CA1051914A - Cyclic phosphamide derivatives - Google Patents

Cyclic phosphamide derivatives

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Publication number
CA1051914A
CA1051914A CA239,381A CA239381A CA1051914A CA 1051914 A CA1051914 A CA 1051914A CA 239381 A CA239381 A CA 239381A CA 1051914 A CA1051914 A CA 1051914A
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CA
Canada
Prior art keywords
methyl
ethyl
compound
tetrahydro
hydroperoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA239,381A
Other languages
French (fr)
Inventor
Akira Takamizawa
Tsuyoshi Iwata
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Original Assignee
Shionogi and Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Application granted granted Critical
Publication of CA1051914A publication Critical patent/CA1051914A/en
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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
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/14—Esters of phosphoric acids containing P(=O)-halide groups
    • C07F9/1403—Esters of phosphoric acids containing P(=O)-halide groups containing the structure Hal-P(=O)-O-unsaturated acyclic group
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2412—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of unsaturated acyclic alcohols
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines

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  • 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE
Cyclic phosphamide derivatives of the general formula:

[wherein X and Y each represents a halogen atom or lower alkanesulfonyloxy (excepting the case in which both X and Y
are halogen atoms and both X and Y are lower alkanesulfonyl-oxys), and R represents a lower alkyl]
being useful as medicaments exhibiting antitumor and immunosuppressive activities.

Description

lOSlgl~
1 The present invention relates to cyclic phosphamide derivatives and process for the production thereof~ More particularly, it relates to novel and therapeutically valuable compounds having antitumor and immunosuppressive activities~
he objective compounds of the present..invention may be represented by the following general formula:

O N-~ OOH
10X-CH C~H -N-P CH
2 2 ~ 2 R O- CEI ( I ) [wherein X and Y each represents a halogen atom or lower alkanesulfonyloxy of 1 - 5 carbon atoms (excepting the case in which both X and Y are halogen atoms concurrently, or both X and Y are lower alkanesulfonyloxys concurrently), and R
represents a lower alkyl of 1 - 5 carbon atoms].
It had been attempted by the present inventors to chemically modi~y phosphorodiamidates for the purpose of developing antitumor agents of alkylating type, and discovered that a series of hydroperoxyoxazaphosphorine derivatives exhibit an excellently selective toxicity against the tumor cells (Japanese Public Inspection NoO 48-86870). The invest-igation on the same series of compounds has been continued thereafter~ and in consequence novel phosphorodiamidates exhibiting more potent anti-neoplastic action but less toxicity have been discovered by the present inventors. The present invention is based on this successful findingO
The objective compounds (I) can be prepared from phosphorodiamidates of the general formula (II) by oxidation with ozoneO ~

105~9~

o 2 2 1 \ / 1 R OCH2CH2CH=C (II) [wherein X, Y and R each has the same meaning as mentioned above; and Rl and R2 each represents a hydrogen atom, alkyl, aryl or aralkyl].
The definition in the above general formulae can be explained in more detail as follows. The halogen atoms indicated by X or Y include chlorine, bromine, and iodineO
The lower alkanesulfonyloxy groups are those of 1 - 5 carbon atoms including methanesulfonyloxy, ethanesulfonyloxy, pro-panesulfonyloxy, and the likeO The lower alkyls represented by R are those of 1 - 5 carbon atoms including methyl, ethyl, propyl, isopropyl, butyl, pentyl, and the like. The atoms or at~mic group~ represented by Rl and R2 may be optional groups insofar as they do not disturb the objective ozone oxidation of the double bond since they never participate in the structure of the objective compounds. Such groups may optionally be selected from hydrogen atom, alkyls (preferably those of 1 - 5 carbon atoms), aryls (preferably those of 6 -10 ca~bon atoms) and aralkyls (preferably those of 7 - 10 carbon atoms).
The starting compounds (I) used in the present invention are novel ones which have not been described in any literatureO
For example, the compounds in which one of X and Y is a chlor-ine and other is a methanesulfonyloxy may be prepared accord-ing to the following reaction scheme.
(1) The case of X = Cl and Y = CH3S03:

105191~
1 11/ Cl / R
Cl-P \+ HocH2cH2cH=

Cl R
Cl-p / Rl 2 2 OCH2CH2CH=C

ClCH2CH2-N-P\ / R

R CH2cH2cH=c\ 1 HCH2CH2NH2 ¦ OCH2cH2CH=C 3 2 Il~ NHCH2CH2OSO2CH3 R OcH2cH2cH=c\ 1 - (2) The case of X = CH3SO3 and Y = Cl:

1l Cl H C~ 1 Cl-P + HCH2CH2C \ R ~`.

