US3729564A - N-secondary alkyl alkanediamines and derivatives thereof as anti-inflammatory agents - Google Patents

N-secondary alkyl alkanediamines and derivatives thereof as anti-inflammatory agents Download PDF

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US3729564A
US3729564A US00098860A US3729564DA US3729564A US 3729564 A US3729564 A US 3729564A US 00098860 A US00098860 A US 00098860A US 3729564D A US3729564D A US 3729564DA US 3729564 A US3729564 A US 3729564A
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alkyl
carbon atoms
compounds
hydroxyethyl
alkanediamines
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Lamore W Mc
Y Chang
G Evanega
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Pfizer Corp Belgium
Pfizer Inc
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Pfizer Corp Belgium
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/04—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems

Definitions

  • Y is alkylene of from 2 to carbon atoms
  • R is alkyl of from 4 to 13 carbon atoms
  • R is hydrogen, 2-hydroxyethyl or ethyl
  • R is Z-hydroxyethyl or R wherein R is alkyl of from 1 to 20 carbon atoms;
  • R is hydrogen, alkyl of from 1 to 20 carbon atoms
  • cycloalkyl of from 3 to 7 carbon atoms; phenyl or substituted phenyl wherein the substituent is halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl;
  • R is R thienyl, pyridyl or furyl
  • R and R when taken together with the carbon atom to which they are attached are cycloalkyl of from 3 to 7 carbon atoms.
  • This invention relates to novel 3-[(w-secondary alkylamino)alkyl]oxazolidines; 1,3 dialkyl 1,3-diazacycloalkanes and N-secondary alkyl alkanediamines for which the aforenamed compounds serve as pro-drugs; and the non-toxic acid addition salts thereof, which are useful as anti-inflammatory agents and immunosuppressants.
  • drugs the therapeutic value and mechanism of action of which are debatable, gold salts, chloroquines, indomethacin and, more recently, alkylating agents such as N,N',N"-triethylenephosphoramide, cyclophosphamide, tris(chloroethyl) amine; urea derivatives and antilymphocyte serum.
  • alkylating agents such as N,N',N"-triethylenephosphoramide, cyclophosphamide, tris(chloroethyl) amine; urea derivatives and antilymphocyte serum.
  • alkylating agents such as N,N',N"-triethylenephosphoramide, cyclophosphamide, tris(chloroethyl) amine; urea derivatives and antilymphocyte serum.
  • such drugs suffer from various shortcomings such as limited eilicacy, toxic sideetfects, short-term response and narrow therapeutic index.
  • Y is alkylene of from 2 to 5 carbon atoms and is selected from the group consisting of ethylene, trimethylene, tetramethylene and pentamethylene;
  • R is selected from the group consisting of alkyl of from 4 to 13 carbon atoms
  • R is selected from the group consisting of hydrogen, 2-
  • R is selected from the group consisting of Z-hydroxyethyl and R wherein R is alkyl of from 1 to 20 carbon atoms;
  • R is selected from the group consisting of hydrogen, alkyl of from 1 to 20 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, phenyl and substituted phenyl wherein the substituent is selected from the group consisting of halogen, lower alkyl, lower alkoxy, cyano and trifluoromethyl;
  • R is selected from the group consisting of R thienyl
  • R and R when taken together with the carbon atom to which they are attached are selected from the group consisting of cycloalkyl of from 3 to 7 carbon atoms.
  • lower alkyl and lower alkoxy are meant those alkyl and alkoxy groups having from 1 to 4 carbon atoms, since such materials are generally more readily available than are compounds having larger alkyl or alkoxy groups.
  • non-toxic acid addition salts are those acid addition salts which are non-toxic at the dosages administered for the purposes of this invention.
  • Representative non-toxic acid addition salts of the above-mentioned bases which may be employed are the water soluble and water insoluble salts such as the hydrochloride, hydrobromide, phosphate, nitrate, sulfate, acetate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butyrate, sulfosalicylate, maleate, laurate, rnalate, fumarate, succinate, oxalate, tartrate, amsonate (4,4' diaminostilbene 2,2- disulfonate), pamoate (LY-methylene bis-2-hydroxy-3- naphthoate), stearate, 3-hydroXy-2-naphthoate, p-toluenesulfonate, picrate, lactate and suramin salt.
