Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/205—Radicals derived from carbonic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/10—Anthelmintics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C271/34—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to naphthoquinones and their use in chemotherapy. More specifically the invention is concerned with novel carbonate and carbamate derivatives of hydroxynaphthoquinones, processes for their preparation, pharmaceutical formulations thereof and their use in the chemotherapy of certain pro ozoal and parasitic infections.
• Parasitic protozoal infections are responsible for a wide variety of diseases of medical and veterinary importance, including malaria in man and various coccidioses in birds, fish and mammals. Many of the diseases are life-threatening to the host and cause considerable economic loss in animal husbandry.
• Parasitic protozoa include the Apicomplexa, such as species of Eimeria, Cryptosporidium, Toxoplasma, and Plasmodium.
• Another parasitic organism of increasing concern is Pneumocvstis carinii. which can cause an often-fatal pneumonia in immunodeficient or immunocompromised hosts, including those infected with HIV. The classification of this organism is unclear and there is still uncertainty as to whether it is a protozoan or a fungus.
• naphthoquinones A wide range of naphthoquinones is known in the art. Such compounds have been variously described as having antimalarial, anticoccidial and antitheilerial activity. Some compounds have also been described as possessing activity against external parasites. Thus, Fieser et. al. J. Amer. Chem. Soc. 1948, 22,, 3156-3165 (and references cited therein) describes a large number of 2-substituted-3-hydroxy-l,4-naph- thoquinones as having antimalarial activity. A number of these compounds have also been described in U.S. Patent Specification No. 2 553 648.
• R is an optionally substituted, C_ non-aromatic hydrocarbon residue and R is inter alia a group -0C0R C , OR , SR or NR e R , which compounds are said to be believed to act as pro-drugs of compounds wherein R is a hydroxyl group.
• R is C. . hydrocarbyl group optionally substituted by one to five substituents, selected from halo, C. ..alkoxy, hydroxy, amino, and mono-or di-C. ,alkyl-amino; and either the dotted line represents a double bond between the 2 and 3 positions of the
• n 2 or 3
• R and R which may be the same or different, each represent a hydrogen atom, a C. - alkyl group, optionally substituted by hydroxy,
• R is a C. -alkyl group optionally substituted by an amino group optionally substituted by one or two alkyl groups, or R and R may each be a group
• R8 is a C. - alkyl group, A is an oxygen atom or
• R represents a hydrogen atom, a C, ,alkyl group optionally substituted by hydroxy, C. , alkoxy or an amino group optionally substituted by one or two C. fi alkyl groups or R 5
• R is a C 1 ,alkyl group or R is a
• R and R are as 7 S hereinbefore defined for R and R or, when m is 1 and n is 2 R
• R 1 ° 4 R , R and R each represent a group
• the .C. __ hydrocarbyl group R may be a straight or branched chain
• C 1 14 e.g. C 1 _ 8
• Z_ lh e.g. C 2 g
• alkenyl group or a C 3 _ 10
• C_ R (e.g. C_ R )cycloalkyI group, each of which may be optionally substituted by a C_ 1f .
• C_ fi (e.g. C_ fi )cycloalkyl group, and each of the aforesaid cycloalkyl groups optionally being substituted by a C.
• hydrocarbyl group R may be a C, .._ (e.g.C, R ) cycloalkyl group substituted by a phenyl group which is optionally substituted by a C ⁇ .. (e.g. C, ,) alkyl group.
• the hydrocarbyl group R preferably contains from 1 to 20 carbon
• Suitable groups R include
• Preferred groups R include:
• a C 1 _ 1() alkyl group a C cycloalkyl group (which may be optionally substituted by a straight or branched chain C. , alkyl group, a halo-CL ..alkyl group, a C. fi alkoxy group or a phenyl group, the phenyl group itself being optionally substituted by one or more substituents selected from C. , alkyl and halogen) ; and
• cycloalkyl moiety may be optionally substituted as defined for the aforementioned C- _ cycloalkyl group.
• R is a C. lfl alkyl group.
• R 15 r is zero or one, and either R is hydrogen and R is selected from halo, halo-C, r alkvl, C, , alkoxv, aralkoxv, C, ,
• R and R are both C. , alkyl or phenyl.
• the compounds of formula (I) wherein R contains a substituted cyclohexyl group may exist as the cis or trans isomer, that is to say that the cyclohexyl ring may be cis or trans substituted by the naphthoquinone nucleus and the subsistent on the cyclohexyl ring.
• Both cis and trans isomers and mixtures thereof in any ratio may be used in accordance with the present invention.
• the trans isomer will be present in an amount of about 50% or will be the predominant isomer but the use of mixtures in which the cis isomer predominates is also included within the scope of the invention.
• the specific ratio of isomers may be varied as required; typical ' mixtures include those in which the cis/trans isomer ratio is about 1:1,40:60 and 5:95.
• the trans isomer of such compounds of formula (I) or a mixture of the cis and trans isomers containing at least 95% e.g. 99% of the trans isomer, is preferred.
• R is the 4-(4-chlorophenyl)cyclo ⁇ hexyl group:
• R 1-6 alkyl this may be straight or branched chain e.g. methyl, ethyl, isopropyl, t-butyl, isopentyl or n-hexyl.
• R , R and R are each hydrogen or a C- , alkyl group. Most suitably R is methyl or
• R is hydrogen, methyl or ethyl, R is hydrogen or a group
• R is C. , alkyl, e.g. t-butyl.
• R and R preferably represent -0 and the dotted line is a bond between the 2 and 3 positions of the naphthyl ring.
• a preferred group of compounds of formula (II) may be represented by the formula (III)
• the compounds of formula (III) are preferably in the form of the trans-isomer.
• a further preferred group of compounds of formula (II) may be represented by the formula (IV) :
• hydrocarbyl group is meant an aliphatic group, e.g. a straight branched chain or cyclic alkyl, alkenyl or alkynyl group, a carbocyclic aryl, an aliphatic group substituted by a carbocyclic aryl group optionally substituted by an aliphatic group or a carbocyclic aryl group substituted by an aliphatic group.
• the carbonate or carbamate derivatives of formula (II) are pro-drugs of the corresponding hydroxynaphthoquinone, that is, the carbamate or carbonate or group is cleaved in vivo to give the compound of formula (I) wherein R Is a hydrox 1 group. It is believed that the compounds of formula (II) will exhibit activity against parasitic protozoa, in particular those organisms against which corresponding hydroxynaphthoquinones have been found to be active, such as Plasmodium species, eg. P.falciparum: Ei eria species eg. E. enella and E.acervulina: Theileria species e.g.
• T.parvum and T. nnulata Crvpt ⁇ sporidium: and Toxoplasma gondii as well as the parasitic organism P ⁇ eumocvstis carinii. and will therefore be useful in the treatment and/or prophylaxis of parasitic infections, such as those caused by parasitic protozoa, eg. malaria, coccidiosis, cryptosporidiosis, toxoplasmosis and those caused by P.carinii eg. P.carinii pneumonia (PCP) in animals, including humans.
• parasitic protozoa eg. malaria
• coccidiosis e.g. cryptosporidiosis
• toxoplasmosis and those caused by P.carinii eg. P.carinii pneumonia (PCP) in animals, including humans.
• PCP P.carinii pneumonia
• a suitable dose for administration to man for the treatment of malaria is in the range of O.lmg to 200mg per kilogram bodyweight per day, for example from lmg/kg to lOOmg/kg, particularly 10 to 40 mg/kg. It will be appreciated that for administration to neonates, lower doses may be required.
• a compound of formula (II) or a salt thereof may also be given less frequently, e.g. as a single dose on alternate days, once or twice per week or once or twice per month.
• the dosage for prophylatic treatment will depend inter alia on the frequency of administration, and, where a depot preparation or controlled release formulation is used the rate of release of the active ingredient.
• a suitable prophylactic dose is in the range 0.1 to 100 mg/kg,e.g. 0.5 to 50 mg/kg particularly 5 to 50 mg/kg. It should be understood that for consistency the dosages referred to above are calculated In terms of the compound of formula (II) per se. and may require adjustment in the event a salt is employed.
• the present invention thus further provides a method for the treatment •and/or prophylaxis of parasitic infections e.g. parasitic protozoal Infections such as malaria, or infections caused by P.carinii. in mammals e.g. humans, which comprises administering to a mammal suffering from or susceptible to said infection, an effective amount of a compound of formula (II) or a physiologically acceptable salt thereof.
• parasitic infections e.g. parasitic protozoal Infections such as malaria, or infections caused by P.carinii. in mammals e.g. humans, which comprises administering to a mammal suffering from or susceptible to said infection, an effective amount of a compound of formula (II) or a physiologically acceptable salt thereof.
• the invention also provides the use of a compound of formula (II) or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of parasitic infections as hereinbefore defined.
• a compound of formula (II) or a physiologically acceptable salt thereof is preferably presented as a pharmaceutical formulation.
• such pharmaceutical formulations will comprise a compound of formula (II) or a physiologically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic and/or prophylactic ingredients.
• the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.
• the present invention therefore, further provides a pharmaceutical formulation comprising a compound of formula (II) or a pharmaceuti ⁇ cally acceptable salt thereof together with a pharmaceutically acceptable carrier therefor.
• a method for the preparation of a pharmaceut ⁇ ical formulation comprising bringing into association a compound of formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.
• a compound of formula (II) or its salt may conveniently be presented as a pharmaceutical formulation in unit dosage form.
• a convenient unit dose formulation contains a compound of formula (II) or a physiologically acceptable salt thereof in an amount of from 10 mg to lg-
• compositions include those suitable for oral, topical (including dermal, buccal and sublingual) , rectal and parenteral (including subcutaneous, intradermal, intramuscular and intravenous) administration.
• the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (II) or a physiologically acceptable salt thereof with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
• compositions suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of the active ingredient(s) .
• a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent.
• Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered active ingredient(s) with any suitable carrier.
• Tablets may be optionally coated and, if uncoated, may optionally be scored.
• Capsules may be prepared by filling the active Ingredient(s) , either alone or In admixture with one or more accessory ingredients, into the capsule shells and then sealing them In the usual manner.
• Cachets are analogous to capsules wherein the active ingredient(s) together with any accessory Ingredient(s) is (are) sealed in a rice paper envelope.
• a compound of formula (II) or a physiologically acceptable salt thereof may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged e.g. in a sachet.
• Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water liquid emulsion, e.g. a syrup, elixir, emulsion or a draught.
• a syrup may be made by adding the active ingredient(s) to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredients which may include flavourings, agents to retard crystallisation of the sugar or agents which increase the solubility of other ingredients such as polyhydric alcohols for example glycerol or sorbitol.
• Formulations for oral administration include controlled release dosage forms e.g. tablets wherein the active ingredient(s) is (are) formulated in an appropriate release - controlling matrix, or coated with a suitable release - controlling film. Such formulations may be particularly convenient for prophylactic use.
• compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
• Suitable carriers include cocoa butter and other materials commonly used in the art.
• the suppositories may be conveniently formed by admixture of the active ingredient(s) with the softened or melted carrier(s) followed by chilling and shaping in moulds.
• compositions suitable for parenteral administration include sterile solutions or suspensions of the active ingredient(s) in aqueous or oleaginous vehicles.
• injectible preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use.
• the active ingredient(s) may be in powder form eg. freeze-dried which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.
• a compound of formula (II) or a physiologically acceptable salt thereof may also be formulated as a long-acting depot preparation, which may be administered by intramuscular injection or by implantation e.g. subcutaneously or intramuscularly.
• Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use.
• the compounds of the invention may be formulated in any known manner, for example as described above, in view of their properties they are particularly suited for formulation, for example as aqueous solutions which may be used for injection.
• 2- rtrans-4-(4-Chlorophen- yl)cyclohexyl] -3- ⁇ N-methyl-N-[2-(methylamino)ethyl]carbamyloxy ⁇ -1,4- naphthoquinone has improved water solubility over the parent hydroxynaphthoquinone.
• the pharmaceutical formulations for the various routes of administration described above may include, as appropriate one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
• additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
• the compounds of the present invention may be administered in combination or concurrently with other therapeutic agents, for example other antimalarial agents, such as 4-amlnoquInolines eg. chloroquine and amodiaquine; 8-aminoquino- lines eg. primaquine; chloroquine; mefloquine; quinine; quinldine; artemesinin; artesumate; artemether; halofantrine; dihydrofolate reductase inhibitors eg. pyrimethamine; sulphonamides eg. sulphadox- ine: proguanil; chloroproguanll; dapsone, hydroxynaphthoquinones; or mixtures eg.
• other antimalarial agents such as 4-amlnoquInolines eg. chloroquine and amodiaquine; 8-aminoquino- lines eg. primaquine; chloroquine; mefloquine; quinine;
• pyrimethamine/sulphadoxine pyrimethamine/dapsone
• pyrimethamine/sulfalene pyrimethamine/sulphadoxine
• antibacterial agents such as trimethopri - sulphamethoxazole mixtures
• anticoccidial agents such as monensin, halofuginone, arprinocid, amprolium, dinitolmide, robenidine or salinomycin
• antibiotics such as cllndamycin, tetracycline, doxycycline, or spiromycin
• agents active against Pneumocvstis carinii such as pentamidine or Eflornithine.
• each compound When compovmds of formula (II) are used in combination with a second therapeutic agent the dose of each compound may vary from that required when the compound Is used alone. Appropriate dosages can be readily determined by those skilled in the art.
• n, A, R and R are as hereinbefore defined; provided . that when it is required to prepare a compound wherein one or more of R and R is hydrogen, the corresponding compound is prepared with a group -C0-0-R in place, instead of hydrogen and this group is then removed.
• the reaction may conveniently be effected in the presence of a solvent which is inert to the reagents.
• Solvents which may be employed include aromatic hydrocarbons e.g. benzene or toluene; halogenated hydrocarbon e.g. chloroform or dichloromethane; dipolar aprotic solvents e.g. dimethylformamide or hexamethylphosphoric triamide; ethers e.g. tetrahydrofuran or dioxan; pyridine; acetonitrile; trimethylphosphate and triethylphosphate.
• the reaction temperature may conveniently be in the range of from -80 C to 100 C, preferably 0°C to 30°C.
• the reaction may advantageously be effected in the presence of a base which may be an organic base, for example pyridine, 4-dimethylamino- pyridine, a tertiary amine such as triethylamine, or 1,8-diazabicy- clo[5,4,0]-7-undecene (DBU) , or an inorganic base, for example an alkali metal carbonate such as potassium carbonate or sodium hydrogen carbonate.
• a base which may be an organic base, for example pyridine, 4-dimethylamino- pyridine, a tertiary amine such as triethylamine, or 1,8-diazabicy- clo[5,4,0]-7-undecene (DBU)
• an inorganic base for example an alkali metal carbonate such as potassium carbonate or sodium hydrogen carbonate.
• Salt formation can also be effected by methods well known in the art, by reacting a compound of formula (II) with an appropriate acid.
• the compounds of the formula (V) may conveniently be prepared in situ from the corresponding hydroxynaphthoquinone, for example when X is chloro by the reaction of the hydroxynaphthoquinone with phosgene in an Inert solvent, as defined above, in the presence of the base used to attach the carbamate side chain. This reaction Is carried out between -50 C and 50 C and suitably at between -10 C and 10 C.
• Compounds of formula (IV) may be prepared according to known methods for the synthesis of hydroxynaphthoquinone derivatives, such as are described in US Patents Nos. 2,553,648; 3,367,830; and 3,347,742; UK Patent No. 1,553,424; European Patents Nos. 2,228; 77,551; 77,550; and 123,238 and European Patent Application No. 362,996.
• a compound of formula (IV) may be prepared by reaction of a 2-halo
• R is an optionally substituted cyclohexyl or optionally substituted cyclohexylmethyl group it may be introduced by reaction with the appropriately substituted cyclohexylcarboxylic acid or cyclohexylacetic acid.
• Compound B 2-f rans-4-(4-Chlorophenyl)cyclohexyl]-3- ⁇ N-[2-(methyl amino)ethyl]carbamoyloxy)-1,4-naphthoquinone hydrochloride monohy- drat .
• Compound C 2- ftrans-4-(4-Chlorophenyl)cyclohexyl] -3-(N-methyl-N- [3-(methylamino)propyl]carbamoyloxy) -1, -naphthoquinone.
• Compounds A, B, C, and (I) were administered orally and intravenously, in the manner described below.
• the test method is a modified version of the 4-day suppressive test.
• the YM strain of P.voelii was maintained in mice by twice weekly passage. Infected blood was collected and diluted with normal saline to give an inoculum of 3x10 parasitized enythrocytes/ml. On the morning of Day 1 the test animals (male CD-I mice weighing 18-20g) were infected intravenously via the tail vein with 0.1ml of inoculum/mouse.
• Test compounds A, B and (I) were formulated by ball milling in 0.25% celacol with stainless steel balls. The total requirement was formulated at the beginning of a test and thereafter stored at 4 C.
• Each test compound was administered orally (p.o.) to four or more usually five groups of mice, each group receiving a different dose level (dilution) .
• a further group of mice was administered celacol only, as a control (ie. a total of 30 mice are used to obtain each ED c -.) .
• the mice were dosed orally 24 hours post-infection.
• Intravenous (i.v... I.v. formulations of test Compounds A and B were prepared by dissolving the compound in water immediately before use, and administered via the tail vein as a single dose 24 hours post-infection.
• Septrin was diluted into drinking water; the dose was calculated on the basis that each mouse would drink a minimum of 2.5 ml/day. Atovaquone was administered as a suspension in 0.25% celacol. The test compound was dissolved in distilled water and the solution administered within 1 hour of preparation. Results
• mice were based on two independent blind examinations, and are expressed as an average infection score of the 10 mice in each group. Data are also expressed as a percentage of the control (dosed daily p.o. with distilled water) .
• Atovaquone 100 mg/kg/day p.o
• a solution for intramuscular injection may be prepared by mixing:-
• Sorbitan monooleate 4.5 parts by weight
• tert-butyl N-methyl-N-f -(methylamino)ethyl carbamate This was prepared from N,N' -dimethylethylenediamine following the procedure of W.S. Saari, J.E. Schwering, P.A. Lyle, S.J. Smith and E.L. Engelhardt. J.Med.Che . vol 33, 97, 1990.

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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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