JP2011520929A - Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8- Inyloxy) acetic acid anhydrous and hydrated forms - Google Patents

Abstract

The present invention relates to lipoxins in anhydrous form exhibiting peaks characteristic at d = 2.48 Å and d = 4.34 並 び に, and in hydrate forms exhibiting peaks characteristic at d = 9.8 Å and d = 4.6 Å for the purpose of crystalline acid a ₄ analogs.

Description

The present invention relates to solid crystalline acids of lipoxin A ₄ analogs, their use in the treatment of pathologies characterized by inflammation, and pharmaceutical compositions comprising the crystalline acids of analogs and their preparation Relating to the method.

  Lipoxins used in combination with leukotrienes, prostaglandins, and thromboxanes constitute a group of biologically active oxygenated fatty acids collectively referred to as eicosanoids. Eicosanoids are all synthesized de novo from membrane phospholipids via the arachidonic acid cascade of enzymes. Since these first discoveries in 1984, it has been clearly shown that lipoxin, a structurally distinct class of eicosanoids, has potent anti-inflammatory properties suggesting that it may have therapeutic potential. (Serhan, CN, Prostaglandins (1997), Vol. 53, pp. 107-137; O'Meara, YM et al., Kidney Int. (Suppl.) (1997), Vol. 58, pp. S56-S61 ; Brady, HR et al., Curr. Opin. Nephrol. Hypertens. (1996), Vol. 5, pp. 20-27; and Serhan, CN, Biochem. Biophys. Acta. (1994), Vol. 1212, pp. 1 -twenty five). In addition to other inflammatory substances such as platelet activating factor, fMLP (formyl-Met-Leu-Phe) peptide, immune complex, and TNFα, lipoxin's ability to antagonize the pro-inflammatory function of leukotrienes is of particular interest. Thus, lipoxins are potent antineutrophils that suppress polymorphonuclear neutrophil (PMN) chemotaxis, homotypic assembly, adhesion, migration across endothelium and epithelial cells, marginal orientation / leakage and tissue infiltration (Lee, TH, et al., Clin. Sci. (1989), Vol. 77, pp. 195-203; Fiore, S., et al., Biochemistry (1995), Vol. 34, pp. 16678-16686; Papyianni, A., et al., J. Immunol. (1996), Vol. 56, pp. 2264-2272; Hedqvist, P., et al., Acta. Physiol. Scand. (1989), Vol. 137, pp. 157- 572; Papyianni, A., et al., Kidney Intl. (1995), Vol. 47, pp. 1295-1302). Furthermore, lipoxin is expressed and adhered to PMN of endothelial P-selectin (Papyianni, A., et al., J. Immunol. (1996), Vol. 56, pp. 2264-2272), bronchial and vascular smooth muscle contraction. Mesangial cell contraction and adhesion (Dahlen, SE, et al., Adv. Exp. Med. Biol. (1988), Vo. 229, pp. 107-130; Christie, PE, et al., Am. Rev. Respir. Dis. (1992), Vol. 145, pp. 1281-1284; Badr, KF, etc., Proc. Natl. Acad. Sci. (1989), Vol. 86, pp. 3438-3442; and Brady, HR, etc. , Am. J. Physiol. (1990), Vol. 259, pp. F809-F815) and eosinophil chemotaxis and degranulation (Soyombo, O., et al., Allergy (1994), Vol. 49, pp. 230-234) can be controlled downward.

Lipoxins, particularly anti-inflammatory properties this particular lipoxin A ₄ relates the treatment of inflammatory or autoimmune diseases, as well as lung and airway inflammation, the use of these potential as therapeutic has attracted attention. Such diseases and inflammation that exhibit significant inflammatory infiltration are of particular interest and include inflammatory bowel diseases such as Crohn's disease, skin diseases (such as psoriasis), rheumatoid arthritis, and respiratory diseases ( Asthma etc.), but is not limited to this.
Like other endogenous eicosanoids, naturally occurring lipoxins are unstable products that are rapidly metabolized and inactivated (Serhan, CN., Prostaglandins (1997), Vol. 53, pp. 107- 137). This has limited development in the field of lipoxin research, particularly in vivo pharmacological evaluation of the anti-inflammatory properties of lipoxins. While having an active site of lipoxin A _4, a plurality of U.S. patents directed to compounds having a longer tissue half-life has been issued. See, e.g., U.S. Patent Nos. 5,441,951 and 5,648,512. These compounds retain lipoxin A ₄ receptor binding activity and potent in vitro and in vivo anti-inflammatory properties of natural lipoxins (Takano, T., et al., J. Clin. lnvest. (1998), Vol. 101, pp. 819-826; Scalia, R, etc., Proc. Natl. Acad. Sci. (1997), Vol. 94, pp. 9967-9972; Takano, T., etc. , J. Exp. Med. (1997), Vol. 185, pp. 1693-1704; Maddox, JF, et al., J. Biol. Chem. (1997), Vol. 272, pp. 6972-6978; Serhan, CN , Et al., Biochemistry (1995), Vol. 34, pp. 14609-14615).

Lipoxin A ₄ analogs of interest of the present invention are disclosed in U.S. Patent No. 6,831,186 and U.S. Patent Application Publication No. 2004/0162433.
One skilled in the art will recognize that solid drug substances are particularly advantageous when they are crystalline rather than non-crystalline. Typically, purification of the crystalline product is achieved during the formation of a crystalline solid by crystallization from solution. The crystalline solid form can be very well characterized and usually shows a high stability compared to the amorphous phase. By using a crystalline solid as a raw material for a drug substance or formulation, potential recrystallization of the amorphous phase, including changes in the characteristics of the drug substance or formulation, is avoided. Thus, stable need for crystalline solid forms of lipoxin A ₄ analogs as disclosed in U.S. Patent No. 6,831,186 and U.S. Patent Application Publication No. 2004/0162433 is present.

