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WO1999033851A1 - Glycerophospho-ethanolamines a substitution n-heterocyclique - Google Patents

Glycerophospho-ethanolamines a substitution n-heterocyclique Download PDF

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Publication number
WO1999033851A1
WO1999033851A1 PCT/US1997/023729 US9723729W WO9933851A1 WO 1999033851 A1 WO1999033851 A1 WO 1999033851A1 US 9723729 W US9723729 W US 9723729W WO 9933851 A1 WO9933851 A1 WO 9933851A1
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WO
WIPO (PCT)
Prior art keywords
het
paf
glycerophosphoethanolamine
substituted
compounds
Prior art date
Application number
PCT/US1997/023729
Other languages
English (en)
Inventor
Haridasan K. Nair
Original Assignee
Clarion Pharmaceuticals, Inc.
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 Clarion Pharmaceuticals, Inc. filed Critical Clarion Pharmaceuticals, Inc.
Priority to JP2000526527A priority Critical patent/JP2001527085A/ja
Priority to PCT/US1997/023729 priority patent/WO1999033851A1/fr
Priority to AU62373/98A priority patent/AU6237398A/en
Priority to KR1020007007270A priority patent/KR20010033747A/ko
Publication of WO1999033851A1 publication Critical patent/WO1999033851A1/fr

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    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/6533—Six-membered rings
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6544—Six-membered rings
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring

Definitions

  • the present invention relates to novel, therapeutically active fatty alkyl and alkenyl ether glycerophospholipids bearing a defined heterocyclic (Het) substituent on the ethanolamine nitrogen, pharmaceutically acceptable salts of these compounds, methods of using these compounds and salts, and pharmaceutical compositions containing same.
  • Het heterocyclic
  • the compounds and salts of the invention have been discovered to possess anti-tumor, anti-psoriatic, anti-inflammatory, and anti-asthma activities.
  • 4,650,791 are synthetic intermediates wherein the substituents are as described in the preceding sentence herein except that there is a hydroxy1 group at the 3-position or hydroxy1 groups at both the 1-position and the 3-position of the glyceryl backbone.
  • Glycerophosphoethanolamines bearing a non-cyclic, substituted amino substituent in the 2- position and a lower C x . 5 alkyl ether substituent in the 1- position of the glyceryl backbone are disclosed in U.S. Patent No. 5,116,992.
  • novel fatty alkyl and alkenyl ether glycero- phosphoethanolamines of the invention which bear a defined heterocyclic (Het) substituent on the ethanolamine nitrogen, and the pharmaceutically acceptable salts thereof, also possess anti-tumor activity.
  • these novel fatty alkyl and alkenyl ether glycerophosphoethanolamines and salts have been discovered to also possess anti- psoriatic, anti-inflammatory, and anti-asthma activities.
  • the invention provides novel fatty alkyl and alkenyl ether glycerophosphoethanolamines bearing a defined heterocyclic (Het) substituent on the ethanolamine nitrogen and pharmaceutically acceptable salts of these compounds.
  • the invention further provides a method of treating a tumor in a mammal with such compounds which comprises administering to the mammal an anti-tumor effective amount of said glycerophosphoethanolamines or pharmaceutically acceptable salts thereof.
  • the invention further comprises a method of treating psoriasis which comprises administering to a mammal suffering therefrom anti- psoriatic effective amounts of said glycerophosphoethanolamines of the invention or pharmaceutically acceptable salts thereof.
  • the invention further provides a method of treating inflammation which comprises administering to a mammal suffering therefrom an anti-inflammatory effective amount of said glycerophosphoethanolamines of the invention or pharmaceutically acceptable salts thereof.
  • the invention further provides a method of treating a disease, such as asthma, associated with PAF which comprises administering to a mammal suffering therefrom a PAF-activity- inhibiting-effective amount of said glycerophosphoethanolamines of the invention or pharmaceutically acceptable salts thereof.
  • the invention further provides a pharmaceutical composition comprising an anti-tumor, anti-psoriatic, anti- inflammatory, or anti-PAF-activity effective amount of said glycerophosphoethanolamines of the invention or pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier.
