GB2465890A - 2-Arylazole derivatives as antiprotozoal agents - Google Patents

2-Arylazole derivatives as antiprotozoal agents Download PDF

Info

Publication number
GB2465890A
GB2465890A GB0921210A GB0921210A GB2465890A GB 2465890 A GB2465890 A GB 2465890A GB 0921210 A GB0921210 A GB 0921210A GB 0921210 A GB0921210 A GB 0921210A GB 2465890 A GB2465890 A GB 2465890A
Authority
GB
United Kingdom
Prior art keywords
ylmethyl
oxazol
amine
alkyl
methylhexyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
GB0921210A
Other versions
GB0921210D0 (en
Inventor
Clare Louise Murray
Matthew David Orr
Robert Anderson Noe
Jessica Marie Sligar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Scynexis Inc
Original Assignee
Scynexis Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scynexis Inc filed Critical Scynexis Inc
Publication of GB0921210D0 publication Critical patent/GB0921210D0/en
Publication of GB2465890A publication Critical patent/GB2465890A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed 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
    • A61K31/395—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

2-Arylazole derivatives of formula (I) or salts or solvates thereof. R1and R2are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyalkyl or aminoalkyl. Y is O or S. R3is hydrogen, alkyl, halogen or aryl. S, T, V, W and X are independently N or C-R4, with the proviso that at least three of S, T, V, W and X are C-R4; or two adjacent groups selected from S, T and V form an optionally substituted phenyl ring. R4is hydrogen, alkyl, halogen, -CH2-R5, -OR6, -SR6or aryl. R5is cycloalkyl, alkenyl, alkynyl, aryl or heteroaryl, which may be substituted with various substituents. R6is alkyl, cycloalkyl, alkenyl, alkynyl, aryl or heteroaryl, which may be substituted with various substituents. Preferably Y = O; X = C-R4; R3= H, CH3; one of R1and R2is H and the other 1-methylhexyl. Examples also relate to 2-thiophenyloxazoles, 2-benzothiophenyloxazoles, 2-cyclohexyloxazoles, 2-benzyloxazoles, 2-benzodioxolyloxazoles and 2-benzonitrileoxazoles; and to oxazole derivatives wherein R1and R2together with the nitrogen they are attached to form a piperidine, morpholine or piperazine ring. The compounds may be useful in the treatment of protozoal infections including American trypanosomiasis, African trypanosomiasis, sleeping sickness, Kala-Azar, leishmaniasis, trichomoniasis, Chagas disease and malaria.

