) avec un polymère réactif représenté par la formule (IV) dans un solvant polaire à une température comprise entre 20 et 90 °C et un pH compris entre 2 et 10.
PCT/IN2003/000354 2002-11-05 2003-11-04 Composes actifs sur le plan biologique hydrolysables chimio-enzymatiquement Ceased WO2004041923A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003300696A AU2003300696A1 (en) 2002-11-05 2003-11-04 Chemoenzymatically hydrolysable biologically active compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN963/MUM/2002 2002-11-05
IN963MU2002 2002-11-05

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WO2004041923A2 true WO2004041923A2 (fr) 2004-05-21
WO2004041923A3 WO2004041923A3 (fr) 2004-08-12

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006116583A3 (fr) * 2005-04-26 2006-12-14 Univ Missouri Compositions comprenant un benzimidazole polymerise et un tampon et procedes permettant de les utiliser

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062248A1 (fr) * 2000-02-24 2001-08-30 Kopran Research Laboratories Limited Derives de benzimidazole antiulcereux a acidite stable administrables oralement

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006116583A3 (fr) * 2005-04-26 2006-12-14 Univ Missouri Compositions comprenant un benzimidazole polymerise et un tampon et procedes permettant de les utiliser

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Publication number Publication date
AU2003300696A1 (en) 2004-06-07
AU2003300696A8 (en) 2004-06-07
WO2004041923A3 (fr) 2004-08-12

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