WO1998025608A1 - Pharmaceutical compositions comprising a 4-arylcoumarin for the treatment of viral infections - Google Patents
Pharmaceutical compositions comprising a 4-arylcoumarin for the treatment of viral infections Download PDFInfo
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- WO1998025608A1 WO1998025608A1 PCT/IT1997/000306 IT9700306W WO9825608A1 WO 1998025608 A1 WO1998025608 A1 WO 1998025608A1 IT 9700306 W IT9700306 W IT 9700306W WO 9825608 A1 WO9825608 A1 WO 9825608A1
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- treatment
- virus
- prevention
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- 210000005036 nerve Anatomy 0.000 description 1
- 231100000028 nontoxic concentration Toxicity 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940079877 pyrogallol Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000046 skin rash Toxicity 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 210000000273 spinal nerve root Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000007442 viral DNA synthesis Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
Definitions
- compositions comprising a 4-arylcoumarin for the treatment of viral infections
- the present invention relates to the use of 4-arylcouma ⁇ ns for the preparation of pharmaceutical composition suitable for the prevention and treatment of viral infections caused by DNA viruses
- viruses include pox viruses, herpes viruses, adeno viruses, hepadna viruses and papilloma viruses which are the etiological agents, respectively, of smallpox, herpes simplex and herpes zoster, conjunctivitis, pharyngitis, hepatitis B and verrucae
- the present invention relates preferably to the use of the aforementioned 4-arylcouma ⁇ ns for the preparation of compositions having an antiviral action against herpes viruses, I e the herpes virus simplex type 1 (HSV-1)
- VZV varicella zoster virus
- CMV cytomegalovirus
- the present invention also relates to pharmaceutical compositions comprising a 4-arylcouma ⁇ n as the active principle and a phannacologicallv acceptable excipient which compositions may be administered orally, parenterally and by means of local applications and are suitable for the prevention and treatment of infections contracted from the viruses above
- Herpes simplex is an infection characterised by the appearance on the skin and mucous membranes of small blisters which occur in single or multiple groups and are full of a clear liquid on an erythematous base
- HSV-1 causes herpes of the lips and keratitis
- HSV-2 herpes of the genitals
- the lesions may appear in any zone of the skin or mucous membrane, but are most frequent around the mouth, the lips, on the conjunctiva and on the cornea, in the case of those caused by HSV- 1.
- He ⁇ es zoster is an acute infection of the central nervous system which affects the ganglions of the dorsal roots and is characterised by neuralgic pain in the skin zones controlled by the pe ⁇ pheral sensitive nerves which branch out from the ganglions of the roots affected by the infection
- Vidarabine the first anti-he ⁇ esvirus drug of proven efficacy, approved in 1977, was used - on account of its high toxicity - only for particularly serious HSV and VZV infections where the patient's life was at risk
- Vidarabine has been largely replaced by acyclovir, approved in 1982, which is more effective and less toxic than vidarabine Acyclovir.
- vidarabine Acyclovir which today is still the preferred antiviral agent for the treatment of he ⁇ es of the lips and genitals and he ⁇ es zoster, is the prototype of a group of antiviral drugs which are phosphorylated intracellularly by a viral kinase.
- acyclovir is the most widely used antiviral agent in the world and the seventh most widely sold drug worldwide (see Pharma Business July/August 1996, No 10), this drug, despite being generally well tolerated, has va ⁇ ous undesirable effects When administered locally, it may cause irritation of the mucous membranes and a brief burning sensation when applied to lesions of the genitals When administered orally, it may cause nausea, diarrhoea and skin rashes
- a further drawback of the antiviral drugs currently sold stems from the dearth of fonns suitable for local application and, even when these can be found, from their limited effectiveness
- acyclovir, famcyclovir, foscarnet, gancyclovir, so ⁇ vudine, valacyclovir and viradabine only acyclovir can also be found in compositions suitable for local application (see Goodmand & Gilman's "The Pharmacological Basis of Therapeuticas", ninth edition.
- R, and R 2 are hydrogen; halogen; linear or branched alkyl having 1-10 carbon atoms, optionally replaced by one or more halogen atoms; alkoxy having 1-10 carbon atoms; and acyloxy having 1-10 carbon atoms, allows the preparation of pharmaceutical compositions which can be administered orally, parenterally and by means of local application and are suitable for the prevention and treatment of viral infections caused by DNA viruses.
- the composition of the present invention are suitable for the prevention and treatment of infections contracted from he ⁇ es viruses such as he ⁇ es virus simplex type 1 (HSV-1 ), he ⁇ es virus simplex type 2 (HSV-2), varicella zoster virus (VZV) or cytomegalovirus (CMV). Therefore, these compositions are particularly well suited for the prevention or treatment of lip he ⁇ es. genital he ⁇ es and he ⁇ es zoster.
- R, and or R 2 as halogens are preferably fluorine or chlorine
- R, and or R 2 as alkyl are preferably methyl, ethyl, propyl, isopropyl. butyl, isobutyl, sec-butyl or tert. -butyl;
- R, and or R 2 as halogen-substituted alkyl are preferably chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 3-chloroethyl, 2,3- dichloroethyl, fluoromethyl, difluoromethyl or trifluoromethyl;
- R, and or R 2 as alkoxy are preferably methoxy, ethoxy, propoxy. isopropoxy, butoxy, sec.-butoxy, tert.-butoxy or benzyloxy;
- R, and/or R 2 as acyloxy are preferably acetoxy, propionyloxy or benzoyloxy
- R, and R 1 are hydrogen, hvdroxvl or acetoxy Of these, 5,7-d ⁇ acetoxy-4-phenylcouma ⁇ n is particularly preferred
- the resultant mixture was poured into about 300 ml of cold water, resulting in a precipitate.
- the precipitate was filtered in vacua and the solid was air dried, giving the crude product yield indicated in table 1.
- the dried compounds were purified by taking them up in ethyl acetate, filtering them and the precipitating them with heptane. This purification procedure was repeated until a compound having a constant melting point was obtained. (follows onpag.10 with Table 1)
- the compound according to Example 1 was mixed with acetic anhydride and pyndine The mixture, after being left to react overnight, was poured into cold water and filtered The solid was purified by recrystallising it twice from boiling heptane The title compound was obtained, with a melting point of 183°C
- the physico-chemical properties of the compound are the following insoluble in water, soluble in chloroform, diethyl ether, acetone and ethanol. soluble in vegetable oils and tween
- compositions suitable for being formulated also in compositions which can be administered orally and parenterally are suitable for being formulated also in compositions which can be administered orally and parenterally, according to a preferred feature of the invention, they are formulated in compositions suitable for local application These compositions are therefore particularly suitable for the treatment of infections of the skin, mouth, eyes and genitals caused by he ⁇ es viruses
- the formulations are preferably applied in the form of creams or ointments containing the active principle in quantities of
- the active pnnciple may be used with a paraffin or water-miscible ointment base
- the active principle may be formulated in the form of a cream with an oil-in-water cream base
- local applications may be performed through the skin by means of an lonophoresis device
- the aqueous phase of the cream base may comprise at least 30%) by weight of a polyhyd ⁇ c alcohol, i e an alcohol having two or more hydroxyl groups, such as for example propylene glycol, butane- 1 , 3-dioL man tol, sorbitol. glycerol or polethylene glycol or mixtures thereof
- the local formulations may suitably comprise a compound which improves the abso ⁇ tion or the penetration of the active principle through the skin and the other cutaneous zones affected by the infection Examples of these agents which promote cutaneous penetration comprise dimethyl sulphoxide and similar compounds
- Formulations suitable for local administration to the eyes comprise eyewashes where the active principle is dissolved or suspended in a suitable vehicle
- Formulations for rectal administration may consist of suppositories whose base comprises for instance cocoa butter or a sahcylate
- Formulations suitable for vaginal administration may be in the form of vaginal suppositories, tampons, creams, foams or sprays containing, in addition to the active principle, vehicles well known to persons skilled in the pharmaceutical art
- the aim of the present study was to enable to perform an estimative and preliminary evaluation of the toxic properties of 5,7-d ⁇ acetoxy-4- phenylcoumann, providing also information on health hazards resulting from a short exposure of the selected ways of administering the compound
- the 5,7-d ⁇ acetoxy-4- phenylcoumann did not cause mortality in any of the animals subjected to the treatment Moreover, the exams carried out to determine the symptoms caused on the alteration of hair, skin and mucous membranes, respiratory and circulatory system, central and peripheral nervous systems, somato-motorial activities, weight and behaviour alterations failed to reveal alterations differing significantly from those observed in the animals of the control group Macroscopic examinations performed on vital organs such as heart, liver, kidneys, lungs, stomach and intestine revealed no significant alterations with respect to the animals of the control group The conclusion is that the 5,7-d ⁇ acetoxy-4-phenylcouma ⁇ n produced no toxic effects in the acute toxicity test, in single dose, in male albino
- the sub-acute toxicity test also yields additional information on organo-alvus and on cumulative effects 4 groups of 16 animals (8 males and 8 females) comprising albino Wistar rats were used One of these groups was taken as control group and it was subjected to the same experimental procedures in order to obtain baseline results After the tests with the various vehicles available, the 5,7-d ⁇ acetoxy-4-phenylcouma ⁇ n was suspended in Tween 82 at 12% for all treatments performed The control group was administered only the vehicle in the dose of 10 ml/kg of body weight Administrations were daily and provided orally, with a maximum volume of 10 ml/kg of body weight using doses of 50, 25, 12, 5 mg/kg of body weight Du ⁇ ng the (35 day) penod of daily administration of the 5,7-d ⁇ acetoxy-4-phenylcouma ⁇ n, body weight was checked daily whereas water and ration ingestion and weight of the excrements of the animals were checked twice a week On the
- ANOVA One-way analysis of variance
- the 5,7-d ⁇ acetoxy-4- phenylcoumann caused no statistically significant alteration in regard to body weight, water consumption, ration ingestion or weight of excrements in the males and in the females when compared to the respective control group
- the goal is to analyse abso ⁇ tion of the 5,7-d ⁇ acetoxy-4-phenylcouma ⁇ n, over different time intervals, after oral administration of 300 mg/kg the rat These results were compared with the data pertaining to the abso ⁇ tion of the antiviral compound acyclovir.
- CMNT minimal non-toxic concentration
- the compound In in vitro tests against the He ⁇ es simplex virus, the compound had an inhibiting activity of 85% at a concentration of 65 ⁇ M and an inhibiting activity of 95% at a concentration of 125 ⁇ M When tested in vitro for the cytomegalovirus, the compound had an inhibiting activity of 78% at a concentration of 65 ⁇ M
- the clinical study was conducted for a period of three months on 5 volunteer patients - 1 man aged 48 and 4 women aged between 55 and 66, suffering from he ⁇ es zoster
- the product in the form of a cream with a concentration of 2% by weight was applied locally three times a day with light massaging of the infected area
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The use of 4-arylcoumarins for the preparation of pharmaceutical compositions suitable in particular for local application for the prevention and treatment of infections caused by DNA viruses, particularly herpes viruses, such as herpes of the lips and herpes of the genitals and herpes zoster.
Description
Pharmaceutical compositions comprising a 4-arylcoumarin for the treatment of viral infections
The present invention relates to the use of 4-arylcoumaπns for the preparation of pharmaceutical composition suitable for the prevention and treatment of viral infections caused by DNA viruses These viruses include pox viruses, herpes viruses, adeno viruses, hepadna viruses and papilloma viruses which are the etiological agents, respectively, of smallpox, herpes simplex and herpes zoster, conjunctivitis, pharyngitis, hepatitis B and verrucae
The present invention relates preferably to the use of the aforementioned 4-arylcoumaπns for the preparation of compositions having an antiviral action against herpes viruses, I e the herpes virus simplex type 1 (HSV-
1 ) and 2 (HSV-2), the varicella zoster virus (VZV) and the cytomegalovirus (CMV)
The present invention also relates to pharmaceutical compositions comprising a 4-arylcoumaπn as the active principle and a phannacologicallv acceptable excipient which compositions may be administered orally, parenterally and by means of local applications and are suitable for the prevention and treatment of infections contracted from the viruses above Herpes simplex is an infection characterised by the appearance on the skin and mucous membranes of small blisters which occur in single or multiple groups and are full of a clear liquid on an erythematous base HSV-1 causes herpes of the lips and keratitis, HSV-2 herpes of the genitals The lesions may appear in any zone of the skin or mucous membrane, but are most frequent around the mouth, the lips, on the conjunctiva and on the cornea, in the case of those caused by HSV- 1. and
on the genitals or peπrectal zones, in the case of those caused by HSV-2 Heφes zoster is an acute infection of the central nervous system which affects the ganglions of the dorsal roots and is characterised by neuralgic pain in the skin zones controlled by the peπpheral sensitive nerves which branch out from the ganglions of the roots affected by the infection
During the last few years notable progress has been made in the development of drugs having an antiviral and in particular anti-heφetic action and in understanding the effects they have, for example on viral replication Nevertheless, at the moment no drug which is sufficiently devoid of toxic and/or undesirable effects and which has a really effective action on the infections contracted both from the heφes simplex virus and the varicella zoster virus, is available on the market In the case of superficial infections of minor gravity, some drugs for local use have demonstrated a certain degree of effectiveness, such as idoxuπdine (IDU) and tπfluπdine
Vidarabine, the first anti-heφesvirus drug of proven efficacy, approved in 1977, was used - on account of its high toxicity - only for particularly serious HSV and VZV infections where the patient's life was at risk Vidarabine has been largely replaced by acyclovir, approved in 1982, which is more effective and less toxic than vidarabine Acyclovir. which today is still the preferred antiviral agent for the treatment of heφes of the lips and genitals and heφes zoster, is the prototype of a group of antiviral drugs which are phosphorylated intracellularly by a viral kinase. thus being converted into inhibitors of viral DNA synthesis Although acyclovir is the most widely used antiviral agent in the world and the seventh most widely sold drug worldwide (see Pharma Business
July/August 1996, No 10), this drug, despite being generally well tolerated, has vaπous undesirable effects When administered locally, it may cause irritation of the mucous membranes and a brief burning sensation when applied to lesions of the genitals When administered orally, it may cause nausea, diarrhoea and skin rashes
A further drawback of the antiviral drugs currently sold stems from the dearth of fonns suitable for local application and, even when these can be found, from their limited effectiveness In fact, among the antiviral drugs specifically intended for the treatment of heφetic infections and currently available commercially (acyclovir, famcyclovir, foscarnet, gancyclovir, soπvudine, valacyclovir and viradabine), only acyclovir can also be found in compositions suitable for local application (see Goodmand & Gilman's "The Pharmacological Basis of Therapeuticas", ninth edition. 1996, page 1 193) However, in the case of infections caused by the heφes simplex virus, local application of acyclovir is much less effective than systemic application, in fact, it has no significant clinical benefits in the case of recurrent genital heφes (see Goodman & Gilman, loc cit page 1 197) A study conducted on rat plasma shows that in high doses of 300 mg/kg taken orally, absoφtion of the acyclovir compound is compromised, probably due to a process saturation caused by the limited solubility and the onset of the gastrointestinal precipitation of the compound, thus giving rise to the reduction in its absorption and the subsequent permanence in the blood, as reported in the literature by Fujioka Y et al , 1991
It is therefore obvious that there is a need for other potent anti-heφetic
agents and the like, which should be substantially devoid of toxic and/or undesirable effects and highly effective even when formulated in the aforementioned compositions for local use
It has now been discovered that the 4-arylcoumaπns which will be defined and described in detail below constitute potent antiviral agents against DNA viruses and in particular heφes viruses The 4-arylcoumaπns of formula (I) and (I'), defined below, present no toxic effects in acute toxicity trials in single dose and sub-acute toxicity trials in repeated doeses Moreover, through a comparison of the plasmatic absoφtion data, reported under Table 2 (obtained from pharmacokinetic trials) for the 4-arylcoumaπns of formula (I) and (I1) and acyclovir, it was determined that in 300 mg/kg doses administered orally the 4-arylcoumaπns show a more rapid absoφtion in greater concentration and protracted for a longer time For some time, 4-arylcoumaπns (or neoflavonoids) have been generating interest among pharmacologists and biochemists in that various compounds containing a differently substituted 4-phenylcoumaπn nucleus have been isolated from the bark of trees originating from Central and South America (in particular Brazil and Mexico), whose extracts are attributed in popular medicine with various therapeutic effects
Thus, for example, eher G and Kraus L J in Journal of Natural Products. Vol 47, No 1 , pp 172-4, 1984, have described the isolation of 5,2'5' - tπhydroxy-7-methoxy-4-phenylcournaπn from a species of the genus Coutarea (Rubiaceae family) The bark extracts of this species, according to popular belief, are said to have an anti-malarial and anti-
diabetic action
Delle Monache et al (Phytochemistry, Vol 22, No 7, pp 1657-8. 1983) have described the isolation of 5, 7, 4' - tπmethoxy-4-phenylcoumaπn, 4'-hydroxy-5.7-dιmethoxy-4-phenylcoumaπn, 3'-hydroxy-5,7-4'- tπmethoxy-4-phenylcoumaπn and 3',4'-dιhydroxy-5.7-dιmethoxy-4- phenylcoumaπn from the stem of the Coutarea hexandra used in popular medicine as a substitute for Cinchona as an anti-malarial agent Subsequently. Delle Monache et al (Phytochemistry, Vol 29, No 12, pp 3984-6 1990) have isolated from the same plant two other neoflavonoids 3'-hydroxy-5,7,8,4'-tetramethoxy-4-phenyIcoumaπn and
8,3'-dιhydroxy-5,7,4'-tπmethoxy-4-phenylcoumaπn Interest in the possible therapeutic properties of these 4-arylcoumaπns has also promoted interest in the sysnthesis of these compounds from various substrates, as an alternative to the purely extractive methods used originally This also had the puφose of comparing the natural products with the synthesised compounds and thus confirm the hypothetised structures
Thus, for example. Delle Monache et al (Phytochemistry, Vol 24. No 6, pp 1355-7) reported the synthesis of a series of 5,7-dιmethoxy-4- arylcoumanns and the corresponding analogous 5,7-dιhvdroxιes in order to confirm the structure of some neoflavonoids isolated by the same Author by means of extraction from the Coutarea hexandra (the teachings of this publication are incoφorated in full in the present description bv reference) As described in this paper, preparation of the 4-arylcoumarιns may be effected by two separate synthesis methods synthesis of coumaπn by the
Perk reaction or the Pechman-Duisberg reaction, which are both well known to persons skilled in the art of organic synthesis According to the first method, an ortho-hydroxyarylaldehyde or -ketone is reacted in the heat with acetic anhydride in the presence of an alkali method acetate, preferably sodium acetate or potassium acetate In the second method, particularly suitable when wishing to obtain a coumaπn substituted in the 4 position of the pyrone ring (for example a 4-phenylcoumaπn), a phenol is condensed with an aryl-β-ketoester in the presence of a strong acid or aluminium chloride
It is essential to note that the therapeutic application of the 4- arylcoumaπns forming the subject matter of the present invention was not known, nor could it have been deduced in any way either on the basis of the presumed therapeutic properties known from popular medicine, or from the studies conducted subsequently
It has now been discovered, in accordance with the present invention, that the use of 4-arylcoumaπns having the general formula (I)
Preferably, the composition of the present invention are suitable for the prevention and treatment of infections contracted from heφes viruses such as heφes virus simplex type 1 (HSV-1 ), heφes virus simplex type 2 (HSV-2), varicella zoster virus (VZV) or cytomegalovirus (CMV). Therefore, these compositions are particularly well suited for the prevention or treatment of lip heφes. genital heφes and heφes zoster. In compounds of formula (I), R, and or R2 as halogens are preferably fluorine or chlorine; R, and or R2 as alkyl are preferably methyl, ethyl, propyl, isopropyl. butyl, isobutyl, sec-butyl or tert. -butyl;
R, and or R2 as halogen-substituted alkyl are preferably chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 3-chloroethyl, 2,3- dichloroethyl, fluoromethyl, difluoromethyl or trifluoromethyl; R, and or R2 as alkoxy are preferably methoxy, ethoxy, propoxy. isopropoxy, butoxy, sec.-butoxy, tert.-butoxy or benzyloxy;
R, and/or R2 as acyloxy are preferably acetoxy, propionyloxy or
benzoyloxy
It has been discovered, moreover, that a particularly preferred subclass of 4-arylcoumanns of formula (I) for the use and the compositions of the present invention comprises the compounds having the general formula
Some non-limiting examples of the preparation of 4-phenylcoumaπns suitable for the used according to the invention are provided below
EXAMPLE 1:
Preparation of 5,7-diacetoxy-4-phenylcoumarin
A mixture of phloroglucinol ( 1,3,5-tπhydroxybenzene) (0 1 mol) in 25 ml of tπfluoracetic acid and 10 ml of anhydrous ethanol is refluxed for
2-3 hours until no β-ketoester is left Once the reaction is complete, 300 ml of cold distilled water is added to the reaction mixture, and the resultant mixture is filtered The residue is washed and purified by means of crystallisation with dry ethyl acetate
The title product is thus obtained (yield approx 85%)
M.p. = 245-247°C
UV λmax (EtOH) (nm) 225.5; 330 (no fluorescence).
EXAMPLE 2:
Preparation of various 4-phenyIcoumarins A mixture of 0.1 mol of the phenol indicated in Table 1 and 0.1 mol of ethyl benzoylacetate in 25 ml of trifluoroacetic acid was refluxed for the duration indicated in Table 1.
At the end of the reaction, the resultant mixture was poured into about 300 ml of cold water, resulting in a precipitate. The precipitate was filtered in vacua and the solid was air dried, giving the crude product yield indicated in table 1. The dried compounds were purified by taking them up in ethyl acetate, filtering them and the precipitating them with heptane. This purification procedure was repeated until a compound having a constant melting point was obtained. (follows onpag.10 with Table 1)
TABLE 1 o PHENOL USED YIELD (%) IN REFLUX M.P. EMPIRICAL CALCULATED
CRUDE TIME (°C) FORMULA FOUND
PRODUCT (hours)
CARBON HYDROGEN CHLORINE A Phloroglucinol 85 2 245-247 Cι5H10O4 70.86 3.96 70.85 4.10 B 2-Methylresorcinol 100 0.5 285 Cif,H,2O, 76.17 4.79 75.94 4.95 C 2-Methylresorcinol 100 0.25 265-266 Cι5H,0O3 69.44 5.29 69.47 5.13 D Resorcinol 80 20 256.5-257 C,5H10O 75.62 4.23 75.48 4.19 E Resorcinol 90 20 194-195 κ)H8O, 68.17 4.57 68.18 4.58 F Orcinol 30 20 226 C1(,H,A 76.17 4.79 75.94 4.73 G 4-Chlororesorcinol 60 20 281 CI5H,ClO3 66.06 3.32 13.06 65.91 3.51 13.28 H 4-Chlororesorcinol 57 20 285-286 C,„lLClO4 56.75 3.81 16.75 56.89 3.65 16.56 1 Pyrogallol 80 5 195-197 Cι5H1(,O4 66. 17 4.44 H,O 66.1 1 4.50
EXAMPLE 3:
Preparation of 5,7-diacetoxy-4-phenyIcoumarin (diacetoxy celodinine)
The compound according to Example 1 was mixed with acetic anhydride and pyndine The mixture, after being left to react overnight, was poured into cold water and filtered The solid was purified by recrystallising it twice from boiling heptane The title compound was obtained, with a melting point of 183°C The physico-chemical properties of the compound are the following insoluble in water, soluble in chloroform, diethyl ether, acetone and ethanol. soluble in vegetable oils and tween
Thin-layer chromatography on silica gel (230 mesh) as absorbant Eluent benzene/methanol (9 1) R, = 0 7
Spectroscopic data Ultraviolet λmax (EtOH) 235, 245 nm. Infrared λmax (KBr) 2980, 2835, 1690, 1600, 1450, 1320 cm ', 'H-NMR (CDC1,) 1 23 (6H), 6 58-7 54 (9H) ppm.
Mass spectrum (El, 70 eV) 238 (M ), 308,195 92
EXAMPLE 4:
Preparation of 5,7,4'-trihydroxy-4-phenylcoumarin
A chilled solution of ethyl p-benzyloxybenzoylactetate (0 6 g) and phloroglucinol (0 28 g) in ethanol (24 ml) was saturated with dry gaseous HC1 After three days, water was added to the reaction mixture and the resultant mixture was concentrated in vacuo Filtration of the concentrate provided a red solid which, upon chromatography on silica gel with a mixture of CHCl -MeOH, provided the title compound (320 mg, yield 60%), M P 294-295°C with decomposition (CHCl,-MeOH).
UV λmax, MeOH nm (logδ), 262 (4 00), 324 (4 18), max MeONa 275,
305, 373; IR max, Kbr cm'1: 3510, 3235, 1662, 1590, 1550, 1510; Η- NMR (Me2CO-d6): δ 7.22 (2H,d,J=8.5 Hz,H-2',H-6'), 6.83 (2H, d, J=8.5 Hz,H-3',H-5'), 6.35 (2H,sH-6,H-8),5.74 ( lH,s,H-3); MS m z (re. int.): 270 [MTC100), 269(22), 242(88), 241 (9), 226(8), 213(32), 197(1 1 ), 135(6), 121(5), 106.5(4). (Found: C, 66.83; H, 3.66. Calculated for C15H10O5: C,
66.67, H, 3.73%). EXAMPLE 5:
Preparation of 5,7,4'-triacetoxy-4-phenylcoumarin The compound of Example 4 (60 mg) upon treatment with pyridine and acetic anhydride overnight provided the title compound (68 mg), M.p.
186-187°C, (Et2O); IR max. (CHC13) cm 1; 1 170, 1732; Η NMR (CDC13): δ 7.38 (2H,</J=8.5 Hz,H-2',H-6'), 7-20 (2H, J=8.5 Hz.H-3'.H- 5'),7,18 (lH,c/,J=2.5 H2.H-8), 6.81 (1H, ,J=2.5 Hz,H-6),2.31 (6H, 7- OAc+4'-OAc), 1.42 (3H,s,5-OAc). EXAMPLE 6:
Methyl derivatives of 5,7,4,-trihydroxy-4-phenylcoumarin A saturated solution of diazomethane in diethyl ether (20 ml) was added to 5,7,4'-trihydroxy-4-phenylcoumarin (270 mg) in chloroform ( 18 ml) and methanol (2 ml) with stirring. After 45 minutes, the reaction mixture was evaporated in vacuo and the residue was run through the silica gel using benzene ethyl acetate (4: 1 ), providing 5,7,4'-trimethoxy-4- phenylcoumarin ( 135 mg, yield 43%) and 5,7-dimethoxy-4'-hydroxy-4- phenylcoumarin ( 150 mg, yield 50%). Although the 4-arylcoumarins of formula (I) and (I1) are suitable for being formulated also in compositions which can be administered orally and parenterally, according to a preferred feature of the invention, they
are formulated in compositions suitable for local application These compositions are therefore particularly suitable for the treatment of infections of the skin, mouth, eyes and genitals caused by heφes viruses For these infections the formulations are preferably applied in the form of creams or ointments containing the active principle in quantities of
0 1 -20%) by weight, preferably 1-10% by weight When formulated in the form of an ointment, the active pnnciple may be used with a paraffin or water-miscible ointment base Alternatively, the active principle may be formulated in the form of a cream with an oil-in-water cream base Moreover, local applications may be performed through the skin by means of an lonophoresis device
If desired, the aqueous phase of the cream base may comprise at least 30%) by weight of a polyhydπc alcohol, i e an alcohol having two or more hydroxyl groups, such as for example propylene glycol, butane- 1 , 3-dioL man tol, sorbitol. glycerol or polethylene glycol or mixtures thereof The local formulations may suitably comprise a compound which improves the absoφtion or the penetration of the active principle through the skin and the other cutaneous zones affected by the infection Examples of these agents which promote cutaneous penetration comprise dimethyl sulphoxide and similar compounds
Formulations suitable for local administration to the eyes comprise eyewashes where the active principle is dissolved or suspended in a suitable vehicle Formulations for rectal administration may consist of suppositories whose base comprises for instance cocoa butter or a sahcylate
Formulations suitable for vaginal administration may be in the form of
vaginal suppositories, tampons, creams, foams or sprays containing, in addition to the active principle, vehicles well known to persons skilled in the pharmaceutical art
By way of example, some data relating to pharmacological and clinical tests carried out using 5,7-dιacetoxy-4-phenylcoumaπn are reported below
A. PHARMACOLOGICAL TESTS
The pharmacological evaluation of 5,7-dιacetoxy-4-phenylcoumaπn was performed in vitro and in vivo for the following activities a) Acute toxicity
The aim of the present study was to enable to perform an estimative and preliminary evaluation of the toxic properties of 5,7-dιacetoxy-4- phenylcoumann, providing also information on health hazards resulting from a short exposure of the selected ways of administering the compound
These tests were conducted on male albino Swiss guinea pigs (25-30 g) randomly grouped in groups of 10 animals One of these groups was taken as the control group and was subjected to the same experimental procedures in order to obtain baseline results After the tests with the vaπous vehicles available, 5,7-dιacetoxy-4-phenylcoumaπn was suspended in Tween 82 at 12% in all treatments performed The control group was only administered the vehicle in the dose of 10 ml/kg of body weight Doses of 5g/kg of body weight were administered orally and 2 g/kg of body weight were administered lntrapeπtoneally using a maximum volume, in both cases, of 10 ml/kg of body weight After administering the 5,7-dιacetoxy-4-phenylcoumaπn, very close
observations were conducted at 30, 60. 90, 120, 240, and 360 minutes and then every 24 hours, for an overall duration of 14 days, with the purpose of observing toxic effects, speed of their manifestation, duration and time of recovery of the animal, and to determine the reversible or irreversible nature of the effects Moreover, special attention was paid to symptoms such as tremors, convulsions, salivation, diarrhoea, lethargy and coma
At the end of the observation period ( 14 days), the 5,7-dιacetoxy-4- phenylcoumann did not cause mortality in any of the animals subjected to the treatment Moreover, the exams carried out to determine the symptoms caused on the alteration of hair, skin and mucous membranes, respiratory and circulatory system, central and peripheral nervous systems, somato-motorial activities, weight and behaviour alterations failed to reveal alterations differing significantly from those observed in the animals of the control group Macroscopic examinations performed on vital organs such as heart, liver, kidneys, lungs, stomach and intestine revealed no significant alterations with respect to the animals of the control group The conclusion is that the 5,7-dιacetoxy-4-phenylcoumaπn produced no toxic effects in the acute toxicity test, in single dose, in male albino
Swiss guinea pigs up to the doses of 5 g kg of body weight (administered orally) and 2 g/kg of body weight (administered lntrapeπtoneally) b) Sub-acute toxicity In order to evaluate the toxic properties and the potential hazards of the 5,7-dιacetoxy-4-phenylcoumaπn. tests in doses repeated for a 35 day duration were performed The sub-acute toxicity test also yields
additional information on organo-alvus and on cumulative effects 4 groups of 16 animals (8 males and 8 females) comprising albino Wistar rats were used One of these groups was taken as control group and it was subjected to the same experimental procedures in order to obtain baseline results After the tests with the various vehicles available, the 5,7-dιacetoxy-4-phenylcoumaπn was suspended in Tween 82 at 12% for all treatments performed The control group was administered only the vehicle in the dose of 10 ml/kg of body weight Administrations were daily and provided orally, with a maximum volume of 10 ml/kg of body weight using doses of 50, 25, 12, 5 mg/kg of body weight Duπng the (35 day) penod of daily administration of the 5,7-dιacetoxy-4-phenylcoumaπn, body weight was checked daily whereas water and ration ingestion and weight of the excrements of the animals were checked twice a week On the 36th day, all ematological parameters were evaluated on the blood drawn from the animals while all biochemical exams were performed on the separated and centπfuged serum
One-way analysis of variance (ANOVA) was applied to the results obtained, with a critical level less than or equal to 0 05 for null hypothesis rejection
At the end of the observation period, the 5,7-dιacetoxy-4- phenylcoumann caused no statistically significant alteration in regard to body weight, water consumption, ration ingestion or weight of excrements in the males and in the females when compared to the respective control group
From the following ematological analysis on the total serum hemaceas
(RBC), hematocnt (HCT), hemoglobin (HGB), mean coφuscle volume (MCV) and leukocytes (WBC) it could be observed that no statistically significant differences took place between the treated groups and the control group In regard to biochemical parameters, no significant alterations were found in hepatic enzymes gamma-GT, AST (GOT), ALT (GTP) and in the cholesterol level
It is concluded that the 5,7-dιacetoxy-4-phenylcoumaπn. subjected to sub-acute toxicity tests for 35 days, presented no relevant toxicological effects in treated male and female rats with respect to the control group c) Pharmacokinetic tests
The goal is to analyse absoφtion of the 5,7-dιacetoxy-4-phenylcoumaπn, over different time intervals, after oral administration of 300 mg/kg the rat These results were compared with the data pertaining to the absoφtion of the antiviral compound acyclovir. taken as a model, also administered orally in the same dose (300 mg/kg) and under the same experimental conditions The animals (Winstar rats, 250-300 g) were anesthetised and a blood sample was drawn from them (about 0 5 ml) after administration both of the 5,7-dιacetoxy-4-phenylcoumaπn and of aciclovir to the respective groups of animals The blood samples were drawn at time 0 (before administering the compounds), 30, 60, 90, 120, 180, 240, 300, 360 and 420 minutes after administration - 5,7-diacetoxy-4-phenylcoumarin test To 0 25 ml of plasma were added 50 μl of methanol for protein precipitation Afterwards, the sample was stirred and centπfuged and the hydroalcoho c phase obtained was stirred further A sample of 50 μl was
injected into an HPLC instrument The 5,7-dιacetoxy-4-phenylcoumaπn was dosed in the rat plasma by means of HPLC analysis with UV withholding at a wavelength of 254 nm The debt of the mobile phase - methanol water ( 1 1) was 1 ml/mm, using a MCH-10 column with 30 cm length and 0 42 cm inner diameter
- Aciclovir test
To a volume of 0 25 ml of plasma were added 50 μl of tπchloroacetic acid and the liquid was centrifuged To the liquid phase, separated from the precipitate, were added 3 ml of dichloromethane. after which the sample was stirred and centπfuged At this point the phases were separated the organic phase was evaporated and re-suspended with 100 μl of mobile phase The final solution was stirred and 50 μl were injected in the HPLC instrument The aciclovir compound was dosed by means of HPCL analysis with UV withholding at a wavelength of 254 nm The debt of the mobile phase was 1 ml/min of the substance to be eluted with the mobile phase of methanol 0 1 M of hydrochloric acid
0 02 M of SHS and 0 25 M of sodium chloride ( 10 10 20 60) The chromatographic columns used were at inverted phases MCH-10 of 30 cm lenght and 0 42 inner diameter (as described in the literature by Smith, R L and Walker, D D and by Fujuoka Y et al )
The data obtained in these pharmacokinetic phases clearly indicate the absoφtion of the 5,7-dιacetoxy-4-phenylcoumann (300 mg/kg) after oral administration into the rat The presence of the 5,7-dιacetoxy-4- phenylcoumaπn in the plasma occurs after 30 minutes from its administration and its presence can be detected in the blood even 6 hours after its oral administration The tests conducted with the model
compound aciclovir confirm the results described in (Fujioka Y et al , 1991), l e at these doses, absoφtion of the aciclovir compound is compromised, probaly due to a process saturation arising as a result of its limited solubility and of the onset of the gastrointestinal precipitation of the compound, thus leading to the reduction of its absoφtion and the subsequent permanence in the plasma of the animals Through the comparison between the plasmatic absoφtion data reported in Table 2 for the 5,7-dιacetoxy-4-phenvlcoumaπn and for aciclovir. it was determined that in doses of 300 mg/kg with oral administration, the 5,7-dιacetoxy-4-phenylcoumaπn
- starts being absorbed in a shorter time,
- throughout the process, is absorbed at higher concentration (on average, 7 times higher),
- is absorbed for a longer period of time (follows on pag.2() with Table 2)
TABLE 2 I ndividi αal Pha πnacok inetic d ata
Tιme(mιn) 30 60 90 120 180 240 300 360 420
Aciclovir
Rl 11 1 35 I 8 238 217 26 224 208 17
R2 118 143 193 279 334 341 238 217 21
R3 138 175 243 256 237 448 26 29 217
R4 127 169 293 22 284 337 291 246 206
Mean 123 156 227 248 268 347 253 240 201
5,7-diaceto y-4-phenylcoumarιn
R 1 816 124 1487 1646 329 3014 1788 1668 825
R2 106 1848 712 1782 356 312 1691 214 914
R3 1101 143 789 1504 301 2504 1 44 1311 8
R4 948 1551 1004 1764 3361 348 157 1597 71
R5 14 2076 161 2043 2729 2031 1893 1907 808
Mean 1066 1629 1120 1748 3190 2830 1777 1725 811
d) Cvtotox icitv:
The minimum non-toxic concentration (CMNT) of the compound is 125 μM e) Antiviral activity;
In in vitro tests against the Heφes simplex virus, the compound had an inhibiting activity of 85% at a concentration of 65 μM and an inhibiting activity of 95% at a concentration of 125 μM When tested in vitro for the cytomegalovirus, the compound had an inhibiting activity of 78% at a concentration of 65 μM
B. CLINICAL STUDIES
B 1 Clinical study of patients affected by Heφes simplex
The clinical study was conducted for 4 years on 80 voluntary patients - 40 men and 40 women aged between 22 and 48 who had already suffered recurring symptoms and used other antiviral drugs The product in the form of a cream with a concentration of 1 5% by weight was applied locally three times a day by means of light massaging of the affected area
In the study a quantity of placebo equivalent to 10% was used The results have shown that, in the entire patient population, 38% began clinical treatment at the first manifestation of the heφes. when they felt a burning or itchy sensation in the region subject to recidivation or immediately after the appearance of small blisters In these patients, the product completely inhibited the pain and infection, in other patients the product was able to reduce the infection over different time periods In those patients who had suffered from more than one recurrence during the clinical evaluation, the infective process was inhibited when they used the product at the start of the heφes infection In those patients who used placebos the clinical picture was typified by the absence of activity Duπng the study, 15% of the population interrupted the treatment B 2 Clinical study of patients affected by heφes zoster
The clinical study was conducted for a period of three months on 5 volunteer patients - 1 man aged 48 and 4 women aged between 55 and 66, suffering from heφes zoster The product in the form of a cream with a concentration of 2% by weight was applied locally three times a day with light massaging of the infected area
In this study, owing to the gravity of the condition, no placebo was used
Three patients began the clinical treatment at the onset of the heφes infection as soon as they felt a burning or itchy sensation in the affected region or immediately after the formation of small blisters In these patients the product partially inhibited the pain and the infection was stopped In the case of the patient infected over a considerable part of the lumbar region the result was not fully evaluated, whilst in the fifth patient the product induced an improvement in the clinical picture
Claims
1. Use of 4-arylcoumaπns having the general formula (I)
with at least one R, on πng A and at least one R2 on ring B in which R, and R;, identical or different are- hydrogen, halogen, linear or branched alkyl having 1-10 carbon atoms, optionally substituted with one or more halogen atoms, alkoxy having 1- 10 carbon atoms, and acyloxy having 1 -10 carbon atoms, for the preparation of pharmaceutical compositions which can be administered orally, parenterally or by means of local application and are suitable for the prevention and treatment of viral infections caused by
DNA viruses
2. Use according to Claim 1, wherein the DNA virus is a heφes virus
3. Use according to Claim 2. wherein the heφes virus is the heφes virus simplex type 1 (HSV-1), heφes virus simplex type 2 (HSV-2), varicella zoster virus (VZV) or cytomegalovirus (CMV).
4. Use according to Claim 3, wherein the composition is suitable for the prevention or treatment of heφes of the lips, genital heφes and heφes zoster.
5. Composition which can be administered orally, parenterally or by means of local application, suitable for the prevention or treatment of viral infections caused by DNA viruses comprising a 4-arylcoumarin having the general formula (I)
6. Composition according to Claim 5, for the prevention and treatment of infections contracted from heφes viruses.
7. Composition according to Claim 5 for the prevention and treatment of infections contracted from the heφes virus simplex type 1 (HSV-1 ), heφes virus simplex type 2 (HSV-2). varicella zoster virus (ZVZ) and cytomegalovirus (CMV)
8. Composition according to Claim 5, for the prevention and treatment of heφes of the lips, heφes of the genitals and heφes zoster.
9. Composition according to any one of Claims 5-8, composing a 4- arylcoumaπn having the general formula (F)
10. Composition according to Claim 9. wherein the 4-arylcoumaπn is 5,7-dιacetoxy-4-phenylcoumaπn
11. Composition according to any one of Claims 5-10, suitable for local application and comprising 0 1 to 20% by weight, preferably 1 to 10% by weight, of 4-arylcoumaπn having the formula (I) or (Y)
12. Composition according to Claim 11 in the form of a cream, ointment, lotion, foam, spray, eyewash, suppository or gel
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU78450/98A AU7845098A (en) | 1996-12-10 | 1997-12-09 | Pharmaceutical compositions comprising a 4-arylcoumarin for the treatment f vir al infections |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITRM96A000851 | 1996-12-10 | ||
| IT96RM000851A IT1289238B1 (en) | 1996-12-10 | 1996-12-10 | PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF VIRAL INFECTIONS INCLUDING A 4 ARILCUMARIN |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998025608A1 true WO1998025608A1 (en) | 1998-06-18 |
Family
ID=11404583
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IT1997/000306 WO1998025608A1 (en) | 1996-12-10 | 1997-12-09 | Pharmaceutical compositions comprising a 4-arylcoumarin for the treatment of viral infections |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU7845098A (en) |
| IT (1) | IT1289238B1 (en) |
| WO (1) | WO1998025608A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999054286A2 (en) * | 1998-04-17 | 1999-10-28 | Parker Hughes Institute | Btk inhibitors and methods for their identification and use |
| US6160010A (en) * | 1998-08-21 | 2000-12-12 | Parker Hughes Institute | BTK inhibitors and methods for their identification and use |
| WO2004101543A1 (en) * | 2003-05-15 | 2004-11-25 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | Coumarins compounds, the preparation and the use thereof |
| US6858602B2 (en) | 2001-06-12 | 2005-02-22 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| JP2009537459A (en) * | 2006-05-16 | 2009-10-29 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Inhibitors of human immunodeficiency virus replication |
| EP2295053A1 (en) | 2002-12-05 | 2011-03-16 | The Institute Of Materia Medica Of Chinese Academy Of Medical Sciences | Novel 2H-chromen-2-one-3-carboxamides for medical uses |
| WO2013164841A3 (en) * | 2012-03-12 | 2014-03-20 | Piramal Enterprises Limited | A method of treatment for acne and an anti-acne formulation |
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| JPH03227923A (en) * | 1990-01-30 | 1991-10-08 | Sawai Seiyaku Kk | Agent for treating human immunoinsufficiency virus disease |
| WO1992004326A1 (en) * | 1990-09-07 | 1992-03-19 | Schering Corporation | Antiviral compounds |
| WO1992004327A1 (en) * | 1990-09-07 | 1992-03-19 | Schering Corporation | Antiviral compounds and antihypertensive compounds |
| WO1992018123A2 (en) * | 1991-04-10 | 1992-10-29 | Octamer, Inc. | A method for inhibition of retroviral replication |
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- 1996-12-10 IT IT96RM000851A patent/IT1289238B1/en active IP Right Grant
-
1997
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- 1997-12-09 AU AU78450/98A patent/AU7845098A/en not_active Abandoned
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| JPH03227923A (en) * | 1990-01-30 | 1991-10-08 | Sawai Seiyaku Kk | Agent for treating human immunoinsufficiency virus disease |
| WO1992004326A1 (en) * | 1990-09-07 | 1992-03-19 | Schering Corporation | Antiviral compounds |
| WO1992004327A1 (en) * | 1990-09-07 | 1992-03-19 | Schering Corporation | Antiviral compounds and antihypertensive compounds |
| WO1992018123A2 (en) * | 1991-04-10 | 1992-10-29 | Octamer, Inc. | A method for inhibition of retroviral replication |
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| REHER, G. ET AL.: "new Neo- flavonoids from Coutarea Latiflora", JOURNAL OF NATURAL PRODUCTS, vol. 47, no. 1, January 1984 (1984-01-01) - February 1984 (1984-02-01), pages 172 - 174, XP002900058 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999054286A2 (en) * | 1998-04-17 | 1999-10-28 | Parker Hughes Institute | Btk inhibitors and methods for their identification and use |
| WO1999054286A3 (en) * | 1998-04-17 | 2000-05-04 | Wayne Hughes Inst | Btk inhibitors and methods for their identification and use |
| US6160010A (en) * | 1998-08-21 | 2000-12-12 | Parker Hughes Institute | BTK inhibitors and methods for their identification and use |
| US6221900B1 (en) | 1998-08-21 | 2001-04-24 | Hughes Institute | BTK inhibitors and methods for their identification and use |
| US6294575B1 (en) | 1998-08-21 | 2001-09-25 | Parker Hughes Institute | BTK inhibitors and methods for their identification and use |
| US6303652B1 (en) | 1998-08-21 | 2001-10-16 | Hughes Institute | BTK inhibitors and methods for their identification and use |
| US6365626B1 (en) | 1998-08-21 | 2002-04-02 | Parker Hughes Institute | BTK inhibitors and methods for their identification and use |
| US6753348B2 (en) | 1998-08-21 | 2004-06-22 | Parker Hughes Institute | BTK inhibitors and methods for their identification and use |
| US7041659B2 (en) | 2001-06-12 | 2006-05-09 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US7863475B2 (en) | 2001-06-12 | 2011-01-04 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US6916848B2 (en) | 2001-06-12 | 2005-07-12 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US6924314B2 (en) | 2001-06-12 | 2005-08-02 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US6946491B2 (en) | 2001-06-12 | 2005-09-20 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US7012071B2 (en) | 2001-06-12 | 2006-03-14 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US8604083B2 (en) | 2001-06-12 | 2013-12-10 | Wellstat Therapeutics Corporation | Method for the treatment of metabolic disorders |
| US7045541B2 (en) | 2001-06-12 | 2006-05-16 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US7101910B2 (en) | 2001-06-12 | 2006-09-05 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US8552062B2 (en) | 2001-06-12 | 2013-10-08 | Wellstat Therapeutics Corporation | Methods for the treatment of metabolic disorders such as diabetes |
| US7329782B2 (en) | 2001-06-12 | 2008-02-12 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US7547802B2 (en) | 2001-06-12 | 2009-06-16 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US8487000B2 (en) | 2001-06-12 | 2013-07-16 | Wellstat Therapertics Corporation | Compound for the treatment of metabolic disorders |
| US6858602B2 (en) | 2001-06-12 | 2005-02-22 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| EP2295053A1 (en) | 2002-12-05 | 2011-03-16 | The Institute Of Materia Medica Of Chinese Academy Of Medical Sciences | Novel 2H-chromen-2-one-3-carboxamides for medical uses |
| US7259265B2 (en) | 2003-05-15 | 2007-08-21 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | Coumarin compounds and method for preparing and using the same |
| WO2004101543A1 (en) * | 2003-05-15 | 2004-11-25 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | Coumarins compounds, the preparation and the use thereof |
| JP2009537459A (en) * | 2006-05-16 | 2009-10-29 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Inhibitors of human immunodeficiency virus replication |
| WO2013164841A3 (en) * | 2012-03-12 | 2014-03-20 | Piramal Enterprises Limited | A method of treatment for acne and an anti-acne formulation |
| US9556138B2 (en) | 2012-03-12 | 2017-01-31 | Piramal Enterprises Limited | Method of treatment for acne and an anti-acne formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1289238B1 (en) | 1998-09-29 |
| ITRM960851A0 (en) | 1996-12-10 |
| ITRM960851A1 (en) | 1998-06-10 |
| AU7845098A (en) | 1998-07-03 |
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