  • Toxic acid addition salts include hydrofluoride, oxalate and picrate.
  • the compounds of this invention of Formula I are prepared by the known reductive alkylation reaction of a ketone and an alkanediamine (H N-Y-NR R as is described in U.S. 3,197,510, issued July 27, 1965 T he reductive alkylation is normally carried out using equimolar proportions of the appropriate ketone and diamine reactant although an excess of one or the other reactant can be used to insure complete reaction. The use of an excess of one reactant is frequently employed in cases wherein the other reactant is not readily available.
  • the reaction can be carried out as a one-step or two-step process.
  • the reaction comprises formation of the Schiffs base by reaction of the appropriate ketone and alkanediamine (H 'N-YNR R usually in the presence of a solvent and at an elevated temperature to permit removal of by-produet water.
  • Any suitable solvent can be used, but it is advantageous to use a solvent which forms an azeotrope with by-product water and thus facilitates its removal and completion of the reaction.
  • the reaction is conducted at a temperature of from about 50 C. to about 200 C. and is normally conducted at the boiling point of the solvent system used.
  • molecular sieves can be used as adsorbents for the water.
  • Suitable adsorbents are the natural and synthetic crystalline aluminosilicates. The latter adsorbents are favored because of their greater water-loading capacity relative to the natural crystalline aluminosilicates. Included among such adsorbents are chabazite, gmelinite and analcite, naturally-occurring materials, the synthetic Linde Molecular Sieves produced and distributed by the Linde Company, such as Types 4A, 5A and 13X, and the Microtraps produced by the Davison Company. Such materials sorb and thus effectively remove Water from the reaction medium.
  • the exhausted or partially exhausted aluminosilicate is separated from the reaction mixture by filtration or decantation.
  • the adsorbent is regenerated by heating to an elevated temperature, e.g., about 150 to 350 C., with simultaneous purging with air or nitrogen to desorb the water.
  • reaction-inert solvent such as benzene, toluene, dimethyl sulfoxide, ethanol or propanol.
  • the Schiifs base thus produced is isolated by methods well known to those skilled in the art such as filtration in cases wherein the Schiffs base precipitates as a solid and/ or by concentration of the solvent. It is then reduced in any suitable manner.
  • the reduction can be accomplished by sodium and alcohol, by aluminum amalgam, by alkali metal hydrides, by catalytic hydrogenation in the presence of a catalyst such as nickel, palladium, platinum, rhodium, etc., and by other methods known to those skilled in the art.
  • the catalyst is composited with a suitable support such as alumina or charcoal.
  • the reduction is normally conducted at greater than atmospheric pressure at a temperature of from about 100 C. to 300 C. Pressures of from about 50 to 3000 psi. are advantageously used to effect reduction. It is preferred to use sodium borohydride reduction since the reaction can be conducted at atmospheric pressure in the original reaction vessel under relatively mild conditions.
  • the reductive alkylation process when conducted as a one-step reaction is afiected in the presence of a suitable catalyst and hydrogen.
  • a favored catalyst for the onestep process because of the satisfactory yields produced, is platinum.
  • Other catalysts which can be used are copper oxide, barium oxide, copper chromite, chromium oxide, etc.
  • the reaction conditions for the one-step process are essentially the same as those for the two-step process.
  • Compounds of Formula III are also conveniently prepared by condensation of an N,N'-disubstituted alkanediamine HN(CHR R )YNHR with an appropriate aldehyde or ketone.
  • the reaction conditions are similar to those described above for formation of the oxazolidine derivatives of Formula II.
  • Acid addition salts of the compounds described herein are prepared by conventional procedures as by mixing the amine compound in a suitable solvent With the required acid and recovering the salt by evaporation or by precipitation by addition of a non-solvent for the salt.
  • Hydrochloride salts are readily prepared by passing dry hydrogen chloride through a solution of the basic compound in an organic solvent such as ether.
  • the compounds of this invention are, as noted, valuable non-steroidal anti-inflammatory agents for animals, including humans. Their anti-inflammatory activity is determined by measuring their ability to suppress the reversed passive Arthus reaction. N-(2-hydroxyethyl)-N- (S-pentadecyl)-1,3-propanediamine is twenty times more active in this experimental model of inflammation induced by antigen-antibody complex than is indomethacin.
