EP0293432A1 - Anhydride d'acides organiques et composition pharmaceutique sur une base promedicamenteuse - Google Patents

Anhydride d'acides organiques et composition pharmaceutique sur une base promedicamenteuse

Info

Publication number
EP0293432A1
EP0293432A1 EP88900014A EP88900014A EP0293432A1 EP 0293432 A1 EP0293432 A1 EP 0293432A1 EP 88900014 A EP88900014 A EP 88900014A EP 88900014 A EP88900014 A EP 88900014A EP 0293432 A1 EP0293432 A1 EP 0293432A1
Authority
EP
European Patent Office
Prior art keywords
organic acid
acid anhydride
alkyl
residue
activity
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.)
Withdrawn
Application number
EP88900014A
Other languages
German (de)
English (en)
Inventor
Frans Herwig Jan Jansen
Etienne Jacquy De Cock
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nv Gantax Pharmaceutica
Original Assignee
Nv Gantax Pharmaceutica
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 Nv Gantax Pharmaceutica filed Critical Nv Gantax Pharmaceutica
Publication of EP0293432A1 publication Critical patent/EP0293432A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms
    • C07C53/128—Acids containing more than four carbon atoms the carboxylic group being bound to a carbon atom bound to at least two other carbon atoms, e.g. neo-acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings

Definitions

  • This invention relates to new organic acid anhydrides and to a pharmaceutical composition on a prodrug base.
  • Prodrugs are compounds which do not exhibit a pharmacological activity by themselves, but which, when absorbed in the body, release the active compound in order to enable the latter to fulfil its therapeutical funtion.
  • Such prodrugs especially are of importance, on the one hand, to prevent the free active compound from undergoing a chemical alteration before reaching its destination in the body, this alteration resulting in the loss of activity, and on the other hand to modify the physico-chemical properties of the medicine in such a way as to enable in the body an appropriate and timely absorption as well as an appropriate and timely release of the medicine:
  • the present invention is directed to new organic acid anhydrides, characterized in that the organic acid anhydride is a mixed acid anhydride of formula 1
  • R 1 is the residue of an organic acid having anti-inflammatory, anti-epileptic, ACE-inhibiting, biocidal, cytostatic , diuretic, antidiarrheal or cerebrotonical activity, or of a steroid acid;
  • R 2 is different from R 1 and represents: either a group of formula 2
  • R 3 , R 4 and R 5 are the same or different and are hydrogen or a C 1 - 20 -alkyl or -alkenyl, cycloalkyl or -alkenyl, aryl, alkaryl, aralkyl group, optionally substituted by alkyl, aryl, alkoxy, aryloxy, alkoxycarbonyl or aryloxycarbonyl and optionally containing one or more heteroatoms; or a steroid fragment; or an amino acid or peptide moiety; and the pharmaceutically acceptable salts thereof.
  • These mixed acid anhydrides of formula 1 possess the for prodrugs particularly advantageous property that the hydrolysis of the mixed acid anhydride to the pharmacologically active compound is independent on the action of enzymes, thereby permitting the adjustment of the degree of hydrolyzability in vivo by selecting for a given R 1 -group a suitable R 2 -group.
  • Inherent to the anhydride form, into which the medicine is converted, is a decreased polarity and acidity and an increased lipophilicity. On the one hand, this reduces the irritation of the gastro-intestinal system in case of oral intake, while on the other hand the ability to be absorbed by the skin increases, such as with transdermal and transmucosal absorption of the mixed acid anhydride.
  • a prodrug can be obtained by proper selection of the mixed anhydrides, which prodrug, when absorbed in the body and hydrolysed to the pharmacologically active organic acid, exhibits the desired pharmacological activity, whereas the physico-chemical properties of the prodrug, such as the degree of hydrolyzability in water and body fluids, the lipophilicity, the taste, odour and colour, the mixability with additives and the processability, are systematically adjustable in dependence on the nature of the medicine, the administration route and the objective. In the pharmaceutical practice this leads to important advantages.
  • the degree of hydrolyzability can be adjusted by defining one or more of the R 3 , R 4 and R 5 groups in formula 2 as hydrogen atoms.
  • R 3 , R 4 and R 5 groups in formula 2 all represent hydrogen, the hydrolysis proceeds quickly. The more hydrogen atoms are replaced, the more the hydrolysis speed decreases.
  • the degree of lipophilicity is adjustable by selecting the chain length of one or more of the groups R 3 , R 4 and R 5 in a suitable manner.
  • the lipophilicity increases with increasing chain length.
  • R 2 By defining R 2 as a steroid fragment or a amino acid or peptide fragment, very specific properties can be obtained.
  • the R 2 group can perform a carrier function in order to transport the active organic acid through the cel membranes.
  • R 1 in formula 1 can be the residue of an organic acid having anti-inflammatory, anti-epileptical, ACE-inhibiting, biocidal, cytostatical, diuretical, anti- diarrhetic or cerebrotonical activity, or of a steroid acid.
  • residues R 1 of free organic acids having anti-inflammatory activity include: residues of tolmetin, zomepirac, tiaprofenic acid, sulindac, niflumi ⁇ acid, ibuprofen, mefenamic acid, ketoprofen, indometacin, flurbiprofen, fenoprofen, fenclofenac, naproxen, fenbufen, diclofenac, etodolac, cinmetacin, acetylsalicylic acid and penicillamine.
  • this recitation is not restrictive, and also other non-steroidal anti-inflammatory organic acid residues may be used.
  • R 1 the residues of ibuprofen, ketoprofen, flurbiprofen, diclofenac, naproxen, etodolac, sulindac and indometacin are particularly preferred.
  • residues of anti-epileptic organic acids are defined by the general formula 3, wherein R 6 and R 7 are the same or different and represent an aliphatic group.
  • R 1 is the residue of valproic acid, R 6 and R 7 in formula 3 both being n-propyl.
  • ACE-inhibiting activity used in the specification and claims stands for “angiotensin-converting enzyme-inhibiting activity”. This activity resides in the inhibition of the renin-angiotensin system and more particularly of the enzym which converts angiotensin. Compounds exhibiting such ACE-inhibiting activity possess anti-hypertensive properties.
  • residues of organic acids having ACE-inhibiting activity are defined by general formula 4 or 5, wherein R 8 is hydrogen, alkyl- or arylcarbonyl, R 9 is hydrogen, alkyl or aminoalkyl, R 10 is alkyl or a C 5-8 - cycloalkyl optionally substituted by alkyl or aryl, R 11 is alkyl or aryl, or R 10 and R 11 together may form a C 3-6 -alkylene or -alkenylene optionally substituted by alkyl or aryl, the C 3-6 -alkylene or -alkenylene optionally being part of a saturated or unsaturated quinoline or isoquinoline group, R 12 is hydrogen or alkyl, R 13 is hydrogen, alkyl or R 2 -C(O)- and R 14 is alkyl or aralkyl.
  • a favourable representative hereof is the residue having formula 4, wherein R 8 is tert-butylcarbonyl, R 9 is methyl, R 10 and R 11 together form a propylene group and R 12 is hydrogen.
  • This residue is the residue of captopril, in which the hydrogen atom of the thiol function is replaced by a tert-butylcarbonyl protecting group.
  • R 1 has formula 4, in which R 8 is tert-butylcarbonyl, R 9 is methyl, R 10 is cyclopentyl and R 11 and R 12 both are hydrogen.
  • This residue is the residue of pivopril in which the hydrogen atom of the thiol function Is replaced by a tert-butylcarbonyl protecting group.
