CH492738A - Chlorethyl group-containing oxazaphosph- - orine derivatives - Google Patents
Chlorethyl group-containing oxazaphosph- - orine derivativesInfo
- Publication number
- CH492738A CH492738A CH1278967A CH1278967A CH492738A CH 492738 A CH492738 A CH 492738A CH 1278967 A CH1278967 A CH 1278967A CH 1278967 A CH1278967 A CH 1278967A CH 492738 A CH492738 A CH 492738A
- Authority
- CH
- Switzerland
- Prior art keywords
- bis
- chloroethyl
- chlorethyl
- oxide
- aminopropanol
- Prior art date
Links
- -1 Chlorethyl group Chemical group 0.000 title abstract description 3
- ZZVDXRCAGGQFAK-UHFFFAOYSA-N 2h-oxazaphosphinine Chemical class N1OC=CC=P1 ZZVDXRCAGGQFAK-UHFFFAOYSA-N 0.000 title abstract 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 8
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 6
- HWAVIYAFGOQVNJ-UHFFFAOYSA-N 4-n,4-n-bis(2-chloroethyl)benzene-1,4-diamine Chemical compound NC1=CC=C(N(CCCl)CCCl)C=C1 HWAVIYAFGOQVNJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 3
- 230000002152 alkylating effect Effects 0.000 abstract description 2
- 201000011510 cancer Diseases 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 230000001900 immune effect Effects 0.000 abstract description 2
- 238000002347 injection Methods 0.000 abstract description 2
- 239000007924 injection Substances 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 230000001926 lymphatic effect Effects 0.000 abstract description 2
- 239000000829 suppository Substances 0.000 abstract description 2
- 230000001085 cytostatic effect Effects 0.000 abstract 1
- 230000001788 irregular Effects 0.000 abstract 1
- 231100000252 nontoxic Toxicity 0.000 abstract 1
- 230000003000 nontoxic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
Chlorethyl group-containing oxazaphosphorine derivatives. 2- Bis-(2-chlorethyl)-aminophenyl-4-amino 2H-1,3,2-oxazaphosphori- ne-tetrahydro-2-oxide and its non-toxic acid addition salts, are alkylating substances with cytostatic properties at low toxicity, suitable for treating malignant tumours, partic. neoplasma of lymphatic and myeloid system and diseases of immunological pattern accompanied by irregular cell increase, and can be given by mouth, injection or as suppositories. The oxide is prepared by reacting a 1,3-aminopropanol, PO2Cl and N,N-bis-(2-chlorethyl)-p-phenylene diamine in any desired sequence.
Description
Verfahren zur Herstellung von 2-[Bis- (2-ehloräthyl)aminophenyl-4- -amino] -2H-1,3,2-oxazaphosphorin-tetrahydro-2-oxid
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von 2-[Bis-(2-chloräthyl)aminophenyl-4ami- noj - 2H - 1,3,2-oxazaphosplorin-tetrahydro-2-oxid (Formel I, siehe Formelblatt) und seinen Säureadditionssalzen, dadurch gekennzeichnet, dass man 1,3-Aminopropanol, Phosphoroxychlorid und N,N-Bis(2-chloräthyl) -p-phenylendiamin in beliebiger zeitlicher Reihenfolge miteinander umsetzt und die so erhaltene Verbindung der Formel I gegebenenfalls auf an sich bekannte Weise durch Reaktion mit organischen oder anorganischen Säuren in ihre Säureadditionssalze überführt.
Das Verfahren wird vorteilhafterweise wie folgt ausgeführt: Zu dem Umsetzungsprodukt von 1,3-Amino- propanol mit Phosphoroxychlorid und einer tertiären Base, vorzugsweise Triäthylamin in einem inerten Lösungsmittel, wie z.B. Methylenchlorid, Äthylenchlorid, Chloroform, Tetrahydrofuran, Dioxan oder Aceton, wird 4 - (N,N - Bis - 2 - chloräthyl)-p-phenylendiamin zugegeben.
Nach Rühren während mehrerer Stunden bei Zimmertemperatur wird eingedampft und das erhaltene 2-[Bis-(2 -chloräthyl)aminophenyl - 4 - amino]- 2H-l,3,2-oxazaphos- phorin-tetrahydro-2-oxid nach an sich bekannten Methoden gereinigt und gegebenenfalls in seine therapeutisch verwertbaren Salze mit organischen oder anorganischen Säuren überführt.