Cl P/ ~ R
2 2CH C \R 2 2 2 >

OCH2CH2CH=C \ 2 2_ _ Il NHCH2CH2Cl HO-CH2CH2-N-p /
R OCH2CH2CH=C\ CH3 2 .
; NHCH CH Cl CH3so2-ocH2cH2-N- 5~ 2 2 ~ R
R 0CH2CH2CH=C

(wherein R, Rl and R2 each has the same meaning as defined above)
- 3 -10519~

1 The other starting compounds (II) in which the symbols X and Y in the above formulae are another species of halogens or lower alkanesulfonyloxys may also be prepared according to the aforementioned reaction scheme.
Representative of the starting compounds (II) are :
3-butcnyl N-methyl-N-(2-methanesulfonyloxyethyl)-N'-(2-chloroethyl)phosphorodiamidate, 3-butenyl N-methyl-N-(2-chloroethyl)-N'-(2-methane-sulfonyloxyethyl)phosphorodiamidate, 3-butenyl N-ethyl-N-(2-methanesulfonyloxyethyl)-N'-(2-chloroethyl)phosphorodiamidate, 3~butenyl N-isopropyl-N-(2-chloroethyl)-N'-(2-methane-sulfonyloxyethyl)phosphorodiamidate, 3-pent~nyl N-butyl-N-(2-chloroethyl)-N'-(2-methanesul-fonyloxyethyl)phosphorodiamidate, ; 4-phenyl-3-butenyl N-methyl-N-(2-bromoethyl)-N'-(2-ethanesulfonyloxyethyl)phosphorodiamidate, 5-phenyl-3-pentenyl N-methyl-N-(chloroethyl)-N'-(2-pr4panesulfonyloxyethyl)phosphorodiamidate,
4,4-diphenyl-3-butenyl N-ethyl-N-(2-iod`oethyl)-N'-(2-methanesulfonyloxyethyl)phosphorodiamidate, and the like.
The reaction of this invention is carried out in a conventional manner for ozone oxidation using a usual apparatus for ozone oxidation. For example, the starting compounds (II) are diss~lved in a suitable solvent, and ozone, or oxygen or air containing ozone may be introduced into the solution at room temperatur~, or if required under cooling. The suitable solvent involves those usually used in ozonization, for example, methyl chloride, ethyl chloride, chloroform, dichloro-methane, dichloroethane, tetrachloroethane, petroleum ether, lOSl91~
1 hexane, cyclohexane, petroleum~benzin, ligroin, benz~ne, toluene, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, or a mixture of them with or without water The reaction mixture containing ozone is usually kept at room temperature or under cooling (from 35C to -20C) for a period of from several hours to several daysO In this reaction, it is appropriate to add a peroxide (eOgO hydrogen peroxide) into the reaction mixture in some cases after the introduction of ozone, but the addition ~f peroxide is not always an essential procedure. The resulting products (I) may be isolated from the reaction mixture and purified in a conventional manner such as extraction, distillation, chromato-graphy, recrystallization and so on.
Representative of the objective compounds (I) are :
2-[N-methyl-~-(2-chloroethyl)amino]-3-(2-methanesul-fonyloxyethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-oxazaphos-phorine 2-oxide9 2-[N-methy~-~N..(2-mèthan~sulfonyloXy~t~ am~no~31(2-chloroethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-~xazaphosphorine 2-oxide, 2-[N-ethyl-N-(2-chloroethyl)amino]-3-(2-methanesulfonyl-oxyethyl)-4-hydroperox~-tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide, 2-[N-isopropyl-N-(2-chloroethyl)amino]-3-(2-methane-sulfonyloxyethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-oxaza-phosphorine 2-oxide, 2-[N-butyl-N-(2-chloroethyl)amino]-3-(2-methanesulfonyl-oxyethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide, 2-[N-methyl-N-(2-bromoethyl)amino]-3-(2-ethanesulfon ~05191~
1 oxyethyl)-4-hydroperoxy-tetrahydro-2H-l~3J2-oxaæaphosphorine 2-oxide, ~ -[N-methyl-N-(2-chloroethyl)amino]-3-(2-propanesul-fonyloxyethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-oxazaphos-phorine 2-oxide, 2-[N-ethyl-N-(2-iodoethyl)amino]-3-(2-methanesulfonyl-oxyethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-oxazaphosphorine 2-o~ide, and the like.
As mentioned above, the compounds (I) produced in this invention are useful as antitumor agents and immunosuppressive agents For example, the antitumor activity of the re~resent-ative compound (I), i.e , 2-[N-methyl-N-(2-chloroethyl)amino]-3-(2-methanesulfonyloxyethyl)-4-hydroperoxy-tetrahydro-2H-1,3, 2-oxazaphosphorine 2-oxide (hereinafter referred to as compound Ia), against L-1210 was compared with a commercially available antitumor agent, c~clophosphamide, as indicated in Table Io Table I. Antitumor activity against L-1210 .
Test Compound , R~ute ILS30 Survivors over 30 days (mg/kg) (optimal dose mg/kg) ._ ... __ _ __ , Cyclophosphamide p.o 35 8/8 (200) i.v. 25 6/7 (200) Compound Ia p.o 10 8/8 (50 - 200) _ i.v. 2 8/8 (25 - 50) _ . .
~ote : ILS30 = 3~rIAcrease of lifespan over control p,o = oral administration i.v. = intravenous injection Test Method:

The test was carried out by means of BDFl mice. The test compounds were administered from the day following intraperitoneal inoculation of 500,000 cells of L-1210. The animals were observed after 30 days, and the ILS% was calcul-1~51gl~
1ated from the survival time and the number of survivor~
As seen from Table I, Compound Ia is 3.5 - 12 times more active than cyclophosphamide in in vivo activity against L-1210.
Fu~hher, the immune suppression activity of the comp-ounds (I) was compared with a commercially available immuno-suppressive agent, cyclophosphamideO Table II indicates the results of test.
Test ~ethod:

.
10To a group of ~R female mice, sheep red blood cells (10 /mouse) were intraperitoneally injected for immunizationO
Test compounds were also intraperitoneally administered at the time of immunization, and their antisera were separatedO
Hemagglutination titer of the antisera was measured according i.to the microtiter method, and expressed as log2 reciprocals of the end point dilution. The antibody resistant to 2-mercapto-ethanol was determined similarly after tr~ating the separated antisera with O.LM 2-mercaptoethanolO

.

1(~51914 , . _ ~ ---_ _ ~q ~
o o o o +1 +1 +l +l ~ In ~ O GO
,~ : .
+ ._ Q~ ~ u~
.~ ~ o o ~ ,, O +1 +1 +l +l ~1 E~ ~ O
00 ~D ~ OD
.':, ~o . .
~ .~ .~ +l I I C+'~ o ~

.` s ~ ~ o o o a ~ o _~ O _i '' .~ .~

~ o +l +l +l +l +l O
E~ O ~ ~ .
O OD -~ O O ~ ~:
, ~ .. - -- --- -I n '~C ~ ~ 1 1` -I

