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WO1997042953A1 - Utilisation de brequinar et de derives contre le rejet chronique de greffes allogeniques et la xenotransplantation - Google Patents

Utilisation de brequinar et de derives contre le rejet chronique de greffes allogeniques et la xenotransplantation Download PDF

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Publication number
WO1997042953A1
WO1997042953A1 PCT/EP1997/002401 EP9702401W WO9742953A1 WO 1997042953 A1 WO1997042953 A1 WO 1997042953A1 EP 9702401 W EP9702401 W EP 9702401W WO 9742953 A1 WO9742953 A1 WO 9742953A1
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alkyl
fluoro
formula
phenyl
methyl
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PCT/EP1997/002401
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English (en)
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Hendrik Schuurman
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Novartis Ag
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Priority to AU28960/97A priority Critical patent/AU2896097A/en
Publication of WO1997042953A1 publication Critical patent/WO1997042953A1/fr

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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings

Definitions

  • the invention relates to a new use for quinohne derivatives in free form or in pharmaceuti ⁇ cally acceptable salt form in the manufacture of a medicament for the treatment and/or pre ⁇ vention of chronic rejection of an allograft; or hyper-acute, acute or chronic rejection of a xenograft, in a mammalian recipient thereof, utilizing quinohne derivatives and salts thereof
  • 2-Carbocycl ⁇ c and 2-heterocycl ⁇ c quinohne carboxylic acids are described in US 5,523,408, incorporated by reference, as potent inhibitors of dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine nucleotide biosynthesis pathway, and therefore have a unique mechanism of action (inhibition of dihydroorotate dehydrogenase) which is distinct from other available immunosuppressive agents. They are useful in the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases in a mammal.
  • Phenylquinoline carboxylic acids and their derivatives are described as tumor inhibiting agents in US 4,680,299, incorporated by reference.
  • US 4,968,701 and US 5,204,329, in ⁇ corporated by reference disclose that the compounds of US 4,680,299 have immunomodu- lating and anti-inflammatory activity, and therefore, alone or with other immunosuppressive agents, would be useful in the treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and myastenia gravis; as well as organ transplantation rejection in general and graft vs. host disease; and also as anti-in- fiammatory agents in the treatment of chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
  • 3-Phenyl-5,6-d ⁇ hydrobenz[c]acr ⁇ d ⁇ ne-7-carboxyl ⁇ c acid compounds and derivatives thereof are described as tumor inhibiting agents in US 4,918,077 and US 5,002,954, incorporated by reference.
  • US 5,135,934 and US 5,190,753 describe the use of these compounds as immunosuppressive or immunomodulatory agents for the treatment and/or prevention of organ transplantation rejection in general, graft versus host disease, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, myasthenia gravis and systemic lupus ery ⁇ thematosus, psoriasis and other chronic inflammatory diseases.
  • Organ transplants of liver, kidney, lung and heart are now regularly performed as treatment for endstage organ disease. Because of the current shortage of human donors for transplantable allografts, attention has focused on the possibility of using xenografts (transplants between species) in transplantation.
  • xenografts transplants between species
  • One of the major obstacles in transplanting successfully xenografts in humans is immunological, especially antibody mediated hyperacute or acute rejection.
  • a further obstacle in allo- and xenotransplantation is the chronic rejection, and thus organ transplantation is not yet a clinically viable solution to irreversible organ disease.
  • Chronic rejection which manifests as progressive and irreversible graft dysfunction, is the leading cause of organ transplant loss, in some cases already after the first postoperative year.
  • the clinical problem of chronic rejection is clear from transplantation survival times, about half of kidney allografts are lost within 5 years after transplantation , and a similar value is observed in patients with heart allografts.
  • Chronic rejection is considered as a multifacto ⁇ al process in which not only the immune reaction towards the graft but also the response of the blood vessel walls in the grafted organ to injury ("response-to-injury" reaction) plays a role.
