BRPI0615976A2 - modulators of interleukin-1 and tumor necrosis factor-a; syntheses of such modulators and methods for using such modulators - Google Patents

Abstract

MODULATORS OF INTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-A; SYNTHESIS OF SUCH MODULATORS AND METHODS FOR THE USE OF SUCH MODULATORS Compounds are described having the chemical structure of Formula (II), (lIA) and (IIB) and their prodrug esters and acid addition salts, which are useful as modulators of Interleukin-1 and Tumor Necrosis Factor-a, and thus are useful in the treatment of various diseases, where the R groups are defined according to the attached claims.

Description

"INTERLEUCIN-1 AND TUMO DENECROSIS FACTOR-α MODULATORS; SYNTHESIS OF SUCH MODULATORS AND METHODS FOR USING SUCH MODULATORS"

Cross-reference with related documents

This application claims priority as per USC 35 § 119 (e) for US Provisional Documents No. 60 / 701,932 filed July 21, 2005, No. 60 / 734,590 deposited November 7, 2005, No. 60 / 734,679 filed on November 7, 2005, No. 60 / 749,542 filed December 12, 2005, and No. 60 / 785,223 filed March 22, 2006, each of which is incorporated herein by reference in its entirety.

Field of the Invention

The invention relates to chemical compounds and pharmaceutical compositions, including their novel compounds and pharmaceutical compositions, useful in the treatment of various disease states. The invention also relates to methods for synthesizing natural products and novel structurally related chemical compounds. More particularly, the present invention relates to novel analogues and processes for preparing its compounds and pharmaceutical compositions useful in treating, for example, inflammation, cancer, cachexia, cardiovascular disease, anti-infections, diabetes, otitis media, sinusitis and transplant rejection.

Background of the Invention

Pancreatic adenocarcinoma is the fifth leading cause of cancer deaths in the United States, with a five-year survival rate of less than five percent. Nuclear Factor Kappa B (FNKB) is a dimeric transcription factor that has been implicated in the suppression of apoptosis, angiogenesis, and metastasis.

Acanthoic acid is a pimaradienoisolated diterpene of the Korean medicinal plant, Acanthopanax Koreanum Nakai (Araliaceae). Acanthopanax Korean root and stem barks have been used in traditional medicine as a tonic and sedative as well as in the treatment of rheumatism and diabetes in Korea. Canthopanax Koreanum Nakai (Araliaceae), which is found natively on Cheju Island in the Republic of Korea, has also traditionally been used as a remedy for, for example, neuralgia, paralysis, and lumbago. Several useful components, including acanthoic acid, a compound having the chemical structure Formula (I), have been isolated from the root bark of this tree. In addition, certain analogs of the compound of Formula (I), for example, where the COOH group is replaced by a methanolic group, a methyl acetyl ether, a methyl group, and a methyl ester have also each been isolated from the root bark of AcanthopanaxKoreanum Nakai (Araliaceae). See Kim, Y.H. and Chung, B.S., J. Nat. Pro. 51, 1080-83 (1988). (Appropriate chemical names of these analogs are provided in this reference.) This reference and all other patents and printed publications cited herein are incorporated in their entirety by reference.

<formula> formula see original document page 3 </formula>

The compound of Formula (I), also known as acanthoic acid, has been reported to have certain pharmacological effects, including, for example, analgesic effect and anti-inflammatory activity. The compound of Formula (I) also exhibits very low toxicity; 1,000 mg / kg is the minimum lethal dose (DLM) when given orally or IV to a rat {SeeLee, YS, "Pharmacological Study for (-) - Pimara-9 (11), 15-Diene-19-oic Acid" , the Component of Acanthopanax Koreanum Nakai ", PhD Thesis, Department of Pharmacy, Seoul National University, Korea (1990)). The naturally occurring compound of Formula (I) and / or its analogues may exhibit these known pharmacological effects by inhibiting leukocyte migration and synthesis of prostaglandin E2 (PGE2), and is a suspected promoter of both interleukin-1 (IL-I) production. ) as Tumor Necrosis Factor-α (TNF-a). Additionally, a process for the preparation of acanthoic acid, and use of acanthoic acid for treating immune diseases is described in International Patent Publication WO95 / 34300 (December 21, 1995).

Also, the compound of Formula (IA), aciduronic acid, and the corresponding analog methyl ester of the compound of Formula (IA), as well as the methanolic reducing analogs of Formula (IA) have been isolated from the root bark of Acanthopanax Koreanum Nakai. (Araliaceae) See Kim, Y.H. and Chung, B.S., J. Nat. Pro., 51, 1,080 (1988). (The very name of the cauranoic acid, (-) - caura-16-eno-19-oic acid, and the known cauranoic acid analogs are provided in this reference.)

<formula> formula see original document page 4 </formula>

Tumor Necrosis Factor-α (wFNT-a "or" TNF ") and / or Interleukin-1 (" IL-1 ") are involved in various biochemical pathways, and thus modulators of TNF-a and / or a activity or production of IL-I and other TNF-α or IL-I-regulated molecules, especially novel TNF-α modulators and / or IL-I activity or new compounds that influence IL-I or TNF-α production, Such compounds and decomposed classes would be valuable in maintaining the human immune system by treating diseases such as tuberculous pleurisy, rheumatoid pleurisy, and diseases unconventionally considered to be immune disorders such as cancer, cardiovascular disease, skin redness, infections. viral diseases, diabetes, and transplant rejection.

Although numerous approaches to regulate TNF-α production and interleukins are known, novel approaches, compounds, and pharmaceutical formulations for regulating TNF-α and interleukin production are highly desirable and have long been sought by those skilled in the art.

Summary of the Invention

Also described is the synthetic and semi-synthetic preparation of the compounds of Formulas (I) and (IA) and their structural analogues, including novel analogs, of the compounds of Formulas (I) and (IA), including compounds containing cyclic amides.

The disclosed compounds also include, for example, compounds having the chemical structure of Formula (II) and compounds having the chemical structure of Formula (IIA). With respect to compounds having the chemical structure of Formula (II), the described compounds include:

<formula> formula see original document page 5 </formula>

And their stereoisomers where if any R3-R5, R7, R8, R11-R13 is not hydrogen, R2 or R6 or R9 is not methyl, or if R10 is not CH2, then R1 can be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, primary amide, C1-C12 secondary amides, (C1-C12) (C1-C12) tertiary amides, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls, and C5-C12 aryls; however, if all R3-R5, R7, R8, R11-R13 are hydrogen, R2, R6, and R9 are each methyl, and if R10 is CH2, then R1 is selected from hydrogen, a halogen, C1-3 carboxylic acids. C12, C1-C12 acyl halides, C1-C12 acyl residues, C2-C12 esters, C2-C12 secondary amides, (C1-C12) amidesterium (C1-C12), C2-C12 alcohols, (C1-C12) ethers ( C 1 -C 12) other than methyl acetyl ether, C 2 -C 12 alkyls, C 1 -C 12 substituted alkyls, C 2 -C 12 alkenyls, C 2 -C 12 substituted alkenyls, C 2 -C 12 aryls and the like;

R 2 and R 9 may each be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 acyl, C 1 -C 10 alcohol C 12, C 5 -C 12 aryl and the like; and

R3-R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl C5 -C12 aryl, and the like;

in particularly preferred embodiments, R 11 may be a C 1 -C 6 alkyl, or C 1 -C 6 substituted alkyl, and all other R 1 groups may be hydrogen;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 14 and R 15 may each be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and similar, and preferably both R1 and R2 are not simultaneously methylated.

With respect to compounds having the chemical structure of Formula (IIA), the described compounds include:

<formula> formula see original document page 6 </formula> And its stereoisomers where, if any R3-R5, R7, R8, R11-R13 is not hydrogen, R2 or R6 is not methyl, R10 is not CH2, or it is not true that R10 is CH2OH and R11 is OH, so you can for example be hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, secondary amides C1-C12, (C1-C12) (C1-C12) amidasterases, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C1-C12 alkenyls, substituted alkenyls C2 -C12 and the like, but if all R3-R5, R7, R8, R11-R13 are hydrogen, R2 and R6 are each methyl, and if R10 is CH2 or CH2OH, then R1 can be, for example, hydrogen, a halogen, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C2-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides, C1-C12 alcohols , (C1-C12) ethers (C1-C12), alkyl C 2 -C 12, C 2 -C 12 substituted alkyls, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl and the like;

R2 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 aryl C12 and the like;

R3, R4, R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, alkynyl C 2 -C 12, and C 5 -C 12 aryl. In particularly preferred embodiments, R 11 may be a C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl, and all other R groups may be hydrogen;

R 6 may be, for example hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like; R14 and R15 may be stereo-specific, and may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C1-C6 substituted alkenyl, C1-C6 alcohol, and aryl C5 -C6, and preferably R1 and R2 are not simultaneously methyl.

It is an additional object to provide compounds having the chemical structure of Formula (IIB), and to provide processes for synthetic and semi-synthetic preparation of compounds having the chemical structure of Formula (IIB). With respect to said compounds having the chemical structure of Formula (IIB), for example, the compounds designated herein as TTL1, TTL2, TTL3, TTL4, and their analogs and derivatives, the invention includes:

<formula> formula see original document page 8 </formula>

and their stereoisomers where R1 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, amides tertiary (C1-C12) (C1-C12), C1-C12 alcohols, (C1-C12) ethers (C1-C12), C1-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls, and C5-C12 aryls. Under these conditions, R1 is preferably selected from C00H, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 secondary amides and C1-C12 esters, and is preferably selected from C00H, cyclic secondary amides and Cl-C6 esters.

R 2 and R 9 may each be, for example, hydrogen, halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, C 1 -C 12 alkynyl, C 1 -C 12 acyl, C 1 -C 10 alcohol C12, C5-C12 aryl and the like R3-R5, R7, R8, and R1-R13 can each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, alkenyl substituted C 2 -C 12, C 2 -C 12 alkynyl, C 5 -C 12 aryl and the like. In particularly preferred embodiments, R 11 is a C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl, and all other R groups are hydrogen;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R14 and R15 are stereo-specific and may each be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, C5 -C6 aryl and the like, preferably R1 and R2 are not simultaneously methyl.

It will also be appreciated that various groups R, more particularly R3, R4, R5, R7, R8, and R11-R13, may be chosen such that a cyclic system is formed. For example, R13 and R12 may be ethylene media and may include a covalent C-C coupling between their respective carbonostermines, generating an additional six-membered ring in the compound of Formula (IIB). As a further example, bis-cyclic rings may be formed by choosing appropriate chemical species for the various R groups, particularly R 3, R 4, R 5, R 7, R 8, and R 11 -R 13 of Formula (IIB).

The disclosed compounds include prodrug esters of any of the described compounds, including, for example, the compounds of Formula (II), (IIA), and (IIB), and the acid addition salts of the compounds of Formula (II). ), (IIA), and (IIB), including cyclic amide containing compounds, and pharmaceutical compositions including a therapeutically effective amount described compounds, including prodrug esters thereof and their acid addition salts, optionally together with a pharmaceutically acceptable carrier. Such compositions are useful, for example, as anti-inflammatory analgesics, in the treatment of immune and autoimmune diseases, as anti-cancer or anti-tumor agents, and are useful in the treatment of cardiovascular disease, skin redness, viral infections, diabetes. , means of otitis, sinusitis and / or transplant rejection. Particularly, a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formulas (II), (IIA), or (IIB), or a prodrug ester and acid addition salt of a compound of Formulas (II), (IIA). , or (IIB), may be used as an anti-cancer agent, anti-tumor agent, anti-viral agent, and may be useful in the treatment of cardiovascular disease, skin redness, viral infections, diabetes, otitis media, sinusitis and / or transplant rejection ..

Methods for synthesizing the above described compounds and analogues thereof are also described, comprising the step of performing a Diels-Alder reaction by reacting a diene having two or more rings with a dienophil compound to obtain a resulting compound having three of more rings; and to obtain a desired synthetic compound. The Diels-Alder reaction, along with diene and dienophil selection, provides for the flexibility in synthesizing a variety of compounds, and allows the use of decomposed combinational chemistry libraries for use in biological assays, including clinical experiments.

Some embodiments relate to each other having the following chemical structure: <formula> formula see original document page 11 </formula>

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) (C1 -C12) tertiary amides, (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls, and the like;

R17 may be, for example, C5 -C2 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; C5 -C12 phenyl aryls, and the like;

R 9 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 aryl, C5-aryl C12, and the like;

R3-R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl C5 -C12 aryl, and the like;

R6 may be, for example, hydrogen, a halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C1-C12 alkenyl, C2-C12 substituted alkenyl, similar C2-C12 alkynyl, -R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like, -

R 14 and R 15 may be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and the like; and

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like; and

wherein the compound also includes prodrug esters of the above compounds, and their acid addition salts.

In some aspects, R 16 may be, for example, hydrogen. In other aspects, R 17 may be, for example, cyclohexane. In still other aspects, R3-R5, R7, R8, R11-R15 may each be, for example, hydrogen.

Another form of incorporation includes the compound:

And their prodrug esters and acid addition salts. Still other forms of incorporation relate to

to methods for treating a disease condition. For example, the condition of the disease may be inflammation, tuberculosis pleurisy, rheumatoid pleurisy, cancer, fatigue reduction associated with cancer or its treatment, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media (inner ear infection), sinusitis and viral infection, shock shock, transplantation, graft versus host disease, ischemia / reperfusion damage, Graves' ophthalmopathy, hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, microbial keratitis, peripheral keratitis, uterine ulcer disease, , vitreoretinal proliferative disease, rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laserretinal photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye infections, eye allergic diseases , retinal detachment, neuritis, scleros and multiple, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, chemotherapy-related mucosal damage, and the like. For example, the methods may include contacting a live tissue compound of said animal, wherein the compound has the following chemical structure:

<formula> formula see original document page 13 </formula>

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) (C1 -C12) tertiary amides, (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R17 may be, for example, C5 -C2 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; phenyl and C5 -C12 aryls and the like; and

R 9 may be, for example hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 acyl, C5-C12 aryl and the like;

R3-R5, R7, R8, and R11-R13 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C5-C5 aryl -C12 and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like; and

R 14 and R 15 may each be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and similar;

wherein the compound may include esters of prodrug compounds above and their acid addition salts. In another aspect, the method for treatment may include contacting a compound with the living tissue of said animal, wherein the compound has the following chemical structure.

<formula> formula see original document page 15 </formula>

And their prodrug esters and acid addition salts.

Further, additional embodiments relate to methods for treating an inflammatory condition in an animal. The methods may include contacting a compound with the live tissue of said animal, wherein the compound has the following chemical structure:

<formula> formula see original document page 15 </formula>

Where R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides (C1-C12) ( (C1-C12) tertiary amides, (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R17 may be, for example, C5 -C2 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; phenyl and C5 -C12 aryls and the like; and

R9 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 acyl, C5-C12 aryl and the like;

R3-R5, R7, R8, and R11-R13 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C5-C5 aryl -C12 and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like; and

R14 and R15 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, C5-C6 aryl and the like; The compound may include prodrug esters above compounds, and their acid addition salts.

In one aspect, the inflammatory condition may be, for example, tuberculous pleurisy, rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, rejection of transplantation, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, disease of graftoversus host, ischemia / reperfusion damage, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, peripheral keratitis, ulcerative keratitis, Behcet's disease, uveitis, proliferative ocular vein disease rabies, Vogt-Koyanagi-Harada disease, retinopathy, retinal laser photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, glaucomaneovascular, eye infections, eye allergic diseases, retinal detachment, optic neuritis, multiple sclerosis, systemic sclerosis, hereditary retinal degeneration ia, trachoma, autoimmune diseases, chemotherapy-related mucosal damage, and the like.

In another aspect, the compound may have the following structure:

<formula> formula see original document page 17 </formula>

And their prodrug esters and acid addition salts.

Some forms of incorporation relate to methods for treating cancer in an animal. The methods may include contacting a compound with the living tissue of said animal, wherein the compound has the following chemical structure:

<formula> formula see original document page 18 </formula>

Where R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides (C1-C12) ( (C1-C12) tertiary amides, (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R17 may be, for example, C5 -C12 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; phenyl and C5-C12 aryls and the like, - and

R9 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 acyl, C5-C12 aryl and R3-R5, R7, R8, and R1-R13 can be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 alkynyl C5 -C12 aryl and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like; and

R14 and R15 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, C5-C6 aryl and the like;

wherein the compound may include prodrug esters of the above compounds, and their acid addition salts.

In one aspect, the cancer may be, for example, multiple myeloma, human prostate adenocarcinoma, and the like.

In another aspect, the compound may have the following structure:

<formula> formula see original document page 19 </formula>

Including its prodrug esters and acid-killing salts. Some forms of incorporation are related having the following chemical structure:

<formula> formula see original document page 20 </formula>

On what:

if any R3-R5, R7, R8, R11-R13 is not hydrogen, R6 is not methyl, R10 is not CH2, or if R10 is CH2OH and R11 is OH, R2 may be, for example, hydrogen, a halogen, COOH, acids C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 alkyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) (C1-C12) amides, C1-C12 alcohols, (C1- C12) (C1-C12), C1-C12 alkyls, substituted C1-C12 alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls and the like;

if all R3-R5, R7, R8, R11-R13 are hydrogen, R6 is methyl, and R10 is CH2 or CH2OH, then R2 may be, for example, hydrogen, a halogen, C1-C12 carboxylic acids, C1-4 alkyl halides. C12, C1-C12 acyl residues, C2-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), C2-C12 alcohol, (C1-C12) (C1-C12) ethers, alkyls C 2 -C 12, C 2 -C 12 substituted alkyls, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl and the like;

R3, R4, R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, alkynyl C 2 -C 12, C 5 -C 12 aryl and the like R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkenyl aliphatic;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R17 may be, for example, C5 -C12 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; C5 -C12 phenyl aryls and the like;

wherein the compound may include prodrug esters of the above compounds, and their acid addition salts.

In one aspect, R 16 may be, for example, hydrogen and the like. In another aspect, R 17 may be, for example, cyclohexane and the like. In yet another aspect, R 3 -R 5, R 7, R 8, R 11-R 15 may each be, for example, similar hydrogen.

In another embodiment the compound may have the following structure: <formula> formula see original document page 22 </formula>

And their prodrug esters and acid addition salts.

Some forms of incorporation relate to a method for treating a disease condition. Examples of the condition may be inflammation, tuberculous pleurisy, pleurisy rheumatoid, cancer, fatigue reduction associated with cancer or its treatment, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media (sinus infection), sinusitis, and viral infection. , septic shock, transplantation, graft versus host disease, ischemia / reperfusion damage, Graves' ophthalmopathy, Hasimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, microbial keratitis, peripheral keratitis ulcer, Behcet's disease, uveitis, retinal disease, rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laserretinal photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular eye infections, eye allergic diseases, retinal detachment neuritis, musculoskeletal multiple, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy-related mucosal damage. The methods may include, for example, contacting a compound with the living tissue of said animal, wherein the compound has the following chemical structure:

<formula> formula see original document page 23 </formula>

On what:

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R3-R5, R7, R8, and R1-R13 can each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 alkenyl, C2-C12 alkynyl C5 -C12 aryl and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like; R 14 and R 15 may each be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and similar;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R 17 may be, for example, C 5 -C 12 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; C5 -C12 phenyl aryls and the like;

wherein the compound may include prodrug esters of the above compounds, and their acid addition salts.

In one aspect, the compound may have the following structure:

<formula> formula see original document page 24 </formula>

And their prodrug esters and acid addition salts.

Other embodiments relate to methods for treating an inflammatory condition in an animal. Examples of such methods include contacting a compound with the living tissue of said animal, wherein the compound has the following chemical structure:

<formula> formula see original document page 25 </formula>

On what:

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R3-R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 alkenyl, C2-C12 alkynyl C5 -C12 aryl and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like; R14 and R15 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, substituted C1-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, C5-C6 aryl and the like;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R17 may be, for example, C5 -C12 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; C5 -C12 phenyl aryls and the like;

wherein the compound may include its prodrug esters and acid addition salts.

In some respects, the inflammatory condition may be, for example, tuberculous pleurisy, rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, rejection of transplantation, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, disease. of graftoversus host, ischemia / reperfusion damage, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, peripheral keratitis, ulcerative keratitis, Behcet's disease, uveitis, proliferative ocular vein disease rabies, Vogt-Koyanagi-Harada disease, retinopathy, retinal laser photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, glaucomaneovascular, eye infections, eye allergic diseases, retinal detachment, optic neuritis, multiple sclerosis, sclerosis, retinal degeneration hered trachoma, autoimmune diseases, chemotherapy-related mucosal damage and the like.

In another aspect, the compound may have the following structure: <formula> formula see original document page 27 </formula>

And their prodrug esters and acid addition salts.

Still another form of embodiment relates to methods for treating cancer in an animal. Examples of such methods include contacting a compound with the live tissue of said animal, wherein the compound has the following chemical structure:

<formula> formula see original document page 27 </formula>

On what:

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R3-R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl C5 -C12 aryl and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like; and

R 14 and R 15 may be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and the like;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R17 may be, for example, C5 -C12 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; C5 -C12 phenyl aryls and the like;

wherein the compound may include its prodrug esters and acid addition salts.

In one aspect, the cancer may be, for example, multiple myeloma and human prostate adenocarcinoma.

In another aspect, the compound may have the following structure: Including its prodrug esters and salts of

acid addition.

Some other forms of incorporation relate to compounds having the following chemical structure:

<formula> formula see original document page 19 </formula>

On what:

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R 9 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 aryl, C5-aryl C12 and the like;

R3-R5, R7, R8, and R11-R13 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C5-C5 aryl -C12 and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 14 and R 15 may each be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and similar; and

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R 17 may be, for example, C 5 -C 2 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; C5 -C12 phenyl aryls and the like;

wherein the compound includes prodrug esters of the above compounds and their acid addition salts.

In one aspect, R 16 may be, for example hydrogen and the like. In another aspect, R 17 may be, for example, cyclohexane and the like. In yet another aspect, R 3 -R 5, R 7, R 8, R 11-R 15 may each be for example hydrogen and similar.

Other forms of incorporation are related with the following structure:

And their prodrug esters and acid addition salts.

Some forms of incorporation relate methods to treat a disease condition. For example, the condition may be inflammation, tuberculosis pleurisy, rheumatoid pleurisy, cancer, fatigue reduction associated with cancer or its treatment, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media (inner ear infection), sinusitis, and viral infection, septic shock, transplantation, graft versus host disease, ischemia / reperfusion damage, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, microbial keratitis, peripheral keratitis, Behcet's disease, uveitis vitreoretinal proliferative disease, rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laserretinal photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye infections, retinal detachment, neuritis, sclerosis m ltipla, systemic sclerosis, hereditary degeneraçãoretinal, trachoma, autoimmune diseases, chemotherapy mucosalrelacionado damage and the like.

Examples of such methods may include contacting a compound with the living tissue of said animal, wherein the compound has the following chemical structure:

<formula> formula see original document page 32 </formula>

On what:

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R 17 may be, for example, C 5 -C 12 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; C5 -C12 phenyl aryls and the like;

R 9 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 aryl, C5-aryl C12 and the like;

R3-R5, R7, R8, and R11-R13 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C5-C5 aryl -C12 and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 14 and R 15 may each be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and the like;

wherein the compound includes prodrug esters of the above compounds and their acid addition salts.

In one aspect, the compound may have the following structure: <formula> formula see original document page 34 </formula>

And its prodrug esters and acid addition salts.

Some other forms of incorporation relate to methods for treating an inflammatory condition in an animal. For example, such methods may include contacting a compound to the living tissue of said animal, wherein the compound has the following chemical structure:

<formula> formula see original document page 34 </formula>

On what:

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R 17 may be, for example, C 5 -C 2 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; C5 -C12 phenyl aryls and the like;

R 9 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 aryl, C5-aryl C12 and the like;

R3-R5, R7, R8, and R11-R13 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C5-C5 aryl -C12 and the like;

R 6 may be, for example, hydrogen, iamhalogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 14 and R 15 may each be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and wherein the compound includes prodrug esters of the above compounds and their acid addition salts.

In one aspect, the inflammatory condition may be, for example, tuberculous pleurisy, rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, rejection of transplantation, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, disease of graftoversus host, ischemia / reperfusion damage, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, peripheral keratitis, ulcerative keratitis, Behcet's disease, uveitis, proliferative ocular vein disease rabies, Vogt-Koyanagi-Harada disease, retinopathy, retinal laser photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, glaucomaneovascular, eye infections, eye allergic diseases, retinal detachment, optic neuritis, multiple sclerosis, systemic sclerosis, hereditary retinal degeneration ia, trachoma, autoimmune diseases, chemotherapy-related mucosal damage and the like.

In another aspect, the compound may have the following structure:

<formula> formula see original document page 36 </formula>

And their prodrug esters and acid addition salts. Another form of incorporation relates methods to treating cancer in an animal. Examples of the methods include contacting a compound with the living tissue of said animal, wherein the compound has the following chemical structure:

<formula> formula see original document page 37 </formula>

On what:

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R16 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12 tertiary amides ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls and the like;

R17 may be, for example, C5 -C12 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; C5 -C12 phenyl aryls and the like; R9 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C1-C12 alcohol, C1-C12 acyl, C5-C12 aryl and the like;

R3-R5, R7, R8, and R11-R13 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C5-C5 aryl -C12 and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 14 and R 15 may each be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and similar;

wherein the compound includes prodrug esters of the above compounds and their acid addition salts.

In one aspect, the cancer may be, for example, multiple myeloma, human prostate adenocarcinoma, and the like.

In another aspect, the compound may have the following structure: <formula> formula see original document page 39 </formula>

And their prodrug esters and acid addition salts.

Some forms of incorporation are related compounds that have the following chemical structure:

<formula> formula see original document page 39 </formula>

Rl can be, for example: <formula> formula see original document page 40 </formula>

Z is 0 or S;

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, substituted C 2 -C 12 alkenyls, C 5 -C 12 aryls, and the like;

R 9 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 aryl, C5-aryl C12, and the like;

R3-R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl C5 -C12 aryl, and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 14 and R 15 may be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and the like; and

R16 and R17 may, for example, be independently selected from hydrogen; mono-substituted, polysubstituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acylalkyl -C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and heteroaryl C 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be joined together to form an optionally substituted hetero-C 2 -C 12 hetero-cycloalkyl, optionally substituted C 4 -C 12 hetero-cycloalkenyl, or optionally substituted C 4 -C 12 hetero-cycloalkyl;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero cycloalkenyl, C4 -C12 hetero cycloalkyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkyl, and the like.

The compound also includes prodrug esters of the above compounds, and their acid addition salts.

In some aspects it may be R16, for example hydrogen. In some aspects, R3-R5, R7, R8, R11-R15 may each be, for example hydrogen.

may be optionally substituted with one or more C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

Some forms of incorporation are related compounds that have the following structure:

Any group that is optionally substituted

<formula> formula see original document page 42 </formula>

R1 can be, for example:

<formula> formula see original document page 42 </formula>

Z is 0 OR S; R 16 and R 17 may, for example, be independently selected from hydrogen; mono-substituted, poly-substituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acylalkyl -C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and heteroaryl C 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be joined together to form an optionally substituted hetero-C 2 -C 12 hetero-cycloalkyl, optionally substituted C 4 -C 12 hetero-cycloalkenyl, or optionally substituted C 4 -C 12 heteroaryl;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero cycloalkenyl, C4 -C12 hetero cycloalkyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

And their prodrug esters and acid addition salts.

Any group which is optionally substituted may be optionally substituted by one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

Some forms of incorporation are related compounds that have the structure:

and their prodrug esters and acid addition salts.

Some forms of incorporation are related together having the following chemical structure: <formula> formula see original document page 45 </formula>

where R1 is selected from the group consisting of:

<formula> formula see original document page 45 </formula>

If any R3-R5, R7, R8, R11-R13 is not hydrogen, R6 is not methyl, R10 is not CH2, or if R10 is CH2OH and R11 is 0H, R2 may be, for example, hydrogen, a halogen, C00H, acids C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 alkyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) (C1-C12) amides, C1-C12 alcohols, (C1- C12) (C1-C12), C1-C12 alkyls, substituted C1-C12 alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls and the like;

if all R3-R5, R7, R8, R11-R13 are hydrogen, R6 is methyl, and R10 is CH2 or CH2OH, then R2 may be, for example, hydrogen, a halogen, C1-C12 carboxylic acids, C1-4 alkyl halides. C12, C1-C12 acyl residues, C2-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), C2-C12 alcohol, (C1-C12) (C1-C12) ethers, alkyls C 2 -C 12, C 2 -C 12 substituted alkyls, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl and the like;

R3, R4, R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, alkynyl C 2 -C 12, C 5 -C 12 aryl and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 16 and R 17 may, for example, be independently selected from hydrogen; mono-substituted, polysubstituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acylalkyl -C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and heteroaryl C 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be linked together to form an optionally substituted C 2 -C 12 hetero-cycloalkyl, an optionally substituted C 4 -C 12 hetero-cycloalkenyl, an optionally substituted C 4 -C 12 hetero-cycloalkyl, or a C 4 -C 12 hetero-aryl optionally substituted;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero cycloalkenyl, C4 -C12 hetero cycloalkyl, and the like;

independently of hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

hydrogen and the like. In another aspect, R3-R5, R7, R8, R11-R15 may each be, for example, hydrogen and the like. Any group which is optionally substituted may optionally be substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

R19, R20, and R21 can be selected.

Where the compound may include prodrug esters of the above compounds, and their acid addition salts.

In one aspect, R16 may be, for example,

In another embodiment the compound may have the following structure:

<formula> formula see original document page 47 </formula> Where R1 is selected from the group consisting of:

<formula> formula see original document page 48 </formula>

Z is O or S;

R16 and R17 may, for example, be independently selected from hydrogen; mono-substituted, poly-substituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acylalkyl -C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and heteroaryl C 5 -C 24 alkyl; and monosubstituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be joined together to form an optionally substituted hetero-C 2 -C 12 hetero-cycloalkyl, optionally substituted C 4 -C 12 hetero-cycloalkynyl, or optionally substituted C 4 -C 12 hetero-cycloalkyl;

R18 may be selected from hydrogen; monosubstituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, polysubstituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cyclo-alkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

And their prodrug esters and acid addition salts.

Any group which is optionally substituted may be optionally substituted by one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

In some respects the compound may be, for example:

<formula> formula see original document page 49 </formula>

Some embodiments relate to compounds having the following chemical structure: <formula> formula see original document page 50 </formula>

Where R1 is selected from the group consisting of:

<formula> formula see original document page 50 </formula>

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C2-C12, substituted C2-C12 alkenyls, C5-C12 aryls, and the like, ·

R 9 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 acyl, aryl C5 -C12, and the like;

R3-R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a -halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 alkenyl, C2-alkynyl C 12, C 5 -C 12 aryl, and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 14 and R 15 may be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 substituted alkenyl, C 5 -C 6 aryl and the like; and

R 16 and R 17 may, for example, be independently selected from hydrogen; mono-substituted, polysubstituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acylalkyl -C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and heteroaryl C 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be joined together to form an optionally substituted hetero-C 2 -C 12 hetero-cycloalkyl, optionally substituted C 4 -C 12 hetero-cycloalkenyl, or optionally substituted C 4 -C 12 hetero-cycloalkyl;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero-cycloalkenyl, C4 -C12 hetero-cycloalkynyl, and the like,

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

The compound also includes prodrug esters of the above compounds, and their acid addition salts.

Any group which is optionally substituted may be optionally substituted by one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

Some forms of incorporation are related compounds that have the following structure:

<formula> formula see original document page 52 </formula>

Where Rl can be, for example: <formula> formula see original document page 53 </formula>

Z is 0 or S;

R16 and R17 may, for example, be independently selected from hydrogen; mono-substituted, polysubstituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acylalkyl -C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and heteroaryl C 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be joined together to form an optionally substituted hetero-C 2 -C 12 hetero-cycloalkyl, optionally substituted C 4 -C 12 hetero-cycloalkynyl, or optionally substituted C 4 -C 12 hetero-cycloalkyl;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero cycloalkenyl, C4 -C12 hetero cycloalkyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

And their prodrug esters and acid addition salts.

Any group which is optionally substituted may be optionally substituted by one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

In some respects the compound may be, for example: <formula> formula see original document page 55 </formula> <formula> formula see original document page 56 </formula> <formula> formula see original document page 57 </formula>

And their prodrug esters and acid addition salts.

In some aspects the compound may be, for example, one or more of the following compounds: <formula> formula see original document page 58 </formula>

And their prodrug esters and acid addition salts.

In some respects the compound may be, for example:

<formula> formula see original document page 58 </formula>

And their prodrug esters and acid addition salts.

Still other forms of incorporation relate to methods for treating a disease condition. For example, the condition may be inflammation, tuberculosis pleurisy, rheumatoid pleurisy, cancer, fatigue reduction associated with cancer or its treatment, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media (inner ear infection), sinusitis, and viral infection, septic shock, transplantation, graft versus host disease, ischemia / reperfusion damage, Graves' ophthalmopathy, Hasimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, microbial keratitis, peripheral keratitis, Behcet's disease, uveitis vitreoretinal proliferative disease, rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laserretinal photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye infections, retinal detachment, neuritis, sclerosis m latter, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, chemotherapy-related mucosal damage, and the like. For example, the methods may include contacting a compound as described above and otherwise including, for example, the compounds of formula II-b, HA-b, and HB-b, to the living tissue of said animal.

Further forms of incorporation further relate to methods for treating an inflammatory condition in a animal. Methods may include contacting a compound with the live tissue of said animal. For example, the compound may be any one or more than one of the compounds of formula β-b, IIA-b, and IIB-b.

Some embodiments relate to methods for treating or inhibiting a neoplastic disease in an animal.

The methods may include the step of administering to the animal a therapeutically effective amount of any one or more of the compounds described above or otherwise pharmaceutically acceptable salts and prodrug esters. For example, neoplastic disease can be cancer, including any of the following: breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, Iymphoma, multiple myeloma, pancreatic cancer, bone cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain cancer (including glioma) or central nervous system (CNS). The cancer may be a multiple myeloma, a colorectal carcinoma, a prostate carcinoma, a breast carcinoma, a non-small cell lung carcinoma, other lung carcinomas, an ovarian carcinoma, a melanoma, and the like.

In some ways, cancer can be a drug resistant cancer. For example, drug-resistant cancer may exhibit at least one of the following: Bcl-2 overexpression, elevated levels of P-glycoprotein efflux pumping, increased protein 1 expression associated with MRP1-encoded multidrug resistance, taken reduced drug use, altered drug target or increasing repair of drug-induced DNA damage, altered apoptotic pathway or activation of cytochrome P450 enzymes. Drug-resistant cancer can be, for example, a multiple myeloma, a sarcoma, a lymphoma (including non-Hodgkin), a leukemia, or any other resistant cancer. The cancer may be one that is naturally resistant or resistant to chemotherapy, biology, radiation, or immunotherapy, for example. Cancer may be resistant to rituximab, Gleevac, velcade, Gleveec, Revlimida, Avastina, Tarceva, Erbitux, bortezomiba, thalidomide, and the like. Some additional specific examples of resistant strains include the MES-SA cell line, its resistant multidrug-derived MES -SA / Dx5, HL-60 and HL-60 / MX2.

Some forms of incorporation relate to resting the compounds as described to treat or inhibit neoplastic diseases, for example to inhibit the growth of tumors, cancers, and other neoplastic tissues. The treatment methods described herein may be employed with any patient suspected of having tumoral, cancerous, or other neoplastic, benign or malignant growth ("tumor" or "tumors" as used herein encompasses tumors, solid tumors, cancers, disseminated neoplastic cells, and neoplastic growths. located). Examples of such growths include, but are not limited to, breast cancers; osteosarcomas, angiosarcomas, fibrosarcomas and other sarcomas; Eukemias; sinus tumors; ovarian, uretal, bladder, prostate, and other genitourinary cancer; colon, esophageal and stomach cancer and other gastrointestinal cancers; Lung cancers; myelomas; pancreatic cancers; kidney cancer cancers; endocrine cancers; skin cancers; melanomasangiomas; and cancers of the brain or central nervous system (CNS; glioma). In general, the tumor or growth to be treated can be any primary or secondary tumor or cancer. Certain forms of incorporation relate to methods for treating neoplastic diseases in animals. The method may include, for example, administering an effective amount of a compound to a patient in need. Other forms of incorporation relate to the use decomposed in the manufacture of a pharmaceutical or medicament for the treatment of a neoplastic disease.

The compounds or compositions may be administered or used in combination with treatments such as chemotherapy, radiation, and biological therapies. Some forms of incorporation relate to methods for treating diseases by administering a compound or composition as described herein in combination with chemotherapy, radiation, immunotherapy or biological therapy. In some embodiments the compounds may be administered or used with a chemotherapeutic agent. Examples of such chemotherapeutic agents include alkaloids, alkylating agents, antibiotics, anti-metabolites, enzymes, hormones, platinum compounds, immunotherapeutics (antibodies, T cells, epitopes), BRMs, and the like. Examples include Vincristine, Vinblastine, Vindesine, Paclitaxel (Taxol), Docetaxel, Topisomerase-inhibiting epipodophyllotoxins (Etoposide (VP-16), Teniposide (VM-26)), Camptothecin, Nitrogen Mustards (Cyclophosphamide), Nitrosoureas, lomustine, dacarbazine, hydroxymethyl melamine, thiopeptide emitocycin C, Dactinomycin (Actinomycin D), deantracycline antibiotics (Daunorabicin, Daunomycin, Cerubidine), Doxorubicin (Adriamycin), Idarubicin (Idacaine), Bicycline ), Plicamycin (Mitramycin, Antifolates (Methotrexate (Folex, Mexato)), Purine anti-metabolites (6-mercaptopurine (6-MP, Purinetol) and 6-Thio-guanine (6-TG). cancers in this category are 6-mercaptopurine and 6-thio-guanine, Chloro-deoxyadenosine and Pentostatin, Pentostatin (2'-deoxy-coformycin), pyrimidine antagonists, fluoropyrimidines (5-fluorouracil (Adrucil), 5-fluoro-deoxy -uridine (FdUrd) (Phloxuridine)), Cytosine Arabinoside (Cytosar, ara-C), Fludarabine, L-Asparaginase, Hydroxyurea, Glucocorticoids, Antiestrogens, Tamoxifen, Non-Steroidal Anti-Androgens, Flutamide, Aromatase Inhibitors (Anastrozole (Arimidex)), Cisplatin, 6-Mercaptopurine and Thio-guanine, Methotrexate, Cytoxane, Cytarabine, L-Asparaginase, Steroids, Prednisone and Dexamethasone. Also proteasome inhibitors such as bortezomiba may be used in combination with the compounds of the moment, for example. Examples of biologies may include agents such as sputtering antibodies, integrins such as alpha-V-beta-3 (ανβ3) and / or other cytokine / growth factors that are involved in angiogenesis, VEGF, EGF, FGF and PDGF. In some aspects, the compounds may be conjugated or distributed with an antibody. The combination methods described above may be used to treat a variety of conditions, including cancer and neoplastic diseases, inflammation, and microbial infections.

Some embodiments relate to pharmaceutical compositions which include a compound as described above and otherwise pharmaceutically acceptable salts thereof and prodrug esters. In some aspects the pharmaceutical composition may further include an antimicrobial agent. The compositions may be used in any of the methods described above, and in other ways.

Some embodiments relate to a compound having the following chemical structure:

Wherein the compound includes prodrug esters of the above, and their acid addition salts.

Some other embodiments relate to a method for preparing a synthetic compound that has the following chemical structure: <formula> formula see original document page 63 </formula>

Wherein the compound includes prodrug esters of the above compound and their acid addition salts, comprising the steps of:

Performing a Diels-Alder reaction by reacting a diene having two or more rings with a dienophilic compound to obtain a resulting compound having three or more rings; and

Get the synthetic compound.

Other embodiments relate to a method for purifying a compound having the following chemical structure:

<formula> formula see original document page 63 </formula>

comprising a chromatography process.

Still other embodiments relate to a method for treating an inflammatory condition or a neoplastic condition in an animal, comprising:

contact a compound to the living tissue of said animal, where the compound has the following chemical structure:

<formula> formula see original document page 63 </formula>

In some respects, the disease may be inflammatory, for example, tuberculous pleurisy, pleurisy rheumatoid, cardiovascular disease, skin redness, diabetes, rejection of transplantation, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, disease graft versus host damage, ischemia / reperfusion damage, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, microbial keratitis, peripheral ulcerative keratitis, Behcet's disease, uveitis, vitreous proliferative disease of rabies virus, Vogt-Koyanagi-Harada disease, retinopathy, retinal laser photocoagulation, acute necroseretinal syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye infections, allergic eye disease, retinal detachment, optic neuritis, sclerosis multiple, systemic sclerosis, hereditary retinal degeneration ia, trachoma, autoimmune diseases, or chemotherapy-related mucosal damage.

In other respects, neoplastic disease is cancer.

In some embodiments, the cancer may be, for example, breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer.

Some embodiments relate to a compound having the following chemical structure: wherein the compound includes prodrug esters of the above compound and their acid addition salts.

Other embodiments relate to a method for preparing a synthetic compound having the following chemical structure:

<formula> formula see original document page 65 </formula>

Wherein the compound includes prodrug esters of the above compound, and their acid addition salts, including steps of:

Performing a Diels-Alder reaction by reacting a diene having two or more rings with a dienophile compound yielded a resulting compound having three or more rings; and

Get the synthetic compound.

Other embodiments relate to a method for purifying a compound having the following chemical structure: Some embodiments relate to a method for treating an inflammatory condition or a neoplastic condition in an animal, comprising:

contacting a compound to the living tissue of said animal, wherein the compound has the following chemical structure:

In some respects, the disease may be inflammatory, for example, tuberculous pleurisy, pleurisy rheumatoid, cardiovascular disease, skin redness, diabetes, rejection of transplantation, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, disease graft versus host damage, ischemia / reperfusion damage, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, microbial keratitis, peripheral ulcerative keratitis, Behcet's disease, uveitis, vitreous proliferative disease of rabies virus, Vogt-Koyanagi-Harada disease, retinopathy, retinal laser photocoagulation, acute necroseretinal syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye infections, allergic eye disease, retinal detachment, optic neuritis, sclerosis multiple, systemic sclerosis, hereditary retinal degeneration laugh, trachoma, autoimmune diseases, and mucosal damage associated with chemotherapy.

In some forms of incorporation, the disease is cancer.

In some aspects, cancer may be, for example, breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, Yinforna, myeloma multiple, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer.

Some forms of incorporation relate to the resting of a compound with the following chemical structure:

In the manufacture of a medicament for treating a disease selected from the group consisting of: pleurisiatuberculosa, rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, transplant rejection, deotitis (inner ear infection), sinusitis and viral infection, septic shock, transplantation, graft versus host disease, ischemia / reperfusion damage, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, microbial keratitis, peripheral keratitis, Behcet's disease, rectal-uveitis, rectal proliferative disease rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laserretinal photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye infections, eye allergic diseases, retinal detachment, neuritis, multiple sclerosis, systemic sclerosis, d hereditary retinal generation, trachoma, autoimmune diseases, and mucosal damage related to chemotherapy, breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, colon cancer, rectal cancer, stomach cancer, lung, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer. Other forms of incorporation relate to the resting of a compound with the following chemical structure:

In the manufacture of a medicament for treating a disease selected from the group consisting of: pleurisiatuberculosa, rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, transplant rejection, deotitis (inner ear infection), sinusitis and viral infection, septic shock, transplantation, graft versus host disease, ischemia / reperfusion damage, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, microbial keratitis, peripheral keratitis, Behcet's disease, rectal-uveitis, rectal proliferative disease rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laserretinal photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye infections, eye allergic diseases, retinal detachment, neuritis, multiple sclerosis, systemic sclerosis, d hereditary retinal generation, trachoma, autoimmune diseases, and mucosal damage related to chemotherapy, breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, colon cancer, rectal cancer, stomach cancer, lung, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer. Still other forms of incorporation relate to a single composition. comprising a pharmaceutically acceptable carrier and at least one compound selected from:

Brief Description of the Figures

Certain preferred embodiments are illustrated in the figures. The figures merely illustrate certain preferred embodiments of the invention and / or certain preferred methods of making and / or using the invention. It is not intended that the figures be limited to the scope of the invention described herein and claimed.

Fig. 1 depicts the structure of acanthoic acid and acanthoic methyl ester ester, a stereo-chemical view of acanthoic acid, and a skeletal view of certain compounds of the invention.

Fig. 2 describes the retrosynthetic analysis and strategic binding associations of certain compounds.

Fig. 3 describes selected approaches for constructing the AB ring of certain compounds, including: Wenkert's approach for the synthesis of (±) podocappric acid; Welch's approach to the synthesis of (±) podocappric acid; and DeGrot's approach for the synthesis of (±) podocactic acid.

Fig. 4 describes a schematic synthetic scheme (Scheme 1) of the synthesis of the acanthoic acid ring system AB and certain compounds.

Fig. 5 depicts a synthetic scheme (Scheme 2) whereby the synthesis of acanthoic acid and certain compounds may be completed. 6 describes the three-dimensional, three-dimensional diene model as described in the detailed description.

Fig. 7 depicts a synthetic scheme (Scheme 3) for the development and application of catalyst 49, as described in the detailed description of the preferred embodiment, an asymmetric Diels-Alder reaction.

Fig. 8 describes a synthetic scheme (Scheme 4) for the synthesis of the compound of Formula (I) and certain compounds based on an asymmetric Diels-Alder methodology.

Fig. 9 describes structure activity relationship studies and structure activity focus focus studies of oleanolic acid, its derivatives, and certain compounds.

Fig. 10 describes studies of identified sites for structural change and structure reactivity relationship of Compound 1.

Fig. 11 depicts preferred representative examples of Compound 1 analogues for use in structure activity-related studies and chemical biological studies.

Fig. 12 describes certain representative representative derivatives of Compound 1 for photo-affinity labeling studies.

Fig. 13 describes certain preferred representative examples of dimers and / or conjugates of Compound 1.

Fig. 14 describes a chemical synthesis of certain compounds identified herein as TTL1 and TTL3 in Figure 17.

Fig. 15 describes a chemical synthesis of a preferred compound labeled with C14, identified as TTL 3 in Figure 17.

Fig. 16 describes the complete chemical synthesis of the compound of Formula (I).

Fig. 17 describes a summary of certain compound syntheses, and the physical properties of these compounds. The compounds TTL1, TTL2, TTL3, and TTL4 are defined as described in this figure. 18 describes a summary of the synthesis of Example 1.

Fig. 19 describes the structures of (-) acanthoic acid and (+) pimaric acid.

Fig. 20 describes the retrosynthetic analysis of (-) acanthoic acid of Example 1.

Fig. 21 describes the synthetic scheme (Scheme 5) of preferred compounds of Formula (IIB) as described in Examples 1-6. The regents, conditions, and percentage obtained from each step were as follows: (a) 0.1 equiv. PTSA (CH 2 OH) 2 / benzene, 80 ° C, 4 h, 90%; (b) 2.2 equiv. Li, liquid NH 3, 1.0 equiv. tBuOH, -78 to -30 ° C, 30 min. then isoprene (excess), -78 to 50 ° C; 1.1 equiv. NC-CO 2 Me, Et 2 O, -78 at 0 ° C, 2 h, 55%; (c) 1.1equiv. NaH, HMPA, 25 ° C, 3h; 1.1 equiv. MoMCl, 25 ° C, 2h, 95%; (d) 7.0 equiv. Li, liquid NH 3, -78 to -30 ° C, 20 min; CH 3 I (excess), -78 to -30 ° C, 1 h, 61%; (e) IN HCl, THF, 25 ° C, 15 min, 95%; (f) 1.6 equiv. Li acetylide, Et 2 O, 25 ° C, 1 h, 91%; (g) Lindlar catalyst (20 wt%), H2, dioxane / pyridine 10 / 1.25 °, 10 min 95%, (h) 4.4 equiv. BF3-Et2 O, benzene / THF4 / 1.80 ° C, 5 h, 95%; (i) 13equiv. pure 103, 8 h, 25 ° C, 100%; (j) 1.4 equiv. NaBH 4, THF MeOH: 10/1, 30 min, 25 ° C, 94%; (k) 1.1 equiv. P-Br-C 6 H 4 COCl 1.5 equiv. pyridine, 0.1 equiv. DMAP, CH 2 Cl 2, 25 °, 2 h, 95% for compound 116, 97% for compound 117.

