JP2011525890A - Macrocyclic lactone compounds and methods for their use - Google Patents

Abstract

The present invention relates to pharmaceutically acceptable excipients and formula (I) wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁸ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ and M ⁷ are each independently a member selected from the group consisting of H, C _1-6 alkyl, OH and C _1-6 hydroxyalkyl; R ⁴ , R ⁷ and R ^{7 9} is each independently selected from the group consisting of C _1-6 alkoxy and OH; R ¹⁰ is H, —OH, —OP (O) Me ₂ , (II), (III), —O—. A member selected from the group consisting of (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ , wherein the subscripts n and m are each Independently 2 to 8, subscript o is 1 to 6; L ¹ and L ⁴ are each independently selected from the group consisting of (IV) and (V), wherein , each M ⁸ , Independently, C _1-6 alkyl, is a member selected from the group consisting of OH and C _1-6 hydroxyalkyl; L ² and L ³ are each independently, (VI), (VII) and Selected from the group consisting of (VIII)]
And a salt, hydrate, isomer, metabolite, N-oxide and prodrug thereof.

Description

Cross-reference of related applications Not applicable

Statement of rights to invention made under federal-sponsored research or development Not applicable

Refer to the Sequence Listing, Table, or Computer Program List Appendix submitted on the compact disc N / A

FIELD OF THE INVENTION The present invention relates to the structure of demethyl, hydroxyl, demethylhydroxyl, epoxide, N-oxide, ring-opening hemiketal ring and seco-macrocyclic lactone, methods for their synthesis, pharmaceutical compositions, and systemic and site-specific. Relates to their use for therapeutic applications.

Rapamycin (sirolimus) is a 31-membered natural macrocyclic lactone [C51H79N1O13; MWt = 914.2] produced by Streptomyces hygroscopicus and was discovered in the 1970s (Patent Document 1; Patent Document 2). Rapamycin (structure shown below) was approved in 1999 by the Food and Drug Administration (FDA) for the prevention of kidney transplant rejection.

  Rapamycin is similar to tacrolimus (binds to the same intracellular binding protein or immunophilin known as FKBP-12) but differs in its mechanism of action. Tacrolimus and cyclosporine inhibit T cell activation by interfering with transcription of lymphokine (eg, IL2) genes, whereas sirolimus binds to mammalian rapamycin target (mTOR) by binding to T cell activation and T lymphocytes. Inhibits sphere proliferation. Rapamycin can act synergistically with cyclosporine or tacrolimus in suppressing the immune system.

  Rapamycin also has systemic lupus erythematosus [Patent Document 3], pneumonia [Patent Document 4], insulin-dependent diabetes [Patent Document 5], skin disorders such as psoriasis [Patent Document 6], intestinal disorders [Patent Document 7] Smooth muscle cell proliferation and intimal thickening following injury [Patent Document 8 and Patent Document 9], Adult T-cell leukemia / lymphoma [Patent Document 10], Eye inflammation [Patent Document 11], Malignant cancer [Patent Document 12] It is also useful in the prevention or treatment of inflammatory diseases of the heart [Patent Document 13], anemia [Patent Document 14] and increased neurite outgrowth [Non-Patent Document 1]

  Although rapamycin can be used to treat a variety of medical conditions, its usefulness as a pharmaceutical agent has its very low and variable bioavailability and its high immunosuppressive capacity and potentially high toxicity. Has been limited by. Rapamycin dissolves very little in water. In order to solve these problems, prodrugs and analogs of the compounds have been synthesized. Water-soluble prodrugs are described that are prepared by derivatizing positions 31 and 42 (formerly positions 28 and 40) of the rapamycin structure to form glycinate, propionate and pyrrolidinobutyrate prodrugs (Patent Document 15). Some rapamycin analogs described in the art include monoacyl and diacyl analogs (Patent Document 16), acetal analogs (Patent Document 17), silyl ethers (Patent Document 18), hydroxy esters (Patent Document 19). ), And alkyl, aryl, alkenyl and alkynyl analogs (Patent Document 20; Patent Document 21; Patent Document 22; Patent Document 23).

  Rapamycin prodrugs and analogs are synthesized by chemical synthesis, where additional synthetic steps are required to protect and deprotect specific positions. Analogs can also be synthesized biologically where Streptomyces strains are genetically engineered to produce such analogs of rapamycin. Analogs need to maintain the position necessary for protein binding or other cellular interactions and should not cause steric hindrance to maintain their activity. The safety of these analogs requires extensive testing through a series of preclinical and clinical experiments.

US Pat. No. 3,929,992 US Pat. No. 3,993,749 US Pat. No. 5,078,999 US Pat. No. 5,080,899 US Pat. No. 5,321,009 US Pat. No. 5,286,730 US Pat. No. 5,286,731 US Pat. No. 5,288,711 US Pat. No. 5,516,781 European Patent Application No. 525,960 US Pat. No. 5,387,589 US Pat. No. 5,206,018 US Pat. No. 5,496,832 US Pat. No. 5,561,138 U.S. Pat. No. 4,650,803 U.S. Pat. No. 4,316,885 US Pat. No. 5,151,413 US Pat. No. 5,120,842 US Pat. No. 5,362,718 US Pat. No. 5,665,772 US Pat. No. 5,258,389 US Pat. No. 6,384,046 International Publication No. 97/35575

Parker, E. M. et al, Neuropharmacology 39, 1913-1919, 2000

  The present invention includes novel macrocyclic lactones and novel uses of macrocyclic lactones, where the compositions can be synthesized chemically or biologically for use in systemic and site-specific applications. It retains at least some immunosuppressive, antiproliferative, antifungal and antitumor properties.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁵、Ｒ⁶、Ｒ⁸、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴、Ｍ⁵、Ｍ⁶およびＭ⁷は、各々独立して、Ｈ、Ｃ_1-6アルキル、ＯＨおよびＣ_1-6ヒドロキシアルキルからなる群から選択されるメンバーであり；Ｒ⁴、Ｒ⁷およびＲ⁹は、各々独立して、Ｃ_1-6アルコキシおよびＯＨからなる群から選択され；Ｒ¹⁰は、Ｈ、−ＯＨ、−ＯＰ(Ｏ)Ｍｅ₂、

−Ｏ−(ＣＨ₂)_n−ＯＨおよび−Ｏ−(ＣＨ₂)_m−Ｏ−(ＣＨ₂)_o−ＣＨ₃からなる群から選択されるメンバーであり、ここで、下付文字ｎおよびｍは、各々独立して、２〜８であり、下付文字ｏは、１〜６であり；Ｌ¹およびＬ⁴は、各々独立して、

からなる群から選択され、ここで、各Ｍ⁸は、独立して、Ｃ_1-6アルキル、ＯＨおよびＣ_1-6ヒドロキシアルキルからなる群から選択されるメンバーであり；Ｌ²およびＬ³は、各々独立して、

からなる群から選択される］
で示される化合物ならびにその塩、水和物、異性体、代謝物、Ｎ−オキシドおよびプロドラッグを含む医薬組成物を提供する。 In one embodiment, the present invention provides a pharmaceutically acceptable excipient and formula:

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁸ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ and M ⁷ are each independently H , C _1-6 alkyl, OH and C _1-6 hydroxyalkyl; R ⁴ , R ⁷ and R ⁹ are each independently C _1-6 alkoxy and OH. R ¹⁰ is selected from the group; R ¹⁰ is H, —OH, —OP (O) Me ₂ ,

A member selected from the group consisting of —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ , wherein the subscripts n and m Are each independently 2-8, the subscript o is 1-6; L ¹ and L ⁴ are each independently

Wherein each M ⁸ is independently a member selected from the group consisting of C _1-6 alkyl, OH and C _1-6 hydroxyalkyl; L ² and L ³ are , Each independently

Selected from the group consisting of]
And a salt, hydrate, isomer, metabolite, N-oxide and prodrug thereof.

  In a second embodiment, the present invention provides an in-vivo device comprising an implant and at least one source of a compound of the present invention.

  In a third embodiment, the present invention provides a method for inhibiting cell proliferation by administering to a subject in need of inhibition of cell proliferation a therapeutically effective amount of a compound of the present invention.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹、Ｒ¹⁰、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴、Ｍ⁵、Ｍ⁶、Ｍ⁷、Ｌ¹、Ｌ²、Ｌ³およびＬ⁴は、上記のとおりである；
ただし、Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶およびＭ⁷がＭｅであり、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵がＨであり、Ｒ⁴、Ｒ⁷およびＲ⁹がＯＭｅであり、Ｒ¹⁰およびＭ⁸がＯＨであり、Ｌ²およびＬ³が−ＣＨ＝ＣＨ−であり、Ｌ¹およびＬ⁴が

である場合、Ｒ²はＯＨ以外のものであり；
ただし、Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶およびＭ⁷がＭｅであり、Ｒ²、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵がＨであり、Ｒ⁷およびＲ⁹がＯＭｅであり、Ｒ¹⁰およびＭ⁸がＯＨであり、Ｌ²およびＬ³が−ＣＨ＝ＣＨ−であり、Ｌ¹およびＬ⁴が

である場合、Ｒ⁴は、ＯＨ以外のものであり；
ただし、Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶およびＭ⁷がＭｅであり、Ｒ²、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵がＨであり、Ｒ⁴およびＲ⁷がＯＭｅであり、Ｒ¹⁰およびＭ⁸がＯＨであり、Ｌ²およびＬ³が−ＣＨ＝ＣＨ−であり、Ｌ¹およびＬ⁴が

である場合、Ｒ⁹は、ＯＨ以外のものであり；
ただし、Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶およびＭ⁷がＭｅであり、Ｒ²、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵がＨであり、Ｒ⁴、Ｒ⁷およびＲ⁹がＯＭｅであり、Ｍ⁸がＯＨであり、Ｌ²およびＬ³が−ＣＨ＝ＣＨ−であり、Ｌ¹およびＬ⁴が

である場合、Ｒ¹⁰は、ＯＨ、−ＯＰ(Ｏ)Ｍｅ₂、

−Ｏ−(ＣＨ₂)_n−ＯＨおよび−Ｏ−(ＣＨ₂)_m−Ｏ−(ＣＨ₂)_o−ＣＨ₃以外のものである］
で示される大環状ラクトン化合物ならびにその塩、水和物、異性体、代謝物、Ｎ−オキシドおよびプロドラッグを提供する。 In a fourth embodiment, the present invention provides the following formula:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ , M ⁷ , L ¹ , L ² , L ³ and L ⁴ are as described above;
However, an ^{R 1, R 6, R 8} , M 6 and M ⁷ is Me, is ^{R 3, R 5, M 1} , M 2, M 3, M 4 and M ⁵ are H, R ^4, R ⁷ and R ⁹ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ² is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁷ and R ⁹ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ⁴ is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ and R ⁷ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ⁹ is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ , R ⁷ and R ⁹ are OMe, M ⁸ is OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ¹⁰ is OH, —OP (O) Me ₂ ,

Other than —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ ]
As well as salts, hydrates, isomers, metabolites, N-oxides and prodrugs thereof.

  In a fifth embodiment, the present invention provides a process for producing a compound of the invention comprising contacting a macrocyclic lactone with an acid to replace the alkoxy group with a nucleophile to produce the compound of the invention. To do.

  In a sixth embodiment, the present invention provides a process for preparing a compound of the present invention comprising preparing a compound of the present invention by contacting a macrocyclic lactone with an epoxidizing agent to change the alkene group to an epoxide. provide.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹、Ｒ¹⁰、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴、Ｍ⁵、Ｍ⁶、Ｍ⁷、Ｌ¹、Ｌ²、Ｌ³およびＬ⁴は、上記のとおりである］
で示される化合物ならびにその塩、水和物、異性体、代謝物、Ｎ−オキシドおよびプロドラッグを含む医薬組成物を提供する。 In a seventh embodiment, the present invention provides a pharmaceutically acceptable excipient and formula:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ , M ⁷ , L ¹ , L ² , L ³ and L ⁴ are as described above]
And a salt, hydrate, isomer, metabolite, N-oxide and prodrug thereof.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹、Ｒ¹⁰、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴、Ｍ⁵、Ｍ⁶、Ｍ⁷、Ｌ¹、Ｌ²、Ｌ³およびＬ⁴は、上記のとおりである］
で示される化合物ならびにその塩、水和物、異性体、代謝物、Ｎ−オキシドおよびプロドラッグを含む医薬組成物を提供する。 In an eighth embodiment, the present invention provides a pharmaceutically acceptable excipient and formula:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ , M ⁷ , L ¹ , L ² , L ³ and L ⁴ are as described above]
And a salt, hydrate, isomer, metabolite, N-oxide and prodrug thereof.

  In a ninth embodiment, the present invention provides a method for treating ocular conditions and diseases by administering to a subject in need of treatment of ocular conditions and diseases a therapeutically effective amount of a compound of the present invention. provide.

FIG. 1 shows the structure of a macrocyclic lactone having several sites that can be chemically modified to provide compounds of the invention. The region marked with a square is the site for demethylation, the region marked with a circle is the site for hydroxylation, and the C = C site (C17 = C18, C19 = C20). =, C21 = C22, C29 = C30) are sites for epoxidation. Figures 2A-2FV show compounds of the invention. FIG. 3 shows an example of the shape of a stent having an expandable structure. FIG. 4 shows a preparative HPLC chromatogram of Compound AR. FIG. 5 shows the proton NMR spectrum of compound AR. FIG. 6 shows the liquid chromatography and mass spectral results of Compound AR. FIG. 7 (a) shows an analytical HPLC chromatogram of Compound AR. FIG. 7 (b) shows an analytical HPLC chromatogram of Compound AR with isomers. FIG. 8 shows the proliferation rate of human smooth muscle cells after exposure to various concentrations of rapamycin and compound AR. FIG. 9 shows the stenosis of a compound AR eluting stent compared to a rapamycin eluting Cypher stent as assessed by quantitative coronary angiography (QCA) 28 days after implantation in a porcine coronary artery model. FIG. 10 shows the tissue concentration of Compound AR at various time points in the porcine coronary artery model. FIG. 11 shows the compound AR release rate from the stent in a porcine coronary artery model. FIG. 12 (a) shows inhibition of IL-6, MMP-9 and MCP-1 released by activated macrophages by exposure to a concentration of 10 nM macrocyclic lactone compound AR and sirolimus. FIG. 12 (b) shows the inhibition of IL-10 released by activated macrophages by exposure to a concentration of 10 nM macrocyclic lactone compound AR and sirolimus. FIG. 13 shows the proliferation rate of human smooth muscle cells after exposure to various concentrations of 17,18-29,30-bis-epoxide macrocyclic lactone and Compound AR. FIG. 14 shows the synthesis of 16-O-demethyl macrocyclic lactone of the present invention. FIG. 15 shows the synthesis of 19,20-bis-hydroxy macrocyclic lactone. FIG. 16 shows the synthesis of 17,18-29,30-bis-epoxide macrocyclic lactone. FIG. 17 shows the synthesis of 31-hydroxyl macrocyclic lactone, 44-hydroxyl macrocyclic lactone and 47-hydroxyl macrocyclic lactone. FIG. 18 shows the synthesis of 43-hydroxyl macrocyclic lactone and 47-hydroxyl macrocyclic lactone.

