WO1999015129A2 - SELECTIVE cPLA2 INHIBITORS - Google Patents

SELECTIVE cPLA2 INHIBITORS Download PDF

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Publication number
WO1999015129A2
WO1999015129A2 PCT/US1998/019426 US9819426W WO9915129A2 WO 1999015129 A2 WO1999015129 A2 WO 1999015129A2 US 9819426 W US9819426 W US 9819426W WO 9915129 A2 WO9915129 A2 WO 9915129A2
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WIPO (PCT)
Prior art keywords
alkyl
phenyl
hydrogen
alkylamino
substituted
Prior art date
Application number
PCT/US1998/019426
Other languages
French (fr)
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WO1999015129A3 (en
Inventor
Jacques Banville
Yonghua Gai
Graham Johnson
Fred Christopher Zusi
James R. Burke
Original Assignee
Bristol-Myers Squibb Company
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Publication date
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to AU93954/98A priority Critical patent/AU730364B2/en
Priority to CA002304503A priority patent/CA2304503A1/en
Priority to EP98947093A priority patent/EP1140791A4/en
Publication of WO1999015129A2 publication Critical patent/WO1999015129A2/en
Publication of WO1999015129A3 publication Critical patent/WO1999015129A3/en

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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines

Definitions

  • Inflammatory diseases of the skin such as psoriasis and atopic dermatitis, afflict greater than 5% of the population.
  • the treatment of these disorders typically involves the use of topical steroids.
  • these agents also have undesirable side effects such as skin atrophy which limit the duration of therapy.
  • topical application of a drug is difficult for many patients where the affected area may be very large.
  • Phospholipase A 2 is the common name for phosphatide 2- acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides and results in production of lysophospholipids and free fatty acids.
  • the fatty acid is arachidonic acid
  • further action by cyclooxygenase and 5-lipoxygenase enzymes results in eicosanoid production, which is implicated in inflammation, and leukotrienes which are linked to asthma.
  • Lysophophospholipid metabolism results in production of platelet activating factor and both lysophospholipids and platelet activating factor also play a role in inflammation.
  • PLA 2 enzymes exist as secreted forms (MW ⁇ 12,000-15,000) and cytosolic forms (MW ⁇ 85,000).
  • the cytosolic or cPLA 2 enzymes appear to play a key role in the pathway leading to the formation of platelet activating factor and the eicosanoids.
  • Inappropriate activation of the cytosolic PLA 2 enzymes can result in a variety of chronic and acute conditions including asthma, cerebral ischemia (Clemens et al, Stroke. 1996, 27, 527-535), Alzheimer's Disease (Stephenson et al, Neurobiology of Stroke. 1996, 3, 51-63 and see also U.S. Patent 5,478,857), rheumatoid arthritis, neutrophil and platelet activation (Huang et al, Mediators of Inflammation. 1994, 3, 307-308), chronic skin inflammation and damage to the skin resulting from exposure to ultraviolet light (Gresham et al, American Tournal of Physiology. 1996, 270; Cell Physiology 39:0037-0050) and macrophage activation (Balsinde et al, Tournal of Biological Chemistry. 1996, 271, 6758- 6765).
  • Selective inhibitors of the cPLA 2 enzymes may, therefore, be of use in controlling a wide variety of inflammatory diseases.
  • the literature describes a significant number of compounds said to be phospholipase A 2 inhibitors, but few selective inhibitors for the cPLA 2 enzymes are available. The present inventors had as their goal the synthesis of novel compounds which would be selective and potent inhibitors of the cPLA 2 enzymes.
  • selective inhibitors of the cPLA 2 enzymes means that the inhibitors inhibit the cPLA 2 enzymes with a potency 20-fold or greater than they inhibit the lower molecular weight synovial PLA 2 enzymes.
  • R is either H or OH.
  • JP09268153A discloses cPLA 2 inhibitors of the formula RCOCF 3 where RCO is an acyl residue of an n-3 series highly unsaturated fatty acid.
  • the compounds are said to be useful as antiinflammatory or antiallergic drugs.
  • B represents a non-aromatic C 3 -C 8 carbocycle, a C 3 -C 8 alkyl group, a heterocycle or an arylalkyl group, each of which is optionally substituted with one or more members independently selected from the group consisting of a halogen atom, a C ⁇ -C 4 alkyl group, a C j -C 4 alkoxy group, cyano, nitro, a heterocycle, an aryl group and an aryloxy group, and
  • X is a member selected from the group consisting of a halogen atom, — S— aryl,— S— heterocycle, and — P0 R 2 wherein each R is independently selected from the group consisting of a hydrogen atom and C j -C j alkyl;
  • R 1 and R 2 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: -(CH 2 ) q -A' wherein q is an integer of 2 to 4, and A' is a member selected from the group consisting of a hydroxyl group, a group represented by the formula:
  • R 5 and R 6 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: ⁇
  • R 7 represents a hydrogen atom, a lower alkyl group, or a group represented by the formula:
  • s is an integer of 2 to 5;
  • R 1 and R 2 each independently represent an unsubstituted cycloalkyl group, or a cycloalkyl substituted with a lower alkyl or halogen or condensed with an aromatic ring, a bicycloalkyl, or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an aliphatic saturated hydrocarbon group made of two or three rings, respectively, with at least two carbon atoms being common to each ring, or an azabicycloalkyl group which is a bicycloalkyl group as described above in which one carbon atom is replaced by a nitrogen atom or a group represented by the formula:
  • g and h are each an integer of 1 to 4, and B' stands for a lower alkyl group, an arylalkyl group, an arylalkyl group substituted by lower alkyl; halogen or a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkyl group substituted with a lower alkyl group, a halogen or a lower alkoxy group; or R 1 and R 2 may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which R 1 and R 2 are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group;
  • R 3 represents a hydrogen atom, a lower alkyl group, or a C 3 -C 8 cycloalkyl group
  • R 4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom
  • n is an integer of 1 to 4, provided that when n is 2, the two R 4 groups may form a cyclohexenyl or phenyl ring together with two adjacent carbon atoms constituting the benzene ring; and any pharmacologically acceptable salts thereof as inhibitors of phospholipase A 2 activity, particularly cPLA 2 .
  • U.S. Patent 5,453,443 discloses a series of biaryl ketones which are reported to inhibit PLA 2 enzymes, but it is not indicated whether these compounds are selective for the cytosolic enzymes or even whether they inhibit the cytosolic enzymes. These compounds have the generic formula
  • R 1 is selected from
  • R 1 and R 5 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
  • R 2 and R 3 are each independently selected from 2 (a) hydrogen,
  • R 5 is as defined above or is selected from
  • R 6 is selected from
  • R 8 , R 9 and R 14 are each independently selected from
  • R 10 , R 15 , R 16 and R 17 are each independently selected from
  • R 11 is selected from
  • R 13 is perfluoro ⁇ alkyl
  • a and B are each independently
  • X 1 is selected from
  • n 0, 1, 2, 3 or 4;
  • n 2, 3, 4, 5, 6 or 7;
  • r and s are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.
  • the present invention is directed to selective cytosolic PLA 2 inhibitor compounds of the formula
  • R 1 is (C ⁇ -C6)alkyl, (C2-C6)alkenyl, (C 2 -C 6 )alkynyl, (C ⁇ -C6)alkoxy,
  • R 2 preferably 1-3, of (C C 6 )alkyl, -COO-(C C 6 )alkyl, — c — - R 3 in which R 2 and R 3 are as defined above, halo, hydroxy, -0-(C 1 -C 6 )alkyl, -S-(C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl;
  • p 0, 1 or 2;
  • A is V-(R c ) n -;
  • R c is a straight or branched chain alkyl group
  • V is O, -S-, -SO-, -S0 2 , -CONH or NHCO when n is an integer of from 1 to 6 or V is (C 2 -C 6 ) alkenyl or a bond when n is 0 or an integer of from 1 to 6;
  • D is -(CH2)m or a bond linking the 1 ⁇ ring to Y;
  • n is an integer of from 1 to 6;
  • Y is -O-, -S-, -SO-, -S ⁇ 2; - — or a bond;
  • R 4 is as defined below for R 7 ;
  • X is S or O
  • q is an integer from 1 to 6;
  • R is hydrogen or ( -C ⁇ alkyl;
  • R is hydrogen, CN, NO2, OH, -0-(C ⁇ -C6)alkyl, (C1-C6) alkyl, phenyl or (Cl-C6)alkylphenyl;
  • R and R 6 are each independently hydrogen or ( - g) alkyl
  • R 7 and R 8 are each independently;
  • R 15 is hydrogen or (C r C 6 ) alkyl, or o R 2 - C- N-R 3 in which R 2 and R 3 are as defined above, ( -C alkyl or (C j -C 6 ) alkyl substituted by one or more, preferably
  • phenyl or heterocyclic groups said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 (for each of the following) halo, 1-3 (C,-C 6 ) alkoxy, 1-3 ( - ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( -C 6 ) alkylthio, amino, 1-3
  • R 16 and R 17 are each independently (C ⁇ -Ci ⁇ )alkyl or (C2-Ci8)alkenyl or (C ⁇ -Ci8)alkyl or (C2-Ci8)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (Ci-C6)alkoxy, l-3(C ⁇ -C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Ci-C6)alkylthio, amino, l-3(Ci-C6)alkylamino, o R 2 1-3 di(C ⁇ -C6)alkylamino, C0 2 H, 1-3 -COO(C ⁇ -C6)alkyl, -C-N- R 3
  • R and R are as defined above for R and R except that they may
  • R 18 19 not be hydrogen, or R and R taken together with the nitrogen to which they are attached represent a 4, 5- or 6-membered heterocyclic ring and Y, R 7 and R 11 are as defined above, or R 18 , R 19 and R 11 taken together with the nitrogen to which they are attached represent pyridinium, said pyridinium group being unsubstituted or substituted by
  • R 13 is (C ⁇ -C ⁇ s)alkyl or (C ⁇ -Cis)alkyl substituted by carboxy
  • R 2 and R 3 are as defined above, hydroxy, -0-(C C 6 ) alkyl, -0-(C C 6 ) alkyl or -S-(C C 6 ) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 (for each of the following phenyl substituents) halo (other than fluoro), (C C 6 ) alkoxy, (C x -C 6 ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( - ) alkylthio, amino, ( - ) alkylamino, di(C,-C 6 ) alkylamino, C0 2 H, COO-(C,-C 6 ) alkyl, S0 3 H, o R 2 S0 2
  • R 2 and R 3 are as defined above;
  • r is 0 or an integer of from 1 to 3;
  • R 7 is as defined above;
  • M is -(CH2-) m T where T is — C— , — C-O , -c-N— , i n which R 2 is as defined above, -S0 2 - or a bond when MR 7 is on nitrogen and providing
  • R 14 is hydrogen or (Cl-C ⁇ )alkyl
  • n 0 or an integer of 1-6;
  • R 7 cannot be hydrogen
  • R 18 and R 19 are phenyl or phenyl substituted by
  • Also provided by this invention are methods for inhibiting cytosolic PLA 2 in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound of formula I and methods for using the compounds of formula I to treat various diseases characterized by inappropriate activation of the cytosolic PLA 2 enzymes such as asthma, allergic rhinitis, cerebral ischemia, Alzheimer's Disease, rheumatoid arthritis, acute pancreatitis, inflammatory bowel disease, psoriasis, gout, neutrophil and platelet activation, chronic skin inflammation, shock, trauma-induced inflammation such as spinal cord injury, damage to the skin resulting from UV light or burns and macrophage activation.
  • the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier and processes for preparing the compounds of formula I.
  • the object of this invention was to discover a selective cPLA 2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA 2 enzymes.
  • a selective cPLA 2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA 2 enzymes.
  • a selective cPLA 2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA 2 enzymes.
  • such compound would also be devoid of undesirable lipid-perturbing activities associated with skin irritation.
  • C M8 alkyl refers to straight and branched chain alkyl groups with 1 to 18 carbon atoms.
  • C 2 -C 18 alkenyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon double bond.
  • C 2 -C 18 alkynyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon triple bond.
  • halogen or halo as used herein refers to fluorine, chlorine, bromine or iodine.
  • Aryl as used herein refers to a C 6 monocyclic aromatic ring system or a C 9 or C 10 bicyclic carbocyclic ring system having one or two aromatic rings such as phenyl or naphthyl.
  • substituted aryl refers to aryl groups substituted with one or more (preferably from 1 to 3) substituents independently selected from (C j -C 6 )alkyl, haloalkyl, ( -C alkoxy, (C j -C alkoxy-carbonyl, ( -C alkanoyl, hydroxy, halo, mercapto, nitro, amino, cyano, ( -C alkylamino, di(C C 6 )alkylamino, carboxy, aryl, aryl (C 1 -C 6 )alkyl, aryl (C 1 -C 6 )alkoxy, heterocyclic, heterocyclic ( -C alkyl and the like.
  • heterocyclic refers to a 4-, 5- or 6- membered ring containing one, two or three heteroatoms selected from N, O and S.
  • the 5-membered ring has 0-2 double bonds and the 6- membered ring has 0-3 double bonds.
  • the nitrogen heteroatoms can be optionally quaternized or N-oxidized.
  • the sulfur heteroatoms can be optionally S-oxidized.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring.
  • Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, pyridyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, furyl, dihydrofuranyl, tetrahydrofuranyl, pyr
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention is meant to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms, and pharmaceutically acceptable salts thereof.
  • the invention also includes pharmaceutically acceptable salts of the compounds of formula I.
  • a compound of the invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups. Accordingly, a compound may react with any of a number of inorganic bases, and organic and inorganic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of formula I which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene-sulfonate, phenylacetate, phenylpropionate,
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • Suitable organic bases include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1- ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N- ethylpiperidine, benzylamine, dicyclohexylamine, or the like pharmaceutically acceptable amines.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • the present invention also includes solvated forms of the compounds of formula I, particularly hydrates, in which the trifluoromethyl ketone group exists as a mixture of ketonic I and hydrated forms ⁇ and are each independently interconvertible and pharmacologically active.
  • the present invention also includes prodrug forms of the compounds of formula I or II above such as trifluoromethylketone enol ester derivatives, enol phosphate derivatives, cyclic or acylic unsubstituted or substituted 0,0-ketals, 0,S-ketals, 0,N-ketals or S,N- ketals such as cyclic cysteamyl derivatives, cyclic glycolates, thioglycolates, glyoxylates or oxalates, and the like. It also includes trifluoromethylalcohols obtained by chemical reduction of trifluoromethylketones. Such forms are physiologically hydrolyzable groups which are converted in vivo to a pharmacologically active compound of formula I or II, or a crystalline form of such compounds, see scheme below.
  • prodrug forms of the compounds of formula I or II above such as trifluoromethylketone enol ester derivatives, enol phosphate derivatives, cyclic or acylic
  • R alkyl or substituted alkyl
  • R ⁇ / R Preferred compounds of formula I are those where the -A-CCF 3 substituent is linked to the phenyl ring at the para or meta position, most preferably at the para position.
  • 11 Preferred embodiments of the compounds of general formula I include
  • R 1 is benzyl; p is 0, 1 or 2; A is V-(CH 2 ) n -; V is
  • X is S or O
  • q is an integer of from 1 to 6;
  • R 9 is hydrogen or ( -C alkyl
  • R 10 is hydrogen, CN, N0 2 , OH, -0-(C r C 6 ) alkyl, (C,-C 6 ) alkyl, phenyl or (C r C 6 ) alkylphenyl;
  • R 5 and R 6 are each independently hydrogen or ( - ) alkyl; and R 7 and R 8 are each independently a) hydrogen; b ) ( -C 18 ) alkyl; c) (C ⁇ -C 18 ) alkyl substituted by one or more of, preferably 1-3,
  • R 15 is hydrogen or (C r C 6 ) alkyl
  • heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
  • R 2 hydrogen or (C C 6 ) alkyl, or - c- N- R 3 in which R 2 and R 3 are each independently hydrogen or ( -C 6 ) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
  • R 16 and R 17 are each independently (C ⁇ -C ⁇ s)alkyl or (C2-Ci8)alkenyl or (C ⁇ -C ⁇ s)alkyl or (C2-C ⁇ )alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C ⁇ -C6)alkoxy, l-3(C ⁇ -C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C ⁇ -C6)alkylthio, amino, 1-3
  • R 2 alkyl or - c- N- R 3 in which R 2 and R 3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • R 7 cannot be hydrogen
  • R 13 is (C ⁇ -C ⁇ 8)alkyl or (C ⁇ -C ⁇ s)alkyl substituted by carboxy, o II O II R I 2 _ _ -c-o-(c r c 12 ) alkyl, - C- N-R 3 in which R and R are as defined above, hydroxy, -0-(C r C 6 ) alkyl, -0-(C C 6 ) alkyl or -S-(C C 6 ) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 halo (other than fluoro), (C ⁇ -C 6 ) alkoxy, ( - ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C j -C 6 ) alkylthio, amino, (C C 6 ) alkylamino, di(C ⁇ -C 6
  • R 2 - c- N- R 3 in which R 2 and R 3 are as defined above; r is 0 or an integer of from 1 to 3;
  • R 7 is as defined above;
  • M is -(CH2-)mT where T is — C— , - C- O , - c - N— , m which R 2 is as defined above, -S0 2 - or a bond when MR 7 is on nitrogen and providing O
  • O O R 14 is -C— , -C-O— , -O-, -S-, -SO-, -S ⁇ 2-, -N— or a bond when MR 7 is on a carbon atom of the heterocyclic ring;
  • R is hydrogen or (Cl-C6)alkyl
  • n 0 or an integer of 1-6;
  • R 7 where R 7 is as defined above, providing that when Y is -SO- or -S0 2 -, R 7 cannot be hydrogen; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • Another preferred embodiment comprises a compound of the formula
  • n is 0 or an integer of from 1 to 6, the substituent -(CH 2 ) n COCF 3 is in the meta or para position of the phenyl ring and Z is
  • R 1 is benzyl; p is 0, 1 or 2; n is 0 or an integer of from 1 to 6; the substituent -(CH 2 ) n COCF 3 is in the meta or para position of the phenyl ring; and Z is il
  • q is an integer of from 1 to 6;
  • X is S or O
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • substituent -(CH 2 ) n COCF 3 is in the para position of the phenyl ring, R 5 and R 6 are both hydrogen, q is 1, 2 or 3, n is 2 or 3, B 1 is
  • R 7 and R 8 are each
  • Another preferred embodiment comprises a compound of the formula 3i
  • n is 0 or an integer of from 1 to 6; the substituent -(CH 2 ) n COCF 3 is in the meta or para position of the phenyl ring; and Z is
  • R 13 , r, M and R 7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • n is 0 or an integer of from 1 to 6, the substituent -(CH 2 ) n COCF 3 is in the meta or para position of the phenyl ring; and Z is
  • R 5 and R 6 are each independently hydrogen or (C ⁇ -C ⁇ 8)alkyl; and Q and R 7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • n is 0 or an integer of from 1 to 6;
  • heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
  • R 15 is hydrogen or ( - ) alkyl, or - c- N- R 3 in which
  • R 2 and R 3 are as defined above, ( -C 6 ) alkyl or ( -C 6 ) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3
  • R 2 and R 3 are each independently hydrogen or ( -C 6 ) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
  • R 16 and R 17 are each independently (Ci-C ⁇ s)alkyl or (C2-C ⁇ s)alkenyl or (C ⁇ -Cis)alkyl or (C2-C ⁇ )alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3
  • R 9 is hydrogen or (C ⁇ -C6)alkyl and R 2 and R 3 are as defined above; and R 18 and R 19 are phenyl or phenyl substituted by
  • n 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.
  • R 25 is -(CH 2 ) 3 CH ' ⁇ v
  • R 25 is -(CH 2 ) 3 C0 2 C 2 H 5 ;
  • R ⁇ is -(CH 2 ) 3 CONHC 2 H 5 ;
  • R 25 is -COCF 3 ;
  • R 25 is -PO(OC 2 H 5 ) 2 ; or a pharmaceutically acceptable salt thereof.
  • R 20 is -CO(CH 2 ) 10 CH 3 ;
  • R 20 is -COCH(p-chlorophenyl) 2 ; and (c) R 20 is -S0 2 (CH 2 ) n CH 3 ; or a pharmaceutically acceptable salt thereof.
  • X" is CI and X 1 " is OCH 3 ; or a pharmaceutically acceptable salt thereof.
  • n 1 and R 21 is CI;
  • n 2 and R 21 is OCH 3 ;
  • n is 1-4 and R 21 is OCH 3 or CI; or a pharmaceutically acceptable salt thereof.
  • R 22 is hydrogen and R 23 is CI;
  • R 22 is -C0 2 CH 3 and R 23 is -OCH 3 ; or a pharmaceutically acceptable salt thereof.
  • R 24 is CI or -OCH 3 ; or a pharmaceutically acceptable salt thereof.
  • R 26 and R 27 are both CH 3 or (C C 6 )alkyl-CF 3 ;
  • R 26 and R 27 are both CI, F or Br;
  • R 26 and R 27 are both OCH 3 or SCH 3 ;
  • R 26 is CI and R 27 is OCH 3 ;
  • R 26 and R 2 are both -COO-(C r C 6 )alkyl; or a pharmaceutically acceptable salt thereof.
  • R 25 (CH 2 )3CH 3
  • R 20 CO(CH2) ⁇ oCH 3
  • R 25 (CH2) 3 C0 2 Et
  • R 25 (CH2) 3 CONHEt
  • R 25 COC 6 H 5
  • R 25 PO(OEt) 2
  • R 22 C0 CH 3
  • R 23 OMe
  • R 4 OCH 3 and Hi
  • R 26 and R 27 are both CH 3 or -(C r C 6 )alkyl-CF 3 ;
  • R 26 and R 27 are both CI, F or Br;
  • R 26 and R 27 are both OCH 3 or SCH
  • R 26 is CI and R 27 is OCH 3 ;
  • R 26 and R 27 are both -COO-(C r C 6 )alkyl.
  • the compounds of the present invention can be prepared by various methods which are known in the art. Illustrative methods of preparation are provided in the reaction schemes which follow and in the Examples.
  • R C C ⁇ 8 alkyl
  • Scheme I shows a method of preparing compounds of general structure 6. Reaction of a phenol 2 bearing a protected carboxylate group with an alcohol 3, triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate under Mitsunobu conditions (O. Mitsunobu, Synthesis, 1, 1981) in a solvent such as tetrahydrofuran or benzene gave the ether 4.
  • the phenol 2 can be alkylated with a substituted alkyl halide (RX) and a base such as potassium carbonate in a solvent such as acetonitrile or dimethylformamide to give the ether 4.
  • the ester group of 4 is then saponified to the acid 5 by treatment with a base such as sodium hydroxide or potassium hydroxide in a solvent such as aqueous ethanol followed by neutralization with a diluted acid.
  • a base such as sodium hydroxide or potassium hydroxide in a solvent such as aqueous ethanol followed by neutralization with a diluted acid.
  • the acid 5 is then treated with oxalyl chloride or thionyl chloride in a solvent such as dichloromethane to give an intermediate acid chloride.
  • the acid chloride is then treated with trifluoroacetic anhydride and a base such as pyridine following conditions similar to those used by S.Z. Zard (Tetrahedron 51, 2573-2584, 1995) to give the trifluoromethyl ketone 6.
  • Scheme 2 describes a method of preparing compounds of structure 12. Reaction of an iodo-substituted phenol 7 with a dibromo alkane of structure Br(CH2)nB r the presence of a base such as potassium carbonate gives 8. The bromide 8 is then displaced with a mono or disubstituted amine in the presence of sodium iodide in a solvent such as isopropanol to give 2 or 10.
  • compound 10 can also be obtained under Mitsunobu conditions as described in Scheme 1.
  • Tertiary amines 10 are also obtained by reaction of 9 with various aldehydes RCHO by reaction with a reducing agent such as sodium cyanoborohydride in a solvent such as methanol. Similar tertiary amines 10 are also prepared by reaction of 9 with an iodo compound R(CH2) n I the presence of a base such as potassium carbonate in a solvent such as isopropanol.
  • Scheme 3 describes a method of preparing quaternary structures of type 14 and 15.
  • the tertiary amine 13 is alkylated with an alkyl iodide such as methyl iodide or ethyl iodoacetate in a solvent such as isopropanol to give the quaternary amine 14.
  • an alkyl iodide such as methyl iodide or ethyl iodoacetate in a solvent such as isopropanol
  • saponification with a base such as potassium hydroxide in a solvent such as aqueous ethanol gives the zwitterionic species 15.
  • Scheme 4 shows a method of preparing various trifluoromethyl ketones 23 from intermediates in which the trifluoromethyl ketone is protected as a ketal group.
  • the trifluoromethyl ketone 17 is prepared using the method described in Scheme 1.
  • the methyl ether 17 is then cleaved with boron tribromide in a solvent such as dichloromethane to give the phenol IS.
  • the ketone group is then protected as a ketal 19 by reaction with an orthoester such as trimethyl orthoformate catalyzed by an acid such as trifluoromethanesulfonic acid and in solvents such as nitromethane and methanol.
  • the phenol 19 is then treated as described for Z in Scheme 2 to give 2Q, 21 and 22-
  • the protected trifluoromethyl ketone in 22 allows various modifications on R such as reduction of an ester group with lithium aluminum hydride or diisobutyl aluminum hydride.
  • the ketal group is then cleaved with an acid such as trifluoroacetic acid to give 23.
  • Scheme 5 describes preparation of tertiary amines by alkylation of intermediate 21 obtained in Scheme 4 by reaction with an alkyl iodide such as iodopropane in a solvent such as isopropanol and in the presence of a hindered base such as N,N-diisopropylethylamine.
  • the ketal 24 is then cleaved as described in Scheme 4 to give the trifluoromethyl ketone 25.
  • Scheme 6 describes preparation of a variety of trifluoromethyl ketones 27 starting from the phenol 19 obtained in Scheme 4. Reaction of 19 with various alcohols of structure ROH under the Mitsunobu conditions described in Scheme 1 gave 26. Deprotection of the ketal group as described in Scheme 4 gives 27 possessing a variety of ether substituents.
  • Scheme 7 shows a synthetic route to acylated or sulfonylated amines 33.
  • Reaction of 4-hydroxybenzaldehyde with a t-butoxycarbonyl- protected amino-alcohol such as 29 under Mitsunobu conditions similar to those described in Scheme 1 gives the aldehyde 3_Q.
  • amide 33 is then acylated with various acyl chlorides such as palmitoyl chloride under Schotten- Baumann conditions in a mixture of solvents such as tetrahydrofuran and saturated aqueous sodium acetate to give amide 33.
  • the amine trifluoroacetate salt can be treated with an alkylsulfonyl chloride such as 1-heptanesulfonyl chloride or an alkyl isothiocyanate such as N- decyl isothiocyanate in presence of a base such as triethylamine and in a solvent such as dichloromethane to give a sulfonamide or a thiourea respectively.
  • Scheme S describes a method of preparing amides of structure 39 which are regioisomers of structures described in Scheme 7.
  • 4- Hydroxybenzaldehyde was treated with 1,1,1-trifluoroacetone as described in Scheme 7 and alkylated with a bromoester such as t-butyl bromoacetate in the presence of a base such as potassium carbonate and in a solvent such as acetone to give 36.
  • a base such as potassium carbonate
  • a solvent such as acetone
  • 36 can be obtained via the same sequence of steps but in inverse order.
  • the phenol 34 can also be acylated with various acid chlorides such as a palmitoyl chloride to give ester derivatives such as 36b.
  • the t-butyl protecting group of 36 is then cleaved with an acid such as trifluoroacetic acid in dichloromethane to give the acid 3_Z.
  • This acid is then reacted with primary and secondary amines such as dodecylamine in the presence of a condensing agent such as N- ethoxycarbonyl-2-ethoxy-l,2-dihydroxyquinoline (EEDQ) to give the amide 3S.
  • EEDQ N- ethoxycarbonyl-2-ethoxy-l,2-dihydroxyquinoline
  • Reduction and oxidation of the enone as described in Scheme 7 gave the amide 39.
  • the enone 36 can be reduced first to 40 and then cleaved as above to the acid 41.
  • Scheme 9 describes a method for making compounds of structure 46. 47 and 48 which contain a sulfur atom.
  • Reaction of an alcohol 43. which contains a sulfur atom, usually obtained by reaction of a thiol with a halogen-substituted alcohol, with phenol 42 under Mitsunobu conditions as described in Scheme 1 gives the ether 44- Preparation of the trifluoromethylketone 46 is then achieved via the two-step sequence also described in Scheme L
  • Oxidation of 4j5 with a peracid such as m- chloroperbenzoic acid gives the sulfone 47.
  • Oxidation of 46 with sodium periodate in a mixture of methanol and water affords the sulfoxide 48.
  • 3 H-arachidonate-labeled U937 membranes were prepared from U937 cells grown in RPMI 1640 medium containing L-glutamine supplemented with 10% fetal calf serum and 50 ⁇ g/ml gentamycin in a 5% C0 2 incubator at 37°C. Sixteen hours prior to harvesting the cells, 3 H- arachidonate (100 Ci/mmol) was added to the cell culture (lxlO 6 cells/ml, 0.5 ⁇ Ci/ml).
  • HBSS Human Serum Albumin
  • HSA Human Serum Albumin
  • Assays of cPLA 2 activity using these 3 H-arachidonate-labeled U937 membranes as substrate typically employ human recombinant cPLA 2 (see Burke et al., Biochemistry 34: 15165-15174, 1995) and membrane substrate (22 ⁇ m phospholipid) in 20 mm HEPES [N-(2-hydroxyethyl) ⁇ iperazine-N 1 - (2-ethanesulfonic acid)] buffer, pH 8, containing 6 mm CaCl 2 , 0.9 mg/ml albumin and 4 m glycerol. Enzyme assays are allowed to proceed for 3 hours at 37°C before removing the non-hydrolyzed membranes. The hydrolyzed, radiolabeled fatty acid is then measured by liquid scintillation counting of the aqueous phase.
  • inhibitor is calculated as percent inhibition of 3 H- arachidonate formation, after correcting for nonenzymatic hydrolysis, as compared to a control lacking inhibitor according to the following formula:
  • the compounds of the present invention are selective inhibitors of cytosolic phospholipase A 2 , they are of value in the treatment of a wide variety of clinical conditions.
  • Inflammatory disorders which may be treated by inhibition of cytosolic cPLA 2 include such conditions as arthritis, psoriasis, asthma, inflammatory bowel disease, gout, trauma-induced inflammation such as spinal cord injury, Alzheimer's Disease, cerebral ischemia, chronic skin inflammation, shock, damage to skin resulting from exposure to ultraviolet light or burns, allergic rhinitis, acute pancreatitis, and the like.
  • the compounds of formula I are usually administered in the form of pharmaceutical compositions. They can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound defined by formula I and a pharmaceutically acceptable carrier.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound is effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • the hydrochloride salt was obtained by treating the amine with anhydrous hydrochloric acid (IM) in ether.
  • IM anhydrous hydrochloric acid
  • the hydrochloride salt was obtained by treating the amine with anhydrous hydrochloric acid (IM) in ether.
  • IM anhydrous hydrochloric acid
  • the hydrochloride was obtained as a syrup.