  • R 1 have formula 5 in which R 9 is methyl of 4-arainobutyl, R 10 and R 11 together form a propylene group, R 12 is hydrogen, R 13 is R 2 -C(O)- and R 14 is phenylethyl.
  • Such anhydrides in which R 13 has the meaning of R 2 -C(O)- could be considered as the dianhydride of enalapril and lysinopril respectively.
  • R 13 is an ethyl group. In the latter case there exists an ester function which should be hydrolysed in vivo, resulting in the disadvantages mentioned-above.
  • R 1 residues of organic acids having biocidal activity the residues of pipemidinic acid, oxolinic acid, flumequin, nalidixic acid and cinoxacin can be mentioned, whereas the residues of oxolinic acid, flumequin and cinoxacin are preferred.
  • R 1 residues of organic acids having cytostatic activity include the residues of chlorambucil and of the free acid of vinblastin, the former being preferred.
  • residues of organic acids having diuretic activity include residues of tienilic acid, ethacrynic acid and furosemid, whereas the latter residue is preferred.
  • residues of organic acids having antidiarrheal activity the residues of the free acid of loperamide and of the free acid of diphenoxylate are mentioned.
  • the residue of the free acid of loperamide is particularly suitable in the present mixed acid anhydrides.
  • residues of organic acids having cerebrotonical activity include the residues of the free acid of piracetam and of the free acid of vincamine, the former residue being preferred.
  • residues of steroid acids are the residues of chenodiol, ursodeoxycholic acid and canrenoic acid.
  • the residue of ursodeoxycholic acid is especially preferred.
  • a special form of the mixed acid anhydrides results if both the R 1 as well as R 2 group represent a residue of a pharmacologically active organic acid. By hydrolysis in vivo of the mixed acid anhydride two active compounds are released, thereby permitting to combine the actions of two medicines. This offers various advantages above the conventional combination preparations, which contain two separate active compounds, optionally each in the form of a prodrug.
  • the preparation of the mixed acid anhydrides according to the invention is performed out on a manner known per se for analogous compounds.
  • problems could arise therein, when beside the anhydride function also free amine, alcohol Or thiol functions are present in the mixed anhydride.
  • Such free amine, alcohol and thiol functions often don't go together with anhydride functions and should therefore be masked by means of protecting groups.
  • Such protecting groups should be easily removable in vivo.
  • Primary and secondary amines could be protected by means of salt formation, preferably hydrochloride salt formation, or by substitution of the or each hydrogen atom of the amine group by a suitable protecting group.
  • the protection of alcohols may be performed by converting the alcohol function in a suitable protecting group.
  • the thiol function can be protected by substituting the hydrogen atom of the thiol group by an alkyl- or arylcarbonyl.
  • the mixed acid anhydrides of the invention may contain asymmetrical carbon atoms in both the R 1 and R 2 group. Accordingly, the mixed acid anhydrides may exist in a certain diastereoisomeric form or as a mixture of various diastereoisomeric forms.
  • racemates or diastereomeres can be used as starting materials for the preparation of the compounds according to the invention racemates or diastereomeres can be used.
  • the products having the desired diastereoisomeric form can be prepared by a specific asymmetrical synthesis.
  • these can be separated by conventional methods, such as chromatography or fractional crystallisation.
  • the amino acid moieties present in the mixed acid anhydrides are preferably in the S-configuration.
  • the present invention is directed to pharmaceutical compositions of the prodrug type, characterized in that these contain as prodrug a mixed anhydride or an pharmaceutically acceptable salt thereof according to the invention, in association with a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions possess the advantages which were mentioned for the mixed acid anhydride of the invention.
  • Such compositions could be applied topically on the required places, because the degree and manner of absorption could be influenced by selecting a suitable R 2 group for a certain R 1 group.
  • the composition could contain a smaller amount of prodrug, decreasing the costs of such a composition and resulting in a reduction of the volume of the composition.
  • compositions of the invention can also comprise physiologically acceptable carriers, vehicles, excipients, binders, preservatives, stabilizers, flavoring agents, penetration promoting agents and such.
  • compositions can be administered orally, anally, sublingually, parenterally. They could be formulated in tablets, dragees, capsules, gelules, suppositoria, aerosol preparations with an inert carrier gas, ointments. Especially the forms suitable for transdermal, transbuccal and oral administration are preferred.
  • the compositions according to the invention may contain penetration promoting agents, such as isopropylmyristate, lauracapram and such.
  • technical assisting means for example adhesive plasters and hypo- or hyperdermic pastilles are advisable. With the aid of such assisting means a time-controlable and more uniform release of the medicine in the blood stream may be obtained.
  • EXAMPLE III Anhydride of ibuprofen and cis-9-octadecenoic acid (oleic acid) Analogous to the method described in example I, 20 g of ibuprofen were reacted with oleolyl chloride, obtained from 27.5 g of oleic acid and thionyl chloride, to form 38 g of the anhydride of ibuprofen and oleic acid. This anhydride was purified by colomn chromatography over SiO 2 using chloroform as eluent.
  • IR spectrum IR (NaCl) : 3350, 3060, 2950, 2910, 1785, 1730,
  • IR spectrum IR (NaCl) : 3440, 3320, 3060, 3020, 2940, 2910,
  • Example I In an analogous manner as described in Example I 2.00 g of ibuprofen were reacted with 1.90 g of 4-toluic acid, chloride, giving 2.94 g (94%) of the title compound.
  • IR spectrum IR (NaCl): 3030, 3010, 2960, 2930, 2880, 1805, 1735, 1610, 1510, 1470, 1455, 1260, 1225, 1210,

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Sont décrits de nouveaux anhydrides d'acides organiques mélangés de formule générale (1) dans laquelle R1 est le résidu d'un acide organique ayant une activité anti-inflammatoire, anti-épileptique, inhibitrice de l'enzyme de conversion de l'angiotensine, biocidale, cytostatique, diurétique, antidiarrhéique ou cérébrotonique, ou bien d'un acide de stéroïde, et R2 est différent de R1 et représente un groupe carbone-hydrogène, un fragment de stéroïde ou bien une partie aminoacide ou peptidique, ainsi que leurs sels pharmaceutiquement acceptables. Ces composés sont utiles comme promédicaments. Sont également décrites des compositions pharmaceutiques contenant un tel anhydride.
EP88900014A 1986-10-31 1987-10-30 Anhydride d'acides organiques et composition pharmaceutique sur une base promedicamenteuse Withdrawn EP0293432A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL8602767 1986-10-31
NL8602767A NL8602767A (nl) 1986-10-31 1986-10-31 Organisch zuuranhydride, alsmede farmaceutisch preparaat op basis van een prodrug.

Publications (1)

Publication Number Publication Date
EP0293432A1 true EP0293432A1 (fr) 1988-12-07

Family

ID=19848767

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88900014A Withdrawn EP0293432A1 (fr) 1986-10-31 1987-10-30 Anhydride d'acides organiques et composition pharmaceutique sur une base promedicamenteuse

Country Status (5)

Country Link
EP (1) EP0293432A1 (fr)
JP (1) JPH01501625A (fr)
KR (1) KR880701546A (fr)
NL (1) NL8602767A (fr)
WO (1) WO1988003020A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2873018A1 (fr) * 2012-07-03 2014-01-09 Cellixbio Private Limited Compositions et methodes de traitement de la douleur moderee a aigue
KR101845203B1 (ko) 2017-09-22 2018-04-05 동아대학교 산학협력단 라우르산 유도체, 이의 제조방법 및 이를 포함하는 항암제

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3686183A (en) * 1969-03-24 1972-08-22 Syntex Corp Preparation of optical isomers of arylalkylacetic acids
YU34425B (en) * 1970-06-01 1979-07-10 Galenka Process for preparing 6-aminopenicillanic acid
GB1388265A (en) * 1971-03-12 1975-03-26 Glaxo Lab Ltd Preparation of antibiotic compounds
US4158012A (en) * 1978-06-19 1979-06-12 Syntex (U.S.A.) Inc. Steroid synthesis process using mixed anhydride
DE3206886A1 (de) * 1982-02-26 1983-10-27 Troponwerke GmbH & Co KG, 5000 Köln Verfahren zur herstellung von 1-(4-chlorbenzoyl)-5-methoxy-2-methyl-3- indolacetoxyessigsaeure
US4570017A (en) * 1983-01-18 1986-02-11 Shell Oil Company Preparation of optically-active (mixed) anhydrides and acids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8803020A1 *

Also Published As

Publication number Publication date
WO1988003020A1 (fr) 1988-05-05
JPH01501625A (ja) 1989-06-08
KR880701546A (ko) 1988-11-03
NL8602767A (nl) 1988-05-16

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