  • Figure 1 is a graphical representation of results from an in vitro MDA-MB-231 cell inhibition assay of a compound of the invention, designated CPR 3005.
  • Figure 2 is a graphical representation of
  • Figure 3 is a graphical representation of results from an in vitro P.AM-212 cell inhibition assay of a compound of the invention, designated CPR 3005.
  • Figure 4 is a graphical representation of results from an in vitro RAW 264.7 cell macrophage inhibition chemiluminescence assay of a compound of the invention, designated CPR 3005.
  • Figure 5 is a graphical representation of results from an in vivo antagonism of PAF (Platelet Activating Factor) -induced increase in TPR (Total Pulmonary Resistance) by a compound of the invention, designated CPR 3005.
  • PAF Platinum Activating Factor
  • the present invention relates to novel fatty alkyl and alkenyl ether glycerophospholipids, also referred to as fatty alkyl and alkenyl ether glycerophosphoethanolamines, which bear a defined heterocyclic (Het) substituent on the ethanolamine nitrogen.
  • the subject compounds are represented by the general formula (I) :
  • R represents a substituted or unsubstituted straight or branched chain Ci 4 _ 20 alkyl or alkenyl, said substituent being one or more of halo, Cj. 3 alkoxy or cyano, provided that a double bond of said alkenyl does not involve the carbon atom of said alkenyl that is bonded to the oxygen of the glyceryl backbone; and Het represents a 5- to 9-membered monocyclic or bicyclic fused ring system with 1 to 3 hetero atoms, each hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, and provided that Het is not an imidazolinyl ring system.
  • R is selected from the group consisting of (1) substituted or unsubstituted, preferably unsubstituted, C 14 _ 20 alkyl groups, preferably C 16 . 18 alkyl, such as, for example, tetra-, penta-, hexa-, hepta-, octa-, nonadecyl-, eicosyl-, or the branched analogs thereof; and (2) corresponding substituted or unsubstituted, preferably unsubstituted, C 14 _ 20 alkenyl groups, preferably C 16 .
  • lg alkenyl whereby a double bond of the alkenyl group does not involve the carbon atom of said alkenyl that is bonded to the oxygen of the glyceryl backbone.
  • Both the aforementioned alkyl and alkenyl groups can be substituted at one or more carbons, preferably at one, with substituents which do not interfere with syntheses of the compounds during the synthetic steps of making them.
  • Preferred substituents are halo, C 3 alkoxy or cyano.
  • halo refers to any of the four halogens, chloro, bromo, iodo and fluoro, with chloro and fluoro being preferred.
  • heterocyclic ring systems included within the term "Het" are such 5- to 9-membered rings, including single infused ring entities, such as, for example, among others, thiazolinyl, thiophenyl, thiazolyl, pyrilidinyl, 5,6-dihydro-4-H-oxazinyl, 5, 6- dihydro-4-H-thiazinyl, pyrazinyl, benzothiazolyl and oxazolopyridinyl.
  • the preferred ring is thiazolinyl.
  • the 2-carbon in the heterocyclic ring system which is bonded to the ethanolamine nitrogen.
  • Said rings may also be substituted with one or more substituents, preferably one, such as C 1"3 alkyl, C 13 alkoxy or a polar substituent such as cyano, nitro, or methylsulfono.
  • the reactants (A) and (B) are mixed in an appropriate organic solvent, e.g., isopropanol, and the mixture is refluxed for several hours. After cooling to room temperature, the solvent is evaporated off. Water is added and the pH is adjusted to about 4-4.5 by addition of acid, e.g., HC1 solution. Conventional workup affords the desired end product (I) .
  • an appropriate organic solvent e.g., isopropanol
  • the starting reactants (A) are identified as compounds (V) in said Application.
  • the method of preparation of the starting reactants (A) is disclosed in said Application as follows:
  • the compounds of Formula (II) are known in the literature or can be obtained by art-recognized procedures. See, for example, A. Hermetter and F.
  • the phosphoethanolamine moiety is introduced by reaction of the hydroxyl in Compound (IV) with P0C1 3 and triethylamine at low temperatures (0-4°C) in an anhydrous solvent such as tetrahydrofuran, followed by reaction with ethanolamine, and treatment with aqueous dilute hydrochloric acid, to yield l-0-R-2-0-methyl-glycero-3- phosphoethanola ine (V) (Compound A herein) .
  • the Formula I compounds have an asymmetric carbon atom (C2 position in the glyceryl backbone) in their structures. Consequently, these compounds may exist in the for.m of different R and S optically isomeric forms (enantiomers) or racemates. Substantially pure forms of either of the R- and S-isomer may be obtained, substantially free of the other, by the application of art-known resolution methodologies such as, for example, column chromatography using chiral columns, starting the preparation from the R- or S-isomer of an appropriate precursor, for example, the starting Compound (II) shown in the reaction scheme.
  • cis- and trans-geometric isomers may also be present in the subject compounds, e.g., when R in Formula I is C 14 _ 20 alkenyl, due to the cis- and trans- configuration inherent with the double bond.
  • R in Formula I is C 14 _ 20 alkenyl
  • the corresponding end product of the Formula I compound will be obtained.
  • Particular compounds within the scope of this invention are: a. l-0-n-octadecyl-2-meth ⁇ 3cy-glycero-3-phospho-N- (2- thiazolinyl) -ethanolamine, also denoted as CPR 3005; b. l-0-n-hexadecyl-2-methoxy-glycero-3-phospho-N- (2- thiazolinyl) -ethanolamine; c. l-0-n-tetradecyl-2-methoxy-glycero-3-phospho-N-(2- thiOphenyl) -ethanolamine; d.
  • the invention also comprehends salts of the Formula I compounds. These salts include acid addition salts, such as, for example, those made with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, carbonic, acetic, citric or lactic acids. The salts may also include those made with bases, such as, for example, sodium hydroxide, potassium hydroxide or calcium hydroxide. The salts of the invention are made by conventional methods well known to those of ordinary skill in the art. The salts for therapeutic use of the Formula I compounds are pharmaceutically acceptable salts, as understood in the art.
  • the compounds of the subject invention and pharmaceutically acceptable salts thereof are useful chemopreven ative and adjuvant agents in several aspects. They are useful for the treatment of cancerous tumors and also for treating inflammation, hyperproliferative skin diseases such as psoriasis, and asthma.
  • the subject compounds and salts may be used alone for such indications or in combination with other compatible medicaments.
  • Anti-tumor activity is to be escpected against a wide spectrum of mammalian (including human) tumors and cancerous growths such as cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx) , esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix uteri, corpus endometrium, ovary, prostate, testes, bladder, kidney and other urinary tissues, eye, brain and central nervous system, thryoid and other endocrine glands, leukemias (lymphocytic, granulacytic
  • the disclosed invention thus provides a method of treating a tumor in a mammal.
  • the treatment comprises administering to said mammal an anti-tumor effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides pharmaceutical compositions comprising an anti-tumor "effective amount of a Formula (I) compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Psoriasis is a chronic inflammatory dermatosis characterized, in part, by hyperproliferation of keratinocytes and release of pro-inflammatory cytokines. Compounds that reduce hyperproliferation of keratinocytes in vitro are therefore likely to have utility in the control of psoriasis.
  • the subject compounds and pharmaceutically acceptable salts thereof markedly inhibit proliferation of these cells in vitro , thus indicating that these compounds and salts are useful in ameliorating psoriasis.
  • the instant invention thus provides a method of treating psoriasis in a mammal afflicted with same comprising administering to said mammal an effective anti-psoriatic amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. It also provides pharmaceutical compositions comprising an effective anti-psoriatic amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Inflammation is a complex process, involving a variety of cell types including acrophages. See, for example, S.L. Kunkel, "Inflammatory Cytokines", pp. 1-15, in Manual of Vascular Mediators, P.A. Ward, Editor, produced by the publishers of Hospital Practice. References relative to macrophages are numerous, including, for example, J. Immunology, Vol. 119, pp. 950- 954 (1977) and Cell, Vol. 15, pp. 261-267 (1978). Macrophages are activated by infection and by a wide variety of non-infectious irritants and proinflammatory agents. Upon activation, macrophages participate in a variety of reactions.
