WO2005105153A1 - Derives d'hydroxyalkyle de composes biologiquement actifs - Google Patents

Derives d'hydroxyalkyle de composes biologiquement actifs Download PDF

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Publication number
WO2005105153A1
WO2005105153A1 PCT/IN2004/000124 IN2004000124W WO2005105153A1 WO 2005105153 A1 WO2005105153 A1 WO 2005105153A1 IN 2004000124 W IN2004000124 W IN 2004000124W WO 2005105153 A1 WO2005105153 A1 WO 2005105153A1
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WO
WIPO (PCT)
Prior art keywords
formula
biologically active
alkyl
active compounds
hydroxyalkyl
Prior art date
Application number
PCT/IN2004/000124
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English (en)
Inventor
Jayant Venkatesh Deshpande
Vaishali Madhukar Kadam
Vandana Sandeep Gupte
Kamlesh Jayantilal Ranbhan
Original Assignee
Kopran Research Laboratories Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kopran Research Laboratories Limited filed Critical Kopran Research Laboratories Limited
Priority to EP04821934A priority Critical patent/EP1744785A1/fr
Priority to PCT/IN2004/000124 priority patent/WO2005105153A1/fr
Publication of WO2005105153A1 publication Critical patent/WO2005105153A1/fr

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Classifications

    • 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
    • A61K47/54—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 compound

