JP2003506324A - Treatment of cyclooxygenase-2-mediated disorders using conjugated fatty acid compounds - Google Patents

Abstract

(57) SUMMARY The present invention is directed to methods for preventing or treating inflammation or other cyclooxygenase-2-mediated disorders. The method comprises administering to the organism a conjugated fatty acid in an amount effective to prevent or treat a cyclooxygenase-2-mediated disorder by inhibiting cyclooxygenase-2. In one embodiment, the method comprises administering a fatty acid compound having Formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; m is 6-11; the sum of m and n is 13-16. In another embodiment, the method comprises administering a fatty acid compound having formula (VI) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is hydrogen, hydrocarbyl or substituted hydrocarbyl. ; ^R 7 is _{-OH, -SO 3 H, -SH,} -NH 2, a _-PO 3 _{H 2} or halogen, v is 7-11, and v and w of the total is 11 to 16. The present invention is also directed to a method for producing a fatty acid compound. The process involves combining an ylide with an aldehyde.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION In general, the present invention relates to methods of preventing or treating medical disorders by reducing the activity of cyclooxygenase. More specifically, the present invention relates to a conjugated fatty acid compound (most preferably, a conjugated eicosadienoic acid compound or coriolic acid (
coriolic acid) compound) to inhibit cyclooxygenase-2 (COX-2) and thereby prevent or treat inflammation and other COX-2-mediated disorders. In a particularly preferred embodiment, COX-2 is selectively inhibited over cyclooxygenase-1 (COX-1). Furthermore, the present invention relates to a method for preparing a fatty acid compound, which is used for COX-
2 mediated disorders can be treated.

BACKGROUND OF THE INVENTION Inflammation is the defense mechanism of an organism caused by physical or chemical stimuli such as injury to tissues. Typical symptoms of inflammation are, for example, pain, heat
, Redness, swelling, and sometimes loss of tissue function. Histologically, inflammation may include, for example, hyperemia (ie, excess blood in the area of the organism), congestion (ie, stagnation of blood flow in the area of the organism), changes in blood composition, changes in the walls of small vessels. (
(Typically in the form of swelling and perforation), and / or various exudates (ie, leakage of blood components from blood vessels and deposition of such components in or at the tissue surface).

Many drugs are available to inhibit inflammatory conditions and to reduce tissue destruction caused by inflammation. One typical class of anti-inflammatory drugs consists of corticosteroids (ie, steroidal anti-inflammatory drugs). Although steroidal anti-inflammatory drugs provide potent anti-inflammatory effects, they also tend to develop powerful side effects such as hypertension, diminished immunity, hyperglycemia, osteoporosis, myopathy, cataracts, growth arrest, and electrolyte abnormalities. is there. These side effects are especially problematic when using such drugs for extended periods of time.

[0004]   The second typical class of anti-inflammatory agents consists of non-steroidal compositions. Non-stero
Id anti-inflammatory drugs are typically arachidone metabolizers that produce prostaglandins.
Dedicated to inhibiting enzymes in the scade. This technique reduces inflammation
It is effective for Because prostaglandins (especially PGG_Two, PGH _Two , And PGE_Two) Plays an important role in the inflammatory process. Non-s
One enzyme often targeted by teroid anti-inflammatory drugs is cyclooxygen.
Nase (sometimes called "COX"), which is the arachidonic acid metabolic cascade
Perform the first reaction in. [Smith, W.L., "Prostanoid Biosynthesis and Me
cahnisms of Action, "Am. J. Physiol., 263, F181-F191 (1992)].
. Originally, the COX enzymes were pro-inflammatory prostaglandins and homeostasis = pro.
It was thought to be a single enzyme that produces both staglandins. But
However, more recently, the COX enzyme was found to be actually two:
Elementary (COX-1) and inducible enzyme (COX-2). COX-1 is stomach, kidney, heart
It is found in almost every tissue in the body, including the organs, brain, liver, and spleen. Normal,
It is associated with the production of homeostatic prostaglandins, which
And many normal tissue functions such as renal function. On the other hand, COX-2 is typical
Are found at sites of inflammation and are associated with pro-inflammatory prostaglandin production
. In addition to causing inflammation, this pro-inflammatory prostaglandin production
Associated with other diseases such as cancer [Belury, M.A., "Conjugated Dienoic
Linoleate: A Polyunsaturated Fatty Acid with Unique Chemoprotective Prop
erties, "Nutrition Reviews, vol. 53, no. 4, 83-89 (1995)].

Although aspirin and many other conventional non-steroidal anti-inflammatory drugs reduce inflammation (and other COX-2-mediated disorders) by inhibiting COX-2, they do not
OX-1 also tends to interfere indiscriminately. This is often undesirable. Because COX-1 inactivation disrupts normal tissue function, such as gastrointestinal damage,
This may result in nephrotoxicity (ie, destruction of renal tissue) and / or impaired hematopoiesis (ie, impairment in blood cell formation). This is especially true when such drugs are used for extended periods of time.

[0006] Given the problems associated with traditional non-steroidal anti-inflammatory drugs that indiscriminately inhibit COX-1, it has been reported that some recent approaches prefer COX-1 over COX-1. It is directed towards developing non-steroidal anti-inflammatory drugs that selectively inhibit 2. For example, in US Pat. No. 5,710,140 (and other related patents), D
ucharme et al. report selective inhibition of COX-2 over COX-1 by phenylheterocycles. In US Pat. No. 5,643,933, Talley et al. Report inhibition of COX-2 over COX-1 by substituted sulfonylphenyl heterocycles. In US Pat. No. 5,436,265, Black et al. Report inhibition of COX-2 over COX-1 by 1-aroyl-3-indolylalkonoic acid compounds. Also, Gierse et al. COX-1 with N- (2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide and 5-bromo-2- (4-fluorophenyl) -3- (4-methylsulfonylphenyl) -thiophene. We report selective inhibition of COX-2 in preference to. [Gierse, JK, Hauser, SD,
Creely, DP, Koboldt, C., Rangwala, SH, Isakson, PC and Seibert, K
., "Expression and Selective Inhibition of the Constitutive and Inducibl
e Forms of Human Cyclo-Oxygenase, "Biochem. J., 305, 479-84 (1995)]. However, these approaches remain limited in both range and number. There remains a need for safe, simple and effective therapies to inhibit, and more particularly for such treatments to selectively inhibit COX-2 over COX-1.

SUMMARY OF THE INVENTION The present invention is for the prevention or treatment of inflammation and other COX-2-mediated disorders in an organism (human or otherwise) by inhibiting the COX-2 enzyme by administration of a conjugated fatty acid compound. To provide a safe, simple and effective way of. The present invention also provides a method for preventing or treating inflammation and other COX-2 mediated disorders in an organism by selective inhibition of COX-2 over COX-1, thereby aspirin and art. There are fewer adverse side effects normally associated with many other conventional COX-2 inhibitors known in the art, allowing inhibition of COX-2.

Conveniently, the present invention is directed to a method of preventing or treating a cyclooxyganase-2 mediated disorder in an organism that has, or is prone to, a cyclooxygenase-2 mediated disorder. . The method comprises administering to the organism a fatty acid compound in an amount effective to prevent or treat a COX-2-mediated disorder by inhibiting COX-2. In one embodiment, the fatty acid compound has the formula (I):

[0009]

[Chemical 16]

Wherein R ¹ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; m is 6 to 11; and the sum of n and m is 13 to 16] or is a pharmaceutically acceptable salt thereof. is there. In another embodiment, the fatty acid compound has the formula (
VI):

[0011]

[Chemical 17]

Wherein R ⁶ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; R ⁷ is —OH, —SO ₃ H, —SH, —NH ₂ , —PO ₃ H ₂ , or halogen;
Is 7 to 11; and the sum of v and w is 11 to 15] or is a pharmaceutically acceptable salt thereof.

The present invention also provides a simple method of preparing fatty acid compounds that can be used to prevent or treat COX-2-mediated disorders. One advantage of this method is that it typically does not produce significant amounts of undesired fatty acid by-products (eg, undesired isomers). The method comprises combining an ylide with an aldehyde. In this embodiment, the fatty acid product has the formula (I):

[0014]

[Chemical 18]

[0015] The ylide reagent has the formula (II):

[0016]

[Chemical 19]

[0017] The aldehyde reagent has the formula (III):

[0018]

[Chemical 20]

[R ¹ , R ² , R ³ and R ⁴ are independently hydrocarbyl or substituted hydrocarbyl; m is 6 to 11; the sum of n and m is 13 to 16; X is 0.
Or 1; and the sum of x and y is 1.]. Other features of the invention will be in part apparent and in part pointed out hereinafter.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows a reaction scheme that can be used to prepare fatty acid compounds containing unsubstituted fatty acid residues having 19 to 22 carbons. This scheme involves producing an ylide and then reacting the ylide with an aldehyde.

Detailed Description of the Preferred Embodiments In accordance with the present invention, inflammation and other CO in an organism is inhibited by inhibiting (ie, reducing its activity) the COX-2 enzyme by administration of a conjugated fatty acid compound.
Methods have been developed to prevent or treat X-2-mediated disorders.

The fatty acid compound is preferably less than about 100 μM, more preferably about 60 μM.
Less, even more preferably less than about 1.5 μM, even more preferably about 1
It has a COX-2IC _{50 of} less than μM, and most preferably less than about 0.5 μM. The fatty acid compound is also preferably greater than about 0.5 μM, more preferably greater than about 1 μM, even more preferably greater than about 1.5 μM, even more preferably greater than about 60 μM, and most preferably about 100 μM. Exceeding C
It has an OX-1 IC ₅₀ . As used herein, an "IC ₅₀ " value is 50% (compared to an uninhibited control) of the activity of a COX enzyme that produces prostaglandin E ₂ (PGE ₂ ) in the presence of arachidonic acid. Represents the concentration of fatty acid compound required to reduce.

[0023]   Preferably, the fatty acid compound also selectively inhibits COX-2 in preference to COX-1.
Hurt. In one embodiment, the fatty acid compound administered to the organism is COX-1IC. _Fifty Lower than COX-2IC_FiftyHave. In this specific example, COX-2
IC_FiftyTo COX-1IC_FiftyThe ratio of at least about 1.5,
More preferably at least about 2, even more preferably at least about 2.5
Even more preferably at least about 3, and most preferably at least about 3.
． It is 5.

In another embodiment, the fatty acid compound administered is a prodrug (ie, the fatty acid compound reacts after administration to produce a different fatty acid compound, which in turn acts on the COX- 2 inhibits the enzyme). For example, when an ester of a fatty acid (eg, the ethyl ester of c11, t13-eicosadienoic acid) is administered orally, it is hydrolyzed during digestion to the corresponding free fatty acid (eg, c1).
1, t13-eicosadienoic acid) and alcohols (eg ethanol) can be formed; in that case, the compound that actually acts to inhibit the COX-2 enzyme is the free fatty acid. The fatty acid compound that actually acts to inhibit the COX-2 enzyme is the C
It is preferred to have a lower _{COX-IC 50} than _{OX-IC 50.} In a particularly preferred embodiment, the fatty acid compound that actually acts to inhibit the COX-2 enzyme is at least about 1.5, more preferably at least about 2, even more preferably at least about 2.5, and even more preferably at least About 3 and most preferably at least about 3.5 of said COX-1I to COX-2IC ₅₀
It has a C ₅₀ ratio.

[0025]   Two types of fatty acid compounds, according to the present invention, are known to inhibit COX-2.
Have been found suitable for: (1) substituted with 19 to 22 carbon atoms
Conjugated fatty acid compounds containing unreacted fatty acid residues; and (2) 18 to 22 charcoal
Having elementary atoms, the following functional groups: hydroxyl group (-OH), sulfo group (-SO_Three H), thio group (-SH), amino group (-NH_Two), A phosphonous acid group (-PO_ThreeH _Two ) Or a conjugated fatty acid compound containing a fatty acid residue substituted with one of the halogens
.

[0026] I. Unsubstituted conjugated fatty acid compound A. Structure of unsubstituted fatty acid compounds   Unsubstituted conjugated fatty acid compounds typically have the formula (I):

[0027]

[Chemical 21]

[Wherein R ¹ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and the sum of n and m is 13 to 16] or is a pharmaceutically acceptable salt thereof. Preferably m is 6 to 11.

In a preferred embodiment, the unsubstituted fatty acid compound is a glyceride, most preferably a triglyceride. In another preferred embodiment, R ¹ is hydrogen or saturated hydrocarbyl (ie, the hydrocarbyl contains no carbon-carbon double or triple bonds). More preferably, R ¹ is hydrogen or saturated hydrocarbyl containing no more than 6 carbon atoms (eg, methyl (
-CH _3), ethyl _(-CH 2 _CH 3), propyl _{(- (CH 2) 2 CH} 3),
Is _{- ((CH 2) 5 CH} 3)) isopropyl _{(-CH (CH 2) 2)} , butyl _{(- - (CH 2) 3} CH 3), pentyl _{((CH 2) 4 CH 3} ), or hexyl . In an even more preferred embodiment R ¹ is methyl. Most preferably R ¹ is ethyl or hydrogen.

In a particularly preferred embodiment, the fatty acid compound contains eicosadienoic acid residues (ie the sum of n and m is 14). In this embodiment m is preferably 7 to 9 (most preferably 9). In one of the more preferred embodiments, the fatty acid compound is a methyl ester of c11, t13-eicosadienoic acid (“c” means cis and “t” means trans), that is, the compound of formula (VIII ):

[0031]

[Chemical formula 22]

Is a compound having In an even more preferred embodiment, the fatty acid compound is the ethyl ester of c11, t13-eicosadienoic acid, ie
IX):

[0033]

[Chemical formula 23]

Is a compound having In the most preferred embodiment, the fatty acid compound is c11
, t13-eicosadienoic acid (ie, formula (VII):

[0035]

[Chemical formula 24]

[0036] Or a pharmaceutically acceptable salt thereof.

As shown in Example 4 below, conjugated eicosadienoic acid reduces COX-2 activity. It is also selective for inhibiting COX-2 over COX-1. Thus, it may be administered to treat COX-2 mediated disorders and favor side effects normally associated with lower selective anti-inflammatory drugs (eg, aspirin) (
Less if any). Furthermore, while the results of Example 4 show that the methyl ester of eicosadienic acid (ie, formula (VIII)) does not act as a COX-2 inhibitor, COX-2 inhibition still indicates that the ester does not release free fatty acids after administration. This can be accomplished by administering the ester as a prodrug in such a way as to form. For example, when the ester is administered orally to a homeotherm, it typically hydrolyzes during digestion to form free fatty acids.

B. Preparation of Compounds Having Formula (I) In general, various methods are known in the art for preparing mixtures comprising a conjugated fatty acid compound having formula (I) or a pharmaceutically acceptable salt thereof. For example, in US Pat. No. 5,855,917, which is incorporated by reference and is incorporated herein by reference, Coo
k et al. (a) Alkali isomerization of c11, t14-eicosadienoic acid; or (b
) It is taught to prepare a mixture containing conjugated eicosadienoic acid by alkaline or enzymatic isomerization of 9,12-octadecadienoic acid, followed by enzymatic extension of the isomerization product.

In a particularly preferred embodiment of the invention, the conjugated fatty acid compound is prepared by forming an ylide and then reacting the ylide with an aldehyde. FIG. 1 shows a general reaction scheme for such an embodiment. Advantages of using this reaction scheme include, for example, the fact that it produces a product composition that contains the desired conjugated fatty acid compound, but little undesired fatty acid by-product (if any). This reaction scheme is particularly preferred for forming carbon-carbon double bonds having a cis configuration. This is because the reaction tends to be highly selective towards forming such configurations, especially at low reaction temperatures (ie, reaction temperatures not exceeding about −30 ° C.). is there. Reactions between ylides and aldehydes (or ketones) are generally prior art (eg [KPC Vollhardt and N.
E. Schore, Organic Chemistry, 657-61 (WH Freeman & Co., 2nd ed., 1994)
] (See citations and considered part of this specification).
Applicants are not aware that such reaction mechanisms have been reported for preparing conjugated fatty acid compounds of formula (I).

[0040]   The ylide preferably used to prepare the conjugated fatty acid compound has the formula (II):

[0041]

[Chemical 25]

[0042] [Wherein m is as defined above for formula (I); R¹, R^Two, R^Three, And R ^Four Are independently hydrocarbyl or substituted hydrocarbyl; and x is
0 or 1]. In fact, the ylide has a positive charge on the phosphorus atom with formula (II).
Load and can resonate between structures with negative charges on adjacent carbon atoms of the fatty acid chain
It should be recognized:

[0043]

[Chemical formula 26]

The term “ylide” and formula (II) as used herein include both structures.

In a particularly preferred embodiment, the ylide is phenyl in which R ² , R ³ and R ⁴ are each substituted with phenyl (-C ₆ H ₅ ) or at least one hydrocarbyl (most preferably R ² , R ³ and R ⁴ are each unsubstituted phenyl). In another particularly preferred embodiment, m is 9. In a further particularly preferred embodiment, x is 0. Combinations of these embodiments are also particularly preferred.

Preferably, the ylide is prepared by first combining a phosphine compound and a haloalkane to give a compound of formula (XI):

[0047]

[Chemical 27]

Formed by a method comprising forming a phosphonium salt having here,
The phosphine compound has the formula (IV):

[0049]

[Chemical 28]

[0050] The haloalkane has the formula (V):

[0051]

[Chemical 29]

[0052] With; R^Two, R^Three, And R^FourIs as defined above for ylide; and R ⁵ Is halogen (preferably bromine).   When preparing the phosphonium salt from the phosphine compound and halocalcane
Preferably, a slight excess of phosphine compound is used (ie
The molar ratio of phosphine compound to benzene is preferably from about 1.1: 1 to about 1.
5: 1, more preferably about 1.1: 1 to about 1.3: 1, and most preferably
Is about 1.25: 1). Preferably, the phosphine compound or the haloalkane
A large excess of any of the cans excludes such excess from the product mixture.
Avoid because of the extra separation costs to leave.

The reaction of the phosphine compound with the haloalkane can be carried out in a wide variety of solvents that can solubilize the phosphine reagent, the haloalkane, and the phosphonium salt product. Typically, suitable solvents are, for example, acetonitrile, toluene,
Dichloromethane, benzene, acetone, N, N-dimethylformamide (DMF
), Dimethyl sulfoxide (DMSO), and hexamethylphosphoric triamide (HMPA). Protic solvents such as methanol, ethanol, and water are typically less preferred. Because they tend to stabilize the haloalkane compound, making it more difficult for the alkyl group of the haloalkane to dissociate from the halogen, allowing it to bond with the phosphine compound. Is. In a particularly preferred embodiment, the solvent is about 2
It has a dielectric constant of about 2 to about 40 at 0 ° C. and atmospheric pressure (dielectric constants for many compounds are well known in the art, see, eg, [Handbook of Chemistry.
and Physics (CRC Press, Inc., Boca Raton, Florida] (cited by reference and considered part of this specification). The solvent preferably has an atmospheric boiling point of at least about 50 ° C, more preferably at least about 80 ° C. Preferably, about 2 to about 100 ml (more preferably about 5 to about 25 ml, and most preferably about 5 to about 10 ml) of solvent are used for each millimol of the phosphine compound.

The environment in which the phosphine compound and the haloalkane react is preferably an inert environment (ie, an environment that does not substantially react with the reagents or reaction products). This environment includes, for example, nitrogen, noble gases (eg, helium, argon and neon).
Or a combination thereof may be included. In some embodiments, a more preferred environment includes a noble gas (more preferably argon) over nitrogen due to the fact that nitrogen can react with the components of the reaction mixture under certain conditions. However, in other embodiments (especially large scale embodiments), the environment contains nitrogen due to its relatively low cost. In any case, the environment is substantially free of oxygen gas or water, more preferably completely free of oxygen gas or water (oxygen gas oxidizes the phosphine compound, water hydrolyzes the resulting ylide). Tend). The temperature is preferably sufficient to dissociate the halogen from the balance haloalkane compound. Typically, the temperature is at least about 50 ° C, more preferably about 50 to about 100 ° C, most preferably about 80 to about 100 ° C. Such temperatures can often be achieved by refluxing the reaction mixture at about atmospheric pressure. The reaction time can vary widely, for example, the temperature at which the reaction is carried out (generally, the higher the temperature, the faster the reaction rate) and the concentration of the reagent (generally, the higher the reagent concentration. , The reaction speed is also faster). Typical minimum reaction times range from about 6 hours to about 5 days, but most typically the reaction time is about 3 days.

After forming the phosphonium salt, the solvent is preferably evaporated and excess phosphine compound is preferably removed from the remaining reaction mixture. Removal of excess phosphine compound can be accomplished, for example, by silica gel chromatography by methods well known in the art. Alternatively, for example, excess phosphine compound may be removed from the reaction mixture by extracting the phosphine compound from the reaction mixture with a non-polar solvent. This extraction is typically performed at a temperature of at least about 20 ° C. Preferably, the extraction solvent has a dielectric constant such that the phosphonium salt is substantially insoluble in the solvent. It is especially preferred that the extraction solvent have a dielectric constant of less than about 2 at about 20 ° C and atmospheric pressure. Often, hydrocarbon solvents (
Hexane and pentane, for example) are suitable for this purpose. The amount of extraction solvent can vary widely. In most cases, it is preferred to use from about 50 ml to about 100 ml of extraction solvent per gram of initially charged phosphine compound. In another alternative embodiment, the phosphine compound is removed from the reaction mixture with a solvent containing both polar and non-polar components. This extraction may be done in addition to (or as an alternative to) extraction entirely with a non-polar solvent. For example, the polar component is dichloromethane. Such polar components typically enhance the amount of phosphine compound extracted from the reaction mixture. However, it tends to dissolve the phosphonium salt, thus reducing the yield. If an extraction solvent containing polar components is used, preferably the polar components make up no more than about half the total volume of the extraction solvent. Preferably, about 50 to about 100 ml of polar / non-polar solvent is used per gram of initially charged phosphine compound.

To form the ylide, the phosphonium salt is combined with a base to deprotonate the phosphonium salt. Various bases are suitable for this reaction, including, for example, lithium hexamethyldisilazane (LiHMDS), butyllithium, sodium hydride and alkoxides. The most preferred base is a hindered base such as LiHMDS (ie, a base that will not substantially attack electrophiles, but can accept electrons). The number of moles of base is preferably substantially equal to the number of moles of phosphonium salt. The reaction is preferably carried out in a solvent with a dielectric constant sufficient to dissolve the phosphonium salt. Often, suitable solvents include
For example, N, N-dimethylformamide (DMF), tetrahydrofuran (THF
), Hexamethylphosphoric triamide (HMPA) and combinations thereof. Preferably about 2 to about 100 ml (more preferably about 5 to about 25 m
l, most preferably about 5 to about 10 ml) of solvent is used for each mmol of phosphonium salt. During deprotonation, the reaction mixture is preferably maintained under an inert environment. Further, the temperature is preferably maintained at about -78 ° C (eg, using liquid nitrogen as a cooling source) to about -30 ° C (eg, using an electronic cooling bath), more preferably about -78 ° C to about. Keep at -50 ° C. Higher temperatures are less preferred. This is because the ylide product at such temperature tends to decompose and form phosphonium oxide. The preferred reaction time depends, for example, on the reaction temperature.
At temperatures of about -78 ° C to about -50 ° C, the preferred reaction time is typically about 30 to about 60 minutes.

Either during or after the ylide formation (most preferably after the ylide formation),
The reaction mixture is combined with the aldehyde to form the desired fatty acid compound. The ylide is so reactive that it is typically not separated from the reaction mixture before it is combined with the aldehyde. The aldehyde is preferably of formula (III):

[0058]

[Chemical 30]

[Wherein n is as defined above for a fatty acid compound (ie formula (I)); y is 0 so that the sum of x and y (as defined for formula (II)) is 1.
Or 1). The preferred amount of aldehyde depends on the amount of phosphonium salt used to form the ylide. Typically, the moles of aldehyde added are preferably slightly less than the moles of phosphonium salt used in the deprotonation reaction to form the ylide, due to the fact that aldehydes are generally more expensive. Typically, the molar ratio of aldehyde to phosphonium salt is about 1:
It is 1.1 to about 1: 1.5. The reaction is preferably performed under an inert atmosphere at about -7.
It is performed at 8 ° C to about -30 ° C for about 30 minutes to about 120 minutes. More preferably, the temperature is in the range of about -50 ° C to about -78 ° C, most preferably about -78 ° C.
℃. As noted above, the use of such low temperatures tends to promote the formation of cis-carbon-carbon double bonds.

After forming the fatty acid compound, the reaction mixture is preferably gradually warmed, for example by placing the reaction mixture in an environment having a temperature of about 20 to about 25 ° C. The excess amount of ylide is preferably hydrolyzed with an aqueous solution of ammonium acetate or ammonium chloride, eg having a pH of about 7. The fatty acid compound may then be separated from the reaction mixture using any of a variety of conventional separation methods known in the art. See, for example, Example 1 below, which uses extraction with a non-polar organic solvent followed by extraction with chromatographic separation on a silica gel column.

The reaction schemes described above are typically used to form esters of fatty acids. In one embodiment of the invention, the ester is further hydrolyzed to form free fatty acids prior to therapeutic administration. Hydrolysis of the ester can be carried out, for example, by acid or base catalyzed hydrolysis. Many variations of such hydrolysis methods are well known in the art. In one embodiment of the invention, the hydrolysis is a base catalyzed reaction carried out in an aqueous solution containing a weak base such as sodium bicarbonate, triethylamine, cesium carbonate and potassium carbonate, with potassium carbonate being most preferred. . If the ester is insoluble in water, alcohol is preferably added to the solution to solubilize the ester. Preferably, the alcohol has the formula R ¹ —OH, where R ¹ is as defined in formula (I) (for example, when the ester is a methyl ester, the alcohol is methanol; If it is an ethyl ester, the alcohol is ethanol; Example 2 described later
Describes this method further. No matter how you hydrolyze the ester,
The hydrolysis is preferably carried out in a non-oxidizing atmosphere (ie an atmosphere which is substantially composed of the non-oxidizing gas (es) such as N ₂ and / or noble gases).

[0062] II. Substituted conjugated fatty acid compound A. Structure of substituted fatty acid compounds   Substituted conjugated fatty acid compounds generally have the following formula (VI):

[0063]

[Chemical 31]

[Wherein R ⁶ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; R ⁷
Is an acidic group; the sum of v and w is 11 to 15, preferably v is 7
To 11 and R ⁷ is preferably —OH, —SO ₃ H, —SH, —NH ₂ ,
Or -PO ₃ H _2, or is a halogen with the most preferred] is -OH, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the fatty acid compound is a glyceride, most preferably a triglyceride. In another preferred embodiment, R ⁶ is hydrogen or saturated hydrocarbyl. More preferably, the saturated hydrocarbyl ^{R 6} is a hydrogen-containing or 6 or fewer carbon atoms (e.g., methyl _(-CH 3), ethyl _(-CH 2 _CH 3), propyl _{(- (CH 2) 2 CH} 3), isopropyl _{(-CH (CH 3) 2)} , butyl _{(- (CH 2) 3 CH} 3), pentyl _{(- (CH 2) 4 CH} 3)
Or hexyl - a _{((CH 2) 5 CH 3} ). In an even more preferred embodiment R ⁶ is methyl. In another even more preferred embodiment, R ⁶ is ethyl. In yet an even more preferred embodiment R ⁶ is hydrogen.

In a particularly preferred embodiment, the sum of v and w is 11. Still more preferably, the sum of v and w is a 11, ^{R 7} is -OH. Still more preferably, the fatty acid compound is a coriolic acid (ie, v is 7, w is 4, R ⁶ is hydrogen and R ⁷ is —OH), It is a salt or ester of coriolic acid. In the most preferred embodiment, the fatty acid compound is 13S-hydroxy-c9, t11-cholioric acid (ie, of the formula (
X)) or a pharmaceutically acceptable salt thereof:

[0067]

[Chemical 32]

As shown in Example 4 below, coriolic acid (similar to eicosadienoic acid)
Selectively inhibits COX-2 in preference to COX-1. Thus, the side effects normally associated with lower selectivity anti-inflammatory drugs such as aspirin may be reduced (or avoided entirely) by using coriolic acid.

The fatty acid compound represented by the formula (VI) and a salt thereof are added to the fatty acid compound represented by the formula (I) or a salt thereof, or as an alternative to the fatty acid compound represented by the formula (I) or a salt thereof. It should be understood that any of these can be administered.

B. Preparation of Compounds Having Formula (VI) Methods for preparing fatty acid compounds of formula (VI) are generally known in the art. For example, hydroxyoctadecadienoic acid occurs naturally in plant and animal tissues and may be isolated therefrom (eg, in plant extracts of nettle root, such acids include free acids and glycerides, ceramides and phosphorus). It has been reported to exist as both the ester component of lipids). Such acids can also be synthesized from oleic acid and from linoleic acid. See, for example, Streber, US Pat. No. 5,102,912, which is hereby incorporated by reference.

Coriolic acid may be prepared from linoleic acid, in particular by the reduction of hydrogen peroxide following lipooxygenation under oxygen pressure (2.5 bar). Martini, D., Iacazio, G., Ferrand, D., Buono, G. and Triantap
hylides, C., "Optimization of Large-Scale Preparation of 13- (S) -hydropero
xy-9z, 11e-octadecadienoic Acid Using Soybean Lipooxygenase. Application
to the Chemoenzymatic Synthesis of (+)-Coriolic Acid ", Biocatalysis, 11,
47-63 (1994), which is incorporated by reference and considered part of this specification. Choriolic acid is described by Bloch, R. and Perfetti, MT, "An Efficient Synthesis of 13 (
S) -hydroxy-9z, 11e-octadecadienoic (Coriolic) Acid ", Tetrahedron Letters
, vol. 31, no. 18, pp. 2577-80 (1990) (cited by reference and considered part of this specification), may also be prepared from optically active lactol starting materials. In addition, coriolic acid is described, for example, in Gargouri, M. and Legoy, MD, "Chemoenzymati.
c Production of (+)-Coriolic Acid from Trilinolein: Coupled Synthesis a
nd Extraction ", JAOCS, vol. 74, no. 6, pp. 641-645 (1997) (cited as a part of this specification) and may also be prepared from trilinolein. Choriolic acid is also used, for example, in Xeranthemu.
m annuum) seed oil, such as from oil (Powel, RC, Smith,
CR and Wolff, IA "Geometric Configuration and Etherification React
ions of Some Naturally Occuring 9-Hydroxy-10, 12- and 13-Hydroxy-9,11-O
ctadecadienoic Acids ", J. Org. Chem., 32, 1442-46 (1966), which is incorporated herein by reference). Example 3 below describes the preparation of coriolic acid. Is further explained.

III. Use of Conjugated Fatty Acid Compounds to Inhibit COX-2 The conjugated fatty acid compounds discussed above are generally administered (alone or in combination) to inhibit all types of inflammation and other COX-2-mediated disorders. It can be prevented or treated. For example, using these fatty acid compounds, swelling, fever, reddening of the skin, pain (eg myotonic headache, migraine, postoperative pain, toothache, myalgia, spinal pain, neck pain, and pain resulting from cancer). ), Arthritis (eg, rheumatoid arthritis, spondyloarthritis pain, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis),
Arthritis diseases, skin diseases (eg dermatitis, psoriasis, eczema, and burns), infections, gastrointestinal diseases (eg inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis), nodules Periarteritis, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, neuromuscular junction disease (eg myasthenia gravis), white matter disease (eg polymorphism) Sclerosis), sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, cardiovascular ischemia, eye diseases (for example, retinitis, retinopathy, uveitis and ocular blindness (ocular phtophobia)), type I diabetes, chronic lung disease, asthma, bronchitis, pulmonary inflammation (eg, inflammation associated with viral infection and pancreatic cystic fibrosis),
From ophthalmic surgery such as allergic reactions (eg, reactions to food, drugs, insects and pets), collagen disease, tendinitis, bursitis, rhinitis, post-operative inflammation (eg, ophthalmic surgery such as cataracts and refractive surgery). ), Vascular disease, cancer (eg, colon cancer, breast cancer, lung cancer, prostate cancer, bladder cancer, cervical cancer, and skin cancer).
, Central nervous system disorders such as Alzheimer's disease and central nervous system injury resulting from stroke, ischemia, and trauma, menstral cramps and premature labor. This list is for illustrative purposes only and is not intended to be an exhaustive list of COX-2 mediated injuries treatable by the fatty acid compounds described above.

As noted above, the fatty acid compounds described herein that selectively inhibit COX-2 over COX-1 have COX-1 over less selective anti-inflammatory agents.
It has few adverse side effects associated with inhibition. Thus, such fatty acid compounds are of particular value for long-term use, such as combined with the prevention or treatment of allergies and chronic illnesses (eg, rheumatoid arthritis). For the same reason, the selective fatty acid compounds of the present invention can be used to treat peptic ulcer, gastritis, localized ileitis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesions, gastrointestinal bleeding, blood clots or other bleeding injury as well as kidney disease It is typically well suited to treat organisms with pre-existing conditions often associated with COX-1 inhibition, such as (eg, impaired renal function). The selective fatty acid compounds of the present invention treat organisms that are (1) susceptible to non-steroidal anti-inflammatory drug-induced asthma, (2) undergoing surgery, and / or taking anticoagulants. Is also typically well suited for.

The fatty acid compounds described herein can generally be used to treat a wide variety of organisms, especially homeotherms. For example, using these fatty acid compounds,
Humans, companion animals (eg dogs and cats), agricultural animals (eg horses, cows, goats, pigs, rabbits and sheep), mice, rats and wild animals can be treated. Most preferably, the fatty acid compound is used to treat a homeothermic animal having a cyclooxygenase-2-mediated disorder or a predisposition to a cyclooxygenase-2-mediated disorder.

The mode of administration can vary widely. In general, the fatty acid compounds of the invention may be administered by any acceptable means that results in the prevention, reduction or elimination of targeted inflammation or other COX-2-mediated disorders. For example, such fatty acid compounds are (eg,
Oral (in the form of tablets, capsules, syrups, solutions, emulsions, food supplements or beverage supplements) (eg via subcutaneous, intramuscular, intrasternal, intravenous or infusion techniques). Parenteral; (eg, in the form of ointments or eye drops), especially if inflammation is localized near the skin surface, topically; via inhalation (eg, in the form of inhalants); via spray nasal drops Or may be administered rectally (eg, in the form of suppositories). For most types of COX-2-mediated disorders, it is typically preferred to administer the fatty acid compound orally.

Prior to administration, the fatty acid compound may be combined with a conventionally used pharmaceutically acceptable compound (s) that is compatible with the fatty acid compound. The pharmaceutically acceptable compound can be another drug, such as lipoxygenase, for example. The pharmaceutically acceptable compound may also be, for example, an adjuvant, excipient, corrective agent (eg, flavoring agent), coloring agent, preservative, or other additive. For example, excipients are inert diluents (eg calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate, peanut oil, liquid paraffin, or olive oil), binders (eg
Starch, gelatin or acacia), granulating or disintegrating agents (eg corn starch or alginic acid), or lubricants (eg magnesium stearate,
Stearic acid or talc). Fatty acid compounds can also be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Such coatings may contain, for example, glyceryl monostearate or glyceryl distearate. For rectal administration, a fatty acid compound is a non-irritating excipient (eg, cocoa butter or polyethylene glycol) that is solid at room temperature but liquid at rectal temperature so that it dissolves in the rectum and releases the drug. It is often preferred to mix with.

In general, the fatty acid compound may be administered with one or more other fatty acid compounds and thus need not necessarily be isolated from the other fatty acid compound prior to administration. Further, when the fatty acid compound is administered orally, it is typically administered in the presence of other compounds normally found in food and beverages (eg, proteins, sugars, fats, vitamins, etc.). obtain.

The preferred dosage is generally sex, age, weight, daily food and drink, excretion rate,
And the physical condition of the recipient; the form of the fatty acid compound; the time and route of administration; the severity, type, stage and location of the inflammation or other COX-2-mediated disorder to be prevented or treated; and any co-treatment. It will vary depending on factors such as existence. Generally, the fatty acid compound is administered to the organism in an amount effective to prevent or treat the targeted cyclooxygenase-2 mediated disorder by reducing the activity of COX-2. When the fatty acid compound is administered orally, the preferred daily dose is typically about 0.0001 to about 2 g / kg (ie 1
grams of fatty acid compound per kg), more preferably from about 0.001 to about 2 g.
/ Kg, and most preferably about 0.001 to about 1 g / kg. Generally, when administered orally, the fatty acid compound will be present in an amount of about 1 to about 10,000 ppm by weight of the recipient's daily food and drink (more preferably about 100 to about 100,000 ppm by weight, and most preferably (About 1,000 to about 10,000 ppm by weight)
Make up. It should be appreciated that the upper limit is not particularly critical as, in most instances, the fatty acid compounds used herein are generally relatively non-toxic. Oral doses are typically administered 1 to 6 times per day, and more typically 1 to 3 times per day.

Definitions Unless otherwise indicated, the following definitions are used: The term “hydrocarbyl” is defined as a group consisting entirely of carbon and hydrogen. The hydrocarbyl may be branched or unbranched, saturated or unsaturated, and may contain one or more rings. Suitable hydrocarbyl groups include alkyl, alkenyl, alkynyl and aryl groups. It also includes alkyl, alkenyl, alkynyl, and aryl groups substituted with other aliphatic or cyclic hydrocarbyl groups such as alkaryl, alkenaryl and alkynaryl.

The term “substituted hydrocarbyl” has at least one hydrogen atom replaced with a group of (1) atoms other than hydrogen and carbon, or (2) atoms containing at least one atom other than hydrogen and carbon. Defined as hydrocarbyl. For example, hydrogen atoms may be replaced by halogen atoms such as chlorine or fluorine atoms. Alternatively, a hydrogen atom may be replaced by an oxygen atom to form, for example, a hydroxy group, ether, ester, anhydride, aldehyde, ketone or carboxylic acid. Also, hydrogen atoms may be replaced by nitrogen atoms to form, for example, amide or nitro functional groups. Further, a hydrogen atom may be replaced with a sulfur atom to form, for example, a thio group or a sulfo group.

The term “pharmaceutically acceptable salt” includes alkali metal salts and free acid or free base addition salts. The nature of the salt is not critical provided it is pharmaceutically acceptable. Mixtures of two or more pharmaceutically acceptable salts may also be used. Suitable pharmaceutically acceptable acid addition salts of therapeutic compounds discussed herein may be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Examples of suitable organic acids include aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carbocyclic and sulfonic acid class organic acids, examples of which include formic acid. , Acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid,
Citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid (mesy
lic), stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid,
Mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alginic acid,
Includes b-hydroxybutyric acid, galactaric acid, and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of therapeutic compounds discussed herein include metal salts, organic salts and ammonium salts. More preferred metal salts include, but are not limited to, alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts,
And salts formed from other physiologically acceptable metals. Such salts include, for example, aluminum, calcium, lithium, magnesium, potassium,
Includes cesium, sodium, copper, iron, silver, and zinc salts. Preferred organic salts may be formed from tertiary amine, quaternary ammonium salts, which include, in part, tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( N-
Methylglucamine) and procaine. It is typically more preferred to use the sodium, potassium, calcium or magnesium salt. Still, ammonium salts are more preferred in some embodiments. In another embodiment, lithium salts are more preferred. In still other embodiments, zinc salts are more preferred. All of the above salts may be prepared by conventional means from the corresponding therapeutic compound discussed herein, eg by reacting the compound with a suitable acid or base.

[0082] Example   The following examples are intended to further illustrate the process of making the present invention.

[0083] Example 1: Preparation of the methyl ester of c11, t13-eicosadienoic acid   In this example, an eicosabienoic acid compound, ie of formula (VIII):

[0084]

[Chemical 33]

A specific example of the method 1 for preparing a methyl ester of c11, t13-eicosadienoic acid having is described.

[0086]   First, the expression [(C₅H₅)_ThreeP⁺-(CH_Two)₁₀CO_TwoCH_Three] Br⁻Have
A phosphonium salt was prepared. Approximately 3.51 g (13.39 mmol) of triphe
Nylphosphine (that is, (C₆H₅)_ThreeP, catalog number T8,440-9
, Aldrich Chemical Co., Milwaukee, WI) and 3.0 g (10.74 mmol).
) Methyl 11-bromoundecanoate (ie Br (CH_Two)₁₀CO_TwoCH _Three , Catalog No. 44,746-3, Aldrich) with 80 ml of acetonitrile (C
H_ThreeCN) in the presence of. Reflux the mixture under a dry nitrogen atmosphere for 5 days.
It was The solvent was then evaporated until a dry mass remained. Triphenylphosphine
, 500 ml of hexane, then 500 ml of dichloromethane and hexane
Contains 500 ml of solvent (volume ratio of dichloromethane to hexane is 1: 2
Was present) was used to extract from the agglomerates. After extraction, about 6.2 g of viscous residual oily substance
Remained. The product was obtained by measuring the molecular weight and carbon of the obtained phosphonium salt compound.
-Using a gas chromatography / mass spectrometer to confirm the position of the carbon double bond
Analyzed.

Next, the phosphonium salt is reacted with a base to give a compound of the formula (C ₆ H ₅ ) ₃ PCH (
A mixture containing an ylide with CH ₂ ) ₉ CO ₂ CH ₃ was formed. Almost 1
0.62 g (3 mmol) of phosphonium salt was added to 15 ml of dry tetrahydrofuran (THF) and 5 ml of dry hexamethylphosphoric triamide (HMPA, ie [N (CH ₃ ) ₂ ] ₃ PO, catalog number H1,160-2, Aldrich. ). The resulting mixture was cooled to -78 ° C and then 3 ml (5
02mg, 3 mmol) of lithium hexamethyldisilazane in (LiHMDS, _{i.e., LiN [Si (CH 3)} 3] 2, Cat. No., 22,577-0, Aldrich
) Was added. The mixture was allowed to stir at −78 ° C. for 45 minutes to give a reaction mixture containing ylide.

This ylide-containing mixture is then reacted with trans-2-nonanal (CH ₃ (CH ₂ ) ₅ (CH) ₂ CHO, catalog number 25,565-3, Aldrich) to give c11, t13-eicosadienoic acid. The methyl ester was formed. More specifically, about 280 mg (2 mmol) trans-2-nonanal in 4 ml dry THF was added to the ylide containing mixture. The mixture was then stirred at −78 ° C. for 1 hour, then allowed to cool and warm to room temperature.

To isolate the methyl ester fatty acid product, 50 ml of 25 with pH 7
% (Wt%) aqueous ammonium acetate was first added to the reaction mixture to hydrolyze excess ylide. Then the methyl ester fatty acid product was added to hexane (about 1
75 ml to 350 ml) and extracted twice from the reaction mixture. The hexane mixture is then mixed with anhydrous sodium sulfate (total mixture containing hexane 100 ml
Dried (about 10 g per gram) and filtered. Hexane was evaporated from the mixture under mild vacuum to form a residual liquid containing the methyl ester fatty acid product. The residual liquid was then separated on a home-made silica gel gravity chromatography with hexane / dichloromethane eluent (volume ratio of hexane to dichloromethane in solvent was 7: 3). Approximately 220 mg of the methyl ester of c11, t13-eicosadienoic acid was obtained. The composition was confirmed using a gas chromatography / mass spectrometer.

Example 2: Preparation of c11, t13-eicosadienoic acid In this example, the methyl ester of c11, t13-eicosadienoic acid prepared in Example 1 was hydrolyzed to form c11, t13-eicosadienoic acid. did. Substantially engaged with of _K 2 CO ₃ 200mg of the methyl ester (0.62 mmol) 20% 856 mg of an aqueous solution of 15ml containing methanol (volume%) (6.2 mmol). The mixture was stirred at room temperature for 48 hours and neutralized with an aqueous solution containing 10% (wt%) HCl. The free fatty acids were extracted with 150 ml ethyl acetate and then the ethyl acetate was evaporated. This gives approximately 130 mg of c
11, t13-eicosadienoic acid was obtained.

Example 3 Preparation of Coriolic Acid Approximately 5 g of linoleic acid (ie t9, t12-octadecadienoic acid, Catalog No. L-1376, Sigma Chemical Co., St. Louis, Missouri) was added to 20 g.
20 ml octane at 160C, 160 ml 0.1M borate buffer (pH = 9.6
) And soybean lipoxygenase (catalog number L-8383, Sigma Chemic
al). The biphasic mixture was stirred with a magnetic stirrer (800 rpm) for 2 hours, during which pure oxygen was bubbled through the mixture at a flow rate of 30 ml / min. The mixture was then centrifuged, the octane layer separated and diluted with 100 ml ethanol and 500 mg NaBH ₄ . The mixture was then stirred for 1 hour. The liquid was then evaporated and the fatty acid product was extracted from the remaining residue with 250 ml ethyl acetate and washed with ample water and brine. The ethyl acetate was evaporated and the resulting residue was separated on a homemade silica gel gravity chromatography column with an eluent containing equal volumes of hexane and ethyl acetate. As a result, about 11 mg of coriolic acid was obtained.

Example 4 Use of Fatty Acid Compounds to Inhibit Cyclooxygenases Several fatty acid compounds were analyzed in vitro and found to be CO 2.
The extent to which the activity of X-1 and COX-2 was reduced was determined. This analysis is based on Gier
se, JK, Hauser, SD, Creely, DP, Koboldt, C., Rangwala, SH, I
sakson, PC and Seibert, K, "Expression and Selective Inhibition of t
he Constitutive and Inducible Forms of Human Cyclo-Oxygenase ", Biochem.
J., 305, 479-84 (1995) (cited by reference and considered part of this specification). Briefly, S expressing COX-1 or COX-2
The f21 insect cells were homogenized. To analyze each fatty acid compound, several samples were prepared, which were (1) 25 mM Tris, (2) enough HCl to give a pH of 8.1, (3) 0.25 M HCl. Sucrose, and (4) 1% (weight / volume) 3- [3-colamidopropyl] dimethylammonio] -1-propane-sulfonic acid (also known as "CHAPS", Sigma, St. Lois). , Misso
uri) containing the crude homogenate suspended in a buffer solution. Each sample contained approximately 2-10 μg of protein from homogenized cells.
Fatty acid compounds were added to the samples at varying concentrations from 0.001 to 100 μM. The sample was then incubated at room temperature for 10 minutes. A sufficient amount of arachidonic acid was then added to each sample to give an arachidonic acid concentration of 10 μM and the sample was reincubated for an additional 10 minutes at room temperature. COX activity was determined by measuring the amount of prostaglandin E ₂ produced (PGE ₂ concentration was e.
(Measured using lisa (Caymen)).

Table 1 shows the results. c11, t13-eicosadienoic acid is COX-
2 and was selective for COX-2 over COX-1 (COX-2
The ratio of _{IC 50} for COX-1 for -2 was at least about 3.8). The methyl ester of c11, t13-eicosadienoic acid was inactive towards inhibiting COX-2, which had a measurable inhibitory effect on COX-1 (c9, t11-CLA Unlike methyl ester of COX-1)
It was also inactive with respect to the inhibition of.

Table 1 shows that 13 (S) hydroxy-c9, t11-(+)-cholioric acid is COX-.
It also shows that it had an inhibitory effect on 2 and was inactive in inhibiting COX-1.

[0095]

[Table 1]

The foregoing description of the preferred embodiments may best suit the needs of a particular use,
It is only intended to familiarize the person skilled in the art with the invention, its principles and its practical application so that it can be adapted and applied in its numerous forms.
Therefore, the present invention is not limited to the specific examples described above, but can be variously modified.

[Brief description of drawings]

FIG. 1 is a reaction scheme that can be used to prepare a fatty acid compound containing an unsubstituted fatty acid residue having 19 to 22 carbons.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI Theme code (reference) A61P 3/10 A61P 5/14 5/14 7/06 7/06 9/00 9/00 9/10 9 / 10 11/00 11/00 11/06 11/06 15/06 15/06 17/00 17/00 17/02 17/02 17/06 17/06 19/02 19/02 19/08 19/08 21/00 21/00 21/04 21/04 25/00 25/00 25/04 25/04 25/06 25/06 25/28 25/28 27/02 27/02 27/16 27/16 29 / 00 29/00 101 101 31/04 31/04 31/12 31/12 35/00 35/00 35/02 35/02 37/02 37/02 37/08 37/08 43/00 111 43/00 111 C07C 51/353 C07C 51/353 57/03 57/03 67/343 67/343 69/587 69/587 A61K 37/48 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES , FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM) GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM , AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR , CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE , SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, U , VN, YU, ZA, ZW (72) Inventor Carol Kobolt United States 63031 Noberg Drive, No. 1634 F term, Florisant, Missouri, USA 4C084 AA02 AA03 AA17 BA44 DC01 MA02 MA13 MA17 MA22 MA23 MA28 MA31 MA35 MA37 MA52 MA58 MA59 MA60 MA63 MA66 NA14 ZA022 ZA072 ZA082 ZA152 ZA162 ZA202 ZA222 ZA332 ZA342 ZA362 ZA402 ZA552 ZA592 ZA662 ZA682 ZA812 ZA892 ZA942 ZA962 ZB072 MA5142 MA0742 MA0243 MA02 MAB02 MA0243B02 ZA06 MAB02 ZC062 A02C022A02 MA55 MA57 MA72 MA78 MA79 MA80 MA83 MA86 NA14 ZA02 ZA07 ZA08 ZA15 ZA16 ZA20 ZA22 ZA33 ZA34 ZA36 ZA40 ZA55 ZA59 ZA66 ZA67 ZA68 ZA81 ZA89 ZA94 ZA96 ZB07 AB22 ZB15 AB22 C22 A25 CB26 A10C22 ZB26 AB20 ZB26 A20C25 ZB26 A10C20

Claims (110)

[Claims] 1. A method of treating or preventing a cyclooxygenase-2 mediated disorder in an organism having a cyclooxygenase-2 mediated disorder or a predisposing organism having a cyclooxygenase-2 disorder.
Comprising administering to the organism a fatty acid compound in an amount effective to prevent or treat a cyclooxygenase-2 mediated disorder by inhibiting 2 the fatty acid compound of formula (I): Where R ¹ is hydrogen, hydrocarbyl or substituted hydrocarbyl;
m is 6-11; and m and n have a sum of 13-16), or a pharmaceutically acceptable salt thereof. 2. The method of claim 1 wherein m is 7-9 and m and n have a sum of 14. 3. The method according to claim 2, wherein m is 7. 4. The method according to claim 2, wherein m is 8. 5. The method according to claim 2, wherein m is 9. 6. The method according to claim 1, wherein the fatty acid compound is triglyceride. 7. The method of administering a fatty acid compound to treat a cyclooxygenase-2 mediated disorder in an organism having a cyclooxygenase-2 mediated disorder.
The method described. 8. The method of claim 1, wherein the fatty acid compound is administered to prevent a cyclooxygenase-2-mediated disorder in an organism predisposed to having the cyclooxygenase-2-mediated disorder. 9. A fatty acid compound is administered to cause swelling, fever, red skin, pain, arthritis, skin disease, infection, gastrointestinal disease, periarteritis nodosa, thyroiditis, aplastic anemia,
Hodgkin's disease, sclerodoma, rheumatic fever, neuromuscular junction disease, white matter disease, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, cardiovascular ischemia, eye disease, type I Diabetes, chronic lung disease, asthma, bronchitis, lung inflammation, allergic reaction, collagen disease, tendinitis, bursitis, rhinitis, postoperative inflammation, vascular disease, central nervous system disorders, cancer, menstrual cramps or premature labor The method according to claim 1, wherein the method is prophylaxis or treatment. 10. The method of claim 1, wherein the fatty acid compound is administered to prevent inflammation. 11. The method of claim 1, wherein the fatty acid compound is administered to treat inflammation. 12. The method according to claim 1, wherein the fatty acid compound is administered to prevent cancer. 13. The method of claim 1, wherein the fatty acid compound is administered to treat cancer. 14. The method according to claim 1, wherein the fatty acid compound is administered to prevent or treat breast cancer, prostate cancer, colorectal cancer, lung cancer, bladder cancer, neck cancer or skin cancer. 15. A fatty acid compound is administered to prevent or treat Alzheimer's disease or central nervous system damage resulting from stroke, ischemia or trauma.
The method described. 16. The method according to claim 1, wherein the fatty acid compound is administered to prevent or treat tension headache, migraine, postoperative pain, toothache, myalgia, backache, neckache, or cancer-related pain. Method. 17. The method according to claim 1, wherein the fatty acid compound is administered to prevent or treat rheumatoid arthritis, spondyloarthropathy, urate arthritis, osteoarthritis, systemic lupus erythematosus or juvenile arthritis. 18. The method of claim 1, wherein the fatty acid compound is administered to prevent or treat dermatitis, psoriasis, eczema or burns. 19. The method according to claim 1, wherein a fatty acid compound is administered to prevent or treat inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome or ulcerative colitis. 20. The method of claim 1, wherein the fatty acid compound is administered to prevent or treat myasthenia gravis. 21. The method of claim 1, wherein the fatty acid compound is administered to prevent or treat multiple sclerosis. 22. The method according to claim 1, wherein the fatty acid compound is administered to prevent or treat retinitis, retinopathy, uveitis, or dazzle of the eye. 23. The method of claim 1, wherein R ¹ is hydrocarbyl containing up to 6 carbon atoms. 24. The method of claim 1, wherein R ¹ is methyl. 25. The method of claim 1, wherein R ¹ is ethyl. 26. The method of claim ¹ , wherein R ¹ is hydrogen. 27. The method of claim 1, wherein the fatty acid compound comprises sodium, potassium, cesium, lithium, zinc, calcium, magnesium, copper, iron, silver or ammonium ions. 28. The fatty acid compound has the formula (VII): The method according to claim 1, wherein the method has the formula or is a pharmaceutically acceptable salt thereof. 29. The fatty acid compound has the formula (VIII): The method of claim 1, comprising: 30. The fatty acid compound has the formula (IX): The method of claim 1, comprising: 31. The method of claim 1, wherein the fatty acid compound is selective for inhibiting cyclooxygenase-2 in preference to inhibiting cyclooxygenase-1. 32. A cyclooxygenase having a fatty acid compound of less than about 0.5 μM.
-2 IC_FiftyAnd IC of cyclooxygenase-1 greater than about 1.5 μM _Fifty The method of claim 1, comprising: 33. A fatty acid compounds, wherein the ratio of the _{IC 50} of cyclooxygenase-1 for _{IC 50} of cyclooxygenase-2 has an _{IC 50} and _{IC 50} of cyclooxygenase-1 cyclooxygenase-2 to be at least about 3.5 The method according to item 1. 34. The method of claim 1, wherein the fatty acid compound is reacted after administration to form a compound that is selective for inhibiting cyclooxygenase-2 in preference to inhibiting cyclooxygenase-1. 35. The fatty acid compound reacts after administration to form a compound having a cyclooxygenase-2 IC ₅₀ of less than about 0.5 μM and a cyclooxygenase-2 IC _{50 of} greater than about 1.5 μM. The method described. 36. A fatty acid compounds are reacted after administration, the _{IC 50} of cyclooxygenase-1 for _{IC 50} of cyclooxygenase-2 ratio of _{IC 50} and cyclooxygenase-1 of cyclooxygenase-2 to be at least about 3.5 The method of claim 1, wherein the compound having an IC ₅₀ is formed. 37. The method of claim 1, wherein the fatty acid compound is administered orally. 38. The method of claim 1, wherein the fatty acid compound is administered via subcutaneous injection, intramuscular injection, intrasternal injection, intravenous injection or infusion. 39. The method of claim 1, wherein the fatty acid compound is administered topically. 40. The method of claim 1, wherein the fatty acid compound is administered via inhalation. 41. The fatty acid compound is administered via a nasal spray.
The method described. 42. The method of claim 1, wherein the fatty acid compound is administered rectally. 43. The amount of the fatty acid compound administered per day is 1 to the total body weight of the organism.
The method of claim 1, wherein the method is equal to about 0.0001 to about 2 g per kg. 44. The amount of the fatty acid compound administered per day is 1 to the total body weight of the organism.
The method of claim 1, wherein the method is equal to about 0.001 to about 2 g per kg. 45. The amount of the fatty acid compound administered per day is 1 to the total body weight of the organism.
The method of claim 1, wherein the method is equal to about 0.001 to about 1 g per kg. 46. The method of claim 1, wherein the amount of fatty acid compound administered per day is equal to about 1 to about 10,000 ppm by weight of the organism's diet. 47. The method of claim 1, wherein the amount of fatty acid compound administered per day is equal to about 100 to about 10,000 ppm by weight of the organism's diet. 48. The method of claim 1 wherein the amount of fatty acid compound administered per day is equal to about 1,000 to about 10,000 ppm by weight of the organism's diet. 49. The method of claim 1, wherein the fatty acid compound is contained in a pharmaceutical composition that also includes lipoxygenase. 50. Formula (VI): embedded image Where R ⁶ is hydrogen, hydrocarbyl or substituted hydrocarbyl,
R ⁷ is —OH, —SO ₃ H, —SH, NH ₂ , —PO ₃ H ₂ or halogen, v is 7-11, and v and w have the sum of 11-15). The method of claim 1, comprising administering a second fatty acid compound or a pharmaceutically acceptable salt. 51. The method of claim 1, wherein R ⁷ is OH. 52. The method of claim 50, wherein v is 7, w is 4 and R ⁷ is —OH. 53. The method of claim 50, wherein the second fatty acid compound is a triglyceride. 54. A method of preventing or treating a cyclooxygenase-2 mediated disorder in an organism having a cyclooxygenase-2 mediated disorder or predisposed to having a cyclooxygenase-2 mediated disorder, said method comprising inhibiting cyclooxygenase-2 by Administering a fatty acid compound to an organism in an amount effective to prevent or treat a cyclooxygenase-2 mediated disorder, wherein:
The fatty acid compound has the formula (VI): Where R ⁶ is hydrogen, hydrocarbyl or substituted hydrocarbyl,
R ⁷ is —OH, —SO ₃ H, —SH, NH ₂ , —PO ₃ H ₂ or halogen, v is 7-11, and v and w have the sum of 11-15). Or a pharmaceutically acceptable salt thereof. 55. A method of claim 54 R ⁷ is -OH. 56. The method of claim 54, wherein v is 7, w is 4 and R ⁷ is -OH. 57. The method of claim 54, wherein the fatty acid compound is triglyceride. 58. The method of claim 54, wherein the fatty acid compound is administered to treat a cyclooxygenase-2-mediated disorder in an organism having a cyclooxygenase-2-mediated disorder. 59. The method of claim 54, wherein the fatty acid compound is administered to prevent a cyclooxygenase-2-mediated disorder in an organism predisposed to having the cyclooxygenase-2-mediated disorder. 60. Swelling, fever, skin redness, pain, administration of a fatty acid compound,
Arthritis, skin disease, infection, gastrointestinal disease, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, neuromuscular junction disease, leukomyopathies, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polyposis Myositis, gingivitis, nephritis, hypersensitivity, cardiovascular ischemia, eye disease, type I diabetes, chronic lung disease, asthma, bronchitis,
55. The method of claim 54, which prevents or treats lung inflammation, allergic reaction, collagen disease, tendinitis, bursitis, rhinitis, post-operative inflammation, vascular disease, central nervous system disorders, cancer, menstrual cramps or premature labor. 61. The method of claim 54, wherein the fatty acid compound is administered to prevent inflammation. 62. The method of claim 54, wherein the fatty acid compound is administered to treat inflammation. 63. The method according to claim 54, wherein the fatty acid compound is administered to prevent or treat tension headache, migraine, postoperative pain, toothache, myalgia, backache, neck pain, or cancer-related pain. Method. 64. The method of claim 54, wherein the fatty acid compound is administered to prevent or treat rheumatoid arthritis, spondyloarthropathy, urate arthritis, osteoarthritis, systemic lupus erythematosus or juvenile arthritis. 65. The method of claim 54, wherein the fatty acid compound is administered to prevent or treat dermatitis, psoriasis, eczema or burns. 66. The method of claim 54, wherein the fatty acid compound is administered to prevent or treat inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome or ulcerative colitis. 67. The method of claim 1, wherein the fatty acid compound is administered to prevent or treat myasthenia gravis. 68. The method of claim 54, wherein the fatty acid compound is administered to prevent or treat multiple sclerosis. 69. The method of claim 54, wherein the fatty acid compound is administered to prevent or treat retinitis, retinopathy, uveitis, or dazzle of the eye. 70. The method of claim 54, wherein the fatty acid compound is administered to prevent or treat colorectal cancer, lung cancer, bladder cancer, cervical cancer or skin cancer. 71. A fatty acid compound is administered to prevent or treat Alzheimer's disease or central nervous system injury resulting from stroke, ischemia or trauma.
4. The method described in 4. 72. The method of claim 54, wherein R ⁶ is hydrocarbyl containing up to 6 carbon atoms. 73. The method of claim 54, wherein R ⁶ is methyl. 74. The method of claim 54, wherein R ⁶ is ethyl. 75. The method of claim 54, wherein R ⁶ is hydrogen. 76. The method of claim 54, wherein the fatty acid compound comprises sodium, potassium, cesium, lithium, zinc, calcium, magnesium, copper, iron, silver or ammonium ions. 77. The fatty acid compound has the formula (X): 55. The method of claim 54, which has or is a pharmaceutically acceptable salt thereof. 78. The method of claim 54, wherein the fatty acid compound is administered orally. 79. The method of claim 54, wherein the fatty acid compound is administered via subcutaneous injection, intramuscular injection, intrasternal injection, intravenous injection or infusion. 80. The method of claim 54, wherein the fatty acid compound is administered topically. 81. The method of claim 54, wherein the fatty acid compound is administered via inhalation. 82. The method of claim 54, wherein the fatty acid compound is administered rectally. 83. The method of claim 54, wherein the fatty acid compound is contained in a pharmaceutical composition that also includes lipoxygenase. 84. The method of claim 54, wherein the fatty acid compound is selective for inhibiting cyclooxygenase-2 in preference to inhibiting cyclooxygenase-1. 85. A cyclooxygenase having a fatty acid compound of less than about 100 μM.
-2 IC_Fifty, And IC of cyclooxygenase-1 greater than about 100 μM _Fifty 55. The method of claim 54, including. 86. A cyclooxygenase having a fatty acid compound of less than about 60 μM.
The method of claim 54 in which 2 the _{IC 50,} and more about 100μM having _{IC 5 0} Large cyclooxygenase -1. 87. fatty compound, _{IC 50} and cyclooxygenase cyclooxygenase as the ratio of the _{IC 50} of cyclooxygenase-1 for _{IC 50} of cyclooxygenase-2 is at least about 1.5 -1I
The method of claim 54 having a C _50. 88. The method of claim 54, wherein the fatty acid compound reacts after administration to form a compound that is selective for inhibiting cyclooxygenase-2 over cyclooxygenase-1. 89. fatty acid compounds are reacted after administration, The method of claim 54, wherein to form a compound having an _{IC 50} of approximately _{IC 50} of 100 [mu] M than the cyclooxygenase-2, and large cyclooxygenase -1 than about 100 [mu] M. Wherein 90 the fatty acid compound is reacted after administration, The method of claim 54, wherein to form a compound having the _{IC 50 IC 50} large cyclooxygenase -1 than and about 100 [mu] M, of cyclooxygenase-2 of less than about 60 [mu] M. 91. the fatty acid compound is reacted after administration, the _{IC 50} of cyclooxygenase-1 for _{IC 50} of cyclooxygenase-2 ratio of cyclooxygenase _{IC 50} of 1 and cyclooxygenase-2 to be at least about 1.5 the method of claim 54 to form a compound having IC _50. 92. The method of claim 54, wherein the amount of fatty acid compound administered per day is equal to about 0.0001 to about 2 g / kg of total body weight of the organism. 93. The method of claim 54, wherein the amount of fatty acid compound administered per day is equal to about 0.001 to about 2 g / kg of total body weight of the organism. 94. The method of claim 54, wherein the amount of fatty acid compound administered per day is equal to about 0.001 to about 1 g / kg of total body weight of the organism. 95. The method of claim 54, wherein the amount of fatty acid compound administered per day is equal to about 1 to about 10,000 ppm by weight of the organism's diet. 96. The method of claim 54, wherein the amount of fatty acid compound administered per day is equal to about 100 to about 10,000 ppm by weight of the organism's diet. 97. The method of claim 54, wherein the amount of fatty acid compound administered per day is equal to about 1,000 to about 10,000 ppm by weight of the organism's diet. 98. A method for producing a fatty acid compound, which comprises combining an ylide and an aldehyde, wherein the fatty acid compound has the formula (I): Wherein the ylide has the formula (II): And the aldehyde has the formula (III): Wherein R ¹ , R ² , R ³ and R ⁴ are independently hydrocarbyl or substituted hydrocarbyl, m is 6-11, and n and m are 13-16.
Wherein x is 0 or 1 and x and y have a sum of 1. 99. The method of claim 98, wherein m is 7-9 and m and n have a sum of 14. 100. The method of claim 98, wherein m is 9. 101. The method of claim 98, wherein x is 0. 102. The method according to claim 9, wherein R ² , R ³ and R ⁴ are each -C ₆ H _5.
8. The method according to 8. 103. The method of claim 98, wherein R ¹ is a hydrocarbyl group having up to 6 carbon atoms. 104. The method of claim 98, wherein R ¹ is -CH ₃ . 105. The method of claim 98, wherein R ¹ is —CH ₂ CH ₃ . 106. The fatty acid compound has the formula (VIII): 99. The method of claim 98, comprising: 107. The fatty acid compound has the formula (IX): 99. The method of claim 98, comprising: 108. A process comprising combining a phosphine compound and a haloalkane to form a phosphonium salt, and then forming a ylido by a process comprising reacting the phosphonium salt with a base, wherein the phosphonium salt is of formula (XI) [Chemical 13] The phosphine compound has the formula (IV): Wherein the haloalkane has the formula (V): It has, and method according to claim 98 R ⁵ is halogen. 109. The process according to claim 108, wherein R ⁵ is bromine. 110. The method of claim 108, wherein said base comprises butyllithium, lithium hexamethyldisilazane, sodium hydride or an alkoxide.