Fig. 22 describes Chem3D representation of ORTEP designs of compounds 116 and 117, showing only selected hydrogen atoms, for clarity.

Fig. 23 describes the synthetic scheme (Scheme 6) of the tricyclic (-) acanthoic acid nucleus of Example 1. The reagents, conditions, and percentage obtained from each step were as follows: (a) 3.0 equiv. PhSH, 0.05 equiv. AIBN, xylenes, 120 ° C, 18 h, 86%, (b) 1.1 equiv., POCl 3, HMPA, 25 ° C, 1 h; 1.1equiv. pyridine, 150 ° C, 18 h 81%; (c) 3.0 equiv. compound 103, 0.2 equiv. SnCl4 (1 M in CH 2 Cl 2), CH 2 Cl 2, -20 to 0 ° C, 20 h, 84%; (d) 1.4 equiv. NaBH 4, EtOH, 25 ° C, 30 min; (e) Raney Ni (excess), THF, 65 ° C, 10 min 91% (more than two steps); (f) 1.3 equiv. periodinane Dess-Martin, CH 2 Cl 2, 25 ° C, 30 min, · (g) 2.7 equiv. P3PhCH3Br, 2.2, equiv. NaHMDS (1.0 in THF), THF, 25 ° C, 18 h, 86% (more than two steps); (h) 3.0 LiBr, DMF, 160 ° C, 3 h, 93%.

Fig. 24 describes two enantiomers of the compounds herein designated TTL, exhibiting the ability to stereoselectively locate the medium designated R6.

Fig. 25 describes a method for synthesizing the (-) enantiomer described in figure 23; The (+) enantiomer described in Figure 23 may be synthesized using (L) -proline instead of (D) -proline.

Fig. 26 describes synthetic steps subsequent to those described in Figure 24.

Fig. 27 describes the use of the described synthetic route to locate the so-called compound compound R9, R10 and R11 of Formula IIB and their stereo-specific stereoisomers in the ring.

Fig. 28 describes the synthesis, isolation and purification of the compound of Formula IEB and its stereoisomers, showing how to purify compounds in which to locate the designated media R9, R10 and R11 in the compounds of Formula IIB and their stereoisomers in a specific manner in ring.

Fig. 29 also describes the synthesis, isolation and purification of the compound of Formula IEB and its stereoisomers, showing how to purify compounds in which to locate the designated media R9, R10 and R11 in the compounds of Formula IIB and their stereoisomers in a stereo-specific manner. in the ring.

Fig. 30 describes a strategy (Strategy 1) for the synthesis of TTL3 analogs, CC-3-02, CC-3-09, TTL-I, LT-1-73, LT-1-78, LT-1-85, and LT-1-74.

Fig. 31 describes a strategy (Strategy 2) for the synthesis of TTL3 analogs, CC-3-02, LT-1-46, CC-3-19, CC-3-17, and CC-3-18.

Fig. 32 describes a strategy (Strategy 3) for the synthesis of TTL3 analogs, CC-3-02, CC-3-09, CC-3-14. CC-3-13, CC-3-13P, CC-3-15, and CC-3-14x.

Fig. 33 depicts a schematic synthetic scheme (Scheme 1) of the synthesis of TTL3 analogs and certain compounds. 34 describes a schematic synthetic scheme (Scheme 2) of the synthesis of TTL3 analogs and certain compounds.

Fig. 35 depicts a schematic synthetic scheme (Scheme 3) of the synthesis of TTL3 analogs and certain compounds.

Fig. 36 describes a schematic synthetic scheme (Scheme 4) of the synthesis of TTL3 analogs and certain compounds.

Fig. 37 describes a schematic synthetic scheme (Scheme 5) of the synthesis of TTL3 analogs and certain compounds.

Fig. 38 describes the decrease caused by Formula (HB-al) in the level of LPS-induced IKBa phosphorylation in Human Peripheral Blood Mononuclear Cells.

Fig. 39 describes the decrease caused by Formula (IIB-al) in the level of LPS-induced ΙκΒα phosphorylation in RPMI8226 cells.

Fig. 40 shows that Formula (IIB-Al) specifically inhibits LPS-induced phosphorylation of IKBa and p38 kinaseMAP in RPMI8226 cells.

Fig. 41 shows that Formula (IIB-Al) inhibits IKBa phosphorylation induced by "surprising" (Toll) receptor ligands in RPMI8226 cells.

Fig. 42 shows that Formula (IIB-Al) reduces LPS-induced IL-8 and IL-10 production in a dose-dependent manner in RPMI8226 cells.

Fig. 43 describes the effect of TTL3 and their analogs on NOS-2, COX-2 and NO on LPS / IFNγ-stimulated RAW264.7 cells.

Fig. 44 describes the effect of TTL3, TTL1, LT-I-45, LT-1-85 and Formula (IIB-Al) on the NIQ / FN-kB pathway.

Fig. 45 describes the effect of TTL3 and Formula (IIB-Al) on CIN activity. Compounds 1 and 5 represent TTL 3e and Formula (IIB-Al).

The fi-g. 46 shows that TTL3 and Formula (IIB-Al) inhibit TPA-induced ear edema. Fig. 47 shows that TTL3 and Formula (IIB-Al) delay D-GalN / LPS lethality.

Fig. 48 describes the 1 H NMR spectrum in CDCl 3 of Formula (IIB-Al).

Fig. 49 describes the 13 C NMR spectrum in CDCl 3 of Formula (IIB-Al).

Fig. 50 describes the COSY spectrum of Formula (IIB-Al).

Fig. 51 describes the 1H-13C HSQC spectrum of Formula (IIB-Al).

Fig. 52 describes the 1H-13C HMBC spectrum of Formula (IIB-Al).

Fig. 53 describes the EMAR spectrum of Formula (IIB-Al).

Fig. 54 describes the 1H-NMR spectrum of NPI-1390 (in CDCl3).

Fig. 55 describes the 13 C-NMR spectrum of NPI-1390 (in CDCl 3).

Fig. 56 describes the 1 H-NMR spectrum of NPI-1391 (in CDCl 3).

Fig. 57 describes the 1H-NMR spectrum of NPI-1308 (in CDCl3).

Fig. 58 describes the 13 C-NMR spectrum of NPI-1308 (in CDCl 3).

Fig. 59 describes the 1H-NMR spectrum of NPI-1387 (in CDCl3).

Fig. 60 describes the 13 C-NMR spectrum of NPI-1387 (in CDCl 3).

Fig. 61 describes the 1H-NMR spectrum of NPI-1388 (in CDCl3).

Fig. 62 shows the percentage of viable P + and normal cells as a function of compound concentration.

Fig. 63 shows the percentage of cell death as a function of NPI-1387 concentration.

Fig. 64 shows the percentage of cell death as a function of NPI-1387 concentration as well as PS-341 concentration. FIG. 65 shows the cell viability percentage for a variety of cell types as a function of compound concentration.

Fig. 66 shows an immunofluorescence dye describing the effect of NPI-1387 on nuclear translocation of FN-kB p65 subunit in LPS-stimulated RAW264.7 cells.

Fig. 67 shows the percentage of viable MM.IS overexpressing Bcl-2 cells and bortezomib-resistant DHL-4 lymphoma cells as a function of NPI-1387 concentration.

Fig. 68 shows the percentage of viable PMBNCs as a function of NPI-1387 concentration.

Fig. 69 shows the apoptotic signaling level in MM cells in the presence and absence of NPI-1387 and the apoptotic signaling level in MM cells as a function of NPI-1387 concentration.

Fig. 70 shows an isobologram analysis of MM.IS cell death percentage as a function of NPI-1387 and PS-341 concentration.

Fig. 71 shows an isobologram analysis of MM.IS cell death percentage as a function of NPI-1387 concentration.

Fig. 72 shows inhibition of TNF-α synthesis in LPS-stimulated RAW264.7 cells as a function of NPI-1387 concentration.

Fig. 73 shows the effect of varying concentrations of NPI-1387 on IRAK1 phosphorylation and IKKa dekinase activity with LPS stimulation in RAW264.7 cells.

Fig. 74 shows the effect of varying concentrations of NPI-1387 on FN-kB DNA binding activity in cancer cells.

Fig. 75 shows the time-dependent and dose-dependent effect of NPI-1387 on PC-3 colony formation.

Detailed Description of Preferred Embodiments Certain compounds described have the chemical structure shown in Formula (II).

<formula> formula see original document page 76 </formula>

The R groups of the compound of Formula (II) may be selected as follows. In the event that (1) any R3-R5, R7, R8, R11-R13 is not hydrogen, (2) R2, R6 or R9 is not methyl, or (3) R10 is not CH2, R1 is selected from the group consisting of hydrogen , a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, primary amide, C1-C12 secondary amides, (C1-C12) (C1-C12) tertiary amides, C1-C12 alcohols, (C1-C12MC1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls, and C5-C12 aryls. Under these conditions, R1 is preferably selected from COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, and C1-C12 esters, and more preferably C1-C12, C00H secondary esters and C1-C12 esters are selected. C6.

However, in the event that (1) all R3-R5, R7, R8, R11-R13 are hydrogen, (2) R2, R6, and R9 are each methyl, and (3) R10 is CH2, R11 is selected from hydrogen, a halogen, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 deacyl residues, C2-C12 esters, primary amide, C2-C12 secondary amides, (C1-C12) tertiary amides (C1-C12 ), C2-C12 alcohols, (C1-C12) (C1-C12) ethers other than methyl acetyl ether, C2-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls, and aryls C2 -C12. Under these conditions, R1 is preferably selected from C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, and C2-C12 esters, and is more preferably a C4-C8.R2 ester and R9 are each one, separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C1-C12 alkynyl, C1-C12 acyl, C1-C12 alcohol, and C5-C12 aryl.

Preferably, R2 and R9 are each separately selected from alkyl and alkenyl residues. Preferably R 2 and R 9 are each methyl residues, although one of R 2 or R 9 may be methyl and the other non-methyl in preferred embodiments of the compound of Formula (II).

R3, R4, R5, R7, R8, and R11-R13 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-alkynyl Preferably R3, R4, R5, R5, R7, R8, and R11-R13 are each hydrogen or a C1-C6 alkyl, and preferably R3, R4, R5, R7, R8, and R11-R13 are each hydrogen. However, any or more of R3, R4, R5, R7, R8, and R11-R13 may be hydrogen, while the others may not be hydrogen, in preferred embodiments of the compound of Formula (II).

R6 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, and C2-C12 alkynyl. Preferably R6 is selected from hydrogen, a halogen, C1-C6 alkyl. More preferably R6 is a C1-C6 alkyl, and preferably R6 is methyl.

R10 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, and C5-C12 aryl. Alloy linking R10 to the rest of the compound of Formula (II) is preferably a C-C double bond, but may be a simple C-C bond, a C-H single bond, or a straight hetero-atomic bond. Preferably R10 is CH2 or CH2 R 'where R1 is a C1-C6 alkyl, or a substituted C1-C6 alkyl. Preferably, R10 is CH2.

R14 and R10 are selected separately from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, and C5-C6 aryl with hydrogen, C1-alkyl -C 6, C 1 -C 6 substituted alkyl being more preferred, and preferably R 1 and R 2 are not simultaneously methyl.

It will also be appreciated that various groups R, more particularly R3, R4, R5, R7, R8, and R11-R13 may be chosen such that a cyclic system is formed. For example, R13 and R12 may be ethylene media and may include a covalent C-C coupling between their respective carbonostermines, generating an additional six-membered ring in the compound of Formula (II). As a further example, bis-cyclic rings may be formed by choosing appropriate chemical species for the various R groups, particularly R 3, R 4, R 5, R 7, R 8, and R 11 -R 13 of Formula (II).

Some forms of incorporation are related compounds that have the following chemical structure:

<formula> formula see original document page 78 </formula>

Where R1 is selected from the group consisting of: <formula> formula see original document page 79 </formula>

Where Z is O or S;

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C2-C12, substituted C2-C12 alkenyls, C5-C12 aryls and the like, -

R 9 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 aryl, C5-aryl C12 and the like;

R 9 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 aryl, C5-aryl C12 and the like;

R3-R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl C5 -C12 aryl and the like;

R6 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, similar C2-C12 alkynyl

R10 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, and similar C5-C12 aryl; and

R 14 and R 15 may each be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 - aryl C6 and the like;

R 16 and R 17 may, for example, be independently selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, acyl-C2-alkyl C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and C 5 -C 24 heteroaryl alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may be optionally substituted together to form an optionally substituted C 2 -C 12 hetero-cycloalkyl, an optionally substituted C 4 -C 12 hetero-cycloalkenyl, an optionally substituted C 4 -C 12 hetero-cycloalkyl, or a C 4 -C 12 heteroaryl aryl optionally substituted;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero cycloalkenyl, C4 -C12 hetero cycloalkyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

Where the compound includes prodrug esters of the above compounds, and acid addition salts.

Any group which is optionally substituted may be optionally substituted by one or more of one C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

Some forms of incorporation are related with the following structure:

<formula> formula see original document page 81 </formula>

Where Rl can be, for example: <formula> formula see original document page 82 </formula>

R 16 and R 17 may, for example, be independently selected from hydrogen; mono-substituted, poly-substituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, acyl-C2-alkyl C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and C 5 -C 24 heteroaryl alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may be optionally substituted together to form an optionally substituted C 2 -C 12 hetero-cycloalkyl, an optionally substituted C 4 -C 12 hetero-cycloalkenyl, an optionally substituted C 4 -C 12 hetero-cycloalkyl, or a C 4 -C 12 heteroaryl aryl optionally substituted;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero cycloalkenyl, C4 -C12 hetero cycloalkyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl;

the mine; uncle; nitro; cyan; straight or branched chain, mono-substituted, poly-substituted or unsubstituted variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

And their prodrug esters and acid addition salts.

Any group which is optionally substituted may optionally be substituted with one or more of one C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano .

Certain compounds described have the structure shown in Formula (IIA).

<formula> formula see original document page 83 </formula>

The R groups of the compound of Formula (IIA) may be selected as follows. In the event that if any R3-R5, R7, R8, R11-R13 is not hydrogen, R2 or R6 is not methyl, R10 is not CH2, or if it is not true that R10 is CH2OH and R11 is OH, R1 is selected from the group. consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, primary amide, C1-C12 secondary amides, tertiary (C1-C12) amides (C1-C12), C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C1-C12 substituted alkenyls. Under these conditions, R1 is preferably selected from COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, and C1-C12 esters, and is preferably selected from COOH and C1-C6 esters.

In the event that all R3-R5, R7, R8, R1-R13 are hydrogen, R2 and R6 are each methyl, and R10 is CH2 or CH2OH, R1 is selected from hydrogen, a halogen, Cl-C12 carboxylic acids, halides C1-C12 acyl residues, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), C2-C12 alcohol, (C1-C12) (C1-C12 ) ethers, C 2 -C 12 alkyls, substituted C 2 -C 12 alkyls, C 2 -C 12 alkenyl, and C 2 -C 12 substituted alkenyl. Under these conditions, R1 is preferably selected from C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, and C2-C12 esters, and preferably C4-C8 ester.

R2 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 acyl, C1-C12 alcohol, and C5-aryl C12. Preferably, R2 and R9 are each separately selected from alkyl and alkenyl residues. Preferably R2 and R9 are each methyl residues, although one of R2 and R9 may be methyl and the other non-methyl, in embodiments. Preferred compounds of the compound of Formula (IIA).

R3, R4, R5, R7, R8, and R11-R13 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-alkynyl Preferably R3, R4, R5, R5, R7, R8, and R11-R13 are each hydrogen or a C1-C6 alkyl, and more preferably R3, R4, R5, R7, R8, and R11-R13 are each hydrogen. However, any one or more of R3, R4, R5, R7, R8, and R11-R13 may be hydrogen, while the others may not be hydrogen, in preferred embodiments of the compound of Formula (IIA). R6 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, and C2-C12 alkynyl. Preferably R6 is selected from hydrogen, a halogen, C1-C6 alkyl. More preferably R 6 is a C 1 -C 6 alkyl, and more preferably R 6 is methyl.

R10 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, and C5-C12 aryl. Alloy that joins R10 to the remainder of the compound of Formula (IIA) is preferably a double C-C bond, but may be a simple C-C bond, a simple C-H bond, or a simple heteroatomic bond. Preferably, R10 is CH2 or CH2R 'where R' is a C1-C6 alkyl, or a substituted C1-C6 alkyl. Preferably R10 is CH2, and preferably R1 and R2 are not simultaneously methyl.

It will also be appreciated that the various groups R, more particularly R3, R4, R5, R7, R8, and R11-R13 may be chosen such that a cyclic system is formed. For example, R13 and R12 may be ethylene media and may include covalent covalent coupling between their respective carbonostermines, generating an additional six-membered ring in the Formula (IIA) compound. As a further example, bis-cyclic rings may be formed by choosing appropriate chemical species for the various R groups, particularly R 3, R 4, R 5, R 7, R 8, and R 11 -R 13 of Formula (IIA).

Some embodiments have been related to compounds having the following chemical structure: <formula> formula see original document page 86 </formula>

Where R1 is selected from the group consisting of:

<formula> formula see original document page 86 </formula>

Where Z is 0 or S;

If any R3-R5, R7, R8, R11-R13 is not hydrogen, R6 is not methyl, R10 is not CH2, or if R10 is CH2OH and R11 is OH, R2 may be, for example, hydrogen, a halogen, COOH, acids C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 alkyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) amidesterium, C1-C12 alcohols, (C1- C12) (C1-C12), C1-C12 alkyls, substituted C1-C12 alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls and the like;

If all R3-R5, R7, R8, R11-R13 are hydrogen, R6 is methyl, and R10 is CH2 or CH2OH, then R2 may be, for example, hydrogen, a halogen, C1-C12 carboxylic acids, C1-4 alkyl halides. C12, C1-C12 acyl residues, C2-C12 esters, C1-C12 secondary amides, (C1-C12) (C1-C12) tertiary amides, C2-C12 alcohol, (C1-C12) (C1-C12) ethers, alkyls C 2 -C 12, C 2 -C 12 substituted alkyls, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl and the like;

R3, R4, R5, R7, R8, and R11-R13 may each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, alkynyl C 2 -C 12, C 5 -C 12 aryl and the like;

R 6 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, and similar C 2 -C 12 alkynyl;

R10 may be, for example, hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 16 and R 17 may, for example, be independently selected from hydrogen; mono-substituted, poly-substituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, acyl-C2-alkyl C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and C 5 -C 24 heteroaryl alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero-cycloalkenyl, C4 -C12 hetero-cycloalkynyl, C6 -C12 arylsulfonyl, C4 -C12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be joined together to form an optionally substituted C 2 -C 12 hetero-cycloalkyl, an optionally substituted C 4 -C 12 hetero-cycloalkenyl, an optionally substituted C 4 -C 12 hetero-cycloalkyl, or a C 4 -C 12 hetero-aryl optionally substituted;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkoxy, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero cycloalkenyl, C4 -C12 hetero cycloalkyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

The compound may include prodrug esters of the above compounds, and their acid addition salts.

In one aspect, R 16 may be, for example, hydrogen and the like. In another aspect, R3-R5, R-7, R8, R11-R13 may each be, for example, hydrogen and the like.

Any group which is optionally substituted may be optionally substituted by one or more of one C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

In another embodiment the compound may have the following structure:

<formula> formula see original document page 88 </formula> Where R1 is selected from the group consisting of:

<formula> formula see original document page 89 </formula>

Where Z is 0 or S,

R 16 and R 17 may, for example, be independently selected from hydrogen; mono-substituted, poly-substituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, acyl-C2-alkyl C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and C 5 -C 24 heteroaryl alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be joined together to form an optionally substituted C 2 -C 12 hetero-cycloalkyl, an optionally substituted C 4 -C 12 hetero-cycloalkenyl, an optionally substituted C 4 -C 12 hetero-cycloalkyl, or a C 4 -C 12 hetero-aryl optionally substituted;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

And their prodrug esters and acid addition salts.

Any group which is optionally substituted may be optionally substituted by one or more of one C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

Certain compounds described, including those compounds designated herein TTL1, TTL2, TTL3, and TTL4 have the chemical structure described in Formula (IIB).

<formula> formula see original document page 90 </formula>

The R groups of the compound of Formula (IIB) may be selected as follows: R1 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1 esters -C12, primary amide, C1-C12 secondary amides, (C1-C12) (C1-C12) tertiary amides, C1-C12 alcohols, (Cl-C12) (C1-C12) ethers, C1-C12 alkyls, substituted C1 -C12, C2 -C12 alkenyls, substituted C2 -C12 alkenyls, and C5 -C12 aryls. Under these conditions, R1 is preferably selected from COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, and C1-C12 esters, and is preferably selected from COOH and C1-C6 esters.

R 2 and R 9 are each separately selected from hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 acyl, C 1 -C 12 alcohol, and C 5 -C 12 aryl. Preferably R 2 and R 9 are each separately selected from alkyl and alkenyl residues. Preferably R 2 and R 9 are each methyl residues, although one of R 2 and R 9 may be methyl and the other non-methyl, in preferred embodiments of the compound of Formula (IIB).

R3, R4, R5, R7, R8, and R11-R13 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-alkynyl Preferably R3, R4, R5, R5, R7, R8, and R11-R13 are each hydrogen or a C1-C6 alkyl, and preferably R3, R4, R5, R7, R8, and R11-R13 are each hydrogen. However, any or more of R3, R4, R5, R7, R8, and R11-R13 may be hydrogen, while the others may not be hydrogen, in preferred embodiments of the compound of Formula (IIB).

R6 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, and C2-C12 alkynyl. Preferably R6 is selected from hydrogen, a halogen, C1-C6 alkyl. More preferably R6 is a C1-C6 alkyl, and preferably R6 is methyl.

R10 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, and C5-C12 aryl. Alloy joining R10 to the remainder of the compound of Formula (II) is preferably a double C-C bond, but may be a simple C-C bond, a simple C-H bond, or a simple heteroatomic bond. Preferably, R10 is CH2 or CH2R1 wherein R 'is a C1-C6 alkyl, or a substituted C1-C6 alkyl. Preferably R10 is CH2, and preferably R1 and R2 are not simultaneously methyl.

It will also be appreciated that the various groups R, particularly R3, R4, R5, R7, R8, and R11-R13 may be chosen such that a cyclic system is formed. For example, R13 and R12 may be ethylene media and may include a covalent C-C coupling between their respective carbonostermines, generating an additional six-membered ring in the compound of Formula (IIB). As a further example, bis-cyclic rings may be formed by choosing appropriate chemical species for the various R groups, particularly R 3, R 4, R 5, R 7, R 8, and R 11 -R 13 of Formula (IIB).

Certain compounds described, including preferred formula (IIB-Al), have the chemical structure shown in the following structure:

<formula> formula see original document page 92 </formula>

On what:

R2 is selected from the group consisting of hydrogen, a halogen, -COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, tertiary amides (C1 -C12) (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-6 substituted alkyls C 12, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, and C 5 -C 12 aryls;

R16 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1- C12) (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, and C 5 -C 12 aryls;

R17 is a cyclic medium including, for example, C5 -C12 cyclic alkyls; C5 -C12 cyclic alkenyls; C5 -C12 cyclic alkyl-substituted alkylsubstituted; C5 -C12 cyclic substituted alkenyls; phenyl and C5 -C12 aryls; wherein R16 and R17 may form a 3-12 membered ring structure;

R9 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-C12 acyl, and C5-aryl C12;

R3-R5, R7, R8, and R11-R13 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, and C5 -C12 aryl;

R6 is selected from hydrogen, a halogen, C1-C12 alkyl, substituted C1-C12 alkyls; C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, and C 2 -C 12 alkynyl;

R10 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, and C5-C12 aryl;

R14 and R15 are selected separately from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, and C5-C6 aryl; and

The compound includes prodrug esters and acid-depleting salts, and may be in any of several possible stereo-forms, including coincident races and optically active enantiomers or diateromers.

Some forms of incorporation are related to Formula ilB-b, its prodrugs and salts, wherein Formula Il-b has the following structure:

<formula> formula see original document page 94 </formula>

R1 may be, for example:

<formula> formula see original document page 94 </formula>

Where Z is 0 or S;

R2 may be, for example, hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, C 2 -C 12 substituted alkenyls, C 5 -C 12 aryls, and the like; R 9 may be, for example, hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 alcohol, C 1 -C 12 acyl, C 5 -C 12 aryl, and the like;

R3-R5, R7, R8, and R11-R13 can each be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-alkynyl C 12, C 5 -C 12 aryl, and the like;

R6 may be, for example, hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkynyl, C2-C12 alkenyl, similars;

R10 can be, for example, hydrogen, vinylogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, C5-C12 aryl and the like;

R 14 and R 15 may be, for example, hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 6 alcohol, C 5 -C 6 aryl and the like; and

R16 and R17 may, for example, be independently selected from hydrogen; mono-substituted, poly-substituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, acyl-C2-alkyl C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and C 5 -C 24 heteroaryl alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be linked together to form an optionally substituted C 2 -C 12 hetero-cycloalkyl, an optionally substituted C 4 -C 12 hetero-cycloalkenyl, an optionally substituted C 4 -C 12 hetero-cycloalkyl, or a C 4 -C 12 hetero-aryl optionally substituted R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 1 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like. [0439] wherein the compound also includes prodrug esters of the above compounds, and their acid-forming salts.

In some aspects, R 16 may be, for example, hydrogen. In some aspects, R3-R5, R7, R8, R11-R15 may each be, for example, hydrogen.

Any group which is optionally substituted may be optionally substituted by one or more of one C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

Some forms of embedding relate to compounds that have the following structure: <formula> formula see original document page 97 </formula>

R1 can be, for example:

<formula> formula see original document page 97 </formula>

Where Z is 0 or S;

R 16 and R 17 may, for example, be independently selected from hydrogen; mono-substituted, poly-substituted or unsubstituted chain or branched variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, acyl-C2-alkyl C 12, C 7 -C 24 arylalkyl, C 1 -C 12 alkylsulfonyl, and C 5 -C 24 heteroaryl alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, C 6 -C 12 arylsulfonyl, C 4 -C 12 heteroaryl sulfonyl, and the like;

R 16 and R 17 may optionally be joined together to form an optionally substituted C 2 -C 12 hetero-cycloalkyl, an optionally substituted C 4 -C 12 hetero-cycloalkenyl, an optionally substituted C 4 -C 12 hetero-cycloalkyl, or a C 4 -C 12 hetero-aryl optionally substituted;

R18 may be selected from hydrogen; mono-substituted, poly-substituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12-ether, C2-acyl-alkyl C 12, C 7 -C 24 arylalkyl, and heteroarylC 5 -C 24 alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C2 -C12 cycloalkyl, C4 -C12 hetero cycloalkenyl, C4 -C12 hetero cycloalkyl, and the like;

R19, R20, and R21 may be independently selected from hydrogen; halogen; hydroxyl; carboxyl; amine; uncle; nitro; cyan; mono-substituted, polysubstituted or unsubstituted straight or branched chain variants of the following residues: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C2-C12 alkoxy, C1-C12 ether, C2-acyl alkyl C 12, C 7 -C 24 arylalkyl, and C 5 -C 24 heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: C3 -C12 cycloalkyl, C3 -C12 cycloalkenyl, C3 -C12 cycloalkoxy, C6 -C12 aryl, C4 -C12 heteroaryl, hetero C 2 -C 12 cycloalkyl, C 4 -C 12 hetero-cycloalkenyl, C 4 -C 12 hetero-cycloalkynyl, and the like.

And their prodrug esters and acid addition salts.

Any group which is optionally substituted may be optionally substituted by one or more of one C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxy, halogen, hydroxyl, carboxyl, amine, thio, nitro, or cyano.

Definitions

As used herein, the term "purifying" or "purified" or "purifying" or "purifying" refers to any species in which at least some of the components with which it is normally associated are removed.

As used herein, the term "alkyl" means any unbranched or branched saturated hydrocarbon with unsubstituted, unbranched, saturated C1-C6 hydrocarbons being preferred, and with methyl, ethyl, isobutyl, eterto-butyl being more preferred. Preferred. Among saturated, substituted hydrocarbons, saturated hydrocarbons and halogen substituted substituted C1-6 mono- and disubstituted amino hydrocarbons are preferred, with perfluoromethyl, perchloromethyl, perfluoro-tert-butyl, and perchlor-tert-butyl being more. Preferred. The term "substituted alkyl" means any branched or unbranched substituted saturated hydrocarbon with unsubstituted C1-C6 alkyl secondary amines, substituted C1-C6 secondary alkyl amines, tertiary C1-C6 alkyl amines being found throughout definition of "substituted alkyl" but not preferred. The term "substituted alkyl" means any unsubstituted or branched substituted substituted hydrocarbon. Compostoscics, both cyclic hydrocarbons and cyclic compounds containing heteroatoms, are within the meaning of "alkyl".

As used herein, the term "substituted" means any substitution of a hydrogen atom with a functional group.

As used herein, the term "functional group" has its common definition, and refers to preferably selected chemical means from the group consisting of a halogen atom, C1-C20 alkyl, substituted C1-C20 alkyl, perhalogenated alkyl, cycloalkyl substituted cycloalkyl, aryl, substituted aryl, benzyl, heteroaryl, substituted heteroaryl, cyano, and nitro. Functional groups may also be selected from the group consisting of -SRs, -OR0, -NRnlRn2, -N = N-Rni, -N + RniRn2Rn3, -P + RniRn2Rn3, -CORc, -C (= NOR0) Rc / -CSRc , -OCORc, -OCONRniRn2, -OCO2Rc, -CONRnlRn2, -C (= N) NRnlRn2, -CO2R0, -SO2NRnlRn2, -SO3R0, -PO (OR0) 2, -NRnlCSNRn2Rn3. The substituents of these functional groups Rn1, Rn2, Rn3 / RoS RS are each separately selected preferably from the group consisting of a hydrogen atom, C1-C20 alkyl, substituted C1-C20 alkyl, cycloalkyl, substituted cycloalkyl , aryl, substituted aryl, benzyl, heteroaryl, substituted heteroaryl and may be parts of an aromatic or aliphatic heterocycle. Rc is preferably selected from the group consisting of a hydrogen atom, C1-C20 alkyl, substituted C1-C20 alkyl, perhalogenated alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryls, benzyl, heteroaryl, hetero- cyano substituted aryl.

As used herein, the terms "halogen" and "halogen atom" refer to any of the radio-stable atoms of column 17 of the Periodic Table of Elements, preferably fluorine, chlorine, bromine, or iodine, with particularly preferred fluorine and chlorine.

As used herein, the term "alkenyl" means any unsaturated, unbranched or branched, substituted or unsubstituted hydrocarbons, with unsubstituted and unsaturated unsubstituted C1-C6 hydrocarbons, being preferred, and hydrocarbons. substituted monounsaturated dihalogen, being more preferred. The term "substituted alkenyl" means any branched or unbranched substituted unsaturated hydrocarbon substituted with one or more functional groups, with unbranched C 2 -C 6 alkenyl secondary amines, substituted unbranched C 2 -C 6 alkenyl amines, and unbranched C 2 -C 6 alkenyl tertiary amines falling within the definition of "substituted alkyl". The term "substituted alkenyl" means any unsubstituted or branched substituted unsaturated hydrocarbon. Cyclic compounds, both unsaturated cyclic hydrocarbons and cyclic compounds having hetero atoms, are within the meaning of "alkenyl".

As used herein, the term "alcohol" means any unsaturated or saturated, unbranched or branched alcohol, with unsubstituted, unbranched, saturated C1-C6 alcohols being preferred, and with methyl, ethyl, isobutyl, alcohol of tert-butyl being more preferred. Among substituted, mono- and disubstituted saturated C1-C6 alcohols, saturated alcohols are preferred. The term "alcohol" includes substituted alkoxy alcohols, and substituted alkenyl alcohols.

As used herein, the term "aryl" embraces the terms "substituted aryl" "heteroaryl", and "heteroaryl substituted" which refer to aromatic hydrocarbon rings having preferably five or six atoms comprising the ring. The term "heteroaryl" and "substituted heteroaryl" refers to aromatic hydrocarbon rings in which at least one heteroatom, for example a deoxygen, sulfur, or nitrogen atom, is in the ring together with at least one atom. carbon. "Aryl", more generally, and "substituted aryls", "heteroaryl," and "substituted heteroaryl" more particularly refer to aromatic hydrocarbon rings, preferably having five or six atoms, and preferably having six atoms comprising the ring. The term "substituted aryls" includes mono- and poly-substituted aryls substituted with, for example, alkyl, aryl, alkoxy, azide, amine, amine groups. "Heteroaryl" and "substituted heteroaryl", if used separately, specifically refers to Aromatic hydrocarbon rings in which at least one heteroatom, for example an oxygen, sulfur, or nitrogen atom, is in the ring together with at least one carbon atom.

The terms "ether" and "alkoxy" refer to any unsubstituted or saturated, unbranched or branched, substituted or unsubstituted ether, unsubstituted, unsubstituted C1-C6 ethers, with preferred dimethylethers being preferred. diethyl, methyl isobutyl, and methyl tert-butyl are more preferred. The terms "ether" and "alkoxy", more generally, and "cycloalkoxy" and "cyclic ether" more particularly refer to any non-aromatic hydrocarbon ring, preferably five to twelve atoms comprising the ring.

The term "ester" refers to any unsubstituted or branched, substituted or unsubstituted, saturated or unsaturated, unsubstituted, saturated, unsubstituted C1-C6 esters, with methyl ester being preferred, and isobutyl ester being more preferred.

The term "prodrug ester", especially when referring to a prodrug ester of the compound of Formula (I), refers to a chemical derivative of the compound which is rapidly transformant in vivo to obtain the compound, for example by hydrolysis in the compound. blood. The term "prodrug ester" refers to adhesives of the compound of the present invention formed by the addition of any of various ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other prior art groups, including a (5-R-2-oxo-1,3-dioxolene-4-yl) group methyl. Other examples of prodrug ester groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugsas Novel Delivery Systems", Vol. 14, A. C. S. , American Chemical Society (1975); and in "Bioreversible Carriersin Drug Design: Theory and Application", edited by Ε. B. Roche, Pergamon Press, New York, 14-21 (1987) (providing examples of esters useful as prodrugs for carboxyl-containing compounds).

The term "pharmaceutically acceptable salt", especially when referring to a pharmaceutically acceptable salt of the compound of Formula (I), refers to any pharmaceutically acceptable salt of a compound, and preferably refers to an acid addition salt of a compound. Preferred examples of pharmaceutically acceptable salts are alkaline metal salts (sodium or potassium), alkaline earth metal salts (calcium or magnesium), or ammonium salts derived from deamonium or pharmaceutically acceptable organic amines, for example C1-C7 alkylamine, cyclohexylamine triethanolamine, ethylenediamine or tris- (hydroxymethyl) aminomethane. With respect to the described compounds which are basic amines, the preferred examples of pharmaceutically acceptable salts are acid addition salts of pharmaceutically acceptable inorganic or organic acids, for example hydrohalic, sulfuric, phosphoric, aliphatic or carboxylic acid, or sulfonic acid, for example acid acetic, succinic, lactic, malic, tartaric, citrus, ascorbic, nicotinic, methanesulfonic, p-toluenesulfonic or naphthalenesulfonic acid. Preferred pharmaceutical compositions of the present invention include pharmaceutically acceptable salts and prodrug esters of the compound of Formulas (II), (IIA), and (IIB). The terms "purified", "substantially purified", and "isolated" as used herein, if refer to a compound described free of other dissimilar compounds with which the compound is normally associated in its natural state, so that the compound comprises at least 0.5%, 1%, 5%, 10%, or 20%, and more preferably. at least 50% or 75% of the weight, by weight, of a given sample. In a preferred embodiment, these terms refer to the compound comprising at least 95% by weight of a given sample.

The terms "anti-cancer", "anti-tumor", and "tumor growth inhibitor", by modifying the term "compound", and the terms "inhibit" and "reduce", by modifying the terms "compound" and / or the term "tumor" means that the present compound in question correlates at least with the reduction in tumor growth rate or cancerous mass. More preferably, the terms "anti-cancer", "anti-tumor", "tumor growth inhibitor", "inhibit" and "reduce" refer to a correlation between the presence of the compound in question and the temporary cessation of tumor growth or massacancerous growth. The terms "anti-cancer", "anti-tumor", "tumor decrease inhibitor", "inhibit" and "reduce" also refer, particularly in the most preferred embodiment, to a correlation between the presence of the compound in question and at least the temporary reduction in tumor mass. These terms refer to cancer and various malignancies in animals, specifically in mammals, and specifically in humans.

The term "skin redness" means any skin redness, especially a chronic redness of the pellet having a neurogenic origin, consistent with, but not limited to, its meaning in EP 7744250, which is incorporated herein by reference in its entirety.

The term "viral infection" means any infection of viral origin including rhinovirus, and preferably, but not exclusively, referring to human immunodeficiency virus (HIV), human cytomegalovirus, hepatitis A virus, hepatitis B virus, and The term "cardiovascular disease" refers to various diseases of the heart and vascular systems, including but not limited to congestive heart failure, cardiac dysfunction, reperfusion damage, and various known peripheral circulatory abnormalities. "Cardiovascular disease" refers to such diseases in animals, specifically mammals, and specifically humans.

As used herein, the term "diabetes" refers to various diseases related to elevated insulin levels, insulin resistance, or Diabetes, including Type 1 Diabetes, Type 2 Diabetes, and various related conditions, including but not limited to Stein Syndrome. -Leventhal or Polycystic Ovary Syndrome (PCOS).

As used herein, the term "transplant rejection" refers to the related conditions and symptoms known as allograft rejection, xenograft rejection, and autograft rejection, and in preferred embodiments, refers to allograft rejection. human-human graft.

As used herein, the term "modulator" or "modulation" refers to the ability of a compound or treatment course to alter the presence or production of a compound, especially TNF-Î ± or IL-I, in an individual. Preferably, "modulator" "or" modulation "refers to the ability of a compound or course of treatment to reduce the presence or production of a modulated compound.

As used herein, the terms TTL1, TTL2, TTL3, TTL4, and TTL5 refer to the specific chemical entities identified, among other figures, in Figure 17.

All other chemical, medical, pharmacological, or in any case technical terms used herein will be understood as they would be understood by persons of ordinary skill in the art.

Interleukin-1 (IL-I)

IL-I is a regulatory factor that participates in a wide range of immune and inflammatory mechanisms and other mammalian defensive mechanisms, especially in the human body (See, for example, Dinarello, DA, FASEB J., 2, 108 (1988)). ). IL-I, first discovered as produced by activated macrophagocytes, is secreted by various cells, for example fibroblasts, gueratinocytes, T cells, B cells, and brain astrocytes, and has several functions, including: stimulating the proliferation of CD4 + cells T, see Mizel, SB, Immunol. Rev. 63, 51 (1982); stimulating the killing effect of thymic Tc cell cells by binding them to a T cell receptor, RCT, see McConkey, D. J., et al. , J. Biol. Chem., 265,3009 (1990); induce the production of various materials participating in inflammatory mechanisms, for example, PGE2, phospholipase A2 (FLA2) and collagenase, see Dejana, E., et al. , Bolid., 69, 695-699 (1987)); induce the production of acute phase proteins in the liver, see Andus, T., et al. , Eur. J. Immunol. , 123, 2928 (1988)); raise blood pressure in the vascular system, see Okusawa, S., et al., J. Clin. Invest., 81, 1162 (1988)); and will induce production of other cytokines, for example IL-6 and TNF-α, see Dinarello, C.A., et al., J. Immunol., 139, 1902 (1987). IL-I amodulation is also known for its effects on rheumatoid arthritis, see Nouri, A.M., et al. , Clin. Exp. Immunol., 58 ,02 (1984); transplant rejection, see Mauri and Teppo, Transplantation, 45, 143 (1988); and septicemia, see Cannon, J.G., et al., Lymphokine Res., 7, 457 (1988); and IL-I can induce fever and pain when administered in large doses. See Smith, J., et al., Am. Soc. Clin. Oncol., 9, 710 (1990)).

Occurrence of septicemia, arthritis, inflammation, and related conditions in animal models can be decreased by inhibiting IL-I binding to its receptors by employing naturally occurring IL-I receptor inhibitors (IL-1 Ra), see Dinarello. , CA and Thompson, RC, Immunol. Today, 12, 404 (1991), and certain methods for inhibiting IL-I activity by employing particular antibodies have also been proposed, see Giovine, D.F.S. and Duff, G.W., Immunol. Today, 11, 13 (1990). In the case of IL-6, myelocyte proliferation in a myeloma patient was suppressed by employing IL-6 antibodies or IL-6 receptors, see Suzuki, H., Eur. J. Immuno., 22,1989 ( 1992). The disease condition treatable according to the invention, by modulation of TNF-α and IL-I induced by the compounds, includes but is not necessarily limited herein to the finger disease conditions described.

Tumor Necrosis Factor (TNF-a)

human TNF-α was first purified in 1985 (Aggarwal, BB; Kohr, WJ, Human Tumor Necrosis Factor.Production, Purification and Characterization ", J. Biol. Chem.1985, 260, 2345-2354). Then cloning cDNA molecular analysis of the TNF cDNA and cloning of the human TNF locus were performed (See Pennica, D.; Nedwin, GE; Hayflick, JS et al. Human Necrosis Factor: Precursor Structure, Expression and Homology to Lymphotoxin ", Nature, 1984, 312, 724-729 Wang, AM; Creasy, A.A.; Ladner, MB "Molecular Cloning of the Complementary DNA for Human Tumor Necrosis Factor", Nature, 1985, 313, 803-806). TNF-α is a trimeric 17-KDa polypeptide produced primarily by macrophages and many other cell types. This peptide is initially expressed as a 26-KDa transmembrane protein from which the 17-KDa subunit is divided and released after proteolytic division by an enzyme known as TACE. This work has clarified the immense and multi-faceted biological implications of TNF-α and spurred the development of therapeutic approaches by targeting its overproduction.

TNF-α is typically produced by multiple cells, for example macrophage cells and activated fibroblasts. TNF-α induces IL-I production, see Dinarello, DA, FASEB J., 2, 108 (1988), is cytotoxic to L929 fibrosarcoma cells, see Espevik and Nissen-Meyer, J. Immunol . Methods, 95, 99 (1986); stimulates fibroblast proliferation, see Sugarman, B.J., et al., Science, 230, 943 (1985); induces the production of arachidonic acid PGE2, both of which may be involved in inflammatory responses, see Suttys, et al., Eur. J. Biochem., 195, 465 (1991); and induces IL-6 production or other decreasing factors, see Van Hinsbergh, et al. , Blood, 72, 1467 (1988). TNF-α also participates, directly or indirectly, in various diseases such as infectious diseases carried by trypanosome lines of the genus Plasmodium, see Cerami, A., et al. Immunol. Today, 9, 28 (1988); autoimmune diseases such as systemic lupus erythematosus (LSE) and arthritis, see Fiers, W., FEBS1 285, 199 (1991); Acquired Immune Deficiency Syndrome (AIDS), see Mintz, M., et al. , Am. J. Dis. Child, 143, 771 (1989); septicemia, see Tracey, K.J., et al., Curr. Opin. Immunol., 1,454 (1989); and certain types of infections, see Balkwill, F.R., Cytoguins in Cancer Therapy, Oxford University Press (1989).

TNF-α and Inflammatory Response

Infection and tissue damage induce a cascade of biochemical changes that activate immune system reactions, collectively referred to as an inflammatory response. The evolution of this response is based at least in part on local vasodilation or increased vascular permeability and vascular endothelial activation, which allows white blood cells to circulate effectively and migrate to the damaged site, thereby increasing their chances of binding and destroying any antigen. The vascular endothelium is then believed to be activated or inflamed. Inflammation is usually a welcome immune response to a variety of unexpected stimuli, and as such exhibits a rapid onset and short duration (acute inflammation). Its persistent or uncontrolled activity (chronic inflammation), however, has detrimental effects on the body and results in the pathogenesis of various immunological diseases such as: shock shock, rheumatic arthritis, inflammatory bowel disease and congestive heart failure. See "Tumor Necrosis Faetors. The Molecule and Their Emerging Role in Medicine", B. Beutler, Ed., Raven Press, N.Y. 1992, pages 1-590.

The deployment of an effective immune response typically requires recruitment of a variety of cells and orchestration of a series of biological events. This complex coordination and intercellular interaction is mediated by locally secreted low molecular weight proteins that are collectively called cytokines. These proteins bind specific receptors on the cell surface and trigger signal transduction pathways that ultimately alter the expression of target cell genes, thereby regulating an efficient inflammatory response.

Cytokines may exhibit properties of depleiotropism (a given protein exerts different effects on different cells), redundancy (two or more cytokines mediate similar functions), synergism (the combined effect of cytokines is greater than the additive effect of each individual protein) and antagonism (the effect cytokine inhibiting the effect of others). For this purpose, some of the cytokines are proinflammatory (induce inflammation), while some are antiinflammatory (inhibit inflammation). The class of proinflammatory cytokines includes: interleukin-1 (IL-I), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). See "TumorNecrosis Factors. The Molecules and Their Emerging Role inMedicine" B. Beutler, Ed., Tven Press, NY 1992, pages 1-590.These cytokines are secreted by macrophages after the onset of the inflammatory response and induce coagulation, increased. vascular permeability and activate the expression of death molecules in vascular endothelial cells, (for example, TNF-A stimulates the expression of β-selection, which binds to recruitaneutrophils to the site of damage). Subsequently, and during a more systemic immune response, these cytokines act on various body organs, including bone marrow and liver, to ensure increased white blood cell production and synthesis of appropriate hormones and acute phase proteins. In addition, they act on the hypothalamus and induce fever which helps to inhibit the growth of pathogens and increase the overall immune reaction.

TNF-a and the Pathogenesis of Miscellaneous Diseases and Conditions

As with any cytokine, TNF-a is neither completely beneficial nor completely destructive to the host. Instead, the balance between its production and regulation is maintained to ensure that the host can effectively react to invading microorganisms without compromising the welfare of the host. in the process. As a mediator of inflammation, TNF-α helps the body in its fight against bacterial infections and tissue damage. However, TNF-α overproduction leads to chronic inflammation, has detrimental effects on the body, and plays a major role in the pathogenesis of various diseases, some of which are summarized below.

Bacterial Septic Shock - This disease typically develops after infection with certain gram-negative bacteria, such as E. Coli, Enterobacter Aerogenes, and Neisseria Meningitidis. These bacteria carry in their cell walls certain lipopolysaccharides (endotoxins) that stimulate macrophages to overproduce IL-I and TNF-a, which in turn causes septic shock. Symptoms of this condition, which is often fatal, include a drop in blood pressure, fever, diarrhea, and widespread blood clotting. In the United States alone, this condition afflicts approximately 500,000 people a year and causes more than 70,000 deaths. The annual cost to treat this disease is estimated at 5-10 billion dollars.

Rheumatoid Arthritis - This is the most common autoimmune disease, affecting approximately 1% of the Western population and is a major source of prostration that, in its former form, leads to death. See Szekanecz, Z .; Kosh, A.E .; Kunkel, S.L .; Strieter, R.M. "Cytokynes in rheumatoid arthritis. Potentialtargets for pharmacological applications", Clinical Pharmacol. 1998, 12, 377-390. Camussi, G .; Lupine, E. "The future role of anti-tumor necrosis factor products in the treatment of rheumatoidarthritis". Drugs, 1998, 55, 613-620. This condition is characterized by inflammation and cell proliferation of the synovium, which results in the invasion of the adjacent cartilage matrix, its subsequent erosion and ultimately bone destruction. Although the origins of this inflammatory response are poorly understood, increased expression of TNF-α and IL-I was found around the erosion area of the cartilage. More recently, the pathogenic role of TNF-α in this disease has been extensively studied and experimentally verified. In addition, clinical data suggest that TNF-α neutralization may be a therapeutic approach to reduce erosion. So far, however, current therapy, while providing temporary relief, has not altered the fundamental mechanisms of disease progression or process. Inflammatory Bowel Diseases and Related Conditions - This class of diseases that includes Crohne's disease ulcerative colitis are debilitating diseases characterized by chronic inflammation. intestinal mucosa and lamina propria.

Although the events that trigger its onset are unknown, they are associated with significant leukocyte infiltration and local production of soluble mediators. TNF-α is therefore considered to be a key mediator in the pathogenesis of these conditions, either by direct cytotoxic action or as an orchestrator of the inflammatory cascade. For example, see Armstrong, A.M .; Gardiner, K.R .; Kirk, S.J .; Halliday, M.J .; Rowlands, B.J., "Tumor necrosisfactor and inflammatory bowel disease", Brit. J. Surgery, 1997.84, 1051-1058. Accepted animal model data also support the reason for a therapeutic study in human IBD aimed at reducing the effect of TNF. See Van Deventer, S.J.H., "Tumor necrosis factor and Crohn's disease", Gut, 1997, 40, 443.

Congestive Heart Failure - Activation of decytokines, and especially TNF-cc, occurs in patients with chronic heart failure and acute myocardial infarction. See Ferrari, R. , "Tumor necrosis factor in CHF: a double facet cytokine", Cardiovascular Res., 1998, 37, 554-559. In addition, TNF-α has been shown to activate the apoptotic process in cardiac myocytes as directly (by binding to, and genetic reprogramming of these cells) as indirectly (through local NO production, which also leads to cell death).

HXV Replication - HIV replication is activated by the inducible transcription factor FN-kB, which in turn is induced by TNF-α. HIV expression can be TNF-induced in macrophage cell lines and T cell clones chronically infected with the virus. Infusion of recombinant TNF in a small number of patients with AIDS-related Kaposi's sarcoma appeared to cause an increase in the level of HIV p24 antigen, a marker of viral replicative activity. See "Therapeutic Modulation of Cytokines", CRC Press Inc., N.Y. 1996, pages 221-23-6. These results provide a mechanistic basis for considering the use of a TNF blocker to reduce the infectious part of HIV.

Other TNF-mediated pathologies - There is an ever-growing list of conditions in which there is some evidence that TNF is involved. "Modulation thrapeutic of cytokines", CRCPress Inc., N.Y., 1996, pages 221-236. In some cases, such as transplants, graft versus host disease, and ischemia / reperfusion damage the potential mechanism of pathogenesis implicates TNF-α proinflammatory activity for a variety of tissue cells. Others, such as suppression of insulin responsiveness in non-insulin dependent diabetes, are related to more selective TNF-α actions that appear to fall outside the standard pro-inflammatory model. TNF-α has been detected locally in patients afflicted with otitis media (internal ear infection, with or without effusion), see for example Willett, DN, Rezaee, RP, Billy, JM, Tighe, MA, and DeMaria, TF, Ann. Rhinol Laryngol., 107 (1998); Maxwell, K., Leonard, G., and Kreutzer, D.L., Arch. Otolarygol. Head Neck Surg., Vol. 123, p.984 (September 1997), and with sinusitis, see for example Nonoyana, T., Harada, T., Shinogi, J., Yoshimura, E., Sakakura, Y., Auris Nasus Larynx, 27 (1) 51-58 (January 2000); BuehringL, Friedrich B., Schaff, J., Schmidt H., Ahrens P., Zielen S., Clin. Exp. Immul., 109 (3), 468-472, September 1997).

Usage Methods

Additional forms of incorporation relate to the use of the described compounds and pharmaceutical compositions including the described compounds in the treatment of diseases detailed above, which include inflammation, cancer, cachexia, otitis media, sinusitis and transplant rejection, and reduced or associated fatigue associated with cancer. and / or its treatment.

Specific examples or other treatable diseases that may be specifically associated with the eye, nose and / or ear include thyroid-related diseases (Hunt et al., Clin.Endocrinol., 55 (4): 491-9 (2001)), such as ophthalmopathy. de Graves (Villanueva et al., Thyroid, 10 (9): 791-8 (2000); Jones et al., Thyroid, 10 (8): 701-7 (2000); Wakelkamp et al., Clin. Exp. Immunol., 121 (3) 453-7 (2000); Song et al., Horm. Metabl Res., 32 (7): 277-82 (2000)), Hashimoto's thyroiditis (Paolieri et al., Ann. NY Aead. Sci., 876: 221-8 (1999)), thyroid-associated ophthalmopathy (OAT) (Pappa et al., Clin. Exp. Immunol., 109 (2): 362-9 (1997)) and goiter nodular (Nygaard et al., Horm. Metabl. Res., 32 (7): 283-7 (2000)); Herpetic stromal keratitis (Keadle et al., Invest. Ophthalmol. Vis. Sci., 41 (1): 96-102 (2000)) and keratithemicrobial and peripheral ulcerative keratitis (Dana et al., Cornea, 19 (5): 625 -43 (2000)); Behcet's disease (Sfikakis et al., Lancet., 358 (9278): 295-6 (2001)); Goossens et al., Ann. Rheuma. Dis., 60 (6): 637 (2001)); Robertson et al., Rheumatology, 40 (4): 473-4 (2001)); Hassard et al. , Gastroenterology, 120 (4): 995-9 (2001); Sakane et al. Expert Opin. Investigation Drugs, 9 (9): 1993-2005 (2000)); uveitis (Lemaitre et al., Invest. Ophthalmol Vis. Sci., 42 (9): 2022-30 (2001)); Shao et al. , Invest. Ophthalmol Vis. Sci., 42 (9): 2016-21 (2001); Baatz et al. , Exp. Eye Res., 73 (1): 101-9 (2001)); Sjogren's syndrome (Magnusson et al., Scand. J. Immunol., 54 (1-2): 55-61 (2001); Koski et al., Clin. Exp. Rheumatol., 19 (2): 131-7 (2001); Fox, R., Expert Opin Investig.Drugs, 9 (9): 2007-16 (2000); Nakamura et al., Lab. Invest., 80 (9): 1421-7 (2000); Guggenbuhl et al., Joint Bone Spine, 67 (4): 290-5 (2000)); tuberculosis (Saita et al., 68 (10): 5991-7 (2000)); inflammatory diseases, such as cochlear inflammation (Ichimiya et al., Int. J. Pediatr. Otorhinolaryngol., 56 (1): 45-51 (2000)) and inflammatory eye diseases (Smith et al., ArthritisRheum., 45 ( 3): 252-7 (2001)); vitreoretinal proliferative disease (Limb et al., Invest. Ophthalmol. Vis. Sci., 42 (7): 1586-91 (2001); El-Ghrably et al., Br. J. Ophthalmol., 85 (4) : 461-70 (2001); rabies virus eye disease (Camelo et al., J. Virol., 75 (7): 3427-34 (2001)); Vogt-Koyanagi-Harada disease (Kitaichi et al., Immunol., 44 (12): 107507 (2000)); retinopathy (Yossucket al., Mol. Genet. Metab., 72 (2): 164-7 (2001)); vernal kerato-conjunctivitis (Leonardi et al. Invest. Ophthalmol. Vis.Sci. 41 (13): 4175-81 (2000)); Retinal laser photocoagulation (Er etal., Ophtalmie Surg. Lasers, 31 (6): 479-83 (2000)). ); acute retinal denecrosis syndrome (Sato et al., Nippon Ganka Gakkai Zasshi, 104 (5): 354-62 (2000)); systemic vasculitis (McKibbin et al., Br.J. Ophthalmol., 84 (4): 395-8 (2000)); sarcoid myopathy (Peris et al., Clin. Rheumatol., 18 (6): 488-91 (1999)); aphthous recurrent stomatitis (EAR) (Freysdottir et al., Clin. Exp. Immunol. , 118 (3): 451-7 (1999)); neovascular glaucoma (Chen et al., Invest.Ophthalmol Vis. Sci., 40 (11): 2627-32 (1999)); bacterial eye infections such as Staphylococcus AureusAndophthalmitis (Giese et al., Invest. Ophthalmol. Vis. Sci., 39 (13): 2785-90 (1998)) and corneal infection of Pseudomonas Aeruginosa (Kernacki et al., Infect. Immun. ., 66 (1): 376-9 (1998)); eye allergic diseases (Hingorani et al., J. Allergy Clin. Immunol., 102 (5): 821-30 (1998)), such as allergic conjunctivitis (Macleod etal., Clin. Exp. Allergy, 27 (11): 1328 -34 (1997)); sarcoidosis (Maniwa et al., Intern. Med., 37 (9): 757-61 (1998)); retinal detachment (Bakunowicz-Lazarczk et al., Klin. Oezna, 99 (2): 87-9 (1997)); optic neuritis (Boiko et al., J. Neurovirol., 6 (Supplement 2): S152-5 (2000); Kivisakk et al., Neurology, 50 (1): 217-23. (1998)); ocular rosacea (Barton et al., Ophthalmology, 104 (11): 1868-74 (1997)), multiple sclerosis (Cooperet al., Med. Hyphoteses, 49 (4): 307-11 (1997)) and sclerosis systemic (Hebbar et al., Arthritis Rheum., 38 (3): 406-12 (1995)); hereditary retinal degeneration (de Kozak et al., Oeul. Immunol. Inflamm., 5 (2): 85-94 (1997)) ; retinal dystrophy (Cotinet et al., Glia., 20 (1): 59-69 (1997)); trachoma (Conway et al., Infect. Immun., 65 (3): 1003-6 (1997)); autoimmune diseases, including autoimmune cryo-adenitis (Takahashi et al., Clin. Exp. Immunol., 109 (3): 555-61 (1997)), autoimmune uve retinitis (Thillaye-Goldenberg et al. , J. Neuroimmunol., 110 (1-2): 31-44 (2000)) and AIDS (Lin et al., Curr. Eye Res., 16 (10): 1064-8 (1997)) and sialo-adeniteauto. -immune (Mustafa et al., Clin. Exp. Immunol., 112 (3): 389-96 (1998)); scleritis (Di Girolamo et al., Am. J. Pathol., 150 (2): 653-66 (1997)); rheumatic diseases such as lupussystemic erythematosus, rheumatic arthritis (al-Janadi et al., J.Clin. Immunol., 13 (l): 58-67 (1993), as mentioned above, rheumatic diseases of the heart (Miller et al. J. Rheumatol., 1989) rheumatoid evasculitis (Flipo et al., Ann. Rheuma. Dis., 56 (1): 41-4 (1997)); optic neuropathy (Madigan et al., Neurol. Res., 18 (3): 233-6 (1996)); ocular toxoplasmosis (Davidson et al., Antimicrob. Agents Chemother., 40 (6): 1352-9 (1996)); vitretrinal diseases (Esser et al. Ger. J. Ophthalmol., 4 (5): 269-74 (1995)); neovascular diseases of the eye (Spranger et al., Med.Klin., 90 (3): 134-7 (1995); endocrine orbitopathy ( Heufelder etal., Med. Klin., 88 (4): 181-4 (1993); GM-CSF granulocyte-macrophage colony stimulating factor diseases (Lang et al., Growth Factors, 6 (2): 131- 8 (1992)); non-neoplastic diseases (Billington, Drug Des. Discov., 8 (1): 3-35 (1991)); Wegener granulomates (Mayet et al., J. Immunol. Methods, 143 (1 ): 57-68 (1991)); ueratoconus (Fabre et al., Curr. Eye Res., 10 (7): 585-92 (1991)); intraocular tumors (Wong et al., Cornea, 10 (2): 131-5 (1991)) such as intraocular melanomas (Ma et al., Invest.Ophthalmol. Vis. Sci., 39 (7): 1067-75 (1998)), retinoblastoma (Detrick et al., Invest. Ophthalmol. Vis. Sci., 32 (6): 1714-22 (1991)) and colorectal carcinoma (Kemeny et al., Cancer, 66 (4): 659-63 (1990)); nasal polyp disease (Saji et al., Auris NasusLarynx, 27 (3): 247-52 (2000)); cholesteatoma (Amar et al., J.Laryngol. Otol., 110 (6): 534-9 (1996); thrombocytopenic thrombotic purpura and hemolytic uremic syndrome (Mauro et al., Am. J.Hematol., 66 (1) : 12-22 (2001)); Still's disease (Cavagna et al., Clin. Exp. Rheumatol., 19 (3): 329-32 (2001)); tonsillar hypertrophy and periodic tonsillitis (Agren et al., ENT J Otorhinolaryngol.Relat Spec., 60 (1): 35-41 (1998)), psoriasis (Mizutani et al., J. Dermatol. Sci., 14 (2): 145-53 (1997)); nucleoside (Andersson etal., Clin. Exp. Immunol., 92 (1): 7-13 (1993)); autoimmune brain myelitis (Weissert, J. Immunol., 166 (12): 7588-99 (2001 )), chronic proliferative dermatitis (HogenEsch et al., J. Immunol., 162 (7): 3890-6 (1999)); retinal venous occlusion (Conway et al., Int.Ophthalm., 19 (4): 249 -52 (1995)); Irvine-Gass syndrome, age-related macular edegeneration (Abe et al., Tohoku J.Exp. Med., 189 (3): 179-89 (1999)). inflammation-associated diseases that can be treated according to The invention includes autoimmune diseases affecting the eyes, nose, throat or ear, such as autoimmune diseases affecting upper and lower respiratory areas, Dewegener granulomatosis (Hewins et al., Curr. Opin. Rheumatol., 12 (1): 3-10 (2000); Yi et al., Semin. Diagn. Pathol., 18 (1): 34-46 (2001)), and autoimmune diseases that affect vision, smell, and taste, Sjogrens syndrome (Carsons, S. (Am. J. Manag. Care, 7 (14 ): S433-43 (2001); Lash et al., Nurse Pract., 26 (8): 50 (2001). More specifically, inflammatory diseases affecting the joints such as systemic inflammatory rheumatic disease involving the spinal joints -iliac, ankylosing spondylitis (Toussirto et al., ExpertOpin. Investig. Drugs, 10 (l): 21-9 (2001)), inflammatory joint diseases, spondyloarthropathies (Braun et al., Curr. Opin. Rheumatol. , 8 (4): 275-87 (1996); Gladman, DD, Am. J.Med. Sci., 316 (4): 234-8 (1998))), arthritis affecting spinal joints, arthritis psoriatic (Gladman et al., Expert Opin.Investig. Drugs, 9 (7): 1511-22 (2000); Scarpa et al., Curr. Opin.Rheumatol., 12 (4): 274-80 (2000)) and joint diseases such as temporomandibular joint disease (Stack et al., Am. Fam.Physician, 46 (l): 143-50 (1992)) are included.

Additional examples of diseases that may be treated according to the invention include diseases associated with oral airway such as molar extractions, chemotherapy-related mucosal damage (Spijkervet et al., Curr. Opin.Oncol., 10 (Supplement 1): S23-7 (1998); Khan et al., J. Natl.Cancer Inst. Monogr., 29: 31-6 (2001)), non-infectious lung damage after bone marrow transplantation, such as respiratory distress syndrome (Hite et al. , Drugs, 61 (7): 897-907 (2001)) and bronchiolitis obliteran pneumonia (Nagai et al., Curr. Opin. Pulm. Med., 2 (5): 419-23 (1996); Epler, GR, Semin Respir Infect., 10 (2): 65-77 (1995)).

TNF-α and IL-I modulation as therapeutic approaches

Prior to TNF-α isolation, the therapeutic approaches employed for the above diseases aimed at reducing chronic inflammation and were based on steroidal and non-steroidal anti-inflammatory treatments. However, recent understanding of TNF-α has led to the development of alternative strategies based on its selective inhibition. These general strategies are summarized below.

Steroid Treatment - This treatment, which includes the use of corticosteroids, causes a reduction in the number and activity of immune cells. The mechanism of action of corticosteroids involves crossing the plasma membrane and binding to receptors in cytosol. The resulting complexes are then transported to the cell nucleus where they bind to specific regulatory DNA sequences, thereby regulating cytokine production. Although currently employed, this strategy has several disadvantages since it is not specific for TNF-α but also down-regulates several other cytokines that may play important roles in an effective immune reaction. In addition, steroid use is also implicated as cancer development (eg prostate cancer).

Non-Steroidal Anti-Inflammatory Treatment This strategy includes the use of compounds such as aspirin that indirectly reduce inflammation. This is usually accomplished by inhibiting the cyclooxygenase pathway by which the etromboxane prostaglandins are produced. This action reduces vascular permeability and provides temporary relief. To this end, this strategy does not regulate cytokine production and has no effect on diseases associated with chronic inflammation.

Anti-TNF Monoclonal Antibodies Created - This strategy involves a selection of monoclonal antibodies that are capable of binding to and neutralizing TNF-α. Although preliminary clinical studies have shown some positive results, this approach is still in its infancy and not generally accepted. One of the problems to be solved is that monoclonal antibodies are of murine origin and in humans they elicit anti-immunoglobulin immune responses that limit their clinical use. Recombinant breeding techniques are being sought to create "humanized" versions of anti-odorant antibodies that will maintain activity against TNF-α and that will be more readily accepted by the human immune system.

Use of soluble TNF-α receptors - The use of soluble TNF-α receptors is a new therapeutic approach. Although these receptors are designed to bind to, and neutralize, TNF-α, they also increase their activity by prolonging their life cycle. blood circulation. In addition, the long-term immune response to this type of treatment is being evaluated. Gene Therapy - The goal of this approach is to decrease inflammation by not decreasing TNF-α expression but increasing local production of anti-inflammatory cytokines. Treatment consists of direct injection of cDNA-expression vector coding for anti-inflammatory cytokines in the inflamed area, which could antagonize the effect of TNF. The effectiveness of this method is currently under investigation in preclinical studies and its long-term effects on the immune response remain unknown. . . .Other disease states and conditions

Additionally, TNF-α and / or IL-I have been identified more recently as participants in modulating angiogenic vascular endothelial degrowth factor (VEGF), see E.M.Paleolog et al. , Arthritis & Rheumatism, 41, 1258 (1998), and may participate in tuberculous pleurisy, rheumatoid pleurisy, and other immune diseases, see T. Soderblom, Eur. Respir. J., 9,1652 (1996). TNF-α has also been reported to express certain cancer cell genes for proteins associated with multidrug resistance (PRM) and pulmonary resistance proteins (PRP), see V. Stein, J. Nat. Canc Inst., 89, 807 (1997), and participating in chronic econgestive heart failure and related cardiovascular diseases, see for example R. Ferrari, Cardiovascular Res., 37, 554 (1998); C. Ceconiet al., Prog. Cardiovascular Dis., 41, 25 (1998), and mediating directly or indirectly viral infections, see D.K.Biswas, et al., J. Acguired Immune Defic. Syndr. Hum. Retrovirol., 18, 426-34 (1998) (HIV-I replication); R. LeNauor, et al., Res. Virol., 145, 199-207 (1994) (same); T. Harrer, et al. , J.Follow. Defie Immune. Syndr., 6, 865-71 (1993) (same); E. Fietz, et al. , Transplantation, 58 (6), 675-80 (1994) (human cytomegalovirus (CMV) regulation); D.F. Zhang, et al., Chin. Med. J., 106, 335-38 (1993) (HCV and HBV infection). In addition, TNF-α antagonists have also been shown to be useful in treating skin redness of neurogenic origin. See EPO-774250-B1 (from De Lacharriere et al.).

TNF-α has also been identified as expressed in increased levels in humans diagnosed as obese or exhibiting insulin resistance, and is thus a dadiabetes modulator. See Hotamisligil, G., Arner, P., Atkuinson, R., Speigelman, B., (1995) .Increased adipose tissue expression of tumor necrosis factor-α (TNF-α) in human obesity and insulin resistance, "J. Clin Invest 95: 2409-2415 TNF-α has also been identified as an important modulator of transplant rejection See Imagawa, D., Millis, J., Olthoff, K., Derus, L., Chia, D. , Sugich, L., Ozawa, M., Dempsey, R., Iwaki, Y., Levy, P., Terasaki, P., Busuttil, R., (1990) "The role of tumor necrosisfactor in allograft rejection", vol 50, no. 2, 219-225.

Pharmaceutical Compositions

Other forms of incorporation relate to pharmaceutical compositions useful in the treatment of various diseases and disease states. Such disclosed pharmaceutical compositions may comprise a pharmaceutically acceptable carrier or diluent, well known in the pharmaceutical art and already described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (ed. R. Gennaro, 1985) and a pharmaceutically effective amount of a chemical compound. Such compositions may comprise preservatives, stabilizers, tinctures, flavoring agents, antioxidants and suspending agents. Further described hereinbelow are various pharmaceutical compositions well known in the art for pharmaceutical use including intraocular, intra nasal, and intra auricular delivery. Pharmaceutical formulations for intraocular delivery include aqueous ophthalmic solutions of the active compounds in water-soluble form, such as eye drops, or gel coat (Shedden et al., Clin. Ther., 23 (3): 440-50 (2001)) or hydro gels (Mayer et al., Ophthalmologica, 210 (2): 101-3 (1996)); ophthalmic ointments; ophthalmic suspensions, such as microparticles, small drug-containing polymeric particles suspended in a liquid carrier medium (Joshi, A., J. Ocul.Pharmaeol., 10 (l): 29-45 (1994)), soluble formulations lipid (Alm et al., Prog. Clin. Biol. Res., 312: 447-58 (1989)), and microspheres (Mordenti, Toxieol. Sci., 52 (1): 101-6 (1999)) ; and eye inserts. Satisfactory pharmaceutical formulations for intraocular distribution are often and preferably formulated to be sterile, isotonic and buffered for stability and comfort. Pharmaceutical compositions for intra-nasal delivery often include drops and sprays prepared to simulate nasal secretions, in many respects to ensure the maintenance of normal ciliary action. As described in Remington's Pharmaceutical Sciences (Mack Publishing, 18th Edition), and well known to those skilled in the art, satisfactory nasal formulations are often preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and often and preferably include condoms. appropriate antimicrobials and drug stabilizers. Pharmaceutical formulations for in-ear delivery include suspensions and ointments for topical ear application. Common solvents for such ear formulations include glycerin and water.

Administration Methods

Still further forms of incorporation will relate to methods for administering the described chemical compounds and pharmaceutical compositions described. Such methods described include, among others, (a) administration by oral routes, the administration of which includes administration in capsules, tablets, granules, sprays, syrups, or other similar forms; (b) administration via non-oral routes, the administration of which includes administration as an aqueous suspension, oily preparation or the like, or as a drip, suppository, ointment, ointment or the like; administration by injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, or the like; as well as (c) topical administration, (d) rectal administration, or (e) vaginal administration, as deemed appropriate by those skilled in the art to bring the compound into contact with living tissue; and (f) administration by controlled release formulations, deposition formulations, and infusion pump delivery. As additional examples of such modes of administration and as further description of the modes of administration, various methods for administering the chemical compounds and the pharmaceutical compositions described herein including modes of intraocular, intranasal, and intra-auricular pathways are described.

These observations highlight the importance and the desire to identify new strategies and / or new compounds and compounds that selectively influence the production of TNF-α and / or IL-I. Small molecules that selectively inhibit these cytokines are therefore particularly important biologically and in medicine to, for example, maintain an active immune system and treat inflammation-based diseases.

Preferred Methods if Synthesis of the Invention

Certain embodiments relate to new methods for making the described compounds, including, for example, compounds having the chemical structure of Formulas (II), (IIA), or (IIB), as well as new methods for making known analogs of known compounds having the same structure. chemical structure of Formulas (II), (IIA), or (IIB), for example, the compounds of Formulas (I) and (IA).

The compounds of the present invention, and specifically those compounds having the chemical structure of Formula (II), (IIA), or (IIB), may be synthetically or semi-synthetically prepared. If prepared synthetically, commonly available starting materials may be used, including, but not limited to, bicyclic compounds having halidareactive means. Compounds with at least three rings of the present invention may be synthesized according to various ring-closing reactions. Such reactions include, but are not limited to, Diels-Alder sandblasting, and Dieckmann's condensation reaction. Diels-Alder cleavage preferably involves the reaction of a diene and a substituted alkenyl medium such that the third ring of the desired compound is formed. Dieckmann's condensation reaction may preferably be followed by reduction of the resulting decyclone ketone medium. The compounds of the present invention may be purified and isolated by such synthetic methods and other well-known synthetic methods by the use of procedures such as chromatography or HPLC as well known to those skilled in the art. have the chemical structure of Formulas (I) and (IA), and certain specific analogs and derivatives, may be extracted and isolated, at least in the form of a crude extract comprising acanthoic acid, from the root bark of AcanthopanaxKoreanum Nakai. Such an extract may preferably be produced according to the following method:

Approximately one kilogram of A. Koreanum Nakai root bark is obtained, smashed, and covered with 1 L to 3 L, and preferably 2 L, of a suitable solvent, preferably methanol. This mixture is kept at a temperature ranging from 20 ° to 60 ° C, and may be kept at room temperature for at least 10 hours, and preferably for 12 hours. The mixture is then filtered to remove and retain the filtrate. This procedure is repeated, preferably at least twice more, and the combined filtrates are concentrated under reduced pressure to obtain an extract.

Approximately 100 grams of the extract are provided with 200 mL to 400 mL, preferably 300 mL, of an aqueous solution, preferably water and 200 mL to 400 mL, preferably 300 mL, of an organic solution, preferably diethyl ether. The organic fraction is separated and then concentrated under reduced pressure to obtain additional extract. Said additional extract is purified, preferably by column chromatography and even more preferably by the use of a silica gel column, using a mixture of suitable organic solvents, preferably hexane and ethyl acetate as an eluent to obtain isolated acanthoic acid.

This isolated compound of Formulas (I) and (IA) may then be synthetically modified to obtain certain compounds of the present invention, specifically compounds having the chemical structure of Formula (II) or (IIA). For example, acanthoic acid R1 ester analogs may be formed according to the acid catalyzed nucleophilic addition of an alkyl alcohol to the acanthoic acid carboxylic acid medium.

Acanthoic acid R1 ether analogs may be formed from primary alkyl halides or alcohols according to Williamson ether synthesis, or by reduction of a primary alcohol medium. Alcoholic, alkyl and R 10 alkenyl analogs of acanthoic acid may be formed by catalytic hydrogenation of the alkenyl group, or by the electrophilic addition of preferably HCl or HBr or other satisfactory alkyl halides. Replacement analogs at the other R acanthoic acid positions may be formed by displacement reactions involving alkyl halides, suitable reactive groups, and related protecting groups are employed to encourage desired sandation. According to this reaction and other well-known synthetic reactions, the production of the full range of compounds of the present invention, given the description of such compounds provided herein, is within the scope of those skilled in the art.

Fully synthetic approaches to the preparation of the compounds of the invention, including the compounds of the general Formulas (I), (IA), (II), (IIA), and (IIB) are described above. The approaches are applicable to any of the compounds described herein, including subgenres of the compounds of Formulas (I), (IA), (II), (IIA), and (IIB), such as, for example, the compounds of Formulas IIAA, IIA- Al, IIBB, IIB-Al, 112, II2-1, and the like. This synthesis includes one or more retro-synthetic analyzes of acanthoic acid and its analogs, syntheses of radiolabeled acanthoic acid and its analogs, synthesized dimer dimers of the compounds of the Formulas. (I), (IA), (II), (IIA), and (IIB). Those skilled in the art will also appreciate that these approaches are fully applicable to the preparation of cauranoic acid and its analogs.

The compound of formula (I) and its analogues naturally occurring

The root bark of Acanthopanax Koreanum Nakai (Araliaceae) that is found natively on Cheju Island in the Republic of Korea has traditionally been used as a tonic and sedative as well as a remedy for the treatment of rheumatism and diabetes. During the popular drug investigation, Chung and co-helpers identified from their pharmacologically active extracts two new diterpenostricyclic acids: acanthoic acid (Compound 1) and its methyl ester (Compound 2), as described in Figure 1. See Kim, YH Chung, BS; Sankawa, U., "Pimaradiene diterpenes from Acanthopax Koreanum", J. Nat. Prod., 1988, 51, 1080-1083. Acanthoic acid is a pimaran (3). However, in sharp contrast to the other members of the pimaran family, (1) is distinguished by an unusual stereo-chemical relationship between the C8 and ClO centers that provide a unique mode of connectivity of the BC ring system. Acanthoic acid may also be obtained by the procedure described below in the synthesis of the compounds of Formulas II-II and IIA-Al.

Extraction and isolation of acanthoic acid from Coleonema Pulchrum roots

Prior to this invention, no complete chemical synthesis existed for the production of the chemical having the structure of Formula (I) or analogs thereof. Importantly, the chemical structure of Formula (I) 1 (Figure 1) has a biological profile as an anti-inflammatory agent. More specifically, invigorous studies with activated (inflamed) monocytes / macrophages revealed that treatment with (1) (about 0.1 to about 1.0 micrograms / ml for 48 hours) leads to approximately 90% inhibition of TNF-α production and IL-I. This inhibition was concentration dependent and specific for cytokine, since under the same conditions the production of IL-6 or IFN-γ (interferon-gamma) was not affected. The in vivo effects of acanthoic acid were evaluated in rats suffering from silicosis (chronic pulmonary inflammation) and cirrhosis (liver inflammation and liver fibrosis). Histological analysis revealed that treatment with compound 1 led to a significant reduction in fibrotic granulomas and a remarkable recovery of cirrhotic liver cells. These dramatic results can be attributed, at least partially, to inhibition of proinflammatory cytokines such as TNF-α and IL-I, mediated by (1). Compound 1 also had very low toxicity in rats and only when administered orally at a high concentration (LD> 300 mg / 100 g body weight). See Kang, H.-S .; Kim, Y.-H., Lee, C.-S .; Lee, J.-J .; Choi, L; Pyun, K.-H., Cellular Immunol., 1996, 770, 212-221. Kang, Η.-S .; Song, Η.K .; Lee, J.-J .; Pyun, Κ.-H .; Choi, I., Mediators Inflamm. 1998, 7, 257-259.

The chemical structure of Formula (I) thus has potent anti-inflammatory and anti-fibrotic effects and reduces the expression of TNF-α and IL-I. Acanthoic acid is thus used as a chemical prototype for the development of new compounds.

Retro-synthetic analyzes of the compounds of Formulas (I), (II) and (IIB)

The compounds of Formulas (I), (II) and (IIB), preferably the compound of Formula (I) and the compounds of Formula (IIB) herein designated TTL1, TTL2, TTL3, and TTL4, may be synthesized according to one aspect of the invention. invention. Binding disconnections of the compounds of Formulas (I) are shown in Figure 2. The new structural arrangement of the BC rings and the presence of the quaternary C13 center is an unusual motif and leads to a new strategy which is an aspect of the invention. This motif is fixed in one step to the desired stereo-chemistry using a Diels-Alder methodology. A diene, for example 14, and a diophile, such as 15 (Y: oxazolidinone-based helper), have been identified as the appropriate starting materials for a selective Diels-Alder end-reaction. To further ensure the desired regio-chemical result of this cycloaddition, diene 14 was transiently functionalized with a straight atom (eg, X = OTBS or SPh), which will subsequently be removed from product 13. The endo-preference generally observed in this reaction was used. to predict the stereo-chemical relationship between the C12 and C13 centers as shown in the product13, while the diasteo-facial selectivity of the process will be controlled by an auxiliary chiral to the dodienophil carbonyl center, or by the use of a chiral catalyst. See Xiang, X.X .; Watson, D.A .; Ling. T .; Theodorakis, E.A., "Total Synthesisof Clerocidin via Novel, Enantioselective Homoallenylboration Methodology", J. Org. Chem., 1998, 63, 6774-6775.

Diene 14 may be formed by a palladium (0) catalyzed construction of the C8-C11 bond, revealing ketone 16 as its synthetic parent. This ketone was formed from the well-known Wieland-Miescher ketone (17), which was readily available by condensing vinyl methyl ketone (19) with 2-methyl 1,3-cyclohexane dione (18) (Figure 2). .

In one aspect of the invention, it is recognized that the functionalities and relative stereo chemistry of the acanthoic acid BC ring system (1) are similar to those in the podocappric acid structure (20). See "The Total Synthesis of Natural Products", ApSimon, Ed .; John Wiley & Sons, Inc., 1973, Volume 8, pages 1-243. Among the various synthetic strategies for (20), the enhancement of some that may be pertinent to the proposed synthesis of (1) is shown in Figure 5. According to the invention, these approaches allowed the prediction of the stereo-chemical result of the synthesis of compounds. of Formula (I), (II) and counter-stereochemistry of the compounds of Formula (IIB), and the compounds of Formula (IIB) which are referred to herein as TTL1, TTL2, TTL3, and TTL4.

<formula> formula see original document page 125 </formula>

Complete syntheses of the compounds of Formulas (I), (II) and (IIB)

The initial step in the synthesis of acanthoic acid (1) and all compounds of Formulas (I), (II) and (IIB) involves the reaction of a Wieland-Miesher ketone (17). This compound was readily available from compounds 18 and 19 as a single enantiomer via a Michael addition / Robinson deletion sequence using catalytic amounts of (R) -proline. Selective protection of the most basic C9 carbonyl group (17), followed by a reductive alkylation of methyl cyano-formate enone 34 gave rise to keto ether 36. The transformation from 36 to 39 was based on previous studies, see Welch , SC; Hagan, CP, "A new stereoselective method for developing ring The ofpodocapric acid compounds", Sinthetic Commun., 1972, 2, 221-225, as described in Figure 3. The reduction in ester functionality of (39), followed by silylation of The resulting alcohol and acid-catalyzed protection of the ketal unit then has acetone 40. The conversion of (40) to the desired diene 42 was accomplished by a two-step sequence involving the transformation of (40) into its corresponding trifolode enol derivative, followed by catalyzed coupling. vinyl estanane palladium 41. See Farine, V .; Hauck, S.L; Firestone R.A. "Synthesis of cephems bearing olefinic sulfoxide side chains potential b-lactamase inhibitors", Bioorg. & Medicinal Chem. Let., 1996, 6, 1613-1618.

The steps that were used in completing the synthesis of acanthoic acid (1), and which are used in completing the syntheses of the compounds of Formulas (I), (II) and (IIB) are described in Figure 5, as Scheme 2. A Cycle Addition of Diels-Alder between diene 42 and dienophile 43, followed by reductive de-sulfurization with Raney's Ni yields the desired tricyclic system 44 with desired stereo-chemistry. The transformation from (44) to the Weinreb amide is followed by the reduction with DIBALH-generated aldehyde 45 which in the Wittig reaction gave olefin 46. The fluoride-induced de-silylation of (46) followed by a two-step oxidation of the resulting alcohol to the. carboxylic acid has produced acanthoic acid (1), and may be used to produce the compounds of Formulas (I), (II) and (IIB) by appropriate substitution of the intermediates.

An important step for the synthesis of the compounds of Formulas (I) and (IA), and the compounds of Formulas (II), (IIA) and (IIB), is the Diels-Alder reaction. This reaction, and the use and selection of one or more suitably substituted dienophiles and / or dienes allows for selective synthesis of the compounds of Formula (II) or selective synthesis of the compounds of Formula (IIB). For example, the following preferred dienophiles may be used in place of the diophiles, for example compound 43 and pimaran (103), as described herein, for example, in Figures 5, 7, 8, 21, and 23, as Reaction Schemes 2, 3, 4, 5, and 6, to selectively obtain the compounds of Formulas (II) and (IIB). Exemplary dienophiles include those of Formulas (III): <formula> formula see original document page 127 </formula>

Wherein the numbered R groups (R 9, R 14, and R 15) are as designated above for the compounds of Formula (IIB), and the unnumbered R groups may be any R 1 to R 15 as assigned above for the compounds of Formula (IIB).

In addition, the electronic conformation of the diene, for example compound (42) and compound (112), as described, for example, in Figures 5, 7, 8, 21, and 23, as Reaction Schemes 2, 3, 4 , 5, and 6, respectively, can be changed by covalently coupling the electron withdrawing group or electron donor, e.g., pHS, to the diene. As exemplified herein, such a group that removes covalently coupled electrons or electron donors directs the dienophile as it enters.

Thus, according to one aspect of the invention, the chiral nature of diene 42 allows it to be used to induce asymmetry during cycloaddition. Examination of a minimized model (42) indicates that the angular methyl in ClO influences the facial selectivity of the reaction and allows a more efficient approach to the diene top face dienophile. This approach produced the means leading to the compounds of Formula (IIB).

This approach also allowed the development of a catalytic asymmetric variant of the Diels-Alder reaction. The dual benefits of chiral catalysts rather than chiral auxiliaries are obvious and well documented in recent literature.

A preferred embodiment is that of catalyst 49, which was developed and applied by Corey for improved asymmetric cassiol synthesis (Scheme 3). See Corey, E.J .; Imai, N .; Zhang, H.-Y., J. Am. Chem. Soc.1994, 116, 3611. Compound 49 has been shown to allow Diels-Alder to be cyclically added to an electronically rich diene 47 with methacrolein (48) and produces exclusively the excellent endo-adduct yield and enantiomeric excess (83% yield, 97% from ee).

The application of the above methodology for a preferred synthesis is described in Figure 8 as Scheme 4. The use of catalyst 49 provided additional versatility and significantly shortened the total steps required to complete the total synthesis of (1).

Summaries of Radio-labeled Compounds of Formula (I)

A radiolabelled sample of a compound of Formulas (I), (II), (IIA) or (IIB) may be synthesized and is useful in pharmacological and pharmacokinetic studies, for example, a C14-labeled methylene carbon is incorporated into the compound of Formula ( I) using aldehyde 52 as a starting material (as described in Figure 4, Scheme 4). The obtained C14-labeled, required for Wittig chemistry, is prepared in two steps from C14-labeled iodomethane and triphenylphosphine, followed by treatment with a base such as NaHMDS. The base-induced protection of the methylyl ester produces a radiolabelled compound of Formulas (I), (II), (IIA) or (IIB).

<formula> formula see original document page 128 </formula> Objectives of the syntheses of the compounds of Formulas (II), (IIA) and (IIB)

One aspect of the invention is the identification of novel anti-inflammatory drugs having the structure of the compounds of Formulas (II), (IIA) and (IIB). The biological framework of the rationally designed synthetic and compound intermediates of Formula (II) provides information and guides design requirements.

The design and synthesis of Formula (II) analogs are based on the following objectives: (a) to define the minimum structural and functional requirements of Formula (II) compounds that are responsible for modulating activity of TNF-α and IL-I (pharmacophorus). Minimum); (b) improving the TNF-α and IL-I demodulation activity of the compounds of Formula (II) by altering the structure, particularly of the minimal pharmacophorus R groups (e.g. SAR studies and molecular recognition experiments); (c) examine the mode of action of the compounds of Formula (II) by photo affinity labeling studies; (d) modify and improve the membrane solubility and permeability of the compounds of Formula (II); (e) synthesize and study dimers or conjugates of the compounds of Formula (II) and selective distribution units, and (f) redesign and refine the target structure by evaluating the biological data obtained.

Of particular significance to the projection of new compounds of the Formulas (II), (IIA) and (IIB) are recent reports that modification of the oleanolic acid ring A and C (53), as described in Figure 9, leads to anti-active activity. -proliferative and increased anti-inflammatory. See Honda, T .; Rounds, B.V.; Gribble, G.W.; Suh, N .; Wang, Y., · Sporn, MB, "Design and synthesis of 2-cyano-3,12-dioxolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitricoxid production in mouse macrophages", Biorg. & Medic. Chem. Let., 1998, 8, 2711-2714. Suh, N. et al. , "Novel syntheticoleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oicacid, with potent differetiating, antiproliferative and anti-inflammatory activity", Cancer Res., 1999, 59, 336- 341 More specifically, SAR studies with (53) commercially available and their semi-synthetic derivatives have led to the recognition that: (a) coupling of electron withdrawing groups, such as comonitrile, at position C2 increases the biological potency of (53) (Figure 9 ); (b) an unsaturated ketone α, β functionality in ring C is a strong potency enhancer. The combination of these observations leads to the semi-synthesis of a designed triterpenoid 54 (Figure 9), which proves to be 500 times more active than any other known triterpenoid by suppressing the inflammatory enzymes of (inducible nitric oxide synthase) and COX-2 (cyclohexane). oxygenase-2) (Figure 9).

Synthesis of the compounds of Formulas (II), (IIA) and (IIB)

The thirteen-step synthesis of the compounds of Formulas (II), (IIA) and (IIB) (as shown in Figures 4 and 8, Schemes 1 and 4, respectively) is efficient and as such allows the preparation of a variety of analogs useful in SAR studies. Biological significance of the unusual tricyclic platform of the compounds of Formulas (II), (IIA) and (IIB) (the C8 epimer is constructed using the appropriate Diels-Alder catalyst). Locations that are easily altered by the synthetic approach of the invention, or by standard modifications of the synthetic intermediates, are shown in Figure 10, and representative examples of the compounds of Formula (II) are shown in Figure 11.

The desired chemical platform of the compounds of Formula (II), (IIA) and (IIB) may also be incorporated into a solid support such as a Wang resin. This enables easy construction of combinatorial libraries of the compounds of Formula (II), (IIA) and (IIB). Further, according to the invention, preferred TNF-α and IL-I modulators can be identified and framed more rapidly than currently possible.

Photo-affinity labeling studies - The "backbone" of the compounds of Formulas (II), (IIA) and (IIB) is also preferably labeled with a reactive crosslinking, which is useful in photo-labeling studies. affinity. . These studies help in vivo target identification of the compounds of Formula (II), (IIA) and (IIB) and provide fundamental insights into acanthoic acid mode of action and TNF-α activation. C19 carboxylic acid or C15 aldehyde (precursor of (1)) are useful in cross-linking experiments with appropriate photosensitive reagents (see 60 and 61, figure 12).

Synthesis of dimers and conjugates of the compounds of Formulas (II), (IIA) and (IIB)

Dimeric forms of the compounds of Formulas (II), (IIA) and (IIB), as for example (62) (n = 1), have been isolated from natural sources and, furthermore, the acanthoic acid-dexamethasone conjugate 63 provides biologically results. interesting for a drug targeting a steroid receptor with potential implications for cancer research. See Chamy, M.C; Piovano, M., · Garbarino, J.A .; Miranda, C .; Vicente, G., Phytochemistry, 1990,9, 2943-2946. While no decomposed biological studies of this class were performed according to the invention, the dimeric analogs of Formulas (II), (IIA) and (IIB) were evaluated. Synthetic acanthoic acid or bioactive analogs of (1) are used as monomeric members and are coupled using standard techniques, including those described herein.

Experimental Techniques

All reactions were performed under an argon atmosphere in freshly distilled solvents under anhydrous conditions unless otherwise specified. Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled from sodium / benzophenone, · dichloromethane (CH 2 Cl 2), hexamethylphosphoramide (HMFA), and toluene from calcium hydroxide; edimethyl formamide (DMF) from calcium chloride. Earnings refer to chromatographically and spectroscopically homogeneous materials (1H NMR) unless otherwise specified. Reagents were purchased at the highest commercial quality and used without further purification unless otherwise specified. Reactions were monitored by thin layer chromatography performed on silica gel plates. 0.25 mm Merck (60F-254) using U.V. 7% phosphomolybdic acid ethanolic, or a solution of p-anisaldehyde and heat as developing agents. E. Merck silica gel (60, particle size -0.040-0.063 mm) was used for chromatography. flash. Preparative separations of thin layer chromatography were performed on ílica silica plates. Merck of 0.25 or 0.50 mm (60F-254). NMR spectra were recorded on 400 and / or 500 MHz Varian instruments and calibrated using a residual undeuterated solvent as an internal reference. The following abbreviations were used to explain multiplicities: s = simple; d = double; t = triple q = quadruple; m = multiple; b = broad. IR spectra were recorded on a FT-IR Nicolet Avatar 320 spectrometer. Optical rotations were recorded on a Perkin Elmer241 polarimeter. High resolution mass spectra (EMAR) were recorded on a VG 7070 HS mass spectrometer under chemical ionization (IQ) conditions or on a VG ZAB-ZSE mass spectrometer under fast atom bombardment (BRA) conditions.

<figure> figure see original document page 132 </figure>

Triguetone 2 - A solution of diquetone 1 (50 g, 0.40 mol) in ethyl acetate (500 ml) was treated with triethylamine (72 ml, 0.52 mol) and methyl vinyl ketone (36 ml, 0 .44mol). The reaction mixture was refluxed at 70 ° C for 10 h and then cooled to 25 ° C. The solvent was removed under pressure and the resulting crude material was directly chromatographed (10-40% ether in hexanes) to obtain triquetone 2 (61 g, 0.31 mol, 78%). 2: colorless oil; Rf = 0.25 (silica, 50% ether in hexanes); 1H NMR (400MHz, CDCl3) δ 2.75-2.59 (m, 4H), 2.34 (t, 2H, J = 7.2 Hz), 2.10 (s, 3H), 2.07- 2.05 (m, 3H), 1.98-1.94 (m, 1H), 1.24 (s, 3H).

<figure> figure see original document page 132 </figure>

Wieland-Miescher Ketone (3) - A solution of detriquetone 2 (61 g, 0.31 mol) in dimethyl sulfoxide (400 ml) was treated with finely grounded D-proline (1.7 g, 0.01 mol). (As noted below, see Examples 18 to 21, atriquetone 2 in dimethyl sulfoxide (400 ml) can also be treated with finely grounded L-proline to obtain the Wieland-Miescher ketone enantiomer (3)). The solution was stirred at 25 ° C for 4 days and then stirred at 40 ° C for an additional day. The resulting purple colored solution was cooled to 25 ° C, diluted with water (300 mL) and brine (100 mL), and poured into a separatory funnel. The mixture was extracted with ethyl ether (3 x 800ml). The organic layers were concentrated (without drying) and subjected to chromatography (10-40% ether in hexanes) to obtain 59g of a crude reddish-violet oil. The material was subjected to chromatography (10-40% ether in hexanes) and concentrated to obtain 57 g of a yellow oil. The oil was dissolved in ethyl ether (400 mL) and kept at 4 ° C for 30 min, after which time a layer of hexanes (100 mL) was added over the ether. The two-layer solution was seeded with a few crystals and placed in a freezer (-28 ° C) overnight. The resulting crystals were collected by filtration, rinsed with ice cold hexanes (2 χ 100 ml), and dried under pressure. Concentration of the source liquor allowed for further harvesting, and the combination of the crystals afforded Wieland-Miescher Ketone (3) (43 g, 0.24 mol, 78%). 3: brown crystals; Rf = 0.25 (silica, 50% ether in hexanes); [α] 25D: -80.0 (c = 1, C6H6); 1H NMR (400 MHz, CDCl3) δ 5.85 (s, 1H), 2.72-2.66 (m, 2H), 2.51-2.42 (m, 4H), 2.14-2.10 (m, 3H), 1.71-1.68 (m, 1H), 1.44 (s, 3H); 13CNMR (100 MHz, CDCl 3) δ 210.7, 198.0, 165.6, 125.7, 50.6, 37.7, 33.7, 31.8, 29.7, 23.4, 23, 0

Acetal 4 - A solution of ketone 3 (43 g, 0.24 mol) in benzene (700 ml) was treated with p-toluenesulfonic acid (4.6 g, 0.024 mol) and ethylene glycol (15 ml, 0.27 mol). The reaction was refluxed with a Dean-Stark apparatus and condensed at 120 ° C. When water stopped collecting in the Dean-Stark apparatus, sandblasting was complete (approximately 4 h). Abandoning the reaction for long periods of time made the reaction mixture tend to darken and decrease its overall yield. The reaction was cooled to 25 ° C, quenched with tri-ethylamine (5 ml, 0.036 mol), and poured into a separatory funnel containing water (300 ml) and saturated sodium combicarbonate (200 ml). The resulting mixture was then extracted with ether (3 x 800 ml). The organic layers were combined, dried over MgSO4, concentrated, and chromatographed (10-40% ether in hexanes) to afford acetal 4 (48g, 0.22 mol, 90%). 4: yellow oil; Rf = 0.30 (silica, 50% ether in hexanes); [α] 25D: -77 ° (c = 1, C6H6); IR (film) Dmax 2943, 2790.1667, 1450, 1325, 1250; 1H NMR (400 MHz, CDCl3) δ 5.80 (s, 1H), 3.98-3.93 (m, 4H), 2.43-2.35 (m, 3H), 2.34-2, 20 (m, 3H), 1.94-1.82 (m, 1H), 1.78-1.60 (m, 3H), 1.34 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 198.9, 167.5, 125.5, 112.2, 65.4, 65.1, 45.1, 34.0, 31.5, 30.1.26 9, 21.8, 20.6.

<formula> formula see original document page 134 </formula>

Ketoester 5 - A solution of lithium (0.72 g, 0.10 mol) in liquid ammonia (400 ml) at -78 ° C was dripped treated with an acetal 4 solution (10 g, 0.045 mol) and tert-butyl alcohol (3.7 ml, 0.045 mol) in ether (40 ml). The resulting blue mixture was allowed to be heated and stirred at reflux (-33 ° C) for 15 min and then cooled to -78 ° C again. Sufficient isoprene (approximately 8 ml) was added by dripping to discharge the residual blue color from the reaction mixture. Sandblasting was then heated in a water bath (50 ° C) and the ammonia evaporated rapidly under a stream of dry nitrogen. The ether was removed under pressure to leave a white foam.

After an additional 5 min under high vacuum, the nitrogen atmosphere was re-established, and lithium enolate was suspended in dry ether (150 ml) and cooled to -78 ° C. Methyl cyanoformate (4.0 mL, 0.050 mol) was then added and the reaction stirred for 40min at -78 ° C. The reaction was heated to 0 ° C and stirred for a further 1 h.

Water (300 mL) and ether (200 mL) were added and the mixture poured into a separatory funnel containing saturated sodium chloride (100 mL). After separating the organic layer, the aqueous phase was extracted with ether (2 x 400 ml). The combined organic layers were dried over MgSO 4, concentrated, and chromatographed (10-40% ether in hexanes) to afford keto ester5 (7.0 g, 0.025 mol, 55%). 5: white powder precipitate; Rf = 0.40 (silica, 50% ether in hexanes; [α] 25D: -2.9 (c = 1, C6H6); IR (film) Dmax 2943, 1746, 1700; 1H NMR (400 MHz, CDCl3); ) δ 4.00-3.96 (m, 2H), 3.95-3.86 (m, 2H), 3.74 (s, 3H), 3.23 (d, 1H, J = 13.2Hz) ), 2.50-2.42 (m, 3H), 2.05-1.92 (m, 1H), 1.79-1.50 (m, 5H), 1.32-1.28 (m 1 H), 1.21 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 205.4.170.0, 111.9, 65.2, 65.1, 59.9, 52.0, 43, 7.41.6, 37.5, 30,3,29.8, 26.2, 22.5, 14.0; HRMS, calculated for C15 H22 O5 (M + Na +) 305.1359, found 305.1354.

<formula> formula see original document page 135 </formula>

Ester 6 - A solution of keto ester 5 (7.0 g, 0.025 mol) in HMFA (50 ml) was treated with sodium hydroxide (0.71 g, 0.030 mol). After stirring for 3 h at 25 ° C, the resulting yellow-brown reaction mixture was quenched with methylchloromethyl ether (2.3 mL, 0.030 mol) and the reaction allowed to react for an additional 2 h at 25 ° C. The resulting white-yellow mixture was then poured into a separatory funnel containing ice-water (100 mL), saturated sodium bicarbonate (50 mL), and ether (200 mL). After the layers were separated, the aqueous layer was extracted with ether (3 x 200 ml). The combined ether extracts were dried over MgSO 4, concentrated, and chromatographed (silica, 10-40% ether in hexanes) to obtain ester 6 (7.7 g, 0.024 mol, 95%). 6: yellow oil; Rf = 0.45 (silica, 50% ether in hexanes); [α] 25D: +26.3 (c = 1, C6H6); IR (film) Omax 2951, 1728, 1690, 1430, 1170; 1H NMR (400 MHz, CDCl3) δ 4.89 (dd, 2H, J = 22.8, 6.4 Hz), 3.93-3.91 (m, 2H), 3.90-3.84 ( m, 2H), 3.69 (s, 3H), 3.40 (s, 3H), 2.72-2.68 (m, 1H), 2.24 (bs, 2H), 1.80-1 , 42 (m, 4H), 1.37-1.15 (m, 2H), 0.960 (s, 3H), 0.95-0.80 (m, 2H); 13CNMR (100 MHz, CDCl 3) δ 167.8, 150.5, 115.8, 112.1, 93.0, 65.2.65.1, 56.3, 51.3, 40.7, 40, 3, 30.3, 26.4, 23.6, 22.9, 22.3, 13.9; HRMS, calculated for C17 H26 O6 (M + Na +) 349.1622, found 349.1621.

<figure> figure see original document page 136 </figure>

Acetal 7 - A solution of lithium (1.1 g, 0.17 mol) in liquid ammonia (400 ml) at -78 ° C was dripped treated with an ester 6 solution (7.7 g, 0.024 mol) in 1 2-DME (30 ml). The blue reaction mixture was allowed to warm and stir at reflux (-33 ° C) for 20 min. The reaction mixture was then cooled to -78 ° C again and quenched with excess iodine-methane (15 mL, 0.24 mol). The resulting white sludge was allowed to stir at reflux (-33 ° C) for 1 h, and then at that time the reaction was heated in a stirred (50 ° C) water bath for 1 h, allowing the ammonium to evaporate. The reaction mixture was washed with water (100 ml), sodium bicarbonate (100 ml), and ether (200 ml) and poured into a separatory funnel. After the layers were separated, the aqueous layer was extracted with ether (3 x 200ml). The combined ether extracts were dried over MgSO4, concentrated, and chromatographed (silica, 10-30% ether in hexanes) to obtain acetal 7 (4.1 g, 0.014 mol, 61%). 7: semi-crystalline yellow oil; Rf = 0.80 (silica, 50% ether and hexanes); [α] 25D: +16.9 (c = 10, C6H6); IR (film) Dmax 2934, 1728.1466, 1379, 1283, 1125, 942; 1H NMR (400 MHz, CDCl3) δ 3.95-3.80 (m, 4Η), 3.64 (s, 3Η), 2.17-2.15 (m, 1Η), 1.84-1, 37 (m, 1H), 1.16 (s, 3Η), 1.05-1.00 (m, 1Η), 0.87 (s, 3Η); 13 C NMR (100 MHz, CDCl 3) δ 177.7, 112.9, 65.2, 64.9, 51.2, 44.0, 43.7, 38.1, 30.7, 30,3,28 , 8, 23.4, 19.1, 14.7; HRMS calculated for C 16 H 26 O 4 (M + H +) 283.1904, found 283.1944.

<formula> formula see original document page 137 </formula>

Ketone 8 - A solution of acetal 7 (4.1 g, 0.014 millimeter) in THF (50 ml) was treated with 1 M drip HCl (approximately 15 ml) at 250 ° C while stirring. The reaction was monitored by thin layer chromatography and neutralized with sodium bicarbonate (30 ml) once the starting material had disappeared. The resulting mixture was poured into a separatory funnel containing water (100 mL) and ether (100 mL). After the layers were separated, the aqueous layer was extracted with ether (3 x 100 ml). The combined ether extracts were dried over MgSO 4, concentrated, subjected to chromatography (silica, 10-20% ether in hexanes) to obtain ketone 8 (3.3 g, 0.014 mol, 95%). 8: white crystals Rf = 0.70 (silica, 50% ether in hexanes); [α] 25D: +3.5 (c = 1.0, C6H6); IR (film) Dmax 2943, 1728, 1449, 1239, 1143, 1095, 985; 1 H NMR (400 MHz, CDCl 3) δ 3.62 (s, 3H), 2.55-2.45 (m, 1H), 2.92-1.95 (m, 5H), 1.8-1.6 (m, 2H), 1.50-1.30 (m, 4H), 1.14 (s, 3H), 0.98-0.96 (m, 1H), 0.90 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 214.8.177.0, 54.4, 51.3, 49.3, 44.2, 37.9, 37.7, 33.1, 28.6, 26.4 , 22.8, 18.8, 17.0; HRMS, calculated for C14H22O3 (M + Na +) 261.1461, found 261.1482. <formula> formula see original document page 138 </formula>

Alkine 9 - A solution of ketone 8 (2.0 g, 8.3 mmol) in ether (50 mL) was treated with lithium acetylide (0.40 g, 13 mmol). The reaction was stirred at 250 ° C by then quenching sodium combicarbonate (20 ml) and water (30 ml). The mixture was poured into a separatory funnel and the layers separated. The aqueous layer was extracted with ether (3 x 50 ml). The organic layers were combined, dried over MgSO4, concentrated, subjected to chromatography (silica, 10-30% ether in hexanes) paradisporine alkyne 9 (2.0 g, 7.6 mmol, 90%). 9: white solid; Rf = 0.65 (silica, 50% ether in hexanes); 1H NMR (400 MHz, CDCl3) δ 3.64 (s, 3H), 2.56 (s, 1H), 2.18-2.10 (m, 1H), 1.92-1.40 (m, 12H), 1.18 (s, 3H), 1.17-1.01 (m, 1H), 0.81 (s, 3H); 13 C NMR (100 MHz, CDCl 3) 177.6, 86.8, 76.5, 75.0, 51.2, 50.5, 43.9, 52.5, 37.9, 35.3, 33, 4.28.8, 23.5, 22.5, 19.1, 11.5; HRMS calculated for C 16 H 24 O 3 (M + H + -H 2 O) 247.1693, found 247.1697.

<figure> figure see original document page 138 </figure>

Alkene 10 - A solution of Alkine 9 (0.50 g, 1.9 mmol) in 1.4 dioxane (20 mL) and pyridine (2 mL) was treated as Lindlar's catalyst (100 mg). The mixture was hydrogenated under pressure (30 lbs / in2) for 7 min. The reaction mixture was then diluted with ether (10 mL), filtered through a pad of celite, and washed with ether (2 x 50 mL). the solvent was evaporated under reduced pressure to afford alkenene 10 (0.48 g, 1.8 mmol, 95%) 10: colorless oil; 1H NMR (400 MHz, CDCl3) δ 6.58 (dd, 1H), 5.39 (d, 5.14 (d, 1H), 3.64 (s, 3H), 2.20-2.11 ( m, 2H), 1.93-1.65 (m, 1.61 (s, 2H), 1.52-1.25 (m, 4H), 1.19 (s, 3H), 1.17- 0.90 (m, 0.89 (s, 3H).

<formula> formula see original document page 139 </formula>

Diene 11 - A solution of de-alkene 10 (0.48 g, 1.8 mmol) in benzene (80 mL) and THF (20 mL) was treated with trifluoride deboron etherate (1 mL, 7.9 mmol), and the mixture The reaction mixture was refluxed at 100 ° C for 5 h. After cooling, the reaction was quenched with 1 N NaOH (1 mL, 26 mmol) and the mixture was poured into a separatory funnel containing water (100 mL) and ether (100 mL). After separating the layers, the aqueous layer was extracted with ether (3 x 100 ml). The organic layers were combined, dried over MgSO 4, concentrated, and chromatographed (silica, 5% ether and hexanes) to afford diene 11 (0.42 g, 1.7 mmol, 95%). 11: colorless oil; Rf = 0.95 (silica, 50% ether in hexanes); 1H NMR (400MHz, CDCl3) δ 6.26-6.23 (dd, 1H), 5.70 (s, 1H), 5.253 (d, 1H, J = 19.2 Hz), 4.91 (d, 1H, J = 12.8 Hz), 3.64 (s, 3H), 2.22-2.12 (m, 2H), 2.10-1.94 (m, 2H) 1.92-1, 67 (m, 3H), 1.60-1.44 (m, 3H), 1.378 (d, 1H, J = 13.6), 1.21 (s, 1H), 1.19-1.00 ( m, 2H), 0.86 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 177.7, 146.7, 136.1, 121.9, 113.3, 53.0.51,2 43.9, 38.0, 37.9, 37.4, 28.5, 27.8, 20.5, 19.5, 18.3.

5.2 mmol) and diene 11 (0.1 g, 0.40 mmol) was stirred for 8 h at 25 ° C under clean conditions. Excess methacrolein was then removed under reduced pressure. The crude product was chromatographed (silica, 10-20% ether in hexanes) to afford aldehydes 12 and 12 * :( 0.13 g, 0.40 mmol, 100%) as a mixture of diastereomers (C13 ratio from 3: 1-4: 1). 12 and 12 *: colorless oil; Rf = 0.55 (silica, 25% ether in hexanes); 12: IR (film) Omax 3441, 2936.1726, 1451, 1233, 1152; 1 H NMR (400 MHz, CDCl 3) 59.70 (s, 1H), 5.58 (m, 1H), 3.62 (s, 3H), 2.38-2.25 (m, 1H), 2.21 -2.18 (m, 1H), 2.17-1.98 (m, 4H), 1.96-1.62 (m, 6H), 1.61-1.58 (m, 1H), 1 57-1.43 (m, 2H), 1.40-1.23 (m, 1H), 1.17 (s, 3H), 1.04 (s, 3H), 0.92 (s, 3H) 13 C (100 MHz, CDCl 3) δ 207.6, 177.7, 148.3, 188.6, 51.3, 47.8.47.0, 44.2, 41.2, 39.3, 38.8, 38.1, 29.5, 28.4, 22.9, 22.5, 21.8,20.6, 20.5, 19.7; 12 *: [OC] 25 D: +36.8 (c = 0.7, C6H6); IR (film) Omax 3441, 2936, 1726, 1451, 1233, 1152; 1H NMR (400 MHz, CDCl3) 59.64 (s, 1H), 5.42 (m, 1H), 3.66 (s, 3H), 2.29-2.10 (m, 4H), 2, 09-1.84 (m, 4H), 1.81-1.77 (m, 2H), 1.75-1.63 (m, 2H), 1.62-1.58 (m, 2H), 1.57-1.45 (m, 1H), 1.43 (s, 1H), 1.13 (s, 3H), 1.03 (s, 3H), 0.87 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 207.3, 177.5, 147.4,114.6, 55.8, 51.3, 47.3, 44.5, 40.7, 40.4, 38.4 , 37.5, 31.5, 28.6.25.0, 24.2, 21.9, 19.9, 19.6, 18.7.

The preferred way to purify the diastereomeric aldehydes is to reduce them with sodium borohydride in MeOH and separate the alcohols. The main compound (top diastereomer) can then be oxidized to the desired aldehyde 12 in the Dess-Martin periodinane treatment.

<formula> formula see original document page 140 </formula>

Some 13 (TTL3) - A solution of (methyl) triphenyl phosphonium bromide (357 mg, 1.0 mmol) in THF (40 ml) was nitrated with 1 M NaHMDS in THF (0.86 ml, 0.86). mmol). The resulting yellow mixture was allowed to stir at 25 ° C for 30 min. After this time, a solution of aldehyde 12 (91 mg, 0.29 mmol) in THF (10 mL) was added to the reaction by cannula. The reaction mixture was stirred at 250 ° C for 8 hours and then quenched with sodium bicarbonate ( 30 ml) and water (20 ml). The mixture was poured into a separatory funnel containing ether (50 ml). After removing the layers, the aqueous layer was extracted with ether (3 x 50ml). The organic layers were combined, dried over MgSO 4, condensed, and chromatographed (silica, 10% ether and hexanes) to afford alkenene 13 (84 mg, 0.28 mmol, 97%). 13: colorless oil; Rf = 0.75 (silica, 25% ether in hexanes); 13: 1 H NMR (400 MHz, CDCl 3) δ 5.96, (dd, 1H, J = 16.8, 11.6 Hz), 5.50 (m, 1H), 4.98 (m, 2H), 3.62 (s, 3H), 2.20-2.11 (m, 1H), 2.10-1.91 (m, 4H), 1.90-1.70 (m, 4H), 1, 69-1.51 (m, 3H), 1.50-1.38 (m, 3H), 1.36-1.24 (m, 1H), 1.17 (s, 3H), 1.04 ( s, 3H), 0.90 (s, 3H); 13 C NMR (100MHz, CDCl 3) 5177.9, 149.1, 143.8, 117.9, 111.7, 51.2, 47.7, 44.4.15 41.4, 41.2, 38, 9, 38.3, 37.7, 34.8, 30.4, 28.4, 24.8, 23.1, 22,3,22.2, 20.6, 19.8.

<figure> figure see original document page 141 </figure>

Acid 14 (TTL1) - A solution of 13th alkene (84mg, 0.28mmol) in dimethyl sulfoxide (20ml) was treated with LiBr (121mg, 1.4mmol). The reaction mixture was refluxed at 180 ° C for 2 days. After cooling, the reaction was diluted with water (30 mL) and extracted with ether (3 χ 50 mL). The organic layers were combined, dried over MgSO4, concentrated, and chromatographed (silica, 30% ether in hexanes) to afford 14 carboxylic acid (TTL1) (78 mg, 0.26 mmol). 14: white solid Rf = 0.30 (silica, 30% ether in hexanes); 1H NMR (400 MHz, CDCl3) δ 5.96 (dd, 1H, J = 14.4, 9.6 Hz), 5.52 (m, 1H), 4.98-4.95 (m, 2H), 2.20-1.72 (m, 10H), 1.64-1.58 (m, 3H), 1.57-1.37 (m, 4H), 1.22 (s, 3H), 1, 04 (s, 3H), 0.99 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 182.9,149.3, 143.9, 118.1, 111.9, 47.5, 44.2, 41.3, 41.2, 38.9, 38.0 , 37.6, 34.8, 28.4, 24.7, 23.0, 22.4, 21.9, 20.3, 19.5. Ph3P Preparation = 14CH2.

Triphenylphosphine (0.16 g, 0.61 mmol) was added to a 15 ml reaction flask and dried overnight under vacuum at 25 ° C. To this flask was added 2 mL of THF (dried and vacuum degassed), followed by 14CH3I (50 mCi, 53mCi / mmol, 0.9 mmol) dissolved in 1 mL of THF and the mixture was stirred for 24 hours under argon. Depotassium hexamethyl disilylamide (2.5 mL, 1.25 mmol, 0.5 M in toluene) was then added and the reddish-yellow mixture was allowed to be stirred for 3 h at 25 ° C.

Wittig reaction with Ph3P = 14CH2.

The above mixture was cooled to -78 ° C and treated with aldehyde 12 (63 mg, 0.2 mmol) in dry THF (1.5 mL). The mixture was allowed to slowly warm to 25 ° C, stirred for 8 h and quenched with sodium bicarbonate (10 mL) and water (10 mL). The mixture was extracted with ether (3 x 50 ml) and the organic layers were combined, dried over MgSO 4, condensed, and subjected to silica gel chromatography (silica, 10% ether in hexanes) to afford alkene 13.

Alcohol 15 - A solution of Alkine 9 (1.10 g, 4.2 mmol), thio-phenol (1.37 g, 12.4 mmol) and 2,2'-azo-bis-isobutyronitrile (AIBN, 34). 0.5 mg, 0.21 mmol) in xylene (25 mL) was stirred at 110 ° C (under argon) for 18 h. The reaction mixture was cooled to 25 ° C and quenched with aqueous saturated sodium bicarbonate (50 mL). The organic layer was extracted with ethyl ether (3 x 50 ml), collected, dried (MgSO4), concentrated and the residue chromatographed (silica, 2-5% ethyl ether in hexane) to afford alcohol 15 (1.35 g, 3.6 mmol, 85.7%); 15: colorless liquid Rf = 0.51 (silica, 5% ethyl ether in hexane); [α] 25D: +24.20 (c = 1.0, benzene); IR (film) λ max 2946.8, 1724.5, 1472.6, 1438.4.1153.5, 740.0, 690.9; 1H NMR (500 MHz, CDCl3) δ 7.20-7.60 (m, 5Η), 5.23 (d, 1Η, J = 10.5 Hz), 5.12 (d, 1Η, J = 10, Hz), 3.62 (s, 3H), 2.08-2.24 (m, 2H), 1.16-1.92 (m, 9H), 1.09 (s, 3H), 0, 86-1.02 (m, 2H), 0.68 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 177.8, 151.7, 133.9, 133.7, 128.8, 127.9, 118.2, 54.9, 53.5, 51.1, 44.3 , 40.4, 38.1, 37.3, 28.7, 27.7, 25.5, 23.5, 19.5, 18.5.

<formula> formula see original document page 143 </formula>

Diene 16 - To a solution of alcohol 15 (1.10 g, 2.94 mmol) in hexamethyl phosphoramide (HMFA, 10 mL) was added drip phosphorous oxychloride (0.50 g, 3.3 mmol) and the mixture was stirred. at 25 ° C until light. Pyridine (0.26 ml, 3.23 mmol) was then added and the mixture was stirred at 150 ° C (sobargon) for 18 h. The reaction mixture was cooled to 25 ° C and quenched with aqueous saturated sodium bicarbonate (50 ml). The organic layer was extracted with ethyl ether (3 X 60 mL), collected, dried (MgSO 4) and concentrated, and the residue was chromatographed (silica, 2-5% ethyl ether in hexane) to afford diene 16 (0, 85 g, 2.38 mmol, 81%); 16: colorless liquid; Rf = 0.60 (silica, 5% ethyl ether in hexanes); [α] 25D: -17.30 (c = 1.08, benzene); IR (film) Omax 2957.0, 1726.6, 1581.6, 1478.3, 1439.0, 1234.7, 1190.8, 1094.8, 1024.4, 739.1; 1H NMR (500 MHz, CDCl3) δ7.20-7.60 (m, 5H), 6.43 (d, 1H, J = 15.0 Hz), 6.36 (d, 1H, J = 14.5Hz) ), 5.72 (m, 1H), 3.64 (s, 3H), 1.48-2.32 (m, 10H), 1.43 (s, 3H), 1.21 (s, 3H) 1.05 (m, 1H); 0.88 (s, 3H); 13 C NMR (125 MHz, CDCl 3) δ177.9, 133.7, 129.1, 128.9, 128.6, 127.5, 126.2, 123.4, 120.9.52.8, 51, 1, 43.7, 37.7, 37.3, 30.2, 28.3, 27.7, 20.1, 19.3, 18.3. <formula> formula see original document page 144 </ formula >

Aldehyde 17 - To a solution of diene 16 (0.51 g, 1.43 mmol) and methacrolein (0.30 g, 4.30 mmol) in dichloromethane (5 ml) at -20 ° C was added under argon chloride dripping (0 , 29 ml of a 1 M solution in dichloromethane, 0.29 mmol) of tin (IV). The resulting mixture was heated to 0 ° C within 1h and stirred at 0 ° C for 18h. The reaction was quenched with aqueous saturated sodium bicarbonate (15 mL) and the organic layer was extracted with ethyl ether (3 x 20 mL). The combined organic layers were dried (MgSO 4) and concentrated, and the residue was chromatographed (silica, 10-15% ethyl ether in hexane) to afford aldehyde 17 (0.51 g, 1.19 mmol, 83.7%). ; 4: colorless liquid; Rf = 0.48 (silica, 10% ethyl ether in hexanes); [α] 25D: +30.0 (c = 1.13, benzene); IR (film) Omax 2930.8, 2871.4, 1724.9, 1458.4, 1226.4,1149.8; 1H NMR (500 MHz, CDCl3) δ 9.51 (s, 1H), 7.20-7.60 (m, 5H), 5.57 (m, 1H), 3.65 (s, 3H), 1 .20-2.32 (m, 15H), 1.17 (s, 3H), 1.05 (s, 3H), 0.91 (s, 3H); 13 C NMR (125 MHz, CDCl 3) δ 203.6, 177.9, 153.7, 133.6, 133.5, 128.9, 127.8, 117.1, 51.3, 49.1, 47.7 , 44.2, 41.6, 38.7, 38.1, 31.2, 28.3, 27.8, 26.9, 21.7, 20.2, 19.3, 18.6.

<formula> formula see original document page 144 </formula>

Alcohol 18 - To a solution of aldehyde 17 (0.50 g, 1.17 mmol) in anhydrous ethanol (5 mL) was added portions of sodium borohydride (50 mg, 1.32 mmol) and the mixture was stirred by 30%. min Aqueous saturated sodium bicarbonate (10 mL) was then added and the mixture was extracted with ethyl ether (3 x 20 mL). The organic layer was collected, dried (MgSO4) and concentrated. The residue was redissolved in tetrahydrofuran (5 ml) and treated with excess Raney Nickel under argon at 65 ° C for 10 min. The reaction mixture was filtered, and the filtrate was dried (MgSO4) and concentrated, and the residue was chromatographed (silica, 2-5% ethyl ether in hexane) to afford alcohol 18 as a main compound (0.21 g, 0.65 mmol, overall yield 56.1% Note: overall yield for the two previous reactions is 91%); 18: colorless liquid; Rf = 0.39 (silica, 30% ethyl ether in hexanes); [α] 25D: -6.70 (c = 1.0, benzene); IR (film) Omax 3436.8.2929.0, 2872.2, 1728.1, 143.9, 1260.6, 1029.7, 801.6; 1H NMR (500MHz, CDCl3) δ 5.37 (m, 1H), 3.62 (s, 3H), 2.28 (bs, 1H), 2.06-2.20 (m, 2H), 1, 20-2.00 (m, 12H), 1.16 (s, 3H), 0.99 (m, 1H), 0.86 (s, 3H), 0.84 (s, 3H); 13 C NMR (125 MHz, CDCl 3) 6178.2, 150.4, 116.4,73.6, 51.2, 47.9, 44.2, 41.9, 38.8, 38.2, 34, 3, 33.9, 28.3, 28.2.27.8, 22.1, 20.3, 20.1, 18.9.

<figure> figure see original document page 145 </figure>

Alkene 19 - To a solution of alcohol 18 (20.0 mg, 0.062 mmol) in dichloromethane (2 ml) was added periodinane-de-Dess-Martin (35 mg, 0.08 mmol) in portions, and the mixture was stirred at 25 °. C for 30 min. The reaction was quenched with aqueous saturated sodium bicarbonate (5 ml) and extracted with ethyl ether (3 x 10 ml). The organic layer was collected, dried (MgSO4) and concentrated. The residue was redissolved in tetrahydrofuran (0.5 ml) and added under argon to a yellow suspension of (methyl) triphenyl phosphonium bromide (60 mg, 0.17 mmol) and bis (trimethylsilyl sodium) amide (0.14 ml 1.0 M in THF) in THF (1.5 ml). After stirring at 25 ° C for 18 h, the mixture was diluted with aqueous saturated sodium bicarbonate (5 mL) and extracted with ethyl ether (3 x 10 mL). The organic layer was collected, dried (MgSO4), concentrated and the residue was chromatographed (silica, 2-5% ethyl ether in hexane) to afford alkenene 19 (16.8 mg, 0.05 mmol, the reaction yield for two steps is 86%); 19: colorless liquid; Rf = 0.74 (silica, 5% ethyl ether in hexanes);

[α] 25D: -14.40 (c = 0.50, benzene); IR (film) Omax 2929.5, 287.4.1726.8, 1637.7, 1460.7, 1376.8, 1225.1, 1150.4, 997.8, 908.7; 1 H NMR (500 MHz, CDCl 3) δ 5.82 (dd, 1H), 5.39 (m, 1H), 4.85-4.94 (dd, 2H), 3.64 (s, 3H), 2, 30 (bs, 1H), 2.14 (m, 1H), 2.02 (m, 1H), 1.80-1.98 (m, 2H), 1.68-1.80 (m, 2H) , 1.20-1.68 (m, 7H), 1.18 (s, 3H), 0.96 - 1.08 (m, 2H), 0.95 (s, 3H), 0.88 (s , 3H); 13 C NMR (125MHz, CDCl 3) 5178.3, 150.4, 125.6, 116.6, 109.2, 51.2, 47.9, 44,3,41.9, 41.8, 38.3 , 38.2, 37.4, 34.8, 30.2, 29.6, 28.6, 28.4, 27.8.22.1, 20.4, 19.0.

<formula> formula see original document page 146 </formula>

Compound of Formula (I) - To a solution of 15 alkene 19 (16.8 mg, 0.05 mmol) in N, N-dimethyl formamide (2 mL) was added lithium bromide (5.0 mg, 0.06 mmol) and the mixture was refluxed at 190 ° C for 1 h. The reaction mixture was then cooled to 25 ° C, diluted with H2O (5 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was collected, dried (MgSO4) and concentrated, and the residue was chromatographed (silica, 15-20% ethyl ether in hexane) to afford Formula (I) (14.9 mg, 0.05mmol, 92, 6%);

Compound of Formula (I) - It is a colorless liquid;

Rf = 0.20 (silica, 30% ethyl ether in hexanes); [α] 25D: -6.0 (c = 0.33, benzene); IR (film) Omax 3080.6, 2928.9, 2857.6,1693.6, 1638.2, 1464.7, 1413.8, 1376.4, 1263.1, 1179.3, 1095.9.1027 , 5, 999.2, 909.2, 801.7; 1H NMR (500 MHz, CDCl3) δ 5.82 (dd, 1H), 5.40 (m, 1H), 4.85-4.95 (dd, 2H), 2.30 (bs, 1H), 2 , 16 (m, 1H), 2.02 (m, 1H), 1.80-1.98 (m, 2H), 1.70-1.84 (m, 2H), 1.10-1.70 (m, 7Η), 1.24 (s, 3Η), 1.00-1.10 (m, 2Η), 0.99 (s, 3Η), 0.95 (s, 3Η); 13 C NMR (125 MHz, CDCl 3) δ 150.3, 149.9, 116.7, 109.2, 47.9.41.8, 41.7, 38.3, 38.2, 37.4, 34 , 8, 31.8, 28.6, 28.5, 27.7, 22.6.22.4, 22.1, 20.3, 18.9.

Formula (IIB-Al): Cyclic Substituted AmideTTL N-cyclohexylamide derivative preparation (Formula IIB-Al)

To a solution of TTL-3 (1.0 g, 3.8 mmol) in dry N-methylpyrrolidone (6 mL) under N 2 was added sodium depropane thiolate (0.37 g, 3.8 mmol) in a portion and the mixture was gently cooled until most of the solid had dissolved. After stirring at room temperature for 1 hour, water was added and the mixture washed with 10% ether in hexane (3x). The aqueous mixture was acidified to pH = 2 with HCl diluent, then extracted (2x) with ether. The organic phases were combined, washed with brine, dried (anhydrous sodium sulfate) and concentrated. The white solid was washed with hexane to remove any propane thiol, providing a pure TTL-I acid.

To a 4 mL vial was added carboxylic acid (320 mg, 1.06 mmol), 1,3-dicyclohexylcarboimide (DCC) (218 mg, 1.06 mmol) and 4-dimethyl catalytic amino pyridine (DMAP). The mixture was immediately placed in a hot water bath and heated at 160 ° C for 5-10 minutes. The mixture was chromatographed (2% ethyl acetate in hexane) to afford the title compound, Formula (IIB-Al), as a viscous oil.

Formula (IIB-Al): Cyclic Substituted Amide <formula> formula see original document page 148 </formula>

i) N-methylpyrrolidone, sodium propane thiolate; ii) DCC, DMAP, 160 ° C

Cyclic substituent amide synthesis (Formula (IIB-Al))

Synthesis of Compounds of Formulas 112-1 and IIA-Al

Acanthoic acid and caurenoic acid may be used respectively in the synthesis of the compounds of Formulas II2-1 and IIA-Al. Acanthoic acid and kaurenoic acid can be obtained from any available source. A method for extracting acanthoic acid from Coleonema Pulchrum, and its isolation, is described below.

Extraction and isolation of acanthoic acid from Coleonema Pulchrum roots

Coleonema Pulchrum (440 g) dry root was extracted with methanol (3 χ 3 L) soaked for 48 h for each extraction step. The combined methanol extracts were concentrated to 500 mL by rotary evaporation and water was added to make up a 9: 1 methanol / water solution, which was extracted with hexanes (3 x500 mL). The combined hexane extracts were concentrated and dried under high vacuum to obtain 5.1 g of acanthoic acid-containing crude extract.

Acanthoic Acid Isolation

The above crude hexane extract (4.5 g) was separated into various fractions by Normal Phase Vacuum Liquid Chromatography (HPLC) using an acetate / hexane / ethyl step gradient as follows:

Column dimensions: 15 χ 3.4 cmSolvent ratios: Fractions

1) 300 mL of 100% hexanes

2) 200 mL of 95% hexanes / 5% ethyl acetate

3) 200 mL 90% hexanes / 10% ethyl acetate

4) 200 mL 85% hexanes / 15% ethyl acetate

5) 200 mL 80% hexanes / 20% ethyl acetate

6) 200 mL 75% hexanes / 25% ethyl acetate

7) 200 mL of 50% hexanes / 50% ethyl acetate

8) 200 mL of 0% hexanes / 100% ethyl acetate

All above fractions were analyzed by TLC and mass spectrometry to identify acanthoic acid containing fractions. Fractions 3 (963 mg) and 4 (327 mg) contained acanthoic acid.

Fractions 3 and 4 were purified by preparative HPLC using the following conditions:

Column: Ace 5 μ C18

Dimensions: 15 cm χ 20 mm D.I.

Flow rate: 14.5 ml / min

Detection: Dual UV wavelength (adjusted to 210 & 250 nm)

Solvent: 80% acetonitrile / water to 100% deacetonitrile in 8 min and 7 min in 100% acetonitrile

Seven fractions were collected based on UV peak height at 210 and 250 nm. Fraction 6 contained acanthoic acid, which was concentrated to obtain approximately 90% pure compound.

Fraction 6 above was further purified using a semi-preparative HPLC method described below to obtain more than 97% pure acanthoic acid:

Column: Ace 5 C18-HLD Dimensions: 25 cm χ 9.4 mm D.I.Flow Rate: 3 ml / minDetection: Double UV Wavelength

(adjusted to 21-0 & 250 nm) Solvent: 80% acetonitrile / water to 100% deacetonitrile in 8 min, and 7 min in 100% acetonitrile

Preparation of acanthoic acid N-cyclohexyl amide derivative (Formula 112-1)

Acanthoic acid, including the compound obtained by the methodology described above, may be dissolved in dry and treated with 10 equivalents of (COCl) 2 followed by two drops of DMF. When the reaction ceases to bubble, the solvent CH2Cl2 and (COCl) 2 may be evaporated under vacuum and the reaction residue may be redissolved in dry benzene and then treated with 5 equivalents of cyclohexylamine to obtain an N-derivative. acanthoic acid cyclohexyl amide.

<formula> formula see original document page 150 </formula>

Preparation of caurenoic acid N-cyclohexyl amide derivatives (Formula IIA-Al)

Caurenoic acid can be dissolved in dry CH 2 Cl 2 and treated with 10 equivalents of (COCl) 2 followed by two DMF exits. When the reaction stops bubbling, the solvent of CH 2 Cl 2 and (COCl) 2 may be evaporated under vacuum and the reaction residue may be redissolved in dry benzene and then treated with 5 equivalents of cyclohexyl amine to obtain an N-cyclic derivative. -hexyl amide of caurenoic acid. <formula> formula see original document page 151 </formula>

Methods for making compounds of Formula II-Scheme 1 - Synthesis of acanthoic acid analogs having amide functionality

<formula> formula see original document page 151 </formula>

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro -1-phenanthrenyl] (1-pyrrolidinyl) methanone (2)

A solution of acanthoic acid 1 (30 mg, 0.10 mmol) in CH 2 Cl 2 (3.0 mL) was treated with oxalyl chloride (0.013 mL, 0.15 mmol) in the presence of a catalytic amount of DMF at room temperature. The reaction mixture was stirred for 3 h at room temperature, distilled under reduced pressure, and then 3 mL of CH 2 Cl 2 was added. Triethylamine (0.03 mL, 0.20 mmol) and pyrrolidine (0.02 mL, 0.20 mmol) were added to the reaction mixture. The reaction mixture was stirred for 30 min, quenched with water and extracted with 5 mL of CH 2 Cl 2. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to afford 25 mg of analog 2 (71%).

1H-NMR (CDCl3, 300 MHz) δ 5.75 (dd, 1H, J = 17.6,10.8 Hz), 5.35 (m, 1H), 4.87 (dd, 1H, J = 10 , 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 3.40-3.53 (m, 4H), 2.38-2.43 ( m, 3H), 0.95 -2.1 (m, 17H), 1.18 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H); IR (neat) 2922, 1624, 1459, 1361 cm -1; LRMS (EI) mlz 355 (M +).

(1S, 4aS, 7R) -N-Isobutyl-1,4a, 7-trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do decahydro-1-phenanthrene carboxamide (3) (SP103)

Analog 3 was prepared (82% yield) according to the same procedure as analogue 2 using deiso-butyl amine instead of pyrrolidine.

1H-NMR (CDCl3, 300 MHz) δ 5.80 (dd, 1H, J = 17.60, 10.8 Hz), 5.75 (m, 1H), 5.35 (m, 1H), 4, 87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 3.03 (m, 2H), 2.05- 2.38 (m, 2H), 0.84-2.01 (m, 15H), 1.17 (s, 3H), 0.92 (s, 3H), 0.88 (s, 3H); (neat) 3390, 2924, 1640, 1518, 1462 cm -1; LRMS (EI) mlz 357 (M +).

(1S, 4aS, 7R) -N-Hexyl-1,4, 7,7-trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a- do-decahydro-1-phenanthrene carboxamide (4) (SP105)

Analog 4 was prepared (74% yield) according to the same procedure as analogue 2 using denhexyl amine instead of pyrrolidine.

1H-NMR (CDCl3, 300 MHz) δ 5.77 (dd, 1H, J = 17.60, 10.8 Hz), 5.60 (m, 1H), 5.36 (m, 1H), 4, 87 (dd, 1H, J = 5.5, 1.4 Hz), 4.82 (dd, 1H, J = 10.8, 1.4 Hz), 3.15-3.21 (m, 2H), 2.05-2.38 (m, 2H), 0.83-2.02 (m, 25H), 1.17 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H); IR (neat) 3387, 2926, 1636, 1522, 1459 cm -1; LRMS (EI) m / z 385 (M +). (1S, 4aS, 7R) -N-Benzyl-1,4a, 7-trimethyl-7 -vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro-1-phenanthrene carboxamide (5) (SP104)

Analog 5 was prepared (75% yield) according to the same procedure as analog 2 using debenzyl amine instead of pyrrolidine.

1H-ISIMR (CDCl3, 300 MHz) δ 7.19-7.28 (m, 5H), 5.83 (m, 1H), 5.73 (dd, 1H, J = 17.6, 10.8 Hz ), 5.32 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz) , 4.34 (d, 2H, J = 5.4 Hz), 2.05-2.38 (m, 2H), 0.85-2.02 (m, 14H), 1.18 (s, 3H ), 0.91 (s, 3H), 0.88 (s, 3H); IR (neat) 3384, 2923, 1640, 1515.1455 cm -1. LRMS (EI) mlz 391 (M +).

Synthesis of acanthoic acid analogs having peptide functionality

<formula> formula see original document page 153 </formula>

2 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do -decahydro-1-phenanthrenyl] carbonyl} amine) acetic acid (6) (SPlll)

A solution of acanthoic acid 1 (40 mg, 0.13 mmol) in CH 2 Cl 2 (5.0 mL) was treated with oxalyl chloride (0.017 mL, 0.20 mmol) in the presence of a catalytic amount of DMF at room temperature. The reaction mixture was stirred for 3 h at room temperature, concentrated under reduced pressure, and then 5 mL of CH 2 Cl 2 was added. Triethylamine (0.04 mL, 0.26 mmol) amino acetic acid methyl ester (14 mg, 0.16 mmol) was added to the reaction mixture. The reaction mixture was stirred for 30 min, quenched with water, and extracted with 5 mL of CH 2 Cl 2. Organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to afford 41 mg of the intermediate peptide (83%). To a solution of the above intermediate peptide (41 mg, 0.11 mmol) in MeOH / THF (1: 1, 6 mL) was added 2N LiOH (0.11 mL, 0.22 mmol). The reaction mixture was stirred for 3 h and then concentrated in vacuo. The residue was acidified with 2N HCl and extracted with 10 ml of ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford 37 mg of analog 6 (96%) 1H-NMR (CDCl3, 300 MHz) δ 6.22 (m, 1H), 5.72 ( dd,

1H, J = 17.6, 10.8 Hz), 5.31 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.40 (bs, 1H), 4.00 (m, 2H), 0.78-2.30 (m, 16H), 1.15 (s, 3H ), 0.89 (s, 3H), 0.85 (s, 3H); IR (neat) 3396, 2925, 1734, 1643, 1519, 1457, 1217 cm -1; LRMS (EI) m / z359 (M +).

3 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do -decahydro-1-phenanthrenyl] carbonyljamine) propanoic acid (7) (SP116)

Analog 7 was prepared (76% yield for 2 steps) according to the same procedure as analog 6 using 3-amine propionic acid methyl ester instead of amino acetic acid methyl ester.

1H-NMR (CDCl3, 300 MHz) δ 6.26 (m, 1H), 5.75 (dd, 1H, J = 17.6, 10.8 Hz), 5.31 (m, 1H), 4, 87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.50 (bs, 1H), 4.01 ( m, 2H), 0.78-2.30 (m, 18H), 1.15 (s, 3H), 0.89 (s, 3H), 0.85 (s, 3H); IR (neat) 3434, 2925, 1714, 1607, 1530, 1455, 1192 cm -1; LRMS (EI) m / z 373 (M +).

(2R) -2 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10 10a-decahydro-1-

phenanthrenyl] carbonyljamine) propanoic acid (8) (SP113) Analog 8 was prepared (73% yield for 2 steps) according to the same procedure as for analog 6 using methyl ester D-alanine instead of acid methyl ester amino acetic.

1H-NMR (CDCl3, 300 MHz) δ 7.70 (bs, 1H), 6.19 (m, 1H), 5.78 (dd, 1H, J = 17.6, 10.8 Hz), 5, 37 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.51 (m, 1H), 2.29 (m, 1H), 0.66-2.11 (m, 15H), 1.43 (d, 3H, J = 6.8 Hz), 1.15 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H); IR (neat) 3433, 2928, 1734.1642, 1514, 1453, 1214 cm -1; LRMS (EI) m / z 373 (M +) -

(2S) -2 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10 , 10a-decahydro-1-phenanthrenyl] carbonyl} amine) propanoic acid (9) (SP114)

Analog 9 was prepared (75% yield for 2 steps) according to the same procedure as analogue 6, using methyl ester L-alanine instead of aminoacetic acid methyl ester.

1H-NMR (CDCl3, 300 MHz) δ 7.73 (bs, 1H), 6.19 (m, 1H), 5.78 (dd, 1H, J = 17.6, 10.8 Hz), 5, 37 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.51 (m, 1H), 2.29 (m, 1H), 0.66-2.11 (m, 15H), 1.43 (d, 3H, J = 6.8 Hz), 1.15 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H); IR (neat) 3432, 2926, 1726.1640, 1513, 1464, 1186 cm -1; LRMS (EI) m / z 373 (M +).

(2S) -2 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10 , 10α-do-decahydro-1-phenanthrenyl] carbonyljamine) -3-methylbutanoic acid (10) (SP153)

Analog 10 was prepared (72% yield for 2 steps) according to the same procedure as analogue 6, using methyl ester L-valine instead of amino acid methyl ester.

1H-NMR (CDCl3, 300 MHz) δ 6.13 (m, 1H), 5.78 (dd, 1H, J = 17.6, 10.8 Hz), 5.37 (m, 1H), 4, 87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.54 (m, 1H), 2.05- 2.26 (m, 2H), 0.66-2.01 (m, 15H), 1.21 (s, 3H), 0.99 (m, 6H), 0.95 (s, 3H), 0 93 (s, 3H); IR (neat) 2925, 1724, 1638, 1511, 1469, 1180 cm -1; LRMS (EI) m / z 401 (M +). (2S) -2 - ({[(S, 4aS, 7R) -1, 4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro-1-phenanthrenyl] carbonylJamine) -4-acid methyl pentanoic (11) (SP115)

Analog 11 was prepared (75% yield for 2 steps) according to the same procedure as for analogue 6 using methyl ester L-heucine instead of amino acid methyl ester.

1H-NMR (CDCl3, 300 MHz) δ 9.65 (bs, 1H), 5.98 (m, 1H), 5.78 (dd, 1H, J = 17.6, 10.8 Hz), 5, 38 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.57 (m, 1H), 1.10-2.31 (m, 19H), 0.88-1.05 (m, 12H), 1.19 (s, 3H); IR (neat) 2926, 1727, 1639, 1513, 1462, 1186 cm -1; LRMS (EI) m / z 415 (M +).

(2S) -2 - ([[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10 , 10a-decahydro-1-phenanthrenyl] carbonyl} amine) -2-phenyletanoic acid (12) (SP154)

Analog 12 was prepared (74% yield for 2 steps) according to the same procedure as analogue 6 using methyl glycine L-phenyl ester instead of aminoacetic acid demethyl ester.

1H-NMR (CDCl3, 300 MHz) δ 8.21 (bs, 1H), 7.33 (m, 5H), 6.60 (m, 1H), 5.78 (dd, 1H, J = 17.6 , 10.8 Hz), 5.51 (m, 1H), 5.34 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd 1H, J = 5.5, 1.4 Hz), 0.72-2.31 (m, 16H), 1.21 (s, 3H), 0.95 (s, 3H), 0.86 ( s, 3H); IR (neat) 2923, 1730, 1643, 1517, 1471, 1182 cm -1; LRMS (EI) m / z 435 (M +).

(2S) -2 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10 , 10α-decahydro-1-phenanthrenyl] carbonyl) amine) -3-phenylpropanoic acid (13) (SP155)

Analog 13 was prepared (72% yield for 2 steps) according to the same procedure as analogue 6 using L-phenyl alanine methyl ester instead of aminoacetic acid demethyl ester.

1H-NMR (CDCl3, 300 MHz) δ 7.16-7.32 (m, 5H), 5.96 (m, 1H), 5.78 (dd, 1H, J = 17.6, 10.8 Hz ), 5.33 (m, 1H), 4.87 (dd, 1H, J = 1-0, -8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1, 4 Hz), 4.77 (m, 1Η), 3.02-3.29 (m, 2Η), 0.79-2.31 (m, 16Η), 1.07 (s, 3Η), 0, 93 (s, 3Η), 0.79 (S, 3Η); IR (neat) 2925, 1724, 1640, 1518, 1459 Cit 1, LRMS (δ) mlz 449 (M +).

(2S) -2 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10 , 10α-decahydro-1-phenanthrenyl] carbonylJaitiine) butane dioic acid (14) (SP156)

Analog 14 was prepared (70% yield for 2 steps) according to the same procedure as analogue 6 using L-aspartic acid dimethyl ester instead of amino acetic acid methyl ester.

1H-NMR (CDCl3, 300 MHz) δ 6.85 (m, 1H), 5.75 (dd, 1H, J = 17.6, 10.8 Hz), 5.31 (m, 1H), 4, 87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.64 (m, 1H), 2.71- 2.96 (m, 2H), 0.79-2.31 (m, 16H), 1.12 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H); (neat) 3431, 1925, 1734, 1720, 1642 cm -1; LRMS (EI) mlz 417 (M +).

(2S) -2 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10 10a-do-decahydro-1-phenanthrenyl] carbonyl -jamine) pentanoic acid (15) (SP157)

Analog 15 was prepared (73% yield for 2 steps) according to the same procedure as for analog 6 using L-glutemic acid dimethyl ester instead of amino acetic acid methyl ester.

1H-NMR (CDCl3, 300 MHz) δ 6.48 (m, 1H), 5.78 (dd, 1H, J = 17.6, 10.8 Hz), 5.36 (m, 1H), 4, 87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.61 (m, 1H), 2.51 ( m, 2H), 0.83-2.41 (m, 18H), 1.13 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H); IR (neat) 3429, 2927, 1736, 1721, 1644, 1513 cm -1; LRMS (EI) m / z 431 (M +).

(2S) -2 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-ynyl-1,2,3,4,4a, 6,7,8,8a, 9, 10,10a-do-decahydro-1-phenanthrenyl] carbonyl-amine) -3- (1H-imidazole-5-yl) acid-propanoate (16) (SP158)

Analog 16 was prepared (82% yield) according to the same procedure as analogue 2 using demethyl ester L-histidine instead of pyrrolidine. 1 H-NMR (CDCl 3, 300 MHz) δ 7.55 (s, 1Η) , 7.37 (m, 1Η), 6.78 (s, 1Η), 5.77 (dd, 1Η, J = 17.6, 10.8 Hz), 5.33 (m, 1Η), 4, 87 (dd, 1Η, J = 10.8, 1.4 Hz), 4.82 (dd, 1Η, J = 5.5, 1.4 Hz), 4.72 (m, 1H), 3.65 (s, 3Η), 3.09 (m, 2Η), 2.51 (m, 2Η), 0.83-2.31 (m, 18Η), 1.12 (s, 3Η), 0.92 ( s, 3Η), 0.89 (s, 3Η); IR (neat) 3420, 2924, 1730, 1644 cm -1; LRMS (δ) mlz 453 (M +).

Sgvenia 3 - Synthesis of acanthoic acid analogs having alcohol functionality

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro -1-phenanthrenyl] methanol (17) (SP033)

To a solution of acanthoic acid 1 (830 mg, 2.7 mmol) in THF (30 mL) was added LAH (310 mg, 8.2 mmol). The reaction mixture was stirred for 12 h and quenched with water (1.55 mL) and 15% NaOH solution (0.31 mL) and filtered through celite. The filtrate was concentrated in vacuo and diluted with ethyl acetate (40 mL). The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to afford 670 mg of analog 17. (85%).

1H-NMR (CDCl3, 300 MHz) δ 5.75 (dd, 1H, J = 17.6,10.8 Hz), 5.29 (m, 1H), 4.87 (dd, 1H, J = 10 , 8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 3.78 (d, 1H, J = 10.9 Hz) 3 3.47 (d , 1H, J = 10.9 Hz), 0.84-1.99 (m, 16Η), 0.97 (s, 3Η), 0.91 (s, 3Η), 0.90 (s, 3Η) ; IR (neat) 3368, 2926, 1328 cm -1; LRMS (δ) mlz 288 (M +).

(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro 1-phenanthrene carbaldehyde (18)

To a solution of analog 17 (180 mg, 0.64 mmol) in CH 2 Cl 2 (7 mL) was added NMO (116 mg, 0.96 mmol) and a catalytic amount of TPAP in the presence of powdered MS-4A. The reaction mixture was stirred for 2 h at room temperature and filtered through silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate: hexane = 1:20) to afford 160 mg of analog 18 (89%).

1H-NMR (CDCl3, 300 δ) δ9.86 (s, 1H), 5.75 (dd, 1H, J = 17.6, 10.8 Hz), 5.33 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 0.86-1.99 (m, 16H), 0 , 96 (s, 3H), 0.90 (s, 3H), 0.86 (s, 3H); IR (neat) 1717 cm -1; LRMS (EI) m / z286 (M +).

(IS) -1 - [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a -do-decahydro-1-phenanthrenyl] -1-ethanol (19) (SP108)

To a solution of analog 18 (20 mg, 0.07 mmol) in THF (5 mL) was added MeLi (1.6 M solution in THF, 0.087 mL, 0.14 mmol) by dripping. The reaction mixture was stirred for 10 min at room temperature and quenched with a saturated NH4 Cl solution. The resulting mixture was concentrated in vacuo and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:10) to afford 20 mg of analog 19 (95%).

1H-NMR (CDCl3, 300 δ) δ5.76 (dd, 1H, J = 17.6.10, 0.8 Hz), 5.34 (m, 1H), 4.87 (dd, 1H, J = 10, 8. 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.33 (m, 1H), 0.85-2.03 (m, 19H), 0.97 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H); IR (neat) 3443, 2922, 1 * 644, 1539.1458, 1372 cm -1; LRMS (EI) m / z 3Ό2 (M +). (IS) -1 - [(1S, 4aS, 7R) -1 , 4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro-1-phenanthrenyl] -2-propene 1-ol (20) (SP099)

Analog 20 was prepared (82% yield) according to the same procedure as analogue 19, using a vinyl magnesium bromide solution instead of a delitium methyl solution.

1H-NMR (CDCl3, 300 δ) δ5.80 (m, 1H), 5.74 (dd, 1H, J = 17.6, 10.8 Hz), 5.31 (m, 1H), 5.02 -5.14 (m, 2H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.59 (m, 1H), 0.81-2.33 (m, 16H), 0.92 (s, 3H), 0.88 (s, 3H), 0.84 (s, 3H), - IR (neat) 3307, 2928, 1641, 1453 cm -1; LRMS (EI) m / z 314 (M +).

(1S, 2E) -1 - [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,4,4a, 6,7,8,8a, 9,10 10a-do-decahydro-1-phenanthrenyl] -2-butenene-1-ol (21) (SP137)

Analog 21 was prepared (85% yield) according to the same procedure as analogue 19 using a 1-propenyl magnesium bromide solution instead of the delithium methyl solution.

1H-NMR (CDCl3, 300 δ) δ5.79 (dd, 1H, J = 17.60, 10.8 Hz), 5.65 (m, 2H), 5.35 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.54 (m, 1H), 0.81-2 , 33 (m, 16H), 1.68 (d, 2H, J = 6.1 Hz), 1.23 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H) ; IR (neat) 3358, 2925, 1645, 1302 cm -1; LRMS (EI) m / z 328 (M +).

(S) - [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do -decahydro-1-phenanthrenyl] (phenyl) methanol (22) (SP101)

Analog 22 was prepared (83% yield) according to the same procedure as analog 19 using a solution of phenyl magnesium bromide instead of lithiomethyl solution.

1H-NMR (CDCl3, 300 MHz) δ 7.17-7.29 (m, 5H), 5.73 (dd, 1H, J = 17.6, 10.8 Hz), 5.26 (m, 1H ), 5.24 (s, 1H), 4.88 (dd, 1H, J = 10.8, 1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz) 0.79-2.33 (m, 16H), 1.68 (d, 2H, J = 6.1 Hz), 1.26 (s, 3H), 0.92 (s, 3H), 0, 90 (s, 3Η); IR (neat) 3382, 2934, 1642, 1431 cm -1; LRMS (EI) m / z 364 (M +).

Synthesis of acanthoic acid analogs having ketone functionality

<formula> formula see original document page 161 </formula>

1 - [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-deca -hydro-1-phenanthrenyl] -1-ethanone (23) (SP138)

To a solution of analog 19 (10 mg, 0.03 mmol) in CH 2 Cl 2 (3 mL) was added NMO (5.8 mg, 0.05 mmol) and a catalytic amount of TPAP in the presence of powdered MS-4A. The reaction mixture was stirred for 2 h at room temperature and filtered through silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl etherhexane acetate = 1:20) to afford 9.4 mg of analog 23 (95%).

1H-NMR (CDCl3, 300 δ) δ5.78 (dd, 1H, J = 17.6.10, 0.8 Hz), 5.26 (m, 1H), 4.88 (dd, 1H, J = 10, 8. 1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 0.79-2.33 (m, 16H), 2.13 (s, 3H), 1.23 (s, 3H), 0.94 (s, 3H), 0.89 (s, 3H); IR (neat) 2924, 1698, 1538, 1458 cm -1; LRMS (EI) M / Z 300 (M +).

1 - [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-deca -hydro-1-phenanthrenyl] -2-propene-1-one (24) (SP100) Analog 24 was prepared (93% yield) from analog 20 by the procedure described for analog 23.

1H-NMR (CDCl3, 300 MHz) 6.79 (dd, 1H, J = 20.4.5.7 Hz), 6.22 (dd, 1H, J = 20.4, 3.1 Hz), 5 , 76 (dd, 1H, J = 17.6,10.8 Hz), 5.57 (dd, 1H, J = 5.7, 3.1 Hz), 5.34 (m, 1H), 4, 93 (dd, 1H, J = 10.8, 1.4 Hz), 4.86 (dd, 1H, J = 5.5, 1.4 Hz), 0.74-2.33 (m, 16H) 1.15 (s, 3H), 0.93 (s, 3H), 0.84 (s, 3H); IR (neat) 3396, 2927, 1684, 1459 cm -1; LRMS (EI) m / z 312 (M +).

(E) -1 - [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a -do-decahydro-1-phenanthrenyl] -2-butene-1-one (25) (SP139)

Analog 25 was prepared (91% yield) from analog 21 by the procedure described for analog 23.

1H-NMR (CDCl3, 300 δ) δ6.77 (m, 1H), 5.49 (d, 1H, J = 16.7 Hz), 5.76 (dd, 1H, J = 17.6, 10, 8 Hz), 5.28 (m, 1H), 4.93 (dd, 1H, J = 10.8, 1.4 Hz), 4.86 (dd, 1H, J = 5.5, 1.4 Hz), 0.74-2.33 (m, 19H), 1.15 (s, 3H), 0.93 (s, 3H), 0.84 (s, 3H); IR (neat) 2924, 1682, 1621, 1457 cm -1; LRMS (EI) m / z 326 (M +).

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro -1-phenanthrenyl] (phenyl) methanone (26) (SP102)

Analog 26 was prepared (90% yield) from analog 22 by the procedure described for analog 23.

1H-NMR (CDCl3, 300 MHz) δ 7.29-7.41 (m, 5H), 5.72 (dd, 1H, J = 17.6, 10.8 Hz), 5.23 (m, 1H ), 4.88 (dd, 1H, J = 10.8,1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 0.74-2.33 ( m, 16H), 1.15 (s, 3H), 0.98 (s, 3H), 0.87 (s, 3H); IR (neat) 2924, 1680, 1539.1457 cm -1; LRMS (EI) m / z 362 (M +).

Synthesis of acanthoic acid analogs having oxime functionality <formula> formula see original document page 163 </formula> (1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3 , 4,4a, 6,7,8,8a, 9,10,10a-do-decahydro-1-phenanthrene carbaldehyde (27) (SP109)

To a solution of analog 18 (20 mg, 0.07 mmol) empiridine (3 mL) was added hydroxylamine hydrochloride (5.8 mg, 0.08 mmol). The reaction mixture was stirred for 1 h at 80 ° C, cooled to room temperature, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1-0) to afford 16 mg of analog 27 (77%).

1H-NMR (CDCl3, 300 δ) δ7.55 (s, 1H), 5.78 (dd, 1H, J = 17.6, 10.8 Hz), 5.35 (m, 1H), 4.88 (dd, 1H, J = 10.8, 1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 0.74-2.33 (m, 16H), 1 0.05 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H); IR (neat) 3307, 2928, 1641, 1453cm-1; LRMS (EI) m / z 301 (M +).

(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro 1-phenanthrene carbaldehyde O-methyl oxime (28) (SP140)

Analog 28 was prepared (72% yield) according to the same procedure as analog 27 using 0-methylamine hydrochloride instead of hydroxylamine hydrochloride.1H-NMR (CDCL3, 300 MHz) δ 7.48 (S, 1Η) 5.78 (dd, 1Η, J = 17.6, 10.8, Hz), 5.35 (m, 1Η), 4.88 (dd, 1Η, J = 10.8, 1.4Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 3.74 (s, 3Η), 0.74-2.33 (m, 16Η), 1.05 (s, 3Η) 0.96 (s, 3Η), 0.91 (s, 3Η); IR (neat) 2927.1716, 1647, 1458 cm -1; LRMS (δ) mlz 315 (M +).

(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro 1-phenanthrene-carbaldehyde O-benzyl oxime (29) (SP141)

Analog 29 was prepared (72% yield) according to the same procedure as analog 27 using O-benzylamine hydrochloride instead of hydroxylamine hydrochloride.

1H-NMR (CDCl3, 300 δ) δ7.54 (s, 1H), 7.18-7.34 (m, 5H), 5.78 (dd, 1H, J = 17.6, 10.8 Hz) , 5.35 (m, 1H), 5.03 (s, 2H), 4.88 (dd, 1H, J = 10.8, 1.4 Hz), 4.83 (dd, 1H, J = 5 1.5 Hz), 3.74 (s, 3H), 0.74-2.33 (m, 16H), 1.05 (s, 3H), 0.96 (s, 3H), 0 91 (s, 3H); IR (neat) 2927, 1646, 1456 cm -1; LRMS (EI) mlz 391 (M +).

(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro 1-phenanthrene carbaldehyde O- (4-fluoro-benzyl) oxyxna (30) (SP142)

Analog 30 was prepared (71% yield) according to the same procedure as for analog 27 using 0- (4-fluoro-benzyl) amine hydrochloride instead of hydroxylamine hydrochloride.

1H-NMR (CDCl3, 300 δ) δ7.93 (s, 1H), 7.02-7.29 (m, 4H), 5.78 (dd, 1H, J = 17.6, 10.8 Hz) , 5.35 (m, 1H), 5.03 (s, 2H), 4.88 (dd, 1H, J = 10.8, 1.4 Hz), 4.83 (dd, 1H, J = 5 , 1.5 Hz), 3.74 (s, 3H), 0.74-2.33 (m, 16H), 1.05 (s, 3H), 0.96 (s, 3H), 0, 91 (s, 3H); IR (neat) 2925, 1654, 1473 cm -1; LRMS (EI) m / z 409 (M +).

Synthesis of acanthoic acid analogs having sulfonate functionality <formula> formula see original document page 165 </formula>

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a # 6,7,8,8a, 9,10,10a-do-decahydro -1-phenanthrenyl] methylamethanesulfonate (31) (SP143)

To a solution of analog 17 (20 mg, 0.070 mmol) in pyridine (3 mL) was added methanesulfonyl chloride (0.0064 mL, 0.083 mmol). The reaction mixture was stirred for 2h at room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to afford 21 mg of analog 31 (85%).

1 H-NMR (CDCl 3, 300 MHz) δ 5.76 (dd, 1H, J = 17.6,10.8 Hz), 5.34 (m, 1H), 4.87 (dd, 1H, J = 10, 8. 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.43 (d, 1H, J = 10.9 Hz), 4.24 (d, 1H, J = 10.9 Hz), 2.98 (s, 3H), 0.72-2.03 (m, 19H), 1.12 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H); IR (neat) 2927, 1647, 1539, 1355 cm -1; LRMS (EI) m / z 366 (M +).

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-decahydro -1-phenanthrenylJmethylabenzenesulfonate (32) (SP144)

Analog 32 was prepared (78% yield) according to the same procedure as analog 31 using benzene sulfonyl chloride instead of methanesulfonyl chloride. 1 H NMR (CDCl 3, 300 MHz) δ 7, 47-7 , 85 (m, 5Η), 5.70 (dd, 1H, J = 17.6, 10.8 Hz), 5.34 (m, 1Η), 4.87 (dd, 1Η, J = 10.8 , 1.4 Hz), 4.83 (dd, 1Η, J = 5.5, 1.4 Hz), 4.19 (d, 1Η, J = 10.9 Hz), 3.87 (d, 1H, J = 10.9 Hz), 2.98 (s, 3Η), 0.79-2.03 (m, 16Η), 1.12 (s, 3Η), 0.90 (s, 3Η), 0, 87 (s, 3Η); IR (neat): 2926, 1646,1365, 1185, 957 cm -1; LRMS (δ) mlz 428 (M +).

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro -1-phenanthrenylJmethyl4-methoxybenzenesulfonate (33) (SP145)

Analog 33 was prepared (83% yield) according to the same procedure as analog 31 using 4-methoxy-benzene sulfonyl chloride instead of methanesulfonyl chloride.

1H-NMR (CDCl3, 300 δ) δ7.78 (m, 2H), 6.95 (m, 2H), 5.70 (dd, 1H, J = 17.6, 10.8 Hz), 5.28 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 4.13 ( d, 1H, J = 10.9 Hz), 3.82 (s, 3H), 3.80 (d, 1H, J = 10.9 Hz), 0.79-2.03 (m, 16H), 0.96 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H); IR (neat) 2927,1596, 1361, 1262, 1026. cm-1; LRMS (EI) m / z 458 (M +). [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl -1,2,3,4,4a, 6,7,8,8a, 9,10,10a-decahydro-1-phenanthrenyl] methyl4-iodo-benzene sulfonate (34) (SP146)

Analog 34 was prepared (81% yield) according to the same procedure as analog 31 using 4-iodo-benzene sulfonyl chloride instead of methanesulfonyl chloride.

1H-NMR (CDCl3, 300 δ) δ7.91 (m, 2H), 7.61 (m, 2H), 5.76 (dd, 1H, J = 17.6, 10.8 Hz), 5.33 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 4.25 ( d, 1H, J = 10.9 Hz), 3.88 (d, 1H, J = 10.9 Hz), 0.79-2.03 (m, 16H), 0.92 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H); IR (neat) 2926, 1645, 1176 cm -1; LRMS (EI) mlz 554 (M +).

4 - ({[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do -decahydro-1-phenanthrenyl] methoxy) sulfonyl) benzene carboxylic acid (35) (SP147) Analog 35 was prepared (78% yield) according to the same procedure for analog 31 using 4- (chloroacetic acid). sulfonyl) benzoic instead of methanesulfonyl chloride.

1H-NMR (CD3OD, 300 δ) δ 8.05 (m, 2H), 7.91 (m, 2H), 5.79 (dd, 1H, J = 17.6, 10.8 Hz), 5.43 (m, 1H), 4.87 (dd, 1H, J = 10.8, 1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 4.65 ( d, 1H, J = 10.9 Hz), 4.18 (d, 1H, J = 10.9 Hz), 0.79-2.03 (m, 16H), 1.23 (s, 3H), 1.17 (s, 3H), 0.87 (s, 3H); IR (neat) 3498, 2926, 1721.1539, 1188 cm -1; LRMS (EI) m / z 472 (M +).

Synthesis of acanthoic acid analogs having ester functionality

<formula> formula see original document page 167 </formula>

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-decahydro -1-phenanthrenyl] methyl2-bromoacetate (36)

To a solution of analog 17 (107 mg, 0.37 mmol) in CH 2 Cl 2 (10 mL) at 0 ° C was added Et 3 N (0.15 mL, 1.1 mmol) and bromo acetyl bromide (0.064 mL, 0 mL). , 74 mmol). The reaction mixture was stirred for 1-0 min, quenched with aqueous NaHCO 3 solution (5 mL) and extracted with CH 2 Cl 2 (10 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:10) to afford 11 mg of analog 36 (93%).

1H-NMR (CDCl3, 300 MHz) δ 5.79 (dd, 1H, J = 17.6, 10.8 Hz), 5.35 (m, 1H), 4.93 (dd, 1H, J = 10 , 1.8, 1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 4.43 (d, 1H, J = 10.9 Hz), 4.10 (d 1H, J = 10.9 Hz), 3.81 (s, 2H), 0.79-2.03 (m, 16H), 1.10 (s, 3H), 1.05 (s, 3H) 0.97 (s, 3H).

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-decahydro -1-phenanthrenyl] methyl2-piperazine acetate (37) (SP148)

To a solution of analog 36 (108 mg, 0.26 mmol) in CH 2 Cl 2 (10 mL) was added piperazine (68 mg, 0.80 mmol). The reaction mixture was stirred for 4 h at room temperature and washed with brine. The organic layer was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to afford 102 mg of analog 37 (93%).

1H-NMR (CDCl3, 300 δ) δ5.79 (dd, 1H, J = 17.6.10, 0.8 Hz), 5.34 (m, 1H), 4.87 (dd, 1H, J = 10, 8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.37 (d, 1H, J = 10.9 Hz), 4.04 (d, 1H, J = 10.9 Hz), 3.19 (s, 2H), 2.57-2.97 (m, 8H), 0.76-2.03 (m, 16H), 1.05 (s , 3H), 0.94 (s, 3H), 0.93 (s, 3H); IR (neat) 3396, 2926.1741, 1622, 1456 cm -1; LRMS (EI) m / z 414 (M +).

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-decahydro -1-phenanthrenyl] methyl2- (4-acetyl piperazine) acetate (38) (SP152)

To a solution of analog 37 (15 mg, 0.04 mmol) in CH 2 Cl 2 (3 mL) was added Et 3 N (0.01 mL, 0.07 mmol) and deacetyl chloride (0.003 mL, 0.04 mmol). The reaction mixture was stirred for 2h at room temperature and quenched with aqueous NaHCO 3 solution (1 mL). The resulting mixture was with CH 2 Cl 2 (1-0 mL). The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to afford 15 mg of analog 38 (94%).

1H-NMR (CDCl3, 300 δ) δ5.79 (dd, 1H, J = 17.6.10, 0.8 Hz), 5.34 (m, 1H), 4.87 (dd, 1H, J = 10, 8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.37 (d, 1H, J = 10.9 Hz), 4.04 (d, 1H, J = 10.9 Hz), 3.49-3.66 (m, 4H), 3.26 (s, 2H), 2.48-2.61 (m, 4H), 0.76-2 .03 (m, 16H), 2.02 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H); IR (neat) 2926, 1741, 1645, 1434 cm -1; LRMS (EI) m / z 456 (M +).

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-

1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro-1-phenanthrenyl] methyl2 - [(methylsulfonyl) piperazine] acetate (39) (SP149 )

Analog 39 was prepared (93% yield) according to the same procedure as analogue 38 using methanesulfonyl chloride instead of acetyl chloride.

1H-NMR (CDCl3, 300 δ) δ5.79 (dd, 1H, J = 17.6.10, 0.8 Hz), 5.34 (m, 1H), 4.93 (dd, 1H, J = 10, 8, 1.4 Hz), 4.84 (dd, 1H, J = 5.5, 1.4 Hz), 4.40 (d, 1H, J = 10.9 Hz), 4.08 (d, 1H, J = 10.9 Hz), 3.35 (m, 4H), 2.81 (s, 2H), 2.78-2.80 (m, 9H), 2.48-2.61 (m 0.76-2.03 (m, 16H), 2.02 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H); IR (neat) 2925, 1735, 1642, 1539, 1182 cm -1; LRMS (EI) mlz 492 (M +).

[(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-Halo -1-phenanthrenyl] methyl2- {4 - [(4- (methylphenyl) sulfonyl) piperazine] acetate (40) (SP150)

Analog 40 was prepared (93% yield) according to the same procedure as analogue 38, using p-toluenesulphonyl chloride instead of acetyl chloride.

1H-NMR (CDCl3, 300 δ) δ7.62 (m, 2H), 7.31 (m, 2H), 5.79 (dd, 1H, J = 17.6, 10.8 Hz), 5.34 (m, 1H), 4.93 (dd, 1H, J = 10.8, 1.4 Hz), 4.84 (dd, 1H, J = 5.5, 1.4 Hz), 4.37 ( d, 1H, J = 10.9 Hz), 4.08 (d, 1H, J = 10.9 Hz), 2.64-3.18 (m, 10H), 2.41 (s, 3H), 0.74-1.97 (m, 16H), 1.08 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H); IR (neat) 2924, 1742, 1455, 1351, 1166 cm -1; LRMS (EI) m / z 568 (M +). [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1 1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-decahydro-1-phenanthrenyl] methyl2- {4 - [(4- (methoxyphenyl) sulfonyl) piperazine] acetate (41) (SP151)

Analog 41 was prepared (92% yield) according to the same procedure as analogue 38 using 4- (methoxy) benzene sulfonyl chloride instead of deacetyl chloride.

1H-NMR (CDCl3, 300 δ) δ7.82 (m, 2H), 7.65 (m, 2H), 5.79 (dd, 1H, J = 17.6, 10.8 Hz), 5.34 (m, 1H), 4.93 (dd, 1H, J = 10.8, 1.4 Hz), 4.84 (dd, 1H, J = 5.5, 1.4 Hz), 4.37 ( d, 1H, J = 10.9 Hz), 4.03 (d, 1H, J = 10.9 Hz), 3.85 (s, 3H), 2.66-3.19 (m, 10H), 0.74-1.97 (m, 16H), 1.03 (s, 3H), 0.94 (s, 3H), 0.88 (s3H); IR (neat) 2926, 1742, 1450, 1065 cm -1; LRMS (EI) m / z 584 (M +).

Synthesis of acanthoic acid analogs having ester functionality

<figure> figure see original document page 170 </figure>

4 - [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-deca -hydro-1-phenanthrenyl] acidomethoxy-4-oxobutanoic acid (42) (SP117)

To a solution of analog 17 (30 mg, 0.10 mmol) empiridine 3 ml) was added succinic anhydride (12 mg, 0.12 mmol). The reaction mixture was refluxed for 3 h and cooled to room temperature. The resulting mixture was diluted with ethyl acetate (10 mL) and washed with brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1) to afford 26 mg of analog 42 (67% ).

1H-NMR (CDCl3, 300 MHz) δ 5.79 (dd, 1H, J = 17.6, 10.8 Hz) 3 5.31 (m, 1H), 4.89 (dd, 1H, J = 10 , 1.8, 1.4 Hz), 4.84 (dd, 1H, J = 5.5, 1.4 Hz), 4.37 (d, 1H, J = 10.9 Hz), 3.98 (d 1H, J = 10.9 Hz), 2.64 (m, 4H), 0.80-2.22 (m, 16H), 1.00 (s, 3H), 0.89 (s, 3H) 0.87 (s, 3H); IR (neat) 2928, 1732, 1708, 1459 cm -1; LRMS (EI) mlz 388 (M +).

4 - [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-deca -hydro-1-phenanthrenyl] acid-methoxy-2,2-dimethyl-4-oxobutanoic acid (43) (SP118)

Analog 43 was prepared (79% yield) according to the same procedure as analogue 42 using succinic anhydride 2,2-dimethyl instead of succinic anhydride.

1 H-NMR (CDCl 3, 300 δ) δ5.79 (dd, 1H, J = 17.6,10.8 Hz), 5.31 (m, 1H), 4.87 (dd, 1H, J = 10 , 1.8, 1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 4.30 (d, 1H, J = 10.9 Hz), 3.94 (d 1H, J = 10.9 Hz), 2.56 (s, 2H), 0.81-2.25 (m, 16H), 1.23 (s, 6H), 1.00 (s, 3H) 0.90 (s, 3H); 0.89 (s, 3H); IR (neat) 2926, 1735, 1706.1467 cm -1; LRMS (EI) mlz 416 (M +).

5 - [(1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-deca -hydro-1-phenanthrenyl] acidomethoxy-2,2-dimethyl-5-oxopentanoic (44) (SP119)

Analog 44 was prepared (99% yield) according to the same procedure as analogue 42 using 2,2-dimethyl glutaric anhydride instead of succinic anhydride.

1H-NMR (CDCl3, 300 δ) δ5.79 (dd, 1H, J = 17.6.10, 0.8 Hz), 5.31 (m, 1H), 4.88 (dd, 1H, J = 10, 8. 1.4 Hz), 4.83 (dd, 1H, J = 5.5, 1.4 Hz), 4.27 (d, 1H, J = 10.9 Hz), 3.95 (d, 1H, J = 10.9 Hz), 2.78 (t, 2H, J = 6.96 Hz), 1.82 (t, 2H, J = 6.96 Hz), 0.68-2.30 ( m, 16H), 1.29 (s, 6H), 1.15 (s, 3H), 1.01 (s, 3H), 0.90 (s, 3H); IR (neat) 2927, 1735, 1714 cm -1; LRMS (EI) m / z 430 (M +).

5-t (1S, 4aS, 7R) -1,4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do-deca -hydro-1-phenanthrenyl] acid-methoxy-3,3-dimethyl-5-oxopentanoic (45) (SP120) Analogue 45 was prepared (74% yield) according to the same procedure as analogue 42 using anhydride3,3- glutaric dimethyl instead of succinic anhydride.

1H-NMR (CDCl3, 300 δ) δ5.80 (dd, 1H, J = 17.60, 10.8 Hz), 5.31 (m, 1H), 5.23 (s, 2H), 4.89 (dd, 1H, J = 10.8, 1.4 Hz), 4.82 (dd, 1H, J = 5.5, 1.4 Hz), 4.43 (d, 1H, J = 10.9 Hz ), 4.20 (s, 2H), 4.09 (d, 1H, J = 10.9 Hz), 0.71-2.25 (m, 16H), 0.96 (s, 6H), 1 .01 (s, 3H); 0.89 (s, 3H); 0.87 (s, 3H); IR (neat) 2925.1748, 1455 cm -1; LRMS (EI) m / z 430 (M +).

2- (2 - [(1S, 4aS, 7R) -If4a, 7-Trimethyl-7-vinyl-1,2,3,4,4a, 6,7,8,8a, 9,10,10a-do decahydro-1-phenanthrenyl] methoxy-2-oxo-ethoxy) acetylic acid (46) (SP121)

Analogue 46 was prepared (72% yield) according to the same procedure as analogue 42 using anhydridodi glycol instead of succinic anhydride.

1H-NMR (CDCl3, 300 δ) δ5.74 (dd, 1H, J = 17.6, 10.8 Hz), 5.26 (m, 1H), 4.84 (dd, 1H, J = 10, 8.14 Hz), 4.78 (dd, 1H, J = 5.5, 1.4 Hz), 4.24 (d, 1H, J = 10.9 Hz), 3.89 (d, 1H, J = 10.9 Hz), 2.35 (m, 4H), 0.82-1.93 (m, 16H), 0.96 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H); IR (neat) 2930, 1765, 1704, 1020 cm -1; LRMS (EI) m / z 404 (M +).

Synthesis and Purification of NPI-1387 and NPI-1388

Scheme 9 <formula> formula see original document page 173 </formula>

A mixture of acanthoic acid (1) and caurenoic acid was treated with lithium aluminum hydroxide to obtain its corresponding hydroxy derivatives which were oxidized with TPAP to result in mixtures of aldehydes. Mixtures of acanthoic acid and caurenoic acid derivative aldehydes were treated with vinyl magnesium bromide to obtain their corresponding vinyl alcohol derivatives, which were oxidized to a mixture of NPI-1387 (24) and NPI-1388 (see scheme -II paraconversion of kaurenoic acid in NPI-1388); analogous conversion of acanthoic acid (1) to NPI-1387 (24) is shown in schemes 3 and 4).

Purification of NPI-1387 (24) and NPI-1388: Mixture of NPI-1387 (24) and NPI-1388 was dissolved in acetone (20mg / mL) and purified by preparative HPLC as described below. <table> table see original document page 174 </column> </row> <table>

Compounds NPI-1387 (24) and NPI-1388 were eluted at 23.5 min and 25.5 min, respectively. Fractions containing compounds NPI-1387 and NPI-1388 were pooled based on the composition of the present compounds, and evaporated under reduced pressure on a rotary evaporator. This process yielded pure NPI-1387 and NPI-1388 compounds.

1H-NMR (CDCl3, 500 MHz) for NPI-1387, see afig. SAW;

13 C-NMR (CDCl 3, 125 MHz) for NPI-1387, see afig. VII;

1H-NMR (CDCl3, 500 MHz) for NPI-1388, see afig. VIII.

Methods for making compounds of Formula IIA-b

The compounds of Formula IIA-b are made following the above procedure to make the compounds of Formula IIbexide which caurenoic acid is used as starting material in place of acanthoic acid (1): Methods for making the compounds of Formula IIB-b

The compounds of Formula IIB-b are made following the above procedure to make the compounds of Formula II-hexide which as starting material, instead of acanthoic acid (1), is used a TTL compound, for example TTL-I, TTL- 2, TTL-3, TTL-4, etc.

Methods to make NPI-1390

NPI-1390 (vinyl ketone derivative of TTL3) was made as shown in Scheme 9:

<formula> formula see original document page 175 </formula>

Compound NPI-1308: To a solution of compound NPI-1301 (315 mg, 1 mmol) in CH 2 Cl 2 (15 mL) was added DIBAL-H (3.0 mL, 1 M in hexane, 3 mmol) slowly at -78 ° C. . The reaction mixture was stirred at -78 ° C for one hour and quenched with MeOH (2 mL). Then the reaction mixture was allowed to warm to room temperature, 1N HCl (30 mL) was added and stirred for approximately 30 min. The resulting mixture was extracted with CH 2 Cl 2 (3 x 50 mL) and the organic layers were combined and concentrated under reduced pressure to obtain NPI-1308 (275 mg, 96% yield).

1H-NMR (CDCl3, 500 MHz) see fig. IR; 13C-NMR (CDCl3, 125 MHz) see fig. V.

Compound NPI-1374: To a solution of compound NPI-1308 (40 mg, 0.14 mmol) in CH 2 Cl 2 (3 mL) was added NMO (116 mg, 0.36 mmol) and a catalytic amount of TPAP in the presence of molecular screens ( 3A). The reaction mixture was stirred for 1 h at room temperature and poured onto a silica column (15 χ30 mm). The column was eluted with 0-15% EtOAc / hexanes to obtain NPI-1374 (38 mg, 96% yield).

Compound NPI-1391: A solution of n-butyllithium (0.2 mL, 2.5 M in hexane, 0.5 mmol) was added to a solution of tetravinyline (35 mg, 0.15 mmol) in THF (1.5 mL) at -78 ° C under N 2. The mixture was stirred at the same temperature for approximately 20 min and then at room temperature for approximately 45 min. A solution of NPI-1374 aldehyde (115 mg, 0.04 mmol) in THF (0.6 mL) was added to the reaction mixture at -78 ° C and the reaction mixture was stirred at -780 ° C for approximately 30 min and then at room temperature for approximately 20 min. Then the reaction mixture was quenched with saturated NH 4 Cl solution (8 mL) and extracted with ethyl ether (3 x 25 mL). The combined organic layer was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (15 x 30 mm; 0-10% EtOAc / hexane) to obtain NPI-1391 (10.3 mg, 83% yield). .

1H-NMR (CDCl3, 500 MHz) see fig. III.

Compound NPI-1390: To a solution of compound NPI-1391 (8.3 mg, 0.026 mmol) in CH 2 Cl 2 (1.5 mL) was added NMO (10 mg, 0.09 mmol) and a catalytic amount of TPAP in the presence of plaques. molecular (3A). The reaction mixture was stirred for 2 h at room temperature and filtered through a silica gel plug. The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography (10χ 200 mm; 0-3% EtOAc / hexanes) to obtain NPI-1390 (2.2 mg).

1H-NMR (-CDCl3, 500 MHz) see fig. 13 C-NMR (CDCl 3, 125 MHz) see fig. II.

Methods of Use of the Invention

The in vitro and in vivo methods described above as part of the present invention also establish the selectivity of a TNF-α or IL-I modulator. It is recognized that chemical substances can modulate a wide variety of biological processes or be selective. Cell panels based on the present invention may be used to determine the specificity of the amodulating candidate. Selectivity is evident, for example, in the field of chemotherapy, where the selectivity of a chemical to be toxic to cancer cells, but not to non-cancer cells, is obviously desirable. Selective modulators are preferable because they have fewer side effects in the clinical setting. Selectivity of a modulator candidate can be established in vitro by testing the toxicity and effect of a modulator candidate on a plurality of cell lines that exhibit a variety of cell pathways and sensitivities. The data obtained from these in vitro toxicity studies can be extended to animal models, including accepted animal model studies and human clinical experiments, to determine the toxicity, efficacy, and selectivity of the amodulating candidate.

The present invention also encompasses the compositions produced by the methods in pharmaceutical compositions comprising a pharmaceutically acceptable carrier prepared for storage and subsequent administration having a pharmaceutically effective amount of the products described above in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are already well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985). Preservatives, stabilizers, tinctures and even flavoring agents may be provided in the pharmaceutical composition. . For example, sodium benzoate, ascorbic acid and dephydroxy benzoic acid esters may be added as preservatives. In addition, antioxidants and suspending agents may be used.

These TNF-α or IL-I35 modulator compositions may be formulated and used as tablets, capsules, or elixirs for oral administration; suppositories for rectal administration; sterile solutions, suspensions for injectable administration; transdermal administration adhesives, and sub-dermal deposition. Injectables may be prepared in conventional forms, such as liquid solutions or suspensions, satisfactory solid forms for solution or suspension in liquid prior to injection, or as emulsions. For example, satisfactory excipients are water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, hydrochloride cysteine, and the like. Furthermore, if desired, injectable pharmaceutical compositions may contain smaller amounts of non-toxic auxiliary substances such as wetting agents, pH buffering agents, and the like. If desired, absorption enhancing preparations (e.g. liposomes) may be used.

The pharmaceutically effective amount of the TNF-α or IL-I modulating composition required as a dose will depend upon the route of administration, the type of animal being treated, and the physical characteristics of the particular animal under consideration. The dose may be adjusted to achieve a desired effect, but will depend on factors such as weight, diet, concurrent medications, and other factors that those skilled in the medical arts will recognize.

In practice of the methods, the products or compositions may be used alone or in combination with each other, or in combination with other therapeutic or diagnostic agents. These products may be used in vivo, commonly in a mammal, preferably in a human, or invitro. When employed in vivo, the products or compositions may be administered to the mammal in a variety of ways, including parenterally, intravenously, subcutaneously, intramuscularly, colonically, rectally, vaginally, nasally or intraperitoneally, employing a variety of dosage forms. Such methods can also be applied to test chemical activity in vivo.

As will be readily apparent to those skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and species of mammals treated, the particular compounds employed, and the specific use for which they are composed. are employed. Determination of effective dosage levels, which are the dosage levels required to achieve the desired result, can be performed by those skilled in the art using routine pharmacological methods. Typically, human clinical applications of products begin with lower dosage levels, with the dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies may be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.

In non-human animal studies, potential product applications begin at higher dosage levels, with dosing decreased until the desired effect is no longer achieved or adverse side effects disappear. Dosage may vary widely, depending on the desired effects and therapeutic indication. Typically, the dosages may be from about 10 micrograms / kg to 100 mg / kg body weight, preferably from about 100 micrograms / kg to 10 mg / kg body weight. Alternatively dosages may be based on and calculated by the patient's surface area, as understood by those skilled in the art. Administration is preferably oral on a daily basis or twice daily.

The exact formulation, route of administration and dosage may be chosen by the physician for the patient condition. See for example, Fingi et al. , in The Pharmacological Basis of Therapeutics, 1975. It should be noted that the physician should know how and when to terminate, discontinue, or adjust administration due to toxicity or organ deficiencies. Conversely, the physician should also be able to adjust treatment to higher levels if clinical response is not adequate (preventing toxicity). The magnitude of a dose administered for the treatment of the disease of interest will vary with the severity of the condition being treated and the route of administration. The severity of the condition may, for example, be assessed in part by standard prognostic assessment methods. Further, the dose and perhaps the frequency of the dose will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used with veterinary medicines.

Depending on the specific conditions being treated, such agents may be formulated and administered systemically or locally. A variety of techniques for formulation and administration can be found in Remington's Pharmaceutical Sciences, 182 Ed., Mack Publishing Co., Easton, PA, USA (1990) which is incorporated herein by reference in its entirety. Satisfactory routes of administration may include oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral distribution, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.

For injection, incorporation agents may be formulated in aqueous solutions, preferably physiologically compatible agents such as Hanks' solution, Ringer's solution, or physiological saline buffers. For such transmucosal administration, suitable penetrants for the barrier to be penetrated are used in the formulation. Such penetrants are generally known from the state of the art. The use of pharmaceutically acceptable carriers to formulate the aqueous compounds described for practicing the incorporation form at dosages unsatisfactory for systemic administration is within the scope of the incorporation form. With the appropriate choice of carrier and satisfactory manufacturing practice, the waterborne compositions, in particular those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds may be readily formulated using pharmaceutically acceptable carriers well known in the art at dosages suitable for oral administration. Such carriers enable the compounds of the incorporation form to be formulated as tablets, pills, capsules, liquids, gels, syrups, dregs, suspensions and the like for oral ingestion by a patient being treated. Agents intended to be administered intracellularly may be administered using techniques well known to those having common skills in art. For example, such agents may be encapsulated in liposomes, then administered as described above. All molecules present in an aqueous solution at formation of deliposomes are incorporated into the aqueous interior. The liposomal contents are both protected from the external microenvironment and, because liposomes fuse with cell membranes, they are effectively distributed in the cytoplasm of cells. Additionally, due to their hydrophobicity, small organic molecules can be directly administered intracellularly.

Pharmaceutical compositions suitable for use as described herein include compositions wherein the TNF-α or IL-I modulators are contained in an effective amount to achieve the modulatory purpose of TNF-α or IL-I. The determination of effective amounts is well within the capability of those skilled in the art, especially in view of the detailed description provided herein. In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising auxiliary and excipients which facilitate the processing of the active compounds and preparations which may be used pharmaceutically. Formulations prepared for oral administration may be in the form of tablets, tablets, capsules, or solutions. The pharmaceutical compositions of the present invention may be manufactured in a well known manner, for example, by conventional mixing, dissolving, granulating, dredging, levitating, emulsifying, encapsulating, capturing, or lyophilizing processes.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as oily suspensions suitable for injection. Satisfactory lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit or almond oil, or synthetic fatty acid esters such as ethylglyceride oleate, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.

Optionally, the suspension may also contain satisfactory stabilizers or solubility enhancing agents of the compounds to allow the preparation of highly concentrated solutions.

Pharmaceutical preparations for oral use may be obtained by combining the active compounds with a solid excipient, optionally comminuting the resulting mixture, and processing the granule mixture, after adding unsatisfactory auxiliaries, if desired, to obtain tablet or nucleus cores. Satisfactory excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, debatate starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a related salt such as sodium alginate. Dragon cores are provided with satisfactory coverage. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and satisfactory organic solvent or solvent mixtures. Dyestuffs or pigments may be added to the tablets or toe caps for identification or to characterize different dose combinations of active compound. For this purpose concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, solvents or mixtures of satisfactory organic solvents. Such formulations may be made using methods known in the art (see, for example, U.S. Patent Nos. 5,733,888 (injectable compositions); 5,726,181 (poorly soluble compounds in water); 5,707,641 (therapeutically reactive proteins or peptides); 5,667,809 (lipophilic agents). ); 5,576,012 (solubilising polymeric agents); 5,707,615 (antiviral formulations), -5,683,676 (particulate medicaments); 5,654,286 (oral formulations); 5,688,529 (oral suspensions); 5,445,829 (extended deliberation formulations); 5,653,987 (liquid formulations); controlled release) and 5,601,845 (spherical formulations).

The compounds of the present invention may be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or a subset of compounds, sharing certain chemical media, may be established by determining in vitro toxicity for a cell line such as as from a mammal, and preferably from a human. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as rats, mice, rabbits, dogs or monkeys, may be determined using known methods. The effectiveness of a particular compound can be established using various methods recognized in the art, such as in vitro methods, animal models, or human clinical trials. Art-recognized in vitro models exist for almost every kind of condition, including conditions weakened by the compounds described herein, including cancer, cardiovascular disease, and various immune deficiencies, infectious diseases. Similarly, acceptable animal models can be used to establish the effectiveness of chemicals to treat such conditions. In selecting a model to determine effectiveness, the skilled artisan may be guided by the state of the art to choose an appropriate model, dosage, rotational administration, and regimen. Of course, human clinical trials can also be used to determine the efficacy of compound in humans.

When used as an anti-inflammatory agent, anti-cancer agent, tumor growth inhibitory compound, or as a means to treat cardiovascular disease, the compounds of Formulas (II), (IIA) may be administered by oral or non-oral pathways. oral. In some aspects the compounds of the Formulas (IIB), including for example HB-a, b, IIA-a, b, and II-a, b and (112) may be administered via such routes. When administered orally, they may be administered as a capsule, tablet, granule, spray, syrup, or otherwise. When administered non-orally, they may be administered as a watery suspension, an oily or similar preparation, or as a cream, suppository, ointment, ointment or the like when administered by injection. or infusion, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, or the like. Similarly, they may be administered topically, rectally, or vaginally, as appropriate by those skilled in the art to make the compound have optimum contact with a tumor, thereby inhibiting tumor growth. Local administration at the site of the tumor or other condition of the disease is also contemplated either before or after tumor resection or as part of a recognized state of the art treatment for the condition of the condition. Controlled release formulations, deposition formulations, Infusion pump distribution are similarly contemplated.

The compounds described herein, including Formulas (II) and (IIA), and preferably (IIB), when used as an anti-tumor agent or as a treatment for any other disease condition identified above, may be administered orally or non-orally to a patient. in the amount of about 0.0007 mg / day to about 7000 mg / day doing active ingredient, and more preferably at 0.07 mg / day to about 70 mg / day of the active ingredient, preferably once daily or, less preferably. , more than two to about ten times a day. Alternatively, and also preferably, the compound may preferably be administered continuously in amounts distributed, for example, by an intravenous syringe. Thus, for a patient weighing 70 kilograms, the preferred daily dose of the anti-tumor active ingredient would be from about 0.0007 mg / kg / day to about 35 mg / kg / day, including 1.0 mg / kg / day and 0, 5 mg / kg / day, and more preferably from 0.007 mg / kg / day to approximately 0.050 mg / kg / day, including 0.035 mg / kg / day. However, as will be appreciated by those skilled in the art, in certain settings it may be necessary to administer the antitumor compound in amounts that exceed or even exceed the above preferred dosage range to effectively and aggressively treat particularly advanced or elective tumors.

To formulate the compounds described herein, including those of Formula (II), the compound of Formula (IIA), or the compound of Formula (IIB), as a tumor-depleting or anti-viral inhibitor compound, surface-recognized active agents, excipients, softening agents, suspending agents and pharmaceutically acceptable film-forming substances and coating assistants, and the like, may be used. Preferably aliphatic sulfated alcohols, esters, alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium metasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, carboxymethyl calcium cellulose, and similar, may be used as excipients; Magnesium stearate, talcum powder, hardened oil and the like can be used as softening agents; Coconut oil, olive oil, desesame oil, peanut oil, and soybean oil can be used as suspending agents or lubricants; cellulose acetate phthalate, as a derivative of a carbohydrate such as cellulose or sugar, or methylacetate methacrylate copolymer as a polyvinyl derivative, may be used as suspending agents; and plasticizers such as ester phthalates and the like may be used as suspending agents. In addition to preservative ingredients and the like may be added to the administered formulation of the compound, particularly when the compound is to be administered orally. If the compound of Formula (II), Formula (IIA), and / or Formula (IIB) is used as a reagent In a chemical test, the compound can be dissolved in an organic solvent or a watery organic solvent and applied directly to any of several cultured cell systems. Usable organic solvents include for example methanol, methyl sulfoxide, and similar ones. For example, the formulation may be a powder, a granular inhibitor or other solid, or a liquid inhibitor prepared using an organic solvent or a hydrous organic solvent. While a preferred concentration of the compound for use as a cell cycle inhibitor is generally in the range of about 1 to about 100 µg / ml, the most appropriate amount of use will vary depending on the type of cultured cell system and purpose of use such as will be appreciated by those with common skills in the art. Also, in certain applications it may be necessary or preferred to those of ordinary skill in the art to use an amount outside the above range.

The present invention also encompasses the compositions of Formula (II), Formula (IIA), and / or Formula (IIB) in pharmaceutical compositions comprising a pharmaceutically acceptable carrier. Such compositions may be prepared for storage and subsequent administration. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit.1985). For example, such compositions may be formulated and used as tablets, capsules or solutions for oral administration, suppositories for rectal or vaginal administration; sterile solutions or suspensions for injectable administration. Injectables may be prepared in conventional forms, such as liquid solutions or suspensions, satisfactory solid forms for solution or suspension in liquid prior to injection, or as emulsions. Satisfactory excipients include, but are not limited to, saline, dextrose, mannitol, lactose, lecithin, albumin, glutamate disodium, cysteine hydrochloride, and the like. Furthermore, if desired, injectable pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances, such wetting agents, pH buffering agents, and the like. If desired, absorption enhancing preparations (e.g. liposomes) may be used.

The pharmaceutically effective amount of composition required as a dose will depend upon the route of administration, the type of animal being treated, and the physical characteristics of the specific animal under consideration. Adose may be adjusted to achieve a desired effect, but will depend on factors such as weight, diet, simultaneous medications, and other factors that those skilled in the medical arts will recognize.

The products or compositions as described above may be used alone or in combination with each other or in combination with other therapeutic or diagnostic agents.

These products may be used in vivo or in vitro. The useful dosage and the most useful modes of administration will vary depending upon the age, weight and animal treated, the particular compounds employed, and the specific use for which this composition or compositions are employed. The magnitude of a dose in administration or treatment for a particular disease will vary with the severity of the condition being treated and the route of administration, and depending on the condition of the disease and its severity, the compositions may be formulated and administered systemically or locally. A variety of techniques for formulation and administration can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, PA, USA (1990).

Various references, publications, and patents are cited herein. To the extent permitted by law, each of these references, publications, and patents is incorporated herein by reference in their entirety.

EXAMPLES

The following examples serve to illustrate preferred specific embodiments of the invention and are not intended to limit the scope of protection provided by the invention. The following examples, specifically Examples 1-8, demonstrate that compounds representative of the compostosa classes described herein were synthesized. Examples 9-17, in mammalian cells presenting an acceptable preliminary model for human efficacy and safety, treated with increasing doses of the compound of Formula (I), as synthesized in Example 1, and compounds of Formula (IIB), as designated herein by TTL1a. TTL4, as synthesized according to the procedures of Example 1, and, more particularly, according to Examples 2-5, at concentrations as high as 10 μg / ml, showed similar viability compared to untreated controls indicating that the inhibitory effects of the compounds evaluated in the synthesis. TNF-α were not mediated by a direct cytotoxic effect.

Subsequent studies with certain preferred compounds demonstrated that TTL1 exhibited approximately ten (10) times more activity compared to the synthetic compound of Formula (I) in inhibiting the synthesis of TNF-α and IL-I. TTL3, which contains additional chemical modification, exhibited approximately 100 times more activity than TTL1. Importantly, similarly to the compound of Formula (I), neither TTL1 nor TTL3 significantly inhibited IL-6 synthesis.

EXAMPLE 1

Stereo-selective synthesis of the compounds of Formulas (I) and (II)

The first stereo-selective synthesis of the compound of Formula (I) was performed. The synthetic plane departs from the Wieland-Miesher (-) ketone (107), see Figure 18, and calls a Diels-Alder cycloaddition reaction for the construction of the Cde ring (101). The synthesis described confirms the proposed stereo-chemistry (101) and represents an efficient entry into an unexplored class of biologically active diterpenes.

The root bark of Acanthopanax Koreanum Nakai (Arallaceae), a deciduous shrub that grows in the Republic of Korea, has traditionally been used as a tonic, sedative, and as a remedy for rheumatism and diabetes. (Medicinal Plants of East and Southeast Asia, Perry, L.M .; Metzger, J. Eds.; MIT Press, Cambridge, MA and London, 1980). In his study of pharmacologically active extracts of this popular drug, Chung and co-workers isolated and structurally characterized a new diterpene, which was subsequently called acanthoic acid (101). (a) Kim, Y.-H., Chung, BS; Sankawa, U., J. Nat. Prod., 1988, 51, 1080-1083; (b) Kang, H.-S.; to Kim, Y.-H.; Lee, C.-S.; Lee, J.-J .; Choi, L.; Pyun, K.-H. Cellular Immunol., 1996, 770, 212-221; (c) Kang, H.-S .; Song, HK; Lee, J.-J.; Pyun, K.-H .; Choi, I., Mediators Inflamm., 1998, 7, 257-259).

From the standpoint of biosynthesis, (101) belongs to a fairly large family of pimaradiene diterpenes, which can best be represented by pimamaric acid (102). (Ruzicka, L.; Sternbach, L., J. Am. Chem. Soc , 1948, 70, 2081-2085; Ireland, RE; Schiess, PW, Tetrahedron Lett., 1960, 25,37-43, - Venkert, E.; Buckwalter, BL, J. Am. Chem. Soc., 1972. , 94,4367-4372; Wenkert, E.; Chamberlin, JW, J. Am. Chem. Soc., 1959.81, 688-693). The structure of the compound of Formula (I) is distinguished by unusual connectivity through the rigid tricyclic nucleus, which may be held responsible for its pharmacological profile. Indeed, the recent isolation of this compound has tempered studies on its biological activity and has verified its medicinal potential. (Kang, H.-S.; Kim, Y.-H.; Lee, C.-S.; Lee, J.-J.; Choi, L.; Pyun, K.-H., Cellular Immunol., 1996 , 170, 212-221; Kang, H.-S.; Song, HK; Lee, J.-J.; Pyun, K.-H.; Choi, I., Mediators Inflamm., 1998, 7, 257- 259)). More specifically, it has been found that acanthoic acid exhibits promising anti-inflammatory and anti-fibrotic activities that presumably arise to inhibit the production of proinflammatory cytokines: tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-I). ). See Tumor Necrosis Faetors. The Molecules and Their Emerging Role in Medicine, B. Beutler, Ed .; Raven Press, N.Y. 1992; Aggarwal, B .; Puri, R., Human Cytokines: Their Role in Disease and Therapy, Blackwell Science, Inc .: U.S.A., 1995; Thorpe, R .; Lodo-Sluis, A. Cytokines, Academic Press: San Diego, 1998; Kurzrock, R., - Talpaz, M., Cytokines: Interleukins and Their Reeeptors, Kluwer Academic Publishers: USA, 1995; Szekanecz, Z .; Kosh, A.E .; Kunkel, S.L .; Strieter, R.M., Clinie Pharmacol., 1998, 12,377-390; Camussi, G .; Lupine, E., Drugs, 1998, 55, 613-620; Newton, R.C; Decic-co, CP, J. Med. Chem., 1999, 42, 2295-2314.This inhibition was concentration-specific for cytokine since under the same conditions the production of IL-6 or IFN-γ (interferon-gamma ) was not affected. In addition, acanthoic acid was found to be active in oral administration and showed minimal experimental toxicity in rats and mice.

The combination of an unusual structure and promising pharmacological activity exhibited by (101) prompted aesthetics of synthetic studies, see Xiang, A.X .; Watson, D.A., Ling. T .; Theodorakis, E.A., J. Org. Chem., 1998, 63, 6774-6775; Ling, T .; Xiang, A.X. ; Theodorakis, E.A., Angew. Chem. Int. Ed.Engl., 1999, 38, 3089-3091, for this biologically important family of metabolites. This example provides a fully stereoselective synthesis of (-) acanthoic acid and the compounds of Formula (II) and, as shown in Examples 2-6, provides the basis for the total synthesis of the compounds of Formula (IIB). This Example also confirms the structure and absolute stereo-chemistry of (101).

The retro-synthetic strategy for acanthoic acid is illustrated in Figure 20. The C-ring of (101) is intended to be constructed by a Diels-Alder cyclo-addition reaction, thus revealing dienophile 103 and a suitably substituted diene such as ( 104) as ideal coupling members. See Oppolzer, W. in Comprehensive Org. Synthesis, Trost, BMEd .; Oxford, N.Y .; Pergamon Press, 1991, 315-399. This reaction introduces both the unsaturation at the C9-C11 bond and the desired stereo-chemical at the C8 and C13 carbons, allowing for convenient branching between the syntheses of the compounds of Formula (II) and the compounds of Formula (IIB). Diene 104 could be produced by functionalizing ketone 105, whose C4 quaternary center was designed to be formed by a stereo-controlled β-keto ester 107 alkylation. This analysis suggested the use of (-) ketone by Wieland-Miesher 107 as a starting material. putative. The application of such a plan for acanthoic acid synthesis is described in Figures 21 and 23 as Schemes 5 and 6. All compounds exhibited satisfactory spectral and analytical data.

Synthesis began with an optically pure enone 107 that was readily available through a D-proline-mediated asymmetric Robinson knockout (75-80% yield,> 95% ee). See Buchschacher, P .; Fuerst, A .; Gutzwiller, j.Org. Synth. Coll. Vol. VII, 1990, 368-3372.). Selective ketalization of the C9 ketone group of (107), followed by reductive alkylation by the functionality of the methyl cyano-formate enone disposed the keto ester 106 in an overall yield of 50%. See Crabtree, S.R .; Mander, L.N .; Sethi, P.S., Org. Synth., 1992, 70,256-263. To introduce the desired functionalization at position C4, a second reductive alkylation procedure has been implemented, see Coates, R.M .; Shaw, J.E., J. Org. Chem., 1970, 35, 2597-2601; Coates, R.M.; Shaw, J.E., J. Org. Chem., 1970, 35, 2601-2605. Compound 106 was first transformed into the corresponding methoxy methyl ether 108, which on treatment with lithium liquid emamonia and iodomethane gave ester 110 in 58% overall yield and as a single diastereomer. See Welch, S. Ç; Hagan, C.P., Synthetic Comm., 1973, 3, 29-32; Welch, S.C. Hagan, C.P .; Kim, J.H .; Chu, P.S., J. Org. Chem., 1977, 42, 2879-2887; Welch, S.C; Hagan, C.P .; White, D.H .; Fleming, W.P .; Troter, J.W. , J. Amer. Chem. Soc., 1977, 99, 549-556. The stereoselectivity of this addition arose from the strong preference of intermediate enolate 109 to undergo alkylation on the less impeded equatorial side.

With the bicyclic core at hand, the C ring was constructed. Ring C was formed by a Diels-Alder reaction between methacrolein 103, see for example figure 21, and sulfur-containing diene104. The synthesis of (104) was initiated with an acid-catalyzed C9-ketone deprotection of (110), followed by alkylation of the resulting ketone 105 with a ethylene diamine complex and lithium acetylide. See Das, J .; Dickinson, R.A .; Kakushima, M .; Kingston, G.M .; Reid, G.R .; Sato, Y. Valenta, Z., Can. J. Chem., 1984, 62, 1103-1111). This sequence arranged Alkaline 111 as a 8: 1 C9 diastereomeric mixture (in favor of the isomer shown), in 86% overall yield. At this time, the diastereo-facial selectivity of the Diels-Alder reaction was evaluated, as was the overall viability of using a non-functionalized diene such as (112). For this purpose, the diastereomeric mixture of propargyl 111 alcohols was partially reduced (H2, Lindlar catalyst) and dehydrated (BF3 * Et20) to produce diene 112 in 90% yield. (Coisne, J.-M .; Pecher, J .; Declercq, J.-P.; Germain, G .; van Meerssche, M., Bull. Soc. Chim. Belg., 1980, 89, 551-557) . Cycloaddition of Diels-Alder between (112) and meta-crolein (103) under pure conditions at 25 ° C yielded in quantitative yield a mixture of two diastereomeric aldehydes which were separated after reduction of sodium comborohydride. The resulting alcohols 114 and 115 were transformed into corresponding p-bromo benzoate esters (compounds 116 and 117 respectively), which on recrystallization from dichloromethane / ethanol yielded suitable crystals for X-ray analysis (Figure 22).

The results of the X-ray analysis established that the tricyclic system had the expected stereo-chemistry at position C4 and confirmed that the Diels-Alder reaction proceeded with exclusive endorientation. Methacrolein has been shown to produce Diels-Alder ex-products by reacting with cyclopentadiene: Kobuke, Y .; Fueno, T .; Furukawa, J., J. Am. Chem. Soc., 1970, 92, 6548-6553. This surprising observation was based on the steric repulsion exhibited by the group: Yoon, T .; Danishefsky, S.J .; de Gala, S., Angew. Chem.Int. Ed. Engl. 1994, 33, 853-855). Second, after reduction, the main product of the cycloaddition was alcohol 114, which had the desired stereo-chemical at center C8, thus demonstrating a strong preference for diene 112 over reaction with (103), see for example figure 21 , from the α-face (attack from below). In addition, these data indicated that acanthoic acid synthesis would require a reversal in the orientation of the dienophile that enters.

As discussed in Example 2-8, below, except for inversion of the incoming dienophile, the completely new compounds of Formula (IIB) were synthesized. The choice of an appropriate substituted diophenyl essentially allows for the limited selection of the R11 and R12 groups of the compounds of Formula (IIB).

The inversion of the required dienophil for the synthesis of the compound of Formula (I), its naturally occurring analogs, and the compounds of Formula (II) and (IIA), was performed by altering the atomic orbital coefficients at the diene terminals, supporting the use of a diene containing hetero atom such as (104) during acyclo addition. See generally Overman, L.B .; Petty, C.B .; Ban, T .; Huang, G.T., J. Am. Chem. Soc. 1983, 105, 6335-6338; Trost, B.M .; Ippen, J .; Vladuchick, W.C., J. Am. Chem. Soc., 1977, 99,8116-8118; Cohen, T .; Kozarych, Z. J. Org. Chem. 1982, 47, 4008-4010; Hopkins, P.B .; Fuchs, P.L., J. Org. Chem., 1978, 43, 1208-1217; Petrzilka, M .; Grayson, J.I., Synthesis, 1981, -753-786). Diene construction 104 and its use for the synthesis of (101) is shown in Figure 23, Scheme 6.

Compound 104 was produced by a standard addition of thiophenol over alkyne 111 (Greengrass, CW; Hughman, JA; Parsons, PJ, J. Chem. Soc. Chem. Commun., 1985, 889-890), followed by mediated dehydration. by POCl3 of the allyl alcohol resultant (Trost, BM; Jungheim, LN, J. Am. Chem. Soc., 1980, 1002, 7910-7925; Mehta, G.; Murthy, AN; Reddy, DS; Reddy, Α.V. , J. Am. Chem. Soc., 1986, 108, 3443-3452) (2 steps, 70% yield). Interestingly, this dehydration was also attempted with BF3 * Et20, but proved ineffective in this case. With a significant amount of (104) by hand, the Diels-Alder reaction was investigated using (103) as the dienophile. Various catalyzed Diels-Alder (-78 to 80 ° C) Lewis acid (BF 3 * Et 2 O, TiCl 4, AlCl 3 and SnCl 4) thermal conditions were tested. The best results were obtained with SnCl 4 in methylene chloride at -20 ° C and aldehyde 118 in 84% yield as a 4.2: 1 mixture of diastereomers. To simplify product characterization and allow proper separation, this mixture was reduced with reductively edeulfurized NaBH4 using Raney Ni. The 119 and 120 alcohols were thus obtained in 91% overall yield. The structure of these compounds was assumed by comparison with the isolated products of the reaction between (103) and (112). Primary dodiastereomer 120 treatment with Dess-Martin periodinane, followed by Wittig methylenation installed the alkene functionality at the C13 center and yielded (121) at 86% yield. The C-19 carboxylic acid was then deprotected. Exposure of (121) to LiBr at DMF reflux gave acanthoic acid 101 in 93% yield by a Sn2-type shift of acyloxyl functionality. See Bennet, C. Re-cambie, R. C., Tetrahedron, 1967, 23, 927-941. Synthetic (101) had identical analytical and spectroscopic data to those reported for the natural product.

This Example provides a concise stereo-selective synthesis of compound 101. The synthetic strategy is enhanced by the implementation of a Diels-Alder reaction between emetacrolein diene 104, which configures stereo-chemistry at the C13 and C8 carbon centers. The described synthesis of (101) requires fourteen steps (starting with enone 107) and proceeds in approximately 9% overall yield. The overall efficiency and versatility of the strategy lays the foundation for the preparation of engineered analogs with improved pharmacological profiles.

EXAMPLES 2-8

Stereo-selective Synthesis of Formula Compounds

The outline of the procedure in Example 1, and described in Figure 23, Scheme 6, may be modified or truncated to obtain the compounds of Formula (II) or Formula IIB).

EXAMPLE 2

The compound herein designated TTL4 was synthesized following the procedures of Example 1 as described in Figure 21 to obtain compound 114, herein designated TTL4.

EXAMPLE 3

The compound designated herein TTL2 was synthesized following the procedures of Example 1 as described in Figure 21 to obtain compound 114. Similar to the reaction described in Figure 23, step (h), compound 114 was then reacted with 3.0 equivalents LiBr in DMF. at 160 ° C for approximately three hours for a yield of approximately 93% of the TTL2 water-bound compound.

EXAMPLE 4

The compound designated herein as TTL 3 was synthesized following the procedures as described in Figure 14 to obtain compound 13. This compound is referred to herein as TTL 3.

EXAMPLE 5 The compound herein designated TTL1 was synthesized following the procedures as described in Figure 14 to obtain compound 13. This compound is designated TTL1 herein.

EXAMPLE 6

A compound of the Formulas (IIB) wherein R15 is a hydrogen and R9 and R15 are selected separately from the group consisting of C1-C6 alkyl and C1-C6 substituted alkyl is synthesized following the procedures of Example 1, except that the odienophile is selected from a group. of the compounds of Formulas (III) wherein R15 is a hydrogen and R9 and R15 are selected separately from the group consisting of C1-C6 alkyl and substituted C1-C6 alkyl as in this Example.

EXAMPLE 7

Specifically, a compound of the Formulas (IIB) wherein R14 is a hydrogen and R9 and R15 are separately selected from the group consisting of C1-C6 alkyl, and C1-C6 substituted alkyl is synthesized following the procedures of Example 1, except that the dienophile is selected from one of the compounds of Formulas (III) wherein R 14 is a hydrogen and R 9 and R 15 are selected separately from the group consisting of C 1 -C 6 alkyl and substituted C 1 -C 6 alkyl as in this Example.

EXAMPLE 8

A compound of Formulas (IIB) wherein R14 is a hydrogen, and R9 and R15 are separately selected from C2 -C6 alkenyl, C2 -C6 substituted alkenyl, C1-C6 alcohol, and C5-C6 aryl are synthesized following the procedures of Example 1, except that the dienophile is selected from one of the compounds of Formulas (III) wherein R14 is a hydrogen and R9 and R15 are selected separately from C2-C6 alkenyl, substituted C2-C6 alkenyl, C1-C6 alcohol, C5-C6 earilla as in this Example .

EXAMPLES 9-17

Materials and methods

Murine macrophage cell RAW264.7 cells (1 χ106 / ml) were pretreated for 30-60 minutes with varying doses of the synthetic compound of Formula (I) and a panel of analogs (diluted in 0.5% DMSO) prior to stimulation. various agents such as lipopolysaccharide (LPS) or a gram-positive agent such as heat-killed Staphilococcus Aureus (SAC). Supernatants collected over a 72 hour period will be analyzed for TNF-α, IL-I, IL-6, IL-10, IL-12 and other cytokine levels by both ELISA and bioassay. Additional studies to evaluate the effects of the synthetic compound of Formulas (I), (II), (IIA) and (IIB) on cytokine signaling pathways such as Caspase activity (Nr-1, Nr-3), factors Transcriptional transcription such as FN-kB, MAP kinase activity (p38, ERK and JNK) will also be performed.

Results

Preclinical studies have shown that murine RAW264.7 cells treated with increasing doses of Formula (I) and (IIB) compounds, specifically those labeled TTL1 and TTL3, at concentrations as high as 10 μα / πιΐ showed similar viability compared to untreated controls. indicating that the inhibitory effect of the compounds of Formulas (I) and (IIB) on TNF-α synthesis were not mediated by a direct cytotoxic effect.

Subsequent studies with the compound of Formula (I) as synthesized according to Example 1, TTL1 (as synthesized according to Example 2) and TTL3 (as synthesized according to Example 4) showed that TTL exhibited approximately 10-fold higher activity. compared to the compound of Formula (I) as synthesized according to Example 1 in inhibiting the synthesis of TNF-α and IL-I. TTL3 as synthesized according to Example 4 contains an additional chemical modification and exhibited activity approximately 100 times greater than TTL1 as synthesized according to Example 2. It is remarkable that, similarly to the compound of Formula (I) significantly synthesized according to With Example 1, neither TTL1 nor TTL3 inhibited IL-6 synthesis. TTL1 exhibited ten (10) fold greater activity compared to the compound of Formula (I) as synthesized according to Example 1 in inhibiting the synthesis of TNF-α and IL-I.

TTL3, which contains an additional chemical modification, exhibited approximately 100 times greater activity than TTL1. It is again important to note that, similarly to the compound of Formula (I) as synthesized according to Example 1, no analog significantly inhibited the synthesis of IL-6.

EXAMPLE 18

The synthesis of compounds has alternative stereo-structure at the ring position covalently linked to R6. Several diastereomers of the compounds designated herein TTL1-TTL5 have been prepared and isolated by (a) using L-proline instead of D-proline in the cyclization of Robinson from triquetone 2 to enone 3e, or (b) purifying the C14 stereoisomers which were produced by the Diels-Alder reaction between diene 104 and ethacrolein (103). The selection of the stereo structure at these chiral centers allows the selection and isolation of four distinct diathereomers that correspond to each TNF-α modulator described herein.

More specifically, enantiomers at the ring position covalently attached to the R6 medium were synthesized by modifying the procedures described in Figure 14 as follows: (L) -proline replaced (D) -proline in the triquetone 2 -Robinson cyclization to enone 3. Cyclization using L-proline thus arranged the (+) enone 3 enantiomer. Figure 14 was in any case followed using the same reactions and conditions as shown. The resulting product was the (+) enantiomer of TTL3.

Similarly, as noted above, the Diels-Alder reaction between diene 104 and methacrolein (103) configures stereo-chemistry at the C13 and C8 carbon centers, or at the C14 and C8 carbon centers depending on the orientation of the dienophile. allow the synthesis and purification, and consequently the use, of at least the diastereomers of the following compounds: <formula> formula see original document page 198 </formula>

Where R1-R15 are as previously defined, and the aquirality at the ring position directly and covalently linked to R6 and at the designated ring position C14 (directly ecovalently linked to R14 and R15 in the anterior structure and R9 in the posterior structure) may be selected separately from any one. (-) or (+), or may represent a racemic mixture of enantiomers. These structures will be understood to be within the meaning of the structures of Formulas (II) and (IIB), as these terms are used herein.

Examples of synthetic routes and isolation routes, as well as certain quoted diastereomers, are described in Figures 24, 25, 26, 27, 28 and 29.

EXAMPLES 19-21

Demurine and human macrophagocyte cell-based cell assays were completed to test the activity of stereoisomers produced and isolated as described in Example 19 of the TTL3 compound.

EXAMPLE 19 LPS stimulation of THP-I human macrophage cell line. THP-I human monocytic cells were washed in a complete RPMI-1640 medium (CRPMI; contains 10% heat-inactivated fetal calf desoro with 2 mM L-glutamine, 10 mM Hepes, 1 mM sodium pyruvate, 4, 5 g / l deglucose, 1.5 g bicarbonate and 0.05 mM 2-mercaptoethanol) at 1,000 rpm for 5 minutes and counted. To induce maturation, THP-I cells were plated at a density of 1 χcells / ml in 24 or 96 plates from a container (Costar) and pre-10 treated with 5 nM phorbol myristate acetate (MPA) during the third. days After three days, CRPMI was discarded and a new name was added. Lipopolysaccharide (LPS, E. Coli0111: B4 or 055: B5 serotype) was diluted to a 1 mg / ml portion in phosphate buffered salin and stored at -80 ° C. Prior to use, the LPS was thawed and vortexed for 30 minutes. To assess the effect of different TTL3 isoforms (including enantiomers, analogs, diastereomers) on LPS-induced TNF-α production, cells were treated with the compounds for 1 hour, followed by a 5 hour incubation with 2 µg LPS. A p38 kinase inhibitor SB203580 (Sigma) was used as a positive control.

EXAMPLE 20

LPS stimulation of a murine macrophage cell line RAW264.7

RAW264.7 cells were plated at 1 x 105 cells / well of a 24 well plate and allowed to adhere and spread overnight at 37 ° C. The following day, the medium was replaced with fresh medium (1 ml / well), and cells were allowed to incubate for 15 to 20 minutes prior to inhibitor pretreatment. The inhibitors tested included TTL3 enantiomer peaks AeBe a p38 MAP kinase control inhibitor, SB203580. 200X of each inhibitor was prepared in 100% DMSO in boro silicate glass vials, and 5 μΐ of this solution was added per container and mixed immediately. DMSO alone (0.5% DMSO in the medium) served as the vehicle control. Cells were pretreated with inhibitors for 1 hour at 37 ° C in concentrations ranging from 10 pg / ml to 10g / ml final concentration. An IPSX IOOX trigger was prepared and added to the cells at a final concentration of 1μg / ml. Cells were stimulated for 12 to 24 hours after supernatants were harvested and analyzed for TNF-Î ± by ELISA (Biosource).

EXAMPLE 21

Example of ELISA methodology for human TNF-α

Supernatants were collected and stored at -80 ° C until testing in a specific TNF-α ELISA. ELISA plates were coated with 100 μL / TNF-Î ± TNF-α antibody container at 5 μg / ml for 20 hours at 4 ° C. The plates were washed twice with wash buffer and blocked by adding 300 μL / blocker solution container for 2 hours at room temperature. The plates were washed 4 times and reconstituted with standards and samples added at 100μL / well. At the same time 50 μL / well of biotinylated antibodies (4 μg / mL) were added and incubated for 2 hours at room temperature with uninterrupted shaking (700 rpm). Plates were washed 4 times and a deestrepavidin-HRP working solution was added. for 30 minutes at room temperature. 100 μL / well TMB was added for 30 minutes and the reaction was stopped by adding 50 μL / 1.8 N H2SO4 well.

Examples 19-21 also demonstrate the amazing ability of both TTL3 enantiomers A and B to inhibit TNF-α synthesis. In the above assays of Examples 19-21, no significant difference was observed with respect to the ability of these stereoisomers to inhibit TNF-α synthesis.

EXAMPLE 22

TTL3 Analog Synthesis Strategy

A. Strategy 1

The compounds designated herein as CC-3-02, CC-3-09, TTL-1, LT-1-73, LT-1-78, LT-1-85, and LT-1-74 were synthesized following the strategy described. in figure 30.

B. Strategy 2 Compounds designated herein as CC-3-02, LT-I-46, CC-3-19, CC-3-17, and CC-3-18 were synthesized following the strategy as described in Figure 31.

C. Strategy 3

The compounds designated herein as CC-3-02, CC-3-09, CC-3-14, CC-3-13, CC-3-13P, CC-3-15, and CC-3-14x were synthesized following the strategy as described in figure 32.

EXAMPLE 23

TTL3 Analog Synthesis Scheme

The synthesis of TTL3 analogs is shown in Figures 33-37 and detailed below with the following descriptions:

Compound 1 (TTL3): colorless oil; Rf = 0.75 (silica, 25% ether in hexanes); 1H NMR (400 MHz, CDCl3) δ 5.96 (dd, 1H, J = 16.8, 11.6 Hz), 5.50 (m, 1H), 4.98 (m, 2H), 3.62 (s, 3H), 2.20-2.11 (m, 1H), 2.10-1.91 (m, 4H), 1.90-1.70 (m, 4H), 1.69-1 , 51 (m, 3H), 1.50-1.38 (m, 3H), 1.36-1.24 (m, 1H), 1.17 (s, 3H), 1.04 (s, 3H ), 0.90 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 177.9,149.1, 143.8, 117.9, 111.7, 51.2, 47.7, 44.4, 41.4, 41.2, 38.9 , 38.3, 37.7, 34.8, 30.4, 28.4, 24.8, 23.1, 22.3, 22.2, 20.6, 19.8.

Compound 2: A well-stirred solution of ester 1 (480 mg, 1.50 mmol) in CH 2 Cl 2 (10 mL) was treated with DIBAL (6.0 mmol, 6.0 mL, 1 M in CH 2 Cl 2) at -78 ° C. After stirring for 30 min, the entire reaction mixture was allowed to warm to room temperature for another 2 h. Methanol (5 mL) was added to quench the reaction mixture, and the entire reaction mixture was diluted with ether (30 mL) and Rochelle salt (20 mL, 1 N water solution). After stirring for another 2 h vigorously at room temperature, the organic layer was extracted with ether (3 x 40 ml) and concentrated. The brown residue was purified by flash chromatography on silica gel using 20% ether / hexane as eluent to afford the desired product 2 (372 mg, 86%). White solid, [α] D = + 70 ° (c = 1, benzene). 1H NMR (CDCl3, 400 MHz) δ 5.95 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.46 (m, 1H), 4.98 (t, J = 8 Hz, 2H), 3.82 (d, J = 12Hz, 1H), 3.52 (d, J = 12Hz, 1H), 2.07-1.57 (m, 6H), 1.51-1.42 (m, 5H), 1.27-1.23 (m, 6H), 1.05 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H); 13 C NMR (CDCl 3, 100 MHz) δ 150.39, 142.47, 117.05, 112.34, 64.85, 45.74, 42.11, 41.10.38.46, 37.46, 35 , 36, 29.78, 26.32, 26.02, 24.95, 23.36, 19.14.18.49; HRMS calculated for C 20 H 32 O: 288.24; found 288 (GC-MS).

Compound 3: To a well-stirred solution of alcohol 2 (360 mg, 1.23 mmol) in CH 2 Cl 2 was added Dess-Martin portion (483 mg, 1.61 mmol) and the mixture was allowed to stir for 3 h. at room temperature until TLC indicated complete consumption of starting material. The entire reaction mixture was extracted with CH 2 Cl 2 (3 x 50 mL), washed with NaHCO 3 and concentrated. The brown residue was purified by silica gel chromatography on silica gel using 15% hexane ether (v / v) as eluent to afford the desired product 3 (266mg, 74%). 3: White solid, [α] D = -142.2 (c = 1, benzene). 1H-NMR (CDCl3, 400 MHz) δ 9.94 (s, 1H), 5.94 (dd, J = 11.6 Hz, J = 12 Hz, 1H), 5.53 (m, 1H), 4 , 96 (t, J = 8Hz, 2H), 2.10-2.03 (m, 4H), 1.95-1.86 (m, 3H), 1.71-1.42 (m, 7H ), 1.28-1.23 (m, 2H), 1.07 (s, 3H), 1.02 (s, 3H), 0.96 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 206.39.148.13, 142.42, 118.10, 112.39, 48.22, 46.55, 41.80, 40.67, 37.70.36, 70, 35.05, 24.96, 24.47, 23.92, 23.27, 20.54, 19.64, 18.47, HRMS calculated for C 20 H 30 O: 309.21 (M + Na) + found 309 (ESI mass spec.).

Ethyl ester 4: To a well stirred solution of NaH (67 mg, 0.43 mmol) in THF (20 mL) at 0 ° C was added triethyl phosphonoacetate (500 mg, 0.60 mmol). The reaction mixture was allowed to reach room temperature for a period of 4 h and treated with a solution (THF, 10 ml) of aldehyde 3 (76 mg, 0.27 mmol) and then the reaction mixture was heated under reflux for 16 h. After quenching with water, the organic layer was extracted with ether (2 x 60 ml). The ether extract was concentrated and purified on silica gel (5% ether / hexane, v / v) to afford the desired ester 4 (68 mg, 70%). 4: Oil (Rf = 0.4, 10% ether / hexane, v / v), 1H-NMRC (CDCl3, 400 MHz) δ 7.34 (d, J = 16 Hz, 1H), 5.90 (dd , J = 11.6 Hz, J = 12 Hz, 1H), 5.76 (d, J = 16 Hz, 1H), 5.48 (m, 1H), 4.97 (m, 2H), 4, 18 (q, J = 8Hz, 2H), 2.09-1.74 (m, 6H), 1.66-1.42 (m, 8H), 1.30-1.17 (m, 5H) 0.1 -06 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 167.10, 154.47,149.15, 142.41, 118.13, 117.43, 112.33, 60.18, 46.75, 42.38.41, 07, 39.93, 38.66, 37.74, 37.03, 29.67, 25.04, 24.81, 23.35,20.19, 19.11, 14.45; HRMS calculated for C 24 H 36 O 2 356.54, found 356.54.

Methyl ester 5: To a well-stirred solution of ester 4 (60 mg, 0.168 mmol) in methanol (10 mL), magnesium powder (50 mg, 6.25 mmol) was added and the entire reaction mixture was added at room temperature by 12 h. HCl (10 ml, 2 M) was added to the reaction mixture to dissolve the magnesistant. The reaction mixture was concentrated under reduced pressure and extracted with ether (2 x 50 ml), and the organic layer concentrated. The desired product 5 was purified by column chromatography using 10% ether / hexane (v / v) as eluent. 5: Oil (50 mg, 87% yield); 1H-NMR (CDCl3, 400 MHz) δ 5.95 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.45 (m, 1H), 4.98 (m, 2H), 3 , 66 (s, 3H), 3.26-1.87 (m, 7H), 1.69-1.51 (m, 11H), 1.24-1.19 (m, 2H), 1.09 (s, 3H), 1.04 (s, 3H), 0.93 (s, 3H); HRMS calculated for C 23 H 36 O 2 344.56, found 344.56.

Acid 6: Ester 5 (50 mg, 0.14 mmol) was dissolved in a mixed solution of THF / H2 O (v / v, 1: 1, 4 mL) and LiOH (30 mg) was added. After stirring for 30 min the reaction mixture was heated under reflux for 12 hours. The reaction mixture was diluted with water, acidified with HCl (3N) solution and extracted with ether (2 x 50 ml). The desired product was purified by silica gel column chromatography using 50% ether / hexane (v / v). 6: White solid (34 mg, 71%); 1H-NMR (CDCl3, 400 MHz) δ 5.95 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.46 (m, 1H), 5.00-4.95 (m, 2H), 2.27-2.17 (m, 3H), 2.09-1.88 (m, 10H), 1.69-1.37 (m, 7H), 1.24-1.18 ( m, 1H), 1.09 (s, 3H), 1.04 (s, 3H), 0.83 (s, 3H); 1 C-NMR (CDCl 3, 100 MHz) δ 178.62, 152.06, 143.69, 118.13,113.52, 67.09, 48.16, 43.67, 42.52, 39.42, 38, 38, 36.98, 31.02.30.45, 29.48, 28.43, 27.33, 26.26, 24.64, 21.17, 20.41, 19.86.16.62; HRMS calculated for C22H34O2 329.24 (M-H) +, found329.20.

Unsaturated Acid 7: To a solution of demethyl ester 4 (60 mg, 0.17 mmol) in THF / H 2 O (1: 1, v / v, 8 mL), LiOH (40 mg, excess) was added at room temperature. After quenching for 30 min the reaction mixture was allowed to flow for 12 h. The reaction mixture was diluted with water and acidified with a HCl solution (3 N, 40 mL) and extracted with ether (2 x 50 mL). The desired product was purified by silica gel column chromatography using ether / hexane (1: 1, v / v). 7: White solid (42 mg, 76%), 1H NMR (CDCl3, 400 MHz) δ 7.45 (d, J = 16 Hz, 1H), 5.94 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.76 (d, J = 16 Hz, 1H), 5.48 (m, 1H), 5.00-4.95 (m, 2H), 2.15-1.74 ( m, 5H), 1.64-1.50 (m, 7H), 1.47-1.42 (m, 5H), 1.06 (s, 3H), 0.99 (s, 3H), 0 95 (S, 3H); 13 C NMR (CDCl 3, 100 MHz) δ 171.03, 157.41,149.02, 142.37, 117.55, 117.20, 112.37, 46.82, 42.36, 41.01,40.18 , 38.50, 38.21, 37.75, 37.01, 29.82, 25.04, 24.75, 23.35,20.18, 19.11; HRMS calculated for C 22 H 32 O 2 351 (M + Na) +; Found351 (ESI Mass Spec).

Vinyl ether 8: Methyl triphenylmethoxy phosphonium chloride was stirred in THF (476.1 mg, 1.39 mmol) and treated with 4.8 equivalent of potassium t-butoxide, followed by addition of aldehyde 3 (80 mg, 0.28 mmol). The reaction was completed within 30 minutes. After the reaction mixture was concentrated, the residue was redissolved in ethyl ether and extracted with a NaCl solution. After column chromatography purification, 87 mg of product (99% yield) was obtained.

Aldehyde 9: To a well stirred solution of compound 8 (50 mg, 0.159 mmol) in acetone (10 mL), p-toluene sulfonic acid (50 mg, 0.26 mmol) was added and the reaction was allowed to stir for 2 hours. h at room temperature. TLC indicated complete formation of the desired product. The solvent was removed and the reaction mixture was extracted with ether (3 x 40 ml) and washed with saturated NaHCO 3 and saturated NaCl solution. The crude product was purified by column chromatography using 4% etherhexane as eluent. 9: Oil (88%), [α] D = +4.4 (c = 1, benzene), 1H-NMR (CDCl3, 400 MHz) δ 5.94 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.48 (m, 1H), 5.01-4.96 (m, 2H), 2.55 (d, J = 12 Hz, 1H), 2.37 (d, J = 12 Hz, 1H), 2.09-1.93 (m, 3H), 1.76-1.71 (m, 2H), 1.63-1.13 (m, 12H), 1.09 (S , 3H), 1.07 (s, 3H), 1.06 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 204.26, 150.23, 142.24, 117.26, 112.46, 47.22, 42.43,40.81, 39.02, 38.08, 37.03, 29.06, 25.59, 25.00, 23.39, 19.90.19, Ό7; HRMS calculated for C21 H32 O 323.25, found 323.23. Acid 10: To a solution of 17 mg aldehyde 10 (0.056 mmol) in tBu0H / H2 O (3: 1) was added 23.3 mg NaH2PO4-H2O (0 , 17 mmol) and the reaction mixture was stirred to dissolve the salt completely before adding 84.5 μΐ of 2 M 1-methyl-2-butene in THF. The reaction was stirred for 30 minutes, then treated with 15.3 mg NaClO2 (0.17 mmol). When the reaction was finished, it was neutralized with NH 4 Cl. The product was collected by extraction with CH 2 Cl 2 and purified by column chromatography to yield 17.0 mg of acid 10 (96%). 10: 1 H-NMR (CDCl 3, 300 MHz) δ 6.00-5.90 (m, 1H), 5.48 (d, J = 3 Hz, 1H), 5.02-4.95 (m, 2H) 2.58 (d, J = 12.6 Hz, 1H), 2.30 (d, J = 12.6 Hz, 1H), 1.25 (s, 3H), 1.07 (s, 3H) 1.02 (s, 3H).

Acid 12: To a well stirred solution of alcohol 2 (70 mg, 0.24 mmol) in DCM (8 mL), DMAP (5 mg, cat.) And anhydridosucinic (30 mg, 0.28 mmol) were added and The reaction mixture is allowed to stir for 8 h at room temperature. The reaction mixture was extracted with DCM (2 x 40 ml) and washed with water (30 ml). The desired product was purified by silica gel column chromatography using 12-16% ether in hexane to provide 12 acid. 12: Solid (73 mg, 78%). IR (neat) 3312, 2920.1732, 1708 cm-1; 1H-NMR (CDCl3, 400 MHz) δ 5.95 (dd, J = 11.2 Hz, 12Hz, 1H), 5.48 (m, 1H ), 5.0-4.96 (m, 2H), 4.34 (d, J = 12Hz, 1H), 4.03 (d, J = 12Hz, 1H), 2.70-2.61 (m, 4H), 2.09-1.91 (m, 4H), 1.80-1.39 (m, 10H), 1.25-1.08 (m, 6H), 1.05 (s 13 C-NMR (CDCl 3, 100 MHz) δ 177.32, 172.02, 150.09, 142.32, 117.24,112.41, 67.12, 45 88, 42.19, 40.99, 37.97, 37.21, 36.11, 29.80.29.01, 26.77, 25.97, 25.00, 23.39, 19.94 , 19.10, 18.78, HRMS calculated for C24H36O4 411.25 (M + Na) +, found 411.25.

Acid 11: This compound was prepared using the procedure described above for acid 12. In this case, anhydridemalema was used instead of succinic anhydride. 11: (68 mg, 71%); 1H-NMR (CDCl3, 500 MHz) δ 6.01 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.46 (brd, 1H), 5.09-4.95 (m, 2H), 4.36 (d, J = 8Hz, 1H), 4.02 (d, J = 8Hz, 1H), 2.48-2.36 (m , 3H), 2.16-1.92 (m, 5H), 1.86-1.38 (m, 9H), 1.35-1.11 (m, 10H), 0.98-0.81 (m, 5H); 13 C-NMR (CDCl 3, 100MHz) δ 173.96, 169.08, 146.28, 138.46, 113.29, 108.44, 93.15.88.18, 62.60, 41.65, 37 , 95, 36.75, 33.71, 32.93, 29.11, 28.66, 25.54, 25.46, 25.43, 22.54, 20.69, 19.06, 15.61 , 14.45; HRMS calculated for C25H38O4 425.26; found 425.26.

Ester 13: To a well stirred solution of alcohol 2 (22 mg, 0.079 mmol) and acid 12 (24 mg, 0.0617 mmol) in DCM (10ml) was added DCC (17 mg, 0.080 mmol) and DMAP (5 mg, cat.) and the reaction mixture was allowed to stir at room temperature for 12 h. The mixture was extracted with DCM (20 x 2 mL) and washed with water (15 mL). The desired product was isolated by silica gel chromatography. 13: Solid (30 mg, 70%); 1H-NMR (CDCl3, 400 MHz) δ 5.95 (dd, J = 11.2 Hz, J = 12 Hz, 2H), 5.48 (m, 2H), 5.00-4.95 (m, 4H), 4.32 (d, J = 12Hz, 2H), 4.03 (d, J = 12Hz, 2H), 2.62 (s, 4H), 2.05-1.70 (m, 6H ), 1.76-1.70 (m, 3H), 1.56-1.42 (m, 23H), 1.20 (s, 6H), 0.98 (s, 6H), 0.93 (s, 6H); 13 C-NMR (CDCl 3, 100 MHz) δ 172.18, 150.10, 142.32, 117.23, 112.41, 66.95.45.87, 42.18, 40.99, 37.97, 37.19, 36.13, 29.40, 26.82, 25.98,25.00, 23.39, 19.95, 19.13, 18.77; HRMS calculated for C44H66O4681.48 (M + Na) +; found 681.48.

Chloroacetyl derivative 14: To a well-mixed solution of alcohol 2 (40 mg, 0.1389 mmol) and DMAP (10 mg, cat.) In DCM (10 ml) at 0 ° C was added chloroacetyl chloride ( 23 mg, 0.20 mmol). The reaction mixture was allowed to stir at room temperature for another 2 h and then quenched with water and extracted with ether (2 x 40 ml). The combined ether layer was concentrated and purified by column chromatography. The desired product was eluted with 8% ether / hexane. 14: Solid (39 mg, 82%). 1H-NMR (CDCl3, 400 MHz) δ 5.93 (dd, J = 11.2 Hz, J = 13 Hz, 1H), 5.48 (brd, 1H), 5.01-4.96 (m, 2H), 4.43 (d, J = 8Hz, 1H), 4.13 (d, J = 8Hz, 1H), 4.06 (s, 2H), 2.09-1.96 (m, 3H), 1.92-1.71 (m, 2H), 1.65-1.42 (m, 14H), 1.22 (s, 3H), 1.14 (s, 3H), 0.97 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 167.28, 149.96, 142.26, 117.37,112.47, 68.58, 45.91, 42.19, 41.06, 40.93, 37, 95, 37.70, 37.37,36.04, 29.80, 26.69, 25.95, 25.01, 23.39, 19.94, 19.09, 18.82.

Morpholine derivative 15: To a well-mixed solution of chloroacetyl derivative 14 (24 mg, 0.066 mmol) in DCM was added morpholine (15 mg, 0.17 mmol). The reaction mixture was heated under reflux for 12 h and the reaction mixture was extracted with DCM (2 x 30 mL) and washed with water (15 mL). The desired product was purified by silica gel column chromatography. 15: Oil (20 mg, 71%); 1H-NMR (CDCl3, 400 MHz) δ 5.94 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.47 (m, 1H), 5.00-4.95 (m, 2H), 4.36 (d, J = 12Hz, 1H), 4.05 (d, J = 12Hz, 1H), 3.75-3.73 (m, 4H), 3.20 (s, 2H), 2.58-2.56 (m, 4H), 2.08-1.42 (m, 16H), 1.24 (s, 3H), 1.05 (s, 3H), 0.92 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 170.15, 150.02, 142.27, 117.28, 112.43, 81.54, 66.82, 59.62, 53.32, 52.0.45, 87, 42.17, 37.96, 37.67, 37.18, 29.78, 26.89, 25.95, 24.99.19.93, 19.10, 18.79; HRMS calculated for C 26 H 41 NO 3 416.31 (M + H) + found 416.31.

Piperazine 16 Derivative: Compound 16 was prepared according to the procedure described above using piperazine instead of morpholine. 16: Oil (77%), 1H-NMR (CDCl3, 400 MHz) δ 5.93 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.48 (brd, 1H), 5, 00-4.95 (m, 2H), 4.37 (d, J = 10 Hz, 1H), 4.05 (d, J = 10 Hz, 1H), 3.20 (s, 2H), 2, 63 (brd, 2H), 2.60-2.57 (m, 5H), 2.4-2.2 (brd, 3H), 2.08-1.94 (m, 5H), 1.71- 1.42 (m, 10H), 1.20 (s, 3H), 1.05 (s, 3H), 0.87 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 170.90,150.28, 117.21, 112.39, 66.71, 59.78, 53.75, 53.47, 51.58, 51.25.45, 84, 42.15, 40.94, 37.93, 37.66, 37.17., 36.16, 29.78, 26.88,25,95, 24.96, 23.25, 19.92 , 19.10, 18.76; HRMS calculated for C 26 H 42 N 2 O 2 415.33 (M + H) +, found 415.33.

Compound 17: To a well stirred solution of product 16 (30 mg, 0.072 mmol) in DCM was added triethylamine (0.4 mL) and tosyl chloride (19 mg, 0.1 mmol). The reaction mixture was allowed to stir at room temperature for 15 h and then quenched with water and extracted with methylene chloride (3 x 30 ml). The desired product was purified on silica gel using 25-30% ether / hexane as eluent. 17: White solid (40 mg, 69%); 1H-NMR (CDCl3, 400 MHz) δ 7.62 (d, J = 8 Hz, 2H), 7.31 (d, J = 8 Hz, 2H), 5.92 (dd, J = 11.2 Hz , 12 Hz, 1H), 5.47 (m, 1H), 5.0-4.95 (m, 2H), 4.36 (d, J = 12 Hz, 1H), 4.03 (d, J = 12 Hz, 1H), 3.24 (brd, 1H), 3.08 (brd, 4H), 2.72 (brd, 3H), 2.44 (s, 3H), 2.42-1.90 (m, 4H), 1.63-1.40 (m, 10 Η), 1.24-1.05 (m, 4H), 1.05 (s, 3H), 1.03 (s, 3H) 0.89 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ194.25, 149.93, 142.28, 131.92, 129.56, 127.72, 117.32, 112.45.55.87, 51.90, 45 , 50, 42.15, 40.89, 37.93, 37.68, 36.15, 29.8 · 0.26.85, 25.94, 24.98, 23.37, 19.92, 19 , 08, 18.79, HRMS calculated for C33H48N2O4S 591.32; found 591.32.

Ester 18: A solution of alcohol 2 (20 mg, 0.069 mmol) and 4-methyl morpholine (20 mg, 0.173 mmol) in methylene chloride (10 mL) was cooled to 0 ° C and treated with propylate deethyl (10 mg, 0 mL). , 10 mmol). The whole reaction mixture was allowed to be stirred overnight. Water (25 ml) was added to the reaction mixture and extracted with methylene chloride (2 χ 30 ml). The combined organic extracts were combined and concentrated. Finally the desired product was purified by silica gel chromatography using 20% ether / hexane (v / v) as eluent. Oil (18 mg, 64%), 1H NMR (CDCl3, 400 MHz) δ 7.61 (d, J = 12 Hz, 1H), 5.93 (dd, J = 11.2 Hz, J = 13 Hz , 1H), 5.48 (brd, 1H), 5.16 (d, J = 13Hz, 1H), 5.02-4.96 (m, 2H), 4.13 (q, J = 8Hz, 2H), 3.99 (d, J = 8Hz, 1H), 3.69 (d, J = 8Hz, 1H), 2.09-1.78 (m, 6H), 1.62-1, 40 (m, 15 Η), 1.06 (s, 3H), 1.04 (s, 3H), 0.97 (s, 3H); 1 C-NMR (CDCl 3, 100 MHz) δ 167.80, 163.03, 149.96, 142.25, 11.17.39, 112.46, 95.71, 73.70, 59.72, 45.76, 42, 15, 40.90, 37.94, 37.60, 35.87, 26.70, 25.96, 24.98, 23.37, 19.93, 19.09, 18.79.14.52.

Acetate 19: 8.7 mg alcohol 2 was dissolved in 0.5 mL CH 2 Cl 2, and treated with 5 equiv. pyridine, and 2.5 equiv. acetic anhydride. The reaction was stirred at room temperature for two hours and then quenched with NaHCO3 / H2O and extracted with ether. After the chromatography column, 8.3 mg of pure product (84%) was obtained. 19: 1 H-NMR (CDCl 3, 400 MHz) δ 5.95 (q, J = II, 6 Hz, 1H), 5.48 (d, J = 4.4 Hz, 1H), 5.01-4, 96 (m, 2H), 4.29 (d, J = 11.2 Hz, 1H), 4.01 (d, J = 10.8 Hz, 1H), 2.05 (s, 3H), 1, 25 (s, 3H), 1.06 (s, 3H), 0.94 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 18.77, 19.14, 19.95, 21.17, 23.39, 25.00, 25.99, 26.83, 29.81,36.14, 37.11, 37.22, 37.70, 41.01, 42.20, 45.86, 66.67, 112.42,117.23, 142.36, 150.15, 171.22.

Amine 20: A solution of aldehyde 3 (40 mg, 0.14 mmol) in dry MeOH (12 mL) was treated with ethylene diamine (0.4 mL, 3.36 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 4 h until TLC confirmed the disappearance of the starting material. The mixture was then cooled to 0 ° C and NaBH4 (11 mg, 0.8 mmol) was added portionwise. The reaction mixture was again allowed to be stirred overnight and was then quenched with a saturated ammonium chloride solution (25 mL). Extraction was done with methylene chloride (2 χ 35 ml). The desired product was purified by silica gel column chromatography. 20: Oil (42 mg, 90%); IR (neat) 3382, 2924 cm-1; 1H-NMR (CDCl3, 400 MHz) δ 5.95 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.45 (brd, 1H) , 5.00-4.95 (m, 2H), 2.78-2.75 (m, 3H), 2.66-2.63 (m, 2H), 2.47 (d, J = 11, 6 Hz, 1H), 2.10-1.83 (m, 6H), 1.63-1.44 (m, 10H), 1.42 (s, 3H), 1.05 (s, 3H), 0.85 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 150.69, 142.47, 116.85,112.24, 53.38, 51.68, 46.35, 42.24, 41 , 31, 38.14, 37.34, 37.24.36.54, 3.38, 27.64, 26.18, 24.98, 23.38, 20.00, 19.33, 18, 54; HRMS calculated for C 22 H 38 N 2 331.31 (M + H) + found 331.31.

Amine 21: Amine 21 was synthesized according to the same procedure as described above for amine 19, using aldehyde 9 as the starting material. 21: 1 H-NMR (CDCl 3, 400 MHz) δ 5.98 (dd, J = 11.2 Hz, J = 12 Hz, 1H), 5.45 (brd, 1H), 5.00-4.95 ( m, 2H), 2.94 (brd, 1H), 2.80 (brd, 1H), 2.82-2.79 (m, 2H), 2.60-2.35 (brd, 4H), 2 0.19-1.90 (m, 6H), 1.67-1.42 (m, 7H); 1.24-1.17 (m, 5H), 1.24 (s, 3H), 1, 10 (s, 3H), 0.85 (s, 3H); 13 C-NMR (CDCl 3, 100MHz) δ 150.82, 142.46, 125.38, 116.89, 112.31, 51.47, 47.14.45.82, 42.46, 41.28, 38 , 23, 37.73, 37.28, 35.65, 31.22, 30.41,28,63, 26.11, 25.03, 23.43, 19.99, 19.36, 18.76 ; HRMS calculated for C23H40N2 344.55; found 344.31.

Component 22: 150 mg of ester 1 (0.475 mmol) and 173 mg of LiBr were dissolved in DMF and heated to 165 ° C for two days. The reaction was quenched with H2O and the product extracted with ethyl ether and purified using chromatography column. Sandation gave 74.6 mg of product 22, a white crystal (52%). 1H-NMR (CDCl3, 400 MHz) δ 5.60 (q, J = 10.4 Hz, 1H), 4.98 (dd, J = 8.4 Hz, 1H), 4.76 (dd, J = 15 2 Hz, 1H), 1.26 (s, 3H), 1.05 (s, 3H), 0.93 (s, 3H); 0tD = -144.06.

Compound 23: 10 mg of compound 22 (0.33 mmol) was dissolved in 2.5 mL of methanol, and treated with 2.5 mL of diazomethane (trimethylsilyl), and 2.5 mL of benzene. The reaction was stirred at room temperature for 20 minutes, then worked up with H2 O, and extracted with ether. The mixture was purified by silica gel column purification to afford 8.2 mg of compound 23. 23: white solid (82% yield). 1H-NMR (CDCl3, 300 MHz) δ 5.61 (q, J = 10.2 Hz, 1H), 4.97 (dd, J = 8.7 Hz, 1H), 4.76 (dd, J = 15.3 Hz, 1H), 3.63 (s, 3H), 1.19 (s, 3H), 1.05 (s, 3H), 0.82 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 19.22, 20.22, 20.93.22.20, 26.29, 27.44, 29.73, 30.00, 37.76, 38.86, 39.00, 40.25.42.56, 45.13, 52.42, 54.81, 113.80, 131.17, 140.28, 147.83179.27; OCd = -121.6.

Compound 24: 7.8 mg of ester 23 (0.025 mmol) was dissolved in dry CH 2 Cl 2 and treated at -78 ° C with 4.0 equivalent DIBALH for 10 minutes. The reaction was quenched with a desalted Rochelle solution and the product was collected by ether extraction and purified by column chromatography. 24: (6.5 mg, 94% yield). 1H-NMR (CDCl3, 300 MHz) δ 5.62 (q, J = 10.5 Hz, 1H), 4.96 (dd, J = 8.4 Hz, 1H), 4.75 (dd, J = 15.3 Hz, 1H), 3.78 (d, J = 10.8 Hz, 1H), 3.48 (d, J = 10.8 Hz, 1H), 1.25 (s, 3H), 1 .04 (s, 3H); 0.99 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 14.15, 14.37, 14.75.16.09, 20.27, 21.57, 22.09, 23.75, 30.75, 31.70, 32.97, 33.77.34.03, 36.48, 61.10, 107.97, 124.66, 135.63, 142.29; OCd = -53.8.

Compound 25: 53.2 mg aldehyde 3 (0.19 mmol) was dissolved in tBuOH / H 2 O (3: 1), and treated with 76.45 mg NaH 2 PO 4 -H 2 O (0.56 mmol). The reaction mixture was stirred to dissolve the salt completely before the addition of 211.5 μΐ of 2 M 1-methyl-2-butene in THF. The reaction was stirred for 30 minutes, then treated with 50.2 mg NaClO2 (0.56 mmol). When the reaction was finished, it was neutralized with NH 4 Cl. The product was collected by extraction with CH2Cl2 and purified by column chromatography to yield 44 mg of compound 25 (78%). 25: white solid; Rf = 0.30 (silica, 30% ether in hexanes); 1H NMR (400MHz, CDCl3) δ 5.96 (dd, 1H, J = 14.4, 9.6 Hz), 5.52 (m, 1H), 4.98-4.95 (m, 2H), 2.20-1.72 (m, 10H), 1.64-1.58 (m, 3H), 1.57-1.37 (m, 4H), 1.22 (s, 3H), 1, 04 (s, 3H), 0.99 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 182.9, 149.3, 143.9, 118.1, 111.9, 47.5, 44.2, 41.3, 41.2,38.9, 38 0.37.6, 34.8, 28.4, 24.7, 23.0, 22.4, 21.9, 20.3, 19.5. Compound 26: 3.5 mg of acid 25 ( 0.012 mmol) was dissolved in dry CH 2 Cl 2 and treated with 10 equivalents of (COCl) 2 followed by two drops of DMF. When the reaction allowed to boil, the CH 2 Cl 2 solvent and excess (COCl) 2 were evaporated under vacuum and the reaction residue was redissolved and then treated with 5 equivalents of N-methylpiperazine. When the reaction was complete, the solvent was evaporated under vacuum, and the product was collected by ether extraction and a solution of NH 4 Cl. After the chromatography column 3.0 mg of pure product 26 (65% yield) was obtained. 26: 1 H-NMR (CDCl 3, 300 MHz) δ 5.95 (q, J = 11.6 Hz, 1H), 5.46 (d, J = 2.4 Hz, 1H), 5.00-4.94 (m, 2H), 3.73-3.68 (m, 4H), 2.48 (s, 3H), 2.10-2.03 (m, 4H), 1.25 (s, 3H), 1.09 (s, 3H), 1.03 (s, 3H); α D = +8.6.

Compound 27: 10 mg of acid 25 (0.033 mmol) was dissolved in dry CH 2 Cl 2 and treated with 10 equivalents of (COCl) 2 followed by two drops of DMF. When the reaction allowed to boil, the CH 2 Cl 2 solvent and excess (COCl) 2 were evaporated under vacuum and the reaction residue was redissolved-dry benzene and then treated with 5 equivalents of di-ethanolamine. The solvent was evaporated under vacuum, and the product was collected by ether extraction and NH4Cl solution. After the chromatography column, 9.2 mg of pure product (75% yield) was obtained. 1H-NMR (CDCl3, 300 MHz) δ 5.95 (q, J = 11.6 Hz, 1H), 5.46 (s, 1H), 4.96 (m, 2H), 2.99 (s, 7H), 2.37 (d, 1H), 1.29 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H); OCd = -41.2.

Amine 28: 5.0 mg of 25 acid (0.017 mmol) was dissolved in dry CH 2 Cl 2 and treated with 10 equivalents of {COCD 2 followed by two drops of DMF. When the reaction allowed to boil, the CH 2 Cl 2 solvent and excess (COCl) 2 were evaporated under vacuum and the reaction residue was redissolved and then treated with 5 equivalents of ethylenediamine. When the reaction was complete, the solvent was evaporated under vacuum, and the product was collected by ether extraction and a solution of NH 4 Cl. After the chromatography column, 3.0 mg of pure product (52% yield) was obtained. Compound 29: 5.0 mg of 25 acid (0.017 mmol) was dissolved in dry CH 2 Cl 2 and treated with 10 equivalents of ( COCl) 2 followed by two drops of DMF. When the reaction allowed to boil, the CH 2 Cl 2 solvent and excess (COCl) 2 were evaporated under vacuum and the reaction residue was redissolved and then treated with 5 equivalents of propylamine. When the reaction was over, the solvent was evaporated. vacuum, and the product was collected by ether extraction and NH4Cl solution. After the chromatography column, 3.7 mg of pure product (63% yield) was obtained.

Compound 30: 4.5 mg of 25 acid (0.015 mmol) was dissolved in dry CH 2 Cl 2 and treated with 10 equivalents of (COCl) 2 followed by two drops of DMF. When the reaction allowed to boil, the CH 2 Cl 2 solvent and excess (COCl) 2 were evaporated under vacuum and the reaction residue was redissolved and then treated with 5 equivalents of morpholine. When the reaction was complete, the solvent was evaporated. , under vacuum, and the product was collected by ether extraction and NH4Cl solution. After the chromatography column, 5.0 mg of pure product (89% yield) was obtained. 1H-NMR (CDCl3, 400 MHz) δ 5.95 (q, J = 11.6 Hz, 1H), 5.47 (s, 1H), 4.99-4.95 (m, 2H), 3, 64-3.60 (m, 8H), 1.29 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 21.24, 22.82, 23.22, 24.90, 25.16, 27.35.34.36, 37.65, 39.71, 40.37, 41.42, 41.62, 46.32, 46.47, 46.71, 1.29, 67.02, 111.68, 117.10, 143.89, 149.84; α D = -47.1.

Compound 31: To a solution of 14.5 mg of 25 acid (0.048 mmol) in THF was added 1 equivalent of KOH dissolved in 200 μΐ of water and the mixture was stirred for 1 h. Evaporative evaporation afforded pure salt 31 (100%).

Compound 32: To a solution of 24.5 mg of 25 acid (0.072 mmol) in THF was added 1 equivalent of NaOHOH dissolved in 200 μΐ of water and the mixture was stirred for 1 h. Evaporation of solvent disposed pure salt 32 (10-0%).

Compound 33: To a solution of 20.1 mg of 25 acid (0.052 mmol) in THF was added 1 equivalent of tri-ethanolamine dissolved in 200 μΐ of methanol and the mixture was stirred for 1 h. Evaporation of the solvent afforded pure salt 33 (10-0%). Compound 34 - To a solution of 20.1 mg of acid 25 (0.052 mmol) in THF was added 1 equivalent of diethanolamine dissolved in 200 μΐ of methanol and the mixture was added. for 1 h. Evaporation of solvent afforded pure salt 34 (100%).

Ester 35 - Methyl Acetate (triphenyl phosphoranylidene) (90.7 mg, 0.27 mmol) and aldehyde 9 (27.3 mg, 0.09 mmol) were dissolved in dry CH 2 Cl 2 and stirred at room temperature. The reaction was completed within one day and then neutralized with NH 4 Cl. Both useful and trans products were collected by extraction with CH2Cl2. They were separated by column chromatography. 24.4 mg and 2.5 mg of trans ester were obtained, and were separated by column chromatography (84% total yield). Trans 35: 1 H-NMR (CDCl 3, 400 MHz) δ 7.00-6.92 (m, 1H), 5.96 (q, J = 11.6 Hz, 1H), 5.80 (d, J = 15.2 Hz, 1H), 4.47 (d, J = 4.4 Hz, 1H), 5.00-4.96 (m, 2H), 3.72 (s, 3H), 2.45 ( m, 1H), 2.35 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H), 0.89 (s, 1H); 13 C-NMR (CDCl 3, 100 MHz) δ 18.82, 19.01, 19.90, 23.37, 24.97.28.84, 35.94, 37.15, 37.22, 37.69, 37.85, 38.11, 40 , 98, 42.40.46.55, 51.42, 112.38, 117.04, 122.38, 142.45, 148.03, 150.67.166.73; OCd = -12.02; Cys: 1H-NMR (CDCl3, 400 MHz) δ 6.32-6.25 (m, 1H), 5.97 (q, J = 11.6 Hz, 1H), 5.83 (d, J = 11 , 6 Hz, 1H), 5.47 (d, J = 8 Hz, 1H), 5.00-4.96 (m, 2H), 3.71 (s, 3H), 3.19-3.13 (m, 1H), 2.61-2.55 (m, 1H), 1.15 (s, 3H), 1.07 (s, 3H), 0.90 (s, 3H).

Acid 36 - 8 mg trans 35 ester (0.023 mmol) and 2.70 mg LiOH (0.113 mmol) were dissolved in 1 ml THF / H2O (1: 1). The reaction mixture was refluxed at 60 ° C overnight. The completed reaction was neutralized with HCl (1 M) and extracted with CH 2 Cl 2. After purification by column chromatography, 7.3 mg of pure product 36 (95%) was obtained. 36: 1 H-NMR (CDCl 3, 400 MHz) δ 7.12-7.04 (m, 1H), 5.96 (q, J = 11.6 Hz, 1H), 5.82 (d, J = 15 , 6 Hz, 1H), 5.48 (d, J = 4.4 Hz, 1H), 5.01-4.97 (m, 2H), 2.53-2.46 (m, 1H), 2 : 23-2.19 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H), 0.88 (S, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 38.12.42.76, 42.93, 43.82, 47.29, 48.87, 48.91, 49.74, 52.77, 53.70, 60.01, 61.21, 61.64, 61.84, 6 2.05, 64.90, 66.35, 70.54, 136.46,141.09, 141.19, 146.10; otD = -15.17.Ester 37 - In a moisture free flask, 5 mg trans 35 ester (0.14 mmol) was dissolved in dry methanol. 1.7 mg of Mg (0.07 mmol), which was recently heat activated, was added to the reaction vial. The reaction was stirred overnight at room temperature. When the reaction was complete, the remaining Mg was dissolved by HCl (2 Μ), and the mixture was then extracted with ether. 2.9 mg of a yellow solid was obtained after the chromatography column (54% yield). 37: 1H-NMR (CDCl3, 400 MHz) δ 5.96 (q, J = 11.6 Hz, 1H), 5.45 (d, J = 4 Hz, 1H), 5.00-4.95 ( m, 2H), 3.67 (s, 3H), 2.27 (m, 2H), 1.25 (s, 3H), 1.05 (s, 3H), 0.83 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 18.59, 19.31.19.99, 20.26, 23.44, 25.05, 26.16, 28.58, 29.81, 32.01, 35.25,36.11, 37.3, 37.35, 37.75, 38.28, 41.41, 42.46, 46.94, 112.25,116.75, 116.73, 142.60, 151.09; OCd = -22.1.

Acid 38 - 5 mg ester 37 (0.014 mmol) and 1.70 mg LiOH (0.07 mmol) were dissolved in 1 mL THF / H2O (1: 1). The reaction mixture was refluxed at 65 ° C. overnight. Completed sandalization was neutralized with HCl (1 M) and extracted with CH2Cl2. After purification by column chromatography, 3.9 mg of pure product 38 was obtained (81%). 1H-NMR (CDCl3, 400 MHz) δ 5.96 (q, J = 11.6 Hz, 1H), 5.45 (d, J = 4 Hz, 1H), 5.00-4.95 (m, 2H), 2.37 (m, 2H), 1.25 (s, 3H), 1.05 (s, 3H), 0.84 (s, 3H); 13 C-NMR (CDCl 3, 100 MHz) δ 18.58, 19.28, 19.98, 23.42, 25.03, 26.12, 28.55.29.79, 30.40, 31.94, 34.91, 36.09, 37.32, 37.73, 38.25, 41.38.42.44, 46.93, 112.24, 116.73, 116.75, 142.55, 151, 04; otD = +3.4.

EXAMPLE 24

The effects of seven different TTL3 analogs on navigability and TNF-α synthesis of THP-I cells were analyzed.

The ability to inhibit TNF-α production has been analyzed in THP-I cells, a human acute monocyte leukemia cell line that is widely used to assess monocyte functions. To induce maturation, THP-I cells were plated at 1 x 106 cells / ml and pretreated with -5 nM MPA for two days. Differentiated THP-I cells were pretreated with various concentrations of TTL 3 or its analogues for 1 hour, followed by a 4 hour incubation with 1 µg LPS (Sigma, St. Louis, MO). The p38 inhibitor (SB 203580; Sigma, St. Louis, MO) was used as a positive control. Supernatants were collected and stored at -80 ° C until TNF-α activity analysis. A resazurin assay was performed for each analog to evaluate the effects on cell metabolism and viability.

A resazurin tincture preparation, commercially available as alamarBlue® (BiosourceInternational Inc., 820 Flynn Road, Camarillo, California), was used for the cytotoxicity assays described herein. The assays and experiments described herein were conducted substantially in the same manner as described in the scientific literature, for example in Magnani, E. and Bettini, E., "Resazurin detection of energy metabolism changes in serum-starved PC12 cells and neuroprotective agent effect", Brain Res. Protoc., July 2000, 5 (3): 266-72, and in Business MM , Shalev A., Benias P., and RussoC.J., "A novel one-step, highly sensitive fluorometric assay to evaluate cell-mediated cytotoxicity", Immunol. Methods, 213, 157-167 (1998), see also U.S. Patent 5,501,959, entitled "Antibiotic and Cytotoxic Drug Susceptibility Assays using Resazurin and Poising Agents", the entire specification of which is incorporated herein by reference.

To detect the presence of human TNF-α, a fluorescence-linked immunosorbent assay or EISUF was developed and improved. 100 μΐ beads (6 μπι, Spherotech) coated with goat anti-mouse IgG (1 mg / ml, R&D Systems) were mixed with 4 μΐ biotin-anti-hFNTa IgG rat (0.1 mg / ml, R&D Systems) and 2 μΐ FMAT streptavidin blue (0.1mg / ml, Applied Biosystems). 50 μΐ of the mixtures were combined with 50 μΐ of the isolated supernatant from treated THP-I cells added to an EISUF (AppliedBiosystems) black wall plate and incubated overnight. The plates were scanned in a factory-configured PMT set, and the values were plotted and analyzed using AppliedBiosystem software. Tables 10-23 also summarize the effects of these analogous TTL3 families on TNF-α viability and synthesis in THP-I cells.

EXAMPLE 25

Reduction of TNF-α levels by formula (IIB-Al) and analogs in LPS-stimulated human mono-nuclear peripheral blood cells

Eighty μl of 3.1 χ 105 / ml Human Mono-Nuclear Peripheral Blood Cells (CSPMH) were plated on a plateCostar 3904 from 96 containers in an LGM-3 medium and cultured for 12h at 37 ° C, 5% CO2 and 95% air humidity. 10 μl LT-1-85, CC-3-19, CC-3-13P, 8-point Serial Thinner Serial Dilutions, prepared in an LGM-3 Medium were grown to cells and incubated for 1 h. Subsequently, 10 µl of 500 ng / ml lipopolysaccharide (LPS) diluted in LGM-3 medium from a 1 mg / ml drive solution was added to the cells and incubated for another 4 h at 37 ° C, 5% CO2e 95% air humidity. SB203580, a known p38 kinase MAP inhibitor and DMSO were used as positive and negative controls, respectively. After 4 h of LPS stimulation, the TNF-α level of each sample was analyzed using the human TNF-α decito-pool ELISA equipment. EC50 values (the drug concentration at which 50% of the maximum observed TNF-α production is inhibited) were determined using a sigmoidal dose response curve-fitting algorithm (Prisma 2.0, GraphPad Software Inc.). Cells were analyzed for cell viability using Resazurin tincture after cell cells were incubated with test compounds for 24 h. Resurface reduction product inflorescence was measured using a Fusion Microplate Fluorometer (Packard Bioscience) with filters of Xex = 535 nm and Xem = 590 nm. EC50 values (drug concentration at which 50% of the observed maximal growth inhibition is established) were determined using a sigmoidal dose response curve fitting algorithm (Prisma2.0, GraphPad Software Inc.). Effects on TNF production -a and cell viability in CSPMH by LT-1-85, CC-3-19, CC-3-13P, formula (IIB-Al) and CC-3-22 are summarized in Table 24. Results indicate that with a EC50 1.4 μΜ, the formula (IIB-Al) is effective in inhibiting TNF-α production in LPS-stimulated CSPMH. Under the tested condition, the formula (IIB-Al) does not inhibit CSPMH cell growth at concentrations up to 26 μΜ.

Table 24 - Effects on LPS-stimulated TNF-α production and cell viability in CSPMH by compounds LT-1-85, CC-3-19, CC-3-13P, formula (IIB-Al) and CC-3-22

<table> table see original document page 217 </column> </row> <table>

* 5 hr drug exposure

# 24 hr drug exposure EXAMPLE 26

Decreased IKBa phosphorylation level inLPS-stimulated Human Mononuclear Peripheral Blood Cells by Formula (IIB-Al)

One ml / well CSPMH at 3x106 / ml was seeded in 6 well plates in LGM-3 medium and grown for 12 h at 37 ° C, 5% CO2 and 95% air humidity. A final concentration of 13 μΜ for formula (IIB-Al) (or 10 μΜ for TTL 3) was increased at CSPMH for 1 h. DMSO was used as a control. The cells were then stimulated with 20 ng / ml LPS diluted in LGM-3 medium from a 1 mg / ml trigger solution for 30 min, 1h, 2h and 4h. At the end of each time point, cells were harvested by centrifugation and cell pellets were washed once with ice cold Phosphate Dulbecco IX Buffered Saline (STFD). To prepare samples for SDS Polyacrylamide Gel Electrophoresis (EGPA-SDS), cells were lysed in PJPA buffer (a 50 mM Tris-HCl cocktail, pH 7.4, 0.9% NaCl, 1% Triton X-100, 0.25% Na-deoxycholate, 1 mM EDTA, 2 mM Na3VO4 and proteaseIX inhibitors) for 15 min on ice. Cell lysates were bleached by centrifugation at 14,000 rpm, 4 ° C for 10 min. Protein concentrations of cell lysates were determined by BCA protein assay equipment prior to EGPA-SDS. An equal amount of protein from various cell lysates was resolved in 10% of NuPage MES preformed gels and transferred to nitro-cellulose membranes according to the manufacturer's instructions. After transfer, the membranes were first blocked in BL0TT0 (5% non-fat dry milk in STFD IX buffer containing 0.1% Tween-20) at room temperature for 2 h and then incubated with appropriate primary antibodies: IKBa (1: 1000) or anti-Tubulin (1: 2000) for 2 h. Tubulin antibodies were used as a control to confirm equal loading of each sample. Following incubation with primary antibodies, the membranes were briefly washed 2-3 times for 10min each with BL0TT0 and again incubated with sheep HRP conjugated mouse anti-corpuscles for 1 h. After incubation with secondary antibodies, the membranes were washed extensively 4 times for 15 min at a time with PBST (STFD IX plus 0.1% Tween-20). HRP activity was visualized by an enhanced chemiluminescence detection (QLA) system.

Figure 38 demonstrates that the formula (IIB-Al) effectively inhibited the level of IKBa phosphorylation in LPS-stimulated CSPMH when compared to the DMSO control.

Example 27

Reduction of LPS-induced IKBa phosphorylation level in RPMI8226 cells by Formula (IIB-Al)

One ml / well of 2x106 / ml RPMI8226 cells (# CCL-155C, American Type Culture Collection) was seeded into 6 well plates in an LGM-3 medium and grown overnight at 37 ° C, 5% CO2 and 95% air humidity. TTL3 and formula (IIB-Al) were added to RPMI8226 cells at the final concentration of 10 μΜ and 13 μΜ for 1 h, respectively. DMSO was used as iam control. Cells were then stimulated with 50 ng / ml LPS diluted in LGM-3 medium from 1 mg / ml triggering solution for 30 min, 1h, 2h and 4h. At the end of each time point, cells were harvested by decentrifugation and cell pellets were washed once in STFD IXfria as ice. To prepare the samples for EGPA-SDS, cells were lysed in RIPA buffer (a 50 mM Tris-HCl cocktail, pH 7.4, 0.9% NaCl, 1% Triton X-100, 0.25% Na-deoxycholate, 1 mM EDTA, 2 mM Na3VO4 and protease inhibitors (X) for 15 min on ice. Cell lysates were bleached by centrifugation at 14,000 rpm, 40 ° C for 10 min. Protein concentrations of cell lysates were determined by BCA protein assay equipment prior to EGPA-SDS. An equal amount of protein from various cell lysates was resolved in 10% of NuPage MES preformed gels and transferred to nitro-cellulose membranes according to the manufacturer's instructions. Then the transfer membranes were first blocked in BLOTTO (5% STFD IX buffered dry fat free milk containing 0.1% Tween-20) at room temperature for 235 h and then incubated with appropriate primary antibodies: anti-phosphO -IKBa (1: 1000) or anti-Tubulin (1: 2000) for 2 h. Tubulin antibodies were used as a control to confirm equal loading of each sample. Membranes were briefly washed 2-3 times for 10 min each with BLOTTO after incubation with primary antibodies, and again incubated with sheep HRP conjugated mouse anti-corpuscles for 1 h. After incubation with secondary antibodies, the membranes were washed extensively 4 times for 15 min at a time with PBST (STFD IX plus 0.1% Tween-20). HRP activity was visualized by an enhanced chemiluminescence detection (QLA) system.

Figure 39 demonstrates that after treatment with formula (IIB-Al), the level of IKBa phosphorylation induced by LPS stimulation in RPMI8226 cells was greatly reduced compared to control of DMSO treated cells. The inhibitory effect on the level of IKBa phosphorylation by LPS in the presence of TTL3 was minimal (Figure 39B).

EXAMPLE 28

Formula (IIB-Al) specifically inhibits LPS-induced phosphorylation of I KBa and MAP p38 kinase in RPMI8226 cells.

One ml / well of 2x106 / ml RPMI8226 cells (# CCL-155C, American Type Culture Collection) was seeded into 6 well plates in an LGM-3 medium and grown overnight at 37 ° C, 5% CO2 and 95% air humidity. The formula (IIB-Al) was added to RPMI8226 cells at the final concentration of 13 μΜ for 1 h. DMSO was used as a control. Cells were then stimulated by LPS (50 ng / ml) or TNF-α (10 ng / ml) for various lengths of time. At the end of each stimulation period, the cells were harvested by centrifugation and cell pellets were washed once in ice cold Dulbecco Phosphate Buffer (STFD) IX Saline. To prepare the samples for EGPA-SDS, cells were lysed in RIPA buffer (a 50 mM Tris-HCl cocktail, pH 7.4, 0.9% NaCl, 1% Triton X-100, 0.25% Na deoxycholate, 1 mM EDTA, 2 mM Na3VO4 and protease inhibitors (IX) for 15 min on gel-o. Cell lysates were bleached by centrifugation at 14,000 rpm, 4 ° C for 10 min. Cell delysed protein concentrations were determined by a BCA protein assay equipment prior to EGPA-SDS. An equal amount of protein from various cell lysates was resolved in 10% of NuPage MES preformed gels and transferred to nitro-cellulose membranes according to the manufacturer's instructions. The transfer membranes were then blocked first in BLOTTO (5% STFD IX buffered dry fat free milk containing 0.1% Tween-20) at room temperature for 2 h and then incubated with appropriate primary co-antibodies: anti-phosphο-ΐκΒα anti-p38 and anti-fluffy-p38 (1: 1000) or anti-Tubulin (1: 2000) for 2 h. Tubulin antibodies were used as a control to confirm the equal loading of each sample. Membranes were briefly washed 2-3 times for 10 min at a time with BLOTTO after incubation with primary antibodies, and again incubated with goat, sheep or rat deanti-HRP conjugated rabbit secondary antibodies for 1 h. Following secondary co-incubation, the membranes were washed extensively 4 times for 15 min at a time with PBST (STFD IX plus 0.1% Tween-20). HRP activity was visualized by an enhanced chemiluminescence detection (QLA) system.

Comparing the effects of treatment with the formula (IIB-Al) on the levels of L38 and TNF-α induced p38 IKBa and MAP kinase phosphorylation in RPMI8226 cells (Figure 40), the data indicate that the formula (IIB-Al) specifically decreases phosphorylation. p38-induced IKBoc and MAP kinase MAP.

EXAMPLE 29

Formula (IIB-Al) inhibits Toll receptor binding-induced IKB phosphorylation in RPMI8226A cells / well RPMI8226 cells at 2x106 / ml (# CCL-155C, American Type Culture Collection) was seeded into 6-well plates in an LGM-3 medium grown overnight at 37 ° C, 5% CO2 and 95% air humidity. The formula (IIB-Al) was added to RPMI8226 cells at the final concentration of 13 μΜ for 1 h. DMSO was used as a control. Cells were then stimulated with 50 ng / ml LPS, 2 µg / ml Lipoic Acid (LTA), and CpG DNA for various lengths of time. At the end of each stimulation period, cells were harvested by centrifugation and cell pellets were washed once in ice cold Dulbecco Phosphate Buffered Saline (STFD) IX. To prepare the samples for EGPA-SDS, cells were lysed in RIPA buffer (50 mM Tris-HCl cocktail, pH 7.4, 0.9% NaCl, 1% Triton X-100, 0.25% Na-deoxycholate, 1 mM EDTA, 2 mM Na3VO4 and protease inhibitors (IX) for 15 min on ice. Cell lysates were bleached by decentrifugation at 14,000 rpm, 4 ° C for 10 min. Protein concentrations of cell lysates were determined by a BCA protein assay equipment prior to EGPA-SDS. An equal amount of protein from various cell lysates was dissolved in 10% of NuPage MES preformed gels and transferred to nitro-cellulose membranes according to the manufacturer's instructions. After the transfer membranes were first blocked in BLOTTO (5% STFD IX buffering non-fat dry milk containing 0.1% Tween-20) at room temperature for 2 h and then incubated with appropriate primary antibodies: anti-phosphο-ΙκΒα ( 1: 1000) or anti-Tubulin (1: 2000) for 2 h. Tubulin antibodies were used as a control to confirm the loading of each sample. Membranes were briefly washed 2-3 times for 10 min each time with BLOTTO after incubation with primary antibodies, and incubated again with sheep HRP conjugated mouse secondary antibodies for 1 h. After incubation with secondary antibodies, the membranes were washed extensively 4 times for 15 min each with PBST (STFD IX plus 0.1% Tween-20). HRP activity was visualized by the enhanced chemiluminescence detection system (QLA).

"In addition to the already demonstrated effect of formula (iib-Al) on LPS-induced ΐκΒα phosphorylation through the well-characterized Toll 4 receptor (RTT4) receptor on CSPMH and RPMI8226 cells (Figures 38, 39 and 40), the formula ( iib-Al) also inhibits Ikboc phosphorylation induced by other Toll receptor ligands.As shown in Figure 41, the formula (iib-Al) inhibits LTA and CpG DNA-induced IKBa phosphorylation, which is imagined through the receptor of the type. Toll 2 (RTT2) and Toll 9 type receptor (RTT9), respectively.

EXAMPLE 30 Reduction of LPS-stimulated IL-8 and IL-10 levels in RPMI8226 cells by Formula (IIB-Al)

Ninety μΐ of RMPI8226 cells at 2.8 χ 105 / ml and 0.5 ml at 5 χ 105 / ml (# CCL-155C, American Type Culture Collection) were seeded in 96-well and 6-well plates in an LGM- 3, respectively. Cells were cultured overnight at 37 ° C, 5% CO2 and 95% air humidity. An 8-point serial dilution of TTL3 or Formula (IIB-Al) was added to the cells for 1 h at a final concentration ranging from 20 μΜ to 0.16 µM. DMSO was used as a control. After 1 h, 50 ng / ml LPS diluted in LGM-3 medium from 1 mg / ml drive solution was added to stimulate cells for an additional 10 h. Supernatants were collected and levels of IL-8 and IL-10 were analyzed using human IL-8 and IL-10 cytotoxic ELISA equipment.

Figures 42A and 42B both demonstrate that formula (IIB-Al) inhibits dose-dependent LPS-induced IL-8 and IL-10 production in RPMI8226. TTL3 inhibits dose-dependent IL-10 production in RPMI8226 cells.

EXAMPLE 31

Cell line growth inhibition

Human prostate adenocarcinoma (PC-3; CRL-1435), multiple myeloma (RPMI8226; CCL-155), and kidney embryonic (HEK-293; CRL-1573) cells were all purchased from ATCC (American Type Culture Collection) American Type Culture Media) and maintained in appropriate culture media. The cells were grown in a 370C incubator in 5% CO2 and 95% air humidity.

For cell growth inhibition analyzes, PC-3 and HEK-293 cells were seeded at 5x103 el, 5x103 cells / well respectively in 90 μΐ of medium containing 1% (v / v) FBS in 96 wells (Corning 3904). of black-walled, transparent-bottomed tissue culture plates, and the plates were incubated overnight to allow the cells to settle and enter the growth phase. RPMI8226 cells were seeded at 2x10 4 cells / well respectively in 90 μΐ of medium containing 1% (v / v) FBS in 96 well plates on the day of the assay. 4 mg / ml trigger solutions of the compounds were prepared in 100% DMSO and stored at -20 ° C. The compounds were seriously diluted and added in triplicate to the test vessels. LT-1-85 was tested at concentrations ranging from 27 μΜ to 8.6 nM. Concentrations ranging from 30 μΜ to 9.7 nM were tested for CC-3-13P. Formula (IIB-Al) was tested at concentrations ranging from 26 μΜ to 8.4 nM. The plates were returned to the incubator for 48 hours. The final DMSO concentration was 0.25% in all samples.

After 48 hours of drug exposure, 10 μΐ of 0.2 mg / ml Resazurin in Mg2 + free phosphate buffered saline, Ca2 + was added to each well and the plates were returned to the incubator for 3-6 hours. Since living cells metabolize Resazurin, the fluorescence of the Resazurin-reducing product was measured using a Fusion microplate fluorometer (Packard Bioscience) with filters of Xex = 535 nm and Àem = 590 nm. Resazurin dye in cell-free medium was used to determine background, which was subtracted from data for all experimental recipients. Data were normalized to the mean fluorescence of cells treated with medium + 0.25% DMSO (100% cell growth) and EC50 values (drug concentration at which 50% of the observed maximal growth inhibition is established). determined using a standard sigmoidal dose response curve fitting algorithm (Prisma 2.0, GraphPad Software Incorporation.). Where the inhibition of maximum cell growth was less than 50%, the EC50 value was not determined. The data in Table 25 summarize the growth inhibitory effects of LT-1-85, CC-3-13P and formula (IIB-Al) against HEK-293, PC-3 and RPMI8226 cells. EC50 values indicate that LT-1-85 and CC-3-13P are cytotoxic against HEK-293, PC-3 and RPMI8226 cells. Formula (IIB-Al) is cytotoxic counter cell RPMI8226.

Table 25 - EC50 values of LT-1-85, CC-3-13Pe formula (IIB-Al) against HEK-293, PC-3 and RPMI8226 cells <table> table see original document page 225 </column> </ row> <table>

Cell viability was determined after 48 h of drug exposure.

Example 32

TTL3, TTL1, LT-1-45, LT-1-85 and formula (IIB-Al) inhibit gene expression mediating inflammation in murine macrophage cell RAW264.7 cell line

RAW264.7 cells were seeded at 6-8 χ 10 4 cells / cm2 in RPMI1640 medium containing 2 mM glutamine, 10% fetal calf desorption (SBF) and 50 μg / ml penicillin, streptomycin and gentamicin. After 2 days in culture the medium was replaced by a red phenol free RPMI1640 medium complete with 0.5 mM arginine and 2% FBS followed by the addition of the indicated stimuli. TTL3, TTL1, LT-1-45, LT-1-85 and formula (IIB-Al) were added to cells at the final concentration of μΜ for 15 min. DMSO was used as a control. The cells were then stimulated with 200 ng / ml LPS and 20 units / ml IFNγ for 18 h. NO release was measured as the accumulation of nitrite and nitrate in the incubation medium (free from reddish). Nitrate was reduced to nitrite with denitrate reductase and was determined spectrophotometrically with Griess reagent. To determine COX-2 and NOS-2 protein levels, cells (1.5 χ 10 6) were washed with PBS and collected by centrifugation. Cell pellets were homogenized with 100μl Buffer A (10mM Hepes; pH 7.9, 1mM EDTA, 1mM DEEGTA, 100mM KCl, 1mM Dithiothreitol, 0.5mM Defenyl-methyl-fluoride). sulfonyl, 2 μg / ml aprotinin, 10 μg / ml deleupeptin, 2 μg / ml chloromethyl ketone Noc-p-tosyl-L-lysine, 5 mM NaF, 1 mM Na3VO4, 1 mM Na2MoO4) . After 10min at 4 ° C, Nonidet P-40 was added to achieve a concentration of 0.5%. The tubes were gently vortexed for 15 seconds and centrifuged at 8,000 g for 15 min. Supernatants were stored at -80 ° C until use. The protein content was analyzed using Bio-Rad protein reagent. Protein extracts were separated by 10% SDS depolyacrylamide gel electrophoresis. The gels were stained on a Hybond P membrane and then incubated with the appropriate primary antibodies: anti-NOS-2 or anti-cyclooxygenase-2. An anti-β-actin corpuscle was used as a control to confirm the loading of each sample. The spots were revealed by QLA. Different exposure times of films were used to ensure that the bands were not saturated. The quantification of the films was performed by laser densitometry.

To determine if the test compounds inducepoptosis, a cytometric measurement of iodine-depropidium dyeing flow (PI) was performed after incubation of cells with 0.005% PI, following published protocols. The cells were analyzed on a FACScan cytometer equipped with a 25 mW deargon laser. The quantification of the percentage of apoptotic cells was calculated using a forward plot plot against the fluorescence of PI. Cell ordering and analysis of viable and apoptotic populations were performed to confirm the threshold criteria.

As shown in Figure 43A, NOS-2 protein levels in LPS / IFNγ-stimulated cells were reduced by 50% to 70% when cells were treated with TTL3, LT-1-45, LT-1-85 and the formula. (IIB-Al). According to these observations, LPS / IFNγ-induced NO synthesis (Figure 43B) was also reduced. When COX-2 levels (Figure 43C) were measured, a decrease of -30-40%, depending on the test compound, was observed.

According to Figure 43D, TTL3, TTL1, LT-1-45, LT-1-85 and formula (IIB-Al), when tested at 10 μΜ, do not affect the viability of RAW264.7 cells.

EXAMPLE 33Effect of TTL3, TTL1, LT-1-45, LT-1-85 and formula (IIB-Al) in the path of NIQ / FN-kB

The (KB3) COnA-LUC plasmid contains three copies of the KB motifs from the repeated human long-term immunodeficiency virus terminator enhancer attached to the minimal deconalbumin promoter and was used to measure FN-kB activity. The ConA.LUC vector, which is missing the complementary KB, was used as a control in the assays. Kinase deficient pRK5-mic-NIQ and deNIQ (K429A / K43 0A, NIQ-DQ) expression vectors were used for transient transfection of RAW264.7 cells. The plasmids were purified using Qiagen Endo-Free columns. When the co-transfection assays were performed, the ratio between NIQ and KB-LUC plasmids was 3 to 1 in molecular terms. Sub-confluent cell cultures (RAW264.7 cells) were washed twice with phosphate buffered saline and maintained with 2 ml RPMI1640 medium and 2% SBF in 6 cm diameter dishes. Cells were transfected for 24 h with JetPEI following supplier instructions. Treatment with the tested compounds was performed 30 min prior to stimulation with LPS / IFNγ. Reporting assays were performed by measuring the luciferase activity of double firefly / renil transfection systems, following the supplier's recommendations.

As shown in Figure 44A, all compounds except TTL1 inhibit FN-kB-mediated reporter deluciferase gene activity in (KB) 3-LUC transfected RAW264.7 cells significantly. When cells were co-transfected with a mic-NIQ plasmid and the (KB) 3-LUC reporter construct. FN-κB-mediated luciferase activity was quaseabolide when cells were treated with the compounds tested (Fig. 44B). These data suggest that NIQ is a relevant target in the nationalization of these compounds. These observations were further supported when cells were co-transfected with a kinase-killed NIQ plasma (NIQ-DQ) and the (KB) 3-LUC reporter construct. As shown in Figure 44C, the inhibitory effects of the compounds tested on FN-κB-mediated luciferase activity were diminished.

Effect of TTL3 and formula (IIB-Al) on NIQ activity

Following transfection of RAW264.7 cells with pRK5-mic-NIQ construct, 1 x 10 7 transfected cells were homogenized in buffer A (10 mM Hepes; pH 7.9, 1 mM EDTA, 1 mM EGTA, 100 mM KCl, 1 mM dithiothreitol, 0.5 mM phenyl methyl sulfonyl defluoride, 2 μg / ml aprotinin, 10 μg / ml leupeptin, 2 μg / ml chloromethyl ketone Na-p-tosyl-L-lysine, 5 mM NaF, 1 mM Na3VO4, 10 mM Na2MoO4). The tubes were vortexed gently for 15 s and centrifuged at 8,000 g per 15 min. The supernatant (1 ml) was pre-bleached, and the NIQ was immunoprecipitated with 1 µg of anti-mic antibody. After extensive washing of the immunoprecipitate with buffer A, the pellet was resuspended in kinase buffer (modified buffer A containing 0.1 mM EDTA, 5 mM MgCl 2 and 10 nM ocadaic acid). kinase was analyzed in 100 μΐ dekinase buffer containing 100 ng of immunoprecipitate, 50 μΜ of [γ-32Ρ] ΑΤΡ (0.5 μΟί) and 100 ng MBP as substrate. When cells transfected with a plasmid

pRK5-mie-NIQ were stimulated with LPS / 1FNy in the presence of TTL3 and formula (IIB-Al), a 70% inhibition of NIQ kinase activity was observed (Figure 45A). To further support this observation, TTL3 at 1 μΜ was added directly to the in vitro NIQ kinase assay from LPS / IFNY stimulated cells. As shown in Figure 45B, NIQ kinase activity was inhibited by 48%.

EXAMPLE 35

Inhibition of myelo peroxidase activity Rat ear edema model by TTL3 and formula (IIB-Al)

2.5 μg TPA dissolved in 20 μΐ DMSO was applied to both surfaces of the right ear of each rat. The left ear (control) received the vehicle (DMSO). The test compounds were administered topically (500 ng per ear in 20μΐ DMSO) simultaneously with the application of TPA. The reference drug indomethacin was administered at the same doses. After 4 h the animals were killed by cervical dislocation and a 6 mm diameter disc from each ear was removed with a metal puncture and weighed. Ear edema was calculated by subtracting the weight of the left ear (vehicle) from the right ear (treatment). Ear sections were homogenized in 750 μΐ saline. After centrifugation at 10,000 χ g for 15 min at 4 ° C, myelo peroxidase (MPO) activity was measured in supernatants.

As shown in the upper panel of figure 46, the activity of myelo peroxidase due to infiltrated neutrophils, and induced by topical application of TPA to the ear, was significantly attenuated when animals received TTL3 or the formula (IIB-Al). Edema was determined by weighing ear-sections and this parameter was significantly reduced by TTL3-treated or formula (IIB-Al) treated.

Example 36

Protection against D-GalN / LPS-induced lethality in rats by TTL3 and formula (IIB-Al)

Male BALB / c mice, 8 to 10 weeks old, were induced to endotoxic shock. Lethal damage was produced by an intraperitoneal (i.p.) injection of LPS (2 μg / kg) in combination with D-GalN (800 mg / kg). 5 μιηοΐ / kg TTL3 or formula (IIB-Al) was administered by i.p. (0.5 ml) 1 hour before D-GalN / LPS attack. Control animals were given saline. Lethality was monitored for up to 24 h after D-GalN / LPS administration.

Figure 47 shows that both TTL3 and formula (IIB-Al) exerted significant protection against lethality induced by an acute dose of D-GalN / LPS, extending the survival time of rats compared to vehicle-controlled three-fold.

Example 37

TNF-α inhibition assay of acanthoic acid analogs

RAW264.7 LPS / FNT Test:

7.5 χ 103 / well RAW264.7 cells were seeded into 96 well plates overnight and the acanthoid acid analogs of an appropriate concentration were added 1 h. prior to stimulation with LPS (10 ng / ml). After 4 h of LPS stimulation, supernatants were harvested and assayed for TNF production by ELISA.

DMSO was used as a control. Identical plaque sets without LPS stimulation were used for evaluation of cytotoxicity.

Table 24 - Inhibitory Activity of TNF-α Acanthoic Acid Analogs Having Epeptide Amide Functionality

<figure> figure see original document page 230 </figure> Table 25 - TNF-α inhibitory activity of acanthoic acid analogs having alcohol functionality

<table> table see original document page 231 </column> </row> <table>

Table 26 - TNF-α inhibitory activity of acanthoic acid analogs having ketone functionality

<table> table see original document page 231 </column> </row> <table>

Table 27 - TNF-α inhibitory activity of acanthoic acid analogs having oxime functionality

<table> table see original document page 231 </column> </row> <table> Table 28 - TNF-α inhibitory activity of acanthoic acid analogs having sulfonate functionality

<formula> formula see original document page 232 </formula>

Table 29 - TNF-α inhibitory activity of acanthoic acid analogs having ester functionality

<formula> formula see original document page 232 </formula>

Example 38

Anti Cancer Trials

The compounds described herein are tested against the National Cancer Institute (NCI) visualization panel, which consists of 60 human tumor cell lines representing leukemia, melanoma, and cancers of the lung, c-clonus, brain, ovary, breast, prostate and kidney. A detailed description of the viewing procedure can be found at the hypertext transfer protocol address (http://dtp.nci.nih.gov/branches/btb/ivclsp.html). The following is a list of cancers:

LUNG: NCI-H23, NCI-H522, A549-ATCC, EKVX, NCI-H226, NCI-H332M, H460, HOP62, HOP92; COLON: HT29, HCC-2998, HCTL16, SW620, COL0205, HCTL5, KM12; BREAST: MCF7, MCF7ADRr, MDAMB231, HS578T, MDAMB435, MDN, BT549, T47D; OVARIAN: 0VCAR3, OVCAR4.0VCAR5, 0VCAR8, IGROV1, SK0V3; LEUKEMIA: CCRFCEM, K562, M0LT4, HL60, RPMI8266, SR; RENAL: U031, SN12C, A498, CAKI, RXF393, 7860, ACHN, TK10; MELANOMA: LOXIMVI, MALME3M, SKMEL2, SKMEL5, SKMEL28, M14, UACC62, UACC257; PROSTATE: PC3, DU145; and CNS: SNB19, SNB75, U251, SF268, SF295, SM539.

In summary, each of the 60 human tumor cell lines grown in RPMI1640 medium was supplemented with 5% fetal bovine desorption and 2 mM L-glutamine. Cells were plated at their appropriate density in 96-well demicroiter plates and incubated at 37 ° C, 5% CO2, 95% air and 100% relative humidity. After 24 hours, 100 μL of 10-fold serial dilutions of a Formula II, IIA, or IIB compound were added to the appropriate containers containing 100 μL of cells, resulting in a final decomposed concentration ranging from 10 nM to 100 μΜ. Cells were incubated for an additional 48 hours and a desulphodamine B protein assay was used to estimate cell viability or growth.

Three dose response parameters were calculated as follows:

GI50 indicates the concentration that inhibits growth by 50%.

LC50 indicates the concentration that is lethal for 50% of cells,

ITC indicates concentration that completely inhibits LC50 indicates concentration that is lethal to 50%

Example 39

Growth Inhibition of Tumor Cell Lines

B16-F10 (ATCC; CRL-6475), DU 145 (ATCC; HTB-81), HEK293 (ATCC; CRL-1573), HT-29 (ATCC; HTB-38), LoVo (ATCC; CCL-229), MDA-MB-231 (ATCC; HTB-26), MIA PaCa-2 (ATCC; CRL-1420), NCI-H292 (ATCC; CRL-1848), OVCAR-3 (ATCC, HTB-161), PANC-I (ATCC; CRL-1469), PC-3 (ATCC; CRL-1435), RPMI8226 (ATCC; CCL-155) and U266 (ATCC; TIB-196) were maintained in appropriate culture media. Cells were recultivated in a 37 ° C incubator in 5% CO2 and 95% air humidity.

For cell growth inhibition assays, B16-F10, DU 145, HEK293, HT-29, LoVo, MDA-MB-231, MIA PaCa-2, NCI-H292, OVCAR-3, PANC-I, PC-3 cells , RPMI8226 and U266 were sown at 1.25 χ 10 ^ 3, 5 χ 10 ^ 3, 1.5 χ 10 ^ 4, 5 χ 10 ^ 3, 5 χ 10 ^ 3, 1 χ10 ^ 4, 2 χ 10 ^ 3 , 4 χ 10 ^ 3, 1 χ 10 ^ 4, 7.5 χ 10 ^ 3, 5 χ 10 ^ 3, 2 χ 10 ^ 4,2,5 χ 10 ^ 4 cells / container, respectively at 90 μΐ of a Corning 3904 black-walled, clear-wall tissue culture plates. 20 mM drive solutions of the compounds of Formula II, IIA, and IIB were prepared in 100% DMSO, quantified and stored at -80 ° C. The compounds of Formulas II, IIA, and IIB were serially diluted and added triplicate to the test vessels resulting in final concentrations ranging from 20 μΜ to 0.2 pM. The plates were returned to the incubator for 48 hours. The final DMSO concentration was 0.25% in all samples.

After 48 hours of drug exposure, 10 μΐ deresazurin at 0.2 mg / ml (obtained from Sigma-Aldrich Chemical Co.) in Mg2 + phosphate buffered saline, Ca2 + was added to each container and plates were returned to the incubator for 3 -6 hours. Since living cells metabolize Resazurin, the inflorescence of the Resazurin reduction product was measured using a Fusion microplate fluorometer (Packard Bioscience) with Xex filters. = 535 nm and λέπι = 590 nm. Resazurin dye in a cell-free medium was used to determine the background, which was subtracted from the data for all experimental recipients. Data were normalized to the mean fluorescence of cells treated with the medium + 0.25% DMSO (100% cell growth) and EC50 values (the drug concentration at which 50% of the observed maximum growth inhibition is established) were determined. using a standard sigmoidal dose response curve fitting algorithm (generated by XLfit 3.0, IDBusiness Solutions Ltd. or Prism 3.0, GraphPad Software Inc).

Example 40

Growth inhibition of tumor cell lines

Compounds 1387 and 1388 were tested as described in Example 39 against RPMI8226, U266, PC-3, HT-29, MDA-MB-231, and B16-F10 melanoma. Results are shown below in Tables 30-31.

Table 30 - In vitro cytotoxicity (48 h) of NPI-1387 and NPI-1388 against various human tumor cell lines

<table> table see original document page 235 </column> </row> <table>

Table 31 - In vitro cytotoxicity (48 h) murine B16-F10 melanoma countercells

<table> table see original document page 235 </column> </row> <table>

The individual values are shown.

Example 40

Treatment / inhibition of multiple resistant myeloma

FN-kB transcription factor is linked to growth and survival of multiple myeloma (MM) cells and blocking of FN-kB activity. NPI-1387 (Formula IIB-b1; compound 24 shown above under Scheme 4), a potent small molecule inhibitor of FN-κB anterior activator, was administered to MM-s-cell and its. The effect on MM cell viability, including those resistant to conventional dexamethasone or doxorubicin agents, is shown. Treatment of MM cell lines (MM.1S, MM.IR, OCI-MyS, OPM-I, Dox-40) with 48 h FN-kB inhibitor induces a significant dose-dependent decrease (P <0.004; η = 2) cell viability in all cell lines at achievable pharmacological concentrations (IC50 range 25 to 40 μΜ). To determine whether the FN-kB inhibitor-induced decrease in MM cell viability is due to apoptosis, several MM cell lines were treated in their IC50 perspective for 48 h, harvested and analyzed for apoptosis.

Significant apoptosis activated by the deFN-kB inhibitor in these cells as measured by a remarkable increase in nuclear condensation indicated by the dAP1 dense dye pattern was observed under phase contrast microscopy. In contrast, untreated control cells exhibited intact and homogeneous nuclei. In addition to nuclear condensation, the deFN-kB inhibitor activated proteolytic division of poly (ribose PAD) polymerase (PRPP), a characteristic of apoptosis. Examination of purified MM cells from patients has shown similar results. The FN-kB inhibitor decreases the cell viability obtained from Bortezomiba refractory MM patients under in vitro conditions. In contrast, no significant FN-kB inhibitor toxicity was observed against peripheral blood mononuclear cells from normal healthy donors. In addition, FN-kB inhibitor does not affect the viability of bone marrow stromal cells (CEMO) derived from MM patients. See figure 62.

Genetic and biochemical evidence indicates that apoptosis proceeds through two major cell death pathways: an intrinsic pathway involving mitochondrial membrane permeabilization and release of various apoptogenic factors, followed by activation of caspase-9; and an extrinsic apoptotic signaling pathway that occurs by caspase-8 activation. Both caspase-8 and caspase-9 further activate caspase-3. FN-kB inhibitor (25 μΜ) induces activation of caspase-8, caspase-9, followed by division of caspase-3. Together, these findings show that FN-kB inhibitor-activated MM cell apoptosis proceeds predominantly through the caspase-8 / caspase-9> caspase-3 signaling pathway. Collectively, these findings show the effectiveness of the FN-kB inhibitor in increasing MM cell death, overcoming drug resistance, and improving MM patient outcomes.

EXAMPLE 41

Novel acanthoic acid-derived FN-kB diterpene inhibitors [NPI-1342 (Formula IIB-a1) and NPI-1387; compound 24 under scheme 4 above) have measurable effects on human pancreatic cancer cell lines in vitro. Nine cell lines were moderately sensitive to death-induced apoptosis of the Tumor Necrosis Factor-related apoptosis-inducing ligand (TNAR) receptor ligand (ILARF). NPI-1342 and NPI-1387 reversed LIARF resistance in Panc-I and HS766T cell lines, which were found to be resistant to LIARF at baseline. Specific silencing of NF-κB / p65 expression mimicked these effects. In addition, the combination treatment of Salinosporamide A and NPI-1342or NPI-1387 led to induction of apoptosis as measured by PI FACS analysis. Specifically, DNA fragmentation levels increased from 4% to 50% in HS7 66T cells and from 4% to 52% in Panc-I cells. The inhibitory effects of NPI-1342, NPI-1387 on FN-kB were evaluated by Electro-Mobility Exchange Assays and confirmed by confocal microscopy.

EXAMPLE 42

In vitro studies have shown that acanthoic acid inhibits the production of proinflammatory cytokines such as TNF-α and IL-I. Two cell-based assays were used to visualize a library of semi-synthetic acanthoic acid analogs. Among these analogs, NPI-1387 inhibited LPS-induced TNF-α synthesis in murine tipomacrophagocyte cell line RAW264.7 most potently. In addition, NPI-1387 also reduced TNF-α-induced nuclear factor KB (FN-kB) activation in the FN-kB / Luciferase HEK293 reporting cell line, suggesting that NPI-1387 is a nocturnal inhibitor of FN-kB signaling. FN-kB is a fundamental transcription factor that regulates survival in many cells, and high levels of activated FN-kB have been shown to protect cancer cells (ie, multiple myeloma and prostate) from apoptosis. . The effects of NPI-1387 on LPS-or TNF-α-induced FN-k DNA binding activity were tested on RPMI8226 multiple myeloma cell line or PC-3 deprostate carcinoma cell line using electrophoretic mobility exchange assays (ETME) ). The results show that NPI-1387 inhibited LPS or TNF-α induced FN-kB DNA deletion activity in both cell lines. In addition, NPI-1387 was more potent in inhibiting proliferation of the myelomamultiple RPMI8226 cell line (IC50 = 5.1 ± 1 μΜ), whereas in PC-3 cloning assays an exposure of 6 h to 20 μΜ of enough NPI-1387 to completely abolish PC-3 colony formation. To elucidate the molecular target (s) of NPI-1387 in the FN-kB deinalization pathway, RAW264.7 cells were treated with NPI -1387 before LPS stimulation and fluorescence and Western blot microscopy analyzes were performed. The results showed that NPI-1387 not only inhibited the phosphorylation of IRAKlendogen and its target of IKBa ahead in a data-dependent manner, but also inhibited the nuclear translocation of activated IRAK1 and FN-kB suggesting that NPI-1387 functions as a previous inhibitor of FN pathway. -kB.

Example 43

The CDDP-resistant Ramos B-NHL cell line was treated with various concentrations of the compounds of formula II, IIA, and IIB (including 1387) for one hour and then treated with a predetermined non-toxic CDDP concentration (15 µg / ml). for an additional 20 hours. Cells were then harvested and examined for apoptosis using the iodide propidium (PI) technique by flow cytometry to examine DNA fragmentation. Combination treatment with one or more of the compounds and CDDP resulted in significant potentiation of cytotoxicity. Moreover, the treatment alone showed cytotoxicity, and significant synergistic cytotoxicity was observed. Similar studies were performed with the Daudi B-NHL cell line. Significant cytotoxicity was observed.

Rituximab (monoclonal anti-CD20 chimeric antibody) was used to treat Non-Hodgkin's Lymphoma alone or in combination with chemotherapy. The clinical response was very encouraging; however, some patients are initially indifferent or develop resistance after treatment. Oclone Daudi RR1 that is resistant to signaling induced by Rituximab has been studied. Unlike wild-type Daudi, Rituximab does not sensitize Daudi RR1 to drug-induced apoptosis. In addition, Daudi RRl also develops the highest degree of drug resistance compared to wild type. The compounds of formula II, IIA and IIB sensitize cells to Rituximab. The compounds were tested to determine their ability to sensitize cells to Rituximab. One or more of the composites sensitize cells to Rituximab.

EXAMPLE 44

NPI-1387 inhibits nuclear translocation of p65 FN-kB subunits in LPS stimulation in RAW264.7 cells

RAW264.7 cells were seeded in lids at a density of 0.5 x 105 cells / well in 12-well plates, and left overnight at 37 ° C, 5% CO 2 and 95% air humidity. Cells were pretreated with NPI-1387 (compound 24 under scheme 4 above) at 5, 10 and 20 μΜ for 1 h, then stimulated with 50 ng / ml LPS for 30 min. Lids were transferred to clear plates, washed twice in Dulbecco phosphate buffered saline (STFD), fixed in 10% deformaldehyde for 10 min, and permeabilized with 0.2% Triton Χ-1Χ0 for an additional 10 min. Blocking media (STFD, 2% BSA, 0.1% Triton X-100) was added for 2 h, and removed by aspiration. Polyclonal goat anti-p65 antibody (Santa CruzBiotechnology) was added at a dilution of 1: 1,000 for 1 h. Containers were washed 3 times with STFD containing 0.1% Triton X-100, and 100 ml of Alexa-488 conjugated goat antibody (1: 1,000 dilution, Molecular Probes) was added for 30 min. The containers were washed again, and the lids were mounted face down on microscopic slides using a Vectashield mounting medium (vector). The slides were viewed under an Olympus fluorescent microscope, images acquired using a Magnafire digital camera, and processed using Adobe Photoshop.

The effect of NPI-1387 on nuclear translocation of FN-kB p65 subunits in RAW264.7 cells is shown in Figure66. Unrelated to a particular theory, the results indicate that NPI-1387 inhibits nuclear translocation of p65 FN-kB subunits in LPS stimulation in RAW264.7 cells.

EXAMPLE 45

NPI-1387 Overcomes Bone Marrow MM Microenvironment Protective Effects

In vitro studies have shown that NPI-1387 does not affect the viability of bone marrow stem cells, but NPI-1387 outweighs the protective effects of IL-6 or IGF-I. These data suggest, without being bound by any particular theory, that NPI-1387 operates by blocking growth of MM cells induced by adhesion to bone marrow stem cells and related cytokine secretion.

EXAMPLE 46

NPI-1387 outperforms Bortezomiba resistance and Bcl-2 mediated resistance

In vitro studies have shown that NPI-1387 outperforms bortezomib resistance and Blcl-2 mediated resistance. Two cell-based assays were treated with NPI-1387 for 48 hours at concentrations of 0, 12, 25 and 50 μΜ. Both Bcl-2 overexpression MM.IS ascells and bortezomib-resistant HDL-4 lymphoma cells were used and the percentage of viable cells from each was recorded. The results showed a noticeable decrease in the percentage of viable cells from both Bcl-2 overexpression MM.IS cells and bortezomib-resistant DHL-4 delymphoma cells, corresponding to the increased concentration of NPI-1387. (See figure 67).

EXAMPLE 47NPI-1387 shows minimal effects on Mononuclear Peripheral Blood Cells (CSPMN) from healthy donors.

In vitro studies show that when variable CSPMNs are subjected to treatment with varying concentrations of NPI-1387, the change in the percentage of viable CSPMNs is relatively minimal. (See figure 68).

EXAMPLE 48

Apoptotic signaling has been shown to be activated by NPI-1387 in MM cells in both intrinsic and extrinsic pathways. (See figure 69).

Example 49

Coadministration of NPI-1387 with other drugs to provide additive anti-MM activity

In vitro assays measuring the percentage of MM cell death after 48 hours were performed with bortezomibae dexamethasone, each in combination with NPI-1387. These assays suggest, without being bound by any particular theory, that co-administration of each drug with NPI-1387 results in additional effects on increasing the percentage of MM cell death (see Figures 70 and 71).

EXAMPLE 50

NPI-1387 inhibits TNF-α synthesis in LPS-stimulated RAW264.7 cells

7.5 χ 103 / well RAW264.7 cells were seeded into 96 well plates and grown overnight at 37 ° C, 5% CO2 and 95% air humidity. Several concentrations of NPI-1387 prepared in DMSO were added to the cells 1 h before stimulation with LPS (10 ng / ml). DMSO was used as a control. After 4 h of LPS stimulation, supernatants were harvested and the TNF-α level of each sample was analyzed using the human TNF-α cytocyte ELISA equipment (Biosource Internationals). IC50 values (drug concentration in which 50% of the maximum observed TNF-α production is inhibited) were determined using a standard sigmoidal dose response curve-fitting algorithm (Prisma 2.0, GraphPad Software Incorporation.). The effect on production of TNF-α in RAW264.7 cells by NPI-1387 is shown in Figure 72. Without being linked to a particular theory, the results indicate that NPI-1387 is effective in inhibiting TNF-α production in LPS-stimulated RAW264.7 cells.

EXAMPLE 51

NPI-1387 inhibits IRAK1 phosphorylation and IKKa kinase activity in a dose-dependent manner with LPS stimulation in RAW264.7 cells.

5 χ 10 ^ 5 / well of RAW264.7 cells were seeded into a 6 well plate and grown overnight at 37 ° C, 5% CO2 and 95% air humidity. Cells were treated with 1, 5, 10 and 20 μΜ NPI-1387 for 1 hour and then stimulated with 10 ng / ml LPS for 10 or 30 min. To determine IRAK1 phosphorylation, whole cell extracts were prepared in RIPA buffer [0.9% NaCl, 50 mM Tris-HCl (pH7.4), 1% Triton X-100, 1 mM EDTA, 0.25% Na-oxycholic acid, 0.1% SDS, 1 mM Na3VO4, 1 mM NaF and deprotease inhibitors]. Insoluble material was removed by decentrifugation, protein concentrations were determined using the BCA protein assay equipment (PierceBiotechnology) and 15 μg aliquots of samples resolved in 10% of NuPAGE MES precast gels (Invitrogen). After electro-transfer, the membranes were blocked in Blotto fat milk (5%, weight / volume) in TBST Ix [20 mM Tris, 0.8% (w / v) NaCl, pH 7.6, 0.1 % (v / v) Tween 20]. The membranes were then incubated with primary antibodies against IRAKl (Santa CruzBiotechnology), total IKBa (Cell Signaling Technology), phospho-ΐκΒα (Cell Signaling Technology) and Tubulin (Lab Vision) in Blottodurante for 2 hours. Membranes were washed in TBST and (where necessary) incubated with the HPRP-conjugated secondary antibody in Blotto for 1 hour before extensive TBST washing. HRP activity was visualized using SuperSignal West Pico or Dura chemiluminescent detection systems (PierceBiotechnology ). To determine in vitro kinase activity of immunoprecipitated AKKa, whole cell extracts were prepared in lysis buffer [150 mM NaCl, 20 mM Tris-HCl (pH 7.5), 1% Triton X-100, 1 mM EDTA, 1 mM EGTA, 1 mM β-glycerophate, 1 mM NaF, 1 mM Na3VO4 and deprotease inhibitors]. Insoluble material was removed by decentrifugation. IKKa (Cell Signaling Technology) antibodies were added to the clarified supernatant and incubated at 40 ° C for 2 h. Immobilized immuno-pure protein G beads (PierceBiotechnology) were added and IKKa was immunoprecipitated at 4 ° C overnight. After the beads were washed briefly in the lysis buffer, they were incubated with GST-IKBa substrate (Santa Cruz Biotechnology) in the ATP-supplemented kinase assay buffer at 30 ° C for 1 h. Protein samples were separated by 10% NuPAGEMES preformed gels (Invitrogen) and the extent of GST-ΐκΒα phosphorylation was assessed by Western dyeing using the phospho-ΙκΒα antibody (Cell Signaling Technology).

The effects of NPI-1387 on LPS-activated IRAK1 phosphorylation and LPS-activated IKKa kinase activity in RAW264.7 cells are shown in Figure 73. Without being linked to a particular theory, the results indicate that NPI-1387 inhibits IRAK1 phosphorylation and reduces IKKa kinase activity delimates dose-dependent manner in LPS stimulation in RAW264.7 cells.

EXAMPLE 52

NPI-1387 inhibits TNF-α or LPS-induced deFN-KB DNA binding activity in cancer cells

RPMI8226 or PC-3 cells seeded in 6 cm tissue culture dishes were pretreated with indicated concentrations of NPI-1387 for 1 h. 0.25% (v / v) DMSO served as the vehicle control. For RPMI8226 cells, 50 ng / ml LPS was used to stimulate cells for 2 h. For cells PC-3.10 ng / ml TNF-α was used to stimulate cells for 0.5h. 0.2% (v / v) STFD was used for unstimulated controls. Nuclear extracts were prepared using NE-PER and cytoplasmic nuclear extraction reagents (PierceBiotechnology) according to manufacturer's instructions in the presence of inhibitors. of protease. Protein concentration of nuclear extracts was determined using BCA protein assay equipment (Pierce Biotechnology) according to the manufacturer's protocol. FN-KB DNA binding activity of nuclear extracts was determined using LightShift Chemiluminescent ETME (Pierce Biotechnology) equipment as detailed by the supplier. The biotin NF-KB probe was prepared by taking 5'-Biotin-AGT TGA GGG GAC TTT CCC AGG C and 5'-GCC TGGGAA AGT CCC CTC AAC T in 10 mM Tris-HCl, 1 mM EDTA and 50 mM NaCl , pH 8.0, using a Thermal Cycle PCR machine. Briefly, the binding reactions consisted of a standardized nuclear extract in IX binding buffer, 2.5% (v / v) glycerol, 5 mM MgCl2 , 50 ng / μΐ poly (dl.dC), 0.05% (v / v) NP-40 and 100 fmol biotin NF-KB probe in a total volume of 20 μΐ. Binding reactions were incubated for 60 minutes at room temperature. Where indicated, 2 μg deanti-p65 (Santa Cruz Biotechnology) or anti-c-Jun antibodies (Santa Cruz Biotechnology) were added to the ligation reaction after 30 minutes. Binding reactions were resolved in a pre-run of 6% polyacrylamide DNA retarding gel (Invitrogen) in 0.5X TBE (Invitrogen) before transferring onto a Biodyne B nylon membrane (PierceBiotechnology). After crosslinking in a UV-illuminator, the spots were probed with a streptavidin-HRP conjugate and visualized with the chemiluminescent substrate.

The effects of NPI-1387 on DNA binding activity in cancer cells RPMI8226 and PC-3 are shown in figure74. Unrelated to a particular theory, the results indicate that NPI-1387 inhibits FN-kB DNA binding activity in a dose-dependent manner in both LPS or TNF-α stimulated cancer cell lines.

EXAMPLE 53

NPI-1387 inhibits colony formation PC-3

PC-3 cells in 10 cm tissue culture dishes (200 cells / dish) were treated with 5 μΜ, 10 μΜ and 20 μΜ deNPI-1387 for 0.5-24 hours in triplicate. DMSO was used as vehicle control. After each time point of drug treatment, the medium was removed, the dishes were washed twice with Dulbecco phosphate buffered saline (STFD), and provided with fresh medium. Cells were cultured for 10 days with the medium refilled every 3 days. On day 10, the dishes were washed with cold STFD, fixed for 10 minutes in 100% ice cold methanol at 4 ° C, and the colonies tinted with 0.5% (w / v) crystalline violet. Colonies were counted manually, and results expressed as% of colonies in relation to their respective vehicle control.

Inhibition of PC-3 cell colony formation by various concentrations of NPI-1387 is shown in Figure 75. If not linked to a particular theory, the results indicate that NPI-1387 inhibits the formation of PC-3 cancer cell colonies. in a time dependent and data dependent manner.

EXAMPLE 54

48 h cytotoxicity; IC50 values of NPI-1387 in human cancer cell lines

HT-29 (ATCC # HTB-38) Prostate Adenocarcinoma PC-3 (ATCC # CRL-1435), Myeloma Breast Adenocarcinoma PC-3 (ATCC # HTB-26), Human Colon Adenocarcinoma Cell Lines Multiple RPMI8226 (ATCC # CCL-155) and U266 (ATCC # TIB-196) and CCD-27sk human normal fibroblast (ATCC # CRL-1475) were all purchased from ATCC (Manassas, VA). Cells were maintained in their respective culture media recommended by ATCC at 37 ° C, 5% CO2 and 95% air humidity.

Cytotoxicity assays were performed by seeding individual cell lines at the appropriate density into 96-well flat-bottom plates and allowed to be attached for 24 hours at 37 ° C, 5% CO 2 and 95% air humidity (RPMI8226 and U266 cells were 96-well plates on the day of compound addition). Serially diluted NPI-1387 was added in triplicate to cells at concentrations ranging from 160 nM to 20 μΜ. A final concentration of 0.25% (v / v) DMSO was used as the vehicle control. Cell aviability was evaluated 48 hours later by measuring the Resazurin reduction product inflorescence by a Fusion microplate fluorometer (PerkinElmer) with filters of λθχ = 535 nm and Xem = 590 nm. IC50 values (the drug concentration at which 50% of the maximum observed cytotoxicity is established) were calculated on XLFit 3.0 or XLFit 4.0 (IDBusiness Solutions Ltd.) using a dose responsemoxy model.

The 48 h IC50 values of NPI-1387 cytotoxicity against various normal-skinned human fibroblast cancer cell lines are shown in Table 32. Without being bound by one particular theory, the results indicate that NPI-1387 is less toxic to cells. normal and demonstrates anti-cancer activity in vitro.

Table 32 - NPI-1387 cytotoxicity profile in human cancer cell lines

<table> table see original document page 246 </column> </row> <table> CCD-27sk (human normal skin fibroblast) = 20 11

* 48h drug exposure

TABLE 1 - Inhibition of LPS-induced TNF-α synthesis by the compound of Formula (I) and TTL1.

<table> table see original document page 246 </column> </row> <table> TABLE 2 - Inhibition of SAC-induced TNF-α synthesis by the compound of Formula (I) and TTL1.

<table> table see original document page 247 </column> </row> <table>

TABLE 4-0 Compound of Formula (I) and TTL1 SAC-Induced IL-6 Synthesis

<table> table see original document page 247 </column> </row> <table>

TABLE 5 - TTL3 inhibits SAC-induced TNF-α synthesis by SAC TABLE 6 - TTL3 inhibits IL-I-induced synthesis

<table> table see original document page 247 </column> </row> <table> <table> table see original document page 248 </column> </row> <table>

TABLE 8 - TTL3 Inhibits mortality after LPS / D-Gal administration

<table> table see original document page 248 </column> </row> <table>

* all treatments were i.p., TTL3 administration 45 minutes before LPS

TABLE 9 - Assays Reflecting Examples 19-21

<table> table see original document page 248 </column> </row> <table>

TABLE 10 - Effect of Series 1 Analogs Cell Navigability

<table> table see original document page 248 </column> </row> <table> <table> table see original document page 249 </column> </row> <table>

* moderate reduction in viability

** noticeable reduction in viability

ND: Data not available

TABLE 11 - Percentage of TNF-α inhibition by Series 1 analogs

<table> table see original document page 249 </column> </row> <table>

TABLE 12 - Effect of Series 2 Analogs Cell Navigability

<table> table see original document page 249 </column> </row> <table>

TABLE 13 - Percentage of TNF-α inhibition by Series 2 analogs

<table> table see original document page 249 </column> </row> <table> <table> table see original document page 250 </column> </row> <table>

TABLE 14 - Effect of Series 3 Analogs Cell Navigability

<table> table see original document page 250 </column> </row> <table>

TABLE 15 - Percentage of TNF-α inhibition by Series 3 analogs

<table> table see original document page 250 </column> </row> <table>

TABLE 16 - Effect of Series 4 Analogs Cell Navigability

<table> table see original document page 250 </column> </row> <table>

TABLE 17 - Percentage of TNF-α inhibition by Series 4 analogs

<table> table see original document page 250 </column> </row> <table> <table> table see original document page 251 </column> </row> <table>

TABLE 18 - Effect of Series 5 Analogs Cell Navigability

<table> table see original document page 251 </column> </row> <table>

TABLE 19 - Percentage of TNF-α inhibition by Series 5 analogs

<table> table see original document page 251 </column> </row> <table>

TABLE 20 - Effect of Series 6 Analogs Cell Navigability

<table> table see original document page 251 </column> </row> <table>

TABLE 21 - Percentage of TNF-α inhibition by Series 6 analogs

<table> table see original document page 251 </column> </row> <table> TABLE 21 - Effect of Series 7 analogs cell navigability

<table> table see original document page 252 </column> </row> <table>

TABLE 22 - Percentage of TNF-α inhibition by Series 7 analogs

<table> table see original document page 252 </column> </row> <table>

While specific embodiments of the broadly described invention have been shown and explained in detail, and exemplified to illustrate its application and the underlying principles of the invention, it will be understood by those skilled in the art that the invention may be incorporated in other ways without departing from such principles.

Claims (61)

1. "INTERLEUCIN-1 AND TUMOR DENECROSIS-FACTOR-α MODULATORS", characterized in that it comprises a compound having the following chemical structure: <formula> formula see original document page 253 </formula> where: R2 is selected from: group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1 (C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C2-C alkenyls C 12, C 2 -C 12 substituted alkenyls, and C 5 -C 12 aryls R 17 is selected from C 5 -C 12 cyclic alkyls, C 5 -C 12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; phenyl and C5-C12 aryls R9 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 alcohol, C1-acyl -C12, and C5-C12 aryl; R3-R5, R7, R8, and R11-R13 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted alkenyls C2-C12, C2-C12 alkynyl, and C5-C12 aryl R6 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, and C2-C alkynyl R12 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, and C5-C12 aryl; R14 and R15 are separately selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, and C5-C6 aryl; eR16 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, tertiary amides (C1-C12 ) (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, and C 5 -C 12 aryls wherein the compound includes the prodrug esters of the above compounds and their acid addition salts. 2. INTERLEUKIN-1 AND TUMOR DENECROSIS-FACTOR-α MODIFIERS "according to claim 1, characterized in that R16 is hydrogen. 3. INTERLEUKIN-1 AND TUMOR DENECROSIS-FACTOR-α MODIFIERS according to claim 1, characterized in that R17 is cyclohexane; R16 is hydrogen; and R3-R5, R7, R8, R11-R15 they are each hydrogen. 4. INTERLEUCIN-1 AND TUMOR DENECROSIS-FACTOR-α "MODULATORS" according to claim 1, characterized in that R16 and R17 form a 3- to 12-membered ring. 5. INTERLUCIN-1 AND TUMOR DENECROSIS-FACTOR-1 "MODULATORS", characterized in that it comprises a compound: <formula> formula see original document page 255 </formula> and their prodrug esters and acid addition salts. 6. "METHODS FOR USING DEINTERLEUCIN-1 AND TUMOR NECROSIS-D-FACTOR MODULATORS", characterized in that they comprise a method for treating a finger-like condition in an animal selected from the group consisting of inflammation, tuberculous pleurisy, rheumatoid pleurisy, cancer. , fatigue reduction associated with cancer or its treatment, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media (inner ear infection), viral infection sinusitis, septic shock, transplantation, host grafting disease, ischemia / reperfusion, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, keratithmicrobial, peripheral ulcerative keratitis, Behcet's disease, uveitis, vitreoretinal proliferative disease, ocular virus disease Koyanagi-Harada, retinopathy, retinal laser photocoagulation, re necrosis syndrome Acute tendon, systemic vasculitis, recurrent aphthous stomatitis, glaucomaneovascular, eye infections, allergic eye diseases, retinal detachment, optic neuritis, multiple sclerosis, sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy-related mucosal damage contacting the compound of claim 1 with the tissue of said animal. "METHODS" according to claim 6, characterized in that the compound is: <formula> formula and its prodrug esters and acid addition salts. 8. METHODS FOR USE OF DEINTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-C "MODULATORS", characterized in that they comprise a method for treating an inflammatory condition in an animal, comprising contacting a claim 1 compound with the living tissue of said animal. 9. "METHODS" according to claim 8, characterized in that the inflammatory condition is selected from the group consisting of: tuberculous pleurisy, rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis (inner ear infection), sinusitis and viral infection, septic shock, transplantation, host grafting disease, ischemia / reperfusion damage, Graves ophthalmopathy, Hashimoto's thyroiditis, thyroid associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, ulcer keratitis, peripheral, Behcet's disease, uveitis, vitreoretinal proliferative disease, rabies virus ocular disease, Vogt-Koyanagi-Harada disease, retinopathy, retinal laser oto-coagulation syndrome, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis , glaucomaneovascular, eye infections, allergic eye diseases, retinal detachment, neur optic disease, multiple sclerosis, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy-related mucosal damage. "METHODS" according to claim 8, characterized in that the compound has the following structure: and its prodrug esters and acid addition salts. 11. "METHODS FOR USING DEINTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-α MODULATORS" characterized in that they comprise a method for treating cancer in an animal comprising contacting the compound of claim 1 with living tissue from said animal. "METHODS" according to claim 11, characterized in that the cancer is selected from the group consisting of multiple myeloma and human prostate adenocarcinoma. "METHODS" according to claim 11, characterized in that the compound has the following structure: including its prodrug esters and acid-killing salts. 14. "INTERLEUCIN-1 AND TUMOR NECROSIS-FACTOR-α MODULATORS", characterized in that it comprises a compound having the following chemical structure: <formula> formula see original document page 258 </formula> where: if any R3- R5, R7, R8, R11-13 non-hydrogen, R6 is not methyl, R10 is not CH2, or if R10 is CH2OH and R11 is OH, R2 is selected from the group consisting of hydrogen, a halogen, COOH, C1-carboxylic acids -C12, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides, C1-C12 alcohols, (C1-C12) ethers ) (C 1 -C 12), C 1 -C 12 alkyls, C 1 -C 12 substituted alkyls, C 2 -C 12 alkenyls, C 2 -C 12 substituted alkenyls; if all R3-R5, R7, R8, R11-R13 are hydrogen, R6 is methyl, and R10 is CH2 or CH2OH, then R2 is selected from hydrogen, a halogen, C1-C12 carboxylic acids, C1-C12 acyl halides, residues C1 -C12 acyl, C2 -C12 esters, C1-C12 secondary amides, (C1-C12) (Cl-C12) tertiary amides, C2-C12 alcohol, (C1-C12) (C1-C12) ethers, C2-C12 alkyl C 2 -C 12 substituted alkyls, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyls R 3, R 4, R 5, R 7, R 8, and R 11-R 13 are each separately selected from hydrogen, a halogen, C 1 -C 12 alkyl, alkyl substituted C 1 -C 12, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, C 2 -C 12 alkynyl, and C 5 -C 12 aryl R 6 is selected from hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl C 2 -C 12 substituted alkenyl and C 2 -C 12 alkynyl R 10 is selected from hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkenyl, C 1 -C 12 alcohol , and arila C5-C12; R16 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, amides (C1-C12) (C1-C12), cyclic (C1-C12) amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, alkyls substituted C 1 -C 12, C 2 -C 12 alkenyls, substituted C 2 -C 12 alkenyls, and C 5 -C 12 aryls; R 17 is selected from C 5 -C 12 cyclic alkyls, C 5 -C 12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; phenyl and C 5 -C 12 aryls, wherein the compound includes the prodrug esters above and their acid addition salts. "" INTERLEUCIN-1 AND TUMOR NECROSIS-FACTOR-α MODULATORS "according to claim 14, characterized in that R16 is hydrogen. "Modulators of interleukin-1 and tumor necrosis factor-α" according to claim 14, characterized in that R17 is cyclohexane; R16 is hydrogen; and R3-R5, R7, R8, R1-R15 are each hydrogen. "" INTERLEUKIN-1 AND TUMOR NECROSIS-FACTOR-α MODULATORS "according to claim 18, characterized in that R16 and R17 form a 3- to 12-membered ring. 18. "INTERLEUCIN-1 AND TUMOR NECROSIS-FACTOR-α MODULATORS", characterized in that it comprises a compound having the following chemical structure: <formula> formula see original document page 260 </formula> and its prodrug esters and acid addition salts. 19. "METHODS FOR USING DEINTERLEUCIN-1 AND TUMOR NECROSIS-FACTOR-α MODULATORS", characterized in that they comprise a method for treating a finger-like condition in an animal selected from the group consisting of: inflammation, tuberculous pleurisy, rheumatoid pleurisy, cancer, reduction of fatigue associated with or treatment of it, cardiovascular disease, skin redness, diabetes, rejection of transplantation, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, host grafting disease, - damage <ie ischemia / reperfusion, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, keratithmicrobial, peripheral ulcerative keratitis, Behcet's disease, uveitis, proliferative vitreoretinal disease, ocular rabies disease -Koyanagi-Harada disease, retinopathy, retinal laser photo-coagulation, necro syndrome if acute retinal, systemic vasculitis, recurrent aphthous stomatitis, glaucomaneovascular, eye infections, eye allergic diseases, retinal detachment, optic neuritis, multiple sclerosis, sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy-related mucosal damage, comprising contacting the compound of claim 14 with the tissue of said animal. "Methods" according to claim 19, characterized in that R16 and R17 form a 3- to 12-membered ring. "Methods" according to claim 19, characterized in that the compound is: <p> formula <tb> <sep> formulates its prodrug esters and acid addition salts. 22. "Methods for the use of deinterleukin-1 and tumor necrosis factor-a modulators", characterized in that they comprise a method for treating an inflammatory condition in an animal, comprising contacting a claim compound 14 with the living tissue of said animal. 23. "METHODS" according to claim 21, characterized in that the inflammatory condition is selected from the group consisting of: tuberculous pleurisy, rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media ( inner ear infection), sinusitis and viral infection, septic shock, transplantation, host grafting disease, ischemia / reperfusion damage, Graves ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, ulcerative keratitis, ulcer Behcet's disease, uveitis, vitreoretinal proliferative disease, rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laser retinal photo-coagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, glaucomaneovascular infections of the eye, allergic eye diseases, retinal detachment, neuritis and optics, multiple sclerosis, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy-related mucosal damage. 24. "METHODS" according to claim 22, characterized in that the compound has the following structure: <formula> formula see original document page 262 </formula> and prodrug esters and their acid addition salts. 25. "METHODS FOR USING REIN DEINTERLEUCIN-1 MODEL AND TUMOR NECROSIS FACTOR-α", characterized in that they comprise a method for treating cancer in an animal, comprising contacting a compound with a living tissue of said animal, wherein The compound has the following chemical structure: wherein: R2 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) (C1-C12) tertiary amides, (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers , C1-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls, and C5-C12 aryls: R3-R5, R7, R8, and R11-R13 are each separately selected from hydrogen a halogen, C1-C12 alkyl, substituted C1-C12 alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyls, C1-C12 alkynyl, and C5-C12 aryl; R6 is selected from hydrogen. hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, and C2-C12 alkynyl; R10 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, alkyl substituted C 1 -C 6, C 2 -C 6 alkenyl, C 2 -C 6 substituted alkenyl, C 1 -C 12 alcohol, and C 5 -C 12 aryl; R14 and R15 are selected separately from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, and C5-C6 aryl; R16 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12) tertiary amides (C1- (C12) cyclic amides, C1-C12 amines, C1-C12 amines, C1-C12 alcohols, (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls C 2 -C 12 substituted alkenyls and C 5 -C 12 aryls R 17 is selected from C 5 -C 12 cyclic alkyls, C 5 -C 12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; phenyl and C5 -C12 aryls, where the compound includes prodrug esters of the above compounds, and acid addition salts. "METHODS" according to claim 25, characterized in that the cancer is selected from the group consisting of multiple myeloma and human prostate adenocarcinoma. "METHODS" according to claim 25, characterized in that the compound has the following structure: <formula> including its prodrug esters and acid-killing salts. "METHODS" according to claim 25, characterized in that R16 and R17 form a 3-membered ring. 29. "T modulus interleukin-1 and Tumor necrosis factor re s", characterized in that it comprises a compound having the following chemical structure: <formula> formula see original document page 265 </formula> where: R2 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, tertiary (C1-C12) amides (C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, alkenyls C 2 -C 12, C 2 -C 12 substituted alkenyls, and C 5 -C 12 aryls R 9 is selected from hydrogen, a halogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl C12, C1-C12 alcohol, C1-C12 acyl, and C5-C12 aryl; R3-R5, R7, R8, and R11-R13 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, substituted alkyls. C1-C12, C2-C12 alkenyl, C2-C12-substituted alkenyls, C2-C12 alkynyl, and C5-C12-aryl R6 is selected from hydrogen, a halogen, C1-C12-alkyl, C1-C12-substituted alkyl, C2-C12-alkenyl C 2 -C 12 substituted alkenyl and C 2 -C 12 alkynyl R 10 is selected from hydrogen, a halogen, CH 2, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkenyl, C 1 -C 12 alcohol , and C5-C12 aryl; R14 and R15 are selected separately from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C1-C6 substituted alkenyl, and C1-C6 aryl C6; eR16 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C2 secondary amides, (C1- C12) (-C1-C12), (C1-C12) cyclic amides, (C1-C12) amines, C1-C12 alcohols, (C1-C12) (C1-C12) ethers, C1-C12 alkyls, C1-6 substituted alkyls C 12 -C 12 alkenyls, substituted C 2 -C 12 alkenyls and C 5 -C 12 aryls R 17 is selected from C 5 -C 12 cyclic alkyls, C 5 -C 12 cyclic alkenyls; C5 -C12 cyclic substituted alkyls; C5 -C12 cyclic substituted alkenyls; phenyl and C 5 -C 12 aryls, wherein the compound includes the prodrug esters above and their acid addition salts. "" INTERLEUCIN-1 AND TUMOR NECROSIS-FACTOR-α MODULATORS "according to claim 29, characterized in that R16 is hydrogen. 31. "INTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-OECD MODULATORS" according to claim 29, characterized in that R17 is cyclohexane; R16 is hydrogen; and R3-R5, R7, R8, R11-R15 are each hydrogen. 32. Interleukin-1 and Tumor Necrosis Factor-Modulators according to Claim 29, characterized in that R16 and R17 form a 3- to 12-membered ring. 33. INTERLEUKIN-1 AND TUMOR NECROSIS FACTOR-MODULATORS ", characterized by: and its prodrug esters and acid addition salts. 34. METHODS FOR USE OF DEINTERLEUCIN-1 AND TUMOR NECROSIS-α FACTOR MODULATORS ", characterized by the fact that they comprise a method for treating a disease condition of an animal selected from the group consisting of inflammation, tuberculous pleurisy, rheumatoid pleurisy, cancer, fatigue reduction associated with cancer or its treatment, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, host grafting disease, ischemia / reperfusion damage , Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, keratithmicrobial, peripheral ulcerative keratitis, Behcet's disease, uveitis, vitreoretinal proliferative disease, Harovan-vogulous disease Harovan-vagic eye disease , retinopathy, retinal laser photo-coagulation, re necrosis syndrome Acute tendon, systemic vasculitis, recurrent aphthous stomatitis, glaucomaneovascular, eye infections, allergic eye diseases, retinal detachment, optic neuritis, multiple sclerosis, sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy-related mucosal damage contacting a compound of claim 29 with living tissue from said animal. "METHODS" according to claim 34, and prodrug esters thereof and acid addition salts. 36. "METHODS" according to claim 34, characterized in that R16 and R17 form a 3 to 12 membered ring. 37. "METHODS FOR USING DEINTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-α MODULATORS", characterized in that they comprise a method for treating an inflammatory condition in an animal, including contacting a claim compound 29 with a living tissue of said animal. 38. "METHODS" according to claim 37, characterized in that the inflammatory condition is selected from the group consisting of: tuberculous pleurisy, rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media ( inner ear infection), sinusitis and viral infection, septic shock, transplantation, host grafting disease, ischemia / reperfusion damage, Graves ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, ulcerative keratitis, ulcer Behcet's disease, uveitis, vitreoretinal proliferative disease, rabies virus ocular disease, Vogt-Koyanagi-Harada disease, retinopathy, retinal laser photo-coagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, glaucomaneovascular infections of the eye, allergic eye diseases, retinal detachment, neuritis and optics, multiple sclerosis, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy-related mucosal damage. 39. "METHODS" according to claim 37, characterized in that the compound has the following structure: <formula> formula see original document page 270 </formula> and its prodrug esters and acid addition salts . 40. "METHODS" according to claim 37, characterized in that R16 and R17 form a 3- to 12-membered ring. 41. METHODS FOR USING DEINTERLEUCIN-1 AND TUMOR NECROSIS OC-FACTOR MODULATORS, characterized in that they comprise a method for treating cancer in an animal, including contacting a compound of claim 29 with living tissue from said animal. 42. "METHODS" according to claim 41, characterized in that the cancer is selected from the group consisting of: multiple myeloma and human prostate adenocarcinoma. 43. "METHODS" according to claim 41, characterized in that the compound has the following structure: <formula> including its prodrug esters and acid-killing salts. 44. "METHODS" according to claim 41, characterized in that R16 and R17 form a 3- to 12-membered ring. 45. "INTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-OLDE MODULATORS", characterized in that it comprises a compound having the following chemical structure: wherein the compound includes the prodrug esters compound above, and their addition salts of acid. 46. "METHODS FOR USING DEINTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-α MODULATORS", characterized in that they comprise a method for preparing a synthetic compound having the following chemical structure: wherein the compound includes the esters of prodrug compound above, and their acid addition salts, comprising the steps of: performing a Diels-Alder reaction by reacting a diene having two or more rings with a dienophil compound to obtain a resulting compound having three or more rings; obtaining the synthetic compound. 47. "METHODS FOR USING DEINTERLEUCIN-1 AND TUMOR NECROSIS FACTOR MODULATORS", characterized in that they comprise a method for purifying a compound having the following chemical structure: <formula> formula see original document page 272 </formula> 48. "METHODS FOR USE OF DEINTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-α MODULATORS", characterized in that they comprise a method for treating an inflammatory condition or a neoplastic condition in an animal, comprising contacting a compound with the living tissue of said animal. where the compound has the following chemical structure: <formula> formula see original document page 272 </formula> 49. "METHODS" according to claim 48, characterized in that the inflammatory disease is selected from the group consisting of: tuberculous pleurisy, pleurisy including a chromatographic process. Rheumatoid, cardiovascular disease, skin redness, diabetes, rejection of transplantation, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, graft versus host disease, damage of ischemia / reperfusion, Graves ophthalmopathy, Hashemoto's thyroiditis, thyroid ophthalmopathy, nodular goiter, herpetic stromal keratitis , microbial keratitis, peripheral keratitis ulcer, Behcet's disease, uveitis, vitreoretinal proliferative disease, rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laserretinal photo-coagulation syndrome, acute retinal necrosis syndrome, systemic vasculitis, recurrent foot-and-mouth disease, neovascular glaucoma, eye infections, allergic diseases Urals, retinal detachment, neuritis, multiple sclerosis, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy-related mucosal damage. 50. "METHODS" according to claim 48, characterized in that the neoplastic disease is cancer. 51. "METHODS" according to claim 50, characterized in that the cancer is selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer. , rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer ). 52 "INTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-α MODULATORS", characterized in that it comprises a compound having the following chemical structure: wherein the compound includes the prodrug esters compound above, and their acid addition salts. 53. "METHODS FOR USING DEINTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-OL MODULATORS", characterized in that they comprise a method for preparing a synthetic compound having the following chemical structure: <formula> formula see original document page 274 </ formula wherein the compound includes the prodrug esters above and their acid addition salts, comprising the steps of: performing a Diels-Alder reaction by reacting a diene having two or more rings with a dienophil compound to obtain a resulting compound having three or more rings; obtaining the synthetic compound. 54. "METHODS FOR USING DEINTERLEUCIN-1 AND TUMOR NECROSIS FACTOR-α MODULATORS", characterized in that they comprise a method for purifying a compound having the following chemical structure: <formula> formula see original document page 275 </ including a chromatography process. 55. "METHODS FOR USING RESIN INTERLEUCIN-1 MODULATOR AND TUMOR NECROSIS FACTOR-α", characterized in that they comprise a method for treating an inflammatory condition or a neoplastic condition in an animal, including contacting a compound with the living tissue of said animal. animal, in which the compound has the following chemical structure: <formula> formula see original document page 275 </formula> characterized by the fact that the inflammatory disease is selected from the group consisting of: tuberculous pleurisy, rheumatoid pleurisy, cardiovascular disease, redness of the skin, diabetes, transplant rejection, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, graft versus host disease, ischemia / reperfusion damage, Graves ophthalmopathy, hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, microbial keratitis, peripheral ulcerative keratitis, Behcet's disease , uveitis, vitreoretinal proliferative disease, rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laserretinal photo-coagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye diseases ocular allergic reactions, retinal detachment, neuritis, multiple sclerosis, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy-related mucosal damage. 56. [Claim missing on original document] 57. "METHODS" according to claim 55, characterized in that the neoplastic disease is cancer. 58. "METHODS" according to claim 57, characterized in that the cancer is selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer. , rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer ). 59. "METHODS FOR USE OF DEINTERLEUCIN-1 AND TUMOR NECROSIS FACTOR MODULATORS", characterized in that they comprise a compound of the following chemical structure: for the manufacture of a medicament for treating a selected disease from the group consisting of: pleurisiatuberculosa , rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, transplant rejection, means deotitis (inner ear infection), sinusitis and viral infection, septic shock, transplantation, graft versus host disease, ischemia / reperfusion damage, ophthalmopathy Severe thyroiditis, Hashimoto, thyroid - associated ophthalmopathy, nodular goiter, herpetic st - romal keratitis, microbial keratitis, peripheral keratitis,. Behcet's disease, uveitis, vitreoretinal proliferative disease, rabies virus eye disease, Vogt-Koyanagi-Harada disease, retinopathy, laserretinal photo-coagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, infections eye disease, allergic eye disease, retinal detachment, neuritis, multiple sclerosis, systemic sclerosis, inherited retinal degeneration, trachoma, autoimmune diseases, and mucosal damage related to chemotherapy, breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer , prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain cancer or the central nervous system (CNS). 60. "METHODS FOR USING REIN DELETERLEUCIN-1 MODEL AND TUMOR NECROSIS OC-FACTOR", characterized in that they comprise a compound of the following chemical structure: for the manufacture of a medicament for treating a disease selected from the group consisting of : pleurisiatuberculosa, rheumatoid pleurisy, cardiovascular disease, skin redness, diabetes, transplant rejection, deotitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, graft versus liospedeiro disease, ischemia / reperfusion, Graves' ophthalmopathy, Hashimoto's thyroiditis, thyroid-associated ophthalmopathy, nodular goiter, herpetic stromal keratitis, microbial keratitis, peripheral keratitis ulcer, Behcet's disease, uveitis, vitreoretinal proliferative disease, rabies virus Kogi-ocular disease -Harada, retinopathy, laserretinal photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye infections, allergic eye disease, retinal detachment, neuritis, multiple sclerosis, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and mucosal damage related to chemotherapy, breast cancer, sarcoma, cancer, Ovarian, Uretal Cancer, Bladder Cancer, Deprostate Cancer, Colon Cancer, Rectal Cancer, Stomach Cancer, Lung Cancer, Iymphoma, Multiple Myeloma, Pancreatic Cancer, Liver Cancer, Kidney Cancer, Endocrine Cancer, Skin Cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer. 61. "INTERLEUCIN-1 AND TUMOR NECROSIS-FACTOR-α MODULATORS", characterized in that it comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound selected from: