WO2002008235A1 - Agent pharmaceutique destine a etre administre par voie orale, contenant des esters d'acide aminopropylphosphonique en tant qu'agent actif - Google Patents

Agent pharmaceutique destine a etre administre par voie orale, contenant des esters d'acide aminopropylphosphonique en tant qu'agent actif Download PDF

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Publication number
WO2002008235A1
WO2002008235A1 PCT/EP2001/008270 EP0108270W WO0208235A1 WO 2002008235 A1 WO2002008235 A1 WO 2002008235A1 EP 0108270 W EP0108270 W EP 0108270W WO 0208235 A1 WO0208235 A1 WO 0208235A1
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group
ester
groups
bis
alkyl
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PCT/EP2001/008270
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German (de)
English (en)
Inventor
Hassan Jomaa
Martin Schlitzer
Jochen Wiesner
Erhard Dreisiedler
Armin Reichenberg
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Jomaa Pharmaka Gmbh
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Priority to AU2001276410A priority Critical patent/AU2001276410A1/en
Publication of WO2002008235A1 publication Critical patent/WO2002008235A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4084—Esters with hydroxyaryl compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4075—Esters with hydroxyalkyl compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Drugs for oral administration containing aminopropylphosphonic acid esters as an active ingredient
  • the drugs aminopropylphosphonic acids such as 3-N-formylhydroxylaminopropylphosphonic acid (fosmidomycin) and 3-N-acetylhydroxylaminopropylphosphonic acid (FR900098), which have highly polar functional groups, have an insufficient absorption from the gastrointestinal tract. This complicates or prevents the oral application of these substances.
  • this route of administration is preferable to parenteral administration in all cases where the patient's condition permits. This is particularly the case with malaria therapeutics, which are mainly used in regions with a poorly developed health system.
  • esters have already been described as prodrugs [Crisis, JP, Stella, VJ Advanced Drug Delicious Reviews 1996, 19, 287-310., Freeman, S., Ross, KC Progress in Medicinal Chemistry 1997, 34, 112- 147]. Inadequate release rates of the active form were frequently observed in simple alkyl esters and in benzyl esters. In general, the structure of the active ingredient has a great influence on the properties of the ester prodrug, so that the usefulness of individual esters can hardly be predicted. The suitability of the various conceivable esters can ultimately only be assessed by the presentation of the corresponding compounds and their investigation.
  • the object of the present invention is therefore the development of so-called "prodrugs", which are derivatives of the active ingredient in which the polar partial structures are temporarily blocked by chemical modification.
  • the aim of the development of these prodrugs must be to find esters which are stable on the one hand it is enough to survive the time in the gastrointestinal tract, with its sometimes extreme pH conditions, until it passes into the blood without any noteworthy cleavage.On the other hand, these esters must be such that they are as complete as possible in the plasma or at the latest in the target cell can be cleaved by the enzymes that occur there, since the polar structures to be labeled are generally essential for their effectiveness, and the ester functions must also be selected so that no toxic cleavage products are formed.
  • R 1 and R 2 are selected independently of one another from the group consisting of hydrogen and -CC alkyl groups
  • R 3 is selected from the group consisting of phenyl esters and R 5 -YR 6
  • R4. is selected from the group consisting of phenyl ester and R 7 -XR 8 , where X and Y are independently selected from the group consisting of sulfur and oxygen
  • R 7 and R 5 are independently selected from the group consisting of consists of C 1-9 alkylene groups and Co -9- alkyl-ar-Co- -alkylene groups
  • R 6 and Rg are independently selected from the group consisting of C 1-9 alkyl groups and Ar- C 1-9 -Alkyl phenomenon exists, wherein each alkyl or alkylene group in R 5 , R 6 , R 7 and R 8 can be substituted with oxo groups and phenyl groups and each aryl or phenyl group with -C -9 alkyl groups, C 1- alkoxy groups
  • R 3 and t together form an alkylene group with 1 to 5 carbon atoms, which connects the two ester-forming oxygen atoms of the phosphorus group with one another, so that a ring is formed
  • the alkylene chain having C 1-9 alkyl groups, C 1-9 alkoxy groups, C 1-9 - Acyl groups and -C -9 -acyloxy groups can be substituted, each alkyl, alkylene, allcoxy and acyl group being branched or unbranched, are excellent prodrugs, since they release the hydroxylaminopropylphosphonic acids well at the desired destination.
  • orally administrable pharmaceutical forms are tablets, dragées, capsules, pills and granules.
  • the medicament preferably contains at least one compound of the formula (II)
  • Ri and R 2 are independently selected from the group consisting of hydrogen and C 1-9 alkyl groups
  • X and Y are independently selected from the group consisting of sulfur and oxygen, R 5 and R are independently selected from the group consisting of C 1-9 -
  • alkyl groups and Ar-C 1-9 alkyl groups where each alkyl group in R 5 , R 6 , R and R 8 can be substituted with oxo groups and phenyl groups and each aryl or phenyl group with C ⁇ - 9 alkyl groups, C ⁇ - 9 - Alkoxy groups, C ⁇
  • Alkylene, alkoxy and acyl group can be branched or unbranched.
  • Rt is preferably selected from the group consisting of hydrogen and methyl, and R 2 is preferably hydrogen.
  • a substituent selected from R and R 8 in the ⁇ -position to X is oxo-substituted and a substituent selected from R 5 and R 6 in the ⁇ -position to Y is oxo-substituted.
  • the two ester groups are preferably identical.
