IL28262A - Process for the production of n,n'-bis halogenoalkyl phosphoric and thiophosphoric acid ester amides - Google Patents
Process for the production of n,n'-bis halogenoalkyl phosphoric and thiophosphoric acid ester amidesInfo
- Publication number
- IL28262A IL28262A IL2826267A IL2826267A IL28262A IL 28262 A IL28262 A IL 28262A IL 2826267 A IL2826267 A IL 2826267A IL 2826267 A IL2826267 A IL 2826267A IL 28262 A IL28262 A IL 28262A
- Authority
- IL
- Israel
- Prior art keywords
- group
- carbon atoms
- formula
- member selected
- alkyl groups
- Prior art date
Links
- -1 halogenoalkyl phosphoric Chemical class 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 6
- 125000004432 carbon atom Chemical group C* 0.000 claims 5
- 125000005843 halogen group Chemical group 0.000 claims 5
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 229940126062 Compound A Drugs 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000003014 phosphoric acid esters Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical group C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241001573476 Filodes Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NVQBAIMDGFLXBX-UHFFFAOYSA-N phosphoric acid;prop-1-ene Chemical compound CC=C.OP(O)(O)=O NVQBAIMDGFLXBX-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000008096 xylene 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
- C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring
-
- 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
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/564—Three-membered rings
-
- 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
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)
Description
PATENTS AND DESIGNS ORDINANCE SPECIFICATION Process for the production of N.K'-bls halogenoalkyl phosphoric and thiophosphoric acid ester amides I (we), ASTA-WERKE AKTIEITGESELLSCHAPT CHEMISCHE PABRIK, incorporated under th© laws of Germany, of 79-91» Bielefelder Strasse, Brackwede/Weetfalen, Germany do hereby'-declare the nature of this invention and in what manner the.same is- to be performed, to' be particularly described and ascertained in and by the following statement :- the Israeli Specification / These compounds- are described in o- r—copGliding applioa' No. 28263 t -tion oxooutod and filod on ovon dato and ontitlod "NEW N ' SUBSTITUTED AMIDES AND ESTER AMIDES OP. PHOSPHORIC AND ^/t TIII OPIIOaPIIORIC ACID AND PR0CE33E3 FOR THE PRODUCTION THEREOF" . ■' Preferably, those compounds of Formula' I are prepared wherein X-| is oxygen. · ' ■ ' : ) · Particular useful in view of their good properties are the compounds of Formula II wherein X, R^ and m have the same meaning as in Formula I .
Most particularly are the compounds of Formula III ■ C1-CH CH0-NH CH~ III ·' wherein 2 is a member selected, from the group consisting of the B-chloroethy1 and the 2f-chloro- propyl group; preferably, R2 is the B-chloroethyl The compounds of Formula I are useful in human and veterinary medicine as cytostatically active compounds. Test results . of pharmacological tests with products .according to the. present invention' are given in the following Tahle I.
Tahle I Curative and lethal doses of various cyclic phosphoric acid- amide esters of the Formula upon intraperitoneal application.
Test compound A = ,N-his-( B-chloroethyl) -amino-N ' , 0· propylene phosphoric acid ester diamide. invention Test compound B = compound of the present exa¾$>i-e-» Determination of 'CD.50 (4) with a Yoshida-Ascites- .Sarkom of rats with a total dose D subdivided to . 4 subsequent days. Start up of therapy at the day of sarkom implantation; Test period: 90 days.
Determination of LD-50 (1) with a single administration to rats of the same race; Test period: 14 days. . invention The compound of the present e-xa-aie is characterized over the known test compound by that the accumulation- of the toxic effectiveness is smaller in the lethality test.
Thus, the LD 50 (4) of compound A is 140 mg./kg.,: and thus lower than the LD 50 (1) while the LD 50 (4) of the com-' invention pound according to the present es^mpl© amounts to 190 mg./kg. and thus is significantly higher than the LD 50 (1). This 15' lower toxic accumulation- is of importance in the treatment over prolonged periods of time. invention ^j Furthermore, the compound according to the present e¾ai&pie- is characterized by a high solubility in water' and furthermore, represents a new type of cytostatics wherein the 2-chloroethyl groups are not bound to one and. the same nitrogen atom as in the nitrogen mustard compounds; on to two different amide nitrogen atoms.
Finally, in comparison to- he known cytostatic ,ΪΓ,N-bis- β-chloroethylamino-lT 1 ,0-propylene phosphoric acid ester diamide. (test compound A) which is well accepted in the medical field, the compounds of the present invention are characterized by an improved stability in aqueous solutions as follows from Table II. When allowing compounds of the present invention to stand in a bicarbonate buffer solution (pH 7.5) for 10 days at 37/«5°C, chlorine, ions are split off in an amount of onl about 1/6 of the amount split off from the known test compound A.
Table II It has been found that the compounds of the above Formula I may be prepared particularly readily when starting from compounds of Formula IV : wherein , , Y, Z and m have the same meaning as in Formula I , and when subjecting these compounds to the action of a hydrohalogenic acid, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, preferably however hydrochloric acid. This reaction may . be carried out in the presence of an inert solvent such as the halogenated hydrocarbons such as methylene dichloride, chloroform, carbontetrachloride , dichloroethane , methyl-iodide, chlorobenzene , dichlorobenzene , or the hydrocarbons such as benzene, toluene or xylene. It is most preferred to carry out the reaction substantially in the absence of water. However, the desired reaction products of Formula I are obtainable, too, in the presence of traces of water.