Definitions

  • This invention relates to hydroxyalkyl derivatives of biologically active compounds
  • This invention also relates to a process for the synthesis of the hydroxyalkyl derivatives of the 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).
  • Anion-binding hydrophilic epichlorohydrin and l-(3- aminopropyl) imidazole copolymeric bile acid sequestrant and its pharmaceutical compositions are reported for use in the treatment of various ailments like diarrhoea, constipation, dumping syndrome or irritable bowel syndrome (US Patent No 5900233).
  • Polymer analogues of cis- dichlorodiamine platinum are also reported for use as antineoplastic agents ["Organometallic polymers as drugs and drug delivery systems" by Gebelein C. G, Koblitz F. K., Biomedical and Dental Applications of polymers, New York, Plenum Press 1981, p 215].
  • PCT Publication No WO 99/63940 discusses low molecular weight polymeric derivatives of benzimidazoles as antiulcer agents.
  • the molecular weight of such polymer is generally in the range of 1000 - 10000.
  • Such polymeric drugs get absorbed from the gastro intestinal tract and elicit systemic activity.
  • Biologically active agents substituted with polymers are also administered as prodrugs.
  • US Patent No 5372807 describes an intravenous Formulation comprising an antifibrotic agent linked to a cis-4-hydroxyl-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 polyscchri.de and an unoxidised, oxidation-sensitive substance, conjugated via amine or imine bonds.
  • US Patent No 4587046 describes biologically active drug such a 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.
  • US Patent No 6254854 describes 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. These biodegradable particles are formed of a functionalized polyester graft copolymer consisting of a ⁇ -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-alkylthioderivaties of cyclophosphamide bound to DINEMA (divinyl ether and maleic anhydride) copolymer via the anhydride groups are reported (Hirano et al, 1980, Cancer Res., 40 : 2263).
  • 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 4587046 describes covalent conjugation of naturally occurring catecholamines and autocoid moieties with monodisperse amino acid polymers or peptides having an alkyl group through ester/amide linkages.
  • US Patent No 5783178 describes conjugation of vinca alkaloids, mitornycins, bleomycins, fluconazole, amphotericm B, paclitaxel derivatives, cytokines, erythroprotein, or polynucleotides with block copolymer of ethyleneoxy monomer or a mixture of ethyleneoxy and the -OCH(CH 3 )CH 2 -monomers through bifunctional linking group.
  • US Patent No 5037883 describes conjugate of anticancer daunomycin with copolymer of N-(2-hydroxypropyl) acrylamide, N-methacrylamide, N-methacryiic acid and /or N-methacryloylated amino acid through peptide group.
  • US Patent No 5976527 describes conjugates of proteins such as albumin, immunoglobulins, blood clotting factors and peptide hormones with polymethylmethacrylate or polymethacrylamide comprising reactive oxirane groups, which after immobilization are used for interaction with biological systems. These compounds on administration , under physiological pH and influence of enzymes, are hydrolysed/cleaved at the point of attachment of the polymer to the drug to release the drug in its original chemical form.
  • R 6 H or CH 3
  • X -OCOCH 2 COO-, — > ⁇ or - CONHCH-NHCO-
  • R 7 H
  • R 1 , R 2 , R 3 , R 4 , R 5 H, C].] alkyl, C 6 - ⁇ 2 (un)substituted aryl, Ci-g alkoxy, C 6 _ ⁇ aryloxy, C ⁇ - 5 alkoxy carbonyl, C 6 - ⁇ aryloxy carbonyl, C ⁇ _ 5 alkoxy alkyl, C 6 _ ⁇ 2 alkoxyaryl, C 1 . 5 haloalkyl, C 1 .
  • polymeric benzimidazole of the Formula I are formed by condensing an antiulcer benzimidazole and a biocompatible partially orally biodegradable synthetic polymer of the Formula HI
  • 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 which is optional — C— O— CH 2 CH 2 -0— C — j — c 6 H 4 — or — CONHCH 2 NHCO — O o
  • L spacer comprising (un) substituted alkyl, hydroxyalkyl or alkoxy alkyl with the condition that the carbon chain length contains 2 to 6 carbon atoms when
  • the biologically active compounds when chemoenzymatically hydrolysed/ cleaved at the hydrolysable ester group viz. -COO- thereof, release hydroxyalkyl derivatives thereof i.e. chemically modified biologically active compounds represented by the Formula NIL
  • L spacer comprising (un)substituted alkyl, hydroxyalkyl or alkoxy alkyl with the condition that the carbon chain length contains 2 to 6 carbon atoms when
  • An object of the invention is to provide hydroxyalkyl derivatives of biologically active compounds represented by the formula N ⁇ which have improved lipophilicity.
  • Another object of the invention is to provide hydroxyalkyl derivatives of biologically active compounds represented by the formula N ⁇ , which are polar.
  • Another object of the invention is to provide hydroxyalkyl derivatives of biologically active compounds represented by the formula VLI, which have improved bioavailabihty and bioefficacy and reduced side effects.
  • Another object of the invention is to provide a process for the synthesis of hydroxyalkyl derivatives of biologically active compounds represented by the formula Nil, which have improved lipophilicity.
  • Another object of the invention is to provide a process for the synthesis of hydroxyalkyl derivatives of biologically active compounds represented by the formula NH, which are polar.
  • Another object of the invention is to provide a process for the synthesis of hydroxyalkyl derivatives of biologically active compounds represented by the formula N ⁇ , which have improved bioavailabihty and bioefficacy and reduced side effects.
  • hydroxyalkyl derivatives of biologically active compounds represented by the formula NH R2 I HO— L— Z'— D
  • L spacer comprising (un)substituted alkyl, hydroxyalkyl or alkoxy alkyl with the condition that the carbon chain length contains 2 to 6 carbon atoms when
  • 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 alkali used may be sodium hydride, triethylamine or ammonia solution or potassium carbonate, preferably potassium carbonate or triethylamine.
  • the condensation is preferably carried out at 30 - 50°C.
  • the organic solvent may be tetrahydrofuran, dichloro methane, methanol or methylene chloride, preferably methanol methylene chloride or tetrahydrofuran.
  • Evaporation of the solvent may be carried out under vacuum.
  • the hydroxyalkyl derivatives of the biologically active compounds of the invention are novel. They are highly lipophilic due to the presence of the spacer or linkage group viz. L. Because of the high lipophilicity they show improved absorption and hence high bioefficacy. Because of the high absorption and bio-efficacy, the compounds of the invention are effective at low doses and have correspondingly reduced side effects.
  • the compounds of the invention are also polar due to the presence of hydroxyl group(s). Because of the high polarity, they show better ionization and absorption.
  • Exposure of spasmogen like Acetylcholine chloride or Histamine causes contraction of bronchial smooth muscle. This method permits the evaluation of bronchodilator drugs by measuring time required to produce convulsion after exposure to spasmogens.
  • 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 drugs.
  • ANTI FUNGAL ACTIVITY Principle 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.
  • 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.
  • Drugs Dose (mg/kg) 1.
  • Compound of formula XIH 42mg/kg 2.
  • Fluoxetine (Standard) 20mg/kg 3.
  • Synthetic compound of formula XX 20 mg/kg
  • 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.
  • Standard drug fluoxetine and test drugs showed less immobility time (sec) when compared to control group.
  • 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-H 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.
  • the animals were divided into 4 groups.
  • Group II received 0.9 mg/kg of Amlodipine (Manufactured by Kopran Ltd.)
  • Parathyroid Hormone increases plasma calcium by stimulating bone resorption 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.
  • Plasma calcium was significantly increased above normal by intravenous injection of bPTH.
  • the plasma calcium level of bPTH injected animals was increased above the normal range at each time point.
  • Standard drug alendronate and the test drugs reduce the increment of plasma calcium level induced by bPTH.

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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)

Abstract

L'invention concerne des dérivés d'hydroxyalkyle de composés biologiquement actifs représentés par la formule (VII) dans laquelle R2 = H, alkyle CI-12, aryle C6-12, ou -OH et D = un agent biologiquement actif possédant des groupes fonctionnels tels que représentés par les formules (a) et (b) (Z'), L = espaceur comprenant alkyle, hydroxyalkyle ou alcoxy alkyle (non) substitués à condition que la chaîne de carbone contienne de 2 à 6 atomes de carbone lorsque Z' = formule (c), ainsi que des sels d'addition acides et des énantiomères pharmaceutiquement acceptables de ceux-ci. L'invention concerne également un procédé pour la synthèse de composés de formule (VII) ainsi que des sels d'addition acides et des énantiomères de ceux-ci pharmaceutiquement acceptables. Ce procédé consiste en la condensation des agents biologiquement actifs possédant des groupes fonctionnels tels que représentés par la formule (d) avec des dérivés d'alkyle substitués dans des conditions alcalines, à 20 - 80 °C, dans un solvant organique.
PCT/IN2004/000124 2004-04-30 2004-04-30 Derives d'hydroxyalkyle de composes biologiquement actifs WO2005105153A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP04821934A EP1744785A1 (fr) 2004-04-30 2004-04-30 Derives d'hydroxyalkyle de composes biologiquement actifs
PCT/IN2004/000124 WO2005105153A1 (fr) 2004-04-30 2004-04-30 Derives d'hydroxyalkyle de composes biologiquement actifs

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000124 WO2005105153A1 (fr) 2004-04-30 2004-04-30 Derives d'hydroxyalkyle de composes biologiquement actifs

Publications (1)

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WO2005105153A1 true WO2005105153A1 (fr) 2005-11-10

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EP (1) EP1744785A1 (fr)
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048572A1 (fr) * 1999-02-18 2000-08-24 Supergen, Inc Derives de promedicament lies a la phosphocholine
WO2001064690A1 (fr) * 2000-02-28 2001-09-07 Pharmacia Corporation Promedicaments gastro-specifiques
WO2003051113A1 (fr) * 2001-12-14 2003-06-26 The University Of Wyoming Methodes et compositions de liberation controlee de medicaments
WO2003055864A1 (fr) * 2001-12-31 2003-07-10 Hans Rudolf Pfaendler Substituants d'alcool gras a chaine longue dans des agents antineoplasiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048572A1 (fr) * 1999-02-18 2000-08-24 Supergen, Inc Derives de promedicament lies a la phosphocholine
WO2001064690A1 (fr) * 2000-02-28 2001-09-07 Pharmacia Corporation Promedicaments gastro-specifiques
WO2003051113A1 (fr) * 2001-12-14 2003-06-26 The University Of Wyoming Methodes et compositions de liberation controlee de medicaments
WO2003055864A1 (fr) * 2001-12-31 2003-07-10 Hans Rudolf Pfaendler Substituants d'alcool gras a chaine longue dans des agents antineoplasiques

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EP1744785A1 (fr) 2007-01-24

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