WO1989007384A2 - Composes a base d'iodure de 2-methylisoquinolinium utilises dans le traitement contre le sida - Google Patents
Composes a base d'iodure de 2-methylisoquinolinium utilises dans le traitement contre le sida Download PDFInfo
- Publication number
- WO1989007384A2 WO1989007384A2 PCT/US1989/000164 US8900164W WO8907384A2 WO 1989007384 A2 WO1989007384 A2 WO 1989007384A2 US 8900164 W US8900164 W US 8900164W WO 8907384 A2 WO8907384 A2 WO 8907384A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- methoxy
- iodide
- methyl
- methylisoquinolinium
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—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
Definitions
- This invention is a novel treatment of patients infected with a human immunodeficiency virus.
- AZT zidovudine
- This invention is a method for treating a human infected with one or more than one strain of a human immunodeficiency virus which comprises administering an effective amount of a compound selected from the group consisting of 2-methylisoquinolinium iodide, 8-hydroxy-7-methoxy-1-(m-methoxybenzyl)-2-methylisoquinolinium iodide, and 6-methoxy-1-[[3-methoxy-2-nitro-4-(phenylmethoxy)phenyl]methyl]-2 -methyl-7-(phenylmethoxy)isoquinolinium iodide or salts thereof, to the infected human.
- a compound selected from the group consisting of 2-methylisoquinolinium iodide, 8-hydroxy-7-methoxy-1-(m-methoxybenzyl)-2-methylisoquinolinium iodide, and 6-methoxy-1-[[3-methoxy-2-nitro-4-(phenylmethoxy)phenyl
- human immunodeficiency virus means human immunodeficiency virus type I, human immunodeficiency virus type II, or strains, apparent to one skilled in the art, which belong to the same viral family and which create similar physiological effects in humans as human immunodeficiency virus types I or II.
- Compound III is condensed with a commercially available methoxy phenyl aldehyde to give Compound IV following known procedures. See Shepard, C.B. and North, J.F., ibid., and Lee, K.H. and Soine, T.O., ibid.
- a mixture of compound IV, phosphorous oxychloride and dry toluene is heated for about 2 hours tinder anhydrous conditions at 115oC.
- the reaction mixture is concentrated to dryness on a rotary evaporator.
- the residue is washed 3 times with Skellysolve B and dissolved in absolute ethanol.
- To the solution is added 10% hydrochloric acid and Compound V precipitates when the solution is cooled in an ice bath. The precipitate is purified by crystallization or chromatography.
- Compound VI is dissolved and dehydrogenated in the presence of 10% palladium on charcoal under an inert atmosphere. The mixture is then heated to 180°C for about 50 minutes under a slow stream of nitrogen. The mixture is cooled to room temperature, diluted with absolute methanol and filtered. The solvent is removed on a rotary evaporator and diethyl ether is added to the residue to give solid Compound VII. A stirred mixture of Compound VII, anhydrous potassium, benzyl bromide and dry methanol is refluxed for 2 to 8 hours to give benzylated Compound VIII.
- a solution of compound VIII in methanol is refluxed with methyl iodide for about 4 hours. More methyl iodide is added and the reflux is continued for about 4 to 5 hours. The mixture is kept at 5°C for about 16 hours and the solvent is removed. The residue is purified by crystallization after trituration with absolute ethanol or by reverse phase chromatography to give Compound IX.
- the benzyl protecting group is removed from Compound IX by standard procedures known in the art to give 8-hydroxy-7-methoxy-1-(m-methoxybenzyl)-2-methyliso-quinolinium iodide.
- Compound IV is benzylated using known methods. For example, a solution of 1.2 equivalents of benzyl chloride in THF is added dropwise to a solution of 1.0 equivalents of Compound IV and 1.2 equivalents of potassium hydroxide in THF. The mixture is brought to reflux for about one hour or until the starting material is consumed. The mixture is cooled and filtered. The filtrate is acidified and concentrated to dryness on a rotary evaporator. Pure Compound V is obtained after preparative reverse phase chromatography.
- Compound V is added to a stirred solution of nitric acid in sulfuric acid at 0.5oC. The reaction is complete after about one to 16 hours and then the mixture is carefully poured onto crushed ice and the mixture of nitrated products is collected by filtration and/or extraction with diethyl ether.
- Compound VI is obtained from this mixture after preparative reverse phase chromatography.
- Compound VI is condensed with Compound III according to the general procedure of Shepard, C.B. and North, J.F., ibid., and Lee, K.H. and Soine, T.O., ibid., to give compound VII.
- Compound VIII is prepared when a mixture of Compound VII, phosphorum oxychloride and dry toluene is heated for 2 hours under dry conditions at 115oC.
- the reaction mixture is concentrated to dryness on a rotary evaporator.
- the residue is washed 3 times with Skellysolve B and dissolved in absolute ethanol.
- the solution is acidified and Compound VIII precipitates when the solution is cooled in an ice bath.
- the precipitate can be purified by crystallization or preparative chromatography.
- Compound IX is dissolved in tetralin and 10% palladium on charcoal is added. Air is removed from the flask by alternately evacuating and flushing with nitrogen. The mixture is then heated to about 180oC for about 50 minutes under a slow stream of nitrogen. The mixture is cooled to room temperature, diluted with absolute methanol and filtered. The methanol is removed on a rotary evaporator and diethyl ether is added to the residue to precipitate Compound X.
- a stirred mixture of Compound X, anhydrous potassium carbonate, benzyl bromide and dry methanol is refluxed for about 2 to 8 hours.
- Compound XI is obtained.
- a solution of Compound XI in methanol is refluxed with methyl iodide for about 4 hours. Additional methyl iodide is added and the reflux is continued for an additional 4 to 5 hours.
- the mixture is kept at 5°C for about 16 hours and the solvent is removed on a rotary evaporator. The residue is purified by crystallization after trituration with absolute ethanol or by preparative reverse phase chromatography.
- compositions or pharmaceutically acceptable salts thereof can be used and administered in practicing the method claimed in this invention.
- Pharmaceutically acceptable salts refers to those salts of the compounds claimed in this invention which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent to the parent compound in properties such as formulation, stability, patient acceptance and bioavailability.
- Those skilled in the art would know how to formulate the compounds used to practice the method claimed in this invention into appropriate pharmaceutical dosage forms. Examples of the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
- an effective amount is from about 1 to 100 mg per kg per day.
- a typical unit dose for a 70 kg human would be from about 200 mg to 1000 mg taken one to four times per day.
- Either solid or fluid dosage forms can be prepared for oral administration.
- Solid compositions are prepared by mixing the compounds used to practice the method claimed in this invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers.
- Capsules are prepared by mixing the compounds used to practice the method claimed in this invention with an inert pharmaceutical diluent and placing the mixture into an appropriately sized hard gelatin capsule.
- Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds used to practice the method claimed in this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum.
- Syrups are prepared by dissolving the compounds used to practice the method claimed in this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives.
- Elixirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent.
- Suspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, tragacanth, or methyl cellulose.
- parenteralry When the compounds used to practice the method claimed in this invention are administered parenteralry, it can be given by injection or by intravenous infusion. An effective amount is from about 1 to 100 mg per kg per day.
- Parenteral solutions are prepared by dissolving the compounds used to practice the method claimed In this invention in water and filter sterilizing the solution before placing in a suitable sealable vial or ampule.
- Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds used to practice the method claimed in this invention are sterilized with ethylene oxide or suitable gas before it is suspended in the vehicle.
- Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human Immunodeficiency virus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, II) isoporiasis, iii) bronchial and pulmonary candidiasis including pneumocystis pneumonia iv) non-Hodgkin's lymphoma or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/mm 3 in the peripheral blood.
- Treatment would consist of maintaining an inhibitory level of the compounds of this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.
- Example 1 Hard Gelatin Capsules One thousand tw ⁇ -piece hard gelatin capsules for oral use, each capsule containing 50 mg of 2-methylisoquinolinium iodide, are prepared from the following: 2-methylisoquinolinium iodide 50 gm Lactose 100 gm
- One thousand tablets, each containing 50 mg of 2-methylisoquinolinium iodide, are prepared from the following: 2-methylisoquinolinium iodide 50 gm Lactose 75 gm
- Example 3 A sterile aqueous solution for parenteral intravenous injection containing 150 mg of 2-methylisoquinolinium iodide in one liter of solution is prepared from the following:
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15534588A | 1988-02-12 | 1988-02-12 | |
US155,345 | 1988-02-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1989007384A2 true WO1989007384A2 (fr) | 1989-08-24 |
Family
ID=22555070
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1989/000164 WO1989007384A2 (fr) | 1988-02-12 | 1989-01-23 | Composes a base d'iodure de 2-methylisoquinolinium utilises dans le traitement contre le sida |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU2943189A (fr) |
WO (1) | WO1989007384A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0476391A2 (fr) * | 1990-08-29 | 1992-03-25 | Kaken Shoyaku Co., Ltd. | Composition anti-SIDA contenant cépharanthine comme agent thérapeutique |
WO1992018123A2 (fr) * | 1991-04-10 | 1992-10-29 | Octamer, Inc. | Procede d'inhibition de la replication retrovirale |
-
1989
- 1989-01-23 WO PCT/US1989/000164 patent/WO1989007384A2/fr not_active Application Discontinuation
- 1989-01-23 AU AU29431/89A patent/AU2943189A/en not_active Abandoned
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0476391A2 (fr) * | 1990-08-29 | 1992-03-25 | Kaken Shoyaku Co., Ltd. | Composition anti-SIDA contenant cépharanthine comme agent thérapeutique |
EP0476391A3 (en) * | 1990-08-29 | 1992-05-06 | Kaken Shoyaku Co., Ltd. | Anti-aids virus composition containing cepharanthine as active compound |
US5534523A (en) * | 1990-08-29 | 1996-07-09 | Kaken Shoyaku Co., Ltd. | Anti-aids virus composition |
WO1992018123A2 (fr) * | 1991-04-10 | 1992-10-29 | Octamer, Inc. | Procede d'inhibition de la replication retrovirale |
WO1992018123A3 (fr) * | 1991-04-10 | 1993-03-04 | Octamer Inc | Procede d'inhibition de la replication retrovirale |
Also Published As
Publication number | Publication date |
---|---|
AU2943189A (en) | 1989-09-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU4074789A (en) | Coumarins to inhibit reverse transcriptase in humans | |
JPH05500824A (ja) | Hiv関連疾病の処置での漢方薬草抽出物 | |
JP2988944B2 (ja) | アリールアルコキシクマリン、その製造方法及びこれを含有する治療剤 | |
EP2555779A1 (fr) | Composés glycomimétiques et méthodes d'inhibition d'une infection par le vih | |
JP2851913B2 (ja) | 新規な5,11―ジヒドロ―6H―ジピリド〔3,2―b:2′,3′―e〕〔1,4〕ジアゼピン―6―オンおよび該化合物を含有するAIDSの予防および治療用医薬組成物 | |
WO1992002530A1 (fr) | Hexa-n-(o-hydroxybenzyl) neomycine b destinee a l'inhibition des retrovirus humains et au traitement du sida | |
JPS63146822A (ja) | レトロウィルスに感染した患者を治療するための2′,3′―ジデオキシシチジン―2′―エン(2′,3′―ジデオキシ―2′,3′―ジデヒドロシチジン)の使用 | |
WO1989007384A2 (fr) | Composes a base d'iodure de 2-methylisoquinolinium utilises dans le traitement contre le sida | |
US20020151584A1 (en) | Antiviral compositions and methods of use | |
AU633499B2 (en) | Method of inhibiting the activity of human immunodeficiency virus (hiv) in vivo | |
WO1990005523A2 (fr) | Esters de phenanthrolinedicarboxylate, derives de 4-aminoquinoline et isoquinoline en tant qu'inhibiteurs de la transcriptase d'inversion de hiv | |
WO1989002741A2 (fr) | Inhibiteurs de la transcriptase inverse de l'hiv servant au traitement du sida | |
US4265910A (en) | Isoprenylamines | |
US4322555A (en) | Nonaprenylamine derivatives | |
WO1989002741A1 (fr) | Inhibiteurs de la transcriptase inverse de l'hiv servant au traitement du sida | |
CZ372792A3 (en) | Pyrrolylbenzodiazepinones, processes of their preparation and medicaments based thereon | |
WO1989009056A1 (fr) | Composition antivirale contenant des diones aromatiques polycycliques et des analogues de nucleosides, et procede de traitement d'infections retrovirales | |
JPH02304024A (ja) | エイズウィルス増殖抑制剤 | |
EP0352299A1 (fr) | Derives de rubradirine pour le traitement de l'infection hiv | |
WO1989009055A1 (fr) | Composition anti-virale contenant des diones polycycliques aromatiques et analogues de nucleoside, et procede de traitement d'infections retrovirales | |
EA001154B1 (ru) | (4r,5s,6s,7r)-гексагидро-1-[5-(3-аминоиндазол)метил]-3-бутил-5,6-дигидрокси-4,7-бис[фенилметил]-2н-1,3-диазепин-2-он и его применение в качестве ингибитора вич-протеазы | |
EP0755393A1 (fr) | Nouvelles formes cristallines de 1-[5-methanesulfonamidoindolyle-2-carbonyle]-4- 3-(1-methylethylamino)-2-pyridinyl]piperazine | |
CA1150268A (fr) | Derives de la decaprenylamine | |
US4380668A (en) | Decaprenylamine derivatives | |
CN114053394A (zh) | 新型化合物在制备预防和/或治疗冠状病毒感染的药物中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AU DK FI JP KR NO US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH DE FR GB IT LU NL SE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1989901909 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1989901909 Country of ref document: EP |