I. Definitions As used herein, the term “acid” refers to any compound that when dissolved in water results in a solution having a pH lower than 7.0. Acids are generally described as compounds that donate hydrogen ions (H +) (Bronsted-Lowry) or as electron-pair acceptors (Lewis acids). Acids useful in the present invention include, but are not limited to, HCl, H ₂ SO ₄ , HNO ₃ and acetic acid. One skilled in the art will appreciate that other acids are useful in the present invention.

  As used herein, the term “administration” refers to systemic and local administration to a subject, or combinations thereof, such as oral administration, administration as a suppository, local contact, parenteral, intravascular, intravenous, intraperitoneal. Intramuscular, intralesional, intranasal, pulmonary, mucosal, transdermal, subcutaneous administration, intrathecal, intraocular, intravitreal administration, temporary device such as catheter, delivery via porous balloon, implant Refers to, for example, delivery via polymer implants, osmotic pumps, prostheses, eg drug eluting stents, or other methods. Those skilled in the art will appreciate that other modes and methods of administering the compounds of the invention are also useful in the present invention.

  As used herein, the term “alkoxy” refers to an alkyl containing an oxygen atom, such as methoxy, ethoxy, and the like. “Halo-substituted alkoxy” is defined as alkoxy in which some or all of the hydrogen atoms are replaced with halogen atoms. For example, halo-substituted alkoxy includes trifluoromethoxy and the like. One skilled in the art will appreciate that other alkoxy groups are useful in the present invention.

As used herein, the term “alkyl” refers to a straight or branched saturated aliphatic group having the indicated number of carbon atoms. For example, C ₁ -C ₆ alkyl includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl and the like. is not. One skilled in the art will appreciate that other alkyl groups are useful in the present invention.

  As used herein, the term “hydroxyalkyl” refers to an alkyl as defined above wherein at least one of the hydrogen atoms is replaced with a hydroxy group. For example, hydroxyalkyl includes hydroxy-methyl, hydroxy-ethyl (1- or 2-), hydroxy-propyl (1-, 2- or 3-), hydroxy-butyl (1-, 2-, 3- or 4). -), Hydroxy-pentyl (1-, 2-, 3-, 4- or 5-), hydroxy-hexyl (1-, 2-, 3-, 4-, 5- or 6-), 1,2- Dihydroxyethyl and the like are mentioned. One skilled in the art will appreciate that other hydroxyalkyl groups are useful in the present invention.

  As used herein, the term “body lumen” refers to the lining or cavity of an artery, vein or organ.

  As used herein, the term “contacting” refers to the process of contacting at least two different chemical species so that they can react. However, it is understood that the resulting reaction product can be generated directly from the reaction between the added reagents or from an intermediate that can be generated in the reaction mixture from one or more added reagents. Should.

  As used herein, the term “hydrate” refers to a compound that is complexed with at least one water molecule. The compounds of the present invention may be complexed with 1 to 100 water molecules.

  As used herein, the term “implant” refers to a medical device that is inserted into the body to treat symptoms. Implants include, but are not limited to, drug eluting devices.

  As used herein, the terms “inhibit,” “inhibit,” and “inhibitor” refer to a compound or inhibitor that inhibits, reduces, attenuates, or reduces a particular action or function. To reduce, reduce, attenuate, or alleviate.

  As used herein, the term “in the body” refers to the mammalian body.

  As used herein, the term “isomer” refers to a compound of the invention having an asymmetric carbon atom (optical center) or a double bond, racemates, diastereomers, enantiomers, geometric isomers, structures All isomers and individual isomers are intended to be included within the scope of the present invention.

  As used herein, the term “organ” refers to any organ of a mammal, such as heart, lung, brain, eye, stomach, spleen, bone, pancreas, kidney, liver, intestine, uterus, colon, ovary, This includes but is not limited to blood, skin, muscle, tissue, prostate, breast and bladder. One skilled in the art will appreciate that other organs are useful in the present invention.

  As used herein, the term “peracid” refers to an acid in which an acidic —OH group is replaced with an —OOH group. The peracid can be a peroxycarboxylic acid of the formula R—C (O) —OOH, where the R group can be a group such as H, an alkyl group, an alkene group or an aryl group. Peracids include, but are not limited to peroxyacetic acid and metachloroperoxybenzoic acid (MCPBA). One skilled in the art will appreciate that other peracids are also useful in the present invention.

  As used herein, the term “peroxide” refers to a compound containing an oxygen-oxygen single bond. Examples of peroxides include but are not limited to hydrogen peroxide. One skilled in the art will appreciate that other peroxides are useful in the present invention.

  As used herein, the term “pharmaceutically acceptable excipient” refers to a substance that assists in the administration and absorption of an active substance by a subject. Pharmaceutical excipients useful in the present invention include polymers, solvents, antioxidants, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, stabilizers, colorants, metals, ceramics and Although a metalloid is mentioned, it is not limited to these. See below for further discussion of pharmaceutically acceptable excipients. One skilled in the art will appreciate that other pharmaceutical excipients are also useful in the present invention.

  As used herein, the term “polymer” refers to a molecule composed of repeating structural units or monomers linked by covalent chemical bonds. Polymers useful in the present invention are described below. One skilled in the art will appreciate that other polymers are useful in the present invention.

  As used herein, the term “prodrug” refers to a compound that is capable of releasing an active substance of a method of the invention when administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to those skilled in the art. These techniques generally modify appropriate functional groups in a given compound. However, these modified functional groups regenerate original functional groups by routine manipulation or in vivo. The prodrug of the active substance of the present invention includes an active substance in which a hydroxy group, amidino group, guanidino group, amino group, carboxyl group or similar group is modified.

  As used herein, the term “salt” refers to an acidic or basic salt of a compound used in the methods of the invention. Specific examples of pharmaceutically acceptable salts include mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, four Secondary ammonium (methyl iodide, ethyl iodide and the like) salts. More information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is hereby incorporated by reference.

  Pharmaceutically acceptable salts of the acidic compounds of the present invention include salts formed with bases, i.e. cationic salts such as alkali metal salts and alkaline earth metal salts such as sodium salts, lithium salts, potassium salts, calcium salts, Magnesium salts, and ammonium salts such as ammonium, trimethylammonium, diethylammonium and tris- (hydroxymethyl) -methyl-ammonium salts.

  If basic groups such as pyridyl form part of the structure, acid addition salts such as mineral acids, organic carboxylic acids and organic sulfonic acids such as hydrochloric acid, methanesulfonic acid, maleic acid are also used. Is also possible.

  The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt types in certain physical properties, such as solubility in polar solvents, but otherwise the salt is the parent of the compound for purposes of the present invention. Equivalent to type.

  As used herein, the term “source” refers to a site on a device of the invention that provides a supply of a compound of the invention or a supply of a therapeutic agent. The apparatus of the present invention may have more than one source, for example first and second sources. Each source can have different compounds and compositions and can be used to treat different indications.

  As used herein, the term “subject” refers to animals, such as mammals, primates (eg, humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, rats, mice. And the like, but are not limited thereto. In certain embodiments, the subject is a human.

  As used herein, the term “therapeutic agent” refers to any agent, compound, or biological molecule that provides a therapeutic effect to a patient receiving the therapeutic agent.

  As used herein, the term “therapeutically effective amount or dose” or “therapeutically sufficient amount or dose” or “effective or sufficient amount or dose” refers to a dose that produces a therapeutic effect for administration purposes. . The exact dose will depend on the therapeutic purpose and can be ascertained by one skilled in the art using known techniques (eg, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective dose in sensitized cells can often be lower than the usual therapeutically effective dose for non-sensitized cells.

  As used herein, the term “vascular prosthesis” refers to a prosthesis for the mammalian circulatory system.

II. Compounds of the Invention In the present invention, macrocyclic lactones, their salts, prodrugs, tautomers and isomers are collectively referred to as “macrocyclic lactones”.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁵、Ｒ⁶、Ｒ⁸、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴、Ｍ⁵、Ｍ⁶およびＭ⁷は、各々独立して、Ｈ、Ｃ_1-6アルキル、ＯＨおよびＣ_1-6ヒドロキシアルキルからなる群から選択されるメンバーであり；Ｒ⁴、Ｒ⁷およびＲ⁹は、各々独立して、Ｃ_1-6アルコキシおよびＯＨからなる群から選択され；Ｒ¹⁰は、Ｈ、−ＯＨ、−ＯＰ(Ｏ)Ｍｅ₂、

−Ｏ−(ＣＨ₂)_n−ＯＨおよび−Ｏ−(ＣＨ₂)_m−Ｏ−(ＣＨ₂)_o−ＣＨ₃からなる群から選択されるメンバーであり、ここで、下付文字ｎおよびｍは、各々独立して、２〜８であり、下付文字ｏは、１〜６であり；Ｌ¹およびＬ⁴は、各々独立して、

からなる群から選択され、ここで、各Ｍ⁸は、独立して、Ｃ_1-6アルキル、ＯＨおよびＣ_1-6ヒドロキシアルキルからなる群から選択されるメンバーであり；Ｌ²およびＬ³は、各々独立して、

からなる群から選択される；
ただし、Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶およびＭ⁷がＭｅであり、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵がＨであり、Ｒ⁴、Ｒ⁷およびＲ⁹がＯＭｅであり、Ｒ¹⁰およびＭ⁸がＯＨであり、Ｌ²およびＬ³が−ＣＨ＝ＣＨ−であり、Ｌ¹およびＬ⁴が

である場合、Ｒ²は、ＯＨ以外のものであり；
ただし、Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶およびＭ⁷がＭｅであり、Ｒ²、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵がＨであり、Ｒ⁷およびＲ⁹がＯＭｅであり、Ｒ¹⁰およびＭ⁸がＯＨであり、Ｌ²およびＬ³が−ＣＨ＝ＣＨ−であり、Ｌ¹およびＬ⁴が

である場合、Ｒ⁴は、ＯＨ以外のものであり；
ただし、Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶およびＭ⁷がＭｅであり、Ｒ²、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵がＨであり、Ｒ⁴およびＲ⁷がＯＭｅであり、Ｒ¹⁰およびＭ⁸がＯＨであり、Ｌ²およびＬ³が−ＣＨ＝ＣＨ−であり、Ｌ¹およびＬ⁴が

である場合、Ｒ⁹は、ＯＨ以外のものであり；
ただし、Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶およびＭ⁷がＭｅであり、Ｒ²、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵がＨであり、Ｒ⁴、Ｒ⁷およびＲ⁹がＯＭｅであり、Ｍ⁸がＯＨであり、Ｌ²およびＬ³が−ＣＨ＝ＣＨ−であり、Ｌ¹およびＬ⁴が

である場合、Ｒ¹⁰は、ＯＨ、−ＯＰ(Ｏ)Ｍｅ₂、

−Ｏ−(ＣＨ₂)_n−ＯＨおよび−Ｏ−(ＣＨ₂)_m−Ｏ−(ＣＨ₂)_o−ＣＨ₃以外のものである］
で示される大環状ラクトン化合物ならびにその塩、水和物、異性体、代謝物、Ｎ−オキシドおよびプロドラッグである。 The compound of the present invention has the following formula:

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁸ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ and M ⁷ are each independently H , C _1-6 alkyl, OH and C _1-6 hydroxyalkyl; R ⁴ , R ⁷ and R ⁹ are each independently C _1-6 alkoxy and OH. R ¹⁰ is selected from the group; R ¹⁰ is H, —OH, —OP (O) Me ₂ ,

A member selected from the group consisting of —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ , wherein the subscripts n and m Are each independently 2-8, the subscript o is 1-6; L ¹ and L ⁴ are each independently

Wherein each M ⁸ is independently a member selected from the group consisting of C _1-6 alkyl, OH and C _1-6 hydroxyalkyl; L ² and L ³ are , Each independently

Selected from the group consisting of:
However, an ^{R 1, R 6, R 8} , M 6 and M ⁷ is Me, is ^{R 3, R 5, M 1} , M 2, M 3, M 4 and M ⁵ are H, R ^4, R ⁷ and R ⁹ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ² is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁷ and R ⁹ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ⁴ is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ and R ⁷ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ⁹ is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ , R ⁷ and R ⁹ are OMe, M ⁸ is OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ¹⁰ is OH, —OP (O) Me ₂ ,

Other than —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ ]
And the salts, hydrates, isomers, metabolites, N-oxides and prodrugs thereof.

である。 In some embodiments, R ¹⁰ is

It is.

である。 In some other embodiments, R ¹⁰ is

It is.

In another embodiment, R ¹⁰ is —OP (O) Me ₂ .

である。 In yet another embodiment, R ¹⁰ is

It is.

である。 In another embodiment, R ¹⁰ is

It is.

であり、Ｌ²およびＬ³は、各々、

である。 In a further embodiment, the compound is the compound shown in FIG. In other embodiments, at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is OH. In yet another embodiment, R ⁴ is OH. In yet another embodiment, R ¹ , R ⁶ and R ⁸ are each methyl, R ² , R ³ and R ⁵ are each H, and R ⁴ and R ¹⁰ are each OH R ⁷ and R ⁹ are each OMe; M ¹ , M ² , M ³ , M ⁴ and M ⁵ are each H; M ⁶ and M ⁷ are each methyl; L ¹ and L ⁴ are each

And L ² and L ³ are each

It is.

  The present invention specifically provides macrocyclic lactone compounds of formula IA, IB, IC and ID.

  In one embodiment, the composition contains macrocyclic lactones, including hydroxy macrocyclic lactones, demethyl macrocyclic lactones, hydroxydemethyl macrocyclic lactones and epoxide macrocyclic lactones.

  The structures of certain macrocyclic lactones having several sites that can be chemically modified to provide compounds of the invention are shown below.

式中、四角形は、デメチル化位置を表し；円は、ヒドロキシル化位置を表し；三角形は、エポキシ化位置を表し；曲線は、Ｎ−オキシド化位置を表し；点線は、開環位置を表し；Ｒ¹⁰は、−ＯＨ、

−ＯＰ(Ｏ)Ｍｅ₂、Ｒ^aＯＨ（ここで、Ｒ^aは、−(ＣＨ₂)₂から−(ＣＨ₂)₇までのようなアルキルである）および−Ｒ^bＯＲ^c（ここで、Ｒ^bは、Ｃ_2-6アルキレンであり、Ｒ^cは、Ｃ_1-5アルキルである）からなる群から選択されるメンバーである。例えば、４０−Ｏ−(エトキシエチル)ラパマイシンである。

Where the square represents the demethylation position; the circle represents the hydroxylation position; the triangle represents the epoxidation position; the curve represents the N-oxidation position; the dotted line represents the ring opening position; R ¹⁰ is —OH,

_{-OP (O) Me 2, R} a OH ( where R ^a is, - (CH ₂₎ from ₂ - (CH _{2) 7} alkyl, such as up) and -R ^b OR ^c (where R ^b is C _2-6 alkylene and R ^c is C _1-5 alkyl). For example, 40-O- (ethoxyethyl) rapamycin.

  In some embodiments, the compounds of the present invention have certain demethyl macrocyclic lactones, such as 16-O-demethyl macrocyclic lactone, 39-, individually or in combination with each other, as shown in Formula IA. O-demethyl macrocyclic lactone, 27-O-demethyl macrocyclic lactone, 16,27-bis-O-demethyl macrocyclic lactone, 27,39-bis-O-demethyl macrocyclic lactone, 16,39-bis-O- Includes demethyl macrocyclic lactone.

式中、
Ｒ⁴、Ｒ⁷およびＲ⁹は、各々、−ＯＣＨ₃および−ＯＨからなる群から選択される。
Ｒ⁴およびＲ⁷は、共に、独立して、−ＯＨおよび−ＯＣＨ₃からなる群から選択される。
Ｒ⁷およびＲ⁹は、共に、独立して、−ＯＨおよび−ＯＣＨ₃からなる群から選択される。
Ｒ⁴およびＲ⁹は、共に、独立して、−ＯＨおよび−ＯＣＨ₃からなる群から選択される。
Ｒ⁴、Ｒ⁷およびＲ⁹は、各々独立して、−ＯＨおよび−ＯＣＨ₃からなる群から選択される。
そして、Ｒ¹⁰は、上記のとおりである。 Formula IA

Where
R ⁴ , R ⁷ and R ⁹ are each selected from the group consisting of —OCH ₃ and —OH.
R ⁴ and R ⁷ are both independently selected from the group consisting of —OH and —OCH ₃ .
R ⁷ and R ⁹ are both independently selected from the group consisting of —OH and —OCH ₃ .
R ⁴ and R ⁹ are both independently selected from the group consisting of —OH and —OCH ₃ .
R ⁴ , R ⁷ and R ⁹ are each independently selected from the group consisting of —OH and —OCH ₃ .
R ¹⁰ is as described above.

  In another embodiment, the compounds of the present invention are hydroxyl macrocyclic lactones, such as 11-hydroxyl macrocyclic lactones, 12-hydroxyl macrocyclic lactones, 14 or individually or in combination with each other, as shown in Formula IB. -Hydroxyl macrocyclic lactone, 24-hydroxyl macrocyclic lactone, 25-hydroxyl macrocyclic lactone, 25-methyl alcohol macrocyclic lactone, 31-methyl alcohol macrocyclic lactone, 35-methyl alcohol macrocyclic lactone, 13-methyl alcohol macrocyclic lactone Includes lactone compositions.

式中、
Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶、Ｍ⁷、Ｍ⁸およびＭ^8aは、−ＣＨ₃、−ＣＨ₂ＯＨおよび−ＯＨからなる群から選択される。Ｒ²、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵は、各々、−Ｈおよび−ＯＨからなる群から選択される。Ｒ⁹は、−ＯＨおよび−ＯＣＨ₃からなる群から選択される。Ｌ²は、

からなる群から選択される。
そして、Ｒ¹⁰は、上記のとおりである。 Formula IB

Where
^{R 1, R 6, R 8} , M 6, M 7, M 8 and M ^8a is, -CH _3, is selected from the group consisting of -CH ₂ OH and -OH. R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are each selected from the group consisting of —H and —OH. R ⁹ is selected from the group consisting of —OH and —OCH ₃ . L ² is

Selected from the group consisting of
R ¹⁰ is as described above.

  In another embodiment, the compounds of the present invention have an epoxide macrocyclic lactone, such as 19,20-21,22-29,30-trisepoxide macrocyclic lactone, 17,18-19, as shown in Formula IC. , 20-21,22-trisepoxide macrocyclic lactone and 17,18-29,30-bisepoxide macrocyclic lactone.

式中、Ｒ¹⁰は、上記のとおりである。 Formula IC

In the formula, R ¹⁰ is as described above.

式中、Ｒ¹、Ｒ⁶、Ｒ⁸、Ｍ⁶、Ｍ⁷、Ｍ⁸およびＭ^8aは、各々独立して、−ＣＨ₃、−ＯＨおよびＣ_1-6ヒドロキシアルキルからなる群から選択される。Ｒ²、Ｒ³、Ｒ⁵、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴およびＭ⁵は、各々独立して、−Ｈおよび−ＯＨからなる群から選択される。Ｒ⁴、Ｒ⁷、Ｒ⁹は、独立して、−ＯＨおよび−ＯＣＨ₃からなる群から選択される。Ｌ²は、

からなる群から選択される。 Formula ID
In another embodiment, the compounds of the present invention comprise an N-oxidized macrocyclic lactone, 11-hydroxyl-10,14 ring-opened macrocyclic lactone, seco-macrocyclic lactone (1,34, as shown in Formula ID). Ring-opening type) compositions.

Wherein R ¹ , R ⁶ , R ⁸ , M ⁶ , M ⁷ , M ⁸ and M ^8a are each independently selected from the group consisting of —CH ₃ , —OH and C _1-6 hydroxyalkyl. . R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are each independently selected from the group consisting of —H and —OH. R ⁴ , R ⁷ and R ⁹ are independently selected from the group consisting of —OH and —OCH ₃ . L ² is

Selected from the group consisting of

  In another embodiment, the compounds of the invention are a combination of Formula IA and Formula IB, 14-hydroxy-39-O-demethyl macrocyclic lactone, 16,39-bis-O, individually or in combination with each other Large demethylhydroxy such as -demethyl-24-hydroxy macrocyclic lactone, 16,27-bis-O-demethyl-24-hydroxy macrocyclic lactone, 27,39-bis-O-demethyl-24-hydroxy macrocyclic lactone Includes cyclic lactone compositions.

  In another embodiment, the compounds of the invention are a combination of Formula IA and Formula IC, and are 17,18-19,20-bis-epoxide-16-O-demethyl macrocyclic lactone, individually or in combination with each other And compositions of epoxide demethyl macrocyclic lactones such as 17,18-29,30-bis-epoxide-16-O-demethyl macrocyclic lactones.

  In yet another embodiment, the compounds of the invention are a combination of formula IA, formula IB and formula IC, and are individually or in combination with 17,18-19,20-bis-epoxide-16-O- Included are compositions of epoxide demethyl hydroxyl macrocyclic lactones such as demethyl-24-hydroxy macrocyclic lactone, 17,18-29,30-bis-epoxide-16-O-demethyl-24-hydroxy macrocyclic lactone.

  The present invention also includes salts, hydrates, isomers, tautomers, metabolites, N-oxides and prodrugs of the compounds of the present invention having the formulas IA, IB, IC and ID.

Among the compounds of the present invention represented by the formulas IA, IB, IC and ID, and combinations thereof, the structures of preferred embodiments (A, B, C,... AA, AB, AC,... FB, FC, FD ) Are shown in Table 1, and some are shown in FIGS.

＊ラパマイシン。全ての−ＯＨ置換基は、Ｒ異性体およびＳ異性体の混合物を表す。

* Rapamycin. All —OH substituents represent a mixture of R and S isomers.

In some embodiments, the compounds of the invention have the following structure:

  The present invention includes compounds where the stereochemistry at the 16-position is racemic (R, S), as well as the R and S stereoisomers at the 16-position, and all other isomers of the compound.

  The present invention includes compounds having various polymorphs. This includes 16-O-demethyl macrocyclic lactones with various polymorphs. For example, various polymorphs of 16-O-demethyl macrocyclic lactone are obtained by using dichloromethylene and by using a mixture of methanol and water.

  There are various numbering schemes proposed for macrocyclic lactones. To avoid confusion, when a particular macrocyclic lactone is named herein, it is named with reference to the macrocyclic lactone using the numbering scheme of the above chemical formula. The present invention also includes all macrocyclic lactones having different names according to different numbering schemes, provided that the same functional group is present at the same position in the chemical structure. For example, 39-O-demethyl macrocyclic lactone is the same compound as 41-O-demethyl macrocyclic lactone, and 16-O-demethyl macrocyclic lactone is the same compound as 7-O-demethyl macrocyclic lactone.

  The compounds of the present invention can be prepared by a variety of methods. In some embodiments, the compounds of the invention are biologically synthesized by genetically manipulating strains of organisms to produce the compounds of the invention, or by other methods.

  In another embodiment, the compounds of the invention are prepared using chemical synthesis. Chemical synthesis of the compounds of the present invention may utilize the 17-18, 19-20, 21-22 triene structure within the macrocyclic lactone, which structure promotes acid-catalyzed nucleophilic substitution of the C16 methoxy group, and many Allows the introduction of different substitutions and allows selective manipulation of the effector domain of the macrocyclic lactone. The C16 methoxy group in the macrocyclic lactone is manipulated towards the acidic reagent to produce the compounds of the invention. For example, substitution of the C16 methoxy group with various nucleophiles such as alcohols, thiols and electron rich aromatic groups can be achieved. This synthetic method can be carried out without protection and deprotection steps.

  This synthetic method using an acidic reagent with a compound having a triene functional group can be applied to other compounds having a triene functional group to synthesize the corresponding compound analog, and the synthesis without the steps of protection and deprotection. Provide a method.

  In some embodiments, the invention provides a method of making a compound of the invention, wherein the compound of the invention is made by contacting a macrocyclic lactone with an acid and substituting an alkoxy group with a nucleophile. A method comprising: In some other embodiments, the macrocyclic lactone is rapamycin. In another embodiment, the nucleophile is a member selected from the group consisting of —OH, —SH and electron rich aromatic groups. One skilled in the art will appreciate that other methods are useful for preparing the compounds of the present invention.

  The synthesis of demethyl macrocyclic lactone is provided in FIG. 14 using 16-O-demethyl macrocyclic lactone as an example. The synthesis of hydroxy macrocyclic lactone is provided in FIG. 15 using 19,20 bis-hydroxy macrocyclic lactone as an example. The synthesis of the epoxide macrocyclic lactone is provided in FIG. 16 using 17,18-29,30-bisepoxide macrocyclic lactone as an example.

  In another embodiment, the present invention provides a compound of the present invention comprising preparing a compound of the present invention by contacting a macrocyclic lactone with a suitable agent such as a peracid or peroxide to convert the alkene group to an epoxide. A method for producing a compound is provided. Peracids useful in the method of the present invention include peroxycarboxylic acids of the formula R—C (O) —OOH, where the R group can be a group such as H, alkyl, alkene or aryl. However, it is not limited to these. In some embodiments, the peracid can be peroxyacetic acid or metachloroperoxybenzoic acid (MCPBA). A peroxide useful in the method of the present invention includes, but is not limited to, hydrogen peroxide. One skilled in the art will appreciate that other epoxidation reagents are also useful in the present invention.

  The compounds of the invention are deuterated if desired.

  In some embodiments, the present invention provides compounds of the invention with similar potency as the corresponding parent macrocyclic lactone. In another embodiment, the invention provides a compound of the invention that is less potent than the corresponding parent macrocyclic lactone to improve the safety profile of the compound.

III. Delivery of compounds of the invention
The compounds of the present invention can be administered in any suitable manner. In some embodiments, the compound is administered orally, intramuscularly, intraperitoneally, subcutaneously, intrapulmonary, mucosal, transdermal, intravascular, intraocular or intravitreal (via the eye), and otherwise. . In other embodiments, the compound is administered site-specificly through temporary or permanent drug delivery means such as an implant, or a combination of systemic and site-specific means. Examples include, but are not limited to, catheters, stents, vascular wraps, pumps, shunts, or other temporary or permanent drug delivery means.

A. In some embodiments, the present invention provides an in-vivo device comprising a vascular prosthesis and a source of at least one compound of the present invention.

  In another embodiment, the present invention provides a device configured to release a compound to a body lumen or organ in the body to inhibit cell proliferation or cell migration. In a further aspect, the device is configured to release a compound to a body lumen or organ in the body to inhibit smooth muscle cell proliferation or angiogenesis.

  In another embodiment of the invention, the drug delivery means is a graft implant, vascular implant, non-vascular implant, implantable luminal prosthesis, wound closure implant, drug delivery implant, suture, biological delivery implant, urinary tract implant Devices such as implants, including intrauterine implants, organ implants, ocular implants, bone implants, eg bone plates, bone screws, dental implants, spinal discs or the like.

  When the device is configured for the treatment of ocular symptoms and diseases, the implants of the invention can be implanted in the eye or in the vitreous by interventional methods. Such implants can be non-biodegradable, biodegradable, removable or permanent. In other embodiments, the implant can be placed adjacent to the eyeball body, in the eye, adjacent to the vitreous, or in the vitreous. One skilled in the art will appreciate that other sites are useful in the present invention.

  Implants usually allow one or more of the following: medical conditions such as hyperproliferative disease, restenosis, cardiovascular disease, inflammation, wound healing, cancer, aneurysm, diabetes, abdominal aortic aneurysm, high calcium For the prevention or treatment of blood pressure, etc., support, contain, put together, affix, plug a body cavity, organ, blood vessel, conduit, muscle, tissue mass or bone, To close, maintain, deliver drugs, deliver biologics.

  The implants of the present invention can be formed of metals, alloys, polymers, ceramics, metalloids, nanocomposites or combinations thereof. For example, the implant is a metal, such as tantalum, iron, magnesium, molybdenum, etc .; a degradable or non-degradable alloy, such as 316L stainless steel, carbon steel, magnesium alloy, NI-Ti, Co-Cr, such as L605, MP35, etc .; Degradable or non-degradable polymers such as polylactic acid, polyglycolic acid, polyesters, polyamides, copolymers, etc., or blends of multiple polymers; metal and metal or alloy combinations such as stainless steel and tantalum layers Implants made from: nanocomposites, such as nanocarbon fibers or carbon nanotubes.

  In another embodiment, the present invention provides a device wherein the implant is a vascular prosthesis. In some embodiments, the vascular prosthesis includes an expandable structure. In other embodiments, the vascular prosthesis includes a stent, an implant, or a scaffold that is at least partially formed from an open lattice. In yet another embodiment, the vascular prosthesis is a stent.

  In another embodiment, the compounds of the invention can be applied adjacent to the surface of the implant. For example, the compounds of the present invention can be incorporated into an implant, included in a coating, or carried on an implant.

  In some embodiments, the invention provides a device comprising a vascular prosthesis, wherein the vascular prosthesis has a luminal surface and a tissue contacting surface, wherein the compound is at least a luminal surface or a tissue contacting surface. Attached to one side.

  In a further embodiment, the compounds of the invention are applied on all implant surfaces. In another embodiment, the compounds of the invention are applied only to the antiluminal or luminal surface. In yet another embodiment, the compounds of the invention are applied only to high stress or low stress regions.

  In another embodiment, the compounds of the invention are contained within corrosive or non-corrosive fibers adjacent to the implant.

  An example of a three-dimensional structure of a stent for carrying a compound of the present invention is shown in a contracted state in FIG. The stent body is formed of a plurality of rings 110. The ring is formed of a crest 120 and struts 130 in a generally expandable wavy three-dimensional structure, such as a zigzag, serrated, sinusoidal, etc. The main bodies are connected by a connecting part or a joint part 140. It is understood that the joints may be of any length or shape, or may not be required if the tops are attached directly to each other. The stent is 0.25-4 mm in diameter, or more preferably 0.7-1.5 mm, and 5-100 mm in length in standard contracted state. In the expanded state, the diameter of the stent is typically at least 2 to 10 times or more than the contracted stent diameter. Thus, a stent with a contracted diameter of 0.7-1.5 mm can expand radially up to 2-10 mm or more.

Drug-eluting stents (Cypher ^™ ) bearing a powerful macrocyclic lactone compound such as rapamycin have a remote internal diameter loss ranging from about 0.01 mm to 0.2 mm in angiographic follow-up from about 4 to 12 months. Produced. The remote inner diameter loss of the bare metal stent during the same period ranged from about 0.70 mm to 1.2 mm. The lower the remote diameter loss, the lower the stenosis rate. However, drug-eluting stents that produce significantly lower remote bore loss compared to bare metal stents can sometimes result in poor coverage of the stent surface with tissue, thereby causing the incidence of late stent thrombosis May increase.

  In a preferred embodiment, the stent having the compound of the present invention has a remote inner diameter loss of about 4 mm to about 12 mm after implantation than the remote inner diameter loss of the stent bearing the corresponding parent macrocyclic lactone. The thickness is 0.6 mm, preferably 0.1 mm to 0.4 mm, more preferably 0.15 to 0.3 mm. For example, the remote inner diameter loss after implantation ranges from 0.01 mm to 0.6 mm, preferably from 0.1 mm to 0.5 mm, and most preferably from 0.2 mm to 0.4 mm. In another embodiment, the invention provides a stent carrying a compound of the invention, wherein the remote bore loss is similar to a stent carrying the corresponding parent macrocyclic lactone. In another preferred embodiment, the present invention provides a stent carrying a compound of the invention, wherein the remote inner diameter loss is higher than a stent carrying the corresponding parent macrocyclic lactone. Higher remote bore loss can increase the coverage of the stent with tissue, thereby improving stent safety.

  In another preferred embodiment, the stenosis rate of a stent carrying a compound of the invention, about 4 to 12 months after implantation, is 1 to 30 percent, preferably less than that of a stent carrying a corresponding parent macrocyclic lactone. Is 3 to 20 percent, more preferably 5 to 15 percent. In yet another preferred embodiment, the present invention provides a stent carrying a compound of the invention, wherein the stenosis rate is similar to a stent carrying a corresponding parent macrocyclic lactone. In another preferred embodiment, the present invention provides a stent carrying a compound of the invention having a higher stenosis rate than a stent carrying a corresponding parent macrocyclic lactone. In another preferred embodiment, the stenosis rate of a stent carrying a compound of the present invention is higher than a stent carrying a corresponding parent macrocyclic lactone, but lower than a bare metal stent. The higher the stenosis, the greater the coverage of the stent by the tissue, which can improve the safety of the stent.

In some embodiments, the present invention provides devices where the amount of the compound of the present invention on the implant is less than about 1 g / cm ² . In other embodiments, the amount of compound on the implant is from about 1 nanogram / cm ² to about 1000 microgram / cm ² , preferably from about 1 microgram / cm ² to about 500 microgram / cm ² , more preferably It can range from about 10 microgram / cm ² to about 400 microgram / cm ² . In yet other embodiments, the amount of compound on the implant is less than about 1 mg. In a further angular embodiment, the amount of the compound on the implant is about 1 μg to about 50 mg, preferably about 100 μg to about 10 mg, more preferably about 200 μg to about 500 μg.

  In a further embodiment, the invention provides that the concentration of the compound of the invention in the tissue adjacent to the implant is from about 0.001 ng to about 1000 μg / g tissue, preferably from about 1 ng to about 500 μg / g tissue, more preferably tissue. A device is provided that is about 100 ng to about 100 μg per gram.

  In another embodiment, the compounds of the invention can be released from the implant for a period ranging from less than 5 minutes to 2 years, preferably from 3 days to 6 months, more preferably from 1 week to 3 months. In another embodiment, the compounds of the invention can be released from the implant for a period of more than 1 day, preferably more than 2 weeks, more preferably more than 1 month. In another embodiment, the compounds of the present invention may require more than 2 years to be fully released from the stent. In some embodiments, the amount of compound released during a given period is at least 25%. In other embodiments, the amount of compound released is at least 50%. In yet other embodiments, the amount of compound released is at least 75%. In still other embodiments, the amount of compound released can be at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99%.

  In a further aspect, the invention provides a device wherein at least 75% of the compound is released during a period of about 1 day to about 2 years. In another embodiment, at least 90% of the compound is released from the device during a period of about 3 days to about 6 months. In yet another embodiment, at least 90% of the compound is released from the device during a period of about 1 week to about 3 months.

  When a compound of the present invention is administered by injection or administered via eyeball or vitreous by eye drops, the concentration of the compound alone, or the concentration of the compound in the polymer matrix, solvent or carrier is between 1 ug / ml and 5 mg. / Ml, preferably 5 ug / ml to 30 ug / ml. Following administration, the concentration of the compound of the present invention in the tissue adjacent to the site of administration may be about 0.1 nM to 500 μM, preferably about 1 nM to 100 μM, more preferably about 10 nM to 10 μM. One skilled in the art will appreciate that other concentrations of the compounds of the invention are useful.

  The compounds of the present invention can be released from the implant through any means known in the art. In some embodiments, the implant releases the compound via active or passive means. In other embodiments, the implant releases the compound via an osmotic pump or diffusion. One skilled in the art will appreciate that other means of releasing the compound from the implant are also useful in the present invention.

  In some embodiments, the present invention provides a device further comprising a therapeutic agent as described below. In some other embodiments, the therapeutic agent is released prior to, simultaneously with, or after the release of the compound. In other embodiments, the compound is released from a first source and the therapeutic agent is released from a second source. In yet other embodiments, the compound and therapeutic agent are released from a single source.

B. Administration The compounds of the invention can be administered systemically based on daily, intermittent, or single doses. The daily systemic dose can range from 0.1 mg to 20 mg, preferably from 0.5 mg to 10 mg, most preferably from 1 mg to 5 mg per day. One skilled in the art will appreciate that other doses are useful in the present invention.

The compounds of the present invention can be from about 1 nanogram / cm ² / day to about 1000 microgram / cm ² / day, preferably from about 1 microgram / cm ² / day to about 200 microgram / cm ² / day, more preferably It can be released from the implant at a rate in the range of about 5 microgram / cm ² / day to about 100 microgram / cm ² / day.

  When the device of the present invention is configured for the treatment of ophthalmic conditions and diseases, the compounds of the present invention may be used as eye drops based on daily, intermittent or one-time doses. Or as an injection. The dose may range from 0.1 [mu] g to 3 mg, preferably 10 [mu] g to 10 mg, most preferably 100 [mu] g to 1 mg per day. One skilled in the art will appreciate that other doses are useful in the present invention.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹、Ｒ¹⁰、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴、Ｍ⁵、Ｍ⁶、Ｍ⁷、Ｌ¹、Ｌ²、Ｌ³およびＬ⁴は上記のとおりである］
で示される化合物ならびにその塩、水和物、異性体、代謝物、Ｎ−オキシドおよびプロドラッグを含む医薬組成物を提供する。 C. Pharmaceutical Formulations In some embodiments, the present invention provides pharmaceutically acceptable excipients and formulas:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ , M ⁷ , L ¹ , L ² , L ³ and L ⁴ are as described above]
And a salt, hydrate, isomer, metabolite, N-oxide and prodrug thereof.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹、Ｒ¹⁰、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴、Ｍ⁵、Ｍ⁶、Ｍ⁷、Ｌ¹、Ｌ²、Ｌ³およびＬ⁴は上記のとおりである］
で示される化合物ならびにその塩、水和物、異性体、代謝物、Ｎ−オキシドおよびプロドラッグを含む医薬組成物を提供する。 In some other embodiments, the present invention provides pharmaceutically acceptable excipients and formulas:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ , M ⁷ , L ¹ , L ² , L ³ and L ⁴ are as described above]
And a salt, hydrate, isomer, metabolite, N-oxide and prodrug thereof.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹、Ｒ¹⁰、Ｍ¹、Ｍ²、Ｍ³、Ｍ⁴、Ｍ⁵、Ｍ⁶、Ｍ⁷、Ｌ¹、Ｌ²、Ｌ³およびＬ⁴は上記のとおりである］
で示される化合物ならびにその塩、水和物、異性体、代謝物、Ｎ−オキシドおよびプロドラッグを含む医薬組成物を提供する。 In yet another embodiment, the present invention provides a pharmaceutically acceptable excipient and formula:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ , M ⁷ , L ¹ , L ² , L ³ and L ⁴ are as described above]
And a salt, hydrate, isomer, metabolite, N-oxide and prodrug thereof.

であり、Ｌ²およびＬ³は、各々、

である。 In another embodiment, the pharmaceutical composition comprises the compound of FIG. In other embodiments, R ¹ , R ⁶ and R ⁸ are each methyl, R ² , R ³ and R ⁵ are each H, and R ⁴ and R ¹⁰ are each OH. , R ⁷ and R ⁹ are each OMe, M ¹ , M ² , M ³ , M ⁴ and M ⁵ are each H, M ⁶ and M ⁷ are each methyl, and L ¹ and L ⁴ are

And L ² and L ³ are each

It is.

  In some embodiments, the invention provides that the pharmaceutically acceptable excipient is a polymer, solvent, antioxidant, binder, filler, disintegrant, lubricant, coating, sweetener, flavor, stabilizer. A pharmaceutical composition that is a member selected from the group consisting of a colorant, a metal, a ceramic and a metalloid. In other embodiments, the pharmaceutically acceptable excipient is a polymer.

  Depending on the mode of administration and the nature of the dosage form, the active ingredients of the present invention can be pharmaceutically acceptable carriers, diluents, adjuvants, excipients or vehicles such as preservatives, fillers, polymers, disintegrants, fluids. It can be mixed with accelerators, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, fragrances, lubricants, acidifying agents, and dispersing agents. Such ingredients, including pharmaceutically acceptable carriers and excipients that can be used to formulate oral formulations, are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986) (part of this specification by reference). To make up. Examples of pharmaceutically acceptable carriers include water, ethanol, polyols, vegetable oils, fats, waxes, polymers (including gel-forming and non-gel forming polymers), and suitable mixtures thereof. Examples of excipients include starch, pregelatinized starch, Avicel, lactose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and lake mixtures. Examples of disintegrants include starch, alginic acid, and certain silicate complexes. Examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycols. One skilled in the art will appreciate that a variety of other excipients can be used in the formulations according to the present invention and that the list provided herein is not exhaustive.

  Suitable non-degradable or slow degrading polymer coatings include polyacrylamide, poly-N-vinylpyrrolidone, polydimethylacrylamide, 2-acrylamido-2-methyl-propane sulfonic acid, including other synthetic or natural polymeric materials , Polymers and copolymers of acrylic and methacrylic acid, polyurethane, polyethyleneimine, ethylene vinyl alcohol copolymer, silicone, C-flex, nylon, polyamide, polyimide, polytetrafluoroethylene (PTFE), parylene, parilast, poly (methyl methacrylate) , Poly (n-butyl methacrylate), poly (butyl methacrylate) copolymer, or poly (ethylene vinyl acetate), poly (methyl methacrylate), poly (2-hydroxyethyl methacrylate), poly (ethylene Tylene glycol methacrylate), poly (vinyl chloride), poly (dimethylsiloxane), poly (ethylene vinyl acetate), polycarbonate, polyacrylamide gel, etc .; including mixtures, copolymers, or combinations thereof, It is not limited to.

  Suitable biodegradable polymer coatings include poly (lactic acid), polylactate, poly (glycolic acid), polyglycolates and copolymers, polydioxanone, poly (ethyl glutamate), poly (hydroxybutyrate), polyhydroxyvalerate and copolymers , Polycaprolactone, polyanhydride, poly (orthoester); poly (ether ester), polyethylene glycol, poly (ethylene oxide), poly (trimethyl carbonate), polyethylene carbonate, poly (ethylene carbonate) and poly (trimethyl carbonate) Copolymer, poly (propylene carbonate), poly (imino carbonate), starch based polymer, cellulose acetate butyrate, polyester amide, polyester amine, polycyanoacrylic acid, polyphosphazene, poly N- Nyl-2-pyrrolidone, polymaleic anhydride, hyaluronic acid (hyaluronate), chondroitin sulfate, dermatan sulfate, carboxymethylcellulose, heparin sulfate, keratan sulfate, carboxymethylhydroxypropylzelulose, carboxymethylhydroxyethylcellulose, cellulose sulfate, Quaternary ammonium compounds including cellulose phosphate, carboxymethyl guar, carboxymethyl hydroxypropyl guar, carboxymethyl hydroxyethyl guar, xanthan gum, carrageenan, anionic polysaccharide, anionic protein and polypeptide, stearyl ammonium chloride and benzyl ammonium chloride, Copolymers, and other aliphatic polyesters, or copolymers of poly (L-lactic acid) and poly (e-caprolactone) Their appropriate copolymer comprising Rimmer; mixtures thereof, copolymers, including but ionic polymers or combinations, but is not limited thereto.

  Suitable natural coatings include: fibrin, albumin, collagen, gelatin, glycosaminoglycans, oligosaccharides and polysaccharides, chondroitin, chondroitin sulfate, hypoxiapatite, phospholipids, phospholipids. Lucolin, glycolipid, fatty acid, protein, cellulose, and mixtures, copolymers, or combinations thereof.

  Suitable non-polymeric coatings include metal coatings such as tungsten, magnesium, cobalt, zinc, iron, bismuth, tantalum, gold, platinum, stainless steel such as 316L, 304, titanium alloys; ceramic coatings such as silicon oxide; Metals such as carbon, nanoporous coatings; or combinations thereof.

  In some embodiments, the pharmaceutically acceptable excipient is polyurethane, polyethyleneimine, ethylene vinyl alcohol copolymer, silicone, C-flex, nylon, polyamide, polyimide, polytetrafluoroethylene (PTFE), parylene, parlast. , Poly (methacrylate), poly (vinyl chloride), poly (dimethylsiloxane), poly (ethylene vinyl acetate), polycarbonate, polyacrylamide gel, poly (methyl methacrylate), poly (n-butyl methacrylate), poly (butyl methacrylate) Copolymer or poly (ethylene vinyl acetate), poly (methyl methacrylate), poly (2-hydroxyethyl methacrylate), poly (ethylene glycol methacrylate), poly (ethylene carbonate), poly L-lactide Glycolide copolymer, poly L lactide - those blended with trimethylene carbonate copolymer and poly L- lactide, it is a polymer selected from the group consisting of. In a further embodiment, the polymer is poly (n-butyl methacrylate).

  In a further embodiment, the invention provides a composition wherein the compound is present at least 10% (w / w) in the mixture of the compound and polymer. In another embodiment, the compound is present at least 20, 25, 30, 40, 50, 55, 60, 70, 75, 80 and 90% (w / w). In other embodiments, the combination is present at least 25% (w / w). In some other embodiments, the compound is present at least 50% (w / w). In still other embodiments, the compound is present at least 75% (w / w). One skilled in the art will appreciate that other compositions are useful in the present invention.

  In another embodiment, the compounds of the invention can be applied onto the stent without a coating. In another embodiment, the compounds of the present invention can be applied onto a stent in combination with a polymer coating, for example, to form a compound-polymer matrix of the present invention. The compounds of the invention may be fully or partially crystallized or in amorphous form. The polymer can be non-degradable, partially degradable or fully degradable. The coating may be a non-polymer, such as a metal coating. In another embodiment, the compounds of the present invention can be applied onto a stent alone or contained in a coating with a polymer or non-polymer topcoat. In another embodiment, the stent includes an underlayer disposed between the stent surface and a compound of the present invention or a compound-polymer matrix of the present invention. Suitable underlayer coatings are polymers such as paraline C, parylene N, ethylene vinyl alcohol (EVOH), polycaprolactone, ethylvinyl hydroxylated acetate (EVA), etc., or combinations thereof, or non-polymers For example, metal or ceramic.

  Coatings include, but are not limited to, spraying, ultrasonic deposition, dipping, inkjet spraying, plasma deposition, ion implantation, sputtering, vacuum deposition, vapor deposition, pyrolysis, electroplating, glow discharge coating, and combinations thereof. It can be applied in any of a variety of ways not intended.

  The thickness of the coating can range from 1 nanometer to 100 micrometers, preferably from 100 nanometers to 50 micrometers, more preferably from 1 micrometer to 20 micrometers.

  The compounds of the present invention can be used in combination with antioxidants or stabilizers to prevent oxidation or degradation by other means. Antioxidants include but are not limited to butylated hydroxytoluene (BHT), ferrous sulfate, ethylenediaminetetraacetic acid (EDTA), and the like. Stabilizers include, but are not limited to amglene, hydroquinone, quinine, sodium metabisulfite and the like. Antioxidants and stabilizers can be used directly with the compound to reduce structural changes or degradation during manufacturing, and increase the shelf life or shelf life of the compound or compound-containing implant, or compound formulations such as compounds It can be mixed with a polymer matrix. The amount of antioxidant, such as BHT, in the compound can range from 0.01% to 10%, preferably from 0.05% to 5% and most preferably from 0.1% to 1%. The amount of stabilizer, such as amylene, in the compound can range from 0.001% to 0.1%, preferably from 0.005% to 0.05%, most preferably from 0.01% to 0.02%. . One skilled in the art will appreciate that other antioxidants and stabilizers are useful in the present invention.

  The compounds of the present invention are administered in combination with therapeutic agents such as antiplatelet agents, antithrombotic agents, anti-inflammatory agents, antiangiogenic agents, antiproliferative agents, immunosuppressive agents, anticancer agents or other agents or combinations thereof. obtain. One skilled in the art will appreciate that other therapeutic agents are also useful in the present invention.

  The therapeutic agent can be incorporated onto the stent with and / or separate from the compound of the present invention. At least a portion of the therapeutic agent can be released from the stent before, simultaneously with, or after the compound of the invention is released from the stent. The therapeutic agent may be given separately through systemic or site-specific administration before, during or after delivery of the compounds of the invention.

  For example, the compounds of the present invention can be given with antiplatelet agents or antithrombotic agents such as heparin, clopidogrel, coumadin, aspirin, chiclid, and the like. In another example, the compounds of the present invention include anti-inflammatory agents such as aspirin, diclofenac, indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen, piroxicam, tenoxicam, tolmethine, ketorolac, oxaprozin, mefenamic acid, phenopro Phen, nabumetone (relaphene), acetaminophen, and mixtures thereof; COX-2 inhibitors such as nimesulide, NS-398, flosside, L-745337, celecoxib, rofecoxib, SC-57666, DuP-697, parecoxib Sodium, JTE-522, valdecoxib, SC-58125, etoroxib, RS-57067, L-748780, L-761066, APHS, etodolac, meloxicam, S 2474, tacrolimus, and mixtures thereof; glucocorticoids such as hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, triamcinolone, parameterzone, fluprednisolone, betamethasone, dexamethasone, fludrocortisone, desoxycorticosterone, etc. Or it can be given together with analogs of the above or combinations thereof.

  In some embodiments, the compounds of the invention are combined with at least one ocular symptom and disease treatment. Suitable therapeutic agents known in the art can be combined with the compounds of the invention for use in the treatment of ocular conditions and diseases. Therapeutic agents that can be combined with the compounds of the present invention include Lucentis, Avastin, McGann, Boloxiximab, Olopatadine, Mydriasis, Dexamethasone, Pilocarpine, Tropicamide, Quinolone, Galentamine, Fluocinolone acetonide, Triamcinolone acetonide, Atropine, Atropine sulfate, atropine hydrochloride, methyl atropine bromide, methyl atropine nitrate, atropine hyperduric, atropine N-oxide, phenylephrine, phenylephrine hydrochloride, hydroxyamphetamine, hydroxyamphetamine hydrobromide, hydroxyamphetamine hydrochloride , Hydroxyamphetamine iodide, cyclopentrate, cyclopentrate hydrochloride, homatropine, homatropine hydrobromide, homatropi Hydrochloride, homatropine methyl bromide, scopolamine, scopolamine hydrobromide, scopolamine hydrochloride, scopolamine methyl bromide, scopolamine methyl nitrate, scopolamine N-oxide, tropicamide, tropicamide hydrobromide, tropicamide hydrochloride, pilocarpine, Examples include, but are not limited to, isopilocarpine, physostigmine, and quaternary ammonium compounds including stearyl ammonium chloride and benzyl ammonium chloride, mixtures thereof, ionic salts and combinations.

  Ophthalmic formulations of the compounds of the present invention can include any of the polymers described above. Polymers useful in such formulations can be of any size. In some embodiments, the polymer can have a molecular weight of about 50 kilodaltons (kD) to 8,000 kD. One skilled in the art will appreciate that other sizes of polymers are useful in the present invention.

  In some embodiments, the compounds of the invention can be administered alone or as part of a compound-polymer formulation, a compound-solvent formulation or a compound-carrier formulation. All formulations of the present invention may contain active and inactive ingredients. Active ingredients include anti-inflammatory agents, immunosuppressants and anti-infective agents, antioxidants, antibodies, antibiotics, anti-angiogenic agents, anti-vascular endothelial growth factor agents, anti-histamine agents and lubricants. It is not limited to. Inactive ingredients include, but are not limited to, carriers, solvents, inorganic substances, pH adjusters, radiopaques, radioactivity, fluorescent agents, NMR contrast agents or other “reporters or indicators”. is not. Examples of solvents in compound-solvent formulations include, but are not limited to water, saline, alcohols and dimethyl sulfoxide. Examples of carriers in compound-carrier formulations include, but are not limited to, glycerin, paraffin, beeswax, ethylene glycol, propylene glycol, polyethylene glycol, and macrogel. Examples of inorganic substances include, but are not limited to, boric acid, calcium chloride, magnesium chloride, potassium chloride, sodium chloride, zinc chloride, sodium borate, povidone, and disodium hydrogen phosphate. . Examples of pH adjusting agents include, but are not limited to, sodium hydroxide, hydrogen chloride, buffers, and other inorganic and organic acids / bases. Examples of preservatives include, but are not limited to, benzalkonium chloride and polyquaternium. Examples of lubricants include, but are not limited to, sodium carboxymethylcellulose, polyethylene glycol, polyethylene glycol, and ethylene glycol. One skilled in the art will appreciate that other active and inactive ingredients and solvents and carriers are also useful in the present invention.

  In some embodiments, the invention provides a composition wherein less than about 5% of the compound is metabolized to rapamycin. In some other embodiments, less than about 1% of the compound is metabolized to rapamycin. In yet other embodiments, less than about 0.1% of the compound is metabolized to rapamycin.

  In another embodiment, this invention provides a dosage form composition having a daily systemic dosage of from about 0.1 mg to about 20 mg of the compound. In some other embodiments, the daily systemic dosage of the compound is from about 0.5 mg to about 10 mg. In another embodiment, the daily systemic dose of the compound is about 1 mg to about 5 mg.

IV. Treatment The compounds of the present invention can be used to treat conditions responsive to a class of compounds commonly known as macrocyclic trienes or macrocyclic lactones.

The compounds of the invention can be used alone or in combination with other agents to treat diseases including, for example, the following symptoms in mammals:
a) Treatment and prevention of transplant rejection of acute or chronic organs or tissues, eg treatment of recipients of heart transplant, lung transplant, cardiopulmonary transplant, liver transplant, kidney transplant, pancreas transplant, skin transplant or corneal transplant. The compounds of the invention can be used for the prevention of graft-versus-host disease (eg after bone marrow transplantation).
b) Treatment and prevention of transplant vascular disorders such as atherosclerosis.
c) Treatment and prevention of cell proliferation and migration leading to intimal thickening, vascular occlusion, occlusive vascular atherosclerosis, restenosis.
d) Etiology including autoimmune diseases and autoimmune components such as inflammatory conditions such as arthritis (eg rheumatoid arthritis, arthritis chronica progrediente and osteoarthritis) and rheumatic diseases Treatment and prevention of inflammatory conditions, having.
e) Treatment and prevention of asthma.
f) Treatment of multidrug resistant conditions such as multidrug resistant cancer or multidrug resistant AIDS.
g) Treatment of proliferative diseases such as tumors, cancer, hyperproliferative skin diseases.
h) Treatment of infections such as fungi, bacteria and viruses.
i) Treatment or prevention of cell proliferation in vascular shunts.
j) Treatment or prevention of ocular symptoms and diseases.
k) Prevention of angiogenesis.

  The efficacy of compound AR and rapamycin (sirolimus) to inhibit human cell proliferation is demonstrated in an in vitro model. The test is shown in Example 2 and the results are shown in FIG. Compound AR inhibited smooth muscle cell proliferation over a concentration range as shown in FIG.

  In some embodiments, the invention inhibits cell proliferation or migration by administering a therapeutically effective amount of a compound of the invention to a subject in need of inhibition of cell proliferation or migration. Provide a method.

  In another embodiment, this invention provides a method wherein a compound of this invention is administered systemically, topically, or a combination thereof.

  In some other embodiments, administration of the compounds of the present invention includes oral administration, administration as a suppository, topical contact, parenteral, intravascular, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, Via pulmonary, mucosal, transdermal, ocular, subcutaneous, or intrathecal administration.

  In yet other embodiments, administration of the compounds of the present invention is via delivery through a temporary device or implant. In another embodiment, the temporary device is selected from the group consisting of a catheter and a porous balloon. In yet another embodiment, the implant is a vascular prosthesis. In yet other embodiments, the vascular prosthesis includes an expandable structure. In another embodiment, the vascular prosthesis includes a stent, an implant, or a scaffold that is at least partially formed from an open lattice.

In one embodiment, the inhibitory concentration (IC ₅₀ ) of a compound of the invention is approximately equal to the IC ₅₀ of the corresponding parent macrocyclic lactone (before modification in FIG. 1). In another embodiment, the IC ₅₀ is higher than the IC ₅₀ of the corresponding parent macrocyclic lactone. In yet another embodiment, the IC ₅₀ is lower than the IC ₅₀ of the corresponding parent macrocyclic lactone. For example, the IC ₅₀ is 1/2 to 1000 times lower than the IC ₅₀ of the corresponding parent macrocyclic lactone.

In a preferred embodiment, the IC ₅₀ of the compounds of the present invention is 1.5 to 1,000 times higher than the corresponding parent macrocyclic lactone, preferably 2 to 100 times higher than the corresponding parent macrocyclic lactone, more preferably Is 5 to 50 times higher than the corresponding parent macrocyclic lactone. In another embodiment, the IC ₅₀ of the compound of the invention is from about 0.1 nM to about 1 μM, preferably from about 1 nM to about 0.5 μM, more preferably from about 5 nM to about 100 nM.

Other means of assessing the effectiveness of the compounds of the invention include measuring effective concentrations (EC ₅₀ ). In one embodiment, EC ₅₀ is approximately equal to the EC ₅₀ for the corresponding parent macrocyclic lactone. In another embodiment, EC ₅₀ is higher than the EC ₅₀ for the corresponding parent macrocyclic lactone. In yet another embodiment, EC ₅₀ is lower than the EC ₅₀ for the corresponding parent macrocyclic lactone.

  In some embodiments, the present invention provides a method wherein the effective dose of the compound is from about 0.1 mg to about 20 mg. In some other embodiments, the effective dose of the compound is from about 0.5 mg to about 10 mg. In yet other embodiments, the effective dose of the compound is from about 1 mg to about 5 mg.

  The compounds, compositions and devices of the present invention are useful for cytokine inhibition. The pro-inflammatory cytokine IL-6 is synthesized in response to a variety of inflammatory stimuli and acts as a key regulatory protein in the inflammatory cascade. IL-6 plays a central role in stimulating the acute phase response after injury, including the release of fibrinogen and C-reactive protein.

  IL-6 also has been shown to stimulate factors that are essential for the development of leukocyte recruitment to the vessel wall and the development of hyperproliferative diseases such as vascular smooth muscle cell proliferation and restenosis. It may also be directly involved in stenosis.

  Matrix metalloproteases (MMP-9) play a key role in cell migration and proliferation, including conditions such as neointimal proliferation and vascular remodeling after stent implantation. MMP release causes an increase in proteoglycan-rich extracellular matrix that increases smooth muscle cell migration following vascular injury.

  Plasma active MMP-9 levels may be a useful independent predictor of bare metal stent ISR. (Elevated Plasma Active Matrix Metalloproteinase-9 Level Is Associated With Coronary Artery In-Stent Restenosis, Arterioscler Thromb Vasc Biol. 2006; 26: e121-e125)

  Monocyte chemotactic protein 1 (MCP-1) is a potent monocyte chemoattractant secreted in vitro by many cells, including vascular smooth muscle and endothelial cells. It has been shown that removal of the MCP-1 gene or blockade of the MCP-1 signal reduces atherogenesis in hypercholesterolemic mice. MCP-1 has been shown to play a role in the pathogenesis of neointimal thickening in monkeys (Importance of Monocyte Chemoattractant Protein-1 Pathway in Neointimal Hyperplasia After Periarterial Injury in Mice and Monkeys, Circ Res. 2002; 90: 1167-1172). MCP-1 is also strongly expressed in small cell subsets in macrophage-rich areas of human and rabbit atherosclerotic lesions (Expression of Monocyte Chemoattractant Protein 1 in Macrophage-Rich Areas of Human and Rabbit Atherosclerotic Lesions, PNAS , Vol 88, 5252-5256). Inhibition of MCP-1 can have a therapeutic impact on the treatment and prevention of inflammatory diseases, proliferative diseases and other conditions discussed above.

  Interleukin-10 (IL-10) is an anti-inflammatory cytokine with a potent inhibitory effect on monocytes. It has been shown that IL-10 reduces intimal thickening after injury (Interleukin-10 Inhibits Intimal Hyperplasia After Angioplasty or Stent Implantation in Hypercholesterolemic Rabbits Circulation. 2000; 101: 908-916). Endogenous production of IL-10 by human monocytes in response to LDL stimulation inhibits the production of IL-12, which indicates a cross-regulatory effect of IL-10 that can balance pro-inflammatory responses. Show.

A. Ocular Symptoms and Diseases In some embodiments, the compounds, pharmaceutical compositions and devices of the present invention are useful for the treatment of ophthalmic conditions and diseases. The compounds, pharmaceutical compositions and devices of the present invention are useful for the treatment of any ocular condition or disease. Ocular symptoms and diseases that can be treated with the compounds and devices of the present invention include eyelid disorders, lacrimal gland and orbital disorders, lacrimal duct blockage, conjunctival disorders, sclera, cornea, iris and chorionic body disorders, Lens impairment, choroidal and retinal impairment, age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, vitreous and ocular disorders, optic nerve and visual tract disorders, eye muscles, binocular movement, perspective accommodation And refractive disorder, visual impairment, and blindness, but are not limited thereto. Additional ocular conditions and diseases that can be treated with the compounds and devices of the present invention include suppression of cell proliferation, prevention of inflammation, prevention of angiogenesis, protection of the neurovasculature, and prevention of immune responses after transplantation. It is done. One skilled in the art will appreciate that other ocular disorders and diseases may be treated using the compounds and devices of the present invention.

  Current treatment methods include surgery and drug therapy. Surgical treatment methods include retinal transplantation, high-speed laser ophthalmic surgery, endothelial transplantation, cataract surgery, glaucoma surgery, refractive surgery, corneal surgery, vitreous retinal surgery, eye muscle surgery, ophthalmoplasty, and eye transplantation The use of stem cells to create a cornea that can be produced or a part thereof.

  Ocular symptoms and diseases can be treated using the compounds, pharmaceutical compositions and devices of the invention as described above. The compounds and pharmaceutical compositions of the invention can be administered by any method known to those of skill in the art. In some embodiments, the compounds of the invention are administered by implant, injection or eye drop. In some other embodiments, administration is in the eye or through the vitreous. In other embodiments, administration is by an implant. In other embodiments, the compound is by an implant that releases the compound through a metal coating, a ceramic coating, or a polymer coating.

  Where administration is via an implant, the compound can be released by any means known in the art. In some embodiments, the release of the compound from the implant can be via osmotic pressure of diffusion. One skilled in the art will appreciate that other means of releasing the compound from the implant are also useful in the present invention.

  In some embodiments, the compounds of the present invention are combined with at least one other therapeutic agent for the treatment of an ocular condition or disease. Any suitable therapeutic agent known to those skilled in the art can be combined with the compounds of the invention for use in the treatment of ocular conditions or diseases. Several. In an embodiment, the therapeutic agent includes an anti-inflammatory agent, an immunosuppressive agent, and an anti-infective agent, an antioxidant, an antibody, an antibiotic, an anti-angiogenic agent, an anti-vascular endothelial growth factor agent, an anti-histamine agent and a lubricant. However, it is not limited to these. Therapeutic agents that can be combined with the compounds of the present invention include Lucentis, Avastin, McGann, Boloxiximab, Olopatadine, Mydriasis, Dexamethasone, Pilocarpine, Tropicamide, Quinolone, Galentamine, Fluocinolone acetonide, Triamcinolone acetonide, Atropine, Atropine sulfate, atropine hydrochloride, methyl atropine bromide, methyl atropine nitrate, atropine hyperduric, atropine N-oxide, phenylephrine, phenylephrine hydrochloride, hydroxyamphetamine, hydroxyamphetamine hydrobromide, hydroxyamphetamine hydrochloride , Hydroxyamphetamine iodide, cyclopentrate, cyclopentrate hydrochloride, homatropine, homatropine hydrobromide, homatropi Hydrochloride, homatropine methyl bromide, scopolamine, scopolamine hydrobromide, scopolamine hydrochloride, scopolamine methyl bromide, scopolamine methyl nitrate, scopolamine N-oxide, tropicamide, tropicamide hydrobromide, tropicamide hydrochloride, pilocarpine, Examples include, but are not limited to, isopilocarpine, physostigmine, and quaternary ammonium compounds including stearyl ammonium chloride and benzyl ammonium chloride, mixtures thereof, ionic salts and combinations.

  It can be appreciated that all embodiments disclosed in the present invention can be utilized alone or in combination with other embodiments or examples of the present invention.

V. Examples Example 1: Preparation of 16-O-demethyl macrocyclic lactone (Compound AR) Macrocyclic lactone rapamycin (1000 mg, 10.75 mmol) in 500 ml of acetonitrile was treated with 500 ml of 0.1N hydrochloric acid. The resulting solution was stirred at room temperature for about 28 hours. The reaction mixture was then extracted with dichloromethane in a separatory funnel. The organic layer is washed with water and brine, then washed twice with 0.1 M sodium phosphate buffer (pH = 7.4) or until pH = 7, then washed three times with distilled (DI) water. did. Finally, the organic layer was dried over Na ₂ SO ₄ and left in the refrigerator overnight. Concentration in vacuo gave an off-white powder of compound AR (about 820 mg).

  Ascentis C18 from SUPECO (21.2 × 250 mm, 10 μm) using methanol: water (80:20) as the mobile phase for 0-12 minutes and 100% methanol for 12.01-20 minutes at a flow rate of 15 ml / min. ) Compound AR was purified by preparative HPLC on a column. The loading concentration was 350 mg / ml and the injection volume was 100 ul. The compound was monitored by UV absorbance at 254 nm. Under these conditions, compound AR eluted between 9.0 and 11.5 minutes, while starting material and by-products eluted between 17.0 and 20.0 minutes.

  Preparative HPLC can be performed using a gradient of acetonitrile: water (starting at 70:30) or can be monitored by UV absorbance at 278 nm. A preparative HPLC chromatogram using this preparative method is shown in FIG.

  Fractions containing Compound AR were collected and pooled together, then the solvent was evaporated by using a rotovac and lyophilizer to give an off-white powder of Compound AR.

¹ H NMR (CDCl, 400 MHz, trans: cisamide rotamer mixture, chemical shifts in parentheses indicate major rotamers) is shown in FIG. δ, ppm 0.532 (q, J = 12Hz, 1H), 0.890 (d, J = 6.8Hz, 3H), 0.921 (d, J = 6.8Hz, 3H), 0.931 (d, J = 6.4Hz, 3H), 0.971 (d, J = 6.8Hz, 3H), 0.991 (d, J = 6.6Hz, 3H), 1.005 (d, J = 6.4Hz, 3H), 1.686 (s, 3H), 1.772 (s, 3H), 1.773 (s, 3H), 1.823 (s, 3H), 3.330 (s, 3H), 3.380 (s, 3H), 3.859 (d, J = 5.2Hz, 1H), 4.001 (d, J = 3.6Hz, 1H ), 4.03 4.07 (m, 1H), 4.22 (br, 1H), 5.21 5.28 (m, 3H), 5.336 (d, J = 11.6Hz, 1H), 5.384 (dd, J = 14.8,9.6Hz, 1H) 6.117 (dd, J = 14.4, 10.8 Hz, 1H), 6.243 (dd, J = 14.4, 10.4 Hz, 1H), 6.376 (dd, J = 14.8, 11.2 Hz, 1H).

  Compared to the proton NMR of the parent compound, the disappearance of the peak at 3.14 ppm indicates demethylation at the C16 position alone and the completion of the reaction. (See Journal of Antibiotics 1991, 44 (6), 688 for assignment of rapamycin NMR spectrum.)

  The chemical structure of Compound AR was also verified by mass spectrometry experiments. The fragmentation pattern showed the presence of 900 m / z, but under the same conditions, rapamycin provides 914 m / z. The results of liquid chromatography and mass spectrometry experiments are shown in FIG. This indicates the identification of compound AR with an m / z of 900.

  The total content of Compound AR was reversed using a Supelco C18 (4.6 × 150 mm, 5 μm) column from Sigma Aldrich with methanol: water (90:10) as the mobile phase at a flow rate of 1 ml / min. Determined by phase HPLC. Compound AR was monitored by UV absorbance at 254 nm. Compound AR had a retention time of 7.97 minutes. FIG. 7 shows an analytical HPLC chromatogram of Compound AR with a total content> 98%. The purity of Compound AR was determined by reverse phase HPLC using a YMC ODS AL C18 (4.6 × 250 mm, 5 μm) column from Waters Corporation using an acetonitrile: water gradient mobile phase at a flow rate of 1.0 ml / min. Were determined. FIG. 7b showed the major isomer of Compound AR with a purity> 98% as monitored by UV absorbance at 278 nm.

  As a means of minimizing the oxidation of Compound AR, 0.1% w / w butyroxy vitoxytoluene (BHT) was added after preparative HPLC.

Example 2: Biological activity of Compound AR The efficacy of Compound AR was determined by an in vitro human smooth muscle cell culture test. After 1, 3 and 8 hours of exposure, various concentrations (0.005, 0.01, 0.05, 0.1, 0.5, and 1 μM) of Compound AR and various concentrations (0.0005, 0 The amount of thymidine incorporated was measured for samples of rapamycin (.001, 0.01, and 0.1 μM). The IC ₅₀ for compound AR and rapamycin after short-term exposure of smooth muscle cells to compound AR and rapamycin for 1 and 3 hours was about 0.05 and 0.01 μM, respectively (see Table 1 and FIG. 8). Indicated). The IC ₅₀ for compound AR and rapamycin after exposure of smooth muscle cells to compound AR and rapamycin for 8 hours was about 0.005 and 0.001 μM, respectively. The IC _{50 of} Compound AR was about 5 times higher than that of rapamycin.

Example 3: Production of patent containing compound AR At room temperature, 15 mg of poly (n-butyl methacrylate) (PBMA) was dissolved in 3 mL of dichloromethane. 10 mg of Compound AR was placed in a vial and dissolved in 2 mL of dichloromethane containing or not containing 0.1% (w / w) BHT. These solutions were combined and further diluted with 10 mL of dichloromethane.

  About 450 ug of drug-containing PBMA solution was applied to the entire surface of an 18 mm metallic stent (available from Elixir Medical Corp., Sunnyvale, Calif.) Using a microprocessor controlled ultrasonic spray device. After coating, the stent was placed in a vacuum chamber. The stent was then placed on the balloon of a 3.0 × 20 mm PTCA delivery device. The catheter was then inserted into the coil and packaged with a Tyvek® pouch. The pouch was sterilized with ethylene oxide. The Tyvek® pouch was further packaged in a foil pouch with an oxygen scavenger, purged with nitrogen, and vacuum packaged.

Example 4: In vivo testing of stents eluting compound AR In a healthy porcine coronary artery model, the efficacy of the compound eluting stent system from Example 3 (manufactured above) and the angiographic results of 28 ± 2 days were compared with rapamycin eluting stents. Evaluated by comparison with the system Cyper ^™ Corning Sent (Cordis Corporation).

  As a result, non-atherosclerotic porcine models have been widely used for stents and angiogenesis studies that provide a wealth of data on vascular reactivity and its correlation with human vascular responses (Schwartz et al, Circulation. 2002; 106: 1867-1873), this model was selected. Animals were raised according to the Guide for the Care and Use of Laboratory Animals established by the National Research Council.

  All animals began pre-treatment with aspirin (325 mg / dose) and clopidogrel (75 mg / dose) at least 3 days prior to intervention and continued throughout the study. After induction of anesthesia, the left or right femoral artery was accessed using standard techniques and an arterial sheath was introduced into the artery and advanced.

  Angiography was performed under fluoroscopic guidance, and 7 Fr. A guide catheter was inserted and advanced to the appropriate position for intracoronary administration of nitroglycerin. A segment of coronary artery with an average lumen diameter ranging from 2.25 to 4.0 mm was selected and a 0.014 ″ guide wire was inserted. Quantitative coronary angiography (QCA) was performed and the reference vessel diameter was recorded.

  An appropriately sized stent was advanced to the deployed position. The balloon was inflated at a constant rate until the pressure was sufficient to achieve a balloon-to-artery ratio of 1.30: 1.0. The pressure was maintained for about 10 seconds. Angiography was performed to record the vessel patency and vessel diameter after treatment.

  Follow-up angiography was performed at the designated endpoint for each animal. Each angiogram was qualitatively evaluated for evidence of stent migration, lumen stenosis, stent adhesion, dissection or aneurysm, and flow characteristics. After completion of follow-up angiography, the animals were euthanized.

  Hearts were removed from each animal and coronary arteries were perfused using 10% buffered formalin at 100-120 mmHg. The heart was immersed in 10% buffered formalin. All myocardial lesions or abnormal findings were reported.

The measured or calculated angiographic parameters included:
• Marginal vessel (proximal and distal) mean lumen diameter (post-stent and final only)
・ Average lumen diameter of target area (all angiograms)
・ Minimum lumen diameter (MLD) of target area (post-stent insertion and final only)
Diameter stenosis [1- (MLD / RVD)] × 100%, where RVD is the calculation result of the reference diameter at the occlusion position (it is a software based repetitive linear to provide interpolation of blood vessels without projected lesions) Measured value obtained by the regression method). (Final angiogram only)
・ Balloon to artery ratio [average lumen diameter before balloon / stent insertion]
・ Stent to artery ratio [average lumen diameter after stent insertion / before stent insertion]
・ Percentage of late loss [final MLD-MLD after stent insertion]

  All animals survived to the specified endpoint. Events such as stent migration, incomplete stent adhesion, persistent dissection or aneurysm evidence were not recorded. Three data points out of range (complete or near complete occlusion) for the Cypher stent were excluded. Compared to the pooled Cypher stent data from this study, where the mean stenosis rate for the Cypher stent was 20.21 ± 11.45 (n = 22) and previous studies using similar protocols, The average stenosis rate for AR stents (drug dose of about 10 micrograms per mm length) was 25.7 ± 17.8 (n = 15) (FIG. 9).

  When implanted in a porcine model for 28 days, the compound AR eluting stent in this example resulted in a higher stenosis rate than the Cypher stent.

Example 5: In vivo pharmacokinetics of Compound AR-eluting stents The pharmacokinetic evaluation of the Compound AR stent system of Example 3 was performed at 6 hours, 3 days, 7 days, and 28 days in a porcine coronary artery model. The intervention procedure used was similar to the in vivo angiography study described in Example 4 until stent implantation.

  An appropriately sized stent was advanced to the deployment site. The balloon was inflated at a constant rate until the pressure was sufficient for a balloon to artery ratio of 1: 1. The pressure was maintained for about 10 seconds. Angiography was performed to record the vessel patency and vessel diameter after treatment. A total of 9 stents (3 per time point) were implanted.

  At the appropriate time, the animals were euthanized and the heart was excised. A stent insertion segment comprising a vessel approximately 10 mm proximal and 10 mm distal to the stent insertion site was excised. The proximal and distal portions were separated and stored in separate vials. The tissue around the stent was carefully removed from the stent and each was placed in a separate vial. All were then frozen at −70 ° C. before analysis using liquid chromatography mass spectrometry (LCMS).

  All animals survived to the specified endpoint. The average tissue concentration and release rate from the stent for Compound AR are shown in FIGS. Compound AR-eluting stents show release of Compound AR from the stent in this example, with more than 40% of the drug being released on day 7.

Example 6: 17,18-29,30- bis - was added epoxide macrocyclic lactone methanol 40ml solution in 5% NaOH-MeOH 0.8mL and 30% H ₂ O ₂ 2ml Preparation rapamycin 1g of (AS) . The reaction mixture was stirred at room temperature for 24 hours. When TLC showed that some rapamycin had not yet reacted, an additional mixture of 0.8 mL 5% NaOH-MeOH and ₂ ml 30% H ₂ O ₂ was added to the reaction solution. Stirring was continued at room temperature until TLC indicated that the reaction was complete. The solution was extracted 3 times with dichloromethane and brine. The organic layers were combined, washed with brine and water, dried over anhydrous MgSO ₄ , filtered MgSO ₄ , and then the solution was evaporated to give the raw product. The raw product was further purified using a TLC plate to obtain 0.40 g of a pale yellow powder (yield 40%). ¹ H NMR (CDCl ₃ ) (approx. 4: 1 mixture of conformers, only major conformer signals are shown) Large change compared to rapamycin: δ (ppm) 1.75 (s, 1H), 1.98 ( s, 1H), 6.71 (ddd, 5H, J1 = 16 Hz, J2 = 8 Hz, J3 = 2.8 Hz). ¹³ C DEPT 135 NMR (CDCl ₃ ) (about 4: 1 mixture of conformers, only major conformer signals are listed): δ (ppm) 152, 140, 133, 128, 127, 126, 84 , 83, 76, 74, 67, 59, 56, 44, 43, 41, 40, 36, 35, 34, 33, 31, 29, 28, 22, 21, 20, 17, 16, 15, 13. Mass spectrum: m / z = 962; m / z = 930 for rapamycin.

Example 7: Biological activity of 17,18-29,30-bis-epoxide macrocyclic lactone (AS) The efficacy of 17,18-29,30-bis-epoxide macrocyclic lactone was tested in vitro in human smooth muscle cell culture. Proved by. 17,18-29,30-bis-epoxide macrocyclic lactones at various concentrations (0.005, 0.01, 0.05, 0.1, 0.5, and 1 μM) and various concentrations (0.0005 , 0.001, 0.01, and 0.1 μM) of the amount of thymidine incorporated into samples of Compound AR was measured after 8 hours exposure. The IC ₅₀ of 17,18-29,30-bis-epoxide macrocyclic lactone and Compound AR after smooth muscle cells have been exposed to 17,18-29,30-bis-epoxide macrocyclic lactone and Compound AR for 8 hours is , About 0.1 and 0.005 μM, respectively (FIG. 13). 17,18-29,30- bis - IC ₅₀ of epoxide macrocyclic lactone was about 20-fold higher than the IC ₅₀ of the compound AR.

Example 8: Preparation of 17,18-19,20-21,22-tris-epoxide macrocyclic lactone (AY) 0.93 g (3.22 mmol) of m-chloroperoxybenzoic acid was added to 0.50 g (0.5371 mmol) of rapamycin. ) In 10 ml of CHCl ₃ at room temperature. The mixture was stirred at room temperature for 24 hours. When TLC showed that some rapamycin had not yet reacted, an additional 0.50 g m-chloroperoxybenzoic acid and 5 mL CHCl ₃ were added. Stirring was continued at room temperature until TLC showed no rapamycin. After completion of the reaction, the solution was diluted with dichloromethane and treated with aqueous sodium sulfite solution until washing gave a negative test result on iodine starch paper. This ensured that all excess peracid was destroyed. The aqueous layer was extracted several times with CH ₂ Cl ₂ . The organic layer was then washed twice with 20 ml of 5% sodium bicarbonate to remove benzoic acid. The combined organic extracts were washed with water, dried over anhydrous MgSO ₄ , filtered and evaporated to give 0.46 g of a crude white solid. This raw product was further purified using TLC plates. MS m / z 978, rapamycin m / z 930.

Example 9: Cytokine inhibition by macrocyclic lactones In cell culture studies, cytokines such as Il-6, MMP-9, MCP-1 and IL-10 were treated by treating the cells with E. coli lipopolysaccharide (LPS). Macrophages were activated to secrete. Inhibition of these cytokines after treatment of activated macrophages with compound AR and rapamycin at a concentration of 10 nM was tested using an ELISA assay. The pro-inflammatory properties and inhibition of cell proliferation and migration-inducing cytokines after exposure to macrocyclic lactones are shown in FIG. 12 (a). Inhibition of anti-inflammatory cytokine IL-10 after exposure to macrocyclic lactone compound AR and sirolimus is shown in FIG. 12 (b).

    Int J Cardiol. MMP-9 levels at 1, 3, 7 days after stent implantation were positively correlated with the distant loss index at 6 months after stent implantation (Elevated matrix metalloproteinase expression after stent implantation is associated with restenosis. Int J Cardiol. 2006; 112 (1): 85 90).

  Compound AR and sirolimus did not show any significant inhibition of IL-6 release. Compared to sirolimus, which increased MMP-9 production and did not affect MCP-1 production, Compound AR significantly reduced the production of both cytokines MMP-9 and MCP-1.

  Compound AR and sirolimus did not show any difference in inhibiting the release of IL-6. On the other hand, sirolimus increased the production of cytokine MMP-9, whereas compound AR decreased the production of MMP-9. Compared to sirolimus, which did not affect MCP-1 production, Compound AR reduced the production of cytokine MCP-1. Both compound AR and sirolimus inhibit the production of anti-inflammatory cytokine IL-10.

  Compounds claimed in the present invention, such as Compound AR, have high levels of anti-inflammatory effects (eg, greater inhibition of the pro-inflammatory cytokine MCP-1), and high levels of anti-cell proliferation and It may provide a better therapeutic response with an anti-cell migration effect (eg, greater inhibition of the proliferation and migration promoting cytokine MMP-9).

Example 10: Testing compound AR-eluting stents in human clinical trials Clinical trials of compound AR-coated stents were conducted on 15 human subjects. The safety of compound AR coated stents was evaluated clinically through assessment of major adverse cardiac events defined as death, myocardial infarction (both Q and non-Q waves) and target lesion revascularization. Efficacy was assessed through 4 month angiography and intravascular ultrasound (IVUS) results. The primary end point of the study was angiographic in-stent remote diameter loss. Secondary endpoints were major adverse cardiac events (MACE) and additional angiography and IVUS assessment. The clinical study was approved by the local ethics committee and all patients signed an ethics committee approved informed consent prior to entering the clinical study.

  All patients began pre-treatment with aspirin and ticlopidine (500 mg / oral) at least one day before or on the day of the index procedure. Aspirin (> 100 mg / day) and clopidogrel (75 mg / day) were continued for at least 6 months. Following the hospital's standard percutaneous norm, the left or right femoral artery was accessed using standard techniques, and an arterial sheath was introduced into the artery and advanced.

  Angiography, which is the procedure of the index, was performed under fluoroscopic guidance, and 6 or 7 Fr. A guide catheter was inserted and advanced to the appropriate position for intracoronary administration of nitroglycerin. A segment of coronary artery with an average lumen diameter ranging from 3.0 mm to 3.5 mm was selected and a 0.014 '' guide wire was inserted. Quantitative coronary angiography (QCA) was performed and the reference vessel diameter was recorded. Prior to stent implantation, the lesion was pre-expanded using standard techniques.

  Following pre-expansion, an appropriately sized stent (3.0 × 18 mm or 3.5 × 18 mm) was advanced to the deployment site. The balloon was inflated at a constant rate until pressure to fully deploy the stent. The pressure was maintained for about 30 seconds. In order to ensure good adherence of the stent to the vessel wall, post-expansion of the stent could be performed as needed. Angiography and intravascular ultrasound imaging (IVUS) were performed and recorded.

  For each patient, follow-up angiography and IVUS were performed at designated endpoints of 4 months. Each angiogram was qualitatively evaluated for evidence of lumen stenosis, stent adhesion and flow characteristics.

The measured or calculated angiographic and IVUS parameters included the following:
• Marginal blood vessels (proximal and distal) mean lumen diameter (after stenting and final)
・ Average lumen diameter of target area (all angiograms)
・ Minimum lumen diameter (MLD) of target area (post-stent insertion and final only)
Diameter stenosis [1- (MLD / RVD)] × 100%, where RVD is the calculation result of the reference diameter at the occlusion position (it is a software based repetitive linear to provide interpolation of blood vessels without projected lesions) Measured value obtained by the regression method). (Final angiogram only)
In-stent distant inner diameter loss [final MLD-MLD after stent insertion]
• Proportion of in-stent neointimal volume assessed by IVUS

  All patients underwent 4 months of clinical and angiographic follow-up. During the follow-up period, no patient experienced any major adverse cardiac events. Angiographic results showed that the primary endpoint of angiographic in-stent remote internal diameter loss was 0.16 ± 0.32 mm. IVUS analysis was performed on 13/15 patients and the results indicated a percentage of in-stent neointimal mass of 3.7 ± 2.7%.

  As a comparison, Cypher stents were tested in a preliminary study and in-stent remote internal diameter at 4 months for a similar clinical safety and sustained release group (currently marketed formulation) with no clinical events. Angiographic results that the loss is 0.09 ± 0.3 mm, and the percentage of in-stent neointimal mass that is 0.3 ± 0.6% by IVUS (Sousa, JE, Circulation 2001; 103; 192-195 )It has been shown.

Example 11: Preparation of 31-hydroxyl macrocyclic lactone, 44-hydroxyl macrocyclic lactone (Compound BG) and 47-hydroxyl macrocyclic lactone (Compound BJ) Macrocyclic lactone rapamycin (1 g, 1.1 mmol) in 100 ml of absolute ethanol Was added to a solution of selenium dioxide (122 mg, 1.10 mmol) in absolute ethanol (50 ml). The mixture was stirred at room temperature until TLC analysis showed the disappearance of rapamycin (about 15 hours). The reaction mixture was concentrated and the residue was partitioned between ether and water and extracted three times with 80 ml of ether. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Preparative HPLC gave the individual pure final products 31-hydroxyl macrocyclic lactone, 44-hydroxyl macrocyclic lactone, 47-hydroxyl macrocyclic lactone.

The characteristic spectral changes compared to the macrocyclic lactone rapamycin are shown as follows:

Example 12: Preparation of 43-hydroxyl macrocyclic lactone (compound BF), 47-hydroxyl macrocyclic lactone (compound BJ) A solution of 1 g (1.1 mmol) of macrocyclic lactone rapamycin was dissolved in 100 ml of acetonitrile. While stirring and purging with nitrogen for 20-30 minutes, 0.3 g (1.1 mmol) of iron sulfide heptahydrate was added to the solution. The mixture was then cooled to −16 ° C. to −18 ° C. using an ice bath. A solution of 1 ml of 30% H ₂ O ₂ in 10 ml of acetonitrile was then slowly added to the above mixture over 30 minutes while stirring and purging with nitrogen. After the hydrogen peroxide addition was complete, stirring and nitrogen purging were continued until TLC analysis showed the disappearance of rapamycin. The solution was extracted 3 times with dichloromethane and brine. The organic layers were combined, washed with brine and water, dried over anhydrous MgSO ₄ , MgSO ₄ was filtered and the solution was evaporated to give the raw product. Preparative HPLC gave pure products 43-hydroxyl macrocyclic lactone, 47-hydroxyl macrocyclic lactone.

The characteristic spectral changes compared to the macrocyclic lactone rapamycin are shown as follows:

  Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. You will understand. In addition, each reference provided herein is incorporated by reference to the same extent as if each reference was individually included by reference.

Claims (97)

Formula for subjects in need of treatment for eye symptoms or disease:

[Where:
R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁸ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ and M ⁷ are each independently H, C ₁₋ A member selected from the group consisting of ₆ alkyl, OH and C _1-6 hydroxyalkyl;
R ⁴ , R ⁷ and R ⁹ are each independently selected from the group consisting of C _1-6 alkoxy and OH;
R ¹⁰ is H, —OH, —OP (O) Me ₂ ,

A member selected from the group consisting of —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ , wherein the subscripts n and m Are each independently 2-8, and the subscript o is 1-6;
L ¹ and L ⁴ are each independently

Wherein each M ⁸ is independently a member selected from the group consisting of C _1-6 alkyl, OH and C _1-6 hydroxyalkyl;
L ² and L ³ are each independently

Selected from the group consisting of:
However, an ^{R 1, R 6, R 8} , M 6 and M ⁷ is Me, is ^{R 3, R 5, M 1} , M 2, M 3, M 4 and M ⁵ are H, R ^4, R ⁷ and R ⁹ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ² is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ and R ⁷ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ⁹ is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ , R ⁷ and R ⁹ are OMe, M ⁸ is OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ¹⁰ is OH, —OP (O) Me ₂ ,

Other than —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ ]
Or ophthalmic symptoms or diseases by treating a ophthalmic condition or disease by administering a therapeutically effective amount of a compound represented by and salts, hydrates, isomers, metabolites, N-oxides and prodrugs thereof A method of treating a disease, wherein the compound is administered to a subject in combination with a pharmaceutically acceptable excipient.   Ocular symptoms or disorders may include eyelid disorders, lacrimal gland and orbital disorders, lacrimal duct blockage, conjunctival disorders, sclera, cornea, iris and chorioles, lens disorders, choroidal and retinal disorders, Consists of age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, vitreous and ocular disorders, optic nerve and visual tract disorders, eye muscles, binocular movement, accommodation and refraction disorders, visual impairment and blindness The method of claim 1, wherein the method is a member selected from the group.   The method according to claim 1, wherein the treatment method is selected from the group consisting of suppression of cell proliferation, prevention of inflammation, prevention of angiogenesis, protection of neurovascular system, and prevention of immune response after transplantation.   2. The method of claim 1, wherein the compound is administered by implant, injection or eye drop.   5. The method according to claim 4, wherein the administration is performed on the eyeball of the eye, inside the eyeball of the eye or inside the vitreous body of the eye.   The method of claim 4, wherein the administration is via an implant.   7. The method of claim 6, wherein the compound is released from the implant by osmotic pressure or diffusion. ^{R 1, R 2, R 3} , R 4, R 5, R 6, R 7, R 8, R 9, M 1, M 2, M 3, M 4, M 5, out of M ⁶ and M ⁷ at least The method of claim 1, wherein one is OH. The method of claim 8, wherein R ⁴ is OH. R ¹ , R ⁶ and R ⁸ are each methyl;
R ² , R ³ and R ⁵ are each H;
R ⁴ and R ¹⁰ are each OH;
R ⁷ and R ⁹ are each OMe;
M ¹ , M ² , M ³ , M ⁴ and M ⁵ are each H;
M ⁶ and M ⁷ are each methyl;
L ¹ and L ⁴ are each

Is;
L ² and L ³ are each

Is
The method of claim 9.   The method of claim 1, wherein the compound is co-administered with at least one therapeutic agent.   The method according to claim 11, wherein the therapeutic agent is a member selected from the group consisting of an antiplatelet agent, an antithrombotic agent, an anti-inflammatory agent, an antiangiogenic agent, an antiproliferative agent, an immunosuppressive agent, and an anticancer agent.   Therapeutic agents are Lucentis, Avastin, McGann, Borociximab, Olopatadine, Mydriatic, Dexamethasone, Pilocarpine, Tropicamide, Quinolone, Galentamine, Fluocinolone acetonide, Triamcinolone acetonide, Atropine, Atropine sulfate, Atropine hydrochloride, Bromide Methyl atropine, methyl atropine nitrate, atropine hyperduric, atropine N-oxide, phenylephrine, phenylephrine hydrochloride, hydroxyamphetamine, hydroxyamphetamine hydrobromide, hydroxyamphetamine hydrochloride, hydroxyamphetamine iodide, cyclopentrate, Cyclopentrate hydrochloride, Homatropine, Homatropine hydrobromide, Homatropine hydrochloride, Methyl homatropine bromide, Scopolamine Scopolamine hydrobromide, scopolamine hydrochloride, methyl scopolamine bromide, methyl scopolamine nitrate, scopolamine N-oxide, tropicamide, tropicamide hydrobromide, tropicamide hydrochloride, pilocarpine, isopilocarpine, physostigmine, and stearyl ammonium chloride and 12. The method of claim 11, wherein the method is a member selected from the group consisting of benzylammonium chloride.   Pharmaceutically acceptable excipients include polymers, solvents, antioxidants, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, stabilizers, colorants, metals, ceramics and metalloids The method of claim 1, wherein the member is a member selected from the group consisting of:   15. The method of claim 14, wherein the pharmaceutically acceptable excipient comprises a polymer.   The polymer is polyurethane, polyethyleneimine, ethylene vinyl alcohol copolymer, silicone, C-flex, nylon, polyamide, polyimide, polytetrafluoroethylene (PTFE), parylene, parilast, poly (methacrylate), poly (vinyl chloride), poly ( Dimethylsiloxane), poly (ethylene vinyl acetate), polycarbonate, polyacrylamide gel, poly (methyl methacrylate), poly (n-butyl methacrylate), poly (butyl methacrylate) copolymer, or poly (ethylene vinyl acetate), poly (methyl methacrylate) ), Poly (2-hydroxyethyl methacrylate), poly (ethylene glycol methacrylate), poly (ethylene carbonate), poly L-lactide-glycolide copolymer, poly-L-lactide-to It is selected from methylene carbonate copolymer and poly L- lactide blended with the group consisting 16. The method of claim 15, wherein.   17. The method of claim 16, wherein the polymer is selected from the group consisting of poly (ethylene carbonate), poly L lactide-glycolide copolymer, and poly (n-butyl methacrylate). Pharmaceutically acceptable excipients and formulas:

[Where:
R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁸ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ and M ⁷ are each independently H, C ₁₋ A member selected from the group consisting of ₆ alkyl, OH and C _1-6 hydroxyalkyl;
R ⁴ , R ⁷ and R ⁹ are each independently selected from the group consisting of C _1-6 alkoxy and OH;
R ¹⁰ is H, —OH, —OP (O) Me ₂ ,

A member selected from the group consisting of —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ , wherein the subscripts n and m Are each independently 2-8, and the subscript o is 1-6;
L ¹ and L ⁴ are each independently

Wherein each M ⁸ is independently a member selected from the group consisting of C _1-6 alkyl, OH and C _1-6 hydroxyalkyl;
L ² and L ³ are each independently

Selected from the group consisting of:
However, an ^{R 1, R 6, R 8} , M 6 and M ⁷ is Me, is ^{R 3, R 5, M 1} , M 2, M 3, M 4 and M ⁵ are H, R ^4, R ⁷ and R ⁹ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ² is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ and R ⁷ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ⁹ is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ , R ⁷ and R ⁹ are OMe, M ⁸ is OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ¹⁰ is OH, —OP (O) Me ₂ ,

Other than —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ ]
And a pharmaceutical composition comprising a salt, hydrate, isomer, metabolite, N-oxide and prodrug thereof.   19. A composition according to claim 18, wherein the compound is the compound of FIG. R ¹ , R ⁶ and R ⁸ are each methyl;
R ² , R ³ and R ⁵ are each H;
R ⁴ and R ¹⁰ are each OH;
R ⁷ and R ⁹ are each OMe;
M ¹ , M ² , M ³ , M ⁴ and M ⁵ are each H;
M ⁶ and M ⁷ are each methyl;
L ¹ and L ⁴ are each

Is;
L ² and L ³ are each

Is
19. A composition according to claim 18.   Pharmaceutically acceptable excipients include polymers, solvents, antioxidants, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, stabilizers, colorants, metals, ceramics and metalloids 19. The composition of claim 18, wherein the composition is a member selected from the group consisting of:   24. The composition of claim 21, wherein the pharmaceutically acceptable excipient is a polymer.   The polymer is polyurethane, polyethyleneimine, ethylene vinyl alcohol copolymer, silicone, C-flex, nylon, polyamide, polyimide, polytetrafluoroethylene (PTFE), parylene, parilast, poly (methacrylate), poly (vinyl chloride), poly ( Dimethylsiloxane), poly (ethylene vinyl acetate), polycarbonate, polyacrylamide gel, poly (methyl methacrylate), poly (n-butyl methacrylate), poly (butyl methacrylate) copolymer, or poly (ethylene vinyl acetate), poly (methyl methacrylate) ), Poly (2-hydroxyethyl methacrylate), poly (ethylene glycol methacrylate), poly (ethylene carbonate), poly L-lactide-glycolide copolymer, poly-L-lactide-to It is selected from methylene carbonate copolymer and poly L- lactide blended with group consisting claim 22 composition.   24. The composition of claim 23, wherein the polymer is selected from the group consisting of poly (ethylene carbonate), poly L-lactide-glycolide copolymer, and poly (n-butyl methacrylate).   24. The composition of claim 23, wherein the compound is present at least 25% (w / w) in the mixture of the compound and polymer.   26. The composition of claim 25, wherein the compound is present at least 50% (w / w).   26. The composition of claim 25, wherein the compound is present at least 75% (w / w).   19. The composition of claim 18, wherein less than about 5% of the compound is metabolized to rapamycin.   19. The composition of claim 18, wherein less than about 1% of the compound is metabolized to rapamycin.   19. The composition of claim 18, wherein less than about 0.1% of the compound is metabolized to rapamycin.   19. The composition of claim 18, in dosage form having a daily systemic dosage of about 0.1 mg to about 20 mg of the compound.   32. The composition of claim 31, wherein the daily systemic dose of the compound is from about 0.5 mg to about 10 mg.   32. The composition of claim 31, wherein the daily systemic dose of the compound is from about 1 mg to about 5 mg. 19. An intracorporeal device comprising: an implant; and at least one source of the compound of claim 18.   35. The device of claim 34, wherein the device is configured to release the compound to a body lumen or organ within the body to inhibit cell proliferation.   36. The device of claim 35, wherein the device is configured to release a compound to a body lumen or organ in the body to inhibit smooth muscle cell proliferation and inflammation.   35. The device of claim 34, wherein the implant is a vascular prosthesis.   38. The device of claim 37, wherein the vascular prosthesis comprises an expandable structure.   38. The apparatus of claim 37, wherein the vascular prosthesis comprises a stent, a graft, or a scaffold that is at least partially formed from an open lattice.   40. The device of claim 39, wherein the vascular prosthesis is a stent.   40. The device of claim 38, wherein the vascular prosthesis has a luminal surface and a tissue contacting surface, wherein the compound is associated with at least one of the luminal surface or the tissue contacting surface. The amount of the compound on the device is about 1 ng / cm ² ~ about 1000 [mu] g / cm ^2, apparatus according to claim 34, wherein. The amount of the compound on the device is about 1 [mu] g / cm ² ~ about 500 [mu] g / cm ^2, apparatus according to claim 42, wherein. The amount of the compound on the device is about 10 [mu] g / cm ² ~ about 400 [mu] g / cm ^2, apparatus according to claim 42, wherein.   35. The device of claim 34, wherein the concentration of the compound in adjacent tissue is from about 0.001 ng to about 1000 [mu] g / g tissue.   46. The device of claim 45, wherein the concentration of the compound in adjacent tissue is from about 1 ng to about 500 [mu] g / g tissue.   46. The device of claim 45, wherein the concentration of the compound in adjacent tissue is from about 100 ng to about 100 [mu] g / g tissue.   35. The device of claim 34, wherein at least 75% of the compound is released from the device between about 1 day and about 2 years.   35. The device of claim 34, wherein at least 90% of the compound is released from the device between about 3 days and about 6 months.   35. The device of claim 34, wherein at least 90% of the compound is released from the device between about 1 week and about 3 months.   35. The device of claim 34, wherein the device further comprises a therapeutic agent.   52. The device of claim 51, wherein the therapeutic agent is a member selected from the group consisting of antiplatelet agents, antithrombotic agents, anti-inflammatory agents, antiangiogenic agents, antiproliferative agents, immunosuppressive agents and anticancer agents.   52. The device of claim 51, wherein the therapeutic agent is released before, simultaneously with, or after the release of the compound.   54. The device of claim 53, wherein the compound is released from a first source and the therapeutic agent is released from a second source.   54. The device of claim 53, wherein the compound and therapeutic agent are released from a single source.   A method of inhibiting cell proliferation by administering to a subject in need of cell proliferation inhibition a therapeutically effective amount of the compound of claim 18.   58. The method of claim 56, wherein the compound of claim 18 is administered systemically, topically, or a combination thereof.   Administration of the compound of claim 18 is oral administration, administration as a suppository, local contact, parenteral administration, intravascular administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration, 57. The method of claim 56, which is by pulmonary administration, mucosal administration, transdermal administration, ocular administration, subcutaneous administration or intrathecal administration.   58. The method of claim 56, wherein administration of the compound of claim 18 is via delivery through a temporary device or implant.   60. The method of claim 59, wherein the temporary device is selected from the group consisting of a catheter and a porous balloon.   60. The method of claim 59, wherein the implant is a vascular prosthesis.   62. The method of claim 61, wherein the vascular prosthesis comprises an expandable structure.   62. The method of claim 61, wherein the vascular prosthesis comprises a stent, a graft, or a scaffold formed at least in part from an open lattice. IC ₅₀ of compound is from about 0.1nM~ about 1 [mu] M, 57. The method of claim 56. IC ₅₀ of compound is from about 1nM~ about 0.5 [mu] M, The method of claim 64, wherein. IC ₅₀ of compound is from about 5nM~ about 100 nM, The method of claim 64, wherein.   57. The method of claim 56, wherein the effective dose of the compound is from about 0.1 mg to about 20 mg.   68. The method of claim 67, wherein the effective dose of the compound is from about 0.5 mg to about 10 mg.   68. The method of claim 67, wherein the effective dose of the compound is from about 1 mg to about 5 mg. formula:

[Where:
R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁸ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ and M ⁷ are each independently H, C ₁₋ A member selected from the group consisting of ₆ alkyl, OH and C _1-6 hydroxyalkyl;
R ⁴ , R ⁷ and R ⁹ are each independently selected from the group consisting of C _1-6 alkoxy and OH;
R ¹⁰ is H, —OH, —OP (O) Me ₂ ,

A member selected from the group consisting of —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ , wherein the subscripts n and m Are each independently 2-8, and the subscript o is 1-6;
L ¹ and L ⁴ are each independently

Wherein each M ⁸ is independently a member selected from the group consisting of C _1-6 alkyl, OH and C _1-6 hydroxyalkyl;
L ² and L ³ are each independently

Selected from the group consisting of:
However, an ^{R 1, R 6, R 8} , M 6 and M ⁷ is Me, is ^{R 3, R 5, M 1} , M 2, M 3, M 4 and M ⁵ are H, R ^4, R ⁷ and R ⁹ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ² is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁷ and R ⁹ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ⁴ is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ and R ⁷ are OMe, R ¹⁰ and M ⁸ are OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ⁹ is other than OH;
Provided that R ¹ , R ⁶ , R ⁸ , M ⁶ and M ⁷ are Me, R ² , R ³ , R ⁵ , M ¹ , M ² , M ³ , M ⁴ and M ⁵ are H; ⁴ , R ⁷ and R ⁹ are OMe, M ⁸ is OH, L ² and L ³ are —CH═CH—, and L ¹ and L ⁴ are

R ¹⁰ is OH, —OP (O) Me ₂ ,

Other than —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ ]
And the salts, hydrates, isomers, metabolites, N-oxides and prodrugs thereof. R ¹⁰ is

71. The compound of claim 70, wherein ^{R 1, R 2, R 3} , R 4, R 5, R 6, R 7, R 8, R 9, M 1, M 2, M 3, M 4, M 5, out of M ⁶ and M ⁷ at least 72. The compound of claim 71, wherein one is OH. R ⁴ is OH, claim 72 A compound according. R ¹⁰ is

71. The compound of claim 70, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ and M ⁷ 75. The compound of claim 74, wherein one is OH. R ⁴ is OH, claim 75 A compound according. R ¹⁰ is -OP (O) Me _2, claim 70 A compound according. ^{R 1, R 2, R 3} , R 4, R 5, R 6, R 7, R 8, R 9, M 1, M 2, M 3, M 4, M 5, out of M ⁶ and M ⁷ at least 78. The compound of claim 77, wherein one is OH. R ⁴ is OH, claim 78 A compound according. R ¹⁰ is

71. The compound of claim 70, wherein ^{R 1, R 2, R 3} , R 4, R 5, R 6, R 7, R 8, R 9, M 1, M 2, M 3, M 4, M 5, out of M ⁶ and M ⁷ at least 81. The compound of claim 80, wherein one is OH. R ⁴ is OH, 81. A compound according. R ¹⁰ is

71. The compound of claim 70, wherein ^{R 1, R 2, R 3} , R 4, R 5, R 6, R 7, R 8, R 9, M 1, M 2, M 3, M 4, M 5, out of M ⁶ and M ⁷ at least 84. The compound of claim 83, wherein one is OH. R ⁴ is OH, 84. A compound according.   71. The compound of claim 70, wherein the compound is the compound of FIG. ^{R 1, R 2, R 3} , R 4, R 5, R 6, R 7, R 8, R 9, M 1, M 2, M 3, M 4, M 5, out of M ⁶ and M ⁷ at least 72. The compound of claim 70, wherein one is OH. R ⁴ is OH, 87. A compound according.   71. A method for producing the compound of claim 70, comprising making the compound of claim 70 by contacting the macrocyclic lactone with an acid to displace the alkoxy group with a nucleophile.   90. The method of claim 89, wherein the macrocyclic lactone is rapamycin.   92. The method of claim 90, wherein the nucleophile is a member selected from the group consisting of -OH, -SH, and an electron rich aromatic group.   71. A method of making a compound of claim 70, comprising making the compound of claim 70 by contacting the macrocyclic lactone with an epoxidizing agent to convert the alkene group to an epoxide.   94. The method of claim 92, wherein the macrocyclic lactone is rapamycin.   94. The method of claim 92, wherein the epoxidizing agent is a member selected from the group consisting of peracids and peroxides.   95. The method of claim 94, wherein the epoxidizing agent is a member selected from the group consisting of metachloroperoxybenzoic acid and hydrogen peroxide. Pharmaceutically acceptable excipients and formulas:

[Where:
R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁸ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ and M ⁷ are each independently H, C ₁₋ A member selected from the group consisting of ₆ alkyl, OH and C _1-6 hydroxyalkyl;
R ⁴ , R ⁷ and R ⁹ are each independently selected from the group consisting of C _1-6 alkoxy and OH;
R ¹⁰ is H, —OH, —OP (O) Me ₂ ,

A member selected from the group consisting of —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ , wherein the subscripts n and m Are each independently 2-8, and the subscript o is 1-6;
L ¹ and L ⁴ are each independently

Wherein each M ⁸ is independently a member selected from the group consisting of C _1-6 alkyl, OH and C _1-6 hydroxyalkyl;
L ² and L ³ are each independently

Selected from the group consisting of]
And a pharmaceutical composition comprising a salt, hydrate, isomer, metabolite and prodrug thereof. Pharmaceutically acceptable excipients and formulas:

[Where:
R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁸ , M ¹ , M ² , M ³ , M ⁴ , M ⁵ , M ⁶ and M ⁷ are each independently H, C ₁₋ A member selected from the group consisting of ₆ alkyl, OH and C _1-6 hydroxyalkyl;
R ⁴ , R ⁷ and R ⁹ are each independently selected from the group consisting of C _1-6 alkoxy and OH;
R ¹⁰ is H, —OH, —OP (O) Me ₂ ,

A member selected from the group consisting of —O— (CH ₂ ) _n —OH and —O— (CH ₂ ) _m —O— (CH ₂ ) _o —CH ₃ , wherein the subscripts n and m Are each independently 2-8, and the subscript o is 1-6;
L ¹ and L ⁴ are each independently

Wherein each M ⁸ is independently a member selected from the group consisting of C _1-6 alkyl, OH and C _1-6 hydroxyalkyl;
L ² and L ³ are each independently

Selected from the group consisting of]
And a pharmaceutical composition comprising a salt, hydrate, isomer, metabolite and prodrug thereof.

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