  • macrophages may phagocytize bacteria and kill them by either oxygen- dependent or oxygen-independent pathways.
  • oxygen-dependent pathways activation of macrophages induces them to increase oxygen consumption and produce reactive oxygen species (for example, radicals such as superoxide) .
  • reactive oxygen species for example, radicals such as superoxide
  • Production of reactive oxygen species by activated macrophages is associated with inflammatory responses.
  • macrophages release a variety of inflammatory cytokines, including several interleukins and tumor necrosis factor ⁇ (TNF ⁇ ) . Inhibition of any of these activation-related processes can lead to reduced inflammation.
  • TNF ⁇ tumor necrosis factor ⁇
  • macrophage activation is of critical importance in studies of the inflammatory process. Agents that reduce macrophage activation are likely to have utility as anti-inflammatories.
  • the subject compounds are thus useful in the treatment of acute and chronic inflammatory diseases, such as, for example, dermatitis, conjunctivitis, bursitis, rheumatoid arthritis and the like.
  • the instant invention thus provides a method of treating inflammation in a mammal' " afflicted with same comprising administering to said mammal an effective anti-inflammatory amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. It also provides pharmaceutical compositions comprising an effective anti-inflammatory amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Platelet-activating factor (PAF) 2(R)acetyl-sn-glyceryl-3-phosphocholine) has been the subject of many reported studies since its discovery in the early 1970s.
  • PAF literature reviews include those of Dean A. Handley, Pharmacological Methods in the Controlled Information, pp. 23-58, 1989, and Matyas Koltai, et al.. Drugs, Vol. 42, pp. 9-29, 1991.
  • Platelet Activating Factor has been shown to be a mediator of inflammation and has been found in lung fluids of asthma patients.
  • PAF is a chemo- attractant and encourages the migration of neutrophiles and eosinophiles to sites of inflammation and to the airways of asthmatic patients.
  • PAF has been shown to be a powerful bronchial constrictor of the airways of asthmatic patients.
  • PAF has been found in the psoriatic lesions of psoriasis patients. Accordingly, antagonists of PAF have potential utility in treating inflammatory diseases, including rheumatoid arthritis, asthma, psoriasis and immediate and delayed type hypersensi ivity reactions.
  • Example 16 hereafter demonstrates the inhibition of the constrictor activity of PAF on the test animal airway, as illustrated with the compound CPR 3005.
  • the subject compounds are thus useful in ameliorating PAF related disease states, including PAF-induced bronchial asthma.
  • the subject invention thus provides a method of inhibiting PAF activity in a host mammal having a susceptible PAF-induced pathophysiological condition which comprises the administration to said mammal of an effective PAF antagonist amount of Formula (I) compound or a pharmaceutically acceptable salt thereof.
  • the invention also provides pharmaceutical compositions comprising an effective PAF antagonist amount of a Formula (I) compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • pharmaceutical compositions for inhalation administration are suitable, such as aerosol inhalation spray, for example, in a metered dose device.
  • the mammals that may be treated with the subject compounds, salts, therapeutic methods and formulations of the invention are, of course, humans.
  • Formulations of the present invention for medical use, comprise an active compound, i.e., a Formula (I) compound or a pharmaceutically acceptable salt thereof, together with an acceptable carrier for it and optionally other therapeutically active ingredients.
  • the carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of it.
  • the formulations include those suitable for oral, rectal, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal, or bronchial administration. Preferred formulations are those suitable for oral or parenteral administration. Topical formulations are also included, for example, anti-psoriatic usage.
  • Formula (I) compounds typically decompose on heating above about 200°C. This characteristic may need to be taken into consideration in, for example, preparing tablets on a commercial scale where the heat of compression may be a factor.
  • Formula (I) compounds are also rather insoluble in water and, accordingly, liquid formulations which account for this factor may be made according to art-recognized pharmaceutical techniques.
  • suitable solvent or co-solvent such as an appropriate polyethylene glycol, or a propylene glycol or the like
  • a sealed gelatin capsule enclosing an oily solution of the active compound
  • a suppository of the active compound in a conventional suppository base such as cocoa butter
  • a liposome formulation for example, the active compound and a glycerophospholipid such as phosphatidylcholine.