  • the variant of chronic rejection with the worst prognosis is an arteriosclerosis-like alteration, also called transplant vascu- lopathy, graft vessel disease, graft arteriosclerosis, transplant coronary disease, etc.
  • This vascular lesion is characterized by migration and proliferation of smooth muscle cells, probably under influence of growth factors that are amongst others synthesized by endo ⁇ thelial cells.
  • Suitable quinohne derivatives are compounds of the formula
  • R 1 , R 2 , R 3 and R 4 are independently H, halogen, CF 3) C ⁇ -C 4 alkyl, S-CH 3 or S(0) m -CrC 5 alkyl, at least two of R 1 , R 2 , R 3 and R 4 being H;
  • R 5 is CO(0)H or CO(O)C 2 -C 4 alkylene-NR 8 R 9 ;
  • R 6 is H or C ⁇ -C 3 alkyl or when R 7 is A 1 , A 2 or A 3 , also -CN, -NR 8 R 9 , -OR 10 , -SR 10 , -NO 2 , -CF 3 ,
  • R 7 is a radical of formula A 1 , A 2 , A 3 or B
  • R 11 is H, halogen, unsubstituted or halogen substituted d-C 3 alkyl, -NR 8 R 9 , -OC r C 3 alkyl or
  • R 12 is aryl or heteroaryl which are optionally substituted by one or more substituents selected from H, halogen, unsubstituted or halogen substituted C ⁇ -C 3 alkyl, -NR 8 R 9 , -OR 10 and -SR 10 ;
  • R 13 and R 14 independently are H or C ⁇ -C 3 alkyl;
  • R 15 is CrC ⁇ 2 alkyl, C 6 cycloalkyl, C 4 heterocycloalkenyl, aryl, aralkyl, O-aryl, O-aralkyl, S(0) m -aryl or S(0) m -aralkyl, wherein m is 0, 1 or 2 and aryl and aralkyl are optionally substi- tuted by one or more substituents selected from H, halogen, unsubstituted or halogen sub ⁇ stituted C r C 5 alkyl, C ⁇ Csalkoxy, N0 2 and OH; R 16 is H, halogen, unsubstituted or halogen substituted C ⁇ -C 5 alkyl, CrC 5 alkoxy, N0 2 and
  • Y is -N- or -C(R 10 )-;
  • Z is -C(R 8 )(R 9 )-, wherein R 8' and R 9 independently are H or C ⁇ -C 3 alkyl; or R 6 and R 7 together form a radical of formula C
  • R 17 and R 18 are H or taken together are S;
  • R ⁇ and R 9 are independently H or C ⁇ -C 3 alkyl; or R 8 and R 9 together form a C 4 - or C 5 alkylene which is optionally interrupted by -NH-, -N(CH 3 )- or -0-; R 10 is H or C ⁇ -C 3 alkyl; m is 0, 1 or 2; with the following provisos for compounds wherein R 7 is a radical of formula B
  • R 15 cannot be C 6 cycloalkyl when R 5 is CO(0)(CH 2 )2-N(CH 3 )2, R 3 is CH 2 CH 3 or R 2 is Cl;
  • R 3 when R 3 is CH 3 , then R 2 cannot be Cl; including their pharmaceutically acceptable salts and prodrug forms.
  • Halogen is to be understood as meaning a representative of the group consisting of fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, especially fluorine and chlorine.
  • Alkyl is intended to include both branched and straight chain saturated aliphatic hydro ⁇ carbon groups having the specified number of carbon atoms. Cycioalkyl may contain preferably 5 to 8 and particularly preferably 5 or 6 ring carbon atoms.
  • aryl or heteroaryl is a five- or six-membered ring or a bicycle consisting of two condensed six- or five-membered rings or one six-membered and one five-membered ring, and in the case of heteroaryl one or more C atoms may be re ⁇ placed, independently of one another, by an atom selected from the group consisting of oxygen, nitrogen and sulfur.