［式中、
Ｒ¹は、−Ｏ−、−Ｓ（Ｏ）ｔ−（ここでtは、0, 1 または2である）、或いは直鎖または分岐のアルキレン鎖であり；そして
Ｒ²は、（アルキル、アルコキシ、ハロ、ハロアルキル及びハロアルコキシから選択される１または複数の置換基によって任意に置換された）アリール或いは（アルキル、アルコキシ、ハロ、ハロアルキル及びハロアルコキシから選択される１または複数の置換基によって任意に置換された）アラルキルである］
のリポキシンＡ₄類似体の結晶性の遊離酸であって、式（II）の化合物が、単一立体異性体または立体異性体の任意の混合物である遊離酸を目的とする。
本発明は、式（II）の遊離酸の結晶性の全形態を含む。 The present invention is a powerful, selective and metabolic / chemically stable in treating conditions characterized by inflammation, such as inflammatory or autoimmune diseases and lung or airway inflammation, in mammals, especially humans an object crystalline acids and their use such lipoxin a ₄ analogs.
Thus, in one aspect, the invention provides a compound of formula (II):

[Where:
R ¹ is —O—, —S (O) t— (where t is 0, 1 or 2), or a linear or branched alkylene chain; and R ² is (alkyl, alkoxy Aryl optionally substituted by one or more substituents selected from: halo, haloalkyl and haloalkoxy) or optionally by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy Is a substituted aralkyl]
A crystalline free acid of the lipoxin A ₄ analog of which the compound of formula (II) is intended to be a single stereoisomer or any mixture of stereoisomers.
The present invention includes all crystalline forms of the free acid of formula (II).

In another aspect, the present invention is directed to a process for preparing a crystalline form of the acid of formula (II), wherein the process comprises i) alkaline hydroxide in a suitable solvent, formula (II) in a suitable solvent. Ii) adjusting the pH of the resulting mixture to pH 3-4; iii) further adjusting the pH of the mixture to pH 1-3 after crystals begin to form; iv Isolating the resulting crystals from the resulting suspension; and v) drying the isolated crystals to provide a crystalline acid.
In a further aspect, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline acid of formula (II) above and a pharmaceutically acceptable excipient or mixture of excipients. To do.

In another aspect, the present invention provides a medicament for the manufacture of a medicament for the treatment of a mammal having a medical condition characterized by inflammation, such as an inflammatory or autoimmune disease or a pulmonary or respiratory inflammatory disease. The aim is to use a crystalline acid of the formula (II).
In another aspect, the present invention is directed to a method of treating a disease state characterized by inflammation in a mammal, eg, a human, said method treating a crystalline acid of formula (II) as defined above in a mammal in need thereof. Administering a top effective amount. The condition may be, for example, an inflammatory or autoimmune disease or an inflammatory disease of the lungs or airways.

DETAILED DESCRIPTION OF THE INVENTION All references cited herein, including US patents, US patent application publications and journal articles, are hereby incorporated by reference in their entirety.

A. Definitions As used herein, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly indicates otherwise. For example, “one (a) compound” refers to one or more of these compounds, while “the enzyme” refers to a particular enzyme, as well as other family members and equivalents thereof well known to those skilled in the art. including.
All percentages used herein are by volume unless otherwise indicated.
Furthermore, the following terms used in the specification and appended claims have the following meanings unless otherwise indicated:

“Alkyl” refers to a group of straight or branched hydrocarbon chains consisting solely of carbon and hydrogen atoms, containing no unsaturation and having 1 to 8 carbon atoms, which are linked to other molecules by a single bond. Examples thereof include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (f-butyl) and the like.
"Alkylene chain" refers to a straight or branched, divalent hydrocarbon chain consisting solely of carbon and hydrogen and containing 1 to 8 carbon atoms free of unsaturation, such as methylene, ethylene, Examples include propylene and n-butylene.

“Alkoxy” refers to _a radical of the formula —OR _a where R _a is an alkyl group as defined above.
“Aryl” refers to a phenyl or naphthyl group. Unless stated otherwise, aryl groups may be optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl or haloalkoxy. Unless stated otherwise, it is understood, particularly in the specification, that such substitution can occur at any carbon of the aryl group.
“Aralkyl” refers to _a group of the formula —R _a R _b where R _a is an alkyl group as described above and R _b is an aryl group as described above, such as benzyl and the like. The aryl group may be optionally substituted as described above.

“Halo” refers to bromo, chloro, iodo or fluoro.
“Haloalkyl” refers to an alkyl group as described above, substituted with one or more halo groups as described above, eg, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 -Fluoromethyl-2-fluoroethyl (1,3-difluoroisopropyl), 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl (1,3-dibromoisopropyl) and the like.

"Haloalkoxy" refers to a radical of the formula -OR _c R _c is the above described haloalkyl groups, e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl 2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy and the like.

  As used herein, “clathrate” refers to a substance that immobilizes a gas, liquid or compound as an inclusion complex, and can be handled in solid form, containing components (or “guest” molecules). ) Can subsequently be released by solvent action or by dissolution. The term “clathrate” is used interchangeably herein with the phrase “inclusion molecule” or the phrase “inclusion complex”. The clathrate used in the present invention is prepared from cyclodextrin. Cyclodextrins are well known as having the ability to form clathrates (ie, inclusion compounds) with various molecules. For example, J. et al. L. Atwood, J .; E. D. Davies, and D.D. D. See inclusion compounds edited by MacNicol (London, Orlando, Academic Press, 1984; Goldberg, I., "The Significance of Molecular Type, Shape and Complementarity in Clathrate Inclusion", Topics in Current Chemistry (1988), Vol. 149, pp. 2- 44; Weber, E. et al., "Functional Group Assisted Clathrate Formation-Scissor-Like and Roof- Shaped Host Molecules", Topics in Current Chemistry (1988), Vol. 149, pp. 45- 135; and MacNicol, DD et al., “Clathrates and Molecular Inclusion Phenomena”, Chemical Society Reviews (1978), Vol. 7, No. 1, pp. 65-87). Conversion to cyclodextrin clathrate is known to increase the stability and solubility of certain compounds, thus facilitating this use as a pharmaceutical. For example, Saenger, W., “Cyclodextrin inclusion compounds in research and industry” (Angew. Chem. Int. Ed. Engl. (1980), Vol. 19, pp. 344-362); US Pat. No. 4,886. , 788 (Schering AG); US Pat. No. 6,355,627 (Takasago); US Pat. No. 6,288,119 (Ono Pharmaceuticals); US Pat. No. 6,110,969 (Ono Pharmaceuticals); US Pat. No. 6,235,780 (Ono Pharmaceuticals); US Pat. No. 6,262,293 (Ono Pharmaceuticals); US Pat. No. 6,225,347 (Ono Pharmaceuticals); and US Pat. No. 4,935,446. See No. (Ono Pharmaceutical).

  “Cyclodextrin” refers to a cyclic oligosaccharide composed of at least six glucopyranose units joined together by α (1-4) linkages. The oligosaccharide ring forms a ring with the first hydroxyl group of the glucose residue located on the narrow end of the torus. The second glucopyranose hydroxyl group is located on the wide end. Cyclodextrins have been shown to form inclusion complexes with the molecules in aqueous solution by binding hydrophobic molecules in their cavities. The formation of such complexes protects “guest” molecules from loss due to evaporation, attack by oxygen, visible and ultraviolet light, and intra- and intermolecular reactions. Such complexes also have the effect of “fixing” volatile materials until the complex encounters a warm and humid environment, upon which the complex dissolves or dissociates into guest molecules and cyclodextrins. For the purposes of the present invention, cyclodextrins containing 6-glucose units are identified as α-cyclodextrins, while cyclodextrins having 7 and 8 glucose residues are respectively β-cyclodextrin and γ-cyclodextrin. Called as dextrin. The other most common of the cyclodextrin nomenclature is the nomenclature of these compounds with cycloamylose.

  As used herein, “commercially available” compounds include Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee Wl, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester PA), Cressent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall U.K.), Lancaster Synthesis (Windham NH), Maybridge Chemical Co. Ltd .. (Cornwall U.K.), Paris Chemical Co. (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockville MD), and Wako Chemicals USA, Inc. It can be purchased from standard chemical supply companies such as (Richmond VA) and other commercial sources, but is not limited to these.

“Mammal” includes domestic animals such as humans and cats, dogs, pigs, cows, sheep, goats, horses, rabbits and the like.
As used herein, “methods well known to those skilled in the art” can be identified through various reference books and data bases. Suitable reference books and articles detailing the synthesis of reactants useful in the preparation of the compounds of the invention, or providing references to articles describing the preparation include, for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc. , New York; R. Sandler et al., “Organic Functional Group Preparations” 2nd Ed. , Academic Press, New York, 1983; O. House, “Modern Synthetic Reactions”, 2nd Ed. , W .; A. Benjamin, Inc. Menlo Park, Calif. 1972; L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed. John Wiley & Sons, New York, 1992; March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed. , Wiley-Interscience, New York, 1992, and the like. Specific and similar reactants can also be identified through the chemical index provided by the Chemical Abstract Service of the American Chemical Society, which is found in most public and university libraries, as well as online databases. (American Chemical Society, Washington, D. C. For more information, please contact www.acs.org). Chemicals that are well known but not commercially available in the catalog can be prepared by custom chemical synthesis companies, and in fact many standard chemical suppliers (eg, companies listed above) offer custom synthesis services To do.

  “Any” or “optionally” or “may be” means that the phenomenon or environment described below occurs or does not occur, and that the description or case occurs or occurs Means not included. For example, “optionally substituted aryl” means that the aryl group is or is not substituted, and that the description includes both substituted and unsubstituted aryl groups.

  “Polymorph” refers to polymorphic forms of the acids of the present invention. Solids exist in either amorphous or crystalline form. In the crystalline form, the molecules are systematically located at three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it crystallizes with a different spatial lattice arrangement, a property called “polymorphism”, and a different crystal form individually called “polymorph”. Different polymorphic forms of a substance may differ from one another in terms of one or more physical properties, such as solubility and degradability, true density, crystal form, compaction behavior, flow properties, and / or solid stability, etc. . In the case of chemicals that exist in two (or more) polymorphic forms, the unstable form generally converts to a thermodynamically stable form at a constant temperature after a sufficient amount of time. To do. If this transformation is not rapid, the thermodynamically unstable form is called the “metastable” form. However, the metastable form can exhibit sufficient chemical and physical stability under normal storage conditions and can be used in commercial form. In this case, the metastable form may exhibit desirable properties due to the properties of the stable form, such as improved solubility or good oral bioavailability, despite low stability.

“Solvate” refers to an aggregate comprising one or more molecules of a compound of the invention having one or more solvent molecules or having no stoichiometric amount of solvent. The solvent can be water, in which case the solvate is called a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the acid of the lipoxin A ₄ analog of formula (II) is monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, ratio water It may exist as a hydrate containing an anhydrous product having no content, etc., and a corresponding solvated form. The acid of formula (II) may actually be a solvate, while in other cases the salt simply retains extraneous water or is a mixture of water with the addition of several extraneous solvents. It may be. Furthermore, the acid of formula (II) may exist in crystalline anhydrous form.
See, for example, Byrn, S et al. “Solid Chemistry of Drugs”, SSCI (1999), regarding polymorphs and solvates, their characterization and properties, and relevance of drug substances and formulations; and salts, their preparation and See Stahl, P and Wermuth, C, “Handbook of Pharmaceutical Salts”, Wiley (2002) for property considerations.

As used herein, “appropriate conditions” for carrying out the synthesis steps are provided explicitly in this or by reference to publications directed to methods used in synthetic organic chemistry. I can understand. The above referenced books and articles detailing the synthesis of reactants useful in the preparation of the compounds of the present invention will also provide suitable conditions for carrying out the synthetic steps of the present invention.
“Suitable solvent” refers to any solvent compatible with the reaction components and reaction conditions. The term includes one solvent or a mixture of solvents, and these include, but are not limited to, organic solvents and water. Suitable solvents are known to those skilled in the art or can be understood by reference to publications directed to methods used in synthetic organic chemistry.

  A “therapeutically effective amount” when administered to a mammal, particularly a human, in need of an acid of the invention is sufficient such acid for effective treatment for a condition characterized by inflammation as defined below. Refers to the amount. The amount of the acid of the present invention that constitutes a “therapeutically effective amount” will vary depending on the salt, its solvated form, the condition being treated and its severity, the age of the mammal being treated, etc. Usually can be determined.

As used herein, “treating” or “treatment” includes treatment of a condition characterized by inflammation in a mammal, preferably a human, eg, an inflammatory or autoimmune disease or an inflammatory disease of the lungs or airways Including
(I) preventing a disease or form of inflammation that occurs in a mammal, particularly if a mammal that has not yet been diagnosed as having the disease suffers from this disease;
(Ii) inhibiting disease or inflammation, ie, inhibiting its progression; or (iii) reducing disease or inflammation, ie, causing regression of the disease or inflammation.

  The acid of formula (II) may contain one or more asymmetric centers and therefore, from the point of absolute stereochemistry, is optical as (R)-or (S)-, or (D)-or (L)- Isomers, diastereomers, and other definable stereoisomeric forms may result. The present invention is meant to include all such possible isomers, as well as all of their racemic and optically pure forms. Optically active (+) and (-), (R)-and (S)-, or (D)-and (L) -isomers can be prepared using chiral synthons or chiral reagents, Alternatively, it can be resolved using conventional techniques such as HPLC using a chiral column. When a compound described herein contains an olefinic double bond or other center of geometric asymmetry, and unless otherwise specified, it is intended that the compound include both E and Z geometric isomers. Is. Likewise, all tautomeric forms are also intended to be included.

を有する酸は、本明細書では、２−（（２Ｓ，３Ｒ，４Ｅ，６Ｅ，１０Ｅ，１２Ｓ）−１３−（４−フルオロフェノキシ）−２，３，１２−トリヒドロキシトリデカ−４，６，１０−トリエン−８−イニルオキシ）酢酸と命名する。 “Stereoisomer” refers to compounds composed of the same atoms joined by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes “optical isomers” that refer to two stereoisomers in which the molecules are non-superimposable mirror images of each other.
The nomenclature used herein is I.D. U. P. A. C. This is a variation of the nomenclature. For example, an acid of formula (II) wherein R ¹ is —O— and R ² is 4-fluorophenyl, ie, the following formula:

In the present specification, an acid having 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6 , 10-triene-8-ynyloxy) acetic acid.

B. The crystalline acid formula (II) compounds of the present invention are described in detail in US Pat. No. 6,831,186 and US Patent Application Publication No. 2004/0162433, the relevant disclosures of which are hereby incorporated by reference. All are incorporated.
Surprisingly, however, it was discovered during the initial phenomenon that the synthesis of the crystalline form of the acid of formula (II) was difficult to confirm. According to the procedure described in the above two publications, the crystalline form was not reliably obtained.
It is a well-known fact that solid forms of pharmaceutical acid crystals can dramatically increase the stability of pharmaceuticals. It is also known that the crystalline form is more stable than the amorphous form.

［式中、
Ｒ¹が、−Ｏ−、−Ｓ（Ｏ）ｔ−（ここでｔが、０、1または２である）、或いは直鎖または分岐のアルキレン鎖であり；そして
Ｒ²は、（アルキル、アルコキシ、ハロ、ハロアルキル及びハロアルコキシから選択される１または複数の置換基によって任意に置換された）アリールまたは（アルキル、アルコキシ、ハロ、ハロアルキル及びハロアルコキシから選択される１または複数の置換基によって任意に置換された）アラルキルである］
の化合物であって、当該式（II）の化合物は単一立体異性体または立体異性体の任意の混合物である化合物の、適当で安定した固体の結晶形態を調製するための合成ルートを発見することを目的に、検討を実施した。 Thus, formula (II):

[Where:
R ¹ is —O—, —S (O) t— (where t is 0, 1 or 2), or a linear or branched alkylene chain; and R ² is (alkyl, alkoxy Aryl optionally substituted by one or more substituents selected from: halo, haloalkyl and haloalkoxy) or optionally by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy Is a substituted aralkyl]
A synthetic route for preparing a suitable and stable solid crystalline form of a compound of formula (II) wherein the compound of formula (II) is a single stereoisomer or any mixture of stereoisomers A study was conducted for this purpose.

を目的とする。 In one embodiment, the invention provides a compound of the formula wherein R ¹ is —O— and R ² is phenyl optionally substituted with one or more substituents selected from fluoro, chloro and iodo. The objective is the crystalline acid (II). In other embodiments, the compounds of the invention are crystalline acids of formula (II), wherein R ¹ is —O— and R ² is 4-fluorophenyl. In a further embodiment, the compound is selected from the group consisting of:
2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-Fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8-ynyloxy) acetic acid ;
2-((2R, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8-ynyloxy) acetic acid ;
2-((2S, 3S, 4E, 6E, 10E, 12S) -13- (4-Fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8-ynyloxy) acetic acid ;
2-((2R, 3S, 4E, 6E, 10E, 12S) -13- (4-Fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8-ynyloxy) acetic acid ;
2-((2S, 3R, 4E, 6E, 10E, 12R) -13- (4-Fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8-ynyloxy) acetic acid ;
2-((2R, 3R, 4E, 6E, 10E, 12R) -13- (4-Fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8-ynyloxy) acetic acid ;
2-((2S, 3S, 4E, 6E, 10E, 12R) -13- (4-fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8-ynyloxy) acetic acid And 2-((2R, 3S, 4E, 6E, 10E, 12R) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6,10-triene-8-ynyloxy ) Acetic acid.
In yet another embodiment, the present invention relates to crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca. -4,6,10-triene-8-ynyloxy) acetic acid:

With the goal.

［式中、Ｒがアルキルまたはアリールである］
を有するエステルの、塩基での処理、続いて、得られる混合物の酸を使用した処理での酸性化によるけん化に基づく。 C. Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8- Preparation of inyloxy) acetic acid 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6,10-triene- The process for preparing the crystalline form of 8-ynyloxy) acetic acid can also be used for the preparation of crystalline acids of other compounds of formula (II). Generally, crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6,10- The process for preparing (triene-8-ynyloxy) acetic acid is represented by the following formula (III):

[Wherein R is alkyl or aryl]
Is based on treatment with an ester, followed by saponification by acidification of the resulting mixture with treatment with an acid.

The resulting mixture forms a suspension and is optionally cooled thereafter. The crystals were isolated from the suspension and dried to obtain the desired hydrate form of the crystalline acid.
In certain embodiments, the ester of formula (III) is dissolved in a suitable solvent such as methanol, ethanol or tetrahydrofuran (THF). Subsequently, an alkaline hydroxide base, such as sodium hydroxide or potassium hydroxide, is dissolved in a suitable solvent, such as methanol, ethanol or water, or a mixture of these solvents. The alkaline hydroxide solution is added to the ester solution, or vice versa. If necessary, a sufficient amount of water is added to produce adequate crystallization of the product by acidification.
The resulting mixture is acidified with a suitable acid, such as hydrochloric acid (HCI), to form an isolated and dry suspension. The drying procedure of the isolated crystals determines the “hydrate form” of the prepared crystalline acid.

D. 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-Fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8-ynyloxy) acetic acid The solid form of 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6, prepared according to the present invention , 10-triene-8-ynyloxy) acetic acid exists as a crystalline anhydrous form, called polymorph I, and a crystalline hydrate form, as well as an amorphous phase.

  Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-S- Inyloxy) acetic anhydride (polymorph I) shows characteristic peaks at d = 2.48 Å and d = 4.34 Å, while 2-((2S, 3R, 4E, 6E, 10E, 12S) The crystalline acid hydrate form of -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6,10-triene-8-ynyloxy) acetic acid is d = 9. Characteristic peaks are shown at 8 and d = 4.6 (see, FIGS. 2 and 3).

Data collection XRPD, germanium - was performed in transmission mode with STOE powder diffractometer automated using monochrome CuKa ₁ radiation (λ = 1.5406Å). An X-ray tube with a copper anode was operated at 40 kV and 30 mA. When using a well plate, an angular resolution of 0.08 ° at 3 ° < 2Θ < 35 ° -2 ° < 2Θ < 35 ° (step width 0.5 °) or 7 ° < 2Θ < 35 ° (step width 0.5 °) A 2Θ scan was performed using a small linear position sensitive detector with In order to avoid the influence of humidity during the measurement, the sample was placed between two polyacetate films bonded with double-sided adhesive tape or between two aluminum foils. Data collection and evaluation was performed using the STOE WinX ^pow software package. One skilled in the art will understand that X-ray diffraction patterns can be obtained with measurement errors that depend on the measurement conditions used. In particular, it is generally known that the intensity in the X-ray diffraction pattern varies according to the nature of the crystal of the raw material used and the measurement conditions. Furthermore, it is understood that the relative intensity also varies according to the experimental conditions, and therefore the exact order of intensity should not be considered. Further, the measurement error of the diffraction angle theta of a normal X-ray diffraction pattern at a predetermined temperature is generally about ± 0.1, and such a measurement error degree is related to the diffraction angle. It should be noted. Accordingly, when the term “about” is used herein with respect to an X-ray powder diffraction pattern, the crystalline form of the present invention is an X-ray diffraction pattern that exactly matches the X-ray diffraction pattern shown in the accompanying figures disclosed herein. Is not limited to crystalline forms that provide Any crystal form that provides an X-ray diffraction pattern substantially identical to that disclosed in the accompanying figures is within the scope of the present invention. The ability to determine whether the polymorphic forms of a compound are the same, even though the X-ray diffraction patterns are not exactly the same, is within the skill of the art.

E. Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8- Inyloxy) acetic acid hygroscopic free acid polymorph I is converted to a hydrate at relative humidity greater than 60%. It is hygroscopic and absorbs about 8% moisture at 80% relative humidity, which corresponds to the dihydrate of the substance. The hydration reaction is reversible. Conversion to polymorph I is observed at relative humidity below 40%. The absorption isotherm is shown in FIG.

Data collection on the hygroscopic examination was conducted with an automatic water absorption analyzer. The studied solid form of about 10 mg of crystalline acid was subjected to a continuous flow of nitrogen at a given and constant relative humidity. The sweep gas rate was set to 200 cm ³ / min. For the basic assay, two full cycles (moisture / desorption) were measured at 25 ° C. In order to remove surface water, the measurement was started at 0% relative humidity. Once a certain mass was reached, the next humidity was automatically set. Under the criteria for starting the first stage described here, water uptake / desorption was studied in 10% increments from 0% to 90% relative humidity. Furthermore, absorption at about 98% relative humidity was examined. Data was acquired using DVSWin software.

F. 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-Fluorophenoxy) -2,3,12-trihydroxytridec-4,6,10-triene-8-ynyloxy) acetic acid In addition to examining the stability region of polymorph I of the acid as a function of relative humidity and temperature, the relative chemical stability was measured.
2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6 over 4 weeks in different storage conditions , 10-triene-8-ynyloxy) acetic acid polymorph I relative chemical stability is shown in Table 2 below.

I. Usefulness of the crystalline acid of the present invention The crystalline acid of formula (II) has biological activity similar to that of natural lipoxin A ₄ but with improved resistance to chemical and metabolic degradation. Have Accordingly, the crystalline acid of formula (II) is useful for the treatment of inflammatory or autoimmune diseases in mammals such as humans. In particular, the crystalline acid of formula (II) is provided by neutrophils, eosinophils, T lymphocytes, NK cells or other immune cells that contribute to the pathogenesis of inflammatory, immune or autoimmune diseases Useful for suppressing acute or chronic inflammation or inflammatory or autoimmune reactions. Crystalline acids of formula (II) are also useful in the treatment of proliferative diseases, including but not limited to those associated with inflammatory or immune responses such as perturbations in cancer and the like. The crystalline acid of formula (II) is also useful as an inhibitor of angiogenic response in the pathogenesis of cancer.

  Thus, the crystalline acid of formula (II) can be used to treat the following inflammatory or autoimmune diseases in mammals, especially humans: anaphylactic reactions, allergic reactions, allergic contact dermatitis, Allergic rhinitis, chemical and non-specific irritant contact dermatitis, hives, atopic dermatitis, psoriasis, fistula associated with Crohn's disease, ileositis, septic or endotoxic shock, hemorrhagic shock, shock -Like syndrome, capillary leak syndrome induced by cancer immunotherapy, acute respiratory distress syndrome, traumatic shock, immune- and pathogen-induced pneumonia, immune complex-mediated lung injury and chronic obstructive pulmonary disease ( Inflammatory bowel disease (including ulcerative colitis, Crohn's disease and post-surgical trauma), gastrointestinal ulcer, (acute myocardial ischemia and infarction, acute renal failure, ischemic bowel disease) Diseases associated with ischemia-reperfusion injury (including acute hemorrhagic or ischemic stroke), immune complex-mediated glomerulonephritis, (insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis and systemic) Autoimmune diseases (including lupus erythematosus), acute and chronic organ transplant rejection, transplanted arteriosclerosis and fibrosis, (hypertension, atherosclerosis, aneurysm, severe leg ischemia, peripheral arterial occlusion) Diseases and cardiovascular diseases (including Lehno syndrome), complications of diabetes (including diabetic nephropathy, neuropathy and retinopathy), eye diseases (including macular degeneration and glaucoma), delayed neurodegeneration of stroke, Alzheimer Disease, including Parkinson's disease, encephalitis and HIV dementia), neurodegenerative diseases, inflammatory and neuropathic pain including joint pain, periodontal disease including gingivitis, ear infection, migraine, benign prostatic hyperplasia Cancers including, but not limited to, leukemia and lymphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, kidney cancer, head and neck tumors and colorectal cancer.

The crystalline acid of formula (II) is also in treating folliculitis induced by epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) kinase inhibitors used in the treatment of solid tumors Useful. Clinical trials have revealed follicular inflammation (hair follicle inflammation manifested by severe acne-like rash on the face, chest and upper back) as a major dose limiting side effect of such treatment. Such folliculitis is associated with neutrophil infiltration, suggesting that the product secreted by activated neutrophils is responsible for inflammation.
The crystalline acid of formula (II) suppresses neutrophil- or eosinophil-mediated inflammation and is therefore useful in the treatment of such folliculitis, and as a result of the life of the cancer patient undergoing treatment. It is possible to improve the quality, increase the dose of the EGF inhibitor or EGFR kinase inhibitor, or extend the duration of the treatment, thereby improving the effectiveness of the target inhibitor.

Crystalline acids of formula (II) also cause asthma, chronic bronchitis, bronchiolitis, obstructive bronchiolitis (including organizing pneumonia, etc.), airway allergic inflammation (including rhinitis and sinusitis) , Eosinophilic granuloma, pneumonia, pulmonary fibrosis, pulmonary symptoms of connective tissue disease, acute or chronic lung injury, chronic obstructive pulmonary disease, adult respiratory distress syndrome, and eosinophil infiltration It is useful in the treatment of lung and respiratory inflammation, including but not limited to other non-infectious inflammatory diseases of the lung. For example, the crystalline acid of formula (II) is eosinophil-mediated inflammation of the lung or tissue; lung neutrophil-mediated inflammation; lung lymphocyte-mediated inflammation; interleukin-5, interleukin-13. And eotaxin-containing cytokines and chemokine production; lipid mediator production including prostaglandin E ₂ and cysteinyl leukotrienes; airway hypersensitivity; and suppression of airway and vascular inflammation.

J. et al. Tests for crystalline acids of formula (II) Prominent features of inflammation are adhesion and migration of neutrophils, eosinophils and other inflammatory cells through the endothelium. A similar process is observed for cell migration through polar epithelial cells that occurs in the lungs, gastrointestinal tract and other organs. Cell culture models of these processes can be obtained, and the human lipoxin A ₄ and stable lipoxin hydrate form analogs through human endothelial cells and epithelial cells including human intestinal epithelial cell line T ₈₄ good Used to show inhibition of neutrophil migration. Accordingly, the crystalline acid of formula (II) is prepared by Colgan, S .; P. J. et al. Clin. Invest. (1993), Vol. 92, no. 1, pp. 75-82; and Serhan, C.I. N. Biochemistry (1995), Vol. 34, no. 44, pp. One skilled in the art will test its ability to inhibit the migration of human neutrophils and eosinophils through human endothelial cells and epithelial cells by performing an assay similar to that described in 14609-14615. Can do.

  The air sac model and / or the mouse zymosan-induced peritonitis model can be used to evaluate the effectiveness of the crystalline acid of formula (II) in vivo in the treatment of inflammatory responses. These are acute experimental models of inflammation characterized by infiltration of inflammatory cells into local sites. For example, Ajuebor, M .; N. Et al., Immunology (1998), Vol. 95, pp. 625-630; Gronert, K .; Am. J. et al. Pathol. (2001), Vol. 158, pp. 3-9; Poliot, M .; Biochemistry (2000), Vol. 39. pp. 4761-4768; Clish, C.I. B. Proc. Natl. Acad. Sci. U. S. A. (1999), Vol. 96, pp. 8247-8252; and Hachicha, M .; J. et al. Exp. Med. (1999), Vol. 189, pp. 1923-30, see in vivo assays.

Animal models (eg, in vivo assays) can also be used to confirm the effectiveness of crystalline acids of formula (II) in the treatment of asthma and lung and airway related diseases. . For example, De Sanctis, GT. Journal of Clinical Investigation (1999), Vol. 103, pp. 507-515; and Campbell, E .; M.M. J. et al. Immunol. (1998), Vol. 161, no. 12, pp. See the assay described in 7047-7053.
Also, in the claimed method of use employing the assays described in US Pat. No. 6,831,186 and US Patent Application Publication No. 2004/0162433, the crystalline acid of formula (II) is tested for its effectiveness. These related disclosures are all incorporated herein in their entirety.

K. Administration of crystalline acids of formula (II) Single stereoisomers or any mixture of stereoisomers, or their cyclodextrin clathrates, or as solvates or polymorphs, crystals of formula (II) Administration of the sex acid can be carried out via the agent alone or in the form of a suitable pharmaceutical composition, via any acceptable mode of administration or agent to provide similar utility. Thus, in solid, semi-solid, lyophilized powder, or liquid dosage forms such as tablets, suppositories, pills, soft capsules and hard gelatin capsules, powders, solutions, suspensions, aerosols, patches, etc., preferably It can be administered in unit dosage forms suitable for simple administration of precise doses, eg, oral, intranasal, parenteral, pulmonary, topical, transdermal, or rectal. The composition may include the crystalline acid of the present invention as its / some active agent and conventional pharmaceutical carriers or excipients, as well as other pharmaceutical agents, pharmaceuticals, carriers, An adjuvant or the like may be included.

The actual preparation of such dosage forms is well known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences , 18th Ed. (Mack Publishing Company, Easton, Pennsylvania, 1990). The composition to be administered will in any case contain a therapeutically effective amount of a crystalline acid of formula (II) for the treatment of a condition characterized by inflammation in accordance with the teachings of the present invention.
Generally, according to the intended method of administration, the pharmaceutically acceptable composition comprises from about 0.1 to about 99.9% by weight of a crystalline acid of formula (II) and a suitable pharmaceutical excipient From about 99.9 to about 0.1 weight percent.

In one embodiment, the preferred route of administration is orally using a convenient daily dosage regimen that can be adjusted according to the severity of the condition being treated. For such oral administration, by incorporating one or more commonly used pharmaceutically acceptable excipient (s), a pharmaceutically acceptable composition containing a crystalline acid of formula (II) is It is formed. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
Suitably such compositions may take the form of capsules, cowplets or tablets and thus generally also contain diluents, disintegrants, lubricants and binders.

Crystalline acids of formula (II) can also be formulated in suppositories that contain active ingredients lined up with a carrier that dissolves slowly in the body, for example, carriers commonly used in this volume.
Liquid pharmaceutically administrable compositions include, for example, any pharmaceutically acceptable adjuvant in the acid and carrier of the present invention, such as dissolution, dispersion, etc. of water, saline, aqueous glucose, glycerol, ethanol, etc. Which results in the formation of solutions or suspensions.
If desired, the pharmaceutical compositions of the present invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants and the like.

  The crystalline acid of formula (II) is the activity of the specific compound used; the metabolic stability and length of action of the crystalline acid of formula (II); age, weight, overall health, gender And the patient's diet; method of administration and time; elimination rate; drug combination; severity of the specific condition (s) being treated; and the host being treated; Administer in an effective amount.

The examples below further illustrate crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6. , 10-triene-8-ynyloxy) acetic acid preparation is described. Crystalline acid other lipoxin A ₄ analogs of formula (II) is also here can be similarly prepared according to the general procedure described in, exemplified in Examples 1-4.

Example 1: Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6,10-triene Preparation of the anhydrous form of -8-ynyloxy) acetic acid tert-Butyl 2-{[(4E, 6E, 10E)-(2S, 3R, 12S) -13- (4-Fluorophenoxy) -2,3,12-tri Hydroxytrideca-4,6,10-trien-8-in-1-yl] oxy} acetate is dissolved in a toluene / methanol mixture, followed by using a mixture of hexane and tert-butyl methyl ether as eluent. Filter through a plug of silica gel. Fractions are collected and subsequently concentrated in vacuo.
3.3 g filtered tert-butyl 2-{[(4E, 6E, 10E)-(2S, 3R, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4 , 6,10-Trien-8-in-1-yl] oxy} acetate is dissolved in 10 ml of methanol.

0.89 ml of 25% (w / w) aqueous sodium hydroxide solution is added. After 1 hour at room temperature, an additional 0.27 ml (w / w) of aqueous sodium hydroxide solution was added.
After complete conversion, 100 ml of water is added. The pH of the resulting solution is adjusted to pH 4 with 3.7 ml of 2N hydrochloric acid and the product begins to crystallize. An additional 1.6 ml of 2N hydrochloric acid is added slowly to pH 2.5. The suspension is stirred at room temperature for 1 hour. Place the reaction flask in an ice / water cooling bath and stir for an additional hour. An additional 1 ml of hydrochloric acid is added. The suspension is filtered and the resulting crystals are washed with water and dried at 30 ° C./200 mbar using nitrogen as the carrier gas in a vacuum drying cabinet.
2.3 g of light brown crystals are isolated.

Example 2: Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6,10- Preparation of the hydrate form of triene-8-ynyloxy) acetic acid Anhydrous crystalline free acid (15 mg) was dissolved in 0.1 mL of hot acetonitrile. The solvent was gradually evaporated at room temperature and the solution was concentrated.

Example 3: Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6,10- Preparation of the hydrate form of triene-8-ynyloxy) acetic acid An anhydrous crystalline free acid (15 mg) was dissolved in 0.1 mL of water at about 100 ° C. The solvent of the resulting solution was gradually evaporated at room temperature and concentrated.

Example 4: Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) -2,3,12-trihydroxytrideca-4,6,10- Preparation of the hydrate form of triene-8-ynyloxy) acetic acid 8 milligrams of the free acid polymorph I was stored at 25 ° C. and 90% relative humidity.

  Although the present invention has been described with reference to particular embodiments, various modifications can be made without departing from the true spirit and scope of the invention, and equivalents can be substituted, and further, the object and spirit of the invention It should be understood by those skilled in the art that many modifications are possible to adapt the particular situation, material, composition of material, method, method step (s) to the scope and scope. All such modifications are intended to be within the spirit of the claims appended hereto.

Claims (12)

Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4-fluorophenoxy) in anhydrous form, showing the characteristic peaks at d = 2.48 Å and d = 4.34 Å ) -2,3,12-trihydroxytrideca-4,6,10-triene-8-ynyloxy) acetic acid.

Crystalline 2-((2S, 3R, 4E, 6E, 10E, 12S) -13- (4- in hydrate form, showing the characteristic peaks at d = 9.8９ and d = 4.6４. Fluorophenoxy) -2,3,12-trihydroxytrideca-4,6,10-triene-8-ynyloxy) acetic acid.

  A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the crystalline acid according to claim 1 or 2.   Use of the crystalline acid according to claim 1 or 2 for the manufacture of a medicament for the treatment of mammals having a pathological condition characterized by inflammation.   5. Use according to claim 4, wherein the mammal is a human.   The use according to claim 4 or 5, wherein the medical condition is an inflammatory disease or an autoimmune disease.   The inflammatory disease or autoimmune disease is anaphylactic reaction, allergic reaction, allergic contact dermatitis, allergic rhinitis, chemical and non-specific irritant contact dermatitis, hives, atopic dermatitis, psoriasis, Fistula associated with Crohn's disease, ileitis, septic or endotoxic shock, hemorrhagic shock, shock-like syndrome, capillary leak syndrome induced by cancer immunotherapy, acute respiratory distress syndrome, traumatic shock , Immune- and pathogen-induced pneumonia, immune complex-mediated lung injury, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory bowel diseases including Crohn's disease and postoperative trauma, gastrointestinal ulcer, acute myocardium Ischemia and infarction, acute renal failure, ischemic bowel disease and diseases related to ischemia-reperfusion injury including acute hemorrhagic or ischemic stroke, immune complex mediated glomerular kidney , Insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, autoimmune diseases including osteoarthritis and systemic lupus erythematosus, acute and chronic organ transplant rejection, transplanted arteriosclerosis and fibrosis, hypertension, atherosclerosis Arteriosclerosis, aneurysm, severe leg ischemia, cardiovascular disease including peripheral arterial occlusive disease and Lehno syndrome, diabetic complications including diabetic nephropathy, neuropathy and retinopathy, macular degeneration and glaucoma Ocular diseases including stroke, delayed neurodegeneration of stroke, Alzheimer's disease, Parkinson's disease, neurodegenerative diseases including encephalitis and HIV dementia, inflammatory and neuropathic pain including joint pain, periodontal disease including gingivitis, ear Including infection, migraine, benign prostatic hyperplasia, leukemia and lymphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, kidney cancer, head and neck tumor and colorectal cancer Cancers including but not limited to record is selected from the group consisting of Use according to claim 6.   7. Use according to claim 6, wherein the inflammatory or autoimmune disease is an inflammatory bowel disease selected from the group consisting of Crohn's disease, ileal cystitis, ulcerative colitis and gastrointestinal ulcer.   Use according to claim 6, wherein the inflammatory or autoimmune disease is Crohn's disease.   6. Use according to claim 4 or 5, wherein the medical condition is an inflammatory disease of the lungs or airways.   The inflammatory diseases of the lungs or airways include asthma, chronic bronchitis, bronchiolitis, obstructive bronchiolitis including bronchiolitis with organizing pneumonia, airway allergic inflammation including rhinitis and sinusitis, favorable Featuring eosinophil granuloma, pneumonia, pulmonary fibrosis, pulmonary symptoms of connective tissue disease, acute or chronic lung injury, chronic obstructive pulmonary disease, adult respiratory distress syndrome, and eosinophil infiltration 11. Use according to claim 10 selected from the group consisting of: other non-infectious pulmonary inflammatory diseases. A method of treating a medical condition characterized by inflammation in a mammal, comprising:
3. A method comprising administering to a mammal in need thereof a therapeutically effective amount of the crystalline acid of claim 1 or 2.