WO2003053944A1 - Pancreatic lipase inhibitor compounds, their synthesis and use - Google Patents

Pancreatic lipase inhibitor compounds, their synthesis and use Download PDF

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Publication number
WO2003053944A1
WO2003053944A1 PCT/US2002/041272 US0241272W WO03053944A1 WO 2003053944 A1 WO2003053944 A1 WO 2003053944A1 US 0241272 W US0241272 W US 0241272W WO 03053944 A1 WO03053944 A1 WO 03053944A1
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Prior art keywords
thieno
alkyl
substituted
oxazin
nmr
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PCT/US2002/041272
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French (fr)
Inventor
David Witter
Arlindo L. Castelhano
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Osi Pharmaceuticals, Inc.
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Priority to MXPA04005863A priority Critical patent/MXPA04005863A/en
Priority to EP02805675A priority patent/EP1467978A4/en
Priority to CA002471098A priority patent/CA2471098A1/en
Priority to JP2003554660A priority patent/JP4668536B2/en
Priority to KR10-2004-7009797A priority patent/KR20040068316A/en
Priority to BR0215080-8A priority patent/BR0215080A/en
Priority to EA200400831A priority patent/EA009368B1/en
Priority to AU2002366810A priority patent/AU2002366810B2/en
Publication of WO2003053944A1 publication Critical patent/WO2003053944A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings

Definitions

  • obesity has become an increasingly common problem in the populations of developed countries.
  • the increased incidence of obesity is partly due to the adoption of a westernised diet in many developed countries - which contains many foods with high fat and low fiber concentrations - and partly due to the lifestyle of westernized society.
  • Obesity is known to increase the risk of contracting disorders such as diabetes, cardiovascular disease and hypertension.
  • the subject invention provides a compound having the structure:
  • X is O, S, CH 2 or NR 5 ;
  • Y is O or S
  • R-i is H, substituted or unsubstituted C 1 -C 1 5 alkyl, C C 8 alkylaryl, -C(O)OR 4> -C(O)NR 4 R 5J -CR 6 R 6' OR 4I -CR 6 R6 ' OC(O)R 4 , -CR 6 R6 C(O)NHR 7l -C(0)NRioR.i, -C(O)NR 8 R 9 NR 8 R 9 , -N(R 5 )C(O)NHR 5 , or CH 2 R 4 ;
  • R 2 is a substituted or unsubstituted, straight chain C--C 30 alkyl or branched C 3 -C 30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; and,
  • R is H or substituted or unsubstituted CrC 6 alkyl or C3-C-10 cycloalkyl, wherein
  • R is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 30 alkyl, aryl, -CH 2 -aryl, aryl -C 1 -C 30 alkyl, heteroaryl-CrC 30 alkyl or C 3 -C 10 cycloalkyl;
  • R 5 is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 30 alkyl, aryl CrC 3 oalkyl, heteroarylalkyl or cycloalkyl;
  • R 6 and R 6' are each independently H, substituted or unsubstituted CrC 6 alkyl, dialkyl or C 3 -C 10 cycloalkyl or together form a 3-7 membered ring system;
  • R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or C 3 - C10 cycloalkyl; and R 8 and R g are each independently H, substituted or unsubstituted d-C ⁇ alkyl, C C 6 alkoxy, C C 6 alkylaryl, or NRs g together form a substituted piperazine or piperidine ring or a dihydro-1 H-isoquinoline ring system, or a specific enantiomer thereof, or a specific tautomer, or a pharmaceutically acceptable salt thereof.
  • the subject invention also provides a compound having the structure:
  • Rio is H or substituted or unsubstituted C1-C 15 alkyl, C 1 -C 15 alkylaryl, or -C(O)R ⁇ 4 , wherein R 1 is hydroxyl, or a substituted or unsubstituted C 1 -C 30 alkyl, alkylamino, dialkylamin ⁇ , alkoxy, benzyloxy, cycloalkyl, alkylheteroaryl, alkylaryl, or a heterocyclic, heteroaryl or aryl ring;
  • Rn is hydrogen or methyl;
  • R 12 is hydrogen or tert-butyl; and
  • R 13 is hydrogen or -C(O)ZRi5, wherein Z is CH 2 , O or N and R 15 is substituted or unsubstituted C 1 -C 1 5 alkyl or aryl.
  • the subject invention also provides a method for treating obesity in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention so as to thereby treat obesity in the subject.
  • the subject invention also provides a method for treating diabetes in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention so as to thereby treat diabetes in the subject.
  • the subject invention also provides a method of inhibiting the hydrolytic activity of pancreatic lipase enzymes in a cell, comprising contacting the cell with an amount of a compound of the invention which is effective in inhibiting the hydrolytic activity of pancreatic lipase enzymes.
  • the subject invention provides compounds having the structure:
  • X is O, S, CH 2 or NR 5 ;
  • Y is O or S
  • Ri is H, substituted or unsubstituted C 1 -C 15 alkyl, C C 8 alkylaryl, -C(O)OR 4 , -C(O)NR 4 R 5 , -CR 6 R 6' OR 4 , -CR 6 R 6 OC(O)R 4 , -CR 6 R 6 C(O)NHR 7 , -C(O)NR 10 R.1, -C(O)NR 8 R 9 NR 8 R 9 , -N(R 5 )C(O)NHR 5 , or CH 2 R ;
  • R 2 is a substituted or unsubstituted, straight chain CrC 30 alkyl or branched C 3 -C 30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R 3 is H or substituted or unsubstituted C C ⁇ alkyl or C 3 -C 1 0 cycloalkyl, wherein
  • R 4 is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 3 o alkyl, aryl, -CH 2 -aryl, aryl -C 1 -C 30 alkyl, heteroaryl-C ⁇ -C 30 alkyl or C 3 -C 10 cycloalkyl;
  • R 5 is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 3 o alkyl, aryl C ⁇ -C 30 alkyl, heteroarylalkyl or cycloalkyl;
  • R 6 and R 6' are each independently H, substituted or unsubstituted C C 6 alkyl, dialkyl or C3-C10 cycloalkyl or together form a 3-7 membered ring system;
  • R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or C 3 - C10 cycloalkyl; and R 8 and Rg are each independently H, substituted or unsubstituted C C 6 alkyl, CrC 6 alkoxy, C- ⁇ -C 6 alkylaryl, or NR 8 R g together form a substituted piperazine or piperidine ring or a dihydro-1 H-isoquinoline ring system, or a specific enantiomer thereof, or a specific tautomer, or a pharmaceutically acceptable salt thereof.
  • the compound has the structure:
  • X is O, S or NR 5 ;
  • Y is O or S;
  • Ri is H, -C(O)OR 4 , -C(O)NR 4 R 5 , -CR 6 R 6 OR 4 , -CR 6 R 6 C(O)R 4 , -CR 6 R6 ' OC(O)NHR 7 , or CH 2 R ;
  • R 2 is a substituted or unsubstituted, straight chain or branched, C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R 3 is H or substituted or unsubstituted C ⁇ -C 6 alkyl or cycloalkyl, wherein,
  • R 4 is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 3 o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R 5 is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 3 o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R 6 and R 6 ' are each independently H, substituted or unsubstituted C ⁇ C 6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
  • R 7 is H or sub lituied or unsubstituted C 1 -C 12 alkyl or cycloalkyl.
  • the compound has the structure:
  • X is O, S or NR 5 ;
  • R! is H, -C(O)OR 4 , -C(O)NR 4 R 5 , -CR 6 R 6 R 4 , -CR 6 R 6 OC(O)R 4 , -CR 6 R 6 OC(O)NHR 7 , or CH 2 R ;
  • R is a substituted or unsubstituted, straight chain or branched C 6 -C 3 o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R3 is H or substituted or unsubstituted d-C ⁇ alkyl or cycloalkyl, wherein,
  • R 4 is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R 5 is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 3 o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R 6 and R 6 - are each independently H, substituted or unsubstituted C C 6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
  • R is H or substituted or unsubstituted C 1 -C 12 alkyl or cycloalkyl.
  • X is O or NR 5 ;
  • RT is -C(O)O-(C 6 -C 30 ) alkyl, -C(O)NH-(C 6 -C 30 ) alkyl or
  • R 2 is C 6 -C 3 n alkyl; and R 3 is C ⁇ -C 6 alkyl. In a further embodiment, R 3 is H or CH 3 .
  • X is O.
  • R 3 is methyl
  • X is N.
  • R is methyl
  • the compound has the structure:
  • Y is O or S
  • XR 2 is -(CH 2 )nCH 3 , -O(CH 2 ) m CH 3 , -OCH(CH 3 ) 2 . -OCH(CH 3 )(CH 2 )5CH3, -OCH 2 CH(CH 3 )2.
  • the compound has the structure:
  • Y is O or S
  • XR 2 is -(CH2.6CH3, -(CH 2 ) ⁇ oCH 3 , -(CH 2 ) 14 CH 3 , -O(CH 2 ) 3 CH 3 , -O(CH 2 ) 5 CH 3 , -O(CH 2 ) 6 CH3, -O(CH 2 ) 7 CH 3 ,
  • R 3 is H, -CH 3 or -CH 2 OCH 3 .
  • the compound is selected from the group consisting of:
  • R 10 is H or substituted or unsubstituted CrC 15 alkyl, C C ⁇ 5 alkylaryl, or -C(O)R ⁇ 4 , wherein R- ⁇ 4 is hydroxyl, or a substituted or unsubstituted d-C 30 alkyl, alkylamino, dialkylamino, alkoxy, benzyloxy, cycloalkyl, alkyl heteroaryl, alkylaryl, or a heterocyclic, heteroaryl or aryl ring; Rn is hydrogen or methyl;
  • R ⁇ 2 is hydrogen or tert-butyl; and R ⁇ 3 is hydrogen or -C(O)ZR ⁇ 5 , wherein Z is CH 2 , O or N and R 5 is substituted or unsubstituted C 1 -C 15 alkyl or aryl.
  • the subject invention also provides a method for treating obesity in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention so as to thereby treat obesity in the subject.
  • the subject invention also provides a method for treating diabetes in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention so as to thereby treat diabetes in the subject.
  • the subject invention also provides a method of inhibiting the hydrolytic activity of pancreatic lipase enzymes in a cell, comprising contacting the cell with an amount of a compound of the invention which is effective in inhibiting the hydrolytic activity of pancreatic lipase enzymes.
  • the above method may contact the cell either in vitro or in vivo.
  • the subject invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the a compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral, topical, parenteral, or nasal administration.
  • the subject invention also provides a process for the manufacture of a pharmaceutical composition comprising admixing a compound of the invention with a pharmaceutically acceptable carrier.
  • the subject invention also provides an article of manufacture comprising packaging material; the above pharmaceutical composition; and instructions for use of the pharmaceutical composition in the treatment of obesity.
  • the subject invention also provides a process of manufacturing a compound having the structure:
  • X is O, S, CH 2 or NR 5 ;
  • Ri is H, substituted or unsubstituted C 1 -C 15 alkyl, CrC 8 alkylaryl,
  • R 2 is a substituted or unsubstituted, straight chain C 1 -C 30 alkyl or branched C 3 -C 30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R 3 is H or substituted or unsubstituted C C 6 alkyl or cycloalkyl;
  • R is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 30 alkyl, aryl, -CH 2 -aryl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R 5 is H or a substituted or unsubstituted, straight chain or branched, C 6 -C 3 o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
  • R 6 and R 6 - are each independently H, substituted or unsubstituted d-C 6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
  • R 7 is H or substituted or unsubstituted CrC ⁇ 2 alkyl or cycloalkyl
  • R 8 and Rg are each independently H, substituted or unsubstituted d-C 6 alkyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylaryl, or NR 8 R 9 together form a substituted piperazine or piperidine ring or a dihydro-1 H-isoquinoline ring system,
  • step (c) reacting the product of step (b) with trifluoroacetic acid (TFA) in the presence of solvent to produce:
  • step (d) reacting the product of step (c) with SOCI 2 in the presence of solvent to produce the compound.
  • the base in step (a) is triethyl amine and the solvent is dimethylformamide (DMF).
  • the solvent in step (c) is dichloromethane
  • the solvent in step (d) is pyridine:CH 2 CI 2 .
  • the subject invention also provides a compound produced by the above process.
  • the subject invention also provides the use of the compounds of the invention for manufacturing a medicament useful for treating obesity in a subject.
  • the subject invention also provides the use of the compounds of the invention for manufacturing a medicament useful for treating diabetes in a subject.
  • the subject invention also provides the use of the compounds of the invention for manufacturing a medicament useful for inhibiting the hydrolytic activity of pancreatic lipase enzymes in a cell.
  • the inhibition of the cell may be effected either in vitro or in vivo.
  • any heterocyclic or heteroaryl ring if present, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.
  • the subject invention also provides any of the above compounds, wherein any substituent, if present, is halogen, hydroxyl, straight chain (d-C 3 o)alkyl, branched chain (C 3 -C 3 o)alkyl, (C -C ⁇ 0 )cycloalkyl, straight chain(d- C 30 )alkylcarbonyloxy, branched chain (C 3 -C 30 )alkylcarbonyloxy, arylcarbonyloxy, straight chain(C .-C 3 o)alkoxycarbonyloxy, branched chain(C 3 -
  • the number of carbons when represented as "(C ⁇ -C 30 )" or “(C 3 -C 30 )” is intended to mean any incremental whole number between 1 and 3 and 30, e.g. 1 , 2, 3, 4, 5 ... or 30.
  • therapeutically effective amount of the compounds of the invention refers to that amount of a therapeutic compound necessary or sufficient to perform its intended function within a mammal.
  • An effective amount of the therapeutic compound can vary according to factors such as the amount of the causative agent already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compounds of the present invention to affect the desired result in the mammal.
  • One of ordinary skill in the art would be able to study the aforementioned factors and make a determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • An in vitro or in vivo assay also can be used to determine an "effective amount" of the . therapeutic compounds described infra. The ordinarily skilled artisan would select an appropriate amount of the therapeutic compound for use in the aforementioned assay or as a therapeutic treatment.
  • a therapeutically effective amount preferably diminishes at least one symptom or effect associated with the disorder being treated by at least about 20%, (more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80%) relative to untreated subjects.
  • Assays can be designed by one skilled in the art to measure the diminishment of such symptoms and/or effects. Any art recognized assay capable of measuring such parameters are intended to be included as part of this invention.
  • animal includes any organism with adenosine receptors. Examples of animals include yeast, mammals, reptiles, and birds. It also includes transgenic animals.
  • alkyl refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C C 3 o for straight chain, C 3 -C 30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • substituted alkyl refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarbox
  • alkylaryl is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • alkyl also includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl refers to the radical of aryl groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonyiamino, carbamoyl and ureido), amidino, imino,
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • the invention contemplates cyano and propargyl groups.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure, even more preferably one to three carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • alkoxyalkyl refers to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • polycyclyl or “polycyclic radical” refer to the radical of two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl,
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. f
  • heterocycle or “heterocyclic system” as used herein is intended to mean a stable 5, 6 or 7-membered monocyclic or 7, 8, 9, 10 or 11- membered bicyclic heterocyclic ring which is saturated or partially unsaturated.
  • Carbocyclic or “heterocyclic” further include spiro compounds, which denote a bicyclic compound in which the two rings have one atom in common and the atom may be carbon or a heteroatom.
  • amino acids includes naturally and unnaturally occurring amino acids found in proteins such as glycine, alanine, valine, cysteine, leucine, isoleucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine, arginine, proline, histidine, phenylalanine, tyrosine, and tryptophan.
  • Amino acid analogs include amino acids with lengthened or shortened side chains or variant side chains with appropriate functional groups. Amino acids also include D and L stereoisomers of an amino acid when the structure of the amino acid admits of stereoisomeric forms.
  • dipeptide includes two or more amino acids linked together.
  • dipeptides are two amino acids linked via a peptide linkage.
  • Particularly preferred dipeptides include, for example, alanine-alanine and glycine- alanine.
  • the structure of some of the compounds of this invention includes asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in this invention.
  • Each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise.
  • Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis.
  • the invention further pertains to pharmaceutical compositions for treating obesity and obesity associated disorders in a mammal.
  • the pharmaceutical composition includes a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. It is to be understood, that all of the compounds described below are included for therapeutic treatment. It is to be further understood that the compounds of the invention can be used alone or in combination with other compounds of the invention or in combination with additional therapeutic compounds, such as antibiotics, antiinflammatories, or anticancer agents, for example.
  • antibiotic is art recognized and is intended to include those substances produced by growing microorganisms and synthetic derivatives thereof, which eliminate or inhibit growth of pathogens and are selectively toxic to the pathogen while producing minimal or no deleterious effects upon the infected host subject.
  • Suitable examples of antibiotics include, but are not limited to, the principle classes of aminoglycosides, cephalosporins, chloramphenicols, fuscidic acids, macrolides, penicillins, polymixin ⁇ , tetracyclines and streptomycins.
  • antiinflammatory is art recognized and is intended to include those agents which act on body mechanisms, without directly antagonizing the causative agent of the inflammation such as glucocorticoids, aspirin, ibuprofen, NSAIDS, etc.
  • anticancer agent is art recognized and is intended to include those agents which diminish, eradicate, or prevent growth of cancer cells without, preferably, adversely affecting other physiological functions.
  • Representative examples include cisplatin and cyclophosphamide.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and mammals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a compound(s) of the present invention within or to the subject such that it can performs its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-f ree water; isotonlc sa
  • certain embodiments of the present compounds can contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts refers to the relatively non-toxic,inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1 -19).
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non- toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like,
  • esters refers to the relatively non-toxic, esterified products of the compounds of the present invention. These esters can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent.
  • Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst.
  • Hydroxyl containing derivatives can be converted into esters via treatment with an esterifying agent such as alkanoyl halides.
  • the term is further intended to include lower hydrocarbon groups capable of being solvated under physiological conditions, e.g., alkyl esters, methyl, ethyl and propyl esters. (See, for example, Berge et al., supra.)
  • the invention further contemplates the use of prodrugs which are converted in vivo to the therapeutic compounds of the invention (see, e.g., R.B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chapter 8).
  • prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter the reactive site of the protease) or the pharmacokinetics of the therapeutic compound.
  • a carboxylic acid group can be esterified, e.g., with a methyl group or an ethyl group to yield an ester.
  • the ester When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively or hydrolytically, to reveal the anionic group.
  • An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound.
  • the prodrug is a reduced form of a sulfate or sulfonate, e.g., a thiol, which is oxidized in vivo to the therapeutic compound.
  • an anionic moiety can be esterified to a group which is actively transported in vivo, or which is selectively taken up by target organs.
  • the ester can be selected to allow specific targeting of the therapeutic moieties to particular reactive sites, as described below for carrier moieties.
  • the compounds of the invention may comprise water-soluble prodrugs which are described in WO 99/33815, International Application No. PCT/US98/04595, filed March 9, 1998 and published July 8, 1999. The entire content of WO 99/33815 is expressly incorporated herein by reference.
  • the water-soluble prodrugs are metabolized in vivo to an active drug, e.g., by esterase catalyzed hydrolysis.
  • Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • Formulations of the present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, acetyl alcohol and glycerol mono
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert dilutents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert dilutents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium sji'oate? and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • An appropriate buffer system e.g., sodium phosphate, sodium acetate or sodium borate
  • sodium phosphate, sodium acetate or sodium borate may be added to prevent pH drift under storage conditions.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and ihtrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time. of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • intravenous and subcutaneous doses of the compounds of this invention for a patient when used for the indicated analgesic effects, will range from about 0.0001 to about 200 mg per kilogram of body weight per day, more preferably from about 0.01 to about 150 mg per kg per day, and still more preferably from about 0.2 to about 140 mg per kg per day.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • a compound of the present invention While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.
  • the present invention also pertains to packaged pharmaceutical compositions for treating obesity or obesity associated disorders in a mammal.
  • the packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one compound of the invention and instructions for using the compound for treating obesity or an obesity associated disorder in the mammal.
  • Method A LC1 method
  • Method B Polar method
  • Method C Polar_Short method
  • Method D Strong_Nonpolar
  • Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester (1.0g, 2.40 mmol) was dissolved in 25 mL of CH 2 CI 2 and 0.25 mL of DMF. Thionyl chloride added as a 2M solution in CH 2 CI 2 (1.2 mL, 2.4 mmol) and the reaction was stirred for
  • Amino-thiophene 18.2 (200 mg, 0.67 mmol) was dissolved in 3 mL CH2CI2 and cooled to 0 9 C. Under N 2 atmosphere, DBU (0.25 mL, 1.68 mmol) was added slowly followed by octyl isocyanate (104mg, 0.67mmol). The reaction slowly warmed to rt and was stirred at room temperature for 5h. The reaction was then diluted with 20 mL CH 2 CI 2 and washed with 1 N HCl and brine. The organic solution was then dried with MgSO and concentrated in vacuo.
  • Aminc-thiophene 18.2 (171 mg, 0.57 mmol) was dissolved in 3 mL CH 2 CI 2 and 2 mL pyridine. Under N 2 atmosphere, lauroyl chloride (126mg, 0.57mmol) was added and the reaction was stirred at room temperature for 6h. The reaction was then diluted with 10 mL CH 2 CI 2 and washed with water, 5% citric acid, and brine. The organic solution was then dried with MgS0 4 and concentrated in vacuo.
  • the sodium salt of the phenol was prepared by dissolving 4-butyl phenol (174 mg, 1.16 mmol) in anhydrous THF (3 mL) and cooling to 0 Q C. Then NaH(60% dispersion in mineral oil) (45 mg, 1.16 mmol) was added to reaction mixture and stirred at 0 -C for V2 hour and was used as stated above. The reaction mixture was partitioned between CHCI 3 and H 2 0 and separated. The H 2 0 layer was extracted again with CHCI 3 (3x) and separated. The combined CHCI 3 layers was washed with 2M NaOH (1x), 1 M HCl (1x), brine (1x) and dried with Na 2 SO 4 filtered and concentrated resulting in 490 mg of a dark orange oil.

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Abstract

The subject invention features compounds having the structure:, wherein X is O, S, CH2 or NR5; Y is O or S; R1 is H, substituted or unsubstituted C1­C15 alkyl, C1-C8 alkylaryl, -C(O)OR4, -C(O)NR4R5, -CR6R6'OR4,-CR6R6'OC(O)R4, - CR6R6'OC(O)NHR7, -C(O)NR1oR11, -C(O)NR8R9 NR8R9, -N(R5)C(O)NHR5, or CH2R4; R2 is a substituted or unsubstituted, straight chain C1-C30 alkyl or branched C3 C30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; R3 is H or substituted or unsubstituted C1-C6 alkyl or C3-C10 cycloalkyl; R4 is H or a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, aryl, -CH2-aryl, aryl -C1-C15 alkyl, heteroaryl-C1-C15alkyl or C3-C10 cycloalkyl; R5 is H or a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, aryl C1-C30alkyl, heteroarylalkyl or cycloalkyl; R6 and R6' are each independently H, substituted or unsubstituted C1-C6 alkyl, dialkyl or C3-C10 cycloalkyl or together form a 3-7 membered ring system; R7 is H or substituted or unsubstituted C1-C12 alkyl or C3-C10 cycloalkyl; R8 and R9 are each independently H, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylaryl, or NR8R9 together form a substituted piperazine or piperidine ring or a dihydro-1H-isoquinoline ring system, or a specific enantiomer thereof, or a specific tautomer, or a pharmaceutically acceptable salt thereof and a method for treating diabetes or obesity by administering a therapeutically effective amount of the compounds of the invention.

Description

PANCREATIC LIPASE INHIBITOR COMPOUNDS. THEIR SYNTHESIS AND USE
This application claims priority of U.S. Provisional Application No. 60/342,617, filed December 20, 2001 , and U.S. Provisional Application No. 60/357,015, filed February 13, 2002, the entire contents of which are hereby incorporated by reference.
Throughout this application, various publications are referenced by full citations. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Background of the Invention
During the last 20 years, obesity has become an increasingly common problem in the populations of developed countries. The increased incidence of obesity is partly due to the adoption of a westernised diet in many developed countries - which contains many foods with high fat and low fiber concentrations - and partly due to the lifestyle of westernized society. Obesity is known to increase the risk of contracting disorders such as diabetes, cardiovascular disease and hypertension.
Pharmacological approaches to the treatment of obesity either try to increase the body's energy expenditure, thereby burning more fat, or reduce the body's energy intake. The latter approach has stimulated the development of a variety of drugs which attempt to reduce the body's ability to absorb fat. These drugs target the enzymes responsible for the digestion of fat in the human digestive cycle. The most important enzymes in the digestion of fat are hydrolytic enzymes. The most significant of these enzymes are lipases, pancreatic lipase in particular. Orlistat, a derivative of lipstatin, a lipase inhibitor, is disclosed as an anti-obesity drug in European Patent Application No. EP129748. Other lipase inhibitors are disclosed in PCT International Publication Nos. WO 00/40569 and WO 00/40247, respectively. Summary of the Invention
The subject invention provides a compound having the structure:
Figure imgf000003_0001
wherein,
X is O, S, CH2 or NR5;
Y is O or S;
R-i is H, substituted or unsubstituted C1-C15 alkyl, C C8 alkylaryl, -C(O)OR4> -C(O)NR4R5J -CR6R6'OR4I -CR6R6'OC(O)R4, -CR6R6 C(O)NHR7l -C(0)NRioR.i, -C(O)NR8R9 NR8R9, -N(R5)C(O)NHR5, or CH2R4;
R2 is a substituted or unsubstituted, straight chain C--C30 alkyl or branched C3-C30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; and,
R is H or substituted or unsubstituted CrC6 alkyl or C3-C-10 cycloalkyl, wherein
R is H or a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, aryl, -CH2-aryl, aryl -C1-C30 alkyl, heteroaryl-CrC30 alkyl or C3-C10 cycloalkyl;
R5 is H or a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, aryl CrC3oalkyl, heteroarylalkyl or cycloalkyl;
R6 and R6' are each independently H, substituted or unsubstituted CrC6 alkyl, dialkyl or C3-C10 cycloalkyl or together form a 3-7 membered ring system;
R7 is H or substituted or unsubstituted C1-C12 alkyl or C3- C10 cycloalkyl; and R8 and Rg are each independently H, substituted or unsubstituted d-Cβ alkyl, C C6 alkoxy, C C6 alkylaryl, or NRs g together form a substituted piperazine or piperidine ring or a dihydro-1 H-isoquinoline ring system, or a specific enantiomer thereof, or a specific tautomer, or a pharmaceutically acceptable salt thereof.
The subject invention also provides a compound having the structure:
Figure imgf000004_0001
wherein,
Rio is H or substituted or unsubstituted C1-C15 alkyl, C1-C15 alkylaryl, or -C(O)Rι4, wherein R1 is hydroxyl, or a substituted or unsubstituted C1-C30 alkyl, alkylamino, dialkylaminό, alkoxy, benzyloxy, cycloalkyl, alkylheteroaryl, alkylaryl, or a heterocyclic, heteroaryl or aryl ring;
Rn is hydrogen or methyl; R12 is hydrogen or tert-butyl; and R13 is hydrogen or -C(O)ZRi5, wherein Z is CH2, O or N and R15 is substituted or unsubstituted C1-C15 alkyl or aryl.
The subject invention also provides a method for treating obesity in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention so as to thereby treat obesity in the subject. The subject invention also provides a method for treating diabetes in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention so as to thereby treat diabetes in the subject.
The subject invention also provides a method of inhibiting the hydrolytic activity of pancreatic lipase enzymes in a cell, comprising contacting the cell with an amount of a compound of the invention which is effective in inhibiting the hydrolytic activity of pancreatic lipase enzymes.
Detailed Description
The subject invention provides compounds having the structure:
Figure imgf000006_0001
wherein,
X is O, S, CH2 or NR5;
Y is O or S;
Ri is H, substituted or unsubstituted C1-C15 alkyl, C C8 alkylaryl, -C(O)OR4, -C(O)NR4R5, -CR6R6'OR4, -CR6R6OC(O)R4, -CR6R6 C(O)NHR7, -C(O)NR10R.1, -C(O)NR8R9 NR8R9, -N(R5)C(O)NHR5, or CH2R ;
R2 is a substituted or unsubstituted, straight chain CrC30 alkyl or branched C3-C30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; and
R3 is H or substituted or unsubstituted C Cδ alkyl or C3-C10 cycloalkyl, wherein
R4 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, aryl, -CH2-aryl, aryl -C1-C30 alkyl, heteroaryl-Cι-C30 alkyl or C3-C10 cycloalkyl;
R5 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, aryl Cι-C30alkyl, heteroarylalkyl or cycloalkyl;
R6 and R6' are each independently H, substituted or unsubstituted C C6 alkyl, dialkyl or C3-C10 cycloalkyl or together form a 3-7 membered ring system;
R7 is H or substituted or unsubstituted C1-C12 alkyl or C3- C10 cycloalkyl; and R8 and Rg are each independently H, substituted or unsubstituted C C6 alkyl, CrC6 alkoxy, C-ι-C6 alkylaryl, or NR8Rg together form a substituted piperazine or piperidine ring or a dihydro-1 H-isoquinoline ring system, or a specific enantiomer thereof, or a specific tautomer, or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound has the structure:
Figure imgf000007_0001
wherein,
X is O, S or NR5; Y is O or S;
Ri is H, -C(O)OR4, -C(O)NR4R5, -CR6R6OR4, -CR6R6 C(O)R4, -CR6R6'OC(O)NHR7, or CH2R ;
R2 is a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl; and
R3 is H or substituted or unsubstituted Cι-C6 alkyl or cycloalkyl, wherein,
R4 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
R5 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
R6 and R6' are each independently H, substituted or unsubstituted Cι C6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system; and
R7 is H or sub lituied or unsubstituted C1-C12 alkyl or cycloalkyl. In a further embodiment, the compound has the structure:
Figure imgf000008_0001
wherein,
X is O, S or NR5;
R! is H, -C(O)OR4, -C(O)NR4R5, -CR6R6 R4, -CR6R6OC(O)R4, -CR6R6OC(O)NHR7, or CH2R ;
R is a substituted or unsubstituted, straight chain or branched C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl; and
R3 is H or substituted or unsubstituted d-Cβ alkyl or cycloalkyl, wherein,
R4 is H or a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
R5 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
R6 and R6- are each independently H, substituted or unsubstituted C C6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system; and
R is H or substituted or unsubstituted C1-C12 alkyl or cycloalkyl.
In a further embodiment of the above compound, X is O or NR5; RT is -C(O)O-(C6-C30) alkyl, -C(O)NH-(C6-C30) alkyl or
-C(O)OCH2(C6H5); R2 is C6-C3n alkyl; and R3 is Cι-C6 alkyl. In a further embodiment, R3 is H or CH3.
In a further embodiment, X is O.
In a further embodiment, R3 is methyl.
In a further embodiment, X is N.
In a further embodiment, R is methyl.
In a further embodiment, the compound has the structure:
Figure imgf000009_0001
wherein,
Y is O or S;
R1 is H, -(CH2)rCH3, -CH(CH3)2, -CH(CH3)CH2C(CH3)3, -CH(CH3)(CH2)3C(=CH2)CH3, -CH(CH3)(CH2)3C(CH3)2OC(O)CH3, -CH(CH3)[CH2]3C(CH3)2OCH3, -CHS(C6H5), -C(O)OH, -C(O)NH(CH2)tCH3, -C(O)O(CH2)uCH3, -C(O)OCH[(CH2)3CH3]2, -C(O)NH(CH2)vCH3, -C(O)N(CH3)2. -C(O)NHCH2(C6H5), -C(O)NHCH2(C5H4N), -C(O)N[(CH2)3CH3]2, -C(O)N[(CH2)5CH3]2, -C(O)N[(CH2)7CH3]2, -C(O)NH(C6Hn), -C(O)(NC4H8N)CH2(C6H5), -C(O)(NC5H9)CH2(C6H5), -C(O)NH(CH2)3θ(C6H5), -C(O)NHCH[(CH2)3CH3]2, -C(O)NH(CH2)3N(CH3)2, -C(O)NHCH2C(O)OCH2(C6H5), -C(O)N(CH3)CH2(C5H3N[CH3]), -C(O)NH(CH2)2(C5H4N), -C(O)N(CH2CH3)(CH2)2(C5H4N), -C(O)NHCH2(C4H3O),
-C(O)(NC4H8N)[CH2]2(NC5H10), -C(O)NHCH2CH(CH3)2, -C(0)NHCH2(C5H4N), -C(O)NHCH2C(CH3)3, -C(O)(NC4H8N)CH2C(O)NHCH(CH3)2, -C(O)(NC9H8)[OCH3]2, -C(0)NHCH2(C6H3[OCH3]2), -C(O)NHCH2(C7H5θ2), -C(0)NH(CH2)20(C6H5), -C(O)NH(CH2)2OCH3, -C(O)NH(CH2)3OCH3, -C(O)NH(CH2) (C6H5), or
-C(O)NH(CH2)3(C6H5); r is an integer from 1 to 15; s is an integer from 0 to 6; t is an integer from 0 to 6; u is an integer from 3 to 8; v is an integer from 5 to 15; XR2 is -(CH2)nCH3, -O(CH2)mCH3, -OCH(CH3)2. -OCH(CH3)(CH2)5CH3, -OCH2CH(CH3)2. -O(CH2)2OCH3, -O(CH2)2OCH2(C6H5), -O(CH2)P(C6H5), -OCH2(C6H4[(CH2)3CH3]), -O(C6H4[(CH2)3CH3]), -O(CH2)2(C6H4[CH3]), -O(CH2)3OCH2(C6H5),
-O(CH2)4OCH2(C6H5), -N([CH2]7CH3)C(O)NH(CH2)7CH3, -N([CH2]6CH3)C(O)NH(CH2)6CH3, -NH(CH2)qCH3, -NH(C6H4)O(C6H5), -N(CH3)(CH2)5CH3- -NHCH[(CH2)3CH3]2, -NHCH(CH3)[CH2]5CH3, or -N([CH2]7CH3)2; n is an integer from 6 to 15; m is an integer from 1 to 15; p is an integer from 0 to 6; q is an integer from 6 to 15; and R3 is H, -CH3 or -CH2OCH3.
diment, the compound has the structure:
Figure imgf000011_0001
wherein,
Y is O or S;
Ri is H, -(CH2)3CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)9CH3, -(CH2) .1CH3, -CH(CH3)2, -CH(CH3)CH2C(CH3)3- -CH(CH3)(CH2)3C(=CH2)CH3, -CH(CH3)(CH2)3C(CH3)2OC(O)CH3, -CH(CH3)[CH2]3C(CH3)2OCH3, -CH2(C6H5), -(CH2)2(C6H5), -(CH2)3(C6H5), -(CH2) (C6H5), -(CH2)5(C6H5), -C(O)OH, -C(O)NHCH3, -C(O)NHCH2CH3, -C(O)NH(CH2)3CH3, -C(O)OCH2(C6H5), -C(O)O(CH2)5CH3l -C(O)0(CH2)6CH3, JC(O)O(CH2)7CH3, -C(O)OCH[(CH2)3CH3]2, -C(O)NH(CH2)5CH3, -C(O)NH(CH2) CH3, -C(O)NH(CH2)9CH3, -C(O)NH(CH2)nCH3, -C(O)NH(CH2)ι5CH3, -C(0)N(CH3)2, -C(O)NHCH2(C6H5), -C(O)NHCH2(C5H4N), -C(O)N[(CH2)3CH3]2, -C(O)N[(CH2)5CH3]2, -C(O)N[(CH2)7CH3]2, -C(0)NH(CβHn), -C(O)(NC4H8N)CH2(C6H5), -C(O)(NC5H9)CH2(C6H5), -C(O)NH(CH2)3O(C6H5), -C(O)NHCH[(CH2)3CH3]2j -C(O)NH(CH2)3N(CH3)2, -C(O)NHCH2C(O)OCH2(C6H5), -C(O)N(CH3)CH2(C5H3N[CH3]), -C(O)NH(CH2)2(C5H4N), -C(O)N(CH2CH3)(CH2)2(C5H4N), -C(O)NHCH2(C4H3O), -C(O)(NC4H8N)[CH2]2(NC5Hιo), -C(O)NHCH2CH(CH3)2, -C(O)NHCH2(C5H4N): -C(O)NHCH2C(CH?)3, -C(O)(NC4H8N)CH2C(O)NHCH(CH3)2, -C(O)(NC9H8)[OCH3]2, -C(O)NHCH2(C6H3[OCH3]2), -C(O)NHCH2(C7H5O2), -C(O)NH(CH2)2θ(C6H5), -C(O)NH(CH2)2θCH3, -C(O)NH(CH2)3OCH3, -C(O)NH(CH2) (C6H5), or
Figure imgf000012_0001
XR2 is -(CH2.6CH3, -(CH2)ιoCH3, -(CH2)14CH3, -O(CH2)3CH3, -O(CH2)5CH3, -O(CH2)6CH3, -O(CH2)7CH3,
-O(CH2)9CH3, -0(CH2)nCH3, -O(CH2)15CH3, -OCH(CH3) , -OCH(CH3)(CH2)5CH3, -OCH2CH(CH3)2, -O(CH2)2OCH3, -O(CH2)2OCH2(C6H5), -O(CH2)4(C6H5), -O(CH2)3(C6H5), -O(CH2)2(C6H5), -O(C6H5), -OCH2(C6H5). -OCH2(C6H4[(CH2)3CH3]), -O(C6H4[(CH2)3CH3]),
-O(CH2) (C6H4[CH3]), -O(CH2)3OCH2(C6H5), -O(CH2)4OCH2(C6H5), -N([CH2]7CH3)C(O)NH(CH2)7CH3, -N([CH2]6CH3)C(O)NH(CH2)6CH3, -NH(CH2)6CH3, -NH(CH2)7CH3, -NH(CH2)ιιCH3, -NH(CH2)i3CH3, -NH(CH2)ι5CH3, -NH(C6H4)O(C6H5), -N(CH3)(CH2)5CH3,
-NHCH[(CH2)3CH3]2, -NHCH(CH3)[CH2]5CH3, or
Figure imgf000012_0002
R3 is H, -CH3 or -CH2OCH3.
In a further embodiment, the compound is selected from the group consisting of:
6-Heptyl-2-octyloxy-thieno[2,3-d][1 .3]oxazin-4-one;
6-Hexyl-2-octyloxy-thieno[2,3-of][1 ,3]oxazin-4-one;
2-Octyloxy-6-(1 ,3,3-trimethyl-butyl)-thieno[2,3-d][1 ,3]oxazin-4-one;
6-Butyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; 6-Heptyl-2-octylamino-thieno[2,3-d][1 ,3]oxazin-4-one;
6-Butyl-2-octylamino-thieno[2,3-d][1 ,3]oxazin-4-one;
6-Benzyl-2-octylamino-thieno[2,3-d][1 ,3]oxazin-4-one;
6-Heptyl-2-undecyl-thieno[2,3-d][1 ,3]oxazin-4-one;
6-(5-Methoxy-1 ,5-dimethyl-hexyl)-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4- one;
6-(1 .5-Dimethyl-hex-4-enyl)-2-octyloxy-thieno[2.3-d][1 ,3]oxazin-4-one;
6-(1 ,5-Dimethyl-hex-5-enyl)-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; Trifluoro-acetic acid 1 ,1-dimethyl-5-(2-octyloxy-4-oxo-4H-thieno[2,3- d][1 ,3]oxazin-6-yl)-hexyl ester;
2-(2-Benzyloxy-ethoxy)-6-decyl-thieno[2,3-d][1 ,3]oxazin-4-one;
6-Heptyl-5-methyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; 6-Methyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one;
2-Octyloxy-6-phenethyl-thieno[2,3-d][1,3]oxazin-4-one;
2-Octyloxy-6-(3-phenyl-propyl)-thieno[2,3-d][1 ,3]oxazin-4-one;
2-Octyloxy-6-(4-phenyl-butyl)-thieno[2,3-d][1 ,3]oxazin-4-one;
2-Octyloxy-6-(5-phenyl-pentyl)-thieno[2,3-d][1 ,3]oxazin-4-one; 6-Decyl-2-(2-methoxy-ethoxy)-thieno[2,3-d][1 ,3]oxazin-4-one;
2-(4-Butyl-phenoxy)-6-decyl-thieno[2,3-d][1 ,3]oxazin-4-one;
2-(3-Benzyloxy-propoxy)-6-decyl-thieno[2,3-d][1 ,3]oxazin-4-one;
2-(3-Benzyloxy-butyloxy)-6-decyl-thieno[2,3-d][1 ,3]oxazin-4-one;
6-lsopropyl-2-octyloxy-thieno[2,3-d][1,3]oxazin-4-one; 6-Octyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one;
6-Dodecyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one;
2-Benzyloxy-6-Decyl-thieno[2,3-d][1 ,3]oxazin-4-one;
2-(4-Butylbenzyloxy)-6-Decyl-thieno[2,3-d][1.3]oxazin-4-one;
6-Decyl-2-(2-p-tolyl-ethoxy)-thieno[2,3-dj[1 ,3]oxazin-4-one; 6-Decyl-2-phenethyloxy-thieno[2,3-d][1 ,3]oxazin-4-one;
3-Methyl-6-octyl-2-octyloxy-5H-thieno[2,3-b]pyridin-4-one;
2-Butoxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one;
2-Hexyloxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one;
2-Dodecyloxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one; 6-Decyl-2-phenoxy-5H-thieno[2,3-b]pyridin-4-one;
2-Decyloxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one;
6-Benzyl-2-octyloxythieno[2,3-c(][1,3]oxazin-4-one;
6-Decyl-2-octyloxythieno[2,3-cf][1 ,3]oxazin-4-one;
6-Decyl-2-(1 -methylheptyloxy)thieno[2,3- ][1 ,3]oxazin-4-one; 6-Heptyl-2-(1-methylheptyloxy)thieno[2,3-cd[1 ,3]oxazin-4-one;
6 "Decyl-2-(4-phenylpropoxy)thieno[2,3-(- ![1 ,3]oxazin-4-one; and
6-Decyl-2-(4-phenylbutoxy)thieno[2,3-cfj[1 ,3]oxazin-4-one. The subject invention also provides compounds having the structure:
Figure imgf000014_0001
wherein, R10 is H or substituted or unsubstituted CrC15 alkyl, C Cι5 alkylaryl, or -C(O)Rι4, wherein R-ι4 is hydroxyl, or a substituted or unsubstituted d-C30 alkyl, alkylamino, dialkylamino, alkoxy, benzyloxy, cycloalkyl, alkyl heteroaryl, alkylaryl, or a heterocyclic, heteroaryl or aryl ring; Rn is hydrogen or methyl;
Rι2 is hydrogen or tert-butyl; and Rι3 is hydrogen or -C(O)ZRι5, wherein Z is CH2, O or N and R 5 is substituted or unsubstituted C1-C15 alkyl or aryl.
The subject invention also provides a method for treating obesity in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention so as to thereby treat obesity in the subject.
The subject invention also provides a method for treating diabetes in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention so as to thereby treat diabetes in the subject.
The subject invention also provides a method of inhibiting the hydrolytic activity of pancreatic lipase enzymes in a cell, comprising contacting the cell with an amount of a compound of the invention which is effective in inhibiting the hydrolytic activity of pancreatic lipase enzymes.
The above method may contact the cell either in vitro or in vivo.
The subject invention also provides a pharmaceutical composition comprising the a compound of the invention and a pharmaceutically acceptable carrier.
In one embodiment, the pharmaceutical composition is formulated for oral, topical, parenteral, or nasal administration.
The subject invention also provides a process for the manufacture of a pharmaceutical composition comprising admixing a compound of the invention with a pharmaceutically acceptable carrier.
The subject invention also provides an article of manufacture comprising packaging material; the above pharmaceutical composition; and instructions for use of the pharmaceutical composition in the treatment of obesity.
The subject invention also provides a process of manufacturing a compound having the structure:
Figure imgf000015_0001
wherein,
X is O, S, CH2 or NR5;
Ri is H, substituted or unsubstituted C1-C15 alkyl, CrC8 alkylaryl,
-C(O)OR4, -C(O)NR4R5, -CR6R6'OR4, -CR6R6OC(O)R4, -CR6R6.OC(O)NHR7, -C(O)NR8R9, -C(O)NR8R9NR8R9, -N(R5)C(O)NHR5, or CH2R4;
R2 is a substituted or unsubstituted, straight chain C1-C30 alkyl or branched C3-C30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; R3 is H or substituted or unsubstituted C C6 alkyl or cycloalkyl;
R is H or a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, aryl, -CH2-aryl, arylalkyl, heteroarylalkyl or cycloalkyl;
R5 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
R6 and R6- are each independently H, substituted or unsubstituted d-C6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
R7 is H or substituted or unsubstituted CrCι2 alkyl or cycloalkyl;
R8 and Rg are each independently H, substituted or unsubstituted d-C6 alkyl, Ci-Cβ alkoxy, Ci-Cε alkylaryl, or NR8R9 together form a substituted piperazine or piperidine ring or a dihydro-1 H-isoquinoline ring system,
comprising
(a) reacting
Figure imgf000016_0001
in the presence of sulfur, a base and solvent to produce:
Figure imgf000017_0001
(b) reacting the product of step (a) with
Figure imgf000017_0002
in the presence of a base to produce:
Figure imgf000017_0003
(c) reacting the product of step (b) with trifluoroacetic acid (TFA) in the presence of solvent to produce:
Figure imgf000017_0004
(d) reacting the product of step (c) with SOCI2 in the presence of solvent to produce the compound.
In one embodiment of the above process, the base in step (a) is triethyl amine and the solvent is dimethylformamide (DMF).
In a further embodiment, the solvent in step (c) is dichloromethane,
In a further embodiment, the solvent in step (d) is pyridine:CH2CI2.
The subject invention also provides a compound produced by the above process.
The subject invention also provides the use of the compounds of the invention for manufacturing a medicament useful for treating obesity in a subject.
The subject invention also provides the use of the compounds of the invention for manufacturing a medicament useful for treating diabetes in a subject.
The subject invention also provides the use of the compounds of the invention for manufacturing a medicament useful for inhibiting the hydrolytic activity of pancreatic lipase enzymes in a cell.
The inhibition of the cell may be effected either in vitro or in vivo.
The subject invention also provides the above compounds, wherein any heterocyclic or heteroaryl ring, if present, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.
The subject invention also provides any of the above compounds, wherein any substituent, if present, is halogen, hydroxyl, straight chain (d-C3o)alkyl, branched chain (C3-C3o)alkyl, (C -Cι0)cycloalkyl, straight chain(d- C30)alkylcarbonyloxy, branched chain (C3-C30)alkylcarbonyloxy, arylcarbonyloxy, straight chain(C .-C3o)alkoxycarbonyloxy, branched chain(C3-
C3o)alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, straight chain(C C30)alkylcarbonyl, branched chain (C3-C3o)alkylcarbonyl, straight chain (d-
C30)alkoxycarbonyl, branched chain (C3-C3o)alkoxycarbonyl, aminocarbonyl, straight chain (d-C3o)alkylthiocarbonyl, branched chain (C3- C30)alkylthiocarbonyl, straight chain (Cι-C o)alkoxyl, branched chain (d- C3o)alkoxyl, phosphate, phosphonato, cyano, amino, straight chain (d- C3o)alkylamino, branched chain (C3-C30)alkylamino, straight chain (d-
C3o)dialkylamino, branched chain (C3-C30)dialkylamino, arylamino, diarylamino, straight chain (CrC3o)alkylarylamino, branched chain (C3-C30)alkylarylamino, acylamino, straight chain (C.-C3o)alkylcarbonylamino, branched chain (C3- C30)alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, imino, sulfhydryl, straight chain (Cι-C30)alkylthio, branched chain (C3-C3o)alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluororηethyl, azido, 4-10 membered heterocyclyl, straight chain (d- C 0)alkylaryl, branched chain (C3-C3o)alkylaryl, benzo(1 ,3)dioxole, or an aromatic or 5-6 membered heteroaromatic moiety, which substituent may be further substituted by any of the above.
The number of carbons when represented as "(Cι-C30)" or "(C3-C30)" is intended to mean any incremental whole number between 1 and 3 and 30, e.g. 1 , 2, 3, 4, 5 ... or 30.
Additional embodiments of the compounds of this invention are described below.
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
"k" and "Ymax" in the above table correspond to values inn the equation appearing on page 159. All compounds listed as oils were oils at room temperature.
The language "therapeutically effective amount" of the compounds of the invention, described infra, refers to that amount of a therapeutic compound necessary or sufficient to perform its intended function within a mammal. An effective amount of the therapeutic compound can vary according to factors such as the amount of the causative agent already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compounds of the present invention to affect the desired result in the mammal. One of ordinary skill in the art would be able to study the aforementioned factors and make a determination regarding the effective amount of the therapeutic compound without undue experimentation. An in vitro or in vivo assay also can be used to determine an "effective amount" of the . therapeutic compounds described infra. The ordinarily skilled artisan would select an appropriate amount of the therapeutic compound for use in the aforementioned assay or as a therapeutic treatment.
A therapeutically effective amount preferably diminishes at least one symptom or effect associated with the disorder being treated by at least about 20%, (more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80%) relative to untreated subjects. Assays can be designed by one skilled in the art to measure the diminishment of such symptoms and/or effects. Any art recognized assay capable of measuring such parameters are intended to be included as part of this invention.
The term "animal" includes any organism with adenosine receptors. Examples of animals include yeast, mammals, reptiles, and birds. It also includes transgenic animals.
The term "mammal" is art recognized and is intended to include an animal, more preferably a warm-blooded animal, most preferably cattle, sheep, pigs, horses, dogs, cats, rats, mice, and humans. Mammals susceptible to obesity associated disorders are included as part of this invention. The term "alkyl" refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C C3o for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
The term "substituted alkyl", refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, suifonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "alkylaryl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). The term "alkyl" also includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The term "aryl" as used herein, refers to the radical of aryl groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonyiamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trif luoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. For example, the invention contemplates cyano and propargyl groups.
Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure, even more preferably one to three carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.
The terms "alkoxyalkyl", "polyaminoalkyl" and "thioalkoxyalkyl" refer to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
The terms "polycyclyl" or "polycyclic radical" refer to the radical of two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.
The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. f
The term "heterocycle" or "heterocyclic system" as used herein is intended to mean a stable 5, 6 or 7-membered monocyclic or 7, 8, 9, 10 or 11- membered bicyclic heterocyclic ring which is saturated or partially unsaturated.
The terms "carbocyclic" or "heterocyclic" further include spiro compounds, which denote a bicyclic compound in which the two rings have one atom in common and the atom may be carbon or a heteroatom.
The term "amino acids" includes naturally and unnaturally occurring amino acids found in proteins such as glycine, alanine, valine, cysteine, leucine, isoleucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine, arginine, proline, histidine, phenylalanine, tyrosine, and tryptophan. Amino acid analogs include amino acids with lengthened or shortened side chains or variant side chains with appropriate functional groups. Amino acids also include D and L stereoisomers of an amino acid when the structure of the amino acid admits of stereoisomeric forms. The term "dipeptide" includes two or more amino acids linked together. Preferably, dipeptides are two amino acids linked via a peptide linkage. Particularly preferred dipeptides include, for example, alanine-alanine and glycine- alanine.
It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in this invention. Each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis.
The invention further pertains to pharmaceutical compositions for treating obesity and obesity associated disorders in a mammal. The pharmaceutical composition includes a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. It is to be understood, that all of the compounds described below are included for therapeutic treatment. It is to be further understood that the compounds of the invention can be used alone or in combination with other compounds of the invention or in combination with additional therapeutic compounds, such as antibiotics, antiinflammatories, or anticancer agents, for example.
The term "antibiotic" is art recognized and is intended to include those substances produced by growing microorganisms and synthetic derivatives thereof, which eliminate or inhibit growth of pathogens and are selectively toxic to the pathogen while producing minimal or no deleterious effects upon the infected host subject. Suitable examples of antibiotics include, but are not limited to, the principle classes of aminoglycosides, cephalosporins, chloramphenicols, fuscidic acids, macrolides, penicillins, polymixinε, tetracyclines and streptomycins.
The term "antiinflammatory" is art recognized and is intended to include those agents which act on body mechanisms, without directly antagonizing the causative agent of the inflammation such as glucocorticoids, aspirin, ibuprofen, NSAIDS, etc.
The term "anticancer agent" is art recognized and is intended to include those agents which diminish, eradicate, or prevent growth of cancer cells without, preferably, adversely affecting other physiological functions. Representative examples include cisplatin and cyclophosphamide.
When the compounds of the present invention are administered as pharmaceuticals, to humans and mammals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a compound(s) of the present invention within or to the subject such that it can performs its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-f ree water; isotonlc saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As set out above, certain embodiments of the present compounds can contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this respect, refers to the relatively non-toxic,inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1 -19).
In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non- toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like,
The term "pharmaceutically acceptable esters" refers to the relatively non-toxic, esterified products of the compounds of the present invention. These esters can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst. Hydroxyl containing derivatives can be converted into esters via treatment with an esterifying agent such as alkanoyl halides. The term is further intended to include lower hydrocarbon groups capable of being solvated under physiological conditions, e.g., alkyl esters, methyl, ethyl and propyl esters. (See, for example, Berge et al., supra.)
The invention further contemplates the use of prodrugs which are converted in vivo to the therapeutic compounds of the invention (see, e.g., R.B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chapter 8). Such prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter the reactive site of the protease) or the pharmacokinetics of the therapeutic compound. For example, a carboxylic acid group, can be esterified, e.g., with a methyl group or an ethyl group to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively or hydrolytically, to reveal the anionic group. An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound. In another embodiment, the prodrug is a reduced form of a sulfate or sulfonate, e.g., a thiol, which is oxidized in vivo to the therapeutic compound. Furthermore, an anionic moiety can be esterified to a group which is actively transported in vivo, or which is selectively taken up by target organs. The ester can be selected to allow specific targeting of the therapeutic moieties to particular reactive sites, as described below for carrier moieties.
The compounds of the invention may comprise water-soluble prodrugs which are described in WO 99/33815, International Application No. PCT/US98/04595, filed March 9, 1998 and published July 8, 1999. The entire content of WO 99/33815 is expressly incorporated herein by reference. The water-soluble prodrugs are metabolized in vivo to an active drug, e.g., by esterase catalyzed hydrolysis. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Formulations of the present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert dilutents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert dilutents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium sji'oate? and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
An appropriate buffer system (e.g., sodium phosphate, sodium acetate or sodium borate) may be added to prevent pH drift under storage conditions.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and ihtrasternal injection and infusion. The phrases "systemic administration," "administered systematically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time. of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 200 mg per kilogram of body weight per day, more preferably from about 0.01 to about 150 mg per kg per day, and still more preferably from about 0.2 to about 140 mg per kg per day.
If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.
The present invention also pertains to packaged pharmaceutical compositions for treating obesity or obesity associated disorders in a mammal. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one compound of the invention and instructions for using the compound for treating obesity or an obesity associated disorder in the mammal.
The features and details of the invention will now be more particularly described and pointed out in the claims. It is to be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention. The invention is further illustrated by the following examples which in no way should be construed as being further limiting. The contents of all references, pending patent applications and published patent applications, cited throughout this application, including those referenced in the background section, are hereby incorporated by reference. It should be understood that the models used throughout the examples are accepted models and that the demonstration of efficacy in these models is predictive of efficacy in humans.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
Compounds in the examples are labeled with whole numbers if the compound appears in the table above and as X.Y, where X is the example number and Y is an index starting at 1 in each example, if they do not appear in the above table.
Experimental Details
All non-aqueous reactions requiring anhydrous conditions were performed under a positive pressure of nitrogen (N2) in oven-dried glassware, which had been cooled under N2. All solvents for anhydrous reactions were purchased from Aldrich. The removal of solvents refers to evaporation in vacuo on a rotary evaporator followed by evacuation to constant sample weight (<0.1 mm Hg). Solvents used for chromatography were purchased HPLC grade. All reagents employed were of American Chemical Society (ACS) grade or finer. Air sensitive reagents were handled under an atmosphere of dry N2.
Where possible all reactions were followed by thin layer chromatography (TLC) and visualized using UV fluorescence, 3% KMnθ4 (aqueous) staining, and/or dodecamolybdophosphoric acid. Commercial thin layer and preparative layer chromatography plates were Si250F and SiδOOF, respectively, from J. T. Baker. Flash chromatography was performed using 40 μm 'Baker' silica gel from J. T. Baker. All solvent mixtures are listed as volume ratios.
Melting points are uncorrected and were determined on a Mel-Temp II
(Laboratory Devices, USA) using open capillary tubes. Mass spectra (MS) were recorded on a Platform 2 Micromass instrument. Nuclear magnetic resonance (NMR) spectra were measured on a Varian 200 instrument in the specified solvent with tetramethylsilane (TMS) as internal standard for 1 H NMR. For 13C NMR spectra, the deuterated solvent peak was used as the reference with its position set relative to TMS.
LCMS Methods: Method A=LC1 method; Method B=Polar method; Method C=Polar_Short method; Method D=Strong_Nonpolar
General Procedure: Amides/Esters a. Route A. The aminothiophene was synthesized using a known protocol (McKibben, B.P., Cartwell, C.H., Castelhano, A.L. Tetrahedron Lett. 1999, 40, 5471 - 5474). Amide protection with trifluoroacetic anhydride followed by TFA deprotection and treatment with sodium carbonate generates the amino acid. Attempts to deprotect with TFA without amide protection results in decarboxylation. The amino acid was reacted with various acid chlorides, and chloroformates to afford the thienoxazinones in moderate yields (Scheme 1). Scheme 1
Figure imgf000051_0001
b. Route B. In general, reacting the f-Bu protected amino acid directly with a chloroformate or an isocyanate followed by TFA deprotection of the f-Bu ester and treatment with thionyl chloride gives the corresponding thienoxazinones in higher yields (Scheme 2)
Scheme 2
Figure imgf000051_0002
O π ι \ A; 50-80 %
Cl XΛ / n
Figure imgf000051_0003
Derivation at the 5-position was achieved through either transesterification of methyl acetoacetate with various alcohols prior to thiophene formation or benzyl deprotection of the diester, followed by EDC coupling with various alcohols and amines to generate esters or amides, respectively. Example 1 : General Procedure for Amino-Thiophene formation
Figure imgf000052_0001
5-Amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-ferf-butyl ester. (1.1) To a suspension of benzyl acetoacetate (20.0 g, 104.1 mmol), t-butyl cyanoacetate (14.7 g, 104.1 mmol), sulfur (3.5 g, 109.3 mmol) and pyridine (120 ml) was added diethyl amine dropwise. After 2 days, the "black solution was concentrated under reduced pressure, dissolved in Et2O and filtered through silica. The eluent was then concentrated. Chromatography (silica, 7:1 hexane/EtOAc) yielded 25.58g (71 %)of a orange oil which slowly crystallizes upon standing: 1H- NMR (CDCI3) 1.58 (s, 9H), 2.70 (s, 3H), 5.27 (s, 2H), 7.38 (m, 5H). 1H NMR was consistent with published data.
Figure imgf000052_0002
5-Amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-heptyl ester 4-ferf-butyl ester. (1.2) The same method as for the preparation of 5-amino-3-methyl-thiophene- 2,4-dicarboxylic acid 2-benzyl ester 4-te/ϊ-butyl ester was employed. Thus, cyclization of tert-butyl cyanoacetate (10.3 mL, 72.0 mmol), heptyl acetoacetate (13.7 g, 68.0 mmol), and sulfur (4.4 g, 0.14 mol) in pyridine (80 mL) with added diethylamine (7.1 mL, 68.0 mmol) afforded 18.4 g thiophene (76%) of an oil after column chromatography (10:1 ; hexanes: EtOAc): 1H NMR (CDCI3) δ 6.47 (bs, 2H), 4.19 (t, 2H, J = 6.6 Hz), 2.67 (s, 3H), 1.80-1.50 (m, 2H), 1.57 (s, 9H), 1.30 (bs, 8H), 0.89 (t, 3H, J = 6.6 Hz).
Figure imgf000052_0003
5-Amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester 4-ferf-butyl ester. (1.3) The same method as for the preparation of 5-amino-3-methyl-thiophene-
2,4-dicarboxylic acid 2-benzyl ester 4-te/t-butyl ester was employed. Thus, cyclization of te/τ-butyl cyanoacetate (6.2 mL, 43.0 mmol), octyl acetoacetate (8.5 g, 41.0 mmol), and sulfur (2.6 g, 82.0 mmol) in pyridine (50 mL) with added diethylamine (4.3 mL, 41.0 mmol) afforded 10.3 g thiophene (68%) of an oil after column chromatography (10:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 6.63 (s, 2H), 4.14 (t, 2H, J = 6.6 Hz), 2.63 (s. 3H), 1.72-1.50 (m, 2H), 1.52 (s, 9H), 1.22 (bs, 10H), 0.83 (t, 3H, J = 6.8 Hz). 13C NMR (CDCI3) δ 165.9, 165.4, 163.0, 147.9, 109.6, 108.0, 81.0, 64.4, 31.7, 29.1 , 28.6, 28.4, 25.9, 22.5, 16.2, 14.0.
Example 2: General Procedure for Cyclization From Chloroformate and Amino- acid
Figure imgf000053_0001
2-Dodecyloxy-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid benzyl ester (6) To a stirring solution of 5-amino-3-methyl-thiophene-2,4- dicarboxylic acid 2-benzyl ester (1.00 g, 3.43 mmol) in pyridine (20 mL) was added dodecyl chloroformate (2.80 mL, 2.56 g, 10.3 mmol). The reaction was stirred at 0 9C for 0.5 h, then solvent was removed under reduced pressure. The product was purified by column chromatography (10:1; hexanes: EtOAc) to give 169mg (10%) of a solid: 1H NMR (CDCI3) δ 7.50-7.25 (m, 5H), 5.35 (s, 2H), 4.17 (t, 2H, J = 6.6 Hz), 2.87 (s, 3H), 1.70-1.40 (m, 2H), 1.40-1.00 (m, 18H), 0.88 (t, 3H, J = 6.4 Hz). MS (El): 486.4 (m++H).
Figure imgf000053_0002
5-Methyl-2-octyloxy-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid benzyl ester (5) The same method as for the preparation of 2-dodecyloxy-5- methyl-4-oxo-4H-thieno[2,3-cl[1 ,3]oxazine-6-carboxylic acid benzyl . ester was employed: 1H NMR (CDCI3) δ 7.53-7.25 (m, 5H), 5.33 (s, 2H), 4.44 (t, 2H, J = 6.6
Hz), 2.83 (s, 3H), 1.80 (quint, 2H, J = 6.6 Hz), 1.26 (bs, 10H), 0.88 (t, 3H, J = 6.6
Hz).
Figure imgf000054_0001
2-Hexadecyloxy-5-methyl-4-oxo-4H-thieno[2,3-t-][1 ,3]oxazine-6-carboxylic acid benzyl ester (7) The same method as for the preparation of 2-dodecyloxy-5-methyl- 4-oxo-4H-thieno[2,3-<-/][1 ,3]oxazine-6-carboxylic acid benzyl ester was employed: 1H NMR (CDCIg) δ 7.50-7.25 (m, 5H), 5.34 (s, 2H), 4.44 (t, 2H, J = 6.6 Hz), 2.83 (s, 3H), 1.80 (quint, 2H, J = 6.6 Hz), 1.26 (bs, 26H), 0.88 (t, 3H, J = 6.6 Hz).
Example 3: General Procedure for Cyclization From Acyl Chloride and Amino- acid
Figure imgf000054_0002
2-Heptyl-5-methyl-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid benzyl ester (1) To a stirring solution of 5-amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester (200 mg, 0.69 mmol) in pyridine (5 mL) was added octanoyl chloride (352 μL, 2.56 g, 10.3 mmol). The reaction was stirred at 0 SC for 0.5 h, then let warm to RT and stirred for 3.5 h. The solvent was removed under reduced pressure. The mixture was diluted in EtOAc, washed with H2O. The organic fraction was dried (MgSO ), and concentrated in vacuo. The product was purified by column chromatography (9:1 ; hexanes: EtOAc) to give 48 mg (18%) of a solid: ): 1H NMR (CDCI3) δ 7.32-7.48 (m, 5H), 5.35 (s, 2H), 2.86 (s, 3H), 2.69 (t, 2H, J = 7.2 Hz), 1.90- 1.70 (m, 2H), 1.45-1.20 (m, 8H), 0.98-0.80 (m, 3H).
Figure imgf000054_0003
5-Methyl-4-oxo-2-pentadecyl-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid benzyl ester (3) The same method as for the preparation of 2-heptyi-5-methyl-4- oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid benzyl ester was employed.
Thus, cyclization with hexadecanoyl chloride (476 mL, 2.06 mmol) yielded 56 mg product (16%) after oil after column chromatography (9:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 7.30-7.55 (m, 5H), 5.35 (s, 2H), 2.86 (s, 3H), 2.69 (t, 2H, J = 7.2 Hz), 2.00- 1.70 (m, 2H), 1.50-1.0 (m, 24H), 1.00-0.90 (m, 3H).
Figure imgf000055_0001
2-Undecyl-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid benzyl ester (2) The same method as for the preparation of 2-heptyl-5-methyl-4- oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid benzyl ester was employed. Thus, cyclization with dodecanoyl chloride (476 mL, 2.06 mmol) yielded 77 mg product (24%) after oil after column chromatography (9:1 ; hexanes: EtOAc): 1H NMR (CDCI3) δ 7.30-7.50 (m, 5H), 5.35 (s, 2H), 2.86 (s, 3H), 2.69 (t, 2H, J = 7.2 Hz), 1 .90- 1 .70 (m, 2H), 1.50-1.20 (m, 16H), 1.00-0.90 (m, 3H).
Example 4: General Procedure for Acylation with Chlorformate of Diester
Figure imgf000055_0002
3-Methoxymethyl-5-octyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 2- benzyl ester 4-ferf-butyl ester. (4.1) To a stirring solution of 5-amino-3- methoxymethyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester (1.16 g, 3.06 mmol) in pyridine (15 mL) was added octyl chloroformate (0.9 mL, 886 mg, 4.6 mmol). The reaction was stirred at 0 SC for 1 h, then solvent was removed under reduced pressure. The product was purified by column chromatography (10:1; hexanes: EtOAc) to give 1.27 g (78%) of a solid: 1H NMR (CDCI3) δ 10.51 (s, 1 H), 7.32 (m, 5H), 5.12 (s, 2H), 4.19 (t, 2H, J = 6.6 Hz), 3.81 (s, 3H), 3.76 (s, 2H), 1 .68 (quint, 2H, J = 6.6 Hz), 1.45 (s, 9H), 1.44-1.21 (m, 10H), 0.89 (t, 3H, J = 5.8 Hz). MS (El): 533.9 (m+).
Figure imgf000056_0001
3-IVIethyl-5-octyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4-ferf-butyl ester 2-octyl ester. (4.2) The same method as for the preparation of 3- methoxymethyl-5-octyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- tert-butyl ester was employed. Thus, acylation with octyl chloroformate (0.171 mL, 168 mg, 0.87 mmol) afforded 80 mg of a solid (26%) after column chromatography (9:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 10.86 (s, 1 H), 4.23 (t, 2H, J = 6.6Hz), 2.67 (s, 3H), 1.80-1.40 (m, 4H), 1.57 (s, 9H), 1.42-1.08 (m, 20H), 0.89 (t, 3H, J= 6.6 Hz). MS (El): 526.0 (m+).
Figure imgf000056_0002
3-Methyl-5-heptyloxycarbonylamino-thiopherie-2,4-dicarboxyl)c acid 4-ferf- butyl ester 2-heptyl ester. (4.3) To a stirring solution of 5-amino-3-methyl- thiophene-2,4-dicarboxylic acid 2-heptyl ester 4-tert-butyl ester (5.0 g, 14.0 mmol) and DBU (5.3 mL, 5.4 g, 35.0 mmol) in CH2CI2 (100 mL) was added heptyl chloroformate (5.0 ml, 5.0 g, 28.0 mmol). The reaction was stirred at room temperature for 20 h, and then solvent was removed under reduced pressure. The product was purified by column chromatography (9:1 ; hexanes:EtOAc) to give 3.1 g (45%) of a solid: 1H NMR (CDCI3) δ 10.86 (s, 1 H), 4.23 (t, 2H, J = 6.6Hz), 2.67 (s, 3H), 1.80-1.40 (m, 4H), 1.57 (s, 9H), 1.42-1.08 (m, 16H), 0.89 (t, 3H, J = 6.6 Hz).
Figure imgf000056_0003
5-Benzyloxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 4-ferf- butyl ester 2-octyi ester. (4.4) The same method as for the preparation of 3- methyl-5-heptyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-heptyl ester was employed. Thus, acylation with benzyl chloroformate (0.154 mL, 185 mg, 1.1 mmol) afforded 138 mg of a solid (52%) after column chromatography (10:1 ; hexanes:EtOAc): Mp 65.0-66.0 SC; 1H NMR (CDCI3) δ 10.97 (s, 1 H), 7.50- 7.30 (m, 5H), 5.28 (d, 2H, J = 4.8 Hz), 4.23 (t, 2H, J = 6.6 Hz), 2.72 (s, 3H), 1.80- 1.55 (m, 2H), 1.58 (s, 9H), 1.28 (bs, 10H), 0.89 (t, 3H, J = 6.6 Hz).
Figure imgf000057_0001
4- ethyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid ethyl ester.
(4.5) The same method as for the preparation of 3-methyl-5- heptyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-heptyl ester was employed. Thus, acylation with octyl chloroformate (1.06 mL, 1.04 g, 5.4 mmol) afforded 254 mg of an oil (28%) after column chromatography (9:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 10.53 (s, 1 H), 6.31 (s, 1 H), 4.34 (q, 2H, J = 6.8
Hz), 4.12 (t, 2H, J = 6.6 Hz).2.34 (s, 3H), 1.67 (bs, 2H), 1.37 (quint, 3H, J = 6.8 Hz),
1.28 (bs, 10H), 0.88 (t, 3H, J = 6.6 Hz). MS (El): 341.9 (m+).
Figure imgf000057_0002
5-/so-Propoxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 4-ferf- butyl ester 2-octyl ester. (4.6) The same method as for the preparation of 3- methyl-5-heptyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-heptyl ester was employed. Thus, acylation with /so-propyl chloroformate in toluene (0.54 mL, 0.54 mmol) afforded 1 17 mg of a solid (95%) after column chromatography (9:1 ; hexanes-EtOAc): 1H NMR (CDCI3) δ 10.82 (s, 1 H), 5.30 (s, 1 H), 5.08 (sept, 1 H, J = 6.2 Hz), 4.23 (t, 2H, J = 6.6 Hz), 2.73 (s, 3H), 1.80-1.60 (m, 2H), 1.60 (s, 9H), 1.34 (d, 6H, J = 6.2 Hz), 1.28 (bs, 10H), 0.88 (t, 3H, J = 6.6 Hz).
Figure imgf000057_0003
5-;so-Butoxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 4-ferf- butyl ester 2-octyl ester. (4.7) The same method as for the preparation of 3- methyl-5-heptyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-heptyl ester was employed. Thus, acylation with /so-butyl chloroformate (0.07 mL, 74.0 mg, 0.54 mmol) afforded 98 mg of a solid (77%) after column chromatography (9:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 10.86 (s, 1 H), 4.23 (t, 2H, J = 6.6 Hz), 4.04 (d, 2H, J = 6.6 Hz), 2.73 (s, 3H), 2.02 (nonet, 1 H, J = 6.6 Hz), 1.80-1.50 (m, 2H), 1.06 (s, 9H), 1.28 (bs, 10H), 1 .00 (d, 6H, J = 6.6 Hz), 0.88 (t, 3H, J = 6.2 Hz).
Example 5: General Procedure for Acylation with Isocyanate of Diester Reaction
Figure imgf000058_0001
3-Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-ferf-butyl ester 2- octyl ester. (5.1) To a stirring solution of 5-amino-3-methyl-thiophene-2,4- dicarboxylic acid 2-octyl ester 4-tert-butyl ester (348 mg, 0.94 mmol) and DBU (0.35 mL, 360 mg, 2.4 mmol) in CH2CI2 (10 mL) was added octyl isocyanate (0.166 mL, 146 mg, 0.94 mmol). The reaction was stirred RT for 16 h, and then solvent was removed under reduced pressure. The product was purified by column chromatography (5:1 ; hexanes: EtOAc) to give 431 mg of a solid (87%): Mp 92.0- 94.0 9C; 1H NMR (CDCI3) δ 12.30 (s, 1 H), 8.64 (s, 1 H), 5.30 (t, 1 H, J- 6.0 Hz), 4.25 (t, 2H, J = 6.4 Hz), 3.29 (q, 2H, J = 6.0 Hz), 2.74 (s, 3H), 1.90-1.50' (m, 4H), 1.61 (s, 9H), 1.28 (bs, 20H), 0.88 (m, 6H). MS (El): 525.1 (m+).
Figure imgf000058_0002
3-Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- ferf-butyl ester. (5.2) The same method as for the preparation of 3-methyl-5-(3- octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-octyl ester was employed. Thus, acylation with octyl isocyanate (3.83 mL, 3.37 g, 21.7 mmol) afforded 3.42 g of a solid (38%) after column chromatography (9:1; hexanes:EtOAc): Mp 119.0-120.05C; 1H NMR (CDCI3) δ 11.03 (s, 1 H), 7.50-7.20 (m, 5H), 5.27 (s, 2H), 5.03 (vt, 1 H), 3.29 (q, 2H, J = 6.6 Hz), 2.71 (s, 3H), 1.63-1.40 (m, 2H), 1.57 (s, 9H), 1.26 (bs, 10H), 0.87 (t, 3H, J = 6.6 Hz). MS (El): 502.8 (m+).
Figure imgf000059_0001
3-Methyl-5-(3-tetradecyl-ureido)-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-ferf-butyl ester. (5.3) The same method as for the preparation of 3-methyl-5-(3- octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-octyl ester was employed. Thus, acylation with tetradecyl isocyanate (0.33 mL, 287 mg, 1.2 mmol) afforded 253 mg of a solid (36%) after column chromatography (9:1 ; hexanes: EtOAc): Mp 104.5-106.09C; 1H NMR (CDCI3) δ 11.04 (s, 1H), 7-50-7.20 (m, 5H), 5.27 (s, 2H), 5.14 (t, 1 H, J = 6.2 Hz), 3.29 (q, 2H, J = 6.2 Hz), 2.71 (s, 3H), 1 .65-1.40 (m, 2H), 1.57 (s, 9H), 1.25 (bs, 22H), 0.88 (t, 3H, J = 6.0 Hz). MS (El): 587.1 (m+).
Figure imgf000059_0002
5-(3-Hexadecyl-ureido)-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-ferf-butyl ester. (5.4) The same method as for the preparation of 3-methyl- 5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-octyl ester was employed. Thus, acylation with hexadecyl isocyanate (0.37 mL, 321 mg, 1.2 mmol) afforded 218 mg of a solid (30%) after column chromatography (9:1 ; hexanes: EtOAc): Mp 104.0-105.02C; 1H NMR (CDCI3) δ 1 1.04 (s, 1 H), 7.50-7.20 (m, 5H), 5.27 (s, 2H), 5.14 (t, 1H, J = 6.2 Hz), 3.29 (q, 2H, J = 6.2 Hz), 2.71 (s, 3H), 1.65-1.40 (m, 2H), 1.57 (s, 9H), 1.25 (bs, 26H), 0.88 (t, 3H, J = 6.0 Hz). MS (El): 615.1 (m+).
Figure imgf000060_0001
5-(3-Dodecyl-ureido)-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-ferf-butyl ester. (5.5) The same method as for the preparation of 3-methyl-5-(3- octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-octyl ester was employed. Thus, acylation with decyl isocyanate (0.29 mL, 254 mg, 1.2 mmol) afforded 265 mg of a solid (40%) after column chromatography (9:1 ; hexanes:EtOAc): Mp 106.8-108.0QC). 1H NMR (CDCI3) δ 11.04 (s, 1 H), 7.45-7.26 (m, 5H), 5.27 (s, 2H), 5.24 (t, 1 H, J = 5.6 Hz), 3.28 (q, 2H, J = 6.6 Hz), 2.72 (s, 3H), 1.60-1.40 (m, 2H), 1.57 (s, 9H), 1.25 (bs, 18H), 0.88 (t, 3H, J = 6.4 Hz). MS (El): 559.0 (m+).
Example 6: General Procedure TFA Deprotection at C-2
Figure imgf000060_0002
3-Methoxymethyl-5-octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2- benzyl ester. (6.1) To a stirring solution of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester (0.60 mg, 0.1 1 mmol) in CH2CI2 (1.0 mL) was added TFA (1.0 mL). The reaction was stirred at room temperature for 12 hrs, then solvent was removed under reduced pressure to give a solid. The product was taken on without further purification: 1H NMR (CDCI3) δ 11.98 (s, 1 H), 10.09 (s, 1H), 7.45-7.20 (m, 5H), 5.14 (s, 2H), 4.22 (t, 2H, J = 6.6 Hz), 3.85 (s, 3H), 3.82 (s, 2H), 1.70 (quint, 2H, J = 6.6 Hz), 1.28 (bs, 10H), 0.88 (t, 3H, J = 5.6 Hz).
Figure imgf000060_0003
3-Methoxymethyl-5-octyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 2- octyl ester. (6.2) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded 64 mg of a solid (68%) after column chromatography (5:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 10.56 (s, 1 H), 4.27 (t, 2H, J = 6.5 Hz), 4.25 (t, 2H, J = 6.5 Hz), 2.81 (s, 3H), 1.80-1.53 (m, 4H), 1.50-1.15 (m, 20H), 0.89 (t, 3H, J = 6.5 Hz). MS (El): 469.9 (m+).
Figure imgf000061_0001
5-Heptyloxycarbonylamino-3-methoxymethyl-thiophene-2,4-dicarboxylic acid 2-heptyl ester. (6.3) The same method as for the preparation of 3-methoxymethyl- 5-octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded 2.7 g of a solid (96%) after tritration with hexanes: 1H NMR (CDCI3) δ 10.53 (s, 1 H), 4.26 (t, 4H, J = 6.6 Hz), 2.81 (s, 3H), 1.90-1.58 (m, 4H), 1.60-1 .12 (m, 16H), 0.89 (t, 3H, J = 6.6 Hz). MS (El): 441 .9 (m+).
Figure imgf000061_0002
5-Benzyloxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester. (6.4) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: Mp 148.0-149.5 SC; 1H NMR (CDCI3) δ 10.56 (bs, 2H), 7.50-7.30 (m, 5H), 5.30 (d, 2H, J = 4.8 Hz), 4.25 (t, 2H, J = 6.6 Hz), 2.79 (s, 3H), 1.83-1.60 (m, 2H), 1.29 (bs, 10H), 0.89 (t, 3H, J = 6.6 Hz).
Figure imgf000062_0001
5-/so-Propoxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester. (6.5) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was taken forward without further purification: Mp 152.0-153.0 gC; 1H NMR (CDCI3) δ 10.45 (s, 1 H), 5.12 (sept, 1 H, J = 6.6 Hz), 4.25 (t, 2H, J = 6.6 Hz), 2.82 (s, 3H), 1 .73 (quint, 2H, J = 6.6 Hz), 1.38 (d, 6H, J = 6.6 Hz), 1 !28 (bs, 10H), 0.89 (t, 3H, J = 6.6 Hz).
Figure imgf000062_0002
5-/so-Butoxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester. (6.6) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2;4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: 1H NMR (CDCI3) δ 10.53 (bs, 2H), 4.26 (t, 2H, J = 6.2 Hz), 4.08 (d, 2H, J
= 6.6 Hz), 2.82 (s, 3H), 2.06 (nonet, 1 H, J = 6.6 Hz), 1.71 (quint, 2H, J = 6.6 Hz),
1.29 (bs, 10H), 1.00 (d, 6H, J = 6.6 Hz), 0.89 (t, 3H, J = 6.6 Hz).
Figure imgf000062_0003
4-Methyl-5-octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid.
(6.7) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: 1H NMR (CDCI3) δ 10.90 (bs, 2H), 5.82-5.62 (m, IH), 5.76-5.60 (m, IH), 3.33 (q, 4H, J = 6.6 Hz), 2.61 (s, 3H), 1.70-1.40 (m, 4H), 1.27 (bs, 20H), 0.88 (m, 6H).
Figure imgf000063_0001
3-Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 2-octyl ester. (6.8)
The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: 1H NMR (CDCI3) δ 12.30 (s, 1 H), 10.91 (bs, 2H), 5.30 (t, 1H, J = 6.0 Hz), 4.25 (t, 2H, J = 6.4 Hz), 3.29 (q, 2H, J = 6.0 Hz), 2.74 (s, 3H), 1.90-1.50 (m, 4H), 1.28 (bs, 20H), 0.88 (m, 6H). MS (El): 468.9 (m+).
Figure imgf000063_0002
5-Benzylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid. (6.9) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: 1H NMR (CDCI3) δ 11.16 (s, 1 H), 7.40-7.10 (m, 5H), 6.19 (t, 1 H, J = 5.4 Hz), 4.56 (d, 2H, J = 5.4 Hz), 3.25 (q, 2H, J = 6.6 Hz), 2.63 (s, 3H), 1.60-1.40 (m, 2H), 1.26 (bs, 10H), 0.86 (t, 3H, J = 6.2 Hz). MS (El): 445.9 (m+).
Figure imgf000063_0003
5-Dimethylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid. (6.10) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: 1H NMR (CDCI3) δ 10.89 (s, 2H), 5.39 (t, 1 H, J = 6.6 Hz), 3.27 (q, 2H, J = 6.6 Hz), 3.05 (s, 6H), 2.28 (s, 3H), 1.65-1.45 (m, 2H), 1.26 (s, 10H), 0.87 (t, 3H, J = 6.2 Hz). MS (El): 383.9 (m+).
Figure imgf000064_0001
3- ethyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 2-benzyl ester. (6.11) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: 1H NMR (CDCI3) δ 10.57 (s, 1 H), 7.45-7.25 (m, 5H), 5.30 (s, 1 H), 4.26 (t, 2H, J= 6.6 Hz), 2.81 (s, 3H), 1.72 (quint, 2H, J = 6.6 Hz), 1.28 (bs, 10H), 0.88 (t, 3H, J = 6.6 Hz).
Figure imgf000064_0002
4- ethyl-5-octylcarbamoyl-2-(3-tetradecyl-ureido)-thiophene-3-carboxylic acid. (6.12) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification.
Figure imgf000064_0003
2-(3-Hexadecyl-ureido)-4-methyl-5-octylcarbamoyl-thiophene-3-carboxylic acid. (6.13) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: MS (El): 580.2 (m+).
Figure imgf000065_0001
2-(3-Dodecyl-ureido)-4-methyl-5-octylcarbamoyl-thiophene-3-carboxylic acid. (6.14) The same method as for the preparation of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: MS (El): 524.1 (m+).
Example 7: Extra TFA Deportection
Figure imgf000065_0002
3-Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid. (7.1) To a stirring solution of 3-methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester (50.0 mg, 0.13 mmol) in CH2CI2 (1 mL) was added TFA (1 mL). The reaction was stirred at RT for 2 h, and then solvent was removed under reduced pressure to give a solid. The product was dissolved in EtOAc, washed with sat. NaHCO3 (aq.), and brine. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure to give 10.0 mg of a solid (22%): 1H NMR (CDCI3) δ 10.45 (bs, 1 H), 6.27 (bs, 1 H), 5.00 (bs, 1 H), 3.50-3.20 (m, 2H), 2.37 (s, 3H), 1.70-1.40 (m, 2H), 1.26 (bs, 10H), 0.88 (t, 3H, J = 6.2 Hz). MS (El): 312.9 (m+-COOH).
Example 8: Ethyl Ester Hydrolysis
Figure imgf000066_0001
4-Methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid. (8.1) To a stirring solution of 4-methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid ethyl ester (254 mg, 0.74 mmol) in ethanol (2 mL) and THF (2 mL) was added LiOH-
H2O (31 mg, 0.74 mmol). The reaction was stirred at RT for 5 days, and then solvent was removed under reduced pressure to give a solid. The product was
- taken on without further purification: 1H NMR (CDCl3) δ 6.02 (s, 1 H), 4.07 (t, 2H, J = 6.6 Hz), 2.32 (s, 3H), 1.60-1.40 (m, 2H), 1.27 (bs, 10H), 0.86 (t, 3H, J = 6.6 Hz).
Example 9: General Procedure for Hydrogenolysis at C-6
Figure imgf000066_0002
5- ethyl-2-octyloxy-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid (11)
To a stirring solution of 2-dodecyloxy-5-methyl-4-oxo-4H-thieno[2,3- ][1 ,3]oxazine-6- carboxylic acid benzyl ester (50 mg, 0.10 mmol) in EtOAc (2 mL) was added 10% Pd/C (5 mg, 10 wt%). The reaction was charged with H2 and stirred at RT for 1 h. The reaction slurry was filtered through a plug of Celite, and the solvent was removed in vacuo. The product was taken on without further purification: 1H NMR (CDCI3) δ 4.47 (t, 2H, J = 6,2 Hz), 4.19 (bs, 1 H), 2.85 (s, 3H), 1.80 (quint, 2H, J= 6.2 Hz), 1.27 (bs, 18H), 0.88 (t, 3H, J = 6.6 Hz). MS (El): 395.4 (m+).
Figure imgf000066_0003
3-Methyϊ-5-(3-GCtyl-ureido)-thiophene-2,4-dicarboxylic acid 4-ferf-butyl ester. (9.1) The same method as for the preparation of 2-dodecyloxy-5-methyl-4-oxo-4H- thieno[2,3- ][1 ,3]oxazine-6-carboxylic acid was employed. Thus, hydrogenolysis afforded a solid, which was used without purification: 1H NMR (CDCI3) δ 11.06 (s, 1 H), 5.14 (vt, 1 H), 3.30 (q, 2H, J = 6.0 Hz), 2.71 (s, 3H), 1.70-1.40 (m, 2H), 1.59 (s, 9H), 1.27 (bs, 10H), 0.87 (t, 3H, J = 6.6 Hz). MS (El): 412.8 (m+).
Figure imgf000067_0001
5-(3-Dodecyl-ureido)-3-methyl-thiophene-2,4-dicarboxylic acid 4-ferf-butyl ester. (9.2) The same method as for the preparation of 2-dodecyloxy-5-methyl-4- oxo-4H-thieno[2,3-cd[1 ,3]oxazine-6-carboxylic acid was employed. Thus, hydrogenolysis afforded 0.198 g of a solid (98%), which was used without purification: Mp 187.0-188.5 C; H NMR (CDCI3) δ 1 1.06 (s, 1 H), 5.21 (bs, 1 H), 3.31 (q, 2H, J = 5.8 Hz), 2.72 (s, 3H), 1.65-1.40 (m, 2H), 1.60 (s, 9H), 1.26 (bs, 18H), 0.88 (t, 3H, J= 6.6 Hz). MS (El): 469.0 (m+).
Figure imgf000067_0002
3-Methyl-5-(3-tetradecyl-ureido)-thiophene-2,4-dicarboxylic acid 4-ferf-butyl ester. (9.3) The same method as for the preparation of 2-dodecyloxy-5-methyl-4- oxo-4H-thieno[2,3-c(][1 ,3]oxazine-6-carboxylic acid was employed. Thus, hydrogenolysis afforded 123 mg of a solid (58%), which was used without purification: Mp 176.0-178.09C; 1H NMR (CDCI3) δ 11.06 (s, 1 H), 7.35 (t, 1 H, J = 6.2 Hz), 5.20 (bs, 1 H), 3.30 (q, 2H, J = 6.2 Hz), 2.72 (s, 3H), 1.70-1.45 (m, 2H), 1.59 (s, 9H), 1 .25 (bs, 22H), 0.88 (t, 3H, J= 6.6 Hz). MS (El): 497.0 (m+).
Figure imgf000067_0003
5-(3-Hexadecyl-ureido)-3-methyl-thiophene-2,4-dicarboxylic acid 4-ferf-butyl ester. (9.4) The same method as for the preparation of 2-dodecyloxy-5-methyl-4- oxo-4--/-thieno[2,3-cf][1 ,3]oxazine-6-carboxylic acid was employed. Thus, hydrogenolysis afforded a solid, which was used without purification: Mp 187.5- 189.0eC; 1H NMR (CDCI3) δ 11.07 (s, 1 H), 5.18 (bs, 1 H), 3.29 (q, 2H, J = 6.2 Hz), 2.72 (s, 3H), 1.70-1.45 (m, 2H), 1.60 (s, 9H), 1.25 (bs, 26H), 0.88 (t, 3H, J = 6.6 Hz). MS (El): 525.0 (m+).
Example 10: General Procedure for Amide/Ester Formation at C-6
Figure imgf000068_0001
4-Methyl-5-octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid fert- butyl ester. (10.1) To a stirring solution of 3-methyl-5-(3-octyl-ureido)-thiophene- 2,4-dicarboxylic acid 4-tert-butyl ester (185 mg, 0.46 mmol) and octyl amine (0.112 mL, 87.3 mg, 0.69 mmol) in CH2CI2 (10 mL) was added EDC (133 mg, 0.69 mmol) and DMAP (2.8 mg, 0.02 mmol). The reaction was stirred at RT for 16 h, washed with H2O, 0.5N citric acid, sat. NaHCO , and brine. The organic fraction was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (9:1 ; hexanes: EtOAc) to give 290 mg of a solid (99%): 1H NMR (CDCI3) δ 10.89 (s, 1 H), 5.82-5.62 (m, 1 H), 5.78-5.60 (m, 1 H), 3.33 (q, 4H, J = 6.6 Hz), 2.61 (s, 3H), 1.70-1.40 (m, 4H), 1.55 (s, 9H), 1.27 (bs, 20H), 0.88 (m, 6H). MS (El): 524.1 (m+).
Figure imgf000068_0002
5-Benzylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid ferf-butyl ester. (10.2) The same method as for the preparation of 4-methyl-5- octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, coupling with benzyl amine (0.061 mL, 60 mg, 0.56 mmol) afforded 202 mg of a solid (99%) after by column chromatography (95:5; CHCI3:MeOH): H NMR (CDCI3) δ 10.90 (s, 1H), 7.40-7.20 (m, 5H), 6.05 (t, 1H, J = 5.4 Hz), 5.33 (t, 1 H, J = 6.6 Hz), 4.55 (d, 2H, J = 5.4 Hz), 3.26 (q, 2H, J = 6.6 Hz), 2.63 (s, 3H), 1.65-1.40 (m, 2H), 1.56 (s, 9H), 1.26 (bs, 10H), 0.87 (t, 3H, J = 6.2 Hz). MS (El): 502.0 (m+).
Figure imgf000069_0001
5-Dimethylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid ferf-butyl ester. (10.3) The same method as for the preparation of 4-methyl-5- octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, coupling with a 40% solution of dimethyl amine in H2O (0.063 mL, 0.56 mmol) afforded 174 mg of a solid (99%) after by column chromatography (95:5; CHCI3:MeOH): H NMR (CDCIg) δ 10.78 (s, 1 H), 5.39 (t, 1 H, J = 6.6 Hz), 3.27 (q, 2H, J = 6.6 Hz), 3.05 (s, 6H), 2.28 (s, 3H), 1.65-1.45 (m, 2H), 1.56 (s, 9H), 1.26 (s, 10H), 0.87 (t, 3H, J = 6.2 Hz). MS (El): 440.0 (m+).
Figure imgf000069_0002
2-(3-Dodecyl-ureido)-4-methyl-5-octylcarbamoyl-thiophene-3-carboxylic acid ferf-butyl ester. (10.4) The same method as for the preparation of 4-methyl-5- octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, coupling with octyl amine (0.111 mL, 87.0 mg, 0.69 mmol) afforded 205 mg of a solid (81 %) after by column chromatography (9:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 10.90 (s, 1 H), 5.74 (t, 1 H, J = 5.4 Hz), 5.47 (t, 1 H, J = 6.2 Hz), 3.32 (vsext, 4H, J = 6.6 Hz), 2.61 (s, 3H), 1.70-1.40 (m, 4H), 1.55 (s, 9H), 1.26 (bs, 28H), 0.88 (t, 6H, J = 6.6 Hz). MS (El): 580.2 (m+).
Figure imgf000070_0001
4- ethyl-5-octylcarbamoyl-2-(3-tetradecyl-ureido)-thiophene-3-carboxylic acid ferf-butyl ester. (10.5) The same method as for the preparation of 4-methyl-5- octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, coupling with octyl amine (0.112 mL, 87.3 mg, 0.69 mmol) afforded 290 mg of a solid (99%) after by column chromatography (9:1 ; hexanes: EtOAc): 1H NMR (CDCI3) δ 10.90 (s, 1 H), 5.74 (t, 1 H, J = 5.4), 5.44 (bs, 1 H), 3.33 (vsext, 4H, J = 6.2 Hz), 2.61 (s, 3H), 1.60-1.40 (m, 4H), 1.56 (s, 9H), 1.26 (bs, 32H), 0.88 (t, 6H, J= 6.6 Hz). MS (El): 608.1 (m+).
Figure imgf000070_0002
2-(3-Hexadecyl-ureido)-4-methyl-5-octylcarbamoyl-thiophene-3-carboxylic acid ferf-butyl ester. (10.6) The same method as for the preparation of 4-methyl-5- octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, coupling with octyl amine (0.080 mL, 62.0 mg, 0.50 mmol) afforded 195 mg of a solid (93% from BnOOC) after by column chromatography (9:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 10.90 (s, 1 H), 5.73 (t, 1 H, J = 5.4), 5.35 (bs, 1 H), 3.33 (vsext, 4H, J = 6.2 Hz), 2.61 (s, 3H), 1.65-1.40 (m, 4H), 1.56 (s, 9H), 1 .26 (bs, 36H), 0.88 (t, 6H, J = 6.6 Hz). MS (El): 636.2 (m+).
Figure imgf000070_0003
2-Heptyl-5-methyl-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylιc acid hexyl ester (4) The same method as for the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido)-fhiophene-3-carboxylic acid tert-butyl ester was employed. Thus, coupling with octyl alcohol (0.125 mL, 1.50 mmol) afforded 20 mg of a solid (21%) after by Prep. TLC (9:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 4.29 (t, 2H, J = 6.6 Hz), 2.84 (s, 3H), 2.87 (t, 2H, J = 7.2 Hz), 2.00-1.60 (m, 4H), 1.15-1.60 (m, 24H), 1.15- 0.70 (m, 6H).
Example 11 : General Procedure for Cyclization with EDCI
Figure imgf000071_0001
5-Methoxy-2-octyloxy-4-oxo-4H-thieno[2,3-cG[153]oxazine-6-carboxylic acid benzyl ester (112) To a stirring solution of 3-methoxymethyl-5- octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester (27 mg, 0.056 mmol) in CH2CI2 (1,0 mL) was added EDC (16.0 mg, 0.084 mmol). The reaction was stirred at RT for 16 h, washed with H2O and brine. The organic fraction was dried (MgSO ), filtered, and concentrated in vacuo. The residue was purified by column chromatography (5:1 ; hexanes: EtOAc) to give 7.0 mg of a solid (27%): 1H NMR (CDCI3) δ 7.42-7.27 (m, 5H), 5.16 (s, 2H), 4.38 (t, 2H, J= 6.6 Hz), 3.89 (s, 3H),
3.85 (s, 2H), 1.78 (quint, 2H, J = 6.6 Hz), 1.50-1.10 (m, 10H), 0.89 (t, 3H, J = 6.6
Hz). MS (EI): 461.9 (m+H+).
Figure imgf000071_0002
5-Methyl-2-octyloxy-4-oxo-4H-thieno[2,3- ][1,3]oxazine-6-carboxylic acid octyl ester (9) The same method as for the preparation of 5-methoxy-2-octyloxy-4-oxo- 4/-/-thieno{2,3-d][1 ,3]oxazine-6-carboxylic acid benzyl ester was employed. Thus, cyclization afforded 15 mg of a solid (24%) after by column chromatography (9:1 ; hexanes: EtOAc): Mp 58.5-60.2eC; 1H NMR (CDCI3) δ 4.45 (t, 2H, J = 6.6 Hz), 4.29 (t, 2H, J = 6.6 Hz), 2.80 (s, 3H), 1.88-1.70 (m, 4H), 1.29 (bs, 20H), 0.89 (t, 6H, J = 6.6 Hz). MS (EI):451.8 (m+). Example 12: General Procedure for Cyclization with SOCI2
Figure imgf000072_0001
5-l\Λethyl-2-heptyloxy-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid heptyl ester (10) To a stirring solution of 5-heptyloxycarbonylamino-3- methoxymethyl-thiophene-2,4-dicarboxylic acid 2-heptyl ester (2.7 g, 6.1 mmol) in pyridine (65 mL) was added thionyl chloride (0.88 mL, 1.4 g, 12.0 mmol). The reaction was stirred RT for 0.5 h, and concentrated in vacuo. The residue was dissolved in CHCI3, washed with H2O, 0.5 N citric acid, sat. NaHCO3, and brine. The organic fraction was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (20:1; hexanes: EtOAc) to give 2.6 g of a solid (99%): 1H NMR (CDCI3) δ 4.45 (t, 2H, J= 6.6 Hz), 4.29 (t, 2H, J= 6.6 Hz), 2.80 (s, 3H), 1.78 (dquint, 4H, J = 13.2, 6.6 Hz), 1.58-1.18 (bs, 16H), 0.90 (t, 6H, J = 7.0 Hz); 3C NMR (CDCI3) δ 168.9, 162.1 , 158.3, 154.0, 144.1, 121.4, 113.9, 71.1 , 65.4, 31.6, 31.6, 28.8, 28.7, 28.6, 28.2, 25.9, 25.5, 22.5, 14.6, 14.0; MS (El): 423.9 ( +).
Figure imgf000072_0002
2-Benzyloxy-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid octyl ester (113) The same method as for the preparation of 5-methyl-2-heptyloxy- 4-oxo-4H-thieno[2,3-αf][1,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 11.0 mg of a solid (10%) after by column chromatography (20:1; hexanes: EtOAc): 1H NMR (CDCI3) δ 7.55-7.30 (m, 5H), 5.48 (s, 2H), 4.29 (t, 2H, J= 6.6 Hz), 2.82 (s, 3H), 1.75 (quint, 2H, J= 6.6 Hz), 1.29 (bs, 10H), 0.89 (t, 3H, J= 6.6 Hz).
Figure imgf000072_0003
2-/*so-Propoxy-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid octyl ester (12) The same method as for the preparation of 5-methyl-2-heptyloxy-4- oxo-4/-/-thieno[2,3-cd[1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 108 mg of a solid (98%) after by column chromatography (20:1 ; hexanes:EtOAc): Mp 47.5-48.0QC; 1H NMR (CDCI3) δ 5.31 (sept, 1 H, J = 6.2 Hz), 4.29 (t, 2H, J - 6.6 Hz), 2.81 (s, 3H), 1.75 (quint, 2H, J = 6.6 Hz), 1.44 (d, 6H, J = 6.2 Hz), 1.29 (bs, 10H), 0.89 (t, 3H, J = 6.4 Hz); MS (El): 381.9 (m+).
Figure imgf000073_0001
2-/so-Butoxy-5-methyl-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid octyl ester (114) The same method as for the preparation of 5-methyl-2-heptyloxy- 4-oxo-4 -/-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 15 mg of a solid (25%) after by column chromatography (20:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 4.31 (q, 2H, J = 6.6 Hz), 4023 (d, 2H, J = 6.6 Hz), 2.82 (s, 3H), 2.13 (nonet, 1 H, J = 6.6 Hz), 1.73 (quint, 2H, J = 6.6 Hz), 1.29 (bs, 10H), 1.03 (d, 6H, J = 6.6 Hz), 0.89 (t, 3H, J = 6.6 Hz); MS (El): 395.9 (m+).
Figure imgf000073_0002
5-Methyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one (23) The same method as for the preparation of 5-methyl-2-heptyloxy-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6- carboxylic acid heptyl ester was employed. Thus, cyclization afforded 44 mg of an oil (20%) after by column chromatography (20:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 6.59 (s, 1 H), 4.41 (t, 2H, J = 6.6 Hz), 2.46 (s, 3H), 1.80 (quint, 2H, J = 6.6 Hz), 1 .29 (bs, 10H), 0.89 (t, 3H, J = 6.6 Hz); MS (El): 295.9 (m+).
Figure imgf000073_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid octylamide (18) The same method as for the preparation of 5-methyl-2-heptyloxy-4- oxo-4H-thieno[2,3- ][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 106 mg of a solid (52% from 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido)-thiophene-3-carboxyϊic acid tert-butyl ester) after by column chromatography (95:5; CHCI3:MeOH): Mp 152.0-152.8eC; 1H NMR (CDCI3) δ 5.70 (bs, 1 H), 5.06 (bs, 1 H), 3.42 (q, 6H, J = 6.2 Hz), 2.71 (s, 3H), 1.70-1.42 (m, 4H), 1.54 (s, 9H), 1.28 (bs, 20H), 0.89 (t, 6H, J = 6.6 Hz); MS (El): 450.5 (m+1 ).
Figure imgf000074_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid octyl ester (20) The same method as for the preparation of 5-methyl-2-heptyloxy-4- oxo-4H-thieno[2,3-o][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 229 mg of a solid (67% from t-Bu ester) after by column chromatography (20:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 5.20 (bs, 1 H), 4.26 (t, 2H, J = 6.6 Hz), 3.51 -3.40 (m, 2H), 2.78 (s, 3H), 1.85-1.48 (m, 4H), 1.28 (bs, 20H), 1 .00-0.80 (m, 6H); MS (El): 451.0 (m+).
Figure imgf000074_0002
5- ethyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid benzylamide (21) The same method as for the preparation of 5-methyl-2- heptyloxy-4-oxo-4H-thieno[2,3-c |[1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 75.0 mg of a solid (49% from 3-methyl-5-(3- octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester) after by column chromatography (95:5; CHCI3:MeOH): 1H NMR (CDCIg) δ 7.40-7.26 (m, 5H), 6.03 (t, 1 H, J = 5.4 Hz), 5.20 (bs, 1 H), 4.62 (d, 2H, J = 5.4 Hz), 3.50-3.30 (m, 2H), 2.72 (s, 3H), 1.73-1.43 (m, 2H), 1.28 (bs, 10H), 0.88 (t, 3H, J = 6.6 Hz). MS (El): 427.9 (m+).
Figure imgf000074_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid dimethylamide (22) The same method as for the preparation of 5-methyl-2- heptyloxy-4-oxo-4H-thieno[2,3-c/][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 17.0 mg of a solid (13% from 3-methyl-5-(3- octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester) after by column chromatography (1 :1 to 1 :5; hexanes: EtOAc): 1H NMR (CDCI3) δ 5.22 (bs, 1 H), 3.41 (q, 2H, J = 5.4 Hz), 3.08 (s, 6H), 2.41 (s, 3H), 1.62 (quint, 2H, J = 6.6 Hz), 1.28 (bs, 10H), 0.88 (t, 3H, J = 6.2 Hz); MS (El): 365.9 (m+).
Figure imgf000075_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid benzyl ester (16) The same method as for the preparation of 5-methyl-2-heptyloxy- 4-oxo-4H-thieno[2,3-cO[1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 108 mg of a solid (63% from 3-methyl-5-(3-octyl-ureido)- thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester) after by column chromatography (9:1 ; hexanes:EtOAc): Mp 153.5-154.0eC; 1H NMR (CDCI3) δ 7.50- 7.30 (m, 5H), 5.44 (bs, 1 H), 5.32 (s, 2H), 3.42 (q, 2H, J = 6.2 Hz), 2.79 (s, 3H), 1.78- 1.50 (m, 2H), 1.27 (bs, 10H), 0.88 (t, 3H, J = 6.4 Hz); MS (El): 428.9 (m+).
Figure imgf000075_0002
2-Heptylamino-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid benzyl ester (17) The same method as for the preparation of 5-methyl-2-heptyloxy-
4-oxo-4H-thieno[2,3-d|[1 ,3]oxazine-6-carboxylic acid heptyl ester was employed.
Thus, cyclization afforded 12 mg of a solid; 1H NMR (CDCI3) δ 7.50-7.30 (m, 5H), 5.32 (s, 2H), 5.24 (bs, 1 H), 3.42 (q, 2H, J = 6.2 Hz), 2.79 (s, 3H), 1.78-1.50 (m, 2H),
1.27 (bs, 8H), 0.88 (t, 3H, J = 6.4 Hz); MS (El): 414.8 (m+).
Figure imgf000076_0001
2-Dodecylamino-5-methyl-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid octylamide (24) The same method as for the preparation of 5-methyl-2-heptyloxy-4- oxo-4H-thieno[2,3-o][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 56 mg of a solid (32% from 2-(3-decyI-ureido)-4-methyl-5- octylcarbamoyl-thiophene-3-carboxylic acid tert-butyl ester) after by column chromatography (9:1 to 5:1 ; hexanes: EtOAc): Mp 137.1-138.0SC; 1H NMR (CDCI3) δ 5.74 (bs, 1 H), 5.30 (bs, 1 H), 3.42 (q, 4H, J = 6.6 Hz), 2.71 (s, 3H), 1.75-1.45 (m, 4H), 1.27 (bs, 28H), 0.89 (t, 6H, J = 6.0 Hz); MS (El): 506.1 (m+).
Figure imgf000076_0002
5-Methyl-4-oxo-2-tetradecylamino-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid octylamide (25) The same method as for the preparation of 5-methyl-2- heptyloxy^-oxo^H-thienoβ.S-cdtl .SJoxazine-e-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 25 mg of a solid (19% from 4-methyl-5- octylcarbamoyl-2-(3-tetradecyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester) after by column chromatography (5:1 ; hexanes:EtOAc): Mp145.0-145.89C; 1H NMR (CDCIg) δ 5.74 (bs, 1 H), 5.30 (bs, 1 H), 3.42 (q, 4H, J = 6.6 Hz), 2.71 (s, 3H), 1.75- 1 .45 (m, 4H), 1.27 (bs, 32H), 0.89 (t, 6H, J = 6.0 Hz); MS (El): 534.1 (m+).
Figure imgf000076_0003
2-Hexadecylamino-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid octylamide (26) The same method as for the preparation of 5-methyl-2- heptyloxy-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 24 mg of a solid (14% from 2-(3-hexadecyl- ureido)-4-methyl-5-octylcarbamoyl-thiophene-3-carboxylic acid tert-butyl ester) after by column chromatography (5:1 ; hexanes: EtOAc): Mp 146.3-147.0eC; 1H NMR (CDCI3) δ 5.74 (bs, 1 H), 5.30 (bs, 1 H), 3.42 (q, 4H, J = 6.6 Hz), 2.71 (s, 3H), 1.75- 1.45 (m, 4H), 1.27 (bs, 36H), 0.89 (t, 6H, J = 6.0 Hz); MS (El): 562.1 (m+).
Figure imgf000077_0001
5-Methyl-4-oxo-2-(4-phenoxy-phenylamino)-4H-thieno[2,3-d][1 ,3]oxazine-6- carboxylic acid octyl ester (19) The same method as for the preparation of 5- methyl-2-heptyloxy-4-oxo-4 -/-thieno[2,3-o][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded a solid, which was purified by recrystalization from EtOAc/Hexanes to give 25 mg of a solid (24%): 1H NMR
(CDCI3) δ 7.50 (d, 2H, J = 8.8 Hz), 7.25-7.45 (m, 2H), 7.40-6.90 (m, 5H), 4.27 (t, 2H,
J = 6.6 Hz), 2.81 (s, 3H), 1.73 (dt, 2H, J = 6.6 Hz), 1.27 (m, 10H), 0.89 (t, 3H, J = 6.0
Hz).
Figure imgf000077_0002
2-Heptyloxy-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid benzyl ester (8) The same method as for the preparation of 5-methyl-2-heptyloxy-4- oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 116 mg of a solid (63%) after by column chromatography (4:1 ; hexanes: EtOAc): 1H NMR (CDCI3) δ 7.50-7.30 (m, 5H), 5.33 (s, 2H), 4.44 (t, 2H, J= 6.2 Hz), 1.90-1.70 (m, 2H), 1.45-1.15 (m, 10H), 1.00-0.80 (m, 3H).
Figure imgf000077_0003
5-l\/lethyl-2-octyloxy-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid octylam-de (15) The same method as for the preparation of 5-methyl-2-heptyloxy-4- oxo-4/-/-thieno[2,3-α [1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 44.0 mg of a solid (44%) after by column chromatography (4:1 ; hexanes:EtOAc): 1H NMR (CDCI3) δ 5.90-5.70 (m, 1H), 4.43 (t, 2H, J = 6.6 Hz), 3.42 (q, 2H, J = 6.6 Hz), 2.72 (s, 3H), 1.90-1.70 (m, 2H), 1.70-1.50 (m, 2H), 1.50- 1.15 (m, 20H), 0.95-0.80 (m, 6H).
Example 13: Carbamate/Urea Intermediates
4-Methyl-2-(3-octyl-ureido)-5-[(pyridin-4-ylmethyl)-carbamoyl]-thiophene-3- carboxylic acid tert-butyl ester (13.1) The compound was purified by column chromatography (100% EtOAc) to yield 175 mg (70%) of a white foam.: (70%). 'H NMR (CDCI3, 200MHz) δ 0.86 (m, 3H), 1.25 (brs, 10H), 1.56 (brs, 11 H), 2.64 (s, 3H), 3.28 (dt, 2H, J= 6.2Hz, J = 6.6Hz), 4.56 (d, 2H, J= 5.8Hz), 5.16 (t, 1 H, J= 5.4Hz), 6.17 (t, 1 H, J= 5.8Hz), 7.24 (d, 2H, J= 5.8Hz), 8.54 (d, 2H, J= 5.8Hz), 10.94 (s, 1 H)
4-Methyl-5-[methyl-(6-methyl-pyridin-2-ylmethyl)-carbamoyl]-2-(3-octyl-ureido)- thiophene-3-carboxylic acid tert-butyl ester (13.2): (84%). 'H NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.25 (brs, 10H), 1.56 (brs, 11 H), 2.32 (s, 3H), 2.52 (s, 3H), 3.01 (s, 3H), 3.28 (dt, 2H, J= 6.2Hz, J = 6.6Hz), 4.74 (s, 2H), 4.95 (t, 1 H, J= 5.4Hz), 7.03 (d, 2H, J= 7.8Hz), 7.55 (t, 1 H, J= 7.6Hz), 10.75 (s, 1 H)
5-[Ethyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-4-methyl-2-(3-octyl-ureido)- thiophene-3-carboxylic acid tert-butyl ester (13.3): (99%). Η NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.11 (t, 3H, J= 7.0Hz), 1.25 (brs, 10H), 1.56 (brs, 11 H), 2.20 (s, 3H), 3.09 (t, 2H, J= 7.0Hz), 3.26 (m, 4H), 3.80 (t, 2H, J= 7.0Hz), 5.08 (t, 1 H, J= 5.0Hz), 7.15 (m, 2H), 7.59 (ddd, 1 H, J= 7.6Hz, J= 7.6Hz, J= 1.4Hz), 8.51 (d, 1 H, J= 4.4Hz), 10.76 (s, 1 H)
5-(Benzyloxycarbonylmethyl-carbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene- 3-carboxylic acid tert-butyl ester (13.4): (95%). Η NMR (CDCI3, 200MHz) δ 0.86 (m, 3H), 1.25 (brs, 10H), 1.58 (brs, 11 H), 2.56 (s, 3H), 3.25 (dt, 2H, J= 6.2Hz, J = 6.6Hz), 4.21 (d, 2H, J= 5.4Hz), 5.21 (s, 2H), 5.49 (brs, 1 H), 6.51 (t, 1 H, J= 5.6Hz), 7.36 (s, 5H), 10.71 (s, 1 H)
5-(6,7-Dimethoxy-3,4-dihydro-1 H-isoquinoline-2-carbonyl)-4-methyl-2-(3-octyl- ureido)-thiophene-3-carboxylic acid tert-butyl ester (13.5): (97%). "H NMR (CDCI3, 200MHz) δ 0.87 (brs, 3H), 1.27 (brs, 10H), 1.57 (s, 11 H), 2.30 (s, 3H), 2.83 (t, 2H, J= 5.8Hz), 3.29 (dt, 2H, J= 6.2Hz, J= 6.6Hz), 3.80 (m, 8H), 4.69 (s, 2H), 4.87 (t, 1H, J= 5.6Hz), 6.55 (s, 1H), 6.60 (s, 1H), 10.83 (s, 1 H) 5-(3,4-Dimethoxy-benzylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid tert-butyl ester (13.6): (97%). 'H NMR (CDCI3) 200MHz) δ 0.86 (brs, 3H), 1.25 (brs, 10H), 1.56 (s, 1 1 H), 2.63 (s, 3H), 3.25 (dt, 2H, J= 6.2Hz, J= 6.6Hz), 3.86 (s, 6H), 4.47 (d, 2H, J= 5.6Hz), 5.05 (t, 1 H, J= 5.8Hz), 5.95 (t, 1 H, J= 5.0Hz), 6.84 (m, 3H), 10.90 (s, 1H)
5-(2-Acetylamino-ethylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid tert-butyl ester (13.7): (58%). Η NMR (CDCI3, 200MHz) δ 0.87 (s, 3H), 1.27 (brs, 10H), 1.57 (brs, 11 H), 2.04 (s, 3H), 2.60 (s, 3H), 3.29 (dt, 2H, J= 6.2Hz, J= 6.6Hz), 3.50 (m, 4H), 4.90 (brs, 1 H), 6.29 (brm, 2H), 10.92 (s, 1 H)
5-[4-(lsopropylcarbamoyl-methyl)-piperazine-1-carbonyl]-4-methyl-2-(3-octyl- ureido)-thiophene-3-carboxylic acid tert-butyl ester (13.8): (61%). 'H NMR (CDCI3, 200MHz) δ 0.86 (brs, 3H), 1.10-1.28 (m, 16H), 1.56 (s, 1 1 H), 2.29 (s, 3H), 2.51 (s, 4H), 2.99 (s, 3H), 3.27 (dt, 2H, J= 6.2Hz, J= 6.6Hz), 3.63 (s, 4H), 4.10 (m, 1 H), 5.05 (brs, 1 H), 6.81 (d, 1 H, J= 8.0Hz), 10.79 (s, 1 H)
3-Methyl-5-(3-octyl-thioureido)-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester (13.9): 'H NMR (CDCI3, 200MHz) δ 0.88 (m, 3H), 1.28 (brs, 10H), 1.59 (m, 11 H), 2.72 (s, 3H), 3.47 (m, 2H), 5.30 (s, 2H), 6.31 (brs, 1 H), 7.36 (m, 5H).
4-Methyl-2-(3-octyl-ureido)-5-[(pyridin-3-yl-methyl)-carbamoyl]-thiophene-3- carboxylic acid tert-butyl ester (13.10). The reaction was passed through a plug of silica gel with ethyl acetate to yield 13.10, 3.42 g (94% crude yield) of an off white solid.
5-[(Furan-2-ylmethyl)-carbamoyl]-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid tert-butyl ester (13.11) white solid (97% yield): 'H NMR (CDCI3, 200MHz) δ 0.86 (t, 3H, J = 6.6 Hz), 1.24-1.27 (m, 10H), 1.54 (bs, 11 H), 2.61 (s, 3H), 3.26 (dt, 2H, J = 6.4, 5.8 Hz), 4.54 (d, 2H, J = 5.4 Hz), 5.31 (bs, 1 H), 6.02 (t, 1 H, J = 5.3 Hz), 6.27 (IH, dd, J = 11.4, 3.2 Hz), 6.30, (d, 1 H, J= 3.2 Hz), 7.34 (s, 1 H), 10.89 (bs, 1 H). ,3C NMR (CDCI3) δ 14.0, 16.0, 22.6, 26.8, 28.4, 29.1 , 29.2, 29.9, 31.7, 36.9, 40.8, 82.3, 107.6, 110.4, 1 12.9, 118.7, 140.5, 142.3, 151.0, 152.7, 153.6, 163.2, 166.4. MS (ES+) 491.95 (M+1), 493.00 (M+2).
4- ethyl-2-(3-octyl-ureido)-5-[(2-pyridin-3-yl-ethyl)-carbamoyl]-thiophene-3- carboxylic acid tert-butyl ester (13.12) white solid (73% yield): 'H NMR (CDCI3, 200MHz) δ 0.85 (t, 3H, J = 6.6 Hz), 1.21 -1.28 (m, 10H), 1.52 (bs, 1 1 H), 2.54 (s, 3H), 2.89 (t, 2H, J = 6.9 Hz), 3.27 (dt, 2H, J = 6.4, 6.2 Hz), 3.61 (dt, 2H, J = 6.6, 6.2 Hz), 5.69 (bs, 1 H), 5.92 (t, 1 H, J = 5.9 Hz), 7.23 (dd, 1 H, J = 6.2, 5.2 Hz), 7.55, (ddd, 1 H, J = 7.6, 1.8, 1.8 Hz), 8.46 (d, 1 H, J = 4.8 Hz), 8.47 (s, 1 H), 10.81 (bs, 1 H). 13C NMR (CDCI3) δ 14.0, 15.9, 22.6, 26.8, 28.3, 29.1 , 29.2, 29.9, 31.7, 33.0, 40.7, 40.9, 82.2, 1 12.7, 1 18.9, 123.5, 134.4, 136.3, 139.9, 147.9, 150.1 , 152.6, 153.6, 163.7, 166.3. MS (ES+) 516.98 (M+1), 518.05 (M+2).
4-l\/lethyl-2-(3-octyl-ureido)-5-[4-(2-piperidin-1-yl-ethyl)-piperazine-1-carbonyl]- thiophene-3-carboxylic acid tert-butyl ester (13.13) yellow oil (80% yield): Η . NMR (CDCI3, 200MHz) δ 0.84 (t, 3H, J = 6.4 Hz), 1.22 (bs, 12H), 1.53 (m, 15H), 2.25, (s, 3H), 2.33-2.52 (m, 8H), 3.23 (dt, 2H, J = 6.6, 6.4 Hz), 3.57 (bs, 2H), 5.63 (bs, 1 H), 10.73 (bs, 1 H). MS (ES+) 592.07 (M+1), 593.13 (M+2).
5-(3-Hexyl-3-methyl-ureido)-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-ferf-butyl ester (13.14). Η NMR (CDCI3, 200MHz) δ 0.87 (t, 3H, J = 6.4 Hz), 1 .25-1.32 (m, 6H), 1.58 (s, 1 1 H), 2.72 (s, 3H), 3.04 (s, 3H), 3.36 (t, 2H, J = 7.7 Hz), 5.26 (s, 2H), 7.27-7.43 (m, 5H), 11.53 (bs, 1 H). I3C NMR (CDCI3) δ 13.9, 15.8, 22.5, 26.3, 27.7, 28.3, 31.4, 34.4, 49.3, 65.8, 82.3, 113.1, 115.2, 127.9, 128.4, 136.1 , 145.5, 153.6, 156.6, 163.0, 166.7. MS (ES+) 557 (M+68).
5-[3-(1-Butyl-pentyl)-ureido]-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-ferf-butyl ester (13.15). 'H NMR (CDCI3, 200MHz) δ θ.86 (t, 6H, J = 6.6 Hz), 1 .25-1.31 (m, 12H), 1.55 (s, 9H), 2.70 (s, 3H), 3.58-3.78 (m, 1 H), 5.04 (bd, 1 H, J = 8.8 Hz), 5.25 (s, 2H), 7.27-7.41 (m, 5H), 10.98 (bs, 1 H). 13C NMR (CDCI3) δ 13.9, 14.0, 15.8, 22.6, 22.7, 28.0, 28.1 , 28.3, 35.1 , 35.6, 65.9, 82.3, 112.8, 115.2, 127.9, 128.4, 136.1 , 145.5, 153.1 , 156.3, 163.0, 166.4, 186.4. MS (ES+) 585 (M+68).
5-(3,3-Dioctyl-ureido)-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-ferf-butyl ester (13.16). Η NMR (CDCI3, 200MHz) δ 0.87 (t, 6H, J = 6.6 Hz), 1.26-1.30 (m, 20H), 1.58 (bs, 13H), 2.72 (s, 3H), 3.32 (t, 4H, J = 7.7 Hz), 5.25 (s, 2H), 7.28-7.43 (m, 5H), 11.58 (bs, 1 H). 13C NMR (CDCI3) δ 14.0, 15.8, 22.6, 26.9, 28.3, 28.5, 29.2, 29.3, 31.8, 47.9, 65.9, 82.3, 113.0, 115.1 , 127.9, 128.0, 128.5, 136.1 , 145.6, 153.3, 156.7, 163.0, 166.7.
5-lsobutylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester (13.17). MS (ES): m/z 467.9 [MH+]. 1H NMR (CDCI3, 200 MHz): δ = 0.83 (m, 9H), 1.26-1.57 (m, 20H), 1.87 (m, 1 H, 6.6 Hz), 2.62 (s, 3H), 3.16-3.30 (m, 4H), 5.1 1 (brs, 1 H), 5.64 (m, 1 H).
5-(2,2-Dimethyl-propylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid tert-butyl ester (13.18). MS (ES): m/z 481.7 [MH+]. 1H NMR (CDCI3, 200 MHz): δ = 0.83 (m, 9H), 1.26-1.57 (m, 23H), 2.62 (s, 3H), 3.16-3.30 (m, 4H), 5.11 (brs, 1 H), 5.64 (m, 1 H).
5-[(2,3-Dihydro-benzofuran-5-ylmethyl)-carbamoyl]-4-methyl-2-(3-octyl-ureido)- thiophene-3-carboxylic acid tert-butyl ester (13.19). MS (ES): m/z 543.87 [MH+].
Figure imgf000082_0001
4-Methyl-2-(3-octyl-ureido)-5-[(pyridin-2-ylmethyl)-carbamoyl]-thiophene-3- carboxylic acid tert-butyl ester (13.20) The same method as for the preparation of 4-methyl-5-octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, coupling with 2-(aminomethyl)pyridine (31.5 mg, 0.36 mmol) afforded 86.9 mg of a solid (71%) after by column chromatography (EtOAc): 1H NMR (CDCI3) δ 0.87 (m, 3H), 1.45-1.20 (m, 10H), 1.70-1.45 (m, 11 H), 2.64 (s, 3H), 3.29 (dt, 4H, J = 6.7, 6.6 Hz), 4.68 (d, 2H, J = 5.8Hz), 4.91 (m, 1 H), 7.02 (m, 1 H), 7.35-7.10 (m, 1 H), 7.65 (t, 1 H, J = 8.0Hz), 8.53 (d, 1H, J = 5.0 Hz), 10.92 (s, 1 H); MS (El): cal'd 502.86, exp 502.94 (MH+).
Figure imgf000083_0001
4-Methyl-2-(3-octyl-ureido)-5-[(pyridin-3-ylmethyl)-carbamoyl]-thiophene-3- carboxylic acid tert-butyl ester (13.21) The same method as for the preparation of 4-methyl-5-octyIcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, coupling with 3-(aminomethyl)pyridine (31.5 mg, 0.36 mmol) afforded 93.1 mg of a solid (76%) after by column chromatography (EtOAc): 1H NMR (CDCIs) δ 0.87 (m, 3H), 1.45-1.20 (m, 10H), 1.70-1.45 (m, 11 H), 2.65 (s, 3H), 3.29 (dt, 4H, J = 6.7, 6.6 Hz), 4.57 (d, 2H, J = 5.6Hz), 4.89 (m, 1 H), 6.05 (t, 1 H, J = 7.0, 5.0Hz), 7.68 (d, 1 H, J = 7.0Hz), 8.53 (d, 1 H, J = 5.0 Hz), 8.58 (s, 1 H), 10.92 (s, 1 H); MS (El): cal'd 502.86, exp 502.94 (MH+).
Figure imgf000083_0002
5-Dibutylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester (13.22) The same method as for the preparation of 4-methyl-5- octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, coupling with dibutylamine (37.6 mg, 0.36 mmol) afforded 56.9 mg of a solid (45%) after by column chromatography (8:2; hexanes: EtOAc): 1H NMR (CDCl3) δ 0.87 (m, 9H), 1.18-1.40 (m, 14H), 1.45-1.68 (m, 15H), 2.23 (s, 3H), 3.20- 3.46 (m, 6H), 5.11 (m, 1 H), 10.74 (s, 1 H); MS (El): cal'd 523.77, exp 524.02 (MH+).
5-(4-Benzyl-piperidine-1-carbonyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid tert-butyl ester (13.23): Η NMR (CDCI3, 200MHz) δ 0.87 (s, 3H), 1.26 (brs, 11 H), 1.56 (brs, 15H), 2.27 (s, 3H), 2.54 (d, 2H, J = 6.6Hz), 2.80 (m, 2H), 3.27 (dt, 2H, J = 6.2Hz, J = 6.6Hz), 4.20 (m, 2H), 5.06 (t, 1 H, J = 5.2Hz), 7.05-7.30 (m, 5H), 10.77 (s, 1 H); MS (ES) 570.1 (M+1 ) 3-Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2- (1-butyl-pentyl) ester (13.24): (60%). Η NMR (CD3OD, 200MHz) δ 0.89 (s, 9H), 1.32 (s, 18H), 1.60 (s, 15H), 2.69 (s, 3H), 3.19 (t, 2H, J = 6.4Hz), 5.00 (p, 1 H, J = 6Hz), 10.95 (s, 1 H); MS (ES) 539.2 (M+1)
4-MethyI-2-(3-octyl-ureido)-5-(3-phenoxy-propylcarbamoyl)-thiophene-3- carboxylic acid tert-butyl ester (13.25): (55%). 'H NMR (CDCI3, 400MHz) δ 0.88 (m, 3H), 1.27 (m, 10H), 1.55 (m, 11 H), 2.07 (m, 2H), 2.62 (s, 3H), 3.30 (dt, 2H, J = 5.6Hz, J = 7.2Hz), 3.59 (dt, 2H, J = 5.6Hz, J = 6.4Hz), 4.07 (t, 2H, J = 5.6Hz), 4.82 (brs, 1 H), 6.14 (brs, 1 H), 6.95 (m, 3H), 7.25 (m, 2H), 10.95 (s, 1 H); MS (ES) 545.95 (M)
5-(1-Butyl-pentylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester (13.26): (92%). Η NMR (CDCI3, 200MHz) δ 0.87 (m, 9H), 1.29 (m, 18H), 1.56 (s, 11 H), 2.61 (s, 3H), 3.29 (dt, 2H, J = 6.6Hz, J = 6.6Hz), 4.02 (brs, 1 H), 5.04 (t, 1 H, J = 5.6Hz), 5.40 (d, 1 H, J = 8.8Hz), 10.91 (s, 1 H)
5-[(Furan-2-ylmethyl)-carbamoyl]-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid ferf-butyl ester (13.27): MS (ES+) 491.88 (M+1).
4-Methyl-2-(3-octyl-ureido)-5-(thiazol-2-ylcarbamoyl)-thiophene-3-carboxylic acid ferf-butyl ester (13.28): MS (ES+) 494.84 (M+1).
4-Methyl-2-(3-octyl-ureido)-5-(2-pyridin-3-yl-ethylcarbamoyl)-thiophene-3- carboxylic acid ferf-butyl ester (13.29): MS (ES+) 516.93 (M+1).
4-Methyl-2-(3-octyI-ureido)-5-[4-(2-piperidin-1-yl-ethyl)-piperazine-1-carbonyl]- thiophene-3-carboxylic acid ferf-butyl ester (13.30): MS (ES+) 592.04 (M+1).
4-Methyl-2-(3-octyl-ureido)-5-(4-phenyl-piperazine-1-carbonyl)-thiophene-3- carboxylic acid ferf-butyl ester (13.31): MS (ES+) 556.94 (M+1).
5-([1 ,4']Bipiperidinyl-1'-carbonyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid ferf-butyl ester (13.32): MS (ES+) 563.01 (M+1 ).
5-(3-lmidazol-1-yl-propylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid ferf-butyl ester (13.33): MS (ES+) 519.95 (M+1 ).
5-Dihexylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester (13.34): (40%). Η NMR (CD3CI, 200MHz) δ 0.85 (s, 9H), 1.24 (s, 22H), 1.56 (s, 15H), 2.24 (s, 3H), 3.31 (m, 6H), 4.83 (t, 1 H, J = 5.2Hz), 10.76 (s, 1 H); MS (ES) 580.21 (M+1 )
5-Dioctylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylϊc acid tert-butyl ester (13.35): (65%). Η NMR (CD3CI, 200MHz) δ 0.86 (m, 9H), 1.23 (s, 32H), 1.56 (s, 15H), 2.25 (s, 3H), 3.31 (m, 6H), 4.80 (t, 1 H, J = 5.6Hz), 10.77 (s, 1 H); MS (ES) 637.00 (M+1 )
5-Cyclohexylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester (13.36): (75%). 'H NMR (CD3CI, 200MHz) δ 0.87 (t, 3H, J = 6.4Hz), 1.26 (m, 16H), 1 .56 (m, 15H), 2.60 (s, 3H), 3.28 (dt, 2H, J = 6.6Hz, J = 6.2Hz), 3.88 (m, 1 H), 4.97 (t, 1 H, J = 5.4Hz), 5.57 (d, 1 H, J = 7.2Hz), 10.78 (s, 1 H); MS (ES) 494.12 (M+1)
5-(4-Benzyl-piperazine-1-carbonyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid tert-butyl ester (13.37): (72%). Η NMR (CD3CI, 200MHz) δ 0.87 (m, 3H), 1.26 (brs, 10H), 1.56 (brs, 1 1 H), 2.28 (s, 3H), 2.44 (brs, 4H), 3.27 (dt, 2H, J = 6.6Hz, J = 6.6Hz), 3.52 (s, 2H), 3.60 (brs, 4H), 4.88 (t, 1H, J = 5.0Hz), 7.30 (brs, 5H), 10.78 (s, 1 H); MS (ES) 571.16 (M+1)
4-Methyl-2-(3-octyl-ureido)-5-[(pyridin-3-ylmethyl)-carbamoyl]-thiophene-3- carboxylic acid tert-butyl ester (13.38). The crude solid was then flashed through a plug of silica gel with ethyl acetate to yield 13.38, 3.84g (98% crude yield) of a tan solid.
5-(3-Dimethylamino-propylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid ferf-butyl ester (13.39): MS (ES+) 496.95 (M+1). 3-Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- ferf-butyl ester (13.40). Mp 119.0-120.0SC; 1H NMR (CDCI3) δ 11.03 (s, 1 H), 7.50-
7.20 (m, 5H), 5.27 (s, 2H), 5.03 (vt, 1 H), 3.29 (q, 2H, J = 6.6 Hz), 2.71 (s, 3H), 1.63- 1.40 (m, 2H), 1.57 (s, 9H), 1.26 (bs, 10H), 0.87 (t, 3H, J = 6.6 Hz). MS (El): 502.8
(m+).
3-Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-ferf-butyl ester 2- octyl ester (13.41) Mp 92.0-94.0 eC; 1H NMR (CDCI3) δ 12.30 (s, 1 H), 8.64 (s, 1 H), 5.30 (t, 1 H, J = 6.0 Hz), 4.25 (t, 2H, J = 6.4 Hz), 3.29 (q, 2H, J = 6.0 Hz), 2.74 (s, 3H), 1.90-1.50 (m, 4H), 1.61 (s, 9H), 1.28 (bs, 20H), 0.88 (m, 6H). MS (El): 525.1 (m+).
4- ethyl-5-octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid ferf- butyl ester (13.42). 1H NMR (CDCI3) δ 10.89 (s, 1 H), 5.82-5.62 (m, 1 H), 5.78-5.60 (m, 1 H), 3.33 (q, 4H, J = 6.6 Hz), 2.61 (s, 3H), 1.70-1.40 (m, 4H), 1.55 (s, 9H), 1.27 (bs, 20H), 0.88 (m, 6H). MS (El): 524.1 (m+).
4-Methyl-2-(3-octyl-ureido)-5-(4-phenyl-butylcarbamoyl)-thiophene-3-carboxylic acid tert-butyl ester (13.43): Η NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.21-1.43 (m, 10H), 1.57 (s, 15H), 2.60 (m, 5H), 3.24-3.43 (m, 4H), 5.22 (brs, 1 H), 5.70 (t, 1 H, J = 5.0Hz), 7.25 (m, 5H), 10.90 (s, 1 H).
4-Methyl-2-(3-octyl-ureido)-5-(3-phenyl-propylcarbamoyl)-thiophene-3- carboxylic acid tert-butyl ester (13.44) 'H NMR (CDCI3, 200MHz) δ 0.87 (m, 3H),
1.21 -1.45 (m, 10H), 1.57 (s, 11 H), 1.89 (tt, 2H, J = 7.4Hz, J = 7.6Hz), 2.65 (m, 5H), 3.24-3.45 (m, 4H), 5.14 (brs, 1 H), 5.73 (t, 1 H, J = 5.2Hz), 7.17-7.31 (m, 5H), 10.90 (s, 1 H).
4-Methyl-2-(3-octyl-ureido)-5-(2-phenoxy-ethylcarbamoyl)-thiophene-3- carboxylic acid tert-butyl ester (13.45): 'H NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.22-1.49 (m, 10H), 1.56 (s, 11 H), 2.61 (s, 3H), 3.28 (dt, 2H, J = 6.2Hz, J = 6.6Hz), 3.78 (dt, 2H, J = 5.2Hz, J = 5.4Hz), 4.09 (t,' 2H, J = 5.2Hz), 5.08 (t, 1H, J = 5.0Hz), 6.21 (t, 1 H, J = 5.4Hz), 6.29 (m, 3H), 7.28 (m, 2H), 10.91 (s, 1 H). 5-(2-Methoxy-ethylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid tert-butyl ester (13.46): Η NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.27-1.45 (m, 10H), 1.57 (brs, 11 H), 2.60 (s, 3H), 3.24-3.37 (m, 5H), 3.54 (m, 4H), 5.05 (t, 1 H, J = 5.2Hz), 6.12 (brs, 1 H), 10.88 (s, 1 H).
5-(3-Methoxy-propylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid tert-butyl ester (13.47): Η NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.21-1.49 (m, 10H), 1.57 (brs, 1 1 H), 1.83 (tt, 2H, J = 5.8Hz, J = 6.2Hz), 2.60 (s, 3H), 3.24-3.35 (m, 5H), 3.49 (m, 4H), 5.13 (t, 1 H, J = 5.6Hz), 6.31 (t, 1H, J = 5.6Hz), 10.90 (s, 1 H).
5-((Benzo(1,3)dioxol-5-ylmethyl)-carbamoyl)-4-methyl-2-(3-octyl-ureido)- thiophene-3-carboxylic acid tert-butyl ester (13.48): Η NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.26-1.43 (brs, 10H), 1.57 (brs, 11 H), 2.63 (s, 3H), 3.27 (dt, 2H, J= 6.2Hz, J= 6.6Hz), 4.44 (d, 2H, J = 5.6Hz), 4.92 (t, 1 H, J = 5.6Hz), 5.94 (s, 2H), 6.76 (s, 2H), 6.81 (s, 1 H), 10.91 (s, 1 H).
Figure imgf000087_0001
3-Methyl-5-(1-methylheptyloxycarbonylamino)thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-ferf-butyl ester (13.49)
Light brownish oil in 82% yield as mixture of two rotatmers (2:1 ratio). Η NMR (CDCI3, 200MHz): δ 7.35-7.40 (m, 5H), 6.49 (brs, 1 H), 5.25 and 5.28 (s, 2H), 4.70-4.80 and 4.80-5.05 (m, 1 H), 2.68 and 2.73 (s, 3H), 1.50-1.61 (m, 9H), 1.20-1.40 (m, 8H), 0.87(m, 3H).
Figure imgf000088_0001
3-Methyl-5-[3-(1-methylheptyl)ureido]thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-ferf-butyl ester (13.50)
Light yellow oil in 99% yield as mixture of two rotatmers. Η NMR (CDCI,, 200MHz): δ 11.00 (brs, 1 H), 7.29-7.43 (m, 5H), 5.24 and 5.26 (s, 2H), 4.60 and 4.68 (brs, 1 H), 3.80-3.95 (brs, 1 H), 3.45-3.90 (m, 1 H), 2.65 and 2.70 (s, 3H), 1.55 and 1.57 (s, 9H), 1.40-1.50(m, 2H), 1.20-1.40 (m, 8H), 1.17 (d, 2H, J = 6.6Hz), 1.09(d, 1 H, J = 6.2Hz), 0.80-0.95(m, 3H).
Example 14: Acid Intermediates
4-Methyl-2-(3-octyl-ureido)-5-[(pyridin-4-ylmethyl)-carbamoyl]-thiophene-3- carboxylic acid (14.1): (99%). Η NMR (CD3OD, 200MHz) δ 0.86 (m, 3H), 1.25 (brs, 10H), 1.56 (m, 2H), 2.64 (s, 3H), 3.28 (m, 2H), 4.56 (d, 2H, J= 5.8Hz) 7.24 (d, 2H, J= 5.8Hz), 8.54 (d, 2H, J= 5.8Hz)
4-Methyl-5-[methyl-(6-methyl-pyridin-2-ylmethyl)-carbamoyl]-2-(3-octyl-ureido)- thiophene-3-carboxylic acid (14.2): (99%). Η NMR (CD3OD, 200MHz) δ 0.86 (m, 3H), 1.28 (brs, 10H), 1.50 (brs, 2H), 2.38 (s, 3H), 2.50 (s, 3H), 3.04 (s, 3H), 3.17 (brs, 2H), 4.74 (s, 2H), 7.15 (m, 2H), 7.55 (t, 1 H, J= 7.6Hz)
5-[Ethyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-4-methyl-2-(3-octyl-ureido)- thiophene-3-carboxylic acid (14.3): (99%). Η NMR (CD3OD, 200MHz) δ 0.85 (m, 3H), 1.20 (brs, 13H), 1.49 (brs, 2H), 2.20 (s, 3H), 3.19 (m, 4H), 3.41 (m, 2H), 3.83 (brs, 2H), 7.38 (m, 2H), 7.84 (t, 1 H, J= 7.2Hz), 8.49 (d, 1 H, J= 3.6Hz)
5-(Benzyloxycarbonylmethyl-carbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene- 3-carboxylic acid (14.4): (99%). 'H NMR (CD3OD, 200MHz) δ 0.86 (m, 3H). 1.28 (brs, 10H), 1.50 (brs, 2H), 2.57 (s, 3H), 3.18 (m, 2H), 4.09 (s, 2H), 7.31 (brs, 5H) 3-Methyl-5-(3-octyl-thioureido)-thiophene-2,4-dicarboxylic acid 2-benzyl ester (14.5): (99%). Η NMR (CD3OD, 200MHz) δ 0.89 (brs, 3H), 1.29 (brs, 10H), 1.61 (brs, 2H), 2.74 (s, 3H), 3.48 (brs, 2H), 5.29 (s, 2H), 7.38 (m, 5H).
4-Methyl-2-(3-octyl-ureido)-5-[(pyridin-3-yl-methyl)-carbamoyl]-thiophene-3- carboxylic acid (14.6) Thiophene (3.42 g, 6.8 mmol) was dissolved in 40 mL CH2CI2. Trifluoroacetic acid (10 mL) was added slowly and the reaction was stirred for 4h at rt. The reaction was concentrated in-vacuo. The residue was dissolved in methanol and saturated NaHCO3 was added until pH~7. The solution was concentrated in vacuo and then resuspended in hot ethyl acetate. The insoluble salts were filtered and the filtrate was concentrated in vacuo to yield 14.6, 2.19 g (72% crude yield) of a tan solid.
5-[(Furan-2-yl-methyl)-carbamoyl]-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.7) white solid (73% yield): Η NMR (CD3OD, 200MHz) δ 0.90 (t, 3H, J = 6.4 Hz), 1.30-1.39 (m, 10H), 1.50-1.60 (m, 2H), 2.56 (s, 3H), 3.20 (t, 2H, J = 6.9 Hz), 4.49 (s, 2H), 6.27 (1 H, d, J = 3.0 Hz), 6.35 (dd, 1 H, J = 3.2, 1.8 Hz), 7.34 (d, 1 H, J =1.8 Hz). MS (ES+) 435.76 (M+1 ), 436.66 (M+2).
4-Methyl-2-(3-octyl-ureido)-5-[(2-pyridin-3-yl-ethyl)-carbamoyl]-thiophene-3- carboxylic acid (14.8) light pink solid (100% yield): 'H NMR (CD3OD, 200MHz) δ 0.90 (t, 3H, J = 9.9 Hz), 1.32 (bs, 10H), 1.51-1.60 (m, 2H), 2.58 (s, 3H), 2.96 (t, 2H, J = 7.0 Hz), 3.20 (t, 2H, J = 6.7 Hz), 3.59 (t, 2H, J = 7.0 Hz), 7.39 (dd, 1 H, J = 7.8, 4.8 Hz), 7.78 (d, 1 H, J =7.8 Hz), 8.39 (d, 1 H, J =4.8 Hz), 8.46 (s, 1 H). MS (ES-) 458.92 (M-1).
4-Methyl-2-(3-octyl-ureido)-5-[4-(2-piperidin-1-yl-ethyl)-piperazine-1-carbonyl]- thiophene-3-carboxylic acid (14.9) peach solid (80% yield): MS (ES-) 534.04 (M- 1).
5-(3-Hexyl-3-methyl-ureido)-3-methyl-thiophene-2,4-dicarboxyiic acid 2-benzyl ester (14.10) light pink solid (100% yield): Η NMR (CDCI3) 200MHz) δ 0.87 (t, 3H, J = 6.4 Hz), 1.25-1.31 (m, 6H), 1.58-1.62 (m, 2H), 2.78 (s, 3H), 3.05 (s, 3H), 3.36 (t, 2H, J = 7.5 Hz), 5.29 (s, 2H), 7.29-7.44 (m, 5H), 10.39 (bs, 1 H), 1 1.18 (bs, 1 H). 13C NMR (CDCI3) δ 13.9, 15.4, 22.4, 26.3, 27.7, 31.4, 34.7, 49.7, 66.4, 110.8, 116.4, 127.9, 128.1 , 128.5, 135.7, 146.1 , 153.5, 158.6, 162.9, 171.3. MS (ES+) 432.74 (M+1 ).
5-(3.3-Dioctyl-ureido)-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester (14.11) light pink solid (84% yield): Η NMR (CDCI3, 200MHz) δ 0.86 (t, 6H, J = 6.6 Hz), 1.26-1.30 (m, 20H), 1.63 (bs, 4H), 2.80 (s, 3H), 3.33 (t, 4H, J = 7.0 Hz), 5.28 (s, 2H), 7.30-7.43 (m, 5H), 1 1.20 (s, 1 H), 11.92 (bs, 1 H).
5-lsobutylcarbamoyl-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid
(14.12). MS (ES): m/z 41 1.8 [MH+].
5-(2,2-Dimethyl-propylcarbamoyl)-4-methyI-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.13). MS (ES): m/z 425.8 [MH+]. 1H NMR (CDCI3, 200 MHz): D = 1.26-1.57 (m, 23H), 2.62 (s, 3H), 3.16-3.30 (m, 4H), 5.11 (brs, 1 H), 5.64 (m, 1 H).
Figure imgf000090_0001
4-Methyl-2-(3-octyl-ureido)-5-[(pyridin-2-ylmethyl)-carbamoyl]-thiophene-3- carboxylic acid (14.14) The same method as for the preparation of 3- methoxymethyl-5-octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: 1H NMR (CDCI3 + 1 drop of CD3OD) δ 0.86 (m, 3H), 1.32-1.20 (m, 10H), 1.60-1.32 (m, 2H), 2.59 (s, 3H), 3.22 (dt, 4H, J = 6.7, 6.6 Hz), 4.76 (s, 2H), 7.40-7.15 (m, 2H), 7.76 (t, 1 H, J = 7.9Hz), 8.53 (d, 1 H, J = 5.0 Hz).
Figure imgf000091_0001
4-Methyl-2-(3-octyl-ureido)-5-[(pyridin-3-ylmethyl)-carbamoyl]-thiophene-3- carboxylic acid (14.15) The same method as for the preparation of 3- methoxymethyl-5-octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection with TFA afforded a solid, which was used without purification: 1H NMR (CDCI3+ 1 drop of CD3OD) δ 0.82 (m, 3H), 1.45-1.20 (m, 10H), 1.70-1.45 (m, 2H), 2.02 (m, 3H), 2.92 (m, 2H), 4.39 (m, 1 H), 7.11 (m, 1 H), 7.55 (m, 1 H), 8.31 (m, 1 H), 8.49 (m, 1 H).
5-(4-Benzyl-piperidine-1-carbonyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.16): (100%). Η NMR (CD3OD, 200MHz) δ 0. 87 (s, 3H), 1.26 (brs, 1 1 H), 1.56 (brs, 6H), 2.27 (s, 3H), 2.54 (d, 2H, J = 6.6Hz), 2.90 (m, 2H), 3.27 (t, 2H, J = 6.6Hz), 4.20 (brs, 2H), 7.05-7.30 (m, 5H)
3-Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 2-(1-butyl-pentyl) ester (14.17): (95%). 1H NMR (CD3OD, 400MHz) δ 0.89 (m, 9H), 1.33 (m, 18H), 1.50-1.70 (m, 6H), 2.73 (s, 3H), 3.19 (t, 2H, J = 6.6Hz), 5.02 (m, 1 H)
5-(1-Butyl-pentylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid (14.18): (100%). Η NMR (CDCI3, 200MHz) δ 0.87 (m, 9H), .1.29 (m, 18H), 1.56 (s, 6H), 2.52 (s, 3H), 3.35 (t, 2H, J = 6.6Hz), 3.90 (brs, 1 H)
4-Methyl-2-(3-octyl-ureido)-5-(3-phenoxy-propylcarbamoyl)-thiophene-3- carboxylic acid (14.19): (100%). 1H NMR (CD3OD, 200MHz) δ 0.89 (m, 3H), 1.32 (s, 10H), 1.55 (brs, 2H), 2.06 (tt, 2H, J = 6.0Hz, J = 6.0Hz), 2.55 (s, 3H), 3.19 (t, 2H, J = 7.0Hz), 3.51 (t, 2H, J = 6.8Hz), 6.90 (m, 3H), 7.24 (m, 2H).
4-Methyl-2-(3-octyl-ureido)-5-(pyridin-3-ylmethyl)-carbamoyl)-thiophene-3- carboxylic acid (14.20):. 14.20, 1 10 mg (100% crude yield) of a tan solid. 5-(3-Dimethylamino-propylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.21): MS (ES-) 438.70 (M-1 ).
5-[(Furan-2-ylmethyl)-carbamoyl]-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.22): MS (ES-) 434.03 (M-1 ).
4-Methyl-2-(3-octyl-ureido)-5-(thiazol-2-ylcarbamoyl)-thiophene-3-carboxylic acid (14.23): MS (ES-) 436.23 (M-1 ).
4-Methyl-2-(3-octyl-ureido)-5-(2-pyridin-3-yl-ethylcarbamoyl)-thiophene-3- carboxylic acid (14.24): MS (ES-) 459.03(M-1).
4-Methyl-2-(3-octyl-ureido)-5-[4-(2-piperidin-1-yl-ethyl)-piperazine-1-carbonyl]- thiophene-3-carboxylic acid (14.25): MS (ES-) 534.20 (M-1).
4-Methyl-2-(3-octyl-ureido)-5-(4-phenyl-piperazine-1-carbonyI)-thiophene-3- carboxylic acid (14.26): MS (ES-) 499.03 (M-1).
5-([1,4']Bipiperidinyl-1'-carbonyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.27): MS (ES-) 505.08 (M-1 ).
5-(3-lmidazoI-1-yl-propylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.28): MS (ES-) 462.09 (M-1 ).
3- ethyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-ferf-butyl ester
(14.29) 1H NMR (CDCI3) δ 11.06 (s, 1 H), 5.14 (vt, 1 H), 3.30 (q, 2H, J = 6.0 Hz), 2.71 (s, 3H), 1.70-1.40 (m, 2H), 1.59 (s, 9H), 1.27 (bs, 10H), 0.87 (t, 3H, J = 6.6 Hz). MS (El): 412.8 (m+).
2-Dodecyloxy-5-methyl-4-oxo-4H-thieno[2,3-cf][1 ,3]oxazine-6-carboxylic acid
(14.30) 1H NMR (CDCI3) δ 4.47 (t, 2H, J = 6.2 Hz), 4.19 (bs, 1 H), 2.85 (s, 3H), 1.80 (quint, 2H, J= 6.2 Hz), 1.27 (bs, 18H), 0.88 (t, 3H, J = 6.6 Hz). MS (El): 395.4 (m+). 4-Methyl-5-octylcarbamoyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid
(14.31) 1H NMR (CDCI3) δ 10.90 (bs, 2H), 5.82-5.62 (m, 1 H), 5.78-5.60 (m, 1 H), 3.33 (q, 4H, J = 6.6 Hz), 2.61 (s, 3H), 1.70-1.40 (m, 4H), 1.27 (bs, 20H), 0.88 (m, 6H).
3-Methoxymethyl-5-octyloxycarbonylamino-thiophene[2,4]dicarboxylic acid 2- benzyl ester (14.32) 1H NMR (CDCI3) δ 1 1.98 (s, 1 H), 10.09 (s, 1 H), 7.45-7.20 (m, 5H), 5.14 (s, 2H), 4.22 (t, 2H, J = 6.6 Hz), 3.85 (s, 3H), 3.82 (s, 2H), 1.70 (quint, 2H, J = 6.6 Hz), 1.28 (bs, 10H), 0.88 (t, 3H, J = 5.6 Hz).
5-(4-(lsopropylcarbamoyl-methyl)-piperazine-1-carbonyl)-4-methyl-2-(3-octyl- ureido)-thiophene-3-carboxylic acid (14.33): Η NMR (CDCI3, 200MHz) δ 0.89 (brs, 3H), 1.15-1.34 (m, 16H), 1.56 (m, 2H), 2.37 (s, 3H), 3.05-3.49 (m, 10H), 3.95 (m, 1 H).
5-((Benzo(1,3)dioxoI-5-ylmethyl)-carbamoyl)-4-methyl-2-(3-octyl-ureido)- thiophene-3-carboxylic acid (14.34): 'H NMR (CDCI3, 200MHz) δ 0.86 (m, 3H), 1.32-1.45 (m, 10H), 1.53 (m, 2H), 2.56 (s, 3H), 3.19 (m,2H), 4.4 (d, 2H, J = 6.0Hz), 5.91 (s, 2H), 6.80 (m, 3H).
5-(3,4-Dimethoxy-benzylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.35): :H NMR (CDCI3, 200MHz) δ 0.88 (brs, 3H), 1.31 -1.45 (m, 10H), 1.56 (m, 2H), 2.56 (s, 3H), 3.18 (dt, 2H, J= 6.2Hz, J= 6.6Hz), 3.80 (s, 3H), 3.82 (s, 3H), 4.43 (s, 2H), 6.89 (s, 2H), 6.97 (s, 1 H).
5-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-4-methyl-2-(3-octyl- ureido)-thiophene-3-carboxylic acid (14.36): Η NMR (CDCI3, 200MHz) δ 0.89 (m, 3H), 1.31-1.45 (m, 10H), 1.51 (brs, 2H), 2.31 (s, 3H), 2.85 (t, 2H, J = 6.0Hz), 3.18 (t, 2H, J = 7.0Hz), 3.79 (m, 8H), 6.71 (s, 1 H), 6.74 (s,1 H).
4-Methyl-2-(3-octyl-ureido)-5-(4-phenyl-butylcarbamoyl)-thiophene-3-carboxylic acid (14.37): Η NMR (CDCI3, 200MHz) δ 0.89 (brs, 3H), 1.26-1.45 (m, 10H), 1.59 (m, 6H), 2.54 (s, 3H), 2.65 (t, 2H, J = 7.0Hz)", 3.19 (m, 4H), 7.21 (m, 5H). 4-Methyl-2-(3-octyl-ureido)-5-(3-phenyl-propylcarbamoyl)-thiophene-3- carboxylic acid (14.38): Η NMR (CDCI3, 200MHz) δ 0.89 (m, 3H), 1.25-1.45 (m, 10H), 1.57 (brs, 2H), 1.89 (tt, 2H, J = 7.4Hz, J = 7.6Hz), 2.55 (s, 3H), 3.17-3.39 (m, 4H), 7.23 (m, 5H).
4- ethyl-2-(3-octyl-ureido)-5-(2-phenoxy-ethylcarbamoyl)-thiophene-3- carboxylic acid (14.39): 'H NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.25-1.41 (m, 10H), 1.56 (brs, 2H), 2.56 (s, 3H), 3.19 (dt, 2H, J = 6.2Hz, J = 6.6Hz), 3.71 (dt, 2H, J = 5.2Hz, J = 5.4Hz), 4.12 (t, 2H, J = 5.2Hz), 6.95 (m, 3H), 7.25 (m, 2H).
5-(2-Methoxy-ethylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.40): Η NMR (CDCI3, 200MHz) δ 0.89 (brs, 3H), 1.25-1.43 (m, 10H), 1.53 (m, 2H), 2.56 (s, 3H), 3.19 (t, 2H, J = 7.0Hz), 3.37 (s, 3H), 3.51 (m, 4H).
5-(3-Methoxy-propylcarbamoyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (14.41): 'H NMR (CDCI3, 200MHz) δ 0.89 (brs, 3H), 1.27-1.44 (m, 10H), 1.51 (brs, 2H), 1.84 (tt, 2H, J = 6.2Hz, J = 6.6Hz), 2.56 (s, 3H), 3.19 (t, 2H, J = 7.0Hz), 3.34 (s, 3H), 3.39 (t, 2H, J = 7.0Hz), 3.49 (t, 2H, J = 6.2Hz).
Figure imgf000094_0001
5-Methyl-2-(1-methylheptyloxy)-4-oxo-4H-thieno[2,3-cι]oxazine-6-carboxylic acid benzyl ester (14.42)
Light yellow oil in 32% yield. 'HNMR (CDCIJ, 200MHZ): δ 10.70 (brs, 1 H), 8.31 (brs, 2H), 7.29-7.43 (m, 5H), 5.27 (s, 2H), 3.45-3.90 (m, 1 H), 2.75 (s, 3H), 1.40-1.60(m, 2H), 1.10-1.40 (m, 11 H), 0.85 (t, 3H, J = 6.6Hz).
Figure imgf000095_0001
3-Methyl-5-[3-(1-methylheptyl)ureido]thiophene-2,4-dicarboxylic acid 2-benzyl ester (14.43)
Light brownish solid in 99% yield.
'HNMR (CDCIJ, 200MHZ): δ 10.52 (s, 1 H), 9.00(brs, 1 H), 7.35-7.39 (m, 5H), 5.28 (s, 2H), 4.70-5.05 (m, 1 H), 2.79 (s, 3H), 1.42-1.62(m, 2H), 1.10-1.40 (m, 8H), 0.87(t, 3H, J = 6.6Hz), MS (ES) [M -1] 444.96.
Figure imgf000095_0002
5-(4-Benzyl-piperazine-1 -carbonyl)-4-methyl-2-(3-octyl-ureido)-thiophene-3- carboxylic acid (37) 1H NMR (DMSO, 200MHz) δ 0.83 (brm, 3H), 1.18-1.41 (brm, 12H), 2.26 (s, 3H), 2.33 (brs, 4H), 2.99 (dt, 2H, J = 5.8Hz, J = 5.8Hz), 3.29 (s, 2H), 3.43 (brm, 4H), 7.21-7.41 (m, 5H)
Example 15: Thienoxazinones
Figure imgf000096_0001
[(5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carbonyl)- amino]-acetic acid benzyl ester (48): 'H NMR (CDCI3, 200MHz) δ 0.88 (m, 3H), 1.30 (brs, 10H), 1.61 (m, 2H), 2.74 (s, 3H), 3.42 (dt, 2H, J= 6.2Hz, J= 7.0Hz), 4.25 (d, 2H, J= 5.0Hz), 5.08 (brs, 1H), 5.23 (s, 2H), 6.29 (brs, 1 H), 7.37 (s, 5H)
Figure imgf000096_0002
5- ethyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid (pyridin-4-ylmethyl)-amide (55): (15%). 'H NMR (CDCI3, 200MHz) δ 0.88 (brs, 3H), 1.25 (brs, 10H), 1 .55 (brs, 2H), 2.75 (s, 3H), 3.38 (dt, 2H, J= 6.4Hz, J= 6.6Hz), 4.60 (d, 2H, J= 5.8Hz), 6.17 (s, 1 H), 7.24 (s, 2H), 8.54 (d, 2H, J= 5.8Hz)
Figure imgf000096_0003
5--vlethyi-2-octyianι.no-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid methyl-(6-methyl-pyridin-2-ylmethyl)-amide (49): (20%). Η NMR (CDCI3, 200MHz) δ 0.86 (m, 3H), 1.26 (brs, 10H), 1.58 (m, 2H), 2.45 (s, 3H), 2.52 (s, 3H), 3.06 (s, 3H), 3.38 (dt, 2H, J= 6.4Hz, J= 6.6Hz), 4.73 (s, 2H), 5.28 (brs, 1 H), 7.05 (d, 2H, J= 7.6Hz), 7.56 (t, 1 H, J= 7.8Hz)
Figure imgf000097_0001
5- ethyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid ethyl-(2-pyridin-2-yl-ethyl)-amide (51): (58%). Η NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.14 (t, 3H, J= 7.0Hz), 1.26 (brs, 10H), 1.59 (m, 2H), 2.31 (s, 3H), 3.10 (t, 2H, J= 7.0Hz), 3.38 (dt, 4H, J= 6.2Hz, J= 7.0Hz), 3.84 (t, 2H, J= 7.6Hz), 5.26 (brs, 1 H), 7.14 (m, 2H), 7.59 (ddd, 1 H, J= 7.4Hz, J= 7.6Hz, J= 1.6Hz), 8.52 (d, 1 H, J= 4.4Hz)
Figure imgf000097_0002
5-Methyl-2-octylamino-4-oxo-4H-thieno[2.3-d][1,3]thiazine-6-carboxylic acid benzyl ester (56): 'H NMR (CD3OD, 200MHz) δ 0.87 (brs, 3H), 1.27 (brs, 10H), 1.61 (m, 2H), 2.82 (s, 3H), 3.45 (dt, 2H, J= 6.2Hz, J= 6.6Hz), 5.31 (s, 2H), 5.42 (brs, 1H), 7.35 (m, 5H)
Figure imgf000097_0003
2-(Hexyl-methyl-amino)-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6- carboxylic acid benzyl ester (57): 'H NMR (CDCI3, 200MHz) δ 0.89 (t, 3H, J = 6.6 Hz), 1.30 (bs, 6H), 1.58-1.64 (m, 2H), 2.77 (s, 3H), 3.1 1 (s, 3H), 3.47-3.50 (m, 2H), 5.29 (s, 2H), 7.30-7.44 (m, 5H). MS (ES+) 414.70 (M+1).
Figure imgf000098_0001
2-(1-Butyl-pentylamino)-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6- carboxylic acid benzyl ester (59). 'H NMR (CDCI3, 200MHz) δ 0.89 (t, 6H, J = 6.4 Hz), 1.22-1.40 (bs, 8H), 1.48-1.66 (m, 4H), 2.79 (s, 3H), 3.90-4.00 (m, 1 H), 5.32 (s, 2H), 5.77 (d, J = 8.4 Hz), 7.31-7.45 (m, 5H).
Figure imgf000098_0002
2-Dioctylamino-5-methyl-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid benzyl ester (60) Η NMR (CDCI3, 200MHz) δ 0.88 (t, 6H, J = 6.6 Hz), 1.26-1.37 (m, 20H), 1.58-1.64 (m, 4H), 2.79 (s, 3H), 3.39-3.53 (m, 4H), 5.31 (s, 2H), 7.29-7.45 (m, 5H).
Figure imgf000098_0003
5-Methyl-2-octylamino-6-[4-(2-piperidin-1-yl-ethyl)-piperazine-1-carbonyl]- thieno[2,3-d][1,3]oxazin-4-one (53) MS (ES): m/z 517.9 [MH+]. 1H NMR (CDCI3, 200 MHz): δ = 0.87-1.59 (m, 9H), 1.18-1.59 (m, 14H), 2.54 (s, 3H), 2.23-2.51 (m, 4H), 3.34 (dt, 2H, J = 7 Hz), 3.61 (m, 3H), 5.21 (brs, 1H)
Figure imgf000099_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid (furan-2-ylmethyl)-amide (52) MS (ES): m/z 417.3 [MH+].
1H NMR (CDCI3, 200 MHz): δ = 1.18-1.41 (m, 14H), 2.67 (s, 3H), 3.43 (t, 2H, J = 8.4 Hz), 4.48 (m, 2H, J = 5.6 Hz), 5.12 (brs, 1H), 6.02-6.57 (m, 3H).
Figure imgf000099_0002
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid (2- pyridin-3-yl-ethyl)-amide (50) MS (ES): m/z 443.5 [MH+]. 1H NMR (CDCI3, 200 MHz): δ = 1.25-1.68 (m, 14H), 2.60 (s, 3H), 2.99 (t, 2H, J = 7.4 Hz), 3.39 (dt, 2H, J = 6.6 Hz), 5.25 (brs, 1H), 5.77 (s, 1 H), 7.25 (m, 2H), 7.61 (d, 1H, J = 19.4 Hz), 8.51 (m, 1 H).
Figure imgf000099_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid isobutyl-amide (54). MS (ES): m/z 393.8 [MH+].
1H NMR (CDCI3, 200 MHz): δ = 0.84-0.88 (m, 20H), 0.95-0.99(d, 6H, ), 1.41 (m, 14H), 2.67 (s, 3H), 3.43 (t, 2H, J = 8.4 Hz), 4.48 (m, 2H, J = 5.6 Hz), 5.12 (brs, 1 H).
Figure imgf000100_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid (2,2-dimethyl-propyl-amide (58). MS (ES): m/z 407.86 [MH+]. 1H NMR (CDCI3, 200 MHz): δ = 0.84-0.93 (m, 14H), 0.96 (s, 9H), 2.72 (s, 3H), 3.24 (s, 2H), 3.42 (m, 2H, J = 6.2 Hz), 5.12 (brs, 1 H), 5.76 (brs, 1 H).
Figure imgf000100_0002
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid dibutylamide (36). The same method as for the preparation of 5-methyl-2- heptyloxy-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 20 mg of a solid after column chromatography (7:3; hexanes: EtOAc) (40% from tert-butyl ester): H NMR (CDCI3) δ 0.88 (m, 9H), 1.18-1.40 (m, 14H), 1.45-1.68 (m, 6H), 2.37 (s, 3H), 3.30-3.46 (m, 6H), 5.19 (br s, 1 H); MS (El): cal'd 449.66, exp 449.95 (MH+).
Figure imgf000100_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid (pyridin-3-ylmethyl)amide (35). The same method as for the preparation of 5- methyl-2-heptyloxy-4-oxo-4 --thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 46 mg of a solid (36.6% from tert-butyl ester) after tritration: 1H NMR (CDCI3) δ 0.87 (m, 3H), 1.42-1.20 (m, 10H), 1.68-1.45 (m, 2H), 2.72 (s, 3H), 3.41 (dt, 4H, J = 6.7, 6.6 Hz), 4.62 (d, 2H, J = 6.0Hz), 5.15 (m, 1 H), 6.07 (m, 1 H), 7.38-7.20 (m, 1 H), 7.70 (d, 1 H, J = 8.6Hz), 8.65-8.52 (m, 2H); MS (El): cal'd 428.56, exp 428.88 (MH+).
Figure imgf000101_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylιc acid (pyridin-2-ylmethyl)amide (34). The same method as for the preparation of 5- methyl-2-heptyloxy-4-oxo-4 --thieno[2,3- /][1 ,3]oxazine-6-carboxylic acid heptyl ester was employed. Thus, cyclization afforded 46 mg of a solid (36.6% from tert-butyl ester) after tritration: 1H NMR (CDCI3) δ 0.87 (m, 3H), 1.45-1.20 (m, 10H), 1.80-1.50 (m, 2H), 2.79 (s, 3H), 3.41 (dt, 4H, J = 6.7, 6.6 Hz), 4.72 (d, 2H, J = 4.4Hz), 5.25 (m, 1H), 7.45-7.18 (m, 2H), 7.69 (t, 1 H, J = 7.6Hz), 8.55 (d, 1H, J = 4.6 Hz); MS (El): cal'd 428.56, exp 428.88 (MH+).
Figure imgf000101_0002
6-(4-BenzyI-piperidine-1-carbonyl)-5-methyl-2-octylamino-thieno[2,3- d][1 ,3]oxazin-4-one (43)
Η NMR (CDCI3) 200MHz) δ 0.88 (brs, 3H), 1.27 (brs, 1 1 H), 1.54-1.70 (m, 6H), 2.40 (s, 3H), 2.57 (d, 2H, J = 7.0Hz), 2.86 (m, 2H), 3.40 (dt, 2H, J = 6.4Hz, J = 6.4Hz), 4.20 (brs, 2H), 5.09 (s, 1 H), 7.1 1-7.35 (m, 5H); MS (ES) 496.69 (M+1 ).
Figure imgf000102_0001
5-Methyl-2-octylamin acid 1- butyl-pentyl ester (39): (73%). lH NMR (CDCI3, 200MHz) δ 0.89 (s, 9H), 1.31 (s, 18H), 1161 (m, 6H), 2.78 (s, 3H), 3.42 (dt, 2H, J = 6.2Hz, J = 6.6Hz), 5.00-5.20 (m, 2H); MS (ES) 465.67 (M+1)
Figure imgf000102_0002
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid (1- butyl-pentyl)-amide (45): (28%). Η NMR (CDCI3, 200MHz) δ 0.87 (m, 9H), 1.29 (m, 18H), 1.56 (s, 2H), 2.65 (s, 3H), 3.40 (dt, 2H, J = 6.6Hz, J = 6.6Hz), 4.02 (brs, 1 H), 5.04 (brs, 1 H), 5.40 (d, 1H, J = 8.8Hz); MS (ES) 464.6 (M+1)
Figure imgf000102_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid (3- phenoxy-propyl)-amide (44): (22%). 'H NMR (CDCI3, 200MHz) δ 0.88 (m, 3H), 1.27 (m, 10H), 1.55 (m, 2H), 2.07 (m, 2H), 2.62 (s, 3H), 3.40 (dt, 2H, J = 5.6Hz, J = 7.2Hz), 3.65 (dt, 2H, J = 5.6Hz, J = 6.4Hz), 4.12 (t, 2H, J = 5.6Hz), 5.05 (brs, 1 H), 6.30 (brs, 1 H), 6.95 (m, 3H), 7.25 (m, 2H); MS (ES) 471.81 (M+1)
Figure imgf000103_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid cyclohexylamide (38): (21 %). 'H NMR (CDCI3, 400MHz) δ 0.87 (s, 3H), 1.26 (m, 16H), 1.56 (m, 6H), 2.60 (s, 3H), 3.40 (dt, 2H, J = 6.6Hz, J = 6.2Hz), 3.88 (m, 1H), 5.07 (brs, 1 H), 5.57 (d, 1 H, J = 7.2Hz); MS (ES) 420.12 (M+1)
Figure imgf000103_0002
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid dioctylamide (41): (61%). Η NMR (CDCI3, 400MHz) δ 0.87 (m, 9H), 1.25 (brs, 30H), 1.58 (m, 6H), 2.38 (s, 3H), 3.39 (m, 6H), 5.12 (brs, 1 H); MS (ES) 562.15 (M+1)
Figure imgf000103_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid dihexylamide (42): (56%). 'H NMR (CDCI3, 400MHz) δ 0.87 (m, 9H), 1.27 (brs, 22H), 1.56 (m, 6H), 2.38 (s, 3H), 3.40 (m, 6H), 5.05 (brs, 1 H); MS (ES) 506.03 (M+1).
Figure imgf000104_0001
6-(4-Benzyl-piperazine-1-carbonyl)-5-methyl-2-octylamino-thieno[2,3- d][1,3]oxazin-4-one (40): (67%). 1H NMR (CD3CI, 200MHz) δ 0.87 (t, 3H, J = 5Hz), 1.27 (brs, 10H), 1.58 (brs, 2H), 2.40 (s, 3H), 2.46 (t, 4H, J = 4.8Hz), 3.39 (dt, 2H, J = 6.6Hz, J = 6.6Hz), 3.52 (s, 2H), 3.62 (brs, 4H), 5.19 (brs, 1 H), 7.30 (s, 5H); MS (ES) 497.1 1 (M+1)
Figure imgf000104_0002
5-MethyI-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid methylamide (31): (70%, off-white solid). Η NMR (CDCI3, 200MHz) δ 0.88 (m, 3H), 1.25-1.4 (m), 1.59-1.65 (m), 2.71 (s, 3H), 2.99 (d, 3H (J=5.2)), 3.41 (q, 2H, J=7 Hz), 5.32 (bs, 1 H), 5.76 (bs, 1 H). MS (ES+) 351.93 (M+1), 352.99 (M+2).
Figure imgf000105_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1 ,3]oxazine-6-carboxylic acid ethylamide (33): (off-white solid). Η NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J=6.5 Hz), 1.21 -1.31 (m, 13H), 1.59-1.65 (m, 2H), 2.71 (s, 3H), 3.36-3.53 (m, 4H), 5.27 (bs, 1 H), 5.72 (bs, 1 H). MS (ES+) 365.95 (M+1 ), 367.01 (M+2).
Figure imgf000105_0002
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid butylamide (32): (off-white solid). Η NMR (CDCI3, 200MHz) δ 0.85-1.00 (m, 6H), 1.28-1.50 (m, 12H), 1.53-1.63 (m, 4H), 2.70 (s, 3H), 3.41-3.43 (m, 4H), 5.53 (bs, 1 H), 5.78 (bs, 1 H). MS (ES+) 393.98 (M+1), 395.05(M+2).
Figure imgf000105_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid hexylamide (27): (off-white solid). 'H NMR (CDCI3, 200MHz) δ 0.88-0.89 (m, 6H), 1.27-1.32 (m, 16H), 1.61 (bs, 4H), 2.70 (s, 3H), 3.41 (2xdt, 4H), 5.44 (bs, 1 H), 5.76 (bs, 1 H). MS (ES+) 422.05 (M+1), 423.13 (M+2).
Figure imgf000106_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid decylamide (28): (off-white solid). 'H NMR (CDCI3, 200MHz) δ 0.85-0.88 (m, 6H), 1.26-1.31 (m, 24H), 1.61 (bs, 4H), 2.70 (s, 3H), 3.41 (2xdt, 4H), 5.27 (bs, 1 H), 5.73 (bs, 1 H). MS (ES+) 478.08 (M+1 ), 479.10 (M+2).
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid dodecylamide (29): (off-white solid). lH NMR (CDCI3, 200MHz) δ 0.85-0.91 (m, 6H), 1.26-1.31 (m, 24H), 1.61 (bs, 4H), 2.70 (s, 3H), 3.41 (2xdt, 4H), 5.30 (bs, 1 H), 5.73 (bs, 1 H). MS (ES+) 506.14 (M+1), 507.14 (M+2).
Figure imgf000106_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid hexadecylamide (30): (off-white solid). 'H NMR (CDCI3, 200MHz) δ 0.84-0.91 (m, 6H), 1.26-1.32 (m, 34H), 1.61 (bs, 4H), 2.70 (s, 3H), 3.41 (2xdt, 4H), 5.21 (bs, 1H), 5.72 (bs, 1 H). MS (ES+) 562.19 (M+1), 563.22 (M+2).
Figure imgf000107_0001
6-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-5-methyl-2- octylamino-thieno(2,3-d)(1,3)oxazin-4-one (65): 'H NMR (CDCI3, 200MHz) δ 0.88 (brs, 3H), 1.28-1.45 (m, 10H), 1.62 (m, 2H), 2.43 (s, 3H), 2.85 (t, 2H, J = 5.6Hz), 3.41 (dt, 2H, J = 6.6Hz, J = 6.6Hz), 3.84 (m, 8H), 4.69 (s, 2H), 5.20 (brs, 1 H), 6.56 (s, 1 H), 6.63 (s,1 H).
Figure imgf000107_0002
5-Methyl-2-octylamino-4-oxo-4H-thieno(2,3-d)(1 ,3)oxazine-6-carboxylic acid (2- (3,4-dimethoxy-phenyl)-methyl)-amide (66): 'H NMR (CDCI3, 200MHz) δ 0.88 (brs, 3H), 1.28-1.43 (m, 10H), 1.59 (m, 2H), 2.71 (s, 3H), 3.41 (dt, 2H, J = 6.6Hz, J = 6.6Hz), 3.88 (s, 6H), 4.55 (d, 2H, J = 5.4Hz), 5.10 (brs, 1 H), 5.96 (brs, 1H), 6.88 (m, 3H).
Figure imgf000107_0003
N-Isopropyl-2-(4-(5-methyl-2-octylamino-4-oxo-4H-thieno(2,3-d)(1,3)oxazine-6- carbonyl)-piperazin-1-yl)-acetamide (64): 'H NMR (CDCI3, 200MHz) δ 0.88 (m, 3H), 1.28-1.45 (tn, 16H), 1.60 (m, 2H), 2.41 (s, 3H), 2.54 (m, 4H), 3.25 (s, 2H), 3.40 (dt, 2H, J = 6.6Hz, J = 6.6Hz), 3.59 (m, 4H), 4.61 (m, 1 H), 5.08 (brs, 1 H).
Figure imgf000108_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno(2,3-d)(1,3)oxazine-6-carboxylic acid (2- benzo(1,3)dioxol-5-yl-methyl)-amide (69): 'H NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 7.0Hz), 1.27-1.45 (m, 10H), 1.60 (m, 2H), 2.71 (s, 3H), 3.44 (dt, 2H, J = 6.4Hz, J = 6.4Hz), 4.51 (d, 2H, J = 5.6Hz), 5.08 (brs, 1 H), 5.96 (s, 3H), 6.79 (m, 3H).
Figure imgf000108_0002
5-Methyl-2-octylamino-4-oxo-4H-thieno(2,3-d)(1 ,3)oxazine-6-carboxylic acid (2- phenoxy-ethyl)-amide (70): Η NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 7.0Hz), 1.27-1.42 (m, 10H), 1.60 (m, 2H), 2.72 (s, 3H), 3.41 (dt, 2H, J = 6.6Hz, J = 6.6Hz), 3.84 (dt, 2H, J = 5.0Hz, J = 5.2Hz), 4.15 (t, 2H, J = 5.0Hz), 5.08 (brs, 1 H), 6.25 (brs, 1 H), 6.93 (m, 3H), 7.30 (m, 2H).
Figure imgf000108_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno(2,3-d)(1 ,3)oxazine-6-carboxylic acid (2- methoxy-ethyl)-amide (72): Η NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.8Hz), 1.28-1.45 (m, 10H), 1.61 (m, 2H), 2.71 (s, 3H), 3.93 (m, 5H), 3.58 (m, 4H), 5.08 (brs, 1 H), 6.15 (brs, 1 H).
Figure imgf000109_0001
5-Methyl-2-octylamino-4-oxo-4H-thieno(2,3-d)(1 ,3)oxazine-6-carboxylic acid (3- methoxy-propyl)-amide (73): 'H NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.8Hz), 1.28-1.44 (m, 10H), 1.61 (m, 2H), 1.87 (tt, 2H, J = 5.8Hz, J = 6.0Hz), 2.70 (s, 3H), 3.40 (m, 5H), 3.57 (m, 4H), 5.09 (brs, 1 H), 6.77 (brs, 1 H).
Figure imgf000109_0002
5-Methyl-2-octylamino-4-oxo-4H-thieno(2,3-d)(1 ,3)oxazine-6-carboxylic acid (4- phenyl-butyl)-amide (79): "H NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.6Hz), 1.28-1.45 (m, 10H), 1.66 (m, 6H), 2.69 (m, 5H), 3.43 (m, 4H), 5.07 (brs, 1 H), 5.68 (brs, 1 H), 7.20 (m, 5H).
Figure imgf000109_0003
5-Methyl-2-octylamino-4-oxo-4H-thieno(2,3-d)(1,3)oxazine-6-carboxylic acid (3- phenyl-propyl)-amide (80): lH NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.6Hz), 1.27-1.44 (m, 10H), 1.58 (m, 2H), 1.96 (tt, 2H, J = 7.0Hz, J = 7.4Hz), 2.72 (m, 5H), 3.43 (m, 4H), 5.71 (brs, 1 H), 7.22 (m, 5H).
Figure imgf000110_0001
5-Methyl-2-(1-methylheptyloxy)-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid benzyl ester (89)
Light yellow oil in 22% yield.
Η NMR (CDCI3, 200MHz): δ 7.31-7.50 (m, 5H), 5.34 (s, 2H), 5.18 (tq, 1 H, J = 6.2, 6.2Hz), 2.82 (s, 3H), 1.58-1.83(m, 2H), 1.40(d, 3H, J = 6.2Hz), 1.10-1.34 (m, 8H), 0.88 (t, 3H, J= 6.6Hz).
Figure imgf000110_0002
5-Methyl-2-(1-methylheptylamino)-4-oxo-4H-thieno[2,3-c.][1,3]oxazine-6- carboxylic acid benzyl ester (71)
Light yellow oil in 40% yield.
Η NMR (CDCI3, 200MHz): δ 7.31-7.43 (m, 5H), 5.32 (s, 2H), 5.13 (d, 1 H, J = 6.2Hz), 4.00 (m, 1 H), 2.79 (s, 3H), 1.42-1.62(m, 2H), 1.10-1.40 (m, 8H), 0.87 (t, 3H, J = 6.6Hz). MS (ES) [M++1 ] 429.10.
Figure imgf000111_0001
2-(1,3-Dioctyl-ureido)-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6-carboxylic acid benzyl ester (13): 'H NMR (CDCI3, 200MHz): δ 9.25 (m, -1 H), 7.31-7.43 (m, 5H), 5.32 (s, 2H), 3.99 (m, 2H), 3.35 (dt, 2H, J = 5.6, 5.6 Hz), 2.83 (s, 3H), 1.70-1.5 (m, 4H), 1.50-1.20 (m, 20H), 0.87 (m, 6H, J = 6.6Hz). MS (ES) [M++1 ] 583.99.
Figure imgf000111_0002
2-(1,3-Diheptyl-ureido)-5-mβthyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-6- carboxylic acid benzyl ester (14): Η NMR (CDCI3, 200MHz): δ 9.25 (m, 1 H), 7.31- 7.43 (m, 5H), 5.32 (s, 2H), 3.99 (m, 2H), 3.35 (dt, 2H, J = 5.6, 5.6 Hz), 2.83 (s, 3H), 1.70-1.5 (m, 4H), 1.50-1.20 (m, 16H), 0.87 (m, 6H, J = 6.6Hz). MS (ES) [M++1] 555.97.
Figure imgf000112_0001
5-Methyl-3-octyl-1H-thieno[2s3-d]pyrimidine-2,4-dione-6-carboxylic acid octylamide (47): Compound 18 (100 mg, 0.22 mmol) was dissolved in 1.8 mL absolute ethanol. Sodium ethoxide (21% by wt in ethanol, 1.1 mL, 2.9 mmol) was added and the solution was refluxed for 1 h. Once cooled to room temperature, the solution was poured into 10 mL of a 1N HCl solution. The resultant precipitate was filtered to provide 47 (116 mg) as an off-white solid (100% yield). 'H NMR (CDCI3, 200MHz) δ 0.87 (m, 6H), 1.27-1.32 (m, 20H), 1.54-1.70 (m, 4H), 2.78 (s, 3H), 3.44 (dt, 2H, J = 7.0, 6.2 Hz), 3.97 (t, 2H, J = 7.7 Hz), 5.86 (t, 1 H, J = 5.4 Hz), 10.39 (s, 1 H).
Example 16: Procedure for reduction of carboxylic acid: 5-Hydroxymethyl-4- methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester (2) 3-
Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester (1.0g, 2.40 mmol) was dissolved in 25 mL of CH2CI2 and 0.25 mL of DMF. Thionyl chloride added as a 2M solution in CH2CI2 (1.2 mL, 2.4 mmol) and the reaction was stirred for
2h. The reaction was rotovaped to a white solid, which was dissolved in 20 mL of dioxane. Sodium borohydride (910 mg, 24.0 mmol) added and the reaction stirred for 2h. The reaction was poured into 100 mL of H2O and extracted with EtOAc. The organic layer was washed with 1N HCl (aq), H2O, dried with MgSO4, and the solvent rotovaped off. The residue was recrystalized from EtOAc/Hexanes to give 600 mg of the title compound.: (62%). XH NMR (CDCI3, 200MHz) δ 0.87 (m, 3H), 1.26 (brs,
10H), 1.57 (brs, 11 H), 2.30 (s, 3H), 3.28 (dt, 2H, J= 6.2Hz, J = 6.6Hz), 4.64 (s, 2H),
4.74 (t, 2H, J = 5.6Hz), 10.77 (s, 1 H) Scheme 3
Ft. 0H
Figure imgf000113_0001
Example 17: Aldehyde Intermediates
For a general procedure to synthesize non-commercial aldehydes 17.1-17.4 see Yoshisuke, Tsuda et al, Chem. Pharm. Bull. 1991 , 39(1 ), 18-22
Figure imgf000113_0002
4-Phenyl-butyraldehyde (17.1) clear liquid (860 mg, 87% yield) Η NMR (CDCI3, 200MHz) δ 1.99 (tt, 2H, J = 7.8, 7.4Hz), 2.45 (dt, 2H, J= 7.0, 1.2Hz), 2.67 (t, 2H, J = 7.4Hz), 7.26 (m, 5H), 9.76 (t, 1 H, J= 1.4Hz).
Figure imgf000113_0003
5-Phenyl-pentanal (17.2) clear liquid (470 mg, 48% yield) Η NMR (CDCI3, 200MHz) δ 1.67 (m, 4H), 2.45 (dt, 2H, J = 4.8, 1.8Hz), 2.64 (brs, 2H), 7.25 (m, 5H), 9.75 (t, 1 H, J = 1.8Hz).
Figure imgf000114_0001
6-Phenyl-hexanal (17.3) pale yellow oil (2.49 g, 84% yield) 1H NMR (CDCI3, 200MHz) δ 1.20-1.43(m, 4H), 1.44-1.76(m, 4H), 2.41 (dt, 2H, J= 7.0, 7.6 Hz), 2.60(t, 2H, J = 7.2 Hz), 7.06-7.35(m, 5H), 9.75(t, 1 H, J = 1.8 Hz); MS (ES) No ionization and no LC was found
Figure imgf000114_0002
5-Phenyl-heptanal (17.4) pale yellow oil (401 mg, 81 % yield) 1H NMR (CDCI3, 200MHz) δ 1.20-1.50(m, 2H), 1.50-1.80(m, 4H), 2.41 (dt, 2H, J = 7.0, 7.4 Hz), 2.61 (t, 2H, J = 7.4 Hz), 7.00-7.20(m, 5H), 9.75(t, 1 H, 2 Hz), MS (ES) No ionization and no LC was found.
Figure imgf000114_0003
Example 18: Aminothiophenes
Figure imgf000114_0004
2-Amino-5-methyl-thiophene-3-carboxylic acid tert-butyl ester (18.1): 1H NMR
(CDCI3) 5 1.54 (s, 9H), 2.24 (s, 3H), 5.65 (br d, 2H), 7.25 (s, 1 H); MS (El): cal'd 213.70, exp 213.96 (MH+).
Figure imgf000115_0001
2-Amino-5-heptyl-thiophene-3-carboxylic acid tert-butyl ester (18.2) yellow oil (5.808 g, 46% yield): 0.88 (t, 3H, J = 6.4 Hz), 1.24-1.32 (m, 8H), 1.54- .57 (m, 11 H), 2.56 (t, 2H, J = 7.5 Hz), 5.69 (bs, 2H), 6.56 (s, 1 H). MS (ES+) 297.
For a general procedure to synthesize 2-amino-5-alkyl-thiophene-3-carboxylic acid tert-butyl esters from aldehydes, see Tinney, F. J.; et al. J. Med. Chem. 1981 , 24, 878-882.
Figure imgf000115_0002
2-Amino-5-butyl-thiophene-3-carboxylic acid tert-butyl ester (18.3) yellow oil (372 mg, 41% yield): 'H NMR (CDCI3, 200MHz) δ 0.91 (t, 3H, J= 7.1 Hz), 1.26-1.41 (m, 4H), 1.53 (bs, 9H), 2.56 (t, 2H, J = 7.3 Hz), 5.77 (bs, 2H), 6.56 (t, 1 H, J = 1.1 Hz). 13C NMR (CDCI3, 50MHz) δ 13.7, 22.0, 28.4, 29.3, 33.2, 79.7, 107.7, 121.8, 126.3, 160.4, 164.9. MS (ES+) 340.4 (M+1).
Figure imgf000115_0003
2-Amino-5-decyl-thiophene-3-carboxylic acid tert-butyl ester (18.4) yellow oil (1 1.32 g, 79% yield): Η NMR (CDCI3, 400MHz) δ 0 88 (t, 3H, J = 6.8 Hz), 1.26-1.30 (m, 14H), 1.52-1.55 (m, 11 H), 2.56 (t, 2H, J = 7.4 Hz), 5.68 (bs, 2H), 6.56 (s, 1 H).
Figure imgf000116_0001
2-Amino-5-benzyl-thiophene-3-carboxylic acid tert-butyl ester (18.5) yellow oil (520 mg, 51 % yield): Η NMR (CDCI3, 200MHz) δ 1.53 (s, 9H), 3.89 (s, 2H), 5.71 (bs, 2H), 6.66 (t, 1 H, J = 1.1 Hz), 7.16-7.33 (m, 5H). I3C NMR (CDCI3, 50MHz) δ 28.4, 35.9, 79.9, 107.8, 123.4, 124.7, 126.5, 128.4, 128.5, 140.0, 161.3, 164.9. MS (ES+) 289.9 (M+1).
Figure imgf000116_0002
2-Amino-5-(.1 ,3,3-trimethyl-butyl)-thiophene-3-carboxylic acid tert-butyl ester (18.6) yellow oil (846 mg, 79% yield): 'H NMR (CDCI3, 200MHz) δ 0.89 (s, 9H), 1.22 (d, 3H, J= 7.0 Hz), 1.39 (dd, 1 H, J= 13.8, 4.6 Hz), 1.54 (s, 9H), 1.59 (dd, 1 H, J = 14.0, 7.0 Hz), 2.80-2.96 (m, 1 H), 5.67 (bs, 2H), 6.55 (s, 1 H).
Figure imgf000116_0003
2-Amino-5-(5-methoxy-1 ,5-dimethyl-hexyl)-thiophene-3-carboxylic acid fert- butyl ester (18.7) yellow oil (2.328 g, 80% yield): 'H NMR (CDCI3, 200MHz) δ 1.12 (s, 6H), 1.22 (d, 3H, J = 6.8 Hz), 1.22-1.54 (m, 18H), 2.74 (dq, 1 H, J = 7.0, 6.2 Hz), 3.16 (s, 3H), 5.70 (bs, 2H), 6.57 (s, 1 H). MS (ES+) 341.93 (M+1).
Figure imgf000117_0001
2-Amino-5-(1 ,5-dimethyl-hex-4-enyl)-thiophene-3-carboxylic acid tert-butyl ester (18.8) yellow oil (2.02g mg, 77% yield): Η NMR (CDCI3, 200MHz) δ 1.21 (d, 3H, J = 6.6 Hz), 1.51-1.54 (m, 11 H), 1.57 (s, 3H), 1.68 (s, 3H), 1.96 (dt, 2H, J = 7.2, 7.0 Hz), 2.75 (tq, 1 H, J = 7.0, 6.6 Hz), 5.08 (t, 1 H, J = 6.4 Hz), 5.69 (bs, 2H), 6.56 (s, 1 H). MS (ES+) 309.g (M+1).
Figure imgf000117_0002
2-Amino-5-phenethyl-thiophene-3-carboxylic acid tert-butyl ester (18.9) yellow solid (1.5 g, 85% yield) Η NMR (CDCI3, 200MHz) δ 1.53 (s, gH), 2.88 (s, 4H), 5.70 (s, 2H), 6.5g (s, 1 H), 7.26 (m, 5H)
Figure imgf000117_0003
2-Amino-5-(3-phenyl-propyl)-thiophene-3-carboxylic acid tert-butyl ester (18.10) yellow oil (440 mg, 48% yield) Η NMR (CDCI3, 200MHz) δ 1.54 (s, gH), 1.90 (tt, 2H, J = 7.8, 7.2Hz), 2.62 (m, 4H), 5.70 (s, 2H), 6.58 (s, 1 H), 7.26 (m, 5H)
Figure imgf000117_0004
2-Amino-5-(4-phenyl-butyl)-thiophene-3-carboxylic acid tert-butyl ester (18.11) yellow oil (1.22 g, 67% yield) Η NMR (CDCI3, 200MHz) δ 0.88 (bt, 2H, J = 6.6 Hz), 1.16-1.31 (m, 2H), 1.54 (s, 9H), 1.57-1.74 (m, 2H), 2.52-2.70 (m, 2H), 5.6g(bs, 2H), 6.56 (t, 1 H, J = 1.2 Hz), 7.11-7.22 (m, 3H), 7.22-7.34 (m, 2H); MS (ES) No Ionization (M+1), tR(method D) = g.l l min.
Figure imgf000118_0001
2-Amino-5-(5-phenyl-pentyl)-thiophene-3-carboxylic acid tert-butyl ester (18.12) yellow oil (638 mg, 36% yield) 1H NMR (CDCI3, 200MHz) δ 1.21-1.50 (m, 2H), 1.50- 1.76 (m, 14H), 2.44-2.72 (m, 4H), 5.6g(bs, 2H), 6.56 (t, 1 H, J = 1.2 Hz), 7.07-7.37 (m, 5H); MS (ES) No Ionization (M+1), -^method D)= No LC trace observed
Figure imgf000118_0002
2-Amino-5-butyl-thiophene-3-carboxylic acid tert-butyl ester (18.13): 1H NMR
(CDCI3, 200 MHz): δ = O.gi (t, J = 7.1 Hz, 3H), 1.10-1.80 (m, 13H), 2.56 (td, J = 0.8, 7.4 Hz, 2H), 5.68 (brs, 2H), 6.56 (t, J = 1.1 Hz, 1 H).
Figure imgf000118_0003
2-Amino-5-isopropyl-thiophene-3-carboxylic acid tert-butyl ester (18.14): 1H
NMR (CDCI3- 200 MHz): δ = 1.23 (dd, J = 2.2, 6.8 Hz, 6H), 1.54 (s, gH), 2.78-3.02 (m, 1 H), 5.68 (brs, 2H), 6.57 (d, J = 1.2 Hz, 1 H).
Figure imgf000118_0004
2-Amino-5-octyl-thiophene-3-carboxylic acid tert-butyl ester (18.15): 1H NMR
(CDCI3, 200 MHz): δ = 0.88 (t, J = 6.6 Hz, 3H), 1.14-1.43 (m, 10H), 1.44-1.68 (m, 11 H), 2.56 (t, J = 7.1 Hz, 2H), 5.67 (brs, 2H), 6.56 (s, 1 H).
Figure imgf000119_0001
2-Amino-5-dodecyl-thiophene-3-carboxylic acid tert-butyl ester (18.16): 1H
NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.6 Hz, 3H), 1.16-1.42 (m, 18H), 1.46-1.68 (m, 11 H), 2.55 (t, J = 7.5 Hz, 2H), 5.68 (brs, 2H), 6.55 (t, J = 1.2 Hz, 1 H).
Figure imgf000119_0002
2-Amino-5-heptyl-4-methyl-thiophene-3-carboxylic acid tert-butyl ester (18.17):
9.561 g (61 %). 1H NMR (CDCI3, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 3H), 1.16-1.40 (m, 10H, 1.55 (s, 9H), 2.12 (s, 3H), 2.41 (t, J = 7.4 Hz, 2H).
Figure imgf000119_0003
2-Amino-5-octyl-4-methyl-thiophene-3-carboxylic acid tert-butyl ester (18.18):
10.202 g (63%). 1H NMR (CDCI3, 200 MHz): δ 0.87 (t, J = 6.8 Hz, 3H), 1.20-1.38 (m, 12 H), 1.55 (s, 9H), 2.12 (s, 3H), 2.41 (t, J = 7.2 Hz, 2H).
Figure imgf000119_0004
2-Amino-6-benzylthiophene-3-carboxylic acid f-butyl ester (18.19)
Light yellow oil in 62% yield.
'H NMR (CDC , 200MHz): δ 7.18-7.38 (m, 5H), 6.66 (t, 1 H, J = 1 .0Hz), 5.70 (brs,
2H), 3.90 (s, 2H), 1.54(s, 9H).
Figure imgf000120_0001
2-Amino-6-decylthiophene-3-carboxylic acid f-butyl ester (18.20)
Dark brownish oil in 74% yield.
'H NMR (CDCI3, 200MHz): δ 6.56 (t, 1 H, J = 1.2Hz), 5.68 (brs, 2H), 2.56 (dt, 2H, J -. 7.6, 1.2Hz), 1.54(s, 9H), 1.20-1.40 (m, 8H), 0.89 (t, 3H, J= 7.6Hz).
Figure imgf000120_0002
2-Amino-6-hexylthiophene-3-carboxylic acid f-butyl ester (18.21)
Dark brownish oil in 9g% yield. Η NMR (CDCI3, 200MHz): δ 6.56 (t, 1 H, J = 1.2Hz), 5.68 (brs, 2H), 2.55 (dt, 2H, J = 8.0, 1.2Hz), 1.54(s, gH), 1.20-1.40 (m, 16H0, 0.88 (t, 3H, J= 7.0Hz).
Example 19: Carbamate/Urea Intermediates
Figure imgf000120_0003
5-Heptyl-4-methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert- butyl ester (19.1): 1H NMR (CDCI3) δ 0.83-0.92 (m, 6H), 1.20-1.40 (m, 18H), 1.50- 1.60 (m, 1 1 H), 1.64-1.72 (m, 2H), 2.20 (s, 3H), 2.62 (t, 2H, J = 7.6 Hz), 4.1 (t, 2H, J = 7.2 Hz); MS (El): cal'd 467.72, exp, did not ionize.
Figure imgf000121_0001
5-Methyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester (19.2):
1H NMR (CDCI3) δ θ.87 (t, 3H, J = 7.2 Hz), 1.20-1.42 (m, 10H), 1.45-1.68 (m, 11 H), 2.32 (s, 3H), 3.27 (dt, 2H, J = 7.2, 7.2 Hz), 4.7g (m, 1 H), 6.70 (s, 1H), 10.2 (br s, 1 H); MS (El): cal'd 368.5, exp 368.87 (MH+).
Figure imgf000121_0002
5-Methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (19.3): 1H NMR (CDCI3) δ θ.88 (t, 3H, J = 7.2 Hz), 1.20-1.42 (m, 10H), 1.55 (s, 9H), 1.62-1.72 (m, 2H), 2.34 (s, 3H), 4.19 (t, 2H, J = 6.8 Hz), 6.74 (s, 1 H), 10.12 (br s, 1H); MS (El): cal'd 369.5, exp,. did not ionize.
Figure imgf000121_0003
General Procedure for urea formation (19.4-19.6):
5-Heptyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester (19.4)
Amino-thiophene 18.2 (200 mg, 0.67 mmol) was dissolved in 3 mL CH2CI2 and cooled to 0 9C. Under N2 atmosphere, DBU (0.25 mL, 1.68 mmol) was added slowly followed by octyl isocyanate (104mg, 0.67mmol). The reaction slowly warmed to rt and was stirred at room temperature for 5h. The reaction was then diluted with 20 mL CH2CI2 and washed with 1 N HCl and brine. The organic solution was then dried with MgSO and concentrated in vacuo. The crude mixture purified by silica gel chromatography (15:1 hexanes: ethyl acetate) to yield 19.4, 73 mg (24% yield) of an off-white solid: Η NMR (CDCI3, 200MHz) δ 0.88 (t, 6H, J = 6.4 Hz), 1.27-1.29 (m, 18H), 1.54-1.58 (m, 13H), 2.64 (t, 2H, J = 7.5 Hz), 3.26 (dt, 2H, J = 7.0, 5.8 Hz), 4.85 (t, 1H, J= 5.7 Hz), 6.69 (s, 1 H), 10.25 (s, 1 H). MS (ES+) 453.1 (M+1).
Figure imgf000122_0001
5-Butyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid tert-butyl ester (19.5) off- white solid (353 mg, 59% yield): Η NMR (CDCI3, 200MHz) δ 0.87 (t, 3H, J = 7.1 Hz), 0.90 (t, 3H, J = 7.1 Hz), 1.25-1.41 (m, 12H), 1.53-1.64 (m, 13H), 2.64 (t, 2H, J = 7.5 Hz), 3.27 (dt, 2H, J = 7.0, 6.2 Hz), 5.29 (t, 1 H, J = 5.7 Hz), 6.69 (s, 1H), 10.27 (bs, 1 H). 13C NMR (CDCI3, 50MHz) δ 1.3.7, 14.0, 22.1 , 22.6, 26.8, 28.3, 29.1 , 29.2, 2g.3, 30.0, 31.7, 33.4, 40.8, 80.7, 110.7, 1 i .8, 133.0, 14g.g, 153.7, 165.6.
Figure imgf000122_0002
5-Benzyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid fert-butyl ester (19.6) pale yellow solid (3 4 mg, 49% yield): Η NMR (CDCI3, 200MHz) δ 0.87 (t, 3H, J = 6.4 Hz), 1.27 (bs, 10H), 1.54 (s, 11 H), 3.25 (dt, 2H, J = 7.0, 5.8 Hz), 3.97 (s, 2H), 4.88 (t, 1 H, J = 5.6 Hz), 6.48 (t, 1 H, J = 1.0 Hz), 7.16-7.32 (m, 5H), 10.26 (bs, 1 H).
Figure imgf000122_0003
General procedure for amide and carbamate formation (19.7-19.17): 2-Dodecanoylamino-5-heptyl-thiophene-3-carboxylic acid fert-butyl ester (19.7)
Aminc-thiophene 18.2 (171 mg, 0.57 mmol) was dissolved in 3 mL CH2CI2 and 2 mL pyridine. Under N2 atmosphere, lauroyl chloride (126mg, 0.57mmol) was added and the reaction was stirred at room temperature for 6h. The reaction was then diluted with 10 mL CH2CI2 and washed with water, 5% citric acid, and brine. The organic solution was then dried with MgS04 and concentrated in vacuo. The crude mixture purified by silica gel chromatography (40:1 hexanes: ethyl acetate) to yield 19.7, 175 mg (63% yield) of a yellow oil: Η NMR (CDCI3, 200MHz) δ 0.87 (t, 6H, J = 6.4 Hz), 1 .25-1.44 (m, 24H), 1.51-1.73 (m, 13H), 2.45 (t, 2H, J = 7.5 Hz), 2.67 (t, 2H, J = 7.5 Hz), 6.77 (s, 1 H), 10.g4 (bs, 1 H). 13C NMR (CDCI3, 50MHz) δ 14.0, 14.1 , 22.5, 22.6, 25.3, 28.3, 28.g, 2g.O, 29.1 , 29.2, 29.3, 29.4, 29.5, 29.6, 31.3, 31.7, 31.9, 36.7, 81.2, 1 13.3, 120.1 , 134.8, 146.3, 165.1 , 169.9.
Figure imgf000123_0001
2-Octyloxycarbonylamino-5-(1 ,3,3-trimethyl-butyl)-thiophene-3-carboxyiic acid tert-butyl ester (19.8) yellow oil (185 mg, 34% yield): Η NMR (CDCI3l 200MHz) δ 0.85-0.91 (m, 12H), 1.26-1.76 (m, 26H), 2.90-3.03 (m, 1 H), 4.20 (t, 2H, J = 6.8 Hz), 6.73 (s, 1 H), 10.15 (bs, 1 H). I3C NMR (CDCI3, 50MHz) δ 14.0, 22.6, 25.8, 26.3, 28.3, 28.8, 29.1 , 29.2, 2g.8, 31.2, 31.8, 32.0, 52.6, 66.3, 81.2, 1 12.3, 118.9, 142.1 , 147.7, 153.3, 164.9.
Figure imgf000123_0002
5-(5-Methoxy-1.5-methyl-hexyl)-2-octyloxycarbonylamino-thiophene-3- carboxyiic acid tert-butyl ester (19.9) pale yellow oil: Η NMR (CDCI3. 200MHz) δ 0.89 (t, 3H, J = 6.4 Hz), 1.11 (s, 6H), 1.26-1.48 (m, 19H), 1.50-1.71 (m, 11 H), 2.74 (dq, 1H, J= 7.0, 7.0 Hz), 3.15 (s, 3H), 4.20 (t, 2H, J = 6.6 Hz), 6.74 (s, 1H), 10.17 (s, 1 H). 13C NMR (CDCI3, 50MHz) δ 14.0, 21.5, 22.5, 22.6, 24.9, 25.7, 28.2, 28.7, 29.1 , 31.7, 35.1 , 3g.3, 3g.5, 48.9, 60.2, 66.2, 74.3, 81..1 , 112.2, 1 19.3, 139.7, 147.9, 153.1 , 164.8.
Figure imgf000124_0001
5-(1 ,5-Dimethyl-hex-4-enyl)-2-octyloxycarbonylamino-thiophene-3-carboxylic acid fert-butyl ester (19.10) brown oil (630 mg, 90% yield): Η NMR (CDCI3, 200MHz) δ 0.89 (t, 3H, J = 6.6 Hz), 1.26-1.42 (m, 13H), 1.55-1.73 (m, 19H), 1.g6 (dt, 2H, J = 7.8, 7.2 Hz), 2.86 (tq, 1 H, J = 7.2, 6.6 Hz), 4.20 (t, 3H, J = 6.6 Hz), 5.08 (t, 1 H, J= 7.2 Hz), 6.74 (s, 1 H), 10.16 (bs, 1 H).
Figure imgf000124_0002
2-Octyloxycarbonylamino-5-phenethyl-thiophene-3-carboxylic acid fert-butyl ester (19.11) white solid (740 mg, 98% yield) Η NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.6Hz), 1.28 (brs, 10H), 1.56 (s, 9H), 1.68 (m, 2H), 2.gβ (s, 4H), 4.20 (t, 2H, J = 6.6Hz), 6.75 (s, 1H), 7.26 (m, 5H), 10.15 (s, 1 H)
Figure imgf000124_0003
2- ctyloxycarbonylamino-5-(3-phenyl-propyi)-thiophene-3-carbϋXyιie acid iert- butyl ester (19.12) yellow oil (270 mg, go% yield) "H NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.6Hz), 1.28 (brs, 10H), 1.64 (brs, 11 H), 1.97 (tt, 2H, J = 7.8, 7.2Hz), 2.69 (m, 4H), 4.20 (t, 2H, J = 6.6 Hz), 6.76 (s, 1 H), 7.26 (m, 5H), 10.15 (s, 1 H)
Figure imgf000125_0001
2-Octyloxycarbonylamino-5-(4-phenyl-butyl)-thiophene-3-carboxylic acid fert- butyl ester (19.13) clear colorless oil (401 mg, 88% yield) 1H NMR (CDCI3, 200MHz) δ 0.88 (bt, 3H, J = 6.2 Hz), 1.15-1.42 (m, 11H), 1.56 (s, 9H), 1.61-1.80 (m, 6H), 2.52-2.80 (m, 4H), 4.20 (t, 2H, J = 6.6 Hz), 6.74 (s, 1 H), 7.09-7.35 (m, 5H), 10.15 (s, 1H); MS (ES) no ionization or LC was observed.
Figure imgf000125_0002
2-Octyloxycarbonylamino-5-(5-phenyl-pentyl)-thiophene-3-carboxylic acid fert- butyl ester (19.14) clear/colorless oil (331 mg, 75% yield) 1H NMR (CDCI3, 200MHz), δ 0.88 (bt, 3H, J = 6.2 Hz), 1.20-1.50 (m, 14H), 1.50-1.75 (m, 15H), 2.50- 2.75 (m, 4H), 4.19 (t, 2H, J = 7.0 Hz), 6.74 (t, 1 H, J = 1.0 Hz), 7.08-7.36 (m, 5H); MS (ES) No LC trace and no ionization came out.
Figure imgf000125_0003
5-Decyl-2-(2-methoxy-ethoxycarbonylamino)-thiophene-3-carboxylic acid fert- butyl ester (19.15) pale yellow oil (307 mg, 76% yield) 1H NMR (CDCI3, 200MHz) δ 0.88 (bt, 3H, J = 6.2 Hz), 1.16-1.43 (m, 14H), 1.55 (s, 9H), 1.57-1.73 (m, 2H), 2.66 (t, 2H, J = 7.8 Hz), 3.41 (s, 3H), 3.58-3.70 (m, 2H), 4.25-4.44 (m, 2H), 6.74 (s, 1 H), 10.27 (bs, 1 H); MS (ES) 442.64 (M+1), - ^method D) = 12.91 min.
Figure imgf000126_0001
2-(4-Butyl-phenoxycarbonylamino)-5-decyl-thiophene-3-carboxylic acid fert- butyl ester (19.16) Amino thiophene 18.4 ( 300 mg, 0.92 mmol) was dissolved in anhydrous THF (4 mL). Under a nitrogen atmosphere was added 4-nitrophenyl chloroformate (184 mg, 0.92 mmol) and was stirred overnight at room temperature. Without any isolation of the 4-nitrophenyl carbamate intermediate the sodium salt of 4-butyl phenol (200 mg, 1.26 mmol) was dropwise added to the solution of the intermediate and was stirred at room temperature for 2 hours followed by heating to 40 gC for an additional hour. The sodium salt of the phenol was prepared by dissolving 4-butyl phenol (174 mg, 1.16 mmol) in anhydrous THF (3 mL) and cooling to 0 QC. Then NaH(60% dispersion in mineral oil) (45 mg, 1.16 mmol) was added to reaction mixture and stirred at 0 -C for V2 hour and was used as stated above. The reaction mixture was partitioned between CHCI3 and H20 and separated. The H20 layer was extracted again with CHCI3 (3x) and separated. The combined CHCI3 layers was washed with 2M NaOH (1x), 1 M HCl (1x), brine (1x) and dried with Na2SO4 filtered and concentrated resulting in 490 mg of a dark orange oil. The crude material was further purified by flash silica chromatography (2% EtOAc in Hexanes) which resulted in 241 mg of a yellow oil (50% yield). 1H NMR (CDCI3, 200MHz) δ 0.83-0.93 (m, 6H), 1.19-1.45 (m, 18H), 1.47-1.72 (m, 14H), 2.55-2.75 (m, 4H), 6.80 (s, 1 H), 7.11 (d, 2H, J = 8.8 Hz), 7.19 (d, 2H, J = 8.8 Hz), 10.58 (s, 1 H).
Figure imgf000127_0001
5-Decyl-2-(4-phenyl-butoxycarbonylamino)-thiophene-3-carboxylic acid tert- butyl ester (19.17) pale yellow oil (241 mg, 89% yield) 1H NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.26-1.38 (m, 14H), 1.56-1.70 (m, 11 H), 1.9g (tt, 2H, J = 12.6, 6.2 Hz), 2.66 (t, 2H, J = 7.5 Hz), 3.58 (t, 2H, J = 6.2 Hz), 4.34 (t, 2H, J = 6.2 Hz), 4.50 (s, 2H), 6.75 (s, 1 H), 7.24-7.34 (m, 5H), 10.16 (s, 1 H). 13C NMR (CDCI3, 50MHz) δ 14.04, 22.60, 28.26, 28.g7, 2g.ig, 2g.23, 2g.27, 2g.45, 2g.48, 2g.51 , 31.25, 31.82, 63.35, 66.35, 72.gβ, 81.Og, 1 12.53, 120.60, 127.48, 127.53, 128.28, 133.87, 138.21 , 147.g7, 152.g7, 164.77.
Example 20: Tert-butyl Ester Intermediates
Figure imgf000127_0002
5-Butyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.1): 1H NMR (CDCI3, 200 MHz): δ = 0.80-1.00 (m, 6H), 1.18-1.49 (m, 12H), 1.50-1.79 (m, 13H), 2.67 (t, J = 7.3 Hz, 2H), 4.19 (t, J = 6.6 Hz, 2H), 6.74 (t, J = O.g Hz, 1 H), 10.14 (brs, 1 H).
Figure imgf000127_0003
5-lsopropyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.2): 1H NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.6 Hz, 3H), 1.16-1.46 (m, 16H), 1.50-1.76 (m, 1 1 H), 2.80-3.16 (m, 1 H), 4.20 (t, J = 6.6 Hz, 2H), 6.75 (d, J = 1.0 Hz, 1 H), 10.15 (brs, 1 H).
Figure imgf000128_0001
5-Octyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.3): H NMR (CDCI3, 200 MHz): δ = 0.7g-0.g8 (m, 6H), 1 .18-1.46 (m, 20H), 1.51-1.78 (m, 13H), 2.66 (td, J = 0.8, 7.5 Hz, 2H), 4.1 g (t, J = 6.6 Hz, 2H), 6.74 (t, J = 1.1 Hz, 1 H), 10.14 (brs, 1 H).
Figure imgf000128_0002
5-Dodecyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.4): 1H NMR (CDCI3, 200 MHz): δ = 0.80-0.g8 (m, 6H), 1.15-1.46 (m, 28H), 1.52-1.78 (m, 13H), 2.66 (t, J = 7.3 Hz, 2H), 4.20 (t, J = 6.8 Hz, 2H), 6.74 (s, 1 H), 10.14 (brs, 1 H).
Figure imgf000128_0003
2-Benzyloxycarbonylamino-5-decyl-thiophene-3-carboxylic acid tert-butyl ester (20.5): 1H NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.18-1.42 (m, 14H), 1.48-1.72 (m, 11 H), 2.66 (t, J = 7.5 Hz, 2H), 5.24 (s, 2H), 6.74 (s, 1 H), 7.31-7.47 (m, 5H), 10.25 (brs, 1 H). General procedure for the preparation of tert-butyl esters 20.6-20.8 from aminothiophene 18.4 and the corresponding commercially available alcohols:
To a solution of 4-butylbenzyl alcohol (0.30 mL, 1.76 mmol) in CH2CI2 (10 mL) was added saturated NaHCO3 (10 mL) and then diphosgene (0.25 mL, 2.07 mmol) dropwise. The mixture was allowed to stir vigorously at ambient temperature for 45 min, and aminothiophene 18.4 (283 mg, 0.83 mmol) was added in one portion. After stirring vigorously for 2 h, the reaction mixture was diluted with Et2O (100 mL), and the organic layer was washed with saturated NaHCO3 (2x20 mL), and brine (40 mL). The organic layer was dried over Na2SO and then filtered. The filtrate was concentrated and the resulting residue was purified by flash column chromatography (40:1 Hexanes/EtOAc) to give tert-butyl ester 20.6 as a light yellow oil (416 mg, 95%).
Figure imgf000129_0001
2-(4-Butylbenzyloxycarbonylamino)-5-decyl-thiophene-3-carboxylic acid tert- butyl ester (20.6): 1H NMR (CDCI3, 200 MHz): δ = 0.82-1.00 (m, 6H), 1.18-1.46 (m, 16H), 1.48-1.72 (m, 13H), 2.54-2.73 (m, 4H), 5.20 (s, 2H), 6.73 (s, 1 H), 7.13- 7.38 (m, 4H), 10.23 (brs, 1 H).
Figure imgf000129_0002
5-Decyl-2-(2-p-tolyl-ethoxycarboπyϊamino)-thioplιeπe-3-carb Λyϊic acid tert- butyl ester (20.7): 1H NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.17- 1.42 (m, 14H), 1.49-1.72 (m, 11 H), 2.32 (s, 3H), 2.66 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 7.1 Hz, 2H), 4.3g (t, J = 7.3 Hz, 2H), 6.74 (s, 1 H), 7.08-7.19 (m, 4H), 10.14 (brs, 1 H).
Figure imgf000130_0001
5-Decyl-2-phenethyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.8): 1H NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.18-1.42 (m, 14H), 1.50-1.72 (m, 1 1 H), 2.66 (t, J = 7.3 Hz, 2H), 3.01 (t, J = 7.5 Hz, 2H), 4.42 (t, J = 7.3 Hz, 2H), 6.74 (s, 1 H), 7.18-7.40 (m, 5H), 10.15 (brs, 1 H).
Figure imgf000130_0002
4-Methyl-5-octyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid fert- butyl ester (20.9): 2.35 g (33%). 1H NMR (CDCI3, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H), 1.30-1.72 (m, 24H), 1.57 (s, 9H), 2.20 (s, 3H), 2.61 (t, J = 7.8 Hz, 2H), 4.18 (t, J = 6.6 Hz, 2H), 10.26 (s, 1 H); 13C NMR (CDCI3, 75 MHz): δ 12.3, 12.9, 20.9, 24.0, 24.1 , 25.4, 26.7, 27.1 , 27.3, 27.4, 27.5, 27.6, 29.6, 30.1, 30.1 , 64.5, 79.7, 1 11.2, 126.2, 127.1 , 146.7, 151.5, 164.0.
Figure imgf000130_0003
2-Butyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid fert-butyl ester (20.10): 693 mg (92%). 1H NMR (CDCI3, 200 MHz): δ 0.83 (t, J = 6.6 Hz, 3H), 0.94 (t, J = 7.0 Hz, 3H), 1.20-1.48 (m, 12H), 1.55 (s, 9H), 1.52-1.75 (m, 4H), 2.65 (t, J = 7.0 Hz, 2H), 4.20 (t, J = 6.6 Hz, 2H), 6.73 (s, 1 H), 10.14 (s 1 H).
Figure imgf000131_0001
2-Hexyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid tert-butyl ester (20.11): 760 mg (98%). H NMR (CDCI3, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 3H), 0.89 (t, J = 6.6 Hz, 3H), 1.18-1.44 (m, 14H), 1.55 (s, 9H), 1.54-1.76 (m, 4H), 2.65 (t, J = 7.0 Hz, 2H), 4.19 (t, J = 6.6 Hz, 2H), 6.73 (s, 1 H), 10.14 (s, 1 H).
Figure imgf000131_0002
2-Dodecyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid fert-butyl ester (20.12): 831 mg (88%). 1H NMR (CDCI3, 200 MHz): o 0.87 (t, J = 6.6 Hz, 6H), 1.051-.50 (m, 28H), 1.55 (s, 9H), 1.50-1.75 (m, 4H), 2.65 (t, J = 7.2 Hz, 2H), 4.19 (t, J = 6.6 Hz, 2H), 6.73 (t, J = 1.2 Hz, 1 H), 10.14 (s, 1 H).
Figure imgf000131_0003
5-Decyl-2-phenyloxycarbonylamino-thiophene-3-carboxylic acid fert-butyl ester (20.13): 696 mg (84%). 1H NMR (CDCIg, 200 MHz): δ 0.88 (t, J = 7.0 Hz, 3H), 1.20-1.36 (m, 14H), 1.52-1.66 (m, 2H), 1.59 (s, 9H), 2.67 (dt, J = 7.4, 1.2 Hz, 2H), 6.78 (t, J = 1.2 Hz, 1 H), 7.14-7.48 (m, 5H), 10.55 (s, 1 H).
Figure imgf000132_0001
2-Decyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid tert-butyl ester (20.14): 863 mg (91%). 1H NMR (CDCI3, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 6H), 1.14- 1.44 (m, 24H), 1.55 (s, 9H), 1.52-1.76 (m, 4H), 2.65 (t, J = 7.2 Hz, 2H), 4.1 g (t, J = 6.6 Hz, 2H), 6.73 (s, 1 H), 10.14 (s, 1 H).
Figure imgf000132_0002
6-Benzyl-2-octyloxycarbonylamino)thiophene-3-carboxylic acid f-butyl ester (20.15)
Light yellow oil in 77% yield.
Η NMR (CDCI3, 200MHz): δ 10.16 (s, 1 H), 7.20-7.40 (m, 5H), 6.82 (s, 1H), 4.17 (t, 2H, J = 6.6Hz), 3.99 (s, 2H), 1.64(q, 2H, J = 6.6Hz), 1.55(s, 9H), 1.10-1.50 (m, 10H), 0.88(t, 3H, J= 6.6Hz).
Figure imgf000132_0003
6-Hexyl-2-(octyloxycarbonylamino)thiophene-3-carboxylic acid f-butyl ester (20.16) light yellow oil in 86% yield. Η NMR (CDCIj, 200MHz): δ 10.14 (brs, 1 H), 6.74 (s, 1 H), 4.19 (t, 2H, J = 6.6Hz), 2.66 (t, 2H, J = 7.6Hz), 1.60-1 .75(m, 2H), 1.56 (s, 9H), 1.10-1.40 (m, 18H), 0.80- 0.95(m, 6H).
Figure imgf000133_0001
6-Decyl-2-(octyloxycarbonylamino)thiophene-3-carboxylic acid f-butyl ester (20.17)
Light yellow oil in g% yield.
'H NMR (CDCI3, 200MHz): δ 10.14 (brs, 1 H), 6.74 (s, 1 H), 4.i g (t, 2H, J = 6.6Hz), 2.66 (t, 2H, J = 8.0Hz), 1.60-1.75(m, 2H), 1.56 (s, OH), 1.08-1.40 (m, 26H), 0.80- 0.g5(m, 6H).
Figure imgf000133_0002
6-Decyl-2-(1-methylheptyloxycarbonylamino)thiophene-3-carboxylic acid f- butyl ester (20.18)
Light yellow oil in gg% yield.
Η NMR (CDCI3, 200MHz): δ 10.10 (brs, 1 H), 6.73 (s, 1 H), 4.82-5.00 (m, 1 H), 2.65 (t,
2H, J = 7.4Hz), 1.50-1.83(m, 15H), 1.08-1.50 (m, 23H), 0.80-1.00(m, 6H).
Figure imgf000133_0003
6-Heptyl-2-(1-methylheptyloxycarbonylamino)thiophene-3-carboxylic acid f- butyl ester (20.19)
Light yellow oil in 78% yield. Η NMR (CDC-3, 200MHz): δ 10.01 (brs, 1 H), 6.73 (s, 1 H), 4.80-5.00 (m, 1 H), 2.65 (t, 2H, J = 7.4Hz), 1.50-1.83(m, 13H), 1.08-1.50 (m, 17H), 0.80-1.00 (m, 6H).
Figure imgf000134_0001
5-Decyl-2-(4-phenylbutoxycarbonylamino)thiophene-3-carboxylic acid f-butyl ester (20.20)
Light brownish oil in 9g% yield.
'H NMR (CDCI3, 400MHz): δ 10.12 (s, 1 H), 7.26-7.31 (m, 2H), 7.19-7.26 (m, 3H), 6.75 (s, 1 H), 4.23 (t, 2H, J = 6.4Hz), 2.73 (t, 2H, J = 7.6Hz), 2.66 (t, 2H, J = 7.2Hz), 1.98- 2.07(m, 2H), 1.59-1.65(m, 2H), 1.52-1.57 (m, 11 H), 1.26-1.30 (m, 12H), 0.88(t, 3H, J = 6.4Hz).
Figure imgf000134_0002
5-Decyl-2-(4-phenylbutoxycarbonylamino)thiophene-3-carboxylic acid f-butyl ester (20.21)
Light brownish oil in 98% yield.
'H NMR (CDCI3, 400MHz): δ 10.1 1 (s, 1 H), 7.26-7.31 (m, 2H), 7.18-7.26 (m, 3H), 6.74 (s, 1 H), 4.26 (brs, 2H), 2.67-2.70 (m, 4H), 1.70-1.80(m, 4H), 1.50-1.70(m, 11 H), 1.18-1.40 (m, 16H), 0.88(t, 3H, J = 6.8Hz).
Example 21: Acid Intermediates
Figure imgf000135_0001
5-Heptyl-4-methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.1):
May contain -10% other isomer; 1H NMR (CDCI3) δ 0.82-0.84 (m, 6H), 1.20-1.46 (m, 18H), 1.50-1.66 (m, 2H), 1.66-1.80 (m, 2H), 2.28 (s, 3H), 2.64 (t, 2H, J = 7.2 Hz), 4.22 (t, 2H, J = 7.0 Hz). There was another peak at 2.70 (t, J = 7.0 Hz), which may be from other isomer; MS (El): cal'd 411.61 , exp, did not ionize.
Figure imgf000135_0002
5-Methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.2): 1H NMR
(CDCIs) δ θ.88 (t, 3H, J = 7.2 Hz), 1.20-1.45 (m, 10H), 1.65-1.75 (m, 2H), 2.37 (s, 3H), 4.23 (t, 2H, J = 6.8 Hz), 6.84 (s, 1H), g.8 (s, 1H); MS (El): cal'd 313.41, exp.
Figure imgf000135_0003
5-Heptyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid (21.3) tan solid (51 mg, 80% yield): Η NMR (CDCI3, 200MHz) δ 0.87 (t, 6H, J = 5.7 Hz), 1.26 (bs, 18H),
1.54-1.61 (m, 4H), 2.63 (t, 2H, J = 7.5 Hz), 3.26 (dt, 2H, J = 7.0, 7.0 Hz), 5.95 (bs,
1 H), 6.77 (s, 1 H), 10.10 (s, 1 H), 11.36 (bs, 1 H). 13C NMR (CDCI3, 50MHz) δ 14.0, 22.6, 26.8, 29.0, 29.2, 29.3, 29.4, 29.7, 31.1 , 31.7, 31.8, 41.0, 88.4, 108.9, 119.6, 134.2, 151.9, 154.1 , 169.9.
Figure imgf000136_0001
5-Butyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid (21.4) purple oil (308 mg, 100% yield): Η NMR (CDCI3, 200MHz) δ 0.87 (t, 6H, J = 5.7 Hz), 1.26 (bs, 18H), 1.54-1.61 (m, 4H), 2.63 (t, 2H, J = 7.5 Hz), 3.26 (dt, 2H, J= 7.0, 7.0 Hz), 5.95 (bs, 1 H), 6.77 (s, 1 H), 10.10 (s, 1 H), 11.36 (bs, 1 H).
Figure imgf000136_0002
5-Benzyl-2-(3-octyl-ureido)-thiophene-3-carboxylic acid (21.5) tan solid (450 mg): Η NMR (CDCI3. 200MHz) δ 0.87 (t, 3H, J = 6.4 Hz), 1.26 (bs, 10H), 1.51 (tt, 2H, J = 12.2, 6.5 Hz), 3.21 (dt, 2H, J = 6.6, 6.0 Hz), 3.96 (s, 2H), 6.33 (bs, 1H), 6.82 (s, 1H), 7.14-7.32 (m, 5H), 10.16 (bs, 1H).
Figure imgf000136_0003
2-Dodecanoylamino-5-heptyl-thiophene-3-carboxylic acid (21.6) dark brown solid (185 mg, 100% yield): Η NMR (CDCI3, 200MHz) δ 0.85-0.gθ (m, 6H), 1.26- 1.40 (m, 24H), 1.54-1.7g (m, 4H), 2.52 (t, 2H, J = 7.5 Hz), 2.71 (t, 2H, J = 7.5 Hz), 6.gi (s, 1 H), 10.53 (bs, 1 H), 10.75 (s, 1 H). MS (ES-) 421.86 (M-1).
5-Heptyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.7) pale yellow solid (76 mg, 54% yield): 'H NMR (CDCI3, 200MHz) δ 0.85-0.gi (m, 6H), 1.30 (bs, 18H), 1.58-1.75 (m, 4H), 2.69 (t, 2H, J = 7.5 Hz), 4.24 (t, 2H, J = 6.6 Hz), 6.86 (s, 1 H), 9.90 (s, 1 H). MS (ES-) 395.g3 (M-1).
Figure imgf000137_0001
2-Octyloxycarbonylamino-5-(1 ,3,3-trimethyl-butyl)-thiophene-3-carboxylic acid
(21.8) waxy tan solid (190 mg, 100% yield): 'H NMR (CDCI3, 200MHz) δ 0.88-0.89 (m, 12H), 1.28-1.76 (m, 17H), 2.90-3.0g (m, 1 H), 4.24 (t, 2H, J = 6.6 Hz), 6.87 (s, 1 H), g.85 (s, 1 H), 10.34 (bs, 1 H).
2-(2-Benzyloxy-ethoxycarbonylamino)-5-decyl-thiophene-3-carboxylic acid
(21.9) tan solid (142 mg): Η NMR (CDCI3, 200MHz) δ 0.89 (t, 3H, J= 6.5 Hz), 1.23- 1.27 (m, 14H), 1.58-1.69 (m, 2H), 2.6g (t, 2H, J = 7.3 Hz), 3.76 (t, 2H, J = 4.6 Hz), 4.43 (t, 2H, J = 4.6 Hz), 4.61 (s, 2H), 6.88 (s, 1 H), 7.28-7.38 (m, 5H), g.gg (s, 1 H), 10.48 (bs, 1 H). MS (ES-) 460.06 (M-1).
Figure imgf000137_0002
2-Octyloxycarbonylamino-5-phenethyl-thiophene-3-carboxylic acid (21.10) white solid (203 mg, g7% yield): Η NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.8Hz), 1.28 (brs, 10H), 2.98 (s, 4H), 4.23 (t, 2H, J = 7.0Hz), 6.84 (s, 1 H), 7.22 (m, 5H), 9.96 (s, 1 H)
Figure imgf000138_0001
2-Octyloxycarbonylamino-5-(3-phenyl-propyl)-thiophene-3-carboxylic acid
(21.11) yellow solid (175 mg, 9% yield): 'H NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.8Hz), 1.28 (brs, 10H), 1.68 (m, 2H), 1.98 (tt, 2H, J = 7.8Hz, 7.2Hz), 4.23 (t, 2H, J = 7.0Hz), 6.87 (s, 1 H), 7.26 (m, 5H), 9.g3 (1 H)
Figure imgf000138_0002
2-Octyloxycarbonylamino-5-(4-phenyl-butyl)-thiophene-3-carboxylic acid
(21.12) white waxy solid (303 mg, 92% yield): H NMR (CD3OD, 400MHz) δ 0.90 (bt, 3H, J = 6.8 Hz), 1.21-1.48 (m, 12H), 1.57-1.76 (m, 6H), 2.57-2.77 (m, 4H), 4.20 (t, 2H, J = 6.4 Hz), 6.82 (s, 1 H), 7.08-7.32 (m, 5H). MS (ES) 430.35 (M-1), t^method D) = 7.74min
Figure imgf000138_0003
2-Octyloxycarbonylamino-5-(5-phenyl-pentyl)-thiophene-3-carboxylic acid
(21.13) off-white solid (331 mg, 90% yield): 1H NMR (CD3OD, 400MHz) δ 0.90 (bt, 3H, J = 6.4 Hz), 1.23-1.45 (m, 14H), 1.58-1.75 (m, 6H), 2.59 (t, 2H, J = 7.6 Hz), 2.68 (t, 2H, J = 7.2 Hz), 4.20 (t, 2H, 6.8 Hz), 6.81 (bs, 1 H), 7.07-7.18 (m, 3H), 7.1 g- 7.27 (m, 2H). MS (ES) 443.58 (M-1), t^method D) = 8.58min
Figure imgf000139_0001
5-Decyl-2-(2-methoxy-ethoxycarbonylamino)-thiophene-3-carboxylic acid
(21.14) off-white solid (256 mg, 5% yield): 1H NMR (CDCI3, 200MHz) δ 0.88 (bt, 3H, J = 6.2 Hz), 1.11-1.44 (m, 14H), 1.47-1.73 (m, 2H), 2.6g (t, 2H, J = 7.8 Hz), 3.43 (s, 3H), 3.62-3.75 (m, 2H), 4.31-4.47 (m, 2H), 6.86 (s, 1 H), 10.00 (s, 1 H). MS (ES) 384.52 (M-1 ), t^method D) = 6.28min.
Figure imgf000139_0002
2-(4-Butyl-phenoxycarbonylamino)-5-decyl-thiophene-3-carboxylic acid (21.15) tan solid (214 mg, g7% yield) Η NMR (CD3OD, 400 MHz) δ 0.8gi (bt, 3H, J = 6.8 Hz), 0.g4g (t, 3H, J = 7.2 Hz), 1.21-1.43 (m, 16H), 1.54-1.71 (m, 4H), 2.63 (t, 2H, J = 7.6 Hz), 2.70 (t, 2H, J = 7.2 Hz), 6.87 (s, 1 H), 7.12 (d, 2H, J = 8.4 Hz), 7.23 (d, 2H, J = 8.8 Hz); MS (ES) no ionization (M-1), tR(method D) = no peak
Figure imgf000139_0003
2-(3-phenoxy-propoxycarbonylamino)-5-decyl-thiophene-3-carboxylic acid
(21.16) off-white solid (137 mg, 80% yield): 1H NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.4 Hz), 1.26-1.38 (m, 14H), 1.64 (tt, 2H, J = 12.4, 7.0 Hz), 2.02 (tt, 2H, J = 12.4, 6.2 Hz), 2.68 (t, 2H, J = 7.3 Hz), 3.60 (t, 2H, J = 6.2 Hz), 4.37 (t, 2H, J = 6.2 Hz), 4.53 (s, 2H), 6.87 (s, 1 H), 7.25-7.34 (m, 5H), g.88 (s, 1 H), 10.85 (bs, 1 H). 2-(4-Benzyloxy-butoxycarbonylamino)-5-decyl-thiophene-3-carboxylic acid
(21.17) off-white solid (55 mg, 55% yield): 1H NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.3 Hz), 1.26-1.38 (m, 14H), 1.61 -1.82 (m, 6H), 2.68 (t, 2H, J = 7.4 Hz), 3.53 (t, 2H, J = 5.8 Hz), 4.27 (t, 2H, J = 5.8 Hz), 4.50 (s, 2H), 6.86 (s, 1H), 7.25-7.33 (m, 5H), 9.92 (s, 1 H).
Figure imgf000140_0001
5-Pentyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.18): 1H
NMR (CDCIg, 200 MHz): δ = 0.78-1.02 (m, 6H), 1.14-1.50 (m, 12H), 1.52-1.82 (m, 4H), 2.69 (t, J = 7.5 Hz, 2H), 4.23 (t, J = 6.8 Hz, 2H), 6.59 (s, 1 H), 9.88(brs, 1 H).
Figure imgf000140_0002
5-lsopropyI-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.19): 1H NMR (CDCIg, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.16-1.50 (m, 16H), 1.60-1.82 (m, 2H), 2.gθ-3.18 (m, 1 H), 4.24 (t, J = 6.8 Hz, 2H), 6.87 (d, J = 1.2 Hz, 1 H), g.81 (brs, 1 H), g.86 (brs, 1 H).
Figure imgf000140_0003
5-Oclyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.20): 1H NMR
(CDCI3l 200 MHz): δ = 0.78-1.00 (m, 6H), 1.12-1.49 (m, 20H), 1.54-1.82 (m, 4H), 2.68 (t, J = 7.3 Hz, 2H), 4.23 (t, J = 6.6 Hz, 2H), 6.86 (s, 1 H), 9.8g (brs, 1 H).
Figure imgf000141_0001
5-Dodecyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.21): 1H
NMR (CDCI3, 200 MHz): δ = 0.78-0.96 (m, 6H), 1.12-1.46 (m, 28H), 1.52-1.78 (m, 4H), 2.68 (t, J = 7.3 Hz, 2H), 4.23 (t, J = 6.8 Hz, 2H), 6.85 (s, 1 H), 9.gθ (brs, 1 H).
Figure imgf000141_0002
2-Benzyloxycarbonylamino-5-decyl-thiophene-3-carboxylic acid (21.22): 1H
NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.14-1.44 (m, 14H), 1.50-1.74 (m, 2H), 2.68 (t, J = 7.1 Hz, 2H), 5.26 (s, 2H), 6.85 (s, 1 H), 7.33-7.4g (m, 5H), g.gδ (brs, 1 H).
Figure imgf000141_0003
2-(4-Butylbenzyloxycarbonylamino)-5-decyl-thiophene-3-carboxylic acid
(21.23): 1H NMR (CDCI3, 200 MHz): δ = 0.78-1.02 (m, 6H), 1.10-1.46 (m, 16H), 1.48-1.76 (m, 4H), 2.52-2.80 (m, 4H), 5.23 (s, 2H), 6.84 (s, 1 H), 7.13-7.40 (m, 4H), 9.93 (brs, 1 H).
Figure imgf000142_0001
5-Decyl-2-(2-p-tolyl-ethoxycarbonylamino)-thiophene-3-carboxylic acid (21.24):
1H NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.16-1.46 (m, 14H), 1.52- 1.78 (m, 2H), 2.33 (s, 3H), 2.6g (t, J = 7.5 Hz, 2H), 3.00 (t, J = 7.3 Hz, 2H), 4.43 (t, J = 7.3 Hz, 2H), 6.87 (s, 1 H), 7.08-7.22 (m, 4H), g.gi (brs, 1 H).
Figure imgf000142_0002
5-Decyl-2-phenethyloxycarbonylamino-thiophene-3-carboxylic acid (21.25): 1H
NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.16-1.46 (m, 14H), 1.52-1.76 (m, 2H), 2.6g (t, J = 7.3 Hz, 2H), 3.05 (t, J = 7.3 Hz, 2H), 4.46 (t, J = 7.5 Hz, 2H), 6.87 (s, 1 H), 7.18-7.42 (m, 5H), 0.92 (brs, 1 H).
Figure imgf000142_0003
4-Methyl-5-octyl-2-octy!oxycarbonylamino-thiophene-3-carboxylic acid (21.26): 520 mg (69%). 1H NMR (CDCI3, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 6H), 1.16-1.62 (m, 24), 2.28 (s, 3H), 2.64 (t, J = 7.2 Hz, 2H), 4.18 (t, J = 6.6 Hz, 2H), 10.26 (s, 1 H).
Figure imgf000143_0001
2-Butyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid (21.27): 366 mg
(67%). 1H NMR (CDCIs, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 3H), O.gβ (t, J = 7.4 Hz, 3H), 1.14-1.82 (m, 16H), 2.67 (t, J = 7.4 Hz, 2H), 4.24 (t, J = 6.6 Hz, 2H), 6.85 (s, 1 H), 9.89 (s, 1H).
Figure imgf000143_0002
2-Hexyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid (21.28): 395 mg (60%). 1H NMR (CDCIs, 200 MHz): δ 0.87 (t, J = 7.0 Hz, 3H), 0.90 (t, J = 6.4 Hz, 3H), 1.12-1.52 (m, 16H), 1.50-1.82 (m, 4H), 2.68 (t, J = 7.2 Hz, 2H), 4.23 (t, J = 7.0 Hz, 2H), 6.68 (s, 1 H), 9.88 (s, 1 H).
Figure imgf000143_0003
2-Dodecyloxycarbonylamino-5-octyl-thiophene-3-carboxyIic acid (21.29): 541 mg (80%). 1H NMR (CDCI3, 200 MHz): δ 0.87 (t, J = 6.4 Hz, 6H), 1.12-1.50 (m, 28H), 1.50-1.80 (m, 4H), 2.68 (t, J = 7.4 Hz, 2H), 4.23 (t, J = 6.6 Hz, 2H), 6.85 (s, 1 H), 9.89 (s, 1H).
Figure imgf000144_0001
5-Decyl-2-phenyloxycarbonylamino-thiophene-3-carboxylic acid (21.30): 46g mg (80%). 1H NMR (CDCI3, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 3H), 1.18-1.44 (m, 14H), 1.54-1.76 (m, 2H), 2.70 (t, J = 7.2 Hz, 2H), 6.gi (s, 2H), 7.17-7.48 (m, 5H), 10.27 (s, 1 H).
Figure imgf000144_0002
2-Decyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid (21.31): 603 mg
(86%). 1H NMR (CDCI3, 200 MHz): δ 0.87 (t, J = 6.2 Hz, 6H), 1.32-1.50 (m, 24H), 1.52-1.82 (m, 4H), 2.67 (t, J = 7.4 Hz, 2H), 4.23 (t, J = 6.6 Hz, 2H), 6.85 (s, 1 H), g.8g (s, 1 H).
Figure imgf000144_0003
6-Benzyl-2-octyloxycarbonylamino)thiophene-3-carboxylic acid (21.32) Light yellow solid in 100% yield.
'H NMR (CDCI3, 200MHz): δ 9.86 (s, 1 H), 7.22-7.34 (m, 5H), 7.00(brs, 1 H), 6.87 (t, 1 H, J = 1.0Hz), 4.21 (t, 2H, J = 6.6Hz), 4.01 (s, 2H), 1.67(q, 2H, J = 7.0Hz), 1.15- 1.45 (m, 10H), 0.88(t, 3H, J = 7.0Hz).
Figure imgf000145_0001
6-Hexyl-2-(octyloxycarbonylamino)thiophene-3-carboxylic acid (21.33)
Light yellow oil in 74% yield. Η NMR (CDCI3, 200MHz): δ 10.87 (brs, 1 H), 9.83 (s, 1 H), 6.86 (s, 1 H), 4.24 (t, 2H, J = 6.6Hz), 2.68 (t, 2H, J = 7.2Hz), 1 .60-1.80(m, 4H), 1.10-1.45 (m, 20H), 0.80-0.g5(m, 6H).
Figure imgf000145_0002
6-Decyl-2-(octyloxycarbonylamino)thiophene-3-carboxylic acid (21.34)
Light yellow solid in 100% yield.
Η NMR (CDCI3, 200MHz): δ g.89 (brs, 1 H), 8.00 (brs, 1 H), 6.85 (s, 1 H), 4.23 (t, 2H, J
= 6.6Hz), 2.68 (t, 2H, J = 7.0Hz), 1 .60-1.80(m, 4H), 1.08-1.40 (m, 24H), 0.80-0.95(m,
6H).
Figure imgf000145_0003
6-Decyl-2-(1-methylheptyloxycarbonylamino)thiophene-3-carboxylic acid (21.35)
Light yellow solid in gβ% yield. Η NMR (CDCI3, 200MHz): δ 9.80 (brs, 1 H), 8.24(brs, 1 H), 6.73 (s, 1 H), 4.82-5.00 (m, 1 H), 2.65 (t, 2H, J = 7.4Hz), 1.50-1.83(m, 15H), 1.08-1.50 (m, 23H), 0.80-1.00(m, 6H).
Figure imgf000146_0001
6-Heptyl-2-(1-methylheptyloxycarbonylamino)thiophene-3-carboxylic acid
(21.36)
Light yellow oil in 100% yield.
'H NMR (CDCI3, 200MHz): δ 9.80 (brs, 1 H), 8.24(brs, 1 H), 6.85 (s, 1 H), 4.90-5.00 (m, 1 H), 2.68 (t, 2H, J = 7.6Hz), 1.50-1 .83(m, 4H), 1.08-1.50 (m, 20H), 0.80-1.00 (m, 6H).
Figure imgf000146_0002
5-Decyl-2-(4-phenylpropoxycarbonylamino)thiophene-3-carboxylic acid (21.37) Light brownish solid in 100% yield.
Η NMR (CDCI3, 400MHz): δ 10.4 (brs, 1 H), 9.88 (s, 1 H), 7.26-7.31 (m, 2H), 7.18-7.21 (m, 3H), 6.87 (s, 1 H), 4.27 (t, 2H, J = 6.4Hz), 2.74 (t, 2H, J = 8.0Hz), 2.68 (t, 2H, J = 7.6Hz), 2.02-2.07(m, 2H), 1.59-1.66(m, 2H), 1.18-1.40 (m, 14H), 0.88 (t, 3H, J = 6.0Hz).
Figure imgf000146_0003
5-Decyl-2-(4-phenylbutoxycarbonylamino)thiophene-3-carboxylic acid (21.38)
Light brownish solid in 100% yield.
'H NMR (CDCI3, 400MHz): δ 12.0 (brs, 1 H), 8. θ (s, 1 H), 7.26-7.31 (m, 2H), 7.17-7.21 (m, 3H), 6.87 (s, 1 H), 4.26 (t, 2H, J = 6.4Hz), 2.67-2.70 (m, 4H), 1.70-1.80(m, 4H), 1.50-1.70(m, 2H), 1.18-1.40 (m, 16H), 0.88(t, 3H, J = 6.8Hz).
Example 22: Thienoxazinones
Figure imgf000147_0001
6-Heptyl-5-methyl-2-octyloxy-thieno[2,3-d][1,3]oxazin-4-one (74) (May contain -10% other isomer); Mp 29-31 9C; 1H NMR (CDCI3) δ 0.82-0.96 (m, 6H), 1.20-1.50 (m, 18H), 1.50-1.68 (m, 2H), 1 .68-1.86 (m, 2H), 2.36 (s, 3H), 2.70 (t, 2H, J = 6.8 Hz), 4.38 (t, 2H, J = 6.6 Hz) Another peak at 2.83 (t, J = 6.7 Hz), which may be from other isomer; MS (El): cal'd 393.59, exp, did not ionize.
Figure imgf000147_0002
6-Methyl-2-octyloxy-thieno[2,3-d][1,3]oxazin-4-one (22.1): 1H NMR (CDCI3) δ θ.88 (t, 3H, J = 7.2 Hz), 1 .20-1.45 (m, 10H), 1.55 (s, 9H), 1.70-1.84 (m, 2H), 2.46 (s, 3H), 4.3g (t, 2H, J = 6.6 Hz), 6.93 (s, 1 H); MS (El): cal'd 2g5.5, exp.
Figure imgf000147_0003
6-Heptyl-2-octylamino-thieno[2,3-d][1,3]oxazin-4-one (61): off-white solid (38 mg, 801% yield): Η NMR (CDCI3, 200MHz) δ 0.87 (t, 6H, J = 6.4 Hz), 1.27-1.30 (m, 18H), 1.58-1.67 (m, 4H), 2.71 (t, 2H, J = 7.3 Hz), 3.38 (dt, 2H, J = 7.0, 6.2 Hz), 5.45 (bs, 1 H), 6.84 (s, 1H).
Figure imgf000148_0001
6-Butyl-2-octylamino-thieno[2,3-d][1,3]oxazin-4-one (63): off-white solid (162 mg, 55% yield): mp g3.0-94.0 eC. Η NMR (CDCI3, 200MHz) δ 0.88 (t, 3H, J = 6.4 Hz), 0.93 (t, 3H, J = 7.3 Hz), 1.27-1.48 (m, 12H), 1.56-1.71 (m, 4H), 2.72 (t, 2H, J = 7.5 Hz), 3.3g (dt, 2H, J = 7.0, 6.2 Hz), 5.73 (bs, 1 H), 6.85 (t, 1 H, J = 1.1 Hz). MS (ES+) 337.23 (M+1).
Figure imgf000148_0002
6-Benzyl-2-octylamino-thieno[2,3-d][1,3]oxazin-4-one (62): off-white solid (182 mg, 55% 2-step yield): mp 123.0-124.0 °C. 'H NMR (CDCl3, 200MHz) δ 0.87 (t, 3H, J = 6.4 Hz), 1.26-1.28 (m, 10H), 1.51 (tt, 2H, J = 13.6, 6.5 Hz), 3.36 (dt, 2H, J = 7.0, 6.6 Hz), 4.02 (s, 2H), 5.81 (bs, 1 H), 6.85 (s, 1 H), 7.20-7.35 (m, 5H). MS (ES+) 371.18 (M+1).
Figure imgf000148_0003
6-Heptyl-2-undecyl-thieno[2,3-d][1,3]oxazin-4-one (67): yellow oil ( 7 mg, 55% yield): lH NMR (CDCI3, 200MHz) δ 0.85-0.91 (m, 6H), 1.26-1.32 (m, 24H), 1.66- 1.83 (m, 4H), 2.69 (t, 2H, J = 7.7 Hz), 2.82 (t, 2H, J = 7.5 Hz), 7.06 (s, 1 H). 13C NMR (CDCI3, 50MHz) δ 14.0, 14.1 , 22.5, 22.6, 26.2, 28.8, 28.9, 2g.0, 2g.2, 2g.3, 2g.4, 29.5, 30.4, 31.0, 31.7, 31.9, 34.7, 117.8, 118.6, 144.3, 155.6, 162.2, 165.2.
Figure imgf000149_0001
6-Heptyl-2-octyloxy-thieno[2,3-d][1,3]oxazin-4-one (68): yellow oil (36 mg, 50% yield): Η NMR (CDCI3, 200MHz) δ 0.85-0.93 (m, 6H), 1.29-1.48 (m, 18H), 1.61- 1.87 (m, 4H), 2.77 (t, 2H, J = 7.5 Hz), 4.41 (t, 2H, J = 6.6 Hz), 6.97 (t, 1H, J= 1.1 Hz).
Figure imgf000149_0002
2-Octyloxy-6-(1 ,3,3-trimethyl-butyl)-thieno[2,3-d][1 ,3]oxazin-4-one (78): colorless oil (92 mg, 51% yield): 'H NMR (CDCI3, 200MHz) δ 0.88-0.89 (m, 12H), 1.30-1.83 (m, 17H), 3.04-3.13 (m, 1 H), 4.41 (t, 2H, J = 6.6 Hz), 6.98 (s, 1 H). 13C NMR (CDCI3, 50MHz) δ 14.0, 22.6, 25.6, 26.2, 28.3, 29.1 , 2g.8, 31.3, 31.7, 32.8, 52.6, 70.5, 1 13.2, 1 16.5, 149.4, 154.5, 156.g, 165.3. MS (ES+) 380.01 (M+1).
Figure imgf000149_0003
6-(5-Methoxy-1,5-dimethyl-hexyl)-2-octyloxy-thieno[2,3-d][1,3]oxazin-4-one
(83): pale yellow oil (3 mg): Η NMR (CDCI3, 200MHz) δ 0.89 (t, 3H, J = 6.6 Hz), 1.11 (s, 6H), 1.26-1.67 (m, 19H), 1.77 (dt, 2H, J= 7.0, 6.6 Hz), 2.g6 (dq, 1 H, J = 7.2, 7.0 Hz), 3.15 (s, 3H), 4.40 (t, 2H, J = 6.6 Hz), 6.98 (s, 1 H). MS (ES+) 424.03 (M+1 ).
Figure imgf000150_0001
6-(1 ,5-Dimethyl-hex-4-enyl)-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one and 6- (1 ,5-Dimethyl-hex-5-enyl)-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one (2:1 mixture of isomers) (81): colorless oil (16 mg): MS (ES+) 3 i .g5, 391.97 (M+1).
Figure imgf000150_0002
Trifluoro-acetic acid 1 ,1 -dimethyl-5-(2-octyloxy-4-oxo-4H-thieno[2,3- d][1,3]oxazin-6-yl)-hexyl ester (82): colorless oil (61 mg): Η NMR (CDCI3) 200MHz) δ 0.89 (t, 3H, J = 6.6 Hz), 1.26-1.69 (m, 8H), 1.76-1.88 (m, 4H), 2.g7 (dq, 1 H, J = 7.0, 6.8 Hz), 4.41 (t, 2H, J = 6.6 Hz), 6.g8 (s, 1 H). ,3C NMR (CDCI3, 100MHz) δ 14.2, 21 .5, 22.7, 22.8, 25.7, 25.8, 28.5, 2g.3, 31.9, 35.8, 38.7, 40.3, 70.8, 89.1 , 113.6, 1 14.6 (q, CF3, J = 285.9 Hz), 1 17.3, 1 17.4, 146.8, 154.7, 156.4 (q, COCF3, J = 40.9 Hz), 157.3, 165.8. MS (ES+) 505.93 (M+1).
Figure imgf000150_0003
2-(2-Benzyloxy-ethoxy)-6-decyl-thieno[2,3-d][1,3]oxazin-4-one (97): yellow oil (68 mg, 50% yield): 'H NMR (CDCI3, 400MHz) δ 0.88 (t, 3H, J = 6.8 Hz), 1.26-1.32 (m, 14H), 1.66 (tt, 2H, J = 14, 7.6 Hz), 2.76 (t, 2H, J = 7.6 Hz), 3.81 (t, 2H, J = 4.4 Hz), 4.57 (t, 2H, J = 4.6 Hz), 4.60 (s, 2H), 6.95 (s, 1 H), 7.25-7.34 (m, 5H). 13C NMR (CDCI3, 100MHz) δ 14.0, 22.6, 28.8, 29.2, 2g.3, 2g.4, 29.5, 30.2, 30.9, 31.8, 67.1 , 69.3, 73.3, 1 13.7, 1 18.2, 127.6, 127.7, 128.4, 137.6, 141.3, 154.2, 156.7, 165.2.
Figure imgf000151_0001
2-Octyloxy-6-phenethyl-thieno[2,3-d][1,3]oxazin-4-one (103): clear oil (84 mg, 88% yield) Η NMR (CDCI3, 200MHz) δ 0.8g (t, 3h, J = 6.8Hz), 1.28-1.43 (m, 10H), 1.79 (tt, 2H, J = 7.6Hz, J = 7.2Hz), 2.98 (t, 2H, J = 7.2Hz), 3.10 (t, 2H, J = 7.6Hz), 4.3g (t, 2H, J = 6.8Hz), 6.g5 (s, 1 H), 7.17-7.31 (m, 5H).
Figure imgf000151_0002
2-Octyloxy-6-(3-phenyl-propyl)-thieno[2,3-d][1,3]oxazin-4-one (104): white solid (72 mg, 75% yield) Η NMR (CDCI3, 200MHz) δ θ.88 (t, 3H, J = 6.6Hz), 1.21-1.50 (m, 10H), 1.79 (tt, 2H, J = 7.0Hz, J = 6.6Hz), 2.01 (tt, 2H, J = 7.8Hz, J = 7.2Hz), 2.69 (t, 2H, J = 7.6Hz), 2.80 (t, 2H, J = 7.2Hz), 4.40 (t, 2H, J = 6.6Hz), 6.98 (s, 1 H), 7.16- 7.35 (m, 5H).
Figure imgf000151_0003
2-Octyloxy-6-(4-phenyl-butyl)-thieno[2,3-d][1,3]oxazin-4-one (92): pale yellow oil (218 mg, 78% yield) 'H NMR (CDCI3, 200MHz) δ 0.887 (bt, 3H, 6.2 Hz), 1.08-1.52 (m, 10H), 1.60-1.90 (m, 6H), 2.54-2.72 (m, 2H), 2.72-2.88 (m, 2H), 4.40 (t, 2H, J = 6.6 Hz), 6.95 (s, 1 H), 7.0g-7.38 (m, 5H); MS (ES) 414.59 (M+1 ), tfl(method D) = 9.71 min.
Figure imgf000151_0004
2-Octyloxy-6-(5-phenyl-pentyl)-thieno[2,3-d][1,3]oxazin-4-one (93): Pale yellow oil (223 mg, 94% yield) 1H NMR (CDCI3, 200MHz) δ 0.887 (bt, 3H, J = 6.2 Hz), 1.20-1.50 (m, 12H), 1.57-1.88 (m, 6H), 2.61 (t, 2H, J = 7,4 Hz), 2.76 ( t, 2H, J = 6.8 Hz), 4.40 ( t, 2H, J = 6.6 Hz), 6.95 (t, 1 H, J = 1 Hz), 7.08-7.35 (m, 5H); MS (ES) 428.62 (M+1), t^method D) = 10.69min.
Figure imgf000152_0001
6-Decyl-2-(2-methoxy-ethoxy)-thieno[2,3-d][1 ,3]oxazin-4-one (96): off-white waxy solid (195 mg, 83% yield); m.p. = 38-41 eC; 1H NMR (CDCI3, 200MHz) δ 0.879 (bt, 3H, J = 6.2 Hz), 1.06-1.43 (m, 14H), 1.52-1.78 (m, 2H), 2.76 (t, 3H, J = 7.0 Hz), 3.43 (s, 3H), 3.62-3.82 (m, 2H), 4.44-4.64 (m, 2H), 6.96 (s, 1 H); MS (ES) 368.52 (M+1), tfi(method D) = δ.OOmin.
Figure imgf000152_0002
2-(4-Butyl-phenoxy)-6-decyl-thieno[2,3-d][1,3]oxazin-4-one (102): light yellow solid (145 mg, 79% yield); m.p. = 55-58 SC; :H NMR (CDCI3, 400 MHz) δ 0.878 (t, 3H, J = 6.0 Hz), 0.046 (t, 3H, J = 7.6 Hz), 1.18-1.45 (m, 18H), 1.55-1.71 (m, 4H), 2.64 (t, 2H, J = 7.6 Hz), 2.76 (t, 2H, J = 7.6 Hz), 6.g (s, 1 H), 7.15 (d, 2H, J = 8.4 Hz), 7.24 (d, 2H, J = 8.4 Hz); MS (ES) 442.64 (M+1 ), tfi (method D) = 12.1 gmin.
Figure imgf000152_0003
2-(3-Benzyloxy-propoxy)-6-decyl-thieno[2,3-d][1 ,3]oxazin-4-one (109): colorless oil (115 mg, 87% yield): Η NMR (CDCL., 200 MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.26- 1.38 (m, 14H), 1.67 (tt, 2H, J = 14.4, 7.4 Hz), 2.09 (tt, 2H, J = 12.4, 6.2 Hz), 2.76 (t, 2H, J = 7.4 Hz), 3.62 (t, 2H, J = 6.2 Hz), 4.51 (s, 2H), 4.53 (t, 2H, J = 6.4 Hz), 6.96 (t, 1 H, J = 1.1 Hz), 7.24-7.33 (m, 5H). 13C NMR (CDCI3, 100MHz) δ 14.04, 22.61 , 28.78, 28.83, 29.22, 29.23, 29.44, 29.50, 30.25, 30.90, 31.82, 65.93, 67.46, 73.06, 1 13.59, 1 18.14, 127.60, 128.31 , 138.09, 141.18, 154.30, 156.73, 165.54.
Figure imgf000153_0001
2-(3-Benzyloxy-butyloxy)-6-decyl-thieno[2,3-d][1,3]oxazin-4-one (111): colorless oil (19 mg, 36% yield): Η NMR (CDCL 200 MHz) δ 0.88 (t, 3H, J = 6.4 Hz), 1.26- 1.38 (m, 14H), 1.63-1.99 (m, 14H), 2.76 (t, 2H, J = 7.7 Hz), 3.54 (t, 2H, J = 6.2 Hz), 4.44 (t, 2H, J = 6.2 Hz), 4.51 (s, 2H), 6.96 (t, 1 H, J = 1.0 Hz), 7.28-7.35 (m, 5H).
Figure imgf000153_0002
6-Butyl-2-octyloxy-thieno[2,3-d][1,3]oxazin-4-one (75): MS (ES/SIR): m/z 338.49 [MH+]. 1H NMR (CDCI3, 200 MHz): δ = 0.78-1.03 (m, 6H), 1.15-1.53 (m, 12H), 1.54-1.90 (m, 4H), 2.77 (t, J = 7.5 Hz, 2H), 4.40 (t, J = 6.6 Hz, 2H), 6.96 (t, J = 0.8 Hz, 1 H).
Figure imgf000153_0003
6-lsopropyl-2-octy!oxy-thieno[2,3-d][1,3]oxazin-4-one (76): MS (ES/SIR): m/z 324.46 [MH+]. 1H NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.6 Hz, 3H), 1.18-1.52 (m, 16H), 1.70-1.88 (m, 2H), 2.g8-3.22 (m, 1 H), 4.40 (t, J = 6.6 Hz, 2H), 6.g8 (d, J = 1.0 Hz, 1 H).
Figure imgf000154_0001
6-Octyl-2-octyloxy-thieno[2,3-d][1,3]oxazin-4-one (85): 1H NMR (CDCI3, 200 MHz): δ = 0.80-1.00 (m, 6H), 1.12-1.52 (m, 20H), 1.57-1.90 (m, 4H), 2.76 (td, J 1.0, 7.6 Hz, 2H), 4.40 (t, J = 6.6 Hz, 2H), 6.95 (t, J = 1.1 Hz, 1 H).
Figure imgf000154_0002
6-Dodecyl-2-octyloxy-thieno[2,3-d][1,3]oxazin-4-one (88): 1H NMR (CDCI3, 200 MHz): δ = 0.80-0.08 (m, 6H), 1.16-1.52 (m, 28H), 1.58-1.88 (m, 4H), 2.76 (t, J = 7.2 Hz, 2H), 4.40 (t, J = 6.6 Hz, 2H), 6.g5 (s, 1 H).
Figure imgf000154_0003
2-Benzyloxy-6-Decyl-thieno[2,3-d][1,3]oxazin-4-one (105): MS (ES/SIR): m/z 400.56 [MH+].1H NMR (CDCI3, 400 MHz): δ = 0.88 (t, J = 6.8 Hz, 3H), 1.17-1.42 (m, 14H), 1.67 (quint., J = 7.4 Hz, 2H), 2.77 (t, J = 7.1 Hz, 2H), 5.44 (s, 2H), 6.96 (s, 1 H), 7.33-7.49 (m, 5H).
Figure imgf000155_0001
2-(4-Butylbenzyloxy)-6-Decyl-thieno[2,3-d][1,3]oxazin-4-one (106): 1H NMR
(CDCIs, 200 MHz): δ = 0.78-1.02 (m, 6H), 1.12-1.47 (m, 16H), 1.50-1.77 (m, 4H), 2.62 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.6 Hz, 2H), 5.40 (s, 2H), 6.96 (s, 1 H), 7.20 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H).
Figure imgf000155_0002
6-Decyl-2-(2-p-tolyl-ethoxy)-thieno[2,3-d][1,3]oxazin-4-one (107): 1H NMR
(CDCIs, 200 MHz): δ = 0.88 (t, J = 6.6 Hz, 3H), 1.14-1.46 (m, 14H), 1.56-1.78 (m, 2H), 2.32 (s, 3H), 2.76 (t, J = 7.4 Hz, 2H), 3.06 (t, J = 7.0 Hz, 2H), 4.58 (t, J = 7.0 Hz, 2H), 6.95 (t, J = 1.1 Hz, 1 H), 7.07-7.22 (m, 4H).
Figure imgf000155_0003
6-Decyl-2-phenethyloxy-thieno[2,3-d][1,3]oxazin-4-one (108): 1H NMR (CDCI3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.14-1.46 (m, 14H), 1.56-1.76 (m, 2H), 2.76 (t, J = 7.2 Hz, 2H), 3.11 (t, J = 7.0 Hz, 2H), 4.60 (t, J = 7.0 Hz, 2H), 6.95 (s, 1 H), 7.18-7.42 (m, 5H).
Figure imgf000155_0004
3-Methyl-6-octyI-2-octyloxy-5H-thieno[2,3-b]pyridin-4-one (87): 51 mg (60%). m.p. 36QC. 1H NMR (CDCI3, 200 MHz): δ 0.88 (t, J = 6.6 Hz, 6H0, 1.10-1.94 (m, 24H), 2.35 (s, 3H), 2.69 (t, J = 7.2 Hz, 2H), 4.38 (t, J = 7.0 Hz, 2H); 13C NMR (CDCI3, 75 MHz): δ 11.1 , 12.3, 20.9, 23.9, 25.7, 26.6, 27.3, 27.4, 27.5, 27.6, 29.4, 30.0, 30.1 , 68.6, 11.5, 126.9, 132.0, 153.1 , 155.1 , 162.g.
Figure imgf000156_0001
2-Butoxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one (95): 265 mg (g3%). 1H NMR (CDCIs, 200 MHz): δ 0.86 (t, J = 6.6 Hz, 3H), O.gβ (t, J = 7.2 Hz, 3H), 1.14-1.88 (m,16H), 2.74 (t, J = 7.4 Hz, 2H), 4.3g (t, J = 6.6 Hz, 2H), 6.g3 (s, 1 H); 13C NMR (CDCI3, 75 MHz): δ 11.9, 12.3, 17.2, 20.9, 27.2, 27.4, 27.5, 28.6, 29.2, 30.1 , 68.5, 101.9, 116.5, 13g.4, 152.7, 155.2, 164.0; MS (SIR): 338.48 (M+1).
Figure imgf000156_0002
2-Hexyloxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one (94): 312 mg (94%). 1H NMR (CDCIs, 200 MHz): δ 0.86 (t, J = 6.6 Hz, 3H), 0.80 (t, J = 6.6 Hz, 3H), 1.15-1.54 (m, 16H), 1.54-1.88 (m, 4H), 2.74 (t, J = 7.0 Hz, 2H), 4.38 (t, J = 6.6 Hz, 2H), 6.94 (t, J = 1.2 Hz, 1 H); 13C NMR (CDCI3, 75 MHz): δ 12.2, 12.3, 20.8, 20.9, 23.6, 26.6, 27.2, 27.4, 27.5, 28.6, 29.2, 29.6, 30.1 , 68.8, 101.9, 116.5, 139.4, 152.7, 155.2, 164.0; MS (SIR): 366.55 (M+1).
Figure imgf000156_0003
2-Dodecyloxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one (100): 322 mg (gi%). 1H NMR (CDCIs, 200 MHz): δ 0.87 (t, J = 6.2 Hz, 6H), 1.04-1.52 (m, 28H), 1.52-1. o (m, 4H), 2.75 (t, J = 7.0 Hz, 2H), 4.38 (t, J = 6.5 Hz, 2H), 6.94 (s, 1 H); 13C NMR (CDCI3, 75 MHz): δ 12.3, 12.4, 20.9, 21.0, 23.9, 26.6, 27.2, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.6, 29.2, 30.1 , 30.2, 68.8, 11.9, 116.5, 139.4, 152.7, 155.2, 164.0; MS (SIR): 450.71 (M+1 ).
Figure imgf000157_0001
6-Decyl-2-phenoxy-5H-thieno[2,3-b]pyridin-4-one (101): 322 mg (86%). 1H NMR (CDCIs, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 3H), 1.15-1.45 (m, 14H), 1.55-1.75 (m, 2H), 2.75 (t, J = 7.0 Hz, 2H), 7.0 (t, J = 1 Hz, 1 H), 7.22-7.51 (m, 5H); 13C NMR (CDCI3, 75 MHz): δ 12.4, 21.0, 27.2, 27.5, 27.6, 27.6, 27.8, 28.6, 29.2, 30.2, 97.7, 97.7, 102.5, 116.5, 119.4, 124.9, 128.0, 140.7, 149.5, 152.3, 154.5, 163.1 ; MS (SIR): 358.48 (M+1).
Figure imgf000157_0002
2-Decyloxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one (110): 313 mg (69%). 1H NMR (CDCI3, 200 MHz): δ 0.85 (t, J = 6.4 Hz, 6H), 1.16-1.50 (m, 24H), 1.50-1 .88 (m, 4H), 2.74 (t, J = 6.8 Hz, 2H), 4.38 (t, J = 6.6 Hz, 2H), 6,93 (s, 1 H); 13C NMR (CDCI3, 75 MHz): δ 12.3, 20.9, 20.0, 23.g, 26.6, 27.2, 27.4, 27.5, 27.6, 27.7, 27.8, 28.6, 2g.2, 30.1 , 30.1 , 68.8, 111.9, 116.5, 139.3, 152.6, 155.2, 164.0.
Figure imgf000158_0001
6-Benzyl-2-octyloxythieno[2,3- ][1 ,3]oxazin-4-one (77)
Light yellow oil in 53% yield.
Η NMR (CDCI3, 200MHz): δ 7.20-7.40 (m, 5H), 6.g8 (t, 1'H, J = 1.0Hz), 4.38 (t, 2H, J =. 6.6Hz), 4.00 (s, 2H), 1.76(q, 2H, J = 7.2-Hz), 1.10-1.50 (m, 10H), 0.88 (t, 3H, J = 7.0Hz). MS (ES) [M++l] 372.51.
Figure imgf000158_0002
6-Hexyl-2-octyloxythieno[2,3-d][1 ,3]oxazin-4-one (84)
Light yellow oil in 30% yield.
Η NMR (CDCI3, 200MHz): δ 6.04 (s, 1 H), 4.3g (t, 2H, J = 6.6Hz), 2.76 (t, 2H, J =
7.2Hz), 1.76(q, 2H, J = 7.4Hz), 1.64 (q, 2H, J = 7.6Hz), 1.08-1.50 (m, 14H), 0.80- O.gδ (m, 6H). MS (ES) [M++l] 366.55.
6-Decyl-2-octyloxythieno[2,3-d][1 ,3]oxazin-4-one (86)
Light yellow oil in 50% yield.
Η NMR (CDCI„ 200MHz): δ 6.g4 (s, 1 H), 4.39 (t, 2H, J = 6.6Hz), 2.76 (t, 2H, J = 7.2Hz), 1.76(q, 2H, J = 7.4Hz), 1.64 (q, 2H, J = 7.6Hz), 1.08-1.50 (m, 20H), 0.80- 0.95 (m, 6H). MS (ES) [M++l] 422.56
Figure imgf000158_0004
6-Decyl-2-(1-methylheρtyloxy)thieno[2.3-c.][1,3]oxazin-4-one (90) Light yellow oil in 22% yield.
!H NMR (CDCI3, 200MHz): δ 6.96 (s, 1 H), 5.13 (tq, 1 H, J = 5.8, 6.2Hz), 2.76 (t, 2H, J
= 7.6Hz), 1.58-1.83(m, 4H), 1.08-1.50 (m, 26H), 0.80-1.00 (m, 6H). MS (ES) [M++l]
380.57.
Figure imgf000159_0001
6-Heptyl-2-(1-methylheptyloxy)thieno[2,3-cf][1,3]oxazin-4-one (91)
Light yellow oil in 28% yield.
Η NMR (CDCI3, 200MHz): δ 6.96 (s, 1 H), 5.13 (tq, 1 H, J = 6.2, 6.6Hz), 2.76 (t, 2H, J = 7.6Hz), 1.58-1.83(m, 4H), 1.08-1.50 (m, 20H), 0.80-1.00 (m, 6H). MS (ES) [M++l] 422.65
Figure imgf000159_0002
6-Decyl-2-(4-phenylpropoxy)thieno[2,3-c.][1 ,3]oxazin-4-one (99)
Light yellow oil in 28% yield.
Η NMR (CDCI3, 200MHz): δ 7.17-7.38 (m, 5H), 6.96 (s, 1 H), 4.42 (t, 2H, J = 6.6Hz), 2.72-2.85 (m, 4H), 2.05-2.20(m, 2H), 1.50-1.75(m, 2H), 1.20-1.40 (m, 16H), 0.88(t, 3H, J = 6.6Hz). MS (ES) [M++l] 428.62.
Figure imgf000159_0003
6-Decyl-2-(4-phenylbutoxy)thieno[2,3-cr][1 ,3]oxazin-4-one (98)
Light yellow oil in 25% yield.
Η NMR (CDCI3, 200MHz): δ 7.10-7.38 (m, 5H), 6.96 (s, 1 H), 4.42 (t, 2H, J = 6.4Hz), 2.60-2.80 (m, 4H), 1.75-1.83(m, 4H), 1.50-1.70(m, 2H), 1.18-1.40 (m, 16H), 0.88(t, 3H, J = 6.4Hz). Example 23: Pancreatic lipase assay
The use of a pancreatic lipase assay has been described in the literature (Hadvary, P. et al. Biochem. J. (1988) 256: 357-361 ; Hadvary, P. et al. Biochem. J. (1991) 266:2021-2027). Pancreatic lipase activity was measured using a 718 Stat Titrino (Brinkmann) programmed to maintain a pH of 8.0 using 0.1 N NaOH. The substrate mixture (pH 8) contained 1 mM taurochenodeoxycholate (Sigma), 9 mM taurodeoxycholate (Sigma), 0.1 mM cholesterol (Sigma), 1 mM phosphatidylcholine (Sigma), 1.5% BSA, 2 mM Tris base, 100 mM NaCl, 10 mM CaCI2l and 3% triolein (Sigma). The mixture (5 mL) was emulsified via sonication at room temperature, and added to the titration vessel with rapid stirring. The Stat Titrino was turned on and lipase (7.0 nM type Vl-S porcine pancreatic lipase (Sigma) dissolved in PBS) was added to the vessel. After 10 min, inhibitor (700 nM dissolved in 100% DMSO) was added and the reaction continued for an additional 12.5 min. The k values were determined for the 12.5 min after the addition of the inhibitor using a one phase exponential association equation, Y=Ymax*(1-exp(-k*X)), k values for lipase alone were 0.0004 ± 0.0001 sec. The k values for compounds disclosed herein are >0.0004 ± 0.0001 sec.
Equivalents
Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

What is claimed is:
1. A compound having the structure:
Figure imgf000161_0001
wherein,
X is O, S, CH2 or NR5; Y is O or S;
Ri is H, substituted or unsubstituted C-1-C15 alkyl, CrC8 alkylaryl, -C(O)OR4, -C(O)NR4R5, -CR6R6OR4, -CR6R6 C(O)R4, -CR6R6 C(O)NHR7, -C(O)NR10Rn, -C(O)NR8R9 NR8R9, -N(R5)C(O)NHR5, or CH2R4;
R2 is a substituted or unsubstituted, straight chain C1-C30 alkyl or branched C3-C30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; and
R3 is H or substituted or unsubstituted d-Cβ alkyl or C3-C10 cycloalkyl, wherein
R is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, aryl, -CH2-aryl, aryl -Cι-C30 alkyl, heteroaryl-Cι-C30 alkyl or C3-C10 cycloalkyl;
R5 is H or a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, aryl CrC3oalkyl, heteroarylalkyl or cycloalkyl;
R6 and R6- are each independently H, substituted or unsubstituted CrC6 alkyl, dialkyl or C3-C10 cycloalkyl or together form a 3-7 membered ring system;
R7 is H or substituted or unsubstituted Cι-C12 alkyl or C3- C10 cycloalkyl; and
Rt. and Rs are each independently H, substituted or unsubstituted CrC6 alkyl, CrC6 alkoxy, CrC6 alkylaryl, or NR8R9 together form a substituted piperazine or piperidine ring or a dihydro-1 H-isoquinoline ring system, or a specific enantiomer thereof, or a specific tautomer, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , having the structure:
Figure imgf000162_0001
wherein,
X is O, S or NR5; Y is O or S;
Ri is H, -C(O)OR4, -C(O)NR4R5, -CR6R6OR4, -CR6R6'OC(O)R4, -CR6R6'OC(O)NHR7, or CH2R4;
R2 is a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl; and
R3 is H or substituted or unsubstituted d-C6 alkyl or cycloalkyl, wherein,
R is H or a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
Rs is H or a substituted or unsubstituted, straight chain or branched, C6-C30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
R6 and R6- are each independently H, substituted or unsubstituted d-C6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system; and
R7 is H or substituted or unsubstituted C1-C12 alkyl or cycloalkyl.
3. The compound of claim 2, having the structure:
Figure imgf000163_0001
wherein,
X is O, S or NR5;
Hi is H, -C(O)OR4, -C(O)NR4R5, -CR6R6OR4, -CR6R6'OC(O)R4, -CR6R6'OC(O)NHR7, or CH2R ;
R2 is a substituted or unsubstituted, straight chain or branched C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl; and
R3 is H or substituted or unsubstituted d-C6 alkyl or cycloalkyl, wherein,
R4 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
R5 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
R6 and R& are each independently H, substituted or unsubstituted d-Cβ alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system; and
R7 is H or substituted or unsubstituted C1-C12 alkyl or cycloalkyl.
4. The compound of claim 3, wherein
X is O or NR5;
Ri is -C(O)O-(C6-C3o) alkyl, -C(O)NH-(C6-C3o) alkyl or
-C(O)OCH2(C6H5);
R2 is Ce-Cso alkyl; and
R3 is C C6 alkyl.
5. The compound of claim 3, wherein R3 is H or CH3.
6. The compound of claim 5, wherein X is O.
7. The compound of claim 6, wherein R3 is methyl.
8. The compound of claim 5 wherein X is N.
The compound of claim 8, wherein R3 is methyl.
10. The compound of claim 1 , having the structure:
Figure imgf000164_0001
wherein,
Y is O or S;
R1 is H, -(CH2)rCH3, -CH(CH3)2. -CH(CH3)CH2C(CH3)3, -CH(CH3)(CH2)3C(=CH2)CH3, -CH(CH3)(CH2)3C(CH3)2θC(O)CH3, -CH(CH3)[CH2]3C(CHs)2OCH3, -CHS(C6H5), -C(O)OH, -C(O)NH(CH2)tCH3, -C(O)O(CH2)uCH3, -C(O)OCH[(CH2)3CH3]2, -C(O)NH(CH2)vCH3, -C(O)N(CH3)2, -C(O)NHCH2(C6H5), -C(O)NHCH2(C5H4N), -C(O)N[(CH2)3CHs]2, -C(O)N[(CH2)5CH3]2, -C(O)N[(CH2)7CH3]2, -C(O)NH(C6H . .), -C(O)(NC4H8N)CH2(C6H5)> -C(O)(NC5H9)CH2(C6H5), -C(O)NH(CH2)3O(C6H5), -C(0)NHCH[(CH2)3CHs]2, -C(O)NH(CH2)3N(CH3)2, -C(0)NHCH2C(O)OCH2(C6H5), -C(O)N(CH3)CH2(C5H3N[CH3]), -C(O)NH(CH2)2(C5H4N), -C(O)N(CH2CH3)(CH2)2(C5H4N), -C(O)NHCH2(C4H3O), -C(O)(NC4H8N)[CH232(NC5H10), -C(O)NHCH2CH(CH3)2, -C(O)NHCH2(C5H4N), -C(O)NHCH2C(CH3)3, -C(O)(NC4H8N)CH2C(O)NHCH(CH3)2- -C(0)(NC9H8)[OCH3]2, -C(O)NHCH2(C6H3[OCH3]2), -C(O)NHCH2(C7H5O2), -C(O)NH(CH2)2θ(C6H5), -C(O)NH(CH2)2θCH3, -C(O)NH(CH2)3OCH3, -C(O)NH(CH2) (C6H5), or -C(O)NH(CH2)3(C6H5); r is an integer from 1 to 15; s is an integer from 0 to 6; t is an integer from 0 to 6; u is an integer from 3 to 8; v is an integer from 5 to 15; XR2 is -(CH2)nCH3, -O(CH2)mCH3, -OCH(CH3)2, -OCH(CH3)(CH2)5CH3, -OCH2CH(CH3)2, -O(CH2)2OCH3, -O(CH2)2OCH2(C6H5), -O(CH2)p(C6H5), -OCH2(C6H4[(CH2)sCH3]), -O(C6H4[(CH2)sCH3]), -O(CH2)2(C6H4[CH3]), -0(CH2)sOCH2(C6H5), -O(CH2) OCH2(C6H5), -N([CH2]7CH3)C(O)NH(CH2)7CH3, -N([CH2]6CH3)C(O)NH(CH2)6CH3, -NH(CH2)qCH3, -NH(C6H4)O(C6H5), -N(CH3)(CH2)5CH3, -NHCH[(CH2)3CH3]2, -NHCH(CH3)[CH2]5CHs, or -N([CH2]7CH3)2; n is an integer from 6 to 15; m is an integer from 1 to 15; p is an integer from 0 to 6; q is an integer from 6 to 15; and is H, -CHs or -CH2OCH3.
1. The compound of claim 10, having the structure:
Figure imgf000166_0001
wherein,
Y is O or S;
Ri is H, -(CH2)3CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)9CHs, -(CH2)iiCH3, -CH(CH3)2, -CH(CH3)CH2C(CH3)3, -CH(CH3)(CH2)3C(=CH2)CH3, -CH(CH3)(CH2)3C(CHs)2OC(O)CH3, -CH(CH3)[CH2]3C(CH3)2OCH3, -CH2(C6H5), -(CH2)2(C6H5), -(CH2)3(C6H5), -(CH2)4(C6H5), -(CH2)5(C6H5), -C(0)OH, -C(O)NHCH3, -C(O)NHCH2CH3, -C(0)NH(CH2)3CH3, -C(O)OCH2(C6H5), -C(O)O(CH2)5CH3, -C(O)O(CH2)6CH3, -C(O)O(CH2) CH3, -C(O)OCH[(CH2)3CH3]2) -C(O)NH(CH2)5CH3, -C(O)NH(CH2)7CH3, -C(O)NH(CH2)9CH3, -C(O)NH(CH2)nCH3, -C(O)NH(CH2)i5CH3, -C(O)N(CH3)2, -C(O)NHCH2(C6H5), -C(O)NHCH2(C5H4N), -C(O)N[(CH2)3CH3]2, -C(O)N[(CH2)5CH3]2, -C(O)N[(CH2)7CH3]2, -C(O)NH(C6Hn), -C(O)(NC4H8N)CH2(C6H5), -C(O)(NC5H9)CH2(C6H5), -C(O)NH(CH2)30(C6H5), -C(O)NHCH[(CH2)3CH3]2, -C(O)NH(CH2)3N(CH3)2, -C(O)NHCH2C(O)OCH2(C6H5), -C(O)N(CH3)CH2(CsH3N[CH3]), -C(O)NH(CH2)2(C5H4N), -C(O)N(CH2CH3)(CH2)2(C5H4N), -C(0)NHCH2(C4H3O), -C(O)(NC4H8N)[CH2]2(NC5H10), -C(O)NHCH2CH(CH3)2, -C(O)NHCH2(C5H4N), -C(O)NHCH2C(CH3)3,
-C(OHNC4H8N)CH2C(O)NHCH(CH3)2, -C(O)(NC9H8)[OCH3]2,
-C(O)NHCH2(C6H3[OCHs]2)- -C(O)NHCH2(C7H502),
-C(O)NH(CH2)2O(C6H5), -C(O)NH(CH2)2OCH3, -C(O)NH(CH2)3OCH3, -C(O)NH(CH2)4(C6H5), or -C(O)NH(CH2)3(C6H5);
XR2 is -(CH2)6CH3, -(CH2) 10CH3, -(CH2)ι4CH3, -O(CH2)3CH3, -0(CH2)5CH3, -O(CH2)6CH3, -O(CH2)7CH3, -O(CH2)9CH3, -0(CH2)nCH3, -O(CH2)ι5CH3, -OCH(CH3)2, -OCH(CH3)(CH2)5CH3, -OCH2CH(CH3)2, -O(CH2)2OCH3, -O(CH2)2OCH2(C6H5), -O(CH2)4(C6H5), -O(CH2)3(C6H5), -O(CH2)2(C6H5), -0(C6H5), -OCH2(C6H5), -OCH2(C6H4[(CH2)3CH3]), -O(C6H4[(CH2)3CH3]), -O(CH2)2(C6H4[CH3]) , -O(CH2)3OCH2(C6H5), -O(CH2)4OCH2(C6H5), -N([CH2]7CH3)C(O)NH(CH2) CH3, -N([CH2]6CH3)C(0)NH(CH2)6CH3, -NH(CH2)6CHs, -NH(CH2)7CH3, -NH(CH2)nCH3, -NH(CH2)ι3CH3, -NH(CH2)ι5CH3, -NH(C6H4)O(C6H5), -N(CH3)(CH2)5CH3, -NHCH[(CH2)3CH3]2, -NHCH(CH3)[CH2]5CH3) or -N([CH2]7CH3)2; and
R3 is H, -CH3 or -CH2OCH3.
12. The compound of claim 1 , wherein the compound is selected from the group consisting of:
6-Heptyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; 6-Hexyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; 2-Octyloxy-6-(1 ,3,3-trimethyl-butyl)-thieno[2,3-d][1 ,3]oxazin-4-one; 6-Butyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; 6-HeptyI-2-octylamino-thieno[2,3-d][1 ,3]oxazin-4-one; 6-Butyl-2-octylamino-thieno[2,3-d][1 ,3]oxazin-4-one; 6-Benzyl-2-octylamino-thieno[2,3-d][1 ,3]oxazin-4-one; 6-Heptyl-2-undecyl-thieno[2,3-d][1 ,3]oxazin-4-one;
6-(5-Methoxy-1 ,5-dimethyl-hexyl)-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; 6-(1 ,5-Dimethyl-hex-4-enyl)-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; 6-(1 ,5-Dimethyl-hex-5-enyl)-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; Trifluoro-acetic acid 1 , 1 -dimethyl-5-(2-octyloxy-4-oxo-4H-thieno[2,3- d][1 ,3]oxazin-6-yl)-hexyl ester;
2-(2-Benzyloxy-ethoxy)-6-decyl-thieno[2,3-d][1 ,3]oxazin-4-one; -Heptyl-5-methyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; -Methyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; -Octyloxy-6-phenethyl-thieno[2,3-d][1 ,3]oxazin-4-one; -Octyloxy-6-(3-phenyl-propyl)-thieno[2,3-d][1 ,3]oxazin-4-one; -Octyloxy-6-(4-phenyl-butyl)-thieno[2,3-d][1 ,3]oxazin-4-one; -Octyloxy-6-(5-phenyl-pentyl)-thieno[2,3-d][1 ,3]oxazin-4-one; -Decyl-2-(2-methoxy-ethoxy)-thieno[2,3-d][1 ,3]oxazin-4-one; -(4-Butyl-phenoxy)-6-decyl-thieno[2,3-d][1 ,3]oxazin-4-one; -(3-Benzyloxy-propoxy)-6-decyl-thieno[2,3-d][1 ,3]oxazin-4-one; -(3-Benzyloxy-butyloxy)-6-decyl-thieno[2,3-d][1 ,3]oxazin-4-one; -lsopropyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; -Octyl-2-octyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; -Dodecyl-2-octyloxy-thieno[2,3-d][1,3]oxazin-4-one; -Benzyloxy-6-Decyl-thieno[2,3-d][1,3]oxazin-4-one; -(4-Butylbenzyloxy)-6-Decyl-thieno[2,3-d][1 ,3]oxazin-4-one; -Decyl-2-(2-p-tolyl-ethoxy)-thieno[2,3-d][1 ,3]oxazin-4-one; -Decyl-2-phenethyloxy-thieno[2,3-d][1 ,3]oxazin-4-one; -Methyl-6-octyl-2-octyloxy-5H-thieno[2,3-b]pyridin-4-one; -Butoxy-6-octyl-5H-thieno[2,3τb]pyridin-4-one; -Hexyloxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one; -Dodecyloxy-6-octyI-5H-thieno[2,3-b]pyridin-4-one; -Decyl-2-phenoxy-5H-thieno[2,3-b]pyridin-4-one; -Decyloxy-6-octyl-5H-thieno[2,3-b]pyridin-4-one; -Benzyl-2-octyIoxythieno[2,3-o][1 ,3]oxazin-4-one; -Decyl-2-octyloxythieno[2,3- ][1,3]oxazin-4-one; -Decyl-2-(1 -methylheptyloxy)thieno[2,3-cd[1 ,3]oxazin-4-one; -Heptyl-2-(1 -methylheptyloxy)thieno[2,3-Qj,[1 ,3]oxazin-4-one; -Decyl-2-(4-phenylpropoxy)thieno[2,3-o [1 ,3]oxazin-4-one; and -Decyl-2-(4-phenylbutoxy)thieno[2,3-αf|[1 ,3]oxazin-4-one.
13. A compound having the structure:
Figure imgf000169_0001
wherein,
Rio is H or substituted or unsubstituted C1-C15 alkyl, C1-C15 alkylaryl, or -C(O)R-4, wherein R1 is hydroxyl, or a substituted or unsubstituted d-C30 alkyl, alkylamino, dialkylamino, alkoxy, benzyloxy, cycloalkyl, alkylheteroaryl, alkylaryl, or a heterocyclic, heteroaryl or aryl ring; R11 is hydrogen or methyl; R12 is hydrogen or tert-butyl; and Rι3 is hydrogen or -C(O)ZRι5, wherein Z is CH2, O or N and R15 is substituted or unsubstituted C1-C15 alkyl or aryl.
14. A method for treating obesity in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 so as to thereby treat obesity in the subject.
15. A method for treating diabetes in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 so as to thereby treat diabetes in the subject.
16. A method of inhibiting the hydrolytic activity of pancreatic lipase enzymes in a cell, comprising contacting the cell with an amount of the compound of claim 1 which is effective in inhibiting the hydrolytic activity of pancreatic lipase enzymes.
17. A pharmaceutical composition comprising the compound of claim 1 , 2, 3, 10 or 11 and a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 17, formulated for oral, topical, parenteral, or nasal administration.
1 g. A process for the manufacture of a pharmaceutical composition comprising admixing the compound of claim 1 , 2, 3, 10 or 11 with a pharmaceutically acceptable carrier.
20. An article of manufacture comprising packaging material; the pharmaceutical composition of claim 17; and instructions for use of the pharmaceutical composition in the treatment of obesity.
21. A process of manufacturing a compound having the structure:
Figure imgf000170_0001
wherein,
X is O, S, CH2 or NR5;
R is H, substituted or unsubstituted C1-C15 alkyl, Cι-C8 alkylaryl, ■ C(O)OR4, -C(O)NR4R5, -CR6R6 R4, -CR6R6 C(O)R4, -CR6R6 C(O)NHR7, -C(O)NR8R9, -C(O)NRsR9NR8R9- -N(R5)C(O)NHR5, or CH2R4;
R2 is a substituted or unsubstituted, straight chain d-C30 alkyl or branched C3-C3o alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl;
R3 is H or substituted or unsubstituted C C6 alkyl or cycloalkyl; R4 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, aryl, -CH2-aryl, arylalkyl, heteroarylalkyl or cycloalkyl;
R5 is H or a substituted or unsubstituted, straight chain or branched, C6-C3o alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
R6 and R6- are each independently H, substituted or unsubstituted CrC6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
R7 is H or substituted or unsubstituted C1-C12 alkyl or cycloalkyl;
R8 and R9 are each independently H, substituted or unsubstituted C Cβ alkyl, d-Cβ alkoxy, C Cβ alkylaryl, or NR8Rg together form a substituted piperazine or piperidine ring or a dihydro-1 H-isoquinoline ring system,
comprising
(a) reacting
Figure imgf000171_0001
in the presence of sulfur, a base and solvent to produce:
Figure imgf000171_0002
(b) reacting the product of step (a) with
Figure imgf000172_0001
in the presence of a base to produce:
Figure imgf000172_0002
(c) reacting the product of step (b) with trifluoroacetic acid (TFA) in the presence of solvent to produce:
Figure imgf000172_0003
(d) reacting the product of step (c) with SOCI2 in the presence of solvent to produce the compound.
22. The process of claim 21 , wherein the base in step (a) is triethyl amine and the solvent is dimethylformamide (DMF).
23. The process of claim 22, wherein the solvent in step (c) is dichloromethane.
24. The process of claim 23, wherein the solvent in step (d) is pyridine:CH2CI2.
25. A compound produced by the process of claim 21.
26. Use of the compound of claim 1 for manufacturing a medicament useful for treating obesity in a subject.
27. Use of the compound of claim 1 for manufacturing a medicament useful for treating diabetes in a subject.
28. Use of the compound of claim 1 for manufacturing a medicament useful for inhibiting the hydrolytic activity of pancreatic lipase enzymes in a cell.
2g. The compound of claim 1 , wherein any heterocyclic or heteroaryl ring, if present, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.
30. The compound of any one of claims 1, 2, 3, 5-0, or 13 wherein any substituent, if present, is halogen, hydroxyl, straight chain (CrC30)alkyl, branched chain (C3-C30) alkyl, (C3-Cι0)cycloalkyl, straight chain(d- C3o)alkylcarbonyloxy, branched chain (C3-C3o)alkylcarbonyloxy, arylcarbonyloxy, straight chain(CrC30)alkoxycarbonyloxy, branched chain(C3-C3o)alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, straight chain(Cι-C30)alkylcarbonyl, branched chain (C3-C30)alkylcarbonyl, straight chain (Cι-C30)alkoxycarbonyl, branched chain (C3-C30)alkoxycarbonyl, aminocarbonyl, straight chain (Cι-C3o)alkylthiocarbonyl, branched chain (C3-C30)alkylthiocarbonyl, straight chain (CrC3o)alkoxyl, branched chain (d-C3o)alkoxyl, phosphate, phosphonato, cyano, amino, straight chain (d- C30)alkylamino, branched chain (C3-C30)alkylamino, straight chain (C C30)dialkylamino, branched chain (C3-C30)dialkylamino, arylamino, diarylamino, straight chain (Cι-C30)alkylarylamino, branched chain (C3- C3o)alkylarylamino, acylamino, straight chain (Cι-C3o)alkylcarbonylamino, branched chain (C3-C30)alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, imino, sulfhydryl, straight chain (CrC3o)alkylthio, branched chain (C3-C30)alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trif luoromethyl, azido, 4-10 membered heterocyclyl, straight chain (CrC3o)alkylaryl, branched chain (C3- C3o)alkylaryl, benzo(1,3)dioxole, or an aromatic or 5-6 membered heteroaromatic moiety, which substituent may be further substituted by any of the above.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7407954B2 (en) 2001-08-30 2008-08-05 Alizyme Therapeutics Limited Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity
WO2016095205A1 (en) * 2014-12-19 2016-06-23 Merck Sharp & Dohme Corp. Heteroaryl orexin receptor antagonists

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090082435A1 (en) * 2005-04-28 2009-03-26 The Regents Of The University Of California Methods, Compositions, And Compounds For Modulation Of Monoacylglycerol Lipase, Pain, And Stress-Related Disorders
EP2414830A2 (en) 2009-03-31 2012-02-08 Robert Zimmermann Modulation of adipose triglyceride lipase for prevention and treatment of cachexia, loss of weight and muscle atrophy and methods of screening therefor
WO2010112569A1 (en) 2009-03-31 2010-10-07 Robert Zimmermann Modulation of adipose triglyceride lipase for prevention and treatment of cachexia, loss of weight and muscle atrophy and methods of screening therefor
ES2900519T3 (en) * 2012-06-22 2022-03-17 Univ Leuven Kath Novel Anticancer Thiophene Compounds
CN107216340B (en) * 2016-03-22 2021-05-04 中国科学院上海药物研究所 Salt form of DPPIV inhibitor and preparation method thereof
CN107216339B (en) * 2016-03-22 2021-05-04 中国科学院上海药物研究所 Polymorphism of DPPIV inhibitor maleate and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760063A (en) * 1985-11-14 1988-07-26 Bayer Aktiengsellschaft Thienooxazinones, processes for their preparation, and their use as growth promoters
WO1997048707A1 (en) * 1996-06-20 1997-12-24 Smithkline Beecham Plc 4h-3,1-benzoxazin-4-one derivatives and analogs as antiviral agents
WO1998045298A1 (en) * 1997-04-10 1998-10-15 Smithkline Beecham Plc Antiviral agents

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2447477A1 (en) * 1974-10-03 1976-04-15 Schering Ag Oxo-thieno-pyridine-carboxylic acid derivs. - prepd. by cyclizing 2-(2-thienylaminomethylene)malonic acid derivs.
US4054656A (en) * 1975-09-10 1977-10-18 Mead Johnson & Company Thieno[2,3-d]pyrimidine antiallergic agents
JPS5772979A (en) * 1980-08-27 1982-05-07 Eastman Kodak Co Manufacture of thiophenes
GB8311426D0 (en) * 1983-04-27 1983-06-02 Beecham Group Plc Compounds
CA1247547A (en) 1983-06-22 1988-12-28 Paul Hadvary Leucine derivatives
JPS62132884A (en) * 1985-12-05 1987-06-16 Mitsubishi Chem Ind Ltd 2-benzylthieno(2,3-d)pyrimidin-4(3h)-one derivative
DE4039734A1 (en) * 1990-12-13 1992-06-17 Basf Ag SUBSTITUTED 2-AMINOTHIOPHENE CONTAINING HERBICIDES
GB9426021D0 (en) 1994-12-22 1995-02-22 Smithkline Beecham Plc Pharmaceuticals
WO1997027200A1 (en) 1996-01-26 1997-07-31 Smithkline Beecham Plc Thienoxazinone derivatives useful as antiviral agents
US6037340A (en) * 1997-05-28 2000-03-14 Cadus Pharmaceutical Corporation Synthesis and use of thiophene- and pyrrole-based heteroaromatic compounds
GB9710928D0 (en) 1997-05-29 1997-07-23 Smithkline Beecham Plc Pharmaceuticals
WO2000030646A1 (en) 1998-11-26 2000-06-02 Novo Nordisk A/S Heterocyclic compounds regulating clotting
AR022204A1 (en) * 1999-01-08 2002-09-04 Norgine Bv COMPOUND, PROCESS FOR PREPARATION, PHARMACEUTICAL COMPOSITION AND EDIBLE PRODUCT THAT UNDERSTANDS IT.
GB9900416D0 (en) * 1999-01-08 1999-02-24 Alizyme Therapeutics Ltd Inhibitors
DK1159279T3 (en) * 1999-03-09 2003-02-17 Upjohn Co 4-Oxo-4,7-dihydro-thieno [2,3-b] pyridine-5-carboxamides as antivirals
WO2001018181A2 (en) * 1999-09-10 2001-03-15 The Procter & Gamble Company Enzyme inhibitors
GB0001572D0 (en) * 2000-01-24 2000-03-15 Alizyme Therapeutics Ltd Inhibitors
CA2458213A1 (en) * 2001-08-30 2003-03-13 Alizyme Therapeutics Limited Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760063A (en) * 1985-11-14 1988-07-26 Bayer Aktiengsellschaft Thienooxazinones, processes for their preparation, and their use as growth promoters
WO1997048707A1 (en) * 1996-06-20 1997-12-24 Smithkline Beecham Plc 4h-3,1-benzoxazin-4-one derivatives and analogs as antiviral agents
WO1998045298A1 (en) * 1997-04-10 1998-10-15 Smithkline Beecham Plc Antiviral agents

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GUTSCHOW ET AL.: "2-(Diethylamino)thieno(1,3)oxazin-4-ones as stable inhibitor of human leucocyte elastase", J. MED. CHEM., vol. 42, 1999, pages 5437 - 5447, XP002220079 *
GUTSCHOW ET AL.: "Novel thieno(2,3.d)(1,3)oxazin-4-ones as stable inhibitor of human leucocyte elastase", J. MED. CHEM., vol. 41, 1998, pages 1729 - 1740, XP002966559 *
See also references of EP1467978A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7407954B2 (en) 2001-08-30 2008-08-05 Alizyme Therapeutics Limited Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity
WO2016095205A1 (en) * 2014-12-19 2016-06-23 Merck Sharp & Dohme Corp. Heteroaryl orexin receptor antagonists
US10239838B2 (en) 2014-12-19 2019-03-26 Merck Sharp & Dohme Corp. Heteroaryl orexin receptor antagonists

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CN1620439A (en) 2005-05-25
JP4668536B2 (en) 2011-04-13
US20030195199A1 (en) 2003-10-16
EA009368B1 (en) 2007-12-28
EP1467978A4 (en) 2005-11-02
KR20040068316A (en) 2004-07-30
EA200400831A1 (en) 2005-08-25
US7064122B2 (en) 2006-06-20
CA2471098A1 (en) 2003-07-03
EP1467978A1 (en) 2004-10-20
MXPA04005863A (en) 2004-10-29
AU2002366810B2 (en) 2009-06-11
JP2005518383A (en) 2005-06-23
BR0215080A (en) 2004-10-05
AU2002366810A1 (en) 2003-07-09

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