CA2133744A1 - 1,4 naphthoquinone derivatives with anti-protozoal and anti-parasitic activity - Google Patents
1,4 naphthoquinone derivatives with anti-protozoal and anti-parasitic activityInfo
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- CA2133744A1 CA2133744A1 CA002133744A CA2133744A CA2133744A1 CA 2133744 A1 CA2133744 A1 CA 2133744A1 CA 002133744 A CA002133744 A CA 002133744A CA 2133744 A CA2133744 A CA 2133744A CA 2133744 A1 CA2133744 A1 CA 2133744A1
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- 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
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- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Compounds of general formula (II) wherein R3 is C1-35 hydrocarbyl group optionally substituted by one to five substituents, selected from halo, C1-6alkoxy, hydroxy, amino, and mono- or di-C1-4alkyl-amino; and either the dotted line represents a double bond between the 2 and 3 positions of the naphthyl ring; R1 and R4 each represent = O; and R2 represents a group (a) wherein n is 2 or 3, R6 and R7 which may be the same or different, each represent a hydrogen atom, a C1-6alkyl group, optionally substituted by hydroxy, C1-6alkoxy or a group (b) wherein R9 is a C1-6alkyl group optionally substituted by an amino group optionally substituted by one or two alkyl groups, or R6 and R7 may each be a group (c) wherein R8 is a C1-6alkyl group, A is an oxygen atom or a group (d) wherein R5 represents a hydrogen atom, a C1-6alkyl group optionally substituted by hydroxy, C1-6 alkoxy or an amino group optionally substituted by one or two C1-6alkyl groups or R5 is a group (e) wherein R10 is a C1-6alkyl group or R5 is a group (f) wherein p is 2 or 3 and R11 and R12 are as hereinbefore defined for R6 and R7 or, when m is 1 and n is 2 R5 may be linked to R6 so that (g) forms a piperazine ring; or the dotted line represents double bonds between the 1, 2 and 3, 4 positions of the naphthyl ring, and R1, R2 and R4 each represent a group (h) (wherein n, A, R6 and R7 are as hereinbefore defined); and physiologically acceptable salts thereof.
Description
~0 93t20044 PCTJCB93/00708 -1,4 NAPHTHOQUINONE DERIVATIVES WITH ANTI-PROTOZOAL AND ANTI-PARASTIC ACTIVITY
The present inven~ion relates .o naphthoquinones and their use in chemotherapy. More specifically the invention is concerned ~i.h novel carbona~e and carbamate deriva~ives ol hydroxynaphthoauinones, processes for their preparation, pnarmaceutical formulaeions .hereof and ~heir use in the chemotherapY of certain protozoal and oarasitic infections.
.
Parasitic ?ro~ozoal infections are responsible for a wide varie~v of diseases of medical and ve~erinary importance, including malaria in man and various coccidioses in birds, fish and mammals. .~any o~ the diseases are life-threa~ening to the hos~ 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 P~eumocvstis cari~i}, which can cause an often-fatal pneumonia in immunodeficient or immunocompromised hosts, including those infected with HIV. The classification of ~his organism is unclear and there is still unCertaLnty as to whether ic is a protozoan or a fungus.
A wide range or naphthoquinones is ~nown in the art. Such compounds have been variously described as having antimalarial, anticoccidial and antitheilerial activity. Ssme compounds have also been described as possessing activity against external parasites. Thus, Fieser et al, J. Amer. Chem-.~Soc- L948, 70, 3156-3165 (and rererences cited therein) describes a large number of 2-substituted-3-hydroxy-1,4-naph-thoquinones as having antimalarial activity. .~ number of these compounds have also been described in U.S. Paeent Specification ~o. 2 553 648. Further classes of 2-substituted-3-hydroxy-1,4-naphtho~ui-nones naving acti~it~ as antimalarial, anticoccidial and/or .. ..
antitheilerial agents are~described in U.S. Patenes Nos. 3 36/ 830, and 3 347 742, U.K. Patent Specification No. 1553424, and European Patent Sp-ciiicaçions Nos. 2 228, 77551, 77550 and 123,238.
W O 93f20~44 .-t~ 't ~ PCT/GB93/007~ -European Patent .~pplication No. 362996 discloses~ for ehe ;_ea~ment and/or prophyla~is or infections caused bv Pneumocvs~ls ~3~inl~, 1,4-naphthoquinones of formula:
! I ¦ (I) _,~ ~,,,\ , where Ra is an optionally substituted, Cl 35 non-aromatic hydrocarbon .
residue and R is inter alia a group -OCOR , OR , SR or NReRf, which compounds are said to be believed to act as pro-drugs of compounds wherein Rb is a hydroxyl group.
It has now been found tha~ a 1,4-naphthoquinone substituted at the
The present inven~ion relates .o naphthoquinones and their use in chemotherapy. More specifically the invention is concerned ~i.h novel carbona~e and carbamate deriva~ives ol hydroxynaphthoauinones, processes for their preparation, pnarmaceutical formulaeions .hereof and ~heir use in the chemotherapY of certain protozoal and oarasitic infections.
.
Parasitic ?ro~ozoal infections are responsible for a wide varie~v of diseases of medical and ve~erinary importance, including malaria in man and various coccidioses in birds, fish and mammals. .~any o~ the diseases are life-threa~ening to the hos~ 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 P~eumocvstis cari~i}, which can cause an often-fatal pneumonia in immunodeficient or immunocompromised hosts, including those infected with HIV. The classification of ~his organism is unclear and there is still unCertaLnty as to whether ic is a protozoan or a fungus.
A wide range or naphthoquinones is ~nown in the art. Such compounds have been variously described as having antimalarial, anticoccidial and antitheilerial activity. Ssme compounds have also been described as possessing activity against external parasites. Thus, Fieser et al, J. Amer. Chem-.~Soc- L948, 70, 3156-3165 (and rererences cited therein) describes a large number of 2-substituted-3-hydroxy-1,4-naph-thoquinones as having antimalarial activity. .~ number of these compounds have also been described in U.S. Paeent Specification ~o. 2 553 648. Further classes of 2-substituted-3-hydroxy-1,4-naphtho~ui-nones naving acti~it~ as antimalarial, anticoccidial and/or .. ..
antitheilerial agents are~described in U.S. Patenes Nos. 3 36/ 830, and 3 347 742, U.K. Patent Specification No. 1553424, and European Patent Sp-ciiicaçions Nos. 2 228, 77551, 77550 and 123,238.
W O 93f20~44 .-t~ 't ~ PCT/GB93/007~ -European Patent .~pplication No. 362996 discloses~ for ehe ;_ea~ment and/or prophyla~is or infections caused bv Pneumocvs~ls ~3~inl~, 1,4-naphthoquinones of formula:
! I ¦ (I) _,~ ~,,,\ , where Ra is an optionally substituted, Cl 35 non-aromatic hydrocarbon .
residue and R is inter alia a group -OCOR , OR , SR or NReRf, which compounds are said to be believed to act as pro-drugs of compounds wherein Rb is a hydroxyl group.
It has now been found tha~ a 1,4-naphthoquinone substituted at the
2-position by a carbamate group exhibits goot acti~ity in v~o ajsainst malaria in mice infected with Plasmodiu~_yoelii.
Thus, in a first aspect the pre5ent invention provides a compound of general formula tII) Rl ' ", ~ (II) I
-' ~/--11 / R2 ~ 1 , wherein PI~J/68~ 3 1 ~ 0 7 0 ~
Thus, in a first aspect the pre5ent invention provides a compound of general formula tII) Rl ' ", ~ (II) I
-' ~/--11 / R2 ~ 1 , wherein PI~J/68~ 3 1 ~ 0 7 0 ~
- 3 ;~ ' 21 FEBRUARY 1994 ~ R3 is Cl 35 hydrocarbyl group optionally substituted by one to five substituents, selected ~om halo, Cl 6 alkoxy, hydroxy, amino, and mono-or di-Cl 4 alkyl-amino; and either the dotted line represents a double bond between the 2 and 3 positions of the naphthyl nng; Rl and R4 each represent = 0; and R2 represents agroup ~
'O--C ~R6 A-~CH2)n- N~
wherein n is 2 or 3, R6 and R7 which may be the same or different, each represent a hydrogen atom, a C1 6 alkyl group, optionally substituted by hydroxy, O
Cl 6 alko~ or a group C-R9 wherein R9 is a Cl 6 aLkyl group optionally substituted by an amino group optionally substituted by one or two alkyl groups,or R6 and R7 may each be a group O
C o-R8 wherein R8 is a C 1-6 aLtcyl group, A is an oxygen atom or a group N wherein R5 represents a hydrogen atom, a C1 6 allyl group optionally substituted by hydroxy, C1 6 alkoxy or an amino group optionally substituted by one or two C 1-6 all~rl groups or R5 O . , is a group -C-O-R10 wherein R10- is a Cl 6 ~LIkyl group or R5 is a Rll group (CH2) -~ wherein p Is 2 or 3 and Rl 1 and Rl2 are as hereinbefore defined for R6 and R7 or, when A is -N- and n is 2 R5 may be linked to R6 so tha~ N(CH ~ N forms a piperazine nng;
-I Pt'1~ 'r , ~ S~
'O--C ~R6 A-~CH2)n- N~
wherein n is 2 or 3, R6 and R7 which may be the same or different, each represent a hydrogen atom, a C1 6 alkyl group, optionally substituted by hydroxy, O
Cl 6 alko~ or a group C-R9 wherein R9 is a Cl 6 aLkyl group optionally substituted by an amino group optionally substituted by one or two alkyl groups,or R6 and R7 may each be a group O
C o-R8 wherein R8 is a C 1-6 aLtcyl group, A is an oxygen atom or a group N wherein R5 represents a hydrogen atom, a C1 6 allyl group optionally substituted by hydroxy, C1 6 alkoxy or an amino group optionally substituted by one or two C 1-6 all~rl groups or R5 O . , is a group -C-O-R10 wherein R10- is a Cl 6 ~LIkyl group or R5 is a Rll group (CH2) -~ wherein p Is 2 or 3 and Rl 1 and Rl2 are as hereinbefore defined for R6 and R7 or, when A is -N- and n is 2 R5 may be linked to R6 so tha~ N(CH ~ N forms a piperazine nng;
-I Pt'1~ 'r , ~ S~
4 f~ 3 ~ O 0 7 0 r~ _ J ~ i 2 l ~EBRUARY 1994 or the dotte~ line represents double bonds between the 1, 2 and 3, 4 positions of thenaphthyl ring, and R1, R2 and R4 each represent a group O ~R6 \ O / C \ ~ (CH2)n--N
(wherein n, A, R6 and R7 are as hereinbefore defined); ~' and physiologically acceptable salts thereo The Cl 35 hydrocarbyl group R3 may be a straight or branched chain Cl l4 (e.g.
Cl-8)aLlYl or C2-14 (e g- C2-8)a~enYI group or a C3 10 (e.g. C3 g)cycloalkyl group, each of which may be optionally substituted by a C3 10 (e.g. C3 6) cycloaL~cyl group, and each of the aforesaid cycloallyl groups optionally bemg substituted by a Cl lo (e.g. Cl~) alkyl group. Alternatively the hydrocarbyl ' `~
group R3 may be a C3 10 (e.g.C3 8) cycloaLtcyl group substituted by a phenyl ~oup which is optionally substituted by a Cl lo (e.g. Cl 4) alkyl group. The hydrocarbyl group R3 preferably contains from 1 to 20 carbon atoms, e.g. I to 14carbon atoms. Suitable groups R3 include C3 10 cycloalkyl-CI g-alkyl, Cl lo alkyl-C3 10 cycloalkyl, Cl loalkyl--C3 10 cycloalkyl-Cl lo alkyl and C3 10-cycloa~l-C3 10 cycIoalkyl. R3 may also be substituted as hereinbefore defined by one to five halo, Cl 6 alkoxy, hydroxy, amin~,- Qr mono - or di-C14 alkyl amino substituents. ~~
PreferredgroupsR3 include:
a Cl 1OaL~cyl group; - -....
,,, i, .~ . " '1 ~
a C5 7 cycloalkyl group (which may be optionally substituted by astraight or branched chain Cl 6 alkyl group, a halo-Cl ,alkyl group, a Cl 6alkoxy group or a phenyl group, the phen~l group itself being optionally substitueed by one or ~ore substituents selected from Cl 6 alkyl and halogen); and a Cl 1Oalkyl-C5 7cycloalkyl group, wherein the cycloalkyl moiety maY be optionally su~stituted as defir.ed for the aforementioned C5 7 Cycloalkyl group.
A particularly preferred class of subscituents R is represented by the formula:
G 'C~3 !CH2)q~
c~3 wherein: !
q i5 zero or one and -R is a Cl 10 alkyl group- ~
Another par~icularly preferred class of substl~uents R is represan~ed by the formula: ~
-(C~2~
wherein:
'i ~l .3 ;~ 7 li~ ~f/~ 9 3 / ~ 0 7 0 ~
r is zero or one, and either R14 is hydrogen and R~5 is selected from halo, halo-Cl 6 alkyl, Cl 6 alkoxy, C1 6 alkyl-C1 6 alkoxy, and phenyl substituted by one or two groups selec~ed from halo and C 1 6 alkyl or R14 and R15 are both C1 6 alkyl or phenyl.