  • the aforementioned characteristics of the Formula (I) compounds are not uncommon in the pharmaceutical area and, accordingly, art-recognized pharmaceutical techniques are employed to prepare appropriate formulations for such compounds as those of Formula (I) or pharmaceutically acceptable salts thereof.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid or solid carrier and then, if necessary, shaping the product into desired unit dosage form.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, boluses or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or in liquid form, e.g., as suspension, solution, syrup, elixir, emulsion, dispersion, liposome preparation, or the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
  • Formulations suitable for parenteral administration conveniently comprise a sterile preparation of the active compound in, for example, a polyethylene glycol 200 or propylene glycol solution which is preferably isotonic with the blood of the recipient.
  • Useful formulations also comprise concentrated solutions or solids containing the compound of Formula (I) which upon dilution with an appropriate solvent give a solution suitable for parenteral administration.
  • compositions suitable for inhalation administration for example, for treating bronchial asthma, wherein the carrier is a solid include a micronized powder or liquid formulation having a particle size in the range of from about 5 microns or less to about 500 microns, for rapid inhalation through the oral passage from a conventional inhalation squeeze or spray container.
  • suitable liquid nasal compositions include conventional nasal sprays, nasal drops and the like, of aqueous solutions of the active ingredient and optional adjuvants.
  • Preparations for topical or local applications which are, for example, conventional for anti-psoriatic usage, and may be useful in treatment of certain cancers, comprise aerosol sprays, lotions, gels, ointments, transferosomes, plasters, etc. and pharmaceutically acceptable vehicles therefore such as, for example, lower aliphatic alcohols, polyols such as glycerol, polyethyleneglycerol, esters of fatty acids, oils and fats, silicones, and other conventional topical carriers, for example, liposomes.
  • pharmaceutically acceptable vehicles therefore such as, for example, lower aliphatic alcohols, polyols such as glycerol, polyethyleneglycerol, esters of fatty acids, oils and fats, silicones, and other conventional topical carriers, for example, liposomes.
  • the compounds of Formula (I) are preferably utilized at concentrations of from about 0.1% to about 5.0% percent by weight.
  • the formulations of this invention may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
  • optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
  • the compounds of Formula (I) and salts thereof of the invention are to be administered under the guidance of a physician or veterinarian.
  • the amount of compound of Formula (I) or salt thereof required to be effective for each of the herein indicated activities will, of course, vary with the individual mammal being treated and is ultimately at the discretion of the medical or veterinary practitioner.
  • the factors to be considered include the condition being treated, the route of administration, the nature of the formulation, the mammal's body weight, surface area, age and general condition, and the particular compound or salt to be administered.
  • the pharmaceutical compositions of this invention contain from about 0.5 to about 500 mg, and preferably, from about 5 mg to about 350 mg of the active ingredient, preferably in a unit dosage form, for each of the indicated activities.
  • a suitable effective dose is in the range of about 0.1 to about 200 mg/kg body weight per day, preferably in the range of about 1 to about 100 mg/kg per day, calcu.lated as the non-salt form of compound of Formula (I) .
  • the total daily dose may be given as a single dose, multiple doses, e.g., two to six times per day, or by intravenous infusion for a selected duration. Dosages above or below the range cited above are within the scope of the present invention and may be administered to the individual patient if desired and necessary.
  • a dose range would be about 7.5 to about 1500 mg per day, and a typical dose would be about 800 mg per day. If discrete multiple doses are indicated, treatment might typically be 200 mg of a compound of Formula (I) given 4 times per day.
  • the pharmaceutical compositions of this invention contain from about 0.5 mg to about 500 mg and, preferably, from about 5 mg to about 350 mg of active ingredient (compound of Formula (I) per se or as part of a pharmaceutically acceptable salt) , preferably in a unit dosage form, for each of the indicated activities of the invention.
