CN1083048A - Heterogeneous ring compound - Google Patents
Heterogeneous ring compound Download PDFInfo
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- CN1083048A CN1083048A CN93105698A CN93105698A CN1083048A CN 1083048 A CN1083048 A CN 1083048A CN 93105698 A CN93105698 A CN 93105698A CN 93105698 A CN93105698 A CN 93105698A CN 1083048 A CN1083048 A CN 1083048A
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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
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- 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
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- 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
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- 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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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The compound of general formula (II) or its physiologically acceptable salt.
Description
The present invention relates to naphthoquinones and their application in chemotherapy.More specifically, the present invention relates to the carbonic ether and the carbamate derivatives of novel hydroxyl naphthoquinone, their preparation method, its pharmaceutical preparation and in chemotherapy is used for the purposes of some protozoon and parasitic infection.
Parasitic protozoan infection comprises the malaria of human body, birds, fish and mammiferous coccidiosis in medical science and veterinarily influential to numerous disease.Many life to the host constitute a threat in these diseases, cause considerable financial loss in animal rearing.Parasitic protozoa comprises Apicocomplexa, as eimeria, and Cryptosporidium, toxoplasma and plasmodium.Another parasitic object that arouses attention is a Pneumocystis carinii, and it can cause lethal often pneumonia on immune deficiency or the immune host (animal) who weakens, comprise by HTV and infecting.The classification of this organism is unclear, can not affirm that it is protozoon or fungi.
Known in the prior art have many naphthoquinones.These compounds are described to have anti-malarial, anticoccidial and anti-safe tired that Pyroplasma activity.The some of them compound is according to describing the activity that also has the opposing epizoon.Fieser equals J.Amer.Chem.Soc.1948, and 70,3156-3165(is hereby incorporated by reference) and many 2-replacement-3-hydroxyls-1 have been described, the 4-naphthoquinones has the anti-malarial activity.Chemical compound lot in these compounds also is described among the US Patent specification No.2553648.Further, has activity and, a few class 2-replacement-3-hydroxyls-1 of anticoccidiosis medicine and/or anti-safe tired your Pyroplasma agent as antimalarial agent, the 4-naphthoquinones is described in US-3,367,830, US-3,347,742, british patent specification No-1553424, and EP-2228, in 77551,77550 and 123238.
The formula I 1 that treats and/or prevents the infection that is caused by cassette lung sac worm is disclosed in EP-A-362996, the 4-naphthoquinones:
R wherein
aBe the C that replaces arbitrarily
1-35The non-aromatic hydrocarbon residue, R
bBe in particular group-OCOR
C, OR
d, SR
dOr NR
eR
f, confirm as R according to stating these compounds
bProdrug for those compounds of hydroxyl.
Have been found that in the 2-position by carbamate groups replace 1, the 4-naphthoquinones shows that it has good (treatment) activity to the malaria that is infected by Plasmodium Yoelii in the mouse body.
Therefore, first aspect of the present invention provides compound and its physiologically acceptable salt of logical formula II:
Wherein
R
3For being selected from halogen, C by one to five
1-6Alkoxyl group, hydroxyl, amino, single or two C
1-4The C that alkyl-amino substituting group replaces arbitrarily
1-35Alkyl; Dotted line is represented two keys of naphthalene nucleus 2 and 3 interdigits; R
1And R
4Representative=0 separately; R
2Represent group
Wherein n is 2 or 3, R
6And R
7Identical or different, represent hydrogen atom separately, by hydroxyl, C
1-6The C that alkoxyl group replaces arbitrarily
1-6Alkyl, or group
, R wherein
9Be the C that is replaced arbitrarily by amino (amino is replaced arbitrarily by one or two alkyl)
1-6Alkyl, perhaps R
6And R
7The group of respectively doing for oneself
, R wherein
8Be C
1-6Alkyl, A are Sauerstoffatom or group
, R wherein
5Represent hydrogen atom, by hydroxyl, C
1-6Alkoxyl group or by one or two C
1-6The amino institute that alkyl replaces arbitrarily replaces C arbitrarily
1-6Alkyl or R
5Be group
, R wherein
10Be C
1-6Alkyl or R
5Be group
Wherein P is 2 or 3, R
11And R
12Be the R that defined in the past
6And R
7Perhaps, when m is 1, n is 2 o'clock, R
5Can be connected to R
6On, make
(wherein n, A, R
6And R
7Definition is the same).
R
3The C of representative
1-35Alkyl can be straight or branched C
1-14(as C
1-8) alkyl or C
2-14(as C
2-8) alkenyl or C
3-10(as C
3-8) cycloalkyl, each group all can be by C
3-10(as C
3-6) cycloalkyl replaces arbitrarily, aforesaid each cycloalkyl can be by C
1-10(as C
1-4) alkyl replaces arbitrarily.Or alkyl R
3Can be the C that replaces arbitrarily by phenyl
3-10(as C
3-8) cycloalkyl, described phenyl can be by C
1-10(as C
1-4) alkyl replaces arbitrarily.Alkyl R
3Preferably contain 1 to 20 carbon atom, as 1 to 14 carbon atom.Suitable R
3Group comprises C
3-10Cycloalkyl-C
1-8Alkyl, C
1-10Alkyl-C
3-10Cycloalkyl, C
1-10Alkyl-C
3-10Cycloalkyl-C
1-10Alkyl and C
3-10Cycloalkyl-C
3-10Cycloalkyl.R
3Also can be as preceding definition by one to five halogen atom, C
1-6Alkoxyl group, group S(O) mR
10, wherein m is 0,1 or 2, R
10Be C
1-6Alkyl, hydroxyl, amino, or single-or two-C
1-4The substituting group of alkylamino replaces.
Preferred R
3Comprise:
C
1-10Alkyl;
C
5-7(it can be by the C of straight or branched for cycloalkyl
1-6Alkyl, halo-C
1-6Alkyl, C
1-6Alkoxyl group or phenyl replace arbitrarily, and described phenyl itself can be by one or more C that are selected from
1-6The substituting group of alkyl and halogen replaces arbitrarily); With
C
1-10Alkyl-C
5-7Cycloalkyl, wherein cycloalkyl moiety can be as the front to C
5-7Like that at random being substituted of cycloalkyl definition.
Substituent R
3A particularly preferred class is expressed from the next:
Wherein:
Q is 0 or 1 He
R
13Be C
1-10Alkyl.
Another kind of particularly preferred R
3The representative of substituting group following formula:
Wherein:
R is 0 or 1, or R
14Be hydrogen, R
15Be selected from halogen, halo-C
1-6Alkyl, C
1-6Alkoxyl group, aryloxy,
C
1-6Alkyl-C
1-6Alkoxyl group is selected from halogen and C by one or two
1-6The phenyl that the group of alkyl replaces.Or
R
14And R
15All be C
1-6Alkyl or phenyl.
Must know R
3The formula I compound that comprises the cyclohexyl of replacement can exist cis or trans-isomer(ide), and cyclohexane ring can be examined cis or trans replacement by naphthoquinones in other words.The mixture of cis and trans-isomer(ide) and arbitrary proportion thereof all is used for the present invention.Usually, when compound exists with the mixture of isomers form, trans-isomer(ide) will exist with about 50% amount or be the advantage isomer, but in used mixture, and preponderating as cis-isomeride then also is contained in the scope of the present invention.The specific ratio of isomer is decided according to need.Typical mixture comprises the cis/trans isomer proportion at about 1: 1, those of 40: 60 and 5: 95.According to the present invention, use the trans-isomer(ide) of formula I compound, or contain at least 95% as the cis of 99% trans-isomer(ide) and the mixture of trans-isomer(ide) be preferred.
Particularly preferred substituent R
3Be the 4-(4-chloro-phenyl-) cyclohexyl:
Particularly the naphthoquinones ring is become trans form.
In the formula II compound, A is preferably group
, R
2Represent carbamate groups
As any R
5, R
6, R
7, R
8, R
10, R
11Or R
12Represent C
1-6During alkyl, it can be straight chain or side chain as methyl, ethyl, sec.-propyl, the tertiary butyl, isopentyl or n-hexyl.Suitable R
5, R
6And R
7Hydrogen or C respectively do for oneself
1-4Alkyl.Only R
5Be methyl or ethyl, R
6Be hydrogen, methyl or ethyl, R
7Be hydrogen or group-CO-O-R
8R wherein
8Be C
1-4Alkyl is as the tertiary butyl.
In the formula II compound, R
1And R
4Preferred representative=0, dotted line is two keys of naphthalene nucleus 2 and 3 interdigits.
Preferred one group of formula II compound and its physiologically acceptable salt are represented by formula III:
R wherein
5, R
6And R
7Definition is the same.
Further preferred formula III compound is the trans-isomer(ide) form.
2-[is trans-the 4-(4-chloro-phenyl-) and cyclohexyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1, the 4-naphthoquinones is a preferred compound of formula III.
Further preferred one group of formula II compound is represented by formula IV:
Wherein, R
5, R
6And R
7Definition is the same.
2-[is anti--(4-tert-butylcyclohexyl) methyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1, the 4-naphthoquinones is a preferred formula IV compound.
Term " alkyl " group refers to aliphatic group, straight chain or cycloalkyl as collateralization, alkenyl or alkynyl group, isocyclic aryl, aliphatic group (isocyclic aryl wherein can be replaced by aliphatic group arbitrarily) that is replaced by isocyclic aryl or the isocyclic aryl that is replaced by aliphatic group.
Non-theory is adhered rigidly to, and it is the prodrug of corresponding hydroxyl naphthoquinone that the carbonic ether of formula II derivative and carbamate are confirmed to be, and that is to say, carbamate or carbonic ether or group are cracked into wherein R in vivo
bFormula I compound for hydroxyl.
The formula II compound is identified and parasitic protozoa shown resistance especially corresponding hydroxyl naphthoquinone is found activated those organisms, and plasmodium for example is as plasmodium falciparum; Eimeria such as Etenella and Eacervulina; Safe tired that Pyroplasma such as Tparvum and Tannulata; Cryptosporidium; With toxoplasma gondii and Parasites body Pneumocystis carinii, so will being used for the treatment of and/or preventing, it parasitizes, as those diseases such as the malaria that causes by parasitic protozoa; Coccidiosis, cryptosporidiosis, toxoplasmosis and comprise on the human body by Pneumocystis carinii such as P.carinii pneumonia(PCP animal) disease that causes.
It should be noted that, when using treatment of formula II compound or its salt or prevention aforementioned diseases, its requirement is got its specific compound that will depend on administration, route of administration especially, age and the body weight of the Mammals (as the people) of treatment, the character and the severity of treatment situation.Usually, treatment people's the appropriate dosage of malaria be every day kg body weight 0.1mg to the scope of 200mg, for example from 1mg/kg to 100mg/kg, particularly 10 arrive 40mg/kg.Be noted that as to the neonatal administration, need use low dosage.
During prophylactic treatment, but the formula II compound or its salt also low-frequency degree take medicine, as, single dose administration every other day, weekly or twice or administration once or twice in every month.The dosage of prophylactic treatment also will depend on administration frequency, as when using storage preparation or sustained release preparation, also will depend on the rate of release of activeconstituents.To administration each time, suitable preventive dose scope is 0.1～100mg/kg, as 0.5～50mg/kg, is 5～50mg/kg especially.
Be appreciated that the dosage of mentioning for denseness is above-mentioned will itself calculate according to the formula II compound, when using its salt, then need to adjust.
Therefore the present invention further provides the method that Mammals such as people parasitize that treats and/or prevents, infect as malaria as parasitic protozoa, or, comprise the Mammals administration that suffers or be sensitive to described infection with acceptable salt pair on the formula II compound of significant quantity or its physiology by the infection that Pneumocystis carinii causes.
(the present invention) also provides acceptable salt on the formula II compound that is used for the treatment of or its physiology, as treats and/or prevents foregoing parasitic disease.
The present invention also provides being used to make and treating and/or preventing the same described medicament that parasitizes of acceptable salt on formula II compound or its physiology.
According to application of the present invention, acceptable salt preferably uses with pharmaceutical dosage forms on formula II compound or its physiology.Usually, these pharmaceutical preparations comprise on a kind of formula II compound or its physiology acceptable salt and one or more pharmaceutically acceptable carriers and other composition that treats and/or prevents arbitrarily.These carriers must acceptablely be meant with preparation in other components compatibility and harmless to its receptor.
Therefore, the present invention further provides a kind of pharmaceutical preparation, comprise on formula II compound or its pharmacology acceptable carrier on the acceptable salt and its pharmacology.
A kind of method of useful in preparing drug formulations also is provided simultaneously, comprises acceptable salt on formula II compound or its pharmacology is combined with its pharmaceutically acceptable carrier.
The formula II compound or its salt is present in the pharmaceutical preparation with unit dosage form usually.The amount that common unit dose formulations contains formula II compound or its physiologically acceptable salt is that 10mg is to 1g.
It is oral that pharmaceutical preparation comprises that those are suitable for, local (comprising skin, cheek and hypogloeeis), rectum and parenteral (comprise subcutaneous, intradermal, intramuscular and intravenously) administration.Suitable preparation normally disperses any method preparation of knowing in dose unit and the available pharmaceutical field.All ways all comprise with acceptable salt on formula II compound or its physiology and liquid vehicle and segmentation solid carrier or both combine its, then as need, product is shaped to required preparation.
The pharmaceutical preparation that is suitable for oral administration of making carrier with solid is unit dose formulations form such as bolus most preferably, capsule or tablet, quantitative activeconstituents before every kind of preparation all contains.Tablet can arbitrarily and one or more supplementary components be compressed together or mold pressing makes.Compressing tablet can be in suitable machine, the activeconstituents of compression free-flowing form such as powder or particle and get, activeconstituents can and caking agent, lubricant, inert solvent, separant, tensio-active agent or dispersion agent mix arbitrarily.The tablet of mold pressing can be in suitable machine, and the activeconstituents of mold pressing powder and any appropriate carrier mixture form.Tablet is dressing at random, if dressing not then can be repaired arbitrarily.Capsule can be by filling activeconstituents, separately or with the mixture of one or more ancillary components in capsule shell, then with the usual method sealing and get.Cachet is similar to capsule, and wherein activeconstituents and any assistant agent are enclosed in the rice paper envelope together.Formula II compound or its physiologically acceptable salt also can be made into discrete particles, for example before administration or being sprinkling upon on the food, it can be scattered in the water.Particle can be packaged in as in the pouch.Carrier is that the preparation that is suitable for oral administration of liquid can be solution or water soluble liq or non-water-soluble liquid suspension agent, or as oil-water liquid emulsion, as syrup, elixir, emulsion or suction potus.Syrup can get by activeconstituents being added in the concentrated aqueous solution of sugar as fructose, wherein also can be added to into any ancillary component, comprises seasonings, makes sugar avoid crystalline reagent or increases the deliquescent reagent of other composition such as polyvalent alcohol such as glycerine or sorbyl alcohol.
The preparation of oral administration comprises sustained release dosage form such as tablet, wherein activeconstituents is worked in the matrix of suitable release control, or with the release-controlling diaphragm dressing that suits.Such preparation is advantageously used in preventing purpose especially.
The pharmaceutical preparation that is suitable for rectal administration of solid carrier most preferably is the suppository of unitary dose.Suitable carrier comprises other raw material commonly used in theobroma oil and this area.Described suppository can be easily makes by in mould activeconstituents and carrier softening or that dissolve being mixed to cool off then and be shaped.
The pharmaceutical preparation that is suitable for administered parenterally comprises sterile solution or the suspended emulsion of activeconstituents in water-soluble or oil soluble medium.Injection formulations can repack big dose injection or continuous infusion into.These preparations can be easily with unitary dose or many multiple doses content form, and it is to seal after introducing required preparation unit.In addition, activeconstituents can be used powder type such as freeze-dried, before use with its with suitable medium as aseptic, the combination of the water of day thermal source.
Formula II compound or its physiologically acceptable salt also can be made into long-acting storage (long-acting depot) preparation, and it can be by intramuscularly or subcutaneous or intramuscular implantation administration.Store agent and comprise, for example, suitable polymer or hydrophobic material or ion exchange resin.Such prolonged action preparation is advantageously used in preventing purpose especially.
The compounds of this invention can be made preparation with any known method, and as according to the above, according to its character, they are particularly suitable for making the aqueous solution preparation that is used to inject.2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1, the 4-naphthoquinones has improved the water-soluble of its parent hydroxy naphthoquinones.
Be appreciated that, except aforesaid carrier components, the pharmaceutical preparation of above-mentioned various route of administration comprises suitable one or more extra carrier components such as thinner, buffer reagent, seasonings, caking agent, tensio-active agent, thickening material, lubricant, sanitas (comprising oxidation inhibitor) or the like, and comprise the material that makes preparation and acceptor blood etc. (oozing).
The compounds of this invention can be combined into administration simultaneously with other therapeutical agent, as other anti-malarial agents, resembles 4-quinolylamine such as chloroquine and amodiaquine; 8-quinolylamine such as primaquine; Chloroquine; The meflo-quinoline; Quinine; The quinine fourth; Artemesinin; Artesumate; Artemether; Halofantrine; Dihydrofolate reductase inhibitor such as pyrimetamine; Sulfanilamide (SN) such as sulphadoxine; Chloroguanide; Chloroproguanil; Dapsone, hydroxyl naphthoquinone; Or mixture such as pyrimetamine/sulphadoxine; Pyrimetamine/dapsone; And pyrimetamine/sulfapyrazinemethoxyine; Antiseptic-germicide such as TMP-sulfalene Yi isoxazole mixture; Anticoccidiosis medicine such as Brazilian leaf tree glucoside, halofuginone, arprinocid, amprolium, dinitolmide, robenidine or Salinomycin.; Or antibiotic such as clindamycin, the Fourth Ring is mould, doxycycline or Spiramycin Base; Or Pneumocystis carinii there are reagent such as the pentamidine or an Eflornithine of resistance.
When the formula II compound was used in combination with second kind of therapeutical agent, the expense the when dosage of every kind of compound uses separately with it was different.The dosage that is fit to is then determined easily by this area professional.
The formula II compound can be by formula (V) compound
R wherein
3As defined above, X is a halogen, makes with the reaction of formula VI compound
N wherein, A, R
6And R
7Definition is the same; Condition is as preparation R
6And R
7In one or more when being hydrogen, preparation hydrogen is group-CO-O-R on the position
8Compound, then this group is sloughed.
Reaction is carried out in that reaction reagent is in the presence of the inert solvent easily.Spendable solvent comprises aromatic hydrocarbon for example benzene or toluene; Halohydrocarbon such as chloroform or methylene dichloride; Dipolar aprotic solvent such as dimethyl formamide or HMPA; Ethers such as tetrahydrofuran (THF) Huo diox; Pyridine; Acetonitrile; Tricresyl phosphate methyl ester and tricresyl phosphate ethyl ester.Temperature of reaction is easily in-80 ℃ to 100 ℃ scopes, preferably at 0 ℃ to 30 ℃.
Reaction is preferably carried out in the presence of alkali, and alkali is organic bases such as pyridine, the 4-Dimethylamino pyridine, and tertiary amine such as triethylamine, or 1,8-diazabicyclo [5,4,0]-7-undecylene (DBU), or mineral alkali such as alkaline carbonate are such as carbon potassium or sodium bicarbonate.
Be preparation R
1, R
2And R
4All represent the formula II compound of carbonic ether or carbamate groups, reaction can be carried out after the reduction of quinone nuclear, and it can carry out in common mode.
Salt formation can carry out with method of the prior art, promptly passes through with formula II compound and suitable acid-respons.
Blocking group-CO-O-R
8Can remove with acid easily, as work as R
8During for the tertiary butyl, available hydrogen chloric acid carries out in ether.
Formula (V) compound can make from corresponding hydroxyl naphthoquinone easily then and there, as when X is chlorine, and can be as in the inert solvent of preceding definition, in the presence of alkali, with corresponding hydroxyl naphthoquinone photoreactive gas reaction, to connect the carboxylamine ester side chain.This reaction can be carried out between-50 ℃ to 50 ℃, suits at-10 ℃ to 10 ℃.
The formula IV compound can make according to the currently known methods of synthesis of hydroxy naphthoquinone derivatives, as is described in United States Patent (USP) the one 2,553,648; 3,367,830; With 3,347,742; English Patent the 1st, 553,424; European patent the 2nd, 228; 77,551; 77,550; With 123,238 and EP-A-362,996, for example, the formula IV compound can pass through 2-halo (as 2-chlorine)-1, the 4-naphthoquinones with required radicals R can be provided
3Compound reaction, make through basic hydrolysis then.Work as R
3When being the cyclohexyl methyl of a cyclohexyl that replaces arbitrarily or replacement arbitrarily, it can be by introducing with suitable substituted cyclohexyl hydroxy acid or cyclohexyl acetic acid reaction.
The present invention is existing to be described further by following non-limiting example:
Anti-Plasmodium yoelii activity in the mouse body.
Test compound
Compd A: 2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1,4-naphthoquinones hydrogenchloride-hydrate.
Compd B: 2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-the 3-(N-[2-(methylamino-) ethyl] carbamoyloxy)-1,4-naphthoquinones hydrogenchloride-hydrate.
Compound C: 2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-(N-methyl-N-[3-(methylamino-) propyl group] carbamoyloxy)-1, the 4-naphthoquinones.
Compound D: anti--the 2-[4-(4-chloro-phenyl-) cyclohexyl]-3-[piperazine-N-carbonyl oxygen base]-1,4-naphthoquinones hydrogenchloride dihydrate.
Compound (I): 2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl] 3-hydroxyl-1, the 4-naphthoquinones.
Compd A, B, C and (I) oral in the following manner and intravenous administration.
Method
This test method is the improved form of 4 days inhibition tests.On mouse, the YM strain of P.yoelii is cultivated weekly twice.Collect the blood that infects, obtain 3 * 10 with the physiological saline dilution
6The inoculum of parasitic enythrocytes/me.In the 1st day the morning, experimental animal (the male CD-1 mouse of 18-20g) carries out intravenously by the tail vein with the dosage of every 0.1ml inoculum to be infected.
Oral (p.o)
Test compound A, B and (I) are worn into 0.25% Celacol with Stainless Steel Ball.When on-test, make that all need, preserve down in 4 ℃ then.
Each test compound is generally five groups of mouse oral (p.o) administration to four groups or more, and every winding is subjected to different dosage (dilution).Another group mouse is with the Celacol administration, in contrast (promptly with total 30 mouse to obtain each ED
50).Mouse is given agent in that back 24 hours of infection is oral.
Intravenously (i.v.)
The i.v. preparation of test compound A and B is by directly compound dissolution being obtained in water before use, infect back 24 hours with single dose by the tail intravenously administrable.
In the 5th day morning, make the smear of its tail blood from every mouse, and calculate parasitaemia.Carry out data analysis to obtain ED by only C shape (sigmoidal) dose response curve
50Value.It the results are shown in following table 1.
The result
Table 1
Dose form
ED
50mg/kg
1XP.O. 1Xi.V.
Compound (I) 0.16 0.12
Compound (A) 0.15 0.12
Compound (B) 0.2 0.27
Compound (C) 0.4 0.29
Compound (D) 0.4-
Anti-Pneumocystis carinii activity in the mouse body
Trial drug
SMZ and TMP compound preparation (Septrin)-every 5ml contain children's's Wellome suspension of 200mg SMZ/40mgTMP
Atovaquone-2-[is anti--the 4-(chloro-phenyl-) and cyclohexyl]-3-hydroxyl-1, the 4-naphthoquinones.
Test compound-2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1,4-naphthoquinones hydrogenchloride-hydrate.
Method
Not with the female SCID(C.B-17/lcr-scid/scid of Pneumocystis carinii (PC)) mouse (20-25g) handles with dexamethasone (2m/L is in tap water), and it is the cold storage mouse deutero-PC(dosage with single agent :～2 * 10
4Tumour is equivalent to about 10
6Trophont) carries out thanking in the tracheae dying and carried out before 7 days.The group of 10 mouse (test) connects medicinal preparation for oral administration every day, and each medicine is from infecting one day after up to test in 42 days, to estimate the preventive effect of medicine.Test stops, and every mouse administration was in the end killed after 24 hours.Remove lung, on behalf of part, picked at random make the press mold section.With the Pneumocystis carinii tumour dyeing of immunofluorescent antibody test box (Detect IF Pneumocystis carinii, Shield Diagnostics Ltd.) to lung sections.The whole section observes and calculates the swollen capsule number of fluorescence under 100 times of amplifications, with the infection by Pneumocystis carinii degree of assessment carrier, all sections are determined its index by following standard
0=does not have tumour/section
+ 1=1 to 5 tumour/section
+ 2=6 to 50 tumour/section
+ 3=51 to 250 tumour/section
+ 4=＞250 tumour/section
Pharmaceutical preparation
Septrin dilutes with tap water; Calculate its dosage to guarantee every mouse minimum drink every day 2.5ml.Carry out administration with the suspension agent of Atovaquone in 0.25%Celacol.Test-compound is dissolved in distilled water and giving in the drug solns of making in 1 hour.
The result
Below in the table 2 result displayed be based on two independently blocking tests (blindexamination), it is represented with 10 the every group average infestation indexs of mouse.The percentage ratio that these data are also represented to contrast (every day oral give agent) with distilled water diluting.
Table 2
Test group average index ± SE % contrast
Contrast 3.6 ± 0.2 100
Septrin (250/50mg/kg/ days) 0.1 ± 0.1 3%
Atovaquone (100mg/kg/ days P.O) 1.5 ± 0.3 43%
Test compound (100mg/kg/ days P.O) 0.1 ± 0.1 3%
Example of formulations
With particular reference to embodiment 2 compounds, can be used for pharmaceutical preparation of the present invention with the following examples explanation.Obviously, other formula II compound can also similar mode be made preparation.
A. injection solution
Intramuscularly solution can make by mixing following raw material:
9.5 parts of 2 compounds of embodiment (weight)
19.0 parts of methyl-sulphoxides (weight)
4.5 parts of polyoxyethylene-sorbitan mono-oleates (weight)
67 parts of Semen Maydis oils (weight)
100.0
B. injection solution
5 parts of 2 compounds of embodiment (weight)
48.3 parts of N-methyl-pyrrolidone (weight)
80 2 parts of Tween (weight)
80 4.7 parts of Span (weight)
812 40 parts of Migtyol (weight)
100.0
C. tablet
Embodiment 2 compound 25.0mg
Lactose BP 48.5mg
Microcrystalline Cellulose BP 10.0mg
（“Avicel PH 101”）
The low hydroxypropylcellulose BP 10.0mg that replaces
（“LHPC LH-11”）
Explotab BP 3.0mg
（“Explotab”）
Povidone BP（“K30”） 3.0mg
Magnesium Stearate BP 0.5mg
100.0mg
D. the cold dried solution of IV
Embodiment 2 compound 50mg
Water for injection is to 10ml
Naphthoquinones is dissolved in water for injection.Sterile filtration.Be packed into and carry out lyophilize in the vial.With the very fast before use preparation again of water for injection.
E. capsule
Embodiment 2 compound 100mg
Starch 1500 150mg
Magnesium Stearate 2.5mg
Mentioned component is filled in the hard gelatin capsule.
F. smoke substance
A) be ground to superfine embodiment 2 compound 1.0mg
The smoke substance propelling agent is to 5.0ml
To be ground to the outstanding breast of superfine compound in the smoke substance propelling agent.By valve opening it is charged in the smoke substance jar of moulding, add to depress and be charged to the 5ml/ jar.
B) be ground to superfine embodiment 2 compound 1.0mg
Arlacel 85 0.1%W/V
The smoke substance propelling agent is to 5ml
Arlacel 85 is distributed in the smoke substance propelling agent.Add embodiment 4 compounds then.By valve opening, this suspended emulsion is filled in the smoke substance jar of moulding, pressurization is charged to the 5ml/ jar.
G. suck powder
Embodiment 2 compounds are ground to superfine 1.0mg
Lactose 29.0mg
Develop and fusion being ground to superfine compound and lactose.The fusion powder of gained is filled in the hard gelatine capsule shell.Each capsule 30mg.
N-methyl-N-[2-(methylamino-) ethyl] t-butyl carbamate
This compound W.S.Saari, J.E.Schwering, P.A.Lyle, S.J.Smith and E.L.Engelhardt. be in J.Med.Chem.Vol33,97,1990 method, and from N, the N'-dimethyl-ethylenediamine makes.
Two (2-[(tert-butoxycarbonyl) amino] ethyl) amine
Diethylenetriamine (10g under be cooled to 0 ℃, stirring; 97ml; Lancaster is synthetic) tetrahydrofuran (THF) (5ml) solution in drip tert-Butyl dicarbonate (10.5g; Tetrahydrofuran (THF) 48mM) (50ml) solution.The gained mixture can rise to room temperature, stirs 18 hours, filters vacuum concentration, partition in salt solution and ethyl acetate.Water-soluble layer with ethyl acetate extraction once, the extracting solution drying (MgSO of merging
4), vacuum concentration gets clarified oil (6.7g).Through silica gel chromatography, with 1: 4 methyl alcohol: it is clean oil (2g that the chloroform wash-out gets title compound; 27%) NMR δ H(CDCl,
3) 3.15-3-3(4H, m), 2.75(4H, t, J 5Hz), 1.45(18H, S).
Embodiment 1
2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-(N-methyl-N-[2-(N-methyl-N-tert-butoxycarbonyl) amino-ethyl] carbamoyloxy)-1, the 4-naphthoquinones.
Under 0 ℃ of nitrogen protection, to stir 2-hydroxyl-3-[down instead-the 4-(4-chloro-phenyl-) cyclohexyl]-1,4-naphthoquinones (3.7g; Toluene solution (the 10ml that adds phosgene in dry methylene chloride 10mmol) (60ml) suspended emulsion at once; 1.25M solution).Drip pyridine (0.8ml; 10mmol), gained solution was in 0 ℃ of following restir 45 minutes.In 15 minutes to wherein adding N-methyl-N-[2-(methylamino-) ethyl] t-butyl carbamate (1.85g; 10.5mmol) and pyridine (0.8ml; 10mmol) the mixture in dry methylene chloride (10ml), the mixture stirring at room of gained 18 hours.Mixture is with methylene dichloride (50ml) dilution, water successively, 1M hydrochloric acid and water washing, dry (sal epsom), concentrate orange oil.Through silica gel chromatography, earlier with 1: 9 ethyl acetate: methylene dichloride is used 1: 2 ether then: hexane develop title compound (3.12g; 54%), m.p.113-115 ℃, NMR δ H(CDCl
3) 8.0-8.2(2H, m), 7.65-7.8(2H, m), 7.1-7.3(4H, m), 3.4-3.7(4H, m), 3.15(3H, 2xs), 3.05-3.25(1H, m), 3.0(3H, 2xs), 1.5-2.15(9H, 2xs).
Embodiment 2
2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1,4-naphthoquinones hydrochloride-hydrate.
In with the saturated ether (30ml) of HCl, add 2-[instead-the 4-(4-chloro-phenyl-) cyclohexyl]-3-(N-methyl-N-[2-(N-methyl-N-tert-butoxycarbonyl) amino-ethyl] carbamoyloxy)-1,4-naphthoquinones (1.74g; 3mmol), solution was in stirring at room 5 hours.Filtering-depositing, with the ether washing, vacuum-drying gets title compound (1.48g; 92%), m.p.＞140 ℃ (decomposition), NMR δ H(CDCl
3) 9.1-9.3(1H, bs), 7.95-8.2(2H, m), 7.65-7.85(2H, m), 7.1-7.35(4H, s), 3.7-4.0(1H, br s), 3.0-3.5(6H, m), 2.8(3H, br s), 2.65(1H, m), 1.75-2.15(8H, m), 1.4-1.75(2H, m).
Below prepare with embodiment 1 similar methods.
From N-methyl-N-(2-amino-ethyl) t-butyl carbamate (w.s.Saari. etc., J.Med.Chem.vol33,97,1990) make 2-[anti--the 4-(4-chloro-phenyl-) cyclohexyl]-3-(N-[2-(N-methyl-N-t-butoxycarbonyl amino) ethyl] carbamoyloxy)-1, the 4-naphthoquinones.m.p.128-131℃，NMRδH（CDCl
3）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（1H，m），3.0（3H，s），2.5-2.7（1H，m），1.75-2.15（6H，m），1.45-1.7（11H，m）。
With N-methyl-N-[3-methylamino-) propyl group] t-butyl carbamate (w.s.Saari etc., J.Med.Chem.vol33,97,1990) make 2-[anti--the 4-(4-chloro-phenyl-) cyclohexyl]-3-(N-methyl-N-[3-(N-methyl-N-tert-butoxycarbonyl amino) propyl group] carbamoyloxy)-1, the 4-naphthoquinones, oil.NMRδH（CDCl
3）8.0-8.2（2H，m），7.65-7.8（2H，m），7.1-7.35（4H，m），3.25-3.6（4H，m），3.0-3.25（4H，m），2.9（3H，s），2.5-2.7（1H，m），1.75-2.15（8H，m），1.4-1.7（11H，m）。
With N-ethyl-N-[2-ethylamino) ethyl] t-butyl carbamate (w.s.Saari etc., J.Med.Chem.vol33,97,1990) make oily 2-[anti--the 4-(4-chloro-phenyl-) cyclohexyl]-3-(N-ethyl-N-[2-(N-ethyl-N-tert-butoxycarbonyl amino) ethyl] carbamoyloxy)-1, the 4-naphthoquinones.
With N-tert-butoxycarbonyl-piperazine (Carpino etc., J.Org.Chem, vol48(5), 664,1983) make oily 2-[anti--the 4-(4-chloro-phenyl-) cyclohexyl]-3-(N-tert-butoxycarbonyl piperazine-N-carbonyl oxygen base)-1, the 4-naphthoquinones.
With the N-(2-hydroxyethyl)-the N-methyl carbonic acid tert-butyl ester (w.s.Saari etc., J.Med.Chem.vol33,97,1990) make 2-[anti--the 4-(4-chloro-phenyl-) cyclohexyl]-3-([2-(N-methyl-N-tert-butoxycarbonyl amino) oxyethyl group] carbonyl oxygen base)-1, the 4-naphthoquinones.m.p.110-111℃，NMRδH（d
6-DMSO）7.9-8.1（4H，m），7.3（4H，s），4.35-4.45（2H，t，J＝4Hz），3.5-3.6（2H，t，J＝4Hz），3.0-3.15（1H，m），2.5-2.7（1H，m），1.7-2.0（6H，m），1.45-1.65（2H，m），1.4（9H，s）。
With two (2-[(tertbutyloxycarbonyl) amino] ethyl) amine make 2-[anti--the 4-(4-chloro-phenyl-) cyclohexyl]-3-(N, N-two [2-(t-butoxycarbonyl amino) ethyl] carbamoyloxy)-1,4-naphthoquinones yellow oil.NMRδH（CDCl
3）8.0-8.2（2H，m），7.65-7.8（2H，m），7.1-7.3（4H，m），3.35-3.7（4H，m），3.15（1H，m），2.62（1H，m），1.8-2.1（4H，m），1.45（9H，br s），1.4（9H，br s）。
Below be with embodiment 2 similar methods, from the carbonic ether or the carbamate preparation of corresponding tertbutyloxycarbonyl protection.
2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-the 3-(N-(methylamino-) ethyl] carbamoyloxy)-1,4-naphthoquinones hydrochloride-hydrate.m.p.194-197℃，NMRδH（d
6-DMSO）9.1-9.3（2H，bs），8.4-8.5（1H，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），1.4-2.15（8H，m）。
2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-(N-methyl-N-[3-(methylamino-) propyl group] carbamoyloxy)-1,4-naphthoquinones hydrochloride-hydrate.m.p.208-210℃，NMRδH（CDCl
3）8.1-8.2（1H，d，J＝5Hz），8.0-8.1（1H，d，J＝5Hz），7.65-7.85（2H，m），7.15-7.3（4H，m），3.05-3.35（7H，m），2.5-2.8（5H，m），1.45-2.1（10H，m）。
2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-(N-ethyl-N-[2-(ethylamino) ethyl] carbamoyloxy)-1,4-naphthoquinones hydrochloride-hydrate, m.p.197-201 ℃, NMR δ H(CDCl
3) 8.1-8.2(1H, d, J=8Hz), and 8.0-8.1(1H, d, J=8Hz), 7.65-7.8(2H, m), 7.1-7.3(4H, m), 3.0-4.1(7H, m), 2.5-2.7(1H, m), 1.25-2.15(14H, m).
2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-[piperazine-N-carbonyl oxygen base]-1,4-naphthoquinones hydrochloride dihydrate, m.p.＞160 ° (decomposition) NMR δ H(d
6DMSO) 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(1H, m), 1.7-2.05(6H, m), 1.4-1.7(2H, m).
2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-[(2-methylamino-oxyethyl group)] ketonic oxygen]-1,4-naphthoquinones hydrochloride, m.p.211-213 ℃, NMR δ H(d
6-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(1H, m), 2.75(3H, s), 2.5-2.7(1H, m), 2.05-2.3(2H, m), 1.8-2.0(2H, m), 1.4-1.7(4H, m).
2-[is anti--the 4-(4-chloro-phenyl-) and cyclohexyl]-3-[N, two (2-amino-ethyl) carbamoyloxies of N-]-1, the two hydrates of the two hydrochlorides of 4-naphthoquinones, m.p.215-218 ℃, NMR δ H(d
6-DMSO) 8.25-8.7(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(1H, m), 1.5-2.2(8H, m).
Embodiment 3
2-[is anti--(4-tert-butylcyclohexyl) methyl]-3-(N-methyl-N-[2-(N-methyl-N-t-butoxycarbonyl amino) ethyl] carbamoyloxy)-1, the 4-naphthoquinones
In nitrogen atmosphere, to stir 2-[down instead-(4-tert-butylcyclohexyl) methyl]-3-hydroxyl-1,4-naphthoquinones (6.76: add phosgene (20mL in dry methylene chloride 19mM) (250mL) solution; 12.5% toluene solution), (1.6ml, 20mM), mixture stirred 1 hour then to drip pyridine.Drip pyridine (1.6mL; 20mM) with N-methyl-N-[2-(methylamino-) ethyl] carboxylamine tertiary butyl ester (3.7g; 21mM), reaction mixture was in room temperature restir 3.5 hours.Vacuum evaporating solvent obtains yellow solid, and through silica gel chromatography, with toluene, use 1: 8 ethyl acetate then: the toluene wash-out gets title compound (3.19g; 31%) m.p.117-118 ℃, NMR δ H(CDCl
3) 8.05-8.15(2H, m), 7.65-7.75(2H, m), 3.45-3.6(4H, m), 3.2-3.1(3H, 2xs), 2.95(3H, 2xs), 2.45-2.55(2H, m), 1.7-1.9(5H, m), 1.5(9H, 2xs), 0.9-1.1(5H, m), 0.85(9H, s).
Embodiment 4
2-[is anti--(4-tert-butylcyclohexyl) methyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1,4-naphthoquinones hydrochloride.
With 2-[anti--(4-tert-butylcyclohexyl) methyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1,4-naphthoquinones (1g) is added to by in the saturated ether of HCl (20ml), solution stirred 1.5 hours in the room temperature lucifuge.Vacuum boils off ether and obtains yellow oil, and it is dissolved in ethyl acetate, filters.Hexanaphthene is added in the filtrate, gets the yellow fragrant plant powder precipitation (0.43g) of title compound.M.p.＞140 ℃ (decomposition).
Claims (22)
1, logical formula II compound and its physiologically acceptable salt
Wherein
R
3For being selected from halogen, C by one to five
1-6Alkoxyl group, hydroxyl, amino, single or two C
1-4The C that alkyl-amino substituting group replaces arbitrarily
1-35Alkyl; Dotted line is represented two keys of naphthalene nucleus 2 and 3 interdigits; R
1And R
4Representative=0 separately; R
2Represent group
Wherein n is 2 or 3, R
6And R
7Identical or different, represent hydrogen atom separately, by hydroxyl, C
1-6The C that alkoxyl group replaces arbitrarily
1-6Alkyl, or group
, R wherein
9Be the C that is replaced arbitrarily by amino (amino replaced arbitrarily) by one or two alkyl
1-6Alkyl, perhaps R
6And R
7The group of respectively doing for oneself
, R wherein
8Be C
1-6Alkyl,
A is Sauerstoffatom or group
, R wherein
5Represent hydrogen atom, by hydroxyl, C
1-6Alkoxyl group or by one or two C
1-6The C of any replacement of amino institute that alkyl replaces arbitrarily
1-6Alkyl or R
5Be group
, R wherein
10Be C
1-6Alkyl or R
5Be group
Wherein p is 2 or 3, R
11And R
12Be the R that defined in the past
6And R
7Perhaps, as A be
N is 2 o'clock, R
5Can be connected to R
6On, make
N forms piperazine ring; Perhaps dotted line is represented two keys of 1,2 of naphthalene nucleus and 3,4 interdigits, and R
1, R
2And R
4Represent group separately
N wherein, A, R
6And R
7Definition is the same.
2, according to the compound of claim 1, R wherein
3For
C
1-10Alkyl;
C
5-7(it can be by the C of straight or branched for cycloalkyl
1-6Alkyl, halo-C
1-6Alkyl, C
1-6Alkoxyl group or phenyl replace arbitrarily, and described phenyl itself can be by one or more C that are selected from
1-6The substituting group of alkyl and halogen replaces arbitrarily); Or
C
1-10Alkyl-C
5-7Cycloalkyl, wherein cycloalkyl moiety can be as the front to C
5-7Like that at random being substituted of cycloalkyl definition.
3, according to the compound of claim 1 or 2, R wherein
3Represent by following formula:
Wherein
Q is 0 or 1 He
R
13Be C
1-10Alkyl.
4, according to the compound of claim 1 or claim 2, R wherein
3Represent by following formula
Wherein:
R is 0 or 1, perhaps R
14Be hydrogen and R
15Be selected from halogen, halo-C
1-6Alkyl, C
1-6Alkoxyl group, aryloxy, C
1-6Alkyl-C
1-6Alkoxyl group is selected from halogen and C by one or two
1-6The phenyl that alkyl replaces, or
R
14And R
15All be C
1-6Alkyl or phenyl
5, according to the compound of claim 4, R wherein
3Be the 4-(4-chloro-phenyl-) cyclohexyl:
6, according to the compound of claim 5, R wherein
3For becoming trans forms corresponding to the naphthoquinones ring.
7, according to the compound of any claim 1 to 6, wherein A is
And R
2Represent carbamate groups.
8, according to the compound of claim 7, R wherein
5, R
6And R
7Hydrogen or C respectively do for oneself
1-4Alkyl.
9, compound according to Claim 8, wherein R
5Be methyl or ethyl, R
6Be hydrogen, methyl or ethyl and R
7Be hydrogen or group-CO-O-R
8(R wherein
8Be the tertiary butyl).
10, the compound of any claim 1 to 9 of basis, wherein R
1And R
4Representative=0, dotted line is the key of naphthalene nucleus 2 and 3 interdigits.
11, according to compound or its physiology acceptable salt of claim 1 by the formula III representative,
R wherein
5, R
6And R
7As preceding definition.
12, according to the compound of claim 11 definition, wherein they are trans-isomer(ide)s.
13, according to the compound of claim 11, wherein compound be 2-[anti--the 4-(4-chloro-phenyl-) cyclohexyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1,4-naphthoquinones or its physiologically acceptable salt.
14, according to the hydrochlorinate compound-hydrate salt of the compound of claim 13.
15, according to the compound of claim 1, wherein compound is compound and its physiologically acceptable salt of formula IV representative,
R wherein
5, R
6And R
7Definition is the same.
16, according to the compound of claim 15, wherein be 2-[anti--(4-tert-butylcyclohexyl) methyl]-3-(N-methyl-N-[2-(methylamino-) ethyl] carbamoyloxy)-1, the 4-naphthoquinones
With its physiologically acceptable salt.
17, a kind of method of the infection that treats and/or prevents that the Mammals parasitic protozoa infects or cause by Pneumocystis carinii, it comprises suffering described infection or to its responsive Mammals, carries out administration with formula II compound or its physiologically acceptable salt of significant quantity.
18, the application of acceptable salt in treatment on formula II compound or its physiology.
19, formula II compound or its physiologically acceptable salt are used to make and treat and/or prevent the medicine that parasitizes.
20, contain formula II compound or physiologically acceptable salt and one or more its pharmaceutically acceptable carrier and other treats and/or prevents the pharmaceutical preparation of composition arbitrarily.
21, contain 10mg to the formula II compound of 1g or the unit dose formulations of its physiologically acceptable salt.
22, the method for preparing acceptable salt on formula II compound and its physiology comprises with following formula (V) compound
R wherein
3Definition is the same, and X is a halogen, reacts with the formula VI compound
N wherein, A, R
6And R
7Definition the same, condition be when the preparation R
6And R
7In one or more when being hydrogen, preparation hydrogen is group-CO-O-R on the position
8Compound, then this group is sloughed.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9207517.5 | 1992-04-06 | ||
| GB929207517A GB9207517D0 (en) | 1992-04-06 | 1992-04-06 | Heterocyclic compounds |
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| Publication Number | Publication Date |
|---|---|
| CN1083048A true CN1083048A (en) | 1994-03-02 |
Family
ID=10713546
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|---|---|---|---|
| CN93105698A Withdrawn CN1083048A (en) | 1992-04-06 | 1993-04-05 | Heterogeneous ring compound |
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| 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) |
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| CN109715147A (en) | 2016-06-20 | 2019-05-03 | 斯克利普斯研究院 | Anti-malarial composition and application thereof |
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| 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 |
| HU208624B (en) * | 1988-08-16 | 1993-12-28 | Wellcome Found | Process for producing pharmaceutical compositions containing naphtoquinone derivatives effective against pneumocystis infections |
-
1992
- 1992-04-06 GB GB929207517A patent/GB9207517D0/en active Pending
-
1993
- 1993-04-05 CZ CZ942429A patent/CZ242994A3/en unknown
- 1993-04-05 EP EP93907992A patent/EP0634996A1/en not_active Withdrawn
- 1993-04-05 AU AU38992/93A patent/AU3899293A/en not_active Abandoned
- 1993-04-05 ZA ZA932458A patent/ZA932458B/en unknown
- 1993-04-05 WO PCT/GB1993/000708 patent/WO1993020044A1/en not_active Application Discontinuation
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- 1993-04-05 MX MX9301962A patent/MX9301962A/en unknown
- 1993-04-05 IL IL105322A patent/IL105322A0/en unknown
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- 1993-04-05 CN CN93105698A patent/CN1083048A/en not_active Withdrawn
- 1993-04-05 CA CA002133744A patent/CA2133744A1/en not_active Abandoned
- 1993-04-05 JP JP5517264A patent/JPH07505388A/en active Pending
-
1994
- 1994-10-05 NO NO943737A patent/NO943737L/en unknown
- 1994-10-05 KR KR1019940703520A patent/KR950700874A/en not_active Application Discontinuation
- 1994-10-05 FI FI944657A patent/FI944657A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL105322A0 (en) | 1993-08-18 |
| KR950700874A (en) | 1995-02-20 |
| NO943737D0 (en) | 1994-10-05 |
| EP0634996A1 (en) | 1995-01-25 |
| HU9402850D0 (en) | 1995-01-30 |
| FI944657A0 (en) | 1994-10-05 |
| NO943737L (en) | 1994-11-29 |
| ZA932458B (en) | 1994-10-05 |
| GB9207517D0 (en) | 1992-05-20 |
| CZ242994A3 (en) | 1995-06-14 |
| WO1993020044A1 (en) | 1993-10-14 |
| SK120994A3 (en) | 1995-07-11 |
| AU3899293A (en) | 1993-11-08 |
| CA2133744A1 (en) | 1993-10-14 |
| MX9301962A (en) | 1993-11-01 |
| HUT68937A (en) | 1995-08-28 |
| JPH07505388A (en) | 1995-06-15 |
| FI944657A (en) | 1994-12-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C03 | Withdrawal of patent application (patent law 1993) | ||
| WW01 | Invention patent application withdrawn after publication |