, U ~ , .~ ' H C ~ H N
a~ ~ ~ ~ g ..
+~ ~ O

, ~ ~` ' ' ~051~14 1 Acute toxicity of Compound Ia is LD50 ( in mice) =
284 mg/kg.
Test Method:
The compound was orally administered as a suspension in a vehicle to BDFl male mice, 40 days old weighing 22 - 23 g.
The animals were observed for 21 days, and LD50 was calculated by Probid's method The cyclic phosphamide derivatives (I) produced in this invention can be admi~istered alone or in combination with pharmaceutically acceptable carriers, the choice of which depends on the preferred route of admmnistration, solubility of the materials, and pharmaceutical practiceO
In general, the dosage of the compounds (~) is approximately of the same order as the practical dosage of cyclophosphamide, that is, they may be adm~mistered in single or divided doses containing from 50 mg to 500 mg of theactive ingredientO
Practical examples of pharmaceutical preparations with the compounds (I) are tablets, capsules, pills, suspensions, emulsion, solutions, suppositories, ointments, granules, and powders, The invention will be better explained by the following examples which are not intended as a limitation thereof ~-Example 1 Into a solution of 2 8 g of 3-butenyl N-methyl-N-(2- ::
methanesulfonyloxyethyl)-N'-(2-chloroethyl)phosphorodiamidate in 50 ml of aqueous acetone (acetone : water = 1 : 1) is ~:
introd~ced 800 mg of ozone within a period of 20 minutes under ice-cooling. Then, 3 ml of 30% hydrogen peroxide is added thereto, and the mixture is kept at 0 - 5C for 2 days~ The reaction mixture is then condensed under reduced pressure, and _ g _ 1051S'1~
l the residual aqueous layer is extracted with chloroform~
The extract is dried over anhydrous sodium sulfate, and evaporated bo drynessO The residue is adsorbed on a column of silica gel, and eluated with a mixture of acetone and chloroform (2 : l) to give 790 mg of 2-~N-methyl-N (2-methane-sulfonyloxyethy])-amino]-3-(2-chloroethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide as a colourless oily materialO NMR: ~ (CDC13): 2.00 - 2D33 (2H, multiplet, CH2), 2 70 (3H, doublet, J = 10 Hz, N-CH3), 3.08 (3H, singlet, SO2-CH3), 3Ol - 3.9 (6H, multiplet, CH2 x 3), 4O32 (2H, triplet, J = 5O8 Hz, CH2-0S02), 5.03 (lH, mul~iple doublet, J = 22 Hz, ; C4-H). Anal. Calcd, for CgHlgN2PO7SCl (%): C, 29056; H, So 24;
N, 7.66.
Found (%): C, 30.06; H, 5.63; N, 7.70.
Example 2 Into a solution of 6.2 g of 3-butenyl ~-methyl-N-(2-chloroethyl)-~'-(2-methanesulfonyloxyethyl)phosphoro-diamidate in 30 ml of aqueous acetone (acetone : water = l : 1) is introduced 2 g of ozone within a period of 37 minutes under ice-coolingO The, 5 ml of 30% hydrogen peroxide is added thereto, and the~mixture is kept at 0C for 2 day~.
The reaction mixture is then condensed under reduced press-ure, and the residual aqueous layer is extracted with chloro-form. The extract is dried over anhydrous sodium sulfate, ` and evaporated to dryness. The residue is adsorbed on a column of silica gel, eluated with a mixture of acetone and chloroform (l : ~), and then recrystallized from an acetone -ether mixture to give 670 mg of 2-[~-methyl-~-(2-chloroethyl) amino]-3-(2-methanesulfonyloxyethyl)-4-hydroperoxytetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide as colourless prisms having mp. 119 - 121C (dec).

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for producing cyclic phosphamide derivatives of the general formula:

wherein X and Y each represents a halogen atom or lower alkanesulfonyloxy of 1 - 5 carbon atoms (where the case in which both X and Y are halogen atoms concurrently, or both X and Y are lower alkanesulfonyloxys concurrently, is excluded), and R represents a lower alkyl of 1 - 5 carbon atoms, which comprises oxidizing phosphorodiamidates of the general formula:

wherein X, Y and R each has the same meaning as mentioned above; and R1 and R2 each represents a hydrogen atom, alkyl, aryl or aralkyl, with ozone in an inert solvent.
2. A process as claimed in Claim 1, wherein the inert solvent is a member selected from the group consisting of methyl chloride, ethyl chloride, chloroform, methylene chloride, dichloroethane, tetrachlorocttlane, petroleum ether, n-hexane, cyclohexane, petroleum benzin, ligroin, benzene, toluene, tetrahydrofuran, dioxane, acetone, a mixture of these solvents, and their aqueous mixture.
3. A process as claimed in Claim 1, wherein the oxidation is carried out at a temperature ranging from -20°C to 35°C.
4. A process as claimed in Claim 1, wherein a peroxide is added to the reaction mixture after the introduction of ozone.
5. A process as claimed in Claim 4, wherein the peroxide is hydrogen peroxide.
6. A process of Claim 1 for preparing 2-[N-methyl-N-(2-methanesulfonyloxyethyl)amino]-3-(2-chloro-ethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide; wherein said process X is 2-methanesulfonyloxy, Y is chloro and R is methyl.
7. A process of Claim 1 for preparing 2-[N-methyl-N-(2-chloroethyl)amino]-3-(2-methanesulfonyloxy-ethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide; wherein said process X is chloro, Y is 2-methane-sulfonyloxy and R is methyl.
8. A compound of the general formula:

wherein X and Y each represents a haolgen atom or lower alkanesulfonyloxy of 1 - 5 carbon atoms (where the case in which both X and Y are halogen atoms concurrently, or both X and Y are lower alkanesulfonyloxys concurrently, is excluded), and R represents a lower alkyl of 1 - 5 carbon atoms, when prepared by the process of Claim 1.
9. A compound claimed in Claim 8, said compound being 2-[N-methyl-N-(2-methanesulfonyloxyethyl)amino]-3-(2-chloro-ethyl)-4-hydroperoxy-tetrahydro-2H-1, 3, 2-oxazaphosphorine 2-oxide, when prepared by the process of Claim 6.
10. A compound claimed in Claim 8, said compound being 2-[N-methyl-N-(2-chloroethyl)amino]-3-(2-methanesulfonyloxy-ethyl)-4-hydroperoxy-tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide, when prepared by the process of Claim 7.
CA239,381A 1974-11-20 1975-11-07 Cyclic phosphamide derivatives Expired CA1051914A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP49133257A JPS5159886A (en) 1974-11-20 1974-11-20

Publications (1)

Publication Number Publication Date
CA1051914A true CA1051914A (en) 1979-04-03

Family

ID=15100374

Family Applications (1)

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Country Status (9)

Country Link
JP (1) JPS5159886A (en)
AU (1) AU500813B2 (en)
CA (1) CA1051914A (en)
CH (1) CH602777A5 (en)
DE (1) DE2552135A1 (en)
FR (1) FR2291763A1 (en)
GB (1) GB1527497A (en)
NL (1) NL7513590A (en)
SE (1) SE7513007L (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3133309A1 (en) * 1980-09-10 1982-04-15 Asta-Werke Ag, Chemische Fabrik, 4800 Bielefeld 4-Carbamoyloxyoxazaphosphorines, processes for their preparation, and pharmaceutical preparations containing these compounds
DE3111428A1 (en) * 1981-03-24 1982-10-07 Asta-Werke Ag, Chemische Fabrik, 4800 Bielefeld OXAZAPHOSPHORIN-4-THIO-ALKANESULPHONIC ACIDS AND THEIR NEUTRAL SALTS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
ZA851062B (en) * 1984-03-01 1985-11-27 Asta Werke Ag Chem Fab Salts of oxazaphosphorine derivatives and process for their production
JP4629238B2 (en) * 1999-05-24 2011-02-09 サザン・リサーチ・インスティテュート Isophosphoamide mustard analog and use thereof
KR20130041384A (en) 2004-10-25 2013-04-24 데크-테크 인코포레이티드 Salts of isophosphoramide mustard and analogs thereof as anti-tumor agents
US7964583B2 (en) 2006-02-17 2011-06-21 Ziopharm Oncology, Inc. Salts of isophosphoramide mustard and analogs thereof as anti-tumor agents
CA2684747A1 (en) 2007-04-06 2008-10-16 Ziopharm Oncology, Inc. Salts of isophosphoramide mustard and analogs thereof

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Publication number Publication date
DE2552135A1 (en) 1976-05-26
SE7513007L (en) 1976-05-21
JPS5159886A (en) 1976-05-25
GB1527497A (en) 1978-10-04
NL7513590A (en) 1976-05-24
AU8681675A (en) 1977-05-26
AU500813B2 (en) 1979-05-10
CH602777A5 (en) 1978-07-31
FR2291763A1 (en) 1976-06-18

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