  • R 3 and j are preferably selected independently of one another from the group consisting of C 1-9 alkoxycarbonyl-C 1-9 alkyl groups, S C 1-9 acylthio-C 1-9 alkyl groups and S benzoylthio C ⁇ g-alkyl groups, wherein each alkyl, alkylene, and acyl group may be branched or unbranched and C ⁇ -9 -alkoxycarbonyl-C 1-9 -alkyl groups having a C 1-9 -Acyloxyphenyl distr may be substituted, or R 3 and t together form a cyclic ester in which the two ester-forming oxygen atoms are connected via an alkyl chain with 1 to 5 carbon atoms.
  • Example 9 4-hydroxycinnamic acid is formed as a secondary product, which is also used as a preservative in the food industry.
  • the compounds are prepared starting from the 3-bromopropylphosphonic acid diethyl ester known from the literature [Hewitt, DG, Teese, MW Aust. J. Chem. 1984, 37, 205.], which is converted in a manner known in principle via the free phosphonic acid into the phosphonic acid dichloride.
  • the corresponding 3-bromopropylphosphonic acid esters are obtained from this using the alcohols, which are either commercially available or prepared by processes known from the literature. These are known in principle with N, O-bis-Boc-hydroxylamine [Staszalc, MA, Doecke, CW Tetrahedron Lett. 1993, 34, 7043]. After acid-catalyzed removal of the protective groups and N-selective acylation, the target compounds are then obtained.
  • Examples 10-18 proceeds analogously in the first 5 stages. In the last stage, it is acylated with O-formyl acetate instead of acetyl chloride.
  • 3rd stage 3-bromopropylphosphonic acid bis (methoxycarbonylmethyl) ester
  • 3rd stage (S) -3-bromopropylphosphonic acid bis- [1 - (methoxycarbonyl) ethyl] ester analogous to Example 1, 3, stage from 3-bromopropylphosphonic dichloride (2.4 g, 10 mmol) and (S) - Lactic acid methyl ester (1.9 ml, 20 mmol).
  • 3rd stage 3-bromopropylphosphonic acid bis (4-methylphenyl) ester
  • 3rd stage 3-bromopropylphosphonic acid bis- (4-trifluoromethyl-phenyl) ester
  • 3rd stage 3-bromopropylphosphonic acid bis (4-methoxyphenyl) ester Analogously to Example 1, 3rd stage from 3-bromopropylphosphonic acid dichloride (3.60 g, 15 mmol) and 4-methoxyphenol (3.72 g, 30 mmol).
  • 6th stage 3 -N- acetylhydroxylaminopropylphosphonic acid bis (4-methoxyphenyl) ester analogous to Example 1, 6th stage from 3-hydroxylaminopropylphosphonic acid bis (4-methoxyphenyl) ester (1.47 g, 4 mmol) and acetyl chloride (0.36 ml, 5 mmol). Yield: 1.04 g (64%)
  • 3rd stage 3-bromopropylphosphonic acid bis- [2- (S-benzoylthio) ethyl] ester analogous to Example 1, 3rd stage from 3-bromopropylphosphonic dichloride (3.60 g, 15 mmol) and 2- (S-benzoylthio) ethanol Lefebve, L, Perigaud, C, Pompon, A., Aubertin, A.-M., Girard, J.-L., Kirn, A., Gosselin, G., Imbach, J.-LJ Med. Chem. 1995, 38, 3941-3950] (5.46 g, 30 mmol). Yield: 6.15 g (77%)
  • 3rd stage 3-bromopropylphosphonic acid bis- [2- (S-pivaloylthio) ethyl] ester
  • 6th stage 3 -N- acetylhydroxylaminopropylphosphonic acid bis- [2- (S-pivaloylthio) ethyl] ester analogous to Example 1, 6th stage from: 3-hydroxylaminopropylphosphonic acid bis- [2- (S-pivaloylthio) ethyl] ester (1.77 g, 4 mmol) and acetyl chloride (0.36 ml, 5 mmol). Yield: 1.05 g (54%)
  • 3rd stage 3-bromopropylphosphonic acid bis- [l - (4-acetyloxyphenyl) -3-ethoxy-3-oxopropyl] ester
  • Example 18 3 -N-Formyl-hydroxylamino-propylphosphonic acid bis- [1 - (4-acetyloxyphenyl) -3-ethoxy-3-oxopropyl] ester
  • mice were i.p. (intraperitoneal) injection of 5 x 107 infected erythrocytes infected by a donor mouse. On day 1, the success of the Giemsa-stained blood smear test was checked. The parasitemia was about 1%. Treatment was carried out on days 1 and 2 by p.o. (Peroral) application of 75 mg / kg of the prodrugs. In parallel, one group was treated with the same dose of FR900098. A third group remained untreated as a control. Parasitemia was determined at different times between days 4 and 11. The table shows the mean of the parasitemia of 3 mice.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les acides aminopropylphosphoniques servant d'agents pharmaceutiques, tels que l'acide 3-N-formylhydroxylaminopropylphosphonique (fosmidomycine) et l'acide 3-N-acétylhydroxylaminopropylphosphonique (FR900098) comportant des groupes fonctionnels très polaires, présentent un pouvoir de résorption insuffisant dans le tractus gastro-intestinal. En revanche, de nombreux esters de ces agents actifs se révèlent être des promédicaments adaptés, par exemple les composés de la formule (I) dans laquelle R1 et R2 sont choisis indépendamment dans le groupe constitué d'hydrogène et de C1-9-alkyle ; R3 est choisi dans le groupe constitué de phénylesters substitués et non substitués et de R5-Y-R6 ; et R4 est choisi dans le groupe constitué de phénylesters substitués et non substitués et de R7-Y-R8, X et Y étant choisis indépendamment dans le groupe constitué de soufre et d'oxygène, R7 et R5 étant choisis indépendamment dans le groupe constitué de groupes C1-9-alkylène et de groupes C0-9-alkyle-ar-C0-9-alkyle, et R6 et R8 étant choisis indépendamment dans le groupe constitué de groupes C1-9-alkylène et de groupes Ar-C1-9-alkylène, ou R3 et R4 formant ensemble un groupe alkylène portant 1 à 5 atomes de carbone, ce dernier groupe liant les deux atomes d'oxygène formant les esters, du groupe phosphore, de manière à former un cycle. Les compositions selon l'invention sont suffisamment stables pour résister à toute division notoire lors de leur séjour dans le tractus gastro-intestinal, mais peuvent être divisées largement dans la cellule cible.
PCT/EP2001/008270 2000-07-20 2001-07-18 Agent pharmaceutique destine a etre administre par voie orale, contenant des esters d'acide aminopropylphosphonique en tant qu'agent actif WO2002008235A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001276410A AU2001276410A1 (en) 2000-07-20 2001-07-18 Medicament for oral application, containing aminopropyl phosphonic acid esters as an active ingredient

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10035189.1 2000-07-20
DE10035189A DE10035189A1 (de) 2000-07-20 2000-07-20 Arzneimittel zur oralen Applikation mit einem Gehalt an 3-N-Formylhydroxylaminopropylphosphonsäureestern oder 3-N-Acetylhydroxylaminopropylphosphonsäureestern als Wirkstoff

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020008189A1 (fr) * 2018-07-04 2020-01-09 University College Cardiff Consultants Ltd Composés de type promédicament phosphoantigène
WO2024146629A1 (fr) * 2023-01-06 2024-07-11 北京清辉联诺生物科技有限责任公司 Modulateur pour favoriser la liaison de la butyrophiline 3a1/2a1

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2733658A1 (de) * 1976-07-27 1978-02-09 Fujisawa Pharmaceutical Co Hydroxylaminohydrocarbylphosphonsaeurederivate, verfahren zur herstellung derselben und diese enthaltende pharmazeutische mittel
WO1991019721A1 (fr) * 1990-06-13 1991-12-26 Arnold Glazier Promedicaments phosphoreux

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19843223A1 (de) * 1998-09-22 2000-03-30 Hassan Jomaa Phosphororganische Verbindungen und ihre Verwendung

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2733658A1 (de) * 1976-07-27 1978-02-09 Fujisawa Pharmaceutical Co Hydroxylaminohydrocarbylphosphonsaeurederivate, verfahren zur herstellung derselben und diese enthaltende pharmazeutische mittel
WO1991019721A1 (fr) * 1990-06-13 1991-12-26 Arnold Glazier Promedicaments phosphoreux

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020008189A1 (fr) * 2018-07-04 2020-01-09 University College Cardiff Consultants Ltd Composés de type promédicament phosphoantigène
JP2021529786A (ja) * 2018-07-04 2021-11-04 ユニバーシティ カレッジ カーディフ コンサルタンツ リミテッド ホスホ抗原プロドラッグ化合物
WO2024146629A1 (fr) * 2023-01-06 2024-07-11 北京清辉联诺生物科技有限责任公司 Modulateur pour favoriser la liaison de la butyrophiline 3a1/2a1

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