  • N-(Z- hydroxyethyl) N (-8 pentadecyl) 1,3 propanediamine is more potent in this test than all known anti inflammatory agents with the exception of colchicine.
  • pro-drug serves as pro-drugs for Formula I compounds since they are readily decomposed by hydrolysis with elimination of the CR R moiety to give Formula I compounds both in vivo and in vitro.
  • pro-drug as used herein is, therefore, intended to include the biological conversion as well as the chemical conversion of the compounds of Formulae II and III to those of Formula I.
  • the nature of the R and R groups is immaterial for the purposes of this invention. The only requirement relates to those prodrugs which are used as such or are converted to the drug prior to administration Without separation of the drug from the aldehyde or ketone degradation product. In such instances, the by-product aldehyde or ketone should be one which is non-toxic at the levels at which it is administered along with the drug.
  • the immunosuppressant activity is determined by the lymphocyte-target cell interaction in vitro according to the procedure of Canty et al., J. Natl. Cancer Institute 45, 761-72 (1970). These compounds are thus found to be of value in suppressing the immune response which is a defensive mechanism in the animal broadly against foreign bodies. They can, therefore, be used to prevent rejection of organ transplants such as renal transplants and skin grafts in lower animals and, on the basis of experience, is extrapolatable to humans.
  • the herein-described compounds are elfective via the oral and parenteral routes of administration.
  • the materials of this invention are used at a level of from about 1 mg./kg. of body weight to about 50 mg./kg. of body weight.
  • the favored range is from about 5 mg./kg. to about 50 mg./kg. of bdoy weight, and the preferred range from about 5 mg./ kg. to about 33 mg./kg. of body weight.
  • Intraarticular administration permits dosages as low as 0.1 mg./kg. of body weight.
  • the dosage of course, is dependent upon the animal being treated and the particular compound involved and is to be determined by the individual responsible for its administration. Generally, small doses will be administered initially with gradual increase in dosage until the optimal dosage level is determined for the particular subject under treatment.
  • Intraperitoneal injections are the preferred method of parenteral injection for several reasons: simplicity, convenience and lower toxicity.
  • Vehicles suitable for parenteral injection may be either aqueous such as water, isotonic saline, isotonic dextrose. Ringers solution, or nonaqueous such as fatty oils of vegetable origin (cottonseed, peanut oil, corn, sesame) and other non-aqueous vehicles which will not interfere with the efiicacy of the preparation and are non-toxic in the volume or proportion used (glycerol, ethanol, propylene glycol, sorbitol).
  • compositions suitable for extemporaneous preparation of solutions prior to administration may advantageously be made.
  • Such compositions may include liquid diluents, for example, propylene glycol, diethyl carbonate, glycerol, sorbitol.
  • the materials of this invention are administered, they are most easily and economically used in a dispersed form in an acceptable carrier.
  • this material means that the particles may be molecular in size and held in true solution in a suitable solvent or that the particles may be colloidal in size and dispersed through a liquid phase in the form of a suspension or an emulsion.
  • the term dispersed also means that the particles may be mixed with and spread throughout a solid carrier so that the mixture is in the form of a powder or dust. This term is also meant to encompass mixtures which are suitable for use as sprays, including solutions, suspensions, or emulsions or the agents of this invention.
  • the compounds employed in this invention may be employed alone, i.e., without other medicinals, as mixtures of more than one of the herein-described compounds, or in combination with other medicinal agents such as analgesics, anesthetics, antiseptics, decongestants, antibiotics, vaccines, buffering agents and inorganic salts to afford desirable pharmacological properties. Further, they may be administered in combination with hyaluronidase to avoid, or at least, to minimize local irritation and to increase the rate of absorption of the compound. Hyaluronidase levels of at least about 150 (U.S.P.) units are effective in this respect although higher or lower levels can, of course, be used.
  • U.S.P. 150
  • the particle sizes of the formulations influence their biological activity apparently through better absorption of the active materials.
  • various surface active agents and protective colloids are used. Suitable surface active agents are the partial esters of common fatty acids, such as lauric, oleic, stearic, with hexitol anhydrides derived from sorbitol; and the polyoxyethylene derivatives of such ester products.
  • homologous and analogous compounds wherein R and R are 2- mercaptoethyl or hydroxyalkyl or mercaptoalkyl groups of from 3 to 8 carbon atoms and such compounds, as well as those of the above formulae, wherein Y is alkylene of 6 carbon atoms are also effective anti-inflammatory and immunosuppressant agents.