2-[Bis-(2-chloräthyl)aminophenyl-4-amino 1,3,2- -oxazaphosphorin-tetrahydro-2-oxid ist eine alkylierende Substanz und zeichnet sich durch ausgeprägte cytostati
EMI1.1
tische Eigenschaften bei geringer Toxizität aus. Es eignet sich für die Behandlung von malignen Tumoren und Sarkomen. Insbesondere findet es in der Therapie von Neoplasmen der lymphatischen und myeloischen Systeme Anwendung, ferner bei anderen Krankheiten, insbesondere des immunologischen Formenkreises, die mit unerwünschter Zellvermehrung einhergehen. 2-[Bis-(2chloräthyl)aminophenyl -4- aminoj - 2H - 1 ,3,2-oxazaphos- phorin-tetrahydro-2-oxid kann als Arzneimittel allein oder in entsprechenden Arzneiformen für enterale oder parenterale Verabreichung verwendet werden.
Zwecks Herstellung geeigneter Arzneiformen wird dieses mit anorganischen oder organischen, pharmakologisch indifferenten Hilfsstoffen verarbeitet. Als Hilfsstoffe werden verwendet z.B.
für Tabletten und Dragees:
Milchzucker, Stärke, Talk usw.
für Sirupe:
Rohrzucker-, Invertzucker-, Glucoselösungen u.a.
für Injektionspräparate:
Wasser, Alkohole, Glycerin, pflanzliche Oele und dgl.
für Suppositorien: natürliche oder gehärtete Oele, Wachse u.a. mehr.
Zudem können die Zubereitungen geeignete Konservierungs-, Stabilisierungs-, Netzmittel, Lösungsvermittler, Süss- und Farbstoffe, Aromantien usw. enthalten.
Die täglich zu verabreichende Dosis soll vorzugsweise 10 bis 500 mg betragen.
In dem nachfolgenden Beispiel, welches die Ausführung des Verfahrens erläutert, den Umfang der Erfindung aber in keiner Weise einschränken soll, erfolgen alle Temperaturangaben in Celsiusgraden.
Beispiel I 2-[BsC2-cAIlorätftyl)aminophenyl-4-amino]-2H-1,3,2-oxa- zaphosphorisz-tetrahyd ro-2-oxid
Man löst 34 ml Phosphoroxychlorid in 500 ml Methylenchlorid, kühlt auf 0 und gibt bei dieser Temperatur 275mol 1,3-Aminopropanol tropfenweise zu. Nach 30 Min. Rühren bei 00 gibt man noch eine Lösung von 51,7ml Triäthylamin in 500 ml Methylenchlorid hinzu, lässt 16 Stunden bei 250 stehen und dampft zur Trockne ab. Man löst den Rückstand in 3000 ml Dioxan, filtriert, gibt dem Filtrat 100 g 4-(N,N-Bis-2-chloräthyl)-p-phenylendiamin und anschliessend noch eine Lösung von 103 ml Triäthylamin in 1000 ml Methylenchlorid zu, rührt 4
Stunden bei 250 und dampft zur Trockne ab.
Man löst den Rückstand in einem Gemisch von Essigester-Wasser, trennt die Phasen, wäscht die organische Phase mit Wasser, trocknet über Natriumsulfat, konzentriert auf 250 ml und lässt das erhaltene 2-[Bis-(2-chloräthyl)-aminophenyl-4-amino]-2H- 1 ,3,2-oxazaphosphorin-tetrahydro-2- -oxid bei 200 auskristallisieren. Smp. 1480.
Beispiel 2 2-EBis-(2-chloräthyl)aminophenyl-4-amino]-2H-1,3,2-oxa- zaphosphorisz-tetrahyd ro-2-oxid
Man löst 34 ml Phosphoroxychlorid in 500 ml Methylenchlorid, kühlt auf 00, tropft unter Rühren bei 0 eine Lösung von 100 g N,N-Bis-(2-chloräthyl)-p-phenylendiamin und 103,4 mol Triäthylamin in 1000ml Methylenchlorid zu. Nach einer Stunde tropft man noch 27,5 ml
1,3-Aminopropanol und anschliessend 51,7 ml Triäthylamin zu. Man lässt die Mischung 16 Stunden bei 250 stehen, wäscht mit Wasser, trocknet über Natriumsulfat und dampft zur Trockne ein. Man kristallisiert das zurückgebliebene 2 - f Bis -(2-chloräthyl)aminophenyl-4-ami- no]-2H-1 ,3,2-oxazaphosphorin-tetrahydro-2-oxid aus Essigester bei - 200 um. Smp. 1480.
Process for the preparation of 2- [bis- (2-ehloroethyl) aminophenyl-4-amino] -2H-1,3,2-oxazaphosphorine-tetrahydro-2-oxide
The present invention relates to a process for the preparation of 2- [bis- (2-chloroethyl) aminophenyl-4aminoj-2H-1,3,2-oxazaphosplorin-tetrahydro-2-oxide (formula I, see formula sheet) and its acid addition salts , characterized in that 1,3-aminopropanol, phosphorus oxychloride and N, N-bis (2-chloroethyl) -p-phenylenediamine are reacted with one another in any chronological order and the compound of formula I thus obtained is optionally reacted in a manner known per se converted into their acid addition salts with organic or inorganic acids.
The process is advantageously carried out as follows: To the reaction product of 1,3-aminopropanol with phosphorus oxychloride and a tertiary base, preferably triethylamine in an inert solvent, such as e.g. Methylene chloride, ethylene chloride, chloroform, tetrahydrofuran, dioxane or acetone, 4 - (N, N - bis - 2 - chloroethyl) -p-phenylenediamine is added.
After stirring for several hours at room temperature, the mixture is evaporated and the 2- [bis- (2-chloroethyl) aminophenyl-4-amino] -2H-1,3,2-oxazaphosphorine-tetrahydro-2-oxide obtained is known per se Methods cleaned and, if necessary, converted into its therapeutically usable salts with organic or inorganic acids.
2- [bis- (2-chloroethyl) aminophenyl-4-amino 1,3,2-oxazaphosphorine tetrahydro-2-oxide is an alkylating substance and is characterized by pronounced cytostati
EMI1.1
excellent properties with low toxicity. It is suitable for the treatment of malignant tumors and sarcomas. In particular, it is used in the therapy of neoplasms of the lymphatic and myeloid systems, and also in other diseases, especially of the immunological type, which are associated with undesired cell proliferation. 2- [bis- (2-chloroethyl) aminophenyl -4-aminoj-2H-1, 3,2-oxazaphosphorine-tetrahydro-2-oxide can be used as a medicament alone or in appropriate dosage forms for enteral or parenteral administration.
In order to produce suitable dosage forms, it is processed with inorganic or organic, pharmacologically indifferent auxiliary substances. The auxiliary materials used are e.g.
for tablets and dragees:
Lactose, starch, talc, etc.
for syrups:
Cane sugar, invert sugar, glucose solutions, etc.
for injection preparations:
Water, alcohols, glycerine, vegetable oils and the like.
for suppositories: natural or hardened oils, waxes, etc. more.
In addition, the preparations can contain suitable preservatives, stabilizers, wetting agents, solubilizers, sweeteners, colorants, flavorings, etc.
The dose to be administered daily should preferably be 10 to 500 mg.
In the following example, which explains the implementation of the method but is not intended to restrict the scope of the invention in any way, all temperatures are given in degrees Celsius.
Example I 2- [BsC2-calloroethyl] aminophenyl-4-amino] -2H-1,3,2-oxazaphosphorus-tetrahydro-2-oxide
34 ml of phosphorus oxychloride are dissolved in 500 ml of methylene chloride, the mixture is cooled to 0 and 275 mol of 1,3-aminopropanol are added dropwise at this temperature. After 30 minutes of stirring at 00, a solution of 51.7 ml of triethylamine in 500 ml of methylene chloride is added, the mixture is left to stand at 250 for 16 hours and evaporated to dryness. The residue is dissolved in 3000 ml of dioxane, filtered, 100 g of 4- (N, N-bis-2-chloroethyl) -p-phenylenediamine and then a solution of 103 ml of triethylamine in 1000 ml of methylene chloride are added to the filtrate, and the mixture is stirred
Hours at 250 and evaporated to dryness.
The residue is dissolved in a mixture of ethyl acetate-water, the phases are separated, the organic phase is washed with water, dried over sodium sulfate, concentrated to 250 ml and the 2- [bis- (2-chloroethyl) -aminophenyl-4- amino] -2H-1, 3,2-oxazaphosphorine-tetrahydro-2-oxide crystallize at 200. M.p. 1480.
