CN101909627A - The new therapeutic uses that contains the binary molecule of peroxide derivative - Google Patents
The new therapeutic uses that contains the binary molecule of peroxide derivative Download PDFInfo
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- CN101909627A CN101909627A CN2008801238819A CN200880123881A CN101909627A CN 101909627 A CN101909627 A CN 101909627A CN 2008801238819 A CN2008801238819 A CN 2008801238819A CN 200880123881 A CN200880123881 A CN 200880123881A CN 101909627 A CN101909627 A CN 101909627A
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- Prior art keywords
- chloroquinoline
- dimethyl
- spiral shell
- hendecane
- diamidogen
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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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
- A61P33/12—Schistosomicides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The hybrid molecule that the present invention relates to contain peroxide derivative is used for the treatment of the new therapeutic uses of schistosomiasis or schistosomicide.
Description
The present invention relates to contain hybrid molecule (hybrid molecule) the treatment schistosomiasis of peroxide derivative or the new therapeutic uses of schistosomicide.
Particularly, in patent application WO 01/77105, WO 05/049619 and WO 2007/144487, this quasi-molecule has been described.The malaria activity of these molecules has been described in above document.Yet, in described document, both do not had to describe and do not pointed out their schistosomicide character yet.
Schistosomicide or to split trematodiasis be the chronic disease (being identified in 1852 by parasitolog Th é odore Bilharz) that is caused by Schistosoma (Schistosoma) class parasite.Nearest WHO report estimates that this disease is attacked 200,000,000 people in the whole world, have 600,000,000 people to live in popular area.
Schistosomicide relates to kidney and bladder function not normal (Schistosoma haematobium (S.haematobium)) or liver and intestinal tract disease (Schistosoma mansoni (S.mansoni), Schistosoma japonicum (S.japonicum), the public schistosomicide (S.mekongi) of river bank or interleave schistosomicide (S.intercalatum)).
Since 2005, praziquantel (Biltricide) became the main therapy of schistosomicide, and to this mankind's indication, the praziquantel of single dose is normally effective.This Drug tolerance is good and effective to described five kinds of pathogenic kinds.Yet, to have described parasite this medicine has been had some cases of resistance, this makes must develop a kind of therapy of resisting the new novelty of this disease.
Astoundingly, the inventor has been found that the character of the anti-schistosomiasis of the molecule of describing among patent application WO 01/77105, WO05/049619 and the WO 2007/14448 now.
Therefore, the present invention relates to as the compounds for treating of defined formula (I) hereinafter or the purposes of prevention schistosomicide.
Described compound-base is in formula (I):
Wherein:
● be selected from following molecule residue:
The quinolin-2-ylamine of formula (IIa):
Wherein:
-R is identical or different with R ', and represents one or more (for example 1-5) substituent group, described substituent group to occupy isolating position on the ring that they link to each other separately, and is selected from:
Hydrogen or halogen atom ,-OH ,-CF
3,-OCF
3Base, aryl ,-O-aryl, heteroaryl, alkyl or-the O-alkyl, described alkyl comprises 1-5 carbon atom,
-N (R
a, R
b), R wherein
aAnd R
bBe identical or different, and represent hydrogen atom independently of one another or comprise the alkyl of 1-5 carbon atom;
-R
4The alkyl of representing hydrogen atom maybe can comprise 1-5 carbon atom maybe can comprise the cycloalkyl of 3-5 carbon atom;
B representative can comprise the cycloalkyl of 3-8 carbon atom, and described cycloalkyl randomly is selected from following group and replaces by one or more:
Hydrogen atom, hydroxyl, the alkyl that can comprise 1-6 carbon atom maybe can comprise the cycloalkyl of 3-6 carbon atom,
● perhaps the B representative can comprise the dicyclo or three cyclic groups of 4-18 carbon atom, the group that the alkyl that described dicyclo or three cyclic groups randomly one or morely are selected from halogen atom, hydroxyl, can comprise 1-6 carbon atom maybe can comprise the cycloalkyl of 3-6 carbon atom replaces
● perhaps B represents 2 cycloalkyl that can comprise 3-6 carbon atom, and described cycloalkyl links together by the singly-bound or the alkylidene chain that can comprise 1 or 2 carbon atom;
● perhaps B represents C1-C5 alkylidene chain straight chain or side chain;
● perhaps B representative-CH
2-CH
2-O-CH
2-CH
2-chain;
R
5Represent hydrogen atom or alkyl or C
1-3-alkylidene cycloalkyl, described cycloalkyl can comprise 3-6 carbon atom;
● when U=-CH<time, represent cyclohexyl,
● perhaps,, represent piperidyl when U=-N<time,
● perhaps representative can comprise (hydrocarbonated) multiring structure of the bicarbonate salinization of 4-18 atom, and described multiring structure randomly comprises nitrogen-atoms,
Z
1Or Z
2In one can represent U and C
jSingly-bound between the atom, Z
1And Z
2Can not contemporary list key;
R
xAnd R
yWith C
jForm the cyclic peroxide that is selected from formula (XI), (XII) and group (XIII) together:
The trioxane of-Shi (XI):
R wherein
3Represent 1-4 identical or different groups, perhaps
The trioxepan of-Shi (XII):
R wherein
3Represent 1-6 identical or different groups, perhaps
The trioxacane of-Shi (XIII):
R wherein
3Represent 1-8 identical or different groups,
Wherein
R
3Represent 1-8 identical or different group, described group occupies the optional position on the carbon atom of described peroxide ring and is selected from following atom and group:
Hydrogen, halogen ,-OH ,-CF
3,-NO
2,-OCF
3Base, aryl ,-O-aryl, heteroaryl, alkyl or-the O-alkyl, described alkyl comprises 1-10 carbon atom,
Perhaps, two R carrying of the same carbon atom of described peroxide ring
3Base forms dicyclo or three cyclic groups (therefore, described dicyclo or three cyclic groups can be arranged with the spiral shell position) that the cycloalkyl that can comprise 3-7 carbon atom maybe can comprise 4-18 carbon atom together on described peroxide ring;
When p=1, U representative-CH<, and when p=0, U is by singly-bound and-(CH
2) the n-connection;
Described chemical compound randomly be alkali or with form, racemic form and/or the isomer of form, hydrate or the solvate of the addition salts of acid and the form of their mixture and diastereomer and their mixture.
Residue A is advantageously introduced the chemical compound of formula of the present invention (I) in (drain) parasite.
The chemical compound of formula (I) can alkali or is existed with the form of the addition salts of acid.This class addition salts also constitutes a part of the present invention.These salt advantageously prepare with pharmaceutically acceptable acid, and still, other sour salt that can be used for the chemical compound of purification or separate type (I) also constitute a part of the present invention.
Chemical compound of the present invention can hydrate or the form of solvate exist, promptly with one or more hydrones or with the association or the bonded form of solvent.This class hydrate and solvate also constitute a part of the present invention.
The present invention relates to the mixture of diastereomer of formula (I) of arbitrary ratio and the diastereomer of pure formula (I).The invention still further relates to the optically pure isomer of the molecule of the racemic mixture of molecule of formula (I) and formula (I), even relate to the described optically pure mixture of isomers of arbitrary ratio.The invention still further relates to achiral molecule.
Unless otherwise noted, in definition above and the hereinafter chemical compound of Chinese style (I):
-halogen atom is represented fluorine, chlorine, bromine or iodine atom; Alkyl is represented straight chain or side chain, saturated, monovalent aliphatic group.Example is methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group and amyl group;
-alkylidene group or chain are represented straight chain or side chain, saturated, aliphatic divalent group.For example, C
1-3-alkyl represent comprises bivalence carbochain straight chain or side chain of 1-3 carbon atom, such as methylene (CH
2-), ethylidene (CH
2CH
2-), 1-methyl ethylidene (CH (CH
3) CH
2-), propylidene (CH
2CH
2CH
2-);
-cycloalkyl is represented saturated, cyclic aliphatic group.Example is cyclopropyl, methyl cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl;
-twin nuclei represents to comprise two structures that comprise the saturated cyclic aliphatic group of 4-18 carbon atom, and described group can be:. condensed, promptly they have total key,
Example is the perhydrogenate naphthyl:
. or bridging, promptly at least two of described twin nuclei atoms link to each other by the carbochain that singly-bound maybe can comprise 1-4 carbon atom,
Example is:
Dicyclo [3.2.1] octyl group
. or be spirally connected, promptly they link to each other by a total carbon atom, and example is Pentamethylene .-spiral shell-cyclobutyl:
-tricyclic structure represents to comprise 3 structures saturated, cyclic aliphatic group that comprise 4-18 carbon atom, and described group can be (the as above definition) of condensed (as above definition) or bridging, and the example of condensed tricyclic structure is the perhydrogenate anthryl:
The example of the tricyclic structure of bridging is an adamantyl, and it is the tricyclic structure that comprises 10 carbon atoms:
-multiring structure is represented dicyclo or tricyclic structure as defined above;
-cyclic peroxide group represents to comprise the cyclic alkyl of 2 adjacent oxygen atoms;
-aryl represents to comprise the monocyclic or polycyclic armaticity system of 6-18 carbon atom, preferred 6-14 carbon atom and preferred 6-10 carbon atom.When described system when being polycyclic, at least one ring is an armaticity.Example is phenyl, naphthyl, tetralyl and indanyl; Heteroaryl is the monocyclic or polycyclic armaticity system that comprises 5-18 chain link, preferred 5-14 chain link, preferred 5-10 chain link and comprise one or more hetero atoms such as nitrogen, oxygen or sulphur atom.When described system when being polycyclic, at least one ring is an armaticity.Described nitrogen-atoms can be the form of N-oxide.The example of bicyclic heteroaryl is thiazolyl, thiadiazolyl group, thienyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals, furyl, oxazolyl, isoxazolyl, oxadiazole base, pyrrole radicals, pyrazolyl, pyrimidine radicals and pyridazinyl.The example of bicyclic heteroaryl is indyl, benzofuranyl, chromen-2-one base (chromen-2-onyl), benzimidazolyl, benzothienyl, benzotriazole base, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, indazolyl, indolizine base, quinazolyl, phthalazinyl, quinoxalinyl, naphthyridinyl, 2,3-dihydro-1H-indyl, 2,3-dihydro benzo furyl, tetrahydric quinoline group, tetrahydro isoquinolyl;
Example as the chemical compound of theme of the present invention is the chemical compound of first group of formula (I), wherein, and A, B, m, n, Z
1, Z
2, p=1, U=-CH<, Z
1+ Z
2+ U+Cj, R
1, R
2, R
5, R
x, R
yAs defined in claim 1, described alkyl can comprise 1-5 carbon atom.
Be based on the chemical compound of the second class formula (I) of formula (I.2) as the example of the chemical compound of theme of the present invention:
Wherein R ', R
4, B, Z
1, Z
2, Ci, C
j, R
1, R
2, R
3, R
5, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
Be based on the chemical compound of another group formula (I) of following formula (I.3) as the example of the chemical compound of theme of the present invention:
Wherein R ', R
4, B, R
3, R
5, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
Be based on the chemical compound of another group formula (I) of following formula (I.4) as the example of the chemical compound of theme of the present invention:
Wherein R ', R
4, B, C
j, R
1, R
2, Z
1, Z
2, R
x, R
y, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
Be based on the chemical compound of another group formula (I) of following formula (I.5) as the example of the chemical compound of theme of the present invention:
Wherein R ', R
4With B, Z
1, Z
2, C
j, R
1, R
2, R
3, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
Be based on the chemical compound of another group formula (I) of following formula (I.6) as the example of the chemical compound of theme of the present invention:
Wherein R ', R
4, B, R
3, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
The example of chemical compound of the present invention is the chemical compound of one group of formula (I), wherein the B representative is selected from following group: cis-1,2-methylene cyclopenta, anti-form-1,2-cyclohexyl, cis-1,2-cyclohexyl, cis-1,2-methylene cyclohexyl, anti-form-1,4-cyclohexyl, cis-1,4-cyclohexyl, cis/trans-1,4-cyclohexyl mixture, cis/trans-1,3-cyclohexyl mixture, cis/trans-1,3-dimethylene cyclohexyl mixture, cis-1,4-dimethylene cyclohexyl, 4,4 '-di-2-ethylhexylphosphine oxide cyclohexane extraction.
Especially, example as the chemical compound of the formula (I) of theme of the present invention is that another group is selected from following chemical compound: PA1079, PA1110, PA1120, PA1140, PA1103, PA1265, PA1251, PA1252, PA1253, PA1255, PA1271, PA1269, PA1259, PA1258, PA1256, PA1268, PA1260, PA1188, PA1261, PA1207, PA1262, PA1263, PA1264, PA1305, PA1308, PA1329, PA1333, PA1335, PA1278, PA1279, PA1280, PA1286, PA1330, PA1331, PA1332, PA1336, PA1338, described chemical compound randomly be alkali or with the form of the addition salts of acid, the form of hydrate or solvate, racemic form, the form of isomer and their mixture and diastereomer and their mixture.
Particularly preferably be most the Compound P A1259 of following formula:
This chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
According to advantageous embodiment, the preferred chemical compound of general formula (I) as defined above, wherein p=1, U=-CiH<, and B representation ring alkyl, dicyclo or three cyclic groups or 2 cycloalkyl are described in application WO2007/144487.
According to advantageous embodiment more, also can quote the chemical compound of general formula (I) as defined above, wherein p=1, U=-CiH<, and B represents C1-C5 alkylidene chain straight chain or side chain, described in application WO01/77105.
According to advantageous embodiment more, also can quote the chemical compound of general formula (I) as defined above, wherein p=0, U=-N<, described in application WO 2005/049619.
The above-mentioned chemical compound that provides among the application WO 2007/144487 that refers to hereinafter definition and the WO2005/049619 of quoting:
PA1079:(7-chloroquinoline-4-yl)-2-[2-(3,3-dimethyl-1,2,5-trioxa-9-azaspiro [5.5] hendecane-9-yl) ethyoxyl] ethyl } amine
PA1110:(7-chloroquinoline-4-yl)-[2-(7,8,16-trioxa-3-azepine two spiral shells [5.2.5.2] hexadecane-3-yl) ethyl] amine
PA1120:(7-chloroquinoline-4-yl)-[2-(6,7,14-trioxa-11-azepine two spiral shells [4.2.5.2] pentadecane-11-yl) ethyl] amine
PA1140:(7-chloroquinoline-4-yl)-[3-(6,7,14-trioxa-11-azepine two spiral shells [4.2.5.2] pentadecane-11-yl) propyl group] amine
PA 1103:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
The diphosphate of PA1278:PA1103
The diacetin of PA1279:PA1103
The dithionate of PA1280:PA1103
PA1265:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-cis-1, the 4-diamidogen
PA1251:N-(2,8-bis trifluoromethyl quinolyl-4)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1252:N-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-(7-Trifluoromethylquinocarboxylic-4-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1253:N-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-(6-dimethylamino quinolyl-4) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1255:N-(7-chloroquinoline-4-yl)-N '-(3,4-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1305:N-(6-trifluoromethoxy quinolyl-4)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1308:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-hexahydrotoluene-cis-1, the 4-diamidogen
PA1329:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-ethyl cyclohexane-cis-1, the 4-diamidogen
PA1333:(7-chloroquinoline-4-yl)-5-trioxa spiral shell [5.5] hendecane-9-base is amino for 3-[(3,3-dimethyl-1,2) methyl] diamantane (obsolete)-1-ylmethyl } amine
PA1335:(7-chloroquinoline-4-yl)-and N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) octahydro pentalene-2, the 5-diamidogen
PA1271:N-(7-chloroquinoline-4-yl)-cis-2-[(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-base is amino) methyl] cyclopenta amine
PA1269:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-1, the 4-diamidogen
PA1259:N-(7-chloroquinoline-4-yl)-N '-(6,7,14-trioxa two spiral shells [4.2.5.2] pentadecane-11-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1258:N-(7-chloroquinoline-4-yl)-N '-(7,8,15-trioxa two spiral shells [5.2.5.2] hexadecane-12-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1256:N-(7-chloroquinoline-4-yl)-N '-(9,9-dimethyl-7,8,12-trioxa spiral shell [5.6] dodecane-3-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1268:N-(7-chloroquinoline-4-yl)-N '-(9,9-dimethyl-7,8,13-trioxa spiral shell [5.7] tridecane-3-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1260:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-cis-1, the 2-diamidogen
PA1188:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 2-diamidogen
PA1261:N-(7-chloroquinoline-4-yl)-cis-2-[(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-base is amino) methyl] cyclo-hexylamine
PA1207:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-1, the 3-diamidogen
PA1262:(7-chloroquinoline-4-yl)-5-trioxa spiral shell [5.5] hendecane-9-base is amino for 3-[(3,3-dimethyl-1,2) methyl] cyclohexyl methyl } amine
PA1263:(7-chloroquinoline-4-yl)-5-trioxa spiral shell [5.5] hendecane-9-base is amino for 4-[(3,3-dimethyl-1,2) methyl] cyclohexyl methyl } amine
PA1264:(7-chloroquinoline-4-yl)-and 4-[4-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-base is amino) cyclohexyl methyl] cyclohexyl } amine
PA 1278:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1,4-diamidogen, diphosphate
PA1279:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1,4-diamidogen, diacetin
PA1280:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1,4-diamidogen, dithionate
PA1286:N-(7-chloroquinoline-4-yl)-N '-[5-spiral shell-(3,3-dimethyl-1,2,5-trioxane-6-yl) octahydro-cis-pentalene-2-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1330:N-(7-chloroquinoline-4-yl)-N '-cyclopropyl methyl-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-1, the 4-diamidogen
PA1331:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-isobutyl group cyclohexane extraction-1, the 4-diamidogen
PA1332:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-amyl group cyclohexane extraction-1, the 4-diamidogen
PA1336:N
4-(7-chloroquinoline-4-yl)-N
4-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) dicyclohexyl-4,4 '-diamidogen
PA1338:N-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-(6-methoxy quinoline-8-yl) cyclohexane extraction-1, the 4-diamidogen;
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
Chemical compound above can according to or adjust that disclosed method prepares among WO 01/77105, WO 2005/049619 and the WO 2007/144487.
Research to the pharmacological property of the coupled product of formula of the present invention (I) has shown that they have antischistosomal activity.
According to its another feature, the present invention relates to the pharmaceutical composition that is used to prevent or treat schistosomicide thus, and described pharmaceutical composition comprises the chemical compound of the present invention as active component.These pharmaceutical compositions contain the chemical compound of formula at least a of the present invention (I) of effective dose or pharmaceutically acceptable salt, hydrate or the solvate of described chemical compound, and at least a pharmaceutically acceptable excipient.Described excipient is selected from conventional excipients known to those skilled in the art according to dosage form and required medication.
In being used for oral, Sublingual, subcutaneous, intramuscular, intravenous, surface (topical), local, trachea, the pharmaceutical composition of the present invention of intranasal, percutaneous or rectally, active component or its possible salt, solvate or hydrate with following formula (I), can with described conventional medicine mixed with excipients, with unit form of medication administration, with prevention or treatment schistosomicide.
Suitable unit form of medication comprises oral form, such as tablet, soft capsule or hard capsule, powder, granule and oral administration solution or suspensoid; In Sublingual, oral, the trachea, the form of ophthalmic, intranasal administration; Inhalation, surface, percutaneous, subcutaneous, intramuscular or intravenous administration form, rectally form and implant.For surface applied, chemical compound of the present invention can be used as ointment, gel, ointment or lotion and uses.Preferred route of administration is oral, rectum and injectable approach.
By the mode of example, the unit form of medication of the chemical compound of the present invention of tablet form can comprise following component:
Chemical compound 50.0mg of the present invention
Mannitol 223.75mg
Cross-linking sodium carboxymethyl cellulose 6.0mg
Corn starch 15.0mg
Hydroxypropyl emthylcellulose 2.25mg
Magnesium stearate 3.0mg
Some special cases are also arranged, and wherein higher or lower dosage is suitable; This class dosage comprises within the scope of the invention.According to conventional practice, the dosage that is fit to each patient is determined according to the method for administration, patient's body weight and his replying treatment by the doctor.
According to its another feature, the invention still further relates to the method for treatment or prevention schistosomicide, this method comprises a kind of in the chemical compound of the formula of the present invention (I) of patient's administration effective dose or its pharmaceutically acceptable salt, hydrate or solvate.
Embodiment
1) obtains schistosomicide
Host/the parasite that is used for this research constitutes Brazilian Schistosoma mansoni (Schistosoma mansoni) strain that two umbilicus spiral shells (B.glabrata) albino by Brazil carries, and remains on the SWISS OF1 mice.
The results of worm's ovum and molluscan infection: the worm's ovum that obtains Schistosoma mansoni from 10 all infected mouse livers before.
Hot and infiltrative dual impact causes egg hatch, discharges miracidium.Take miracidium away and placement in the presence of Mollusca.After 24 hours, be placed on Mollusca in the dish and maintenance under 25 ℃ in the equilibrated photoperiod (12-12).
The infection of results cercaria and mice: after contacting for 5 weeks, Mollusca discharges cercaria.Use the Pasteur pipet to take out cercaria, (160-400) is placed in the little glass crystallizer in batches, makes the skin of mouse web portion contact 45 minutes with this solution.
Bilharzial recovery: infected the back 21-49 days, and put to death mice, from the blood of mice, reclaim parasite.Infect and reclaimed the adult schistosomicide in back 49 days, infect and reclaimed schistosomulum (schistosomicide of larva form) in back 21 days.Filtering blood, the use micropipet takes out schistosomicide and washs in the RPMI solution that has replenished the 25mMHepes+2mM L-glutaminate.Cultivate schistosomicide at 37 ℃.
2) chemosensitivity test
Twice of each molecular testing.On 24 orifice plates, schistosomulum is tested, in petri diss (diameter 3cm), adult is tested.1mL is contained in each hole, each petri diss contains the RPMI solution that 3mL has replenished 25mM Hepes+2mM L-glutaminate.Artemether and praziquantel are with comparing molecule.9-29 bar schistosomulum (average 14) and 6-20 bar adult schistosomicide (average 10) are positioned in the container.Then, located, remove the different molecular of desired concn and measure survival rate at 15 minutes, 30 minutes, 45 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours and 7 hours.Between each is measured, contain the container of worm in 37 ℃ of cultivations.If observe outside (muscle, suction ...) or inner (digestive tract, Excretory system ...) motion, think worm death so.
Preliminary research can be demarcated the scope of contrast molecule to adult schistosomicide and schistosomulum.For the adult schistosomicide, the proof load of praziquantel is 10,5,1 and 0.25 μ g/mL, and the proof load of Artemether is 300,100,50 and 10 μ g/mL.For schistosomulum, tested the praziquantel of 10,5 and 1 μ g/mL, tested the Artemether of 300,100 and 50 μ g/mL.For each level, carried out untreated contrast.
The PA1259 molecule is 300,100,10 and 5 μ g/mL to schistosomulum and the bilharzial proof load of adult.For each experiment, three contrasts have been carried out: the contrast of 10 μ g/ml praziquantel, the contrast of 300 μ g/ml Artemether and untreated contrast.
3) result
The parasiticide of Artemether, praziquantel and PA1259 is renderd a service
Chemical compound
*Effectiveness to schistosomulum (D21)
*Indication is killed the required Cmin of 100% parasite of cultivating and is obtained the required time of this effectiveness.
Chemical compound
*Effectiveness to adult schistosomicide (D49)
*Indication is killed the required Cmin of 100% parasite of cultivating and is obtained the required time of this effectiveness.
*Under the situation of 300 μ g/mL Artemether, cultivate and still have the survival of 45% schistosomicide after 7 hours.
Claims (11)
1. be used to prevent or treat the chemical compound of schistosomicide, described compound-base is in following formula (I):
Wherein:
● be selected from following molecule residue:
The quinolin-2-ylamine of formula (IIa):
Wherein:
-R is identical or different with R ', and represents one or more (for example 1-5) substituent group, described substituent group to occupy isolating position on the ring that they link to each other separately, and is selected from:
Hydrogen or halogen atom ,-OH ,-CF
3,-OCF
3Base, aryl ,-O-aryl, heteroaryl, alkyl or-the O-alkyl, described alkyl comprises 1-5 carbon atom,
-N (R
a, R
b), R wherein
aAnd R
bBe identical or different, and represent hydrogen atom independently of one another or comprise the alkyl of 1-5 carbon atom;
-R
4The alkyl of representing hydrogen atom maybe can comprise 1-5 carbon atom maybe can comprise the cycloalkyl of 3-5 carbon atom;
B representative can comprise the cycloalkyl of 3-8 carbon atom, and described cycloalkyl randomly is selected from following group and replaces by one or more:
Hydrogen atom, hydroxyl, the alkyl that can comprise 1-6 carbon atom maybe can comprise the cycloalkyl of 3-6 carbon atom,
● perhaps the B representative can comprise the dicyclo or three cyclic groups of 4-18 carbon atom, the group that the alkyl that described dicyclo or three cyclic groups randomly one or morely are selected from halogen atom, hydroxyl, can comprise 1-6 carbon atom maybe can comprise the cycloalkyl of 3-6 carbon atom replaces
● perhaps B represents 2 cycloalkyl that can comprise 3-6 carbon atom, and described cycloalkyl links together by the singly-bound or the alkylidene chain that can comprise 1 or 2 carbon atom;
● perhaps B represents C1-C5 alkylidene chain straight chain or side chain;
● perhaps B representative-CH
2-CH
2-O-CH
2-CH
2-chain;
R
5Represent hydrogen atom or alkyl or C
1-3-alkylidene cycloalkyl, described cycloalkyl can comprise 3-6 carbon atom;
Z
1And Z
2Be identical or different, and representative-(CH
2)
2-Ji, therefore, Z
1+ Z
2+ U+C
j:
● when U=-CH<time, represent cyclohexyl,
● perhaps,, represent piperidyl when U=-N<time,
● perhaps representative can comprise the multiring structure of the bicarbonate salinization of 4-18 atom, and described multiring structure randomly comprises nitrogen-atoms,
Z
1Or Z
2In one can represent U and C
jSingly-bound between the atom, Z
1And Z
2Can not contemporary list key;
R
xAnd R
yWith C
jForm the cyclic peroxide that is selected from formula (XI), (XII) and group (XIII) together:
The trioxane of-Shi (XI):
R wherein
3Represent 1-4 identical or different groups, perhaps
The trioxepan of-Shi (XII):
R wherein
3Represent 1-6 identical or different groups, perhaps
The trioxacane of-Shi (XIII):
R wherein
3Represent 1-8 identical or different groups,
Wherein
R
3Represent 1-8 identical or different groups, described group occupies the optional position on the carbon atom of described peroxide ring and is selected from following atom and group:
Hydrogen, halogen ,-OH ,-CF
3,-NO
2,-OCF
3Base, aryl ,-O-aryl, heteroaryl, alkyl or-the O-alkyl, described alkyl comprises 1-10 carbon atom,
