NL2009671C2 - New antiviral use for acidic cannabinoids. - Google Patents

New antiviral use for acidic cannabinoids. Download PDF

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NL2009671C2
NL2009671C2 NL2009671A NL2009671A NL2009671C2 NL 2009671 C2 NL2009671 C2 NL 2009671C2 NL 2009671 A NL2009671 A NL 2009671A NL 2009671 A NL2009671 A NL 2009671A NL 2009671 C2 NL2009671 C2 NL 2009671C2
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acid
cannabis
plant extract
thc
treatment
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Henricus Adriaan Anna Jacobus Korthout
Cornelius Adrianus Maria Broers
Sandra Bergen
Frederik Pius Horssen
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Fytagoras B V
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/045Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05Phenols
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/192Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/3533,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/20Antivirals for DNA viruses
    • A61P31/22Antivirals for DNA viruses for herpes viruses

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Description

Title: New antiviral use for acidic cannabinoids
The invention
The invention relates to the field of medicine, more particularly the field of infection. In particular, the invention relates to therapy of viral infection, more particularly to reducing the effects of viral infection, especially of herpes viruses, more particularly of Epstein-Barr virus or sarcoma-associated herpesvirus, by administering medicinal 5 acidic cannabinoids.
BACKGROUND
A9-Tetrahydrocannabinol (THC) is naturally found in cannabis. THC has been reported to have use as an analgesic, for instance for patients suffering from 10 rheumatoid arthritis. A side effect of THC is its psychoactive activity. Further, conventionally THC is administered by smoking, which may be detrimental to general health, in particular to the lungs and the coronary system.
WO 89/01332 describes an acidic metabolite of THC, wherein the methyl group at the 9-position, a major metabolite formed in humans and other mammals, is substituted 15 by a carboxyl group. This metabolite is reported to be non-psychoactive. Its use as a therapeutic agent for such purposes as the treatment of chronic pain and tissue inflammation often associated with illnesses such as rheumatoid arthritis is suggested. The Examples show a mouse hot plate test for analgesia, which indicates that, in mice, the metabolite shows about the same analgesic activity as THC and a 20 somewhat lower activity than naproxen. The Examples further indicate that the metabolite does not induce the formation of gastric lesions in an animal test under conditions wherein aspirin does.
In a review by Bhargava (Gen. Pharmac. Vol 9 (1978), No 4, pages 195-213), potential uses of cannabinoids are mentioned in rather general terms. Bhargava mentions that 25 several cannabinoids have been pharmacologically tested, without disclosing in any detail, a specific medical activity for carboxylated cannabinoids (THC acids), such as A9-tetrahydrocannabinolic acid or the like. In addition, reference is made to the analgesic activity of THC and several other cannabinoids compared to morphine. THC
2 is reported to perform equi-analgesic with morphine, but other tested cannabinoids are reported to be much less potent or even inactive.
Williamson and Evans (Drugs 2000, Dec. 60(6):1303-1314 discuss in general terms a potential clinical use of cannabis. The specific use of THC acids, such as Δ9-5 tetrahydrocannabinolic acid or the like, as the active pharmaceutical ingredient, is not disclosed.
GB-A 2 384 707 relates to the use of a cannobinoid acid, in particular cannabidiol (CBD) and cannabidiol acid (CBDA) for use as an active pharmaceutical substance in the treatment of nausea, vomiting, emesis and motion sickness. The compounds may 10 be obtained by extraction from cannabis. As a result of the extraction, relatively small amounts of THC-acids may be present in the extract, but the use of a THC-acid as an active pharmaceutical substance is not mentioned.
WO 2005/072719 describes medical uses of novel acidic cannabinoids obtained from plants for relieving pain, for suppression of an inflammatory response, preferably for 15 suppressing release of a pro-inflammatory cytokine (such as TNF-α), and/or stimulating the release of an anti-inflammatory cytokine (such as IL-10).
Appendino et al. (J. Nat. prod. 2008, 71:1427-1430) describe the antibacterial effect of cannabinoids, amongst which also acidic cannabinoids such as THC-acid, cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), which proved effective in 20 particular against Staphylococcus aureus (MRSA).
There remains a continuing desire for further alternative therapeutic applications of cannabinoids. It is therefore an object of the invention to provide such a further therapeutic application.
25
SUMMARY OF THE INVENTION
The present inventors now have discovered that acidic cannabinoids are useful in 30 antiviral therapy, especially in therapy against infection of herpesviruses, more particularly in infection with Epstein-Barr virus (EBV) or other oncogenic herpesviruses such as sarcoma-associated herpesvirus (KSHV). Preferably, said acidic cannabinoid is selected from the group consisting of Δ9-tetrahydrocan na 1)inolic acid or 3 THC acid (THCA), cannabidiolic acid (CBD-A), cannabidiol (CBD), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabinolic acid (CBN-A) and cannabinol (CBN), cannabichromenic acid (CBC-A) and cannabichromene (CBC), more preferably said compound is Δη-te tra hydrocan nabi nolic acid (THCA).
5 Further comprised in the invention is a method of treating an animal subject with an acidic cannabinoid as defined above or a plant extract comprising such an acidic cannabinoid, which treatment comprises administering the acid cannabinoid in acidic form, for therapy in viral infection. Preferably, in such a method the animal subject is chosen from the group consisting of a human, a cow, a sheep, a pig, a horse, a fish and 10 a culture of other animals (shrimps, lobster, bivalves).
Further comprised in the invention is a pharmaceutical composition comprising an acidic cannabinoid as defined above or a plant extract as defined above and a further antiviral agent. Preferably said pharmaceutical composition comprises an acidic cannabinoid or a plant extract.
15
LEGENDS TO THE FIGURES
Figure 1. Effect of different concentrations of THC-acid on infection of Akata 20 Burkitt’s lymphoma cells with Epstein-Barr virus.
DETAILED DESCRIPTION OF THE INVENTION 25 Within the context of the invention, the term “acidic” is used to describe a compound having a carboxyl group, unless specified otherwise. In general, an acidic precursor of THC is transformable into THC by decarboxylation, optionally in combination with one or more other reactions, such as a cyclisation of a precursor having two of the rings forming the core of the THC to form the third ring, 30 (de)alkylation, (de)hydroxylation and the like. Besides the compounds of formula la and of lb, examples of acidic THC precursors are cannabidiolic acid (CBDA), cannabichromenic acid (CBCA), cannabinorolic acid (CBNRA), cannabigerolic acid (CBGA), cannabinolic acid (CBNA) and functional and structural analogues 4 thereof. It is known from e.g. WO 2005/072719 that a compound according to the invention is only lowly psychoactive or even non-psychoactive. Besides, it is expected that the risk for gastro-intestinal damage as a result of using a compound according to the invention is low, and in particular less than for at least some 5 commercially very successful drugs, e.g. aspirin.
More in particular, the present invention relates to an acidic cannabinoid represented by formula la, lb or Ic R
X
A
Formula la 10
R
A
X
XX
D HO Z
A
Formula lb 15 5
R
Λ.
*h JL
H [ [
A
Formula Ic for use in antiviral therapy.
In these formulae X, Z and A each represent a different group selected from the 5 groups -OH, hydrogen and a first alkyl; accordingly, each of these four groups are present in the compound. The first alkyl is preferably a C1-C10 linear or branched alkyl, more preferably a C4-C7 linear or branched alkyl, even more preferably n-pentyl. The first alkyl is preferably Z.
D represents -OH or alkyl, preferably a C1-C3 linear or branched alkyl, in 10 particular a methyl.
R represents a hydrogen, a CJHRn-OH, a CiJRn-COOH or a second alkyl; The n in these groups is an integer, preferably 0, 1 or 2. R is preferably a C1-C3 linear or branched alkyl, more preferably -CH3.
Preferably, the acidic cannobinoid of the present invention is Δ9-15 tetrahydrocannabinolic acid , THC acid (THCA), i.e. the structure of formula la, in which X is OH, D and R are methyl, A is hydrogen, and Z is n-pentyl, or cannabidiolic acid, CBD acid (CBDA), i.e, the structure of formula Ic, in which X is OH, R is methyl, A is hydrogen and Z is n-pentyl.
20 In principle, it is possible to synthesise a compound according to the invention (bio)chemically. The skilled person will know how to perform such synthesis based upon common general knowledge and the present disclosure.
It is however an advantage of the invention that an acidic cannabinoid - in particular a compound wherein the first alkyl at the aromatic ring is n-pentyl (such 25 as Z in formula la, lb or Ic, or in the equivalent position in an acidic precursor of 6 THC in general) - may be derived from a natural source, such as cannabis. An acidic cannabinoid can be used (for antiviral treatment) directly without further chemical modifications, such as decarboxylising the compound into THC and subsequently metabolising the THC.
5 A compound according to the invention may be used in isolated form or in an extract from a natural source, in particular from flower tops of cannabis. Particular suitable is a plant or a part thereof, comprising at least 5 wt. % of acidic cannabinoids, e.g. 5-15 wt. %. Very good results have been achieved with Cannabis sativa or Cannabis indica. . Suitable methods to extract an acidic compound 10 according to the invention are known in the art and include liquid extraction, e.g. with an apolar phase, such as chloroform and a polar phase, in particular an aliphatic alcohol, such as methanol or ethanol. In such an extraction the acidic cannabinoid typically is found in the apolar phase, especially if the extraction procedure is carried out at pH lower than 7. The skilled person will know how to 15 carry out a suitable extraction and further process the acidic cannabinoid, based on common general knowledge and the information disclosed herein. It has been found that an extract according to the invention, comprising an acidic cannabinoid is effective in antiviral therapy.
20 Infection with viruses is common for all kinds of animals, from human beings down to unicellular animals and even prokaryotes suffer from viral attacks (so-called bacterial phages). Viral infection typically starts with introduction of the virus into a cell of the infected animal, after which the viral genetic information directly or indirectly will be replicated in the cell using the replication machinery of the host.
25 After replication the virus particles are, still inside the cell, assembled and the cell will disintegrate and release the assembled viral particles, which will then be capable of infecting new cells. Any disturbance of this ‘life cycle’ will cause a therapeutic effect in that the rate of replication of and re-infection by the viruses will be decreased or even stopped.
30 Oncogenic herpesviruses such as Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) and EBV are viruses that have been widely distributed in the human population and have a major impact as a tumor virus.
7 EBV is a human gammaherpesvirus (large enveloped DNA virus) that is carried by over 90% of the adult population worldwide. EBV infects B lymphocytes and epithelial cells; the virus persists for life in all infected individuals, residing in latently infected B cells. During latency, a limited set of EBV genes is expressed 5 and no viral progeny is produced; however, the viral genome is maintained and replicates with the dividing B cells. Productive or lytic EBV infection serves to generate virus for infection of new hosts or host cells and involves cellular expression of over 80 viral proteins.
Primary infection with EBV occurs mostly asymptomatically, but causes infectious 10 mononucleosis in up to 50% of cases especially during adolescence or adulthood.
Moreover, EBV is associated with a wide range of malignancies, including Burkitt’s lymphoma (BE), nasopharyngeal carcinoma (NPC), Hodgkin’s lymphoma (HL), gastric carcinoma (GC), and - in the immunosuppressed - post-transplant lymphoproliferative disease.
15 EBV is present in 100% of NPC and BL. Endemic BL is the most common cancer of childhood in equatorial Africa and malaria and HIV infections are predisposing factors. In Europe and the US, the incidence of HL shows a young adult peak and then plateaus through later life. For HL, EBV association ranges from 40-90% depending on the subtype. GC is the second most common malignancy of the 20 gastrointestinal tract and remains one of the leading causes of cancer-related deaths worldwide. EBV is considered to be an etiological factor in about 10% of conventional GC and this percentage increases to 30% in relapsing cases. Several other malignancies demonstrate association with EBV, including T-cell and NK-lymphomas and certain types of smooth muscle cell tumors. Additionally, EBV 25 causes lymphoproliferative disorders in immunocompromised patients, such as transplant recipients and HIV patients. The incidence of EBV-associated malignancies in transplant recipients ranges from 1-5% for renal and liver transplants to 5-20% for heart-lung and small bowel transplants. Oral hairy leukoplakia, a wart-like lesion on the lateral borders of the tongue, is an early 30 clinical sign of failing immune control over EBV infection. This disease was first observed in AIDS-patients, but also occurs in transplant settings and occasionally in otherwise healthy individuals.
8
In conclusion, EBV is associated with a broad range of malignancies. A vaccine is not expected to become available in the near future; therefore, compounds with potential activity against EBV, preventing primary infection, establishment of latency, replication and/or oncogenic transformation, deserve ample attention.
5 A further oncogenic virus is human papillomavirus (HPV), which is a member of the paillomaviruses. These viruses replicate on keratinocytes, especially squamous epithelium and are responsible for provoking warts, but also epithelial carcinomas. The latter effect is established through the E6 and E7 proteins of the virus that are capable of modulating the tumor suppressor p53 protein. Papillomavirus induced 10 tumors are especially related to the urogenital tract, where cervix carcinoma is one of the major diseases caused by this virus, but also epithelia of the oropharynx, leading to head and neck squamous epithelial cancers are frequently affected.
As is shown in the examples, it has been established that the acidic cannabinoids of 15 the invention are able to decrease the viral infection rate and/or the occurrence of oncogenesis from viral sources. It has especially been shown that viral replication is inhibited. It is believed that this is a general phenomenon, which is not limited to viral replication, but also plays a role in replication of other organisms, such as bacteria, fungi or parasites that need a host for their replication. In this respect, it 20 is believed that treatment with an acidic cannabinoid is able to prevent such a bacterial infection, such as Mycobacterium tuberculosis infection.
For this purpose, the acidic cannabinoid of the invention can be provided as an isolated compound, or in an extract from a natural source.
25
The preparation of an extract in accordance with the invention is generally carried out under essentially non-decarboxylising conditions to avoid an excessive formation of THC, which may be undesired for its psycho-active side effects and/or for legal reasons, THC at present being illicit in many states. In practice, it is 30 therefore preferred to perform the extraction at a temperature not exceeding 95 °C, more preferably at a temperature of less then about 50 °C, even more preferably of less than about 25 °C. Very good results have been achieved with extraction at a 9 temperature not exceeding about 4 °C. The lower limit for the temperature is not particularly critical, as long as the extraction medium remains fluid.
The extract may then be further processed in any way, without excessive exposure to heat to maintain essentially non-decarboxylising conditions and thus avoid 5 excessive formation of THC. In particular such conditions are met if the extract is not excessively exposed to temperatures of about 200 °C or more. Preferably the extract is processed at a temperature not exceeding about 50 °C. More preferably any further processing of the extract takes place at a temperature of about 25 °C or less. Accordingly, the solvent of the extract is preferably removed by lyophilisation. 10 In practice, conditions are considered to be essentially non-decarboxylising heat treatment is considered to be non-excessive when the amount of THC as a percentage of the total dry weight of the extract is less than 5 wt. %, preferably less than 2 wt. %, even more preferably less than 0.5 wt. %. For practical reasons the amount of THC is preferably less than the maximum allowable amount to allow 15 use as a non-prescription medicament, as determined by law. In this respect it is interesting to note that the present invention allows for the preparation of extracts with less than about 0.15 wt. % as a percentage of the dry weight without a need for selective removal of THC from the extract.
THC may be totally absent (i.e. non-determinable by a conventional analytical 20 technique) in an extract or other composition according to the invention. For practical reasons some THC may be present, such as about 0.01 wt. % as a percentage of the dry weight or more.
Good results with respect to its pharmaceutical properties and low side effects have been achieved with an extract or other composition according to the invention 25 wherein the amount of THC as a weight percentage of the amount of the at least one acidic cannabinoid is 0- 2 wt. %, preferably less than about 1 wt. %. As indicated above, THC may be absent, although some THC may be present; as such, for practical reasons a preferred lower limit for the amount of THC as a weight percentage of the amount of the at least one acidic cannabinoid is about 0.01 wt. %, 30 more in particular about 0.1 wt. %.
Good results have inter alia been achieved with an extract - in particular a cannabis extract - comprising at least about 10 mg/ g based upon the dry weight, preferably at least about 15 mg/g based upon the dry weight, of the acidic 10 cannabinoid. Very good results have been achieved with an extract comprising at least about 20 mg/g based upon the dry weight of the acidic cannabinoid. The upper limit is not particularly critical. For practical reasons the upper limit is preferably about 500 mg/g, more preferably 250 mg/g dry weight.
5 Preferably, a composition according to the invention, such as a (cannabis) extract, comprises at least one compound selected from the group consisting of Δ9-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBD-A), cannabidiol (CBD), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabinolic acid (CBN-A) and cannabinol (CBN), cannabichromenic acid(CBC-A) and cannabichromene 10 (CBC). The amount of the compounds of this group may be chosen within wide limits. Good results have inter alia been achieved with a composition, in particular an extract, wherein the total amount is in the range of about 0.01-200 %, more in particular about 1-100 wt. % based upon the amount of the at least one acidic cannabinoid. In particular in this range indications exist that synergy occurs.
15 An extract according to the invention may be employed in any form. It may for instance very suitably be in a dry form or in a liquid form, in particular solubilised in ethanol, water, a vegetable oil or a liquid comprising any of these compounds alone or in a combination. Particularly combinations of the compound(s) or extract of the invention with medicinal herbs and/or pharmaceutical compounds are 20 envisaged.
An extract may very suitably be present in the form of a paste, cream or ointment. Such form is in particular attractive for topical applications, e.g. for treating a dermal inflammation.
An acidic compound or extract according to the invention may very suitably be 25 present in a pharmaceutical preparation, further comprising a pharmaceutically acceptable carrier. A preparation may for instance have the form of a tincture, an ointment, a spray, an inhalant, a powder, a granulate, a suppository, a tablet or a capsule.
Of particular interest is administration as a liquid preparation for oral use or 30 dermal application as a cream or ointment. Applications via the nasal or inhalatory route are in particular attractive for purified acids.
11
The skilled person will know how to determine a particular dosage regime, depending upon the medical indication, the condition of the subject and the type of administration.
The acidic cannabonoid is preferably administered in acidic form. This means in 5 particular that the cannabinoid is administered under essentially non- decarboxylising conditions, in contrast to conventional ways of administering cannabinoids, i.e. by smoking (heating and inhaling) dried flower tops of cannabis plants. Besides avoiding the psycho-active side-effects (as a result of the formation of THC during heating), the present form of administration does not impose any 10 health risks normally associated with smoking. Suitable forms of administration include oral administration (such as ingestion or inhalation) and any other conventional medical ways of administering a medicament. In case of a combination of the cannabinoids of the present invention with herbs, these herbs can be administered in the same way.
15 Accordingly, the invention further relates to the use of an acidic cannabinoid, optionally in the form of an extract or a pharmaceutical preparation as described herein, in the manufacture of a medicament for treating viral infection in a subject. With respect to the present invention, the subject is an animal, preferably a human, a mammalian animal (preferably a farm animal or a pet), a vertebrate, 20 such as fish, or an insect.
Further, the compounds and extracts of the present invention are useful as addition to known therapies, either therapies directed to treat viral infection or to ameliorate the conditions that are caused by the viral infection, such as Hodgkin’s 25 lymphoma, Burkitt’s lymphoma, cervix carcinoma and the like..
A main beneficial effect of a combination of the compounds and extracts of the invention with existing therapies, is that the acidic cannabinoids of the invention also have been proven to have antibacterial (see e.g. Appendino G. et al., 2008, J. Nat. Prod. 71:1427-1430) and anti-inflammatory effects (see e.g. WO 2005/072719) 30 and to have a general use in increasing the natural resistance of an animal (see PCT/NL2012/050241).
Also part of the invention is a combined pharmaceutical preparation comprising an antiviral drug and an acidic cannabinoid according to the present invention.
12
An antiviral agent can be chosen from the group of abacavir, acyclovir, adefovir, amantidine (Symmetrel®), amdoxovir, amprenavir (Agenerase®), apricitabine, arbidol, atazanavir (Reyataz®), bevirimat, BI224436, boceprevir (Victrelis®), cathegins such as EGCG, ceragenins, cidofovir, cobicistat, Combivir®, cyanovirin-5 N, darunavir (Prezista®), delaviridine (Rescriptor®), diarylpyrimidines, didanosine (Videx®), docosanol, dolutegravir, edoxudine, efavirenz (Sustiva®), elvitegravir (Stribild®), elvucitabine, emtricitabine (Atripla®), enfuvirtide, entecavir, famciclovir (Famvir®), festinavir, fomivirsen (Vitravene®), fosamprenavir (Telzir®), foscarnet, fosfonet, ganciclovir, globoidnan A, griffithsin, ibacitabine, 10 IDX899, imunovir (inosine pranobex), idoxuridine, imiquimod, indinavir (Crixivan®), inosine, integrase inhibitor, interferon, lamivudine, lersivirine, lopinavir, loviride, maraviroc (Celsentri®), MK-2048, methisazone, miltefosine (Impavido®), moroxydine, MPC-9055 (Vivecon), nelfinavir (Viracept®), nevirapine (Viramune®), nexavir, nucleoside analogues, oseltamivir (Tamiflu®), penciclovir, 15 peramivir, pleconaril, podophyllotoxin (Condylox®), racivir, raltegravir (Isentress®), RDEA806, reverse transcriptase inhibitor, ribavirin, rilpivirine, rimantadine (Flumadine®), rintantolimod (Ampligen®), ritonavir (Norvir®), pyramidine, saquinavir (Fortovase®), seliciclib, stampidine, stavudine (Zerit®), tea tree oil, taribavirin (viramidine), telaprevir (Incivek®), tenofovir (Viread®), 20 tipranavir (Aptivus®), trichosanthin, trifluridine (Viroptic®), Trizivir®, tromantadine (Viru-Merz®), truvada®, valciclovir (Valtrex®) valganciclovir (Valcyte®), viciviroc, vidarabine, zalcitabine (Hivid®), zanamivir (Relenza®), zidotudine (azidothymidine, AZT, Retrovir®) and more preferably for treating herpesviruses idoxuridine.
25
The invention will now be illustrated by the following example.
Example
Evaluation of anti-EBV activity ofTHC derivatives 30 To determine whether THC derivatives can interfere with EBV infection and oncogenesis an in vitro model for primary EBV infection was used. Fluorescent viruses (EBV-GFP) are used to infect an EBV-negative B cell line (2A8), under optimized conditions. By looking at GFP levels in the individual B cells at 2-5 days 13 post EBV infection in the presence or absence of compounds, an early estimation of (inhibition of) infection is obtained. Further B-cell transforming capacity is assessed by following outgrowth ofB cell lymphoblastoid cell lines (B-LCL) upon infection of primary B cells with EBV (GFP) in the presence or absence of test compound.
5 Further, productive EBV infection is tested in the Akata EBV-positive BE cell line (Takada, K. et al., Virus genes 5:147-156, 1991), in which productive infection in 20-60% of cells by crosslinking surface IgG (the B cell receptor) is induced. Into the Akata BL cell line, a reporter fusion protein under the control of an EBV lytic cycle promoter (AKBM cells) is introduced, allowing identification (GFP signal in FACS) 10 or magnetically sort (MACS based on surface ratCD2 display) almost pure populations of productively EBV-infected B cells (Ressing et al. 2005 J. Immunol.). In the current experiments this system is used to analyze whether the presence of compounds such as THC reduce the efficiency of/ block EBV reactivation and the production of EBV (proteins).
15 In the current experiments as described (Ressing et al. 2005 J Immunol 174: 6829), viral activation in EBV+ AKBM cells was induced by cross-linking surface Ig with 10 gg/ml goat anti-human IgG Ab (Cappel); mock-induced AKBM cells were taliën along as controls. Immediately thereafter, 100 ul of the AKBM cells (0.8 million/ml, + anti-IgG = induced; - anti-IgG = control) was added to titrations of THCA (40-20-20 10-5-2.5-1.25-0 gg/ml final cone, in 120 pi, with final cone. 0.1% DMSO) as triplicates in a 96 wells tissue culture plate. After overnight incubation at 37°C, 5%CÖ2, cells were harvested, washed in PBS/BSA/NaN3, and fixed in 1%PFA. Induction efficiencies of EBV replication were determined by flow cytometry, with the rat.CD2-GFP-positive cells representing the cells supporting productive EBV 25 infection. From Tables 1,2 and figure 1, a clear dose-dependent effect of THCA on viral replication is observed.
30 14
Table 1 - replication of EBV in Aka I a Burkitt’s lymphoma cells treated with different amounts of THCA EBV replication (% of cells)
IgG I IgG
medium 0 49 0.1 % DMSO ”5 43 1.25 ”5 4Ö 2.5 “Ö 38 “5 Ö 34 1Ö Ö 23 20 ”5 ΪΊ ~4Ö Ö Ö
Table 2 - viability of Akata Burkitt’s lymphoma cells treated with different 5 amounts of THCA
cellular viability (% of cells) +
IgG IgG medium 85 77 0.1% DMSO 85 76 T25 86 75 ~Z5 85 77 “5 85 75 1Ö 85 76 ~20 73 64 ~40 32 39

Claims (13)

1. Een cannabiszuur voorgesteld door formule Ia, Ib of Ic R A^S X J A Formule Ia R A X V. ^ S<(>^^C00H XI D HO z A1. A cannabis acid represented by formula Ia, Ib or Ic R A ^ S X J A Formula Ia R A X V. ^ S <(> ^^ C00H XI D HO z A 2. Cannabiszuur volgens conclusie 1, waarbij genoemd cannabiszuur is gekozen uit de groep bestaande uit A9-tetrahydrocannabinol zuur of THC zuur (THCA), cannabidiol zuur (CBD-A), cannabidiol (CBD), cannabigerol zuur (CBGA), cannabigerol (CBG), cannabinol zuur (CBN-A) en cannabinol (CBN), cannabichromeen zuur (CBC-A) en cannabichromeen (CBC). 20The cannabis acid according to claim 1, wherein said cannabis acid is selected from the group consisting of A9 tetrahydrocannabinol acid or THC acid (THCA), cannabidiol acid (CBD-A), cannabidiol (CBD), cannabigerol acid (CBGA), cannabigerol (CBG) ), cannabinol acid (CBN-A) and cannabinol (CBN), cannabichromic acid (CBC-A) and cannabichromene (CBC). 20 3. Cannabiszuur volgens conclusie 1 of 2, waarbij genoemd cannabiszuur THCA is.The cannabis acid according to claim 1 or 2, wherein said cannabis acid is THCA. 4. Plantenextract, omvattende ten minste een cannabiszuur zoals 25 gedefinieerd in een der voorgaande conclusies, waarbij de hoeveelheid Δ9- tetrahydrocannabinol als een gewichtspercentage van het totale drooggewicht van het extract 0-5 gew% is, voor toepassing bij de behandeling van virale infecties.4. Plant extract comprising at least one cannabis acid as defined in any one of the preceding claims, wherein the amount of Δ9-tetrahydrocannabinol as a weight percentage of the total dry weight of the extract is 0-5 wt%, for use in the treatment of viral infections. 5. Plantenextract volgens conclusie 4, omvattende ten minste een 30 verbinding gekozen uit de groep bestaande uit A9-tetrahydrocannabinol zuur of THC zuur (THCA), cannabidiol zuur (CBD-A), cannabidiol (CBD), cannabigerol zuur (CBGA), cannabigerol (CBG), cannabinol zuur (CBN-A) en cannabinol (CBN), cannabichromeen zuur (CBC-A) en cannabichromeen (CBC), bij grotere voorkeur waarbij genoemde verbinding Λ9-tetrahydrocann a bi nol zuur (THCA) is.5. Plant extract according to claim 4, comprising at least one compound selected from the group consisting of A9-tetrahydrocannabinol acid or THC acid (THCA), cannabidiol acid (CBD-A), cannabidiol (CBD), cannabigerol acid (CBGA), cannabigerol (CBG), cannabinolic acid (CBN-A) and cannabinol (CBN), cannabichromic acid (CBC-A) and cannabichromic (CBC), more preferably wherein said compound is Λ9-tetrahydrocannic biol acid (THCA). 5 Formule Ib R A λΧπ I Η I A Formule Ic waarin X, Z en A elke een verschillende groep voorstellen, gekozen uit de groepen -OH, waterstof en een eerst alkyl, waarbij genoemde eerste alkyl bij voorkeur een C1-C10 lineaire of vertakte alkyl is, bij grotere voorkeur een C4-C7 lineaire of vertakte alkyl, bij nog grotere voorkeur n-pentyl, 5. represents -OH or alkyl, preferably a C1-C3 bnear or branched alkyl, in particular a methyl, D -OH of alkyl voorstelt, bij voorkeur een C1-C3 lineaire of vertakte alkyl, in het bijzonder methyl, R een waterstof, een CrJRn-OH, een CJRn-COOH of een tweede alkyl 10 voorstelt, waarbij n in deze groepen een geheel getal is, bij voorkeur 0, 1 of 2; waarin bij voorkeur een C1-C3 lineaire of vertakte alkyl is, bij grotere voorkeur -CHs, voor toepassing bij de behandeling van virale infecties.Formula Ib RA λΧπ I Η IA Formula Ic wherein X, Z and A each represent a different group selected from the groups -OH, hydrogen and a first alkyl, said first alkyl preferably being a C1-C10 linear or branched alkyl , more preferably a C 4 -C 7 linear or branched alkyl, even more preferably n-pentyl, 5. represents -OH or alkyl, preferably a C 1 -C 3 bnear or branched alkyl, in particular a methyl, D represents -OH or alkyl , preferably a C1-C3 linear or branched alkyl, in particular methyl, R represents a hydrogen, a CrJRn-OH, a CJRn-COOH or a second alkyl, wherein n in these groups is an integer, preferably 0 , 1 or 2; wherein preferably a C 1 -C 3 is linear or branched alkyl, more preferably -CH 3, for use in the treatment of viral infections. 6. Farmaceutische samenstelling omvattende een cannabiszuur zoals 5 gedefinieerd in een der conclusies 1 - 3 of een plantenextract volgens conclusie 4 of 5 en een additioneel antiviral middel.A pharmaceutical composition comprising a cannabis acid as defined in any one of claims 1 to 3 or a plant extract according to claim 4 or 5 and an additional antiviral agent. 7. Farmaceutische samenstelling omvattende een cannabiszuur zoals gedefinieerd in een der conclusies 1 - 3 of een plantenextract volgens conclusie 10. of 5 en een middel gekozen uit de groep bestaande uit abacavir, acyclovir, adefovir, amantidine (Symmetrel®), amdoxovir, amprenavir (Agenerase®), apricitabine, arbidol, atazanavir (Reyataz®), bevirimat, BI224436, boceprevir (Victrelis®), cathegines zoals EGCG, ceragenines, cidofovir, cobicistat, Combivir®, cyanovirin-N, darunavir (Prezista®), delaviridine (Rescriptor®), diarylpyrimidines, 15 didanosine (Videx®), docosanol, dolutegravir, edoxudine, efavirenz (Sustiva®), elvitegravir (Stribild®), elvucitabine, emtricitabine (Atripla®), enfuvirtide, entecavir, famciclovir (Famvir®), festinavir, fomivirsen (Vitravene®), fosamprenavir (Telzir®), foscarnet, fosfonet, ganciclovir, globoidnan A, griffithsine, ibacitabine, IDX899, imunovir (inosine pranobex), idoxuridine, imiquimod, 20 indinavir (Crixivan®), inosine, integrase remmer, interferon, lamivudine, lersivirine, lopinavir, loviride, maraviroc (Celsentri®), MK-2048, methisazone, miltefosine (Impavido®), moroxydine, MPC-9055 (Vivecon), nelfinavir (Viracept®), nevirapine (Viramune®), nexavir, nucleoside analoga, oseltamivir (Tamiflu®), penciclovir, peramivir, pleconaril, podophyllotoxin (Condylox®), racivir, raltegravir 25 (Isentress®), RDEA806, reverse transcriptase remmer, ribavirine, rilpivirine, rimantadine (Flumadine®), rintantolimod (Ampligen®), ritonavir (Norvir®), pyramidine, saquinavir (Fortovase®), seliciclib, stampidine, stavudine (Zerit®), theeboomolie, taribavirine (viramidine), telaprevir (Incivek®), tenofovir (Viread®), tipranavir (Aptivus®), trichosanthine, trifluridine (Viroptic®), Trizivir®, 30 tromantadine (Viru-Merz®), truvada®, valciclovir (Valtrex®) valganciclovir (Valcyte®), viciviroc, vidarabine, zalcitabine (Hivid®), zanamivir (Relenza®), zidotudine (azidothymidine, AZT, Retrovir®) en bij groetere voorkeur idoxuridine.A pharmaceutical composition comprising a cannabis acid as defined in any one of claims 1 to 3 or a plant extract according to claim 10. or 5 and an agent selected from the group consisting of abacavir, acyclovir, adefovir, amantidine (Symmetrel®), amdoxovir, amprenavir ( Agenerase®), apricitabine, arbidol, atazanavir (Reyataz®), bevirimat, BI224436, boceprevir (Victrelis®), cathegines such as EGCG, ceragenins, cidofovir, cobicistat, Combivir®, cyanovirin-N, darunavir (Preziridircript) ®), diarylpyrimidines, didanosine (Videx®), docosanol, dolutegravir, edoxudine, efavirenz (Sustiva®), elvitegravir (Stribild®), elvucitabine, emtricitabine (Atripla®), enfuvirtide, entecavir, famvir, finavvir, finavc fomivirsen (Vitravene®), fosamprenavir (Telzir®), foscarnet, phosphonet, ganciclovir, globoidnan A, griffithsin, ibacitabine, IDX899, imunovir (inosine pranobex), idoxuridine, imiquimod, indinavir (in Crixivine®, remix) er, interferon, lamivudine, lersivirine, lopinavir, loviride, maraviroc (Celsentri®), MK-2048, methisazone, spleen phosphine (Impavido®), moroxydine, MPC-9055 (Vivecon), nelfinavir (Viracept®), nevirapine (Viramune®) , nexavir, nucleoside analogues, oseltamivir (Tamiflu®), penciclovir, peramivir, pleconaril, podophyllotoxin (Condylox®), racivir, raltegravir (Isentress®), RDEA806, reverse transcriptase inhibitor, ribavirin, rilantivin, rilpadine rifpantine, rilpadine rifpantine (Ampligen®), ritonavir (Norvir®), pyramidine, saquinavir (Fortovase®), seliciclib, stampidine, stavudine (Zerit®), tea tree oil, taribavirin (viramidine), telaprevir (Incivek®), tenofovir (Viread®), tipranavir ( Aptivus®), trichosanthine, trifluridine (Viroptic®), Trizivir®, tromantadine (Viru-Merz®), truvada®, valciclovir (Valtrex®) valganciclovir (Valcyte®), viciviroc, vidarabine, zalcitabine (Hividiv), zividiv Relenza®), zidotudine (azidothymidine, AZT, Retrovir®) and more preferably i doxuridine. 8. Een cannabiszuur zoals gedefinieerd in een der conclusies 1 - 3 of een plantenextract volgens conclusie 4 of 5 of een farmaceutische samenstelling volgens conclusie 6 of 7 voor toepassing bij de behandeling van virale infecties, waarbij een dergelijke virale infectie wordt veroorzaakt door een herpesvirus of een 5 papillomavirus.A cannabis acid as defined in any one of claims 1 to 3 or a plant extract according to claim 4 or 5 or a pharmaceutical composition according to claim 6 or 7 for use in the treatment of viral infections, wherein such a viral infection is caused by a herpes virus or a papilloma virus. 9. Een cannabiszuur of een plantenextract of een farmaceutische samenstelling volgens conclusie 8, waarbij genoemd herpesvirus gekozen is uit Eppstein-Barr virus en Kaposi’s Sarcoma-geassociaeerd Herpesvirus. 10A cannabis acid or a plant extract or a pharmaceutical composition according to claim 8, wherein said herpes virus is selected from Eppstein-Barr virus and Kaposi's Sarcoma-associated Herpes virus. 10 10. Een cannabiszuur zoals gedefinieerd in een der conclusies 1 - 3 of een plantenextract volgens conclusie 4 of 5 of een farmaceutische samenstelling volgens conclusie 6 of 7 voor toepassing bij de behandeling van virale infecties, waarbij behandeling de toediening van het cannabiszuur in zure vorm omvat. 15A cannabis acid as defined in any one of claims 1 to 3 or a plant extract according to claim 4 or 5 or a pharmaceutical composition according to claim 6 or 7 for use in the treatment of viral infections, wherein treatment comprises the administration of the cannabis acid in acid form . 15 11. Werkwijze voor het behandelen van een dier dat lijdt aan een virale infectie door toediening van een cannabiszuur zoals gedefinieerd in een der conclusies 1 - 3 of een plantenextract volgens conclusie 4 of 5 of een farmaceutische samenstelling volgens conclusie 6 of 7 voor toepassing bij de behandeling van virale 20 infecties.A method of treating an animal suffering from a viral infection by administering a cannabis acid as defined in any one of claims 1 to 3 or a plant extract according to claim 4 or 5 or a pharmaceutical composition according to claim 6 or 7 for use in the treatment of viral infections. 12. Werkwijze voor het behandelen van een dier met een cannabiszuur zoals gedefinieerd in een der conclusies 1 - 3 of een plantenextract volgens conclusie 4 of 5 of een farmaceutische samenstelling volgens conclusie 6 of 7, welke behandeling 25 omvat het toedienen van het cannabiszuur in zure vorm, waarin behandeling de behandeling van een virale infectie omvat..12. A method of treating an animal with a cannabis acid as defined in any one of claims 1 to 3 or a plant extract according to claim 4 or 5 or a pharmaceutical composition according to claim 6 or 7, which treatment comprises administering the cannabis acid in acid form in which treatment comprises the treatment of a viral infection. 13. Werkwijze volgens conclusie 11 of 12, waarbij het dier is gekozen uit de groep bestaande uit een mens, een koe, een schaap, een varken, een paard, een vis 30 of een dierlijke kweek (garnalen, kreeft, tweekleppigen).13. Method as claimed in claim 11 or 12, wherein the animal is selected from the group consisting of a human, a cow, a sheep, a pig, a horse, a fish or an animal culture (shrimp, lobster, clams).
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