  • Ethyl bromoacetate (3.0 g, 18.0 mmol) was added dropwise to a boiling solution of zinc powder (1.7 g, 26.0 at g) and iodine (30.0 mg) in dichloromethane (5 ml) to form the Reformatsky reagent (K. Bott, Tetrahedron Lett., 1984, 35, 555-556).
  • the mixture was then cooled to 0°C and treated dropwise with a solution of 4,4'-dichlorobenzhydryl chloride (5.11 g, 15.8 mmol) in dichloromethane (10 ml) and the resulting mixture was stirred at 22°C for 3 h.
  • N-Hexyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy] ethyl] dodecylamine (353mg, 0.63mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trifluoro-3-oxobut-l-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester .
  • the residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 94 : 6) to afford the title compound (253mg, 78%) as a pale yellow oil.
  • N-Ethyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy]ethyl]dodecylamine (123mg, 0.244mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trifluoro-3-oxobut-l-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (60mg, 54%) as a pale yellow oil.

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Abstract

Selective inhibitors of the cPLA2 enzymes are provided which are of use in controlling a wide variety of inflammatory diseases. The inhibitors of the present invention have general formula (i), where (R1), p, D, Y, Z, Ra, Rb and A are as defined in the specification.

Description

SELECTIVE cPLAz INHIBITORS
BACKGROUND OF THE INVENTION
Inflammatory diseases of the skin, such as psoriasis and atopic dermatitis, afflict greater than 5% of the population. Currently, the treatment of these disorders typically involves the use of topical steroids. However, these agents also have undesirable side effects such as skin atrophy which limit the duration of therapy. In addition, topical application of a drug is difficult for many patients where the affected area may be very large.
Phospholipase A2 (PLA2) is the common name for phosphatide 2- acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides and results in production of lysophospholipids and free fatty acids. When the fatty acid is arachidonic acid, further action by cyclooxygenase and 5-lipoxygenase enzymes results in eicosanoid production, which is implicated in inflammation, and leukotrienes which are linked to asthma. Lysophophospholipid metabolism results in production of platelet activating factor and both lysophospholipids and platelet activating factor also play a role in inflammation.
PLA2 enzymes exist as secreted forms (MW ~ 12,000-15,000) and cytosolic forms (MW ~ 85,000). The cytosolic or cPLA2 enzymes appear to play a key role in the pathway leading to the formation of platelet activating factor and the eicosanoids. L
Inappropriate activation of the cytosolic PLA2 enzymes, therefore, can result in a variety of chronic and acute conditions including asthma, cerebral ischemia (Clemens et al, Stroke. 1996, 27, 527-535), Alzheimer's Disease (Stephenson et al, Neurobiology of Stroke. 1996, 3, 51-63 and see also U.S. Patent 5,478,857), rheumatoid arthritis, neutrophil and platelet activation (Huang et al, Mediators of Inflammation. 1994, 3, 307-308), chronic skin inflammation and damage to the skin resulting from exposure to ultraviolet light (Gresham et al, American Tournal of Physiology. 1996, 270; Cell Physiology 39:0037-0050) and macrophage activation (Balsinde et al, Tournal of Biological Chemistry. 1996, 271, 6758- 6765).
Selective inhibitors of the cPLA2 enzymes may, therefore, be of use in controlling a wide variety of inflammatory diseases. The literature describes a significant number of compounds said to be phospholipase A2 inhibitors, but few selective inhibitors for the cPLA2 enzymes are available. The present inventors had as their goal the synthesis of novel compounds which would be selective and potent inhibitors of the cPLA2 enzymes. As used herein, the term "selective inhibitors of the cPLA2 enzymes" means that the inhibitors inhibit the cPLA2 enzymes with a potency 20-fold or greater than they inhibit the lower molecular weight synovial PLA2 enzymes.
Biochemistry 32: 5935-5940, 1993, discloses a trifluoromethyl ketone analog of arachidonic acid having the formula
Figure imgf000005_0001
as a selective inhibitor of cPLA2-
Bioorganic Med. Chem. Lett. 5: 519-522, 1995, discloses selective
CPLA2 inhibitors of the formula
Figure imgf000005_0002
where R is either H or OH.
Japanese published patent application JP09268153A (Derwent No. 97-554679/51) discloses cPLA2 inhibitors of the formula RCOCF3 where RCO is an acyl residue of an n-3 series highly unsaturated fatty acid. The compounds are said to be useful as antiinflammatory or antiallergic drugs.
Published PCT Application WO 98/25893 discloses arylsulfonamide compounds of the general formula
Figure imgf000005_0003
wherein T
A represents a C4-C10 alkyl group, an aryl group, an arylalkyl group, radicals selected from the group consisting of — CH=CH— B, -O— B,— S-B, and — NH — B, or radicals of formula CH2 ~ X,
wherein
B represents a non-aromatic C3-C8 carbocycle, a C3-C8 alkyl group, a heterocycle or an arylalkyl group, each of which is optionally substituted with one or more members independently selected from the group consisting of a halogen atom, a Cα-C4 alkyl group, a Cj-C4 alkoxy group, cyano, nitro, a heterocycle, an aryl group and an aryloxy group, and
X is a member selected from the group consisting of a halogen atom, — S— aryl,— S— heterocycle, and — P0 R2 wherein each R is independently selected from the group consisting of a hydrogen atom and Cj-Cj alkyl;
R1 and R2 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: -(CH2)q-A' wherein q is an integer of 2 to 4, and A' is a member selected from the group consisting of a hydroxyl group, a group represented by the formula:
Figure imgf000006_0001
wherein R5 and R6 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: ≤
Figure imgf000007_0001
wherein R7 represents a hydrogen atom, a lower alkyl group, or a group represented by the formula:
Figure imgf000007_0002
wherein s is an integer of 2 to 5; or
R1 and R2 each independently represent an unsubstituted cycloalkyl group, or a cycloalkyl substituted with a lower alkyl or halogen or condensed with an aromatic ring, a bicycloalkyl, or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an aliphatic saturated hydrocarbon group made of two or three rings, respectively, with at least two carbon atoms being common to each ring, or an azabicycloalkyl group which is a bicycloalkyl group as described above in which one carbon atom is replaced by a nitrogen atom or a group represented by the formula:
_ /(CH2)gs (OW
wherein g and h are each an integer of 1 to 4, and B' stands for a lower alkyl group, an arylalkyl group, an arylalkyl group substituted by lower alkyl; halogen or a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkyl group substituted with a lower alkyl group, a halogen or a lower alkoxy group; or R1 and R2 may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which R1 and R2 are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group;
R3 represents a hydrogen atom, a lower alkyl group, or a C3-C8 cycloalkyl group;
R4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom;
n is an integer of 1 to 4, provided that when n is 2, the two R4 groups may form a cyclohexenyl or phenyl ring together with two adjacent carbon atoms constituting the benzene ring; and any pharmacologically acceptable salts thereof as inhibitors of phospholipase A2 activity, particularly cPLA2.
Drugs 1998, Vol. 1, No. 1, pp. 49-50 discloses cPLA2 inhibitors of the type
Figure imgf000008_0001
Figure imgf000009_0001
U.S. Patent 5,453,443 discloses a series of biaryl ketones which are reported to inhibit PLA2 enzymes, but it is not indicated whether these compounds are selective for the cytosolic enzymes or even whether they inhibit the cytosolic enzymes. These compounds have the generic formula
Figure imgf000009_0002
wherein:
R1 is selected from
(a) hydrogen,
(b) — Cι-6alkyl , and
(c) — C1-6alkyl-phenyl;
or wherein R1 and R5 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms; R2 and R3 are each independently selected from 2 (a) hydrogen,
(b) — Ci-βalkyl , and
(c) — C1-6alkyl-phenyl ,
or wherein two R2 or two R3 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
R5 is as defined above or is selected from
(a) hydrogen
(b) — Ci-βalkyl
(c) — C 1-6alkyl-phenyl C1-6alky 1 ,
(d) - OH ,
— O— C1-6alkyl< ©r
(e)
(f) — C 1-6alkyl-phenyl C1-6alkyl ;
R6 is selected from
(a) hydrogen (b) — Ci-βalkyl
(c) — C^galkyl-phenyl, wherein the phenyl is optionally substituted with Cx.2alkyl;
(d) - CH ,
Figure imgf000011_0001
(f) —o—
Figure imgf000011_0002
wherein the phenyl is optionally substituted with C^alkyl;
or wherein two R6 are joined to form o= or are joined together such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
R8, R9 and R14 are each independently selected from
(a) H,
(b) — Chalky!
(c) halo
(d) - CN
(e) - OH (O
( ) - OCi^alkyl,
— OCi^alkyl-phenyl
(g)
00 ■ SR u
S(0)R 11
(i) , or
-.n
(j) SW ;
R10, R15, R16 and R17 are each independently selected from
(a) hydrogen,
(b) -CM alkyl, and
(c) -C..6 alkyl-phenyl;
R11 is selected from
(a) -CM alkyl,
(b) -C2.6 alkenyl,
(c) -CF3 ,
(d) -phenyl(R12)2, or (e) -C2.6 alkenyl-phenyl(R12)2,
R^ is
(a) hydrogen,
(b) - .6 alkyl,
(c) CI, F, I or Br;
R13 is perfluoro ^alkyl;
A and B are each independently
(a) covalent bond,
(b) O,
(c) s,
( ) S(O), or
(e) S(0)2 ;
Q is selected from
(a) - CH(OH)R13, • 2-
(b) "COR13,
(c) -COR16, or
(d) ~ C1-4alkylCOCOOR17 ;
X1 is selected from
(a) -°— ,
( ) ~s — ,
(0 -S(°)-/
(d) -S(θ)2— .
Z is
(a) H, or
( ) —phenyl (R14)3/
m is 0, 1, 2, 3 or 4;
n is 2, 3, 4, 5, 6 or 7; and
r and s are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8. SUMMARY OF THE INVENTION
The present invention is directed to selective cytosolic PLA2 inhibitor compounds of the formula
Figure imgf000015_0001
wherein W is CH=CH, CH=N, O or S;
R1 is (Cι-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cι-C6)alkoxy,
O R2
II 1 -
(Ci-C6)alkylthio, halo, hydroxy, cyano, — c — N— R3 in which R and R are each independently hydrogen or (Ci-C6)alkyl, -COO-(C1-C6)alkyl, CF3,
(C1-C6)alkylphenyl, phenyl or phenyl substituted by one or more,
0 R2 preferably 1-3, of (C C6)alkyl, -COO-(C C6)alkyl, — c — - R3 in which R2 and R3 are as defined above, halo, hydroxy, -0-(C1-C6)alkyl, -S-(C1-C6)alkyl or (C2-C6)alkenyl;
p is 0, 1 or 2;
A is V-(Rc)n -;
Rc is a straight or branched chain alkyl group;
n is 0 or an integer of from 1 to 6; H Ra and Rb when taken together form an oxo (=0) group, or Ra and Rb are each independently hydrogen or OH;
V is O, -S-, -SO-, -S02, -CONH or NHCO when n is an integer of from 1 to 6 or V is (C2-C6) alkenyl or a bond when n is 0 or an integer of from 1 to 6;
D is -(CH2)m or a bond linking the 1 ^ ring to Y;
m is an integer of from 1 to 6;
R4
Y is -O-, -S-, -SO-, -Sθ2; - — or a bond;
R4 is as defined below for R7;
Z is:
Figure imgf000016_0001
in which B is:
NR 10
— c— o— c— — N-c— — N-c— — so2— or a bond;
R9 R9
X is S or O;
q is an integer from 1 to 6; R is hydrogen or ( -C^alkyl;
.10 .
R is hydrogen, CN, NO2, OH, -0-(Cι-C6)alkyl, (C1-C6) alkyl, phenyl or (Cl-C6)alkylphenyl;
R and R6 are each independently hydrogen or ( - g) alkyl;
R7 and R8 are each independently;
(a) hydrogen;
(b) (Ci-Ci8)alkyl;
(c) (Cl-Ciδ)alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 (for each of the following phenyl substituents) halo (other than fluoro), 1-3
(Ci-C6)alkoxy, l-3(Ci-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cι-C6)alkylthio, amino, 1-3
( -C6) alkylamino, di(Ci-C6)alkylamino, -CO2H, -COO-
(Cι-C6)alkyl, -SO3H, -S02NHR15 in which R15 is hydrogen
or (Ci-C6)alkyl, or — ° c— N R2— R3 in which R 2 and R 3 are as defined above; (3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more of, preferably 1-3, phenyl, phenyl substituted by 1-3 (for each of the following) halo, (Cι-C6)alkoxy, ( -C alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C,-C6) alkylthio, amino, (C C6) alkylamino, di(C C6) alkylamino, C02H, -COO-(C C6) alkyl, -S03H,
S02NHR15 in which R15 is hydrogen or (CrC6) alkyl, or o R2 - C- N-R3 in which R2 and R3 are as defined above, ( -C alkyl or (Cj-C6) alkyl substituted by one or more, preferably
1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 (for each of the following) halo, 1-3 (C,-C6) alkoxy, 1-3 ( - ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( -C6) alkylthio, amino, 1-3
(C C6) alkylamino, di(C C6) alkylamino, COOH, -COO-
(CrC6) alkyl, -S03H, -S02NHR15 in which R15 is hydrogen or o R2 (C C6) alkyl, or - c- N- R3 in which R2 and R3 are each independently hydrogen or (C,-C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or -COO-(CrC6) alkyl; n
(6) hydroxy, halo, -0-(CrC6) alkyl or -S-(CrC6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halo, trifluoromethyl or trifluoroacetyl;
(9) CH2 L-R16 in which L is
>17 R 17
I O II
— N- — O— — S- • so- . - so, — N — C- N— , ■ c-
I o17
— O- C— , — C- O— , — - C— — C- N— ,
R 7 R17
or -0-SiR16R18R19 or a bond in which R16 and R17 are each independently (Cι-Ciδ)alkyl or (C2-Ci8)alkenyl or (Cχ-Ci8)alkyl or (C2-Ci8)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (Ci-C6)alkoxy, l-3(Cι-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Ci-C6)alkylthio, amino, l-3(Ci-C6)alkylamino, o R2 1-3 di(Cι-C6)alkylamino, C02H, 1-3 -COO(Cι-C6)alkyl, -C-N- R3 Qr
-S02NHR9 in which R9 is hydrogen or (Cι-C6)alkyl and R2 and R3 are as defined above; »3
R5
(b) (CH2)q-C- R6
N— B*— R'
Rβ
in which B is
NR 10
— c- r — c— o— — c— N- R9 , — c- NR9 , — so2-, -PO(ORv)2 or a bond;
providing that when B1 is -PO(OR9)2, then R7 becomes R9, and when B1 X is — c-o— °r "S02-, then R7 cannot be hydrogen;
X, q, R5, R6, R7, R8, R9 and R10 are as defined in (a);
Figure imgf000020_0001
in which q, R5 and R6 are as defined above;
18 19 11 7 8 R , R and R are as defined above for R and R except that they may
18 19 not be hydrogen, or R and R taken together with the nitrogen to which they are attached represent a 4, 5- or 6-membered heterocyclic ring and Y, R7 and R11 are as defined above, or R18, R19 and R11 taken together with the nitrogen to which they are attached represent pyridinium, said pyridinium group being unsubstituted or substituted by
(Ci-Ci2)alkyl, (Ci-Ci2)alkoxy, amino, (Ci-Ci2)alkylamino, di fl
O
II O R2
(Cι-Ci2)alkylamino, — c— o — (CrC6)alkyl, -S-(Cι-C 12) alkyl, — C-N- R3 in
2 wwhhiicchh RR aanndd R are as defined above, phenyl or phenyl
(Cl-Cιo)alkyl;
d)
Figure imgf000021_0001
in which R 13 is (Cι-Cιs)alkyl or (Cι-Cis)alkyl substituted by carboxy,
0 O R2
-c-o-(c c12) alkyl, - C- N- R3 in which R2 and R3 are as defined above, hydroxy, -0-(C C6) alkyl, -0-(C C6) alkyl or -S-(C C6) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 (for each of the following phenyl substituents) halo (other than fluoro), (C C6) alkoxy, (Cx-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( - ) alkylthio, amino, ( - ) alkylamino, di(C,-C6) alkylamino, C02H, COO-(C,-C6) alkyl, S03H, o R2 S02NHR15 in which R15 is hydrogen or (CrC6) alkyl or - c- N- R3 in which
R2 and R3 are as defined above;
r is 0 or an integer of from 1 to 3;
R7 is as defined above;
O I I o M 0 | R I 2
M is -(CH2-)mT where T is — C— , — C-O , -c-N— , in which R2 is as defined above, -S02- or a bond when MR7 is on nitrogen and providing
O that when T is — G— or -SO- or -S02-, then R7 cannot be hydrogen, and T 26
O O ,14
II is — C— , — C-O— , -O-, -S-, -SO-, -Sθ2-, -N— or a bond when MR7 is on a carbon atom of the heterocyclic ring;
R14 is hydrogen or (Cl-Cβ)alkyl;
m is 0 or an integer of 1-6;
Rb e) -(CH2^ -R6 Q R7
wherein Q is -O-, -S-, -SO- or -SO-.-, and q, R5, R6 and R7 are as defined above, providing that when Q is -SO- or -S02-, R7 cannot be hydrogen;
f) R7 wherein R7 is defined above, providing that when Y is -SO- or
-S02-, R7 cannot be hydrogen; and
R18 and R19 are phenyl or phenyl substituted by
1-3 halo, (C,-C6) alkoxy, (Cx-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( -C6) alkylthio, amino, (C C6) alkylamino, di(Cj-C6) alkylamino, C02H, -COO-(C C6) alkyl, -S03H, S02NHR15 in which R15 is o R2 hydrogen or ( -C alkyl, or - c- N- R3 in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.
Also provided by this invention are methods for inhibiting cytosolic PLA2 in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound of formula I and methods for using the compounds of formula I to treat various diseases characterized by inappropriate activation of the cytosolic PLA2 enzymes such as asthma, allergic rhinitis, cerebral ischemia, Alzheimer's Disease, rheumatoid arthritis, acute pancreatitis, inflammatory bowel disease, psoriasis, gout, neutrophil and platelet activation, chronic skin inflammation, shock, trauma-induced inflammation such as spinal cord injury, damage to the skin resulting from UV light or burns and macrophage activation. In further aspects, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier and processes for preparing the compounds of formula I.
DETAILED DESCRIPTION
The object of this invention was to discover a selective cPLA2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA2 enzymes. Preferably such compound would also be devoid of undesirable lipid-perturbing activities associated with skin irritation.
The above-mentioned objectives have been met by the compounds of formula I described above.
In the present application the numbers in the subscript after the symbol "C" define the number of carbon atoms a particular group can contain. For example, CM8alkyl refers to straight and branched chain alkyl groups with 1 to 18 carbon atoms. Similarly, C2-C18 alkenyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon double bond. Likewise, C2-C18 alkynyl refers to a straight or branched unsaturated hydrocarbon group containing from 2 to 18 carbon atoms and at least one carbon-carbon triple bond.
The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine or iodine.
Aryl as used herein refers to a C6 monocyclic aromatic ring system or a C9 or C10 bicyclic carbocyclic ring system having one or two aromatic rings such as phenyl or naphthyl. Unless otherwise indicated, "substituted aryl" refers to aryl groups substituted with one or more (preferably from 1 to 3) substituents independently selected from (Cj-C6)alkyl, haloalkyl, ( -C alkoxy, (Cj-C alkoxy-carbonyl, ( -C alkanoyl, hydroxy, halo, mercapto, nitro, amino, cyano, ( -C alkylamino, di(C C6)alkylamino, carboxy, aryl, aryl (C1-C6)alkyl, aryl (C1-C6)alkoxy, heterocyclic, heterocyclic ( -C alkyl and the like.
The term "heterocyclic" as used herein refers to a 4-, 5- or 6- membered ring containing one, two or three heteroatoms selected from N, O and S. The 5-membered ring has 0-2 double bonds and the 6- membered ring has 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized or N-oxidized. The sulfur heteroatoms can be optionally S-oxidized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring. Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, pyridyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, furyl, dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, dioxolanyl, thienyl, benzothienyl and diaxanyl.
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms, and pharmaceutically acceptable salts thereof.
As mentioned above the invention also includes pharmaceutically acceptable salts of the compounds of formula I. A compound of the invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups. Accordingly, a compound may react with any of a number of inorganic bases, and organic and inorganic acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- sulfonate, napthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. Suitable organic bases include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1- ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N- ethylpiperidine, benzylamine, dicyclohexylamine, or the like pharmaceutically acceptable amines. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
The present invention also includes solvated forms of the compounds of formula I, particularly hydrates, in which the trifluoromethyl ketone group exists as a mixture of ketonic I and hydrated forms π and are each independently interconvertible and pharmacologically active.
Figure imgf000027_0001
I π
The present invention also includes prodrug forms of the compounds of formula I or II above such as trifluoromethylketone enol ester derivatives, enol phosphate derivatives, cyclic or acylic unsubstituted or substituted 0,0-ketals, 0,S-ketals, 0,N-ketals or S,N- ketals such as cyclic cysteamyl derivatives, cyclic glycolates, thioglycolates, glyoxylates or oxalates, and the like. It also includes trifluoromethylalcohols obtained by chemical reduction of trifluoromethylketones. Such forms are physiologically hydrolyzable groups which are converted in vivo to a pharmacologically active compound of formula I or II, or a crystalline form of such compounds, see scheme below.
Figure imgf000028_0001
R = alkyl or x = o,s substituted alkyl NH, O, S
Figure imgf000028_0002
Ior fl
Figure imgf000028_0003
R = alkyl or substituted alkyl
R\ /R Preferred compounds of formula I are those where the -A-CCF3 substituent is linked to the phenyl ring at the para or meta position, most preferably at the para position. 11 Preferred embodiments of the compounds of general formula I include
(a) compounds of formula I wherein W is CH=CH, D is a bond linking Y to the ring and Y is -O-;
(b) compounds of (a) immediately above wherein R1 is benzyl, A is V-(CH2)n-, V is (C2-C6) alkenyl or a bond, p is 0, 1 or 2, and n is 0 or an integer of from 1 to 6; and
(c) compounds of (b) immediately above wherein A is -(CH2)n, n is 0 or an integer of from 1 to 6, and the group -(CH2)nCOCF3 is in the meta or para position of the phenyl ring.
Another preferred embodiment comprises a compound of the formula
Figure imgf000029_0001
wherein R1 is benzyl; p is 0, 1 or 2; A is V-(CH2)n-; V is
(C2-C6) alkenyl or a bond; n is 0 or an integer of from 1 to 6; Ra and Rb are as defined above and Z is 2?
Figure imgf000030_0001
in which B is
X X
II II NR 10
-c— ,o- c— , -N-C— , - N- c so2 — or a bond; h«
X is S or O;
q is an integer of from 1 to 6;
R9 is hydrogen or ( -C alkyl;
R10 is hydrogen, CN, N02, OH, -0-(CrC6) alkyl, (C,-C6) alkyl, phenyl or (CrC6) alkylphenyl;
R5 and R6 are each independently hydrogen or ( - ) alkyl; and R7 and R8 are each independently a) hydrogen; b) ( -C18) alkyl; c) (Cα-C18) alkyl substituted by one or more of, preferably 1-3,
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (Cj- ) alkoxy, 1-3 ( - ) alkyl, nitro, cyano, hydroxy, 2°! trifluoromethyl, (C C6) alkylthio, amino, 1-3 (C C6) alkylamino, di(C,-C6) alkylamino, -C02H, -COO-(C C6) alkyl;
-S03H, - S02NHR15 in which R15 is hydrogen or (CrC6) alkyl, or
O R2 - C- N-R3 in which R2 and R3 are each independently hydrogen or
( -C6) alkyl;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more of, preferably 1-3, phenyl, phenyl substituted by 1-3 halo, (Ci-C6)alkoxy,
(Cl-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C C6) alkylthio, amino, ( - ) alkylamino, d^ - ) alkylamino, C02H,
-COO-(CrC6) alkyl, -S03H, S02NHR15 in which R15 is hydrogen or o R2 (C C6) alkyl, or - c- N- R3 in which R2 and R3 are as defined above,
( - ) alkyl or ( - ) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3 ( - ) alkoxy, 1-3
(C C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, 1-3 ( - ) alkylamino, di(Cj-C6) alkylamino,
COOH, -COO-(CrC6) alkyl, -S03H, -S02NHR15 in which R15 is
O R2 hydrogen or (C C6) alkyl, or - c- N- R3 in which R2 and R3 are each independently hydrogen or ( -C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or -COO-(Cj.-C6) alkyl; (6) hydroxy, halo, -0-(C--C6) alkyl or -S(C C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms; So
(7) cyano;
(8) halogen, trifluoromethyl or trifluoroacetyl; or
(9) CH2 L-R16 in which L is
R 17
R17C O
II
— N — O— — S— -SO- , -S02- , —N-C—, —C-N—, ■c— .
317
0 II 0 II s II s II
— 0-C— , > — C-0— ,' — N|-C— I —C-N ,—,
R17 R17
or -0-SiR16R18R19 or a bond in which R16 and R17 are each independently (Cχ-Cχs)alkyl or (C2-Ci8)alkenyl or (Cχ-Cιs)alkyl or (C2-Cχδ)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (Cχ-C6)alkoxy, l-3(Cχ-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Cι-C6)alkylthio, amino, 1-3
(Cχ-C6)alkylamino,l-3 di(Cχ-C6)alkylamino, C02H, 1-3 o R2 -COO(Ci-C6)alkyl, -c-N- R3 or -S02NHR9 in which R9 is hydrogen or (Ci-C6)alkyl and R2 and R3 are as defined above; and R18 and R19 are phenyl or phenyl substituted by 1-3 halo, ( -C6) alkoxy, ( - ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cj-C6) alkylthio, amino, ( - ) alkylamino, di( -C6) alkylamino, C02H, -COO- ( - ) alkyl, -S03H, S02NHR15 in which R15 is hydrogen or (C C6)
0 R2 alkyl, or - c- N- R3 in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.
Figure imgf000033_0001
in which B1 is
X NR 10
II
— c- r — c— o— — c— N- R9 , — c- NR9 , — so2-, -PO(OR 2 or a bond;
providing that when B1 is -PO(OR9)2, then R7 becomes R9, and when B1 is X
— c-o— or -S02-, then R7 cannot be hydrogen; and
X, q, R5, R6, R7, R8, R9 and R10 are as defined above in (a);
Figure imgf000033_0002
in which R 13 is (Cχ-Cχ8)alkyl or (Cχ-Cιs)alkyl substituted by carboxy, o II O II R I 2 _ _ -c-o-(crc12) alkyl, - C- N-R3 in which R and R are as defined above, hydroxy, -0-(CrC6) alkyl, -0-(C C6) alkyl or -S-(C C6) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 halo (other than fluoro), (Cα-C6) alkoxy, ( - ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cj-C6) alkylthio, amino, (C C6) alkylamino, di(Cα-C6) alkylamino, C02H, COO-
(C C6) alkyl, S03H, S02NHR15 in which R15 is hydrogen or (C C6) alkyl or
O R2 - c- N- R3 in which R2 and R3 are as defined above; r is 0 or an integer of from 1 to 3;
R7 is as defined above;
O o o R2
M is -(CH2-)mT where T is — C— , - C- O , - c- N— , m which R2 is as defined above, -S02- or a bond when MR7 is on nitrogen and providing O
II that when T is — e— or -SO- or -S02-, then R cannot be hydrogen, and T
O O R14 is -C— , -C-O— , -O-, -S-, -SO-, -Sθ2-, -N— or a bond when MR7 is on a carbon atom of the heterocyclic ring;
R is hydrogen or (Cl-C6)alkyl;
m is 0 or an integer of 1-6;
(d)
Figure imgf000034_0001
wherein Q is -O-, -S-, -SO-, or -S02- and q, R5, R6 and R7 are as defined above, providing that when Q is -SO- or -S02-, R7 cannot be hydrogen; or
(e) R7 where R7is as defined above, providing that when Y is -SO- or -S02-, R7 cannot be hydrogen; or a pharmaceutically acceptable salt, solvate or prodrug thereof. Another preferred embodiment comprises a compound of the formula
Figure imgf000035_0001
(CH2)nCOCF3
wherein n is 0 or an integer of from 1 to 6, the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring and Z is
R5 (CH2^C-R6
B-N-R7
R8
X in which B is — Q — or a bond; X is S or O; q is an integer of from 1 to 6; and R5, R6, R7 and R8 are as defined above; or a pharmaceutically acceptable salt, hydrate or prodrug thereof.
Another preferred embodiment comprises a compound of the formula
o-z
(CH2)nC0CF3
in which R1 is benzyl; p is 0, 1 or 2; n is 0 or an integer of from 1 to 6; the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is il
Figure imgf000036_0001
in which B1 is
10
X X X NR
— c- -C-0-, -c- N- R9, - c - NR9, — so2— or a bond;
q is an integer of from 1 to 6;
X is S or O;
and R5, R6, R7, R8, R9 and R10 are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof. Within this embodiment, it is preferred that the substituent -(CH2)nCOCF3 is in the para position of the phenyl ring, R5 and R6 are both hydrogen, q is 1, 2 or 3, n is 2 or 3, B1 is
X X X NR1° -c— , -C-0-, -C-N-R9, -C-NR9, or — S02-, and R7 and R8 are each
independently hydrogen or ( - g) alkyl. Especially preferred are compounds where q is 1, n is 2 and B1 is X II X x 'I Q
— C — , -C-0-, -C-N-R9 or — S02— .
Another preferred embodiment comprises a compound of the formula 3i
Figure imgf000037_0001
wherein n is 0 or an integer of from 1 to 6; the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is
Figure imgf000037_0002
in which R13, r, M and R7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Another preferred embodiment comprises a compound of the formula
Figure imgf000037_0003
in which n is 0 or an integer of from 1 to 6, the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is
Figure imgf000037_0004
wherein q is an integer of from 1 to 6; R5 and R6 are each independently hydrogen or (Cχ-Cχ8)alkyl; and Q and R7 are as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Another preferred embodiment comprises a compound of the formula
Figure imgf000038_0001
in which n is 0 or an integer of from 1 to 6; the substituent
-(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is
(a) hydrogen;
(b) (Ci-C18)alkyl;
(c) (Cχ-Cχ8)alkyl substituted by one or more, preferably 1-3, of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), l-3(Cχ-C6)alkoxy, l-3(Cι-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Ci-C6)alkylthio, amino, 1-3
( - ) alkylamino, di(Ci-C6)alkylamino, -CO2H, -COO- 3?
(Cι-C6)alkyl, -SO3H, -S02NHR15 in which R15 is hydrogen
O R2 2 3 or (Ci-C6)alkyl, or — c— N— R3 in which R and R are each independently hydrogen or ( - ) alkyl;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more, preferably 1-3, of phenyl, phenyl substituted by 1-3 halo, (Cχ-C6)alkoxy, (Cj-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl,
(C1-C6) alkylthio, amino, (C C6) alkylamino, di(C1-C6) alkylamino, C02H, -COO-(C,-C6) alkyl, -S03H, S02NHR15 in
O R2 which R15 is hydrogen or ( - ) alkyl, or - c- N- R3 in which
R2 and R3 are as defined above, ( -C6) alkyl or ( -C6) alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3
(C C6) alkoxy, 1-3 ( - ) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C,-C6) alkylthio, amino, 1-3 (C1-C6) alkylamino, di( -C6) alkylamino, COOH, -COO-(C C6) alkyl,
-S03H, -S02NHR15 in which R15 is hydrogen or (CrC6) alkyl,
0 R2 or -c- N- R3 in which R2 and R3 are each independently hydrogen or ( -C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or -COO-(C C6) alkyl; (6) hydroxy, halo, -O^ - ) alkyl or -S-(C1-C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halogen, trifluoromethyl or trifluoroacetyl;
(9) CH2 L-R16 in which L is
>17
R170 O
— N- -O — — s— - so- S02- , — N- C- - C- N- , - C- ,
I
R17
0- C— I — C- O— ,> — i - C— > — C- N I — ,
R17 R17
or -0-SiR16R18R19 or a bond in which R16 and R17 are each independently (Ci-Cχs)alkyl or (C2-Cχs)alkenyl or (Cχ-Cis)alkyl or (C2-Cχδ)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3
(Cχ-C6)alkoxy, l-3(Cχ-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl,
1-3 (Cχ-C6)alkylthio, amino, l-3(Cι-C6)alkylamino, o R2 1-3 di(Cι-C6)alkylamino, C02H, 1-3 -COO(Cι-C6)alkyl, —c-N- R3 or
-S02NHR9 in which R9 is hydrogen or (Cχ-C6)alkyl and R2 and R3 are as defined above; and R18 and R19 are phenyl or phenyl substituted by
1-3 halo, (Cα-C6) alkoxy, ( -C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C C6) alkylthio, amino, (C C6) alkylamino, di(C1-C6) alkylamino, C02H, -COO-(CrC6) alkyl, -S03H, S02NHR15 in which R15 is o R2 hydrogen or (C C6) alkyl, or - c- N- R3 in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.
Another preferred embodiment comprises a compound of the formula
Figure imgf000041_0001
in which n is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.
Preferred embodiments comprise a compound selected from those of the following
Figure imgf000041_0002
wherein
(a) R25 is -(CH2)3CH '■v
(b) R25 is -(CH2)3C02C2H5;
(c) R^ is -(CH2)3CONHC2H5;
(d) R25 is -COCF3;
(e) R >2255 i •s -COC6H5; and
(f) R25 is -PO(OC2H5)2; or a pharmaceutically acceptable salt thereof.
Still other preferred embodiments comprise a compound of the formula
Figure imgf000042_0001
wherein
(a) R20 is -CO(CH2)10CH3;
(b) R20 is -COCH(p-chlorophenyl)2; and (c) R20 is -S02(CH2)nCH3; or a pharmaceutically acceptable salt thereof.
Still other preferred embodiments comprise a compound selected from those of the following
Figure imgf000043_0001
wherein
(a) X" and X1" are CI;
(b) X" and X"1 are F;
(c) X" and X1" are OCH3; and
(c) X" is CI and X1" is OCH3; or a pharmaceutically acceptable salt thereof.
Another preferred embodiment comprises a compound of the formula
Figure imgf000044_0001
wherein
(a) n is 1 and R21 is OCH 3'
(b) n is 1 and R21 is CI;
(c) n is 2 and R21 is OCH3; and
(d) n is 1-4 and R21 is OCH3 or CI; or a pharmaceutically acceptable salt thereof.
Another preferred embodiment comprises a compound of the formula
Figure imgf000044_0002
wherein M
(a) R22 is hydrogen and R23 is CI; or
(b) R22 is -C02CH3 and R23 is -OCH3; or a pharmaceutically acceptable salt thereof.
Another preferred embodiment comprises a compound of the formula
Figure imgf000045_0001
wherein R24 is CI or -OCH3; or a pharmaceutically acceptable salt thereof.
Another preferred embodiment comprises a compound of the formula
Figure imgf000045_0002
MM wherein
(a) R26 and R27are both CH3 or (C C6)alkyl-CF3;
(b) R26 and R27are both CI, F or Br;
(c) R26 and R27are both OCH3 or SCH3;
(d) R26 is CI and R27 is OCH3; or
(e) R26 and R2 are both -COO-(CrC6)alkyl; or a pharmaceutically acceptable salt thereof.
Still other preferred embodiments comprise a compound selected from those of the following
Figure imgf000046_0001
wherein
(a) n is 0; M
(b) n = 1; and
(c) n = 2; or a pharmaceutically acceptable salt thereof.
Still other preferred embodiments comprise a compound selected from those of the formula
Figure imgf000047_0001
wherein
(a) n = 0;
(b) n = 1; and
(c) n = 2; or a pharmaceutically acceptable salt thereof.
Some specific preferred embodiments of the present invention are:
Figure imgf000048_0001
R25 = (CH2)3CH3 R20 = CO(CH2)ιoCH3 R25 = (CH2)3C02Et R20 _ C0CH(PhpCI)2 R25 = (CH2)3CONHEt R20 = S02(CH2)nCH3 R25 - COCF3 R25 = COC6H5 R25 = PO(OEt)2
Figure imgf000048_0002
X" and X"' are CI n = 1, R 211 = 0CH3 X" and X"' are F n = 1 R2 =CI X" and X'" are OCH3 n - 2 , R21 = OCH3
32 X"isClandXm is OCH 3 n = 1-4, R^1 = OCH3, CI
Figure imgf000048_0003
R22=H, R23 = CI R24=CI
R22 = C0 CH3, R23 = OMe R 4=OCH3 and Hi
Figure imgf000049_0001
wherein
(a) R26 and R27 are both CH3 or -(CrC6)alkyl-CF3;
(b) R26 and R27 are both CI, F or Br;
(c) R26 and R27 are both OCH3 or SCH
(d) R26 is CI and R 27 is OCH3; or
(e) R26 and R27 are both -COO-(CrC6)alkyl.
Especially preferred embodiments of the present invention include:
^
Figure imgf000050_0001
Figure imgf000050_0002
X = 0 X = C
Figure imgf000051_0001
The compounds of the present invention can be prepared by various methods which are known in the art. Illustrative methods of preparation are provided in the reaction schemes which follow and in the Examples.
S
Scheme 1
Figure imgf000052_0001
Figure imgf000052_0002
2) TFAA-Pyridine 5 S
J»ι
Scheme 2
Figure imgf000053_0001
(CH2)nR2 (CH2)nR2
Figure imgf000053_0002
τ~
Scheme 3
11 D2 / R
Figure imgf000054_0001
(CH2)mCOCF3 (CH2)mCOCF3
13 14
Figure imgf000054_0002
(CH2)mCOCF3
15
S>
Scheme 4
dichlo
Figure imgf000055_0001
Figure imgf000055_0002
20 21
nRz
Figure imgf000055_0003
22 22 SH
Scheme 5
Figure imgf000056_0001
25
Scheme 6
Figure imgf000057_0001
Figure imgf000057_0002
s'
Scheme 7
Figure imgf000058_0001
28 29 30
Figure imgf000058_0002
31 32
TFA
Figure imgf000058_0003
33a 33b
SI
Scheme 8
Figure imgf000059_0001
BrCH2C02tBu
BrCH2Cθ2tBu acetone acetone potassium carbonate potassium carbonate (or R2COCI)
Figure imgf000059_0002
3Z 38
Figure imgf000059_0003
39 tt
Scheme 8 (cont.)
Figure imgf000060_0001
36 40
TFA dichloromethane
Figure imgf000060_0002
41 39
<
Scheme 9
RSH BrCH2CH2OH ► RSCH2CH2OH
DMF 4, potassium carbonate —
Figure imgf000061_0001
42 44
Figure imgf000061_0002
mCPBA . Nal04 dichloromethane , methanol
Figure imgf000061_0003
47 48
R = C Cι8 alkyl
= (C Cβ) alkyl X(C β) mono or bis aryl or mono or bis heterocycles
X = N-R10, S, SO, S02 Method of Preparation
Preparation of compounds of formula I may be accomplished via one or more of the synthetic schemes which are described below.
Scheme 1
Scheme I shows a method of preparing compounds of general structure 6. Reaction of a phenol 2 bearing a protected carboxylate group with an alcohol 3, triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate under Mitsunobu conditions (O. Mitsunobu, Synthesis, 1, 1981) in a solvent such as tetrahydrofuran or benzene gave the ether 4. Alternatively, the phenol 2 can be alkylated with a substituted alkyl halide (RX) and a base such as potassium carbonate in a solvent such as acetonitrile or dimethylformamide to give the ether 4. The ester group of 4 is then saponified to the acid 5 by treatment with a base such as sodium hydroxide or potassium hydroxide in a solvent such as aqueous ethanol followed by neutralization with a diluted acid. The acid 5 is then treated with oxalyl chloride or thionyl chloride in a solvent such as dichloromethane to give an intermediate acid chloride. The acid chloride is then treated with trifluoroacetic anhydride and a base such as pyridine following conditions similar to those used by S.Z. Zard (Tetrahedron 51, 2573-2584, 1995) to give the trifluoromethyl ketone 6.
Scheme 2
Scheme 2 describes a method of preparing compounds of structure 12. Reaction of an iodo-substituted phenol 7 with a dibromo alkane of structure Br(CH2)nBr the presence of a base such as potassium carbonate gives 8. The bromide 8 is then displaced with a mono or disubstituted amine in the presence of sodium iodide in a solvent such as isopropanol to give 2 or 10. Alternatively, compound 10 can also be obtained under Mitsunobu conditions as described in Scheme 1. Tertiary amines 10 are also obtained by reaction of 9 with various aldehydes RCHO by reaction with a reducing agent such as sodium cyanoborohydride in a solvent such as methanol. Similar tertiary amines 10 are also prepared by reaction of 9 with an iodo compound R(CH2)nI the presence of a base such as potassium carbonate in a solvent such as isopropanol.
Reaction of secondary amine 9 with a Michael-type acceptor CH2=CH2-EWG such as ethyl acrylate or acrylonitrile in a solvent such as ethanol also yields substituted amines IQ. Reaction of iodophenol 10 with 4,4,4-trifluorobut-l-en-3-ol (J.A. Pegolotti and W.G. Young, J. Am. Chem. Soc, 1961, S3, 3251), under Heck-type conditions (T. Jeffery, J. Chem. Soc. Chem. Commun., 1287, 1984) in the presence of a palladium catalyst such as palladium (II) acetate in a solvent such as N,N-dimethylformamide gives the allylic alcohol 11. Hydrogenation of this allylic alcohol in the presence of a catalyst such as palladium on activated carbon in a solvent such as ethyl acetate gave an intermediate alcohol which was oxidized to the ketone 12 with the Dess-Martin periodinane (D.B. Dess and J.C. Martin, J. Org. Chem., 1983, 48, 4155) in a solvent such as dichloromethane.
Scheme 3
Scheme 3 describes a method of preparing quaternary structures of type 14 and 15. The tertiary amine 13 is alkylated with an alkyl iodide such as methyl iodide or ethyl iodoacetate in a solvent such as isopropanol to give the quaternary amine 14. In the case where one of the R groups contains an ester group, saponification with a base such as potassium hydroxide in a solvent such as aqueous ethanol gives the zwitterionic species 15.
Scheme 4
Scheme 4 shows a method of preparing various trifluoromethyl ketones 23 from intermediates in which the trifluoromethyl ketone is protected as a ketal group. Starting from the acid 16 which is commercially available, the trifluoromethyl ketone 17 is prepared using the method described in Scheme 1. The methyl ether 17 is then cleaved with boron tribromide in a solvent such as dichloromethane to give the phenol IS. The ketone group is then protected as a ketal 19 by reaction with an orthoester such as trimethyl orthoformate catalyzed by an acid such as trifluoromethanesulfonic acid and in solvents such as nitromethane and methanol. The phenol 19 is then treated as described for Z in Scheme 2 to give 2Q, 21 and 22- The protected trifluoromethyl ketone in 22 allows various modifications on R such as reduction of an ester group with lithium aluminum hydride or diisobutyl aluminum hydride. The ketal group is then cleaved with an acid such as trifluoroacetic acid to give 23.
Scheme 5
Scheme 5 describes preparation of tertiary amines by alkylation of intermediate 21 obtained in Scheme 4 by reaction with an alkyl iodide such as iodopropane in a solvent such as isopropanol and in the presence of a hindered base such as N,N-diisopropylethylamine. The ketal 24 is then cleaved as described in Scheme 4 to give the trifluoromethyl ketone 25.
Scheme 6
Scheme 6 describes preparation of a variety of trifluoromethyl ketones 27 starting from the phenol 19 obtained in Scheme 4. Reaction of 19 with various alcohols of structure ROH under the Mitsunobu conditions described in Scheme 1 gave 26. Deprotection of the ketal group as described in Scheme 4 gives 27 possessing a variety of ether substituents.
Scheme 7
Scheme 7 shows a synthetic route to acylated or sulfonylated amines 33. Reaction of 4-hydroxybenzaldehyde with a t-butoxycarbonyl- protected amino-alcohol such as 29 under Mitsunobu conditions similar to those described in Scheme 1 gives the aldehyde 3_Q. Aldol condensation of 30 with 1,1,1-trifluoroacetone catalyzed by piperidine and acetic acid using conditions similar to those used by R.S.H. Liu (Tetrahedron Lett., 26, 2873, 1985) gave the enone 3 The enone 31 was then hydrogenated in the presence of a catalyst such as palladium on barium sulfate and treated with Dess-Martin periodinane as described in Scheme 2 to re-oxidize the laJ partially reduced carbonyl group to give 32. The t-butoxycarbonyl- protected amino derivative 32 is then treated with an acid such as trifluoroacetic acid in a solvent such as dichloromethane to give an intermediate amine as a trifluoroacetate salt. This amine is then acylated with various acyl chlorides such as palmitoyl chloride under Schotten- Baumann conditions in a mixture of solvents such as tetrahydrofuran and saturated aqueous sodium acetate to give amide 33. Alternatively, the amine trifluoroacetate salt can be treated with an alkylsulfonyl chloride such as 1-heptanesulfonyl chloride or an alkyl isothiocyanate such as N- decyl isothiocyanate in presence of a base such as triethylamine and in a solvent such as dichloromethane to give a sulfonamide or a thiourea respectively.
Scheme 8
Scheme S describes a method of preparing amides of structure 39 which are regioisomers of structures described in Scheme 7. 4- Hydroxybenzaldehyde was treated with 1,1,1-trifluoroacetone as described in Scheme 7 and alkylated with a bromoester such as t-butyl bromoacetate in the presence of a base such as potassium carbonate and in a solvent such as acetone to give 36. Alternatively 36 can be obtained via the same sequence of steps but in inverse order. The phenol 34 can also be acylated with various acid chlorides such as a palmitoyl chloride to give ester derivatives such as 36b. The t-butyl protecting group of 36 is then cleaved with an acid such as trifluoroacetic acid in dichloromethane to give the acid 3_Z. This acid is then reacted with primary and secondary amines such as dodecylamine in the presence of a condensing agent such as N- ethoxycarbonyl-2-ethoxy-l,2-dihydroxyquinoline (EEDQ) to give the amide 3S. Reduction and oxidation of the enone as described in Scheme 7 gave the amide 39. Alternatively, the enone 36 can be reduced first to 40 and then cleaved as above to the acid 41. The acid 41 is then treated with oxalyl chloride in dichloromethane to give an intermediate acid chloride. Reaction of this acid chloride with primary and secondary amines such as p-chlorobenzhydrylamine hydrochloride in a mixture of tetrahydrofuran and saturated aqueous sodium acetate also gives amides of structure 39. feH Scheme 9
Scheme 9 describes a method for making compounds of structure 46. 47 and 48 which contain a sulfur atom. Reaction of an alcohol 43. which contains a sulfur atom, usually obtained by reaction of a thiol with a halogen-substituted alcohol, with phenol 42 under Mitsunobu conditions as described in Scheme 1 gives the ether 44- Preparation of the trifluoromethylketone 46 is then achieved via the two-step sequence also described in Scheme L Oxidation of 4j5 with a peracid such as m- chloroperbenzoic acid gives the sulfone 47. Oxidation of 46 with sodium periodate in a mixture of methanol and water affords the sulfoxide 48.
Biological Activity
Assay for determining activity as cPLA2 inhibitors:
3H-arachidonate-labeled U937 membranes were prepared from U937 cells grown in RPMI 1640 medium containing L-glutamine supplemented with 10% fetal calf serum and 50 μg/ml gentamycin in a 5% C02 incubator at 37°C. Sixteen hours prior to harvesting the cells, 3H- arachidonate (100 Ci/mmol) was added to the cell culture (lxlO6 cells/ml, 0.5 μCi/ml). After washing the cells with HBSS (Hank's Balanced Salts) containing 1 mg/ml HSA (Human Serum Albumin), the cells were lysed by nitrogen cavitation and the homogenate was centrifuged at 2,000x g for 10 minutes. The supernatant was further centrifuged at 50,000x g for 30 minutes after which the pellet was resuspended in water and autoclaved at 120°C for 15 minutes to inactivate any residual phospholipase A2 activity. This suspension was then recentrifuged at 50,000x g for 30 minutes and the pellet resuspended in distilled water.
Assays of cPLA2 activity using these 3H-arachidonate-labeled U937 membranes as substrate typically employ human recombinant cPLA2 (see Burke et al., Biochemistry 34: 15165-15174, 1995) and membrane substrate (22 μm phospholipid) in 20 mm HEPES [N-(2-hydroxyethyl)ρiperazine-N1- (2-ethanesulfonic acid)] buffer, pH 8, containing 6 mm CaCl2, 0.9 mg/ml albumin and 4 m glycerol. Enzyme assays are allowed to proceed for 3 hours at 37°C before removing the non-hydrolyzed membranes. The hydrolyzed, radiolabeled fatty acid is then measured by liquid scintillation counting of the aqueous phase.
The effects of inhibitor are calculated as percent inhibition of 3H- arachidonate formation, after correcting for nonenzymatic hydrolysis, as compared to a control lacking inhibitor according to the following formula:
percent inhibition = ((Control DPM - Inhibitor DPM)/ Control DPM) x 100%
Various concentrations of an inhibitor were tested, and the percent inhibition at each concentration was plotted as log concentration (abscissa) versus percent inhibition (ordinate) to determine the IC50 values.
In this assay the compounds of Examples 1-274 below exhibited cPLA2 ICS0 values in the range of from about 1 to 50 μm.
Since the compounds of the present invention are selective inhibitors of cytosolic phospholipase A2, they are of value in the treatment of a wide variety of clinical conditions. Inflammatory disorders which may be treated by inhibition of cytosolic cPLA2 include such conditions as arthritis, psoriasis, asthma, inflammatory bowel disease, gout, trauma-induced inflammation such as spinal cord injury, Alzheimer's Disease, cerebral ischemia, chronic skin inflammation, shock, damage to skin resulting from exposure to ultraviolet light or burns, allergic rhinitis, acute pancreatitis, and the like.
The compounds of formula I are usually administered in the form of pharmaceutical compositions. They can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound defined by formula I and a pharmaceutically acceptable carrier.
In making the compositions employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active compound is effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
SPECIFIC EXAMPLES
The following examples further illustrate the preparation of the compounds of formula I. The examples are illustrative only and are not intended to limit the scope of the invention in any way. The following abbreviations have the indicated meanings:
AcOH acetic acid
EWG electron-withdrawing groups
DIAD diisopropyl azodicarboxylate
TFAA trifluoroacetic anhydride tθ r.t. room temperature
THF tetrahydrofuran
TFA trifluoroacetic acid
EEDQ N-ethoxycarbonyl-2-ethoxy-l,
2-dihydroxyquinoline
DMF N,N-dimethylformamide
DEAD diethyl azodicarboxylate
CPBA m-chloroperbenzoic acid
Me CH3
Ph phenyl tBu tert-butyl
Scheme 1
2Me
Figure imgf000071_0001
R R
Figure imgf000071_0002
2) TFAA-Pyridine l
Example 1
4-r4-F2-(N-Dodecyl-N-methylamino)ethoxy)phenyni.l,l-trifluoro-2- butanone
N-Methyl-N-Dodecylethanolamine
Figure imgf000072_0001
A solution of iodododecane (18.1 g, 61.09 mmol) and 2- (methylamino)ethanol (23.0 g, 0.3 mol) in isopropanol (75 ml) was heated under reflux for 3 h. The cooled mixture was diluted with ether (500 ml), washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure and distillation of the residue under vacuum gave 14.5 g (97%) of N-methyl-N-dodecylethanolamine as a clear oil: b.p. 100-lll°C/0.3 torr (bulb to bulb distillation, air bath temperature). IR (NaCl, film) umax (cm"1) 3400 (OH).
1H NMR 400 MHz (CDCI3) d (ppm): 0.89 (3H, t, J=5.36 Hz, CH3), 1.1-1.5 (20H, br m, (CH2)lθ)/ 2.24 (3H, s, NCH3), 2.39 (2H, t, J=7.4 Hz, NCH2), 2.52 (2H, t, J=5.35 Hz, OCH2CH2N), 3.58 (2H, t, J=5.35 Hz, OCH?CH?N).
1\
3-[4-[2-fN-Dodecyl-N-methylaminokthoxy]phenyl]-propanoic acid methyl ester
Figure imgf000073_0001
A solution of methyl 3-(4-hydroxyphenyl)propionate (10.0 g, 55. 5 mmol), N-methyl-N-dodecylethanolamine (13.5 g, 55.5 mmol) and triphenylphosphine (16.0 g, 61.0 mmol) in dry tetrahydrofuran (200 ml) was treated at 22°C with diisopropyl azodicarboxylate (12.3 g, 61.0 mmol) added dropwise over 50 min. After 3 h at 22°C, the reaction mixture was evaporated under reduced pressure and the residue was triturated with hexane. The solid formed was filtered, washed with hexane and the combined filtrate was chromatographed on silica gel using a gradient of ethyl acetate in hexane (20% - 60%) as eluent. Distillation under vacuum then gave 18.0 g (75%) of 3-{4-[2-(N-dodecyl-N- methylamino)ethoxy]phenyl} propanoic acid, methyl ester as a clear oil: b.p. 180-183°C/0.02 torr (bulb to bulb distillation, air bath temperature). αH NMR 400 MHz (CDCI3) d (ppm): 0.89 (3H, t, J=6.8 Hz, CH3), 1.2-1.6 (20H, m, CH2)10)/ 2.33 (3H, s, NCH3), 2.43 (2H, t, J=7.6 Hz, NCH2), 2.60 (2H, t, J=7.77 Hz, CH2-2), 2.78 (2H, t, J=6.06 Hz, OCH2CH2N), 2.89 (2H, t, J=7.77 Hz, CH2-3), 3.67 (3H, s, OCH3), 4.04 (2H, t, J=6.06 Hz, OCH2CH2N), 6.84 (2H, d, J=8.55 Hz, aromatic), 7.11 (2H, d, J=8.55 Hz, aromatic). The hydrochloride salt was obtained by treating the amine with anhydrous hydrochloric acid (IM) in ether. Anal. Calcd. for C25H43NO3.HCI: C 67.92, H 10.03, N 3.17. Found: C 67.74, H 9.46, N 3.25.
3-[4-[2-fN-Dodecyl-N-methylamino)ethoxy1phenyl]-propanoic acid. hydrochloride salt.
Figure imgf000074_0001
CH2CH2C02Me CH2CH2C02H
A solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid methyl ester (2.30 g, 5.69 mmol) in ethanol (25 ml) was treated with potassium hydroxide (0.64 g, 11.4 mmol) and water (5 ml) and stirred at 22°C for 2 h. The reaction mixture was then acidified to pH 4 with IM hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSθ4) and evaporated under reduced pressure to give a white solid. Recrystallization from ethyl acetate gave 2.20 g (89%) of 3-[4-[2-(N-dodecyl-N- methylamino)ethoxy]phenyl]propanoic acid as white crystals.
IR (KBr) Umax (cm"1) : 1725 (C=0 of carboxylate).
!H NMR 400 MHz (CDCI3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.2-1.4 (18H, br m, (CH2)9), 1-8 (2H, m, NCH2CH2), 2.61 (2H, t, J=7.5 Hz, CH2-2),
2.87 (3H, s, NCH3), 2.88 (2H, t, J=7.5 Hz, CH2-3), 3.11 (2H, br t, NCΗ2CH2),
3.44 (2H, br t, OCH2CH2N), 4.41 (2H, br t, OCH9CH9N). 6.81 (2.11, d, J=8.58
Hz, aromatic), 8.56 (2H, d, J=8.58 Hz, aromatic).
Anal. Calcd. for C24H41NO.HCI: C 67.34, H 9.89, N 3.27. Found: C 67.08, H 9.82, N 3.18. 4-[4-[2-(N-Dodecyl-N-methylamino ethoxy]phenyl]l.l.l-trifluoro-2- butanone
Figure imgf000075_0001
A solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid hydrochloride salt (3.30 g, 7.71 mmol) in dry dichloromethane (35 ml) was treated with oxalyl chloride (1.61 g, 12.7 mmol) and a small drop of N,N- dimethylformamide. After 1 h at 22°C, the solvent and excess reagent were evaporated under reduced pressure and the residue was dissolved in dry dichloromethane (35 ml). This solution was then added to a solution of trifluoroacetic anhydride (5.31 g, 24.2 mmol) in dry dichloromethane (30 ml) cooled to 0°C and treated dropwise with pyridine (1.4 ml, 17.3 mmol). After stirring for 30 min at 0°C and another 1.5 h at 22°C, the reaction mixture was cooled again to 0°C and treated dropwise with water (13 ml). After 30 min at 0°C and another 30 min at 22°C, the reaction mixture was adjusted to pH 8-9 with solid sodium bicarbonate and diluted with dichloromethane (200 ml). The organic phase was then washed with brine and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the residual oil was chromatographed on silica gel. Elution with a gradient of ethyl acetate in hexane gave an oil which was distilled under vacuum to give 2.45 g (71%) of 4-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]l,l,l- trifluoro-2-butanone as a clear oil: b.p. 160°C/0.02 torr (bulb to bulb distillation, air bath temperature). IR (NaCl, film) umax (cm"1) : 1760 (C=0). NMR 400 MHz (CDCI3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.1-1.6 (20H, m, (CH2)10)/ 2.32 (3H, s, NCH3), 2.44 (2H, t, J=7.6 Hz, NCH2), 2.79 (2H, t, J=6.0 Hz, OCH2CH2N), 2.94 and 3.0 (2 x 2H, 2m, CH2-3 and 4), 4.06 (2H, t, J=6.0 Hz, OCH2CH2N), 6.86 (2H, d, J=8.6 Hz, aromatic), 7.10 (2H, d, J=8.6 Hz, aromatic). Anal. Calcd. for C25H40F3NO2.O.6 H2O: C 68.08, H 9.09, N 3.16. Found: C 68.08, H 9.19, N 3.11.
The hydrochloride salt was obtained by treating the amine with anhydrous hydrochloric acid (IM) in ether.
Anal. Calcd. for C25H40F3NO2.HCI . 1.1 H2O: C 60.07, H 8.71, N 2.80.
Found: C 59.99, H 8.62, N 2.98.
Example 2
4-f4-[3-(N-Dodecyl-N-methylamino)propoxy1phenyn-l.l,l-trifluoro-2- butanone
3-(N-dodecyl-N-methylamino propanol
A solution of 3-(methylamino)propanol (5.71 g, 64.0 mmol, S. Koepke, R. Kupper, and C.J. Michejda, J. Org. Chem., 44, 2718, 1979)), and iodododecane (7.58 g, 25.6 mmol) was reacted as described in example 1 to give 6.33 g (96%) of the title material as an oil, b.p. 100-105°C/0.04 torr. 3-[4-[3-(N-dodecyl-N-methylamino)propoxy]phenyl]propanoic acid- methyl ester.
Methyl 3-(4-hydroxyphenyl)propanoate (1.0 g, 5.5 mmol) and 3-(N- dodecyl-N-methylamino)propanol (1.43 g, 5.5 mmol) were reacted as described in example 1 to give 1.57 g (43%) of title material as an oil. Anal. Calcd. for C26H45 O3: C 74.42, H 10.81, N 3.34.
Found: C 74.02, H 10.54, N 3.49.
3-[4-[3-(N-Dodecyl-N-methylamino)propoxy]phenyl]propanoic acid, hydrochloride
3-[4-[3-(N-dodecyl-N-methylamino)propoxy]phenyl]propanoic acid, methyl ester (1.53 g, mmol) was reacted as described in example 1 to give 1.20 g (74%) of the starting material as an amorphous solid. Anal. Calcd. for C26H45NO3: C 74.42, H 10.81, N 3.34.
Found: C 74.02, H 10.54, N 3.49.
4- 4-[3-(N-Dodecyl-N-methylamino)propoxy]phenylll.l.l-trifluoro-2- butanone
3-[4-[3-(N-dodecyl-N-methylamino)propoxy]phenyl]propanoic acid, hydrochloride (0.45 g, 1.11 mmol) was reacted as described in example 1 to give 0.185 g (36%) of the title material as an oil, b.p. 140-160°C/0.04 torr (bulb to bulb distillation, air bath temperature).
Anal. Calcd. for C26H42F3NO2.O.2H2O: C 67.71, H 9.27, N 3.04.
Found: C 67.75, H 9.35, N 2.90.
The hydrochloride was obtained as a syrup. Ho Example 3
4-[4-[4-(N-Dodecyl-N-methylamino)butoxy1phenyni.l,l-trifluoro-2- butanone
Methyl 3-[4-(4-brornobutoxy')phenyllpropanoate
A mixture of methyl 3-(4-hydroxyphenyl) propionate (1.19 g, 6.6 mmol), 1,4-dibromobutane (10 g, 46.3 mmol) and powdered anhydrous potassium carbonate (2.3 g) was maintained at 80°C and stirred vigorously for 24 h. Alter cooling, the solid was filtered and washed with a mixture of hexane and ethyl acetate (4:1). The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel. Elution with a gradient of ethyl acetate (0-3%) in toluene gave 1.80 g (86%) of the title material as an oil.
Anal. Calcd. for Ci4Hi9Brθ3: C 53.25, H 6.08.
Found: C 53.24, H 5.74.
3-[4-[4-(N-Dodecyl-N-methylamino butoxy1phenyl]-propanoic acid, methyl ester
A mixture of methyl 3-(4-bromobutoxy)phenyl]propanoate (1.46 g, 4.63 mmol), N-methyldodecylamine (2.31 g, 11.6 mmol) and sodium iodide (50 mg) in acetonitrile (17 ml) was heated at 75°C for 3 h. The reaction mixture was then cooled, diluted with dichloromethane, washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure and the residue was chromatographed on silica gel. Elution with 11 a gradient of methanol (0 - 5%) in ether gave 1.69 g (85%) of the title material as an oil.
Anal. Calcd. for C27H47NO3: C 79.48, H 10.92, N 3.23.
Found: C 74.62, H 10.58, N 3.25.
3-[4-[4-(N-Dodecyl-N-methylamino butoxy]phenyl]-propanoic acid, hydrochloride
3-[4-[4-N-dodecyl-N-methylamino)butoxy]phenyl]propanoic acid, methyl ester (0.800 g, 1.84 mmol) was saponified as described in example 1 to give 0.778 g (93%) of the title material as white crystals after crystallization from ethyl acetate; m.p. 109 - 111°C Anal. Calcd. for C26H45NO3.HCI: C 68.47, H 10.17, N 3.07.
Found: C 68.49, H 9.92, N 3.07.
4- [4- [4-f N-Dodecy l-N-methylamino')butoxy ] phenyl] -1.1,1 -trifluoro-2- butanone
3-[4-[4-(N-dodecyl-N-methylamino)butoxy]phenyl]-propanoic acid, hydrochloride (0.740 g, 1.76 mmol) was reacted as described in example 1 to give 0.420 g (51%) of the title material as an oil: b.p. 150 - 180°C/0.025 torr (bulb to bulb distillation, air bath temperature). Anal. Calcd. for C27H44F3NO2: C 68.76, H 9.40.
Found: C 68.52, H 9.38.
The hydrochloride was obtained as a syrup.
Anal. Calcd. for C27H44F3NO2.HCI.O.5 H2O: C 62.71, H 8.97, N 2.71.
Found: C 62.69, H 8.71, N 2.76. Example 4
f2-[2-(N-Dodecyl-N-methylamino)ethoxy1phenyn-2.2,2-trifluoroethanone
2-Trifluoroacetylphenol (Matsumoto, S. ; Kobayashi, H. and Ueno, K. Bull.Chem. Soc. Jpn. 1969, 42, 960) (490mg, 2.57mmol) and 2-[N-dodecyl-N- methylamino] ethanol (627mg, 2.58mmol) were reacted by the general procedure as described in example 1 and afforded the title compound (654mg, 61%) as a pale yellow oil.
Analysis for C23H36F3NO2 .3H2O calcd. C 65.63%, H 8.76%, N 3.33%;
Found: C 65.44%, H 8.74%, N 3.48%.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a white waxy solid. Analysis for C23H36F3NO2ΗCIO.5H2O calcd. C 59.92%, H 8.31%, N 3.04%;
Found: C 59.67%, H 8.49%, N 3.16%.
Example 5
4-f4-l2-(N-Dodecyl-N-methylamino)ethoxyl-2-methoxyphenyn-l,l,l- trifluoro-2-butanone
7- 2-(N-Dodecyl-N-methylamino ethoxy]-2H-l-benzopyran-2-one
7-Hydroxycoumarin (6.0g, 37.0mmol) and 2-[N-dodecyl-N-methylamino] ethanol (9.0g, 37.0mmol) were reacted by the general procedure as described in example 1 and afforded the title compound (6.7g, 47%) as a white solid. Analysis for C24H37NO3 calcd C 74.38%, H 9.62%, N 3.61%; Found: 74.35%, H 9.45%, N 3.66%.
7-[2-(N-Dodecyl-N-methylamino ethoxy]-3.4-dihydro-2H-l-benzopyran-2- one
7-[2-(N-Dodecyl-N-methylamino)ethoxy]-2H-l-benzopyran-2-one (5.62g, 14.5mmol) in ethyl acetate was hydrogenated over palladium on activated carbon uder 30 psi and afforded the title compound (4.7g, 84%) as a white solid. Treatment of the above free amine with anhydrous hydrogen chloride (1.0
M in ether) gave the hydrochloride salt as a white solid.
Analysis for C24H39N O3-HC.l-O.7H2O calcd. C 65.72%, H 9.51%, N 3.19%;
Found: C 65.76% H 9.35% N 3.26%.
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-hydroxyphenyl]propanoic acid, methyl ester
A solution of 7-[2-(N-Dodecyl-N-methylamino)ethoxy]-3,4-dihydro-2H-l- benzopyran-2-one (2.0g, 5.13mmol) in methanol (30ml) was stirred at 22°C for 0.5h. The solvent was then removed in vacuo at 40°C to afford the title compound (2.14g, 100%) as a white solid.
3-[4-f2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]propanoic acid, methyl ester
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-hydroxyphenyl]propanoic acid, methyl ester (500mg, 1.18mmol) and methanol (0.096ml, 2.37mmol) were reacted under Mitsunobu conditions as described in example 1 and afforded the title compound (471mg, 81%) as a pale yellow oil.
3-r4-[2-fN-Dodecyl-N-methylamino ethoxy]-2-methoxyphenyl]propanoic acid, hydrochloride
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]propanoic acid, methyl ester (468mg, 1.07mmol) was saponified as described in the preparation of 3-[4-[2-(N-dodecyl-N- methylamino)ethoxy]phenyl]propanoic acid, hydrochloride and afforded the title compound (280mg, 62%) as a white solid. Analysis for C25H43NO4 calcd. C 64.60%, H 9.46%, N 3.01%; Found: C
64.69%, H 9.52%, N 3.22%.
4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]-l,l,l- trifluoro-2-butanone
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]propanoic acid, hydrochloride (274mg, 0.598mmol) was reacted by the general procedure as described in the preparation of 4-[4-[2-(N-dodecyl-N- methylamino)- ethoxy]phenyl]-l,l,l-trifluoro-2-butanone and afforded the title compound (165mg, 58%) as a pale yellow oil (b.p. 138- 140°C/0.015mmHg). Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a off-white sticky solid. Analysis for C26H4.2F3NO3-HCl-O.7H2O calcd. C 58.80%, H 8.76%, N 2.74%;
Found: C 58.89%, H 8.53%, N 2.64%.
Example 6
7-r2-(N-Dodecyl-N-methylamino)ethoxyl-3,4-dihydro-2-(trifluoromethyl)- 2H-l-benzopyran-2-ol
A mixture of 4-[4-[2-(N-dodecyl-N-methylamino)ethoxy]-2- methoxyphenyl]-l,l,l-trifluoro-2-butanone (157mg, 0.33mmol) and hydrobromic acid (47%, 3ml) was refluxed for 3.5h. After cooling to r.t, the mixture was diluted with water, extracted with dichloromethane. The organic layer was washed with sat. sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (ethyl acetate /acetone 3 : 1) to afford the title compound (60mg, 40%) as a clear oil.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a off-white sticky solid. Analysis for C25H40F3NO3ΗCIO.3H2O calcd. C 59.88%, H 8.36%, N 2.79%; Found: C 59.84%, H 8.29%, N 2.79%.
Example 7
4-f4-f2-(N-Dodecyl-N-methylamino)ethoxy1-2-vinylphenyn-l,l.l-trifluoro- 2-butanone
3-r4-r2-(N-Dodecyl-N-methylamino')ethoxyl-2- ftrifluoromethanesulfonyloxy] phenyl] propanoic acid, methyl ester S i
To a solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]-2- hydroxyphenyl]propanoic acid, methyl ester (2.53g, ό.Ommol) and dry pyridine (1.94ml, 24.0mmol) in dichloromethane (30ml) at 0°C was added dropwise trifluoromethanesulfonic anhydride (2.1ml, 12.0mmol). After stirring for 20h at 22°C, the mixture was diluted with ethyl acetate
(120ml), washed with water (3x50ml), brine (50ml), dried over magnesium sulfate and concentrated in vacuo. The residue was placed at 0°C and triturated with diethyl ether. The formed solid (trifluoromethanesulfonic acid salt of the title compound) was dissolved in dichloromethane, washed with sat. sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was removed in vacuo to afford the title compound (2.15g, 69%) as a brown oil which solidified upon standing.
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyllpropanoic acid. methyl ester
To a solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]-2- [trifluoromethanesulfonyloxy]- phenyl]propanoic acid, methyl ester (250mg, 0.48mmol) in 1,4-dioxane (2.5ml) were added tributylvinyltin (1.2ml, 4.0mmol), lithium chloride (123mg, 1.44mmol), tetrakis(triphenylphosphine)-palladium(0) (10mg) and 2,6-di-terf-butyl-4- methylphenol (lOmg). The resulting mixture was then stirred at 100°C for 5h. After cooling to r.t., the mixture was diluted with diethyl ether, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (diethyl ether/acetone 100 : 0 to 80 : 20) to afford the title compound (170mg, 80%) as a yellow oil.
3-[4-[2-(N-Dodecyl-N-methylamino ethoxy]-2-vinylphenyl]propanoic acid. hydrochloride
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]propanoic acid, methyl ester (178mg, 0.412mmol) was saponified as described in the preparation of 3-[4-[2-(N-dodecyl-N- methylamino)ethoxy]phenyl]propanoic acid, hydrochloride and afforded the title compound (175mg, 93%) as a clear oil. n.
4-[4-[2-(N-Dodecyl-N-methylamino')ethoxy]-2-vinylphenyl1-l,l,l-trifluoro- 2-butanone
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]propanoic acid, hydrochloride (830mg, 1.83mmol) was reacted by the general procedure as described in the preparation of 4-[4-[2-(N-dodecyl-N-methylamino)- ethoxy]phenyl]-l,l,l-trifluoro-2-butanone. The residue was chromatographed on silica gel (ethyl acetate) to afforded the title compound (0.46g, 54%) as a pale purple oil. Analysis for C27H42F3 O2-0.5H2O calcd. C 67.75%, H 9.06%, N 2.93%;
Found: C 67.85%, H 8.92%, N 2.90%.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale green sticky solid. Analysis for C27H42F3NO2ΗCM.3H2O calcd. C 61.24%, H 8.68%, N 2.65%; Found: C 61.07%, H 8.42%, N 2.63%.
Example 8
8-r2-(N-Dodecyl-N-methylamino)ethoxyl-3-hydroxy-l-(hydroxymethyl)-3- (trifluoromethyl)-l,3,4,5-tetrahydro-2-benzoxepin
A solution of 4-methylmorpholine N-oxide (31mg, 0.23mmol) and osmium tetroxide (lmg, 0.004mmol) in acetone (1ml) and water (2.5ml) was treated with 4-[4-[2-(N-dodecyl-N-methylamino)ethoxy]-2- vinylphenyl]-l,l,l-trifluoro-2-butanone (lOOmg, 0.21mmol) dissolved in tert-butanol (1ml). After stirring at 22°C for 16h, the mixture was treated with aqueous sodium bisulfite (20%, 5ml) and extracted with diethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (diethyl ether /acetone 80 : 20 to 50 :50) to afford the title compound (40mg, 39%) as a clear oil.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as an off-white solid. Analysis for C27H4 F3NO4-HC1-0.7H2O calcd. C 58.67%, H 8.46%, N 2.53%; Found: C 58.67%, H 8.18%, N 2.45%. Si Example 9
4-r4-f2-fN-[Bis-(4-chlorophenyl)methynN-methylamino1ethoxy1phenyl1- lfl.l-trifluoro-2-butanone.
2-fN-[Bis-("4-chlorophenyDmethyl]N-methylamino]ethanol
Figure imgf000085_0001
A solution of 4,4'-dichlorobenzhydryl chloride (5.20 g, 19.1 mmol) and 2- (methylamino)ethanol (9.0 g, 0.106 mol) in acetonitrile (100 ml) was treated with powdered anhydrous potassium carbonate (10 g) and the resulting mixture was heated under reflux for 4 h. The cooled mixture was filtered and the filtrate was concentrated in vacuo. The residual oil was diluted with ethyl acetate, washed with water and brine and then dried over anhydrous magnesium sulfate. Evaporation of the solvent i n vacuo followed by chromatography on silica gel (elution toluene-ethyl acetate 9:1) gave 4.29 g (79%) of the title material as a white solid: mp 49- 50°C. Anal. Calcd. for Cι6Hi7Cl2N0: C 61.95, H 5.52, N 4.52. Found: C 61.58, H 5.43, N 4.61. SH
3-[4-[2-[N-[Bis-(4-chloropheny methyl]-N-methylamino]ethoxy]phenyl]- propanoic acid methyl ester.
Figure imgf000086_0001
A solution of methyl 3-[4-hydroxyphenyl)propanoate (0.594 g, 3.3 mmol) and 2-[N-[bis-(4-chlorophenyl)methyl]-N-methylamino]ethanol and triphenylphosphine (0.952 g, 3.63 mmol) in tetrahydrofuran (12 ml) was treated dropwise at 22°C with diisopropyl azodicarboxylate (0.734 g, 3.63 mmol). After 3 h, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution hexane-ethyl acetate 83:17) to give 1.12 g (72%) of the title material as an oil. Anal. Calcd. for C26H27CI2NO3. 0.4 H20: C 65.11, H 5.84, N 2.92. Found: C 65.34, H 5.89, N 3.08.
3-r4-[2-[N-[Bis-(4-chlorophenyDmethynmethyl]-N- methylamino]ethoxy]phenyl]propanoic acid.
Figure imgf000087_0001
A solution of 3-[4-[2-(bis-(4-chlorophenyl)methyl]-N- methylamino]ethoxy]phenyl]-propanoic acid methyl ester (0.80 g, 1.7 mmol) in ethanol (7 ml) was treated with potassium hydroxide (0.2 g, 3.5 mmol) in water (2.4 ml) and the resulting mixture was stirred at 45°C for 2 h. The cooled mixture was adjusted to pH 4 with HCI IN and concentrated in vacuo. The residue was partitioned between dichloromethane and water and the aqueous phase was extracted a second time with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and evaporated to give 0.746 g (95%) of the title material as an amorphous solid.
Anal. Calcd. for C25H25CI2NO3.O.I C7H8: C 66.01, H 5.56, N 3.00. Found: C 66.21, H 5.91, N 3.01. 4-[4-[2-[N-[Bis-(4-chlorophenyl)methyl]-N-methylamino]ethoxy]phenyl]- 1.1 ,1-trif luoro-2-butanone.
Figure imgf000088_0001
A solution of 3-[4-[2-[N-[Bis-(4-chlorophenyl)methyl]-N- methylamino]ethoxy]phenyl]-propanoic acid (0.592 g, 1.29 mmol) in dichloromethane (10 ml) was treated at 22°C with oxalyl chloride (0.25 g, 1.97 mmol) and the resulting mixture was stirred for 1.5 h. The solvent was evaported in vacuo and the crude acid chloride was diluted with toluene (20 ml) and cooled to 0°C. Then trifluoroacetic anhydride (0.81 g, 3.87 mmol) was added followed by pyridine (0.22 g, 2.8 mmol) added dropwise over 10 min. The resulting mixture was then stirred at 22°C for 2.5 h. The mixture was then cooled to 0°C and treated dropwise with water (1 ml) and stirred for 15 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried (magnesium sulfate). Evaporation of the solvent in vacuo and chromatography of the residue on silica gel (elution toluene ethyl acetate, 92:8) gave 0.465 g (70%) of title material as an oil. Anal. Calcd. for C26H24CI2F3NO2: C 61.19, H 4.74, N 2.74. Found: C 61.17, H 4.60, N 2.96.
The hydrochloride salt was obtained as an amorphous solid. Anal. Calcd. for C26H24CI2F3NO2.HCI: C 57.11, H 4.61, N 2.56. Found: C 57.09, H 4.97, N 2.38.
Example 10
4-r4-r2-rN-f3-Bis-(4-chlorophenyl)propyllN-methylamino1ethoxylphenyn- l,l.l-trifluoro-2-butanone.
3-Bis-(4-chloropheny propanoic acid, ethyl ester.
Figure imgf000089_0001
Ethyl bromoacetate (3.0 g, 18.0 mmol) was added dropwise to a boiling solution of zinc powder (1.7 g, 26.0 at g) and iodine (30.0 mg) in dichloromethane (5 ml) to form the Reformatsky reagent (K. Bott, Tetrahedron Lett., 1984, 35, 555-556). The mixture was then cooled to 0°C and treated dropwise with a solution of 4,4'-dichlorobenzhydryl chloride (5.11 g, 15.8 mmol) in dichloromethane (10 ml) and the resulting mixture was stirred at 22°C for 3 h. The reaction mixture was then diluted with ether, washed with 10% sulfuric acid, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo gave an oil which was chromatographed on silica gel to give 2.99 g (59%) of the title material as an oil: bp 110-115°C/0.1 torr. Anal. Calcd. for C17H16CI2O2: C 63.17, H 4.99. Found: C 62.94, H 4.90. %1
3-Bis-(4-chlorophenyl)propanoic acid.
Figure imgf000090_0001
A solution of 3-Bis-(4-chlorophenyl)propanoic acid, ethyl ester (2.80 g, 8.66 mmol) in ethanol (40 ml) was treated with potassium hydroxide (1.0 g, 15.2 mmol) in water (10 ml) and the resulting mixture was heated at 60°C for 1 h. The cooled mixture was concentrated in vacuo, water and dichloromethane were added and the aqueous phase was adjusted to pHβ with 2N hydrochloric acid. The aqueous phase was extracted two times with dichloromethane and the combined organic extracts were dried (magnesium sulfate). Evaporation of the solvent gave 2.40 g (94%) of the title material as a white solid: mp 188-189°C.
XI
N-(2-HydroxyethylVN-methyl-3-bis-(4-chlorophenyDpropanamide.
Figure imgf000091_0001
A solution of 3-Bis-(4-chlorophenyl)propanoic acid (2.33 g, 7.89 mmol) in dry dichloromethane (75 ml) was treated at 22°C with oxalyl chloride (2.18 g, 17.2 mmol) and a small drop of N,N-dimethyl formamide. After lh, the solvent and excess reagent were evaporated in vacuo. The residual oil was diluted with dry tetrahydrofuran (10 ml) and added dropwise to a vigorously stirred solution of 2-(methylamino) ethanol (0.75 g, 10.0 mmol) in tetrahydrofuran (15 ml) and water (15 ml) containing sodium bicarbonate (1 g). After 2 h at 22°C, the mixture was diluted with ethyl acetate, washed with brine and dried (magnesium sulfate). Evaporation of the solvent under vacuum and chromatography of the residue on silica gel (elution dichloromethane-methanol 95:5) gave 2.63 g (93%) of the title material as an oil.
2-[N-[3-Bis-(4-chlorophenyl propyl]-N-methylamino1ethanol.
Figure imgf000092_0001
A solution of N-(2-hydroxyethyl)-N-methyl-3-bis-(4- chlorophenyl)propanamide (2.63 g, 7.47 mmol) in dry tetrahydrofuran (35 ml) was treated with solid lithium aluminum hydride (0.66 g, 17.4 mmol) added in small portion over 10 min. The resulting mixture was then heated at 60°C for 2.5 h. The cooled solution was then quenched by successive addition of water (1 ml), 10% sodium hydroxide (1 ml) and water (2 ml). The solid formed was filtered and the filtrate was dried (magnesium sulfate) and concentrated in vacuo. The residual oil was chromatographed on silica gel (elution ethyl acetate and methanol 0-20%) to give 1.72 g (68%) of the title material as an oil. Anal. Calcd. for Cι8H2ιCl2NO: C 63.91, H 6.26, N 4.14. Found: C 63.95, H 6.13, N 3.81.
3-[4-[2-[N-[3-Bis-(4-chlorophenyl)propyl]-N-methylamino]ethoxy]phenyl]- propanoic acid, methyl ester.
Figure imgf000093_0001
A solution of methyl 3-(4-hydroxyphenyl)propanoate (0.80 g, 4.44 mmol), 2-[N-[3-bis-(4-chlorophenyl)propyl]-N-methylamino]ethanol (1.62 g, 4.79 mmol) and triphenyl-phosphine (1.51 g, 5.76 mmol) in dry benzene (20 ml) was treated dropwise at 22°C with diethyl azodicarboxylate (1.00 g, 5.77 mmol). After 3h at 22°C, the reaction mixture was diluted in the ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate).
Evaporation of the solvent under vacuo and chromatography of the residue on silica gel (elution toluene-ethyl acetate 0-15%) gave 0.893 g (40%) of the title material as an oil.
Anal. Calcd. for C28H31CI2NO3.O.2 H20: C 66.72, H 6.28, N 2.78. Found: C 66.60, H 6.31, N 2.92. 3-[4-[2-[N-[3-Bis-(4-chlorophenyl)propyl]-N-methylamino]ethoxy]phenyl]- propanoic acid, hydrochloride salt.
Figure imgf000094_0001
A solution of 3-[4-[2-[N-[3-Bis-(4-chlorophenyl)propyl]-N- methylamino]ethoxy]phenyl]-propanoic acid, methyl ester (0.801 g, 1.60 mmol) in ethanol (16 ml) was treated with potassium hydroxide (0.25 g, 3.8 mmol) in water (4 ml) and the resulting mixture was heated at 60°C for 1 h. After cooling, the reaction mixture was concentrated in vacuo and the residue was diluted with water and dichloromethane. The aqueous phase was adjusted to pH 4 with 2N hydrochloric acid and extracted two times with dichloromethane. The combined organic extracts were dried (magnesium sulfate) and evaported in vacuo to give 0.700 g (90%) of the title material as a white foam.
Anal. Calcd. for C27H29CI2NO3.O.7 HCI: C 63.34, H 5.85, N 2.74.
Found: C 63.13, H 5.88, N 2.73. ^3 4-[4-[2-[N-[3-Bis-(4-chlorophenyl)propyl]-N-methylamino]ethoxy]phenyl]- 1.1 ,1-trif luoro-2-butanone.
Figure imgf000095_0001
A solution of 3-[4-[2-[N-[3-Bis-(4-chlorophenyl)propyl]-N- methylamino]ethoxy]phenyl] propanoic acid, hydrochloride salt (0.660 g, 1.36 mmol) in dry dichloromethane (30 ml) was treated with oxalyl chloride (0.45 g, 3.5 mmol) and a trace of N,N-dimethylformamide. After 1 h at 25°C, the solvent and excess reagents were evaporated in vacuo. The residual oil was dissolved in dry toluene (30 ml), cooled to 0°C and then treated with trifluoroacetic anhydride (0.6 ml, 4.25 mmol) followed by pyridine 0.3 ml, 3.71 mmol) added dropwise over 10 min. The resulting mixture was then stirred at 22°C for 2.5 h. After cooling again to 0°C, water (5 ml) was added dropwise and the mixture was stirred at 22°C for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent under vacuum and chromatography of the residue on silica gel (elution gradient of toluene-ethyl acetate 1:1 to ethyl acetate) gave 0.307 g (42%) of the title material as an oil.
Anal. Calcd. for C28H28CI2F3NO2.O.5 H 0: C 61.43, H 5.34, N 2.56. Found: C 61.46, H 5.13, N 2.60. The hydrochloride salt was obtained as a white foam.
Anal. Calcd. for C28H28CI2F3NO2.HCI. H20: C 56.72, H 5.27, N 2.36.
Found: C 56.95, H 4.97, N 2.23.
The following compounds may be prepared by the general procedure of Scheme 1.
SCHEME 1 TABLE A
Figure imgf000097_0001
(CH2)nCOCF3
Figure imgf000097_0002
SCHEME 1 TABLE B
Figure imgf000098_0001
Figure imgf000098_0002
<Λ!
TABLE B (cont'd.)
Figure imgf000099_0001
Figure imgf000099_0002
°ιX
Scheme 1, Table B (continued)
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000101_0001
Figure imgf000102_0001
\ \
Figure imgf000103_0001
10
15
20 SCHEME 1 TABLE C
Figure imgf000104_0001
Figure imgf000104_0002
1*3
Scheme 2
nol
Figure imgf000105_0001
9 10
Figure imgf000105_0002
Example 48
4-rN-Dodecyl-N-r2-.4-(3-oxo-4,4,4-trifluorobut-l- yDphenoxylethyllaminolbutanoic acid, ethyl ester
Method I
l-[2-Bromoethoxy]-4-iodobenzene
A mixture of 4-iodophenol (15. Og, 68.2mmol) and 1,2-dibromoethane
(50ml, 580mmol) and potassium carbonate (14. Og, O.lmol) was stirred and refluxed for 22h. After cooling to r.t, the mixture was filtered, washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane /ethyl acetate 40 : 1 to 20 : 1) to afford the title compound (18.7g, 84%) as a white solid.
N-2-[4-Iodophenoxy]ethyldodecylamine
A mixture of dodecylamine (30g, 162mmol), diisopropylethylamine (22ml, 128mmol), sodium iodide (1.3g, 8.5mmol), l-[2-bromoethoxy]-4- iodobenzene (13.9g, 42.5mmol) and isopropanol (250ml) was stirred and refluxed for 24h. After cooling to r.t., the mixture was filtered, washed with dichloromethane and concentrated in vacuo . The residue was chromatographed on silica gel (dichloromethane /methanol 50: 1 to 20 : 1) to afford the title compound (15g, 82%) as a white solid.
Analysis for its hydriodide salt C20H34NIO-HI calcd. C 42.95%, H 6.31%, N
2.50%; Found: C 42.73%, H 6.16%, N 2.50%.
4-[N-dodecyl-N-2-[4-iodophenoxy]ethylamino]butanoic acid, ethyl ester
To a mixture of N-2-[4-iodophenoxy]ethyldodecylamine ( 4.0g, 9.3mmol) and sodium cyanoborohydride (1.45g, 23mmol) in methanol (80ml) was added dropwise a solution of ethyl 4-oxobutyrate (Fournet, G. ; Balme, G.; Barieux, J.J. and Gore, J. Tetrahedron, 1988, 44, 5821) (2.4g, lδmmol) in methanol (20ml) over a period of lOmin. The resulting mixture was stirred at 22°C for 24h, and then diluted with ethyl acetate (600ml), washed with brine (3x250ml). The aqueous phase was extracted with ethyl acetate (150ml), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane /ethyl acetate 8 : 1 to 6 : 1) to afford the title compound (4.5g, 89%) as a colorless oil. Analysis for C26H44N IO3O.3H2O, calcd. C 56.68%, H 8.16%, N 2.54%;
Found: C 56.4% H 7.77%, N 2.63%.
4-rN-dodecyl-N-2-f4-(/EVr3-hydroxy-4.4.4-trifluorobut-l-en-l- yl1phenoxy]ethylamino]butanoic acid, ethyl ester
To a solution of 4-[N-dodecyl-N-2-[4-iodophenoxy]ethylamino]butanoic acid, ethyl ester (4.5g, 8.3mmol) and 4,4,4-trifluorobut-l-en-3-ol (Pegolotti, J.A. and Young, W.G. /. Amer. Chem. Soc, 1961, 83, 3251) (complex with 1 tetrahydrofuran, 3.3g, 16.6mmol) in N, N-dimethylformamide (17ml) were added sodium bicarbonate (1.75g, 20.8mmol), tetrabutyl ammonium chloride hydrate (2.5g, 8.32mmol) and palladium (II) acetate (56mg, 0.25mmol). The resulting mixture was stirred at 50°C for 24h, and then diluted with ethyl acetate (300ml), washed with brine (100ml), sat. aq. sodium thiosulfate (2x100ml), brine (2x100ml), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 4: 1 to 2 : 1) to afford the title compound (3.5g, 78%) as a colorless oil and 0.3g (6.6%) of 4-[N- Dodecyl-N-[2-[4-(4,4,4-trifluoro-3-oxo-but-l- yl)phenoxy] ethyl] amino]butanoic acid, ethyl ester. Analysis for C30H48F3N O4 calcd. C 66.27%, H 8.90%, N 2.58%; Found: C
65.92%, H 8.73%, N 2.59%
4-r,N-Dodecyl-N-2-r4-r3-hydroxy-4.4.4- trifluorobutyl]phenoxy]ethylamino]butanoic acid, ethyl ester
A mixture of 4-[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-l-en-l- yl]phenoxy]ethylamino] butanoic acid, ethyl ester (3.5g, 6.46mmol), palladium on activated carbon (10%, 0.6g) and ethyl acetate (250ml) was hydrogenated under 30psi for 6h. After filtration, the solvent was removed in vacuo to give the title compound (3.3g, 94%) as a colorless oil. 4-[N-Dodecyl-N-[2-f 4-f 3-oxo-4.4 ,4-trifluorobut-l - yPphenoxy] ethyl] amino]butanoic acid, ethyl ester
A suspension of 1,1, l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (Dess-Martin periodinane, 1.7g, 4.0mmol) in dichloromethane (20ml) was treated with 4-[N-dodecyl-N-2-[4-[4,4,4-trifluoro-3- hydroxybutyl]phenoxy]ethylamino]butanoic acid, ethyl ester (430mg, 0.79mmol) dissolved in dichloromethane (5ml). The mixture was stirred at 22°C for 4h, poured into a saturated aqueous sodium bicarbonate and sodium thiosulfate (100ml) and extracted with ethyl acetate (2x100ml). The combined oganic layers were washed with sat. sodium bicarbonate (2x60ml), brine (60ml), dried over sodium sulfate and concentrated in vacuo . The residue was chromatographed on silica gel (hexane /ethyl acetate 2 : 1 to 1.5 : 1) to afford the title compound (333mg, 77%) as a colorless oil.
Analysis for C30H48F3N O4 .IH2O calcd. C 63.94%, H 8.98%, N 2.49%;
Found: C 63.55% H 8.55% N 2.61%.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0
M in ether) gave the hydrochloride salt as a pale yellow syrup.
Example 49
3-rN-Dodecyl-N-r2-r4-(3-oxo-4,4.4-trifluorobut-l- yPphenoxylethyllaminolpropanoic acid, ethyl ester
3-[N-Dodecyl-N-[2-[4-iodophenoxy]ethyl]amino]propanoic acid, ethyl ester
A mixture of N-2-[4-iodophenoxy]ethyldodecylamine (l.Og, 2.3mmol), ethyl acrylate (1.2g, 12mmol) and ethanol (3ml) was stirred and refluxed for 6h, and then concentrated in vacuo . The residue was chromatographed on silica gel (hexane /ethyl acetate 8 : 1) to afford the title compound (1.05g, 86%) as a colorless oil. Analysis for C25H42IN O3 calcd. C 56.49%, H 7.97%, N 2.64%; Found: C 56.79% H 8.10% N 2.59%. lcn
3- N-Dodecyl-N-2-[4-(EVf3-hydroxy-4,4.4-trifluorobut-l-en-l- yl]phenoxy]ethylamino]propanoic acid, ethyl ester
[N-Dodecyl-N-[2-[4-iodophenoxy]ethyl]amino]propanoic acid, ethyl ester (0.95g, 1.79mmol) and 4,4,4-trifluorobut-l-en-3-ol (complex with 0.7 THF, 0.95g, 5.4mmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-l-en-l- yl]phenoxy]ethylamino]butanoic acid, ethyl ester (Example 48 ) and afforded the title compound (0.633g, 76%) as a colorless oil.
3-.N-Dodecyl-N-2-[4-r3-hydroxy-4.4.4- trifluorobutyl]phenoxy]ethylamino]propanoic acid, ethyl ester
[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-l-en-l- yl]phenoxy]ethylamino]propanoic acid, ethyl ester (620mg, 1.17mmol) was hydrogenated as described in the preparation of 4-[N-dodecyl-N-2-[4-[3- hydroxy-4,4,4-trifluorobutyl]phenoxy]ethylamino]butanoic acid, ethyl ester (Example 48) and afforded the title compound (573mg, 92%) as a clear oil. Analysis for C29H48F3N O4 calcd. C 65.51%, H 9.10%, N 2.63%; Found: C 65.83% H 9.41% N 2.50%.
3-rN-Dodecy1-N-f2-14-f3-oxo-4.4,4-trifluorobut-l- yl1phenoxy]ethyl]amino]propanoic acid, ethy ester
3-[N-Dodecyl-N-2-[4-[3-hydroxy-4,4,4- trifluorobutyl]phenoxy]ethylamino]propanoic acid, ethyl ester (320mg, 0.60mmol) was oxidized as described in the preparation of 4-[N-dodecyl-N- [2-[4-(3-oxo-4,4,4-trifluorobut-l-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester (Example 48 ) and afforded the title compound (216mg, 68%) as a pale yellow oil.
Analysis for C29H46F3N θ4-0.8H2θcalcd. C 64.02%, H 8.82%, N 2.57%;
Found: C 63.94% H 8.85% N 2.59%.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow syrup. Analysis for C29H46F3N 04-HCM.5H20 calcd. C 58.72%, H 8.50%, N
2.36%; Found: C 58.45% H 8.22% N 2.55%.
Example 50 \c"4
(2S. 4S)-l-N-Dodecyl-4-r4-(3-hydroxy-4.4.4-trifluorobut-l- yl)phenoxy1pyrrolidine-2-carboxylic acid, methyl ester
frflns-4-Hydroxy-L-proline. methyl ester, hydrochloride
To a freshly prepared sat. solution of hydrogen chloride in methanol (100ml) was added irαns-4-hydroxy-L-proline (lO.Og, 76.26mmol). The resulting mixture was stirred at 22°C for 24h, concentrated in vacuo and triturated with acetone at 0°C. Filtration afforded the title compound (12.8g, 92%) as a white solid.
f2S. 4R)-l-N-Dodecyl-4-hydroxypyrrolidine-2-carboxylic acid, methyl ester
A solution of rπms-4-hydroxy-L-proline, methyl ester, hydrochloride (4.0g, 22.02mmol) and 1-iodododecane (3.04g, 44.04mmol) in methanol (30ml) was treated with potassium carbonate. The mixture was stirred and refluxed for 7h, cooled to r.t., diluted with ethyl acetate (700ml), washed with water (400ml), brine (200ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (petroleum ether /ethyl acetate 60 : 40 to 40 : 60) to afford the title compound (3.72g, 54%) as a white solid.
(2S, 4SVl-N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2-carboxylic acid. methyl ester
(2S, 4R)-l-N-Dodecyl-4-hydroxypyrrolidine-2-carboxylic acid, methyl ester (1.75g, 7.94mmol) and 4-iodophenol (2.26g, 7.22mmol) were reacted under Mitsunobu conditions as described in the preparation of 3-[4-[2-(N- Dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, methyl ester. The residue was chromatographed on silica gel (hexane /ethyl acetate 15 : 1 to 10 : 1) to afford the title compound (3.23g, 79%) as a white solid. [a]o= - 30.80 (C lι0/ CHCI3) Analysis for C24H38INO3 calcd. C 55.92%, H 7.43%, N 2.72%; Found: C 55.87%, H 7.48%, N 2.68%. t/2S, 4SVl-N-Dodecyl-4-[4-(EV[3-hydroxy-4.4.4-trifluorobut-l-en-l- yl]phenoxy]pyrrolidine-2-carboxylic acid, methyl ester
(2S, 4S)-l-N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2-carboxylic acid, methyl ester (800mg, 1.55mmol) and 4,4,4-trifluorobut-l-en-3-ol (complex with 1 tetrahydrofuran, 620mg, 3.1mmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-[3- hydroxy-4,4,4-trifluorobut-l-en-l-yl]phenoxy]ethylamino]butanoic acid, ethyl ester and afforded the title compound (575mg, 72%) as a colorless oil [[a]D= - 8.70 (c 0.8, CHCI3)] and (2S, 4S)-l-N-dodecyl-4-[4-(3-oxo-4,4,4- trifluorobut-l-yl)phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (68mg, 9%) as a pale yellow oil. Analysis for C28H42F3N O4 O.3H2O calcd. C 64.79%, H 8.27%, N 2.70%;
Found: C 64.74% H 8.23% N 2.87%.
(2S. 4SVl-N-Dodecyl-4-[4-r3-hydroxy-4.4.4-trifluoro-l- butyl]phenoxy]pyrrolidine-2-carboxylic acid, methyl ester
(2S, 4S)-l-N-Dodecyl-4-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-l-en-l- yl]phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (552mg., 1.07mmol) was hydrogenated as described in the preparation of 4-[N-dodecyl-N-2-[4- [3-hydroxy-4,4,4-trifluorobutyl]phenoxy] ethylamino]- butanoic acid, ethyl ester, and afforded the title compound (546mg, 99%) as a clear oil. [a]D= - 89.00 (c 0.4, CHCI3) Analysis for C28H44F3N O4 calcd. C 65.22%, H 8.60%, N 2.72%; Found: C 65.13% H 8.59% N 2.68%.
Example 51
(2S.4S)-l-N-Dodecyl-4-r4-(3-oxo-4.4.4-trifluorobut-l- yl)phenoxy1pyrrolidine-2-carboxylic acid, methyl ester
(2S, 4S)-l-N-Dodecyl-4-[4-[3-hydroxy-4,4,4- trifluorobutyl]phenoxy]pyrrolidine-2-carboxylic acid, methyl ester_(425mg, 0.825mmol) was oxidized as described in the preparation of 4-[N-dodecyl- N-[2-[4-(3-oxo-4,4,4-trifluorobut-l-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester.and afforded the title compound (272mg, 64%) as a pale yellow oil.
Analysis for C28H42F3N O4O.4H2O calcd. C 64.57%, H 8.28%, N 2.69%;
Found: C 64.61% H 8.08% N 2.76%.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0
M in ether) gave the hydrochloride salt as a pale yellow foam. [a]D= -9.2°
(c 0.74, CHCI3)
C28H43F3N O4ΗCM.2H2O calcd. C 58.82%, H 8.00%, N 2.45%; Found: C
58.79% H 7.85% N 2.41%.
Example 52
(2S, 4S)-l-Dodecyl-4-f4-(3-oxo-4.4,4-trifluorobut-l-yl)phenoxylpyrrolidine- 2-propanoic acid, methyl ester
(2S, 4SVl-N-Dodecyl-4-(4-iodophenoxy')pyrrolidine-2-methanol
To a solution of (2S, 4S)-l-N-dodecyl-4-(4-iodophenoxy)pyrrolidine-2- carboxylic acid, methyl ester (2.09g, 4.06mmol) in tetrahydrofuran (20ml) at -78°C was added dropwise diisobutylaluminum hydride (1.0M in hexane, 15.0ml, 15.0mmol). After stirring at this temperature for 5min. and at 0°C for 2.5h, the reaction was quenched with water at 0°C. After stirring at r.t. for lOmin., the mixture was diluted with ethyl acetate (250ml), washed with 2N sodium hydroxide (3x100ml), 35% sodium and potassium tartrate (2x100ml), brine (100ml), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate 3 : 1 to 2 : 1) to afford the title compound (1.65g, 79%) as a colorless oil. [a]D= -18.5° (c 0.92, CHCI3). Analysis for C23H38F3INO2 calcd. C 56.67%, H 7.86%, N 2.87%; Found: C 56.65% H 7.39% N 2.95%.
(2S, 4SVl-N-Dodecyl-4-(4-iodophenoxy')pyrrolidine-2-propenoic acid, methyl ester
To a solution of oxalyl chloride (1.1ml, 12.1mmol) in dichloromethane (17ml) at -60°C was added dropwise dimethylsufoxide (1.7ml, 24.2mmol). After stirring for 5min., a solution of (2S, 4S)-l-N-dodecyl-4-(4- iodophenoxy)- pyrrolidine-2-methanol (1.18g, 2.42mmol) in dichloromethane (6ml) was then added dropwise. The resulting mixture was stirred, and the temperature allowed to rise gradually to -20°C over a period of 2h. The reaction was quenched with sat. ammonium chloride, diluted with dichloromethane , washed three times with sat. ammonium chloride, brine and dried over sodium sulfate . The solvent was removed in vacuo to afford the corresponding aldehyde which was directly used in the next step.
The above material was dissolved in dichloromethane (20ml) and treated with methyl (triphenyl-phosphoranylidene) acetate (1.44g, 4.3mmol). The mixture was stirred at 22°C for 22h and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate 15 :1 to 10 : 1) to afford E- (2 S, 4S)-l-N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2- propenoic acid , methyl ester (934mg, 61%) as a white solid [m.p. 60-61°C, [a]D= -42.2° (c 0.96, CDCI3)] and Z- (2 S, 4S)-l-N-dodecyl-4-(4- iodophenoxy)pyrrolidine-2-propenoic acid, methyl ester (149mg, 9%) as a clear oil. [a]o= -79.30 (c 1.24, CHCI3).
Analysis for E-isomer C26H40INO3 calcd. C 57.67%, H 7.45%, N 2.59%; Found: C 57.41% H 7.50% N 2.64%.
(2S. 4SVl-N-Dodecyl-4-[4-lEV[3-hydroxy-4.4.4-trifluorobut-l-en-l- yllphenoxy]pyrrolidine-2-propenoic acid, methyl ester
(2S, 4S)-l-N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2-propenoic acid, methyl ester (677mg, 1.24mmol) and 4,4,4-trifluorobut-l-en-3-ol (complex with 1 tetrahydrofuran, 1.23g, 6.2mmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-[3- hydroxy-4,4,4-trifluorobut-l-en-l-yl]phenoxy]ethylamino]butanoic acid, ethyl ester and afforded the title compound (250mg, 37%) as a colorless oil. Analysis for C30H44F3N O4 .2H2O calcd. C 66.32%, H 8.24%, N 2.58%;
Found: C 66.14% H 8.03% N 2.55%. l »
(2S. 4SVl-N-Dodecyl-4-i4-r3-hydroxy-4.4.4-trifluoro-l- butyl]phenoxy]pyrrolidine-2-propanoic acid, methyl ester
(2S, 4S)-l-N-Dodecyl-4-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-l-en-l- yl]phenoxy]pyrrolidine-2-propenoic acid, methyl ester (260mg.,
0.482mmol) was hydrogenated as described in the preparation of 4-[N- dodecyl-N-2-[4-[3-hydroxy-4,4,4-trifluorobutyl]phenoxy] ethylamino]- butanoic acid, ethyl ester.and afforded the title compound (185mg, 71%) as a colorless oil. [a]D= -35.3° (c 0.85, CHCI3) Analysis for C30H48F3N O4 .IH2O calcd. C 66.05%, H 8.91%, N 2.57%; Found: C 65.89% H 8.68% N 2.51%.
(2S. 4S -l-N-Dodecyl-4- 4-(3-oxo-4.4.4-trifluorobut-l- ylφhenoxy pyrrolidine-2-propanoic acid, methyl ester
(2S, 4S)-l-N-Dodecyl-4-[4-[3-hydroxy-4,4,4- trifluorobutyl]phenoxy]pyrrolidine-2-propanoic acid, methyl ester (150mg,
0.276mmol) was oxidized as described in the preparation of 4-[N-dodecyl-
N-[2-[4-(3-oxo-4,4,4-trifluorobut-l-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (70mg, 47%) as a pale yellow oil. [a]D= -35.70 (c 0.84, CDCI3)
Treatment of the above free amine with anhydrous hydrogen chloride (1.0
M in ether) gave the hydrochloride salt as a pale yellow foam.
C30H46F3N O4ΗCM.IH2O calcd. C 60.26%, H 8.29%, N 2.34%; Found: C 60.29% H 8.10% N 2.34%.
The following compounds may be prepared by the general procedure of Scheme 2.
SCHEME 2 TABLE A
(CH2)nR1
Figure imgf000115_0001
Figure imgf000115_0002
ιt^\
Figure imgf000116_0001
\
Scheme 3
Figure imgf000117_0001
13 14
NaOhL.
Figure imgf000117_0002
15
ι.ς
Example 60
N.N-Dimethyl-N-r2-r4-(3-oxo-4.4.4-trifluorobut-l-yl)-phenoxy1ethyn dodecyl- ammonium, iodide
A solution of 4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-l,l,l- trifluoro-2-butanone (250mg, 0.56mmol) in isopropanol (6ml) and methyl iodide (2ml) was heated to reflux for 0.5h. After cooling to r.t., the mixture was evaporated in vacuo and the last traces of isopropanol co-evaporated with dichloromethane to afford the title compound (327mg, 100%) as a yellow waxy solid. Analysis for C26H43F3INO2 .7H2O calcd. C 52.21%, H 7.48%, N 2.34%;
Found: C 52.21%, H 7.43%, N 2.40%.
Example 61
N.N-Dimethyl-N-r2-r3-(3-oxo-4.4.4-trifluorobut-l-yl)-phenoxylethyn dodecyl- ammonium, iodide
4-[3-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (300mg, 0.68mmol) was reacted by the general procedure as described in the preparation of N,N-dimethyl-N-[2-[4-(3-oxo4,4,4- trifluorobut-l-yl)-phenoxy]ethyl] dodecyl- ammonium, iodide and afforded the title compound (397mg, 100%) as a yellow syrup. Analysis for C26H43F3INO2 H2O calcd. C 51.74%, H 7.52%, N 2.32%;
Found: C 51.90%, H 7.58%, N 2.32%.
Example 62
N.N-Dimethyl-N-f2-l2-(3-oxo-4.4.4-trifluorobut-l-yl)-phenoxylethyn dodecyl- ammonium, iodide
4-[2-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (417mg, 0.94mmol) was reacted by the general procedure as described in the preparation of N,N-dimethyl-N-[2-[4-(3-oxo4,4,4- trifluorobut-l-yl)-phenoxy]ethyl] dodecyl- ammonium, iodide and afforded the title compound (550mg, 100%) as a yellow syrup. M =r Analysis for C26H43F3INO2 .5H2O calcd. C 52.53%, H 7.46%, N 2.36%; Found: C 52.46%, H 7.42%, N 2.42%.
Example 63
N.N-Dimethyl-N-f2-f2-(trifluoroacetyl)phenoxy1ethyn dodecylammonium. iodide
[2-[2-fN.N-Dimethylamino')ethoxy1phenyl]-2.2,2-trifluoroethanone
A mixture of 2-trifluoroacetylphenol (380mg, 2.0mmol), 2-[N, N- dimethylamino]ethyl chloride, hydrochloride (432mg, ό.Ommol) potassium carbonate (1.38g, lOmmol) and toluene (5ml) was refluxed for 3.5h. After cooling to r.t., the mixture was treated with water and ether. The organic layer was washed twice with brine, dried over sodium sulfate and concentrated in vacuo . The residue was chromatographed on silica gel (acetone /ether 1 : 1 to 1 : 0) to give the title compound (375mg, 72%) as a white solid.
N,N-Dimethyl-N-[2- 2-(trifluoroacetyDphenoxy]ethyl] dodecylammonium. iodide
A mixture of [2-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2- trifluoroethanone (416mg, 1.59mmol), 1-iodododecane (l-42g, 4.8mmol) and isopropanol (20ml) was refluxed for 24h. After cooling to r.t., the solvent was removed in vacuo. The residue was chromatographed on silica gel [dicloromethane /methanol /ammonium hydroxide (28%) 90 : 10 : 1 to 85 : 15 : 1] to give a pale yellow solid. Recrystallization from acetone/ether (1 : 3) afforded the title compound (512mg, 58%) as fine needles.
Analysis for C24H39F3INO2 calcd. C 51.71%, H 7.05%, N 2.51%; Found: C
51.83%, H 7.07%, N 2.51%. Example 64
N.N-Dimethyl-N-[2-f2-(trifluoroacetyl)phenoxy1ethyn octadecylammonium. iodide
[2-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethanone (400mg, 1.5mmol) and 1-iodooctadecane (1.8g, 4.8mmol) were reacted by the general procedure as described in the preparation of N,N-dimethyl-N- [2-[2-(trifluoroacetyl)phenoxy]ethyl] dodecylammonium, iodide. Recrystallization from Acetone/ether (1 : 2) afforded the title compound (500mg, 52%) as fine needles. Analysis for C30H51F3INO2 calcd. C 56.16%, H 8.01%, N 2.18%; Found: C
56.06%, H 7.90%, N 2.13%.
Example 65
NfN-Dimethyl-N-[2-f4-(trifluoroacetyl)phenoxylethyn octadecylammonium, iodide
N,N-Dimethyl-2-(4-bromophenoxy ethylamine
A mixture of 4-bromophenol (5.0g, 28.9mmol), 2-(N, N- dimethylamino) ethyl chloride, hydrochloride (6.24g, 43.4mmol), sodium iodide (600mg, 4mmol), cesium carbonate (28g, 86.7mmol) and methyl ethyl ketone (120ml) was heated to reflux for 4h. After cooling to r.t., the mixture was filtered and washed with acetone. The combined filtrates were concentrated in vacuo, and the residue was chromatographed on silica gel (dichloromethane /methanol 95 : 5 to 90 : 10) to give a pale yellow liquid. Bulb-to-bulb distillation (80-84°C/0.05mmHg) afforded the title compound (5.19g, 74%) as a colorless liquid.
[4-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethanone
To a solution of N,N-dimethyl-2-(4-bromophenoxy)ethylamine (l.Og, 4.1mmol) in tetrahydrofuran (10ml) at -78°C was added dropwise n- butyllithium (1.5M in hexane, 2.7ml, 4.1mmol). The mixture was stirred at this temperature for 15min. and then transferred via a cannula into a pre-cooled solution of ethyl trifluoroacetate (0.64g, 4.5mmol) in ether (8ml) at -78°C. The resulting mixture was stirred and the temperature allowed to rise gradually to r.t. over a period of 1.5h. The reaction mixture was then quenched with water (5ml) and diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo . Bulb-to-bulb distillation (82-84°C/0.01mmHg) afforded the title compound (423mg, 39%) as a pale yellow oil. Analysis for C12H14F3NO2 -0.3H2O calcd. C 54.05%, H 5.52%, N 5.25%; Found: C 54.12%, H 5.39%, N 5.28%.
N.N-DimethyI-N-[2-[4-(trifluoroacetyDphenoxy]ethyl] octadecylammonium. iodide
[4-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethanone (343mg, 1.31mmol) and 1-iodooctadecane (1.16g, 53.93mmol) were reacted by the general procedures as described in the preparation of N,N- dimethyl-N-[2-[2-(trifluoroacetyl)phenoxy]ethyl] dodecylammonium, iodide. The residue was chromatographed on silica gel [dichloromethane/methanol/ammonium hydroxide (28%) 98 : 2 : 0.5 to 90 : 10 : 1] to give the title compound (722mg, 86%) as a white solid.
Analysis for C30H51F3INO2 calcd. C 56.16%, H 8.01%, N 2.18%; Found: C
56.33%, H 7.79%, N 2.09%.
Example 66
N.N-Dimethyl-N-f2-f3-(trifluoroacetyl)phenoxy1ethyn octadecylammonium. iodide
N,N-Dimethyl-2-(3-bromophenoxy ethylamine
3-Bromophenol (5.0g, 28.9mmol) and 2-(N, N-dimethylamino)ethyl chloride, hydrochloride (6.24g, 43.3mmol) were reacted by the general procedures as described in the preparation of N,N-dimethyl-2-(4- bromophenoxy)ethylamine. The residue was chromatographed on silica gel (dichloromethane /methanol 100 : 0 to 90 : 10) to give the title compound (5.2g, 74%) as a pale yellow liquid. \2d [S-fΣ-CN.N-Dimethylaminolethoxylpheny^-Σ.Σ.Σ-trifluoroethanone
N,N-Dimethyl-2-(3-bromophenoxy)ethylamine (2.87g, 11.7mmol) and ethyl trifluoroacetate (2.5g, 17.6mmol) were reacted by the general procedure as described in the preparation of [4-[2-(N,N- dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethanone. The residue was distilled under reduced pressure to afford the title compound (1.34g, 44%) as a pale yellow liquid. Analytically pure sample was obtained by a second distillation under reduced pressure. Analysis for C12H14F3NO2 -0.8H2O calcd. C 52.29%, H 5.70%, N 5.08%; Found: C 52.61%, H 5.53%, N 4.96%.
N.N-Dimethy1-N-[2-r3-ι/Trifluoroacetylφhenoxy1ethyl] octadecylammonium. iodide
[3-[2-(N,N-Dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethanone
(438mg, 1.67mmol) and 1-iodooctadecane (1.9g, 5.0mmol) were reacted by the general procedure as described in the preparation of N,N-dimethyl-N- [2-[2-(trifluoroacetyl)phenoxy]ethyl] dodecylammonium, iodide. Recrystallization from acetone/ether (1 : 2) afforded the title compound (530mg, 50%) as fine needles.
Analysis for C30H51F3INO2O.2H2O calcd. C 55.84%, H 8.03%, N 2.17%; Found: C 55.79%, H 7.98%, N 2.10%.
Example 67
N-r(Ethoxycarbonyl)methyn-N-r2-r4-(3-oxo-4.4.4-trifluorobut-l- yl)phenoxylethyll-N-(methyl)- dodecylammonium. iodide
A solution of 4-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]-l,l,l- trifluoro-2-butanone (620mg, 1.4mmol) and ethyl iodoacetate (0.5ml, 4.2mmol) in ethanol (20ml) was heated to reflux for 3h. After cooling to r.t., the mixture was concentrated in vacuo . The residue was chromatographed on silica gel [dichloromethane/methanol/ ammonium hydroxide (28%) 95 : 5 : 0.5 to 90 : 10 : 1] to give a colorless syrup. This material was dissolved in aqueous tetrahydrofuran (90%), evaporated in vacuo and co-evaporated with acetonitrile to afford the title compound (855mg, 93%) as a colorless syrup. 12.) Example 68
N-(Carboxymethyl)-N-f2-f4-(3-oxo-4,4,4-trifluorobut-l-yl)phenoxy1ethyll- N-(methyl)dodecyl ammonium, hydroxide, inner salt
A solution of N-[(ethoxycarbonyl)methyl]-N-[2-[4-(3-oxo-4,4,4-trifluorobut- l-yl)phenoxy]ethyl]-N-(methyl)- dodecylammonium, iodide (617mg, 0.938mmol) in ethanol (95%, 20ml) was treated with potassium hydroxide (63mg, 1.12mmol). The mixture was stirred at 22°C for 3h, and then concentrated in vacuo. The residue was chromatographed on silica gel [dichloromethane/methanol/ ammonium hydroxide (28%) 90 : 10 : 1 to 85 : 15 : 1] to give a white solid. Recrystallization from ethanol-water (1 : 1) afforded the title compound (300mg, 64%) as fine needles. Analysis for C27H42F3NO4Η2O calcd. C 62.41%, H 8.54%, N 2.70%; Found: C 62.30%, H 8.70%, N 2.56%.
Example 69
N.N-Dimethyl-N-r2-r2-benzyl-4-(3-oxo-4.4.4-trifluorobut-l- yDphenoxylethyll dodecyl- ammonium, iodide
4-[3-Benzyl-4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]-l,l,l- trifluoro-2-butanone (180mg, 0.338mmol) was reacted by the general procedure as described in the preparation of N,N-dimethyl-N-[2-[4-(3-oxo- 4,4,4-trifluorobut-l-yl)-phenoxy]ethyl] dodecyl- ammonium, iodide and afforded the title compound (228mg, 100%) as a yellow syrup. Analysis for C33H49F3IN02-1.1H20 calcd. C 56.99%, H 7.42%, N 2.01%; Found: C 56.98%, H 7.25%, N 2.07%.
Example 70
N-r(Ethoxycarbonyl)methyn-N-f2-f2-benzyl-4-(3-oxo-4.4,4-trifluorobut-l- yl)phenoxylethyn-N-(methyl)- dodecylammonium. iodide
4-[3-Benzyl-4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]-l,l,l- trifluoro-2-butanone (340mg, 0.638mmol) was reacted by the general procedure as described in the preparation of N-[(ethoxycarbonyl)methyl]- ,2-Z
N-[2-[4-(3-oxo-4,4,4-trifluorobut-l-yl)phenoxy]ethyl]-N-(methyl)- dodecylammonium, iodide and afforded the title compound (455mg, 93%) as a yellow waxy solid. Analysis for C36H53F3INO4 calcd. C 57.83%, H 7.14%, N 1.87%; Found: C 57.83%, H 7.56%, N 1.78%.
Example 71
N-(Carboxymethyl)-N-f2-f2-benzyl-4-(3-oxo-4,4,4-trifluorobut-l- yl)phenoxylethyn-N-(methyl)dodecyl ammonium, hydroxide, inner salt
N-[(Ethoxycarbonyl)methyl]-N-[2-[2-benzyl-4-(3-oxo-4,4,4-trifluorobut-l- yl)phenoxy]ethyl]-N-(methyl)- dodecylammonium, iodide (330mg, 0.442mmol) was saponified as described in the preparation of N- (carboxymethyl)-N-[2-[4-(3-oxo-4,4,4-trifluorobut-l-yl)phenoxy]ethyl]-N- (methyl)dodecyl ammonium, hydroxide, inner salt, and afforded the title compound (182mg, 70%) as a white foam. Analysis for C34H48F3NO4Η2O calcd. C 66.19%, H 8.30%, N 2.27%;
Found: C 66.21%, H 8.15%, N 2.29%.
Example 72
N-f(Ethoxycarbonyl)methyn-N-f2-[2-benzyl-4- (trifluoroacetyl)phenoxylethyn-N-(methyl)- dodecylammonium, iodide
[3-Benzyl-4- [2-(N-dodecyl-N-methylamino)ethoxy jphenyl] -2,2,2- trifluoroethanone (2.81g, 5.56mmol) was reacted by the general procedure as described in the preparation of N-[(ethoxycarbonyl)methyl]-N-[2-[4-(3- oxo-4,4,4-trifluorobut-l-yl)phenoxy]ethyl]-N-(methyl)- dodecylammonium, iodide and afforded the title compound (2.1g, 52%) as a yellow solid. Analysis for C34H48F3INO4 calcd. C 56.75%, H 6.86%, N 1.95%; Found: C
57.14%, H 6.94%, N 2.05%. , 23 Example 73
N-(Carboxymethyl)-N-f2-f2-benzyl-4-(trifluoroacetyl)phenoxylethyn-N- (methyl)dodecyl ammonium, hydroxide, inner salt
N-[(Ethoxycarbonyl)methyl]-N-[2-[2-benzyl-4-
(trifluoroacetyl)phenoxy]ethyl]-N-(methyl)- dodecylammonium, iodide (500mg, 0.69mmol) was saponified as described in the preparation of N- (carboxymethyl)-N-[2-[4-(3-oxo-4,4,4-trifluorobut-l-yl)phenoxy]ethyl]-N- (methyl)dodecyl ammonium, hydroxide, inner salt, and afforded the title compound (259mg, 65%) as an off-white solid. Analysis for C32H44F3NO4 .7H2O calcd. C 66.69%, H 7.94%, N 2.43%;
Found: C 66.63%, H 8.00%, N 2.42%.
U
Scheme 4
dichlo
Figure imgf000126_0001
nR2
Figure imgf000126_0002
23
22 ιz/
Example 74
4-rN-Dodecyl-N-r2-r4-(3-oxo-4,4.4-trifluorobut-l- yDphenoxylethynaminolbutanoic acid, ethyl ester
Method II
4-[4-Methoxyphenyl]-l ,1 ,1-trifluoro— 2-butanone
To a solution of 3-[4-methoxyphenyl]propionic acid (40.0g, 0.222mol) in dichloromethane (300ml) at 22°C was added slowly oxalyl chloride (29ml, 0.333mol). After stirring for 2.5h, the solvent and excess reagent were removed in vacuo . The residue was dissolved in dichloromethane (300ml), and was then added to a solution of trifluoroacetic anhydride (294ml, 0.666mol) in dichloromethane (300ml) at 0°C (ice bath). Pyridine (36ml, 0.444mol) was then added dropwise at 0°C , and the reaction mixture was stirred for 0.5h at which time the cooling bath was removed. After stirring at 22°C for 3h, the reaction was cooled again to 0°C and quenched with distilled water (100ml). The mixture was stirred at 22°C for lh, neutralized with solid sodium bicarbonate, diluted with dichloromethane (IL), washed with sat. aq. sodium bicarbonate (300ml), brine (300ml), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by bulb-to-bulb distilation (96-98°C, 0.2mmHg) to afford the title compound (43.5g, 84%) as a yellow liquid. Analysis for C11H11F3O2 calcd. C 56.90%, H 4.78%; Found: C 56.61% H
4.98%.
4-[4-Hydroxyphenyl]-l ,1 ,l-trifluoro-2-butanone
To a solution of l,l,l-trifluoro-4-[4-methoxyphenyl]-2-butanone (43.5g, 0.187mol) in dichloromethane (500ml) at -78°C (dry ice-acetone) was added dropwise boron tribromide (53ml, 0.561mol). The mixture was then stirred at 0°C (ice bath) for 3h, and cautiously quenched by dropwise addition of ice-water (200ml) over a period of lh. The aqueous phase was saturated with solid sodium chloride, extracted with dichloromethane (500ml) followed by diethyl ether (500ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by bulb-to-bulb distilation (96-100°C, 0.2mmHg) to afford the title compound (34.4g, 84%) as a yellow liquid which solidified upon standing. Analysis for C10H9F3O2 -0.5H2O calcd. C 52.87%, H 4.44%; Found: C 52.93% H 4.53%.
4-(3,3-Dimethoxy-4,4,4-trifluorobut-l-yl')phenol')
To a solution of l,l,l-trifluoro-4-[4-hydroxyphenyl]-2-butanone (40.4g, 0.185mol) in nitromethane (300ml) were added methanol (40ml), trimethyl orthoformate (100ml) and trifluoromethanesulfonic acid (1ml). The resulting mixture was heated to 75°C for 20h, then cooled to r.t. and poured into sat. sodium bicarbonate (700ml). After stirring for lOmin., the mixture was extracted with ethyl acetate (2x2L). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 97 : 3) to afford the title compound (21.5g, 44%) as a yellow oil and l,l,l-trifluoro-4[4-hydroxyphenyl]-2- butanone (23g, 57%). Analytically pure sample (20.2g, 41%) of 4-(4,4,4- trifluoro-3,3-dimethoxybut-l-yl)phenol was obtained by bulb-to-bulb distilation (98-102°C, 0.02mmHg).
r2-f4-(3.3-Dimethoxy-4,4,4-trifluorobut-l-yl)phenoxy ethyl] bromide
A mixture of 4-(3,3-dimethoxy-4,4,4-trifluorobut-l-yl)phenol (1.64g,
6.2mmol), potassium carbonate (1.3g, 9.3mmol) and 1,2-dibromoethane (5ml, 58mmol) was stirred and heated under reflux (130°C) for 26h. After cooling to room temperature, the mixture was filtered and washed with ethyl actate. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate 20 : 1 to 4 : 1) to give the title compound (2.0g, 85%) as a colorless liquid. Analysis for Ci Hi8BrF3θ3 calcd. C 45.30%, H 4.89%; Found: C 45.57% H
4.72%. ill
N-[2-[4-(/3.3-Dimethoxy-4.4.4-trifluorobut-l- yl)phenoxy]ethyl]dodecanamine
A mixture of 4-[4-(2-bromoethoxy)phenyl]-l,l,l-trifluoro-2-butanone, dimethyl ketal (5.0g, 13.5mmol), dodecylamine (12.5g 67.4mmol), disopropylethylamine (7.0ml, 40.4mmol), Nal (2.0g, 13.5mmol) and isopropanol(lθθml) was stirred and heated under reflux for 16h. After cooling to room temperature, the mixture was concentrated in vacuo, diluted with ethyl acetate (300ml), washed with brine (100ml), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 96 : 4) to afford the title compound (5.3g, 83%) as a colorless syrup. Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a white solid. Analysis for C26H44F3N O3ΗCI calcd. C 60.98%, H 8.86%, N 2.74%;
Found: C 60.73% H 8.56% N 2.73%.
4-rN-Dodecyl-N-[2-[4-(3.3-Dimethoxy-4.4.4-trifluorobut-l- v phenoxy] ethyl] aminolbutanoic acid, ethyl ester
A solution of N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l-yl)phenoxy]- ethyl]dodecanamine (2.0g, 4.2mmol) in methanol (50ml) was treated with sodium cyanoborohydride (0.55g, 8.4mmol) and ethyl 4-oxobutyrate (1.04g, 8.4mmol). The resulting mixture was stirred at 22°C for 16h, diluted with diethyl ether (350ml), washed with water (200ml), brine (200ml), dried over magnesium sulfate and concentrated in vacuo . The residue was chromatographed on silica gel (hexane /AcOEt 9 : 1 to 6 : 1) to afford the title compound (1.8g, 73%) as a liquid. Analysis for C32H54F3N O5 -0.3H2O calcd. C 64.58%, H 9.25%, N 2.35%; Found: C 64.54% H 9.02% N 2.39%.
4-rN-Dodecyl-N-[2-[4-(3-oxo-4.4.4-trifluorobut-l- v phenoxy] ethyl] amino]butanoic acid, ethyl ester
A solution of 4-[N-Dodecyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy]ethyl]amino]- butanoic acid, ethyl ester (315mg, 0.53mmol) in trifluoroacetic acid (5ml) was heated to 70°C for 2h, and then concentrated \2 in vacuo . The residue was diluted with ethyl acetate (100ml), washed with sat. sodium bicarbonate (30ml), brine (30ml), dried over magnesium sulfate and concentrated in vacuo . The residue was chromatographed on silica gel (Hexane/ethyl acetate 2 : 1 to 1.5 : 1) to afford the title compound (224mg, 77%) as a colorless oil.
The following compounds may be prepared by the general procedure of Scheme 4.
,2^
SCHEME 4 Table
(CH2)nR
Figure imgf000131_0001
Figure imgf000131_0002
\^
Figure imgf000132_0001
V"Λ
Scheme 5
Figure imgf000133_0001
Example 84
4-r4-r2-(N-Dodecyl-N-propylaminolethoxylphenyn-l,l,l-trifluoro-2- butanone
N-Propyl-N-[2-[4-C3.3-dimethoxy-4.4.4-trifluorobut-l- y phenoxy] ethyl] dodecy lamine
A solution of N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy]ethyl]dodecylamine (500mg, 1.05mmol), diisopropyl ethylamine (0.35ml, 2.1mmol) and 1-iodopropane (0.26ml, 2.66mmol) in isopropanol was heated to reflux for 21 h. After cooling to r.t., the mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo , and the residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 95 : 5) to afford the title compound (0.526g, 73%) as a colorless oil.
4-[4-[2-(N-Dodecyl-N-propylamino]ethoxy]phenyl]-l,l,l-trifluoro-2- butanone
N-Propyl-N-[2-[4-(4,4,4-trifluoro-3,3-dimethoxybut-l- yl)phenoxy]ethyl]dodecylamine (300mg, 0.58mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trif luoro-3-oxobut-l -y l)phenoxy ] ethyl] amino]butanoic acid, ethyl ester and afforded the title compound (169mg, 62%) as a pale yellow oil. Analysis for C27H44F3NO2O.9H2O calcd. C 66.47%, H 9.46%, N 2.87%;
Found: C 66.39%, H 9.10%, N 2.87%.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow syrup. Analysis for C27H44F3NO2ΗCM.2H2O calcd. C 61.22%, H 9.02%, N 2.64%;
Found: C 61.38%, H 8.61%, N 2.75%. I 3 Example 85
4-f4-r2-(N-Dodecyl-N-hexylamino1ethoxy1phenyll-l,l,l-trifluoro-2- butanone
N-Hexyl-N-r2-r4-t/3.3-dimethoxy-4.4.4-trifluorobut-l- v phenoxy] ethyl] dodecylamine
N-[2-[4-(3,3-Dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy] ethyl] dodecylamine (500mg, 1.05mmol) and 1-iodohexane
(0.186ml, 1.26mmol) were reacted as described in the preparation of N- propyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy] ethyl] dodecylamine and afforded the title compound (390mg, g, 67%) as a liquid.
4-[4-[2-(,N-Dodecyl-N-Hexylamino]ethoxy]phenyl1-l,l,l-trifluoro-2- butanone
N-Hexyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy] ethyl] dodecylamine (353mg, 0.63mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trifluoro-3-oxobut-l-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester . The residue was chromatographed on silica gel (dichloromethane/methanol 98 : 2 to 94 : 6) to afford the title compound (253mg, 78%) as a pale yellow oil.
Analysis for C30H50F3NO2 calcd. C 70.14%, H 9.81%, N 2.73%; Found: C
69.79%, H 9.82%, N 2.76%.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow syrup. Analysis for C30H50F3NO2ΗCIO.7H2O calcd. C 64.02%, H 9.39%, N 2.49%;
Found: C 64.09%, H 9.05%, N 2.61%. U M
Scheme 6
Figure imgf000136_0001
Figure imgf000136_0002
27
Example 86
4-f4-r2-(N-dodecyl-N-ethylamino1ethoxy1phenyn-l,l,l-trifluoro-2- butanone
2-[N-Dodecyl-N-ethylamino]ethanol
2-[Dodecylamino]ethanol (2.0g, 8.73 mmol) ,1-iodoethane (1.63g, 10.48 mmol) and N,N-diisopropylethylamine ( 2.51 g,l 7.5 mmol) in isopropanol ( 25 ml )were heated under reflux for 4 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate washed with aqueous sodium bicarbonate, brine and dried (magnesium sulfate ). Evaporation of the solvent followed by chromatography on silica gel (ethyl acetate /methanol 90 : 10 to 80 : 20) afforded the title compound (1.65g, 73%) as a white solid.
N-Ethy 1-N-r 2- f4-f 3.3-dimethoxy-4.4.4-trifluoro-but-l - y phenoxy ] ethyl] dod ecy lamine
2-[N-Dodecyl-N-ethylamino]ethanol (250mg, 0.96mmol) and 4-(3,3- dimethoxy-4,4,4-trifluorobut-l-yl)phenol (230mg, 0.87mmol) were reacted under Mitsunobu conditions as described in the preparation of 3-[4-[2-(N- dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, methyl ester. The usual work-up followed by chromatography on silica gel (Hexane/ethyl acetate 95 : 5 to 80 : 20) afforded the title compound (200mg, 46%) as a colorless oil.
4-[4-r2-(N-dodecyl-N-ethylamino]ethoxy1phenyl]-l,l,l-trifluoro-2- butanone
N-Ethyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-l- yl)phenoxy]ethyl]dodecylamine (123mg, 0.244mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4- (4,4,4-trifluoro-3-oxobut-l-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (60mg, 54%) as a pale yellow oil.
Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow syrup. Analysis for C26H42F3NO2-HC1-0.6H2O calcd. C 60.45%, H 8.64%, N 2.69%; Found: C 60.19%, H 8.27%, N 3.08%.
The following compounds may be prepared by the general procedure of Scheme 6.
~
SCHEME 6 Tables
Figure imgf000139_0001
Figure imgf000139_0002
f
Figure imgf000140_0001
SCHEME 6 - Table (continued)
Figure imgf000141_0001
Figure imgf000141_0002
W
Figure imgf000142_0001
Figure imgf000143_0001
i HI
Figure imgf000144_0001
10
15
20 IH3
Scheme 7
Figure imgf000145_0001
28 29 30
Figure imgf000145_0002
31 32
TFA
Figure imgf000145_0003
33a 33b Example 119
N-r2-f4-(4.4,4-trifluoro-3-oxo-l-butyl)phenoxy1ethyn-N-methyl dodecanamide
N-[2-(4-formylphenoxy)ethyl]-N-methylcarbamic acid, 1,1-dimethylethyl ester
A solution of N-(2-hydroxyethyl)-N-methylcarbamic acid, 1,1- dimethylethyl ester (7.05 g, 40.2 mmol; W.S. Saari and all, J. Med. Chem. 33, 97 (1990)), 4-hydroxybenzaldehyde (3.75 g, 30.7 mmol) and triphenylphosphine (10.57 g, 40.3 mmol) in dry benzene (120 ml) was cooled to 15°C and treated with diisopropyl azodicarboxylate (8.15 g, 40.3 mmol) in dry benzene (20 ml) added dropwise over 20 min. After 16 h at 22°C, and chromatography on silica gel (elution toluene-ethyl acetate 9:1- 8:2) gave 4.40 g (52%) of the title material as white cubes: mp 62-65°C (ether-hexane).
Anal. Calcd. for C15H21NO4: C 64.50, H 7.58, N 5.01.
Found: C 64.25, H 7.59, N 5.00.
E-N-f2-f4-(4-trifluoro-3-oxo-l-butenyl)phenoxy1ethyn-N-methylcarbamic acid, 1,1-dimethylethyl ester
A solution of N-[2-(4-formylphenoxy)ethyl]-N-methylcarbamic acid, 1,1- dimethylethyl ester (3.72 g, 13.3 mmol) in dry tetrahydrofuran (65 ml) was cooled to 10°C and treated with acetic acid (1.4 ml) and piperidine (1.4 ml). Then 1,1,1-trifluoroacetone (7 ml) in dry tetrahydrofuran was added dropwise over 10 min. After 2 h and 4 h at 20°C, two other successive portions of 1,1,1-trifluoromethylacetone (2 x 7 ml) were also added. After another 2 h at 22°C, the reaction mixture was diluted with ethyl acetate (300 ml) washed with water, saturated ammonium chloride, saturated sodium bicarbonate and brine. The organic phase was then dried, concentrated and chromatographed on silica gel. Elution with a gradient of ethyl acetate in hexane (0 - 20%) gave 3.05 g (61%) of the title material as yellow crystals: mp 76-77°C (hexane).
Anal. Calcd. for C18H22NO4F3: C 57.90, H 5.94, N 3.75. Found: C 57.82, H 5.92, N 3.72.
N-f2-f4-(4-trifluoro-3-oxo-l-butyl)phenoxylethyn-N-methylcarbamic acid, 1,1-dimethylethyl ester
A solution of (E)-N-[2-[4-(4-trifluoro-3-oxo-l-butenyl)phenoxy]ethyl]-N- methylcarbamic acid, 1,1-dimethylethyl ester (1.10 g, 2.95 mmol) in ethyl acetate (80 ml) was hydrogenated at atmospheric pressure over 5% palladium on barium sulfate (0.20 g) for 1 hour. The catalyst was then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (60 ml) and then treated at 22°C with Dess-Martin periodinane reagent (2.50 g, 5.90 mmol). After 1 hour, the reaction mixture was diluted with ethyl acetate, washed with 10% aqueous sodium thiosulfate and saturated sodium bicarbonate. After drying, the organic phase was concentrated and chromatographed on silica gel. Elution with a gradient of ethyl acetate (0 - 10%) in toluene gave 0.880 g (79%) of the title material as an amorphous solid. By 'H NMR this product is a mixture of ketone and hydrated ketone.
Anal. Calcd. for C18H24NO4F3. 0.7 H2O: C 55.72, H 6.60, N 3.61. Found: C 55.80, H 6.52, N 3.52.
N-f2-r4-(4-trifluoro-3-oxo-l-butyl)phenoxylethyll-N-methyldodecanamide
A solution of N-[2-[4-(4-trifluoro-3-oxo-l-butyl)phenoxy]ethyl]-N- methylcarbamic acid, 1,1-dimethylethyl ester (0.200 g, 0.53 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (1 ml) and stirred at 22°C for 1 h. The solvent was evaporated in vacuo and the residue was co-evaporated with toluene three times. The product was then dissolved in tetrahydrofuran (10 ml) treated with 40% sodium acetate in water (10 ml) and while stirred vigorously treated with lauroyl chloride (0.116 g, 0.53 g mmol) added dropwise over 2 min. After 1 hour at 22°C, the reaction mixture was diluted with ethyl acetate (150 ml), washed with water, saturated sodium bicarbonate and brine. After drying (magnesium sulfate) the solvent was evaporated in vacuo and the residue was chromatographed on silica gel. Elution with a gradient of ethyl acetate (0 - 30%) in toluene gave 0.181 g (74%) of the title material as a waxy solid. By Η NMR, this product is a mixture of ketone and hydrated ketone.
Anal. Calcd. for C25H38F3NO3. H2O: C 63.14, H 8.48, N 2.95. Found: C 63.26, H 8.03, N 2.87.
The following compounds may be prepared by the general procedure of Scheme 7.
m
SCHEME 7
Figure imgf000149_0001
Figure imgf000149_0002
Figure imgf000150_0001
M^
SCHEME 7 (continued)
Figure imgf000151_0001
Figure imgf000151_0002
|S&
Scheme 8
Figure imgf000152_0001
BrCH C0 tBu
BrCH2C02tBu acetone acetone potassium carbonate potassium carbonate (or R2COCI)
Figure imgf000152_0002
3Z 3S
Figure imgf000152_0003
39 '■^t
Figure imgf000153_0001
36 40
TFA dichloromethane
Figure imgf000153_0002
41 23
Example 133
N-Dodecyl-4-(4,4,4-trifluoro-3-oxo-l-butyl)phenoxyacetamide
(E)-l ,1 ,l-trifluoro-4-(4-hydroxyphenyP-3-buten-2-one
A solution of 4-hydroxybenzaldehyde (5.0 g, 40.9 mmol) in tetrahydrofuran (165 ml) was treated with acetic acid (3.5 ml) and piperidine (3.5 ml). Then 1,1,1-trifluoroacetone (8 ml) was added dropwise. After 2 h at 22°C, another portion of 1,1,1-trifluoroacetone (8 ml) was added and the mixture was stirred for another 3 h. The reaction mixture was then diluted with ethyl acetate, washed with water, saturated ammonium chloride, saturated sodium bicarbonate, and brine. The organic phase was dried (magnesium sulfate), concentrated under reduced pressure and chromatographed on silica gel. Elution with a gradient of ethyl acetate (0 - 5%) in toluene gave 4.16 g (47%) of title material as yellow needles after crystallization from ether-hexane: mp 106- 107°C.
Anal. Calcd. for C10H7F3O2: C 55.57, H 3.26. Found: C 55.30, H 3.27.
(E -4-(4,4,4-trifluoro-3-oxo-l-butenyl)phenoxyacetic acid, 1,1-dimethylethyl ester
A solution of (E)-l,l,l-trifluoro-4-(4-hydroxyphenyl) 3-buten-2-one (0.105 g, 0.49 mmol) in acetone (6 ml) was treated with powdered potassium carbonate (0.3 g) and tert-butyl bromoacetate (0.20 g, 1.02 mmol) and stirred at 22°C for 3 h. The reaction mixture was then diluted with toluene, washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 2%) and gave 0.150 g (94%) of the title material as yellow needles: mp 112-113°C.
Anal. Calcd. for C16H17F3O4: C 58.18, H 5.19. Found: C 58.12, H 5.18. (E)-4-('4.4,4-trifluoro-3-oxo-l-butenyl)phenoxyacetic acid
A solution of (E)-4-(4,4,4-trifluoro-3-oxo-l-butenyl)phenoxyacetic acid, 1,1- dimethylethyl ester (1.578 g, 4.77 mmol) in dichloromethane (90 ml) was treated with trifluoroacetic acid (10 ml) and stirred at 22°C for 4 h. The solvent and excess reagent were evaporated under reduced pressure and the last traces of trifluoroacetic acid were co-evaporated with toluene. Crystallization of the residue from ethyl acetate-hexane gave 1.29 g (98%) of the title material as white cubes: mp 156-156.5°C. Anal. Calcd. for C12H9F3O4: C 52.57, H 3.31. Found: C 52.66, H 3.29.
(E N-dodecyl-4-(4,4,4-trifluoro-3-oxo-l-butenyDphenoxyacetamide
A solution of (E)-4-(4,4,4-trifluoro-3-oxo-l-butenyl)phenoxyacetic acid (0.810 g, 2.95 mmol) in tetrahydrofuran (20 ml) was treated with EEDQ (0.767 g, 3.10 mmol) and dodecylamine (0.575 g, 3.10 mmol). After 2 h at 22°C, the reaction mixture was diluted with ethyl acetate, washed with water, 0.1N hydrochloric acid, saturated sodium bicarbonate, brine and dried. Evaporation of the solvent under reduced pressure gave a solid which was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (8:12) gave 0.750 g (58%) of the title material as white needles after recrystallization from ethyl acetate-hexane: mp 78.5- 79°C. Anal. Calcd. for C24H34F3NO3: C 65.29, H 7.76, N 3.17. Found: C 65.30, H 7.73, N 3.13.
N-dodecyl-4-(4.4,4-trifluoro-3-oxo-l-butyl)phenoxyacetamide
(E)-N-dodecyl-4-(4,4,4-trifluoro-3-oxo-l-butenyl)phenoxyacetamide (0.530 g, 1.20 mmol) was hydrogenated and re-oxidized as described in example 119 to give 0.490 g (92%) of the title material as an amorphous solid.
Anal. Calcd. for C24H36F3NO3H2O: C 62.45, H 8.30, N 3.03. Found: C 62.54, H 8.19, N 3.18. I Example 134
N-rBis-(4-chlorophenyl)methyl1-4-(4,4,4-trifluoro-3-oxo-l-butyl)- phenoxyacetamide
4-(4.4,4-trifluoro-3-oxo-l-butyl)-phenoxyacetacetic acid. 1 ,1-dimethylethyl ester
E-(4,4,4-trifluoro-3-oxo-l-butenyl)-phenoxyacetacetic acid, 1,1- dimethylethyl ester (1.95 g, 5.90 mmol) was hydrogenated and re-oxidized as described in example 133 to give 1.93 g (98%) of the title material as a wax.
Anal. Calcd. for C16H19F3O4: C 55.43, H 5.99. Found: C 55.32, H 5.90.
4-(4.4,4-trifluoro-3-oxo-l-butyl')phenoxyacetic acid
4-(4,4,4-trifluoro-3-oxo-l-butyl)phenoxyacetic acid 1,1-dimethylethyl ester (0.450 g, 1.35 mmol) was treated with trifluoroacetic acid as described in example (133) to give 0.373 g (100%) of the material as a white solid.
N-[Bis-(4-chloropheny methyl]-4-C4.4.4-trifluoro-3-oxo-l- butyDphenoxyacetamide
A solution of 4-(4,4,4-trifluoro-3-oxo-l-butyl)phenoxyacetic acid (0.374 g, 1.35 mmol) in dichloromethane (10 ml) was treated with oxalyl chloride (0.17 ml, 2.03 mmol) and a trace of N,N-dimethylformamide. After 30 min at 22°C, the solvent and excess reagent were evaporated under reduced pressure and the residual oil obtained was dissolved in anhydrous tetrahydrofuran (10 ml). This solution was then added dropwise to a vigorously stirred solution of p-chlorobenzhydrylamine hydrochloride (0.39 g, 1.35 mmol) in a mixture of tetrahydrofuran (10 ml) and 40% aqueous sodium acetate (10 ml). After 30 min at 22°C, the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried. Evaporation of the solvent under reduced pressure gave a solid which was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (8:2) gave 0.603 g (87%) of the title product as white crystals: mp 145-146°C.
Anal. Calcd. for C25H20CIF3NO3: C 58.84, H 3.85, N 2.74, CI 13.89, F 11.17. Found: C 58.73, H 4.07, N 2.82, CI 13.60, F 10.46.
liTfo
Scheme 9
CH3(CH2)nSH + BrCH2CH2OH (CH3)(CH2)nSCH2CH2OH
DMF potassium carbonate
Figure imgf000158_0001
42 44
Figure imgf000158_0002
mCPBA . Nal04 dichloromethane methanol
0 q yO VS(CH2)nCH3 S(CH2)nCH3
Example 135
4-f4-r2-(Dodecylthio)ethoxyphenyn-lr1 -tιifluoro-2-butanone
2-(Oodecyrthio^ Ethanol
Figure imgf000159_0001
A mixture of 2-bromoethanol (6.08 g, 48.7 mmol), dodecanethiol (9.86 g, 48.7 mmol) and potassium carbonate (11 g) in dry N,N- dimethylformamide (100 ml) was stirred at 22°C for 10 h. The reaction mixture was then diluted with toluene (400 ml) washed with water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the residue was filtered through a silica gel pad (toluene - ethyl acetate 95:5) and distilled under vacuum to give 9.18 g (77%) of 2-
(dodecylthio)ethanol as a clear oil which solidified on standing: b.p. 100-
105°C/0,01 torr (bulb to bulb distillation, air bath temperature); m.p. 31-
32°C.
IR (NaCl, film) μ^ (cm-1) : 3380 (OH). NMR 400 MHz (CDCI3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, CH3), 1.2-1.7
(20H, m, (CH2)10), 2.16 (IH, br t, OH), 2.52 (2H, t, J=7.4 H, SCH2), 2.74 (2H, t,
J=6.0 Hz, OCH2CH2S), 3.7 (2H, q, J=6.0 Hz, OCH2CH2S.
Anal. Calcd. for C14H30OS: C 68.23, H 12.27, N 13.01.
Found: C 68.06, H 12.29, N 12.95. 3-[4-[2-(Dodecylthio)ethoxy]phenyl]propanoic acid methyl ester
Figure imgf000160_0001
A solution of methyl 3-[4-hydroxyphenyl)propionate (2.46 g, 13.6 mmol), 2-(dodecylthio)ethanol (3.40 g, 13.7 mmol) and triphenylphosphine (3.60 g, 13.8 mmol) in dry benzene (50 ml) was treated at 22°C with diethyl azodicarboxylate (2.43 g, 13.9 mmol) added dropwise over 10 min. After 3 h at 22°C, the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation under reduced pressure gave an oil which was triturated with hexane to precipitate the triphenylphosphine oxide and the hydrazine side products. The filtrate was chromatographed on silica gel using a gradient of ethyl acetate (0-5%) in hexane as eluent to give 4.70 g(84%) of 3-[4-[2- (dodecylthio)ethoxy]phenyl]propanoic acid methyl ester as a white solid. Recrystallization from methanol gives white leaflets : m.p. 48°C. IR (KBr) μ^ (cm-1) : 1729 (C=0 of ester).
1H NMR 400 MHz (CDCI3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, CH3), 1.2-1.7 (20H, m, (CH2)10), 2.6 (4H, br t, SCH2 and CH2CO), 2.9 (4H, br t, OCH2CH2S and PhCH?), 3.68 (3H, s, OCH3), 4.11 (2H, t, J=7.03 Hz, OCH2CH2S), 6.83 (2H, d, J=8.7 Hz aromatic), 7.12 (2H, d, J=8.7 Hz, aromatic).
Anal. Calc. for C24H40O3S: C 70.54, H 9.87, S 7.85.
Found: C 70.25, H 9,38, S 7.87. 3-[4-[2-(Oodecylthio')ethoxy]phenyl]propanoic acid
H2)ι ι CH3 (CH2)^ 1 CH3
Figure imgf000161_0001
Figure imgf000161_0002
A suspension of 2-[4-[2-(dodecylthio)ethoxy]phenyl]propanoic acid methyl ester (4.70 g, 11.5 mmol) in 80% ethanol (100 ml) was treated with a solution of potassium hydroxide (1.33 g, 20.1 mmol) in water (10 ml) and the mixture was stirred at 55°C for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (100 ml) and dichloromethane (250 ml). The solution was then adjusted to pH 2 with diluted hydrochloric acid and the aqueous phase was extracted a second time with dichloromethane. The combined organic extracts were washed with brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure and crystallization of the residue from ethyl acetate-hexane gave 3.56 g (78%) of 3-[4-[2-
(dodecylthio)ethoxy]phenyl]propanoic acid as white prisms: m.p. 68-69°C. IR (NaCl, film) μmaχ (cm-1) : 1710 (C=0).
XH NMR 400 MHz (CDCI3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.1-1.7 (20H, m, (CH2)10), 2.63 (4H, m, SCH2 and CH2CO), 2.90, (4H, m, OCH2CH2S and PhCH?). 4.12 (2H, t, J=6.99, OCH2CH2S), 6.84 (2H, d, J=8.5
Hz, aromatic), 7.13 (2H, d, J=8.5 Hz, aromatic).
Anal, calcd. for C23H38O3S . 0.1 H2O: C 69.69, H 9.71, S 8.09.
Found: C 69.55, H 9.86, S 8.15. 4-[4-[2-(Dodecyrthio')ethoxy]phenyl]-l ,1 ,l-trifluoro-2-butanone
Figure imgf000162_0001
A solution of 3-[4-[2-(dodecylthio)ethoxy]phenyl]propanoic acid (14.13 g, 35.8 mmol) in dichloromethane (400 ml) was treated with oxalyl chloride (6.5 ml) and a drop of N,N-dimethylformamide and the resulting mixture was stirred at 22°C for 1 h. The solvent and excess reagent were evaporated under reduced pressure and the residue was dissolved in dry dichloromethane (200 ml). This solution was added to a cold (0°C) solution of trifluoroacetic anhydride (19.2 ml, 0.107 mol) in dichloromethane (200 ml). Then pyridine (6.1 ml, 75.4 mmol) was added dropwise and the resulting solution was stirred at 0°C for 30 min and then at 22°C for 2 h. Water (50 ml) was added and the mixture was stirred for another 30 min. The organic phase was then washed with brine, dried and concentrated under reduced pressure. Chromatography on silica gel (elution with a gradient of ethyl acetate 0-10% in toluene) gave 10.50 g (66%) of 4-[4-[2-(dodecylthio)ethoxy]phenyl]-l,l,l-trifluoro-2-butanone as an amorphous solid. IR (NaCl, film) μ^ (cm-1) : 1758 (C=0).
*H NMR 400 MHz (CDCI3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.2-1.7 (20H, m, (CH2)10), 2.62 (2H, t, J=7.46 Hz, SCH2), 2.89 (2H, t, J=6.95 Hz, OCH2QI2S), 2.9-3.1 (4H, m, CH9CH9CO).4.12 (2H, t, J=6.95 Hz, OCH2CH2S), 6.85 (2H, d, J=8.7 Hz, aromatic), 7.11 (2H, d, J=8.7 Hz, aromatic). Anal. Calcd. for C24H37F3O2S: C 64.54, H 8.35. Found: C 64.47, H 8.32.
Example 136
4-[4-[2-(Dodecylsulfiny ethoxy]phenyl]-l.l,l-trifluoro-2-butanone
Figure imgf000163_0001
A solution of 4-[4-[2-(dodecylthio)ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (0.340 g, 0.76 mmol) in methanol (15 ml) was treated with a solution of sodium periodate (0.165 g, 0.77 mmol) in water (3 ml) and the resulting mixture was stirred at 22°C for 18 h. The solid formed was filtered and washed with methanol. This filtrate was then concentrated under reduced pressure and then partitioned between water and ethyl acetate. The organic phase was then dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 1:1) to give 0.335 g (90%) of 4-[4-[2- (dodecylsulfinyl)ethoxy]phenyl]-l,l,l-trifluoro-2-butanone as a white solid. By 'HNMR this product was a 6:4 mixture of trifluoromethyl ketone and hydrated trifluoromethyl ketone. The pure hydrate precipitates from ethyl acetate-hexane: m.p. 98-100°C. IR (NaCl, film) μ (cm-1) : 3400 (OH), 1650. iCl
*H NMR 400 MHz (CDCI3) d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.3, 1.45 and 1.8 (16H, 2H and 2N, 3m, (CH2)lθ), 2.09 (2H, br t, J=8 Hz, CH2CH2CO), 3.7 (2H, br, OH), 4.4 (2H, m, OCH2), 6.84 (2H, d, J=8.5 Hz, aromatic), 7.15
(2H, d, J=8.5 Hz, aromatic). Anal. Calcd. for C24H37F3S.H2O: C 59.98, H 8.18, S 6.67.
Found: C 60.06, H 8.17, S 6.67.
Example 137
4-[4-[2-(Dodecylsulfony ethoxy]phenyl]-l,l.l-trifluoro-2-butanone
Figure imgf000164_0001
A solution of 4-[4-[2-(dodecylthio)ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (0.394 g, 0.88 mmol) in dichloromethane (25 ml) was treated at 22°C with 85% m-chloroperbenzoic acid (0.40 g, 1.8 mmol) and the resulting mixture was stirred for 2.5 h. The reaction mixture was then washed with aqueous sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation and chromatography on silica gel (elution with a gradient of ethyl acetate 0-20% in toluene) gave 0.344 g (82%) of 4-[4-[2-
(dodecylsulfonyl)ethoxy]phenyl]-l,l,l-trifluorobutanone as an amorphous solid. By 'HNMR, this product is a -1:1 mixture of trifluoromethylketone and hydrated trifluoromethyl ketone: m.p. 55-56°C IR (NaCl, film) umax (cm"1) : 3400 (OH) and 1760 (C=0). H NMR 400 MHz (CDCI3) .
Ketone form : d (ppm) : 0.89 (3H, t, J=6.8 Hz, -CH3), 1.28, 1.45 and 1.9 (16H, 2H and 2H, 3 m, (CH2)lθ), 3.0 (4H, m, CH9CH9CO . 3.12 (2H, m, Sθ9CH? 3.4 (2H, t, J=5.35 Hz, OCH2CH2S), 4.41 (2H, t, J=5.35 Hz, OCU2CH2S), 6.84 (2H, d, J=8.6 Hz, aromatic), 7.15 (2H, d, J=8.6 Hz, aromatic).
Hydrate form : d (ppm) : 2.14 (2H, br t, J=8.1 Hz, CH2CH2CO), 2.87 (2H, br t, J=8.1 HJz, CU2CH2CO), 6.86 (2H, d, J=8.6 Hz, aromatic), 7.2 (2H, d, J=8.6 Hz, aromatic).
Anal. Calcd. for C24H37F3O4S . 0.6 H2O: C 58.90, H 7.87, S 6.55.
Found: C 58.86, H 7.79, S 6.63.
Example 138
4-r4-r2-r2-rBis(4-chlorophenyl)methoxy1ethylsulfonynethoxy1phenyll-l,l.l- trifluoro-2-butanone
2-[Bis(4-chlorophenyl)methoxy]ethyl bromide.
Figure imgf000165_0001
A mixture of 4,4'-dichlorobenzhydrol (4.40 g, 0.17 mmol) and 2- bromoethanol (3.0 g, 24.0 mmol) in benzene (50 ml) was treated with sulfuric acid (0.25 ml) and the resulting mixture was heated under reflux ι ^ for 1 h. The cooled mixture was diluted with ethyl acetate (200 ml), washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was chromatographed on silica gel using a mixture of toluene and hexane (1:1) as eluent to give the title compound as a clear oil (5.13 g, 82%).
2-[2-[Bis(4-chlorophenyDmethoxy]ethylthio]ethanol
Figure imgf000166_0001
A solution of 2-[bis(4-chlorophenyl)methoxy]ethyl bromide (5.13 g, 14.2 mmol) in N,N-dimethylformamide (50 ml) was treated at 22°C with powdered anhydrous potassium carbonate (3.0 g, 21.7 mmol) followed by 2-mercaptoethanol (1.25 g, 16.0 mmol). The resulting mixture was stirred at 22° for 18 h. The reaction mixture was then diluted with toluene (400 ml) washed with water, brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was chromatographed on silica gel (elution ethyl acetate 0-10% in toluene) to give 4.93 g (96%) of the title material as a clear oil. Anal. Calcd. for C17H18CI2O2S: C 57.15, H 5.08, S 8.97. Found: C56.99, H
4.82, S 9.05. \ -.
3-[4-[2-[2-[Bis(4-chlorophenyDmethoxy]ethylthio]ethoxy]phenyl]propionic acid methyl ester
Figure imgf000167_0001
A solution of methyl 3-(4-hydroxyphenyl) propionate (1.40 g, 7.77 mmol), 2-[2-[bis(4-chlorophenyl)methoxy]ethylthio]ethanol (2.80 g, 7.80 mmol) and triphenylphosphine (2.0 g, 7.8 mmol) in dry benzene (30 ml) was treated at 22°C with diethyl azodicarboxylate (1.34 g, 7.8) added dropwise over 5 min. After 18 h at 22°C, the reaction mixture was diluted with ethyl acetate (200 ml) washed with saturated sodium bicarbonate and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was triturated in a mixture of hexane and toluene (6:4) to crystallize the triphenylphosphine oxide and the hydrazine side products. The filtrate was chromatographed on silica gel (elution ethyl acetate 0-5% in toluene) to give 2.90 g (71%) of the title material as an oil. Anal. Calcd. for C27H28CI2O4S: C 62.43, H 5.43, S 6.17. Found: C 61.89, H
5.21, S 6.11. 3-[4-[2-[2-[Bis(4-chlorophenyDmethoxy]ethylthio]ethoxy]phenyl]propionic acid
Figure imgf000168_0001
A mixture of 3-[4-[2-[2-[Bis(4- chlorophenyl]methoxy]ethylthio]ethoxy]phenyl] propionic acid methyl ester (2.76 g, 5.31 mmol) and 80% aqueous ethanol (50 ml) was treated with a solution of potassium hydroxide (0.7 g, 10.6 mmol) in water (3 ml) and the resulting mixture was heated at 60°C for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (30 ml) and dichloromethane (50 ml) and acidified to pH4 with 2N hydrochloric acid. The aqueous phase was extracted a second time with dichloromethane and the combined organic extracts were washed with brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure gave 2.63 g (98%) of the title acid as a white solid. Anal. Calcd. for C26H26 I2O4S: C 61.78, H 5.18, S 6.34. Found: C 61.42, H
5.11, S 6.34. 4-[4-[2-[2-[Bis('4-chloropheny methoxy]ethylthio]ethoxy]phenyl]-l.l,l- trifluoro-2-butanone
Figure imgf000169_0001
A solution of 3-[4-[2-[2-[bis(4- chlorophenyl)methoxy]ethylthio]ethoxy]phenyl]propionic acid (2.49 g, 4.93 mmol) in dry dichloromethane (25 ml) was treated at 22°C with oxalyl chloride (1.5 g, 11.8 mmol) and a small drop of N,N-dimethylformamide. After 1 h, the solvent and excess reagent were evaporated in vacuo and the residue was diluted with dry toluene (75 ml). The solution was then cooled to 0-5°C, treated with trifluoroacetic anhydride (3.12 g, 14.9 mmol) followed by pyridine (0.98 g, 12.4 mmol) added dropwise over 10 min. The reaction mixture was then allowed to warm up to 20°C and stirred for another 2 h. Then water (5 ml) was added dropwise and the mixture was stirred for another 15 min. The reaction mixture was then diluted with ethyl acetate (300 ml) washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation gave an oil which was chromatographed on silica gel. Elution with a gradient of ethyl acetate (0- 4%) in toluene gave 2.35 g (85%) of the title material as an oil.
Anal. Calcd. for C27H25CI2F3O3S.O.4 H2O: C 57.43, H 4.63, S 5.68. Found: C
57.42, H 4.41, S 5.49. 4-[4-[2-[2-[Bis(4-chloropheny methoxy]ethylsulfinyl]ethoxy]phenyl]-l.l.l- trifluoro-2-butanone
Figure imgf000170_0001
A solution of 4-[4-[2-[2-[bis(4- chloropheny 1) methoxy ] ethyl thio ] ethoxy ] phenyl] - 1 , 1 , 1 -trifluoro-2- butanone (0.88 g, 1.58 mmol) in methanol (40 ml) was treated at 22°C with a solution of sodium periodate (0.34 g, 1.58 mmol) in water (2 ml). After 6.5 h the solid formed was filtered and the filtrate was evaporated in vacuo. The residue was diluted with ethyl acetate, washed successively with sodium bicarbonate, water and brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel (elution ethyl acetate) to give 0.691 g (76%) of the title material as an oil. Anal. Calcd. for C27H25 I2F3O4S. 0.6 H2O: C 55.51, H 4.52, S 5.49. Found:
C 55.37, H 4.31, S 5.39.
4-[4-[2-[2-[Bis(4-chloropheny methoxy]ethylsulfonyl]ethoxy]phenyl]-l.l.l- trifluoro-2-butanone
Figure imgf000171_0001
A solution of 4-[4-[2-[2-[bis(4- chlorophenyl)methoxy]ethylthio]ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (1.51 g, 2.71 mmol) in dichloromethane (50 ml) was treated at 22°C with m-chloroperbenzoic acid (0.94 g, 5.4 mmol) and the resulting mixture was stirred for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation and chromatography on silica gel (elution toluene-ethyl acetate 8:2) gave 1.46 g (92%) of the title material as an oil which crystallized upon standing: mp 98-100°C. IR (NaCl, film) umax (cm"1) 1755. αH NMR 400 MHz (CDCI3) d (ppm): 2.97 (2H, m), 3.02 (2H, m), 3.45 (2H, t, J=5.6 Hz), 3.53 (2H, t, J=5.6 Hz), 3.92 (2H, t J=5.6 Hz), 4.41 (2H, m), 5.39 (IH, s), 6.92 and 7.1-7.3 (12H, aromatic). Hydrated form: 2.15 and 2.87 (2m). Anal. Calcd. for C27H25CI2F3O5S: C 55.02, H 4.27, S 5.44. Found:
C 54.83, H 4.36, S 5.54.
The following compounds may be prepared by the general
procedure of Scheme 9. no
SCHEME 9
Figure imgf000172_0001
Figure imgf000172_0002
OI
Scheme 9 (continued)
Figure imgf000173_0001
Figure imgf000173_0002
ni.
Figure imgf000174_0001
<>3
Figure imgf000175_0001
,
Scheme 9B.
Figure imgf000176_0001
\ ^ Example 159
4-f4-r2-r2-Hydroxyethylthio1ethoxylphenyn-l,l,l-trifluoro butanone.
3-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl]propanoic acid, methyl ester
Figure imgf000177_0001
A solution of methyl 3-[4-hydroxyphenyl) propionate (30.0 g, 0.166 mol), 2,2'-thiodiethanol (61.0 g, 0.50 mol) and triphenylphosphine (48.0 g, 0.183 mol) in dry benzene (450 ml) was treated at 22°C with diethyl azodicarboxylate (33.2 g, 0.19 mol) added dropwise over 10 min and the resulting mixutre was stirred at 22°C for 5 h. The reaction mixture was then diluted with ether (300 ml) washed with water, saturated sodium bicarbonate and brine. After drying (magnesium sulfate) the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution toluene-ethyl acetate 85:15) to give 37.64 g (79%) of the starting material as a white solid: mp 47-48°C. Anal. Calcd. for C14H20O4S: C 59.13, H 7.09. Found: C 58.94, H 7.04. 3-r4-r2-(2-hydroxyethylthiolethoxy]phenyn propanoic acid.
Figure imgf000178_0001
A solution of 3-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl] propanoic acid, methyl ester (37.64 g, 0.132 mol) in 80% aqueous ethanol (300 ml) was treated with a solution of potassium hydroxide (17.0 g, 0.257 mol) in water (25 ml) and the resulting mixture was stirred at 22°C for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (200 ml) and dichloromethane (200 ml). The aqueous phase was then adjusted to pH 2 with 6N hydrochloric acid and extracted several times with dichloromethane. The combined organic extracts were washed with brine, dried (magnesium sulfate) and evaporated to give 35.67 g (100%) of the title material as a white solid: mp 64-65°C. Anal. Calcd. for C13H18O4S: C 57.76, H 6.71. Found: C 57.74, H 6.80.
1 7"?
3-f4-r2-(2-acetoxyethylthiolethoxylphenyll propanoic acid.
Figure imgf000179_0001
A solution of 3-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl] propanoic acid, (35.67 g, 0.13 mol) in a mixture of toluene (500 ml) and acetic acid (500 ml) was treated with p-toluenesulfonic acid (1.2 g) and then heated under reflux using a Dean-Stark apparatus for 2 h. The cooled mixture was concentrated in vacuo and the residue was diluted with ethyl acetate, washed with water and dried (magnesium sulfate). Evaporation of the solvent under vacuum gave a solid which was crystallized from hexane to give 36.13 g (88%) of title material as a white solid: mp 48-49°C.
4-r4-r2-(2-acetoxyethylthiolethoxylphenyll-l,l,l-trifluoro-2-butanone.
Figure imgf000180_0001
A solution of 3-[4-[2-(2-acetoxyethylthio)ethoxy]phenyl] propanoic acid, (36.13 g, 0.115 mol) in dichloromethane (250 ml) was treated with oxalyl chloride (24 ml) and a drop of N,N-dimethylformamide. After 1 h at 25°C, the solvent and excess reagent were evaporated in vacuo. The residual oil was dissolved in toluene (250 ml) cooled to 0°C and treated with trifluoroacetic anhydride (49.0 ml, 0.347 mol). Then pyridine (19.0 ml,
0.232 mol) was added dropwise over 30 min and the resulting mixture was stirred at 22°C for 3 h. The solution was then cooled again to 0°C, treated dropwise with water (70 ml) and then stirred at 22°C for 30 min. The solution was then diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo gave an oil which was chromatographed on silica gel. Elution with a mixture of dichlorimethane and ethyl acetate (0 - 2%) gave 26.10 g (62%) of the title material as an oil. \ T\
4-r4-f2-(2-hydroxyethylthio1ethoxy1phenyl1-l,l,l-trifluoro-2-butanone.
Figure imgf000181_0001
A solution of 4-[4-[2-(2-acetoxyethylthio)ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (26.10 g, 71.6 mmol) in ethanol (275 ml) was treated at 22°C with a solution of potassium hydroxide (6.0 g, 91.0 mmol) in water (70 ml) and the resulting mixture was stirred for 30 min. The solvent was then evaporated in vacuo and the residual oil was dissolved in ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent gave 23.0 g (100%) of the title material as an oil. Anal. Calcd. for C14H17F3O3S. 0.3 H2θ: C 51.31, H 5.41. Found: C 51.11, H
5.42.
Example 160
4-f4-r2-f2-rBis(4-methylphenyl)methoxylethylthio1ethoxy1phenyn-l,l.l- trifluoro-2-butanone.
Figure imgf000182_0001
A solution of 4-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (1.20 g, 3.72 mmol), 4,4'-dimethylbenzhydrol (0.95 g, 4.47 mmol) and p-toluenesulfonic acid (0.035 g) in toluene (20 ml) was heated under reflux for 15 min. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo and chromatography of the residue on silica gel (elution with a gradient of ethyl acetate 20-40% in hexane) gave 1.81 g (94%) of the title material as an oil.
Anal. Calcd. for C29H31F3O3S: C 67.42, H 6.05. Found: C 67.43, H 6.08.
The following compounds may be prepared by the general procedure of Scheme 9B. Table 9B
Figure imgf000183_0001
Figure imgf000183_0002
λl
Figure imgf000184_0001
»*3
Figure imgf000185_0001
l*M
Figure imgf000186_0001
1Y
Figure imgf000187_0001
Figure imgf000188_0001
v
Figure imgf000189_0001
λ%$
Figure imgf000190_0001
Λ^\
Figure imgf000191_0001
φc
Figure imgf000192_0001
Λ<¥i
Figure imgf000193_0001
■^1-
Figure imgf000194_0001
r
Example 244
Figure imgf000195_0001
58 53
mCPBA
Figure imgf000195_0003
Figure imgf000195_0002
60 SI 4-f4-f2-f4-Bis(4-methylphenyl)butylsulfonyllethoxylphenyl-l,l,l-trifluoro- 2-butanone.
l-Chloro^^-di-M-chlorophenyPbutane
Figure imgf000196_0001
A solution of 4,4'-dichlorodiphenylmethane (4.37 g, 18.4 mmol) (Blackwell, J. et all, J. Chem. Soc, 1961, 1405) in dry tetrahydrofuran (50 ml) was treated at 0°C with butyllithium (12.1 ml of 1.6 M, 19.36 mmol) added dropwise over 15 min. After 15 min, the red solution was then added dropwise to a cold (-78°C) solution of l-chloro-3-iodopropane (15.0 g, 73.4 mmol) in dry tetrahydrofuran (120 ml). After 20 min at -78°C, the reaction mixture was quenched by the addition of saturated ammonium chloride (100 ml) and diluted with toluene. The organic phase was washed with brine and dried. The oil obtained after evaporation of the solvent was purified on silica gel (elution hexane- toluene 85:15) and distilled under vacuum to give 2.54 g (44%) of the title material as a clear oil: bp 110-130°C/1.5 torr (air bath temperature). ><k l-Iodo-4,4-di-ι/4-chloropheny butane
Figure imgf000197_0001
A solution of methyl l-chloro-4,4-di-(4-chlorophenyl)butane (1.77 g, 5.64 mmol) in 2-butanone (20 ml) was treated with sodium iodide (1.5 g) and heated under reflux for 18 h. The solid formed was filtered, the filtrate was evaporated and purified on silica gel (elution hexane-toluene 96:5) to give 2.13 g (93%) of the title material as a clear oil.
n
2- [4-Bis-C4-chloropheny butylthio] ethanol
Figure imgf000198_0001
A solution of l-iodo-4,4-di-(4-chlorophenyl)butane (3.22 g, 7.96 mmol) in N,N-dimethyl formamide (45 ml) was treated at 22°C with powdered anhydrous potassium carbonate (2.2 g) followed by 2-mercaptoethanol (0.71 g, 9.20 mmol) and the resulting mixture was stirred at 22°C for 18 h. The reaction mixture was then diluted with toluene (400 ml) washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (elution toluene-ethyl acetate 8:2) to give 2.58 g (92%) of the title material as a clear oil. Anal. Calcd. for Ci8H2oCl2OS: C 60.84, H 5.67, S 9.02. Found: C 61.12, H 5.75, S 9.28.
S-^-t∑-^-Bis-^-chloropheny butylthiojethoxyjphenyljpropionic acid, methyl ester
Figure imgf000199_0001
A solution of methyl 3-(4-hydroxyphenyl)propionate (1.22 g, 6.77 mmol), 2-[4-bis-(4-chlorophenyl)butylthio]ethanol (2.58 g, 7.26 mmol) and triphenylphosphine (1.95 g, 7.43 mmol) in dry benzene (30 ml) was treated at 22°C with diethyl azodicarboxylate (1.29 g, 7.41 mmol) added drowise over 10 min. After 3 h at 22°C, the solvent was evaporated and the residue was chromatographed on silica gel (elution hexane ethyl acetate, 84:16) to give 3.17 g (91%) of the title material as a clear oil. Anal. Calcd. for C28H30CI2O3S: C 64.99, H 5.84, S 6.20. Found: C 65.01, H 5.86, S 6.38.
3-[4-[2-[4-Bis-(4-chloropheny butylthio]ethoxy]phenyl]propionic acid.
Figure imgf000200_0001
A suspension of 3-[4-[2-[4-bis-(4- chlorophenyl)butylthio]ethoxy]phenyl]propionic acid, methyl ester (3.09 g, 5.98 mmol) in ethanol (25 ml) was treated with a solution of potassium hydroxide (0.8 g, 14.3 mmol) in water (9.5 ml) and the resulting mixture was maintained at 35°C for 2 h. The pH of the solution was then adjusted to 4.0 with IN hydrochloric acid and the mixture was extracted with dichloromethane. The organic extract was dried (magnesium sulfate) and evaporated to give a white solid. Recrystallization from cyclohexane gave 2.93 g (97%) of the title material as a white solid: mp 89-92°C.
4-[4-[2-[4-Bis-(4-chloropheny butylthio]ethoxy]phenyl]-l.l,l-trifluoro-2- butanone.
Figure imgf000201_0001
A solution of 3-[4-[2-[4-bis-(4- chlorophenyl)butylthio]ethoxy]phenyl]propionic acid (2.85 g, 5.66 mmol) in dichloromethane (25 ml) was treated with oxalyl chloride (1.65 g, 13.0 mmol) and a small drop of N,N-dimethylformamide. After 1 h at 22°C, the solvent and excess reagent were evaporated in vacuo and the residual acid chloride was dissolved in dry toluene (85 ml). The solution was then cooled to 0°C and treated with trifluoroacetic anhydride (3.57 g, 17.0 mmol) in dry toluene (15 ml) added dropwise over 10 min. After 3.5 h at 22°C, the mixture was cooled again to 0°C and treated dropwise with water (5 ml) and stirred for 15 min. The reaction mixture was then diluted with toluene (200 ml), washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with a mixture of hexane and ethyl acetate (75:25) gave 2.62 g (83%) of the title material as an oil. Anal. Calcd. for C28H27CI2F3O2S: C 60.54, H 4.90, S 5.77. Found:
C 60.43, H 4.85, S 5.88. o ϋ
4-[4-[2-[4-Bis-(4-chlorophenyl)butylsulfinyl]ethoxy]phenyl]-l,l,l-trifluoro- 2-butanone.
Figure imgf000202_0001
A solution of 4-[4-[2-[4-bis-(4-chlorophenyl)butylthio]ethoxy]phenyl]-l,l,l- trifluoro-2-butanone (0.741 g, 1.33 mmol) in methanol (35 ml) was treated with a solution of sodium periodate (0.32 g, 1.5 mmol) in water (1.5 ml) and the resulting mixture was stirred at 22°C for 18 h. The solid formed was filtered and the filtrate was evaporated in vacuo. The residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo gave an oil which was chromatographed on silica gel. Elution with a gradient of ethyl acetate in dichloromethane (40 - 90%) gave 0.654 g (86%) of the title material as a white solid: mp 31-35°C.
Anal. Calcd. for C28H27CI2F3O3S. 0.4 H20: C 58.12, H 4.84, S 5.54. Found: C 58.05, H 4.97, S 5.73. 2e!
4-[4-[2-[4-Bis-ι4-chloropheny butylsulfonyl]ethoxy]phenyl]-l,l,l-trifluoro- 2-butanone.
Figure imgf000203_0001
A solution of 4-[4-[2-[4-bis-(4-chlorophenyl)butylthio]ethoxy]phenyl]-l,l,l- trifluoro-2-butanone (0.583 g, 1.05 mmol) in dichloromethane (25 ml) was treated at 22°C with m-chloroperbenzoic acid (0.592 g, 3.43 mmol) and the resulting mixture was stirred for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo and chromatography of the residue on silica gel (elution ethyl acetate-hexane 1:1) gave 0.533 g (70%) of the title material as a clear oil. Anal. Calcd. for C28H27CI2F3O4S. 0.4 H20: C 56.55, H 4.71 S 5.39. Found: C 56.43, H 4.61, S 5.46.
ID ^
The following compounds may be prepared by the general procedure shown above.
Table 10
Figure imgf000204_0001
Figure imgf000204_0002
3
Figure imgf000205_0001
ZoM
Table 11
Figure imgf000206_0001
Figure imgf000206_0002
Example 260
(Z)-4-[4-[2-(Dodecylsulfonyl)ethoxy]phenyl]-l,l,l-trifluoro-2-acetoxy-2- butene.
Figure imgf000207_0001
A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (1.10 g, 2.30 mmol) in dichloromethane (15 ml) was cooled to - 25°C and treated with triethylamine (0.5 ml) and 4- dimethylaminopyridine (0.560 g, 4.58 mmol). Then acetic anhydride (0.65 ml, 6.9 mmol) was added and the resulting mixture was stirred at -25°C for 2.5 h. The solution was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica gel (elution toluene-ethyl acetate, 9:1) to give 0.94 g (78%) of a solid which was recrystallized from hexane to give white crystals: mp 48-49°C. Anal. Calcd. for C26H39F3O5S: C 59.98, H 7.55, S 6.16. Found: C 59.95, H 7.51, S 6.38. •zJbiβ
Example 261
4-r4-f2-fBis(4-chlorophenyl)methoxy1ethylsulfonynethoxy1phenyn-l.l.l- trifluoro-2-butanol.
Figure imgf000208_0001
A solution of 4-[4-[2-[bis(4- chlorophenyl)methoxy]ethylsulfonyl]ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (0.77 g, 1.30 mmol) in tetrahydrofuran (45 ml) and water (5 ml) was treated with sodium borohydride (0.10 g, 2.6 mmol) and the resulting mixture was stirred at 22°C for 1 h. The reaction mixture was then diluted with ethyl acetate, washed successively with water and brine and then dried (magnesium sulfate). Evaporation of the solvent under reduced pressure gave an oil which was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (8:2) gave the title material as a white solid: mp 75-76°C.
Anal. Calcd. for C27H27CI2F3O5S: C 54.83, H 4.60, S 5.42. Found: C 54.84, H 4.39, S 5.07. -to")
Example 262
(Z)-4-r4-r2-rBis-(4-chlorophenyl)methoxy)ethylsulfonyl)ethoxy1phenyn- l.l.l-trifluoro-2-acetoxy-2-butene.
Figure imgf000209_0001
Reaction of 4-[4-[2-[bis(4-chlorophenyl)methoxy] ethy lsulf ony 1] ethoxy] phenyl] - 1,1,1 -tr ifluoro-2-butanone with acetic anhydride as described in example 260 gave the title material as an oil (85%). Anal. Calcd. for C29H27CI2F3O6S. 0.5 H2O: C 54.38, H 4.41, S 5.01. Found:
C 54.38, H 4.26, S 4.86.
Example 263
(Z)-4-f4-r2-(Dodecylsulfonyl)ethoxylphenyll-l.l.l-trifluoro-2-propionyloxy- 2-butene.
Figure imgf000210_0001
Reaction of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (0.87 g, 1.82 mmol) with propionic anhydride using the procedure described above gave 0.866 g (89%) of the title material as a white solid: mp 60-63°C.
Anal. Calcd. for C27H41F3O5S: C 60.65, H 7.73, S 6.00. Found: C 60.51, H 7.83, S 6.01.
Example 264
4-r4-r2-(Dodecylsulfonyl)ethoxy1phenyll-l,l,l-trifluoro-2-butanone. glycolic acid-ketal ester.
Figure imgf000210_0002
A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-l,l,l-trifluoro-2- butanone (0.80 g) in toluene (40 ml) was treated with glycolic acid (0.16 g) and p-toluene sulfonic acid (0.10 g) and the resulting mixture was heated under reflux for 6 h. Additional quantities of glycolic acid (5 x 0.16 g) and p-toluenesulfonic acid (5 x 0.06 g) were added periodically after every hour of heating. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution toluene-ethyl acetate 8:2) gave 0.187 g (21%) of the title material as a white solid: mp 69- 71°C. Anal. Calcd. for C26H39F3O6S: C 58.19, H 7.33, S 5.97. Found: C 58.11, H 7.35, S 6.09.
Example 265
4-[4-f2-(Dodecylsulfonyl)ethoxylphenyn-l,l,l-trifluorobutanone, thiazolidine derivative with 2-aminoethanethiol.
Figure imgf000211_0001
A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-l,l,l- trifluorobutanone (0.60 g, 1.25 mmol) in dry toluene (50 ml) was heated under reflux and then treated with 2-aminoethanethiol (3 x 0.20 g) added in three portions over 12 h. The reaction mixture was then washed with brine and dried over magnesium sulfate. Evaporation of the solvent in 2.[ vacuo and chromatography of the residue on silica gel (elution toluene- ethyl acetate 85:15) gave 0.603 g (89%) of the title thiazolidine as a syrup. Anal. Calcd. for C26 I42F3NO3S2: C 58.07, H 7.87, N 2.60, S 11.93. Found: C 57.93, H 8.09, N 2.52, S 11.46.
Example 266
(Z)-4-r4-r2-(Dodecylsulfony ethoxy1phenyn-l.l.l-trifluoro-2- diethylphosphoryloxy-2-butene.
Figure imgf000212_0001
A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]ρhenyl]-l,l,l- trifluorobutanone (1.50 g, 3.13 mmol) in dry dichloromethane (40 ml) was cooled to 0°C and treated with triethylamine (0.87 ml) and 4- dimethylaminopyridine (0.77 g) then diethyl phosphorochloridate (1.35 ml) was added dropwise and the resulting mixture was stirred at 0°C for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with sodium bicarbonate, brine and dried (magnesium sulfate). After evaporation of the solvent under reduced pressure, the residue was chromatographed on silica gel (elution toluene-ethyl acetate, 8:2) to give 1.539 (80%) of the title enol phosphate as white crystals (hexane) : mp 33°C. i l l
Anal. Calcd. for C28H46F3O7PS: C 54.71, H 7.54, S 5.22. Found: C 54.82, H 7.64, S 5.39.
Example 267
(Z)-4-r4-r2-(Dodecylsulfonyl)ethoxy1phenyn-l.l.l-trifluoro-2- ethylphosphoryloxy-2-butene sodium salt and (Z)-4-r4-r2-(Dodecylsulfonyl)ethoxylphenyll-l.l.l-trifluoro-2- phosphoryloxy-2-butene, disodium salt.
Figure imgf000213_0001
A solution of (Z)-4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-l,l,l-trifluoro-2- diethylphosphoryloxy-2-butene (0.778 g, 1.27 mmol) in acetonitrile (20 ml) was treated with chlorotrimethylsilane (1.0 ml) and potassium iodide (0.63 g) and the resulting mixture was heated under reflux for 5 h. The cooled mixture was then treated with sodium bicarbonate (1 g) and water (5 ml) and stirred for 30 min. The solid was then removed by filtration and the filtrate was concentrated in vacuo. The residue was then purified on silica gel using a mixture of ethyl acetate, methanol and water (7:3:0 to 65:35:5) as eluent.
The first fractions gave the ethyl-phosphoryloxy sodium salt (0.210 g, 27%) as a white solid. Anal. Calcd. for C26H4iF3θ7PSNa. 0.3 H20: C 50.86, H 6.83, S 5.22. Found:
C 50.81, H 6.98, S 5.32.
The tail fractions gave the phosphoryloxy disodium salt (0.259 g, 34%) as a white solid.
Anal. Calcd. for C24H36F3θ7PSNa2. 0.3 H20: C 43.90, H 6.45, S 4.88. Found:
C 43.97, H 6.08, S 5.08.
The following prodrugs may be prepared by the general procedure described above.
Table: Pro-drugs (1)
Figure imgf000214_0001
Figure imgf000214_0002
2-1?)
Table: Pro-drugs (2)
Figure imgf000215_0001

Claims

CLAIMS We claim:
1. A compound of the formula
Figure imgf000216_0001
wherein W is CH=CH, CH=N, O or S;
R1 is (Cι-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)alkoxy, o R2 (Ci-C6)alkylthio, halo, hydroxy, cyano, — c — N— R3 in which R2 and R3 are each independently hydrogen or (Ci-C6)alkyl, -COO-(C1-C6)alkyl, CF3, ( -C alkylphenyl, phenyl or phenyl substituted by one or more of o R2 (CrC6)alkyl, -COO-(C1-C6)alkyl, — c — N- R3 in which R2 and R3 are as defined above, halo, hydroxy, -0-(C1-C6)alkyl, -S^ -C alkyl or
(C2-C6)alkenyl;
p is 0, 1 or 2;
A is V-(RC) -;
Rc is a straight or branched chain alkyl group;
n is 0 or an integer of from 1 to 6; Ά<
Ra and Rb when taken together form an oxo group; or Ra and Rb are each independently hydrogen or OH;
V is O, -S-, -SO-, -S02, -CONH or NHCO when n is an integer of from 1 to 6 or V is (C2-C6) alkenyl or a bond when n is 0 or an integer of from 1 to 6;
D is -(CH2)m or a bond linking the ll ,w ring to Y;
m is an integer of from 1 to 6;
I
Y is -O-, -S-, -SO-, -Sθ2, -N-R4 or a bond;
R4 is as defined below for R7;
Z is:
Figure imgf000217_0001
in which B is:
NR 10
— C - O— C— . — N-C— " N-C" , — SO, or a bond;
R9 R9
X is S or O;
q is an integer from 1 to 6; R9 is hydrogen or (C1-C6)alkyl;
R10 is hydrogen, CN, NO2, OH, -0-(Cι-C6)alkyl, (Cι-C6)alkyl, phenyl or
(Ci-C6)alkylphenyl;
R and R6 are each independently hydrogen or ( - g) alkyl;
R7 and R8 are each independently;
(a) hydrogen;
(b) (Ci-Ci8)alkyl;
(c) (Ci-Ci8)alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), l-3(Cι-C6)alkoxy, l-3(Ci-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cι-C6)alkylthio, amino, 1-3
( -C6) alkylamino, di(Ci-C6)alkylamino, -CO2H, -COO-
(Cι-C6)alkyl, -SO3H, -S02NHR15 in which R15 is hydrogen
O R2 2 3 or (Ci-C6)alkyl, or — c— N— R3 in which R and R are as defined above;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl; O
(4) heterocyclic substituted by one or more of phenyl, phenyl substituted by 1-3 halo, (Cι-C6)alkoxy, (Cι-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( - ) alkylthio, amino, ( - ) alkylamino, di(Cx-C6) alkylamino, C02H,
5 -COO-(CrC6) alkyl, -S03H, S02NHR15 in which R15 is
0 R2 hydrogen or ( -C6) alkyl, or - c- N-R3 in which R2 and R3 are as defined above, ( -C6) alkyl or ( - ) alkyl substituted by one or more phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or
10 substituted by 1-3 halo, 1-3 (CrC6) alkoxy, 1-3 (CrC6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( -C alkylthio, amino, 1-3 ( -C6) alkylamino, di -C alkylamino,
COOH, -COO-(C C6) alkyl, -S03H, -S02NHR15 in which
O R2 R15 is hydrogen or (CrC6) alkyl, or - c- N- R3 in which R2 l-> and R3 are each independently hydrogen or ( -C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
0 (5) carboxy or -COO-(CrC6) alkyl;
(6) hydroxy, halo, -0-(C C6) alkyl or -S-( -C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
25
(7) cyano; -2.1?
(8) halogen, trifluoromethyl or trifluoroacetyl;
(9) CH2 L-R16 in which L is
R 17
R170 O
■N- — o- -SO- , -S02- , —N-C—, —C-N—, — C— ,
.17
— O-C— , — C-O— , — N-C— —C-N—,
R17 R 7
or -0-SiR16R18Rl9 or a ond m which R16 and R17 are each independently (Cι-Cιs)alkyl or (C2-Ci8)alkenyl or (Cι-Cιs)alkyl or (C2-Ci8)alkenyl substituted by one or more phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1- 5 fluoro, 1-3 halo (other than fluoro), 1-3 (Cl-C6)alkoxy, l-3(Ci-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Ci-C6)alkylthio, amino, l-3(Ci-C6)alkylamino, 1-3 di(Ci-C6)alkylamino, C02H, 1-3 -COO(Ci- o R2 C6)alkyl, —c-N- R3 or -S02NHR9 in which R9 is hydrogen or (Ci-C6)alkyl and R2 and R3 are as defined above;
R5
(b) (CH2)q-C-R6
N— B1- R7
R8
in which B1 is
x x x NR10
— - . — c-o— , -C-N-R9 ,— c-NR9 , - so2-, -PO(OR9)2 or a bond; l|=ι
providing that when B1 is -PO(OR9)2, then R7 becomes R9, and when B1 is X
II _ ., „7
— c-o— or -S02-, then R cannot be hydrogen;
X, q, R5, R6, R7, R8, R9 and R10 are as defined in (a);
Figure imgf000221_0001
in which q, R5 and R6 are as defined above;
18 19 11 7 8 R , R and R are as defined below for R and R except that they may not be hydrogen, or R 18 and R 19 taken together with the nitrogen to which they are attached represent a 4, 5- or 6-membered heterocyclic ring and Y, R7 and R11 are as defined above, or R18, R19 and R11 taken together with the nitrogen to which they are attached represent pyridinium, said pyridinium group being unsubstituted or substituted by
(Cι-Cχ2)alkyl, (Cι-Ci2)alkoxy, amino, (Cι-Ci2)alkylamino, di o ,
II ° R
(Cι-Ci2)alkylamino, -c-o — (CrC6)alkyl, -S-(Cι-Ci2)alkyl, — C-N- R3 in which R 2 and R 3 are as defined above, phenyl or phenyl (Cl-Clθ)alkyl;
d)
Figure imgf000221_0002
Z2C in which R 13 is (Cι-Ciδ)alkyl or (Cι-Cιs)alkyl substituted by carboxy, o O R2
-c-o-(crc12) alkyl, - C- N-R3 in which R2and R3 are as defined above, hydroxy, -0-(CrC6) alkyl or -S-(CrC6) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 halo (other than fluoro), ( - ) alkoxy, ( -C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( -C alkylthio, amino, (CrC6) alkylamino, di(C C6) alkylamino, C02H, COO-(C C6) alkyl,
O R2 S03H, S02NHR15 in which R15 is hydrogen or (C C6) alkyl or - C- N- R3 in which R2 and R3 are as defined above;
r is 0 or an integer of from 1 to 3;
R7 is as defined above;
O o 0 R2 M is -(CH2-)mT where T is - C— , - C- O , - C- N— , in which R2 is as defined above, -S02- or a bond when MR7 is on nitrogen and providing
O
11 that when T is — G — or -SO- or -S02-, then R cannot be hydrogen, and T
0 I I ° 11 R K14 is - — , — C-O— , -o-, -S-, -SO-, -SO2-, -N— or a bond when MR7 is on a carbon atom of the heterocyclic ring;
R is hydrogen or (Ci-C6)alkyl;
m is 0 or an integer of 1-6;
Figure imgf000222_0001
wherein Q is -O-, -S-, -SO- or -S02-, and q, R5, R6 and R7 are as defined above, providing that when Q is -SO- or -S02-, R7 cannot be hydrogen;
f) R7 wherein R7 is defined above, providing that when Y is -SO- or -S02-, R7 cannot be hydrogen; and
R18 and R19 are phenyl or phenyl substituted by 1-3 halo, C_-C6) alkoxy,
(Cα-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( - ) alkylthio, amino, (C C6) alkylamino, di(C C6) alkylamino, C02H, -COO-(C C6) alkyl,
O R2 -S03H, S02NHR15 in which R15 is hydrogen or ( -C6) alkyl, or - C- N- R3 in which R2 and R3 are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
2. A compound of claim 1 wherein W is CH=CH, D is a bond linking Y to the ring and Y is -O-.
3. A compound of claim 2 wherein R1 is benzyl; p is 0, 1 or 2; A is V -(CH2)n- wherein V is (C2-C6) alkenyl or a bond; and n is 0 or an integer of from 1 to 6.
4. A compound of claim 3 wherein A is -(CH2)n; n is 0 or an integer of from 1 to 6; and the group -(CH2)n-COCF3 is in the meta or para position of the phenyl ring.
5. A compound of the formula
Figure imgf000224_0001
wherein R1 is benzyl; p is 0, 1 or 2; A is V-(CH2)n-; V is (C2-C6) alkenyl or a bond; n is 0 or an integer of from 1 to 6; Ra and Rb when taken together form an oxo group, or Ra and Rb are each independently hydrogen or OH; and Z is
(a)
Figure imgf000224_0002
in which B is
;
Figure imgf000224_0003
X is S or O;
q is an integer of from 1 to 6;
R9 is hydrogen or (C:-C6) alkyl;
R10 is hydrogen, CN, N02, OH, -0-(C C6) alkyl, (C C6) alkyl, phenyl or ( -C8) alkylphenyl;
2.13
R5 and R6 are each independently hydrogen or ( - ) alkyl; and R7 and R8 are each independently a) hydrogen; b) (C C18) alkyl; c) ( - g) alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro),
1-3 ( - ) alkoxy, 1-3 (Cj-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( -C alkylthio, amino, 1-3 ( - ) alkylamino, di(C1-C6) alkylamino, -C02H, -COO-(C1-C6) alkyl; -S03H, - S02NHR15
O R2 in which R15 is hydrogen or (C C6) alkyl, or - c- N- R3 in which R2 and R3 are each independently hydrogen or (Cj-C6) alkyl;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl; (4) heterocyclic substituted by one or more of phenyl, phenyl substituted by 1-3 halo, (Ci-C6)alkoxy, (Ci-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C C6) alkylthio, amino, (C C6) alkylamino, di( -C6) alkylamino, C02H, -COO-( -C6) alkyl, -S03H,
O R2 S02NHR15 in which R15 is hydrogen or ( -C6) alkyl, or - c- N- R3 in which R2 and R3 are as defined above, ( -C alkyl or (Cj-C6) alkyl substituted by one or more phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by
1-3 halo, 1-3 ( - ) alkoxy, 1-3 ( -C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( - ) alkylthio, amino, 1-3 ( - ) alkylamino, di(CrC6) alkylamino, COOH, -COO-(C C6) alkyl, -S03H, -S02NHR15 o R2 in which R15 is hydrogen or (Cα-C6) alkyl, or - c- N- R3 in which R2 and R3 are each independently hydrogen or (C C6) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or -COO^ - ) alkyl;
(6) hydroxy, halo, -0-(C C6) alkyl or -S(Cα-C6) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halogen, trifluoromethyl or trifluoroacetyl; or
(9) CH2 L-R16 in which L is
R 17
R17Q O II
— N- — O— -s— - so- - S02- , — N- C— , — C- N— , — c— .
31
O O s s
— O- C— , — C-O— — N- C— — C- N— ,
' ' | ' I
R 7 R17
or -0-SiR16R!8Rl9 or a bond in which R16 and R17 are each independently (Cι-Ciδ)alkyl or (C2-Ci8)alkenyl or (Ci-Cis)alkyl or (C2-Cχ8)alkenyl substituted by one or more phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (Cι-C6)alkoxy, l-3(Cι-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Ci-C6)alkylthio, amino, 1-3 (Ci-C6)alkylamino,l-3 di(Ci-C6)alkylamino, C02H, 1-3 -COO o R2 (Ci-C6)alkyl, -c-N- R3 or -S02NHR9 in which R9 is hydrogen or
(Ci-C6)alkyl and R2 and R3 are as defined above; and R18 and R19 are phenyl or phenyl substituted by 1-3 halo, ( -C6) alkoxy, ZXff"
(Cj-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C:-C6) alkylthio, amino, ( -Cg) alkylamino, di(C -Cg) alkylamino, C02H,
-COO-(C1-C6) alkyl, -S03H, S02NHR15 in which R15 is hydrogen or o R2 (Cj-Cg) alkyl, or - c- N- R3 in which R2 and R3 are as defined above;
( )
Figure imgf000227_0001
in which B1 is
— 2 or a bond;
Figure imgf000227_0002
providing that when B1 is -PO(OR9)2, then R7 becomes R9, and when B1 is X
— c-o— or -S02-, then R7 cannot be hydrogen; and
X, q, R5, R6, R7, R8, R9 and R10 are as defined above in (a);
313
(c)
(CH2) -7
13 in which R is (Ci-Cis)alkyl or (Ci-Cis)alkyl substituted by carboxy, o O R2
-C-o-(c C12) alkyl, - C- N- R3 in which R2and R3 are as defined above, hydroxy, - -(C_-<Z_) alkyl or -S-(C1-C6) alkyl substituted by 1 or 2 phenyl or
1.1 ic substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 halo (other than fluoro), ( - ) alkoxy, (Cj-C8) alkyl, nitro, cyano, hydroxy, trifluoromethyl, ( -Cg) alkylthio, amino, ( -Cg) alkylamino, di(C1-C6) alkylamino, COzH, COO-(C1-C6) alkyl, o R2 S03H, S02NHR15 in which R15 is hydrogen or (C C6) alkyl or -c-N- R3 in which R2 and R3 are as defined above;
r is 0 or an integer of from 1 to 3;
R7 is as defined above;
O I I o n o || R f 2
M is -(CH2-)mT where T is - C— , - C~ O , — c- N— , m which R2 is as defined above, -S02- or a bond when MR7 is on nitrogen and providing ft that when T is — G— or -SO- or -S02-, then R cannot be hydrogen, and T
O O R14 is -C— , — C-O— -O-, -S-, -SO-, -SO2-, — N— or a bond when MR7 is on a carbon atom of the heterocyclic ring;
14 R is hydrogen or (Ci-C6)alkyl;
m is 0 or an integer of 1-6;
(d)
Figure imgf000228_0001
wherein Q is -O-, -S-, -SO-, or -S02- and q, R5, R6 and R7 are as defined above, providing that when Q is -SO- or -S02-, R7 cannot be hydrogen; or
(e) R7 where R7is as defined above, providing that when Y is -SO- or -S02-, R7 cannot be hydrogen; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
6. A compound of the formula
Figure imgf000229_0001
(CH2)nCOCF3
wherein n is 0 or an integer of from 1 to 6, the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring and Z is
Figure imgf000229_0002
x in which B is — Q — or a bond; X is S or O; q is an integer of from 1 to 6;
R5 and R6 are each independently hydrogen or (CrClg) alkyl; and R7 and R8 are each independently
(a) hydrogen;
(b) (Ci-Ci8)alkyl; (c) (Ci-Ciδ)alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro),
1-3 ( -Cg) alkoxy, 1-3 (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-C6) alkylthio, amino, 1-3 (Q-Cg) alkylamino, di(C1-C6) alkylamino, -C02H, -COO-(C1-C6) alkyl;
-S03H, - S02NHR15 in which R15 is hydrogen or (C C6) alkyl, o R2 or - C- N- R3 in which R2 and R3 are each independently hydrogen or (Q-Q) alkyl;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more of phenyl, phenyl substituted by 1-3 halo, (Ci-C6)alkoxy, (Ci-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Cg) alkylthio, amino, (Q-Cg) alkylamino, di(Q-Q) alkylamino, COzH, -COO-(Q-Q) alkyl, -S03H, S02NHR15 in which R15 is
0 R2
II hydrogen or (Q-Q) alkyl, or -c-N-R3 in which R2 and R: are as defined above, (Q-Q) alkyl or (Q-Q) alkyl substituted by one or more phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3 (Q-Q) alkoxy, 1-3 (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Cg) alkylthio, amino, 1-3 (Q-C6) alkylamino, di(Q-Q) alkylamino, COOH, -COO-(C C6) alkyl, -S03H, -S02NHR15 in which o R2 R15 is hydrogen or (Q-Q) alkyl, or -c-N-R3 in which R2 and R3 are each independently hydrogen or (Q-Q) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or -COO-(Q-Q) alkyl;
(6) hydroxy, halo, -O-(Q-Q) alkyl or -S-(Q-Q) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halogen, trifluoromethyl or trifluoroacetyl;
(9) CH2 L-R16 in which L is
R 17
R170
— N- — o— — s- SO- , -S02- , —N-C— , — C-N— , — C— ,
>17
— O-C— , —C-O— , — N-C— —C-N— , i ' I ' l R17 R17
or -0-SiR16R!8Rl9 or a bond in which R16 and R17 are each independently (Ci-Cis)alkyl or (C2-Ci8)alkenyl or (Ci-Cis)alkyl or (C2-Cχ8)alkenyl substituted by one or more phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-
5 fluoro, 1-3 halo (other than fluoro), 1-3 (Cι-C6)alkoxy, l-3(Cι-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Ci-C6)alkylthio, amino, l-3(Cι-C6)alkylamino, 1-3 di(Cι-C6)alkylamino, C02H, 1-3 -COO
O R2 (Cι-C6)alkyl, —c-N- R3 or -S02NHR9 in which R9 is hydrogen or
(Ci-C6)alkyl and R2 and R3 are as defined above; and R18 and R19 are phenyl or phenyl substituted bY 1-3 halo, (Q-Q) alkoxy, (Q-Q) alkyl, ^^ cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, C02H, -COO-(Q-Q) alkyl, -S03H,
O R2 S02NHR15 in which R15 is hydrogen or (Q-Q) alkyl, or - c- N- R3 in which
R2 and R3 are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
7. A compound of the formula
Figure imgf000232_0001
in which R1 is benzyl; p is 0, 1 or 2; n is 0 or an integer of from 1 to 6; the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is
Figure imgf000232_0002
V i
in which B1 is
0 x NR 1
II
-c— , c- 0-, - c- N- R9, - C - NR9, — so2— or a bond;
q is an integer of from 1 to 6;
X is S or O;
R5 and R6 are each independently hydrogen or (Cχ-Ci8) alkyl;
R9 is hydrogen or (C1-C6) alkyl;
R10 is hydrogen, CN, N02, OH, -0-(Cι-C6) alkyl or (Ci-Cό) alkyl; and R7 and R8 are each independently
(a) hydrogen;
(b) (Cι-Ci8)alkyl;
(c) (Ci-Ci8)alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro),
1-3 (Q-Q) alkoxy, 1-3 (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, 1-3 (Q-Q) Z - alkylamino, di(Q-Q) alkylamino, -COzH, -COO-(C1-C6) alkyl;
-S03H, - S02NHR15 in which R15 is hydrogen or (Q-Q) alkyl, o R2 or - c- N- R 3 in which R2 and R3 are each independently hydrogen or (Q-Q) alkyl;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more of phenyl, phenyl substituted by 1-3 halo, (Cι-C6)alkoxy, (Cι-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, C02H,
-COO-(Q-Q) alkyl, -S03H, S02NHR15 in which R15 is
O R2 hydrogen or (Q-Q) alkyl, or - C- N- R3 in which R2 and R3 are as defined above, (Q-Q) alkyl or (Q-Q) alkyl substituted by one or more phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3 (Q-Q) alkoxy, 1-3 (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, 1-3 (Q-Q) alkylamino, di(Q-Q) alkylamino,
COOH, -COO-(Q-Q) alkyl, -S03H, -S02NHR15 in which o R2 R15 is hydrogen or (Q-Q) alkyl, or -c- N-R3 in which R2 and R3 are each independently hydrogen or (Q-Q) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl; (5) carboxy or -COO-(Q-Q) alkyl;
(6) hydroxy, halo, -O-(Q-Q) alkyl or -S-(Q-Q) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halogen, trifluoromethyl or trifluoroacetyl;
(9) CH2 L-R16 in which L is
— ,
Figure imgf000235_0001
O II O II s II s II
— O- C— , — C- O— , — N- C— ( — C- N— ,
R17 R17
or -0-SiR16R18R19 or a bond in which R16 and R17 are each independently (Ci-Cιs)alkyl or (C2-Ci8)alkenyl or (Cι-Cιs)alkyl or
(C2-C 18) alkenyl substituted by one or more phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-
5 fluoro, 1-3 halo (other than fluoro), 1-3 (Cι-C6)alkoxy, l-3(Ci-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Ci-C6)alkylthio, amino, l-3(Ci-C6)alkylamino, 1-3 di(Ci-C6)alkylamino, C02H, 1-3 -COO o R2 (Ci-C6)alkyl, —c-N- R3 or -S02NHR9 in which R9 is hydrogen or
(Ci-C6)alkyl and R2 and R3 are as defined above; and R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (Q-Q) alkoxy, (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, C02H, -COO-(C1-C6) alkyl, -S03H,
0 R2 S02NHR15 in which R15 is hydrogen or (Q-Q) alkyl, or -C-N-R3 in which
R2 and R3 are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
8. A compound according to claim 7 wherein the substituent -(CH2)nCOCF3 is in the para position of the phenyl ring, R5 and R6 are both hydrogen, q is 1, 2 or 3, n is 2 or 3, B1 is x x x NR1°
-C — , -C-O—, -C-N-R9, -C-NR9, or — S02—
and R7 and R8 are each independently hydrogen or (Ci-C s)alkyl.
9. A compound according to claim 8 wherein q is 1, n is 2 and B X X x is-C — , -C-O-, -c-N-R9, or — S02— .
10. A compound of the formula
Figure imgf000236_0001
wherein n is 0 or an integer of from 1 to 6; the substituent
-(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is
Figure imgf000236_0002
in which R 13 is (Cι-Cιs)alkyl or (Cι-Cιs)alkyl substituted by carboxy, o O R2
-c-o-(c c12) alkyl, -C- N-R3 in which R2and R3 are each independently hydrogen or (Q-Q) alkyl, hydroxy, -O-(Q-Q) alkyl or -S-(Q-Q) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 halo (other than fluoro), (Q-Q) alkoxy, (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl,
(Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, C02H,
COO-(Q-Q) alkyl, S03H, S02NHR15 in which R15 is hydrogen or (Q-Q) o II R I2 - alkyl or -c-N- R3 in which R and R are as defined above;
r is 0 or an integer of from 1 to 3;
R7 is as defined below;
O II o II o K R I 2 M is -(CH2-)mT where T is - C— , - c- O , - C- N— , m which R2 is as defined above, -S02- or a bond when MR7 is on nitrogen and providing
that when T is — ft G — or -SO- or -S02-, then R cannot be hydrogen, and T
9 I I ° I I R K14 is — C— , -C-O— , -o-, -S-, -SO-, -Sθ2-, -N— or a bond when MR7 is on a carbon atom of the heterocyclic ring;
14 R is hydrogen or (Ci-C6)alkyl;
m is 0 or an integer of 1-6; and
R7 is
(a) hydrogen;
.36
(b) (Cι-Ci8)alkyl;
(c) (Cι-Ci8)alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro),
1-3 (Q-Q) alkoxy, 1-3 (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, 1-3 (Q-Q) alkylamino, di(Q-Q) alkylamino, -COzH, -COO-(Q-Q) alkyl;
-S03H, - S02NHR15 in which R15 is hydrogen or (Q-Q) alkyl,
O R2 or - c- N- R 3 in which R2 and R3 are each independently hydrogen or (Q-Q) alkyl; 5
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more of phenyl, phenyl 0 substituted by 1-3 halo, (Ci-C6)alkoxy, (Cl-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, C02H,
-COO-(Q-Q) alkyl, -S03H, S02NHR15 in which R15 is
O R2 hydrogen or (Q-Q) alkyl, or - c- N-R3 in which R2 and R3 ^ are as defined above, (Q-Q) alkyl or (Q-Q) alkyl substituted by one or more phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or LSI-
substituted by 1-3 halo, 1-3 (Q-Q) alkoxy, 1-3 (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, 1-3 (Q-Q) alkylamino, di(Q-Q) alkylamino,
COOH, -COO-(Q-Q) alkyl, -S03H, -S02NHR15 in which o R2 R15 is hydrogen or (Q-Q) alkyl, or -c-N- R3 in which R2 and R3 are each independently hydrogen or (Q-Q) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or -COO-(Q-Q) alkyl;
(6) hydroxy, halo, -O-(Q-Q) alkyl or -S-(Q-Q) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halogen, trifluoromethyl or trifluoroacetyl;
(9) CH2 L-R16 in which L is
>17
FV'C
■N — o- — S— -SO- , -S02- , —N-C—, — C-N— , — C— ,
.17
s II s II
•O-C— , —C-O— , —N-C— f —C-N— ,
R17 R17 or -0-SiR16R18R19 or a bond in which R16 and R17 are each independently (Ci-Cιs)alkyl or (C2-Ci8)alkenyl or (Ci-Ciδ)alkyl or (C2-Ci8)alkenyl substituted by one or more phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3
(Cι-C6)alkoxy, l-3(Cι-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C -C6)alkylthio, amino, 1-3
(Cι-C6)alkylamino,l-3 di(Ci-C6)alkylamino, C02H, 1-3 -COO
O R2 (Cι-C6)alkyl, —c-N- R3 or -S02NHR9 in which R9 is hydrogen or (Cι-C6)alkyl and R2 and R3 are as defined above; and R18 and R« are phenyl or phenyl substituted by 1-3 halo, (Q-Q) alkoxy,
(Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, C02H,
-COO-(Q-Q) alkyl, -S03H, S02NHR15 in which R15 is hydrogen or O R2 (Q-Q) alkyl, or - C- N- R3 in which R2 and R3are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
11. A compound of the formula
Figure imgf000240_0001
in which n is 0 or an integer of from 1 to 6, the substituent -(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is R5
-(CH2^C-R6
Q-R7
wherein q is an integer of from 1 to 6; R5 and R6 are each independently hydrogen or (Ci-Cis)alkyl;
Q is -O-, -S-, -SO-, or -S02- ; and
R7 is
(a) hydrogen;
( ) (Ci-Ci8)alkyl;
(c) (Cl-Ci8)alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro),
1-3 (Q-Q) alkoxy, 1-3 (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, 1-3 (Q-Q) alkylamino, di(Q-Q) alkylamino, -C02H, -COO-(Q-Q) alkyl;
-S03H, - S02NHR15 in which R15 is hydrogen or (Q-Q) alkyl,
O R2 or - c- N- R3 in which R2 and R3 are each independently hydrogen or (Q-Q) alkyl;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl; i¥0
(4) heterocyclic substituted by one or more of phenyl, phenyl substituted by 1-3 halo, (Cι-C6)alkoxy, (Cι-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, C02H,
-COO-(Q-Q) alkyl, -S03H, S02NHR15 in which R15 is
O R2 hydrogen or (Q-Q) alkyl, or - c- N- R3 in which R2 and R3 are as defined above, (Q-Q) alkyl or (Q-Q) alkyl substituted by one or more phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3 (Q-Q) alkoxy, 1-3 (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, 1-3 (Q-Q) alkylamino, di(Q-Q) alkylamino,
COOH, -COO-(Q-Q) alkyl, -S03H, -S02NHR15 in which
O R2 R15 is hydrogen or (Q-Q) alkyl, or - c- N- R3 in which R2 and R3 are each independently hydrogen or (Q-Q) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or -COO-(Q-Q) alkyl;
(6) hydroxy, halo, -O-(Q-Q) alkyl or -S-(Q-Q) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano; 2_H \
(8) halogen, trifluoromethyl or trifluoroacetyl;
(9) CH2 L-R16 in which L is
?17 i17,
R170
• N- — O— ( — S— - SO - , - S02- , — N- C— , — C- , — C-
Figure imgf000243_0001
- O- C— , — C- O— , — N- C— — C- N— ' ' I ' l
R17 R17
or -0-SiR16R18R19 or a bond in which R16 and R17 are each independently (Cι-Cis)alkyl or (C2-Ciδ)alkenyl or (Cι-Ciδ)alkyl or (C2-Ciδ)alkenyl substituted by one or more phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (Cl-C6)alkoxy, l-3(Ci-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Ci-C6)alkylthio, amino, 1-3 (Cι-C6)alkylamino,l-3 di(Cι-C6)alkylamino, C02H, 1-3 -COO o R2 (Cι-C6)alkyl, —c-N- R3 or -S02NHR9 in which R9 is hydrogen or
(Ci-C6)alkyl and R2 and R3 are as defined above; and R18 and RW are phenyl or phenyl substituted by 1-3 halo, (Q-Q) alkoxy, (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, COzH,
-COO-(Q-Q) alkyl, -S03H, S02NHR15 in which R15 is hydrogen or
O R2
(Q-Q) alkyl, or - c- N- R3 in which R2 and R3 are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
12. A compound of the formula
Figure imgf000244_0001
in which n is 0 or an integer of from 1 to 6; the substituent
-(CH2)nCOCF3 is in the meta or para position of the phenyl ring; and Z is
(a) hydrogen;
(b) (Ci-Ci8)alkyl;
(c) (Ci-Ciδ)alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), l-3(Ci-C6)alkoxy, l-3(Ci-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Cι-C6)alkylthio, amino, 1-3
(Q-Q) alkylamino, di(Cι-C6)alkylamino, -CO2H, -COO- (Ci-C6)alkyl, -SO3H, -S02NHR15 in which R15 is hydrogen,
0 ^2 2 3
(Ci-C6)alkyl, or — c— N— R3 in which R and R are each independently hydrogen or (Q-Q) alkyl;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl; (4) heterocyclic substituted by one or more of phenyl, phenyl substituted by 1-3 halo, (Cι-C6)alkoxy, (Cι-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, C02H, -COO-(Q-Q) alkyl, -S03H, S02NHR15 in which R15 is
O R2 hydrogen, (Q-Q) alkyl, - c- N- R3 in which R2 and R3 are as defined above, (Q-Q) alkyl or (Q-Q) alkyl substituted by one or more phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 halo, 1-3 (Q-Q) alkoxy, 1-3 (Q-Q) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, 1-3 (Q-Q) alkylamino, di(Q-Q) alkylamino,
COOH, -COO-(Q-Q) alkyl, -S03H, -S02NHR15 in which
O R2 R15 is hydrogen or (Q-Q) alkyl, or - c- N- R3 in which R2 and R3 are each independently hydrogen or (Q-Q) alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or -COO-(Q-Q) alkyl;
(6) hydroxy, halo, -O-(Q-Q) alkyl or -S-(Q-Q) alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano; (8) halogen, trifluoromethyl or trifluoroacetyl;
(9) CH2 L-R16 in which L is
317
R I 170 n
■ N- -O— — S- - so- , - so2- , — N- C— , — C- N— , —
517
— O- C— , — C- 0— , — N- C— — C- N— , ' ' | ' I R17 R 7
or -0-SiR16R18Rl9 Gr a bond in which R16 and R17 are each independently (Cι-Cιs)alkyl or (C2-C18) alkenyl or (Cι-Cιs)alkyl or
(C2-C is) alkenyl substituted by one or more phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-
5 fluoro, 1-3 halo (other than fluoro), 1-3 (Cι-C6)alkoxy, l-3(Cι-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (Cι-C6)alkylthio, amino, 1-
3(Ci-C6)alkylamino, 1-3 di(Ci-C6)alkylamino, C02H, 1-3 -COO o R2 (Cι-C6)alkyl, —c-N- R3 or -S02NHR9 in which R9 is hydrogen or (Cι-C6)alkyl and R2 and R3 are as defined above; and R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (Q-Q) alkoxy, (Q-Q) alkyl, nitro cyano, hydroxy, trifluoromethyl, (Q-Q) alkylthio, amino, (Q-Q) alkylamino, di(Q-Q) alkylamino, C02H, -COO-(Q-Q) alkyl, -S03H, o R2 S02NHR15 in which R15 is hydrogen or (Q-Q) alkyl, or - c- N- R3 in which R2 and R3 are as defined above; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
13. A compound selected from those of the following: 6 -I 1*
Figure imgf000247_0001
wherein
(a) R25 is -(CH2)3CH L 3'
(b) R25 is -(CH2)3C02QH5;
(c) R^ is -(CH2)3CONHC2H5;
(d) R25 is -COCF3;
(e) R25 is -COC6H5; and
(f) R is -PO(OC2H5)2; or a pharmaceutically acceptable salt thereof.
14. A compound selected from those of the following:
Figure imgf000247_0002
wherein 2, <o
(a) R20 is -CO(CH2)10CH3
(b) R20 is -COCH(p-chlorophenyl)2; and
(c) R20 is -S02(CH2)nCH3; or a pharmaceutically acceptable salt thereof.
15. A compound selected from those of the followiing:
Figure imgf000248_0001
wherein
(a) X" and X1" are CI;
(b) X" and X1" are F;
(c) X" and X" are OCH3; or
(d) X" is CI and X'"is OCH3; or a pharmaceutically acceptable salt thereof.
16. A compound selected from those of the following:
Figure imgf000249_0001
wherein
(a) n is 0;
(b) n = 1; and
(c) n = 2; or a pharmaceutically acceptable salt thereof.
17. A compound selected from those of the following:
Figure imgf000249_0002
wherein
(a) n = 0;
(b) n = 1; and (c) n = 2; or a pharmaceutically acceptable salt thereof.
18. A compound of the formula:
Figure imgf000250_0001
or a pharmaceutically acceptable salt thereof.
19. A compound of the formula
Figure imgf000250_0002
or a pharmaceutically acceptable salt thereof.
20. A compound of the formula /- 1Η
Figure imgf000251_0001
or a pharmaceutically acceptable salt thereof.
21. A compound selected from those of the following:
Figure imgf000251_0002
wherein
(a) R26 amd R27 are both CH3 or -(Q-Q)alkyl-CF3;
(b) R26 and R27 are both CI, F or Br;
(c) Xa and Xb are both OCH3 or SCH3;
(d) Xa is CI and Xb is OCH3; and
(e) Xa and Xb are both C02-(Q-Q)alkyl; or a pharmaceutically acceptable salt thereof. z-st
22. A compound selected from those of the following:
Figure imgf000252_0001
wherein
(a) R20 is -CO(CH2)10CH3;
(b) R20 is
Figure imgf000252_0002
(c) R20 is -S02(CH2)nCH3; or a pharmaceutically acceptable salt thereof.
23. A compound selected from those of the following:
2.- ",
Figure imgf000253_0001
wherein
(a) n is 1 and R21 is OCH.
(b) n is 1 and R21 is CI;
(c) n is 2 and R21 is OCH3; and
(d) n is 1-4 and R21 is OCH3 or CI; or a pharmaceutically acceptable salt thereof.
24. A compound selected from those of the following:
Figure imgf000253_0002
wherein (a) R22 is hydrogen and R23 is CI;
(b) R22 is -C02CH3 and R23 is -OCH3; or a pharmaceutically acceptable salt thereof.
25. A compound selected from those of the following:
Figure imgf000254_0001
wherein
(a) R24 is CI; and
(b) R 4 is -OCH3; or a pharmaceutically acceptable salt thereof.
26. The compound of the formula
Figure imgf000254_0002
2 "3
27. The compound of the formula
Figure imgf000255_0001
28. The compound of the formula
Figure imgf000255_0002
29. The compound of the formula
Figure imgf000255_0003
^
30. The compound of the formula
Figure imgf000256_0001
31. A compound of the formula
Figure imgf000256_0002
32. The compound of the formula
Figure imgf000256_0003
33. A pharmaceutical composition for the inhibition of cytosolic phospholipase A2 comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
34. A method of inhibiting cytosolic phospholipase A2 in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.
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AU9395498A (en) 1999-04-12
EP1140791A4 (en) 2001-10-10
PE122999A1 (en) 2000-02-17
US6255496B1 (en) 2001-07-03
AU730364B2 (en) 2001-03-08
CA2304503A1 (en) 1999-04-01
WO1999015129A3 (en) 2001-07-26
CO4970751A1 (en) 2000-11-07

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