  • homologs of Formula II compounds wherein the 3-oxazolidino moiety is replaced by a 3-(5-a1kyl substituted)oxazolidino, a 3- tetrahydro-l,3-oxazino or a 3-(6-alky1 substituted)-tetrahydro-1,3-oxazino moiety, or the corresponding sulfurcontaining heterocyclic moieties are valuable anti-inflammatory and immunosuppressant agents.
  • Such compounds are prepared from compounds of Formula I wherein at least one of R and R is a fi-hydroxyalkyl, a -hydroxyalkyl, or corresponding mercaptoalkyl moiety and an appropriate aldehyde or ketone in the same manner as is described above for the preparation of compounds of Formula II.
  • CHR R is replaced by an unsymmetrical secondary alkyl moiety, such as 2-pentadecyl-, 3-octadecyland 5- octadecyl-, or by phenyl or substituted phenyl (halo, lower alkyl, lower alkoxy, CF etc.); and compounds of the formula are also effective antibacterial and immunosuppressant agents.
  • the reaction is exothermic and reaches a temperature of 45 to 50 C.
  • the mixture is refluxed for one and one-half hours, then cooled and the solvent removed under reduced pressure.
  • the residue is partitioned between ether (200 ml.) and 3 N aqueous sodium hydroxide (200 ml.) and the ether layer then separated. It is extracted with 3 N hydrochloric acid (150 ml.), and the acid solution extracted twice with ether.
  • the acid solution is then made alkaline, extracted with ether and the ethereal solution dried over anhydrous sodium sulfate and evaporated.
  • the residue is distilled in vacuo to give the product as an oil in 61 percent yield.
  • B.P. 190l91 C. at 0.02 mm.
  • reaction is worked up by addition of 5 N sodium hydroxide ml.) and stirred for two hours to decompose the borohydride-amine complex. Thereafter, water (160 ml.) is added and the ben-
  • N( C H2) n-N Rr-C y NWMMNWWWWNWNWWOJCDW 5 mmmmmmmm CgHs 99999:.
  • Example VI The procedure of Example VI is repeated but using the appropriate N,N-di-alkylalkanediamines of Examples II

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4049417A (en) * 1975-04-28 1977-09-20 Merck & Co., Inc. Alicyclic alkylene polyamine microorganism and algae growth inhibitors
US5900213A (en) * 1993-04-28 1999-05-04 Alcon Laboratories, Inc. Use of diamines to disinfect and clean contact lenses and preserve ophthalmic compositions
US20050154065A1 (en) * 2003-12-09 2005-07-14 Alcon, Inc. Use of bis-amines to enhance the antimicrobial activity of aqueous compositions
US9738593B2 (en) 2014-06-25 2017-08-22 Acuitas Therapeutics Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
US10166298B2 (en) 2015-10-28 2019-01-01 Acuitas Therapeutics, Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
US10221127B2 (en) 2015-06-29 2019-03-05 Acuitas Therapeutics, Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
US20200392070A1 (en) * 2017-12-20 2020-12-17 Rhodia Operations New cationic quaternary ammonium compounds and compositions comprising same and processes for their manufacture
US11246933B1 (en) 2011-12-07 2022-02-15 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
US11357856B2 (en) 2017-04-13 2022-06-14 Acuitas Therapeutics, Inc. Lipids for delivery of active agents
US11453639B2 (en) 2019-01-11 2022-09-27 Acuitas Therapeutics, Inc. Lipids for lipid nanoparticle delivery of active agents
US11524932B2 (en) 2017-08-17 2022-12-13 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
US11542225B2 (en) 2017-08-17 2023-01-03 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
US11639329B2 (en) 2017-08-16 2023-05-02 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
US11820728B2 (en) 2017-04-28 2023-11-21 Acuitas Therapeutics, Inc. Carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids
US11976019B2 (en) 2020-07-16 2024-05-07 Acuitas Therapeutics, Inc. Cationic lipids for use in lipid nanoparticles
US12065396B2 (en) 2017-08-17 2024-08-20 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
US12129223B2 (en) 2021-12-16 2024-10-29 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
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US4049559A (en) 1975-10-09 1977-09-20 Merck & Co., Inc. Composition for secondary and tertiary oil recovery
US4100193A (en) * 1976-06-10 1978-07-11 Merck & Co., Inc. Novel dibicyclo [2.2.2] octyl and dibicyclo [2.2.2] octenyl polyamines and methods for their preparation