.
It will be appreciated that the compounds of formula (I) wherein R3 contains a substituted cyclohexyl group may e~ist as the cis or trans isomer, th~t is to say that the cyclohexyl ring may be cls or trans~ substituted by the naphthoguinone 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. In general when the compound is in the forrn of a mixture of isomers the trans isomer will be present in an arnount of about 50% or will be the `
predominant isomer but the use of mixtures in which the ~ isomer predominates is also included within the scope of the invention. The specific ratio of isomers may be varied as required; typical mixh~es include those in which the cis/trans isomer ratio is about 1:1,40:60 and 5:9~. For use according to the present invention the trans isorner 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.
An especially preferred substituent R3 is the 4-(4-chlorophenyl3cyclo-hexyl group:
~ y \\
in particular in the trans forrn with respect to the naphthoquinone ring. I
~J ~ ; ' , r ; i ~ S
P'`T ~ " ~ t ~,i~ ; ~~~~ ' ` ' ~ I -~? ~
W O 93/20044 ~ i PCT/GB93/00708 n the compounds or rormula (II) .~ is preferably a group _~T_ and R
represents a carbamate group O
, (CH ) 6 \o/ \ N/ \ N/ R
\
y of the groups R , R , R , R8, R10 Rl1 or R
alkyl, this may be straight or branched chain e.g. methyl, ethyl, isopropyl, t-butyl, isopentyl or n-hexyl. Suieably R, R and R are each hydrogen or a Cl 4 alkyl group. Most suit~bly R5 is methyl or - ethyl, R6 is hydrogen, methyl or ethyl, R ic hydrogen or a group -C0-0-R wherein R is Cl 4 alkyl, e.g. t-butyl.
In the compounds of formula (II) R and R preferably represen~ -O and -.he dotted line is a bond between the 2 and 3 positions of the naphehyl ring.
A preferred group of compounds of formula (II) may-be-represented by .he formula (III) ~ - -~ j G~\/~j /--~ R6 j C~Z)n N
~herein R , R and R are as hereinbefore defined, and physiolo~ically acceptable sales ~hereof.
W O 93/~'0044 , ~ 8 - PCT/GB93/0070~
~ ~urthermore ~he compounds of formula ~III) are prererably in the form of the ~rans-isomer.
''-[t-ans-4-(4-Chlorophenvl)cyclohexyl]-3-lN-methyl-~-;2-(methylamino)-ethyl]arbamoyloxv~ -naphthoquinone is a preferred compound of ~he formula (III).
A fur~her preferred group of compounds of formula (II) may be represen~ed by ,he formula (IV~:
9 ,~ (IV) ~/ \ I ~ Q R
. ~ ~ J ~ ¦ ~6 `(CH2)n N
wherein R5, R6 and R are as hereinbefore defined 2-~trans-~4-~-butylcyclohexyl)methyl]-3-~N-meehyl-N-[2-(meehylamino)-ethyl]carbæmoyloxy)-1,4-naphthoquinone is a preferred compound of the formula (IV). _ -By the term "hydrocarbyl" group is meant an aliphatic group, e.g. astraight branched chai~-or-cyc:l-ic 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.
Without wishing -o be bound by theory, it is believed that the carbonate or carbamate ;derivatives of formula (II) are pro-drugs of the corresponding hydroxvnaphthoquinone, that is, the carbamate or carbonate or group is cleaved in vivo to give the compound of formula (I) wherein Rb is a hydroxyl group.
!
~1 -f ~ `-~ rl ~ ' ~ ~ I j J ~ L ! ' WO 93/20044 PCr/(~B93/0070~ .`
q It is believed that the compounds of formuia (II) ~ xhibit activity against parasi~ic protozoa, in particular those organisms against which corresponding hydroxvnaphthoquinones have been found to be acti~e. such as Plasmodium species, eg. P. alci~arum; ~imeria s?ecies eg. _.~enella and E.ace~lina; rheileria species a.g T parvum and T annulata; Cr~tos~oridium; and To~oolasma ~ondii as well as .he parasitic organism Pnewmocvstis carinii, and ~ill .herefore be useîul in the ereatmene and/or prophylaxis of parasitic infections, such as those caused bv parasitic protozoa, eg. malaria, coccidiosis, cryptosporidiosis, toxoplasmosis and those caused by ~_sL~i~iL eg. P.carinii pneumonia (PCP) in animals, including humans.
It will be appreciated that the amount of a compound of formula (II) or its salt required for use in the treatment or prophylaxis of the above-mentioned diseases will depend inter ~lia on ~he particular compound administered, the route of administration, the age and weight of the mammal ~e.g. human) to be treated and the nature and se~erity of the condition being treated. In general, a suitable dose for administra~ion 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 .o lOOmg/kg, particularly 10 to 40 mg/kg. It will be apprecia~ed that for administration to neonates, lower doses may be required. ~ ~ -For prophylactic treatment a compound of formula (II) Qr a saltthereof may also be given less fre~uently, e.g. as a-s mgla dose on alternate days, once or t~ice 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 formula~ion is used the raee of release of the active ingredient. Thus for once-weekly administracion a suitable prophylactic dose is in che range 0.1 to 100 mg/k~,e.g. O.S ~o 50 mg/kg par~icularly 5 to 50 mgjkg.
W O ~3/20044 ~ 7 /~ ! PCT/GB93/0070~
=
'. snouid be understood ~hat for consistency the dosages referred to above are calculated in terms of ~he compound of formula (II) ~ se, and mav ~equire adjustmene in the evenc a salt is emploved.
Ihe present invention ~hus rurther 2rovides a method for the treatment and/or propnylaxis of parasieic inrections e.g. parasitic protozoal infections such as malaria, or infections caused ~y 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 .hereof.
There is also pro~ided a compound of formula (II) or a physiologically acceptable salt thereof for use in therapy, e.g. in the treatment and~or prophylaxis of parasitic diseases as hereinbefore defined.
!
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. ' For use according to the present in~ention a compound of formula tII) -or a ?hysiologically acceptable-~salt thereof is preferably presented as a pharmaceutical formulation. In general such pharmaceutical formulations will comprise - ? compound of formula (Il) or a physiologically acceptable sait thereof together with one or more pharmaceutically acceptable carriers therefor and optionally other ~herape~tic and/or prophylactic ingredients. The carrier(s) must be acceptable in the sense o ~eing compatible with the other ingredients of the formula and not de-Leeerious to the recipient thereof, .
:, The present invention, -therefore, further provides a pharmaceutical 'ormula~ion comprising a compound of formula ~II) or a pharmaceuti-cally acceptable sar; ehereof cogeeher with a pharmaceutically acceveable carrier ~herefor.
' '' 1 !" . ~
W O 93~20044 PCT/GB93/00708 There is aiso provided a method ror the preparation of a pharmaceut-ical for~ulation comprising bringing into associazion a compound o~
~ormula (I ) or a pharmaceu~ically acceptable salt thereof, and a ?harmaceutically acceptable carrier therefor.
.~ co~oound of formuia (II) or ies salt may conveniently be presen~edas a pharmaceuticai formulation in unic dosage form. A convenient unit dose formulation contains a compound of formuia (Il) or a physiologicallv acceptable salt thereof in an amount of from 10 mg ~o lg.
Iharmaceu~ical formulations include those suitable for oral, _oplcal ~including dermal, buccal and sublingual), rectal ~nd parenteral (including subcutaneous, intradermal. intramuscular and intravenous) administration. The formulation may, where appropriate, be convenienrly presen~ed 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 j (II) or a physiologically acceptable salt thereof with liquid carriers or finel,v dividec solid carriers or both and then, if necessary, shaping ~he product into the desired formulation.
, Pharmaceutical formulations suitable for oral administration wherein the carr-er 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 tab-let--m~y be made by compression or moulding, op~ionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the ac~ive ingredient(s) in a free-flowin~ form such as a powder or granules optionally mixed with a binder, -lubricant, inert diluent, lubricating agent, surface-acrive agent or dLspersing agen~. Moulded tablets may be made by moulding in a suitaUe machine a mi~rure of the powdered active ingrediene(s) with any suitable carrier. Table~s may be optionallv coated and, if uncoated, ~ay optionally be scored. Capsules may be prepared by filling the active W O 93/20044 i! ' "! ~ -1 ,1 ,, PCT/GB93/0070f ,_, , ),, ~, 1 1 ingredien~(s) , either alone or in aomixture ~ith one or ~ore accessory ingredients. ineo the capsule sh~lls and .hen seaiing he~
in the usual manner. Cachets are analogous ~o capsules wherein ~he active ingredien~(s) ~ogether wi.h anv accessorv ingredient(s) is (~re) seaied ln a rice paper envelo~e. .~ co~pound or formula (II) or a physiologically accepta~le salt .hereof ~av also be rormulated as dispersible granules, ~hich may for example be suspended in ~ater before administration, or sprinkled on food. The granules mav be packaged e.g. in a sache~. Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous lîquid or a non-aqueous liquid, or as an oil-in-wa~er liquid emulsion, e.g. a sYrup, elixir, emuision or a draught. A syrup may be made by adding the active ingredien~(s) eo 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 oeher ingredients such as polyhvdric alcohols for example glycerol or sorbitol.
Formulations for oral administration include controlled release dosage forms e.g. tablets wherein the ac~ive ingredient(s) is (are) formulated in an appropriate-release - controlling matri~, or coated with a suitable release -~con~rollIng film. Such formulations mav be particularly convenient for prophylactic use.
F
Pharmaceueical formulations 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. -----Pharmaceutical formulati-ons suitable for parenteral administration include sterile solutions or suspensions of the active ingredient(s) ? ~ -'? 7,1 ' W O 93~20044 ~ ' PCT/GB93/00708 in aaueous or oleaginous vehicles. Injec~ible preparations may be adapted for bolus injec~ion or continuou~ infusion. Such preparations are con~eniently presented in ~nit dose or multi-dose containers which are sealed after introduction of the formula~ion until requ~red for use. .~lternatively, the active ingredient(s) may be in powder form eg. freeze-dried which is constituted with a s~litable vehicle, such as s~erile, pyrogen-free water, before use.
A compound oî formula (II) or a physiologicallv acceptable salt thereof mav also be formulated as a long-acting depot preparation, which mav be administered by intramuscular injection or by implanta~ion e.g. subcutaneously or intramuscularly.~epoe preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-e~change resins. Such long-acting formulations are particularly ~onvenient for prophylactic use.
I
Uhilst 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-[erans-4-(4-chlorophen yl)cyclohexyl~-3-~N-methyl-N-[2-(methylamino)ethyllcarbamyloxy)-1,4-naphthoq~inone has improved water solubility over the parent hydroxynaphtho~uinone. ~ ~
It should be understood that in addition to the aforemen~ioned carrier ingretien~s the pharmaceutical formulations for the various routes o~
administration described above may include, as appropriate one or more additional carrier ingredients such as diluen~s, buffers, flavouring agents, binders, surface active agents, thickeners, lubricanti, preser~atives (including an~i-oxidants) and ~he like, and substances included for the purpose of rendering the formulation iso~onic _~th the bloot of the intended recipient. -~ ~
The compounds of the present invention may be administered in combination or concurren~ly wi~h other ~herapeu~ic agen~s, for example W 0 93t20044 ~ PCT/GB93/~070 other antimalarial agen~s, such as 4-aminoquinolines eg. chloroquine and amodiaauine; 8-aminoquino- lines eg. primaquine; chloroquine;
mefloquine; quinine; quinidine; artemesinin; ar~esumate; ar~emether; ~ ;
haloîantrine; dihydrofolate reductase inhibi~ors eg. pyrime~hamine; r.~
sulphonamides eg. sulphadox- ine: proguanil; chloroproguanil;
dapsone, hydroxvnaphthoquinones: or ~ixtures eg.
pyrimethamine/sulphadoxine; pyrime~hamine/dapsone; and ' ;
pyrime~hamine/sulfalene; antibac~erial agents such as trimethoprim-sulphamethoxazole mixtures; an~icoccidial agents such as monensin, ha}ofuginone, arprinocid. amprolium. dinitolmîde, robenidine or salinomycin; or antibio~ics such as clindamycin, tetracycline, ¦-doxvcycline, or spiromycin; or agen~s active against Pneumocvstis carinii sucn as pen~amidine or Eflornithine.
~hen compounts of formula (II) are used in combina~ion 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 ar~. ¦
Compounds of formula (II) may be prepared by reaction of a compound of formula (V) ~ ~3 ''~/\ ~ (V) O ..
wherein R3 is as hereinbelore defined and-X is halo, with a compound of the formula (Vl) HA(C~)n N\ (VI) R
? ~ 1 r/ ,1, wherein n, .~, R and R are as nereinbefore defined; 2rovided ~hat when it is required to prepare a compound wherein one or more of R
and R is hvdrogen. the corresponding compound is prepared with a group -ÇO-O-R in place, instead or hydrogen and this group is ~hen removed.
The reaction may con~eniently be effecced in the presence of a solvent which is inert tO the reagents. Solvents which may be emploved include aromatic hydrocarbons e.g. benzene or toluene; halogenated hydrocarbon e.g. chloroform or dichloromethane; dipolar apro~ic soivents e.g. dimethylformamide or hexamethylphosphoric ~riamide;
e~hers e.g. tetrahydrofuran or dioxan; pyridine; acetonitrile;
trimethylphospha~e and triethylphosphate. The reaction temperature may conveniently be in the range of from -80 C tO 100 C, preferably 0C to 30C.