  • Examples are derived from benzene, naphthalene, indene, furan, pyrrole, pyrazole, imidazole, isoxazole, oxazole, furazan, thiadiazole, thiophene, thiazole, oxadiazole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzo- thiazole, pyran, pyridine, pyridazine, triazine, pyrimidine, pyrazine, isoquinoline, cinnoline, phthalazine, quinohne, quinazoline, pterdine, benzotriazine or quinoxaline.
  • Aryl is preferably naphthyl and phenyl. Phenyl is particularly preferred.
  • Heteroaryl is preferably furanyl, pyri- dinyl and pyrimidinyl.
  • salts and prodrugs refer to derivatives of the disclosed compounds that are modified by making acid or base salts, or by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids; acetate, formate and benzoate derivatives of alcohols and amines; and the like.
  • Salts of carboxylic acid residues may include, but are not limited to, sodium, potassium, diethanolamine, N- methyl-D-glucamine, procaine, lysine, choline or tris-(hydroxymethyl)aminomethane.
  • compositions of the compounds of this invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publising Company, Easton, PA 1985, p. 1418, the disclosure of which is hereby inco ⁇ orated by reference. In a preferred embodiment the compounds which can be used according to the invention have the formula la, lb or Ic
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 , X, Y and Z have the above meanings; including their pharmaceutically acceptable salts and prodrug forms.
  • More preferred compounds according to the invention are compounds of formula la, lb or Ic wherein R 12 is phenyl, 2-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl or 3-tr ⁇ f luoromethylphenyl.
  • Specifically preferred compounds useful in the present invention are compounds selected from the following:
  • Certain of the compounds of formula la, lb and Ic may contain one or more asymmetric car ⁇ bon atoms and may be isolated in optically active or racemic forms. All chiral, diastereome- ric, and racemic forms are included in the present invention. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, trom optically active starting materials. All chiral, diastereomeric, racemic forms and all geo ⁇ metric isomeric forms of a structure are intended, unless the specific stereochemistry or iso ⁇ mer form is specifically indicated.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 and R 16 have the above meanings; including their pharmaceutically acceptable salts and prodrug forms; with the following provisos
  • R 15 cannot be C 6 cycloalkyl when R 5 is CO(0)(CH 2 ) 2 -N(CH 3 ) 2l R 3 is CH 2 CH 3 or R 2 is Cl;
  • R 1 , R 2 , R 3 and R 4 are inde ⁇ pendently H, F, Cl, Br, I, CH 3 , CF 3 , SCH 3 or CH 2 CH 3 , at least two of R 1 , R 2 , R 3 and R 4 being H;
  • R 5 is CO(O)H or CO(O)C 2 -C 4 alkylene-NR 8 R 9 ;
  • R 6 is H, C,-C 2 alkyl or Od-C 3 alkyl;
  • R 8 and R 9 are independently H or C ⁇ -C 3 alkyl;
  • R 15 is d-C ⁇ alkyl, C 6 cycloalkyl, aryl, aralkyl, O-aryl, O-aralkyl, S(0) m -aryl or S(O) m -aralkyl, wherein m is 0, 1 or 2 and aryl and aralkyl are optionally substituted by one or more substituents selected from H, F, Cl, Br, I
  • R 1 and R 2 are independently H or F, Cl, Br or I; R 3 and R 4 are independently H, F, Cl, Br, I, CH 3 or CF 3 , at least two of R 1 , R 2 , R 3 and R 4 being H;
  • R 5 is CO(0)H, CO(0)K, CO(0)Na or CO(0)C 2 -C 4 alkylene-NR 8 R 9 ;
  • R 6 is H or d-C 2 alkyl;
  • R 8 and R 9 are independently d-C 3 alkyl;
  • R 15 is cyclohexyl, phenyl, phenyl substituted with one halogen, Ci-C 5 alkyl, CF 3 , phenoxy, phenoxy substituted with one halo ⁇ gen or C ⁇ -C 5 alkyl; and
  • R 16 is H.
  • R 3 and R 4 are independently H, halogen or CF 3 , provided that both R 3 and R 4 are not H;
  • R 5 is CO(O)H, CO(O)K, CO(O)Na or CO(O)C 2 -C 4 alkylene-NR 8 R 9 ;
  • R 6 is H or d- C 2 alkyl;
  • R 8 and R 9 are independently C ⁇ -C 3 alkyl;
  • R 15 is cyclohexyl, phenyl, phenyl independently substituted with one or two substituents selected from halogen, d-C 3 alkyl and CF 3 , phenoxy, phenoxy substituted with one or two substituents selected from halogen, C ⁇ -C 5 alkyl and CF 3 , provided that when R 15 is phenyl or phenoxy, and R 4 is H, then R 3 cannot be Br; and that when R 15 is cyclohexyl and R 6 is H, R 3 must be Cl or F
  • Specifically preferred compounds useful in this invention are:
  • R 3 , R 4 , R 5 , R 17 and R 18 have the above meanings; including their pharmaceutically acceptable salts and prodrug forms.
  • R 3 and R 4 are independently H, F, Cl, Br, I, CH 3 , CH 2 CH 3 , CF 3 or SfOJ m -d-Csalkyl;
  • R 5 is CO(O)H or CO(O)C 2 -C 4 alkylene-NR 8 R 9 ;
  • R 8 and R 9 are independently H or d-C 3 alkyl;
  • R 17 and R 18 are H or taken together are S; including their pharmaceutically acceptable salts and prodrug forms, in one embodiment, with the proviso that when R 5 is CO(O)Na then R 3 is not F.
  • Most preferred compounds useful in the method of the present invention are those com ⁇ pounds of formula III wherein (a) R 5 is CO(0)H or CO(0)Na; and/or (b) R 4 is H or Cl; and/or (c) R 3 is H, F, Cl or CF 3 .
  • Particularly preferred compounds useful in the method of the present invention are those compounds of formula III wherein (a) R 4 is H; and/or (b) R 3 is H, F or CF 3 .
  • Specifically preferred compounds useful in the method of the present invention are:
  • salt form e.g., sodium salt form
  • phar ⁇ maceutically acceptable salt form thereof e.g., sodium salt form
  • a pharmaceuti ⁇ cally acceptable salt form e.g. sodium salt form
  • the compounds of formula I and their pharmaceutically acceptable salts and prodrug form are useful for the treatment and/or prevention of chronic rejection of an organ or tissue allograft; or hyper-acute, acute or chronic rejection of an organ or tissue xenograft, in a mammalian recipient thereof
  • the invention thus provides:
  • a method of treating or preventing (i) chronic rejection of an allograft, or (n) hyperacute, acute, or chronic rejection of a xenograft, comprising administering a therapeutically or pro- phylactically effective amount of a compound of formula I (in particular, 5,6-d ⁇ hydro- 3-phenyl-9-tr ⁇ fluoromethyl-benz[c]ac ⁇ d ⁇ ne-7-carboxyhc acid, 6-fluoro-2-(2'-fluoro-1 ,1'-b ⁇ - phenyl-4-yl)-3-methyl-4-qu ⁇ nohne carboxylic acid, 6-fluoro-3-methyl-2-(4-phenyl-1- ⁇ ndol ⁇ nyl)- qu ⁇ nol ⁇ ne-4-carboxyl ⁇ c acid or 6-fluoro-3-methyl-2-(4-phenyl-1 - ⁇ ndolyl)-qu ⁇ nol ⁇ ne-4-carboxyl ⁇ c acid or a pharmaceutically acceptable salt form thereof
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a com ⁇ pound of formula I (in particular, 5,6-d ⁇ hydro-3-phenyl-9-t ⁇ fluoromethyl-benz[c]acr ⁇ d ⁇ ne- 7-carboxyl ⁇ c acid, 6-fluoro-2-(2'-fluoro-1 ,1 '-b ⁇ phenyl-4-yl)-3-methyl-4-qu ⁇ nol ⁇ ne carboxylic acid, 6-fluoro-3-methyl-2-(4-phenyl-1- ⁇ ndoi ⁇ nyl)-qu ⁇ nol ⁇ ne-4-carboxyl ⁇ c acid or 6-fluoro- 3-methyl-2-(4-phenyl-1 - ⁇ ndolyl)-qu ⁇ nohne-4-carboxyl ⁇ c acid in free acid or pharmaceutically acceptable salt form) (e.g., sodium salt form), together with a pharmaceutically acceptable diluent or carrier, for use in the treatment or prevention of (i) chronic rejection of an allograf
  • Organs or tissues may be transplanted from a donor to a recipient of the same species (allograft) or different species (xenograft).
  • organs or tissues and given illustratively are heart, lung, combined heart-lung, trachea, liver, kidney, spleen, pancreatic (complete or partial, e.g. Langerhans islets), skin, bowel, or cornea or a combination of any of the foregoing.
  • Dosages of compounds of formula I required in practicing the present invention will vary de ⁇ pending on the compound of formula I employed, the host, the mode of administration, and the nature and severity of the condition to be treated.
  • the compounds of formula I may be administered by conventional means, preferably orally, e.g., in the form of tablets of capsu ⁇ les, or parentally, e.g., in the form of injectable solutions or suspensions.
  • satis ⁇ factory results are obtained on oral administration at dosages of from about 0.1 to about 100 mg/kg/day, preferably from 1 to 20 mg/kg/day, e.g., 3 to 10 mg/kg/day, administered in 1 , 2, 3, or 4 doses/day.
  • Suitable daily dosages for oral administration to larger mammals, e.g., humans are generally about 50 to 1500 mg, preferably in the order of from 200 to 800 mg.
  • the compounds can also be administered topically as an ointment, cream, gel, spray, in ⁇ haler, solution, aerosol, liposome, patch, etc.
  • Dosage forms used to administer the active ingredient usually contain suitable carriers, di ⁇ luents, preservatives, or other excipients, as described in Remington's Pharmaceutical Sciences, Mack Publishing Comapny, a standard reference text in the field.
  • the compounds of formula I for use in the treatment or prevention of xenograft rejection or chronic rejection may be administered alone or in combination with one or more other anti- inflammatory or immunosuppressive agents, e.g., as described above in connection with allograft rejection, for example in combination with cyclosporin A and analogs thereof, FK- 506 and analogs thereof, rapamycin and analogs thereof, mycophenolic acid, mycophenol- ate mofetil, mizoribine, 15-deoxyspergualine, leflunomide, steroids, cyclophosphamide, aza- thioprene (AZA), or anti-lymphocyte antibodies or immunotoxins such as monoclonal anti ⁇ bodies to leukocyte receptors, e.g.
  • T-cell suppressant e.g., cyclosporin A or FK-506.
  • combination therapy is further comprised within the scope of the invention, e.g., a method according to 1 above fur ⁇ ther comprising administration concomitantly or in sequence of a therapeutically or synergi- stically effective amount of such a second immunosuppressive or anti-inflammatory agent.
  • the hamster-into-rat xenograft combination is a so-called difficult concordant combination. Rats do not have natural anti-hamster antibody in sufficient amounts to yield immediate hyperacute rejection as observed in concordant combinations; however, rejection in un ⁇ treated recipients occurs within 3 to 4 days, by antibodies in combination with complement. This is visualized in histology by destruction of blood vessels, exsudation and extravasation of erythrocytes, and influx by polymorphonuclear granulocytes; often there are signs of hemorrhage and thrombosis. Once this rejection has been overcome by effective inhibition of antibody synthesis or complement inactivation, a cellular rejection can emerge later on.
  • Such animals do reject a hamster xenograft within 3 to 4 days in a similar fashion as euthymic rats, indicative that (at least part of) anti- hamster antibody synthesis in rats occurs following a thymus-independent B-cell response.
  • Such recipients are useful in hamster xenografting to evaluate rejection by thymus-indepen ⁇ dent antibody-mediated rejection.
  • the heart of a Syrian hamster is heterotopically transplanted in the abdomen of a male Lewis (RTI') rat, with anastomoses between the donor and recipient's aorta and the donor right pulmonary artery to the recipient's inferior vena cava.
  • the graft is monitored daily by palpation of the abdomen. Rejection is concluded in case of cessation of heart beat.
  • Ani ⁇ mals are weighed weekly. In the present series of experiments, the endpoint is set to 28 days. Animals are subjected to autopsy; apart from the graft, weight and histology is assessed for thymus, spleen, liver, seminal vesicles and testes. Blood is taken and pro ⁇ Ended to serum for the determination of cytolytic anti-hamster erythrocyte antibody and hemolytic complement activity.
  • Compounds are dissolved in water and administered daily or twice daily (b.i.d.) orally in a volume of 2 ml/kg body weight. Administration of 5 to 30 mg/kg/day (e.g., 10 mg/kg/day) b.i.d.
  • RT1 a male DA
  • RT1 1 male Lewis
  • All animals are treated with cyclosponne A at 7.5 mg/kg/day per os for 14 days starting on the day of transplantation, to prevent acute cellular rejection Contralateral nephrectomy is not performed.
  • Each experimental group treated with a distinct dose of a compound of formula I or placebo comprises six animals
  • the recipient animals are treated per os for another 69 to 72 days with a compound of formula I or receive placebo.
  • animals are subjected to graft assessment by magnetic resonance imaging (MRI) with perfusion measurement of the kidneys (with comparison of the grafted kidney and the own contralateral kidney). This is repeated at days 53 to 64 after transplantation and at the end of the experiment.
  • the animals are then autopsied.
  • Rejection parameters such as MRI score, relative perfusion rate of the grafted kidney and histologic score of the kidney allograft for cellular rejection and vessel changes are determined and statistically analyzed Administration of a compound of formula I, e.g.

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Abstract

On a découvert que les analogues de bréquinar, par exemple de formule (I), sont utiles dans le traitement et la prévention du rejet chronique de greffes allogéniques et de rejet suraigu, aigu ou chronique de xenogreffes.
PCT/EP1997/002401 1996-05-10 1997-05-09 Utilisation de brequinar et de derives contre le rejet chronique de greffes allogeniques et la xenotransplantation WO1997042953A1 (fr)

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WO2015077535A2 (fr) 2013-11-22 2015-05-28 Genzyme Corporation Nouvelles méthodes pour traiter des maladies neurodégénératives
WO2019246603A1 (fr) 2018-06-22 2019-12-26 Ohio State Innovation Foundation Procédés et compositions pour inhiber la dihydroorotate déshydrogénase
US11033666B2 (en) 2016-11-15 2021-06-15 Giner Life Sciences, Inc. Percutaneous gas diffusion device suitable for use with a subcutaneous implant
CN115361948A (zh) * 2019-12-26 2022-11-18 俄亥俄州国家创新基金会 抑制二氢乳清酸脱氢酶的方法和组合物
US11642501B2 (en) 2017-05-04 2023-05-09 Giner, Inc. Robust, implantable gas delivery device and methods, systems and devices including same
US11701215B2 (en) 2013-09-24 2023-07-18 Giner, Inc. System for gas treatment of a cell implant

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WO2019246603A1 (fr) 2018-06-22 2019-12-26 Ohio State Innovation Foundation Procédés et compositions pour inhiber la dihydroorotate déshydrogénase
US11999697B2 (en) 2018-06-22 2024-06-04 Ohio State Innovation Foundation Methods and compositions for inhibition of dihydroorotate dehydrogenase
EP4438042A3 (fr) * 2018-06-22 2024-12-04 Ohio State Innovation Foundation Procédés et compositions pour inhiber la dihydroorotate déshydrogénase
CN115361948A (zh) * 2019-12-26 2022-11-18 俄亥俄州国家创新基金会 抑制二氢乳清酸脱氢酶的方法和组合物

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