CA2522632A1 - Ccr5 receptor antagonist molecules - Google Patents

Ccr5 receptor antagonist molecules Download PDF

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Publication number
CA2522632A1
CA2522632A1 CA002522632A CA2522632A CA2522632A1 CA 2522632 A1 CA2522632 A1 CA 2522632A1 CA 002522632 A CA002522632 A CA 002522632A CA 2522632 A CA2522632 A CA 2522632A CA 2522632 A1 CA2522632 A1 CA 2522632A1
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3alkyl
compound
carbon atoms
compounds
alkoxy
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French (fr)
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Robert D. Williams
Ahmad Fawzi
El Hassane Lahlou
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AVANCE PHARMA INC.
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Priority to CA002522632A priority Critical patent/CA2522632A1/en
Priority to PCT/CA2006/001648 priority patent/WO2007038875A1/en
Publication of CA2522632A1 publication Critical patent/CA2522632A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

Compounds and pharmaceutical compositions are provided for the treatment of AIDS.

Description

Title : CCR5 Receptor Antagonist Molecules Background HIV is a retrovirus which causes the disease commonly known as AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. HIV-2, seen more often in western Africa, and has a slower course than HIV-1.
Antiretroviral therapy has been effective in reducing morbidity and mortality in HIV-1 infected patients. The emergence of resistance to existing drugs, combined with the lack of adherence due to complicated dosing regimens causing side effects, led to an increase in the number of patients who are currently failing therapy. The elucidation of the different mechanistic steps by which HIV enters the host cell revealed many new targets for pharmacological intervention. Inhibitors of these new targets most likely will not be cross resistant to protease as well as reverse transcriptase inhibitors since they will interfere at different steps in the life cycle of HIV. Three discrete steps have been recognized in the entry process of HIV. In the first step the attachment of the HIV
envelop to the CD4 receptor on host cells that are susceptible to infection takes place.
Attachment results in a conformational change in the HIV envelop that triggers the second step namely, interaction with a co receptor, CCRS or CXCR4. Finally, fusion takes place between gp4l; the viral envelop component, and the host cell membrane resulting in infection of the susceptible cell. Inhibitors of each of these steps have been identified and progressed into clinical trials. The most advanced has been the peptide, a fusion inhibitor that has been approved by the FDA in early 2003 and marketed as Fusion by Roche/Trimmers.
Another possible mechanism to combat this disease is through primary prevention of the infection through microbicides. Microbicides are compounds that can be applied inside the vagina or rectum to protect against sexually transmitted infections (STIs) including HIV. They can be formulated as gels, creams, films, or suppositories.
Microbicides may or may not have spermicidal activity (contraceptive effect). At present, an effective microbicide is not available.

The chemokine receptor, CCRS, is a member of the G protein-coupled receptor superfamily. Chemokine receptors expressed on the surface of immune cells such as monocytes, macrophages, dendritic cells, and T cells are known to play a critical role in HIV infection and transmission. The prevalence of the CCR5432 homozygous genotype, amounting to about 1 % of the Caucasian population, and results in no major impact on health while being strongly protective against HIV infection made this target very attractive for pharmacological intervention. Furthermore, CCR5 knockouts in mice have a benign phenotype with a very subtle impact on immune function. Hence, an antagonist specific for CCR5 may cause few, if any, mechanism-based side effects. These and other studies established that HIV-1 virus invades macrophages and primary T-cells by binding to the cell surface protein CD4 and the chemokine receptor CCRS. Thus small molecule CCR5 receptor antagonists may inhibit HIV-1 viral invasion of CD4+
host immune cells and provide a powerful new therapeutic avenue for HIV therapy (Maeda K, Nakata H, Ogata H, Koh Y, Miyakawa T, and Mitsuya H (2004) Current Opinion in Pharmacology 4: 447-452) The hallmark of inflammatory disease is the infiltration of inflammatory cells into target organs. CCR5 receptors have been reported to mediate cellular transfer in inflammatory diseases such as rheumatoid arthritis, arthritis, asthma, psoriasis, atopic dermatitis, and allergies. Thus inhibitors of CCR5 receptor are expected to be of therapeutic benefit in these diseases and in other disease conditions such as inflammatory bowel syndrome, multiple sclerosis, organ transplant rejection and graft versus (v.) host disease.
The present invention relates to certain molecules as CCR5 receptor antagonists, pharmaceutical compositions containing the compounds, and methods of treatments using the compounds. The invention also relates to the use of a combination of receptor antagonists of this invention with one or more antiviral agents or other agents in the treatment of HIV-1. The invention further relates to the use of CCR5 receptor antagonists of this invention, alone or in combination with other agents, in the treatment of rheumatoid arthritis, arthritis, atopic dermatitis, psoraiasis, asthma, allergies, multiple sclerosis, solid organ transplant rejection, and graft v. host disease. As shall be discussed herein below molecules of the present invention may, for example, be derived from plant cell culture(s).
Summary of the Invention Thus the present invention relates to molecules or compounds of general formulae 17, 18, 19, 19a, 19b, 20, 21 and 22 as set forth below. The present invention further relates to the treatment of HIV comprising administering to a human in need of such treatment an effective dose of a CCR5 receptor antagonist as described herein (i.e.
compounds of general formulae 17, 18, 19, 19a, 19b, 20, 21 and 22 and for example in particular the molecules or compounds as set forth in Table 1 below). In accordance with another aspect of the invention there is provided a pharmaceutical composition for treatment of HIV comprising a pharmaceutically acceptable carrier and (an effective amount of) a CCR5 receptor antagonist as described herein (i.e. compounds of general formulae 17, 18, 19, 19a, 19b, 20, 21 and 22 and for example in particular the molecules or compounds as set forth in Table 1 below). This invention also relates to the use of these compounds as microbicides i.e. in an appropriate pharmaceutical composition.
In addition, another aspect of this invention relates to the use of the above mentioned compounds for the treatment of solid organ rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies, or multiple sclerosis, In other words to pharmaceutical composition for treatment of HIV comprising a pharmaceutically acceptable carrier and (an effective amount of) a CCR5 receptor antagonist as described herein for such applications.
Detailed Description of the Invention The compounds of the present invention may be used for treating HIV infection.
They may preferably be administered in substantially pure form. By "substantially pure" is meant that a compound as described herein may either be synthesized or be purified from a naturally derived state such that the compound is associated with only trace quantities of undesired materials or compounds that occur with it as a result of its synthesis or derivation from a natural state (e.g., the undesired materials or compounds are present in amounts whereby no unacceptable effect on a patient may be observed).
By "isolated" is meant that the compound is in a state which is free or essentially free of being associated with other undesired or unacceptable molecules or compounds.
If desired, synthesized, isolated or purified compounds may be present in a formulation along with a pharmaceutical carrier as described herein below.
Thus, for example, many of the compounds of the present invention may be isolated or extracted from natural sources such as, for example, Hernandia ovigera and Oreocereus bruennowii. Several suitable methods for extracting the compounds of the present invention are known in the art. A highly preferred extraction method typically comprises crushing of a desired plant material (e.g., plant cell culture), blending the crushed material with a polar, preferably aqueous, solvent, filtering the slurry of crushed material t0 and polar solvent and purifying the filtrate. Several purification methods like one-step or multi-step liquid-liquid extraction, solid phase extraction, chromatography and the like are known from the state of the art.
Compounds according to the invention may also be synthesized, for example using compounds as shown in table 1 below as starting intermediates. The compounds according to the invention can also be semi-synthesized. Compounds of the present invention may for example be synthesized from intermediated compounds extracted from plant cell culture as described herein.
One of ordinary skill in the art will recognize that some of the compounds of the present invention may exist in different geometrical isomeric forms. In addition, compounds of the present invention may possess one or more asymmetric carbon atoms and may thus capable of existing in the form of optical isomers, as well as in the form of racemic or nonracemic mixtures thereof, and in the form of diastereomers and diastereomeric mixtures inter alia. All of these compounds, including cis isomers, traps isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, and substantially pure and pure enantiomers, are within the scope of the present invention.
Substantially pure enantiomers for example are to be understood herein as containing no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1 %.
The optical isomers may be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers may be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids may be then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral High Performance Liquid Chromatography (HPLC) columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC
columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, may also useful. The optically active compounds of the present invention may likewise be obtained by chiral syntheses utilizing optically active starting materials.
The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts and prodrugs of all the compounds of the present invention. A prodrug is to be understood herein as a compound that the body is able to convert into active drug; stated in another way, a prodrug is a pharmacological substance (drug) which is administered in an inactive (or significantly less active) form;
however, once administered, the prodrug is metabolised in the body (in vivo) into an active compound..
Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, malefic acid, succinic acid and citric acid.
Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, mangnesium, ammonium, and choline salts. Those skilled in the art will further recognize that additional salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
The following are further examples of acid salts that may be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.
Preferably, the salts formed may be pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds may be suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent. The free base may then be, if desired, be converted to a pharmaceutically acceptable acid addition salt.
The compounds of the present invention may be used for treating HIV infection alone or with co- infections e.g., opportunistic infections such as viral, bacterial or parasitic co-infection. Thus another aspect of the invention relates to the administration of the compounds of the present invention along with an effective amount of an agent to treat the co-infection. Typical opportunistic infections ("OI's") and other disorders commonly present with HIV disease may be bacterial and mycobacterial infections such as, for example, Mycobacterium Avium Complex (MAC, MAI), Salmonellosis, Syphilis, Neuroshyphilis, Turberculosis (TB) and Bacillary angiomatosis (cat scratch disease);
fungal infections such as, for example, Aspergillosis, Candidiasis (thrush, yeast infection), Coccidioidomycosis, Cryptococcal Meningitis and Histoplasmosis;
malignancies such as, for example, Kaposi's Sarcoma, Lymphoma, Systemic Non-Hodgkin's Lymphoma (NHL) and Primary CNS Lymphoma; protozoal infections such as, for example, Cryptosporidiosis, Isosporiasis, Microsporidiosis, Pneumocystis Carinii Pneumonia (PCP) and Toxoplasmosis; viral infections such as, for example, Cytomegalovirus (CMV), Hepatitis, Herpes Simplex (HSV, genital herpes), Herpes Zoster (HZV, shingles), Human Papiloma Virus (HPV, genital warts, cervical cancer), Molluscum Contagiosum, Oral Hairy Leukoplakia (OHL) and Progressive Multifocal Leukoencephalopathy (PML); neurological conditions such as, for example, AIDS
Dementia Complex (ADC) and Peripheral Neuropathy. Other conditions and complications of HIV infection include, for example, Apthous Ulcers, malabsorption, depression, diarrhea, thrombocytopenia, wasting syndrome, idiopathic thrombocytopenic purpura, Listeriosis, pelvic inflammatory disease, Burkitt's lymphoma and immunoblastic lymphoma. Treatment for these opportunistic infections and other disorders are conventionally known. Suitable agents, which may be co-administered or used in combination therapy with the compounds of the present invention, can be found, for example, at http://www.aegis.com/topics/oi/.
The activity of the compounds of the present invention may be determined by any one of a number of known assays available to one skilled in the art. The activity of the compounds according to the invention may also be determined by assays such as those described in the Examples.
The compounds (including salts, prodrugs, etc.) of the invention may be administered alone, but preferably as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical compositions containing a compound of the present invention and one or more pharmaceutically acceptable carriers, excipients etc.
Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).
In view of their potentially high degree of efficacy in reducing HIV viral load, the compounds of the present invention may be administered to anyone requiring or desiring reduction in HIV viral load, including patients having HIV with co-infection.
Administration may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration.
Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds (including salts, prodrugs, etc.) of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
Various liquid oral dosage forms may also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms may also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution.
Other preparations are also possible.
Suppositories for rectal administration of the compounds of the present invention may be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.
For topical administration the pharmaceutical composition may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose.
Topical administration may also involve transdermal administration via means such as transdermal patches.
Aerosol formulations suitable for administering via inhalation also may be made. For example, the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions. The aerosol formulation may be placed into a pressurized acceptable propellant.
The compounds (including salts, prodrugs, etc.) of the present invention may be administered as the sole active agent or in combination with one or more, preferably one to eight, anti-viral agents useful in anti-HIV-1 therapy e.g., protease inhibitors, reverse transcriptase inhibitors, fusion inhibitors ("FI"s) or other antiviral drugs such as ribavirin.
Suitable antiviral agents which may be co-administered or used in combination therapy include, for example, suitable nucleoside and nucleotide reverse transcriptase inhibitors ("NRTI" s) including, for example, zidovudine (AZT) available under the RETROVIR
tradename from Glaxo-Welicome Inc., Research Triangle, N.C. 27709; didanosine (ddl) available under the VIDEX tradename from Bristol-Myers Squibb Co., Princeton, N.J.
08543; zalcitabine (ddC) available under the HIVID tradename from Roche Pharmaceuticals, Nutley, N.J. 07110; stavudine (d4T) available under the ZERIT
trademark from Bristol-Myers Squibb Co., Princeton, N.J. 08543; lamivudine (3TC) available under the EPIVIR tradename from Glaxo-Wellcome Research Triangle, N.C.
27709; abacavir (1592U89) disclosed in W096/30025 and available under the ZIAGEN
trademark from Glaxo-Wellcome Research Triangle, N.C. 27709; adefovir dipivoxil [bis(POM)-PMEA] available under the PREVON tradename from Gilead Sciences, Foster City, Calif. 94404; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533 and under development by Bristol-Myers Squibb, Princeton, N.J. 08543; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH-10619) under development by Biochem Pharma, Laval, Quebec H7 V 4A7, Canada; emitricitabine [(-)-FTC]
licensed from Emory University under Emory Univ. U.S. Pat. No. 5,814,639 and under development by Triangle Pharmaceuticals, Durham, N.C. 27707; beta-L-FD4 (also called beta-L-D4C and named beta-L-2',3'-dicleoxy-5-fluoro-cytidene) licensed by Yale University to Vion Pharmaceuticals, New Haven Conn. 06511; DAPD, the purine nucleoside, (-)-beta-D-2,6,-diamino-purine dioxolane disclosed in EP 0656778 and licensed by Emory University and the University of Georgia to Triangle Pharmaceuticals, Durham, N.C. 27707; and lodenosine (FddA), 9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, an acid stable purine-based reverse transcriptase inhibitor discovered by the NIH and under development by U.S. Bioscience Inc., West Conshohoken, Pa. 19428.
Typical suitable non-nucleoside reverse transcriptase inhibitors ("NNRTI"s) include nevirapine (BI-RG-587) available under the VIRAMUNE tradename from Boehringer Ingelheim, the manufacturer for Roxane Laboratories, Columbus, Ohio 43216;
delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia & Upjohn Co., Bridgewater N.J. 08807; efavirenz (DMP-266) a benzoxazin-2-one disclosed in W094/03440 and available under the SUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, Del. 19880-0723; PNU-142721, a furopyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater N.J.
08807;
AG-1549 (formerly Shionogi #S-1153); 5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-t0 pyridyl)methyl-1 H-imidazol-2-ylmethyl carbonate disclosed in WO 96/10019 and under clinical development by Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(iH,3H)-pyrimidinedione) discovered by Mitsubishi Chemical Co. and under development by Triangle Pharmaceuticals, Durham, N.C. 27707; and (+)-calanolide A (NSC-675451 ) and B, coumarin derivatives disclosed in NIH U.S. Pat. No. 5,489,697 licensed to Med Chem Research, which is co-developing (+) calanolide A with Vita-Invest as an orally administrable product.
Protease inhibitors ("PI") include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g.
CRIXIVAN
(available from Merck) as well as nonpeptide protease inhibitors e.g., VIRACEPT
(available from Agouron).
Typical suitable Pls include, for example, saquinavir (Ro 31-8959) available in hard gel capsules under the INVIRASE tradename and as soft gel capsules under the FORTOVASE tradename from Roche Pharmaceuticals, Nutley, N.J. 07110-1199;
ritonavir (ABT-538) available under the NORVIR tradename from Abbott Laboratories, Abbott Park, III. 60064; indinavir (MK-639) available under the CRIXIVAN
tradename from Merck & Co., Inc., West Point, Pa. 19486-0004; nelfnavir (AG-1343) available under the VIRACEPT tradename from Agouron Pharmaceuticals, Inc., LaJolla Calif.
92037-1020; amprenavir (141 W94), tradename AGENERASE, a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, Mass.

4211 and available from Glaxo-Wellcome, Research Triangle, N.C. under an expanded access program; lasinavir (BMS-234475) available from Bristol-Myers Squibb, Princeton, N.J. 08543 (originally discovered by Novartis, Basel, Switzerland (CGP-61755);
DMP-450, a cyclic urea discovered by Dupont and under development by Triangle Pharmaceuticals; BMS-2322623, an azapeptide under development by Bristol-Myers Squibb, Princeton, N.J. 08543, as a 2nd-generation HIV-1 PI; ABT-378 under development by Abbott, Abbott Park, III. 60064; and AG-1549 an orally active imidazole carbamate discovered by Shionogi (Shionogi #S-1153) and under development by Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020.
Other antiviral agents include, for example, hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607. Hydroyurea (Droxia), a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T-cells, was discovered at the NCI and is under development by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine. IL-2 is disclosed in Ajinomoto EP-0142268, Takeda EP-0176299, and Chiron U.S. Pat. Nos. RE 33,653, 4,530,787, 4,569,790, 4,604,377, 4,748,234, 4,752,585, and 4,949,314, and is available under the PROLEUKIN
(aldesleukin) tradename from Chiron Corp., Emeryville, Calif. 94608-2997 as a lyophilized powder for IV infusion or sc administration upon reconstitution and dilution with water; a dose of about 1 to about 20 million IU/day, sc is preferred; a dose of about 15 million IU/day, sc is more preferred. IL-12 is disclosed in W096/25171 and is available from Roche Pharmaceuticals, Nutley, N.J. 07110-1199 and American Home Products, Madison, N.J. 07940; a dose of about 0.5 microgram/kg/day to about microgram/kg/day, sc is preferred. Pentafuside (DP-178, T-20) a 36-amino acid synthetic peptide, disclosed in U.S. Pat. No. 5,464,933 licensed from Duke University to Trimeris which is developing pentafuside in collaboration with Duke University;
pentafuside acts by inhibiting fusion of HIV-1 to target membranes. Pentafuside (3-100 mg/day) is given as a continuous sc infusion or injection together with efavirenz and 2 PI's to positive patients refractory to a triple combination therapy; use of 100 mg/day is preferred. Yissum Project No. 11607, a synthetic protein based on the HIV-1 Vif protein, is under preclinical development by Yissum Research Development Co., Jerusalem 91042, Israel. Ribavirin, 1-f3-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif; its manufacture and formulation are described in U.S. Pat. No. 4,211,771.
The term "anti-HIV-1 therapy" as used herein means any anti-HIV-1 drug found useful for treating HIV-1 infections in human beings either alone, or as part of multidrug combination therapies, especially the HAART (highly active antiretroviral therapy) triple and quadruple combination therapies; HAART - a combination of protease inhibitors taken with reverse transcriptase inhibitors. Typical suitable known anti-HIV-1 therapies include, but are not limited to multidrug combination therapies such as (i) at least three anti-HIV-1 drugs selected from two NRTIs (non-nucleoside reverse transcriptase inhibitor - an antiviral drug used against HIV; binds directly to reverse transcriptase and prevents RNA conversion to DNA), one PI, a second PI, and one NNRTI (an antiviral drug used against HIV; is incorporated into the DNA of the virus and stops the building process; results in incomplete DNA that cannot create a new virus); and (ii) at least two anti-HIV-1 drugs selected from NNRTIs and Pls. Typical suitable HAART-multidrug combination therapies include:
~ (a) Triple combination therapies such as two NRTIs and one PI; or (b) two NRTIs and one NNRTI; and (c) quadruple combination therapies such as two NRTIs, one PI and a second PI or one NNRTI. In treatment of naive patients, it is preferred to start anti-HIV-1 treatment with the triple combination therapy;
the use of two NRTIs and one PI is prefered unless there is intolerance to Pls. Drug compliance is essential. The CD4+ and HIV-1-RNA plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug, e.g., one PI
or one NNRTI could be added. Typical therapy schemes are described below:

A. Triple Combination Therapies ~ 1. Two NRTIs +one PI
~ 2. Two NRTIs +one NNRTI
B. Quadruple Combination Therapies ~ Two NRTIs+one PI+a second PI or one NNRTI
C. ALTERNATIVES:
~ Two NRTI
~ One NRTI +one PI
~ Two PI's~one NRTI or NNRTI
~ One PI +one NRTI +one NNRTI
~ One PI +one NRTI +one NNRTI + one FI
In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below its usual dosage range.
The dosages of the compounds of the present invention depend upon a variety of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations.
The compounds of the invention may typically be administered at therapeutically effective dosage levels and in a mammal an amount customary for HIV viral load reduction such as those known compounds mentioned above. For example, the compounds may be administered, in single or multiple doses, by oral administration at a dosage level of, for example, 0.01-100 mg/kg/day, such as 0.1-70 mg/kg/day, and in particular 0.5-10 mg/kg/day. Unit dosage forms may contain, for example, 0.1-50 mg of active compound. For intravenous administration, the compounds may be administered, in single or multiple dosages, at a dosage level of, for example, 0.001-50 mg/kg/day, such as 0.001-10 mg/kg/day, and in particular 0.01-1 mg/kg/day. Unit dosage forms may contain, for example, 0.1-10 mg of active compound. A therapeutically effective amount may be an amount sufficient to lower HIV-1 RNA plasma levels.
In carrying out the procedures for the preparation of compounds of the present invention it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented.
For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.
The present invention will now be further described by way of the following non-limiting examples. In applying the disclosure of these examples, it should be kept clearly in mind that other and different embodiments of the methods disclosed according to the present invention will no doubt suggest themselves to those of skill in the relevant art.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
It is to further be understood herein, that if a "class", "range", "group of substances", etc.
is mentioned with respect to a particular characteristic (e.g., temperature, concentration, time and the like) of the present invention, the present invention relates to and explicitly incorporates herein each and every specific member and combination of sub-classes, sub-ranges or sub-groups therein whatsoever. Thus, any specified class, range or group is to be understood as a shorthand way of referring to each and every member of a class, range or group individually as well as each and every possible sub-class, sub-range or sub-group encompassed therein; and similarly with respect to any sub-class, sub-ranges or sub-groups therein. Thus, for example, with respect to the number of carbon atoms, the mention of the range of 1 to 6 carbon atoms is to be understood herein as incorporating each and every individual number of carbon atoms as well as sub-ranges such as, for example, carbon atoms, 3 carbon atoms, 4 to 6 carbon atoms, etc.;
with respect to reaction or extraction time, a time of 1 minute or more is to be understood as specifically incorporating herein each and every individual time, as well as sub-range, above 1 minute, such as for example 1 minute, 3 to 15 minutes, 1 minute to 20 hours, 1 to 3 hours, 16 hours, 3 hours to 20 hours etc.;
etc...
It is in particular to be understood herein that for any group or range, no matter how defined, a reference thereto is a shorthand way of mentioning and including herein each and every individual member described thereby as well as each and every possible class or sub-group or sub-class of members whether such class or sub-class is defined as positively including particular members, as excluding particular members or a combination thereof; for example an exclusionary definition for a formula may read as follows: "provided that when one of A and B is -X and the other is Y, - X may not be Z ".
The entire disclosures of all applications, patents and publications, cited above and below, are hereby incorporated by reference.
EXAMPLE I
Cell line generation General description Biological material is obtained from commercial seed or plant sources, the Jardin de Botanique de Montreal or naturally collected. All culture protocols are based on methods traditionally used for the culture of plant cells. See for example R.A. Dixon Ed:
Plant Cell Culture a practical approach.1995 IRL Press Limited, Oxford.
Thus generally speaking, biological materials (plant material, seeds, etc.) may be sterilized with 5% sodium hypochlorite containing 1 % surfactant (e.g. Triton X-100).
Sterilized materials are placed on typical media solidified with agar (0.8%) or phytagel (0.4%). Medium may consist of the inorganic salts proposed by Gamborg et al.
(1968) Nutrient requirements of suspension cultures of soybean root cells. Exp. Cell Res. 50:
151-158 or Murashige and Skoog (1962) A revised medium for rapid growth and bioassays with tobacco tissue cultures. Physiol. Plant. 15: 473-497, 3%
sucrose and various combinations of plant growth regulators (including 2,4-diphenoxyacetic acid, naphthaleneacetic acid, benzyladenine, kinetin, etc.) to select for suitable cell lines.
Cell lines (and medium) may be selected from these plates based solely on the growth of the resulting calli, generated from the sterilized material, and may be subsequently transferred (every two months) onto the selected medium. Once the cell lines are stabilized (6-8 transfers) they are initiated into liquid cultures using the identical medium as for the solid transfer without the solidifying agent. Once fully established (3 months or more) cell lines are then scaled up by serial transfer (every fourteen days) into larger Erlenmeyer flasks. Cell lines are prepared for biosynthesis of metabolites by culturing into 1 L flasks for use as inocula.
More particularly, a) for Hernandia ovigera 1-lernandia ovigera seeds (Banana Tree Inc.) were washed (2 min) with 70%
EtOH, surface sterilized with 5% sodium hypochlorite containing 1 % Triton X-100 (60 min) and washed three times with sterile water. Sterile seeds were placed on wetted filter paper (Whatman #4) in Petri dishes, sealed with parafilm and placed at room temperature until germination. Seedlings' meristems were cut with a sterile scalpel and place on medium solidified with 0.8% phytagel (Sigma). The medium consisted of the inorganic salts proposed by Gamborg et al. (1968) [Nutrient requirements of suspension cultures of soybean root cells. Exp. Cell Res. 50: 151-158], 3% sucrose, 0.2 mg/L of dichlorophenoxyacetic acid and 0.1 mg/L kinetin. Callus developed on this medium were subsequently transferred unto the identical medium every two months. Once the cell lines were stabilized (6-8 transfers) they were initiated into liquid cultures using the identical medium as above without the solidifying agent. These cell lines are maintained by culture every 2 weeks by transfer of material (30%) into fresh medium. Once fully established (3 months) cell lines are then scaled up by serial transfer (every fourteen days) into larger Erlenmeyer flasks at the identical 30% inocula to medium ratio. Finally, cell lines are prepared for biosynthesis of metabolites of interest by culturing into 1 L
flasks, as above, for use as inocula.
b) for Oreocereus bruennowii Oreocereus bruennowii plants were purchased (Rona Inc.). Leaf material was washed (2 min) with 70% EtOH, surface sterilized (30 min) with 5% sodium hypochlorite containing 1 % Triton X-100 and washed repeatedly (3x) with sterile water.
Plant material was cut with a sterile scalpel and placed on medium solidified with 0.8%
phytagel. Medium consisted The medium consisted of the inorganic salts proposed by Gamborg et al. (1968) [Nutrient requirements of suspension cultures of soybean root cells. Exp. Cell Res. 50: 151-158], 3% sucrose, 1.0 mg/L of dichlorophenoxyacetic acid and 0.1 mg/L kinetin. Established cell cultures were treated identically as above.
Example II
Biosynthesis Compound biosynthesis may be conducted in 4 L sterile glass bioreactors equipped with an impeller, dissolved oxygen probe, inoculating and sampling ports. These bioreactors may be connected to peristaltic pumps for feeding nutrients (inorganic salts, glucose, etc), two mass flow controllers supply and control the dissolved oxygen and carbon dioxide concentrations at 120% and 4%, respectively. Finally the gas exhaust may be connected to a carbon dioxide monitor. All instrumentation may be connected to a real time control system to perform control algorithms and data monitoring.
All components of the bioreactor may be either glass or stainless steel and are steam sterilized. Cultures were inoculated with a suitable volume of a plant cell suspension (as mentioned above) from 1 L flasks (30%) into defined medium to obtain levels of the inorganic salts proposed by Gamborg et al. (1968) [Nutrient requirements of suspension cultures of soybean root cells Exp. Cell Res. 50: 151-158], 3% glucose, and 0.2 mg/L of dichlorophenoxyacetic acid and 0.1 mg/L kinetin. Sampling 0100 mL) is done every 48 h for measurement of biomass concentrations (wet weight and dry weight) and nutrient level determinations (HPLC, Dionex). All off-line and on-line information is collected by an expert control system allowing quality control of the bioprocess. This system also adjusts rate and composition of nutrient feeds to optimize levels present at inoculation.
Once optimal growth is achieved secondary metabolites are induced by elicitation of secondary metabolism. Cells may be elicited with chitin (0.9% v/v), the addition of a concentrated nutrient solution, and absorbent resin (100 g XAD-7, 100 g XAD-16: Rhom & Hass)). The concentrated nutrient solution consisted of inorganic salts based on Murashige and Skoog (1962) A revised medium for rapid growth and bioassays with tobacco tissue cultures. Physiol. Plant. 15: 473-497. Concentrations were adjusted to achieve nutrient levels typical of inoculation, however, glucose levels were adjusted to 5%. All solutions during the production phase were and plant growth regulator and phosphate free.

After 10 days of production, the culture is harvested by filtration to separate the solid phase (cells and resin), which contains the compounds of interest, from the medium.
This material is used for the isolation of active compounds.
Example III
Biochemical Assay A High-Throughput screen for inhibitors of ['251]MIP-1a binding to Chinese hamster ovary (CHO) cell membranes expressing the chemokine CCR5 receptor were performed as described by Strizki et al. (Proc. Natl. Acad. Sci USA 98: 12717-127723).
Briefly, 1 p,g CHO cell membranes over expressing the CCR5 receptor was incubated with 10 p,g of plant cell fractions in 100 p1 reaction mixture containing 50 mM HEPES pH 7.4, 5 mM
MgCl2, 1 mM CaCl2, 0.2% Bovine serum albumin, 2% Dimethylsulfoxide, and about pM ['251]MIP-1a (PerkiElmer). Reactions were carried out for 90 min at room temperature and were terminated by rapid filtration over UnifiIterR-96 GF/C
filter plates (PerkinElmer) pre-soaked in 0.3% Polyethyleneimine and washed four times with 1 ml cold (4 °C) buffer containing 10 mM HEPES pH 7.4, 500 mM NaCI, and 0.1 % Bovine serum albumin. Fifty pL MicroscintT"" 0 (PerkinElmer) was added to dried filter plate wells and radioactivity retained on filters was counted in TopCount NXT HTS
Microplate Scintillation and Luminescence counter (PerkinElmer). Non-specific binding was determined in the presence of 1 p,M SCH-351125. About 110,000 fractions derived from plant cell cultures present in the library were screened and several fractions were obtained that show greater than 50% inhibition of ['251]MIP-1a binding to the receptor. These fractions were further purified and the active compounds were identified.
Finally the structures of these compounds were elucidated.
Example IV
Chemistry General Protocol for Isolation of Active compounds from Plant cell cultures Compounds 1-8 (see table 1 below) were isolated from the extract of Hernandia ovigera plant cell cultures. The active fractions identified by HTS were further purified using preparative HPLC (C-18 Luna, ACE and/or Synergy columns) with water/acetonitrile gradients. Active fractions identified from Oreocereus bruennowii were treated in the same way as Hernandia ovigera to isolate compounds 10-14 (see table 1 below).
Compound 9 (Totarol) is a commercially available plant natural product. It was first isolated from the bark of Podocarpus nagi (Podocarpaceae) as an antimicrobial agent (Kubo I, Muroi H, and Himejima M (1992) J. Nat. Prod. 55, 1436-40). Up until the present invention, no CCR5 activity has been described for compound 9.
Thus more particularly, the solid materials harvested from biosynthesis were all treated in an identical manner. The solid material was extracted five times using acidified methanol (0.1 % v/v acetic acid)). The resulting methanolic extracts are combined, concentrated in vacuo and dried onto C4 stationary phase material (Macherey &
Nagel Polygoprep RP4 300-50 or alike). This C4 material is packed into 50 mm injection columns and then the metabolites are separated using a SEPBOXT"", a two dimension automated preparative chromatography, fractionation and collection system (SEPIAtec GmbH, Berlin, Germany). Standard reverse phase separation methods are used at every level.
Level one separation is achieved using C4 (Merck LiChrospher 100 RP4e, 100A, l5,um or Daisogel SP-120-15-CA-P) as stationary phase (250 X 50 mm column) and a methanol:formate buffer (0.02 M ammonium formate pH 4) gradient from 0 to 100%
methanol (17 min) followed by 100% methanol (10 min), at a flow rate of 109 mUmin.
Eluting compounds are adsorbed onto 18 C4 trap columns (Macherey & Nagel Polygoprep RP4 300-50) strictly based on time fractionation.
In the second level of separation, each trap column is eluted individually and compounds are separated based on polarity using various stationary phases (250 X 25 mm columns) and mobile phase gradients (30 mUmin) consisting of acetonitrile (CH3CN) and 0.02 M
ammonium formate (pH 4). Table 2 summarizes the type of stationary phase and gradients used for separating the compounds from each of the 18 trap columns.
At this level, automated fractionation is based on UV or ELSD (evaporative light scattering detector) signals or time. All fractions are then freed from buffer using solid phase extraction (Merck LiChrolut EN, 40,um) prior to collection.
3s Table 1. Compounds of the present invention.
CCR5 MIP-1 a Binding HIV
Compound Formula No. AVA-No Structure Weight % Inhibition Ki (~.M) IC50 (~,M) @ 10 ~,g/m I

( Id) 1168 ~ ~ 360 96 0.97 -o -2 1170 ~ \ °" 390 28 (new) of 3 1178 \ I \ 374 41 (new) _o i ..>,°,,, °
(o d) 1175 ~ ~ 360 25 OH
OH
new 1176 / 302 38 ( ) I
I
6 1023 \ 286 77 10.8 (old) o d 1177 \ ~ ~ 346 44 ( ) ., _o .:
HO
HO /
8 1180 \ 362 20 (new) ~oH
~o OH

(old) ERCIAL ~ 286 98 w 1185 ~ ~ 270 83 (new) (new) 1186 ~ / ~ 300 80 °

\ a~
12 ~° \ ° /

(new) /
Ho O
y o o a, 13 1188 "° ~ ~ I , ~' 432 44 (new) ~ ~ I - a"

14 N w w (new) 1189 ~ I ~ o ~ 313 28 HO
\ \CH3 O OH
(old) ERCIA
H3C ~CH3 HO
O \ \CHs (old) ERCtA 'o H3C ~CH3 The chemical names of compounds shown in Table 1 are as follows:
Compound No. Name 1 7~i,1 O~i-epoxy-7-hydroxy-12-methoxy-8,12-icetexadiene-11,14-dione 2 19,20-epoxy-8-methyl-2-(1-methylethyl)-1,4-dihydroxy-3,19-dimethoxy-4b,5,6,7,8,8a,9,10-octahydrophenanthren-10-one 3 19,20-epoxy-8-methyl-2-(1-methylethyl)-1,4-dihydroxy-3-methoxy-4b,5,6,7,8,8a,9,10-octahydrophenanthren-10,19-dione 4 10,14-dihydroxy-11,12-methylene ether-8,11,13-icetexatrien-7-one 5 4b,8,8-trimethyl-1-(1-methylethyl)-4b,5,6,7,8,8a,9,10-t 5 octahydrophenanthren-2,5-diol 6 4b,8,8-trimethyl-2-(1-methylethyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-of 7 4b,8,8-trimethyl-2-(1-methylethyl)-1,4-dihydroxy-3-methoxy-4b,5,6,7,8,8a,9,10-octahydrophenanthren-10-one 8 8,8-dimethyl-2-(1-methylethyl)-4b-hydroxymethyl-1,4-hydroxy-3-methoxy-4b,5,6,7,8,8a,9,10-octahydrophenanthren-10-one 9 4b,8,8-trimethyl-1-(1-methylethyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthren-2-of 10 6,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one 11 6,7,8-trihydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one 12 6,7,8-trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one 13 6,7,8-trihydroxy-2-(4-glucopyranosylphenyl)-4H-chromen-4-one 14 (2E)-N[2-(4-hydroxy-2-methoxyphenyl)ethyl]-3-(4-hydroxyphenyl)acrylyamide 5,6-dihydroxy-1,1-dimethyl-7-propan-2-yl-2,3,4,9,10,1 Oa-hexahydrophenanthrene-4a-carboxylic acid 10 16 5,6-dihydroxy-1,1-dimethyl-7-(1-methylethyl)-1,3,4,9,10,1 Oa-hexahydro-4a-(epoxymethano)phenanthren-12-one 15 Table 2. General separation methodology. In all cases solvents were CH3CN
and 0.02 M
ammonium formate buffer.
Trap Stationary Mobile phase compositionMobile phase composition # Phase METHOD A METHOD B

k M

;
erc 2 LiChrospher NA NA

3 RP-Select NA NA
B, 12,um g Cl8e, 120A, NA NA

um , NA NA

10 0 min 24% CH3CN 0 min 24% CH3CN

50 min 41 % CH3CN 80 min 41 % CH3CN

60 min 100% CH3CN 90 min 100% CH3CN

11 0 min 28% CH3CN 0 min 28% CH3CN

50 min 51% CH3CN 80 min 51% CH3CN

60 min 100% CH3CN 90 min 100% CH3CN

13 Merck NA NA

14 LiChrospher 0 min 35% CH3CN 0 min 35% CH3CN

RP18, l2,um 50 min 70% CH3CN 80 min 70% CH3CN

60 min 100% CH3CN. 90 min 100% CH3CN

15 0 min 50% CH3CN 0 min 50% CH3CN

50 min 98% CH3CN 80 min 98% CH3CN

60 min 100% CH3CN 90 min 100% CH3CN
NA = not applicable In the following, the references to Compound nos. [1] to [16] are to be understood as respectively being a reference to a so designated compound numbered as set forth in Table 1 above.
Compound no. [1]:
Purification Initial fractionation (SEPBOXT"") of Hernandia ovigera extract as described led to two sets of fractions with CCR5 binding inhibitory activity. The first active fraction eluted with 100% methanol at 20 minutes (Trap column #14) in level one separation and was eluted between 61 and 67 minutes in level two separation using method B (Table 2).
The second active fraction also eluted with 100% methanol at 21 minutes (Trap column #15) in level one separation and subsequently eluted between 30 and 36 minutes in level two separation using method B (Table 2 above).
Further separations by reverse phase C18 semi-preparative chromatography (150 X
21.1 mm column packed with Phenomenex Luna C18(2), 100A, l0,um) using an acetonitrile:water gradient at a flow rate of 10 mUmin (Gradient A) resulted in CCR5 binding inhibitory fractions that eluted at 16 minutes. Active fractions with similar LC-MS
profiles were pooled and subjected to another reverse phase C18 semi-preparative HPLC purification (150 X 21,1 mm column packed with Phenomenex Luna C18(2), 100A, 10 ,um) at 10 mUmin utilizing an acetonitrile:aqueous trifluoroacetic acid buffer (0.01% TFA v/v): (Gradient B) Compound no. [1] eluted at 31 minutes.
GRADIENT GRADIENT
A B

Time (min)% CH3CN % H20 Time (min) % CH3CN % Aq TFA

Structure determination:
NMR data for compound no. [1]
'H NMR (CDCI3, 500 MHz) 8 0.86 (3H, s, CH3-19), 0.95 (3H, s, CH3-18), 1.15 (1 H, m, H-3a), 1.21 (6H, d, J=7.0 Hz, CH3-16 and 17), 1.59 (1 H, m, H-3~), 1.60 (2H, m, H-1 ), 1.71 (1 H, t, J-- 8.2 Hz, H-5), 1.73 (1 H, m, H-2a), 2.01 (1 H, m, H-2~), 2.04 (1 H, dd, J=12.8, 8.0 Hz, H-6(3), 2.25 (1 H, d, J= 19.5 HZ, H-20a), 2.30 (1 H, dd, J--13.0, 8.5 Hz, H-6a), 2.55 (1 H, d, J--19.5 Hz, H-20~i), 3.23 (1 H, sep, J--7.0, H-15), 3.98 (3H, s, OCH3).
'3C NMR (CDCI3, 500 MHz) S 15.87, 20.64, 20.68, 24.56, 27.32, 29.98, 30.54, 31.37, 32.25, 39.23, 45.96, 51.66, 61.43, 79.60, 101.13, 137.31, 139.16, 142.32, 156.34, 183.81, 189.36.
The NMR data and the molecular weight suggested the structure of compound no.
[1]
this was identical to that described (Uchiyama, N. et al., J. Nat. Prod. 2003, 66, 128-131 ). This compound no. 1 was previously known as showing trympanocidal activity Compound no. [2]:
Purification An extract of Hernandia ovigera prepared as for Compound no. [1] was dried under in vacuo. The resulting material was suspended in water and extracted twice with ethyl acetate. The combined organic fraction was subjected to manual low pressure reverse phase flash chromatography (SiliCycle RP-C18, 60A, 40-63,um) using a gradient-like sequence of discrete mobile phase volumes composed of acetonitrile and water (FLASH 1 ). The fraction eluted at 100% CH3CN was subjected to reverse phase C18 semi-preparative HPLC chromatography purification (150 X 2l,imm column packed with Phenomenex Luna C18(2), 100A, l0,um) utilizing an acetonitrile:aqueous trifluoroacetic acid buffer (0.01 % TFA v/v) at 15 mUmin (Gradient C).
Compound no.
[2] eluted at 55 minutes.

C

CH3CN Vol (mL) Time % CH3CN % TFA

Structure determination:
NMR data for compound no. [2]
'H NMR (CDCI3, 500 MHz) 8 0.97 (3H, s, CH3-18), 1.31-1.41 (2H, m, H-ia, H3a), 1.37 (3H, d, J--4.5 Hz, CH3-16), 1.39 (3H, d, J=4.5 Hz, CH3-17), 1.62 (3H, m, H-3~3 and H-2), 1.87 (1 H, dd, J= 15.2, 2.5 Hz, H-5), 2.67 (1 H, dd, J=16.5, 3.5 Hz, H-6a), 3.29 (3H, s, OCH3), 3.30 (2H, m, H-6~ and H-15), 3.42 (1 H, dd, J=9.5, 3.5 Hz, H-1 a), 3.78 (3H, s, OCH3), 3.93 (1 H, dd, J= 11.5 Hz, H-20a), 4.28 (1 H, s, H-19), 4.36 (1 H, d, J-- 11.5 Hz, H-20~), 5.69 (1 H, s, OH), 13.04 (1 H, s, OH).
'3C NMR (CDC13, 500 MHz) S 20.51, 20.54, 21.93, 23.50, 26.29, 35.00, 36.59, 37.60, 39.03, 39.71, 44.54, 55.05, 59.84, 62.33, 105.60, 113.37, 127.20, 128.50, 140.07, 152.22, 157.93, 205.65.

This NMR was similar to that previously decribed in Uchiyama, N. et al., J.
Nat. Prod., 2003, 66, 128-131. The presence of the ester linkage is consitent with the above data as confimed by comparison with chemical shifts of compounds isolated from Salvia (Esquivel et al. Phytochem. 1997 46: 531-534). The structure of compound no.
[2] was confirmed by 2D NMR (Figure 1 to 3).
Compound no. [3]:
Purification An extract of Hernandia ovigera cell culture was prepared and subjected to low pressure reverse phase chromatography as described for compound 2 (FLASH 1 ). Material eluted with 100 CH3CN was purified (8 runs) over polar end-capped C18 reverse phase preparative HPLC (250 X 25 mm column packed with Phenomenex Synergi Fusion)using acetonitrile:water at mUmin. (GRADIENT D): Fractions eluted at about 64:36 acetonitrile:water were pooled and further purified through reverse phase C18 semi-preparative HPLC (150 X 21,1mm column packed with Phenomenex Luna C18(2), 100A, l0,um) using a methanol:water gradient at 10 mUmin: (GRADIENT E):
Compound no. [3] eluted at 53 minutes.
GRADIENT GRADIENT E
D

Time % CH3CN % H20 Time % MeOH % H20 Structure determination NMR data for compound no. [3]

'H NMR (CDC13, 500 MHz) 8 1.30 (3H, s, CH3-18), 1.38 (3H, d, J=3.0 Hz, CH3-17), 1.39 (3H, d, J--3.0 Hz, CH3-16), 1.47 (1 H, m, H-1 a), 1.64 (2H, m, H-3), 1.93 (2H, m, H-2), 2.20 (1 H, dd, J--13.2, 3.0 Hz, H-5), 2.52 (1 H, t, H-6a), 2.84 (1 H, dd, J=
16.9, 3.2 Hz H-6~), 3.31 (1 H, sep, J=3.0 Hz, H-15), 3.60 (1 H, d, J= 13.5 Hz, H-1 ~), 3.81 (3H, s, OCH3), 4.57 (1 H, dd, J= 12.0 Hz, H-20a), 5.01 (1 H, d, J= 12.0 Hz, H-20(3), 5.79 (1 H, s, OH), 12.95 (1 H, s, OH).
'3C NMR (CDCI3, 500 MHz) 8 20.43, 21.27, 23.27, 26.40, 34.93, 36.91, 40.42, 42.97, 46.54, 62.54, 72.65, 112.29, 126.31, 128.44, 140.28, 152.84, 158.75, 175.43, 202.22.
The chemical shift were similar to compound no. [2], however, the differing molecular weights and chemicals shift suggested the presence of a lactone. This is very similar to compounds isolated from salvia (Esquivel et al. Phytochem. 1997 46: 531-534).
The structure of compound no. [3], was confirmed by 2D NMR (Figure 4 to 6).
Compound no. [4]:
Purification Initial purification of Compound 3 also afforded fractions eluting at about 76:24 acetonitrile: water. These were pooled and further purified through reverse phase C18 semi-preparative HPLC (150 X 21,1mm column packed with Phenomenex Luna C18(2), 100A, l0,um) using a methanol:water gradient (GRADIENT F) at 10 mUmin.
Compound no. [4] eluted at 51 minutes.
GRADIENT
F

Time % MeOH % H20 Structure determination NMR data for compound no. [4]
'H NMR (CDCI3, 500 MHz) 8 0.86 (3H, s, CH3-19), 0.99 (3H, s, CH3-18), 1.13 (1 H, m, H-3a), 1.27 (3H, d, J=7.5 Hz, CH3-17), 1.30 (3H, d, J=6.5 Hz, CH3-16), 1.43 (2H, m, H-3~
and H-5), 1.53-1.57 (2H, m, H-1 a and H-2[i), 1.73 (1 H, d, ,~ 13.5 Hz, H-1 ~), 1.87 (1 H, m, H-2(3), 2.62 (1 H, d, H-6a), 2.74 (1 H, d, J= 14.0 HZ, H-20a), 3.00 (1 H, dd, J=18.0, 9.0 Hz, H-6(3), 3.02 (1 H, d, J--14.0 Hz, H-20a), 3.40 (1 H, sep, J--7.0, H-15), 5.92 (1 H, s, OCH20), 5.94 (1 H, s, OCH20), 13.42 (1 H, s, OH).
'3C NMR (CDC13, 500 MHz) S 18.91, 20.83, 20.96, 21.65, 24.60, 32.27, 34.24, 38.77, 40.28, 40.81, 41.60, 49.80, 49.87, 73.89, 101.03, 112.73, 114.99, 117.34, 139.49, 150.87, 160.85, 208.84.
These NMR spectra suggested an icetaxane. This compound no. [4], was identifed as cyclocoulterone previosly isolated by Uchiyama, N. et al., J. Nat. Prod., 2003, 66, 128-131.
Compound no. [5]:
Purification Initial purification of Compound 3 also afforded fractions eluting at about 70:30 acetonitrile: water. These were pooled and further purified through reverse phase C18 semi-preparative HPLC (150 X 21,1mm column packed with Phenomenex Luna C18(2), 100A, l0,um) using a methanol:water gradient (GRADIENT G) at 10 mUmin:
Compound no. [5] eluted at 33 minutes.

GRADIENT
G

Time % MeOH % H20 m Structure determination NMR data for compound no. [5]
'H NMR (CDCI3, 500 MHz) S 0.92 (6H, s, CH3-18 and CH3-19), 1.23 (3H, s, CH3-20), r S 1.34 (3H, d, J-- 5.0 Hz, CH3-17), 1.35 (3H, d, J= 5.0 Hz, CH3-16), 2.80-2.93 (2H, m, H-7a and H-7[3), 3.30 (1 H, sep, J=7.0 Hz, H-15), 4.64 (1 H, s, OH), 6.51 (1 H, d, J= 9.0 Hz, H-11 ), 7.97 (1 H, d, J= 9.0 Hz, H-14).
'3C NMR (CDCI3, 500 MHz) 8 18.30, 19.45, 20.59, 21.45, 27.48, 28.31, 30.70, 32.90, 33.42, 39.78, 44.02, 49.00, 78.29, 114.35, 115.51, 125.96, 131.01, 143.10, 152.64.
Spectral data suggested as abietane diterpene. Which was identified as a new compound of structure of compound no. [5]; for comparison see old compounds described in Ying, B-P. et al., Phytochemistry, 1991, 30: 1951 and to old compound [9].
Compound no. [6]:
Purification Initial purification of Compound no. . [3] also afforded fractions eluting at about 84:16 acetonitrile: water These were pooled and further purified through reverse phase C18 semi-preparative HPLC (150 X 21,1mm column packed with Phenomenex Luna C18(2), 100A, l0,um) using a methanol:water gradient (GRADIENT H) at 10 mUmin.
Compound no. [6] eluted at 29 minutes.

GRADIENT
H

Time % MeOH % H20 65 95 5 -' Structure determination NMR data for compound no. [6]
'H NMR (CDCI3, 500 MHz) 8 0.93 (3H, s, CH3-19), 0.95 (3H, s, CH3-18), 1.18 (3H, s, CH3-20), 1.24 (3H, d, J= 7.0 Hz, CH3-17), 1.26 (3H, d, J-- 7.0 Hz, CH3-16), 2.78- 2.90 (2H, m, H-7a and H-7~i), 3.13 (1 H, sep, J--7.0 Hz, H-15), 6.64 (1 H, s, H-11 ), 6.85 (1 H, s, H-14).
'3C NMR (CDC13, 500 MHz) 8 19.48, 19.57, 21.88, 22.83, 23.02, 25.07, 27.02, 30.02, 33.58, 33.69, 37.74, 39.09, 41.90, 50.58, 111.22, 126.85, 127.52, 131.65, 148.90, 150.90.
The spectral data was consistent with ferruginol. This old compound no. [6]
has previously been shown to possess potent antimicrobial activity.
Compound no. [7]:
Purification From the purification of Compound no. [6], Compound no. [7] eluted at 27 minutes.
Structure determination NMR data for compound no. [7]
'H NMR (CDCI3, 500 MHz) 8 0.94 (3H, s, CH3-19), 0.96 (3H, s, CH3-18), 1.36 (3H, s, CH3-20), 1.37 (3H, d, J= 6.5 Hz, CH3-17), 1.39 (3H, d, J= 6.5 Hz, CH3-16), 2.64 (2H, m, H-6a and H-6~i), 3.32 (2H, m, H-15 and H-1 Vii), 3.78 (3H, s, OCH3), 5.70 (1 H, s, OH), 13.37 (1 H, s, OH).

'3C NMR (CDC13, 500 MHz) 8 18.12, 19.28, 20.56, 20.61, 21.80, 26.28, 33.37, 33.64, 36.11, 36.66, 40.56, 41.37, 49.87, 62.29, 112.73, 126.34, 136.11, 138.84, 152.42, 158.49, 206.42.
This NMR was identical to that described in Frontana et al., Phytochemistry, 1994, 36:
739.
Compound no. [8]
Purification Initial purification of Compound 3 also afforded fractions eluting at about 72:28 acetonitrile: water. These fractions were pooled and further purified through polar end-capped C18 reverse phase preparative HPLC (250 X 25 mm column packed with Phenomenex Synergi Fusion using a methanol:water gradient (GRADIENT I):
Compound no. [8] eluted at 53 minutes.
GRADIENT
I

Time % MeOH % H20 Structure determination NMR data for compound no. [8]
'H NMR (CDCI3, 500 MHz) S 0.94 (3H, s, CH3-19), 0.98 (3H, s, CH3-18), 1.35 (3H, d, J-6.5 Hz, CH3-17), 1.37 (3H, d, J= 6.5 Hz, CH3-16), 2.61 (1 H, dd, J=14.0, 3.0 Hz, H-6a), 2.79 (1 H, t, J=15.0 Hz, H-6~), 3.38 (2H, m, H-15 and H-1 (i), 3.82 (3H, s, OCH3), 4.04 (1 H, d, J=11.5 Hz, H-20a), 4.34 (1 H, d, J=11.5 Hz, H-20~i), 13.51 (1 H, s, OH).

1~C NMR (CDC13, 500 MHz) S 19.14, 20.62, 20.73, 22.35, 25.84, 32.46, 33.46, 33.68, 35.75, 41.10, 45.83, 50.05, 61.96, 65.26, 113.05, 127.87, 132.35, 140.47, 154.10, 159.19, 205.77.
The spectral data points to a structure as compound no. [8] ; comfirmed by 2D
NMR
spectroscopy (Figure 7 to 9).
Compound no. [9] (Totarol), no. [15] (carnosic acid), and no. [16] (carnasol) Compound nos. [9], [15], and [16] are commercially available plant natural products.
Totarol was first isolated from the bark of Podocarpus nagi (Podocarpaceae) as an antimicrobial agent (Kubo I, Muroi H, and Himejima M (1992) J. Nat. Prod. 55, 1436-40).
Carsosic acid is an anti-oxidant. (Munne-Bosch a tal. 1999 Plant Physiol 121:

1052). Carnosol also shows anti-oxidant activity (Bozan et al., Chemistry of Natural Compounds, 2002, 38, 198-200) and has anti-proliferative properties (Costa-Lotufo,et al., Pharmazie 2004 59 :78-79).
Up until the present invention no CCR5 antagonist activity has been described for compound [9], [15] or [16].
Compound nos. [10 tol4]
Active fractions identified from Oreocereus bruennowii are treated in the same way as Hernandia ovigera above so as to isolate compound nos. [10 to 14].
Compound no. [10]:
Upon general preparative fractionation (SEPBOXT"") of Oreocereus bruennowii methanol plant cell culture extract, active fractions containing a mixture of compound nos. [10], [11], and [14] eluted at about 92% methanol after 17 minutes (Trap column #11) in level one separation and eluted subsequently between 35 and 45 minutes in level two separation using the appropriate 60-minute long method (Table "Z"). These fractions were pooled and subjected to C12 reverse phase preparative HPLC purification (250 X
25 mm column packed with Phenomenex Synergi Max RP) using a methanol:aqueous trifluoroacetic custom method (GRADIENT J) at 10 mUmin to afford compound nos.

[10], [11] and [14]. Compound no. [10] eluted as a broad peak between 38 and minutes, Compound no. [11] eluted between 44 and 50 minutes, and Compound no.
[14] eluted between 26 and 29 minutes GRADIENT
J

Time % MeOH % Aq TFA

Structure determination NMR data for compound no. [10]
' H NMR (CDCI3, 500 MHz) 8 6.60 (1 H, s, H-3), 6.71 (1 H, s, H-5), 7.55 (2H, d, J= 7.5 Hz, H2' and H6'), 7.56 (1 H, s, H-8), 7.97 (2H, d, ,~ 7.5 Hz, H3' and H5').
isC NMR (CDCI3, 500 MHz) 8 93.86, 104.18, 104.67, 126.19, 129.03, 129.55, 131.55, 131.74, 150.97, 153.72, 164.38, 183.02.
The spectral data pointed to the simple flavanoid of structure as for compound no. [10].
This was confirmed by 2D NMR spectroscopy.
Compound [11]
Purification Compound no. [11] was isolated as describe for Compound no. [10].
Structure determination NMR data for compound no. [11]
'H NMR (CDCI3, 500 MHz) 8 3.89 (3H, s, OCH3), 6.58 (1 H, s, H-3), 6.61 (1 H, s, H-5), 7.07 (2H, d, J-- 8.5 Hz, H2' and H6'), 7.92 (2H, d, ,~ 8.5 Hz, H3' and H5') The spectral data pointed to a simple flavanoid with a methoxy substitution and a hydroxyl of structure as for compound no. [11].
Compound no. [12]:
Upon general preparative fractionation (SEPBOXT"") of Oreocereus bruennowii methanol plant cell culture extract, the active fraction containing compound nos. [12]
and [13]
eluted at 86% methanol after 16 minutes (Trap column #10) in level one separation and eluted subsequently between 16 and 18 minutes in level two separation using method A
(Table "Z"). This fraction was further purified through reverse phase C18 semi-preparative HPLC (150 X 21,1mm column packed with Phenomenex Luna C18(2), 100A, l0,um) using a methanol:aqueous trifluoroacetic gradient (GRADIENT K) at ml/min. Compound no. [12] eluted at 26 minutes and Compound no. [13] eluted at minutes.
GRADIENT
K

Time % MeOH % Aq. TFA

Structure determination NMR data for compound no. [12]
'H NMR (CDCI3, 500 MHz) b 6.58 (1 H, s, H-3), 6.59 (1 H, s, H-5), 6.92 (2H, d, J= 8.5 Hz, H2' and H6'), 7.84 (2H, d, ,~ 8.5 Hz, H3' and H5') The spectral data for compound no. [12] was almost identical to that of compound no.
[11] except the lack of the methoxy group.
Compound no. [13]
Compound no. [13] was isolated as described for Compound no. [12].

Structure determination NMR data for compound [13]
'H NMR (CDCI3, 500 MHz) b 3.44-3.99 (6H, m, H-2', 3', 4', 5' and 6'), 5.08 (1 H, d, J-- 7.5 Hz, H-1'), 6.79 (1 H, s, H-3), 7.06 (1 H, s, H-5), 7.56 (2H, d, J-- 7.5 Hz, H2' and H6'), 8.03 (2H, d, J-- 7.5 Hz, H3' and H5') The'H-NMR signals at 3.44-3.99 suggest the presence of a glycoside. The remaining chemical shifts indicated that it was a 4' glycosyl of compound no. [10].
Compound 14:
Purification Compound no. [14] was isolated as described for Compound no. [10].
Structure determination NMR data for compound no. [14]
'H NMR (CDC13, 500 MHz) 8 2.74 (2H, t, J= 6.7 Hz, H-T), 3.48 (2H, t, J= 6.7 Hz, H-8'), 3.81 (3H, s, OCH3), 6.58 (1 H, d, u'= 16.5 Hz, H-7), 6.67 (1 H, d, J-- 7.5 H-5'), 6.72 (1 H, s, H-3'), 6.84 (1 H, d, J=8.0 Hz, H-6'), 7.37 (2H, d, J= 7.0 Hz, H2' and H6'), 7.52 1 H, d, J=
15.5 Hz, H-8), 7.54 (2H, d, J-- 7.0 Hz, H3' and H5').
'3C NMR (CDC13, 500 MHz) b 34.78, 41.28, 48.69, 55.28, 111.74, 115.63, 119.78, 120.69, 127.64, 128.77, 129.63, 132.23, 135.12, 140.47, 146.34, 146.49, 167.43.
The spectral data for compound no. [14] was consistent with an amide with two hydroxyls and a methoxy. 13C and 2D NMR confirmed this structure.
General Structure The present invention further provides compounds of the generic structures which are described below.
From the above examples, it is expected that Compounds of the generic structures which follow, should exhibit CCR5 activity, namely Icetaxanes [17, 20], abietataxanes [18, 19, 19a, 19b], flavanoids [21] and cinnamoyl amides [22].
The compounds of the following generic structures may comprise groups such as hydroxyl, alkoxy, alkyl, halo, haloalkyl, alkylcarbonyloxy, etc., as well as (aliphatic, cyclic, aromatic or basic) amino acid residues. In accordance with the present invention, an alkyl group or moiety may be straight or branched and may itself be unsubstitiuted or substituted by a substituent group. Thus, for example a compound of a generic formula which follows may comprise an aminoalkylcarbonyloxy group. The alkyl moiety of an aminoalkylcarbonyloxy group may be straight or branched (e.g. be an isopropyl group) and may itself be unsubstituted or substituted; if substituted an alkyl moiety may, for example, be substituted by one or more amino groups. Thus an aminoalkylcarbonyloxy group may for example be amino-(C1_3alkyl)-COO-, and in particular an amino acid residue of formula N(R4)(R5)-(C1-C3-alkyl)carbonyl wherein R4 and R5 may for example be independently selected from the group consisting of -H, C,-C3-alkyl, C1-C$-alkylcarbonyl, etc.; more particularly an alpha amino acid residue of formula R-CH(NH2)COO-wherein R may be a substituent group of any (known) essential or alpha amino acid and may have the example values as set forth below:

COMMON a-AMINO ACIDS, R-CH(NH2)C02H
ISOELECTRIC

NAME (ABBREVIATION) R POINT (pI) glycine (gly) H- 5.97 alanine (ala ) 6.02 valine (val) (CH3)2CH- 5.97 leucine (leu) (CH3)QCHCHZ- 5.98 isoleucine (ile, ileu)CH3CH2CH(CH3)- 6.02 H

prolinea (pro) N 6.10 COzH

H
%

N

hydroxyproline~ (hypro)Cp2H 5.78 HO

phenylalanine (phe) CsHsCH2- 5.88 tryptophan (try) 5.88 N
H

methionine (met) CH3SCHzCHz- 5.75 aspartic acid (asp) H02CCH2- 2.87 asparagine (asp(NH2) HzlVC(O)CHZ 5.41 or asn) glutamic acid (glu) HOZCCHZCH2- 3:22 glutamine (glu(NHZ) HzNC(O)CH2CHz 5.65 or gln) lysine (lys) HZNCHzCH2CH2CH2- 9.74 HN

\

arginine (arg) C-NH-CH2CH2CH2- 10.76 N

histidine (his) C~ 7.58 ~

N

H

serine (ser) HOCH2 5.68 threonine (thr) CH3CH(OH)- 5.08 ' /
\

tyrosine (tyr) HO 5.65 cysteine (cySH) HSCHZ- 5.02 cystine (cyS-Scy) -CHZS-SCH2- 5.06 The present invention further includes esters compounds which may operate as prodrugs, hydrolyzing under normal physiological conditions to provide therapeutically active compounds.

Thus the present invention relates to the following compounds, namely:
a compound of formula 17 E

where R1 and Rya together represent O or alternatively Rya is H and R1 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C~_3alkyl-O-, e.g. CH3-O-), halogen (e.g. F, CI, or Br,) haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e. halo-C1_3alkyl, (e.g.
fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example alkylcarbonyloxy having from 1 to 3 carbon atoms C1_3alkyl-COO-, (e.g. Acetyl0-);
where R2 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C,_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e. halo-C,_3alkyl, (e.g. fluro-C1_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C,_3alkyl-COO-, (e.g. Acetyl0-);
where R3 and R3a together represent O or alternatively R3a is H and R3 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. Ci_3alkyl-O-, e.g. CH3-O-), halogen (e.g. F, CI, or Br,) haloalkyl R. Ria r, such as for example halo-C~_3alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C,_3alkyl-COO-, (e.g. -OAcetyl);
where R~, is selected from the group consisting of -OH, alkoxy such as for example example alkoxy having from 1 to 3 carbon atoms ((i.e. C,_3alk-O-,( e.g. OCH3), halogen (e.g. F, CI, or Br,) haloalkyl such as for example halo-C,_3alkyl, (e.g. fluro-Ci_3alkyl, e.g.
-CF3), alkylcarbonyloxy such as for example C,_3alkyl-COO-, (e.g. Acetyl0-);
a compound of formula 18 Rs CH3 R, I -R$
~~CHg R8a Rsa 1 Rs where R5 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C,_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e. halo-Ci_3alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example -C,_3alkyl-COO-, (e.g. Acetyl0-);
where R6 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C,_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e. halo-C1_3alkyl, (e.g. fluro-Ci_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. Acetyl0-);
where R, is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. Ci_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e. halo-Ci_3alkyl, (e.g. fluro-C1_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example -C1_3alkyl-COO-, (e.g. Acetyl0-);
where R$ and Rsa together represent O or alternatively Rsa is H and R$ is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g. F, CI, or Br,) haloalkyl such as for example halo-C1_3alkyl, (e.g. fluro-C1_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example Ci_3alkyl-COO-, (e.g. -OAcetyl);
where R9 and R9a together represent O or alternatively R9a is H and R9 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g. F, CI, or Br,) haloalkyl such as for example halo-Ci_3alkyl, (e.g. fluro-C1_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. -OAcetyl).
compounds of formula 19, 19a and 19b R,~ R1s R14 R12 ~ R14 R15 ~~ \R15 I R1s i Rl6a H~C CHs 19 19a R12 ~ R14 w Ris CH3 Risa 19b 5 where Rio is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e. halo-Cl.3alkyl, (e.g. fluro-Cl.3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example Ci_3alkyl-COO-, (e.g. Acetyl0-);
where R11 is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C1_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C1_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloaikyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C1_ 3alkyl, (e.g. fluro-C1_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example Ci_3alkyl-COO-, (e.g. Acetyl0-), carboxyl and carboxylalkyl such as for example carboxylalkyl having from 1 to 3 carbon atoms in the alkyl moitie i.e. HCOO-Ci_3alkyl;
where R12 is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C1_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C1_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-Ci_ 3alkyl, (e.g. fluro-C1_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example Cl.3alkyl-COO-, (e.g. Acetyl0-);

where R,3 is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C,_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C,_ 3alkyl, (e.g. fluro-Ci_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. Acetyl0-);
where R~4 is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C,.3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C1_3alkyl, (e.g. fluro-C~_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C,_ 3alkyl-COO-, (e.g. Acetyl0-);
where R,5 is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C~_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C,_ 3alkyl, (e.g. fluro-Ci_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. Acetyl0-);
where R,6 and R,sa together represent O or R,6 and R,sa each represents H, or alternatively R,sa is H and R16 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C~_3alkyl-O-, e.g. CH3-O-), halogen (e.g. F, CI, or Br,) haloalkyl such as for example halo-C,_3alkyl, (e.g. fluro-C,_ 3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C,_3alkyl-COO-, (e.g.
-OAcetyl), or alternatively one of R,6 and R,sa represents H and the other together with R11 defines a bridging group of formula -COO- extending between the carbon atoms to which they are respective attached;

a compound of formula 20 RiR R...
R2o ~zza where R" is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C,_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C~_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C~_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C1_ 3alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C,_3alkyl-COO-, (e.g. Acetyl0-);
where R,$ and Ri9 are the same or different and each is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g. F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e. C,_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C1_3alkyl, (e.g.
hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e. halo-C,_3alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. Acetyl0-); or alternatively R,$ and R~9 together define a bridging group of formula -OCH20-so as to form, with the carbon atom to which they are respective attached, a 5 member heterocyclic ring;
where R2o is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C,.3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-Ci_ 3alkyl, (e.g. fluro-C~_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. Acetyl0-);
where R2, is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C~_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C,_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C,_ 3alkyl, (e.g. fluro-C1_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C,_3alkyl-COO-, (e.g. Acetyl0-);
where R22 and R22a together represent O or R22 and R22a each represents H, or alternatively R,sa is H and R,s is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C~_3alkyl-O-, e.g. CH3-O-), halogen (e.g. F, CI, or Br,) haloalkyl such as for example halo-C1_3alkyl, (e.g. fluro-C~_ 3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C,_3alkyl-COO-, (e.g.
-OAcetyl).

a compound of formula 21 O
where R23 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C,_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C1_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C,_ 3alkyl, (e.g. fluro-Ci_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. Acetyl0-);
where R24 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C,-salkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C1_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C~_ 3alkyl, (e.g. fluro-C1_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C,_~alkyl-COO-, (e.g. Acetyl0-);
where R25 is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C,_3alkyl-O-, e.g. CH3-O-), halogen (e.g.

F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C,_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,.3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C~_ alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C~_3alkyl-COO-, (e.g. Acetyl0-);
where R26 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
Ci_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-Cl.3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C,_ 3alkyl, (e.g. fluro-Ci_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. Acetyl0-); an oxygen linked carbohydrate residue, namely a carbohydrate residue linked via an oxygen of an hydroxyl group of the carbohydrate to the phenyl group (e.g. a monosaccharide residue, a disaccharide residue, a trisaccharide residue or other glycoside residue which yields a sugar substance on hydrolysis, e.g. a O-linked residue of glucose, fructose, lactose, mannose, galactose, etc. which on hydrolysis yields glucose, fructose, lactose, etc..) a compound of formula 22 \ Rso NH
\ ~/ ~/ ~/ ~ R3i O
R2, ~ _ R29 R2s where R2, is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. Cl.3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C~_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C~_ 3alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C~_3alkyl-COO-, (e.g. Acetyl0-);
where R28 is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. Ci_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C1_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C,_ 3alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. Acetyl0-);
where R29 is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C~_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C1_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C,_ 3alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C1_3alkyl-COO-, (e.g. Acetyl0-);
where R3o is selected from the group consisting of -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C,.3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C1_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C,_ 3alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example Ci_3alkyl-COO-, (e.g. Acetyl0-);
where R31 is selected from the group consisting of H, -OH, alkoxy such as for example alkoxy having from 1 to 3 carbon atoms ((i.e. C1_3alkyl-O-, e.g. CH3-O-), halogen (e.g.
F, CI, or Br,) alkyl such as for example alkyl having from 1 to 3 carbon atoms i.e.
C,_3alkyl, hydroxyalkyl such as for example hydroxyalkyl having from 1 to 3 carbon atoms i.e. HO-C,_3alkyl, (e.g. hydroxyl-CH2-, 2-hydroxy-ethyl, 1-hydroxy-ethyl, etc.), haloalkyl such as for example haloalkyl having from 1 to 3 carbon atoms i.e.
halo-C1_ 3alkyl, (e.g. fluro-C,_3alkyl, e.g. -CF3), alkylcarbonyloxy such as for example C,_3alkyl-COO-, (e.g. Acetyl0-);
Compounds of the above generic formulae may, for example, be obtained starting from the compounds set forth in table 1 above, i.e. the compounds of table 1 may be used as intermediate compounds for the preparation of other compound of the generic structures by appropriate oxidation of alcohol to carbonyl, reduction of carbonyl to alcohol, alkylation of , esterification etc..
Thus the synthesis of compounds derived from those in Table 1 may be achieved in a variety of ways. Compounds in Table 1 may be used directly for synthesis on reactive sites of each of the molecules. For example hydroxyls may undergo a wide variety of well-known reactions involving oxidation, reduction, substitution as well as many reaction types to afford a variety of compounds. Similar compound available from other sources may act as starting materials for derivatives.

Pharmaceutical compositions of the present invention may, as mentioned, comprise any of the compounds (including salts, prodrugs, etc.) of the present invention, along with any pharmaceutically acceptable carrier, adjuvant or vehicle.
The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable adjuvant" and "physiologically acceptable vehicle" refer to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethyleneglycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of this invention may as mentioned be administered orally, parenterally by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. It is therefore understood herein that oral administration or administration by injection are encompassed by the present invention. For example, compounds of the present invention, may, for example, be orally administered in an aqueous solution. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are amino acid, water, Ringer's solution and isotonic sodium chloride solution.
The pharmaceutical compositions of this invention may, for example, be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspension and solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Claims (3)

1. Compounds (including salts, prodrugs, etc.) as described in the above disclosure.
2. Pharmaceutical compositions comprising a compound (including salts, prodrugs, etc.) as described in the above disclosure and a pharmaceutically acceptable carrier.
3. The use of a compound (including salts, prodrugs, etc.) as described in the above disclosure for the treatement of AIDS.
CA002522632A 2005-10-06 2005-10-06 Ccr5 receptor antagonist molecules Abandoned CA2522632A1 (en)

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