The reaction may adYantageously be effected in the presence of a base which may be an organic base, for example pyridine, 4-dimethylamino-pyridine, a terti~ry amine such as .riethylamine, or l,8-diazabicy-clo~5,4,0]-7-undecene (D W), or an inorganic base, for example an alkali metal carbonate such as potassium carbonate or sodium hydrogen carbonate.
- To prepare a compou~d of-formula (II) wherein Rl, R2 and R4 each represent a carbonate- or- carbamate group che reaction should be effected after reduction of the quinone nucleus, which mav be effected in conventional manner.
Sale formation can also be effected by methods well known in the art, I
by reacting a c~mpoun~ of formula (II) with an appropria~e acid.
. _ RemoYal of the pro~ecting ~roup -C0-0-R is conveniently carried out by acid, for example when R is tertiary butyl hydrogen chloride in ether.
- o The compounds or ~he rormula (V) mav convenien~l~ be prepared ~n situ from the corresponding hvdroxvnaph~hoquinone, ror example when .~ is chloro bv the reaction oI the hydroxynaph~hoquinone wi~h phosgene in an inert soi~ent, as defined above, ln the presence of the base used .o actach ~he carbama~e side chain. This reaction is carried ou~
between -~0 C and 50 C and suitably ~t between -10 C and 10 C.
5Ompounds of formula ~IV) may be prepared according to known ~ethods for the svnthesis or hydroxynaphthoquinone deriva~ives, such as are described in US Parents ~os. 2,553,648; 3,367,830; and 3,347,742; UK
Paten~ No. 1,553,424; European Patents Nos. 2,228; 77,551; '7,550; and 123,238 and European Patent Applica~ion No. 362,996. Thus for example a compound of formula (IV) may be prepared by reaction or a 2-halo (e.g. 2-chloro)-1,4-naphthoquinone with a compound serving tO include ehe required R group, followed by alkaline hydrolysis. Where R is an optionally substituted cyclohexyl or optionally substituted cyclohexylmethyl group it may be in~roduced by reaction with the appropriately substituted cyclohexylcarboxylic acid or cyclohexylacetic acid.
The i~vention will now be further illustrated by the following non-limiting examples:-In vi~o Activitv a~ain~t ~lasmodium ~elii_in mice.
Tes~ Com~ounds Compound A: 2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-~N-methyl-N-~ ~2-(methylamino)ethyl]carbamoyloxy)-1,4-naphthoquinone hydrochloride mo- nohydrate. I
_ Com~ound B: 2-[trans-4-(4-Chlorophenyl)cyclohexyl ! - 3-lN-[2-(methvl amino)ethyl~car~amoYloxy~-1,4-naph~hoquinone hydrochloride monohy-drate.
.~,t ~,.-7 ,~ , l7 , Co~ound C: 2-[trans-4-(4-Chlorophenyl~cyclohexylj-3-~N-me~hvl-~'3-(me~hvlamino)propyl]carbamoyloxy)-1,4-naphthoquinone Com~ound _D- trans-2-~4-(4-Chlorophenyl)cyclohexyl]-3-~piperazine-N-carbonyloxyj-1,4-naphthoquinone hydrochloride dihydra~e, Com~ound (1~: 2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-hydrox~-1,4-naphthoquinone.
Compounds A, B, C, and (I) were administered orally and intravenously, in the manner described below, METHOD
I
The test method is a modified version of the 4-day suppressive tes~.
The YM strain of P,voelii uas maineained in mice by twice weekly passage. Infected blood was collected and diluted with normal saline to give an inoculum of 3X106 parasitized enythrocytes/ml. On the morning of Day 1 the test animals (male CD-l mice weighing 18-20g) were infected intravenously via the tail vein with 0,lml of inoculum~mouse.
I
Oral (p.o.) Test compounds A, B and ~ -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 fi~e groups of mice, each group recei~ing 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 ED50). The mice were dosed orally 24 hours post-infection.
Intravenous (~,v ~
WO 93/20044 ;1 ~ r~ ~; r~ 18 - PCT/G~93/0070~
I.-. formuiations of .es~ Compounds .~ and B were pre~ared by dissolving the compound in wa~er lmmediately berore use, and administered via the .ail vein as a single dose 24 hours post-infection.
On ~he morning of day ~ smears ot tail blood were prepared from each mouse and the parasitaemia coun~ed. 3ata were analysed to yield EDj~
values bv the best fit to a sigmoidal dose response curve. The results are presented in Table 1 below.
Results Table 1 Dosing Schedule ED50 mg/kg I ~: P.o. 1 ~ i.v, I
Com~ound (I~ 0.16 0.12 ~- Compound (A) O.15 0.12 - Co ound (B) 0.2 0.27 .
., Com~ound (C~ O.4 0.29 ~ ~ Com~u~ (D) O.4 -In vi~o Act vit~ a~ainst Pneumoc~stis carinii in mice .
Dru~s .ested ~ Septrin - Wellcome Paediatric Suspension con~aining 200 mg sulfamethoxazole/40 mg trimethoprim per 5 ml '~ ?~
W O 93/20044 PCT/GB93/00,08 l9 ~tovaquone-2- .rans-4- (4-chlorophenyl)cyclonexyl]-3-hydroxy-1, 4-naphthoquinone Test compound-2-[trans-4-(4-chlorophenyl)cvclohexyl~-3-~N-me~hyl-N- E 2-(methylamino)e~hyl~ carbamovloxy)-1,4-naphtho-quinone hydrochloride monohvdrate ~ethod ?neumocvs~is_carinii (PC~-free female SCID (C.B-i7/lcr-scid/scid) mice (20-25g) were started on dexamethasone (2m/L in drinking water), 7 days prior to in~ratracheal infection wi~h single dose of cryo-preserved mouse-derived PC (dose:-2 x lO cysrs equivalent to about 106 .rophozoites). Drugs were evaluated for prophylaxis bv continuous daily oral dosing of groups of 10 mice wieh each drug from 1 dav post infection until day 42. Trials were terminated and all the mice killed 24 n after the last dose. The lungs were removed and an impression smear prepared ~from a representative portion of lung ; - selected a~ random. Lung smears were stained for P.carinii cysts usin~ an immunofluorescent antibody test kit ~Detect IF P. carinii, Shield Diagnostics Ltd.) Slites were scored for the intensity of P.
carinii infection by scanning the entire smear a~ lOOx magnification and coun~ing the highly fluorescent cysts. Smears were assigned one of the following scores~.
0 - no cysts/smear +1 ~ 1- to 5 ~ys~s/smear , +2 - 6 to 50 cysts/smear +3 51 to 250 cysts/smear +4 ~250 cvsts/smear Drug formulation~
Septrin was diluted int~ ~-drinking water; the dose was calculated on the basis that each mouse would drin~ 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 L hour of preparation.
WO 93/20044 ~ r~ ~ . PCT/GB93/0070 ~esul tS
Ihe results v~hich are presen~ed in Table 2 below, were based ~n two independen~ blind examinations, and are expressed as an a~erage infection score oî the 10 mice in each group. Data are also expressed ' as a percen~age of the control (dosed daily p.o. wl~h dis~illed water).
Treatment GroupMean score'+ SE % of Control Control 3.6+ 0.2100 Septrin (2S0/50 mg/kg/day) 0.1+ 0.1 3~
A~ovaquone ~100 mg/kg/dav p.o) 1.5+ 0.3 43%
Test,compound (100 mg.kg.day p.o) 0.1+ 0.1 3%
FormLulation ~xamPLes The following examples i}lustrate, with particular reference to ehe compound of Example 2, pharmaceutical formulations which may be employed in accordance with the present invention. It will be appreciated that other compounds of form~la (II) may be formulaced in similar manner-.
. Iniectable solut-on A solution for intramuscular injection may be prepared by ~ ixing:-=,_~- , Compound of Example 29.5 par~s by weight ~~ Dimethyl sulphoxide19.0 parts by weight Sorbitan monooleace4.5 parts by weight Corn oil 67 0 parts by weight .100 . O
W O 93/20044 ,~ iPCT/GB93J0070 B. Injec~able solution Compound of Example 2 5 parts by weigh~ .
N-me~hvl-pyrollidone 48.3 parts by weight Tween 80 2 parts by weight Span 80 4.7 parts by weight Miglyol 812 4~l parts by weight C. Table~
Compound of Example 2 25.0 mg Lactose BP 48.5 mg Microcrystalline Cellulose BP 10.0 mg ("Avicel pH 101") Low-substituted Hydroxypropyl; 10.0 mg Cellulose BP (~LHPC LH-ll") Sodi~m Starch Glycollate BP 3.0 mg ("Explotab") ~:~ Povidone BP (~K30") 3.0 mg Magnesium Stearate BP 0.5 mg _ - 100 0 mg D. IV Solution Freeze Dried - - j Compound of Example 2 50mg Water ~or Inj ections to lOml Dissolve the naphtho~uinone in the ~ater for Injections.
Sterilise by fi~tration. Fill into glass vials and freeze dry.
Recons~itute-:shortly before use with Water for Injec~ions, WO 93/20044 ~ ~ I q ' PCT/GB~3/00708 ~ _ rj rJ i . ~ - 2 2 E. ~a~sule Compound of Example 2 100 mg Starch 1500 150 mg ~agnesium stearate 2.5 mg filled into a hard gelatin capsule F. Aerosol Formula~ions a) Compound of Example 2, micronised 1.0 mg Aerosol propellant to 5.0 ml Suspend the micronised campound in ~he aerosol propellan~. ~
- Fill this suspension ineo preformed aerosol cannisters, Sj ~-ml~cannister under pressure, through the valve orifice.I ~
`~
b) Compound of Example 2, micronised 1.0 mg Arlacel 85 Q.l~ w/v Aerosol propellane to 5 ml !
Disperse the Arlacel 85 in the aerosol propellant and then add compound of Example 4. Fill the _suspension into preformed aerosol cannisters, Sml/cannis~er under pressure, through ~he valve orifice.
: ~~ ~~ G. Powder Inhalation ; Compound of Example 2, micronised 1.0 mg Lactose 29.0 mg ': ' .
Tritura~e and blend the micronised compound with the lactose.
~~ F~ll ehe resuleing powder blend into hard gelatin capsule shells, 30 mg per capsule.
tert-butvl ~-methvl-~-F2-(me~hvlamino)et~v11carbamate O 93/20044 PCT/~B93/00708 - ~3 -This was ?re~ared from N,N'-dimethvlethylenediamine rollowing rhe procedure of W.S. Saari. J.E. Schwering, P..~. Lyle, S.J. Smith and E.T. Engeihardt. J.~ed.Chem. vol 33, 97, L990.
~is_'2-~ r~-butoxvcarbonvl~Laminole~hvllamine To a stirred solu~ion or diethylenetriamine (lOg; 97 ml; Lancaster synehesis) ~n tetrahydrofuran (5ml) cooled to O C was added dropwise a solution of di-tert-bu~yl dicarbonate (10.5g; 48mM) in tetrahydrofuran (50 ml). The mixture was allowed to warm ~o room temperature and stirred for 18 hours. filtered concentrated Ln vaeuo snd partitioned be~ween brine and ethyl acetate. The aqueous layer was extrac~ed once with ethYl acetate and the combined extracts were dried (MgS04) and concentra~ed Ln vacuo to leave a clear 3il (6.7g). Chomatography on silica gel with 1:4 methanol: chloroform gave the title compound as a clear oil (2g; 27%), NMR ~H (CDC13) 3.15-3-3 (4H, m), 2.75 (4H
t,J5Hz), 1.~5 (18 H,s).
Exam~le 1 2- r trans-~-t~-~hloro~hen~l)c~clohex~ 3-~N-me~hYl-~-~2-(N-methYl-~-tert-butoxvcarbonvl2_minoethyllcarbamovloxYl-1.4-nashtho~uinone To a stirred suspension of 2-hydroxy-3-ttrans-4-(4-chlorophenyl)cyclo-xy1]-1,4-naphthoquinone (3.~g;-lOmmol) in dry dichloromethane (60ml), cooled to O C under nitrogen, -was added all at once a solution of phosgene in toluene (lOml;- 1.25M solution). Pyridine (0.8ml; lOmmol) was added dropwise and the solution stirred for a further 45 minutes at 0C. .~ mixture of~` ~ -butyl N-methyl-N-[2-(methYlamino)echyl~
carbamate (1.85g; -10.5mmol) and pyridine (0.8ml; lOmmol) in dry dichlorome~hane (lOm}.~ was atded dropwise o~er 15 minutes and the mixture lert stirring-a-t roo~ temperature for 18 hours. The mixture was diluted with dichloromethane (50 ml), washed with water, lM
hydrochloric acid and water, dried (magnesium sulphate) and concentrated ;o lea~e an orange oil. Chromatography on silica with W 0 93t20044 ~ ' PCT/GB93/0070~ -1:9 ethyl aceta~e:dichlorome~hane followed bv tr.turation with 1:2 e~her:hexane gave ~he title compo~nd (3.12g; ~4%), ~.p. 113-115 C, NMR
~H (CDC13) 3.0-8.2 (2H, m), 7.65-/.8 (2H. m)~ '.L-7.3 (4H, m), 3.4-3.7 (4H, m), '.'5 (3H, 2~s), ~.05-3.25 (1~. m), 3.0 (3H, 2~s), 1.5-2.15 '`
(9H, 2xs).
Exam~le 2 2-~trans~ -Chloro~nenvl)cvclohex~11-3-~N-methvl N-~2-l~ethylamino) ethvllcarDamovloxY~-1.4-na~h~ho~uinone hvdrochloride monohvdrate !
To ether sa~ura~ed with HCL (30ml) was added 2-[crans-4-(4-Chlorophen-yl)cvclohexvl]-3-(N-methyl-N-~2-(N-methyl-N-tert-butoxvcarbonyl)amino ~., ethyl]carbamoyloxy~-1,4-naphthoquinone ~1.74g, 3mmol) and the solution s~irred at room temperature for 5 hours. The precipi~a~e was filtered off, wasned with ether and dried in vacuQ to give ~he title compound (1.48g; 92%), m.p. >140 C tdecomposes). ~MR ~H (CDC13) 9.1-9.3 (lH, bs), 7.95-8.2 (2H, m),7.65-7.85 (2H, m), 7.1-7.35 (4H, s), 3.7-4.0 ~lH, br s), 3.0-3.5 (6H, m), 2.8 (3H, br s), 2.65 (lH, m), 1.75-2.15 (8H, m), 1.~-1.75 (2H, m).
The following were prepared in a similar manner ~o example 1:
2-[trans-4-(4-Chlorophenyl)cyclohexylJ-3-~N-[2-(N-methyl-~-ter~-butoxy carbonylamino)ethyl~carbamoyloxy)-1,4-naphthoquinone, from tert-butyl N-me~hyl-N-(2-aminoethyl)car~ama~e (W.S. Saari et al. J.Med.Chem. vol 33, 97, 1990), m.p. 128-131 C, NMR ~H (CDC13) 8.05-8.15 (2H, m), 7.65-7.8 (2H, m), 7.15-7.3 (4H, m), 3.5 (4H, m), 3.0-3.2 (lH, m), 3.0 (3H, s), 2.~-2.7 (lH, m), 1.75-2.15 (6H, m), 1.45-1.7 (llH, m).
,, -- = 2-[trans--(4-Chlorophenyl)cyclohexyl]-3-(N-methyl-N-[3-(N-meehyl-N-- _ tert-butoxvcar~onyla~ino)propyl]carbamoyloxy)-1,4-naphehoquinone, from tert-butyl N-methyl-N-[3-(methylamino)propyl]carbama~e (W.S. Saari e~
_ al. J.Med.Chem. vol 33, 97, 1990), oil, NMR SH (C~C13) 8.0-8.2 (2H, =), 7.65-;.8 (ZU~ m~, 7.1-7.35 (4U, m), 3.25-3.6 (4U, =~, 3.0-3.25 ~ , 7 1 ~
(4H, m), 2.? (3H~ s), ~.5-2.7 (lH, m), 1.75-2.15 (8H, m), 1.'1-1.7 (llH, m).
',~
2-~trans-4-(4-Chlorophenvl)cyclohexyl]-3-(N-ethvl-~-[2-(N-e~hyl-N-tert-butoxycarbonylamino)ethyl~carbamoyloxy~ napAthoquinone, from tert-butyl ~-ethyl-N-[2-(ethylamino)ethyl]carbama~e (W.S. Saari ~t al.
J.Med Chem. vol 33, 97, 1990), oil.
2-[trans-4-(4-Chlorophenvl)cyclohexyl]-3-~N-tert-butoxy-carbonylpiper-azine-N-carbonyloxyj-l,'l-naphthoq~inone, from N-tert-butoxycarbonyl- ¦
piperazine (Carpino et al J.Or~.Chem., vol 48(5), 664, lg83), oil.
2-[erans-4-(4-Chlorophenyl)cyclohexyl~-3-l[2-(N-methyl-N-tert-bu~oxy-carbonyl amino)ethoxy]carbonyloxy~-1,4-naphthoq~inone, from tert-butyl N-(2-hydroxyethyl)-N-methylcarbonate ~W.S. Saari et al. J.Med.Chem.
vol 33, 97, 1990), m.p. 110-lll C, NMR ~H (d6-DMSO) 7.9-8.1 (4H, m~, 7.3 (4H, s), 4.35-4.45 (2H, t, J-4H~)), 3.5-3.6 (2H, t, J-4Hz), 3.0-3.15 (lH, m), 2.5-2.7 (IH, m), 1.7-2.0 (6H, m), 1.45-1.65 (2H, m), 1.4~(9H, s).
2-ltrans-4-(4-Chlorophenyl)cyclohexyl]-3-~N,N.-bis~2-(tert-butoxy ~`
carbonylamino)ethyl]~carbamoyloxy~-1,4~naphthoquinone, from bis ~2-[(tert-butoxycarbonyi)aminolethyl~ amine, yellow oil, NMR ~H
(CDC13) 8.0-8.2 (2H,m), 7.65-7.8 (2H, m), 7.1-7.3 ~4H, m), 3.'5-3.7 (4H,m), 3.15(1H, m), 2.62~ , m), 1.8-2.1 (4H, m), 1.45 (9H,br s), 1.4(9H,br s) -- -, .
The following were prepared in a similar manner tO example 2 from the corresponding tert-buto~ycarbonyl pro~ected carbonates or carbamates :
,..................................................... ~;.
2-~,trans-4-(4-Ch,lorQphènyl)cyclohexyl]-3-~N-[2-(methylamino)ethyl)car-bamoyloxy~-1,4-nap~~`t~oq~inone hydrochloride monohydrate, m.p.
194-197 C, ~MR ~H (d6-DMSO) 9.1-9.3 (2H, bs), 8.4-8.5 (lH, t),7.8-8.1 (4H, m), 7.3 (4H, s), 3.4-3.6 (2H, m), 3.0-3.2 (3H, m), 2.55-2.75 (4H, m), 1.4-Z.15 (8H, m).
W O ~3/20044 PCT~GB93/0070f ,-,.~.~ r)~t ~ - 26 -, . _ . ~ ~
2-~trans~ 4-Chloropnenyl)cyclohe~yl3-3-lN-me~hvl-N-[3-(~ethylamino) propyl] carbamoYloxYl-1,4-naphthoq~inone hvdroc~loride monohvdrate, m.p. 208-210 C, NMR ~H (CDCl3) 8 1-8.2 (lH, d, J~5Hz), 8.0-8.1 (l~, d, i~SHz), 7.5;-~.85 (2H, m), 7.15-7.3 (4H, m), 3.05-3.35 (7H, m), 2.;-2.8 (5H. m), 1.45-2.1 (lOH, m).
2-~trans-4-~4-Chlorophenyl)cyclohexyl]-3-~N-ethvl-N-~2-(e~hylamino) ethvl]carbamovloxy)-1,4-n~phthoquinone hydrochloride ~onohvdrate, m.p.
197-201 C. NMR SH (CDC13) 8.1-8.2 (lH, d, JJ8Hz), 8.0-8.1 (lH, ~, -J~8Hz), 7.65-7.8 (2H, m), 7.1-7.3 (4H, m), 3.0-4.1 (7H, m), 2.5-2.7 (lH, m), 1.25-2.15 (14H, m).
2-[erans-4-(4-Chlorophenyl)cyclohexyl]-3-[piperazine-N-carbonyloxy]-1,4-naph~hoquinone hydrochloride dihydrate,-m.p. ?160 C (decomposes), NMR ~H (d6 DMSO) 7.8-8.1 (4H, m), 7.25-7.4 (4H, m), 3.6-4.0 (4H, m), 3.0-3.5 (5H, m), 2.5-2.7 (lH, m), 1.7-2.05 (6H, m), 1 4-1.7 (2H, m). ~, 2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-~(2-methylaminoethoxy)carbon-yloxy]-1,4-naph~hoq~inone hydrochloride, m.p. 2Ll-213 C, NMR ~H (d6 DMSO) 7.95-8.05 (2H, m), 7.74-7.9 (2H, m), 7.33 (4H, s), 4.2-4.3 (2H, m), 3.5-3.6 (2H, m), 3.0-3.2 (lH, m), 2.75 (3~, s), 2.5-2.7 (lH, m), 2.05-2.3 (2H, m), 1.8-2.0 (2H, m), 1.4-1.7 (4H, m).
2-i~rans-4-~4-Chlorophenyl)cyclohexyl]-3-[N.N.-bis (2-aminoethyl) car-bamoyloxyj-1,4-naphthoquinone dihydrochloride dihydrate, m.p.
~~ -215-218 C, ~MR ~H (d6-DMS0)8.2S-8.7 (4H, br) 7.85-8.15 (4H, m), 7.3-7.45 (4H,m) 3.5-4.0(4H,m), 3.0-3.4 (5H, m) 2.7 (lH, m), 1.5-2.2 (8H, m) , - ~ Exam~le 3 - ~~ ~ 2 - ~ trans - t ~ - tert - Butv l ~Yc loh~xy~ e thvl l - 3 - ~ N - me thyl - N - ~ 2 - ~ N
,-methvl-N--~ert-~e~arbonylamino~ethvllcarbamovloxy!-l.4- , na~hthoauinone ',' ~ ?'~
~'0 93t20044 PCT/GB93/00708 o a stirred solution or ~-itrans-(~-ter~-butylcvclohexyl~ethyl]-~-nvdroxy-i,4-naph~hoquinone (6.76:19mM) in drv dichloromethane (2S0 mL) under nitrogen, was added phosgene (20 mL; 12.5% solution in ~ol~ene), _ollowed bv pyridine (1.6 ml.20 mM) added dropwise, and the mixture was stirred for 1 hour. A solution of pyridine (1.6 mL; 20~M) and tert-butyl-N-me~hyl-N-[2-(~ethylamino)ethyl]carbamate (3.7g;21mM) was added dropwise. and ehe reaction ~ixture stirred at room temperature for a further 3.S hours. Evapora~ion of the solvents in vacuo gave a yellow solid, which was chromatographed on silica.
elut.r.g with toluene and ~hen 1:8 ethyl acetate:toluene, to give ,he .itle compound (3.19g; 31~) m.p. 117-118 C, NMR ~H (CDCl3) 8.05-8.15 (2H,mj, 7.65-7.75 (2H,m), 3.45-3.6 (4H, m), 3.2-3.1 (3H, ~xs), 2.95(3H, 2xs), 2.45-2.;5 (2H, m), 1.7-l.9 (5H, m) 1.5 (9H, 2xs), 0.9-1.1(5H, m), 0.85(9H,s).
'.:
Exam~le 4 2-~trans-(4-tert-Butvlcyclohex~l)methvll-3-(N-methYl-N-~2-tmethYla-ino)ethvll carbamovloxY)-l~ na~hthoquinone hvdrochloride ~
`
2-f~3L~-(4-tert-butylcyclohexyl)methyl]-3-(N.methyl-N-[2- ;j;
(me~hylamino)ethyl] carbamoyloxy)-l, 4-naphthoquinone (lg) was added ,o ether satura~ed with HC1(20 ~1) and the solution scirred at room temperature in the dark for 1.5 hours. The ether was evaporated ~
acuo to leave a yellow oil, which was dissolved in ethyl acetate and filtered. Cyclohexane was atded to the filtrate, resulting in the precipitation of thé eitle co~pound as a yellow powder (0.4ig) m.p.>
140 C (decomposes).
, ..
(wherein n, A, R6 and R7 are as hereinbefore defined); ~' and physiologically acceptable salts thereo The Cl 35 hydrocarbyl group R3 may be a straight or branched chain Cl l4 (e.g.
Cl-8)aLlYl or C2-14 (e g- C2-8)a~enYI group or a C3 10 (e.g. C3 g)cycloalkyl group, each of which may be optionally substituted by a C3 10 (e.g. C3 6) cycloaL~cyl group, and each of the aforesaid cycloallyl groups optionally bemg substituted by a Cl lo (e.g. Cl~) alkyl group. Alternatively the hydrocarbyl ' `~
group R3 may be a C3 10 (e.g.C3 8) cycloaLtcyl group substituted by a phenyl ~oup which is optionally substituted by a Cl lo (e.g. Cl 4) alkyl group. The hydrocarbyl group R3 preferably contains from 1 to 20 carbon atoms, e.g. I to 14carbon atoms. Suitable groups R3 include C3 10 cycloalkyl-CI g-alkyl, Cl lo alkyl-C3 10 cycloalkyl, Cl loalkyl--C3 10 cycloalkyl-Cl lo alkyl and C3 10-cycloa~l-C3 10 cycIoalkyl. R3 may also be substituted as hereinbefore defined by one to five halo, Cl 6 alkoxy, hydroxy, amin~,- Qr mono - or di-C14 alkyl amino substituents. ~~
PreferredgroupsR3 include:
a Cl 1OaL~cyl group; - -....
,,, i, .~ . " '1 ~
a C5 7 cycloalkyl group (which may be optionally substituted by astraight or branched chain Cl 6 alkyl group, a halo-Cl ,alkyl group, a Cl 6alkoxy group or a phenyl group, the phen~l group itself being optionally substitueed by one or ~ore substituents selected from Cl 6 alkyl and halogen); and a Cl 1Oalkyl-C5 7cycloalkyl group, wherein the cycloalkyl moiety maY be optionally su~stituted as defir.ed for the aforementioned C5 7 Cycloalkyl group.
A particularly preferred class of subscituents R is represented by the formula:
G 'C~3 !CH2)q~
c~3 wherein: !
q i5 zero or one and -R is a Cl 10 alkyl group- ~
Another par~icularly preferred class of substl~uents R is represan~ed by the formula: ~
-(C~2~
wherein:
'i ~l .3 ;~ 7 li~ ~f/~ 9 3 / ~ 0 7 0 ~
r is zero or one, and either R14 is hydrogen and R~5 is selected from halo, halo-Cl 6 alkyl, Cl 6 alkoxy, C1 6 alkyl-C1 6 alkoxy, and phenyl substituted by one or two groups selec~ed from halo and C 1 6 alkyl or R14 and R15 are both C1 6 alkyl or phenyl.
.
It will be appreciated that the compounds of formula (I) wherein R3 contains a substituted cyclohexyl group may e~ist as the cis or trans isomer, th~t is to say that the cyclohexyl ring may be cls or trans~ substituted by the naphthoguinone 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. In general when the compound is in the forrn of a mixture of isomers the trans isomer will be present in an arnount of about 50% or will be the `
predominant isomer but the use of mixtures in which the ~ isomer predominates is also included within the scope of the invention. The specific ratio of isomers may be varied as required; typical mixh~es include those in which the cis/trans isomer ratio is about 1:1,40:60 and 5:9~. For use according to the present invention the trans isorner 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.
An especially preferred substituent R3 is the 4-(4-chlorophenyl3cyclo-hexyl group:
~ y \\
in particular in the trans forrn with respect to the naphthoquinone ring. I
~J ~ ; ' , r ; i ~ S
P'`T ~ " ~ t ~,i~ ; ~~~~ ' ` ' ~ I -~? ~
W O 93/20044 ~ i PCT/GB93/00708 n the compounds or rormula (II) .~ is preferably a group _~T_ and R
represents a carbamate group O
, (CH ) 6 \o/ \ N/ \ N/ R
\
y of the groups R , R , R , R8, R10 Rl1 or R
alkyl, this may be straight or branched chain e.g. methyl, ethyl, isopropyl, t-butyl, isopentyl or n-hexyl. Suieably R, R and R are each hydrogen or a Cl 4 alkyl group. Most suit~bly R5 is methyl or - ethyl, R6 is hydrogen, methyl or ethyl, R ic hydrogen or a group -C0-0-R wherein R is Cl 4 alkyl, e.g. t-butyl.
In the compounds of formula (II) R and R preferably represen~ -O and -.he dotted line is a bond between the 2 and 3 positions of the naphehyl ring.
A preferred group of compounds of formula (II) may-be-represented by .he formula (III) ~ - -~ j G~\/~j /--~ R6 j C~Z)n N
~herein R , R and R are as hereinbefore defined, and physiolo~ically acceptable sales ~hereof.
W O 93/~'0044 , ~ 8 - PCT/GB93/0070~
~ ~urthermore ~he compounds of formula ~III) are prererably in the form of the ~rans-isomer.
''-[t-ans-4-(4-Chlorophenvl)cyclohexyl]-3-lN-methyl-~-;2-(methylamino)-ethyl]arbamoyloxv~ -naphthoquinone is a preferred compound of ~he formula (III).
A fur~her preferred group of compounds of formula (II) may be represen~ed by ,he formula (IV~:
9 ,~ (IV) ~/ \ I ~ Q R
. ~ ~ J ~ ¦ ~6 `(CH2)n N
wherein R5, R6 and R are as hereinbefore defined 2-~trans-~4-~-butylcyclohexyl)methyl]-3-~N-meehyl-N-[2-(meehylamino)-ethyl]carbæmoyloxy)-1,4-naphthoquinone is a preferred compound of the formula (IV). _ -By the term "hydrocarbyl" group is meant an aliphatic group, e.g. astraight branched chai~-or-cyc:l-ic 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.
Without wishing -o be bound by theory, it is believed that the carbonate or carbamate ;derivatives of formula (II) are pro-drugs of the corresponding hydroxvnaphthoquinone, that is, the carbamate or carbonate or group is cleaved in vivo to give the compound of formula (I) wherein Rb is a hydroxyl group.
!
~1 -f ~ `-~ rl ~ ' ~ ~ I j J ~ L ! ' WO 93/20044 PCr/(~B93/0070~ .`
q It is believed that the compounds of formuia (II) ~ xhibit activity against parasi~ic protozoa, in particular those organisms against which corresponding hydroxvnaphthoquinones have been found to be acti~e. such as Plasmodium species, eg. P. alci~arum; ~imeria s?ecies eg. _.~enella and E.ace~lina; rheileria species a.g T parvum and T annulata; Cr~tos~oridium; and To~oolasma ~ondii as well as .he parasitic organism Pnewmocvstis carinii, and ~ill .herefore be useîul in the ereatmene and/or prophylaxis of parasitic infections, such as those caused bv parasitic protozoa, eg. malaria, coccidiosis, cryptosporidiosis, toxoplasmosis and those caused by ~_sL~i~iL eg. P.carinii pneumonia (PCP) in animals, including humans.
It will be appreciated that the amount of a compound of formula (II) or its salt required for use in the treatment or prophylaxis of the above-mentioned diseases will depend inter ~lia on ~he particular compound administered, the route of administration, the age and weight of the mammal ~e.g. human) to be treated and the nature and se~erity of the condition being treated. In general, a suitable dose for administra~ion 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 .o lOOmg/kg, particularly 10 to 40 mg/kg. It will be apprecia~ed that for administration to neonates, lower doses may be required. ~ ~ -For prophylactic treatment a compound of formula (II) Qr a saltthereof may also be given less fre~uently, e.g. as a-s mgla dose on alternate days, once or t~ice 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 formula~ion is used the raee of release of the active ingredient. Thus for once-weekly administracion a suitable prophylactic dose is in che range 0.1 to 100 mg/k~,e.g. O.S ~o 50 mg/kg par~icularly 5 to 50 mgjkg.
W O ~3/20044 ~ 7 /~ ! PCT/GB93/0070~
=
'. snouid be understood ~hat for consistency the dosages referred to above are calculated in terms of ~he compound of formula (II) ~ se, and mav ~equire adjustmene in the evenc a salt is emploved.
Ihe present invention ~hus rurther 2rovides a method for the treatment and/or propnylaxis of parasieic inrections e.g. parasitic protozoal infections such as malaria, or infections caused ~y 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 .hereof.
There is also pro~ided a compound of formula (II) or a physiologically acceptable salt thereof for use in therapy, e.g. in the treatment and~or prophylaxis of parasitic diseases as hereinbefore defined.
!
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. ' For use according to the present in~ention a compound of formula tII) -or a ?hysiologically acceptable-~salt thereof is preferably presented as a pharmaceutical formulation. In general such pharmaceutical formulations will comprise - ? compound of formula (Il) or a physiologically acceptable sait thereof together with one or more pharmaceutically acceptable carriers therefor and optionally other ~herape~tic and/or prophylactic ingredients. The carrier(s) must be acceptable in the sense o ~eing compatible with the other ingredients of the formula and not de-Leeerious to the recipient thereof, .
:, The present invention, -therefore, further provides a pharmaceutical 'ormula~ion comprising a compound of formula ~II) or a pharmaceuti-cally acceptable sar; ehereof cogeeher with a pharmaceutically acceveable carrier ~herefor.
' '' 1 !" . ~
W O 93~20044 PCT/GB93/00708 There is aiso provided a method ror the preparation of a pharmaceut-ical for~ulation comprising bringing into associazion a compound o~
~ormula (I ) or a pharmaceu~ically acceptable salt thereof, and a ?harmaceutically acceptable carrier therefor.
.~ co~oound of formuia (II) or ies salt may conveniently be presen~edas a pharmaceuticai formulation in unic dosage form. A convenient unit dose formulation contains a compound of formuia (Il) or a physiologicallv acceptable salt thereof in an amount of from 10 mg ~o lg.
Iharmaceu~ical formulations include those suitable for oral, _oplcal ~including dermal, buccal and sublingual), rectal ~nd parenteral (including subcutaneous, intradermal. intramuscular and intravenous) administration. The formulation may, where appropriate, be convenienrly presen~ed 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 j (II) or a physiologically acceptable salt thereof with liquid carriers or finel,v dividec solid carriers or both and then, if necessary, shaping ~he product into the desired formulation.
, Pharmaceutical formulations suitable for oral administration wherein the carr-er 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 tab-let--m~y be made by compression or moulding, op~ionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the ac~ive ingredient(s) in a free-flowin~ form such as a powder or granules optionally mixed with a binder, -lubricant, inert diluent, lubricating agent, surface-acrive agent or dLspersing agen~. Moulded tablets may be made by moulding in a suitaUe machine a mi~rure of the powdered active ingrediene(s) with any suitable carrier. Table~s may be optionallv coated and, if uncoated, ~ay optionally be scored. Capsules may be prepared by filling the active W O 93/20044 i! ' "! ~ -1 ,1 ,, PCT/GB93/0070f ,_, , ),, ~, 1 1 ingredien~(s) , either alone or in aomixture ~ith one or ~ore accessory ingredients. ineo the capsule sh~lls and .hen seaiing he~
in the usual manner. Cachets are analogous ~o capsules wherein ~he active ingredien~(s) ~ogether wi.h anv accessorv ingredient(s) is (~re) seaied ln a rice paper envelo~e. .~ co~pound or formula (II) or a physiologically accepta~le salt .hereof ~av also be rormulated as dispersible granules, ~hich may for example be suspended in ~ater before administration, or sprinkled on food. The granules mav be packaged e.g. in a sache~. Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous lîquid or a non-aqueous liquid, or as an oil-in-wa~er liquid emulsion, e.g. a sYrup, elixir, emuision or a draught. A syrup may be made by adding the active ingredien~(s) eo 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 oeher ingredients such as polyhvdric alcohols for example glycerol or sorbitol.
Formulations for oral administration include controlled release dosage forms e.g. tablets wherein the ac~ive ingredient(s) is (are) formulated in an appropriate-release - controlling matri~, or coated with a suitable release -~con~rollIng film. Such formulations mav be particularly convenient for prophylactic use.
F
Pharmaceueical formulations 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. -----Pharmaceutical formulati-ons suitable for parenteral administration include sterile solutions or suspensions of the active ingredient(s) ? ~ -'? 7,1 ' W O 93~20044 ~ ' PCT/GB93/00708 in aaueous or oleaginous vehicles. Injec~ible preparations may be adapted for bolus injec~ion or continuou~ infusion. Such preparations are con~eniently presented in ~nit dose or multi-dose containers which are sealed after introduction of the formula~ion until requ~red for use. .~lternatively, the active ingredient(s) may be in powder form eg. freeze-dried which is constituted with a s~litable vehicle, such as s~erile, pyrogen-free water, before use.
A compound oî formula (II) or a physiologicallv acceptable salt thereof mav also be formulated as a long-acting depot preparation, which mav be administered by intramuscular injection or by implanta~ion e.g. subcutaneously or intramuscularly.~epoe preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-e~change resins. Such long-acting formulations are particularly ~onvenient for prophylactic use.
I
Uhilst 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-[erans-4-(4-chlorophen yl)cyclohexyl~-3-~N-methyl-N-[2-(methylamino)ethyllcarbamyloxy)-1,4-naphthoq~inone has improved water solubility over the parent hydroxynaphtho~uinone. ~ ~
It should be understood that in addition to the aforemen~ioned carrier ingretien~s the pharmaceutical formulations for the various routes o~
administration described above may include, as appropriate one or more additional carrier ingredients such as diluen~s, buffers, flavouring agents, binders, surface active agents, thickeners, lubricanti, preser~atives (including an~i-oxidants) and ~he like, and substances included for the purpose of rendering the formulation iso~onic _~th the bloot of the intended recipient. -~ ~
The compounds of the present invention may be administered in combination or concurren~ly wi~h other ~herapeu~ic agen~s, for example W 0 93t20044 ~ PCT/GB93/~070 other antimalarial agen~s, such as 4-aminoquinolines eg. chloroquine and amodiaauine; 8-aminoquino- lines eg. primaquine; chloroquine;
mefloquine; quinine; quinidine; artemesinin; ar~esumate; ar~emether; ~ ;
haloîantrine; dihydrofolate reductase inhibi~ors eg. pyrime~hamine; r.~
sulphonamides eg. sulphadox- ine: proguanil; chloroproguanil;
dapsone, hydroxvnaphthoquinones: or ~ixtures eg.
pyrimethamine/sulphadoxine; pyrime~hamine/dapsone; and ' ;
pyrime~hamine/sulfalene; antibac~erial agents such as trimethoprim-sulphamethoxazole mixtures; an~icoccidial agents such as monensin, ha}ofuginone, arprinocid. amprolium. dinitolmîde, robenidine or salinomycin; or antibio~ics such as clindamycin, tetracycline, ¦-doxvcycline, or spiromycin; or agen~s active against Pneumocvstis carinii sucn as pen~amidine or Eflornithine.
~hen compounts of formula (II) are used in combina~ion 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 ar~. ¦
Compounds of formula (II) may be prepared by reaction of a compound of formula (V) ~ ~3 ''~/\ ~ (V) O ..
wherein R3 is as hereinbelore defined and-X is halo, with a compound of the formula (Vl) HA(C~)n N\ (VI) R
? ~ 1 r/ ,1, wherein n, .~, R and R are as nereinbefore defined; 2rovided ~hat when it is required to prepare a compound wherein one or more of R
and R is hvdrogen. the corresponding compound is prepared with a group -ÇO-O-R in place, instead or hydrogen and this group is ~hen removed.
The reaction may con~eniently be effecced in the presence of a solvent which is inert tO the reagents. Solvents which may be emploved include aromatic hydrocarbons e.g. benzene or toluene; halogenated hydrocarbon e.g. chloroform or dichloromethane; dipolar apro~ic soivents e.g. dimethylformamide or hexamethylphosphoric ~riamide;
e~hers e.g. tetrahydrofuran or dioxan; pyridine; acetonitrile;
trimethylphospha~e and triethylphosphate. The reaction temperature may conveniently be in the range of from -80 C tO 100 C, preferably 0C to 30C.
The reaction may adYantageously be effected in the presence of a base which may be an organic base, for example pyridine, 4-dimethylamino-pyridine, a terti~ry amine such as .riethylamine, or l,8-diazabicy-clo~5,4,0]-7-undecene (D W), or an inorganic base, for example an alkali metal carbonate such as potassium carbonate or sodium hydrogen carbonate.
- To prepare a compou~d of-formula (II) wherein Rl, R2 and R4 each represent a carbonate- or- carbamate group che reaction should be effected after reduction of the quinone nucleus, which mav be effected in conventional manner.
Sale formation can also be effected by methods well known in the art, I
by reacting a c~mpoun~ of formula (II) with an appropria~e acid.
. _ RemoYal of the pro~ecting ~roup -C0-0-R is conveniently carried out by acid, for example when R is tertiary butyl hydrogen chloride in ether.
- o The compounds or ~he rormula (V) mav convenien~l~ be prepared ~n situ from the corresponding hvdroxvnaph~hoquinone, ror example when .~ is chloro bv the reaction oI the hydroxynaph~hoquinone wi~h phosgene in an inert soi~ent, as defined above, ln the presence of the base used .o actach ~he carbama~e side chain. This reaction is carried ou~
between -~0 C and 50 C and suitably ~t between -10 C and 10 C.
5Ompounds of formula ~IV) may be prepared according to known ~ethods for the svnthesis or hydroxynaphthoquinone deriva~ives, such as are described in US Parents ~os. 2,553,648; 3,367,830; and 3,347,742; UK
Paten~ No. 1,553,424; European Patents Nos. 2,228; 77,551; '7,550; and 123,238 and European Patent Applica~ion No. 362,996. Thus for example a compound of formula (IV) may be prepared by reaction or a 2-halo (e.g. 2-chloro)-1,4-naphthoquinone with a compound serving tO include ehe required R group, followed by alkaline hydrolysis. Where R is an optionally substituted cyclohexyl or optionally substituted cyclohexylmethyl group it may be in~roduced by reaction with the appropriately substituted cyclohexylcarboxylic acid or cyclohexylacetic acid.
The i~vention will now be further illustrated by the following non-limiting examples:-In vi~o Activitv a~ain~t ~lasmodium ~elii_in mice.
Tes~ Com~ounds Compound A: 2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-~N-methyl-N-~ ~2-(methylamino)ethyl]carbamoyloxy)-1,4-naphthoquinone hydrochloride mo- nohydrate. I
_ Com~ound B: 2-[trans-4-(4-Chlorophenyl)cyclohexyl ! - 3-lN-[2-(methvl amino)ethyl~car~amoYloxy~-1,4-naph~hoquinone hydrochloride monohy-drate.
.~,t ~,.-7 ,~ , l7 , Co~ound C: 2-[trans-4-(4-Chlorophenyl~cyclohexylj-3-~N-me~hvl-~'3-(me~hvlamino)propyl]carbamoyloxy)-1,4-naphthoquinone Com~ound _D- trans-2-~4-(4-Chlorophenyl)cyclohexyl]-3-~piperazine-N-carbonyloxyj-1,4-naphthoquinone hydrochloride dihydra~e, Com~ound (1~: 2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-hydrox~-1,4-naphthoquinone.
Compounds A, B, C, and (I) were administered orally and intravenously, in the manner described below, METHOD
I
The test method is a modified version of the 4-day suppressive tes~.
The YM strain of P,voelii uas maineained in mice by twice weekly passage. Infected blood was collected and diluted with normal saline to give an inoculum of 3X106 parasitized enythrocytes/ml. On the morning of Day 1 the test animals (male CD-l mice weighing 18-20g) were infected intravenously via the tail vein with 0,lml of inoculum~mouse.
I
Oral (p.o.) Test compounds A, B and ~ -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 fi~e groups of mice, each group recei~ing 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 ED50). The mice were dosed orally 24 hours post-infection.
Intravenous (~,v ~
WO 93/20044 ;1 ~ r~ ~; r~ 18 - PCT/G~93/0070~
I.-. formuiations of .es~ Compounds .~ and B were pre~ared by dissolving the compound in wa~er lmmediately berore use, and administered via the .ail vein as a single dose 24 hours post-infection.
On ~he morning of day ~ smears ot tail blood were prepared from each mouse and the parasitaemia coun~ed. 3ata were analysed to yield EDj~
values bv the best fit to a sigmoidal dose response curve. The results are presented in Table 1 below.
Results Table 1 Dosing Schedule ED50 mg/kg I ~: P.o. 1 ~ i.v, I
Com~ound (I~ 0.16 0.12 ~- Compound (A) O.15 0.12 - Co ound (B) 0.2 0.27 .
., Com~ound (C~ O.4 0.29 ~ ~ Com~u~ (D) O.4 -In vi~o Act vit~ a~ainst Pneumoc~stis carinii in mice .
Dru~s .ested ~ Septrin - Wellcome Paediatric Suspension con~aining 200 mg sulfamethoxazole/40 mg trimethoprim per 5 ml '~ ?~
W O 93/20044 PCT/GB93/00,08 l9 ~tovaquone-2- .rans-4- (4-chlorophenyl)cyclonexyl]-3-hydroxy-1, 4-naphthoquinone Test compound-2-[trans-4-(4-chlorophenyl)cvclohexyl~-3-~N-me~hyl-N- E 2-(methylamino)e~hyl~ carbamovloxy)-1,4-naphtho-quinone hydrochloride monohvdrate ~ethod ?neumocvs~is_carinii (PC~-free female SCID (C.B-i7/lcr-scid/scid) mice (20-25g) were started on dexamethasone (2m/L in drinking water), 7 days prior to in~ratracheal infection wi~h single dose of cryo-preserved mouse-derived PC (dose:-2 x lO cysrs equivalent to about 106 .rophozoites). Drugs were evaluated for prophylaxis bv continuous daily oral dosing of groups of 10 mice wieh each drug from 1 dav post infection until day 42. Trials were terminated and all the mice killed 24 n after the last dose. The lungs were removed and an impression smear prepared ~from a representative portion of lung ; - selected a~ random. Lung smears were stained for P.carinii cysts usin~ an immunofluorescent antibody test kit ~Detect IF P. carinii, Shield Diagnostics Ltd.) Slites were scored for the intensity of P.
carinii infection by scanning the entire smear a~ lOOx magnification and coun~ing the highly fluorescent cysts. Smears were assigned one of the following scores~.
0 - no cysts/smear +1 ~ 1- to 5 ~ys~s/smear , +2 - 6 to 50 cysts/smear +3 51 to 250 cysts/smear +4 ~250 cvsts/smear Drug formulation~
Septrin was diluted int~ ~-drinking water; the dose was calculated on the basis that each mouse would drin~ 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 L hour of preparation.
WO 93/20044 ~ r~ ~ . PCT/GB93/0070 ~esul tS
Ihe results v~hich are presen~ed in Table 2 below, were based ~n two independen~ blind examinations, and are expressed as an a~erage infection score oî the 10 mice in each group. Data are also expressed ' as a percen~age of the control (dosed daily p.o. wl~h dis~illed water).
Treatment GroupMean score'+ SE % of Control Control 3.6+ 0.2100 Septrin (2S0/50 mg/kg/day) 0.1+ 0.1 3~
A~ovaquone ~100 mg/kg/dav p.o) 1.5+ 0.3 43%
Test,compound (100 mg.kg.day p.o) 0.1+ 0.1 3%
FormLulation ~xamPLes The following examples i}lustrate, with particular reference to ehe compound of Example 2, pharmaceutical formulations which may be employed in accordance with the present invention. It will be appreciated that other compounds of form~la (II) may be formulaced in similar manner-.
. Iniectable solut-on A solution for intramuscular injection may be prepared by ~ ixing:-=,_~- , Compound of Example 29.5 par~s by weight ~~ Dimethyl sulphoxide19.0 parts by weight Sorbitan monooleace4.5 parts by weight Corn oil 67 0 parts by weight .100 . O
W O 93/20044 ,~ iPCT/GB93J0070 B. Injec~able solution Compound of Example 2 5 parts by weigh~ .
N-me~hvl-pyrollidone 48.3 parts by weight Tween 80 2 parts by weight Span 80 4.7 parts by weight Miglyol 812 4~l parts by weight C. Table~
Compound of Example 2 25.0 mg Lactose BP 48.5 mg Microcrystalline Cellulose BP 10.0 mg ("Avicel pH 101") Low-substituted Hydroxypropyl; 10.0 mg Cellulose BP (~LHPC LH-ll") Sodi~m Starch Glycollate BP 3.0 mg ("Explotab") ~:~ Povidone BP (~K30") 3.0 mg Magnesium Stearate BP 0.5 mg _ - 100 0 mg D. IV Solution Freeze Dried - - j Compound of Example 2 50mg Water ~or Inj ections to lOml Dissolve the naphtho~uinone in the ~ater for Injections.
Sterilise by fi~tration. Fill into glass vials and freeze dry.
Recons~itute-:shortly before use with Water for Injec~ions, WO 93/20044 ~ ~ I q ' PCT/GB~3/00708 ~ _ rj rJ i . ~ - 2 2 E. ~a~sule Compound of Example 2 100 mg Starch 1500 150 mg ~agnesium stearate 2.5 mg filled into a hard gelatin capsule F. Aerosol Formula~ions a) Compound of Example 2, micronised 1.0 mg Aerosol propellant to 5.0 ml Suspend the micronised campound in ~he aerosol propellan~. ~
- Fill this suspension ineo preformed aerosol cannisters, Sj ~-ml~cannister under pressure, through the valve orifice.I ~
`~
b) Compound of Example 2, micronised 1.0 mg Arlacel 85 Q.l~ w/v Aerosol propellane to 5 ml !
Disperse the Arlacel 85 in the aerosol propellant and then add compound of Example 4. Fill the _suspension into preformed aerosol cannisters, Sml/cannis~er under pressure, through ~he valve orifice.
: ~~ ~~ G. Powder Inhalation ; Compound of Example 2, micronised 1.0 mg Lactose 29.0 mg ': ' .
Tritura~e and blend the micronised compound with the lactose.
~~ F~ll ehe resuleing powder blend into hard gelatin capsule shells, 30 mg per capsule.
tert-butvl ~-methvl-~-F2-(me~hvlamino)et~v11carbamate O 93/20044 PCT/~B93/00708 - ~3 -This was ?re~ared from N,N'-dimethvlethylenediamine rollowing rhe procedure of W.S. Saari. J.E. Schwering, P..~. Lyle, S.J. Smith and E.T. Engeihardt. J.~ed.Chem. vol 33, 97, L990.
~is_'2-~ r~-butoxvcarbonvl~Laminole~hvllamine To a stirred solu~ion or diethylenetriamine (lOg; 97 ml; Lancaster synehesis) ~n tetrahydrofuran (5ml) cooled to O C was added dropwise a solution of di-tert-bu~yl dicarbonate (10.5g; 48mM) in tetrahydrofuran (50 ml). The mixture was allowed to warm ~o room temperature and stirred for 18 hours. filtered concentrated Ln vaeuo snd partitioned be~ween brine and ethyl acetate. The aqueous layer was extrac~ed once with ethYl acetate and the combined extracts were dried (MgS04) and concentra~ed Ln vacuo to leave a clear 3il (6.7g). Chomatography on silica gel with 1:4 methanol: chloroform gave the title compound as a clear oil (2g; 27%), NMR ~H (CDC13) 3.15-3-3 (4H, m), 2.75 (4H
t,J5Hz), 1.~5 (18 H,s).
Exam~le 1 2- r trans-~-t~-~hloro~hen~l)c~clohex~ 3-~N-me~hYl-~-~2-(N-methYl-~-tert-butoxvcarbonvl2_minoethyllcarbamovloxYl-1.4-nashtho~uinone To a stirred suspension of 2-hydroxy-3-ttrans-4-(4-chlorophenyl)cyclo-xy1]-1,4-naphthoquinone (3.~g;-lOmmol) in dry dichloromethane (60ml), cooled to O C under nitrogen, -was added all at once a solution of phosgene in toluene (lOml;- 1.25M solution). Pyridine (0.8ml; lOmmol) was added dropwise and the solution stirred for a further 45 minutes at 0C. .~ mixture of~` ~ -butyl N-methyl-N-[2-(methYlamino)echyl~
carbamate (1.85g; -10.5mmol) and pyridine (0.8ml; lOmmol) in dry dichlorome~hane (lOm}.~ was atded dropwise o~er 15 minutes and the mixture lert stirring-a-t roo~ temperature for 18 hours. The mixture was diluted with dichloromethane (50 ml), washed with water, lM
hydrochloric acid and water, dried (magnesium sulphate) and concentrated ;o lea~e an orange oil. Chromatography on silica with W 0 93t20044 ~ ' PCT/GB93/0070~ -1:9 ethyl aceta~e:dichlorome~hane followed bv tr.turation with 1:2 e~her:hexane gave ~he title compo~nd (3.12g; ~4%), ~.p. 113-115 C, NMR
~H (CDC13) 3.0-8.2 (2H, m), 7.65-/.8 (2H. m)~ '.L-7.3 (4H, m), 3.4-3.7 (4H, m), '.'5 (3H, 2~s), ~.05-3.25 (1~. m), 3.0 (3H, 2~s), 1.5-2.15 '`
(9H, 2xs).
Exam~le 2 2-~trans~ -Chloro~nenvl)cvclohex~11-3-~N-methvl N-~2-l~ethylamino) ethvllcarDamovloxY~-1.4-na~h~ho~uinone hvdrochloride monohvdrate !
To ether sa~ura~ed with HCL (30ml) was added 2-[crans-4-(4-Chlorophen-yl)cvclohexvl]-3-(N-methyl-N-~2-(N-methyl-N-tert-butoxvcarbonyl)amino ~., ethyl]carbamoyloxy~-1,4-naphthoquinone ~1.74g, 3mmol) and the solution s~irred at room temperature for 5 hours. The precipi~a~e was filtered off, wasned with ether and dried in vacuQ to give ~he title compound (1.48g; 92%), m.p. >140 C tdecomposes). ~MR ~H (CDC13) 9.1-9.3 (lH, bs), 7.95-8.2 (2H, m),7.65-7.85 (2H, m), 7.1-7.35 (4H, s), 3.7-4.0 ~lH, br s), 3.0-3.5 (6H, m), 2.8 (3H, br s), 2.65 (lH, m), 1.75-2.15 (8H, m), 1.~-1.75 (2H, m).
The following were prepared in a similar manner ~o example 1:
2-[trans-4-(4-Chlorophenyl)cyclohexylJ-3-~N-[2-(N-methyl-~-ter~-butoxy carbonylamino)ethyl~carbamoyloxy)-1,4-naphthoquinone, from tert-butyl N-me~hyl-N-(2-aminoethyl)car~ama~e (W.S. Saari et al. J.Med.Chem. vol 33, 97, 1990), m.p. 128-131 C, NMR ~H (CDC13) 8.05-8.15 (2H, m), 7.65-7.8 (2H, m), 7.15-7.3 (4H, m), 3.5 (4H, m), 3.0-3.2 (lH, m), 3.0 (3H, s), 2.~-2.7 (lH, m), 1.75-2.15 (6H, m), 1.45-1.7 (llH, m).
,, -- = 2-[trans--(4-Chlorophenyl)cyclohexyl]-3-(N-methyl-N-[3-(N-meehyl-N-- _ tert-butoxvcar~onyla~ino)propyl]carbamoyloxy)-1,4-naphehoquinone, from tert-butyl N-methyl-N-[3-(methylamino)propyl]carbama~e (W.S. Saari e~
_ al. J.Med.Chem. vol 33, 97, 1990), oil, NMR SH (C~C13) 8.0-8.2 (2H, =), 7.65-;.8 (ZU~ m~, 7.1-7.35 (4U, m), 3.25-3.6 (4U, =~, 3.0-3.25 ~ , 7 1 ~
(4H, m), 2.? (3H~ s), ~.5-2.7 (lH, m), 1.75-2.15 (8H, m), 1.'1-1.7 (llH, m).
',~
2-~trans-4-(4-Chlorophenvl)cyclohexyl]-3-(N-ethvl-~-[2-(N-e~hyl-N-tert-butoxycarbonylamino)ethyl~carbamoyloxy~ napAthoquinone, from tert-butyl ~-ethyl-N-[2-(ethylamino)ethyl]carbama~e (W.S. Saari ~t al.
J.Med Chem. vol 33, 97, 1990), oil.
2-[trans-4-(4-Chlorophenvl)cyclohexyl]-3-~N-tert-butoxy-carbonylpiper-azine-N-carbonyloxyj-l,'l-naphthoq~inone, from N-tert-butoxycarbonyl- ¦
piperazine (Carpino et al J.Or~.Chem., vol 48(5), 664, lg83), oil.
2-[erans-4-(4-Chlorophenyl)cyclohexyl~-3-l[2-(N-methyl-N-tert-bu~oxy-carbonyl amino)ethoxy]carbonyloxy~-1,4-naphthoq~inone, from tert-butyl N-(2-hydroxyethyl)-N-methylcarbonate ~W.S. Saari et al. J.Med.Chem.
vol 33, 97, 1990), m.p. 110-lll C, NMR ~H (d6-DMSO) 7.9-8.1 (4H, m~, 7.3 (4H, s), 4.35-4.45 (2H, t, J-4H~)), 3.5-3.6 (2H, t, J-4Hz), 3.0-3.15 (lH, m), 2.5-2.7 (IH, m), 1.7-2.0 (6H, m), 1.45-1.65 (2H, m), 1.4~(9H, s).
2-ltrans-4-(4-Chlorophenyl)cyclohexyl]-3-~N,N.-bis~2-(tert-butoxy ~`
carbonylamino)ethyl]~carbamoyloxy~-1,4~naphthoquinone, from bis ~2-[(tert-butoxycarbonyi)aminolethyl~ amine, yellow oil, NMR ~H
(CDC13) 8.0-8.2 (2H,m), 7.65-7.8 (2H, m), 7.1-7.3 ~4H, m), 3.'5-3.7 (4H,m), 3.15(1H, m), 2.62~ , m), 1.8-2.1 (4H, m), 1.45 (9H,br s), 1.4(9H,br s) -- -, .
The following were prepared in a similar manner tO example 2 from the corresponding tert-buto~ycarbonyl pro~ected carbonates or carbamates :
,..................................................... ~;.
2-~,trans-4-(4-Ch,lorQphènyl)cyclohexyl]-3-~N-[2-(methylamino)ethyl)car-bamoyloxy~-1,4-nap~~`t~oq~inone hydrochloride monohydrate, m.p.
194-197 C, ~MR ~H (d6-DMSO) 9.1-9.3 (2H, bs), 8.4-8.5 (lH, t),7.8-8.1 (4H, m), 7.3 (4H, s), 3.4-3.6 (2H, m), 3.0-3.2 (3H, m), 2.55-2.75 (4H, m), 1.4-Z.15 (8H, m).
W O ~3/20044 PCT~GB93/0070f ,-,.~.~ r)~t ~ - 26 -, . _ . ~ ~
2-~trans~ 4-Chloropnenyl)cyclohe~yl3-3-lN-me~hvl-N-[3-(~ethylamino) propyl] carbamoYloxYl-1,4-naphthoq~inone hvdroc~loride monohvdrate, m.p. 208-210 C, NMR ~H (CDCl3) 8 1-8.2 (lH, d, J~5Hz), 8.0-8.1 (l~, d, i~SHz), 7.5;-~.85 (2H, m), 7.15-7.3 (4H, m), 3.05-3.35 (7H, m), 2.;-2.8 (5H. m), 1.45-2.1 (lOH, m).
2-~trans-4-~4-Chlorophenyl)cyclohexyl]-3-~N-ethvl-N-~2-(e~hylamino) ethvl]carbamovloxy)-1,4-n~phthoquinone hydrochloride ~onohvdrate, m.p.
197-201 C. NMR SH (CDC13) 8.1-8.2 (lH, d, JJ8Hz), 8.0-8.1 (lH, ~, -J~8Hz), 7.65-7.8 (2H, m), 7.1-7.3 (4H, m), 3.0-4.1 (7H, m), 2.5-2.7 (lH, m), 1.25-2.15 (14H, m).
2-[erans-4-(4-Chlorophenyl)cyclohexyl]-3-[piperazine-N-carbonyloxy]-1,4-naph~hoquinone hydrochloride dihydrate,-m.p. ?160 C (decomposes), NMR ~H (d6 DMSO) 7.8-8.1 (4H, m), 7.25-7.4 (4H, m), 3.6-4.0 (4H, m), 3.0-3.5 (5H, m), 2.5-2.7 (lH, m), 1.7-2.05 (6H, m), 1 4-1.7 (2H, m). ~, 2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-~(2-methylaminoethoxy)carbon-yloxy]-1,4-naph~hoq~inone hydrochloride, m.p. 2Ll-213 C, NMR ~H (d6 DMSO) 7.95-8.05 (2H, m), 7.74-7.9 (2H, m), 7.33 (4H, s), 4.2-4.3 (2H, m), 3.5-3.6 (2H, m), 3.0-3.2 (lH, m), 2.75 (3~, s), 2.5-2.7 (lH, m), 2.05-2.3 (2H, m), 1.8-2.0 (2H, m), 1.4-1.7 (4H, m).
2-i~rans-4-~4-Chlorophenyl)cyclohexyl]-3-[N.N.-bis (2-aminoethyl) car-bamoyloxyj-1,4-naphthoquinone dihydrochloride dihydrate, m.p.
~~ -215-218 C, ~MR ~H (d6-DMS0)8.2S-8.7 (4H, br) 7.85-8.15 (4H, m), 7.3-7.45 (4H,m) 3.5-4.0(4H,m), 3.0-3.4 (5H, m) 2.7 (lH, m), 1.5-2.2 (8H, m) , - ~ Exam~le 3 - ~~ ~ 2 - ~ trans - t ~ - tert - Butv l ~Yc loh~xy~ e thvl l - 3 - ~ N - me thyl - N - ~ 2 - ~ N
,-methvl-N--~ert-~e~arbonylamino~ethvllcarbamovloxy!-l.4- , na~hthoauinone ',' ~ ?'~
~'0 93t20044 PCT/GB93/00708 o a stirred solution or ~-itrans-(~-ter~-butylcvclohexyl~ethyl]-~-nvdroxy-i,4-naph~hoquinone (6.76:19mM) in drv dichloromethane (2S0 mL) under nitrogen, was added phosgene (20 mL; 12.5% solution in ~ol~ene), _ollowed bv pyridine (1.6 ml.20 mM) added dropwise, and the mixture was stirred for 1 hour. A solution of pyridine (1.6 mL; 20~M) and tert-butyl-N-me~hyl-N-[2-(~ethylamino)ethyl]carbamate (3.7g;21mM) was added dropwise. and ehe reaction ~ixture stirred at room temperature for a further 3.S hours. Evapora~ion of the solvents in vacuo gave a yellow solid, which was chromatographed on silica.
elut.r.g with toluene and ~hen 1:8 ethyl acetate:toluene, to give ,he .itle compound (3.19g; 31~) m.p. 117-118 C, NMR ~H (CDCl3) 8.05-8.15 (2H,mj, 7.65-7.75 (2H,m), 3.45-3.6 (4H, m), 3.2-3.1 (3H, ~xs), 2.95(3H, 2xs), 2.45-2.;5 (2H, m), 1.7-l.9 (5H, m) 1.5 (9H, 2xs), 0.9-1.1(5H, m), 0.85(9H,s).
'.:
Exam~le 4 2-~trans-(4-tert-Butvlcyclohex~l)methvll-3-(N-methYl-N-~2-tmethYla-ino)ethvll carbamovloxY)-l~ na~hthoquinone hvdrochloride ~
`
2-f~3L~-(4-tert-butylcyclohexyl)methyl]-3-(N.methyl-N-[2- ;j;
(me~hylamino)ethyl] carbamoyloxy)-l, 4-naphthoquinone (lg) was added ,o ether satura~ed with HC1(20 ~1) and the solution scirred at room temperature in the dark for 1.5 hours. The ether was evaporated ~
acuo to leave a yellow oil, which was dissolved in ethyl acetate and filtered. Cyclohexane was atded to the filtrate, resulting in the precipitation of thé eitle co~pound as a yellow powder (0.4ig) m.p.>
140 C (decomposes).
, ..
Claims
1. Compounds of general formula (II) and physiologically acceptable salts thereof (II) wherein R3 is C1-35 hydrocarbyl group optionally substituted by one to five substituents, selected from halo, C1-6alkoxy, hydroxy, amino, and mono-or di-C1-4alkyl-amino; and either the dotted line represents a double bond between the 2 and 3 positions of the naphthyl ring; R1 and R4 each represent = O; and R2 represents a group wherein n is 2 or 3, R6 and R7 which may be the same or different, each represent a hydrogen atom, a C1-6 alkyl group, optionally substituted by hydroxy, C1-6alkoxy or a group wherein R9 is a C1-6alkyl group optionally substituted by an amino group optionally substituted by one or two alkyl groups, or R6 and R7 may each be a group -?-O-R8 wherein R8 is a C1-6 alkyl group, A is an oxygen atom or a group wherein R5 represents a hydrogen atom, a C1-6alkyl group optionally substituted by hydroxy, C1-6 alkoxy or an amino group optionally substituted by one or two C1-6alkyl groups or R5 is a group -?-O-R10 wherein R10 is a C1-6alkyl group or R5 is a group wherein p is 2 or 3 and R11 and R12 are as hereinbefore defined for R6 and R7 or, when A is and n is 2 R5 may be linked to R6 so that forms a piperazine ring;
or the dotted line represents double bonds between the 1, 2 and 3, 4 positions of the naphthyl ring, and R1, R2 and R4 each represent a group wherein-n, A, R6 and R7 are as hereinbefore defined.
2. Compounds as claimed in claim 1 wherein R3 is a C1-10alkyl group;
a C5-7 cycloalkyl group (which may be optionally substituted by a straight or branched chain C1-6 alkyl group, a halo-C1-6alkyl group, a C1-6alkoxy group or a phenyl group, the phenyl group itself being optionally substituted by one or more substituents selected from C1-6 alkyl and halogen); or a C1-10alkyl-C5-7cycloalkyl group, wherein the cycloalkyl moiety may be optionally substituted as defined for the aforementioned C5-7 cycloalkyl group.
Compounds as claimed in claim 1 or claim 2 wherein R3 is represented by the formula:
wherein:
q is zero or one and R13 is a C1-10 alkyl group.
4. Compounds as claimed in claim 1 or claim 2 wherein R3 is represented by the formula:
wherein:
r is zero or one, and either R14 is hydrogen and R15 is selected from halo, halo-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl-C1-6 alkoxy, and phenyl substituted by one or two groups selected from halo and C1-6 alkyl or R14 and R15 are both C1-6 alkyl or phenyl.
5. Compounds as claimed in claim 4 wherein R3 is the 4-(4-chlorophenyl)cyclohexyl group:
6. Compounds as claimed in claim 5 wherein R3 is in the trans form with respect to the naphthoquinone ring.
7. Compounds as claimed in any of claims 1 to 6 wherein A is and R2 represents a carbamate group 8. Compounds as claimed in claim 7 wherein R5, R6 and R7 are each hydrogen or a C1-4 alkyl group.
9. Compounds as claimed in claim 7 wherein R5 is methyl or ethyl R6 is hydrogen, methyl or ethyl and R7 is hydrogen or a group -CO-O-R8 wherein R8 is t-butyl.
10. Compounds as claimed in any of claims 1 to 9 wherein R1 and R4 represent =O and the dotted line is a bond between the 2 and 3 positions of the naphthyl ring.
11. Compounds as claimed in claim 1 represented by the formula (III) (III) wherein R5, R6 and R7 are as hereinbefore defined, and physiologically acceptable salts thereof.
12 Compounds as claimed in claim 11 in the form of the trans-isomer.
13. The compound 2-(trans-4-(4-Chlorophenyl)cyclohexyl]-3(N-methyl-N-[2-(methylamino)ethyl]carbamoyloxy)-1,4-naphthoquinone as claimed in claim 11 and physiologically acceptable salts thereof.
14. The hydrochloride monohydrate salt of the compound according to claim 13.
15. Compounds as claimed is claim 1 represented by the formula (IV):
(IV) wherein R5, R6 and R7 are as hereinbefore defined and physiologically acceptable salts thereof.
16. The compound 2-[trans-(4-t-butylcyclohexyl)methyl]-3-(N-methyl-N-[2-(methylamino)ethyl]carbamoyloxy)-1,4-naphthoquinone as claimed in claim 15 and physiologically acceptable salts thereof.
17. A method for the treatment and/or prophylaxis of parasitic protozoal infections or infections caused by P.carinii, in mammals, which comprises administering to a mammal suffering from or susceptible to said infection, an effective amount or a compound of formula (II) or a physiologically acceptable salt thereof.
18. A compound of formula (II) or a physiologically acceptable salt thereof for use in therapy.
19. 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.
20. A pharmaceutical formulation comprising 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.
21. A unit dose formulation containing a compound of formula (II) or a physiologically acceptable salt thereof in an amount of from 10mg to 1g.
22. A process for the preparation of compounds of formula II and physiologically acceptable salts thereof which comprises reaction of a compound of formula (V) (V) wherein R3 is as hereinbefore defined and X is halo, with a compound of the formula (VI) (VI) wherein n, A, R6 and R7 are as hereinbefore defined provided that when it is required to prepare a compound wherein one or more of R6 and R7 is hydrogen, the corresponding compound is prepared with a group or -CO-O-R8 in place, instead of hydrogen and this group is then removed and further provided that where it is required to prepare a compound of formula (II) wherein R1, R2 and R4 each represent a carbonate or carbamate group, the reaction is effected after reduction of the quinone nucleus.
or the dotted line represents double bonds between the 1, 2 and 3, 4 positions of the naphthyl ring, and R1, R2 and R4 each represent a group wherein-n, A, R6 and R7 are as hereinbefore defined.
2. Compounds as claimed in claim 1 wherein R3 is a C1-10alkyl group;
a C5-7 cycloalkyl group (which may be optionally substituted by a straight or branched chain C1-6 alkyl group, a halo-C1-6alkyl group, a C1-6alkoxy group or a phenyl group, the phenyl group itself being optionally substituted by one or more substituents selected from C1-6 alkyl and halogen); or a C1-10alkyl-C5-7cycloalkyl group, wherein the cycloalkyl moiety may be optionally substituted as defined for the aforementioned C5-7 cycloalkyl group.
Compounds as claimed in claim 1 or claim 2 wherein R3 is represented by the formula:
wherein:
q is zero or one and R13 is a C1-10 alkyl group.
4. Compounds as claimed in claim 1 or claim 2 wherein R3 is represented by the formula:
wherein:
r is zero or one, and either R14 is hydrogen and R15 is selected from halo, halo-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl-C1-6 alkoxy, and phenyl substituted by one or two groups selected from halo and C1-6 alkyl or R14 and R15 are both C1-6 alkyl or phenyl.
5. Compounds as claimed in claim 4 wherein R3 is the 4-(4-chlorophenyl)cyclohexyl group:
6. Compounds as claimed in claim 5 wherein R3 is in the trans form with respect to the naphthoquinone ring.
7. Compounds as claimed in any of claims 1 to 6 wherein A is and R2 represents a carbamate group 8. Compounds as claimed in claim 7 wherein R5, R6 and R7 are each hydrogen or a C1-4 alkyl group.
9. Compounds as claimed in claim 7 wherein R5 is methyl or ethyl R6 is hydrogen, methyl or ethyl and R7 is hydrogen or a group -CO-O-R8 wherein R8 is t-butyl.
10. Compounds as claimed in any of claims 1 to 9 wherein R1 and R4 represent =O and the dotted line is a bond between the 2 and 3 positions of the naphthyl ring.
11. Compounds as claimed in claim 1 represented by the formula (III) (III) wherein R5, R6 and R7 are as hereinbefore defined, and physiologically acceptable salts thereof.
12 Compounds as claimed in claim 11 in the form of the trans-isomer.
13. The compound 2-(trans-4-(4-Chlorophenyl)cyclohexyl]-3(N-methyl-N-[2-(methylamino)ethyl]carbamoyloxy)-1,4-naphthoquinone as claimed in claim 11 and physiologically acceptable salts thereof.
14. The hydrochloride monohydrate salt of the compound according to claim 13.
15. Compounds as claimed is claim 1 represented by the formula (IV):
(IV) wherein R5, R6 and R7 are as hereinbefore defined and physiologically acceptable salts thereof.
16. The compound 2-[trans-(4-t-butylcyclohexyl)methyl]-3-(N-methyl-N-[2-(methylamino)ethyl]carbamoyloxy)-1,4-naphthoquinone as claimed in claim 15 and physiologically acceptable salts thereof.
17. A method for the treatment and/or prophylaxis of parasitic protozoal infections or infections caused by P.carinii, in mammals, which comprises administering to a mammal suffering from or susceptible to said infection, an effective amount or a compound of formula (II) or a physiologically acceptable salt thereof.
18. A compound of formula (II) or a physiologically acceptable salt thereof for use in therapy.
19. 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.
20. A pharmaceutical formulation comprising 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.
21. A unit dose formulation containing a compound of formula (II) or a physiologically acceptable salt thereof in an amount of from 10mg to 1g.
22. A process for the preparation of compounds of formula II and physiologically acceptable salts thereof which comprises reaction of a compound of formula (V) (V) wherein R3 is as hereinbefore defined and X is halo, with a compound of the formula (VI) (VI) wherein n, A, R6 and R7 are as hereinbefore defined provided that when it is required to prepare a compound wherein one or more of R6 and R7 is hydrogen, the corresponding compound is prepared with a group or -CO-O-R8 in place, instead of hydrogen and this group is then removed and further provided that where it is required to prepare a compound of formula (II) wherein R1, R2 and R4 each represent a carbonate or carbamate group, the reaction is effected after reduction of the quinone nucleus.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929207517A GB9207517D0 (en) | 1992-04-06 | 1992-04-06 | Heterocyclic compounds |
| GB9207517.5 | 1992-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2133744A1 true CA2133744A1 (en) | 1993-10-14 |
Family
ID=10713546
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002133744A Abandoned CA2133744A1 (en) | 1992-04-06 | 1993-04-05 | 1,4 naphthoquinone derivatives with anti-protozoal and anti-parasitic activity |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0634996A1 (en) |
| JP (1) | JPH07505388A (en) |
| KR (1) | KR950700874A (en) |
| CN (1) | CN1083048A (en) |
| AU (1) | AU3899293A (en) |
| CA (1) | CA2133744A1 (en) |
| CZ (1) | CZ242994A3 (en) |
| FI (1) | FI944657A (en) |
| GB (1) | GB9207517D0 (en) |
| HU (1) | HUT68937A (en) |
| IL (1) | IL105322A0 (en) |
| MX (1) | MX9301962A (en) |
| NO (1) | NO943737L (en) |
| SK (1) | SK120994A3 (en) |
| WO (1) | WO1993020044A1 (en) |
| ZA (1) | ZA932458B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9169232B2 (en) * | 2011-09-16 | 2015-10-27 | Alkem Laboratories Limited | 3-(5-methyl-2-oxo-l, 3-dioxol-4-yl) methyloxy-2-trans-[(4-chloro phenyl) cyclohexyl][1,4]naphthaquinone-atovaquone prodrug |
| WO2017222996A1 (en) | 2016-06-20 | 2017-12-28 | The California Institute For Biomedical Research | Antimalarial compositions and uses thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4485116A (en) * | 1981-10-16 | 1984-11-27 | Hudson Alan T | Antiprotozoal compounds |
| GB8310141D0 (en) * | 1983-04-14 | 1983-05-18 | Wellcome Found | Naphthoquinone derivatives |
| FI893835A (en) * | 1988-08-16 | 1990-02-17 | Wellcome Found | LAEKEMEDEL. |
-
1992
- 1992-04-06 GB GB929207517A patent/GB9207517D0/en active Pending
-
1993
- 1993-04-05 AU AU38992/93A patent/AU3899293A/en not_active Abandoned
- 1993-04-05 ZA ZA932458A patent/ZA932458B/en unknown
- 1993-04-05 CZ CZ942429A patent/CZ242994A3/en unknown
- 1993-04-05 CA CA002133744A patent/CA2133744A1/en not_active Abandoned
- 1993-04-05 EP EP93907992A patent/EP0634996A1/en not_active Withdrawn
- 1993-04-05 CN CN93105698A patent/CN1083048A/en not_active Withdrawn
- 1993-04-05 IL IL105322A patent/IL105322A0/en unknown
- 1993-04-05 SK SK1209-94A patent/SK120994A3/en unknown
- 1993-04-05 MX MX9301962A patent/MX9301962A/en unknown
- 1993-04-05 HU HU9402850A patent/HUT68937A/en unknown
- 1993-04-05 JP JP5517264A patent/JPH07505388A/en active Pending
- 1993-04-05 WO PCT/GB1993/000708 patent/WO1993020044A1/en not_active Application Discontinuation
-
1994
- 1994-10-05 NO NO943737A patent/NO943737L/en unknown
- 1994-10-05 FI FI944657A patent/FI944657A/en unknown
- 1994-10-05 KR KR1019940703520A patent/KR950700874A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU3899293A (en) | 1993-11-08 |
| NO943737L (en) | 1994-11-29 |
| EP0634996A1 (en) | 1995-01-25 |
| FI944657A0 (en) | 1994-10-05 |
| NO943737D0 (en) | 1994-10-05 |
| FI944657A (en) | 1994-12-02 |
| MX9301962A (en) | 1993-11-01 |
| JPH07505388A (en) | 1995-06-15 |
| KR950700874A (en) | 1995-02-20 |
| GB9207517D0 (en) | 1992-05-20 |
| SK120994A3 (en) | 1995-07-11 |
| IL105322A0 (en) | 1993-08-18 |
| WO1993020044A1 (en) | 1993-10-14 |
| HUT68937A (en) | 1995-08-28 |
| CZ242994A3 (en) | 1995-06-14 |
| CN1083048A (en) | 1994-03-02 |
| ZA932458B (en) | 1994-10-05 |
| HU9402850D0 (en) | 1995-01-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |