WO1998009968A1 - Dicetopiperazines terpenylees (drimentines) - Google Patents

Dicetopiperazines terpenylees (drimentines) Download PDF

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Publication number
WO1998009968A1
WO1998009968A1 PCT/IB1997/001425 IB9701425W WO9809968A1 WO 1998009968 A1 WO1998009968 A1 WO 1998009968A1 IB 9701425 W IB9701425 W IB 9701425W WO 9809968 A1 WO9809968 A1 WO 9809968A1
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Prior art keywords
drimentine
drimentines
active ingredient
structural
bond
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PCT/IB1997/001425
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English (en)
Inventor
Ernest Lacey
Michelle Power
Zemin Wu
Rodney Warren Rickards
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Novartis Animal Health Australasia Pty. Limited
Microbial Screening Technologies Pty. Limited
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Application filed by Novartis Animal Health Australasia Pty. Limited, Microbial Screening Technologies Pty. Limited filed Critical Novartis Animal Health Australasia Pty. Limited
Priority to AU47203/97A priority Critical patent/AU4720397A/en
Publication of WO1998009968A1 publication Critical patent/WO1998009968A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system

Definitions

  • the present invention relates to a novel class of antibiotics, the drimentines, and to structural and functional derivatives thereof.
  • the chemical structure of drimentines is presented below.
  • the present invention further relates to a process for producing said drimentines, to the use of this novel class of antibiotics in a wide range of therapeutic applications which include but are not limited to the treatment of bacteria, fungi, endoparasite and ectoparasite infections, cancer and other malignant diseases in human and animal health.
  • the present invention relates to microoganisms capable of producing a drimentine.
  • the present invention is based on the isolation of a soil-borne microorganism that produces the drimentines as a novel class of antibiotics.
  • Said microorganism is an Actinomycete strain which was isolated from under an Acacia sp. tree in a dry creek bed near the township of Dungog, New South Wales, Australia.
  • V_ V_
  • Actinomycete strain produces a complex of substances which after purification could be resolved into five individual components, named: drimentines A, B, C, D and E.
  • Drimentine E formula (le )
  • the physico-chemical and biological properties of the drimentines compared with known antibiotics confirmed the drimentines to be a novel class of antibiotics possessing a new terpenylated diketopiperazine structure which is not similar to any chemical structure of any known class of antibiotics.
  • HREIMS High resolution electron impact mass spectrometry
  • UV Ultraviolet spect.ophotometry
  • IR Infra-red spectrophotometry
  • Optical rotatory analysis [ ]
  • CD Circular dichroism analysis
  • NMR Nuclear magnetic resonance spectrometry
  • the present invention is based on: (1 ) the discovery of a microorganism that provides the drimentines as a novel class of antibiotics, (2) the drimentines per se as well as structural derivatives and functional analogues, (3) a process for their production which comprises culturing a microorganism capable of producing drimentines, preferably a drimentine- producing bacterial, more preferably a drimentine-producing Actinomycete strain, most preferably Actinomycete strain MST-8651 or an optimized strain derived therefrom, (4) isolation of a drimentine from the culture product, (5) the use of a drimentine in a broad range of therapeutic applications and (6) the conversion of a drimentine into a structural derivative thereof or to another therapeutically useful compound by chemical or biological means as exemplified below by the preparation of the derivative 3,25-dihydrodrimentine E of formula If and by the conversion of one drimentine into a
  • a structural derivative of a drimentine is a molecule that still contains the basic structural elements shown under formula ( A ) but may contain one or more substituents.
  • a functional derivative may show greater structural modifications but displays still a similar spectum of activity.
  • the term 'chemical means' embraces but is not limited to chemical manipulations such as exposing the drimentine-producing strain to chemical stress (e.g. culturing in the presence of a chemical mutating agent), or to the incorporation of one or more chemical substituents at one or more reactive positions of the molecule by suitable chemical reactions such as halogenation, alkylation, halo-alkylation, acylation, halo-acylation, hydrogenation, hydroxylization, esterification, etherification, etc. Such reactions are widely used in chemistry and well known to the skilled artisan.
  • biological means embraces but is not limited to biological or microbiological manipulations such as fusion of a producing strain with a non-producing strain, the isolation of the gene or gene cluster responsible for the production of a drimentine and the incorporation of said gene or gene cluster into a different strain or microorganism or even into a cell of a higher organism by means of genetic engineering.
  • the drimentines A to E and 3,25-dihydrodrimentine E of the present invention show the following chemical structures:
  • the drimentines can be produced by culturing an appropriate microorganism, preferably a drimentine-producing microorganism, more preferably a drimentine-producing bacterial strain, even more preferably a drimentine-producing Actinomycete strain, most preferably Actinomycete strain MST-8651 or any optimized strain derived therefrom, in an suitable culture medium.
  • Suitable culture media are those containing nutrients which are commonly utilized by said microorganism.
  • culture media are used which are commonly utilized by Actinomycetes.
  • the carbon sources there may be used glucose, glycerol, sucrose, dextrin, starch, etc.
  • the nitrogen sources there may be employed soybean meal, wheat embryo, peptone, meat extract, yeast extract, corn steep liquor, an ammonium salt, etc. Further, if necessary, inorganic salts such as calcium carbonate, potassium chloride, magnesium sulfate and phosphates may be used.
  • a culturing method a liquid or solid phase fermentation is suitable. The culturing conditions such as the cultivation temperature, time, etc. are selected so that they are suitable for the growth of the microorganism used, and for the production of the antibiotic at the maximum yield. The production of the antibiotics reaches the maximum when the cultivation with aeration-agitation is conducted at a cultivation temperature from 25 to 35 C C for 92 to 144 h.
  • the drimentines are produced and accumulated in the mycelia and may be isolated and purified by means of conventional methods. For example, a method utilizing the differing partitioning behavior of the antibiotics and impurities between organic and aqueous solutions, a method of utilizing the difference in the solubility between the antibiotic and impurities, and a method of utilizing the difference in the adsorption may be used individually or in combination, or repeatedly.
  • the drimentines of the invention have broad therapeutic activity, for example, antibacterial activity against Gram positive and Gram negative bacteria; antifungal activity against fungi and yeasts; anthelmintic activity against nematodes, cestodes and trematodes, and other endoparasites; activity against a broad range of important accarina, insecticidal activity against a range of ectoparasites; anticancer activity against a range of malignant cells types.
  • the compounds of the invention are therefore of use in treating animals and humans with a broad range of therapeutic needs.
  • Ectoparasites and endoparasites infect humans and a variety of animals and are particularly prevalent in farm animals such as pigs, sheep, cattle, goats and poultry (for example, chickens and turkeys), horses, rabbits, game-birds, caged birds, and domestic animals such as dogs, cats, guinea pigs, gerbils and hamsters. Parasitic infection of livestock, leading to anaemia, malnutrition and weight loss is a major cause of economic loss throughout the world.
  • Examples of genera of endoparasites infecting such animals and/or humans are Ancylostoma, Ascaridia, Ascaris, Aspicularis, Brugia, B ⁇ nostomum, Capillaria, Chabertia, Cooperia, Dictyocauius, Dirofilaria, Dracunculus, Enterobi ⁇ s, Haemonchus, Heterakis, Loa, Necator, Nematodirus, Nematospiroides (Heligomoroides) Nippostrongyius, Oesophagostom ⁇ m, Onchocerca, Ostertagia Oxyuris, Parascaris, Strongylus, Strongyloides, Syphacia, Toxasca s, Toxocara, Trichonema, Trichostrongylus, Trichinella, Trichuris, Triodontophorus, Uncinaria and Wuchereria.
  • arthropod ectoparasites such as biting insects, blowfly, fleas, lice, mites, sucking insects, ticks and other dipterous pests.
  • Examples of genera of such ectoparasites infecting animals and/or humans are Ambylomma Boophilus, Ctenocephalides , Chorioptes, Calliphora, Demodex, Damalinia, Dermatobia, Gastrophilus, Haematobia, Haematopinus, Haemaphysalis, Hyaloma, Hypoderma, Ixodes, Linognathus, Lucilia, Melophagus, Oestrus, Otobius, Otodectes, Psorergates, Psoroptes, Rhipicephalus, Sarcoptes Stomoxys and Tabam y s.
  • Compounds of the invention are also of use as anti-fungals, for example, against strains of Candida sp.
  • Pests of soil and plant crops including cereals (for example, wheat, barley, maize and rice), cotton, tobacco, vegetables (for example, soya), fruit (for example, apples, vines and citrus) as well as root crops (for example, sugarbeet, potatoes) may usefully be treated.
  • pests are fruit mites and aphids such as Aphis fabae, Aulacorthum circumflexum, Myzus persicae, Nephotettix cincticeps, Nilparvats lugens, Panonych ⁇ s ulmi, Photodon humuli, Phyllocoptmta oleivora, Tetranychus ⁇ rticae and members of the genera T ale ⁇ roides; nematodes such as members of the genera Aphelencoides, Globodera, Heterodera, Meloidogyne and Panagrellus; Lepidoptera such as Heliothis, Plutella and Spodoptera; gram weevils such as Anthonom ⁇ s grandis and Sitophil ⁇ s granarius; flour beetles such as Tribolium castaneum; flies such as Musca domestica; fire ants; leaf miners; Pear p ⁇ ylla; Thrips
  • the present invention provides the drimentines as a novel class of antibiotics. They may be formulated for administration purposes in any convenient way for use in human or veterinary medicine and the invention therefore includes within its scope pharmaceutical compositions comprising as active ingredient a drimentine or a derivative thereof. Depending on the medical indication the compounds and pharmaceutical compositions in accordance with the invention can be adapted for the specific use in human or veterinary medicine. Such compositions may be presented for use in conventional manner with the aid of one or more suitable carriers or excipients. Suitable carriers or excipients are those which are physiologically acceptable to the organism to which the drimentine has to be administered. Carriers or excipients that cause no undesirable side- effects are preferred.
  • the compositions of the invention include those in a form especially formulated for parenterai (including intramammary administration), oral, rectal, topical, transdermal, implant, ophthalmic, nasal or genito-urinary use.
  • the drimentines according to the invention may be formulated for use in human or veterinary medicine by injection and may be presented in unit dose form, in ampoules, or other unit-dose containers, or in multi-dose containers, if necessary with an added preservative.
  • the compositions for injection may be in the form of suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, solubilising and/or dispersing agents.
  • the active ingredient may be in sterile powder form for reconstitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.
  • Oily vehicles include polyhydric alcohols and their esters such as glycerol esters, fatty acids, vegetable oils such as arachis oil or cottonseed oil, mineral oils such as liquid paraffin, and ethyl oleate and other similar compounds. Other vehicles such as propylene glycol may also be used.
  • Compositions for veterinary medicine may also be formulated as intramammary preparations in either long acting or quick-release bases and may be sterile solutions or suspensions in aqueous or oily vehicles optionally containing a thickening or suspending agent such as soft or hard paraffins, beeswax, 12-hydroxy stearin, hydrogenated castor oil, aluminum stearates, or glyceryl monostearate. Conventional non-ionic, cationic or anionic surface active agents may be used alone or in combination in the composition.
  • the drimentines of the invention may also be presented for human or veterinary use in a form suitable for oral administration, for example in the form of solutions, syrups or suspensions, or a dry powder for constitution with water or other suitable vehicle before use, optionally with flavouring and coloring agents.
  • Solid compositions such as tablets, capsules, lozenges, pills, boluses, powder, pastes, granules, pellets or premix preparations may also be used.
  • Solid and liquid compositions for oral use may be prepared according to methods well known in the art. Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.
  • suitable pharmaceutically acceptable carriers for use in solid dosage forms include binding agents (for example, pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (for example, lactose, micro-crystalline cellulose or calcium phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or sodium starch glycollate); or wetting agents (for example, sodium lauryl sulphate). Tablets may be coated by methods well known in the art.
  • binding agents for example, pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers for example, lactose, micro-crystalline cellulose or calcium phosphate
  • lubricants for example, magnesium stearate, talc or silica
  • disintegrants for example, potato starch or sodium starch glycollate
  • wetting agents for example, sodium lauryl sulphate
  • suitable pharmaceutically acceptable additives for use in liquid dosage forms include suspending agents (for example, sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (for example, almond oil, oily esters or ethyl alcohol); and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid); stabilizing and solubilising agents may also be included.
  • suspending agents for example, sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents for example, lecithin or acacia
  • non-aqueous vehicles for example, almond oil, oily esters or ethyl alcohol
  • preservatives for example, methyl or propyl p-hydroxybenzoates or sorbic acid
  • stabilizing and solubilising agents may also be included.
  • Pastes for oral administration may be formulated according to methods well known in
  • suitable pharmaceutically acceptable additives for use in paste formulations include suspending or gelling agents for example, aluminum distearate or hydrogenated castor oil; dispersing agents for example, polysorbates, non-aqueous vehicles for example, arachis oil or oily esters; stabilizing and solubilising agents.
  • suspending or gelling agents for example, aluminum distearate or hydrogenated castor oil
  • dispersing agents for example, polysorbates, non-aqueous vehicles for example, arachis oil or oily esters
  • stabilizing and solubilising agents include suspending or gelling agents for example, aluminum distearate or hydrogenated castor oil; dispersing agents for example, polysorbates, non-aqueous vehicles for example, arachis oil or oily esters; stabilizing and solubilising agents.
  • the compounds of the invention may also be administered in veterinary medicine by incorporation thereof into animals' daily solid or liquid dietary intake, for example, as part of the daily animal feed or drinking water.
  • the compounds of the invention may also be administered orally in veterinary medicine in the form of a liquid drench such as a solution, suspension or dispersion of the active ingredient together with a pharmaceutically acceptable carrier or excipient.
  • a liquid drench such as a solution, suspension or dispersion of the active ingredient together with a pharmaceutically acceptable carrier or excipient.
  • the drimentines of the invention may also, for example, be formulated as suppositories for example, containing conventional suppository bases for use in human or veterinary medicine or as pessaries for example, containing conventional pessary bases.
  • Drimentines according to the invention may be formulated for topical administration, for use in veterinary and human medicine, as ointments, creams, lotions, shampoos, powders, pessaries, sprays, dips, aerosols, drops (for example, eye or nose drops) or pour-ons.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.
  • Pour-ons may, for example, be formulated for veterinary use in oils containing organic solvents, optionally with formulatory agents for example, stabilizing and solubilising agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Powders may be formed with the aid of any suitable powder base.
  • Drops may be formulated with an aqueous or non aqueous base also comprising one or more dispersing agents, stabilizing agents, solubilising agents or suspending agents. They may also contain a preservative.
  • the drimentines according to the invention may be delivered for use in human or veterinary medicine in the form of an aerosol spray presentation or an insufflator.
  • the drimentines of the present invention may be administered in combination with other pharmaceutically active ingredients to broaden the spectrum of activity.
  • the total daily dosages of drimentines ot the invention employed in both veterinary and human medicine will suitably be in the range 0,01-2000 mg/kg body-weight, preferably from 0,1 -1000 mg/kg body-weight, preferably from 1 -100 mg/kg and these may be administered as single or divided doses. However, they can also be administered as depot preparations (implants, slow-release formulations, etc.) weekly, monthly or at even longer intervals. In such cases the dosage will be much higher than the daily one and has to be adapted to the administration form, the body weight and the concrete indication.
  • the appropriate dosage can be determined by conducting model tests, preferably via animal models.
  • the drimentines according to the invention may be formulated in any convenient way for horticultural or agricultural use and the invention therefore includes within its scope compositions comprising a compound according to the invention adapted for horticultural or agricultural use.
  • Such formulations include dry or liquid types, for example dusts, including dust bases or concentrates, powders, including soluble or wettable powders, granulates, including microgranules and dispersible granules, pellets, flowables, emulsions such as dilute emulsions or emulsifiable concentrates, dips such as root dips and seed dips, seed dressings, seed pellets, oil concentrates, oil solutions, injections for example, stem injections, sprays, smokes and mists.
  • Such formulations will include the compound in association with a suitable carrier or diluent.
  • a suitable carrier or diluent may be liquid or solid and designed to aid the application of the compound either by way of dispersing it where it is to be applied or to provide a formulation which can be made by the user into a dispersible preparation.
  • Such formulations are well known in the art and may be prepared by conventional methods such as, for example, by blending and/or grinding of the active ingredient(s) together with the carrier or diluent, for example, solid carrier, solvent or surface active agent.
  • Suitable solid carriers for use in formulations such as dusts, granulates and powders may be selected from, for example, natural mineral fillers, such as diatomite, talc, kaolinite, montmorillonite, prophyllite or attapulgite. Highly dispersed acid or highly dispersed absorbent polymers may, if desired, be included in the composition.
  • Granulated adsorptive carriers which may be used may be porous (such as pumice, ground brick, sepiolite or bentonite) or non-porous (such as calcite or sand).
  • Suitable pregranulated materials which may be used may be organic or inorganic including dolomite and ground plant residues.
  • Suitable solvents for use as carriers or diluents include but are not limited to: aromatic hydrocarbons, aliphatic hydrocarbons, alcohols and glycols or ethers thereof, esters, ketones, acid amides, strongly polar solvents, optionally epoxidized vegetable oils and water.
  • non ionic, cationic or anionic surface-active agents for example, ethoxylated alkyl phenols and alcohols, alkali metal or alkaline earth metal salts of alkyl benzene sulphonic acids, lignosulphonic acids or sulphosuccinic acids or sulphonates of polymeric phenols which have good emulsifying, dispersing and/or wetting properties may also be used either alone or in combination in the compositions.
  • Stabilizers anti-caking agents, anti-foaming agents, viscosity regulators, binders and adhesives, photostabilisers, as well as fertilisers, feeding stimulants or other active substances may, if desired, be included in the compositions.
  • the compounds of the invention msy also be formulated in admixture with other therapeutically active compounds.
  • the concentration of active material is generally from 0.01 to 99% and more preferably between 0.01 % and 40% by weight.
  • Commercial products are generally provided as concentrated compositions to be diluted to an appropriate concentration, for example from 0.001 to 0.0001% by weight, for use.
  • the compounds of the invention can be prepared by the processes described in detail below. If other producing microorganisms are used the culture medium and the culturing condition have to be adapted to the corresponding microorganism.
  • the following examples exemplify the production of drimentines but do not limit the scope of the present invention to these specific examples.
  • Example 1 Fermentation and isolation of the drimentines
  • Agar slope cultures (ISP-2 agar comprising: Yeast Extract 0.4%, Malt Extract 1%, Glucose 0.4%, Agar 2% made up to volume, adjusted to pH 7.3 and sterilized by autoclaving prior to use) of Actinomycete strain MST-8651 are grown for 5 days, covered with sterile distilled water, and the surface is gently scraped to produce a suspension of the organism. The suspension is dispensed into baffled Erlenmeyer flasks (250 ml) containing seed medium (ISP-2 broth comprising ISP-2 agar without Agar, 100 ml), using one slope for two flasks, and incubated at 28°C for 2 days with shaking (200 rpm).
  • baffled Erlenmeyer flasks 250 ml
  • seed medium ISP-2 broth comprising ISP-2 agar without Agar, 100 ml
  • the resulting inoculum is dispensed into production medium (ISP-2 broth) in baffled Erlenmeyer flasks (10 ml inoculum, 100 ml medium per 250 ml flask), which are then incubated with shaking (200 rpm) at 28°C for 4 days.
  • the fermentation (3 I) at harvest is adjusted from pH 8.5 to 5.5 with concentrated hydrochloric acid, and the cell mass is separated by centrifugation and filtration.
  • the culture filtrate is extracted with ethyl acetate (3 x 650 ml), and the combined extracts after drying over anhydrous sodium sulphate are evaporated to give the crude medium extract (234 mg).
  • the cell mass is extracted by stirring gently for 1 h with acetone (2 x 500 ml).
  • the combined acetone extracts are concentrated on a rotary evaporator to an aqueous residue (20 ml, pH 5.5), which is extracted with ethyl acetate (3 x 20 ml) to give after drying the crude cell extract (700 mg).
  • CD (c. 1.8x10 * 2) (c. 1.6x10-2) (c. 2.5x10 *2 ) (c. 4.5x10" 2 ) (c. 9.7x10 *3 ) nm ⁇ 326 -0.13 342 0 317 0 342 0 316 0
  • Drimentine D (6 mg) in chloroform (1 ml) is stirred with hydrochloric acid (2N, 0.1 ml) for 58 h. After adding dichloromethane (15 ml) and saturated aqueous sodium carbonate (2 ml), the organic layer is separated, dried over anhydrous sodium sulphate, and evaporated under vacuum. Chromatography of the residue on silica gel in ethyl acetate/hexane afforded drimentine A (2.6 mg, 43%), identified by R* value on TLC and 1 H NMR spectrum in comparison with authentic material, together with starting material (3.4 mg).
  • drimentine E (6 mg) with hydrochloric acid as for drimentine D gives drimentine B (2.8 mg, 47%), identified similarly, together with recovered material (3.2 mg).
  • Drimentine E (5 mg) in ethanol (2 ml) is stirred with 10% palladium on charcoal catalyst (5 mg) under hydrogen for 1 .5 h. The catalyst is removed by filtration and the solvent evaporated under vacuun * to give 3,25-dihydrodrimentine E (5 mg, 100%), mp 180-182°C; Found; M + , m/z 487.3196. Calc. for C 31 H 4 .N 3 O m/z 487.3199.
  • Example 7 Conversion of 3.25-dihvdrodrimentine E into drimentine C
  • drimentine E (4.5 mg) treated with hydrochloric acid as for drimentine D for 65 h gives drimentine C (1.6 mg, 36%), purified by chromatography on silica gel in acetone/dichloromethane and identified by R ( value on TLC and 1 H NMR spectrum in comparison with authentic material, together with recovered material (2.8 mg).
  • Example 8 Antitumor activity of the drimentines: f 3 Hl thvmidine uptake test:
  • Stock solutions of drimentines A to E (1 mg/ml, 200 ⁇ l) are individually serially diluted with methanol (100 ⁇ l) to provide a range of 12 concentrations from 1000 ⁇ g/ml to 0.45 ⁇ g/ml. An aliquot (10 ⁇ l) of each dilution is then transferred to the appropriate wells of a 96-well microtitre plate and evaporated to dryness.
  • NS-1 murine myeloma cells suspended in RMPI 1640 media (50,000 cells/ml, 190 ⁇ l) and [ 3 H]thymidine (ICN 2406601 , 10 ⁇ l) are added to each well and the plates are incubated for 6 h before the cells are harvested onto glass fibre mats and the tritium content of the cells is measured by liquid scintillation spectroscopy. The percent inhibition of cell growth is determined by:
  • Table 7 Percentage inhibition of f 3 H] thvmidine uptake in NS-1 murine beta lymphocyte myeloma cells by drimentines A to E.
  • a stock solution of drimentine E (1 mg/ml, 200 ⁇ l) is serially diluted with methanol (100 ⁇ l) to provide a range of 12 concentrations from 1000 ⁇ g/ml to 0.45 ⁇ g/ml.
  • An aliquot (10 ⁇ l) of each dilution is then transferred to the appropriate wells of a 96-well microtitre plate, evaporated to dryness then reconstituted in 10% (v/v) dimethyl sulfoxide (DMSO) in water (10 ⁇ l).
  • DMSO dimethyl sulfoxide
  • the cooled agar is inoculated with a dilute suspension of Bacillus subtilis (5 ⁇ l) and incubated at 28°C for 24 h after which the wells are inspected for bacterial growth.
  • Drimentine E shows antibacterial activity against Bacillus subtilis down to 50 ⁇ g/ml.
  • compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
  • pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture and processing the mixture of granules, if desired or necessary after the addition of suitable excipients, to form tablets or dragee cores.
  • compositions for the use in human health illustrate the invention described above, but do not imply any limitation of the scope thereof.
  • Example 10 Tablets each comprising 20 mg of active ingredient (drimentine A) are prepared in the customary manner, for example in the following composition: Composition: active ingredient 20 mg wheat starch 60 mg lactose 50 mg colloidal silica 5 mg talc 9 mg magnesium stearate 1 m ⁇
  • the active ingredient is mixed with a portion of the wheat starch, with lactose and colloidal silica and the mixture is forced through a sieve.
  • a further portion of the wheat starch is made into a paste with 5 times the amount of water on a water bath and the powder mixture is kneaded with the paste until a slightly plastic mass is obtained.
  • the plastic mass is pressed through a sieve of about 3 mm mesh size and dried, and the resulting dry granules are forced through a sieve once more.
  • the remainder of the wheat starch, the talc and the magnesium stearate are admixed and the mixture is pressed to form tablets each weighing 145 mg and having a breaking notch.
  • Example 1 1 Tablets each comprising 1 mg of active ingredient (drimentine A) are prepared in the customary manner in the following composition:
  • composition active ingredient 1 mg wheat starch 60 mg lactose 50 mg colloidal silica 5 mg talc 9 mg magnesium stearate 1 m ⁇
  • composition active ingredient 2500 mg talc 200 mg colloidal silica 50 mg
  • the active ingredient is homogeneously mixed with talc and colloidal silica, and the mixture is forced through a sieve of 0.5 mm mesh size and introduced in portions of 1 1 mg into hard gelatine capsules of a suitable size.
  • Capsules each comprising 25 mg of active ingredient, for example one of the compounds of the formula I described in the preceding examples, are prepared as follows:
  • composition active ingredient, gelucire 44/14 (gelucire 44/14 is an admixture of esters of saturated C 8 -C ⁇ 8 -fatty acids with glycerol and polyethylene glycol having a molecular weight of approximately 1500; produced by Gatte-fosse, F-69800 Saint Priest, France).
  • Preparation A portion of gelucire 44/14 is melted at a temperature of from 50°C to 100°C.
  • the active ingredient is mixed with the liquid gelucire 44/14 in a heated mortar to form a paste.
  • the remainder of the gelucire 44/14 is then also melted and is added to the paste.
  • the mixture is stirred at 50°C until a solution is obtained. This is introduced into the capsules while warm and is cooled.
  • the wax so obtained comprises 12 % by weight active ingredient.
  • he wax-like dispersion can also be processed in water by ultrasound treatment to form a milky liquid that can be administered orally.
  • compositions for the use in animal health are provided.
  • Example 14 Tablets comprising 25 mg of active ingredient (drimentine A) can be prepared as follows: Constituents (for 1000 tablets) active ingredient 25.0 g lactose 100.7 g wheat starch 7.5 g polyethylene glycol 6000 5.0 g talcum 5.0 g magnesium stearate 1.8 g demineralised water q.s.
  • Example 15 Tablets comprising 0.02 g of active ingredient (drimentine A) are prepared as follows:
  • composition for 10 000 tablets
  • active ingredient 200.00 g lactose 290.80 g potato starch 274.70 g stearic acid 10.00 g talcum 200.00 g magnesium stearate 2.50 g colloidal silica 32.00 g ethanol q.s.
  • a mixture ot the active ingredient, the lactose and 194.70g of potato starch is moistened with an ethanolic solution of the stearic acid and granulated through a sieve. After drying, the remaining potato starch, the talcum, the magnesium stearate and the colloidal silica are mixed in and the mixture is compressed to form tablets each weighing 0.1 g, which may, if desired, be provided with dividing notches for finer adaptation of the dose.
  • Example 16 Tablets comprising 25 mg of active ingredient (drimentine A) can be prepared as follows using a direct compression process: Constituents (for 1000 tablets) active ingredient 25.0 g lactose, spray-dried 46.0 g microcrystalline cellulose 20.0g corn starch 5.0 g talcum 3.5 g magnesium stearate 0.5 g
  • Capsules comprising 0.025 g of active ingredient can be prepared as follows:
  • composition for 1000 capsules
  • active ingredient 25.00 g lactose 249.80 g gelatin 2.00 g corn starch 10.00 g talcum 15.00 g water q.s.
  • the active ingredient is mixed with the lactose, the mixture is moistened uniformly with an aqueous solution of the gelatin and granulated through a sieve having a mesh size of 1.2- 1.5 mm.
  • the granules are mixed with the dried corn starch and the talcum and introduced in 300 mg portions into hard gelatin capsules.
  • Example 18 Premix (food additive) 0.25 part by weight of active ingredient (drimentine A) and 4.75 parts by weight of secondary calcium phosphate, alumina, Aerosil, carbonate or chalk are mixed until homogeneous with 95 parts by weight of an animal food.
  • Example 19 Premix (food additive! 0.40 part by weight of active ingredient (drimentine A) and 5.00 parts by weight of Aerosil/chalk (1 :1) are mixed until homogeneous with 94.6 parts by weight of a commercial dry food.
  • Example 20 Emulsifiable concentrate 20 parts by weight of active ingredient (drimentine A) are mixed with 20 parts by weight of the emulsifier, e.g. a mixture of alkylarylpolyglycol ether with alkylarylpolysulfonates, and with 60 parts by weight of a solvent, until the solution has been completely homogenised.
  • the emulsifier e.g. a mixture of alkylarylpolyglycol ether with alkylarylpolysulfonates
  • Emulsions of the desired concentration are obtained by dilution with water.
  • Example 21 Solutions (e.g. for use as a drink additive) 15 percent by weight active ingredient (drimentine A) in 2,2-dimethyl-4-hydroxymethyl-
  • Example 22 Soluble powder 25 parts by weight of active ingredient (drimentine A)
  • the ingredients are mixed together and ground with one another until homogeneous.
  • Other biologically active compounds or adjuvants that are neutral towards the active ingredients and that have no adverse effect on the host animal to be treated, as well as mineral salts or vitamins, can be added to the compositions described.
  • Pest control composition for use in plant protection :
  • pesticides are, depending on the intended aims and the prevailing circumstances, emulsifiable concentrates, suspension concentrates, ready-to-spray or ready-to-dilute solutions, spreadable pastes, dilute emulsions, soluble powders, dispersable powders, wettable powders, dusts, granules or encapsulations in polymeric substances, all of these comprising the compound of the formula ( I ) (drimentine A).
  • the active ingredient is employed in pure form, for example the solid active ingredients in a specific particle size, or, preferably, together with - at least - one of the auxiliaries conventionally used in the art of formulation, such as extenders, for example solvents or solid carriers, or surface-active compounds (surfactants).
  • auxiliaries conventionally used in the art of formulation, such as extenders, for example solvents or solid carriers, or surface-active compounds (surfactants).
  • solvents which are suitable are: unhydrogenated or partially hydrogenated aromatic hydrocarbons, preferably the fractions C ⁇ to C, 2 of alkylbenzenes, such as xylene mixtures, alkylated naphthalene or tetrahydronaphthalene, aliphatic or cycloaliphatic hydrocarbons, such as paraffins or cyclohexane, alcohols, such as ethanol, propanol or butanol, glycols and their ethers and esters, such as propylene glycol, dipropylene glycol ether, ethylene glycol, ethylene glycol monomethyl ether or ethylene glycol monoethyl ether, ketones, such as cyclohexanone, isophorone or diacetone alcohol, strongly polar solvents, such as N-methylpyrrolid-2-one, dimethyl sulfoxide or N,N-dimethylformamide, water, unepoxidized or epoxidized vegetable oils, such as unepoxidized
  • Solid carriers which are used for example for dusts and dispersable powders are, as a rule, ground natural minerals, such as calcite, talc, kaolin, montmorillonite or attapulgite. Highly- disperse silicas or highly-disperse absorptive polymers may also be used to improve the physical properties.
  • Suitable particulate, adsorptive carriers for granules are porous types, such as pumice, brick gi ' t, sepiolite or bentonite, and suitable non-absorptive carrier materials are calcite or sand.
  • suitable non-absorptive carrier materials are calcite or sand.
  • a large number of granulated materials of inorganic or organic nature, in particular dolomite or comminuted plant residues may be used.
  • Suitable surface-active compounds are, depending on the nature of the active ingredient to be formulated, non-ionic, cationic and/or anionic surfactants or surfactant mixtures having good emulsifying, dispersing and wetting properties.
  • the surfactants listed below are only given by way of example; a large number of other surfactants conventionally used in the art of formulation and suitable according to the invention are described in the relevant literature.
  • Suitable non-ionic surfactants are mainly polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated or unsaturated fatty acids and alkylphenols, which can have 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon radical and 6 to 18 carbon atoms in the alkyl radical of the alkylphenols. Also suitable are water-soluble polyethylene oxide adducts with polypropylene glycol, ethylene diaminopolypropylene glycol and alkyl polypropylene glycol having 1 to 10 carbon atoms in the alkyl chain and comprising 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups.
  • the above-mentioned compounds conventionally have 1 to 5 ethylene glycol units per propylene glycol unit.
  • examples which may be mentioned are nonylphenol polyethoxyethanols, castor oil polyglycol ether, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxypolyethoxyethanol.
  • fatty acid esters or polyoxyethylene sorbitan such as polyoxyethylene sorbitan trioleate.
  • the cat i onic surfactants are mainly quaternary ammonium salts which have, as substituents, at least one alkyl radical having 8 to 22 carbon atoms and as further substituents lower, halogenated or unhalogenated alkyl, benzyl or lower hydroxyalkyl radicals.
  • the salts are preferably in the form of halides, methylsulfates or ethylsulfates. Examples are stearyl-trimethyl-ammonium chloride and benzyl di-(2- chloroethyl)ethylammonium bromide.
  • Suitable anionic surfactants can be water-soluble soaps and also water-soluble synthetic surface-active compounds.
  • Soaps which are suitable are the alkali metal salts, alkaline earth metal salts and substituted or unsubstituted ammonium salts of higher fatty acids (C ⁇ o- C 22 ), such as the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained, for example, from coconut or tall oil; fatty acid methyl- taurinates should furthermore be mentioned.
  • fatty sulfonates are, as a rule, in the form of alkali metal salts, alkaline earth metal salts or substituted or unsubstituted ammonium salts and have, as a rule, an alkyl radical of 8 to 22 carbon atoms, even if alkyl is the alkyl moiety of acyl radicals, for example the sodium salt or calcium salt of lignosulfonic acid, of the dodecylsulfuric ester or of a fatty alcohol sulfate mixture prepared from natural fatty acids.
  • T s group also includes the salts of the sulfuric esters and sulfonic acids of fatty alcohol/ethylene oxide adducts.
  • the sulfonated benzimidazole derivatives comprise preferably 2 sulfonyl groups and a fatty acid radical having approximately 8-22 carbon atoms.
  • Alkylarylsulfonates are, for example, the sodium salts, calcium salts or tri- ethanolammonium salts of dodecylbenzenesulfonic acid or of a naphthalenesulfonic acid/formaldehyde condensate.
  • Suitable phosphates for example salts of the phosphoric ester of a p- ⁇ onylphenol/(4-14)-ethylene oxide adduct, or phospholipids, are also suitable.
  • Emulsifiable concentrates factive ingredient (drimentine A)]:
  • Surfactant 1 to 30 %, preferably 10 to 20 %
  • Solvent 5 to 98 %, preferably 70 to 85 % Dusts [active ingredient (drimentine A)l;
  • Solid carrier 99.9 to 90 %, preferably 99.9 to 99 %
  • Surfactant 1 to 40 %, preferably 2 to 30 %
  • Surfactant 0.5 to 20 %, preferably 1 to 15 %
  • Solid carrier 5 to 99 %, preferably 15 to 98 %
  • Solid carrier 99.5 to 70 %, preferably 97 to 85 %
  • compositions according to the invention can also comprise other solid or liquid auxiliaries, such as stabilizers, for example epoxidized or unepoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or adhesives, and also fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematicides, molluscicides or herbicides.
  • auxiliaries such as stabilizers, for example epoxidized or unepoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or adhesives, and also fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematicides, molluscicides or
  • compositions according to the invention are prepared in a known manner, for example in the absence of auxiliaries by grinding, screening and/or compressing a solid active ingredient or mixture of active ingredients, for example to a specific particle size, and, in the presence of at least one auxiliary, for example by intimately mixing and/or grinding the active ingredient or mixture of active ingredients with the auxiliary (auxiliaries).
  • auxiliaries for example by grinding, screening and/or compressing a solid active ingredient or mixture of active ingredients, for example to a specific particle size
  • auxiliary for example by intimately mixing and/or grinding the active ingredient or mixture of active ingredients with the auxiliary (auxiliaries).
  • the compound of the formula ( I ) is preferably employed with the auxiliaries conventionally used in the art of formulation and are therefore processed in a known manner to give, for example, emulsifiable concentrates, ready-to-spray or ready-to-dilute solutions, dilute emulsions, wettable powders, soluble powders, dusts, granules, and also encapsulations, for example in polymeric substances.
  • the methods of application such as spraying, atomizing, dusting, wetting, scattering or pouring, and the type of composition are selected to suit the intended aims and the prevailing circumstances.
  • compositions i.e. the methods of controlling pests of the abovementioned type, such as spraying, atomizing, dusting, brushing on, seed dressing, scattering or pouring, which are to be selected to suit the intended aims and the prevailing circumstances, and also the use of the compositions for controlling pests of the above- mentioned type are further subject-matters of the invention.
  • Typical rates of application are between 0.1 and 1000 ppm, preferably between 0.1 and 500 ppm, of active ingredient.
  • the rate of application can varv within wide limits and depends on the nature of the soil, the type of application (foliar application; seed treatment; use in the seed furrow), the crop plant, the pest to be controlled, the respective climate prevailing, and other factors determined by type of application, timing of application and target crop.
  • the rates of application per hectare are generally 1 to 2000 g of active ingredient per hectare, in particular 10 to 1000 g/ha, preferably 20 to 600 g/ha.
  • a preferred method of application in the field of crop protection is application to the foliage of the p'cnts (foliar application), it being possible to adjust frequency and rate of application depending on the risk of infestation of the pest in question.
  • the active ingredients can reach the plants via the root system (systemic action), by drenching the locus of the plants with a liquid composition or by incorporating the active ingredients in solid form into the locus of the plants, for example the soil, for example in the form of granules (soil application). In the case of paddy rice, such granules can be metered into the flooded paddy-field.
  • compositions according to the invention are al ⁇ o suitable for protecting plant propagation material, for example seed, such as fruits, tubers or kernels, or nursery plants, against animal pests.
  • the propagation material can be treated with the composition before planting, for example seed can be dressed before sowing.
  • the active ingredients according to the invention can also be applied to seed kernels (coating), either by soaking the kernels in a liquid composition or by coating them with a solid composition.
  • the composition can be applied to the planting site when planting the propagation material, for examp'c* into the seed furrow during sowing.
  • Example 23 Emulsion concentrates a) b) c)
  • Emulsions of any desired concentration can be prepared from such concentrates by dilution with water.
  • Example 24 Solutions a) b) c) d)
  • the solutions are suitable for use in the form of microdrops.
  • Example 25 Granules a) b) c) d)
  • the active ingredients are dissolved together in dichloromethane, the solution is sprayed onto the carrier, and the solvent is subsequently evaporated in vacuo.
  • the active ingredients are mixed with the additives and ground thoroughly in a suitable mill. This gives wettable powders which can be diluted with water to give suspensions of any desired concentration.
  • Example 28 Emulsion concentrate
  • Emulsions of any desired concentration can be prepared from this concentrate by dilution with water.
  • Kaolin m 92*5 Ready-to-use dusts are obtained by mixing the active ingredients with the carrier and grinding the mixture in a suitable mill.
  • Example 30 Extruder granules
  • the active ingredients are mixed with the additives, and the mixture is ground and moistened with water. This mixture is extruded, granulated and subsequently dried in a stream of air.
  • the finely ground active ingredients are applied uniformly to the kaolin which has been moistened with polyethylene glycol. In this manner, dust-free coated granules are obtained.
  • the biological activity of the compounds of the present invention can be determined by conducting one or more of the following tests or any other appropriate tests.
  • Example B1 Action against Bemisia tabaci
  • Dwarf bean plants are placed into gauze cages and populated with Bemisia tabaci adults. After oviposition, all adults are removed. 10 days later, the plants and the nymphs thereon are sprayed with an aqueous suspension spray mixture comprising 50 ppm of the active ingredient. After a further 14 days, the percentage hatching rate of the eggs is evaluated in comparison with untreated control batches.
  • Example B2 Action against Spodoptera littoralis caterpillars
  • Young soya plants are sprayed with an aqueous emulsion spray mixture comprising 360 ppm of the active ingredient. After the spray coating has dried on, the soya plants are populated with 10 third-instar Spodoptera littoralis caterpillars and placed in a plastic container. The test is evaluated 3 days later. The percentage reduction in population or the percentage reduction of feeding damage (% action) is determined by comparing the number of dead caterpillars and the feeding damage on the treated plants with those on the untreated plants.
  • Example B3 Ovicidal action against Lobesia botrana
  • Lobesia botrana eggs deposited on filter paper are immersed briefly into a test solution comprising 400 ppm of the active ingredient to be tested in acetone/water. After the test solution has dried on, the eggs are incubated in Petri dishes. After 6 days, the percentage hatching rate of the eggs is evaluated in comparison with untreated control batches (% reduction in hatching rate).
  • Example B4 Ovicidal action against Heliothis virescens
  • Heliothis virescens eggs deposited on filter paper are immersed briefly into a test solution comprising 400 ppm of the active ingredient to be tested in acetone/water. After the test solution has dried on, the eggs are incubated in Petri dishes. After 6 days, the percentage hatching rate of the eggs is evaluated in comparison with untreated control batches (% reduction in hatching rate).
  • Example B5 Action against Plutella xylostella caterpillars
  • Young cabbage plants are sprayed with an aqueous emulsion spray mixture comprising 440 ppm of the active ingredient. After the spray coating has dried on, the cabbage plants are populated with 10 third-instar Plutella xylostella caterpillars and placed in a plastic container. The test is evaluated 3 days later. The percentage reduction in population or the percentage reduction in feeding damage (% action) is determined by comparing the number of dead caterpillars and the feeding damage on the treated plants with those on the untreated plants.
  • Example B6 Action against Ctenocephalides felis (cat flea)

Abstract

La présente invention se rapporte à l'isolement de drimentines comprenant les éléments structurels illustrés par la formule A Ces nouveaux antibiotiques peuvent être utilisés pour une large gamme d'applications thérapeutiques, y compris et de manière non limitative, le traitement des infections dues à des bactéries, des champignons, des endoparasites et des ectoparasites, le cancer et autres affections malignes chez l'homme et l'animal.
PCT/IB1997/001425 1996-09-09 1997-09-05 Dicetopiperazines terpenylees (drimentines) WO1998009968A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47203/97A AU4720397A (en) 1996-09-09 1997-09-05 Terpenylated diketopiperazines, (drimentines)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP96810592 1996-09-09
EP96810592.4 1996-09-09

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WO1998009968A1 true WO1998009968A1 (fr) 1998-03-12

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US9956217B2 (en) 2014-08-18 2018-05-01 Ampio Pharmaceuticals, Inc. Treatment of joint conditions
US10881710B2 (en) 2011-10-28 2021-01-05 Ampio Pharmaceuticals, Inc. Treatment of rhinitis
US11389512B2 (en) 2015-06-22 2022-07-19 Ampio Pharmaceuticals, Inc. Use of low molecular weight fractions of human serum albumin in treating diseases

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US9561226B2 (en) 2000-08-04 2017-02-07 Ampio Pharmaceuticals, Inc. Method of using diketopiperazines and composition containing them
US10039760B2 (en) 2000-08-04 2018-08-07 Ampio Pharmaceuticals, Inc. Method of using diketopiperazines and composition containing them
US8916568B2 (en) 2000-08-04 2014-12-23 Ampio Pharmaceuticals, Inc. Method of using diketopiperazines and composition containing them
US11369598B2 (en) 2003-05-15 2022-06-28 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
US9707227B2 (en) 2003-05-15 2017-07-18 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
US8962568B2 (en) 2003-05-15 2015-02-24 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
US8969308B2 (en) 2003-05-15 2015-03-03 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
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US9730924B2 (en) 2003-05-15 2017-08-15 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
US8871772B2 (en) 2008-05-27 2014-10-28 Ampio Pharmaceuticals, Inc. Therapeutic methods and compounds
US9522893B2 (en) 2008-05-27 2016-12-20 Ampio Pharmaceuticals, Inc. Therapeutic methods and compounds
JP5220862B2 (ja) * 2008-08-26 2013-06-26 公益財団法人微生物化学研究会 新規化合物シグナマイシン、その製造方法、及びその用途
US8058455B2 (en) 2008-08-26 2011-11-15 Kinki University Compound signamycin, method for production thereof, and use thereof
CN102224252A (zh) * 2008-08-26 2011-10-19 学校法人近畿大学 新型化合物西格纳霉素、其制造方法以及其用途
WO2010023725A1 (fr) * 2008-08-26 2010-03-04 財団法人微生物化学研究会 Nouveau composé de signamycine, procédé pour la production de celui-ci, et utilisation de celui-ci
US9034878B2 (en) 2010-09-07 2015-05-19 Ampio Pharmaceuticals, Inc. Treatment of diseases
US9623072B2 (en) 2011-10-10 2017-04-18 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
US8980834B2 (en) 2011-10-10 2015-03-17 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
US11058798B2 (en) 2011-10-10 2021-07-13 Ampio Pharmaceuticals, Inc. Implantable medical devices with increased immune tolerance, and methods for making and implanting
US9925300B2 (en) 2011-10-10 2018-03-27 Ampio Pharmaceuticals, Inc. Implantable medical devices with increased immune tolerance, and methods for making and implanting
US10842847B2 (en) 2011-10-10 2020-11-24 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
US9060968B2 (en) 2011-10-10 2015-06-23 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
US10251930B2 (en) 2011-10-10 2019-04-09 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
US10471178B2 (en) 2011-10-10 2019-11-12 Ampio Pharmaceuticals, Inc. Implantable medical devices with increased immune tolerance, and methods for making and implanting
US10881710B2 (en) 2011-10-28 2021-01-05 Ampio Pharmaceuticals, Inc. Treatment of rhinitis
CN103570731B (zh) * 2012-07-30 2016-05-18 中国科学院广州生物医药与健康研究院 嘧啶并三环或嘧啶并四环类化合物及其药用组合物和应用
CN103570731A (zh) * 2012-07-30 2014-02-12 中国科学院广州生物医药与健康研究院 嘧啶并三环或嘧啶并四环类化合物及其药用组合物和应用
US11026940B2 (en) 2013-03-15 2021-06-08 Ampio Pharmaceuticals, Inc. Compositions for the mobilization, homing, expansion and differentiation of stem cells and methods of using the same
US9808454B2 (en) 2013-03-15 2017-11-07 Ampio Pharmaceuticals, Inc. Compositions for the mobilization, homing, expansion and differentiation of stem cells and methods of using the same
US10342793B2 (en) 2014-08-18 2019-07-09 Ampio Pharmaceuticals, Inc. Treatment of joint conditions
US9956217B2 (en) 2014-08-18 2018-05-01 Ampio Pharmaceuticals, Inc. Treatment of joint conditions
US11090301B2 (en) 2014-08-18 2021-08-17 Ampio Pharmaceuticals, Inc. Treatment of joint conditions
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