The cleavage of the ethylene imine ring by means of acids is known as such.. However, this reaction has not yet been described with N-phospho yl ethylene imides'. It is furthermore surprising with the new process. 'that the second ring in the molecule containing the phosphamide bond is not attacked since the readiness of the cleavage of this ring by means of acids is known, too.
The starting products 'of the present process may be produced, for instance, as described in our above mentioned copending application executed and filed on eve date.
The following Example serves to further illustrate the present invention.
Example : N ,1ST ' -Bis-( 2-chloroethyl) -N ' ,0-propylene phosphoric acid ester diamide 1 mol (224.6 g.) of ,N-ethylene-N « -( 2-chloroethyl) - N' , O-propylene phosphoric acid ester diamide is dissolved in 1000 cc. of substantially anhydrous methylene dichloride. 1 mol (36.5 g. ) of anhydrous ethereal hydrochloric acid is added dropwise thereto with stirring. During the addition period, the solution is. caused to "boil by the liberated reaction heat. After cooling, the reaction solution is washed twice with 5 cc. each time of ice-cold water and then is dried over anhydrous sodium sulfate.
Thereafter, the reaction mixture is evaporated in a ■' vacuum and the oily residue is triturated with 200 cc. of ether. The mixture is inocculated and is cooled to produce crystallization..The precipitated crystals are . filtered off. with suction and washed with a small amount of ether. Yield: 166 g. (63.6 o of the theoretical).
M ?p. : 39' - 41 C.
Claims (1)
1. HAVING NOW particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is 1. Process for the production of Ν,Ν' -bis-halogenoalkyl- phosphoric and thiophosphoric acid ester amides of the Formula I 5 wherein X is a halogen, is a member selected 6 from the group consisting of the lower alkyl' 7 groups having from 1 to carbon atoms and being 8 substituted by one halogen atom and the lower 9 alkyl groups having from 1 to 4 carbon atoms and 10. being substituted . by several halogen atoms, X^.is-11 a member selected from the group consisting of •12 oxygen and. sulphur, Y is a member selected from 13 the group consisting of oxygen, -NH- and -NZ^-, 14 Zij being a member selected from the group 15 consisting of the lower alkyl groups having from 16 1 to 4. carbon atoms, the 'lower alkyl groups having 17 from 1 to 4 carbon atoms and being substituted by one 18 halogen atom and the lower 'alkyl groups having 19 from 1 · to 4 carbon atoms and being substituted the Z radicals are the same or different and represent 20 - } // by several halogen atoms, Z—i& a member selected 21 from the group consisting of hydrogen, the lower alkyl groups having from 1 to 4 careen atoms , the halogens, the hydroxy group. and the hydroxy' ; methyl group, and m is- a numeral selected from the group consisting of 2 and 3, comprising subjecting a compound of the Formula IV-.. wherein' R-|, X^, Y, Z and m have the same meaning as in the above Formula I, to reaction with a hydrohalogenic acid, and recovering the compound of Formula I from the reaction mixture. Process as claimed in claim 1 , wherein the reaction is carried out in the presence of an inert solvent. Process as claimed in claim 1 , wherein the reaction is carried out in the absence of water. Dated this 4th day of July, 1967 For the Applicants DR. REINHOLD pOHN & CO.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEA0052990 | 1966-07-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL28262A true IL28262A (en) | 1971-05-26 |
Family
ID=6938756
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL2826267A IL28262A (en) | 1966-07-11 | 1967-07-05 | Process for the production of n,n'-bis halogenoalkyl phosphoric and thiophosphoric acid ester amides |
Country Status (9)
| Country | Link |
|---|---|
| AT (1) | AT265313B (en) |
| BE (1) | BE700713A (en) |
| CH (1) | CH484200A (en) |
| DE (1) | DE1645922A1 (en) |
| DK (1) | DK121232B (en) |
| GB (1) | GB1190054A (en) |
| IL (1) | IL28262A (en) |
| NL (1) | NL158182B (en) |
| SE (1) | SE327203B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL140732B1 (en) * | 1984-07-31 | 1987-05-30 | Polska Akad Nauk Centrum | Method of obtaining 2-/2-halogenethylamino/-2-oxo-3-/2-halogenethylo/-1,3,2-oxazophosphorianytes |
-
1966
- 1966-07-11 DE DE19661645922 patent/DE1645922A1/en active Pending
-
1967
- 1967-06-27 AT AT597867A patent/AT265313B/en active
- 1967-06-30 SE SE997167A patent/SE327203B/xx unknown
- 1967-06-30 BE BE700713D patent/BE700713A/xx not_active IP Right Cessation
- 1967-07-05 IL IL2826267A patent/IL28262A/en unknown
- 1967-07-07 CH CH967467A patent/CH484200A/en not_active IP Right Cessation
- 1967-07-10 DK DK353567A patent/DK121232B/en not_active IP Right Cessation
- 1967-07-11 NL NL6709607A patent/NL158182B/en not_active IP Right Cessation
- 1967-07-11 GB GB3184867A patent/GB1190054A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CH484200A (en) | 1970-01-15 |
| NL158182B (en) | 1978-10-16 |
| NL6709607A (en) | 1968-01-12 |
| GB1190054A (en) | 1970-04-29 |
| SE327203B (en) | 1970-08-17 |
| DE1645922A1 (en) | 1971-01-28 |
| DK121232B (en) | 1971-09-27 |
| BE700713A (en) | 1967-12-01 |
| AT265313B (en) | 1968-10-10 |
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