Perhaps, two R carrying of the same carbon atom of described peroxide ring
3Base forms dicyclo or three cyclic groups (therefore, described dicyclo or three cyclic groups are arranged with the spiral shell position) that the cycloalkyl that can comprise 3-7 carbon atom maybe can comprise 4-18 carbon atom together on described peroxide ring;
When p=1, U representative-CH<, and when p=0, U is by singly-bound and-(CH
2)
n-connect;
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
2. the chemical compound of the formula of claim 1 (I), wherein, A, B, m, n, Z
1, Z
2, p=1, U=-CH<, Z
1+ Z
2+ U+Cj, R
1, R
2, R
5, R
x, R
yAs defined in claim 1, described alkyl can comprise 1-5 carbon atom,
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
3. any one chemical compound in the above claim, described compound-base are in following formula (I.2):
Wherein R ', R
4, B, Z
1, Z
2, Ci, C
j, R
1, R
2, R
3, R
5, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
4. any one chemical compound in the above claim, described compound-base are in following formula (I.3):
Wherein R ', R
4, B, R
3, R
5, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
5. the chemical compound of claim 1, described compound-base are in following formula (I.4):
Wherein R ', R
4, B, C
j, R
1, R
2, Z
1, Z
2, R
x, R
y, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
6. any one chemical compound among the claim 1-5, described compound-base are in following formula (I.5):
Wherein R ', R
4With B, Z
1, Z
2, C
j, R
1, R
2, R
3, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
7. any one chemical compound in the claim 1,5 and 6, described compound-base are in following formula (I.6):
Wherein R ', R
4, B, R
3, m and n define as the chemical compound about formula (I);
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
8. the chemical compound of any one formula (I) in the above claim, wherein the B representative is selected from following group:
Cis-1,2-methylene cyclopenta, anti-form-1,2-cyclohexyl, cis-1,2-cyclohexyl, cis-1,2-methylene cyclohexyl, anti-form-1,4-cyclohexyl, cis-1,4-cyclohexyl, cis/trans-1,4-cyclohexyl mixture, cis/trans-1,3-cyclohexyl mixture, cis/trans-1,3-dimethylene cyclohexyl mixture, cis-1,4-dimethylene cyclohexyl, 4,4 '-di-2-ethylhexylphosphine oxide cyclohexane extraction.
9. any one chemical compound in the above claim, described chemical compound is selected from:
PA1079:(7-chloroquinoline-4-yl)-2-[2-(3,3-dimethyl-1,2,5-trioxa-9-azaspiro [5.5] hendecane-9-yl) ethyoxyl] ethyl } amine
PA1110:(7-chloroquinoline-4-yl)-[2-(7,8,16-trioxa-3-azepine two spiral shells [5.2.5.2] hexadecane-3-yl) ethyl] amine
PA1120:(7-chloroquinoline-4-yl)-[2-(6,7,14-trioxa-11-azepine two spiral shells [4.2.5.2] pentadecane-11-yl) ethyl] amine
PA1140:(7-chloroquinoline-4-yl)-[3-(6,7,14-trioxa-11-azepine two spiral shells [4.2.5.2] pentadecane-11-yl) propyl group] amine
PA1103:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
The diphosphate of PA1278:PA1103
The diacetin of PA1279:PA1103
The dithionate of PA1280:PA1103
PA1265:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-cis-1, the 4-diamidogen
PA1251:N-(2,8-bis trifluoromethyl quinolyl-4)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1252:N-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-(7-Trifluoromethylquinocarboxylic-4-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1253:N-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-(6-dimethylamino quinolyl-4) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1255:N-(7-chloroquinoline-4-yl)-N '-(3,4-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1305:N-(6-trifluoromethoxy quinolyl-4)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1308:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-hexahydrotoluene-cis-1, the 4-diamidogen
PA1329:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-ethyl cyclohexane-cis-1, the 4-diamidogen
PA1333:(7-chloroquinoline-4-yl)-5-trioxa spiral shell [5.5] hendecane-9-base is amino for 3-[(3,3-dimethyl-1,2) methyl] diamantane (obsolete)-1-ylmethyl } amine
PA1335:(7-chloroquinoline-4-yl)-and N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) octahydro pentalene-2, the 5-diamidogen
PA1271:N-(7-chloroquinoline-4-yl)-cis-2-[(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-base is amino) methyl] cyclopenta amine
PA1269:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-1, the 4-diamidogen
PA1259:N-(7-chloroquinoline-4-yl)-N '-(6,7,14-trioxa two spiral shells [4.2.5.2] pentadecane-11-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1258:N-(7-chloroquinoline-4-yl)-N '-(7,8,15-trioxa two spiral shells [5.2.5.2] hexadecane-12-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1256:N-(7-chloroquinoline-4-yl)-N '-(9,9-dimethyl-7,8,12-trioxa spiral shell [5.6] dodecane-3-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1268:N-(7-chloroquinoline-4-yl)-N '-(9,9-dimethyl-7,8,13-trioxa spiral shell [5.7] tridecane-3-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1260:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-cis-1, the 2-diamidogen
PA1188:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1, the 2-diamidogen
PA1261:N-(7-chloroquinoline-4-yl)-cis-2-[(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-base is amino) methyl] cyclo-hexylamine
PA1207:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-1, the 3-diamidogen
PA1262:(7-chloroquinoline-4-yl)-5-trioxa spiral shell [5.5] hendecane-9-base is amino for 3-[(3,3-dimethyl-1,2) methyl] cyclohexyl methyl } amine
PA1263:(7-chloroquinoline-4-yl)-5-trioxa spiral shell [5.5] hendecane-9-base is amino for 4-[(3,3-dimethyl-1,2) methyl] cyclohexyl methyl } amine
PA1264:(7-chloroquinoline-4-yl)-and 4-[4-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-base is amino) cyclohexyl methyl] cyclohexyl } amine
PA1278:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1,4-diamidogen, diphosphate
PA1279:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1,4-diamidogen, diacetin
PA1280:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-anti-form-1,4-diamidogen, dithionate
PA1286:N-(7-chloroquinoline-4-yl)-N '-[5-spiral shell-(3,3-dimethyl-1,2,5-trioxane-6-yl) octahydro-cis-pentalene-2-yl) cyclohexane extraction-anti-form-1, the 4-diamidogen
PA1330:N-(7-chloroquinoline-4-yl)-N '-cyclopropyl methyl-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) cyclohexane extraction-1, the 4-diamidogen
PA1331:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-isobutyl group cyclohexane extraction-1, the 4-diamidogen
PA1332:N-(7-chloroquinoline-4-yl)-N '-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-amyl group cyclohexane extraction-1, the 4-diamidogen
PA1336:N
4-(7-chloroquinoline-4-yl)-N
4-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl) dicyclohexyl-4,4 '-diamidogen
PA1338:N-(3,3-dimethyl-1,2,5-trioxa spiral shell [5.5] hendecane-9-yl)-N '-(6-methoxy quinoline-8-yl) cyclohexane extraction-1, the 4-diamidogen;
Described chemical compound randomly be alkali or with form, racemic form, isomer and their mixture of form, hydrate or the solvate of the addition salts of acid and the form of diastereomer and their mixture.
10. be used to prevent or treat the pharmaceutical composition of schistosomicide, it is characterized in that, described pharmaceutical composition comprises the chemical compound of formula any among the claim 1-9 (I).
11. the purposes that the chemical compound of any one formula (I) is used to prepare treatment or prevents the pharmaceutical composition of schistosomicide among the claim 1-9.
Applications Claiming Priority (3)
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FR0759550 | 2007-12-04 | ||
FR0759550A FR2924343A1 (en) | 2007-12-04 | 2007-12-04 | NOVEL THERAPEUTIC USES OF DUAL MOLECULES CONTAINING A PEROXYDIC DERIVATIVE. |
PCT/EP2008/066651 WO2009071553A1 (en) | 2007-12-04 | 2008-12-02 | New therapeutic uses of dual molecules containing a peroxide derivative |
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CN (1) | CN101909627A (en) |
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WO2019057123A1 (en) * | 2017-09-20 | 2019-03-28 | 杭州英创医药科技有限公司 | Polycyclic compound acting as ido inhibitor and/or ido-hdac dual inhibitor |
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US6486199B1 (en) * | 2001-06-21 | 2002-11-26 | Medicines For Malaria Venture Mmv International Centre Cointrin | Spiro and dispiro 1,2,4-trioxolane antimalarials |
US6825230B2 (en) * | 2002-06-21 | 2004-11-30 | Medicines For Malaria Venture Mmv | Spiro and dispiro 1,2,4-trixolane antimalarials |
US6906205B2 (en) * | 2002-06-21 | 2005-06-14 | Medicines For Malaria Venture Mmv | Spiro and dispiro 1,2,4-trioxolane antimalarials |
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