WO2001014331A2 - Inhibiteurs exempts de quinoline de parasites du paludisme - Google Patents

Inhibiteurs exempts de quinoline de parasites du paludisme Download PDF

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WO2001014331A2
WO2001014331A2 PCT/US2000/023338 US0023338W WO0114331A2 WO 2001014331 A2 WO2001014331 A2 WO 2001014331A2 US 0023338 W US0023338 W US 0023338W WO 0114331 A2 WO0114331 A2 WO 0114331A2
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compound according
compound
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alkyl
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Jin Mi Kim
Jonathan A. Ellman
Daniel Goldberg
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Regents Of The University Of California
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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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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

Definitions

  • a number of serious diseases affecting humans, and domestic and livestock animals are caused by protozoal organisms such as, Kinetoplastida, Apicomplexa, Anaerobic protozoa, Microsporidia and Plasmodium, for example.
  • the best known of these diseases is malaria. Malaria is caused by organisms of the genus Plasmodium which infect and multiply within erythrocytes.
  • Blood-stage infection is usually characterized by severe fever, sometimes accompanied by anemia, hypoglycemia, pulmonary edema, renal or hepatic failure, and coma which may occasionally prove fatal. Immunity may develop so as to reduce the severity of infection but takes many years and in individuals living in endemic areas complete elimination of parasites rarely occurs.
  • the World Health Organization estimates that 280 million people are infected with malaria yearly (Gibbons, Science, 256, 1135 (1992)). Although various classes of antimalarial agents exist, the most widely used are the quinoline-derived compounds. For example, chloroquine has been a particularly effective drug for both prophylaxis and therapy. The appearance of malaria strains which are resistant to quinoline-derived drugs poses a threat to travelers and people in countries where malaria is endemic. Reports of multi-drug resistant strains of malaria parasites render the search for new antimalarial agents especially urgent.
  • the present invention provides new drugs and methods of using these drugs to treat and prevent protozoal diseases in general, and malaria specifically.
  • the present invention provides a novel genus of compounds having antiprotozoal activity. These compounds are particularly useful in interrupting the life cycle of plasmodia, such as Plasmodium falciparum, the causative agent of malaria.
  • the present invention provides compounds having the general structure:
  • R 1 has a structure selected from Formulae II-IV, below:
  • R 2 is a member selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, C ⁇ - Cio alkyl and substituted C ⁇ -C 10 alkyl; and R 3 is a member selected from
  • Figure 2 A representative template for performing SAR at various regions of a scaffold of the invention and exemplary SAR at different the different regions of this template: (A) Representative template for optimizing SAR; (B) SAR in the R 2 region; (C) SAR in the linker region; (D) SAR in the R 1 region; (E) SAR in the R 3 region
  • Figure 3 (A-C).
  • Exemplary compounds of the invention having various substitution patterns: (A) at the R 1 region; (B) at the R 3 region; (C) at the Figure 4.
  • Figure 5. An exemplary synthetic scheme leading to compounds 6 and 8.
  • Figure 6. An exemplary synthetic scheme leading to compounds 9 and 10.
  • Figure 7. An exemplary synthetic scheme leading to compounds 14-21.
  • Figure 8. An exemplary synthetic scheme leading to compound 60.
  • Figure 9. An exemplary synthetic scheme leading to compounds 22-33.
  • Figure 10. An exemplary synthetic scheme leading to compounds 37-40.
  • Figure 11. An exemplary synthetic scheme leading to compounds 12-13 and
  • the present invention provides an array of novel compounds and libraries of these novel compounds.
  • these compounds act as inhibitors of protozoal enzymes and are useful pharmaceutical agents for treating and preventing protozoal infections.
  • the discussion that follows is principally focused on compounds of the invention that inhibit enzymes relevant to the organism Plasmodium falciparum, the causative agent of malaria. This focus is intended to be illustrative and not limiting.
  • Those of skill in the art will recognize that there is a great deal of structural homology and substrate specificity and activity overlap between the enzymes of P. falciparum and other protozoa.
  • the compounds of the invention are also applicable in methods of treating and preventing diseases caused by a wide range of protozoa.
  • Substituted generally refers to an alkyl or aryl group that is elaborated with one or more of a wide range of substituents.
  • the substituent(s) can be pendent from the alkyl group, can interrupt the alkyl group or the substituent(s) can be both pendent from, and interrupt, the alkyl group.
  • alkyl is used herein to refer to a branched or unbranched, saturated or unsaturated, hydrocarbon radical having from 1-30 carbons and preferably, from 4-20 carbons and more preferably from 6-18 carbons. When the alkyl group has from 1-6 carbon atoms, it is referred to as a "lower alkyl. " Suitable alkyl radicals include, for example, structures containing one or more methylene, methine and/or methyne groups. Branched structures have a branching motif similar to i-propyl, t- butyl, i-butyl, 2-ethylpropyl, etc. As used herein, the term encompasses "substituted alky Is. "
  • Substituted alkyl refers to alkyl as just described including one or more functional groups such as lower alkyl, aryl, acyl, halogen (i.e., alkylhalos, e.g., CF 3 ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, heteroatoms, both saturated and unsaturated cyclic hydrocarbons, heterocycles and the like. These groups may be attached to any carbon of the alkyl moiety.
  • functional groups such as lower alkyl, aryl, acyl, halogen (i.e., alkylhalos, e.g., CF 3 ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, heteroatoms, both saturated and unsaturated cyclic hydrocarbons,
  • aryl is used herein to refer to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings which are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety.
  • the common linking group may also be a carbonyl as in benzophenone.
  • the aromatic ring(s) may include phenyl, napthyl, biphenyl, diphenylmethyl and benzophenone among others.
  • aryl encompasses "arylalkyl.”
  • alkylarene is used herein to refer to a subset of "aryl” in which the aryl group is substituted with an alkyl group as defined herein.
  • Substituted aryl refers to aryl as just described including one or more functional groups such as lower alkyl, acyl, halogen, alkylhalos (e.g. CF 3 ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto and both saturated and unsaturated cyclic hydrocarbons which are fused to the aromatic ring(s), linked covalently or linked to a common group such as a methylene or ethylene moiety.
  • the linking group may also be a carbonyl such as in cyclohexyl phenyl ketone.
  • substituted aryl encompasses "substituted arylalkyl.”
  • acyl is used to describe a ketone substituent, — C(O)R, wherein R is alkyl or substituted alkyl, aryl or substituted aryl as defined herein.
  • halogen is used herein to refer to fluorine, bromine, chlorine and iodine atoms.
  • hydroxy is used herein to refer to the group — OH.
  • amino is used to describe primary amines, — NRR', wherein R and R' are independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl and substituted heterocyclyl as defined herein.
  • alkoxy is used herein to refer to the — OR group, wherein R is a lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl wherein the alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl groups are as described herein.
  • Suitable alkoxy radicals include, for example, methoxy, ethoxy, phenoxy, substituted phenoxy, benzyloxy, phenethyloxy, t-butoxy, etc.
  • unsaturated cyclic hydrocarbon is used to describe a non- aromatic group with at least one double bond, such as cyclopentene, cyclohexene, etc. and substituted analogues thereof.
  • heteroaryl refers to aromatic rings in which one or more carbon atoms of the aromatic ring(s) are substituted by a heteroatom such as nitrogen, oxygen or sulfur.
  • Heteroaryl refers to structures which may be a single aromatic ring, multiple aromatic ring(s), or one or more aromatic rings coupled to one or more non-aromatic ring(s). In structures having multiple rings, the rings can be fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety.
  • the common linking group may also be a carbonyl as in phenyl pyridyl ketone.
  • rings such as thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, etc. or benzo-fused analogues of these rings are defined by the term "heteroaryl.”
  • Alkylheteroaryl defines a subset of “heteroaryl” substituted with an alkyl group, as defined herein.
  • Substituted heteroaryl refers to heteroaryl as just described wherein the heteroaryl nucleus is substituted with one or more functional groups such as lower alkyl, acyl, halogen, alkylhalos (e.g. CF 3 ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, etc.
  • substituted analogues of heteroaromatic rings such as thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, etc. or benzo-fused analogues of these rings are defined by the term "substituted heteroaryl.”
  • heterocyclic is used herein to describe a saturated or unsaturated non- aromatic group having a single ring or multiple condensed rings from 1- 12 carbon atoms and from 1-4 heteroatoms selected from nitrogen, sulfur or oxygen within the ring.
  • heterocycles are, for example, tetrahydrofuran, morpholine, piperidine, pyrrolidine, etc.
  • substituted heterocyclic as used herein describes a subset of “heterocyclic” wherein the heterocycle nucleus is substituted with one or more functional groups such as lower alkyl, acyl, halogen, alkylhalos (e.g. CF 3 ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, etc.
  • functional groups such as lower alkyl, acyl, halogen, alkylhalos (e.g. CF 3 ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, etc.
  • alkylheterocyclyl defines a subset of "heterocyclic” substituted with an alkyl group, as defined herein.
  • substituted heterocyclicalkyl defines a subset of “heterocyclic alkyl” wherein the heterocyclic nucleus is substituted with one or more functional groups such as lower alkyl, acyl, halogen, alkylhalos (e.g. CF ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, etc.
  • functional groups such as lower alkyl, acyl, halogen, alkylhalos (e.g. CF ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, etc.
  • the present invention provides compounds having the general structure:
  • R 1 has a structure selected from Formulae II-IV, below:
  • R 2 is a member selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, C ⁇ - Cio alkyl and substituted Cj-Cio alkyl; and R 3 is a member selected from
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are members independently selected from a single bond, — O — , — C(O) — , — CO 2 — , — C(O)NH— , — C(O)NR 14 — , and— SO 2 — ;
  • R 4 , R 5 , R 8 , R 9 and R 11 are members independently selected from H, — OH, alkoxy, Ci-Cio alkyl and C t -Cio substituted alkyl;
  • R 6 , R 7 , R 10 , R 12 and R 13 are members independently selected from — C(O) — , — CO 2 — , — C(O)NH— , — C(O)NR 15 — , and— SO_— ;
  • a substituted alkyl moiety is selected from straight-chain, branched-chain or cyclic alkyl groups having from 1-10 carbon atoms.
  • the carbon chain is optionally interrupted by from 1 to 5 heteroatoms.
  • Preferred heteroatoms include, N, O, P and S. When more than one heteroatom is present, each heteroatom is selected independently of the others.
  • the alkyl moiety can be substituted with other groups.
  • Preferred groups include, alkyl, aryl, heteroaryl, carboxy ester, carboxamide, amino, N-acylamino, alkoxy, hydroxy, mercapto, phosphono, sulfono and the like.
  • the compounds have a structure according to Formulae VII-XI, below:
  • R 2 has a structure according to Formula XII:
  • R 2 has a structure according to
  • n is an integer between 1 and 5, inclusive and more preferably, an integer between 2 and 4, inclusive.
  • the compounds of the invention have a structure according to Formula I, in which R 1 has a structure according to Formula XVI, below:
  • R 1 has a structure according to Formula XVII, below:
  • R 3 has a structure according to Formula
  • R 50 and R 51 are members independently selected from H, aryl, substituted aryl, heteroaryl and substituted heteroaryl groups; and n is a number from 0 to 5, inclusive.
  • R 50 and R 51 are both benzene.
  • Presently preferred compounds of the invention are displayed in Table 1.
  • the present invention also provides methods for synthesizing these compounds. Representative examples of synthetic pathways leading to the compounds of the invention are set forth in Figure 4 through Figure 13.
  • FIG. 4 sets forth the synthesis of compound 7, from 4-amino-l- benzylpiperidine using a multistep procedure.
  • step a 4-amino-l-benzylpiperidine is alkylated using l-bromo-3-chloropropane.
  • step b the adduct of this reaction is amine- protected at the exocyclic amine by the action di-t-butyl dicarbonate.
  • the amine- protected chloro derivative is then reacted with NaN 3 , to replace the chloro group with an azido moiety in step c.
  • the azide is reduced to the corresponding amine, in step d, by the action of SnCl .
  • the amine is coupled to 4-benzyloxy-3,5- dimethoxybenzoic acid, in step e.
  • the t-Boc protected amine is subsequently deprotected, in step/, by the action of TFA.
  • the amido carbonyl moiety is reduced by the action of LiAlH 4 .
  • Figure 5 sets forth the synthesis of compounds 6 and 8. These compounds vary in the number of carbon atoms included in the linker arm (R 2 ) portion. Substantially as described above, 4-amino-l-benzylpiperidine is alkylated, converted to the azide, amine protected, the azide is reduced, the resulting amine is coupled with 4-benzyloxy- 3,5-dimethoxybenzoic acid, the t-Boc protect amine is deprotected and the amide carbony is reduced, thereby producing compounds 6 and 8.
  • Figure 6 sets forth the synthesis of compounds 9 and 10.
  • step a 4- benzyloxy-3,5-dimethoxybenzyl alcohol is alkylated at the alcohol hydroxy with 4-(N- Boc-N'-3-chloropropyl)amino-l-benzylpiperidine.
  • step b the t-Boc groups is removed, substantially as described above.
  • Figure 7 sets forth the synthesis of a library of compounds consisting of compounds 14-21. The libraries are synthesized from amine precursors by coupling carboxylic acids to them using polymer-bound EDC.
  • FIG 8 sets forth the synthesis of compound 60 from compound 47.
  • step a compound 47 is reductively debenzylated using Pd/C and H 2 .
  • the piperidine secondary amine is amidated using allyl chloroformate in step b.
  • the resulting compound is converted to the azide, the azide is reduced to the amine and the amine is acylated with 4-benzyloxy-3,5-dimethoxybenzoic acid substantially as described above.
  • the allyl protected secondary amine is deprotected, in step/ Figure 9 sets forth the preparation of a library of compounds of the invention consisting of compounds 22-33 from compound 60. This library is prepared by reductively aminated using an array of aldehydes and sodium cyanoborohydride and purified using ion exchange.
  • FIG. 10 sets forth the synthesis of compounds 37-40.
  • step a 4- benzyloxy-3,5-dimethoxybenzoic acid is aminated using an alkyldiamine.
  • the resulting amine is treated with a keto-piperidine derivative in step b and the amide group of the resulting amide is reduced substantially as described above.
  • FIG 11 sets forth the synthesis of compounds 12-13 and 41-42.
  • the aniline amine is converted to an amide using N- Boc-4-aminobutyric acid, in step a.
  • the Boc group is removed and, in step c, the free amine is used to reductively aminate a keto-piperidine derivative.
  • Figure 12 sets forth the synthesis of compounds 43 and 44 from a common precursor, compound 55.
  • the piperidine secondary amine is protected, the chloro group is converted to an azide, which his reduced to an amine, the amine is used in a reductive animation and the Boc is removed substantially as described above.
  • Figure 13 sets for the deprotection, by removal of the Boc group of compound 60 to produce compound 45.
  • Figure 14 sets forth the synthesis of compound 100. This scheme begins with the acylation of the secondary amine of a piperidine compound and the reduction of the resulting amide to the corresponding amine. The chloro group is converted to an azide, which his reduced to an amine, the amine is used in a reductive animation and the Boc is removed substantially as described above.
  • (B) sets forth a substanially similarroute to compound 110.
  • Figure 15 sets forth the synthesis of compounds 120 and 130 from a common precursor amine. The amine is used to reductively aminate a benzaldehyde derivative. Compound 120 is produced by simple Boc deprotection. Compound 130 is produced by a second reductive amination using acetaldehyde.
  • Figure 16 sets forth the synthesis of compounds 140 and 150 from a common precursor using methods described above.
  • the present invention also provides a library comprising at least two compounds of the invention.
  • the library comprises at least 5 compounds, preferably at least 50 compounds and more preferably at least 5000 compounds.
  • the libraries of the invention can be selected using calculational structure-activity methods (I. D. Kuntz, Science 257, 1078-1082 (1992).; I. D. Kuntz, et al., Accts. Chem. Res. 27, 117-123 (1994)) and prepared using combinatorial chemistry (L. A. Thompson, et al., Chem Rev.
  • An element of any library design is the procedure for selecting the compounds to synthesize. This includes the choice of the scaffold, the basic reactions and the nature of the building blocks. If the building blocks are readily available components such as amines, aldehydes or carboxylic acids, the number of potential compounds to be considered can be quite large. For example, combining three building blocks with thousands of components at each position leads to over 1 billion compounds.
  • the standard strategies for reducing potential choices are diversity selection and directed selection.
  • Diversity approaches attempt to maximize the sampling of chemical and biological properties given a fixed number of compounds (R. J. Simon, et al, Proc. Natl Acad. Sci. U.S.A. 89, 9367-9371 (1992)).
  • directed libraries the size, and often the diversity, of the library is reduced by selecting those building blocks that are predicted to have favorable interactions with the target, or by eliminating candidates that are a priori believed to have unfavorable interactions.
  • a directed library can be based on substrate preferences, information about known inhibitors or, on an assessment of the potential interaction of specific functional groups with the target. Both diverse and directed strategies permit a multistage attack with second libraries generated from active compounds found in the first round.
  • Potent inhibitors of protozoal enzymes can be readily accessed by the incorporation of an isostere that mimics the geometry of the tetrahedral intermediate in place of the scissile bond of the peptide substrate.
  • these inhibitors have limited therapeutic utility due to the poor oral availability and/or short circulating half- lives that result from their peptidic nature.
  • Non-peptidic inhibitors of protozoal enzymes exhibit more efficacious pharmacokinetic and pharmacodynamic profiles.
  • the present invention will generally apply structure-based design and combinatorial chemistry techniques to develop non-peptide inhibitors of protozoal enzymes.
  • the compounds of the present invention are useful as inhibitors of enzymes that are implicated in the life cycle of protozoa.
  • Preferred compounds of the invention have an activity towards one or more selected protozoal enzymes. This activity is preferably of sufficient magnitude to allow the compound to be used in the treatment and prevention of a disease caused by the protozoa.
  • compounds of the invention having sufficient activity can be used in biological and pharmacological assays and screening procedures involving the protozoa and/r the enzymes.
  • the term “inhibition” refers to both reduction and cessation of activity. Details of the life cycle and pathogenicity of parasites are given in standard texts (see, for example, Schmidt et al.
  • the invention provides a compound according to Formula I having an IC50 towards a protozoal enzyme of less than 5000 nanomolar, preferably less than 500 nanomolar, and more preferably less than 50 nanomolar. Even more preferred are compounds that have an IC50 of from about 0.05 nanomolar to about 40 nanomolar, and more preferably from about 1 nanomolar to about 20 nanomolar.
  • Proteases are normally divided into four main classes of serine, cysteine (thiol), aspartyl (carboxyl) and metallo-proteases. Proteases are involved in important physiological processes that range from protein catabolism or post-translational modification as found in lysosomal metabolism, to involvement in extracellular digestion of dietary proteins.
  • the compounds of the invention can be used to inhibit the activity of a range of protozoal enzymes.
  • the enzyme is selected from cysteine protease, aspartyl protease and combinations thereof.
  • the enzymes inhibited by the compounds of the invention are components of essentially and known protozoal organism.
  • the enzyme comprises a component of an organism selected from Kinetoplastida, Apicomplexa, Anaerobic protozoa, Microsporidia and Plasmodium.
  • the present invention relates to the treatment and prophylaxis of protozoal infections caused by protozoa, including Kinetoplastida, Apicomplexa, Anaerobic protozoa, Microsporidia and Plasmodium. More particularly the invention is concerned with the use of compounds according to Formula I and physiologically acceptable salts and physiologically functional derivatives thereof.
  • Kinetoplastida include the Trypanosomes of which Trypanosoma rhodiense, Trypanosoma gambiense and Trypanosoma cruzi are of particular importance.
  • T. rhodiense and T. gambiense cause sleeping sickness, which is fatal in humans unless treated.
  • the trypanosome parasites live and multiply initially in the blood and tissue fluid of their host, producing a febrile condition which may be quite mild. After a few months (T. rhodiense) or a year or so (T. gambiense) the parasites invade the central nervous system and multiply in the cerebrospinal fluid, ultimately causing brain damage which leads to the coma from which the disease gets its name.
  • T. cruzi causes Chagas disease in humans. In children, the disease takes the form of an acute fever which can cause death. In adults, the infection is chronic, involves the heart or the alimentary tract and can be fatal.
  • the Kinetoplastida also include the genus Leishmania which cause leishmaniasis in humans.
  • the parasites are also frequently found in dogs and rodents which may serve as reservoirs for the parasite. Leishmania parasites are ingested by the macrophage cells of their host, but instead of being destroyed the parasites thrive and multiply within the macrophages. In visceral leishmaniasis, caused by L.donovani, parasitized macrophages occur in all tissues, including the blood, and although the disease is slow, it is usually fatal unless treated.
  • L.tropica causes cutaneous leishmaniasis in which the parasites are restricted to ulcers in the skin.
  • L-Braziliensis causes mucocutaneous leishmaniasis which is a very severe disease; the mucous membranes of the nose, mouth and pharynx become infected and ultimately destroyed.
  • the Apicomplexa include the Babesia parasites which inhabit erythrocytes and which are of veterinary as well as medical importance.
  • B.divergens is the European species that causes bovine babesiosis and, although not normally parasitic in man, it can cause a life threatening disease in splenectomized individuals, for which there is no recommended chemotherapy.
  • the disease is usually associated with anemia, fever, enlargement of the spleen and, blocking of the capillaries in various tissues (including the brain), which may damage the cells by depleting their oxygen supply.
  • the anemia may be accompanied by the lysis of erythrocytes and excretion of the released hemoglobin in the urine.
  • the Isospora are a genus of Apicomplexa which may infect humans and cause diarrhea.
  • Another genus of Apicomplexa which may infect humans are the Sarcocystis which commonly infect herbivores. All species of Sarcocystis are almost entirely restricted to the muscle fibers of their host. If the infection is heavy, degeneration of the surrounding muscle fibers and consequent muscular weakness results along with some pain.
  • Parasitic anaerobic protozoa include species of Acanthanamoeba which normally inhabit soil and mud but which can cause throat infections in humans, particularly in infants.
  • Entamoeba histolytica is an anaerobic protozoan which normally inhabits the gut as a harmless commensal. Occasionally however, the parasites penetrate the mucosa and invade the sub-mucosa where they multiply to form a flask-shaped lesion or ulcer. Secondary bacterial infection of the ulcer may also occur. As the submucosa is eroded, many blood vessels are broken and bloody dysentery results. A common complication is the spread of amoebae via blood vessels to other organs, where they invade and destroy the organ tissue and cause amoebic abscesses. The commonest site for development of such abscesses is the liver, because most of the blood from the gut is carried there by the hepatic portal system.
  • Giardia lamblia is a species of anaerobic protozoa which inhabits the small intestine of humans, monkeys and pigs. It is common in humans, especially in children, and can cause a disease called giardiasis or lambliasis. Heavy infections may cause acute diarrhea and epigastric pain. The parasites are thought sometimes to swim up the bile duct into the gall bladder where they may produce symptoms of jaundice, nausea and vomiting.
  • Trichomonas vaginalis is an anaerobic protozoan which inhabits the female vagina and the male urethra or prostrate and is common throughout the world, particularly in women. Most commonly, the parasite is non-pathogenic. However, the organism may be responsible for vaginal inflammation associated with a discharge in women and, more rarely, for inflammation of the urethra in males.
  • Microsporidia such as Enterocytozoon bieneuisi or Encephalitozoon cuniculi causes an increase in the size of infected cells to such an extent that those cells cannot perform their natural function.
  • Encephalitozoon cuniculi can cause an encephalitis in humans in which the parasites are present in the cerebrospinal fluid.
  • malaria Upon infecting a host, the malaria parasite avidly consumes the host hemoglobin as its source of nutrients.
  • Plasmepsin I and II are proteases from Plasmodium falciparum that are necessary during the initial stages of hemoglobin hydrolysis and digestion, which primarily occurs in the .alpha.chain, between Phe 33 and Leu 34, although other sites may serve as substrates for hydrolysis as well. It has been shown in cultures inhibition of plasmepsin by a peptidomimetic inhibitor is effective in preventing malarial hemoglobin degradation and in killing the parasite (Francis et al, EMBOJ, 13: 306-317 (1994)). Thus, persons of skill in the art expect inhibitors of P. falciparum enzymes to provide effective antimalarial therapy.
  • Immune deficiency may furthermore be caused by viral infections, including human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • the compounds of the invention are used to treat infections in subjects that are immune compromised.
  • the activity of the compounds described herein can be measured by any art-recognized method to acquire IC50 data from enzymes. Moreover, the activity of the compounds can be assessed by observing their effect on intact protozoa in culture.
  • library compounds are examined for inhibitory activity against aspartyl protease plasmepsin II in a high through-put fluorogenic assay.
  • the enzyme activity is determined by observing an increase in fluorescence as the peptide substrate is cleaved by the enzyme.
  • the substrate peptide is DABCYL-GABA-Glu-Arg-Nle-Leu-Phe-Ser-Phe-Pro-EDANS.
  • Compounds are screened at 1 ⁇ M concentration in a 100 mM sodium acetate buffer (pH 5.0), containing 10% glycerol, and 0.01% Tween 20. Typical enzyme concentrations of approximately 2.5 nM and substrate concentrations of 1.25 ⁇ M are used.
  • DMSO dimethyl sulfoxide
  • the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises at least one additional antiprotozoal agent.
  • the additional antiprotozoal agent is preferably active against a member selected from Kinetoplastida, Apicomplexa, Anaerobic protozoan, Microsporidia and Plasmodium.
  • the at least one additional antiprotozoal agent is active against a Plasmodium that causes malaria.
  • Exemplary compounds include, artemether, arteether, artemisinine, dihydroartemisinine, artesunate, quinidine, mefloquine and combinations thereof.
  • compositions comprise the active ingredient (that is, the compound of Formula I or a physiologically acceptable salt or other physiologically functional derivative thereof) together with one or more pharmaceutically acceptable carriers thereof and optionally other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.
  • a convenient unit dose formulation preferably contains the active ingredient in an amount of from about 10 mg to about 3 g, more preferably from about 50 mg to about 1 g.
  • An exemplary unit dose may contain for example 50 mg, 1 g, 2 g or 3 g of the active ingredient.
  • Pharmaceutical formulations include those suitable for oral, topical
  • the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of the active ingredient.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Molded tablets may be made by molding an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored.
  • Capsules may be prepared by filling the active ingredient, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner.
  • Cachets are analogous to capsules wherein the active ingredient together with any accessory ingredient(s) is sealed in a rice paper envelope.
  • the compound of Formula I or a physiologically acceptable salt or other physiologically functional derivative thereof may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged e.g. in a sachet.
  • Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water liquid emulsion.
  • Formulations for oral administration include controlled release dosage forms e.g. tablets wherein the active ingredient is formulated in an appropriate release- controlling matrix, or is coated with a suitable release-controlling film. Such formulations may be particularly convenient for prophylactic use.
  • the active ingredient may also be formulated as a solution or suspension suitable for administration via a nasogastric tube.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • compositions suitable for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oleaginous vehicles.
  • injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use.
  • the active ingredient may be in powder form which is constituted with a suitable vehicle, such as sterile, pyro gen-free water, before use.
  • the compound of Formula I or a physiologically acceptable salt or other physiologically functional derivative thereof may also be formulated as a long-acting depot preparation, which may be administered by intramuscular injection or by implantation e.g. subcutaneously or intramuscularly.
  • Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use.
  • the pharmaceutical formulations for the various routes of administration described above may include, as appropriate one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • the compound of Formula I or a physiologically acceptable salt or other physiologically functional derivative thereof may also be used in accordance with the present invention in combination or concurrently with other therapeutic agents, for example agents used in the treatment of immunocompromised patients, including antibacterial agents; antifungal agents; anticancer agents such as interferons e.g.
  • the compound of Formula I may also be administered in combination with a 4-pyridinol compound, as described in EPA 123,239 e.g. 3,5- dichloro-2,6-dimethylpyridinol (meticlorpindol).
  • the compound of Formula I may also be administered in combination or concurrently with anti-diarrheal agents such as loperamide hydrochloride and/or diphenoxylate hydrochloride, or with morphine sulphate. Oral rehydration therapy may also be carried out concurrently.
  • compositions suitable for veterinary use include those adapted for oral, parenteral, and intrarumenal administration.
  • drenches oral liquid dosing
  • tablets boluses, pastes, or in-feed preparations in the form of powders, granules or pellets.
  • compositions may be adapted to be administered parenterally by subcutaneous, intramuscular or intravenous injection of a sterile solution or suspension, by implantation or as an intramammary injection whereby a suspension or solution is introduced into the udder via the teat.
  • the present invention also provides various methods for using these compounds and formulations.
  • the present invention provides a method for interrupting the reproductive cycle of a protozoan.
  • the method includes: (a) contacting the protozoan with a compound according to Formula I, in an amount effective to interrupt said reproductive cycle.
  • the present invention provides a method for inhibiting polymerization of heme caused by a protozoan. The method includes: (a) contacting the protozoan with a compound according to Formula I, in an amount effective to interrupt said reproductive cycle.
  • the invention provides a method for inhibiting a protozoal enzyme.
  • the method includes: (a) contacting said enzyme with a compound according to Formula I, in an amount effective to inhibit said enzyme.
  • the enzyme is a digestive enzyme of said protozoan.
  • the enzyme is a protease and it is a member selected from serine, cysteine, aspartyl, metalloproteases and combinations thereof.
  • the protozoa is preferably a member selected from Kinetoplastida, Apicomplexa, Anaerobic protozoan, Microsporidia and Plasmodium, and even more preferably, the protozoa is a causative agent of malaria.
  • the method is used either in vitro or in vivo.
  • the method is used in vivo and it is a method of treating or preventing a protozoal infection in a subject. The method includes: (a) administering to the subject the pharmaceutical composition of the invention in an amount effective to treat or prevent said infection.
  • these compounds to be effective pharmaceutical agents they should be of acceptable stability and toxicity and should have effective dosages that are conveniently obtainable.
  • compositions suitable for use in the methods of the invention include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
  • a therapeutically effective amount i.e., in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
  • such compositions will contain an amount of active ingredient effective to achieve this result. Determination of an effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.
  • the therapeutically effective amount can be initially determined from cell culture assays.
  • Target plasma concentrations will be those concentrations of active compound(s) that are capable of inducing inhibition of the target protozoal enzyme.
  • the enzyme activity is at least 25% inhibited.
  • Target plasma concentrations of active compound(s) that are capable of inducing at least about 50%, 75%, or even 90% or higher inhibition of the enzyme are presently preferred.
  • the percentage of inhibition of the enzyme channel in the patient can be monitored to assess the appropriateness of the plasma drug concentration achieved, and the dosage can be adjusted upwards or downwards to achieve the desired percentage of inhibition.
  • therapeutically effective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve a circulating concentration that has been found to be effective in animals.
  • a particularly useful animal model for sickle cell disease is a mouse malaria model.
  • two cohorts of mice are infected with P. falciparum.
  • One cohort receives the pharmaceutical formulation (e.g., about three injections a day for about 4 days to about one week) and the other cohort (i.e., the control group) is untreated.
  • the efficacy of the compound and/or dosage level is evaluated by comparing parasitemia and survival of the two cohorts.
  • Other models utilizing other protozoal infections can be utilized in a substantially similar manner.
  • a useful dosage can be calculated in humans. Upon administration in humans, the dosage can be adjusted by monitoring enzyme inhibition and adjusting the dosage upwards or downwards, as described above.
  • a therapeutically effective dose can also be determined from human data for compounds which are known to exhibit similar pharmacological activities.
  • the applied dose can be adjusted based on the relative bioavailability and potency of the administered compound as compared with the other compound.
  • the systemic circulating concentration of administered compound will not be of particular importance.
  • the compound is administered so as to achieve a concentration at the local area effective to achieve the intended result.
  • a circulating concentration of administered compound of about 0.001 ⁇ M to 20 ⁇ M is considered to be effective, with about 0.01 ⁇ M to 5 ⁇ M being preferred.
  • Patient doses for oral administration of the compounds described herein typically range from about 1 mg/day to about 10,000 mg/day, more typically from about 10 mg/day to about 1,000 mg/day, and most typically from about 50 mg/day to about 500 mg/day. Stated in terms of patient body weight, typical dosages range from about 0.01 to about 150 mg/kg/day, more typically from about 0.1 to about 15 mg/kg/day, and most typically from about 1 to about 10 mg/kg/day.
  • dosage amount and interval can be adjusted individually to provide plasma levels of the administered compound effective for the particular clinical indication being treated.
  • a compound according to the invention can be administered in relatively high concentrations multiple times per day.
  • an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial toxicity and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient.
  • This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
  • the ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD 50 (the amount of compound lethal in 50% of the population) and ED 50 (the amount of compound effective in 50%) of the population).
  • LD 50 the amount of compound lethal in 50% of the population
  • ED 50 the amount of compound effective in 50%
  • Compounds that exhibit high therapeutic indices are presently preferred.
  • Therapeutic index data obtained from cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans.
  • the dosage of such compounds preferably lies within a range of plasma concentrations that include the ED 5 o with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g.
  • Another factor contributing to the pharmaceutical efficacy of the compounds of the invention is their stability under biologically relevant conditions. Compounds that are not rapidly degraded in vivo are expected to demonstrate better bioavailability and fewer side effects than analogous compounds that are rapidly degraded.
  • the stability of the compounds in various biological milieus can be assayed by methods known in the art.
  • the stability of the compounds is assayed in an in vitro preparation.
  • the in vitro preparation is a liver microsome preparation.
  • the results of such in vitro assays provide data relevant to the in vivo stability of the compounds of the invention.
  • Other in vitro assays useful in assaying the stability of the compounds of the invention are known in the art.
  • in vivo methods such as pharmacokinetic studies can be performed in a range of animal models.
  • One or more compounds of the invention can be administered to an animal, preferably a rat, at different dosages and/or by different routes (e.g., i.v., i.p., p.o).
  • Blood, urine and/or feces samples can be collected at serial time points and the samples assayed for the presence and/or concentration of the compound(s) of the invention and/or the metabolites of the compound(s).
  • Any appropriate quantity can be utilized to compare data from different compounds. Exemplary quantities include, half-life, bioavailability, amount of compound remaining intact after a predetermined time period and the like. In a preferred embodiment, the amount of compound remaining intact after a predetermined time period is utilized.
  • "intact” refers to compound that has not been metabolized or other wise degraded into a species different from the original compound.
  • the predetermined time period is from about two hours to about seventy-two hours, more preferably from about 4 hours to about twenty- four hours.
  • the amount of intact compound remaining after a predetermined time period of two hours is at least 40% of the initial dosage, preferably at least 50% and more preferably at least 70%.
  • any technique that allows the detection and, preferably, the quantitation of the compound(s) and/or metabolites is appropriate for use in assaying the compounds of the invention.
  • These methods include, but are not limited to, spectrometric methods (e.g., NMR (e.g., 19 F NMR), MS, IR, UV/vis), chromatographic methods (e.g., LC, GC, HPLC) and hybrid methods utilizing both spectrometric and chromatographic methods (e.g.,
  • the methods can utilize detectable labels such as compounds of the invention that are labeled with radioisotopes (e.g., 3 H, 15 N, 14 C) or fluorescent labels (e.g., fluorescein, rhodamine).
  • detectable labels such as compounds of the invention that are labeled with radioisotopes (e.g., 3 H, 15 N, 14 C) or fluorescent labels (e.g., fluorescein, rhodamine).
  • radioisotopes e.g., 3 H, 15 N, 14 C
  • fluorescent labels e.g., fluorescein, rhodamine
  • the present invention provides "cocktails" including one or more of the compounds of the invention and, generally, one or more known anti protozoal agents. Using such multidrug cocktails, it is often possible to combat drug resistant forms of the protozoa. Thus, the invention also provides for methods as discussed above in which a multidrug "cocktail" is utilized.
  • Blood Schizontocidal Activity The initial evaluation of blood schizontocidal activity is carried out using the "4 day suppressive test" (see, Ann. Trop. Med. Parasit., 64: 41-51 (1970)).
  • a battery of strains of rodent malaria comprised of a range of drug-sensitive and drug-resistant lines of Plasmodium berghei and P. yoelii, is maintained for this purpose.
  • the compounds are tested initially against drug-sensitive P. berghei N and P. y. nigeriensis NIG strain together with chloroquine-resistant P. yoelii sp NS strain. These strains of .
  • yoelii are incorporated into the preliminary screen because they have been found to be a far better model for P. falciparum than P. berghei. P. berghei N strain is also included since most of the lines resistant to standard antimalarials, which have been developed over the years, have this as their parent strain. Compounds which show activity in these preliminary tests are further tested against a range of resistant lines and tested for curative action.
  • mice are free of E. coccoides and if there is any evidence of these organisms being present, treatment with either neoarsphenamine benzoate or tetracycline is commenced immediately.
  • N( Keyberg 173): Sensitive to all standard antimalarial drugs. Does not product gametocytes. Maintained by syringe passage; ANKA: Sensitive to all standard antimalarials. Maintained by cyclical passage through A. stephensi.
  • N Highly resistant to primaquine. Maintained by syringe passage under primaquine pressure (60 mg/kg/day s.c); B ⁇ derived from N: Highly resistant to cycloguanil. Maintained by syringe passage under cycloguanil pressure (60 mg/kg/day s.c);
  • PYR derived from NK 65: Highly resistant to pyrimethamine. Maintained by syringe passage under pyrimethamine pressure (100 mg/kg/i.p. x 1); ORA—derived from NK 65: Highly resistant to sulfonamides. Maintained by syringe passage under sulfaphenazole pressure (1000 mg/s.c xl);
  • Q ⁇ derived from N Highly resistant to quinine. Maintained by syringe passage under drug pressure (600 mg/kg quinine hydrochloride po x 1).
  • P. yoelii nigeriensis (N67; NIG) ⁇ Maintained by syringe passage or cyclical transmission through A. stephensi (Beech strain) without drug pressure. Used as a model for chloroquine-sensitive P. falciparum for causal prophylaxis studies;
  • MEF NS1100— derived from NS: Highly resistant to mefioquine. Maintained by syringe passage under drug pressure (60 mg/kg s.c. x 1 at passage);
  • SPN derived from NS: Highly resistant to pyronaridine. aintained by syringe passage under drug pressure (10 mg/kg sc x 1 at passage); SAM— derived from NS: Highly resistant to amodiaquine Maintained by syringe passage under drug pressure (100 mg/kg sc x 1 at passage).
  • PET Sensitive to all standard antimalarials. Syringe passaged, synchronous strain;
  • mice Male, random-bred Swiss albino mice weighing 18-22 grams are inoculated intravenously with 10 7 parasitized red blood cells of the above strains. Animals are then dosed once daily for four consecutive days beginning on the day of infection. Compounds are dissolved or suspended, using ultrasonication, where necessary to achieve an even suspension, in sterile distilled water with Tween 80 and administered subcutaneously, intraperitioneally, orally or by such other route as may be required Where exceptional difficulty is encountered in preparing an aqueous preparation, the test compound is first dissolved in dimethyl sulfoxide and subsequently aqueous dilutions are prepared for use. he total amount of compound required is 250- 1500 mg depending on active dose level found in preliminary screen.
  • the parasitaemia is determined on the day following the last treatment and the ED..50 and ED.90 (i.e. 50% and 90% suppression of parasites when compared with untreated controls), estimated from a plot of log dose against activity. Standard error is calculated with the aid of Table 48, Geigy Scientific Tables, 6th Edition. The degree of cross resistance is determined by comparing activity in the sensitive and resistant strains.
  • the "4-day test" technique has proved itself to be a sensitive system for detecting interactions between drugs. If two compounds are simultaneously administered in an appropriate series of dilutions then it is possible to determine the influence of one compound upon the ED90 of the other in a series or ratios of combination. The ED90 values obtained with combinations in a test of this type may be compared with those of the individual compounds to obtain an isobolar equivalent. These are plotted for each compound in an isobologram in order to demonstrate the presence of synergism, antagonism or a simple additive action.
  • the compounds, compositions and methods of the present invention are further illustrated by the examples that follow. These examples are offered to illustrate, but not to limit the claimed invention. EXAMPLES
  • EXAMPLE 4 This Example describes the general procedures used to assemble libraries of the compounds of the invention based on the scaffold of compound 49.
  • the library assembly steps described herein are referenced to Scheme 4 set forth in Figure 7.
  • Polymer bound EDC (0.71 mmol/g, 0.30 g) was added to the solution of an acid (0.086 mmol) in CHC1 3 (2 mL) in a screw cap vial and stirred for 5 min.
  • a solution of the amine (0.029 mmol) in CHC1 3 (1 mL) was then added to the suspension of the resin and the mixture was shaken for 6h at room temperature.
  • the mixture was filtered using a polystyrene cartridge with 70 ⁇ m PE frits attached to a Teflon stopcock for the work-up process.
  • the resin was washed with CHC1 3 (3x1 mL). Approximately 0.3 g of an ion exchange resin was added to the filtrate and the mixture was shaken for an additional 5h.
  • the mixture was transferred into a cartridge and the resin was washed with CH 2 C1 2 (2x2 mL) and MeOH (2x2 mL).
  • the resin was then treated with 2M NH 3 in MeOH (5 mL) and the mixture was shaken for 30 min.
  • the azide derivative 57 was prepared in quantitative yield according to the procedure described previously (see, Example 1, part c); ! H NMR (CDC1 3 ) ⁇ 1.43 (s,
  • This Example describes the general procedures used to assemble libraries of the compounds of the invention based on the scaffold of compound 60.
  • the library assembly steps described herein are referenced to Scheme 6 set forth in Figure 9.
  • Amide 65 was prepared according to the procedure described previously (R a : 95%, R b : 90%), (see, Example 3, part c).
  • Compound 68 was prepared according to the procedure described previously (R ⁇ : 61%, R b : 70%), (see, Example 7, part b).
  • the compounds 43 and 4 4 were prepared according to the procedure described previously (R a : 94%, R b : 91%), (see, Example 2, part d).
  • This Example provides a tabulation of elemental analysis and NMR and mass spectral data for many of the compounds of the invention

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Abstract

Cette invention a trait à de nouveaux composés permettant d'inhiber des enzymes de protozoaires.
PCT/US2000/023338 1999-08-24 2000-08-23 Inhibiteurs exempts de quinoline de parasites du paludisme WO2001014331A2 (fr)

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WO2002083641A2 (fr) * 2001-04-17 2002-10-24 Actelion Pharmaceuticals Ltd. Amino-aza-cyclohexanes
US6624162B2 (en) 2001-10-22 2003-09-23 Pfizer Inc. Imidazopyridine compounds as 5-HT4 receptor modulators
WO2004105762A1 (fr) * 2003-05-30 2004-12-09 Actelion Pharmaceuticals Ltd Utilisation medicale de derives de diazabicyclononene utilises comme inhibiteurs des proteases aspartiques parasites
US6979690B2 (en) 2002-01-07 2005-12-27 Pfizer Inc. Oxo or oxy-pyridine compounds as 5-HT4 receptor modulators
US7053088B2 (en) 2002-05-22 2006-05-30 Amgen Inc. Vanilloid receptor ligands and their use in treatments
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US7276612B2 (en) 2003-04-07 2007-10-02 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
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US7368572B2 (en) 2003-08-20 2008-05-06 Pharmacyclics, Inc. Acetylene derivatives as inhibitors of histone deacetylase
US7511044B2 (en) 2004-02-11 2009-03-31 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7534798B2 (en) 2004-02-11 2009-05-19 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7595329B2 (en) 2004-06-15 2009-09-29 Pfizer Inc Benzimidazolone carboxylic acid derivatives
US7737163B2 (en) 2004-06-15 2010-06-15 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
US7745638B2 (en) 2003-07-22 2010-06-29 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8013163B2 (en) 2005-01-21 2011-09-06 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8084623B2 (en) 2006-12-19 2011-12-27 Roche Palo Alto Llc Pyrrolidinyl and piperidinyl ketone derivatives and uses thereof
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof
US9128096B2 (en) 2007-01-30 2015-09-08 Pharmacyclics, Inc. Methods for determining cancer resistance to histone deacetylase inhibitors
US9403032B2 (en) 2009-04-17 2016-08-02 Pharmacyclics Llc Formulations of histone deacetylase inhibitor and uses therof
US9408816B2 (en) 2006-12-26 2016-08-09 Pharmacyclics Llc Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy
US9492423B2 (en) 2011-09-13 2016-11-15 Pharmacyclics Llc Formulations of histone deacetylase inhibitor in combination with bendamustine and uses thereof
WO2017142821A1 (fr) * 2016-02-18 2017-08-24 Merck Sharp & Dohme Corp. Composés pour le traitement du paludisme

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US6979690B2 (en) 2002-01-07 2005-12-27 Pfizer Inc. Oxo or oxy-pyridine compounds as 5-HT4 receptor modulators
US7053088B2 (en) 2002-05-22 2006-05-30 Amgen Inc. Vanilloid receptor ligands and their use in treatments
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US7396831B2 (en) 2002-05-22 2008-07-08 Amgen Inc. Vanilloid receptor ligands and their use in treatments
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US8779171B2 (en) 2003-04-07 2014-07-15 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
EP1625111A4 (fr) * 2003-04-18 2007-04-25 Univ California Derives de thyronamine et analogues et des methodes d'utilisation de ces composes
AU2004231999B2 (en) * 2003-04-18 2010-08-26 Oregon Health & Science University Thyronamine derivatives and analogs and methods of use thereof
WO2004105762A1 (fr) * 2003-05-30 2004-12-09 Actelion Pharmaceuticals Ltd Utilisation medicale de derives de diazabicyclononene utilises comme inhibiteurs des proteases aspartiques parasites
US7745638B2 (en) 2003-07-22 2010-06-29 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US9051278B2 (en) 2003-07-22 2015-06-09 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8779147B2 (en) 2003-07-22 2014-07-15 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8080666B2 (en) 2003-07-22 2011-12-20 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US7368572B2 (en) 2003-08-20 2008-05-06 Pharmacyclics, Inc. Acetylene derivatives as inhibitors of histone deacetylase
US7534798B2 (en) 2004-02-11 2009-05-19 Amgen Inc. Vanilloid receptor ligands and their use in treatments
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US7737163B2 (en) 2004-06-15 2010-06-15 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
US7705020B2 (en) 2004-06-15 2010-04-27 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
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US8013163B2 (en) 2005-01-21 2011-09-06 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8293767B2 (en) 2005-01-21 2012-10-23 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
US7301022B2 (en) 2005-02-15 2007-11-27 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US8084623B2 (en) 2006-12-19 2011-12-27 Roche Palo Alto Llc Pyrrolidinyl and piperidinyl ketone derivatives and uses thereof
US9408816B2 (en) 2006-12-26 2016-08-09 Pharmacyclics Llc Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy
US9128096B2 (en) 2007-01-30 2015-09-08 Pharmacyclics, Inc. Methods for determining cancer resistance to histone deacetylase inhibitors
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