Example 2 2-EBis- (2-chloroethyl) aminophenyl-4-amino] -2H-1,3,2-oxazaphosphorus-tetrahydro-2-oxide
34 ml of phosphorus oxychloride are dissolved in 500 ml of methylene chloride, cooled to 00, a solution of 100 g of N, N-bis (2-chloroethyl) -p-phenylenediamine and 103.4 mol of triethylamine in 1000 ml of methylene chloride is added dropwise with stirring at 0. After one hour, 27.5 ml are added dropwise
1,3-aminopropanol and then 51.7 ml of triethylamine. The mixture is left to stand at 250 for 16 hours, washed with water, dried over sodium sulfate and evaporated to dryness. The remaining 2 - f bis - (2-chloroethyl) aminophenyl-4-amino] -2H-1,3,2-oxazaphosphorine-tetrahydro-2-oxide is crystallized from ethyl acetate at -200 μm. M.p. 1480.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1278967A CH492738A (en) | 1967-09-13 | 1967-09-13 | Chlorethyl group-containing oxazaphosph- - orine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1278967A CH492738A (en) | 1967-09-13 | 1967-09-13 | Chlorethyl group-containing oxazaphosph- - orine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH492738A true CH492738A (en) | 1970-06-30 |
Family
ID=4386413
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1278967A CH492738A (en) | 1967-09-13 | 1967-09-13 | Chlorethyl group-containing oxazaphosph- - orine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH492738A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000052015A2 (en) * | 1999-03-05 | 2000-09-08 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing prodrugs |
| EP1634886A2 (en) * | 1999-03-05 | 2006-03-15 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing prodrug |
| US7205404B1 (en) | 1999-03-05 | 2007-04-17 | Metabasis Therapeutics, Inc. | Phosphorus-containing prodrugs |
| US9994600B2 (en) | 2014-07-02 | 2018-06-12 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses therof |
| US10449210B2 (en) | 2014-02-13 | 2019-10-22 | Ligand Pharmaceuticals Inc. | Prodrug compounds and their uses |
| US11970482B2 (en) | 2018-01-09 | 2024-04-30 | Ligand Pharmaceuticals Inc. | Acetal compounds and therapeutic uses thereof |
-
1967
- 1967-09-13 CH CH1278967A patent/CH492738A/en not_active IP Right Cessation
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7816345B2 (en) | 1999-03-05 | 2010-10-19 | Metabasis Therapeutics, Inc. | Phosphorus-containing prodrugs |
| WO2000052015A2 (en) * | 1999-03-05 | 2000-09-08 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing prodrugs |
| EP1634886A2 (en) * | 1999-03-05 | 2006-03-15 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing prodrug |
| EP1634886A3 (en) * | 1999-03-05 | 2006-03-29 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing prodrug |
| EP1724276A1 (en) * | 1999-03-05 | 2006-11-22 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing prodrugs |
| US7205404B1 (en) | 1999-03-05 | 2007-04-17 | Metabasis Therapeutics, Inc. | Phosphorus-containing prodrugs |
| WO2000052015A3 (en) * | 1999-03-05 | 2001-02-15 | Mets Asis Therapeutics Inc | Novel phosphorus-containing prodrugs |
| US8080536B2 (en) | 1999-03-05 | 2011-12-20 | Metabasis Therapeutics, Inc. | Phosphorus-containing prodrugs |
| US8664195B2 (en) | 1999-03-05 | 2014-03-04 | Metabasis Therapeutics, Inc. | Phosphorus-containing prodrugs |
| US10449210B2 (en) | 2014-02-13 | 2019-10-22 | Ligand Pharmaceuticals Inc. | Prodrug compounds and their uses |
| US11278559B2 (en) | 2014-02-13 | 2022-03-22 | Ligand Pharmaceuticals Incorporated | Prodrug compounds and their uses |
| US9994600B2 (en) | 2014-07-02 | 2018-06-12 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses therof |
| US10150788B2 (en) | 2014-07-02 | 2018-12-11 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses thereof |
| US11970482B2 (en) | 2018-01-09 | 2024-04-30 | Ligand Pharmaceuticals Inc. | Acetal compounds and therapeutic uses thereof |
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