US4033748A (en) 1976-07-02 1977-07-05 Merck & Co., Inc. Dibicyclo[3.1.1] and [2.2.1] heptyl and dibicyclo [3.1.1] and [2.2.1] heptenyl polyamines having a piperidine moiety
GB8400984D0 (en) * 1984-01-14 1984-02-15 Hepburn C Polychloroprene rubber

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4049417A (en) * 1975-04-28 1977-09-20 Merck & Co., Inc. Alicyclic alkylene polyamine microorganism and algae growth inhibitors
US5900213A (en) * 1993-04-28 1999-05-04 Alcon Laboratories, Inc. Use of diamines to disinfect and clean contact lenses and preserve ophthalmic compositions
US20050154065A1 (en) * 2003-12-09 2005-07-14 Alcon, Inc. Use of bis-amines to enhance the antimicrobial activity of aqueous compositions
WO2005056515A3 (en) * 2003-12-09 2005-12-01 Alcon Inc Use of bis-amines to enhance the antimicrobial activity of aqueous compositions
US7445771B2 (en) 2003-12-09 2008-11-04 Alcon, Inc. Use of bis-amines to enhance the antimicrobial activity of aqueous compositions
US20090030085A1 (en) * 2003-12-09 2009-01-29 Alcon, Inc. Use of bis-amines to enhance the antimicrobial activity of aqueous compositions
AU2004297269B2 (en) * 2003-12-09 2010-11-18 Alcon Inc. Use of bis-amines to enhance the antimicrobial activity of aqueous compositions
US7871602B2 (en) 2003-12-09 2011-01-18 Alcon, Inc. Use of bis-amines to enhance the antimicrobial activity of aqueous compositions
US11633479B2 (en) 2011-12-07 2023-04-25 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
US11679158B2 (en) 2011-12-07 2023-06-20 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
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US11633480B2 (en) 2011-12-07 2023-04-25 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
US11612657B2 (en) 2011-12-07 2023-03-28 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
US11590229B2 (en) 2011-12-07 2023-02-28 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
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US11246933B1 (en) 2011-12-07 2022-02-15 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
US12350338B2 (en) 2011-12-07 2025-07-08 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
US11382979B2 (en) 2011-12-07 2022-07-12 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
US9738593B2 (en) 2014-06-25 2017-08-22 Acuitas Therapeutics Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
US10106490B2 (en) 2014-06-25 2018-10-23 Acuitas Therapeutics, Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
US9737619B2 (en) 2014-06-25 2017-08-22 Acuitas Therapeutics, Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
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US10221127B2 (en) 2015-06-29 2019-03-05 Acuitas Therapeutics, Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
US10166298B2 (en) 2015-10-28 2019-01-01 Acuitas Therapeutics, Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
US11648324B2 (en) 2015-10-28 2023-05-16 Acuitas Therapeutics, Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
US11040112B2 (en) 2015-10-28 2021-06-22 Acuitas Therapeutics, Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
US11712481B2 (en) 2015-10-28 2023-08-01 Acuitas Therapeutics, Inc. Lipid nanoparticle formulations
US11357856B2 (en) 2017-04-13 2022-06-14 Acuitas Therapeutics, Inc. Lipids for delivery of active agents
US11820728B2 (en) 2017-04-28 2023-11-21 Acuitas Therapeutics, Inc. Carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids
US11639329B2 (en) 2017-08-16 2023-05-02 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
US11524932B2 (en) 2017-08-17 2022-12-13 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
US12065396B2 (en) 2017-08-17 2024-08-20 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
US11542225B2 (en) 2017-08-17 2023-01-03 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
US11773053B2 (en) * 2017-12-20 2023-10-03 Rhodia Operations Cationic quaternary ammonium compounds and compositions comprising same and processes for their manufacture
US20200392070A1 (en) * 2017-12-20 2020-12-17 Rhodia Operations New cationic quaternary ammonium compounds and compositions comprising same and processes for their manufacture
US12329857B2 (en) 2018-09-21 2025-06-17 Acuitas Therapeutics, Inc. Systems and methods for manufacturing lipid nanoparticles and liposomes
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