  • active ingredient compound of Formula (I) per se or as part of a pharmaceutically acceptable salt
  • 500 Grams (1.85 mol) of l-octadecanol is suspended with stirring in 2500 ml methylene chloride and 224.5 g (2.22 mol; 310 ml) triethylamine is added with cooling (cold water).
  • 254 Grams (2.215 mol; 171.5 ml) of methanesulfochloride dissolved in 500 ml methylene chloride is then added in such a way that the reaction temperature is maintained between 20° and 25°C. Stirring at ambient temperature (18-23°C) is continued for 1.5 hours.
  • the methylene chloride is removed under vacuum at a temperature of 35°C maximum.
  • methanesulfonates are obtained: n-tetradecylmethanesulfonate; n-hexadecyl ethanesulfonate; n-eicosylmethanesulfonate; cis-9-octadecenylmethanesulfonate;: trans-9-octadecenylmethanesulfonate;; cis-9-hexadecenylmethanesulfonate; trans-9-hexadecenylmethanesulfonate;: 2-chloro-n-octadecylmethanesulfonate ; 2-methoxy-n-octadecylmethanesulfonate; and 2-cyano-n-hexadecylmethanesulf
  • EJLAMPLE 2 A. l-0-n-Octadecyl-Glycerol (Batylalcohol)
  • n-octadecanol Another impurity is n-octadecanol which should be removed in any case because in the next reaction step it may form phospholipids that cannot be separated from the product.
  • Purification 500 Grams raw methyl-batylalcohol are dissolved in 1500 ml toluene and slowly filtered through a bed of 1500 g alumina on a glass frit. (Note: "The alumina bed is prepared by filtering a slurry of alumina in toluene) . The alumina is washed with 1500 ml toluene. The toluene phases are combined and evaporated to dryness under reduced pressure. Recrystallization from n-hexane at -20°C yields 402.2 g methyl-batylalcohol (IV) of sufficient purity to be used in the next step.
  • TLC KG 6OF (Merck) ;
  • a mixture of 40 ml anhydrous tetrahydrofuran (THF) and 36.8 g P0C1 3 (240 mmol) is cooled to 0°C.
  • a mixture of 72 g (200 mmol) methyl-batylalcohol (IV), 36.4 g (360 mmol) triethylamine and 240 ml THF is added dropwise as the temperature is maintained at 0-4°C. Some material precipitates.
  • the cooling device is removed and a mixture of 14.7 g (240 mmol) ethanolamine, 36.4 g (360 mmol) triethylamine and 180 ml THF is added to the stirred solution within 15 minutes.
  • honey-like residue is taken up in 500 ml methylene chloride and a slight turbidity is removed by adding charcoal followed by filtration over a glass filter. Half of the methylenechloride is distilled off and 200 ml acetone are added. Upon cooling to 0°C for two hours, 91.2 g (94.7%) of raw product (V) precipitates. This material is dissolved in 800-900 ml boiling isopropanol. The solution is passed over a filter and cooled to room temperature. On standing overnight at room temperature 86.3 g (89.5%) of crystalline l-0-n-octadecyl-2-0-methyl-glycero-3- phosphoethanolamine (V) is obtained. TLC:KG 60 F (Merck) ;
  • Mobile phase 1 CHC1 3 / CH 3 OH / c. NH 3 ; 65/35/5 per vol. ;
  • Mobile phase 2 CHC1 3 / CH 3 OH / acOH / HOH; 100/60/20/5 per vol.;
  • Example 8 The procedure of Example 8 is followed, except that an equivalent amount of each l-O-R-2-O-methyl- glycero-3-phospho-ethanolamine of Formula (A) of Example 7 is employed as the starting material, to yield the following respective compounds of Formula (I) : the corresponding 1-O-n-tetradecyl-, 1-0-n-hexadecyl-, 1-O-n- eicosyl-, l-0-(9-octadecenyl) -, l-0-(9-hexadecenyl)-, 1- O- (2-chloro-n-octadecyl) -, 1-0- (2-methoxy-n-octadecyl) - and l- ⁇ -(2-cyano-n-hexadecyl)- derivatives of 2-O-methyl- glycero-3-phospho-N- (2-thiazolinyl) -ethanolamine.
  • Formula (I)
  • E3CAMPLE 11 l-0-n-Hexadecyl-2-0-Methyl-Glycero-3-Phospho-N- (2-Thiazolinyl) -Ethanolamine.
  • Example 8 The Procedure of Example 8 is followed except that an equivalent amount of l-O-hexadecyl-2-O-methyl- glycero-3-phosphoethanolamine is used as the starting material (A) to yield the titled compound as the final product.
  • Culture media a. for cell line 1-a: Dulbecco's Modified Eagle's Medium (DMEM) plus 10% Fetal Bovine Serum (FBS) ; and b. for cell line 1-b: 1:1 DMEM and Ham's F-12 (DMEM/F12) plus 10% FBS.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FBS Fetal Bovine Serum
  • Assay Procedure a. After cell passage, count cells with a hemocytometer; b. Adjust concentration to approximately 5,000 cells per lOO ⁇ L; c. Pipette lOO ⁇ L cell suspension per well of a standard 96-well microtiter plate; d. Preincubate 24 hours to allow cells to attach; e. Add 100 ⁇ L of test compound dispersed in phosphate buffered saline (PBS) and diluted in DMEM (for MDA-MB-231 cells) or DMEM/F12 (for HT-29 cells) to achieve final concentration levels ranging from 0 to 100 ⁇ M; and f. Incubate 48 hours under standard culture conditions and determine end points.
  • PBS phosphate buffered saline
  • DMEM for MDA-MB-231 cells
  • DMEM/F12 for HT-29 cells
  • End Point a. Remove media and add 100 ⁇ L/well of cold (4°C) 10% (w/v) trichloroacetic acid (TCA) in water; b. After 1 hour at 4°C, remove TCA and rinse cells 5 times with tap water; c. Air-dry plates; d. Add 50 ⁇ L/well of 0.4% (w/v) sulforhodamine B (SRB) in 1% (v/v) acetic acid in water; e. After 30 minutes at room temperature, rinse cells 4 times with 1% (v/v) acetic acid in water to remove residual stain; f. Air-dry plates; g.
  • Dissolve stain by adding 100 ⁇ L/well of unbuffered Tris base, pH 10.5; h. Read absorbance at 564 nm using a standard 96- well microtiter plate reader. Absorbance readings are linear with dye concentrations below 1.8 absorbance units. To reduce absorbance, decrease wavelength at which measurements are taken.
  • Cell line PAM-212 murine keratinocyte cell line isolated and cultivated from newborn BALB/c mice (see S.H. Yuspa et al. , Cancer Research, Vol. 40, pp. 4694-4703, 1980) that appears to retain many characteristics of normal keratinocytes.
  • Methodology is the same as that described previously in part 4 of Example 13, except that, with reference to part 4 (b) , cell concentration is adjusted to 1,000 cells per 100 ⁇ L (rather than 5,000 cells per 100 ⁇ L) , and, with reference to part 4(e), test compounds are diluted in DMEM/F12 prior to addition to cell wells.
  • the RAW 264.7 cell line (available from the University of the Renishaw
  • ATCC under accession no. TIB 71 is a murine monocyte/ macrophage line the cells of which show many of the differentiative functions of a macrophage. Like macrophages, the cells are capable of phagocytosis and undergo a respiratory burst (increased oxygen consumption) and production of oxygen radicals (e.g., superoxide) in response to appropriate activation signals.
  • oxygen radicals e.g., superoxide
  • the respiratory burst and corresponding production of oxygen radicals that accompany macrophage activation can be measured in a variety of ways,
  • chemiluminescence generated from luminol in the culture medium of macrophage cell lines is recognized in the art as a marker of macrophage activation.
  • Cell line RAW 264.7 (ATCC TIB 71);
  • Culture medium DMEM with 10% FBS (attachment dependent) ;
  • Standard protocol for culturing cell lines in T-75 or T-150 flasks; 37°C; 95% air; 5% C0 2 ; 100% humidity;
  • test compound at concentrations of 0, l, 3, 10, or 30 ⁇ M;
  • EX.i ⁇ MPLE 16 Assay for Anti-PAF Activity in Anesthetized Guinea Pigs Guinea pigs of 650-1000g were used in order to facilitate catheterization of the jugular vein and carotid artery. The guinea pigs were anesthetized with 35-45 mg/kg pentobarbital sodium. When or if the recordings described below were unstable, anesthetic additions were made during the course of the intervention. The cutdown was a ventral medial incision over the cervical area so that the trachea, jugular vein and carotid artery could be cannulated. The animals were immediately attached to a volume regulated Harvard® rodent respirator.
  • Model 683 via a tracheostomy and the respirator was set at 60 respirations per minute and a volume of 8ml/kg to maintain a normal arterial P ⁇ 2 of approximately 40 mm Hg.
  • Pancuronium bromide a muscle relaxant
  • a tube was connected to the respirator pump and the endotracheal catheter was attached to a pressure-transducing strain gauge and then to a 2-channel Gilson® physiological recorder.
  • One channel of the recorder inscribed the pressure tracing from the airway; the second channel inscribed the pressure tracing from a similar strain gauge attached directly to a catheter inserted into the carotid artery.

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Abstract

L'invention se rapporte à de nouveaux glycérophospho-éthanolamines d'alkyles gras et d'éthers d'alcényle à activité thérapeutique, qui possèdent un substituant à cycle hétérocyclique sur l'azote d'éthanolamine. L'invention concerne également des procédés d'utilisation desdits composés, leurs sels pharmaceutiquement acceptables et des compositions pharmaceutiques les contenant. Les nouveaux composés de la présente invention à activité thérapeutique ainsi que leurs sels possèdent des activités anti-tumorales, anti-psoriasiques, anti-inflammatoires et sont dirigés contre le facteur PAF.
PCT/US1997/023729 1997-12-29 1997-12-29 Glycerophospho-ethanolamines a substitution n-heterocyclique WO1999033851A1 (fr)

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JP2000526527A JP2001527085A (ja) 1997-12-29 1997-12-29 Ｎ−ｈｅｔ置換グリセロホスホエタノールアミン類
PCT/US1997/023729 WO1999033851A1 (fr) 1997-12-29 1997-12-29 Glycerophospho-ethanolamines a substitution n-heterocyclique
AU62373/98A AU6237398A (en) 1997-12-29 1997-12-29 N-het-substituted glycerophosphoethanolamines
KR1020007007270A KR20010033747A (ko) 1997-12-29 1997-12-29 Ｎ-Ｈｅｔ-치환 글리세로포스포에탄올아민

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GB0015981D0 (en) * 2000-06-29 2000-08-23 Glaxo Group Ltd Novel process for preparing crystalline particles

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4650791A (en) * 1984-01-11 1987-03-17 Takedo Chemical Industries, Ltd. Certain 3-alkoxy-2-cyclic-imido-propyl-phosphate-ethyl-cyclic ammonium hydroxide inner salts which inhibit activities of platelet activating factor
WO1996016041A1 (fr) * 1994-11-22 1996-05-30 Clarion Pharmaceuticals Inc. Desoxy glycero-phosphoethanolamines substituees par heteroaryle
US5665714A (en) * 1995-12-07 1997-09-09 Clarion Pharmaceuticals Inc. N-substituted glycerophosphoethanolamines
US5703062A (en) * 1995-12-07 1997-12-30 Clarion Pharmaceuticals Inc. N-het-substituted glycerophosphoethanolamines

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4650791A (en) * 1984-01-11 1987-03-17 Takedo Chemical Industries, Ltd. Certain 3-alkoxy-2-cyclic-imido-propyl-phosphate-ethyl-cyclic ammonium hydroxide inner salts which inhibit activities of platelet activating factor
WO1996016041A1 (fr) * 1994-11-22 1996-05-30 Clarion Pharmaceuticals Inc. Desoxy glycero-phosphoethanolamines substituees par heteroaryle
US5665714A (en) * 1995-12-07 1997-09-09 Clarion Pharmaceuticals Inc. N-substituted glycerophosphoethanolamines
US5703062A (en) * 1995-12-07 1997-12-30 Clarion Pharmaceuticals Inc. N-het-substituted glycerophosphoethanolamines

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