Description

Novel Heterocyclic Derivatives
FIELD OF THE INVENTION
[0001] The present invention relates to novel 2-arylazole derivatives, compositions containing them, processes for their preparation and their use as pharmaceutically active agents.
BACKGROUND OF THE INVENTION
[0002] Human or non-human mammalian diseases attributable to infection of the individual by a parasite, especially those prevalent in developing countries in regions of the world such as sub-Saharan Africa, India, Southeast Asia, Central and Southern America, are poorly treated with existing medicaments. For example, treatment of African sleeping sickness, a disease caused by infection of an individual with Trypansoma brucei parasites, is currently compromised by the poor efficacy, high toxicity and difficult administration requirements of existing drugs such as eflomithine, melarsoprol and suramin. Similarly, treatment of Chagas disease, a disease caused by infection of an individual with Trypanosoma cruzi parasites, is compromised by the ineffectiveness of current drugs such as nifurtimox and benznidazole. Existing therapies for diseases caused by Leishmania sp. parasites, visceral and cutaneous leishmaniasis, including treatment by drugs such as meglumine antimonite, sodium stibogluconate and amphotericin B also suffer from potential toxicity and limited efficacy of these agents. Therefore, there exists a need for new pharmaceutical agents for the effective and safe treatment of these tropical diseases.
[0003] The present invention also seeks to provide compounds, stereoisomeric forms and/or pharmaceutically acceptable salts of the 2-arylazole family which can be used as pharmaceutically active agents, especially for prophylaxis and/or treatment of tropical diseases caused by leishmania, trypanosome, protozoa, and plasmodium falciparum such as South American trypanosomiasis, African trypanosomiasis, sleeping sickness, Kala-Azar, visceral leishmaniasis, Baghdad boil or Aleppo boil, cutaneous leishmaniasis (CL), espundia, Chagas disease, mucocutaneous leishmaniasis (MCL), trichomoniasis, urogenital trichomonosis, giardiasis, lamblia dysentery, amoebiasis, primary amebic meningoencephalitis (PAM), keratitis or meningitis, coccidiosis, sarcosporidosis, toxoplasmosis, malaria tropica, malaria tertiana, malaria quartana, pneumocystis carinii, pneumonia, pneumocystosis, Balantidium dysentery, and oriental sore.
SUMMARY OF THE INVENTION
[0004] The invention provides novel 2-arylazole derivatives of formula (I): R' (I) [00051 wherein R1 and R2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl; [0006] R3 is hydrogen, alkyl, halogen, or aryl; [0007] S, T, V, W and X are independently C-R4 or N; with the proviso that at least three of S, T, V, W and X are independently C-R4; or two adjacent groups selected from S, T and V together form an optionally substituted phenyl ring; 10008] R4 is independently hydrogen, alkyl, halogen, -CH2R5, -OR6, -SR6 or aryl; [0009] R5 is cycloalkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted, or optionally substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl; [0010] R6 is alkyl, cycloalkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted, or optionally substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl; [0011] Y is oxygen or sulfur; [0012] or a pharmaceutically acceptable salt or solvate thereof.
[0013] These compounds are useful as pharmaceutically active agents, especially for prophylaxis and/or treatment of tropical diseases caused by Trypanosoma sp., Leishmania sp., Balantidiuin colt, Etmeria sp., Entainoeba histolytica, Giardia intestinalis, Isospira sp. Naegl eria fowl en, Plasmodium sp. and Trichomonas vaginalis such as African trypanosomiasis, Chagas disease, visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), diffuse cutaneous leishmaniasis, Balantidium dysentery, coccidiosis, amoebiasis, giardiasis, primary amebic meningoencephalitis (PAM), malaria and trichomoniasis.
DETAILED DESCRIPTION
Definitions [0014] "Alkyl" refers to both straight and branched carbon chains; references to individual alkyl groups are specific for the straight chain (e.g. butyl = n-butyl). In one embodiment of alkyl, the number of carbons atoms is 1-20, in another embodiment of alkyl, the number of carbon atoms is 1-8 carbon atoms and in yet another embodiment of alkyl, the number of carbon atoms is 1-4 carbon atoms. Other ranges of carbon numbers are also contemplated depending on the location of the alkyl moiety on the molecule; [0015] "Alkenyl" refers to both straight and branched carbon chains which have at least one carbon-carbon double bond. In one embodiment of alkenyl, the number of double bonds is 1-3, in another embodiment of alkenyl, the number of double bonds is one. In one embodiment of alkenyl, the number of carbons atoms is 2-20, in another embodiment of alkenyl, the number of carbon atoms is 2-8 and in yet another embodiment of alkenyl, the number of carbon atoms is 2-4. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule; 100161 "Alkynyl" refers to both straight and branched carbon chains which have at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3; in another embodiment of alkynyl, the number of triple bonds is one. In one embodiment of alkynyl, the number of carbons atoms is 2-20, in another embodiment of alkynyl, the number of carbon atoms is 2-8 and in yet another embodiment of alkynyl, the number of carbon atoms is 2-4. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule; 100171 "Aryl" refers to a C6-Cio aromatic ring structure. n one embodiment of aryl, the moiety is phenyl, naphthyl, tetrahydronapthyl, phenylcyclopropyl and indanyl; in another embodiment of aryl, the moiety is phenyl.
[0018] "Alkoxy" refers to -0-alkyl, wherein alkyl is as defined above; [0019] "Alkanoyl" refers to formyl (-C(=O)H) and -C(=O)-alkyl, wherein alkyl is as defined above; [0020] "Alkanoyloxy" refers to -O-C(=O)-alkyl, wherein alkanoyl is as defined above; [0021J "Alkanoylamino" refers to -NH2-C(=O)-alkyl, wherein alkanoyl is as defined above and the amino (NH2) moiety can be substituted by alkyl as defined above; [0022] "Aminocarbonyl" refers to -NH2-C(=O), wherein the amino (NH2) moiety can be substituted by alkyl as defined above; [0023] "Alkoxycarbonyl" refers to -C(==O)-O-alkyl, wherein alkoxy is as defined above; [0024] "Alkenoyl" refers to -C(=O)-alkenyl, wherein alkenyl is as defined above; [0025] "Alkynoyl" refers to -C(=O)-a[kynyl, wherein alkynyl is as defined above; 100261 "Aroyl" refers to -C(=O)-aryl, wherein aryl is as defined above; 100271 "Alkylsulfinyl" refers to -S(=O)-alkyl, wherein alkyl is as defined above; 10028] "Alkylsulfonyl" refers to -S02-alkyl, wherein alkyl is as defined above; [0029] "Cyclo" as a prefix (e.g. cycloalkyl, cycloalkenyl, cycloalkynyl) refers to a saturated or unsaturated cyclic ring structure having from three to twelve carbon atoms in the ring the scope of which is intended to be separate and distinct from the definition of aryl above. In one embodiment of cyclo, the range of ring sizes is 4-10 carbon atoms; in another embodiment of cyclo the range of ring sizes is 3-4. Other ranges of carbon numbers are also contemplated depending on the location of the cyclo-moiety on the molecule; 100301 "Halogen" means the atoms fluorine, chlorine, bromine and iodine. The designation of "halo" (e.g. as illustrated in the term haloalkyl) refers to all degrees of substitutions from a single substitution to a perhalo substitution (e.g. as illustrated with methyl as chloromethyl (-CH2C1), dichloromethyl (-CHCI2), trichloromethyl (-Cd3)); [0031] "Heterocycle", "heterocyclic" or "heterocyclo" refer to fully saturated or unsaturated, including aromatic (i.e. hetaryl') cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyt, morphotinyl, thiamorpholinyt, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1 -dioxothienyl, triazolyl, triazinyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzoftuyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3 -c]pyridinyl, furo [3,2-b]pyridinyl]or furo [2,3 -b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
[0032] "Pharmaceutically acceptable salt" refers to any salt of a compound of this invention which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. The compounds of the present invention may be basic and may form salts with organic or inorganic acids.
Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfuric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, mandelic acid, o methylmandelic acid, benzenesulfonic acid, adipic acid, d-o-tolyltartaric acid, tartaric acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. In case, the compound bear acidic substituents, the formation of salts with inorganic or organic bases may be possible. Examples of such bases are sodium or potassium hydroxide, ammonium hydroxide, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example, by treatment of a solution of the compound of the general formula (T) with a solution of an acid, selected out of the group mentioned above.
10033] Some of the compounds of the present invention may be crystallized or recrystallized from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
[0034] In the case of chiral substituents, compounds of the general formula (I) may exist in the form of optical isomers, e.g. enantiomers, diastereomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. Where a compound according to the general formula (I) contains an alkene moiety, the alkene can be presented as a cis or trans isomer or mixture thereof When an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1% w/w of the other isomer(s).
[0035] In a first embodiment of the invention there are provided compounds of formula (I) wherein: 100361 R' is C110 alkyl, CL12 cycloalkyl, Ciio hydroxyalkyl, C11o alkoxyalkyl, or C110 aminoalkyl; [0037] R2 is hydrogen; [0038] R3 is hydrogen or methyl; and [0039] Y is oxygen.
[0040] In a second embodiment of the invention, there are provided compounds of formula (I) wherein: [0041] R' is Ciio alkyl or cycloalkyl, Ciio hydroxyalkyl, Ciio alkoxyalkyl, or C110 aminoalkyl; 100421 R2 is hydrogen; 100431 R3 is hydrogen or methyl; and [0044] Y is sulfur.
[0045] In a third embodiment of the invention, there are provided compounds of formula (I) wherein: [0046] R' is Ciio alkyl or cycloalkyl, C11o hydroxyalkyl, C110 alkoxyalkyl, or C110 aminoalkyl; [0047] R2 is hydrogen; 100481 R3 is hydrogen or methyl; 100491 Yis oxygen.
100501 T, V, W, and X are independently C-R4; [0051] S is nitrogen; [0052j R4 is independently hydrogen, alkyl, -CH2R5, -OR6 or -SR6.
[0053] In a fourth embodiment of the invention, there are provided compounds of formula (I) wherein: [0054] R' is Ciio alkyl or cycloalkyl, Ciio hydroxyalkyl, C11o alkoxyalkyl, or C110 aminoalkyl; 100551 R2 is hydrogen; 10056] R3 is hydrogen or methyl; [0057] Y is oxygen.
[0058] 5, V, W, and X are independently C-R4; [0059] T is nitrogen; [0060] R4 is independently hydrogen, alkyl, -CH2R5, -OR6 or -SR6.
[0061] In a fifth embodiment of the invention, there are provided compounds of formula (I) wherein: 100621 R' is C110 alkyl or cycloalkyl, Ciio hydroxyalkyl, C110 alkoxyalkyl, or Ciio aminoalkyl; 10063] R2 is hydrogen; [0064] R3 is hydrogen or methyl; [00651 Y is oxygen; [0066] S, T, V, W, and X are independently C-R4; and [0067] R4 is independently hydrogen, alkyl, -CH2R5, -OR6 or -SR6.
[0068] In a sixth embodiment of the invention, there are provided compounds of formula (I) wherein: 100691 R' is Ciio alkyl or cycloalkyl, C11o hydroxyalkyl, C110 alkoxyalkyl, or C110 aminoalkyl; [0070] R2 is hydrogen; [0071] R3 is hydrogen; [0072] Y is oxygen [0073] S, T, V, W, and X are independently C-R4; and [0074] R4 is independently hydrogen, alkyl, -CH2R5, -OR6 or -SR6.
[00751 In a seventh embodiment of the invention, there are provided compounds of formula (I) wherein: 100761 R' is Ciio alkyl or cycloalkyl, C11o hydroxyalkyl, C110 alkoxyalkyl, or C110 aminoalkyl; [0077] R2 is hydrogen; [0078] R3 is hydrogen; [0079] Y is sulfur; [0080] S, T, V, W, and X are independently C-R4; [0081] R4 is independently hydrogen, alkyl, -CH2R5, -OR6 or -10 - 100821 R5 is cycloalkyl, which is unsubstituted or substituted, or optionally substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, alkylthio, alkoxy, alkoxycarbonyl, aroyl, alkylsulfinyl and alkylsulfonyl; and [0083] R6 is alkyl, or optionally substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, alkylthio, atkoxy, alkoxycarbonyl, aroyl, alkylsulfinyl and alkylsulfonyl.
[0084] In a ftirther embodiment of the present invention Y is oxygen. In a stilt further embodiment of the present invention S, T, V, W, and X are independently C-R4. In a still further embodiment of the present invention R' is Ciio alkyl, C312 cycloalkyl, C110 hydroxyallcyl, C110 alkoxyalkyl or C110 aminoalkyl. In a still further embodiment of the present invention R2 is hydrogen. n a still further embodiment of the present invention R3 is hydrogen or alkyl. In a still further embodiment of the present invention R4 is independently hydrogen, alkyl, -CH2R5, -OR6 or -SR6.
[0085] In a further embodiment of the invention, the compound of formula (I) is selected from: [0086] 1. [2-(4-Ethoxyphenyl)-oxazol-4-ylmethyt] -((1 R,2R, 5 S)-2,6,6-trimethyt-bicyclo[3.1.1]hept-3-yl)-amine 10087] 2. [2-(4-Ethoxyphenyl)-oxazol-4-ylmethyl] -(3,3,5 -trimethyl-cyclohexyl)-amine [0088] 3. Adamantan-2-yl-[2-(4-ethoxyphenyl)-oxazol-4-ylmethyl] -amine [9989] 4. Bicyclo[2.2.1]hept-2-yl-[2-(4-ethoxyphenyl)-oxazol-4-ylmethyl]-amine [0090] 5. [2-(4-Ethoxyphenyl)-oxazol-4-ylmethyl] -(1 -methyl-hexyl)-amine [0091] 6. ((1 S,2R,5 S)-6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-[2-(4-ethoxyphenyl) -oxazot-4-ytmethyl] -amine [00921 7. [2-(4-Ethoxyphenyl)-oxazol-4-ytmethyfl-( 1 -propyl-butyl)-amine 10093] 8. (1 -Methylhexyl)-(2-phenyl-oxazol-4-ylmethyl)-amine 100941 9. (1 -Methylhexyl)-(2-o-tolyl-oxazol-4-ylmethyl)-amine 100951 10. (1 -Methylhexyl)-(2-m-tolyl-oxazol-4-ylmethyl)-amine [0096] 11. (1 -Methylhexyl)-(2-p-tolyl-oxazol-4-ylmethyl)-amine [0097] 12. [2-(3 -Ethoxyphenyl)-oxazol-4-ylmethyl]-( 1 -methyl-hexyl)-amine [0098] 13. [2-(2-Chlorophenyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine [0099] 14. [2-(3 -Chlorophenyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine [001001 15. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine [001011 16. 2-{4-[( 1 -Methy1hexy1amino)-methy1]-oxazo1-2-y1 -phenol 100102] 17. [2-(3 -Methoxyphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 100103] 18. [2-(4-Methoxyphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00104] 19. [2-(3,4-Dichlorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00105] 20. [2-(3 -Fluorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00106] 21. [2-(4-tert-Butylphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00107] 22. (1 -Methylhexyl)-(2-naphthalen-2-yl-oxazol-4-ylmethyl)-arnine [00108] 23. [2-(2-Fluorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [001091 24. [2-(4-Fluorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 1001101 25. (1 -Methylhexyl)-(2-naphthalen-1 -yl-oxazol-4-ylmethyl)-amine 100111] 26. [2-(2-Ethoxyphenyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine [00112] 27. (1 -Methyihexyl)-[2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl] -amine [00113] 28. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00114] 29. [2-(4-Bromophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00115] 30. (1 -Methylhexyl)-[2-(2-trifluoromethoxyphenyl)-oxazol-4-ylmethyl] -amine -12 - 100116] 31. (1 -Methyihexyl)-[2-(3 -trifluoromethoxyphenyl)-oxazol-4-ylmethyl] -amine 100117] 32. (1 -Methyihexyl)-[2-(4-trifluoromethoxyphenyl)-oxazol-4-ylmethyl] -amine [00118] 33. [2-(4-Chlorophenyl)-oxazol -4-ylmethyl]-((R)-I -methylhexyl)-amine 1100119] 34. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl]-((S)-1 -methylhexyl)-amine 1100120] 35. [2-(4-Isopropoxy-phenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 1100121] 36. [2-(4-Butoxy-phenyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine 100122] 37. (2-Biphenyl-4-yl-oxazol-4-ylmethyl)-( 1 -methylhexyl)-amine 100123] 38. (1 -Methyihexyl)-[2-(4-trifluoromethylsulfanyl-phenyl)-oxazol-4-ylmethyl] -amine 100124] 39. (1 -Methylhexyl)-(2-thiophen-2-yl-oxazol-4-ylmethyl)-amine 1100125] 40. (2-Benzo [b]thiophen-2-yl-oxazol-4-ylmethyl)-( 1 -methylhexyl)-amine 1100126] 41. [2-(2,4-Difluorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 1100127] 42. [2-(3,4-Difluorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 1100128] 43. [2-(3, 5 -Difluorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 11001291 44. [2-(2, S -Difluorophenyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine 100130] 45. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -((1 R,2R,5 S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine 1100131] 46. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl]-(( 1 S,2R,5 S)-6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-amine 1100132] 47. Bicyclo [2.2.1]hept-2-yl-[2-(4-chlorophenyl)-oxazol-4-ylmethyl]-amine 1100133] 48. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -(3,3,5 -trimethyl-cyclohexyl)-amine 100134] 49. Adamantan-2-yl-[2-(4-chlorophenyl)-oxazol-4-ylmethyl] -amine -13 - 100135] 50. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl]-cyclopentyl-amine 100136] 51. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl]-cyclohexyl-amine 1100137] 52. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl]-cycloheptyl-amine 1100138] 53. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl]-cyclohexyl-methyl-amine 1100139] 54. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -(1 -propyl-butyl)-amine 1100140] 55. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -((R)-1 -cyclohexyl-ethyl)-amine 1001411 56. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -((S)-1 -cyclohexyl-ethyl)-amine 100142] 57. Adamantan-2-yl-[2-(4-butyl-phenyl)-oxazol-4-ylmethyl] -amine 100143] 58. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -(3,3,5 -trimethyl-cyclohexyl)-amine 1100144] 59. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -((1 R,2R,3R,5 S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine 1100145] 60. Adamantan-2-yI-[2-(4-bromophenyl)-oxazol-4-ylmethyl] -amine 1100146] 61. [2-(4-Bromophenyl)-oxazol-4-ylmethyl] -(3,3,5 -trimethyl-cyclohexyl)-amine 100147] 62. [2-(4-Bromophenyl)-oxazol-4-ylmethyl]-(( 1 R,2R,3R,5 S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine 1100148] 63. Adamantan-2-yl-(2-biphenyl-4-yl-oxazol-4-ylmethyl)-amine 1100149] 64. [2-(2,3 -Difluorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 11001501 65. [2-(2,6-Difluorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 11001511 66. Adamantan-2-yl-[2-(4-tert-butyl-phenyl)-oxazol-4-ylmethyl] -amine 1100152] 67. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -((is,2R, 5 S)-6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-amine 1001 53J 68. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -cycloheptyl-amine -14 - 100154] 69. [2-(4-Bromophenyl)-oxazol-4-ylmethyl]-cycloheptyl-amine 100155] 70. [2-(4-tert-Butylphenyl)-oxazol-4-ylmethyl] -cycloheptyl-amine 100156] 71. [2-(4-Butoxy-phenyl)-oxazol-4-ylmethyl] -(3,3,5 -trimethyl-cyclohexyl)-amine [001 57J 72. [2-(4-Butoxy-phenyi)-oxazoi-4-yimethyij-((1 R,2R,3R,5 S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine [00158] 73. [2-(4-Butoxy-phenyl)-oxazol-4-ylmethyl]-(( iS,2R,5 S)-6,6-dimethyl-bicyclo[3.1.i]hept-2-ylmethyl)-amine [001591 74. [2-(4-Butoxy-phenyl)-oxazol-4-ylmethyl]-cycloheptyl-amine 100160] 75. (2-Biphenyl-4-yl-oxazol-4-ylmethyl)-(3,3,5 -trimethyl-cyclohexyl)-amine [00161] 76. (2-Biphenyl-4-yl-oxazol-4-ylmethyl)-(( 1 R,2R,3R,5 S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine [00162] 77. (2-Biphenyl-4-yl-oxazol-4-ylmethyl)-(( 15,2R,5 S)-6,6-dimethyl-bicyclo[3.1.i]hept-2-ylmethyl)-amine [00163] 78. (2-Biphenyl-4-yl-oxazol-4-ylmethyl)-cycloheptyl-amine [00164] 79. Adamantan-2-yl-[2-(4-butoxyphenyl)-oxazol-4-ylmethyl] -amine [00165] 80. Cycloheptyl-{2-(4-ethoxyphenyl)-oxazol-4-ylmethyl]-amine 100166] 81. Adamantan-2-yl-[2-(4-pentyloxyphenyl)-oxazol-4-ylmethyl]-amine [00167] 82. [2-(4-Pentyloxyphenyl)-oxazol-4-ylmethyl]-(3,3,5 -trimethyl-cyclohexyl)-amine [00168] 83. [2-(4-Pentyioxyphenyi)-oxazoi-4-yimethyi]-(( 1 R,2R,3R,5 S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine [00169] 84. ((1 S,2R,5 S)-6,6-Dimethyl-bicyclo[3.1. i]hept-2-ylmethyl)-[2-(4-pentyloxyphenyl)-oxazol-4-ylmethyl] -amine [001701 85. Cycloheptyl-[2-(4-pentyloxyphenyl)-oxazol-4-ylmethyl] -amine 100171] 86. (1 -Methyihexyl)-[2-(4-propoxyphenyl)-oxazol-4-ylmethyl]-amine -15 - 100172] 87. Adamantan-2-yl-[2-(4-propoxyphenyl)-oxazol-4-ylmethyl] -amine 100173] 88. [2-(4-Propoxyphenyl)-oxazol-4-ylmethyl]-(3,3,5 -trimethyl-cyclohexyl)-amine [00174] 89. Cycloheptyl-[2-(4-propoxyphenyl)-oxazol-4-ylmethyl]-amine [00175] 90. (1 -Methylhexyl)-[2-(4-pentyloxyphenyl)-oxazol-4-ylmethyl]-amine [00176] 91. [2-(4-Propoxyphenyl)-oxazol-4-ylmethyl] -((1 R,2R,3R,5 S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine [00177] 92. ((1 S,2R,5 S)-6,6-Dimethyl-bicyclo[3.1. 1]hept-2-ylmethyl)-[2-(4-propoxyphenyl)-oxazol-4-ylmethyl]-amine 100178] 93. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -(3 -pyrrolidin-1 -yl-propyl)-amine [00179] 94. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -(3 -piperidin-1 -yl-propyl)-amine [00180] 95. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -[2-( 1 -methyl-pyrrolidin-2-yl)-ethyl] -amine [00181] 96. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -(2,6-dimethoxybenzyl)-amine [00182] 97. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -(4-methylbenzyl)-amine [00183] 98. {2-(4-Butylphenyl)-oxazol-4-ylmethyl] -(4-methoxybenzyl)-amine 100184] 99. (1 -Methyihexyl)-[2-(2-phenoxyphenyl)-oxazol-4-ylmethyl] -amine [00185] 100. (1 -Methyihexyl)-[2-(3 -phenoxyphenyl)-oxazol-4-ylmethyl] -amine [00186] 101. (1 -Methyihexyl)-[2-(4-phenoxyphenyl)-oxazol-4-ylmethyl] -amine [00187] 102. [2-(4-Decyloxyphenyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine [00188] 103. {2-[4-(2,2-Dimethyl-propoxy)phenyl] -oxazol-4-ylmethyl} -(1-methylhexyl)-amine [00189] 104. [2-(4-Cyc Iohexyloxyphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine -16- 1001901 105. [2-(4-Cyclohexyloxyphenyl)-oxazol-4-ylmethyl]-(( 1 R,2R,3R,5 S)- 2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine 1001911 106. Cycloheptyl-[2-(4-cyclohexyloxyphenyl)-oxazol-4-ylmethyl] -amine 1001921 107. [2-(4-Ethylphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [001 93J 108. Cycloheptyl-[2-(4-isopropoxyphenyl)-oxazol-4-ylmethyl}-amine 1001941 109. [2-(4-Isopropoxyphenyl)-oxazol-4-ylmethyl] -(3,3,5 -trimethyl-cyclohexyl)-amine 1100195] 110. [2-(4-Isopropoxyphenyl)-oxazol-4-ylmethyl]-(( 1 R,2R,3R,5 S)-2,6,6-trimethyl-bicyclo [3.1.1]hept-3 -yl)-amine 100196] 111. ((1 S,2R,5 S)-6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-[2-(4-isopropoxyphenyl) -oxazol-4-ylmethyl] -amine [00197] 112. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -ethyl-amine [00198] 113. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-( 1 -methyl-butyl)-amine [00199] 114. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -pentyl-amine [00200] 115. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -isopropyl-amine [00201] 116. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -propyl-amine [00202] 117. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-( 1 -ethyl-propyl)-amine 1002031 118. sec-Butyl-[2-(4-butylphenyl)-oxazol-4-ylmethyl] -amine 1002041 119. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -hexyl-amine [00205] 120. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -cyclobutyl-amine [00206] 121. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -cyclopentyl-amine [00207] 122. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-cyclopropyl-amine [00208] 123. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-( 1 phenyl-ethyl)-amine [00209] 124. (R)-[2-(4-Butylphenyl)-oxazol-4-ylmethyl] -(1 phenyl-ethyl)-amine [00210] 125. Benzyl-[2-(4-butylphenyl)-oxazol-4-ylmethyl] -amine 1002111 126. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-phenethyl-amine -17 - 100212] 127. Butyl-[2-(4-butylphenyl)-oxazol-4-ylmethyl]-amine 100213] 128. [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -cyclohexyl-amine 1100214] 129. [2-(4-Cyclopentyloxyphenyl)-oxazol-4-ylmethyl]-( 1 -methyihexyl)-amine [00215J 130. [2-(4-Isobutoxyphenyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine [002161 131. [2-(4-sec-Butoxyphenyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine [002171 132. 1 -[2-(4-Butylphenyl)-oxazol-4-ylmethyl] -4-methyl-piperazine [002181 133. {2-[4-(2-Ethoxy-ethoxy)phenyl]-oxazol-4-ylmethyl} -(1-methylhexyl)-amine 1002191 134. (1 -Methyihexyl)-[2-(4-nitrophenyl)-oxazol-4-ylmethyl] -amine 100220] 135. [2-(4-Cyclobutoxyphenyl)-oxazol-4-ylmethyl] -(1 -methyihexyl)-amine 1100221] 136. {2-[4-( 1 -Ethyl-propoxy)phenyl] -oxazol-4-ylmethyl} -(1-methylhexyl)-amine [00222] 137. [2-(4-Methoxybenzyl)-oxazol-4-ylmethyl]-( 1 -methylhexyl)-amine [00223] 138. (2,6-D imethoxybenzyl)-[2-(4-isopropoxyphenyl)-oxazol-4-ylmethyl]-amine 100224] 139. (2-Cyclohexyl-oxazol-4-ylmethyl)-( 1 -methylhexyl)-amine 1002251 140. [2-(4-Difluoromethoxyphenyl)-oxazol-4-ylmethyl] -(1 -methyihexyl)-amine [00226] 141. (1 -Methyihexyl)-{2-[4-( 1,1,2,2-tetrafluoro-ethoxy)phenyl]-oxazol-4-ylmethyl) -amine [00227] 142. [2-(4-Cyc Iohexylphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00228] 143. [2-(4-Isopropylphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00229] 144. (1 -Methylhexyl)-[2-(4-pentylphenyl)-oxazol-4-ylmethyl]-amine 1002301 145. [2-(3,4-Dimethylphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine -18 - [00231] 146. [2-(4-Butoxy-3 -Fluorophenyl)-oxazol-4-ylmethyl] -(1 -methyihexyl)-amine 1002321 147. [2-(4-Butoxyphenyl)-oxazol-4-ylmethyl] -(2,2-dimethyl-propyl)-amine [00233] 148. {2-[4-(2,2-Dimethyl-propoxy)phenyl] -oxazol-4-ylmethyl} -(2,2-dimethyl-propyl)-amine [00234] 149. [2-(4-Benzyloxyphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00235] 150. [2-(3,5 -Bis-trifluoromethylphenyl)-oxazol-4-ylmethyl] -(1-methylhexyl)-amine 1002361 151. [2-(3,5 -DiMethoxyphenyl)-oxazol-4-ylmethyl] -(1 -methyihexyl)-amine [00237] 152. 1 -(4-Hydroxy-3 -{4-[( 1 -Methylhexylamino)-methyl]-oxazol-2-yl} phenyl)-ethanone [00238] 153. 4-Chloro-2-(4-[(1 -Methylhexylamino)-methyl]-oxazol-2-yl} -phenol [00239] 154. [2-(4-tert-Butylphenyl)-oxazol-4-ylmethyl] -(2,6-dimethoxybenzyl)-amine [00240] 155. [2-(4-Butoxyphenyl)-oxazol-4-ylmethyl]-[2-( 1 -methyl-pyrrolidin-2-yl)-ethyl] -amine 1002411 156. [2-( 1 -Methyl-pyrrolidin-2-yl)-ethyl]-[2-(4-pentyloxyphenyl)-oxazol- 4-ylmethyl] -amine [00242] 157. N'-[2-(4-Butylphenyl)-oxazol-4-ylmethyl]-N,N-dimethyl-propane- 1,3-diamine [00243] 158. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-(2-pyrrolidin-1 -yl-ethyl)-amine [00244] 159. N'-[2-(4-Butylphenyl)-oxazol-4-ylmethyl]-N,N-dimethyl-ethane-1,2-diamine [00245] 160. { 2-[4-(4-Chlorobenzyloxy)phenyl]-oxazol-4-ylmethyl} -(1-methylhexyl)-amine -19 - 1002461 161. (1 -Methyihexyl)-[2-(4-phenethyloxyphenyl)-oxazol-4-ylmethyl] -amine 100247] 162. 2-(4-{4-[( 1 -Methylhexylamino)-methyl]-oxazol-2-yl} -phenoxy)- 1 phenyl-ethanone [00248] 163. {2-[4-(4-Methylbenzyloxy)phenyl] -oxazol-4-ylmethyl} -(1 -methylhexyl)-amine [00249] 164. 2-{4-[(1 -Methylhexylamino)-methyl] -oxazol-2-yl} -benzonitrile [00250] 165. [2-(2,4-Dichlorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine [00251] 166. [2-(2,6-Dichlorophenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 100252] 167. (1 -Methyihexyl)-[2-(4-p-tolyloxyphenyl)-oxazol-4-ylmethyl]-amine 100253] 168. {2-[4-(4-Chloro-phenoxy)phenyl] -oxazol-4-ylmethyl} -(1-methylhexyl)-amine [00254] 169. {2-[4-(4-Methoxy-phenoxy)phenyl]-oxazol-4-ylmethyl} -(1-methylhexyl)-amine [00255] 170. {2-[4-(4-Ftuoro-phenoxy)phenyl]-oxazol-4-ylmethyl} -(1-methylhexyl)-amine [00256] 171. [2-(3 -Methoxy-4-methylphenyl)-oxazol-4-ylmethyl] -(1-methylhexyl)-amine 100257] 172. {2-[4-(4-Fluorobenzyloxy)phenyl] -oxazol-4-ylmethyl} -(1-methylhexyl)-amine [00258] 173. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-(3 -morpholin-4-yl-propyl)-amine [00259] 174. N'-[2-(4-Butylphenyl)-oxazol-4-ylmethyl]-N,N-diethyl-propane-1,3 -diamine [00260] 175. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-[2-(3 H-imidazol-4-yl)-ethyl] -amine [00261] 176. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-(3 -imidazol-1 -yl-propyl)-amine -20 - 1002621 177. (1 -Benzyl-piperidin-4-yl)-[2-(4-butylphenyl)-oxazol-4-ylmethyl] -amine 1002631 178. N' -[2-(4-Butylphenyl)-oxazol-4-ylmethyl] -2,2-dimethyl-propane- 1,3-diamine [00264] 179. N'-[2-(4-Butylphenyl)-oxazol -4-ylmethyl]-2,2,N,N-tetramethyl -propane-i,3-diamine [002651 180. {2-[4-(3,4-Dichlorobenzyloxy)phenyl] -oxazol-4-ylmethyl} -(1-methylhexyl)-amine [00266] 181. (3-{ [2-(4-Butylphenyl)-oxazol-4-ylmethyl] -amino -propyl)-carbamic acid tert-butyl ester 1002671 182. 1 -Amino-3 -{ [2-(4-butylphenyl)-oxazol-4-ylmethyl] -amino} -propan-2-ol [00268] 183. [2-(4-Cyclopentyloxyphenyl)-oxazol-4-ylmethyl] -[2-( i-methyl-pyrroli din-2-yl)-ethyl] -amine [00269] 184. [2-(4-Butoxy-3 -methylphenyl)-oxazol-4-ylmethyl] -(1 -methyihexyl)-amine [00270] 185. [2-(4-Butoxy-3 -Methoxyphenyl)-oxazol-4-ylmethyl]-( 1-methylhexyl)-amine 1002711 186. [2-(3 -Butoxyphenyl)-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 1002721 187. N'-[2-(4-Methoxyphenyl)-5 -methyl-oxazol-4-ylmethyl] -N,N-dimethyl-propane-1,3-diamine [00273] 188. [2-(4-Methoxyphenyl)-5 -methyl-oxazol-4-ylmethyl]-[2-( i-methyl-pyrrolidin-2-yl)-ethylj-amine [00274] 189. [2-(3 -Methoxyphenyl)-5 -methyl-oxazol-4-ylmethyl]-[2-( 1-methyl-pyrrolidin-2-yl)-ethyl] -amine [00275] 190. [2-( 1 -Methyl-pyrrolidin-2-yl)-ethyl] -(5 -methyl-2-p-tolyl-oxazol-4-ylmethyl)-amine -21 - 1002761 191. [2-( 1 -Methyl-pyrrolidin-2-yl)-ethyl] -(5 -methyl-2-m-tolyl-oxazol-4-ylmethyl)-amine 1002771 192. [2-(4-Methoxyphenyl)-5 -methyl-oxazol-4-ylmethyl] -(1-methylhexyl)-amine [00278] 193. [2-(3 -Methoxyphenyl)-5 -methyl -oxazol -4-ylmethyl] -(1-methylhexyl)-amine [00279] 194. (1 -Methylhexyl)-(5 -methyl-2-p-tolyl-oxazol-4-ylmethyl)-amine [00280] 195. (1 -Methylhexyl)-(5 -methyl-2-m-tolyl-oxazol-4-ylmethyl)-amine [002811 196. [2-(2-Fluorophenyl)-5 -methyl-oxazol-4-ylmethyl] -(1 -methylhexyl)-amine 1002821 197. (2-Benzo [1,3]dioxol-5 -yl-oxazol-4-ylmethyl)-( 1 -methylhexyl)-amine [00283] 198. Benzyl-[2-(4-Ethoxyphenyl)-oxazol-4-ylmethyl] -amine [00284] 199. Bis-[2-(4-Ethoxyphenyl)-oxazol-4-ylmethyl] -methyl-amine [002851 200. [2-(4-Ethoxyphenyl)-oxazol-4-ylmethyl]-(( 1 R,2S,5 S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine [00286] 201. Adamantan-1 -yl-[2-(4-Ethoxyphenyl)-oxazol-4-ylmethyl] -amine [00287] 202. Bis-[2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -((R)-1 -methylhexyl)-amine 1002881 203. Adamantan-l-yl-[2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -amine [00289] 204. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl]phenyl-amine [00290] 205. [2-(4-Chlorophenyl)-oxazol-4-ylmethyl]-diethyl-amine [002911 206. 1 -[2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -piperidine [00292] 207. Adamantan-2-yl-[2-(3 -chloro-thiophen-2-yl)-oxazol-4-ylmethyl] -amine [00293] 208. [2-(3 -Chloro-thiophen-2-yl)-oxazol-4-ylmethyl] -(3,3,5 -trimethyl-cyclohexyl)-amine -22 - 1002941 209. [2-(3-Chloro-thiophen-2-yl)-oxazol-4-ylmethyl]-(( 1 R,2R,3R,5 S)- 2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine 1002951 210. [2-(4-tert-Butylphenyl)-oxazol-4-ylmethyl] -(3,3,5 -trimethyl-cyclohexyl)-amine [00296] 211. [2-(4-tert-Butylphenyl)-oxazol-4-ylmethyl]-((IR,2R,3R,SS)-2,6, 6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine [00297] 212. [2-(4-Bromophenyl)-oxazol-4-ylmethyl]-((1 S,2R,5S)-6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-amine [00298] 213. [2-(4-tert-Butylphenyl)-oxazol-4-ylmethyl]-(( 1 S,2R,5 S)-6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-amine 1002991 214. [2-(3-Chloro-thiophen-2-yl)-oxazol-4-ylmethyl]-(( 1 S,2R,5 S)-6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-amine [00300] 215. [2-(3 -Chloro-thiophen-2-yl)-oxazol-4-ylmethyl] -cycloheptyl-amine [00301J 216. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-(4-chlorobenzyl)-amine [00302] 217. [2-(4-Decyloxyphenyl)-oxazol-4-ylmethyl]-(( 1 R,2R,3R,5 S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yI)-amine [00303] 218. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-pyridin-2-ylmethyl-amine [00304] 219. [2-(4-Butylphenyl)-oxazol-4-ylmethyl]-pyridin-3 -ylmethyl-amine 1003051 220. 4-[2-(4-Butylphenyl)-oxazol-4-ylmethyl] -morpholine 1003061 221. 1-[2-(4-Butylphenyl)-oxazol-4-ylmethyl] -4phenyl-piperazine [00307] 222. N'-[2-(4-Tsobutoxyphenyl)-oxazol-4-ylmethyl]-N,N-dimethyl-propane-i, 3-diamine [00308] 223. N'-[2-(4-Cyclopentyloxyphenyl)-oxazol-4-ylmethyl] -N,N-dimethyl-propane-i,3-diamine [00309] 224. N'-[2-(4-Isopropylphenyl)-oxazol-4-ylmethyl] -N,N-dimethyl-propane-i,3-diamine -23 - 1003101 225. N,N-Dimethyl-N'-[2-(4-phenethyloxyphenyl)-oxazol-4-ylmethyl] -propane-i,3-diamine 1003111 226. N'-[2-(4-sec-Butoxyphenyl)-oxazol-4-ylmethyl]-N,N-dimethyl-propane-i, 3-diamine [00312] 227. N'-{2-[4-( 1 -Ethylpropoxy)phenyl] -oxazol -4-ylmethyl} -N,N-dimethyl-propane-i,3-diamine [003131 228. [2-(2-Fluorophenyl)-5 -methyl-oxazol-4-ylmethyl] -[2-( i-methyl-pyrrolidin-2-yl)-ethyl] -amine [00314] The numbers 1 to 228 are assigned to these compounds for reference and identification hereafter.
1003151 The compounds of the invention can be prepared, isolated or obtained by any method apparent to those of skill in the art. Exemplary methods of preparation are described in detail in the examples below.
[00316] The compounds of the invention can be prepared, isolated or obtained by any method apparent to those of skill in the art. Exemplary methods of preparation are described in detail in the examples below.
[003171 According to a feature of the present invention compounds of formula (I) can be obtained by treatment of an 2-arylazol-4-ylmethylene chloride of formula (II), with an appropriate substituted amine, wherein R' and R2 are as defined above, optionally in the presence of a solvent and a non-nucleophilic base, for example, as illustrated in the reaction scheme below: R' / Cl N H Triethylamine N 2 w_X\3 + R1R2 Solvent w_X\3 R
V
T (II) "T5 (I) [003181 It will be appreciated by those skilled in the art that alternatives to triethylamine (e.g. potassium or cesium carbonate, sodium hydride, diisopropylethylamine) may be employed, and that a variety of solvents (e.g. -24 -tetrahydrofuran, dimethyformamide, acetonitrile) may be used (or by using an excess of R'R2NH, that this may act as both solvent and base), and that the choice of exact reaction conditions will be dictated by the properties of the individual components of the reaction, for example, solubility of the either the chioromethylarylazole and/or amine in the solvent to be employed.
Pharmaceutical Compositions and Methods of Administration [00319] According to a further feature of the invention there are provided compositions which comprise a 2-arylazole derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, carrier or diluent. The composition of the invention can also be in a variety of forms which include, but are not limited to, oral formulations, injectable formulations, and topical, dermal or subdermal formulations.
[00320] The composition of the invention may be in a form suitable for oral use, for example, as dietary supplements, troches, lozenges, chewables, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, dispersible powders or granules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
100321] Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
-25 - 1003221 Formulations for oral use may be hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. Capsules may also be soft gelatin capsules, wherein the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
[00323] The compositions of the invention may also be in the form of oil-in-water or water-in-oil emulsions. The oily phase maybe a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these.
Suitable emulsifying agents may be naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening agents, bittering agents, flavoring agents, and/or preservatives.
[00324] In one embodiment of the formulation, the composition of the invention is in the form of a microemulsion. Microemulsions are well suited as the liquid carrier vehicle. Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids.
t003251 Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
[00326] In one embodiment of the oily phase, the oily phase can be fonned from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds. In one embodiment of the oily phase, the oily phase comprises of triglycerides; in another embodiment of the oily phase, the triglycerides are medium-chain triglycerides, for example, C8-C10 caprylic/capric triglyceride. n another embodiment of the oily phase will represent a -26 - % v/v range selected from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of the microemulsion.
1003271 The aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In one embodiment of the glycol derivatives, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof Generally, the aqueous phase will represent a proportion from about 1 to about 4% v/v in the microemulsion.
[00328] Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropyelene glycol monomethyl ether, polyglycolyzed C8-C10 glycerides or polyglyceryl-6 dioleate. Tn addition to these surfactants, the cosurfactants include short-chain alcohols, such as ethanol and propanol.
[00329] Some compounds are common to the three components discussed above, for example, aqueous phase, surfactant and cosurfactant. However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation. In one embodiment for the amount of surfactant/cosurfactant, the cosurfactant to surfactant ratio will be from about 1/7 to about 1/2. In another embodiment for the amount of cosurfactant, there will be from about 25 to about 75% v/v of surfactant and from about 10 to about 55% v/v of cosurfactant in the microemulsion.
1003301 Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, atachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid, or other known preservatives.
[00331] Aqueous suspensions may contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, -27 -hydroxy-propylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occuring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth above.
[00332] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, bittering, flavoring and coloring agents, may also be present.
[00333] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and/or coloring agent(s).
[00334] The compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-aceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. Preservatives, such as phenol or benzyl alcohol, may be used.
1003351 In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[00336] Topical, dermal and subdermal formulations can include emulsions, creams, ointments, gels or pastes.
[00337] Organic solvents that can be used in the invention include but are not limited to: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.
[00338] As vehicle or diluent, mention may be made of plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (such as C8-C12) triglycerides.
[00339] Dosage forms may contain from about 0.5 mg to about 5 g of an active agent. In one embodiment of the dosage form, the dosage is from about 1 mg to about 500 mg of an active agent, typically about 25 mg, about 50 mg, about 100 mg, about mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000 rng.
[00340] In one embodiment of the invention, the active agent is present in the formulation at a concentration of about 0.05 to 10% weight/volume. In another embodiment of the invention, the active agent is present in the formulation as a -29 -concentration from about 0.1 to 2% weight'volume. Tn yet another embodiment of the invention, the active agent is present in the formulation as a concentration from about 0.25 to about 1.5% weight/volume. In still another embodiment of the invention, the active agent is present in the formulation as a concentration about 1% weight/volume.
[00341] According to a further feature of the invention there is provided a method of treating or preventing infection in a subject, the method comprising administering to the subject a therapeutically effective amount of 2-arylazole derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof [00342] The compounds of the invention are especially useful for the prophylaxis and/or treatment of South American trypanosomiasis, African trypanosomiasis, sleeping sickness, Kala-Azar, visceral leishmaniasis, Baghdad boil or Aleppo boil, cutaneous leishmaniasis (CL),espundia, Chagas disease, mucocutaneous leishmaniasis (MCL), trichomoniasis, urogenital trichomonosis, giardiasis, lamblia dysentery, amoebiasis, primary amebic meningoencephalitis (PAM), keratitis or meningitis, coccidiosis, sarcosporidosis, toxoplasmosis, Malaria tropica, Malaria tertiana, Malaria quartana, pneumocystis carinii, pneumonia, pneumocystosis, Balantidium dysentery, and oriental sore.
[00343] The pharmaceutical preparation comprising the 2-arylazole derivatives of the invention, for delivery to a human or other mammal, is preferably in unit dosage form, in which the preparation is subdivided into unit doses containing an appropriate quantity of the active component. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet or lozenge itself, or it can be an appropriate number of any of these in packaged form.
[00344] The quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 1000 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
-30 - 1003451 In therapeutic use for the treatment of a parasitic infection in a human or other mammal, the compounds utilized in the pharmaceutical method of the invention are administered at an initial dosage of about 0.00 1 mg/kg to about 100 mg/kg daily.
The dosages may be varied depending on the requirements of the patient, for example, the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the potency of the compound being used.
Determination of the proper dosage and route of administration for a particular situation is within the skill of the practitioner. Generally, the treatment will be initiated with smaller dosages which are less than the optimum dose of the compound, which can be increased in small increments until the optimum effect under the particular circumstances of the infection is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
1003461 The following Examples illustrate the synthesis of representative compounds used in the present invention and the following Reference Examples illustrate the synthesis of intermediates in their preparation. These examples are not intended, nor are they to be construed, as limiting the scope of the invention. It will be clear that the invention may be practiced otherwise than as particularly described herein. Numerous modifications and variations of the present invention are possible in view of the teachings herein and, therefore, are within the scope of the invention.
Abbreviations CH2C12: dichioromethane EtOAc: ethyl acetate ELS: Evaporative Light Scattering HCO2H: formic acid MeOH: Methanol THF: tetrahydrofuran [00347] The following are registered trade marks: Teflon, Tygon, Supelco, All temperatures are given in degrees Centigrade. Room temperature means 20 to 25°C.
Reagents were purchased from commercial sources or prepared following standard literature procedures. Unless otherwise noted, reactions were carried out under a positive pressure of nitrogen. Reaction vessels were sealed with either rubber septa or Teflon screw caps. Nitrogen was introduced through Tygon tubing, fitted with a large -31 -bore syringe needle. Concentration under vacuum refers to the removal of solvent on a Büchi Rotary Evaporator.
1003481 Analytical HPLC was performed using a Supelco� discovery C 18 15 cm x 4.6 mm / 5 tm column coupled with an Agilent 1050 series VWD UV detector at 210 nm. Conditions: Solvent A: H20/1% acetonitrile/0.1% HCO2H; Solvent B: methanol.
[00349] Proton magnetic resonance (H NMR) spectra were recorded on a Varian INOVA� NMR spectrometer [400 MHz (H) or 500 MHz (H)]. All spectra were determined in the solvents indicated. Although chemical shifts are reported in ppm downfield of tetramethylsilane, they are referenced to the residual proton peak of the respective solvent peak for H NMR. Interproton coupling constants are reported in Hertz (Hz).
[00350] LCMS spectra were obtained using a ThermoFinnigan� AQA MS ESI instrument utilizing a Phenomenex� Aqua 5 micron C18 125 A 50 x 4.60mm column. The spray setting for the MS probe was at 350 iL/min with a cone voltage at mV and a probe temperature at 450 °C. The spectra were recorded using ELS and T.JV (254 nm) detection. Alternatively, LCMS spectra were obtained using an Agilent� 12005L HPLC equipped with a 6130 mass spectrometer operating with electrospray ionization.
[00351] Silica gel chromatography was carried out on a Teledyne IISCO CombiFlash� Companion Flash Chromatography System with a variable flow rate from 5-100 mL/min. The columns used were Teledyne TSCO RediSep� Disposable Flash Columns (4, 12, 40, 80, or 120 g prepacked silica gel), which were run with a maximum capacity of 1 g crude sample per 10 g silica gel. Samples were preloaded on Celite in Analogix� Sample Loading Cartridges with frits (1/in, 1/out). The eluent was 0-100% EtOAc in heptane or 0-10% MeOH in CH2CI2 as a linear gradient over the length of the run (14-20 minutes). Peaks were detected by variable wavelength 1.JV absorption (200-3 60 nm). The resulting fractions were analyzed, combined as appropriate, and evaporated under reduced pressure to provide purified material.
-32 - 1003521 HPLC purification was performed using a 50 mm Varian Dynamax� HPLC 21.4 mm Microsorb Guard-8 Cl 8 column, Dyonex Chromeleon� operating system coupled with a Varian Prostar� 320 UV-vis detector (254 nm) and a Sedex55 ELS detector. Conditions: Solvent A: H20/1% acetonitrile/0.1% HCO2H; Solvent B: methanol. The appropriate solvent gradient for purification was determined based on the results of analytical HPLC experiments. The resulting fractions were analyzed, combined as appropriate, and evaporated under reduced pressure to provide purified material.
[00353] The following experimental sections illustrate procedures for the preparation of intermediates and methods for the preparation of products according to this invention. Tt should be evident to those skilled in the art that appropriate substitution of both the materials and methods disclosed herein will produce the examples illustrated below and those encompassed by the scope of the invention.
Example 1
[00354] To a solution of 4-chloromethyl-2-(4-ethoxyphenyl)-oxazole (50 mg, 0.21 mmol), prepared according to Reference Example 1 below, in dry acetonitrile (10 mL) was added triethylamine (0.3 mL, 2.1 mmol) and 2-aminoheptane (0.1 mL, 0.63 mmol). The reaction was headed to 78°C for 16 hours, and then cooled to room temperature. The solution was concentrated to dryness by rotary evaporation, and the resultant material was partitioned between dichloromethane (20 mL) and aqueous sodium hydroxide (1M, 10 mL). The organic layer was dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel to yield the [2-(4-ethoxyphenyl)-oxazol-4-ylmethyl]-(1-methyl-hexyl)-amine (Compound 5) as a clear oil. Calculated for C,9H28N202; 316. Observed; 317 (M+H)+. H NMR (400 MHz, chloroform-d) ppm 0.83 -0.93 (m, 3 H) 1.09 (d, J=6.2 Hz, 3 H) 1.21 -1.38 (m, 7 H) 1.44 (t, J=6.9 Hz, 3 H) 1.48 -1.56 (m, 1 H) 1.68 (br. s., 2 H) 2.71 (tq, J=6.2, 6.0 Hz, 1 H) 3.66 -3.87 (m, 2 H) 4.09 (q, J=7.0 Hz, 2 H) 6.90 -7.00 (m, 2 H) 7.52 (t, J0.9 Hz, 1 H) 7.90 -7.99 (m, 2 H).
[00355] By proceeding in a similar manner, the following compounds were prepared: -33 - 1003561 (1 -Methylhexyl)-(2-phenyl-oxazol-4-ylmethyl)-amine [Compound 8]; Calculated for C,7H24N20; 272. Observed; 273 (M+H)+. H NMR (400 MHz, chloroform-d) ppm 0.85 -0.93 (m, 3 H) 1.10 (d, J=6.2 Hz, 3 H) 1.23 -1.41 (m, 7 H) 1.44 -1.59 (m, 2 H) 2.72 (tq, J=6.2, 6.0 Hz, 1 H) 3.71 -3.88 (m, 2 H) 7.42 -7.51 (m, 3 H) 7.58 (s, 1 H) 8.00 -8.07 (m, 2 H).
[00357] (1 -Methylhexyl)-(2-thiophen-2-yl-oxazol-4-ylmethyl)-amine [Compound 39]; Calculated for C,5H22N20S; 278. Observed; 279 (M+H)+. H NMR (400 MHz, chloroform-d) ppm 0.85 -0.93 (m, 3 H) 1.09 (d, J=6.2 Hz, 3 H) 1.22 -1.38 (m, 7 H) 1.42 -1.56 (m, 1 H) 1.66 (hr. s., 1 H) 2.70 (tq, J=6.2, 5.9 Hz, 1 H) 3.68 -3.84 (m, 2 H) 7.11 (dd, J=5.1, 3.7 Hz, 1 H) 7.42 (dd, J=4.9, 1.2 Hz, 1 H) 7.51 (s, 1 H) 7.66 (dd, J3.7, 1.2 Hz, 1 H).
1003581 [2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -cyclohexyl-amine [Compound 51]; Calculated for C,6H,9C1N20; 290. Observed; 291 (M+H)+. H NMR (400 MHz, chloroform-d) ppm 1.01 -1.38 (m, 5 H) 1.52-1.69 (m, 2 H) 1.69-1.83 (m, 2 H) 1.85 -2.05 (m, 2 H) 2.52 (tt, J=10.3, 3.7 Hz, I H) 3.80 (d, J=1.0 Hz, 2 H) 7.36 -7.50 (m, 2 H) 7.57 (s, 1 H) 7.89 -8.07 (m, 2 H).
[00359] (2-Cyclohexyl-oxazol-4-ylmethyl)-( 1 -methylhexyl)-amine [Compound 139]; Calculated for C,7HoN2O; 278. Observed; 279 (M+H)+. H NMR (400 MHz, methanol-d4) ppm 0.91 -0.96 (m, 3 H) 1.26 -1.49 (m, 10 H) 1.35 (d, J=6.4 Hz, 3 H) 1.51-1.65 (m,3H) 1.70-1.86(m,4H)2.01 -2.10(m,2H)2.85 (tt,J=11.1,3.7 Hz, 1 H) 3.24-3.34 (m, 1 H) 4.10 -4.20 (m, 2 H) 7.92 (s, 1 H).
1003601 (1 -Methylhexyl)-[2-(4-p-tolyloxyphenyl)-oxazol-4-ylmethyl] -amine [Compound 167]; Calculated for C24H30N2O2; 378. Observed; 379 (M+H)+. H NMR (400 MHz, chloroform-d) ppm 0.86 -0.93 (m, 3 H) 1.07 -1.12 (m, 3 H) 1.23 -1.40 (m, 7 H) 1.46-1.56 (m, 1 H) 1.60 (br. s., 1 H) 2.66-2.77 (m, 1 H) 3.67-3.86 (m, 2 H) 6.94 -6.99 (m, 2 H) 7.00 -7.05 (m, 2 H) 7.14 -7.22 (m, 2 H) 7.54 (s, 1 H) 7.92 -8.02 (m, 2 H).
[003611 Bis-[2-(4-chlorophenyl)-oxazol-4-ylmethyl]-((R)-1 -methylhexyl)-amine [Compound 202]; Calculated for C27H29C12N3O2; 497. Observed; 498 (M+H)+. H NMR (400 MHz, chloroform-d) 5 ppm 0.85 (t, J7.0 Hz, 3 H) 1.06 (d, J=6.6 Hz, 3 H) -34 - 1.14-1.44 (m, 7 H) 1.51 -1.65 (m, 1 H) 2.89 (sxt, J=6.6 Hz, 1 H) 3.62-3.83 (m, 4 H) 7.38 -7.46 (m, 4 H) 7.70 (s, 2 H) 7.91 -8.00 (m, 4 H).
1003621 [2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -phenyl-amine [Compound 204]; Calculated for C,6H,3C1N20; 284. Observed; 285 (M+H)+. H NMR (400 MHz, chloroform-d) ppm 4.34 (s, 2 H) 6.66 -6.74 (m, 2 H) 6.73 -6.81 (m, 1 H) 7.15 - 7.25 (m, 2 H) 7.39 -7.49 (m, 2 H) 7.60 (s, 1 H) 7.94 -8.01 (m, 2 H).
[00363] 1-[2-(4-Chlorophenyl)-oxazol-4-ylmethyl] -piperidine [Compound 206]; Calculated for C,5H,7C1N20; 276. Observed; 277 (M+H)+. H NMR (400 MHz, chloroform-d) ppm 1.39 -1.49 (m, 2 H) 1.61 (quin, J=5.7 Hz, 4 H) 2.48 (br. s., 4 H) 3.49 (d, J=O.8 Hz, 2 H) 7.38 -7.46 (m, 2 H) 7.57 (s, 1 H) 7.95 -8.01 (m, 2 H).
1003641 N'-[2-(4-Tsopropylphenyl)-oxazol-4-ylmethyl]-N,N-dimethylpropane-1,3 -diamine [Compound 224]; Calculated for C,8H27N30; 301. Observed; 302 (M+H)+.
H NMR (400 MHz, chloroform-d) ppm 1.24 (d, J=6.8 Hz, 6 H) 2.29 -2.40 (m, 2 H) 2.92 (quin, J=6.9 Hz, 1 H) 3.04 (t, J=6.2 Hz, 2 H) 3.39 (s, 6 H) 3.83 -3.91 (m, 2 H) 4.94 (s, 2 H) 7.27 (d, J8.4 Hz, 2 H) 7.87 (d, J8.4 Hz, 2 H) 8.49 (s, 1 H).
[00365] By proceeding in a similar manner to the reactions described in Example 1 above, Compounds 1-4, 6-7, 9-38, 40-50, 52-138, 140-166, 168-201, 203, 205, 207- 223, and 225-228 were also prepared.
Reference Example 1
1003661 4-Chloromethyl-2-(4-ethoxyphenyl)-oxazole. To a disposable 40 mL glass reaction vial was added 1,3-dichloroacetone (3.07 g, 24.2 mmol) and 4-ethoxybenzamide (2g, 12.1 mmol). The reaction was submerged into a preheated oil bath (130°C), at which time the heterogeneous solid mixture melted into a brown oil.
The reaction was stirred for two hours, and then cooled to room temperature. The resultant material was dissolved in CH2C12 (100 mL) and washed with aqueous sodium hydroxide (1M, 50 mL) and brine (50 mL). The organic portion was dried over sodium sulfate and concentrated under vacuum. The crude product was chromatographed on silica gel to provide 4.-chloromethyl-2-(4-ethoxyphenyl)-oxazole as a white ciystalline solid (1.3g). Calculated for C12H12C1N02; 237. Observed; 228 -35 - (M+H)+. H NMR (400 MHz, chloroform-d) Sppm 1.45 (t, J=6.9 Hz, 3 H) 4.09 (q, J7.O Hz, 2 H) 4.57 (d, J0.8 Hz, 2 H) 6.96 (ddd, J9.3, 2.7, 2.4 Hz, 2 H) 7.65 (t, J=O.9 Hz, 1 H) 7.97 (ddd, J=93, 2.8, 2.5 Hz, 2 H).
Trypanosome Strain and Cultivation [00367] All experiments were conducted with the bloodstream-form trypanosome T. brucei brucei 427 strain. Parasites were cultured in T-25 vented cap flasks and kept in humidified incubators at 37°C and 5% CO2. The parasite culture media was complete HMI-9 medium (c.f. Hirumi, Journal of Parasitology 1989, Volume 75, page 985 etseq) containing 10% FBS, 10% Serum Plus medium and penicillinlstreptomycin. To ensure log growth phase, trypanosomes were sub-cultured at appropriate dilutions every 2-3 days.
-36 -In Vitro Drug Sensitivity Assays 1003681 Log phase cultures were diluted 1:10 in HMT-9 and 10 iL was counted using hemocytometer to determine parasite concentration. Parasites were diluted to 2 x 105/mt in HMI-9 to generate a 2-fold working concentration for assay. Compounds to be tested were serially diluted in DMSO and 0.5 iL added to 49.5 iL HMI-9 in triplicate 96-well plates using a Biomek� NX liquid handler. Parasites from the diluted stock were added to each well (50 L) using a Multidrop 384 dispenser to give a final concentration of 1.0x105/mI parasites in 0.4% for DMSO. Trypanosomes were incubated with compounds for 72 hrs at 37°C with 5% CO2. Resazurin� (20 iL of 12.5 mg/mI stock) from Sigma-Aldrich was added to each well and plates were incubated for an additional 2-4 hrs. Assay plates were read using an EnVision plate reader at an excitation wavelength of 544 nm and emission of 590 nm. Triplicate data points were averaged to generate sigmoidal dose response curve and determine IC50 values using XLfit� curve fitting software from IDBS (Guildford, UK).
[003691 Under these assay conditions, Compounds 1 to 228 of the invention gave an IC50 value in the range of from 0.07 to >5 tg/ml.

Claims (10)

  1. CLAIMS1. A 2-arylazole derivative of formula (I): R' /N \TS (I)wherein R' and R2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl; R3 is hydrogen, alkyl, halogen, or aryl; S, T, V, W and X are independently C-R4 or N; with the proviso that at least three of 5, T, V, W and X are independently C-R4; or two adjacent groups selected from 5, T and V together form an optionally substituted phenyl ring; R4 is independently hydrogen, alkyl, halogen, -CH2R5, -OR6, -SR6 or aryl; R5 is cycloalkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted, or optionally substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl; R6 is alkyl, cycloalkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted, or optionally substituted aryl or heteroaryl, whereby the substituents are independently selected from the group consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, arylthio, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, aminocarbonyl, alkoxycarbonyl, alkenoyl, alkynoyl, aroyl, alkylsulfinyl and alkylsulfonyl; Y is oxygen or sulfur; or a pharmaceutically acceptable salt or solvate thereof.
    -38 -
  2. 2. The compound according to Claim 1 in which Y is oxygen.
  3. 3. The compound according to Claim 1 or 2 in which S, T, V, W, and X are independently C-R4.
  4. 4. The compound according to Claim 1, 2 or 3 in which R' is C110 alkyl, C312 cycloalkyl, C110 hydroxyallcyl, C11o alkoxyalkyl or Ciio aminoalkyl.
  5. 5. The compound according to Claim 1, 2, 3 or 4 in which R2 is hydrogen.
  6. 6. The compound according to any one of Claims 1 to 5 in which R3 is hydrogen or alkyl.
  7. 7. The compound according to Claim 1 which is selected from Compound Numbers 1 to 228.
  8. 8. A composition comprising a 2-arylazole derivative as defined in any one of Claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier or diluent.
  9. 9. A method of treating or preventing infection in a subject, the method comprising administering to the subject a therapeutically effective amount of a 2-arylazole derivative of formula (I) as defined in any one of Claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof
  10. 10. The use of a 2-arylazole derivative of formula (I) as defined in any one of Claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, for -39 -prophylaxis and/or treatment of South American trypanosomiasis, African trypanosomiasis, sleeping sickness, Kala-Azar, visceral leishmaniasis, Baghdad boil or Aleppo boil, cutaneous leishmaniasis (CL),espundia, Chagas disease, mucocutaneous leishmaniasis, trichomoniasis, urogenital trichomonosis, giardiasis, lamblia dysentery, amoebiasis, primary amebic meningoencephalitis (PAM), keratitis or meningitis, coccidiosis, sarcosporidosis, toxoplasmosis, Malaria tropica, Malaria tertiana, Malaria quartana, pneumocystis carinii, pneumonia, pneumocystosis, Balantidium dysentery, or oriental sore.
GB0921210A 2008-12-05 2009-12-03 2-Arylazole derivatives as antiprotozoal agents Withdrawn GB2465890A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US12030308P 2008-12-05 2008-12-05

Publications (2)

Publication Number Publication Date
GB0921210D0 GB0921210D0 (en) 2010-01-20
GB2465890A true GB2465890A (en) 2010-06-09

Family

ID=41641888

Family Applications (1)

Application Number Title Priority Date Filing Date
GB0921210A Withdrawn GB2465890A (en) 2008-12-05 2009-12-03 2-Arylazole derivatives as antiprotozoal agents

Country Status (1)

Country Link
GB (1) GB2465890A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014063597A1 (en) * 2012-10-23 2014-05-01 中国科学院广州生物医药与健康研究院 New cycloalkylamine compound useful in resisting mutant influenza virus
WO2014081756A1 (en) * 2012-11-20 2014-05-30 Biogen Idec Ma Inc. S1p and/or atx modulating agents
EP3476389A1 (en) * 2017-10-31 2019-05-01 Commissariat à l'Energie Atomique et aux Energies Alternatives Adamantane or bicyclic monoterpenoid derivatives for use in the treatment of leishmaniasis
WO2024026359A1 (en) * 2022-07-26 2024-02-01 The Board Of Trustees Of The University Of Illinois Compounds and methods for the treatment of diseases associated with parasitic worms

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102020587A (en) * 2010-11-25 2011-04-20 大连凯飞精细化工有限公司 Method for synthesizing 2-methoxy-4-cyano benzaldehyde

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5430167A (en) * 1977-08-11 1979-03-06 Mitsubishi Chem Ind Ltd 4-aminomethyl-2-phenyloxazoles and their pharmaceutically acceptable acid salts
EP0389699A1 (en) * 1988-03-08 1990-10-03 Pfizer Inc. Thiazolidinedione derivatives as hypoglycemic agents
JPH1017569A (en) * 1996-07-05 1998-01-20 Yamanouchi Pharmaceut Co Ltd Medicine containing substituted thiazole derivative as active ingredient and new compound
US5925656A (en) * 1995-04-10 1999-07-20 Dr. Reddy's Research Foundation Compounds having antidiabetic, hypolipidemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
JP2003128548A (en) * 2001-08-10 2003-05-08 Yamanouchi Pharmaceut Co Ltd Medicinal composition containing condensed imidazolium derivative
WO2007058338A2 (en) * 2005-11-15 2007-05-24 Otsuka Pharmaceutical Co., Ltd. Oxazole compound and pharmaceutical composition

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5430167A (en) * 1977-08-11 1979-03-06 Mitsubishi Chem Ind Ltd 4-aminomethyl-2-phenyloxazoles and their pharmaceutically acceptable acid salts
EP0389699A1 (en) * 1988-03-08 1990-10-03 Pfizer Inc. Thiazolidinedione derivatives as hypoglycemic agents
US5925656A (en) * 1995-04-10 1999-07-20 Dr. Reddy's Research Foundation Compounds having antidiabetic, hypolipidemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
JPH1017569A (en) * 1996-07-05 1998-01-20 Yamanouchi Pharmaceut Co Ltd Medicine containing substituted thiazole derivative as active ingredient and new compound
JP2003128548A (en) * 2001-08-10 2003-05-08 Yamanouchi Pharmaceut Co Ltd Medicinal composition containing condensed imidazolium derivative
WO2007058338A2 (en) * 2005-11-15 2007-05-24 Otsuka Pharmaceutical Co., Ltd. Oxazole compound and pharmaceutical composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Apollo Scientific Intermediates for Research and Development; 12 June 2009. CHEMCATS Accession No. 2076329757. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014063597A1 (en) * 2012-10-23 2014-05-01 中国科学院广州生物医药与健康研究院 New cycloalkylamine compound useful in resisting mutant influenza virus
WO2014081756A1 (en) * 2012-11-20 2014-05-30 Biogen Idec Ma Inc. S1p and/or atx modulating agents
US9771326B2 (en) 2012-11-20 2017-09-26 Biogen Ma Inc. S1P and/or ATX modulating agents
EP3476389A1 (en) * 2017-10-31 2019-05-01 Commissariat à l'Energie Atomique et aux Energies Alternatives Adamantane or bicyclic monoterpenoid derivatives for use in the treatment of leishmaniasis
WO2019086514A1 (en) * 2017-10-31 2019-05-09 Commissariat A L'energie Atomique Et Aux Energies Alternatives Adamantane or bicyclic monoterpenoid derivatives for use in the treatment of leishmaniasis
WO2024026359A1 (en) * 2022-07-26 2024-02-01 The Board Of Trustees Of The University Of Illinois Compounds and methods for the treatment of diseases associated with parasitic worms

Also Published As

Publication number Publication date
GB0921210D0 (en) 2010-01-20

Similar Documents

Publication Publication Date Title
JP6898493B2 (en) One or two substituted indole derivatives as dengue virus replication inhibitors
Dürüst et al. Synthesis and anti-protozoal activity of novel dihydropyrrolo [3, 4-d][1, 2, 3] triazoles
KR101736643B1 (en) Crystalline forms of 1-(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'h-spiro[azetidine-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone
Li et al. Artemisinin derivatives bearing Mannich base group: synthesis and antimalarial activity
EP0000928B1 (en) Nitroimidazoles and pharmaceutical compositions containing them as well as their preparation
US10562914B2 (en) Imidazoles as histone demethylase inhibitors
ES2618891T3 (en) N, N'-diariltioureas and N, N¿-cyclic N-diarylureas as androgen receptor antagonists, anticancer agent, method of producing and using it
GB2465890A (en) 2-Arylazole derivatives as antiprotozoal agents
WO2023061095A1 (en) 14-CHLORO-β-ELEMENE NITRIC OXIDE DONOR TYPE DERIVATIVE, PREPARATION AND APPLICATION THEREOF
Bayrak et al. Structure based design, synthesis, and evaluation of anti-CML activity of the quinolinequinones as LY83583 analogs
US5324739A (en) Compound exhibiting antiproliferative activity against cells
EP3992184B1 (en) Hydrazone amide derivatives and use thereof in preparation of anti-osteoporosis drugs
WO2011063223A1 (en) TETRAHYDRO-β-CARBOLINE DERIVATIVES, SYNTHESIS AND USE THEREOF
BG60317B2 (en) Indenoindole compounds
SU936815A3 (en) Process for producing 4,1-benzoxazepines or their thia-analogs
JP2021503465A (en) Single enantiomer antiparasitic compound
CN112194629B (en) Phenethyl azole derivative and preparation method and application thereof
CN109485607B (en) Beta-azole-phenyl ketone derivative and application thereof
SU1493106A3 (en) Method of producing isoxasol derivatives
GB2461167A (en) N-substituted amidoxime derivatives for the prophylaxis and/or treatment of tropical diseases
WO2021167554A1 (en) Use of synthesized compounds as an inhibitor of ef2-kinase enzyme
WO1999032115A1 (en) Modulators of ryanodine receptors comprising 2-(aryl)-4,7-dioxobenzothiazoles and analogues thereof
JP7499942B2 (en) Salts of dihydropyrido[2,3-d]pyrimidinone derivatives, their preparation method and use
RU2817789C1 (en) Use of (z)-6-methoxy-2-(2-oxobutylidene)indolin-3-one as antifungal agent against yeast fungi
RU2803747C1 (en) Use of (z)-2-(2-oxopropyliden)indolin-3-one as an antifungal agent against yeasts

Legal Events

Date Code Title Description
WAP Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1)