AP333A - Phenyl-substituted pyridyl aliphatic compounds for treating leukotriene-related diseases. - Google Patents

Phenyl-substituted pyridyl aliphatic compounds for treating leukotriene-related diseases. Download PDF

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AP333A
AP333A APAP/P/1992/000428A AP9200428A AP333A AP 333 A AP333 A AP 333A AP 9200428 A AP9200428 A AP 9200428A AP 333 A AP333 A AP 333A
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methoxyphenyl
carboxyethenyl
phenyl
thia
ethyl
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APAP/P/1992/000428A
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Pamela Anne Chambers
Robert A Daines
Dalia R Jakas
William D Kingsbury
Israel Pendrak (Nmi)
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Smithkline Beecham Corp
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

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Abstract

This invention relates to certain acids and amines which are useful as leukotriene antagonists.

Description

COMPOUNDS FOR TREATING LEUKOTRIENE-RELATED DISEASES
Scope of the Invention
This invention relates to certain compounds containing a substituted pyridyl group linked to a substituted phenyl group by an alkyl or heteroatom-containing tether and their use for treating diseases arising from or related to leukotrienes, particularly leukotriene B4. As such their utility lies in antagonizing the effects of leukotrienes.
Background of the Invention
The family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular, and gastrointestinal systems. The leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C4, D4 and E4) and the dihydroxyleukotrienes (leukotriene B4). This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes.
Leukotrienes are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic Fibrosis, psoriasis, and inflammatory bowel disease.
LTB4 has been established as an inflammatory mediator in vivo. It has also been associated with airway hyper-responsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction.
By antagonizing the effects of LTB4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the present invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a factor.
Summary of the Invention
This invention relates to novel compounds of formula I
3C or an N-oxide, or a pharmaceutically acceptable salt where Z is O, NH, NCH3 or S(O)q where q is 0> 1 or 2, m is 0 - 5;
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R is Cj to C2()-aliphatic, unsubstituted or substituted phenyl Cj to CjQ-aliphatic where substituted phenyl has c>ne or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is Cj to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl Cj to CiQ-aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
Rj is -(Ci to C5 aliphatic)R4, -(Cj to C5 aliphaticjCHO. -(Ci to C5 aliphatic)CH2ORg, -R4, -CH2OH, or CHO;
R2 is H, halo, lower alkyl, lower alkoxy, -CN, -(ΟΗ2)η^4, -CH(NH2)(R4), or -(CH2)nR9 where n is 0 - 5 and where R9 is -N(R7>2 where each R7 is independently H, or an aliphatic group of 1 to 10 carbon atoms, or acyl of 1-6 carbon atoms, or a cycIoalkyl-(CH2)n- group of 4 to 10 carbons where n is 0-3, or both R7 groups fam a ring having 4 to 6 carbons; or
R3 is hydrogen, lower alkyl, lower alkoxy, halo, -CN, COR5, NHCONH2, or
OH;
each R4 group is independently -COR5 where R5 is -OH, a pharmaceutically acceptable ester-forming group -OR6, or -OX where X is a pharmaceutically acceptable cation, or R5 is -N(R7)2 where each R7 is independently H, or an aliphatic group of 1 to 10 carbon atoms, or a cycloalkyl-(CH2)n- group of 4 to 10 carbons where n is 0-3, or both R7 groups form a ring having 4 to 6 carbons, or R4 is a sulfonamide, or an amide, or tetrazol-5-yl; and
Rg is hydrogen, Cj to (¼ alkyl, or Ci to C6-acyl, with the proviso that R2 and R3 are not 2,6-dihalo, 2,6-di(lower alkyl), 2,6diflower alkoxy) or 2,6-dicyano.
In another aspect, this invention covers pharmaceutical compositions containing the instant compounds and a pharmaceutically acceptable excipient.
Treatment of diseases related to or caused by leukotrienes, particularly LTB4, or related pharmacologically active mediators at the end organ are within the scope of this invention. This treatment can be effected by administering one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient.
Processes for making these compounds are also included in the scope of this invention, which processes comprise:
a) forming a salt, or
b) hydrolyzing an ester to give a salt or acid;
c) forming an ester,
d) forming an amide;
e) oxidizing a thio ether;
BAD ORIGINAL fi
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f) forming a compound of formula I by treating a 6halomethylpyridyl compound with tha appropriate mercaptobenzoate or hydroxybenzoate.
DETAfLED DESCRIPTION OF THE INVENTION
The following definitions are used in describing this invention and setting out what the inventors believe to be their invention herein.
Aliphatic is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination. The phrase lower alkyl means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form. Lower alkoxy means the group lower alkyl-O-. Halo means fluoro, chloro, bromo or iodo. Acyl means the radical having a terminal carbonyl carbon.
When reference is made to a substituted phenyl ring, it is meant that the ring can be substituted with one or more of the named substituents as may be compatible with chemical synthesis. Multiple substituents may be the same or different, such as where there are three chloro groups, or a combination of chloro and alkyl groups and further where this latter combination may have different alkyl radicals in the chloro/alkyl substituent pattern.
The phrase a pharmaceutically acceptable ester-forming group in R2 and R3 covers all esters which can be made from the acid function(s) which may be present in these compounds. The resultant esters will be ones which are acceptable in its application to a pharmaceutical use. By that it is meant that the mono or diesters will retain the
5 biological activity of the parent compound and will not have an untoward or deleterious effect in their application and use in treating diseases. Such esters are, for example, those formed with one of the following radicals: Cl to C6 alkyl, phenyl Cl-C6alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl. The most preferred ester-forming radicals are those where R3 is alkyl, particularly alkyl of 1 to 10 carbons, (ie CH3(CH2)n* where n is 0-9), or phenyl-(CH2)n- where n is 0-4.
When R2 is referred to as being an amine, that includes the radical -NH2 and mono- or dialkylate derivatives of this -NH2 radical. Preferred alkylated amines are the mono- or disubstituted amines having 1 to 6 carbons. When R2 is referred to as being an amide, that includes all acylate derivatives of the NH2 radical. The preferred amides are those having 1 to 6 carbons._______________________ ______ bad original
P50046-1-2
Where there is an acid group, amides may be formed. The most preferred amides are those where -R^ is hydrogen or alkyl of 1 to 6 carbon atoms. Particularly preferred is the diethylamide or dimethylamide.
Pharmaceutically acceptable salts of the instant compounds are intended to be 5 covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
Pharmaceutically acceptable salts are prepared in a standard manner, in a suitable 10 solvent. The parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of acid addition salts, or an excess of organic or inorganic base in the case where R4 is OH.
N-oxides may also be prepared by means of selected oxidizing agents. These oxides are useful as intermediates in preparing the compounds of formula I and have useful pharmaceutical activity in and of themselves. Hence one can administer the Noxides of formula I to a subject who is susceptible to or is suffering from a disease related to or caused by LTB4 or similar leukotrienes.
If by some combination of substituents, a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are intended to be covered herein. These compounds may be used as a racemic mixture or the racemates may be separated and the individual enantiomer used alone.
Olefins may have the cis or trans configuration (E or Z); either are useful in the practice of this invention.
As leukotriene antagonists, these compounds can be used in treating a variety of
5 disease assoicated with or attributing their origin or affect to leukotrienes, particularly LTB4. Thus it is expected that these compounds can be used to treat allergic diseases such of a pulmonary and non-pulmonary nature. For example these compounds will be useful in antigen-induced anaphylaxis; for treating asthma and allergic rhinitis; psoriasis, or irritable bowel disease; ocular diseases such as uveitis, and allergic conjunctivitis.
The preferred compounds are those where Z is O or S(O)q; m is 0-3; n is 0-2; R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted pheny-Cj to C]0aliphatic-O-; and R] is -(Cj to C5 aliphaticjFCj or -(Ci to C5-aliphatic)CH2ORg. The more preferred compounds of this invention are those where Rj is R4CH=CH- and R2 is -COR5 or -NHSO2CF3. Another set of preferred compounds are the anilines, those where R2 is N(R7>2, particularly where R7 is hydrogen. A third set of preferred compounds are those where both R2 and R3 are hydrogen.
The most preferred compounds are:_____
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1- fluoro-3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy]6-pyridyl]propyl]benzene, lithium salt;
3-[2-thia-3-[2-(E-2-carboxyethenyl )-3-(4-t4-methoxyphenyl)buty loxy ]-6pyridyl]propyl]benzene, lithium salt;
3-(2-thia-3-(2-(2-carboxyethanyl)-3-(4-(4-methoxyphenyljbutyloxy]-6pyridyl]propyl]benzene, lithium salt;
2- [2-thia-3-[2-(2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy]-6pyridyl]ethyl]benzene, lithium salt;
l-fluoro-4-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-610 pyridyl]propyl]benzene, lithium salt;
1- fluOTo-4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]6-pyridyl]propyl]benzene, lithium salt;;
3- (l'thia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyIoxy]-6pyridyl]ethyl]benzoic acid,
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy]-6pyridyl]ethyl]benzoic acid,
3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid,
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid,
3-[l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid,
2- [l-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, lithium salt
N-[3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]25 phenyljtrifluoromethanesulfbnamide,
N-[3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl)trifluoromethanesulfonamide,
N-[3-(l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]-trifluoromethanesulfonamide,
N-[3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]-phenyl su 1 fon amide,
N-[3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]-phenyl]phenylsulfonamide,
3- [l-oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid,
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyl]ethyl)benzoic acid,
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octan-l-yl)-6pyridyl]ethyl]benzoic acid, _______________________________
BAD ORIGINAL ft
P50046-1-2
4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-metboxypbenyl)octyloxy]-6pyridyljpropyl]benzoic acid,
4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyljpropyljbenzoic acid,
3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyljpropyljbenzoic acid,
3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyl]propyl]benzoic acid,
3-[2-thia-3-[2-(2-carboxyethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyljpropyljbenzoic acid,
3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyIoxy)-6pyridyl]propyl]-N,N,-dimethylbenzamide, lithium salt
3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6pyridylJpropyl]-N,N-dimethylbenzamide, lithium salt,
3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-phenylbutyloxy]-6pyridyl]propyl]benzoic acid,
3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-phenyloctyloxy]-6pyridyljpropyl]benzoic acid,
3- [2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyljpropyljbenzoic acid,
4- [2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyljpropyljphenylacetic acid,
4-[2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyljpropyljbenzoic acid,
3- [2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyljpropyljbenzoic acid,
4- [2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyljpropyljphenylacetic acid,
3-[2-dioxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyljpropyljbenzoic acid,
5- [3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxv]-6pyridyljpropyljphenyljtetrazole
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyljethyljaniline,
5-carboxy-3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,
3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyljethyljaniline, _______________________ _____
BAD original A
P50046-1-2
3-(l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trinuoromethylphenyl)octyloxy)-6pyridyl]ethyl]aniline,
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)octyloxy)6-pyridyI]ethyl]aniline, lithium salt
3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyloctyloxy)-6pyTidyl]ethyl]aniline, lithium salt
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-fluorophenyl)octyloxy)-6pyridyl]ethyl]aniline,
3-[l-oxythia-2-(2-(E-2-carboxyethenyl)-3-(8-phenyl)octyloxy)-610 pyridyl]ethyl]aniline,
3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]-N,N-dimethylaniline,
3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6pyridyl]ethyl]aniline, lithium salt
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6pyridyl]ethyl]aniline, lithium salt
3-[l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyI)butyloxy)-6pyridyl]ethyl]anilinc, lithium salt
3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-620 pyridyl]propyl]-N,N-dimethylaniline,
3-[ l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]aniline,
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]-N,N-dimethylaniline,
3-[l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]aniline, (E)-sodium 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(phenylthio)methylJ2-pyridinyl]-2-propenoate (E)-lithium 3-[3-[4-(4-methoxypheny!)butyloxy]-6-[(3,43 0 dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoate (E)-lithium 3-[3-[4-(4-methoxyphenyl)butyloxy]6-((4-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butyloxyi-6-[(4-fluorophenylthio)methyl]2-pyridinyl]-2-propenoate (E) lithium 3-[3-(4-(4-methoxyphenyl)butyloxy]-6-[(2-chlorophenylthio)methyl]2-pyridinyl-2-propenoate, (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2-chlorobphenylthio)methyl]2-pyridinyl]-2-propenoate _ bad original
P50046-1-2 (E)-sodium 3-(3-[4-(4-methoxyphenyl)butoxy]-6-[(2-methylphenylthio)methyl]2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(3-chlorophenylthio)methyl]2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2methoxyphenylthio)methyl]-2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2,4dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2-bromobenzylthio)methyl]2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2-cyano-6chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate.
Synthesis
There are several methods for preparing these compounds. One generic process comprises preparing a 6-(halomethyl)pyridyl adduct and then condensing this fragment with the appropriate mercaptan or alcohol to make compounds where Z is sulfur or oxygen. Usually, functional groups such as acid groups will be protected; any acid group may be derivatized in some manner to render it unreactive. After the condensation reaction, protecting groups may be removed to provide the parent functionality, e.g. an acid. Further modification of these reactive groups can then be carried out, such as forming a salt, an amide, an ester or the like. Sulfonamides are prepared from the corresponding amines by literature methods. Tetrazoles are prepared from the corresponding acid halide, e.g., the acid chloride, by literature methods.
More specific illustrations of chemistry for making these compounds is provided in the following reaction schemes. Scheme I outlines a means for making a substituted phenylalkyl tail which is R.
Scheme I
OH
ΚΑΡΑ
BuPh2SiCI
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P50046-1-2
The starting alcohol, represented here as the 3-octyn-l-ol, is commercially available (Lancaster Synthesis). To migrate the triple bond to the w-carbon, KH and 1,3diaminopropane are combined and stirred to a homogeneous mix. This can be done at ambient temperature or thereabouts. This mix is then cooled, preferably to about 0°C or thereabouts, whereupon the alcohol is added. Stirring is then commenced at about room temperature for 15 to 20 hours or so. Water is added to quench the reaction and the product is recovered.
Protecting the alcohol is accomplished by forming a silyl ether illustrated here as the f-butyldiphenylsilyl ether. Other silyl ethers could be used. The alcohol is dissolved in a polar solvent, for example dimethylformamide, and imidazole is added followed by the desired silane. All this is carried out under an inert atmosphere such as argon. Ambient temperature is acceptable for effecting the reaction.
Adding the phenyl group is done in a dry environment using an amine for a solvent and an inert atmosphere. To a flask containing a solvent such as triethylamine under argon is added the silylether followed by a halophenyl compound, eg. iodoanisole, a palladium catalyst (Ph3P)2PdCl2 and Cul, both of the latter in catalytic amounts. Heat is used to effect the reaction, usually a temperature of up to about 50°C will be sufficient. Two or more hours, up to six but often about four at the elevated temperature will usually cause the reaction to go to completion.
The triple bond is then saturated, preferably by catalytic hydrogenation. For example, the silyl ether can be dissolved in a saturated solvent such as an alcohol, a heavy metal catalyst added (Pd-C) and the mixture put under H2 for a time sufficient to reduce the triple bond. Stirring for 2 to 6 hours will usually effect the reaction.
Recovering the alcohol is done by treating the silyl ether with a fluoride source such as tetrabutylammonium fluoride. Reactants are combined at a mildly reduced temperature, eg. 0°C, then the reaction is allowed to run its course at ambient temperature
BAD ORIGINAL ft
P50046-1-2 or there about. Several hours may be needed for the reaction to go to completion. Product was recovered by extraction means.
Converting the alcohol to the iodo compound is accomplished using a phosphine, imidazole and I2· In actual practice, this transformation is accomplished by adding to a solution of alcohol under argon, a molar excess of triphenylphosphine, for example, and a three-fold excess of imidazole followed by iodine. Materials are combined at room temperature, but then the reaction pot may be heated to between 50 - 70°C for a brief period, 10 minutes to an hour to complete the reaction. Standard procedures are then used to recover and purify the product.
Scheme Π illustrates an alternative process for making R groups.
Scheme Π
While the methoxyphenyl compound is illustrated here, this series of steps and reagents may be used to make other substituted-w-phenylaliphatic groups denoted by R. The starting material, the benzaldehydes, are commercially available or can be readily made by known methods.
To make the acid, first an alky lsi lazide is added to an inert solvent under an inert atmosphere. Then the phosphonium salt is added. This addition can be done at room temperature or thereabouts. After a brief period of mixing, this mixture is usually a suspension, the benzaldehyde is added slowly at about room temperature. A slight molar excess of the phosphonium salt is employed. After an additional brief period of stirring at about room temperature, the reaction is quenched with water. The solution is acidified and the acid extracted with a suitable organic solvent. Further separatory and purification procedures may be employed as desired.
The alcohol is made by reducing the acid using a reducing agent. Lithium aluminum hydride or similar reducing agents may be employed, and conditions may be varied as needed to effect the reduction.
The tosylate is prepared in an inert solvent employing a base such as pyridine.
Suitable conditions include carrying out the reaction at room temperature or thereabouts for a period of 1 to 5 hours. Other leaving groups similar in function to the tosylate may be prepared and will be useful as a means for forming the R moiety._
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These procedures can be used to make the full spectrum of radicals represented by
R where it has a terminal phenyl group, including the substituted phenylaliphatic radicals.
Benzyl mercaptans, or analogous compounds where m is 1 or greater, are commercially available or may be made by the process of Scheme III.
Scheme ΠΙ XT0!-CO2R
X= Cl, Br R= alkyl
S h2n nh2 „ Base + J T TTC°2R -► lglN IXrlg
Br
H
Alcohol
Acid
-|f^-CO2Me
Starting material, the haloalkylbenzoates, are commercially available or can be made by methods known in the ait. Thiourea is added to a solution of haloalkylbenzoate at ambient temperature or thereabouts. Any appropriate solvent may be used, acetone for example. A precipitate of the thiouronium salts should form under these conditions. The precipitate is collected and dissolved in water and the pH adjusted to about 10.5 with a base, for example a solution of NaOH. Refluxing is then commenced for between 1 and 4 hours. Product, as the free acid, is then recovered by some other separatory and purification means. Esterification is then carried out by mixing the acid with an alcohol, bubbling HCI through the solution, and letting sit the resulting solution for a time not more than several days; two days usually is sufficient to effect the reaction.
Compounds of formula I where Z is oxygen can be made by the sequence of steps given in Scheme IV.
Scheme IV
HO
HO
1. MnO2, CH2CI2
2. C12H25I, K2CO3 CH 3· (Ph)3PCHCO2Me
H25C12OS
MeO2C^ N'^CH3
1. MCPBA, CH2CI2
2. TFAA, DMF
3. K2CO3, MeOH
4. SOCI2
H25C12O
COoMe
MeO2C^^N CH2CI HCI (n-Bu)4N I’. K2CO3 bad original
P50046-1-2
MeO
1. LiOH, THF, MeOH h2_c (2c)
2. H+ CO2Me
HO2C
MCPBA
Μθ<
The starting material is available from Aldrich. It is treated with a mild oxidizing agent such as Mn02 to oxidize the 2-hydroxyethyl group to the corresponding aldehyde. The R group is then formed. In this case an ether is prepared under basic conditions using an a-halo intermediate. A tosylate made as per Scheme III, can also be used in this step. Introducing the acid function at position 2 is accomplished by means of a triphenylphosphoranylidene reagent. The acetate form is illustrated here but other similar reagents could be used. The N-oxide is then formed by means of a peroxy acid. Trifluoroacetic anhydride is used to oxidize the 6-position methyl group. This hydroxymethyl group is then converted to the corresponding halide, (in the hydrohalide form) in this case the chloride, by means of thionyl chloride. An alkyl hydroxybenzoate is then reacted with the 6-chloromethyI compound in the presence of tetrabutylammonium iodide and a weak base. The resulting diester can be hydrolyzed to the salt or, further, acidified to give the free acid. An oxidant can be used to regenerate the N-oxide which can then be treated with base to hydrolyze the esters. Esters can be converted to salts, the free acids and other derivatives. Catalytic hydrogenation can be used to reduce the
2C double bond in the Rj group described here.
Scheme V illustrates a method for making compounds where Z is a S and m is 0.
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P50046-1-2
Scheme V
MCPBA aq LiOH
CO2H
The starting hydrochloride is described in Scheme IV. Instead of treating the hydrochloride with an alcohol, in this instance the mercapto analog of the hydroxybenzoate described above is used. The resulting thioether can be hydrolyzed to give the salt or treated further to give the free acid from which other derivatives of the carboxyl function can be prepared, including alcohols and aldehydes. Also, the double bond in the Rj group can be reduced by catalytic means using a heavy metal catalyst and hydrogen.
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Once the thioether is prepared, the sulfone and sulfoxide can be prepared by treating the thioether with an oxidizing agent. A peroxy acid or other oxidizing agent can be used.
A method for making compounds where R is alkyl or subsituted alkyl is given in 5 Scheme VI
Scheme VI
HO
HO2C
Rn
MeO2C^hr
1. HCl/MeOH _
2. Tf2O / pyridine
TfO
MeO2C
1. DIBAL_
2. (C6H5)3PCHCO2Me MeO2C r-£Q »
Pd(OAc)2 / dppf / DMF
1. MCPBA
2. TFAA, DMF r
3. Tf2O, pyridine
4. Pd(OAc)2, dppf MeOH, CO
In this Scheme, 2-hydroxypicolinic acid is converted to the alkyl ester using the corresponding alcohol and an acid to catalyze the reaction. The hydroxyl group is then converted to the trifluoromethysulfonate by means of trifluoromethanesulfonic anhydride and a base, e.g. pyridine. The lipid tail is attached using the appropriate alkyl catechol boronate under palladium coupling conditions. For example, 1-iododecene and catechol borane are reacted to form the alkyl catechol boronate. Then the alkylation reaction is effected using Pd(OAc)2- The ester is reduced to the corresponding aldehyde with a hydride such as diisobutylaluminum hydride (DIBAL). A Wittig olefination is then___
©AD ORIGINAL 0
P50046-1-2 carried out using, for example, methyl(triphenylphosphoranylidene)acetate. The resulting pyridyl methyl acrylate is then oxidized to the N-oxide with an oxidizing agent such as 3-chloroperoxybenzoic acid. This oxide is then rearranged to the 2-pyridone with trifluoroacetic anhydride. A trifluoromethylsulfonate is then formed using trifluoromethanesulfonic anhydride and pyridine. Carbomethylation is then effected by means of Pd(OAc)2, a simple alcohol, and carbon monoxide. Selectively reducing the pyridyl-ester (using a hydride such as NaBH4 in a low molecular weight alcohol) yields the 2-(hydroxymethyl)-pyridine. This compound is treated with thionyl chloride to form the 6-chloromethyl compound. This intermediate is transformed to the ethers or thioether of formula I in the same manner as is illustrated in Schemes IV - VL
Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of the formula (I)· The compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the compositon to effect the treatment intended. These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.
The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension.
For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, and drops suitable for administration to the eye, ear, or nose.
For oral administration the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, com oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
_________
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The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
Formulations for treating psoriasis can take the form of oral or topical 5 preparations. Topically applied formulations are preferred. Ointments, creams, liniments, lotions, pastes and similar preparations are examples of preferred topical formulations. Aerosols may also be used. These dosage forms will contain between 0.01 and 5 percent by weight of the active ingredient.
Usually a compound of formula 1 is administered, that is applied, to a subject in a 10 composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease state. When administered orally, the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg. When a topical formulation is used, the amount applied will depend on the size of the affected area and the severity and progress of the disease, ie. psoriasis.
Included within the scope of this disclosure is the method of treating a disease mediated by LTB4 which comprises administering to a subject a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition. For example, inhibiting the inflammatory response resulting from psoriasis by administration of an effective amount of a compound of formula I is included within the scope of this disclosure. The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically required. However, the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the condition or disease being treated, and so forth.
Pharmaceutical compositions and their method of use also include the combination of a compound of formula I with Hj blockers where the combination contains sufficient amounts of both compounds to treat antigen-induced respiratory anaphylaxis or similar allergic reaction. Representative H1 blockers useful here include: cromolyn sodium, compounds from the ethanolamines class (diphenhydramine), ethylenediamines (pyrilamine), the alkylamine class (chlorpheniramine), the piperazine class (chlorcyclizine), and the phenothiazine class (promethazine). Hj blockers such as
2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid-3-yl)methyl]-4pyrimidone are particularly useful in this invention.
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Bioassays
The specificity of the antagonist activity of a number of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, carbachol, histamine and PGF2.
The receptor binding affinity of the compounds used in the method of this invention is measured by the ability of the compounds to bind to [^H]-LTB4 binding sites on human U937 cell membranes. The LTB4 antagonist activity of the compounds used in the method of this invention is measured by their ability to antagonize in a dose dependent manner the LTB4 elicited calcium transient measured with fura-2, the fluorescent calcium probe. The methods employed were as follows:
U-937 Cell Culture Conditions
U-937 cells were obtained from Dr. John Bomalaski (Medical College of PA) and Dr. John Lee (SmithKline Beecham Corp., Dept. of Immunology) and grown in RPMI1640 medium supplemented with 10% (v/v) heat inactivated fetal calf serum, in a humidified environment of 5% CO2,95% air at 37°C. Cells were grown both in T-flasks and in Spinner culture. For differentiation of the U937 cells with DMSO to macrophagelike cells, the cells were seeded at a concentration of 1 x 10^ cells/ml in the above medium with 1.3% DMSO and the incubation continued for 4 days. The cells were generally at a density of 0.75-1.25 x 10^ cells/ml and were harvested by centrifugation at 800 x g for 10 min.
Preparation of U-937 Cell Membrane Enriched Fraction
Harvested U-937 cells were washed with 50 mM Tris-HCl, pH 7.4 at 25° C containing 1 mM EDTA (buffer A). Cells were resuspended in buffer A at a concentration of 5 x 10? cells/ml and disrupted by nitrogen cavitation with a Parr bomb at 750 psi for 10 min at 0°C. The broken cell preparation was centrifuged at 1,000 x g for 10 min. The supernatant was centrifuged at 50,000 x g for 30 min. The pellet was washed twice with buffer A. The pellet was resuspended at about 3 mg membrane protein/ml with 50mM Tris-HCl, pH 7.4 at 25°C and aliquots were rapidly frozen and stored at -70°C.
Binding of pHI-LTBd to U-937 Membrane Receptors pH]-LTB4 binding assays were performed at 25°C, in 50 mM Tris-HCl (pH 7.5) buffer containing 10 mM CaCl2, 10 mM MgCl2, pH]-LTB4, U937 cell membrane protein (standard conditions) in the presence or absence of varying concentrations of LTB4, or test compounds. Each experimental point represents the means of triplicate determinations. Total and non-specific binding of pH]-LTB4 were determined in the absence or presence of 2 mM of unlabeled LTB4, respectively. Specific binding was calculated as the difference between total and non-specific binding. The radioligand competition experiments were performed, under standard conditions, using
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P50046-1-2 approximately 0.2 nM [-H]-LTB4, 20-40 mg of U937 cell membrane protein, increasing concentrations of LTB4 (0.1 mM to 10 mM) or other competing ligands (0.1 mM to 30 mM) in a reaction volume of 0.2 ml and incubated for 30 minutes at 25°C. The unbound radioligand and competing drugs were separated from the membrane bound ligand by a vacuum filtration technique. The membrane bound radioactivity on the filters was determined by liquid scintillation spectrometry.
Saturation binding experiments for U937 cells were performed, under standard conditions, using approximately 15-50 mg of U-937 membrane protein and increasing concentrations of pH]-LTB4 (0.02-2.0 nM) in a reaction volume of 0.2 ml and incubation at 22°C, for 30 minutes. LTB4 (2 mM) was included in a separate set of incubation tubes to determine non-specific binding. The data from the saturation binding experiments was subjected to computer assisted non-linear least square curve fitting analysis and further analyzed by the method of Scatchard.
Loading Differentiated U-937 Cells with Fura-2
Harvested cells were resuspended at 2 x 10^ cells/ml in Krebs Ringer Hensilet buffer containing 0.1% BSA (RIA grade), 1.1 mM MgSO4, 1.0 mM CaCl2 and 5 mM HEPES (pH 7.4, buffer B). The diacetomethoxy ester of fura-2 (fura-2/AM) was added to a final concentration of 2 mM and cells incubated in the dark for 30 minutes at 37°C. The cells were centrifuged at 800 x g for 10 minutes and resuspended at 2 x 10^ cells/ml in fresh buffer B and incubated at 37°C for 20 minutes to allow for complete hydrolysis of entrapped ester. The cells were centrifuged at 800 x g for 10 minutes and resuspended in cold fresh buffer B at 5 x 10^ cells/ml. Cells were maintained on ice in the dark until used for fluorescent measurements.
Fluorescent Measurements - Calcium Mobilization
The fluorescence of fura-2-containing U937 cells was measured with a fluorometer designed by the Johnson Foundation Biomedical Instrumentation Group. A fluorometer was equipped with temperature control and a magnetic stirrer under the cuvette holder. The wave lengths are set at 339 nm for excitation and 499 nm for emission. All experiments were performed at 37°C with constant mixing.
U-937 cells were diluted with fresh buffer (B) to a concentration of 1 x 10^ cells/ml and maintained in the dark on ice. Aliquots (2 ml) of the cell suspension were put into 4 ml cuvettes and the temperature brought up to 37°C, (maintained in 37°C, water bath for 10 min). Cuvettes were transferred to the fluorometer and fluorescence measured for about one minute before addition of stimulants or antagonists and followed for about 2 minutes post stimulus. Agonists and antagonists were added as 2 ml aliquots.
Antagonists were added first to the cells in the fluorometer in order to detect potential agonist activity. Then after about one minute 10 nM LTB4 (a near maximal
P50046-1-2 effective concentration) was added and the maximal Ca-+ mobilization was calculated using the following formula:
'u-.· ->·, JF-F/zu'zi] lCa’ *1' = 22*tFi^7Fj
F was the maximum relative fluorescence measurement of the sample. Fmax was determined by lysing the cells with 10 ml of 10% Triton X-100 (final Concentration 0.02%). After Fmax was determined 67 mJ of 100 mM EDTA solution (pH 10) was added to totally chelate the Ca2+ and quench the fura-2 signal and obtain the Fmin. The [Ca2+]i level for 10 nM LTB4 in the absence of an antagonist was 100% and basal [Ca2+]i was 0%. The IC50 concentration is the concentration of antagonist which blocks 50% of the lOnM LTB4 induced [Ca2+]j mobilization. The EC50 for LTB4 induced increase in [Ca2+]j mobilization was the concentration for half maximal increase. The Kj for calcium mobilization was determined using the formula:
Ki =
1+
IC50
ILTB^ [EC50]
With the experiments described, the LTB4 concentration was 10 nM and the EC50 was 2 nM.
Specific Embodiments
The following examples are given to illustrate how to make and use the compounds of this invention. These Examples are just that, examples, and are not intended to circumscribe or otherwise limit the scope of this invention. Reference is
5 made to the claims for defining what is reserved to the inventors by this document.
Example 1
8-(4-Methoxvphenyl)octan-1 -(4-toluenesulfonate)
1(a) 7-Octvn-l-ol,
35% KH in mineral oil (27g, 240mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0°°C and 3octyn-l-ol (lOg, 79mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O
5 (50mL) and the product was extracted into ether. The organic layer was washed with
10% HCl (3X15mL) and brine and dried (MgSO4). Evaporation gave the title product which was used without further purification: NMR (90MHz, CDCI3) d 3.65 (t,
P50046-1-2
J=5 Hz, 2H, OCH2), 2.23 (m, 2H, CH2), 2.0 (m, IH, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) umax 3350, 2930, 2125 crn'l.
1(b) 7-Octyn-l-r-butyldiphenvlsilyl ether,
7-Octyn-l-ol (3.8g) was dissolved in dimethylformamide (lOmL) and treated with r-butylchlorodiphenylsilane (10.2mL, 33mmol) and imidazole (3.65g, 45mmol) at O>= C. The reaction was stirred at 0°« C for 10 minutes and at room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue purified by flash column chromatography (silica, hexanes) to give a yellow oil: NMR (250MHz, CDCl3)d7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl),
3.63 (t, 2H, OCH2), 2.23 (m, 2H, CH2), 1.97 (t, IH, acetylenic), 1.6-1.3 (m, 8H, (CH2)4). 105 (s. 9H, r-butyl); IR (filrn)umax 3321, 2940, 2125 cm*L
1(c) 8-(4-Methoxyphenyl)-7-octyn-l-r-butyldiphenylsilyl ether
To a flame-dried flask under an argon atmosphere was added 4-iodoanisole (5.34g, 22mmol) in triethyiamine (50mL) followed by the addition of 7-octyn-l-tbutyldiphenylsilyl ether (9.84g, 27mmol), (Ph3P)2PdCl2 (350mg, 0.44mmol), and Cul (200mg, O.88mmol). The resulting mixture was heated at 50°°C for 4 hours Upon
0 cooling to room temperature the reaction mixture was filtered and the solvent evaporated. The residue was partitioned between ethyl acetate and H2O and the organic layer was collected and washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 1% ethyl acetate in hexanes) to give an oil: NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H,
5 aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.7 (t, 2H, OCH2), 2.4 (t, 2H, CH2), 1.7-1.3 (m, 8H, (CH2)4), 1.05 (s, 9H, r-butyl).
1(d) 8-(4-Methoxyphenyl)octan-l-r-butvldiphenvlsilyl ether.
To 8-(4-methoxyphenyl)-7-octyn-l-t-butyldiphenylsilyl ether (2.16g, 4.6mmol) in ethanol (lOmL) and ethyl acetate (10 mL) was added 5% Pd/C (lOOmg). The mixture was subjected to 75 psi of H2 for 4 hours. The reaction was filtered through Celite and the solvent evaporated to give an oil: NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl),
7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH2), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6). 10 (s, 9H, r-butyl).
1(e) 8-(4-Methoxyphenyl)octan-l-ol,
8-(4-Methoxyphenyl)octan-l-r-butyldiphenylsilyl ether (2.18g, 4.6mmol) in tetrahydrofuran (20mL) was cooled to 0°°C and treated with tetrabutylammonium fluoride (14mL, 14mmol, IM in tetrahydrofuran). The cooling bath was removed and __—BAD ORIGINAL
P50046-1-2 the reaction was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 0-20% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCI3) δ 7.15 (d,
2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OCH3), 3.68 (t, 2H, OCH2), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6).
1(f) 8-(4-Methoxyphenyl)octan-l-(4-toluenesulfonate).
6-(4-Methoxyphenyl)octan-l-ol (5.9lg, 25mmol) was dissolved in dry CH2CI2 (100mL) under an argon atmosphere and cooled to O«C. To this was added pyridine (2.5mL, 30mmol) and 4-toluenesulfonyl chloride (5.4g, 28mmol). The reaction was stirred at 0°°C for 20 minutes and at room temperature for 24 hours. The reaction solution was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue purified by flash column chromatography (silica, 0-10% ethyl acetate in hexanes) to give a white solid: IH NMR (250MHz, CDCI3) δ 7.79 (d, 2H, aryl), 7.35 (d, 2H, aryl), 7.09 (d, 2H, aryl), 6.82 (d, 2H, aryl), 4.04 (s, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.55 (t, 2H, benzylic), 2.46 (s, 3H, CH3), 1.75-1.15 (m, 12H, (CH2)6).
Example 2
6-(4-MethoxyphenvDhexan-1 -(4-toluenesulfonate)
2(a) 5-Hexyn-l-f-butyldiphenylsilyI ether
5-Hexyn-l-ol (3g, 30mmol, Aldrich) was dissolved in dimethylformamide (lOmL) and treated with f-butylchlorodiphenylsilane (10.2mL, 33mmol) and imidazole (3.65g, 45mmol) at 0°°C. The reaction was stirred at O»C for 10 minutes and at room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H2O and brine and dried (Na2SO4).
The solvent was evaporated and the residue purified by flash column chromatography (silica, hexanes) to give a yellow oil: NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl),
7.4 (m, 6H, aryl), 3.65 (t, 2H, OCH2), 2.2 (m, 2H, CH2), 1.9 (t, 1H, acetylenic), 1.7 (m, 4H, CH2-CH2), 1.05 (s, 9H, r-butyl).
2(b) 6-(4-Methoxyphenyl)-5-hexyn-l-t-butyldiphenylsilyl ether.
To a flame-dried flask under an argon atmosphere was added 4-iodoanisole (5.34g, 22mmol) in triethylamine (50mL) followed by the addition of 5-hexyn-l-fbutyldiphenylsilyl ether (8.83g, 27mmol), (Ph3P)2PdCl2 (350mg, 0.44mmol), and Cul (200mg, O.88mmol). The resulting mixture was heated at 5O»C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered and the solvent evaporated.
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P50046-1-2
The residue was partitioned between ethyl acetate and H2O and the organic layer was collected and washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 1% ethyl acetate in hexanes) to give an oil: NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.7 (t, 2H, OCH2), 2.4 (t, 2H, CH2), 1.7 (m, 4H, CH2-CH2), 1.05 (s, 9H, (-butyl).
2(c) 6-(4-Methoxyphenyl)hexan-l-(-butyldiphenvlsilyl ether.
To 6-(4-methoxyphenyl)-5-hexyn-l-f-butyldiphenylsilyl ether (2.0g, 4.6mmol) in ethanol (lOmL) and ethylacetate (lOmL) was added 5% Pd/C (lOOmg). The mixture was subjected to 75 psi of 1¾ for 4 hours. The reaction was filtered through Celite and the solvent evaporated to give an oil: NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH2), 2.5 (t, 2H, benzylic), 1.55 (m, 4H, CH2-CH2), 1.3 (m, 4H, CH2-CH2), 1.0 (s, 9H, (-butyl).
2(e) 6-(4-Methoxyphenyl)hexan-1 -ol,
6-(4-Methoxyphenyl)hexan-l-r-butyldiphenylsilyl ether (2.0g, 4.6mmol) in tetrahydrofuran (20mL) was cooled to 0°°C and treated with tetrabutylammonium fluoride (14mL, 14mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 0-20% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCI3) δ 7.05 (d,
2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.65 (t, 2H, OCH2), 2.55 (t, 2H, benzylic), 1.6 (m, 4H, CH2-CH2), 1.4 (m, 4H, CH2-CH2).
2(f) 6-(4-Methoxyphenyl)hexan-l-(4-toltienesulfonate).
6-(4-Methoxyphenyl)hexan-l-ol (5.36g, 25mmol) was dissolved in dry CH2C12 (lOOmL) under an argon atmosphere and cooled to 0~C. To this was added pyridine (2.5mL, 30mmol) and 4-toluenesulfonyl chloride (5.4g, 28mmol). The reaction was stirred at 0»C for 20 minutes and at room temperature for 24 hours. The reaction solution was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue purified by flash column chromatography (silica, 0-10% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCI3) δ 1.6-1.3 (m, 8H, (CH2)4), 2.4 (s, 3H, CH3), 2.5 (t, 2H, benzylic), 3.8 (s, 3H, OCH3), 4.0 (t, 2H, OCH2), 6.80 (d, 2H, aryl), 7.0 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.8 (d, 2H, aryl).
Example 3
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P50046-1-2
E-6-(4-methoxyphenvl)-l -(4-toluenesulfonate)-5-hexene
3(a) E-4-Methoxyphenyl-5-hexenoic acid.
To a freshly prepared solution of lithium hexamethyldisilazide (64mmol) in tetrahydrofuran (30mL), under an argon atmosphere, was added a suspension of (4carboxybutyl)triphenylphosphonium bromide (17.6g, 30mmol) in tetrahydrofuran (45mL) at room temperature. The reaction was stirred for 15 minutes during which time the orange-red color of the ylide developed. A solution of 4-anisaldehyde (4.5g, 30mmol) in tetrahydrofuran (30mL) was added dropwise and stirring was continued for an additional 20 minutes. The reaction was quenched with H2O (50mL) and diluted with ether (30mL). The aqueous layer was acidified to pH 1.0 with 3N HCl and the product was extracted into ethyl acetate (3X50mL). The combined organic layers were dried (MgSC>4) and the product was purified by flash column chromatography (silica, 1% methanol in CH2CI2) to yield the E-olefin as a solid: Hi NMR (200MHz, CDCI3) δ 7.3 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.3 (d, IH, olefin), 6.0 (m, IH, olefin), 3.8 (s, 3H, OCH3), 2.3 (m, 4H, allylic CH2 and CH2CO2), 1.8 (q, 2H, CH2).
3(b) E-4-Methoxyphenvl-5-hexen-1 -ol,
E-4-MethoxyphenyI-5-hexenoic acid (l.lg, 5.0mmol) in dry ether (lOmL) was slowly added to a suspension of L1AIH4 (240mg, 6.0mmol) in ether (lOmL) under an argon atmosphere. The reaction mixture was refluxed for 45 minutes. Upon cooling to room temperature the reaction was quenched with H2O (lOmL) followed by 6N H2SO4 (7mL). Ethyl acetate (20mL) was added and the organic layer was separated and dried (MgSO4); evaporation gave a white crystalline solid: mp. 65-66«»C; ^HNMR (200MHz, CDCI3) δ 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.3 (d, IH, olefin), 6.1 (m,
IH, olefin), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH2), 2.2 (q, 2H, allylic), 1.5 (m, 4H, CH2- CH2); Anal. Calcd. for Ο13Η18Ο2: C, 75.65; H, 8.80, found: C, 75.45; H,
8.95; MS (CI): 207 (M+H).
3(c) E-6-(4-methoxyphenvl)-1 -(4-toluenesulfonate)-5-hexene,
E-4-Methoxyphenyl-5-hexen-l-ol (1.6g, 7.0mmol) was dissolved in dry CH2CI2 (50mL) under an argon atmosphere and treated with 4-toiuenesulfonyl chloride (7.0g, 36mmol) and pyridine (3mL). The reaction solution was stirred at room temperature for
3.5 hours. Water (40mL) was added to the reaction and the organic layer was separated and dried (MgSO4). The product was purified by flash column chromatography (silica, 10% ethyl acetate in hexane) to give an oil: NMR (200MHz, CDCI3) δ 7.8 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.2 (d, IH, olefin), 6.0 (m,
IH, olefin), 4.1 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.4 (s, 3H, CH3), 2.1 (q, 2H, allylic ), 1.6 (m, 4H, CH2- CH2); MS (CI): 361 (M+H).
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Example 4 l-Iodo-8-(4-methoxvphenvboctane
4(a) 7-Octyn-l-ol. Potassium hydride, (35%) in mineral oil (27g. 240mmol) under an argon atmosphere was washed with hexane and treated dropwise with
1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0°C and 3-octyn-l-ol (lOg, 79mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50mL) and the product was extracted into ether. The organic layer was washed with 10% HC1 and brine and dried (MgSO4). Evaporation gave the captioned product as a colorless oil which was used without further purification: *H NMR (90MHz, CDCI3) δ 3.65 (t, J=5Hz, 2H, O-CH2), 2.23 (m, 2H, CH2), 2.0 (m, IH, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) nmax 3350, 2930, 2125 cm-I.
4(b) 7-Octyn-1-tbutyldiphenylsilyl ether. To a cooled (0°C) solution of 7-octyn-l-ol (9.3g, 73.7mmol) in dimethylformamide (DMF) (70mL) under an argon atmosphere was added imidazole (7.5g, 1 lOmmol) followed by the dropwise addition of r-butylchlorodiphenylsilane (21 mL, 81 mmol). The reaction was then stirred at room temperature for 2 hours. The reaction solution was diluted with Et20 and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 3% EtOAc in hexane) provided the product as a colorless oil: Ih NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, O-CH2), 2.23 (m, 2H, CH2), 1.97 (t, IH, acetylenic), 1.6-1.3 (m, 8H, (CH2)4). 105 (s, 9H, tbutyl); IR (film) nmax 3321, 2940, 2125 cm* I.
4(c) 8-(4-Methoxyphenyl)-7-octyn-l-f-butyldiphenylsilvl ether. To a flame dried flask containing triethylamine (140mL) under an argon atmosphere was added 4-iodoanisoIe (13.3g, 56.9mmol), 7-octyn-1 -f-butyldiphenylsilyl ether (24.9g, 68.3mmol), (Ph3P)2PdCl2 catalyst (793mg, 1.13mmol), and Cul (43lmg, 2.27mmol). The resulting mixture was heated at 50°C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered, the solids were washed with Et20 and the solvent was evaporated. The residue was diluted with Et20 and washed with 5% HC1, H2O,
NaHCO3, and brine and dried (MgSC>4). Purification by flash column chromatography (silica, 2% EtOAc in hexane) gave the product as an orange oil: Ih NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.7 (t, 2H, O-CH2), 2.4 (t, 2H, CH2), 1.7-1.3 (m, 8H, (CH2)4), 1-05 (s, 9H, rbutyl)._________________________________________
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4(d) 8-(4-Methoxyphenyl)octan-1 -r-butvldiphenvlsilvl ether.
8-(4-Methoxyphenyl)-7-octyn-l-/-butyldiphenyIsilyl ether(30g, 63.7mmol) was dissolved in EtOH (125mL) and EtOAc (125mL) and treated w ith 5% Pd-C catalyst (3g). The reaction was vigorously stirred under an H2 atmosphere (balloon pressure) for 4 hours. The reaction mixture was filtered through a pad of Celite and the solvent was evaporated. The resulting pale yellow' oil w as pure by nmr analysis and was used directly for the next step: NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, O-CH2),
2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6). 10 (s, 9H, /-butyl).
4(c) 8-(4-Methoxvphenyl)octan-l-ol. To a cooled (0°C) solution of 8-(4-methoxyphenyl)octan-l-i-butyldiphenylsiIyl ether (63mmol) was added tetrabutylammonium fluoride (70mL, 70mmol; IM solution in THF). The cooling bath was removed and the reaction was stirred at room temperature for 4.5 hours. The solvent was evaporated and the residue was dissolved in Et2O. This was washed with H2O, 5% HCl, NaHCO3, and brine and dried (MgSC>4). Purification by flash column chromatography (silica, 30% EtOAc in hexane) gave the product as a colorless solid: NMR (250MHz, CDCI3) 5 7.15 (d, J=8.6Hz, 2H, aryl), 6.86 (d, J=8.6Hz, 2H, aryl), 3.85 (s, 3H, OCH3), 3.68 (t, j=6.5Hz, 2H, O-CH2), 2.62 (t, J=7.6Hz, 2H, benzylic),
1.75-1.3 (m, 12H, (CH2)6); MS (CI): 254.2 (M+NH4); mp 47-49°C.
4(0 l-Iodo-8-f4-methoxyphenyl)octane. To a stirred solution of 8-(4methoxyphenyl)octan-l-ol (12.3g, 52mmol) in dry toluene (200mL) under an argon atmosphere was added triphenylphosphine (17.8g, 67.6mmol) and imidazole (10.6g,
156mmol). After the imidazole had dissolved, I2 (17.1 g, 67.6mmol) was added. The reaction was then heated at 65°C for 30 minutes. Upon cooling to room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et20 and washed with H2O and brine and dried (MgSC>4). The solvent was removed and the resulting residue was dissolved in CH2CI2 and applied to a flash chromatography column (silica). Elution with 2% EtOAc in hexane provided the product as a colorless oil (slight contamination with triphenylphosphine): ^H NMR (250MHz, CDCI3) δ 7.08 (d, J=8.6Hz, 2H, aryl), 6.82 (d, J=8.6Hz, 2H, aryl), 3.78 (s, 3H, OCH3), 3.17 (t,
J=7.4Hz, 2H, I-CH2), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.31 (m, 8H, aliphatic); MS (CI): 364.2 (M+NH4).
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Example 5
3-i l-Oxythia-2-f2-(E-2-carboxyethenyl)-3-dodecyloxv-6-p\ ridyllethvilbenzoic acid, dilithium salt
1(a) 3-Hvdroxv-6-methyl-2-pyridine carboxaldehyde.
2,6-Lutidine-a2,3-diol (l.Og, 7.18mmol, Aldrich) was suspended in dry' CH2CI2 (40mL) and treated with MnC>2 (6.1 g, 70mmol). The reaction was stirred at room temperature for 6 hours. The reaction mixture was filtered through a pad of Celite and the solvent was removed in vacuo. The aldehyde was used directly in the next step without further purification: NMR (250MHz, CDCI3): δ 10.65 (s, IH, OH), 10.30 (s, IH, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 2.55 (s, 3H, CH3).
5(b) 3-Dodecyloxy-6-methyl-2-pyridine carboxaldehyde.
3-Hydroxy-6-methyl-2-pyridine carboxaldehye obtained above was dissolved in 15 dry dimethylformamide (lOmL) and treated with 1-iodododecane (2.1mL, 8.62mmol) and anhydrous K2CO3 (3.0g, 21.7mmol) under an argon atmosphere. The reaction was heated at 90° C for lh with vigorous stirring. Upon cooling to room temperature the reaction mixture was poured into ethyl acetate (lOOmL); the ethyl acetate solution was washed with H2O (3X20mL) and brine and dried (MgSO4). The solvent was removed under reduced pressure and the crude product was used directly in the next step without further purification: ^H NMR (250MHz, CDCI3): δ 10.40 (s, IH, CHO), 7.30 (m, 2H,
4-pyridyl, 5- pyridyl), 4.07 (t, J=6.5Hz, 2H, OCH2), 2.6 (s, 3H, CH3), 1.85-0.89 (m, 23H, aliphatic).
5(c) 2-(E-2-Carboxymethvlethenyl)-3-dodecyloxy-6-methvlpvridine·
5 3-Dodecyloxy-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (12mL) under an argon atmosphere and treated with methyl (triphenylphosphoranylidene)acetate (5.0g, 15mmol). The reaction was heated for 1 hour at 5O°C. Upon cooling to room temperature the reaction was diluted with ethyl acetate (lOOmL) and washed with H2O (2X20mL) and brine and dried (MgSO4).
Purification by flash column chromatography (silica, 7.5% ethyl acetate in petroleum ether) gave a colorless solid: NMR (250MHz, CDCI3): δ 8.07 (d, J=15.7Hz, IH, olefin), 7.10 (m, 2H, 4-pyridyl, 5-pyridyl), 7.05 (d, J=15.7Hz, IH, olefin), 3.98 (t, J=6.6Hz, 2H, OCH2), 3.80 (s, 3H, CO2CH3), 2.49 (s, 3H, CH3), 1.88-0.85 (m,
23H, aliphatic).
5(d) 2-(E-2-Carboxymethylethenvl)-3-dodecyloxy-6-methylpyridine N-oxide.
2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine (2.15g, 5.95mmol) was dissolved in dry CH2CI2 (20mL) and cooled to 0°°C; 85% inch loroperoxy ben zoic acid (1.45g, 7.14mmol) was added and the reaction was stirred at _-----’
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O»C for 30 minutes and at room temperature for 16 hours. The reaction solution was poured into saturated aqueous NaHCO3 (20mL). The aqueous phase was extracted with CH2CI2 (3X20mL) and the combined CH2CI2 extracts were washed with H2O (20mL) and brine and dried (MgSO4). The crude pale yellow solid was used directly in the next step without further purification: NMR (250MHz, CDCI3): δ 8.23 (d, J=16.2Hz,
IH, olefin), 7.58 (d, J=16.2Hz, IH, olefin), 7.13 (d, J=8.8Hz, IH, 5- pyridyl), 6.79 (d, J=8.8Hz, IH, 4-pyridyl), 4.06 (t, J=6.6Hz, 2H, 0CH2), 3.81 (s, 3H, CO2CH3), 2.45 (s, 3H, CH3), 1.92-0.85 (m, 23H, aliphatic); MS (CI): 378.2 (M+H).
5(c) 2-(E-2-Carboxvmethvlethenvn-3-dodecvloxv-6-(hvdroxvmethvl)pvridine.
2-(E-2-Caiboxymethylethenyl)-3-dodecyloxy-6-methylpyridine N-oxide obtained above was suspended in dry dimethylformamide (20mL) and cooled to 0°°C under an argon atmosphere. To this was slowly added trifluoroacetic anhydride (8.5mL, 60.2mmol). The reaction was stirred at 0«°C for 10 minutes and then at room temperature for 16 hours; thin layer chromatography indicated that two reaction products were present (alcohol and trifluoroacetate). The reaction solution was slowly added to a cooled (0°°C) saturated aqueous Na2CO3 solution (lOOmL). The aqueous solution was extracted with ethyl acetate (2X50mL) and the combined ethyl acetate extracts were washed with H2O (2X20mL) and brine and dried (MgSO4); the solvent was removed in vacuo. The product mixture was dissolved in methanol (20mL), treated with anhydrous K2CO3 (500mg), and vigorously stirred for 20 minutes. The reaction was diluted with ethyl acetate (75mL) and washed with H2O (30mL). The aqueous phase was extracted with ethyl acetate (2X20mL) and the combined ethyl acetate extracts were washed with brine (2X20mL) and dried (MgSO4). Purification by flash column chromatography (silica, 25% ethyl acetate in petroleum ether) gave a colorless solid: NMR (250MHz,
CDCI3): δ 8.09 (d, J=15.8Hz, IH, olefin), 7.24 (d, J=8.6Hz, IH, 5-pyridyl), 7.16 (d,
J=8.6Hz, IH, 4-pyridyl), 7.03 (d, J=15.8Hz, IH, olefin), 4.69 (d, J=4.2Hz, 2H,
CH2), 4.03 (t, J=6.6Hz, 2H, OCH2), 3.82 (s, 3H, CO2CH3), 3.61 (t, J=4.2Hz, IH, OH), 1.91-0.85 (m, 23H, aliphatic); MS (CI): 378.3 (M+H).
5(f) 2-(E-2-Carboxyrnethvlethenvl)-3-dodecyloxy-6-(chloromethyl)pyridine hydrochloride,
2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(hydroxymethyl)pyridine (250mg, 0.662mmol) was dissolved in dry toluene (lOmL) under an argon atmosphere and cooled to O»C. Thionyl chloride (0.50mL, 6.85mmol) was slowly added and the solution was stirred at 0°°C for 30 minutes followed by lh at room temperature. The solvent and excess thionyl chloride were removed at reduced pressure. The crude hydrochloride salt was then used directly in the next step without further purification.
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5(g) Methyl 3-f l-thia-2-f2-(E-2-carboxvmethylethenvl)-3-dodecyloxy-6pyridyllethvllbenzoate.
2- (E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridine hydrochloride (0.662mmol), prepared as previously described, was dissolved in dry dimethylformamide (ImL) and sequentially ffeated with methyl 3-mercaptobenzoate (167mg, 0.993mmol), anhydrous CS2CO3 (970mg, 2.98mmol), and tetrabutylammonium iodide (25mg, 0.068mmol) under an argon atmosphere. The reaction was heated at 65°°C for 45 minutes. Upon cooling to room temperature the reaction was diluted with ethyl acetate (30mL) and washed with H2O (2X15mL) and brine and dried (MgSO4). Purification by flash column chromatography (silica, petroleum ether CH202 :e^iy^ acetate, 70: 25: 5) gave a colorless oil: NMR (250MHz, CDCI3): 8 8.04 (s, 1H, 2-phenyl), 8.03 (d, J=15.7Hz, 1H, olefin), 7.81 (d, J=7.9Hz, 1H, 4-phenyl), 7.52 (d, J=7.9Hz, 1H, 6-phenyl), 7.31 (dd, J=7.9Hz, 1H, 5phenyl), 7.29 (d, J=8.6Hz, 1H, 5-pyridyl), 7.12 (d, J=8.6Hz, 1H, 4-pyridyl), 6.98 (d,
J=15.7Hz, 1H, olefin), 4.26 (s, 2H, CH2S), 3.97 (t, J=6.6Hz, 2H, OCH2), 3.90 (s,
3H, CO2CH3), 3.81 (s, 3H, CO2CH3), 1.85-0.85 (m, 23H, aliphatic).
Proceeding in a similar manner, but substituting the appropriate thiol for 3mercaptobenzoate, and using known chemistry where appropriate, the following compounds were made:
N-[3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyI)octyioxy)-6pyridyl]ethyl]phenyl]oxamic acid, dilithium salt,
3- [l'thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6pyridyl]ethyl]benzene, lithium salt,
3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-62 5 pyridyl]ethyl]anisole, lithium salt,
N-[3-[l-thia-2-[2-(E-2-carboxyethenyI)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]benzene-sulfonamide, dilithium salt
N-[3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6pyridyl]ethyl]phenyl]-trifluoromethane-sulfonamide, dilithium salt, and
3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]benzoic acid, dilithium salt.
5(h) Methyl 3-fl-oxythia-2-f2-(E-2-carboxymethylethenyl)-3-dodecyloxv-6pyridyllethyllbenzoate.
Methyl 3-[l-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6pyridyl]ethyl]benzoate (320mg, 0.606mmol) was dissolved in dry CH2Cl2 (2.5mL) and cooled to 0°°C. 85% zn-Chloroperoxybenzoic acid (130mg, 0.64mmol) was added and the solution was stirred for 10 minutes at 0°°C. The reaction was diluted with ethyl acetate (60mL) and washed with saturated aqueous NaHCO3 (2X20mL) and brine and
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P50046-1-2 dried (MgSO4). Purification by Hash column chromatography (silica,
CH2Cl2:petroIeum ether:ethyl acetate, 50:25:25) gave a colorless solid: NMR (250MHz, CDC13): δ 8.11 (d, J=7.9Hz, IH, 4-phenyl), 8.10 (s, IH, 2-phenyl), 7.94 (d, J=15.7Hz, IH, olefin), 7.67 (d, J=7.9Hz, IH, 6-phenyl), 7.53 (dd, J=7.9Hz, IH, 5-phenyl), 7.19 (d, J=8.6Hz, IH, 5-pyridyl), 7.14 (d, J=8.6Hz, IH, 4- pyridyl), 6.68 (d, J=15.7Hz, IH, olefin), 4.21 (d, J=12.5Hz, IH, CHS), 4.15 (d. J=12.5 Hz, IH, CH'S), 3.99 (t, J=6.6Hz, 2H, OCH2), 3.93 (s, 3H, CO2CH3), 3.81 (s, 3H,
CO2CH3), 1.87-0.85 (m, 23H, aliphatic); Anal. Calcd. for C30H41O6NS: C, 66.27;
H, 7.60, N, 2.58, found: C, 65.97; H, 7.22; N, 2.46; MS (CI): 544.3 (M+H).
5iil-3-[l-QxYthia-2-f2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyngthyllbcnzoicacid.
dilithium salt
Methyl 3-[l-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6pyridyl]ethyl]benzoate (120mg, 0.221mmol) was dissolved in tetrahydrofuran (1.3mL) and methanol (0.66mL) under an argon atmosphere and treated with 1M LiOH (0.66mL, 0.66mmol). The reaction was stirred at room temperature for 18 hours. The tetrahydrofuran and methanol were removed under reduced pressure and the product was purified by Reversed Phased MPLC (RP-18 silica, 10-65% methanol in H2O) and isolated by lyophilization to give a colorless amorphous solid: ^H NMR (250MHz, CD3OD): δ 8.27 (s, IH, 2-phenyl), 8.11 (d, J=7.9Hz, IH, 4-phenyl), 7.77 (d, J=15.7Hz, IH, olefin), 7.60 (d, J=7.9Hz, IH, 6-phenyl), 7.58 (dd, J=7.9Hz, IH, 5phenyl), 7.27 (d, J=8.6Hz, IH, 5-pyridyl), 7.04 (d, J=15.7Hz, IH, olefin), 7.01 (d, J=8.6Hz, IH, 4-pyridyl), 4.33 (d, J=12.5Hz, IH, CHS), 4.25 (d, J=12.5Hz, IH, CH’S), 4.04 (t, J=6.5Hz, 2H, OCH2), 1.88-0.86 (m, 23H, aliphatic); Anal. Calcd. for C28H35°6NSLi2 · 2 H2O: C, 59.68; H, 6.97; N, 2.49, found: C, 59.49; H, 6.98; N, 2.58; FAB-MS: (+ve), 528.5 (M+H).
Example 6
3-f l-Dioxythia-2-f2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyllethyllbenzoic acid.
dilithium salt
6(a) Methyl 3-fl-dioxythia-2-f2-fE-2-carboxymethyl-ethenyl)-3-dodecyloxy-6pyridynethyllbenzoate.
Methyl 3-[l-thia-2-[2-(E-2-carboxymethyIethenyl)-3-dodecyloxy-6pyridyl]ethyl]benzoate (107mg, 0.l97mmol) was dissolved in dry CH2CI2 (2mL), cooled to 0«>C, and treated with 85% m-chloroperoxybenzoic acid (44mg, 0.217mmol). The reaction was stirred at O»C for 1.5 hours. The reaction was diluted with ethyl acetate (30mL) and washed with saturated aqueous NaHCO3 (15mL) and brine and dried (MgSCty). The product was purified by flash column chromatogrphy (silica, petroleum
P50046-1-2 ether: CH2Cl2:ethyl acetate, 60:25:15) to give a colorless solid: NMR (250MHz,
CDCI3): δ 8.30 (s, IH, 2-phenyl), 8.26 (d, J=7.7Hz, IH, 4-phenyl), 7.83 (d.
J=7.7Hz, IH, 6-phenyl), 7.82 (d, J=15.7Hz, IH, olefin), 7.55 (dd, J=7.7Hz, IH, 5phenyl), 7.42 (d, J=8.6Hz, IH, 5-pyridyl), 7.21 (d, J=8.6Hz, IH, 4-pyridyl), 6.28 (d, J= 15.7Hz, IH, olefin), 4.52 (s, 2H, CH2SO2), 4.00 (t, J=6.6Hz, 2H, 0CH2), 3.92 (s, 3H, CO2CH3), 3.78 (s, 3H, CO2CH3), 1.87-0.85 (m, 23H, aliphatic); Anal. Calcd. for C30H41O7NS: C, 64.38; H, 7.38; N, 2.50, found: C, 64.71; H, 7.41; N, 2.57; MS (CI): 560.3 (M+H).
6(b) 3-ri-Pioxythia-2-f2-(E-2-carboxyethenyl)-3-dodecvloxy-6-pyridylkthvHbenzoic acid, dilithium salt
Methyl 3-[l-dioxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6pyridyljethyl]benzoate (20,170mg, 0.303mmol) was dissolved in tetrahydrofuran (3.0mL) and methanol (l.OmL) and treated with IM LiOH (l.OmL, l.Ommol). The reaction was stirred at room temperature for 24 hours. The tetrahydrofuran and methanol were removed under reduced pressure and the product was purified by Reversed Phased MPLC (RP-18 silica, 10-65% methanol in H2O) and isolated by lyophilization to give a colorless amorphous solid: NMR (250MHz, CD3OD): δ 8.40 (s, IH, 2-phenyl),
8.22 (d, J=7.9Hz, IH, 4-phenyl), 7.69 (d, J=7.9Hz, IH, 6-phenyl), 7.67 (d,
J=15.7Hz, IH, olefin), 7.53 (dd, J=7.9Hz, IH, 5-phenyl), 7.30 (d, J=8.6Hz, IH, 5pyridyl), 7.18 (d, J=8.6Hz, IH, 4-pyridyl), 6.85 (d, J=15.7Hz, IH, olefin), 4.62 (s,
2H, CH2SO2), 4.03 (t, J=6.5Hz, 2H, OCH2), 1.87- 0.86 (m, 23H, aliphatic); Anal. Calcd. for C28H35O7NSL12 · 7/4 H2O: C, 58.48; H, 6.74; N, 2.44, found: C, 58.58;
H, 6.74; N, 2.67; FAB-MS: (+ve), 544.3 (M+H); (-ve), 536.2 (M-Li).
Example 7
4-fl-Oxythia-2-i2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridynethyllbenzoic acid.
dilithium salt
4-[l-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, was prepared according to the procedure described for 3-[l-oxythia2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt substituting methyl 4-mercaptobenzoate for methyl 3-mercaptobenzoate.
7(a) Methyl 4-f 1 -thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6pyridyllethyllbenzoate NMR (250MHz, CDCI3); δ 8.05 (d, J=15.7Hz, IH, olefin), 7.90 (d, J=8.5Hz, 2H, aryl), 7.37 (d, J=8.5Hz, 2H, aryl), 7.35 (d. J=8.6Hz,
IH, 5- pyridyl), 7.14 (d, J=8.6Hz, IH, 4-pyridyl), 7.01 (d, J=15.7Hz, IH, olefin),
4.29 (s, 2H, CH2S), 3.98 (t, J=6.5Hz, 2H, OCH2), 3.88 (s, 3H, CO2CH3), 3.86 (s, 3H, CQ2CH3), 1.86-0.85 (m, 23H, aliphatic).
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7(b) Methvl 4-[ l-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxv-6pyridyllethynbenzoate. mp. 107- 109«C; NMR (250MHz, CDCI3) δ 8.13 (d,
J=8.5Hz, 2H, aryl), 7.95 (d, J=15.7Hz, IH, olefin), 7.56 (d, J=8.5Hz, 2H, aryl), 7.18 (d, J=8.6Hz, IH, 5-pyridyl), 7.11 (d, J=8.6Hz, IH, 4-pyridyl), 6.62 (d, J=15.7Hz,
IH, olefin), 4.22 (d, J=12.5Hz, IH, CHS), 4.13 (d, J=12.5 Hz, IH, CH'S), 4.03 (t, J=6.5Hz, 2H, OCH2), 3.99 (s, 3H, CO2CH3), 3.78 (s, 3H, CO2CH3), 1.92-0.85 (m, 23H, aliphatic); Anal. Calcd. for C30H41O6NS: C, 66.27; H, 7.60; N, 2.58, found: C, 65.99; H, 7.55; N, 2.27; MS (CI): 544 (M+H).
7(c) 4-ri-Oxvthia-2-f2-(E-2-carboxyethenvl)-3-dodecvloxv-6-pyridvnethvnbenzoic acid, dilithium salt, mp. 205-207~C (dec.); JH NMR (250MHz, CD3OD); δ 8.09 (d, J=8.5Hz, 2H, aryl), 7.78 (d, J=15.7Hz, IH, olefin), 7.59 (d, J=8.5Hz, 2H, aryl), 7.26 (d, J=8.6Hz, IH, 5-pyridyl), 7.07 (d, J=15.7Hz, IH, olefin), 6.98 (d, J=8.6Hz, IH, 415 pyridyl), 4.33 (d, J=12.5Hz, IH, CHS), 4.22 (d, J=12.5Hz, IH, CH'S), 4.04 (t, J=6.5Hz, 2H, OCH2), 1.88-0.86 (m, 23H, aliphatic); Anal. Calcd. for c28H35°6NSLi2 3/2 H2O: C, 60.64; H, 6.91; N, 2.53, found: C, 60.41; H, 6.73; N, 2.60; FAB-MS; (+ve), 528.5 (M+H).
Example 8
2-il-Oxythia-2-i2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyllethynbcnzoic acid.
dilithium salt.
2-[l-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, was prepared according to the procedure described for 3-[l-oxythia25 2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, but substituting methyl 2-mercaptobenzoate for methyl 3-mercaptobenzoate.
8(a) Methyl 2-f l-thia-2-12-(E-2-carboxymethylethenyl)-3-dodecyloxv-6pyridyllethynbenzoate, NMR (250MHz, CDCI3): δ 8.07 (d, J=15.7Hz, IH, olefin), 7.96 (d, J=7.8Hz, IH, 3- phenyl), 7.56 (d, J=7.8Hz, IH, 6-phenyl), 7.43 (d,
J=8.6Hz, IH, 5- pyridyl), 7.42 (m, IH, aryl), 7.14 (d, J=8.6Hz, IH, 4-pyridyl), 7.10 (m, IH, aryl), 7.06 (d, J=15.7Hz, IH, olefin), 4.27 (s, 2H, CH2S), 3.98 (t, J=6.6Hz,
2H, OCH2), 3.91 (s, 3H, CO2CH3), 3.83 (s, 3H, CO2CH3), 1.86-0.86 (m, 23H, aliphatic).
8(b) Methyl 2-fl-oxythia-2-f2-(E-2-carboxvmethylethenyl)-3-dodecyloxy-6pyridyllethyllbenzoate, mp. 60-62«C;
ΪΗ NMR (250MHz, CDCI3): δ 8.13 (d, J=7.8Hz, IH, 3-phenyl), 7.87 (d, J=15.7Hz,
IH, olefin), 7.68 (d, J=7.8Hz, IH, 6-phenyl), 7.53 (m, 2H, aryl), 7.33 (d, J=8.6Hz,_
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IH, 5-pyridyl), 7.16 (d, J=8.6Hz, IH, 4-pyridyl), 6.46 (d, J=15.7Hz, IH, olefin),
4.42 (d, J=12.6Hz, IH, CHS), 4.30 (d, J=12.6Hz, IH, CH S), 4.03 (s, 3H,
CO2CH3), 4.0 (t, J=6.6Hz, 2H, OCH2), 3.81 (s, 3H, CO2CH3), 1.87-0.85 (m, 23H, aliphatic); Anal. Calcd. for C30H41O6NS: C, 66.27; H, 7.60; N, 2.58, found: C,
66.37; H, 7.67; N, 2.56; MS (CI): 544 (M+H).
8(c) 2-ri-oxythia-2-f2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyllethyllbenzoic acid.
dilithium salt, mp. 235~C (dec); ^H NMR (250MHz, CD3OD): δ 8.07 (d, J=7.8Hz, IH, 3-phenyl), 7.76 (d, J=7.8Hz, IH, 6-phenyl), 7.71 (d, J=15.7Hz, IH, olefin), 7.53 (m, 2H, aryl), 7.31 (s, 2H, pyridyl), 6.92 (d, J=15.7Hz, IH, olefin), 4.72 (d,
J=12.6Hz, IH, CHS), 4.12 (d, J=12.6Hz, IH, CH S), 4.05 (t, J=6.5Hz, 2H, OCH2), 1.88-0.86 (m, 23H, aliphatic); FAB-MS: (+ve), 528.3 (M+H).
In addition, by subsisting the appropriate reagents and intermediates for those recited in 4(a) - 4(c), and by using chemistry available in the an, the following compounds were made:
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]benzoic acid, dilithium salt,
N-[3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6pyridyl]ethyl]phenyl]trifluoro-methanesulfonamide, dilithium salt,
N-[3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]trifluoro-methanesulfonamide, dilithium salt,
N-[3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]-benzenesulfonamide, di lithium salt
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-625 pyridyl]ethyl]anisole, lithium salt,
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]benzene, lithium salt.
Example 9
3-il-Oxa-2-f2-(E-2-carboxyethenvl)-3-dodecyloxy-6-pyridyHethyllbenzoic acid, dilithium salt
9(a) Methyl 3-fl-oxa-2-i2-(E-2-carboxymethylethenyl)-3-dodecyl-oxy-6pyridynethynbenzoate.
2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridine hydrochloride, prepared as per Example 1(a) - 1(f), was dissolved in dry dimethylformamide (2mL) and treated sequentially with methyl 3-hydroxybenzoate (152mg, l.OOmmol, Aldrich), anhydrous K2CO3 (500mg, 3.62mmol), and ___ —— '
BAD ORIGINAL β
P50046-1-2 tetrabutylammonium iodide (24.4mg, 0.066mmol) under an argon atmosphere. The reaction was heated at 90=»C for 1 hour. Upon cooling to room temperature the reaction was diluted with ethyl acetate (50mL) and washed with H2O (3X15mL) and brine and dried (MgSO4). Purification by flash column chromatography (silica, CH2C12:
petroleum ether: ethyl acetate, 50:48:2) gave a colorless solid: NMR (250MHz,
CDCI3): δ 8.09 (d, J=15.8Hz, IH, olefin), 7.69 (s, IH, 2-phenyl), 7.65 (d, J=7.9Hz, IH, 4- phenyl), 7.44 (d, J=8.6Hz, IH, 5-pyridyl), 7.34 (dd, J=7.9Hz, IH, 5-phenyl), 7.22 (d, J=8.6Hz, IH, 4-pyridyl), 7.16 (d, J=7.9Hz, IH, 6-phenyl), 7.07 (d, J=15.8Hz, IH, olefin), 5.18 (s, 2H, CH2), 4.02 (t, J=6.6Hz, 2H, OCH2), 3.91 (s,
3H, CO2CH3X 3.82 (s, 3H, CO2CH3), 1.90-0.88 (m, 23H, aliphatic): Anal. Calcd.
for C30H41O6N · 1/8 mole toluene: C, 70.88; H, 8.09; N, 2.68, found; C, 70.98; H, 8.19; N, 2.64; MS (CI): 512.4 (M+H).
9(b) 3-f l-Oxa-2-f2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl1ethyllbenzoic acid, dilithium salt.
Methyl 3-[l-oxa-2-f2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6pyridyl]ethyl]benzoate (80mg, 0.156mmol) was dissolved in tetrahydrofuran (1.34mL) and methanol (0.50mL) and treated with 1M LiOH (0.50mL, 0.50mmol). The reaction was stirred at room temperature for 20 hours. The tetrahydrofuran and methanol were removed at reduced pressure and the product was purified by Reversed Phased MPLC (RP-18 silica, 10-65% methanol in H2O) and isolated by lyophilization to give a Λ colorless amorphous solid: NMR (250MHz, CD3OD): δ - 7.81 (d, J=15.7Hz, IH, olefin), 7.62 (s, IH, 2-phenyl), 7.56 (d, J=7.9Hz, IH, 4-phenyl), 7.44 (d, J=8.6Hz, IH, 5-pyridyl). 7.40 (d, J=8.6Hz, IH, 4-pyridyl), 7.26 (dd, J=7.9Hz, IH, 5- phenyl),
7.07 (d, J=15.7Hz, IH, olefin), 7.05 (d, J=7.9Hz, IH, 6- phenyl), 5.13 (s, 2H, CH2),
4.07 (t, J=6.5Hz, 2H, OCH2), 1.89-0.89 (m, 23H, aliphatic); Anal. Calcd. for C28H35°6^rLi2 · 5/2 H2O: C, 62.22; H, 7.46; N, 2.59, found: C, 62.06; H, 7.37; N, 2.82; FAB- MS: (+ve), 502.3 (M+Li); (-ve), 488.2 (M-Li).
9(c) 3-fl-Oxa-2-f2-fE-2-carboxvethenyl)-3-dodecyloxv-6-pvridvnethylIbenzoic acid. Noxide, dilithium salt.
Methyl 3-f 1 -oxa-2-f2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6pyridyllethyllbenzoate, N-oxide. Methyl 3-( 1 -oxa-2-[2-(E-2-carboxymethylethenyl)-33 5 dodecyloxy-6-pyridyl]ethyl]benzoate (130mg, 0.254mmol) was dissolved in dry
CH2C12 (1.5mL), cooled to 0°°C, and treated with 85% w-chloroperoxybenzoic acid (57mg, 0.28mmol). The reaction was stirred at 0°°C for 10 minutes and then for 20 hours at room temperature. The reaction was diluted with ethyl acetate (30mL) and washed with saturated aqueous NaHCO3 (15mL), H2O (lOmL), and brine and dried
BAD ORIGINAL
P50046-1-2 (MgSO4)· The product was purified by flash column chromatography (silica, CH2Cl2:
petroleum ether: ethyl acetate, 50: 40: 10) to give a colorless solid. NMR (250MHz, CDCI3): 5 8.24 (d, J=16.2Hz, IH, olefin), 7.71 (d, J=8.0Hz, IH, 4-phenyl), 7.68 (s, IH, 2-phenyl), 7.60 (d, J=16.2Hz, IH, olefin), 7.46 (d, J=9.0Hz, IH, 5-pyridyl), 7.38 (dd, J=8.0Hz, IH, 5-phenyl), 7.22 (d, J=8.0Hz, IH, 6-phenyl), 6.9 (d, J=9.0Hz, IH,
4-pyridyl), 5.32 (s, 2H, CH2), 4.10 (t, J=6.6Hz, 2H, OCH2), 3.92 (s, 3H, CO2CH3), 3.83 (s, 3H, CO2CH3), 1.94-0.88 (m, 23H, aliphatic); Anal.Calcd. for C3oH4107N: C, 68.29; H, 7.83; N, 2.65, found: C, 68.27; H, 7.82; N, 2.66; MS (CI): 528.3 (M+H).
9(d) 3-fl-Qxa-2-i2-(E-2-carboxyetheny1)-3-dodecyloxy-6-pvridynethvl1benzoic acid.
N-oxide. dilithium salt
Methyl 3-[l-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6pyridyl]ethyl]benzoate, N-oxide (1 lOmg, 0.208mmol) was dissolved in tetrahydrofuran (2mL) and methanol (0.65mL) and treated with 1M LiOH (0.65mL). The reaction was stirred at room temperature for 20 hours. The tetrahydrofuran and methanol were removed under reduced pressure and the product was purified by Reversed Phase MPLC (RP-18 silica, 10-65% methanol in H2O) and isolated by lyophilization to give a colorless amorphous solid. NMR (250MHz, CD3OD): δ 7.99 (d, J=16.2Hz, IH, olefin), 7.64 (s, IH, 2-phenyl), 7.60 (d, J=8.0Hz, IH, 4-phenyl), 7.52 (d, J=9.0Hz,
IH, 5-pyridyl), 7.45 (d, J=16.2Hz, IH, olefin), 7.30 (d, J=9.0Hz, IH, 4-pyridyl),
7.29 (dd, J=8.0Hz, IH, 5-phenyl), 7.08 (d, J=8.0Hz, IH, 6-phenyl), 5.30 (s, 2H, CH2), 4.17 (t, J=6.6Hz, 2H, OCH2), 1.95-0.86 (m, 23H, aliphatic); Anal. Calcd. for 028^507^2 · 3H2O: C- 59·47; H> 7·3N- 2·48- found: C, 59.46; H, 6.91; N,
2.50; FAB-MS: (+ve), 512.2 (M+H); (-ve), 504.5 (M-Li).
Proceeding in a similar manner, but substituting the appropriate intermediates, the following compounds were made:
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt,
3-[l-oxa-2-[2-(E,E-4-carboxybuta-l,3-dienyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt,
3- [l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-nonyloxy)-6pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt,
N-[3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6pyridyl]ethyl]phenyl]trifluoromethane-sulfonamide, N-oxide, dilithium salt,
4- methoxy-3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoic acid, dilithium salt,
N-[3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]acetamide, N-oxide, lithium salt,_ 34
6ad original $
P50046-1-2
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(7-(4-methoxybenzyl-sulfonyl)heptyIoxy)6-pyridvl]ethyl]benzoic acid, N-oxide, dilithium salt,
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(7-(4-meihoxyphenyl-sulfonyl)heptyloxy)6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt,
3-[l-oxa-2-[2-(E-2-diethylphosphonoethenyl)-3-dodecyloxy-6pyridyl]ethyl]benzoic acid, N-oxide, lithium salt,
N-[3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]oxamic acid, dilithium salt,
N- [6-methoxy-3-[ 1 -oxa-2-[2- (E-2-carboxyetheny 1)-3- (8 -(4methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]-tri fluoromethane-sulfonamide, Noxide, dilithium salt,
N-[6-methoxy-3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]-tri fluoromethane-sulfonamide, dilithium salt,
N-[3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6pyridyl]ethyl]phenyl]oxamic acid, N-oxide, dilithium salt,
3-[l-oxa-2-(2-(E-2-ethylphosphonoethenyl)-3-dodecyloxy-6pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt,
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyIoxy)-6pyridyl]ethyl]benzene, lithium salt,
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6pyridyl]ethyl]phenylurca, lithium salt,
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6pyridyl]ethyl]benzonitrile, lithium salt,
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6pyridyl]ethyl]phenol, lithium salt, and
3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6pyridyl]ethyl]benzamide, lithium salt.
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Example 10
3-f l-Oxa-2-f2-(E-2-carboxvethenyl)-3-(8-(4-methoxvphenyl)octyloxy)-6pyridyilethyllaniline lithium salt
10(a) 7-Octvn-1 -ol. 35% KH in mineral oil (27g, 240mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane.
The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0° C and 3-octyn-l-ol (1 Og, 79mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50mL) and the product was extracted into ether. The organic layer was washed with 10% HCl and brine and dried (MgSC>4). Evaporation gave a colorless oil which was used without further purification: NMR (90MHz, CDCI3) δ 3.65 (t,
J=5Hz, 2H, O-CH2), 2.23 (m, 2H, CH2), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) nmax 3350, 2930, 2125 cm-1.
10(b) 7-Octyn-1 -Ibutyldiphenylsilyl ether. To a cooled (0° C) solution of 7-octyn- l-ol (9.3g, 73.7mmol) in DMF (70mL) under an argon atmosphere was added imidazole (7.5g, 1 lOmmol) followed by the dropwise addition of lbutylchlorodiphenylsilane. The reaction was then stirred at room temperature for 2 hours. The reaction solution was diluted with Et20 and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 3% EtOAc in hexane) provided a colorless oil: !H NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, O-CH2),
2.23 (m, 2H, CH2), 1.97 (t, 1H, acetylenic), 1.6-1.3 (m, 8H. (CH2)4), L05 (s, 9H, lbutyl); IR (film) nmax 3321, 2940,2125 cm* L
10(c) 8-(4-Methoxyphenyl)-7-octyn-l-lbutvldiphenylsilyl ether.
To a flame dried flask containing triethylamine (140mL) under an argon atmosphere was added 4-iodoanisole (13.3g, 56.9mmol), 7-octyn-1-f-butyldiphenylsilyl ether (24.9g, 68.3mmol), (Ph3P)2PdCl2 catalyst (793mg, 1.13mmol), and Cul (43lmg,
2.27mmol). The resulting mixture was heated at 50° C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered, the solids were washed w ith Et^O and the solvent was evaporated. The residue was diluted w-ith Et20 and washed with 5%
HCl, H2O, NaHCO3, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 2% EtOAc in hexane) gave an orange oil: Ή NMR (250MHz,
CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe), 3.7 (t, 2H, O-CH2), 2.4 (t, 2H, CH2), 1.7-1.3 (m, 8H, (CH2)4), 1-05 (s, 9H, tbutyl)._______
γ r BAD ORIGINAL
P50046-1-2
10(d) 8-(4-Methox>phenyl)octan-l-U?uty1diphenylsilyl ether.
8-(4-MethoxyphenyI)-7-octyn-l-r-butyldiphenylsilyl ether (30g, 63.7mmol) was dissolved in EtOH (125mL) and EtOAc (125mL) and treated with 5% Pd-C catalyst (3g). The reaction was vigorously stirred under an H2 atmosphere (balloon pressure) for 4 hours. The reaction mixture was filtered through a pad of celite and the solvent was evaporated. The resulting pale yellow oil was pure by nmr analysis and was used directly for the next step: !H NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe), 3.6 (t, 2H, O-CH2), 2.5 (t, 2H, benzylic), 1.75-1.3 (ro, 12H, (CH2)6), 1.0 (s, 9H, ‘butyl).
10(e) 8-f4-MethoxyphenyDoctan-l-ol. To a cooled (0° C) solution of 8-(4-methoxyphenyl)octan-l-tbutyldiphenylsilyl ether (63mmol) was added tetrabutylammonium fluoride (70mL, 70mmol; 1M solution in THF). The cooling bath was removed and the reaction was stirred at room temperature for 4.5 hours. The solvent was evaporated and the residue was dissolved in Et2O. This was washed with H2O, 5% HCl, NaHCO3, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 30% EtOAc in hexane) gave a colorless solid: JH NMR (250MHz, CDCI3) δ 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OMe), 3.68 (t, 2H, O-CH2), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6); MS (CI): 254.2 (M+NH4); mp 47-49 °C.
10(f) l-Iodo-8-(4-methoxyphenyl)octanc. To a stirred solution of 8-(4methoxyphenyl)octan-l-ol (12.3g, 52mmol) in dry toluene (200mL) under an argon atmosphere was added triphenylphosphine (17.8g, 67.6mmol) and imidazole (10.6g,
156mmol). After the imidazole had dissolved I2 (17.1 g, 67.6mmol) was added. The reaction was then heated at 65° C for 30 minutes. Upon cooling to room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et2O and washed with H2O and brine and dried (MgSO4). The solvent was removed and the resulting residue was dissolved in CH2C12 and applied to a flash chromatography column (silica). Elution with 2% EtOAc in hexane provided a colorless oil (slight contamination with triphenylphosphine): JH NMR (250MHz, CDCI3) δ 7.08 (d, J=8.6Hz, 2H, aryl), 6.82 (d, J=8.6Hz, 2H, aryl), 3.78 (s, 3H, OMe), 3.17 (t, J=7.4Hz, 2H, I-CH2), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.31 (m, 8H, aliphatic); MS (CD: 364.2 (M+NH4).
10(g) 3-Hydroxy-6-methyl-2-pyridine carboxaldehyde. 2,6-Lutidine-a2,3-diol (15g,
107.8mmol; Aldrich) was suspended in dry CH2C12 (200mL) and treated with MnC^ (47g, 539mmol). The reaction was stirred at room temperature for 6 hours. The reaction
BAD ORIGINAL
P50046-1-2 mixture was filtered through a pad of celite and the solvent was evaporated. The crude aldehyde was obtained as a tan solid and was used directly for the next step: 'H NMR (250MHz, CDCI3) δ 10.65 (s. IH, OH), 10.30 (s, IH, aldehyde), 7.30 (m, 2H, 4.5pyridyl), 2.55 (s, 3H, methyl).
10(f) 3-[8-(4-Methoxvphenyl)octyloxy1-6-methyl-2-pyridine carboxaldehyde. To a solution of l-iodo-8-(4-methoxyphenyI)octane (16.3g, 47. lmmol) in dry DMF (45mL) under an argon atmosphere was added 3-hydroxy-6-methyl-2-pyridine carboxaldehyde (7.7g, 56.2mmol) and anhydrous K2CO3 (32g, 235mmol). The reaction was vigorously stirred at 90 °C for 1.5 hours. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O, aq NH4CI, and brine and dried (MgSO4).
Evaporation provided crude aldehyde as a dark oil that was used without further purification.
10(g) 2-(E-2-CarboxymethyIethenyl)-3-f8-(4-methoxyphenyl)octvloxyl-6methylpyridine. 3-[8-(4-Methoxyphenyl)octyloxy]-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (lOOmL) under an argon atmosphere and treated with methyl (triphenylphosphoranylidene)acetate (16g, 48mmol). The reaction was heated for 1 hour at 50° C. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 20% EtOAc in hexane) gave a pale yellow oil: JH NMR (250MHz, CDCI3) 8 8.07 (d, J=15.7Hz, IH, olefin), 7.10 (m, 4H, phenyl, 4,5pyridyl), 7.07 (d, J=15.7Hz, IH, olefin), 6.81 (d, J=8.6Hz, 2H, phenyl), 3.97 (t,
J=6.5Hz, 2H, O-CH2), 3.79 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t,
J=7.6Hz, 2H, benzylic), 2.48 (s, 3H, methyl), 1.85 (m, 2H, CH2), 1.60 (m, 2H,
CH2), 1.37 (m, 8H, aliphatic); MS (CI): 412.3 (M+H).
10(h) 2-fE-2-Carboxvmethvlethenyl)-3-f8-(4-methoxyphenyl)octvloxyl-6methylpvridine N-oxide. 2-(E-2-Carboxymethylethenyl)-3-[8-(4methoxyphenyl)octyloxy]-6-methylpyridine (17.lg, 41.5mmol) was dissolved in dry
CH2CI2 (105mL) and cooled to 0°C; 50% /nCPBA (15.8g, 45.8mmol) was added in three portions over 10 minutes. The cooling bath was removed and the reaction was stirred for 15 hours at room temperature. The reaction was poured into aqueous
NaHCC>3 and the product extracted into CH2CI2. The organic extract was washed with
H2O and brine and dried (MgSC>4). The crude product was obtained as a yellow solid and was used without further purification.__
fiBAD ORIGINAL d
P50046-1-2
10(i) 2-(E-2-Carbox\Tnethylethenyl)-3-f8-(4-methoxyphenvl'>octylo\yl-6hydroxymethvlpyridine. 2-(E-2-Carboxymethylethenyl)-3-{8-(4methoxyphenyl)octyloxy]-6-methylpyridine N-oxide obtained above was suspended in dry DMF (130mL) and cooled to 0 °C under an argon atmosphere. To this was slowly added trifluoroacetic anhydride (56mL, 400mmol). The reaction was maintained at 0 °C for 20 minutes followed by 18 hours at room temperature. The reaction solution was slowly added to a solution of saturated aqueous Na2CO3 and stirred for 1 hour. The product was then extracted into EtOAc; the combined organic extracts were washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica,
EtOAc:hexane:CH2Cl2,30:20:50) gave a waxy solid: *H NMR (250MHz, CDCI3) δ 8.08 (d, J=15.7Hz, IH, olefin), 7.23 (d, J=8.6Hz, IH, 5-pyridyl), 7.16 (d, J=8.6Hz, IH, 4-pyridyl), 7.09 (d, J=8.6Hz, 2H, phenyl), 7.03 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.69 (d, J=4.1Hz, 2H, CH2-OH), 4.01 (t, J=6.5Hz, 2H, OCH2), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.62 (t, J=4.1Hz, IH, OH), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.58 (m, 2H, CH2), 1.44 (m, 8H, aliphatic); MS (CI): 428.2 (M+H).
10(i) 3-Aminophenol tbutylcarbamatc. 3-Aminophenol (2.0g, 18.3mmol; Aldrich) was dissolved in CH2C12 (18mL) and DMF (6mL) and treated with di-Hjutyl dicarbonate (5.0mL, 21.7mmol). The reaction was stirred under an argon atmosphere for 18 hours.
The reaction solution was diluted with EtOAc and washed with H2O and brine and dried (MgSO4>. Purification by flash column chromatography (silica, EtOAc:hexane<H2Cl2, 15:60:25) gave a colorless solid: lH NMR (250MHz, CDCI3) δ 7.15 (m, 2H, aryl),
6.72 (m, IH, aryl), 6.53 (m, 2H, aryl, OH), 6.0 (s, IH, NH), 1.54 (s, 9H, ‘butyl); MS
5 (CI): 210.2 (M+H); mp 95-97 °C.
10(k) 2-fE-2-Carboxymethylethenyl)-3-i8-(4-methoxvphenyl)octvloxy1-6-f(3aminolphenoxymethvllpyridine tbutylcarbamate. To a cooled (0 °C) solution of SOC12 (0.5 ImL, 7.0mmol) in dry toluene (2mL) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyI)-3-[8-(4-methoxyphenyl)octyloxy]-6hydroxymethylpyridine (300mg, 0.70mmol) in toluene (5mL). After 5 minutes the cooling bath was removed and the reaction was stirred for 2 hours at room temperature. The toluene and excess SOC12 were evaporated. To this was added dry DMF (0.90mL), 3-aminophenol ‘butylcarbamate (209mg, l.Ommol), and anhydrous CS2CO3 (1.63g,
5.0mmol). The reaction was heated at 90 °C under an atmosphere of argon for 2 hours.
Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H20,10% NaOH, H2O, and brine and dried (MgSO4). Purification by flash column chromatography (silica, EtOAc:hexane:CH2Cl2, 7:63:30) yielded a colorless oil: !H
Ρ50046-1-2 aryl), 7.15 (m, 5H, aryl), 7.05 (d, J=15.7Hz, IH, olefin), 6.90 (m, IH, aryl), 6.82 (d,
J=8.6Hz, 2H, aryl), 6.65 (m, IH, aryl), 6.51 (s, IH, NH), 5.12 (s, 2H, CH2-O), 4.0 (t, J=6.5Hz, 2H, O-CH2), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t,
J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH2), 1.51 (s, 9H, lbutyl), 1.46 (m, 10H, aliphatic).
10(1) 3-f l-Oxa-2-f2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6pyridyllethyllaniline.
2-(E-2-Carboxymethyletheny 1)-3-[8-(4-methoxyphe nyl)-octy loxy]-6-[(3amino)phenoxymethyl]pyridine lbutylcarbamate (348mg, 0.562mmol) was dissolved in dry CH2CI2 (3.0mL) under an argon atmosphere and cooled to Ο» C. Anisole (0.09mL,
0.83mmol) was added followed by trifluoroacetic acid (0.6mL). The reaction was stirred for 1 hour at 0° C and then for 3 hours at room temperature. The reaction was quenched with aqueous NaHCO3- The product was extracted into CH2CI2 and the organic extracts were washed with brine and dried (MgSOzj). Purification by flash column chromatography (silica, EtOAc:hexane:CH2Cl2, 20:50:30) gave a pale yellow oil: 'H NMR (250MHz, CDCI3) δ 8.09 (d, J=15.7Hz, IH, olefin), 7.44 (d, J=8.6Hz, IH, 5pyridyl), 7.17 (d, J=8.6Hz, IH, 4-pyridyl), 7.08 (m, 3H, aryl), 7.05 (d, J=15.7Hz,
IH, olefin), 6.88 (d, J=8.6Hz, 2H, aryl), 6.42 (m, IH, aryl), 6.31 (m, IH, aryl), 6.29 (m, IH, aryl), 5.10 (s, 2H, CH2-O), 4.02 (t, J=6.5Hz, 2H, O-CH2), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.70 (broad singlet, 2H, NH2), 2.54 (t, J=7.6Hz,
2H, benzylic), 1.88 (m, 2H, CH2), 1.62 (m, 2H, CH2), 1.40 (m, 8H, aliphatic);
Analysis calcd for C31H38N2O5 · 1/2 H2O: C, 70.56; H, 7.45; N, 5.31; found: C,
70.74; H, 7.36; N, 5.06; MS (CI): 519.3 (M+H).
10(m) 3-fl-Oxa-2-f2-(E-2-carboxyethenvl)-3-(8-(4-methoxyphenyl)-octvloxy)-6pyridynethvllaniline, lithium salt. 3-[l-Oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pvridyl]ethyl]aniline (30mg, 0.0578mmol) was dissolved in THF (0.36mL) and MeOH (0.24mL) and treated with 1.0M LiOH (0.12mL, 0.12mmol).
The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2OMeOH gradient). Lyophilization yielded a colorless amorphous solid: Ή NMR (250MHz, d4-MeOH) δ 7.80 (d, J=15.7Hz, IH, olefin), 7.38 (s, 2H, 4,5-pyridyl), 7.06 (d, J=15.7Hz, IH, olefin), 7.05 (d, J=8.6Hz, 2H, phenyl), 6.97 (t, J=8.0Hz, IH, 5’phenyl), 6.78 (d, J=8.6Hz, 2H, phenyl), 6.39 (m, IH, 2'-phenyl), 6.35 (m, 2H, 4',6'phenyl), 5.04 (s, 2H, CH2-O), 4.04 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe),
2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.57 (m, 4H, aliphatic), 1.36 (m,
6H, aliphatic); Analysis calcd for C30H35N2O5L1 · 9/4 H2O: C, 65.38; H, 7.22; N,
5.08; found: C, 65.39; H, 7,24; N, 5.23; MS (FAB): 511 (M+H), 517 (M+Li),_
BAD ORIGINAL
P50046-1-2
Example 11
5-Carboxv-3-ri-oxa-2-i2-fE-2-carboxyethenyl)-3-(8-f4-methoxvphenyI)octvloxy)-6pvridvllethyllaniline, dilithium salt 5
11(a) 3-Amino-5-carboxymethylphenol. HCl gas was bubbled through a solution of 3amino-5-hydroxybenzoic acid hydrochloride (1.9g, lOmmol; Lancaster Synthesis) in MeOH (50mL) at 0 °C for 30 minutes. The reaction was stoppered and allowed to sit for 5 hours. The solvent was removed in vacuo and the residue was dissolved in H2O.
The aqueous solution was neutralized with 5% Na2CO3 and the product was extracted into EtOAc. The organic solution was then dried (MgSO4) and evaporated producing 1.5g (89%) of ester as an off-white solid that was used without additional purification:
IH NMR (250MHz, CDC13) δ 6.85 (dd, J=1.9Hz, IH, aryl), 6.80 (dd, J=1.9Hz, IH, aryl), 6.30 (dd, J=1.9Hz, 1H, aryl), 3.80 (s, 3H, methyl ester).
11(b) 3-Amino-5-carboxymethylphenol Ibutylcarbamate. A solution of 3-amino-5carboxymethylphenol (1.5g, 8.0mmol) in DMF (8mL) under an argon atmosphere was treated with di-lbutyldicarbonate (2.1 g, lOmmol). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc and washed with H2O and brine and dried (MgSO4). Recrystallization from Et2O - hexane gave a tan solid: lH NMR (250MHz, CDCI3) δ 7.35 (dd, J=1.9Hz, IH, aryl), 7.15 (dd, J=1.9Hz, 1H, aryl), 6.65 (dd, J=1.9Hz, IH, aryl), 6.45 (s, IH, NH), 3.80 (s, 3H, methyl ester), 1.4 (s, 9H, tbutyl).
life) 2-(Έ-2-Carboxvmethylethenvl)-3-f8-(4-methoxyphenyl)-octvloxy^-6-ί(3-amino5-carboxymethyl)phenoxymethvllpyridine Ibutylcarbamate. To a cooled (0 °C) solution of SOC12 (0.34mL, 4.6mmol) in dry toluene (1.5mL) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6hydroxymethylpyridine (197mg, 0.46mmol) in toluene (3mL). After 5 minutes the cooling bath was removed and the reaction was stirred for 2 hours at room temperature.
The toluene and excess SOC12 were evaporated. To this was added dry DMF (l.OmL),
3-amino-5-carboxymethylphenol %utylcarbamate (150mg, 0.5mmol), and anhydrous CS2CO3 (l.Og, 3.0mmol). The reaction was heated at 90 °C under an atmosphere of argon for 2 hours. Upon cooling to room temperature the reaction was diluted with
EtOAc and washed with H20,10% NaOH, H2O, and brine and dried (MgSO4).
Purification by flash column chromatography (silica, 20% EtOAc in hexane) yielded a colorless oil: JH NMR (250MHz, CDCI3) δ 8.09 (d, J=15.7Hz, IH, olefin), 7.55 (dd,
J=1.9Hz, IH, aryl), 7.9 (dd, J=1.9Hz, IH, aryl), 7.46 (d, J=8.6Hz, IH, 5-pyridyl), _ 7.38(dd, J=1.9Hz, IH, aryl), 7.22 (d, J=8.6Hz, IH, 4-pyridyl), 7.12 (d, J=8.6Hz, 2H, _
---—
BAD ORIGINAL
P50046-1-2 phenyl), 7.07 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenvl), 6.58 (s, IH, NH), 5.16 (s, 2H, CH2-O), 4.04 (t, J=6.5Hz, 2H, 0-CH2), 3.92 (s, 3H, methyl ester), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.58 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH2), 1.55 (s, 9H, lbutyl), 1.46 (m, 10H, aliphatic); MS (CI): 677 (M+H).
11(d) 5-Carboxvmethyl-3-fl-oxa-2-f2-(E-2-carboxymethylethenvl)-3-(8-(4methoxyphenyl)octyloxy)-6-Pvridyl1ethyllaniline. 2-(E-2-Carboxymethylethenyl)-3-[8(4-methoxyphenyl)octyloxy]-6-[(3-amino-5-carboxymethyl)phenoxymethyl]pyridine tbutylcarbamate (200mg, 0.29mmol) was dissolved in dry CH2CI2 (3.0mL) under an argon atmosphere and cooled to 0 °C. Anisole (0.05mL, 0.46mmol) was added followed by trifluoroacetic acid (0.3mL). The reaction was stirred for 30 minutes at 0°C and then for 3.5 hours at room temperature. The reaction was quenched with aqueous NaHCQj. The product was extracted into CH2CI2 and the organic extracts were washed with brine and dried (MgSC>4). Purification by flash column chromatography (silica,
25% EtOAc in hexane) gave a colorless oil: !H NMR (250MHz, CDCI3) δ 8.09 (d, J=15.7Hz, IH, olefin), 7.44 (d, J=8.6Hz, IH, 5-pyridyl), 7.17 (d, J=8.6Hz, IH, 4pyridyl), 7.08 (m, 3H, aryl), 7.05 (d, J=15.7Hz, IH, olefin), 6.96 (dd, J=1.9Hz, IH, aryl), 6.88 (d, J=8.6Hz, 2H, phenyl), 6.49 (dd, J=1.9Hz, IH, aryl), 5.12 (s, 2H, CH2O), 4.04 (t, J=6.5Hz, 2H, O-CH2), 3.92 (s, 3H, methyl ester), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH2), 1.62 (m, 2H, CH2), 1.40 (m, 8H, aliphatic); Analysis calcd for C33H40N2O7 · I/2H2O: C, 67.67; H, 7.06; N, 4.78; found; C, 67.42; H, 6.96; N, 4.69; MS (CD: 577 (M+H).
11(e) 5-Carboxv-3-f l-oxa-2-i2-(E-2-carboxvethenyl)-3-(8-(4methoxyphenyl)octyloxv)-6-pyridynethyllaniline, dilithium salt.
5-Carboxymethyl-3-[l-oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (120mg, 0.208mmol) was dissolved in THF (l.OmL) and MeOH (0.5mL) and treated with 1.0M LiOH (0.5mL, 0.5mmol). The reaction was stirred under an argon atmosphere for 16 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2OMeOH gradient). Lyophilization yielded a colorless amorphous solid: 'HNMR (250MHz, d4-MeOH) δ 7.80 (d, J=15.7Hz, IH, olefin), 7.42 (d, J=8.6Hz, IH, 5pyridyl), 7.38 (d, J=8.6Hz, IH, 4-pyridyl), 7.06 (d, J=15.7Hz, IH, olefin), 7.05 (d, J=8.6Hz, 2H, phenyl), 6.98 (dd, J=1.9Hz, IH, aryl), 6.92 (dd, J=1.9Hz, IH, aryl), 6.80 (d, J=8.6Hz, 2H, phenyl), 6.47 (dd, J=1.9Hz, IH, aryl), 5.11 (s, 2H, CH2-O), 4.05 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.57 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic); Analysis calcd for C3iH34N2O5Li2 · 21/5 H2O: C, 58.04; H, 6.70; N, 4.36; found: C, 57.87; H, 6.34; N,
P50046-1-2
Example 12
3-f l-Thia-2-12-(E-2-carboxyethenyl)-3-(8-(4-methoxvphenvl)octyloxy)-6pyndyllethynanilire, lithium salt 5
12(a) 3-f l-Thia-2-f2-(E-2-carboxvmethylethenyl)-3-f8-(4-methoxy-phenyl)octyloxy)6-pyridyllethyllanilinc. To a cooled (0° C) solution of SOCI2 (0.26mL, 3.5mmol) in dry toluene (ImL) under an argon atmosphere was added a solution of 2-(E-2carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine ♦ » (150mg,0.35mmol) in toluene (2.5ipL). After 5 minutes the cooling bath was removed and the reaction was stirred for 2 hours at room temperature. The toluene and excess SOQ2 were evaporated. The crude product was dissolved in dry DMF (ImL) and added to a solution of sodium 3-aminothiophenoxide, prepared from 3-aminothiophenol (0.09mL, 0.84mmol; Aldrich) and NaH (34mg, 0.084mmol; 60% in mineral oil) in DMF (2mL), under an argon atmosphere. The reaction w'as stirred at room temperature for 3 hours. The reaction was diluted with EtOAc and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 30% EtOAc in hexane) gave a colorless solid: lH NMR (250MHz, CDCI3) δ 8.06 (d, J=15.7Hz, IH, olefin), 7.27 (d, J=8.6Hz, IH, 5-pyridyl), 7.08 (m, 5H, 4-pyridyl, 5'-phenyl, olefin, phenyl),
6.81 (d, J=8.6Hz, 2H, phenyl), 6.74 (m, 2H, 2,4’-phenyl), 6.46 (ddd, J=8.0, 1.9Hz,
IH, 6'-phenyl), 4.20 (s, 2H, CH2-S), 3.96 (t, J=6.5Hz, 2H, O-CH2), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.65 (broad singlet, 2H, NH2), 2.55 (t, J=7.6Hz,
2H, benzylic), 1.83 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.35 (m, 6H, aliphatic); Analysis calcd for C31H38N2O4S 1/4 H2O: C, 69.06; H, 7.20; N, 5.20;
found: C, 69.02; H, 7.16; N, 5.21; MS (CI): 535 (M+H); mp 57-60 °C.
12(b) 3-fl-Thia-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxvphenyl)octy1oxy)-6pyridyHethyHanilinc, lithium salt. 3-[l-Thia-2-(2-(E-2-carboxymethylethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (75mg, 0.14mmol) was dissolved in
THF (0.56mL) and MeOH (0.28mL) and treated with 1.0M LiOH (O.28mL, 0.28mmol). The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, Η2ΟMeOH gradient). Lyophilization yielded a colorless amorphous solid: JHNMR (250MHz, d4-MeOH) 5 7.76 (d, J=15.7Hz, IH, olefin), 7.25 (d, J=8.6Hz, IH, 535 pyridyl), 7.24 (d, J=8.6Hz, IH, 4-pyridyl), 7.09 (d, J=8.6Hz, 2H, phenyl), 7.04 (d, J=15.7Hz, IH, olefin), 6.97 (dd, J=8.0Hz, IH, 5'-phenyl), 6.80 (d, J=8.6Hz, 2H, phenyl), 6.72 (dd, J=1.9Hz, IH, 2'-phenyl), 6.67 (ddd, J=8.0, 1.9Hz, IH, 4'-phenyl), 6.51 (ddd, J=8.0, 1.9Hz, IH, 6’-phenyl), 4.16 (s, 2H, CH2-S), 4.00 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.80 (m, 2H, CH2), _______
BAD ORIGINAL
P50046-1-2
1.49 (m, 4H, aliphatic), 1.33 (m, 6H. aliphatic); Analysis calcd for CiofbsN^ChSLi · 5/2 H2O: C, 63.03; H, 7.05; N, 4.90; found: C, 62.67; H, 6.72; N, 4.72; MS (FAB): 527 (M+H), 521 (M+H; free acid).
Proceeding in a similar manner, but substituting the appropriate intermediates for those indicated here, and using chemistry well known in the art, the following compounds were prepared:
3’[l-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6pyridyl]ethyl]aniline, lithium salt;
Colorless amorphous solid: JH NMR (360MHz, d^-DMSO) δ 7.43 (d, J=15.7Hz, IH, olefin), 7.33 (d, J=8.6Hz, IH, pyridyl), 7.23 (d, J=8.6Hz, 1H,' pyridyl), 7.13 (d, J=8.6Hz, 2H, phenyl), 6.92 (dd, J=7.8Hz, IH, 5*-phenyl), 6.86 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 6.61 (s, IH, 2’ phenyl), 6.51 (d, J=7.8Hz, IH, 4’-phenyl), 6.37 (d, J=7.8Hz, IH, 6’-phenyl), 5.10 (broad singlet, 2H, NH2), 4.16 (s, 2H, CH2-S), 4.01 (t, J=6.5Hz, 2H, O-CH2), 3.72 (s, 3H, OMe), 2.58 (t, J=7.6Hz, 2H, benzylic), 1.71 (m, 4H, aliphatic); Analysis calcd for C26H27N2O4SL1 · 13/4H2O: C, 62.20; H, 6.12; N, 5.58; found: C, 62.23; H, 5.82; N, 5.44; MS (ES+): 464.3 (M+; free acid); (ES*): 463.0 (M-H; free acid);
3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4- tri fluorome thylphenyl)octyloxy)- 6pyridyl]ethyl]aniline, lithium salt;
Colorless amorphous solid: NMR (250MHz, d4-MeOH) δ 7.78 (d,
J=15.7Hz, 1H, olefin), 7.53 (d, J=8.6Hz, 2H, phenyl), 7.34 (d, J=8.6Hz, 2H.^_ phenyl), 7.25 (d, J=8.6Hz, IH, pyridyl), 7.24 (d, J=8.6Hz, IH, pyridyl), 7.04 (d? J=15.7Hz, IH, olefin), 6.97 (dd, J=8.0Hz, IH, 5'-phenyl), 6.72 (dd, J=1.9Hz, IH, 2'-phenyI), 6.67 (ddd, J=8.0, 1.9Hz, IH, 4’-phenyI), 6.51 (ddd, J=8.0, 1.9Hz, IH, 6'-phenyl), 4.16 (s, 2H, CH2-S), 4.01 (t, J=6.5Hz, 2H, O-CH2), 2.68 (t, J=7.6Hz,
2H, benzylic), 1.85 (m, 2H, CH2), 1.68 (m, 2H, CH2), 1.50 (m, 2H, CH2), 1.37 (m, 6H, aliphatic); Analysis calcd for C30H32F3N2O3SL1 · 1 '/2 H2O: C, 60.91; H, 5.96; N, 4.74; found: C, 60.53; H, 5.56; N.4.51; MS (ES+): 559.0 (M+H; free acid), (ES-): 557.0 (M-H; free acid); and
3-[l-thia-2-[2-(E-2-carboxvethenyl)-3-(8-phenyl)octyloxy-6pyridyl]ethyl]aniline, lithium salt
Colorless amorphous solid: ’H NMR (250MHz, d4-MeOH) δ 7.72 (d,
J=15.7Hz, IH, olefin), 7.20 (m, 7H, pyridyl, phenyl), 7.04 (d, J=15.7Hz, IH, olefin), 6.97 (dd, J=8.0Hz, IH, 5'-phenyl), 6.72 (dd, J=1.9Hz, IH, 2'-phenyl), 6.67 (ddd, J=8.0, 1.9Hz, IH, 4'-phenyl), 6.51 (ddd, J=8.0, 1.9Hz, IH, 6'-phenyl), 4.16 (s, 2H, CH2-S), 4.02 (t, J=6.5Hz, 2H, O-CH2), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.83 (m, 2H, CH2), 1.59 (m, 2H, CH2), 1.50 (m, 2H, CH2), 1.37 (m, 6H, aliphatic); MS (ES+): 491.0 (M+H; free acid), (ES-): 489.0 (M-H; free acid).
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Example 13
3-fl-Oxvthia-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridvllethvllaniline, lithium salt 5
13(a) 3-f 1 -Oxythia-2-f 2-(E-2-carboxvmethylethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pvridynethyHaniline. To a cooled (-15° C) solution of 3-[ 1thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyljethyljaniline (150mg, 0.28mmol) in CH2C12 (4mL) under an argon atmosphere was added 85% mCPBA (63mg, 0.31 mmol) in two portions over 15 minutes. The reaction was maintained at -15 °C for a total of 40 minutes. The reaction was quenched with aq NaHCQj solution and the product extracted into EtOAc. The organic extract was washed with H2O and brine and dried (MgSCty). The product was recrystallized from EtOAc - hexane to give a colorless solid: !H NMR (250MHz, CDCI3) δ 8.03 (d,
J=15.7Hz, IH. olefin), 7.22 (dd, J=8.0Hz, IH, 5'-phenyl), 7.15 (m, 2H, 4,5-pyridyl),
7.11 (d, J=8.6Hz, 2H, phenyl), 6.92 (m, IH, 2'-phenyl), 6.85 (d, J=15.7Hz, IH, olefin), 6.80 (m, 3H, phenyl, 4'-phenyl), 6.73 (ddd, J=8.0, 1.9Hz, IH, 6'-phenyl),
4.12 (s, 2H, CH2-S), 4.00 (t, J=6.5Hz, 2H, O-CH2), 3.99 (broad singlet, 2H, NH2), 3.82 (s, 3H, methyl ester), 3.79 (s, 3H, OMe), 2.56 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.36 (m, 6H, aliphatic);
Analysis calcd for C31H38N2O5S: C, 67.61; H, 6.95; N, 5.09; found: C, 67.73; H,
7.17; N, 4.82; MS (CI): 551 (M+H); mp 109-111 °C.
13(b) 3-fl-Oxythia-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-pheny1)octyloxy)-625 pvridvnethvllaniline, lithium salt. 3-[lOxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (l09mg, O.198mmol) was dissolved in THF (0.80mL) and MeOH (0.40mL) and treated with 1.0M LiOH (0.40mL, 0.40mmol). The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded a colorless amorphous solid: JH NMR (250MHz, d4-MeOH) δ 7.75 (d. J=15.7Hz, IH, olefin), 7.28 (d, J=8.6Hz, IH,
5-pyridyl), 7.15 (dd, J=8.0Hz, IH, 5'-phenyl), 7.03 (m, 4H, 4-pyridyl, olefin, phenyl), 6.86 (dd, J=1.9Hz, IH, 2'-phenyl), 6.75 (m, 4H, 4',6'-phenyl, phenyl), 4.20 (q, J=13Hz, 2H, CH2-S), 4.02 (t, J=6.5Hz, 2H, 0-CH2), 3.72 (s. 3H, OMe), 2.52 (t,
J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.53 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); Analysis calcd for C30H35N2O5SL1 · 2 H2O: C, 62.27; H, 6.79; N, 4.84;
found: C, 62.13; H, 6.89; N, 5.01; MS (FAB): 543 (M+H), 537 (M+H; free acid).
Proceeding in a similar manner, there was made
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3-[ l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxypheny 1))-6pyridyl]ethyl]aniline, lithium salt;
Colorless amorphous solid: NMR (250MHz, d4-MeOH) δ 7.75 (d,
J=15.7Hz, IH, olefin), 7.28 (d, J=8.6Hz, IH, pyridyl), 7.20 (d, J=8.6Hz, IH, pyridyl), 7.12 (d, J=8.6Hz, 2H, phenyl), 7.06 (s, IH, 2'-phenyl), 7.02 (d, J=7.8Hz, IH, 4'-phenyl), 6.81 (m, 5H, 5',6'-phenyl, olefin, phenyl), 4.20 (q, J=13Hz, 2H, CH2-S(O)), 4.02 (t, J=6.5Hz, 2H, O-CH2), 3.72 (s, 3H, OMe), 2.62 (t, J=7.6Hz, 2H, benzylic), 1.80 (m, 4H, aliphatic); Analysis calcd for C26H27N2O5SLi · 2½ H2O: C, 58.50; H, 6.09; N, 5.25; found; C, 58.18; H, 5.67; N, 5.12; MS (ES+): 481.2 (M+H;
free acid), (ES-): 479.0 (M-H; free acid). . *
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)octyloxy)6-pyridyl]ethyl]aniline, lithium salt;
Colorless amorphous solid: JH NMR (250MHz, d4-MeOH) δ 7.75 (d,
J=15.7Hz, IH, olefin), 7.53 (d, J=8.6Hz, 2H, phenyl), 7.34 (d, J=8.6Hz, 2H, phenyl), 7.24 (d, J=8.6Hz, IH, pyridyl), 7.18 (d, J=8.6Hz, IH, pyridyl), 7.04 (d,
J=8.0Hz, IH, 4'-phenyl), 7.02 (d, J=15.7Hz, IH, olefin), 6.89 (s, IH, 2'-phenyl),
6.78 (m, 2H, 5',6'-phenyl), 4.20 (q, J=13Hz, 2H, CH2-S(O)), 4.02 (t, J=6.5Hz, 2H, O-CH2), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH^, 1.69 (m, 2H, CH2),
1.50 (m, 2H, CH2), 1.39 (m, 6H, aliphatic); Analysis calcd for C30H32F3N2O4SL1 ·
1¾ H2O: C, 58.87; H, 5.85; N, 4.58; found: C, 58.92; H, 5.55; N, 4.48; MS (ES+):
575.2 (M+H; free acid);
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyl)octyloxy-6pyridyl]ethyl]aniline, lithium salt;
Colorless amorphous solid: JH NMR (250MHz, d4-MeOH) δ 7.75 (d,
J=15.7Hz, IH, olefin), 7.20 (m, 7H, pyridyl, phenyl), 7.04 (d, J=8.0Hz, IH, 4'phenyl), 7.02 (d, J=15.7Hz, IH, olefin), 6.89 (s, IH, 2'-phenyl), 6.78 (m, 2H, 5',6'phenyl), 4.20 (q, J=13Hz, 2H, CH2-S(O)), 4.02 (t, J=6.5Hz, 2H, O-CH2), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH2), 1.69 (m, 2H, CH2), 150 (m, 2H, CH2), 1.39 (m, 6H, aliphatic); Analysis calcd for C29H33N2O4SL1 · 1 H2O: C, 65.65; H,
6.65; N, 5.28; found: C, 65.62; H, 6.39; N, 4.90; MS (ES+): 507.0 (M+H; free acid), (ES-): 505.0 (M-H; free acid);
3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-fluorophenyl)octyloxy)-6pyridyl]ethyl]aniline, lithium salt;
Colorless amorphous solid: JH NMR (250MHz, d4-MeOH) δ 7.75 (d,
J=15.7Hz, IH, olefin), 7.30 - 6.90 (multiplet, 8H, pyridyl, phenyl, olefin, 4'-phenyl),
6.89 (s, IH, 2’-phenyl), 6.78 (m, 2H, 5',6'-phenyl), 4.20 (q, J=13Hz, 2H, CH2S(O)), 4.02 (t, J=6.5Hz, 2H, O-CH2), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH2), 1.59 (m, 2H, CH2), 1.50 (m, 2H, CH2), 1.39 (m, 6H, aliphatic); MS (ES+):
525.2 (M+H; free acid), (ES-): 523.0 (M-H; free acid).
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Example 14
3-f 1 -Dioxythia-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxvphenvIloctyloxv )-6pyridvllethynaniline, lithium salt 5
14(a) 3-f l-Dioxythia-2-f2-(E-2-carboxymethylethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-Pvridynethvllaniline· To a cooled (0 °C) solution of 3-[lthia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]aniline (75mg, 0.14mmol) in CH2CI2 (3mL) under an argon atmosphere was added 85% mCPBA (63mg, 0.308mmol). After 1 hour the reaction was quenched with aq NaHCQ) solution and the product extracted into EtOAc. The organic extracts were washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 50% EtOAc in hexane) gave a colorless solid: !H NMR (250MHz, CDCI3) δ 7.90 (d, J=15.7Hz, IH, olefin), 7.39 (d, J=8.6Hz, IH, 5-pyridyl),
7.21 (t, J=8.0Hz, IH, 5'-phenyl), 7.19 (d, J=8.6Hz, IH, 4-pyridyl), 7.11 (d, J=8.6Hz,
2H, phenyl), 7.03 (m, 2H, 2’,4'-phenyl), 6.86 (m, IH, 6'-phenyl), 6.81 (d, J=8.6Hz, 2H, phenyl), 6.54 (d, J=15.7Hz, IH, olefin), 4.46 (s, 2H, CH2-S), 3.99 (t, J=6.5Hz, 2H, O-CH2), 3.86 (broad singlet, 2H, NH2), 3.79 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.82 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.35 (m, 6H, aliphatic); Analysis calcd for C31H38N2O6S · 1/3 mol
C6H14: C, 66.57; H, 7.22; N, 4.70; found: C, 66.45; H, 7.24; N, 4.89; MS (CI): 567 (M+H); mp 92-95 °C.
14(b) 3-fl-Dioxythia-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-625 pyridyllethynaniline, lithium salt.
3-[l-Dioxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (5lmg, 0.09mmol) was dissolved in THF (0.30mL) and MeOH (0.18mL) and treated with 1.0M LiOH (0.18mL, 0.18mmol). The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2OMeOH gradient). Lyophilization yielded a colorless amorphous solid: JH NMR (250MHz, d4-MeOH) δ 7.65 (d, J=15.7Hz, IH, olefin), 7.26 (d, J=8.6Hz, IH, 5pyridyl), 7.24 (d, J=8.6Hz, IH, 4-pyridyl), 7.17 (dd, J=8.0Hz, IH, 5'-phenyl), 7.06 (d, J=8.6Hz, 2H, phenyl), 6.97 (dd, J=1.9Hz, IH, 2'-phenyl), 6.85 (m, 2H, 4’,6'35 phenyl), 6.78 (d, J=8.6Hz, 2H, phenyl), 6.75 (d, J=15.7Hz, IH, olefin), 4.55 (s, 2H, CH2-S), 4.04 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.86 (m, 2H, CH2), 1.55 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); MS (FAB): 559 (M+H), 553 (M+H; free acid). __
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Example 15
3-f l-Thia-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methox\ phenvDoctvloxv)-6-pyridvre:hvl1N.N-dimethylaniline, lithium salt
15(a) 3-f l-Thia-2-f2-(E-2-carboxvmethylethenyI )-3-(8-(4-methoxyphenyl )octyloxv)-6pyridynethyll-N.N-dimethylaniline. To a solution of 3-[ 1 -thia-2-[2-(E-2carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (75mg, 0.14mmol) in acetonitrile (ImL) was added formaldehyde (0.25mL, 3. lmmol; 37% aqueous solution) and NaCNBHj (50mg, 0.80mmol). The reaction was stirred at room temperature for 15 minutes. The reaction solution was made neutral by the addition of glacial acetic acid and stirred for an additional 2 hours. The reaction was diluted with H2O and the product extracted into EtOAc. The organic layer was washed with H2O and brine and dried (MgSO^). Purification by flash column chromatography (silica, 20% EtOAc in hexane) gave a pale yellow oil: lH NMR (250MHz, CDCI3) δ 8.06 (d,
J=15.7Hz, IH, olefin), 7.35 (d, J=8.6Hz, IH, 5-pyridyl), 7.08 (m, 4H, 4-pyridyl, 5'phenyl, phenyl), 7.04 (d, J=15.7Hz, IH, olefin), 6.83 (d, J=8.6Hz, 2H, phenyl), 6.74 (m, 2H, T/T-phenyl), 6.52 (dd, J=8.0, 1.9Hz, IH, 6’-phenyl), 4.23 (s, 2H, CH2-S), 4.00 (t, J=6.5Hz, 2H, O-CH2), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.89 (s, 6H, Me2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.83 (m, 2H, CH2), 1.60 (m, 2H, CH2),
1.45 (m, 2H, CH2), 1.35 (m, 6H, aliphatic); MS (CI); 563 (M+H).
15(b) 3-il-Thia-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxv)-6pvridyHethvn-N.N-dimethvlaniline, lithium salt. 3-( 1 -Thia-2-[2-(E-2carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N25 dimethylaniline (lOOmg, 0.178mmol) was dissolved in THF (0.72mL) and MeOH (0.36mL) and treated with 1.0M LiOH (0.36mL, 0.36mmol). The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient).
Lyophilization yielded a colorless amorphous solid: *H NMR (250MHz, d4-MeOH) δ
7.78 (d, J=15.7Hz, IH, olefin), 7.25 (s, 2H, 4,5-pyridyl), 7.07 (m, 4H, phenyl, olefin,
5'-phenyl), , 6.80 (d, J=8.6Hz, 2H, phenyl), 6.72 (dd, J=1.9Hz, IH, 2 -phenyl), 6.67 (ddd, J=8.0, 1.9Hz, IH, 4’-phenyl), 6.55 (ddd, J=8.0, 1.9Hz, IH, 6'-phenyl), 4.20 (s, 2H, CH2-S), 4.00 (t, J=6.5Hz, 2H, O-CH2), 3.76 (s, 3H, OMe), 2.85 (s, 6H, Me2), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.55 (m, 4H, aliphatic), 1.33 (m,
6H, aliphatic); Analysis calcd for C32H39N2C>4SLi. 5/4 H2O: C, 66.59; H, 7.25; N,
4.85; found: C, 66.50; H, 7.01; N, 4.75; MS (FAB): 555.2 (M+H).
P50046-1-2
3-f l-Oxythia-2-f2-fE-2-carboxvethenvl)-3-(8-(4-me[hoxyphenvl)octvloxy )-6pyridylkthyn-N.N-dimethyfaniline, lithium salt
16(a) 3-fl-Oxythia-2-f2-(E-2-carboxymethylethenvl)-3-(8-(45 methoxyphenyl)octyloxy)-6-pyridyl1ethylI-N.N-dimethylaniline. Prepared from 3-[lthia-2-[2-(E-2-carboxymethyIethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]-N,N-dimethylaniline according to the procedure described for the preparation of 3-[l-oxythia-2-[2-(E-2-carboxymethylethenyI)-3-(8-(4methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline: ]H NMR (250MHz, CDCI3) δ 8.01 (d, J= 15.7 Hz, IH, olefin), 7.22 (dd, J=8.0Hz, IH, 5’-phenyl), 7.17 (d, J=8.6Hz, IH,
5-pyridyl), 7.13 (d, J=8.6Hz, IH, 4-pyridyl), 6.80 (m, 6H, phenyl, 2',4',6’-phenyl, olefin), 4.12 (s, 2H, CH2-S), 4.00 (t, J=6.5Hz, 2H, O-CH2), 3.82 (s, 3H, methyl ester), 3.79 (s, 3H, OMe), 2.95 (s, 6H, Me2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.36 (m, 6H, aliphatic); MS (CI): 579.2 (M+H).
16(b) 3-fl-Oxythia-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxypheny1)octyloxy)-6pyridyllethyll-N.N-dimethylaniline. lithium salt. Prepared from 3-ll-oxythia-2-[2-(E-2carboxymethyl-ethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N2 0 dimethylaniline according to the procedure described for the preparation of 3-[l-oxythia2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxypheny!)octy]oxy)-6-pyridyl]ethyl]aniline, lithium salt Colorless amorphous solid: JH NMR (250MHz, d4-MeOH) δ 7.75 (d, J=15.7Hz, IH, olefin), 7.31 (dd, J=8.0Hz, IH, 5’-phenyl), 7.24 (d, J=8.6Hz, IH, 5pyridyl), 7.03 (m, 3H, 4-pyridyl, phenyl), 6.95 (d, J=15.7Hz, IH, olefin), 6.80 (m,
4H, aryl), 6.70 (m, IH, aryl), 4.21 (q, J=13Hz, 2H, CH2-S), 4.02 (t, J=6.5Hz, 2H,
O-CH2), 3.74 (s, 3H, OMe), 2.84 (s, 6H, Me2), 2.56 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.53 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); MS (FAB): 571.3 (M+H)
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Example 17
Preparation of 3-fN-f 2-[2-(E-2-Carbox vethenyl)-3-(8-i4-met hoxypheny Boctvlo\v)-6pyridyUmethylllaminobenzoic acid, dilithium salt
The captioned compound was prepared according to the method set out in Scheme 5 above by reacting the appropriate r-BOC-protected aminobenzoic acid with 2-(E-2carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)-pyridine hydrochloride or a similar intermediate, the captioned compound was prepared.
In a similar manner 3-[N-[2-[2-(E-2-carboxyethenyl)-3-(8-(4methoxyphenyl)octyloxy)-6-pyridyl]-methyl]]aminobenzoic acid, N-oxide, dilithium salt and 3-[N-[2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6pyridyl]methyl]-N-methyl]aminobenzoic acid, dilithium salt were made.
Example 18
4-f2-Thia-3-f2-(E-2-carboxyethenyl)-3-f8-(4-methoxyphenyl)octyloxyl-6pyridyllpropyllbenzoic acid, dilithium salt
18(a). 3-Hydroxy-6-methvl-2-pyridine carboxaldehyde. 2,6-Lutidine-a2,3-diol (15g, 107.8mmol; Aldrich) was suspended in dry CH2CI2 (200mL) and treated with Mn02 (47g, 539mmol). The reaction was stirred at room temperature for 6 hours. The reaction mixture was filtered through a pad of Celite and the solvent was evaporated. The crude aldehyde was obtained as a tan solid and was used directly for the next step: ^H NMR (250MHz, CDCI3) δ 10.65 (s, IH, OH), 10.30 (s, IH, aldehyde), 7.30 (m, 2H, 4,5** F pyridyl), 2.55 (s, 3H, methyl).
18(b). 3-i8-(4-Methoxyphenvlk>ctvloxvl-6-methyl-2-pvridine carboxaldehyde. To a solution of l-iodo-8-(4-methoxyphenyl)octane (16.3g, 47.1 mmol) in dry DMF (45mL) under an argon atmosphere was added 3-hydroxy-6-methyl-2-pyridine carboxaldehyde (7.7g, 56.2mmol) and anhydrous K2CO3 (32g, 235mmol). The reaction was vigorously stirred at 90°C for 1.5 hours. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O, aq NH4CI, and brine and dried (MgSO4). Evaporation provided crude aldehyde as a dark oil that was used without further purification.
18(c). 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy1-6methylpyridine. 3-[8-(4-Methoxyphenyl)octyloxy]-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (lOOmL) under an argon atmosphere and treated with methyl (triphenylphosphoranylidene)acetate (16g, 48mmol). The reaction was heated for 1 hour at 50°C. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 20% EtOAc in hexane) gave the product as a pale
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P50046-1-2 yellow oil: !h NMR (250MHz, CDCI3) δ 8.07 (d, J = 15.7Hz, IH, olefin), 7.10 (m,
4H, phenyl, 4,5-pyridyl), 7.07 (d, J=15.7Hz, IH, olefin), 6.81 (d, J=8.6Hz, 2H, phenyl), 3.97 (t, J=6.5Hz, 2H, O-CH2), 3.79 (s, 3H, OCH3), 3.78 (s, 3H, methyl ester), 2.54 (t, J=7.6Hz, 2H, benzylic), 2.48 (s, 3H, methyl), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.37 (m, 8H, aliphatic); MS (CI): 412.3 (M+H).
18(d). 2-(E-2-Carboxvmethylethenyl)-3-18-(4-methoxyphenyl)-octyloxyl-6methylpvridine N-oxide. 2-(E-2-Carboxymethyl-ethenyl)-3-(8-(4methoxyphenyl)octyloxy]-6-methylpyridine (17. lg, 41.5mmol) was dissolved in dry
CH2CI2 (105mL) and cooled to 0°C; 50% zn-chlorperbenzoic acid (15.8g, 45.8mmol) was added in three portions over 10 minutes. The cooling bath was removed and the reaction was stirred for 15 hours at room temperature. The reaction was poured into aqueous NaHCO3 and the product extracted into CH2CI2. The organic extract was washed with H2O and brine and dried (MgSCty). The crude product was obtained as a yellow solid and was used without further purification.
18(e). 2-(E-2-Carboxymethylethenyl)-3-i8-(4-methoxyphenyl)-octyloxyl-6hydrgxymcthyjpyridipg· 2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4methoxyphenyl)octyloxy]-6-methylpyridine N-oxide obtained above was suspended in dry DMF (130mL) and cooled to 0°C under an argon atmosphere. To this was slowly added trifluoroacetic anhydride (56mL, 400mmol). The reaction was maintained at 0°C i-: .·* . -f- .
for 20 minutes followed by 18 hours at room temperature. The reaction solution was slowly added to a solution of saturated aqueous Na2CO3 and stirred for 1 hour. The product was then extracted into EtOAc; the combined organic extracts were washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, EtOAc:hexane:CH2Cl2, 30:20:50) gave a waxy solid: NMR (250MHz,
CDCI3) 5 8.08 (d, J=15.7Hz, IH, olefin), 7.23 (d, J=8.6Hz, IH, 5-pyridyl), 7.16 (d,
J=8.6Hz, IH, 4-pyridyl), 7.09 (d, J=8.6Hz, 2H, phenyl), 7.03 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.69 (d, J=4.1Hz, 2H, CH2-OH), 4.01 (t, J=6.5Hz, 2H, O-CH2), 3.82 (s, 3H, OCH3), 3.78 (s, 3H, methyl ester), 3.62 (t, J=4.1Hz, IH, OH), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.58 (m, 2H, CH2), 1.44 (m, 8H, aliphatic); MS (CI): 428.2 (M+H).
18(f) Methyl 4-r2-thia-3-f2-(E-2-carboxy-methylethenyl)-3-f8-(435 methoxyphenyI)octyloxyl-6-pyridyllpropyllbenzoate. To a cooled (0°C) solution of
SOCI2 (0.51mL, 7.0mmol) in dry toluene (2mL) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6hydroxymethylpyridine (300mg, 0.70mmol) in toluene (5mL). After 5 minutes the
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P50046-1-2 cooling bath was removed and the reaction was stirred for 2 hours at room temperature.
The toluene and excess SOC12 were evaporated. To this was added dry DMF (2mL), methyl 4-mercaptomethylbenzoate (180mg, 0.7mmol) [prepared from 4mercaptomethylbenzoic acid (Bader) and methanolic HCl], and anhydrous CS2CO3 (1.63g, 5.0mmol). The reaction was heated at 60°C under an atmosphere of argon for 2 hours. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O, 10% NaOH, H2O, and brine and dried (NlgSO4). Purification by flash column chromatography (silica, 15% EtOAc in hexane) yielded a colorless waxy solid: lH NMR (250MHz, CDCI3) δ 8.05 (d, J=15.8Hz, 1H, olefin), 7.93 (d,
J=8.6Hz, 2H, phenyl), 7.35 (d, J=8.6Hz, 2H, phenyl), 7.18 (d, J=8.6Hz, 1H,. . , pyridyl), 7.06 (d, J=8.6Hz, 1H, pyridyl), 7.02 (d, J=8.6Hz, 2H, phenyl), 6.98 (d, J=15.8Hz, 1H, olefin), 6.78 (d, J=8.6Hz, 2H, phenyl), 3.92 (t. J=6.5Hz, 2H, OCH2), 3.85 (s, 3H, methyl ester), 3.75 (s, 3H, OCH3), 3.72 (s, 3H, methyl ester), 3.64 (s, 2H, SCH2), 3.59 (s, 2H, SCH2), 2.49 (t, J=7.6Hz, 2H, benzylic), 1.78 (m, 2H,
CH2), 1.40 (m, 10H, aliphatic); MS (CI): 592 (M+H).
18(g). 4-i2-Thia-3-f2-(E-2-carboxyethenyl)-3-f8-(4-methoxy-phenvl)octvloxyl-6pyridvnpropyllbenzoic acid, dilithium salt. Methyl 4-[2-thia-3-(2-(E-2carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyIoxy]-6-pyridyl]propyl]benzoate (80mg, 0.13mmol) was dissolved in tetrahydrofuran (THF) (1,5mL) and MeOH (1.5mL) and treated with 1.0M LiOH (0.8mL, 0.8mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated arid the product purified by Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded a colorless amorphous solid: ^H NMR (250MHz, d^-MeOH) δ 7.87 (d, J=8.6Hz, 2H, phenyl), 7.79 (d, J=15.8Hz, 1H, olefin), 7.34 (m, 3H, phenyl, pyridyl), 7.23 (d, J=8.6Hz, 1H, pyridyl), 7.08 (d, J=15.8Hz, 1H, olefin), 7.06 (d, J=8.6Hz, 2H, phenyl), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.04 (t, J=6.5Hz, 2H, OCH2), 3.74 (s, 2H, SCH2), 3.73 (s, 3H, OCH3), 3.69 (s, 2H, SCTD). 2.55 (t, J=7.6Hz, 2H, benzylic), 1.87 (m, 2H, CH2), 1.50 (m, 10H, aliphatic); Analysis calcd for C32H35NO6SL12 ·
3H2O: C, 61.04; H, 6.56; N, 2.22; found: C, 60.96; H, 6.35; N, 2.39; MS (FAB): 576 (M+H), 582.3 (M+Li).
Example 19
4-f2-Oxythia-3-f2-(E-2-carboxyethenyl)-3-f8-(4-methoxyphenyl)octyloxyl-635 pyridyllpropvllbenzoic acid, dilithium salt
19(a). Methyl 4-f2-oxvthia-3-f2-(E-2-carboxymethylethenyl)-3-f8-(4methoxyphenyl)octyloxyl-6-pvridynpropynbenzoate· Methyl 4-[2-thia-3-[2-(E-2carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (11 Omg, 0.186mmol) was dissolved in dry CH2CI2 (4mL) under an argon atmosphere
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P50046-1-2 and cooled to -20°C. To this was added 85% zn-chloroperoxybenzoic acid (36mg, 0.18mmol) in two portions 15 minutes apart. The reaction was stirred for 15 minutes at -20°C following the second addition and then quenched with 5% NaHC03. The product was extracted into CH2CI2 and the organic extracts were dried (.\lgSO4). Purification by flash column chromatography (silica, 50% EtOAc in hexane) gave a white solid: 'H NMR (250MHz, CDCI3) δ 8.10 (d, J=15.8Hz, IH, olefin), 8.07 (d, J=8.6Hz, 2H, phenyl), 7.50 (d, J=8.6Hz, 2H, phenyl), 7.28 (d, J=8.6Hz, IH, pyridyl), 7.20 (d, J=8.6Hz, IH, pyridyl), 7.12 (d, J=8.6Hz, 2H, phenyl), 7.07 (d, J=15.8Hz, IH, olefin), 6.83 (d, J=8.6Hz, 2H, phenyl), 4.19 (d, J=12.8Hz, IH, SCH), 4.12 (d,
J=12.8Hz, IH, SCH), 4.04 (t, J=6.5Hz, 2H. OCH2). 3 94 (s, 3H, methyl ester), 3.92 (m, 2H, SCH2), 3.83 (s, 3H, OCH3), 3.79 (s, 3H, methyl ester), 2.56 (t, J=7.6Hz,
2H, benzylic), 1.87 (m, 2H, CH2), 1.40 (m, 10H, aliphatic); Analysis calcd for C34H41NO7S: C, 67.19; H, 6.80; N, 2.30; found: C, 66.80; H, 7.12; N, 2.25; MS (CD: 608 (M+H).
19(b). 4-f2-Oxythia-3-f2-(E-2-carboxyethenyl)-3-f8-(4-methoxyphenyl)octyloxyl-6pyridynpropvllbenzoic acid, dilithium salt. Methyl 4-[2-oxythia-3-[2-(E-2carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (90mg, 0.148mmol) was dissolved in THF (1.5mL) and MeOH (1.5mL) and treated with 1.0M LiOH (0.8mL, 0.8mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded a colorless amorphous solid: *H NMR (250MHz, d4-MeOH) δ 7.98 (d, J=8.6Hz, 2H, phenyl), 7.81 (d, J=15.8Hz, IH, olefin), 7.40 (d, J=8.6Hz, 2H, phenyl), 7.39 (d,
J=8.6Hz, IH, pyridyl). 7.27 (d, J=8.6Hz, IH, pyridyl), 7.09 (d, J=15.8Hz, IH, olefin), 7.05 (d, J=8.6Hz, 2H, phenyl), 6.77 (d, J=8.6Hz, 2H, phenyl), 4.35 (d, J=12.8Hz, IH, SCH), 4.25 (d, J=12.8Hz, IH, SCH), 4.06 (m, 4H, OCH2, SCH2),
3.73 (s, 3H, OCH3), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.86 (m, 2H, CH2), 1.55 (m,
4H, aliphatic), 1.35 (m, 6H, aliphatic); MS (FAB): 592 (M+H), 500 (M+H; free acid).
Example 20
3-f2-Thia-3-f2-(E-2-carboxyethenyl)-3-f8-(4-methoxvphenyl)octyloxy1-6pyridyllpropyll ben zoic acid, dilithium salt 20(a). Methyl 3-mercaptomethylbenzoate. To a solution of methyl 3bromomethylbenzoate (6.9g, 30mmol; Lancaster) in dry acetone (lOmL) was added via dropwise addition a solution of thiourea (2.28g, 30mmol) in dry acetone (40mL) at room temperature. After 15 minutes the precipitated thiouronium salt was collected by filtration; the solids were washed with acetone and dried. The thiouronium salt was dissolved in H2O (65mL) and the pH was adjusted to 10.5 by the addition of 10%
NaOH. The mixture was refluxed for 2 hours. After cooling to room temperature the
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P50046-1-2 solution was extracted with EtOAc and the organic layer w as discarded. The aqueous solution was acidified to pH 1.5 and extracted three times w ith EtOAc. The organic extracts were dried (MgSO4), filtered and the solvent evaporated. The crude acid was then dissolved in anhydrous MeOH (125mL), cooled to 0;C, and dry HCl gas was bubbled through the solution for 30 minutes. The reaction was then left for two days at room temperature. The mixture was concentrated in vacuo and the product was purified by flash column chromatography (silica, 5% EtOAc in hexane) providing a colorless oil: *H NMR (250MHz, CDCI3) δ 8.00 (s, 1H, 2-phenyl), 7.91 (d, J=7.6Hz, 1H, 6phenyl), 7.52 (d, J=7.6Hz, 1H, 4-phenyl), 7.39 (dd, J=7.6Hz, 1H, 5-phenyl), 3.92 (s, 3H, methyl ester), 3.78 (d, J=7.7Hz, 2H, SCH2), 1.79 (t, J=7.7Hz, 1H, SH).
20(b). Methyl 3-f2-thia-3-f2-(E-2-carboxy-methylethenvl)-3-f8-(4methoxyphenyl)octyloxyl-6-pyridyllpropyllbenzoate. To a cooled (0°C) solution of SOCI2 (2.5mL, 35mmol) in dry toluene (25mL) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6hydroxymethylpyridine (1.5g, 3.5mmol) in toluene (lOmL). After 5 minutes the cooling bath was removed and the reaction was stirred for 4 hours at room temperature. The toluene and excess SOCI2 were evaporated. To this was added dry DMF (5mL), methyl 3-mercaptomethylbenzoate (600mg, 3.3mmol), and anhydrous CS2CO3 (6.6g,
20mmol). The reaction was heated at 60°C under an atmosphere of argon for 1.5 hours. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H20,10% NaOH, H2O, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 15% EtOAc in hexane) yielded a colorless waxy solid: ^H NMR (250MHz, CDCI3) δ 8.07 (d, J=15.8Hz, 1H, olefin), 7.99 (s, 1H, 2-phenyl), 7.90 (d, J=7.7Hz, 1H, 6-phenyl), 7.54 (d, J=7.7Hz, 1H, 4-phenyl), 7.37 (dd,
J=7.7Hz, 1H, 5-phenyl), 7.28 (d, J=8.6Hz, 1H, pyridyl), 7.14 (d, J=8.6Hz, 1H, pyridyl), 7.11 (d, J=8.6Hz, 2H, phenyl), 7.08 (d, J=15.8Hz, 1H, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 3.99 (t, J=6.5Hz, 2H, OCH2), 3.91 (s, 3H, methyl ester), 3.81 (s, 3H, OCH3), 3.78 (s, 3H, methyl ester), 3.71 (s, 2H, SCH2), 3.68 (s, 2H, SCH2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.78 (m, 2H, CH2), 1.5 (m, 10H, aliphatic); MS (CI):
592.2 (M+H).
20(c). 3-12-Thia-3-f2-(E-2-carboxyethenyl)-3-f8-(4-methoxyphenyl)octyloxyl-6pyridyHpropynbenzoic acid, dilithium salt. Methyl 3-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (1.5g, 2.5mmol) was dissolved in THF (20mL) and MeOH (20mL) and treated with 1.0M LiOH (11.5mL, 11.5mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H20-Me0H gradient). Lyophilization yielded a colorless amoiphous
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P50046-1-2 solid: IH NMR (250MHz, d4-MeOH) δ 7.96 (s. IH, 2-phenyl), 7.85 (d, J=7.7Hz, IH,
6-phenyl), 7.79 (d, J=15.8Hz, IH, olefin), 7.30 (m, 4H, 4,5-phenyl, 4,5-pyridyl), 7.08 (d, J=15.8Hz, IH, olefin), 7.06 (d, J=8.6Hz, 2H. phenyl), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.04 (t, J=6.5Hz, 2H, OCH2), 3.74 (s, 2H, SCH2), 3.73 (s, 3H, OCH3),
3.69 (s, 2H, SCH2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.87 (m, 2H, CH2), 1.50 (m,
10H, aliphatic); Analysis calcd for C32H35NC>6SLi2 · 5/4H2O: C, 64.32; H, 6.32; N, 2.34; found: C, 64.28; H, 6.24; N, 2.32; MS (FAB): 564.2 (M+H; free acid).
Proceeding in a similar manner, but substituting another alcohol for 8-(4methoxyphenyl)octan-l-ol, such as 4-(4-methoxyphenyl)butan-l-ol, preparing or purchasing the appropriate mercaptan and the appropriate benzoate or aniline, ther following compounds were make! 1
3- [2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyI)butyloxy]-6pyridyljpropyl]benzoic acid, dilithium salt;
2- [2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyIoxy]-615 pyridyl]propyl]benzoic acid, dilithium salt;
4- [2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyl]ethyl]phenylacetic acid, dilithium salt;
l-fluoro-3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]6-pyridyl]propyl]benzene, lithium salt
3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyl]propyl]benzene* lithium salt l-fluoro-4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]6-pyridyl]propyl]benzene, lithium salt
3- [2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-625 pyridyl]propyl]aniline, dilithium salt;
N-[3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyl]propyl]phenyltrifluoro-methanesulfonamide; [Mercaptan prepared by the method of Tagawa, H. and Veno, K., Chem. Pharm, Bull., 26(5), 1384 (1978)]; and
N-[3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-630 pyridyl]propyl]benzene-methanseulfonamide, [Mercaptan prepared by the method of
Lutter, E., Chem. Ber., 30, 1065 (1897)].
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P50046-1-2
Example 21
3-f2-Oxythia-3-f2-(E-2-carboxve:hen\H-3-f8-(4-metho\vphen \ Boctyloxyl-6Dvridyllpropvllbenzoic acid, dilithium salt and 3-12-Dioxythia-3-f2-(E-2carboxyethenyl)-3-i8-(4-methoxyphenylk>ctyloxy]-6-pvridvllpropvl]benzoic acid, dilithium salt
21(a). Methvl 3-f2-oxvthia-3-f2-(E-2-carboxymethylethenyl)-3-f8-(4methoxyphenyl)octvloxyl-6-pyridvl]propvllbenzoate and methvl 3-f2-dioxythia-3-f2-(E2-carboxymethylethenyl)-3-f8-(4-methoxyphenyl)octyloxvl-6-pyridyIlpropvllbenzoate·
Methyl 3-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(410 methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (150 mg, 0.25mmol) was dissolved in dry CH2CI2 (5mL) under an argon atmosphere and cooled to -20°C. To this was added 85% m-chloroperoxybenzoic acid (52mg, 0.26mmol) in two portions 15 minutes apart The reaction was stirred for 25 minutes at -20 °C following the second addition and then quenched with 5% NaHCC>3. The product was extracted into CH2C12 and the organic extracts were dried (MgSO4). Purification by flash column chromatography (silica, 20 and 50% EtOAc in hexane) gave the sulfoxide as a white solid and the sulfone as a white solid.
Sulfoxide: JH NMR (250MHz, CDCI3) δ 8.07 (d, J=15.8Hz, 1H, olefin), 8.01 (s, 1H, 2-phenyl), 7.97 (d, J=7.7Hz, IH, 6-phenyl), 7.55 (d, J=7.7Hz, 1H, 4-phenyl),
7.46 (dd, J=7.7Hz, IH, 5-phenyl), 7.28 (d, J=8.6Hz, IH, pyridyl), 7.20 (d, J=8.6Hz,
IH, pyridyl), 7.07(d, J=8.6Hz, 2H, phenyl), 7.05 (d, J=15.8Hz, IH, olefin), 6.78 (d, J=8.6Hz, 2H, phenyl), 4.12 (d, J=12.8Hz, IH, SCH), 4.05 (d, J=12.8Hz, IH, SCH), 4.04 (t J=6.5Hz, 2H, OCH2), 3.94 (s, 3H, methyl ester), 3.92 (m, 2H, SCH2), 3.83 (s, 3H, OCH3), 3.79 (s, 3H, methyl ester), 2.56 (t, J=7.6Hz, 2H, benzylic), 1.87 (m,
2H, CH2), 1.40 (m, 10H, aliphatic); Analysis calcd for C34H41NO7S · 1/4H2O: C,
66.70; H, 6.83; N, 2.29; found: C, 66.54; H, 6.68; N, 2.30; MS (CI): 608.2 (M+H);
Sulfone: !H NMR (250MHz, CDCI3) δ 8.23 (s, IH, 2-phenyl), 8.13 (d, J=15.8Hz, IH, olefin), 8.08 (d, J=7.7Hz, IH, 6-phenyl), 7.74 (d, J=7.7Hz, IH, 4phenyl), 7.51 (dd, J=7.7Hz, IH, 5-phenyl), 7.46 (d, J=8.6Hz, IH, pyridyl), 7.24 (d,
J=8.6Hz, IH, pyridyl), 7.12 (d, J=8.6Hz, 2H, phenyl), 7.11 (d, J=15.8Hz, IH, olefin), 6.84 (d, J=8.6Hz, 2H, phenyl), 4.30 (s, 4H, SCH2), 4.06 (t, J=6.5Hz, 2H, OCH2), 3.93 (s, 3H, methyl ester), 3.83 (s, 3H, OCH3), 3.79 (s, 3H, methyl ester),
2.56 (t, J=7.6Hz, 2H, benzylic), 1.9 (m, 2H, CH2), 1.5 (m, 10H, aliphatic); MS (CI):
624.2 (M+H).
21(b). 3-f2-Oxythia-3-f2-(E-2-carboxvethenyl)-3-f8-(4-methoxyphenyl)octyloxyl-6pyridyllpropyllbenzoic acid, dilithium salt. Methyl 3-[2-oxythia-3-[2-(E-2carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyIoxy]-6-pyridyl]propyl]benzoate (lOOmg, 0.165mmol) was dissolved in THF (1.5mL) and MeOH (1.5mL) and treated _---BAD ORIGINAL
P50046-1-2 with l.OM LiOH (0.8mL, 0.8mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded a colorless amorphous solid: NMR (250MHz, d4-MeOH) δ 7.95 (m, 2H, 2,65 phenyl), 7.82 (d, J=15.8Hz, IH, olefin), 7.40 (m, 2H, 4,5-phenyl), 7.37 (d, J=8.6Hz, IH, pyridyl), 7.29 (d, J=8.6Hz, IH, pyridyl), 7.10 (d, J=15.8Hz, IH, olefin), 7.06 (d, J=8.6Hz, 2H, phenyl), 6.79 (d, J=8.6Hz, 2H, phenyl), 4.36 (d, J=12.8Hz, IH, SCH), 4.25 (d, J=12.8Hz, IH, SCH), 4.08 (m, 4H, OCH2, SCH2), 3.73 (s, 3H, OCH3), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.87 (m, 2H, CH2). 1.55 (m, 4H, aliphatic), 1.37 (m,
6H, aliphatic); Analysi$^$/Qr.C32H35NO7SLi2 · 7/4H2O: C, 61.68; H, 6.23; N,
2.25; found: C, 61.79; H, 6.10; N, 2.39; MS (FAB): 592.2 (M+H). r**·
This reaction was also used to prepare 3-[2-oxythia-3-[2-(E-2-carboxyethenyl)-3[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoic acid, lithium salt.
(c). 3-f2-E>ioxvthia-3-f2-(E-2-carboxyethenyl)-3-i8-(4-methoxyphenyl)octyloxyl-615 pyridyllpropynbenzoic acid, dilithium salt. Methyl 3-[2-dioxythia-3-[2-(E-2carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (20mg, 0.032lmmol) was dissolved in THF (0.5mL) and MeOH (0.5mL) and treated with 1.0M LiOH (0.2mL, 0.2mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated and the product purified by
Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded a colorless amorphous solid: 1H NMR (250MHz, d4-MeOH) δ 8.08 (s, IH, 2-phenyl), _ **4Ey ·/
7.96 (d, J=7.7Hz, IH, 6-phenyI), 7.85 (d, J=15.8Hz, IH, olefin), 7.58 (d, J=7.7Hz, IH, 4-phenyl), 7.39 (m, 3H, 5-phenyl, 4,5-pyridyl), 7.13 (d, J=15.8Hz, IH, olefin), 7.08 (d, J=8.6Hz, 2H, phenyl), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.86 (s, 4H, SCH2),
4.10 (t, J=6.5Hz, 2H, OCH2), 3.75 (s, 3H, OCH3), 2.52 (t, J=7.6Hz, 2H, benzylic),
1.87 (m, 2H, CH2), 1.55 (m, 4H, aliphatic), 1.40 (m, 6H, aliphatic); Analysis calcd for C32H35NO8SLi2 · 9/4H2O: C, 59.30; H, 6.14; N, 2.16; found: C, 59.29; H, 6.20; N, 2.39; MS (FAB): 608.2 (M+H).
This reaction can also be used to make other sulfoxides and sulfones of this inventions including 3-[2-dioxythia-[2-(E-2-carboxyethenyl)-3-[4-(4methoxyphenyl)butyloxy]-6-pyridyl]propyI]benzoic acid, dilithium salt, and 3-[2oxythia-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyl]propyl]benzoic acid, dilithium salt.______
P50046-1-2
Example 22
3-i 2-Thia-3-i2-(2-carbox vethanvl )-3-18-(4-methoxyphenvl )octyloxv 1-6pyridynpropyllbenzoic acid, dilithium salt 22(a). 2-(2-CarboxymethyIethanyl)-3-i8-(4-metho\yphenvl)-octvloxy]-65 hydroxymethylpyridine. 2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (300mg, 0.702mmol) was dissolved in MeOH (3mL) and treated with 5% Pd-C catalyst (30mg). The reaction was stirred under an atmosphere of H2 (balloon pressure) for 5 hours. The reaction was diluted with CH2CI2. and filtered through Celite, and concentrated. Purification by flash column chromatography (silica, EtOAc:CH2Cl2:hexane, 25:50:25) gave a pale yellow oil:
NMR (250MHz, CDCI3) δ 7.09 (m, 4H, phenyl, pyridyl), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.62 (s, 2H, CH2), 3.93 (t, J=6.5Hz, 2H. OCH2), 3.77 (s, 3H, OCH3), 3.68 (s, 3H, methyl ester), 3.16 (dd, J=7.3, 7.2Hz, 2H, CH2), 2.77 (dd, J=7.3, 7.2Hz, 2H, CH2), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.79 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.44 (m, 2H, CH2), 1.34 (m, 6H, aliphatic); MS (Cl): 430.2 (M+H).
22(b). Methyl 3-12-thia-3-f2-(2-carboxymethy lethan vl)-3-18-(4methoxyphenvDoctyloxyl-6-pvridyllpropynbenzoate· To a cooled (0°C) solution of SOCI2 (0.17mL, 2.33mmol) in dry toluene (1.5mL) under an argon atmosphere was added 2-(2-carboxymethylethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6hydroxymethylpyridine (lOOmg, 0.233mmol). After 5 minutes the cooling bath was removed and the reaction was stirred for 1.5 hours at room temperature. The toluene and excess SOC12 were evaporated. To this was added dry DMF (0.5mL), methyl 3mercaptomethylbenzoate (47mg, O.258mmol), and anhydrous CS2CO3 (380mg, 1.16mmol). The reaction was heated at 60° C under an atmosphere of argon for 1 hour. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O, 10% NaOH, H2O, and brine and dried (MgSO4). Purification by flash column chromatography (silica, EtOAc:CH2Cl2:hexane, 15:25:65) yielded a pale yellow oil: NMR (250MHz, CDCI3) δ 7.99 (s, IH, 2-phenyl), 7.92 (d, J=7.7Hz, IH, 6-phenyl), 7.54 (d, J=7.7Hz, IH, 4-phenyl), 7.37 (dd, J=7.7Hz, IH, 5-phenyl), 7.09 (m, 4H, pyridyl, phenyl), 6.88 (d, J=8.6Hz, 2H, phenyl), 3.93 (t, J=6.5Hz, 2H, OCH2), 3.91 (s, 3H, methyl ester), 3.78 (s, 3H, OCH3), 3.71 (s, 2H, SCH2), 3.65 (s, 3H, methyl ester), 3.64 (s, 2H, SCH2), 3.14 (dd, J=7.3, 7.2Hz, 2H, CH2), 2.79 (dd, J=7.3, 7.2Hz, 2H, CH2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.80 (m, 2H, CH2), 1.58 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.34 (m, 6H, aliphatic); Analysis calcd for C34H43NO6S: C, 68.77; H, 7.30; N, 2.36; found: C, 68.87; H, 7.21; N, 2.17; MS (CI): 594.6 (M+H).
BAD ORIGINAL £
P50046-1-2
22(c). 3-f2-Thia-3-f2-(2-carboxvethanvl)-3-[8-(4-methoxy-phenyl)octyloxvl-6pyridyllpropynbenzoic acid, dilithium salt. Methyl 3-f2-thia-3-[2-(2carboxymethylethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (116mg, 0.195mmol) was dissolved in THF (2.25mL) and MeOH (0.75mL) and treated with 1.0M LiOH (0.75mL, 0.75mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded a colorless amoiphous solid: NMR (250MHz, d^-MeOH) δ 7.90 (s, IH, 2-phenyl),
7.83 (d, J=7.7Hz, 1H, 6-phenyl), 7.34 (m, 2H, 4,5-phenyl), 7.25 (d, J=8.6Hz, IH, pyridyl), 7.14 (d, J=8.6Hz, 1H, pyridyl), 7.07 (d. J=8.6Hz, 2H, phenyl), 6.83 (d, ,.,. J=8.6Hz, 2H, phenyl), 4.01 (t, J=6.5Hz, 2H, OCH2), 3.77 (s, 3H, OCH3), 3.73 (s, 2H, SCH2), 3.71 (s, 2H, SCH2), 3.07 (dd, J=7.3, 7.2Hz, 2H, CH2), 2.47 (m, 4H, CH2, benzylic), 1.81 (m, 2H, CH2), 1.50 (m, 4H, aliphatic), 1.30 (m, 6H, aliphatic); Analysis calcd for C32H37NO6SL12 · 9/4H2O: C, 62.18; H, 6.77; N, 2.27; found: C,
61.93; H, 6.48; N, 2.10; MS (ES): 566 (M+H; free acid), 564 (M-H; free acid).
In a similiar manner, the following compounds were made: 3-[l-thia-2-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyljethyl] benzene, lithium salt;
3- [2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-620 pyridyl]propyl]benzene, lithium salt; and l-fluoro-4-[2-thia-3-[2-^carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyl]propyl]benzene, lithium salt
Example 23
4- f2-Thia-3-f2-(E-2-carboxyethenyl)-3-f8-(4-methoxvpheny0octyloxy1-6pyridynpropyllphenvlaceric acid, dilithium salt 23(a). Methyl 4-mercaptoroethylphenylacetate.
4-Bromomethyl-phenylacetic acid (lg, 4.4mmol) and thiourea (334mg, 4.4mmol) were heated (35-4O°C) in acetone (20mL) until a homogeneous solution resulted. Upon cooling to room temperature the thiouronium salt precipitated. The solvent was evaporated and the residue suspended in H2O (lOmL). The pH was adjusted to 12 with 10% NaOH. The mixture was then refluxed for two hours. The solution was acidified with 6N HC1 and the product was extracted into EtOAc. The organic extracts were washed with H2O and dried (MgSO4). The crude acid was dissolved in MeOH (20mL) and treated with cone. H2SO4 (O.33mL); the reaction was refluxed for 1.5 hours. Upon cooling to room temperature the reaction was diluted with H2O and the product was extracted into EtOAc. The organic extracts were washed with H2O and dried (MgSO4).
The methyl ester was obtained as an oil; crude product was used without further_ ___----BAD ORIGINAL
P50046-1-2 purification: NMR (250MHz, CDCI3) δ 7.23 (m, 4H. aryl), 3.71 (d, J=7.6Hz, 2H,
SCH2), 3.68 (s, 3H, methyl ester), 3.60 (s, 2H, CHg’. l.“4 u, J=7.6Hz, IH, SH); IR (film) nmax 2570 (SH), 1740 (CO) cm’1.
23(b). Methyl 4-f2-thia-3-f2-(E-2-carboxvmethyletheny 1)-3-18-(4methoxyphenyl)octyloxyl-6-pyridynpropvnphenylacetate. To a cooled (0°C) solution of SOC12 (0.44mL, 6.2mmol) in dry toluene (7mL) under an argon atmosphere was added
2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6hydroxymethylpyridine (270mg, 0.62mmol). After 5 minutes the cooling bath was 10 removed and the reaction was stirred for 2 hours at room temperature. The toluene and excess SOC12 were evaporated. To this was added dry DMF (3mL), methyl 4-mercaptomethylphenylacetate (183mg, 0.93mmol), and anhydrous CS2CO3 (907mg, 2.79mmol). The reaction was heated at 60°C under an atmosphere of argon for 1 hour. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H20,10%
NaOH, H2O, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 20% EtOAc in hexane) yielded a pale yellow oil: 'H NMR (250MHz, CDCI3) δ 8.08 (d, J=15.8Hz, IH, olefin), 7.22 (m, 6H, phenyl, pyridyl),
7.12 (d, J=8.6Hz, 2H, phenyl), 7.07 (d, J=15.8Hz, IH, olefin), 6.83 (d, J=8.6Hz, 2H, phenyl), 4.00 (t, J=6.5Hz, 2H, OCH2), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H,
OCH3), 3.70 (s, 3H, methyl ester), 3.68 (s, 2H, SCH2), 3.67 (s, 2H, SCH2), 3.62 (s, 2H, CH2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.50 (m, 2H, CH2), 1.37 (m, 6H, aliphatic); MS (CI): 605 (M+H).
23(c). 4-f2-Thia-3-f2-(E-2-carboxyethenyl)-3-f8-(4-methoxyphenyl)octyloxyl-625 pyridyllpropynphenylacetic acid, dilithium salt. Methyl4-(2-thia-3-[2-(E-2carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octylo.xy]-6-pyridyl]propyl]phenylacetate (lOOmg, 0.165mmol) was dissolved in THF (1.4mL) and MeOH (0.5mL) and treated with 1.0M LiOH (0.5mL, 0.5mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated and the product purified by
Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded a colorless amorphous solid: JH NMR (250MHz, d4-MeOH) δ 7.76 (d. J=15.8Hz, IH, olefin), 7.21 (m, 6H, phenyl, pyridyl), 7.06 (d, J=8.6Hz, 2H, phenyl), 7.05 (d, J=15.8Hz, IH, olefin), 6.77 (d, J=8.6Hz, 2H, phenyl), 4.02 (t, J=6.5Hz, 2H, OCH2), 3.72 (s, 3H, OCH3), 3.66 (s, 4H, SCH2), 3.44 (s, 2H, CH2), 2.51 (t, J=7.6Hz, 2H, benzylic), 1.86 (m, 2H, CH2), 1.53 (m, 4H, aliphatic), 1.34 (m, 6H, aliphatic); MS (FAB): 578.2 (M+H; free acid).
P50046-1-2
4-f2-Oxythia-3-12-(E-2-carboxyethenyl)-3-f 8-(4-methoxvphenyl )octvloxyl-6pyridyllpropvnphenylaceric acid, dilithium salt 24(a). Methvl 4-f2-oxythia-3-f2-(E-2-carboxymethylethenyl)-3-f 8-(4methoxyphenyl)octyloxvl-6-pyndyllpropvllphenylacetate.
Methyl 4-[2-thia-3-(2-(E-2-carboxymethylethenyl)-3-[8-(4methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylacetate (17Img, 0.28mmol) was dissolved in dry CH2CI2 (5mL) under an argon atmosphere and cooled to - 10°C, To this was added 85% m-chloroperoxybenzoic acid (67mg, 0.31 mmol) in two portions 15 minutes apart. The reaction was stirred for 20 minutes at -10°C following the second addition and then quenched, with aq NaHCCty. The product was extracted into EtOAc and the organic extracts were washed with H2O and brine and dried (MgSO4). ^ 4 Purification by flash column chromatography (silica, 30% EtOAc in hexane) gave the sulfoxide as a white solid: lH NMR (250MHz, CDCI3) δ 8.00 (d, J=15.8Hz, IH, olefin), 7.30 (d, J=8.2Hz, 2H, phenyl), 7.23 (d, J=8.2Hz, 2H, phenyl), 7.20 (d,
J=8.6Hz, IH, pyridyl), 7.13 (d, J=8.6Hz, IH, pyridyl), 7.01 (d, J=8.6Hz, 2H, phenyl), 6.98 (d, J=15.8Hz, IH, olefin), 6.76 (d, J=8.6Hz, 2H, olefin), 4.05 (d, J=12.9Hz, IH, SCH), 4.02 (d, J=12.9Hz, IH, SCH), 3.94 (t. J=6.5Hz, 2H, OCH2), 3.83 (d, J=12.9Hz, IH, SCH), 3.80 (d, J=12.9Hz, IH, SCH), 3.74 (s, 3H, methyl ester), 3.70 (s, 3H, OCH3), 3.62 (s, 3H, methyl ester), 3.56 (s, 2H, CH2), 2.47 (t,
J=7.6Hz, 2H, benzylic), 1.78 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.39 (m, 2H, CH2),
1.28 (m, 6H, aliphatic); MS (FAB): 622.3 (M+H); mp 87-89°C.
•
24(b). 4-f2-Oxythia-3-i2-(E-2-carboxyethenyl)-3-f8-(4-methoxyphenyl)octvloxvl-6pyridvHpropyllphenylacetic acid, dilithium salt. Methyl 4-[2-oxythia-3-[2-(E-2-carboxy25 methylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]-propyl]phenylacetate (1 lOmg, 0.177mmol) was dissolved in THF (l.OmL) and MeOH (0.53mL) and treated with 1.0M LiOH (O.53mL, 0.53mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded a colorless amorphous solid: ]H NMR (250MHz, d4-MeOH) 5 7.79 (d, J=15.8Hz, IH, olefin), 7.34 (m, 6H, phenyl, pyridyl), 7.09 (d, J=15.8Hz, IH, olefin), 7.06 (d,
J=8.6Hz, 2H, phenyl), 6.79 (d, J=8.6Hz, 2H, phenyl), 4.29 (d, J=12.9Hz, IH, SCH), 4.18 (d, J=12.9Hz, IH, SCH), 4.04 (m, 4H, SCH2, OCH2), 3.73 (s, 3H, OCH3),
3.48 (s, 2H, CH2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.55 (m, 4H, aliphatic), 1.35 (m, 6H, aliphatic); MS (FAB): 606.3 (M+H), 594.4 (M+H; free acid).
BADORIGINAL ft
P50046-1-2
Example 25
3-f 2-Thia-3-f2-(E-2-carbox vethenyl)-3-(8-(4-met hox\T>henvl')oct vloxv )-6pyridYllpropvll-N.N-dimethylbenzamide, lithium salt 25(a). 3-f2-Thia-3-f2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenvl)octvloxv)-65 pyridyllpropyllbenzoic acid. To a cooled (0 °C) solution of SOCI2 (O.85mL, 11,7mmol) in dry toluene (5mL) under an argon atmosphere was added a solution of 2-(E-2carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (500mg, 1.17mmol) in toluene (6mL). After 5 minutes the cooling bath was removed and the reaction was stured for 2 hours at room temperature. The toluene and excess
SOCI2 were evaporated. To this was added dry DMF (2mL), 3-mercaptomethyl-benzoic acid (216mg, 129mmol) in DMF (2mL), and anhydrous CS2CO3 (3.8g, 11.7mmol). The reaction was heated at 60°C under an atmosphere of argon for 6 hours. Upon cooling to room temperature the reaction was diluted with H2O and washed with EtOAc. The aqueous phase was acidified to pH 1.2 and extracted with EtOAc. The combined organic extracts were washed with H2O, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 5% MeOH in CH2C12) yielded a paJe yellow oil:
IH NMR (250MHz, CDCI3) δ 8.07 (d, J=15.7Hz, IH, olefin), 8.05 (s, IH, 2-phenyl), 7.96 (d, J=7.6Hz, IH, 6-phenyl), 7.58 (d, J=7.6Hz, IH, 4-phenyl), 7.39 (dd,
J=7.6Hz, IH, 5-phenyl), 7.24 (d, J=8.6Hz, IH, pyridyl), 7.13 (d. J=8.6Hz, IH, pyridyl), 7.08 (d, J=8.6Hz, 2H, phenyl), 7.06 (d, J=15.7Hz, IH, olefin), 6.82 (d,
J=8.6Hz, 2H, phenyl), 4.01 (t, J=6.5Hz, 2H, O-CH2), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.72 (s, 2H, S-CH2), 3.69 (s, 2H, S-CH2), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.49 (m, 2H, CH2), 1.35 (m, 6H, aliphatic).
25(b). 3-i2-Thia-3-f2-(E-2-carboxymethvlethenvl)-3-(8-(4-methoxyphenyl)octvloxy)-6pyridyllpropyll-N.N-dimethylbenzamide. 3-[2-Thia-3-[2-(E-2-carboxymethylethenyl)3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl]benzoic acid (98mg, 0.17mmol) was dissolved in SOC12 (5mL) and refluxed for 1 hour. The excess SOC12 was removed in vacuo. The resulting acid chloride was dissolved in dry CH2C12 (5mL), cooled to 0 °C, and treated with triethyiamine (52mL, 0.37mmol). Diethylamine was then introduced into the reaction via a cooling finger; reaction was stirred for 15 minutes. The solvent was removed in vacuo and the product was purified by flash column chromatography (silica, 35% EtOAc in hexane) to give a pale yellow oil: JH NMR (250MHz, CDCI3) δ
8.07 (d, J=15.7Hz, IH, olefin), 7.38 (m, 4H, 4,5,6-phenyl, pyridyl), 7.29 (s, IH, 2phenyl), 7.20 (d, J=8.6Hz, IH, pyridyl), 7.11 (d, J=8.6Hz, 2H, phenyl), 7.03 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.02 (t, J=6.5Hz, 2H, O-CH2),
P50046-1-2
CH2), 3.12 (s, 3H, N-Me), 2.97 (s, 3H, N-Me), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.86 (m, 2H, CH2). 1.6-1.3 (m, 10H, aliphatic).
25(c). 3-f 2-Thia-3-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxvphenyl)octyloxy )-65 pyridyHpropyll-N.N-dimethylbenzamide, lithium salt. 3-[2-Thia-3-[2-(E-2carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyndyl]propyl]-N,Ndimethylbenzamide (80mg, 0.132mmol) was dissolved in THF (1.5mL) and MeOH (1.5mL) and treated with 1.0M LiOH (0.4mL, 0.4mmol). The reaction was stiiTed under an argon atmosphere for 24 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded a colorless amorphous solid: !H NMR (250MHz, d4-MeOH) δ 7.79 (d, J= 15.7Hz, IH, olefin), 7.33 (m, 6H, 2,4,5,6-phenyl, 4,5-pyridyl), 7.07 (d, J=8.6Hz, 2H, phenyl),
7.05 (d, J=15.7Hz, olefin), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.03 (t, J=6.5Hz, 2H, OCH2), 3.76 (s, 2H, S-CH2), 3.74 (s. 3H, OMe), 3.69 (s, 2H, S-CH2), 3.09 (s. 3H, N15 Me), 2.97 (s, 3H, N-Me), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.86 (m, 2H, CH2), 1.54 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic).
Example 26
5-r3-r2-Thia-3-r2-fE-2-carboxvethenyl)-3-f8-(4-methoxyphenvl)octvloxy1-620 pvridyllpropyllphenylltetrazole, dilithium salt
This tetrazole is prepared via the acid chloride described above according to
Duncia, Pierce, and Santella, J. Org. Chem., 1991,56, 2395-2400.
Example 26bis (E)-Sodium 3-f3-f4-(4-methoxyphenyl)butyloxyl-6-fphenylthiomethyll-2-pyridinyn-2propenoate
26bis(a)_(E)-Methyl 3-f3-f4-(4-methoxyphenyl)butyloxyl-6-fphenylthiomethvn-2pvridinyll-2-propenoate, Thiophenol (0.017mL, 0.166mmol) was dissolved in dry MeCN (0.30mL) and treated with 2-(E-2-carboxymethylethenyl)-3-[4-(430 methoxyphenyl)butyloxy]-6-chloromethylpyridine hydrochloride (65mg, 0.152mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.08mL, 0.532mmol). The reaction was stirred under an atmospere of argon at 50 °C for 3h. The reaction solution was diluted with EtOAc and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, EtOAc: CH2C12: hexane, 10: 15: 75) gave a colorless waxy solid: Ή NMR (250MHz, CDCI3) δ 8.04 (d, J=15.7Hz, IH, vinyl), 7.36-7.07 (m, 9H, aryl), 6.99 (d, J=15.7Hz, IH, vinyl), 6.83 (d, J=8.7Hz, 2H, phenyl), 4.21 (s,
2H, CH2-S), 3.97 (t, J=6.1Hz, 2H, CH2-O), 3.81 (s, 3H, OMe), 3.78 (s, 3H, methyl ester), 2.64 (t, J=7.2Hz, 2H, benzylic), 1.81 (m, 4H, CH2CH2); analysis calcd. for
BAD ORIGINAL Ά
P50046-1-2
C27H29NO4S · 3/gH2O: C, 68.95; Η, 6.38; Ν, 2.98, found: C, 68.S9; Η, 6.23; Ν,
2.94; MS (ES+): 464.2 (M+H).
Proceeding in a similar manner, but substituting for the intermediates listed in above, the appropriate chloromethylpyridine and thiophenol or mercaptoalkylphenyl adducts, the following compounds can be prepared:
methyl 3-[3-[8-(4-methoxyphenyl)octyloxy]-6-[(3-carbomethoxybenzylthio)methyl] -2-pyridinyl] -2-propenoate, methyl 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[phenyIthiomethyl]-2-pyridinyl]2-propenoate.
- 4 .!..*· · --
26bis(b)_(EFSodium 3-f3-f4-f4-methQXVDhenvl)butvloxyl-6-rphenylthiomethyll2-pvridinvl1-2-propenoate. (E)-Methyl 3-[3-[4-(4-methoxyphenyl)butyloxy]-6[phenylthiomethyl]-2-pyridinyl]-2-propenoate (55mg, 0.119mmol) was dissolved in THF (l.OmL) and MeOH (0.30mL) and treated with 1.0M NaOH (0.25mL, 0.25mmol).
The reaction was stirred under an argon atmosphere for 20h. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-MeOH gradient). Lyophilization yielded the captioned product as a colorless amorphous solid: *H NMR (250MHz, d6-DMSO) δ 7.42 (d, J=15.7Hz, IH, vinyl), 7.40-7.20 (m, 7H, aryl), 7.12 (d, J=8.7Hz, 2H, phenyl), 6.83 (d, J=8.7Hz, 2H, phenyl), 6.82 (d,
J=15.7Hz, IH, vinyl), 4.26 (s, 2H, CH2-S), 4.01 (t, J=6.1Hz, 2H, CH2-O), 3.71 (s,
3H, OMe), 2.61 (t, J=7.2Hz, 2H, benzylic), 1J3 (m, 4H, CH2CH2); analysis.calcd. for C26H26NO4SNa · 3/4H2O: C, 64.38; H, 5.71; N, 2.89; found: C, 64.46; H, 6.04; N, 2.97; MS (ES+): 450.2 (M+H, free acid), (ES-): 448.0 (M-H, free acid).
Proceeding in a similar manner, the following compounds were made:
(E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(phenylthio)methyl]2-pyridinyl]-2-propenoate (E)-lithium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(3,4dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoate (E)-lithium 3-[3-[4-(4-methoxyphenyl)butyloxy]3 0 6-[(4-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(4-fluorophenylthio)methyl]2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(3-chlorobenzylthio)methyI]2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2-chlorobenzylthio)methyl]2-pyridiny 1] - 2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2methoxybenzylthio)methyl]-2-pyridinyl]-2-propenoate
BAD ORIGINAL
P50046-1-2 (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2,4dichlorobenzylthio)methyl]-2-pyridinyl]-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-((2-bromobenzylthio)methyl]2-pyridiny 1] - 2- propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2-cyano-6chlorobenzylthio)methyl]-2-pyridinyl]-2-propenoate.
Example 27
Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Means for making various formulations can be found in standard texts such as Remington's Pharmaceutical Sciences, and similar publications and compendia. Specific examples of formulations are given below.
Tablets
Ingredients Per Tablet Per 10,000 Tablets
1. Active ingredient (Cmpd of
Form. I) 40 mg 400 g
2. Com Starch 20 mg 200g
3. Alginicacid 20 mg 200 g
4. Sodium alginate 20 mg 200 g
5. Magnesium stearate 1-3 mg _12g
101.3 mg 1013 g
Procedure for making tablets:
Step 1. Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender. Step 2. Add sufficient water portionwise to the blend from Step 1 with careful mixing
0 after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
Step 3. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
Step 4. The wet granules are then dried in an oven at 410°F (60°C) until dry.
Step 5. The dry granules are lubricated with ingredient No. 5.
Step 6. The lubricated granules are compressed on a suitable tablet press.
Suppositories:
BAD ORIGINAL
P50046-1-2
Ingredients Per Supp. Per 1000 Supp.
1. Formula I compound Active ingredient 4.0 mg 40 g
2. Polyethylene Glycol 1000 135.0 mg 1,350 g
3. polyethylene glycol 4000 45.0 mg 450 g
184.0 mg 1,840 g
Procedure:
Step 1. Melt ingredient No. 2 and No. 3 together and stir until uniform.
Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform. Step 3. Pour the molten mass from Step 2 into supository moulds and chill.
Step 4. Remove the suppositories from moulds and wrap.
Example 28 Inhalation Formulation
A compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic saline and 10 aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired amount of drug per use.
Example 29 Topical formulations
Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Means for making various formulations can be found in standard texts such as Remington's Pharmaceutical Sciences, and similar publications and compendia. Specific examples of formulations are given below.
Ingredients
Cholesterol S teary 1 Alcohol White Wax Active Ingredient White Petolatum
Ointments
Hydrophyllic Petrolatum
Amount (% Weight/weight)
30.Og 30.0g 78.Og
2.0g
860.0g
The stearyl alcohol, white wax and white petrolatum are melted together (steam 25 bath for example) and cholesterol and the active ingredient are added. Stirring is
BAD ORIGINAL
P50046-1-2 commenced and continued until the solids disappear. The source of heat is removed and the mix allowed to congeal and packaged in metal or plastic tubes.
Emulsion Ointment
Ingredients Methylparaben Propylparaben Sodium Lauryl Sulfate Active Ingredient Propylene Glycol Stearyl Alcohol White Petrolatum Purified Water
Amount (% U'/W)
0.25g
0.15 lO.Og
5.0g
120.0g
250.0g
250.0g
QS to lOOO.Og
The stearyl alcohol and white petrolatum are combined over heat. Other ingredients are dissolved in water, then this solution is added to the warm (ca 50 to 100°C) alcohol/petrolatum mixture and stirred until the mixture congeals. It can then be packed in tubes or another appropriate package form.

Claims (5)

  1. What is claimed is:
    1. A compound of formula I or an N-oxide, or a pharmaceutically acceptable salt where
    Z is 0, NH, NCH3 or S(O)q where q is 0,1 or 2, misO- 5;
    R is Cj to C2()-aliphatic, unsubstituted or substituted phenyl Cj to CiQ-aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is Cj to C20*aliphatic-O-, or R is unsubstituted or substituted phenyl Cj to Cjo-aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
    Rl is -(Ci to C5 aliphatic)R4, -(Ci to C5 aliphatic)CHO> -(Cj to C5 aliphatic)CH2ORgt -R4, -CH2OH, or CHO;
    R2 is H, halo, lower alkyl, lower alkoxy, -CN, -(CH2)nR4, -CH(NH2XR4), or -(CH2)nR9 where n is 0 - 5 and where R9 is -N(R7)2 where each R7 is independently H, or an aliphatic group of 1 to 10 carbon atoms, or acyl of 1 -6 carbon atoms, or a cycloalkyl-(CH2)n- group of 4 to 10 carbons where n is 0-3, or both R7 groups form a ring having 4 to 6 carbons; or
    R3 is hydrogen, lower alkyl, lower alkoxy, halo, -CN, CORs, NHCONH2, or
    OH;
    each R4 group is independently -COR5 where R5 is -OH, a pharmaceutically acceptable ester-forming group -OR$, or -OX where X is a pharmaceutically acceptable cation, or R5 is -N(R7)2 where each R7 is independently H, or an aliphatic group of 1 to 10 carbon atoms, or a cycloalkyl-(CH2)n- group of 4 to 10 carbons where n is 0-3, or both R7 groups form a ring having 4 to 6 carbons, or R4 is a sulfonamide, or an amide, or tetrazol-5-yl; and
    R8 is hydrogen, Ci to Q alkyl, or Cj to C6-acyl, with the proviso that R2 and R3 are not 2,6-dihalo, 2,6-di(lower alkyl), 2,6-
    BAD ORIGINAL
    P50046-1-2
  2. 2. A pharmaceutical composition comprising an effective amount of a compound of formula I according to claim 1, alone or in combination with a pharmaceutically acceptable excipient.
  3. 3. A method for treating psoriasis, which method comprises administering 5 an effective amount of a compound of formula I according to claim 1, alone or in combination with a pharmaceutically acceptable excipient.
  4. 4. A pharmaceutical composition comprising an effective amount of a compound of formula I according to claim 36, alone or in combination with a pharmaceutically acceptable excipient
    -4 ►
    10 5. A method for treating psoriasis, which method comprises administering an effective amount of a compound of formula I according to claim 36, alone or in combination with a pharmaceutically acceptable excipient.
    BAD ORIGINAL
    6. A compound of claim 1 where Z is S(O)q, m is 0, R is alkoxy of 3 to 15 5 carbon atoms, or unsubstituted or substituted phenyl-Cj to CjQ-alkyl-O- where substituted phenyl is substituted with fluoro, tri fluoromethyl or methoxy; R; is R4CH=CH- or R4CH2CH2-, and R2 is -COR5 or -NHSO2CF3.
    7. A compound of claim 6 which is 3-[l-thia-2-[2-(E-2-carboxyethenyl)-3[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]benzoic acid, **** 10 3-[l-oxythia-2-{2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyl0xy]-6pyridyl]ethyl]benzoic acid, * *
    2- [l-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid,
    3- [ 1 -thia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzo:c acid,
    15 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyI]ethyl]benzole acid,
    3-[l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid
    N-[3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-620 pyridyl]ethyl]phenyl]trifluoromethanesulfonamide,
    N-[3-[ 1 -thia-2-[2-(E-2-carboxyetheny 1)-3 - (8-(4- methoxypheny l)oct^oxy)-6pyridyl]ethyl]phenyl]trifluoromethanesulfonamide,
    N-[3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]-trifluoromethanesulfonamide,
    25 N-[3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]phenylsulfonamide, or
    N-[3-[l-thia-2-[2-(E-2-carboxyethenyI)-3-(8-(4-methoxyphenyl)octyIoxy)-6pyridyl]ethyl]phenyl]phenylsulfonamide, or a pharmaceutically acceptable salt thereof.
    30 8. A compound of claim 1 where Z is 0, m is 0, R is alkoxy of S to 15 carbon atoms, or unsubstituted or substituted phenyl-Ci to CjQ-alkyl-O- where substituted phenyl is substituted with fluoro, trifluoromethyl or methoxy; Rj is R4CH=CH- or R4CH2CH2-, and R2 is -COR5 or -1NHSO2CF3.
    9. A compound of claim 8 which is 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-335 dodecyloxy-6-pyridyl]ethyl]benzoic acid, or 3-[ 1 -oxa-2-[2-(E-2-carboxyethenyl)-3-[3(4-methoxyphenyl)octyloxy]-6-pyridyl]ethy!]benzoic acid, or an N-oxide ora pharmaceutically acceptable salt thereof.
    BAD ORIGINAL ft
    10. A compound of claim I where Z is 0, m is 0, R is alkoxy of 8 to 15 carbon atoms, or imsubstitmed or substituted phenyl Cj to CiQ-aikyl where substituted pheny! is substituted with fluoro, trifluorontethyl or methoxy.
    11. A compound of claim 10 which is 3-[l-cxa-2-[2-(E-2-carboxyetheny’)-3[3-(4-methoxyphenyl)octan-I-yl]-6-pyridyl]ethyl]benzoic acid, its dilithium salt, the free acid, or another pharmaceutically acceptable salt.
    12. A compound of claim 1 where Z is NH or NCH3, m is 0, R is alkoxy of 8 to 15 carbon atoms, or unsubstituted or substituted phenyl-Cj to CiQ-alkyl-O- where substituted phenyl is substituted with fluoro, trifluoromethyl or methoxy;
    R4CH=CH- or R4CH2CH2-, and R2 is -COR5 ortSHSO2CF3.
    • A-w 1
    13. A compound of claim 1 where Z is S(O)q where q is 0,1 or 2, m is 1-3, R is alkoxy of 8 to 15 carbon atoms, phenylC4 to Cjo alkyl-O- or substituted phenyl-C410 CjQ-alkyl-O-; Rj is R4, -(Ci-C3-alkyl)R4, or -(C2-C3-alkenyl)R4·
    14. A compound of claim 13 where R is alkoxy of 8 to 15 carbon atoms, or substituted phenylC4 to C]Qalkyl-O- where substituted phenyl is substituted with fluoro, trifluoromethyl or methoxy; Rj is -CH2CH2R4 or -CH=CHR4; and R2 is -(CH2)nR4 where n is 0 or 1.
    15. A compound of claim 14 which is
    4-[2-thia-3-[2-(E-2-carbo,\yethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyl]propyl]benzoic acid;
    4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4rmethoxyphenyl)butyloxy^8??^»^ pyridyllpropyl] benzoic acid,
    3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyl]propyl]benzoic acid;
    3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyIoxy]-6pyridyljpropyljbenzoic acid;
    3-[2-thia-3-[2-(2-carboxyethanyI)-3-[8-(4-methoxyphenyl)octyIoxy]-6pyridyl]propyl]benzoic acid;
    3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyI)octyIoxy]-6pyridyl]propyl]-N,N-dimethy!benzamide, lithium salt;
    3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6pyridyl]propyI]-N,N-dimethylbenzamide, lithium salt;
    3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-phenylbutyloxy]-6pyridyl]propyl]benzoic acid, dilithium salt;
    3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-phenyloctyloxy]-6pyridyl]propyl]benzoic acid, dilithium salt;
    3-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyl]propyl]benzoic acid, dilithium salt;
    4-[2-thia-3-[2-(E-2-carboxyeilienyl)-3-[S-(4-methoxyp!’1enyl)octyloxy]-6pyridyljpropyilphenylacetic acid, or
    4-[2-oxy :hia-3-[2-(E-2-carbo\yethen\ ’.)-3-[8-(4-methoxyphcnyl)octy'.oxy]-6pyridyljpropyl]benzoic acid;
    3- [2-oxythia-3-[2-(E-2-carbo\yethenyl)-3-[8-(4-methoxyphenyl)octy!oxy]-6pyridyljpropyl J benzoic acid;
    4- [2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6pyridyl]propyl]phenylacetic acid;
    3-[2-dioxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-’ pyridyl]propyl]benzoic aci3Tor **>«-»*-* a pharmaceutically acceptable ^1? thereof.
    16. A compound of claim 1 where Z is S(O)q where q is 0, 1 or 2, m is 1-3, R is alkoxy of 8 to 15 carbon atoms, or unsubstituted or substituted phenylC4 to CjQalkyl0- R) is -CH2CH2R4 or -CH=CHR4; R2 is H, halo, lower alkyl, lower alkoxy, -CN; and R3 is hydrogen, halo, -CN, or lower alkyl, excluding those compound where R2 and R3 are both hydrogen.
    17. A compound of claim 1 where R4 is tetrazol-5-yl.
    18. A compound according to claim 17 which is 5-[3-[2-thia-3-[2-(E-2carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyi]propyl]phenyl] tetrazole, dilithium salt or another pharmaceutically acceptable salt thereof.
    19. A compound of claim 1 where Z is O, m is 1-3, R is alkoxy of 8 to 15,^ carbon atoms, unsubstituted or substituted phenylC4 to Cjq alkyl-O-; and Rj is R4, -CH2CH2R4 or -CH=CHR4.
    20. A compound of claim 1 where Z is NH or NCH3, ni is 1-3, R is alkoxy of 8 to 15 carbon atoms, unsubstituted or substituted phenylCi to Cjq alkyl-O- where substituted phenyl is substituted with fluoro, trifluoromethyl or methoxy; and Rj is -CH2CH2R4 or -CH=CHR4.
    21. A compound of claim 1 where Z is O, m is 0 or 1, R is alkoxy of 8 to 15 carbon atoms, or unsubstituted or substituted phenyl Cj to CjQ-alkyl-O- where substituted phenyl is substituted with fluoro, trifluoromethyl or methoxy, and R) is -CH2CH2R4 or -CH=CHR4 and R2 is -(CH2)nR9 where n is 0, 1 or 2.
    22. A compound of claim 21 which is 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3(8-(4-methoxyphenyl)octyloxy)-6-pyridyI]ethyl]aniline, lithium salt,_or 5-carboxy-3-[loxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]aniline, its dilithium salt, or the free acid, or another pharmaceutically acceptable salt thereof.
    23. A compound of claim 1 where Z is S(O)q, m is 0 or 1, R is alkoxy of 8 to 15 carbon atoms, or unsubstituted or substituted phenyl Cj to CjQ-alkyl-O- where
    BAD ORIGINAL substituted phenyl is substituted with fluoro, tri fluorome thyl or methoxy, and Rj is -CH2CH2R4 or -CH=CHRq and R2 is -(CH'2)nR9 where n is 0, 1 or 2.
    24. A compound of claim 23 w hieh is 3-[l-thia-2-[2-(E-2-carboxyethenyl)-3(8-(4-methoxypheny!)octyloxyj-6-pyridyl'e;hyl]aniline, lithium salt;
  5. 5 3-[l-thia-2-(2-(E-2-carboxyethenyI)-3-(4-(4-methoxyphenyl)butyloxy)-6pyridyl]ethyl]aniline, lithium salt;
    3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]-N,N-dimethylaniline, lithium salt;
    3-( l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)<>ctyloxy)-610 pyridyl]ethyl]aniline, lithium salt; » » 3-( 1 -thia-2-[2-(E-2%arboxyethenyl)-3-(8-phenyloctyloxy)-6- 0 pyridyljethyl]aniline, lithium salt;
    3-(2-thia-3-(2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]propyl]-N,N-dimethylaniline, lithium salt,
    15 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6pyridyl]ethyl]aniline, lithium salt;
    3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4trifluoromethylphenyI)octyloxy)-6-pyridyl]ethyl]aniline, lithium salt;
    3-[l-oxy thia-2-[2-(E-2-carboxyetheny l)-3-(8-(4-fluorophenyl)octyloxy)-620 pyridyljethyljaniline, lithium salt;
    3-( 1 -oxy thia-2-[2-(E-2-carboxycthenyl)-3-(8-(4-methoxyphenyl)octyj.^y)-6pyridyl]ethyl]aniline, lithium salt; or
    3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyloctyloxy)-6pyridyljethyljaniline, lithium salt;
    25 3-[ 1 -oxy thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]-N,N-dimethylaniline, lithium salt;
    3-[l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6pyrid> 1 jethyljaniline, lithium salt; or
    3-(l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxypheny!)octyloxy)-630 pyridyl]ethyl]uni!ine, lithium salt or the acid thereof, or a pharmaceutically acceptable salt.
    25. A compound of claim 1 where Z is NH or NCH3, m is 0 or 1, R is alkoxy of 8 to 15 carbon atoms, or unsubstituted or substituted phenyl C; to CjQ-alkyl-Owhere substituted phenyl is substituted with fluoro, trifluoromethyl or methoxy, and R|
    35 is -CH2CH2R4 or -CH=CHR4 and R2 is -(CH2)nR9 where n is 0, 1 or 2.
    26. A compound according to claim 1 where R2 and R3 are hydrogen.
    27. A compound according to claim 26 where Z is S(O)q, m is 0 or 1, R is alkoxy of 8 to 15 carbon atoms, or unsubstituted or substituted phenyl Cj to CjQ-alkyl
    where substituted phenyl is substitueted with methoxy, fluoro, cr •.rhfluorcmethvl :.r,d Ri is -CH2CH2R4 cr -CH=CiiR4.
    28. A compound according to claim 27 which is 3-i2-thia-3-i2-i.E-2-carco\yethsn\ lj-3-[4-(4-me:ho\yph.‘nyijbut\ loxyj-6pyridyl]propyl]benzene, lithium salt;
    3-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyl]propyl]benzene, lithium salt; or
    3-[l-thia-2-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyljethyl]benzene, lithium salt or the free acid or another pharmaceutically acceptable salt
    29. A compound according to claim 26 where Z is O and m is 0 or 1.
    30. A compound according to claim 26 where Z is NH or NCH3 and m is 0 or 1.
APAP/P/1992/000428A 1991-09-19 1992-09-17 Phenyl-substituted pyridyl aliphatic compounds for treating leukotriene-related diseases. AP333A (en)

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US79093191A 1991-11-12 1991-11-12
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CN93103596A CN1092409A (en) 1991-09-19 1993-03-19 The compound that is used for the treatment of leukotriene-related disease

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CN1095713A (en) * 1992-06-30 1994-11-30 史密丝克莱恩比彻姆公司 Make the method for some thioether
GB9313145D0 (en) * 1993-06-25 1993-08-11 Smithkline Beecham Plc Process
IL115420A0 (en) 1994-09-26 1995-12-31 Zeneca Ltd Aminoheterocyclic derivatives
DE69609820T2 (en) * 1995-03-02 2001-03-08 Smithkline Beecham Corp., King Of Prussia Use of substituted pyridine compounds for the treatment of atopic dermatitis and contact dermatitis
GB9508137D0 (en) * 1995-04-21 1995-06-07 Smithkline Beecham Plc Formulation
GB9602166D0 (en) 1996-02-02 1996-04-03 Zeneca Ltd Aminoheterocyclic derivatives
EP0880501A1 (en) 1996-02-02 1998-12-02 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
US5929096A (en) * 1996-02-29 1999-07-27 Smithkline Beecham Corporation Method for treating atopic dermatitis and contact dermatitis
PL331599A1 (en) * 1996-08-14 1999-08-02 Zeneca Ltd Substituted derivatives of pyrimidine and their pharmaceutical application
EP0942903A1 (en) 1996-09-26 1999-09-22 Novartis AG Aryl-substituted acrylamides with leukotriene b4 (ltb-4) receptor antagonist activity
UA56197C2 (en) 1996-11-08 2003-05-15 Зенека Лімітед Heterocyclic derivatives
EP0966460A1 (en) 1997-02-13 1999-12-29 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
EP0966462B1 (en) 1997-02-13 2003-06-11 AstraZeneca AB Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
GB9715895D0 (en) 1997-07-29 1997-10-01 Zeneca Ltd Heterocyclic compounds
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