US3910982A - Alkylsulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds - Google Patents

Alkylsulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds Download PDF

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US3910982A
US3910982A US436173A US43617374A US3910982A US 3910982 A US3910982 A US 3910982A US 436173 A US436173 A US 436173A US 43617374 A US43617374 A US 43617374A US 3910982 A US3910982 A US 3910982A
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formula
compounds
acid esters
oxazaphospha
same meaning
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US436173A
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Herbert Arnold
Friedrich Bourseaux
Jurgen Potel
Norbert Brock
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Asta Medica GmbH
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Asta Werke AG Chemische Fabrik
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Priority claimed from DE2107936A external-priority patent/DE2107936C3/en
Priority claimed from DE19722201675 external-priority patent/DE2201675A1/en
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    • 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
    • C07F9/547—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
    • C07F9/65844—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a five-membered ring which may be condensed with another ring system

Definitions

  • R is a halogen atom, preferably a chlorine atom, R, is hydrogen and R is a lower alkyl group with l to 4 carbon atoms which is substituted with a lower alkyl sulfonic ester group having a straight or branched lower alkyl chain with l to 6 carbon atoms, and alk represents a straight or branched alkylene group with 2 or 3 carbon atoms in the chain and, if branched, with a total of 3 or 4 carbon atoms, X represents oxygen, Z represents a hydrogen atom and m is 3.
  • those compounds of formula I are preferred, wherein alk is the group CH CH CH Among this group of compounds those compounds show a particularly high immunsuppressing activity and therefore are most preferred wherein the lower sulfonic acid ester group is the methylsulfonic acid ester group. It is surprising that the compounds of formula I show a strong immunsuppression which activity has not been known up to now with alky sulfonic acid esters. The immunactivity in connection with the Brucella immunisation of rats is used to demonstrate this activity.
  • the new compounds of formula I are produced by using methods known as such.
  • the process for the production of the compounds according to the present invention comprises A. subjecting a compound of formula [V wherein R, has the same meaning as R in formula I or is a hydroxy group, R, has the same meaning as R, in formula I alk and X have the same meaning as in formula I and X, is a halogen atom, preferably a chlorine atom, to reaction with a compound of formula V wherein R, has the same meaning as R, in formula IV and Z and m have the same meaning as in formula I, or B.
  • the reactions are preferably carried out in the presence of an inert solvent such as acetonitrile or a lower halogenate hydrocarbon such as chloroform or methylene chloride, or in an ether such as diethylether or dioxane, or in an aromatic hydrocarbon such as benzene or toluene.
  • an inert solvent such as acetonitrile or a lower halogenate hydrocarbon such as chloroform or methylene chloride
  • an ether such as diethylether or dioxane
  • aromatic hydrocarbon such as benzene or toluene.
  • the reactions are preferably carried out in the presence of an acid binding agent.
  • the acid binding agent should be present in an amount ranging from 1 to 2 mole equivalents.
  • alkaline compounds which may be used as acid binding agents such as alkali metal and alkaline earth metal carbonates and bicarbonates and particularly tertiary amines such as triethylamine and pyridine.
  • Usual carn'er products for pharmaceutical preparations which may contain a compound according to formula l as active agent are pharrnacologically inert products as they are known for the production of tablets, dragees, suppositories and injection solutions.
  • the methylene chloride phase is decanted off from the highly viscous precipitate.
  • the methylene chloride solution is filtered over activated charcoal and evaporated in a vacuum.
  • the resulting oil is dissolved in methylene chloride and ether is added in such an amount to yield a methylene chloride ether proportion of l:l.
  • the precipitated oil is again dissolved in methylene chloride and ether is added as previously and these steps are repeated until the precipitated oil is no more soluble in methylene chloride.
  • the combined methylene chloride/ether extracts are filtered over activated charcoal and evaporated in a vacuum.
  • the resulting oily product is dissolved in methylene chloride and the solution is washed three times with chilled water and dried. The solvent is evaporated, thus yielding into a yellow viscous oil.
  • EXAMPLE 3 The following recipe is used for the production of 100,000 dragees containing each 50 mg. of the active compound according to the present invention:
  • auxiliary products of the above recipe are sieved and thoroughly admixed and 100,000 dragess are pressed each weighing mg., having a diameter of 7 mm. and a camber diame ter of 6 mm.
  • the resulting kernels are coated in manner known per se by first applying a lager resistant to the gastric juices giving each kernel a weight of 170 mg., then applying a cover until a kernel weight of 205 mg., smoothing the surfaces of the kernels until a kernel weight of 2l5 mg. and thereafter applying colorlayers up to a kernel weight of 240 mg. Finally, the coated kernels are rendered glossy by applying a layer of hard wax.
  • EXAMPLE 4 A dry mix of active compound and sodium chloride is filled into glass to be for the production of injection solution.
  • the solution thereof is passed through a filter holding back germs.
  • the further processing is effected under aseptic conditions.
  • the crystallized compound is separated by centrifugation and dried and held in an atmosphere of ethylene oxide.
  • a sample is taken and checked for purity and sterility.
  • the compoun is mixed with steril sodium chloride pa. in a weight proportion of l00 to 45 under aspetic conditions, thus producing a finely divided homogenous mix.
  • Another sample is taken and tested for its content in active compound, for sterility and freedom of pyrogenous compounds.
  • the compounds according to the present invention are useful in the treatment of autoimmune diseases (autoaggressive diseases) in humans, such as chronic rheumatoid arthritis, psoriatic arthropathy, autoimmun-haemolytic anemia, cold agglutination disease, lupus erythematodes, Sjoegrens disease, sklerodermia, severe myasthenia, polyarteritis nodosa and nephrotic syndrome.
  • the compounds are preferably applied in a daily dose ranging from 2 to 4 mg./kg..
  • a particularly useful and therefore most preferred compound is that of example I.
  • alk is -CH CH 3.
  • R is chlorine.

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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

New alkyl sulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds of formula I

These new compounds produce a high immunsuppressing activity in humans.

Description

United States Patent Arnold et al.
[ ALKYLSULFONIC ACID ESTERS OF 1,3,2-OXAZAPHOSPHA-CYCLIC COMPOUNDS [75] Inventors: Herbert Arnold, Heidelberg;
Friedrich Bourseaux, Brackwede; Jurgen Potel, Gadderbaum; Norbert Brock, Uerentrup, all of Germany [73] Assignee: Asta-Werke Aktiengesellschaft,
Brackwede, Westphalia, Germany [22] Filed: Jan. 24, 1974 [2|] App]. No: 436,173
Related US. Application Data [62] Division of Ser. No, 225,273, Feb. l0, 1972, Pat. No,
[451 Oct. 7, 1975 [56] References Cited FOREIGN PATENTS OR APPLICATIONS 2,125,595 l 1/1972 France 0. 260/456 A Primary Examiner lames 0. Thomas, Jr Assistant Examiner-Nicky Chan Attorney, Agent, or FirmMcNenny, Farrington, Pearne & Gordon 5 71 ABSTRACT New alkyl sulfonic acid esters of l,3,2oxazaphosphacyclic compounds of formula I These new compounds produce a high immunsuppressing activity in humans.
4 Claims, No Drawings ALKYLSULFONIC ACID ESTERS OF 1,3,2-OXAZAPHOSPHA-CYCLIC COMPOUNDS RELATED APPLICATION wherein R is a halogen atom, preferably a chlorine atom, R, is hydrogen and R is a lower alkyl group with l to 4 carbon atoms which is substituted with a lower alkyl sulfonic ester group having a straight or branched lower alkyl chain with l to 6 carbon atoms, and alk represents a straight or branched alkylene group with 2 or 3 carbon atoms in the chain and, if branched, with a total of 3 or 4 carbon atoms, X represents oxygen, Z represents a hydrogen atom and m is 3.
Because of their favourable compatibility their high immunsuppressing activity those compounds of formula I are preferred, wherein alk is the group CH CH Among this group of compounds those compounds show a particularly high immunsuppressing activity and therefore are most preferred wherein the lower sulfonic acid ester group is the methylsulfonic acid ester group. It is surprising that the compounds of formula I show a strong immunsuppression which activity has not been known up to now with alky sulfonic acid esters. The immunactivity in connection with the Brucella immunisation of rats is used to demonstrate this activity.
The new compounds of formula I are produced by using methods known as such. The process for the production of the compounds according to the present invention comprises A. subjecting a compound of formula [V wherein R, has the same meaning as R in formula I or is a hydroxy group, R, has the same meaning as R, in formula I alk and X have the same meaning as in formula I and X, is a halogen atom, preferably a chlorine atom, to reaction with a compound of formula V wherein R, has the same meaning as R, in formula IV and Z and m have the same meaning as in formula I, or B. subjecting a compound of the general formula VI wherein R and R, have the same meaning as in formula l V and alk has the same meaning as in formula I, to reaction with a compound of formula V" wherein X, has the same meaning as in formula IV, R has the same meaning as in formula V and X, Z and m have the same meaning as in formula I, or
C. subjecting a compound of formula Vlll N Z alk NP X C VIII V wherein R,-, has the same meaning as in formula V and X, Z, alk and m have the same meaning as in formula I, to reaction with a compound of formula lX Home m wherein R, has the same meaning as in formula IV, and converting the hydroxy group in the resulting compounds of formula X wherein R carried a hydroxy group, into the group -OSO R,,, R being a straight or branched lower alkyl group having from I to 6 carbon atoms, by subjecting said hydroxy compound to reaction with a sulfonic acid halogenide R,,SO Hal, R having the same meaning as above and Hal being a halogen atom, preferably a chlorine atom.
The reactions are preferably carried out in the presence of an inert solvent such as acetonitrile or a lower halogenate hydrocarbon such as chloroform or methylene chloride, or in an ether such as diethylether or dioxane, or in an aromatic hydrocarbon such as benzene or toluene. The reaction is carried out at an elevated temperature ranging from room temperature to the boiling point of the reaction mixture.
The reactions are preferably carried out in the presence of an acid binding agent. The acid binding agent should be present in an amount ranging from 1 to 2 mole equivalents. There are numerous known alkaline compounds which may be used as acid binding agents such as alkali metal and alkaline earth metal carbonates and bicarbonates and particularly tertiary amines such as triethylamine and pyridine.
Usual carn'er products for pharmaceutical preparations, which may contain a compound according to formula l as active agent are pharrnacologically inert products as they are known for the production of tablets, dragees, suppositories and injection solutions.
The following examples further illustrate the present invention without however limiting the same thereto. The compounds according to the present invention are characterized by their infrared spektra and show characteristic P=O- bands at 1188 to 1275 cm",
C-SO C bands at 1330 to I376, l 165 to H75, 905 to 975 and 787 to 805 cm,
POC bands at about I050 and 975 cm and NH bands at 3200 to 3300 cm.
EXAMPLE I 2-( 2-Chloroethylamino )-3-( 3-methylsulfonoxypropyl tetrahydro-ZH- l ,3 ,2-oxazaphosphorine-2-oxide A solution of 39.2 g. of 2-chloroethyl-phosphoric acid amide dichloride in I60 cc. of anhydrous dioxane is added to a solution of 26.7 g. of dipropanolamine and 42 g. of triethylamine in I20 cc. of anhydrous dioxane dropwise at room temperature within an hour. Stirring is continued for further 2 hours and the precipitated triethylamine hydrochloride is filtered off with suction. The filtrate is evaporated in a water jet vacuum and the residue is dissolved in chloroform. The solution is neutralized with ethereal hydrochloric acid, the solution thereafter is dried and the solvent is again evaporated. 2-( 2-chloroethylamino-3-( 3-hydroxypropyl tetrahydro-ZH-l,3,2-oxazaphosphorine-2-oxide is obtained as a yellow-brown oil.
Yield: 14.4 g. (28% of the theoretical) A solution of 14.4. g of the above compound and 5.7 g. of triethylamine in l cc. of anhydrous dioxane is added to a solution of 6.45 g. of methanesulfonylchloride in 65 cc. of anhydrous dioxane dropwise with stirring at a temperature of 30 C. within 30 minutes. The separated triethylamine hydrochloride is filtered off and the filtrate is evaporated in-a vacuum. The residue is dissolved in a mixture of 1 part of isopropanol and l pan of ether. The solution is allowed to stand for 2 hours in an ice-bath with scratching at intervals. The separated crystals are filtered off with suction and are washed in a mixture of isopropanol and ether and thereafter with ether alone. The product is purified by extraction with ether in a soxhlet apparatus.
Yield: 6.5 g (34.6% of the theoretical) EXAMPLE 2 2-( 2-Chloroethylamino )-3-( 2-methysulfon0xyethyl tetrahydro-ZH-l ,3,2-oxazaphosphorine-2-oxide A solution of 26.5 cc. of HCl in ether 159.7 mg./cc.) is added to a solution of 32.9 g. of 2-ethyleneimino-3- (2-mesyloxyethyl )-tetrahydro-2H- l ,3 ,2-oxazaphosphorine-Z-oxide in I75 cc. of anhydrous methylene chloride dropwise with vivid stirring within minutes at 30 C. Thereafter, the methylene chloride phase is decanted off from the highly viscous precipitate. The methylene chloride solution is filtered over activated charcoal and evaporated in a vacuum. The resulting oil is dissolved in methylene chloride and ether is added in such an amount to yield a methylene chloride ether proportion of l:l. The precipitated oil is again dissolved in methylene chloride and ether is added as previously and these steps are repeated until the precipitated oil is no more soluble in methylene chloride. The combined methylene chloride/ether extracts are filtered over activated charcoal and evaporated in a vacuum. The resulting oily product is dissolved in methylene chloride and the solution is washed three times with chilled water and dried. The solvent is evaporated, thus yielding into a yellow viscous oil.
Yield: 20.8 g.
EXAMPLE 3 The following recipe is used for the production of 100,000 dragees containing each 50 mg. of the active compound according to the present invention:
Compound according to Example 1 5.000 kg. Corn starch 4.000 kg. Polyvinylpyrrolidone 0.060 kg. Talcum 0.575 kg. Magnesium stearate 0.250 k The crystalline active compound is passed together with 3 kg. of corn starch through a sieve having a mesh size of l mm. The products are thoroughly mixed and a paste is formed with a 10% solution of the polyvinylpyrrolidon in isopropanol. The moist product is granulated by passing it through a sieve having a mesh size of 3 mm. It is then dried and ground to a particle size of l mm. Finally, the remaining auxiliary products of the above recipe are sieved and thoroughly admixed and 100,000 dragess are pressed each weighing mg., having a diameter of 7 mm. and a camber diame ter of 6 mm. The resulting kernels are coated in manner known per se by first applying a lager resistant to the gastric juices giving each kernel a weight of 170 mg., then applying a cover until a kernel weight of 205 mg., smoothing the surfaces of the kernels until a kernel weight of 2l5 mg. and thereafter applying colorlayers up to a kernel weight of 240 mg. Finally, the coated kernels are rendered glossy by applying a layer of hard wax.
EXAMPLE 4 A dry mix of active compound and sodium chloride is filled into glass to be for the production of injection solution. In the last step of purification by recrystalli zation of the active compound according to Example 1, the solution thereof is passed through a filter holding back germs. The further processing is effected under aseptic conditions. The crystallized compound is separated by centrifugation and dried and held in an atmosphere of ethylene oxide. A sample is taken and checked for purity and sterility. After clearance of further processing is obtained, the compoun is mixed with steril sodium chloride pa. in a weight proportion of l00 to 45 under aspetic conditions, thus producing a finely divided homogenous mix. Another sample is taken and tested for its content in active compound, for sterility and freedom of pyrogenous compounds. After clearance of further processing, mg. of the mix are filled into flasks of 10 ml. each under aseptic conditions and in an atmosphere of nitrogen. The flasks are closed with aseptic stoppers of butyl 'caoutchouc. The final check is made in accordance with the recommendations of the Section Testing for good quality and sterility" of the German Federal Health Administration. In order to produce injection solutions, 5 cc. of water purifled for injection solutions are added to the content of a flask which is dissolved therein. The compounds according to the present invention are useful in the treatment of autoimmune diseases (autoaggressive diseases) in humans, such as chronic rheumatoid arthritis, psoriatic arthropathy, autoimmun-haemolytic anemia, cold agglutination disease, lupus erythematodes, Sjoegrens disease, sklerodermia, severe myasthenia, polyarteritis nodosa and nephrotic syndrome. The compounds are preferably applied in a daily dose ranging from 2 to 4 mg./kg.. A particularly useful and therefore most preferred compound is that of example I.
What we claim is:
l. Alkyl sulfonic acid esters of l,3,2-oxazaphospha cyclic compounds of formula I wherein R represents a halogen atom, R, is hydrogen, and R is a lower alkyl group having from I to 4 carbon atoms which is substituted with a lower alkyl sulfonic acid ester group having a straight or branched lower alkyl group with l to 6 carbon atoms, and alk represents a straight or branched alkylene group having 2 or 3 carbon atoms in the chain and, if branched, having a total number of 3 or 4 carbon atoms, X represents oxygen, Z represents hydrogen, and m is 3.
2. A compound according to claim I wherein alk is -CH CH 3. A compound according to claim 2 wherein R is chlorine.
4. 2-( 2-chloroethylamino )-3-( 2- methylsulfonoxyethyl )-tetrahydro-2H- l ,3 ,2- oxazaphosphorine-Z-oxide.

Claims (4)

1. ALKYL SULFONIC ACID ESTERS OF 1,3,2-OXAZAPHOSPHACYCLIC COMPOUNDS OF FORMULA I
2. A compound according to claim 1 wherein alk is -CH2CH2-.
3. A compound according to claim 2 wherein R is chlorine.
4. 2-(2-chloroethylamino)-3-(2-methylsulfonoxyethyl)-tetrahydro-2H-1,3,2 -oxazaphosphorine-2-oxide.
US436173A 1971-02-19 1974-01-24 Alkylsulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds Expired - Lifetime US3910982A (en)

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Applications Claiming Priority (3)

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DE2107936A DE2107936C3 (en) 1971-02-19 1971-02-19 Alkyl sulfonic acid esters of 2-oxo-13,2-oxazaphosphorinanes and pharmaceutical preparations containing them
DE19722201675 DE2201675A1 (en) 1972-01-14 1972-01-14 1,3,2-oxaza phospha-cyclic sulphonic acid alkyl esters - - as immuno-suppressors
US436173A US3910982A (en) 1971-02-19 1974-01-24 Alkylsulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2125595A1 (en) * 1971-02-19 1972-09-29 Asta Werke Ag Chem Fab

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2125595A1 (en) * 1971-02-19 1972-09-29 Asta Werke Ag Chem Fab

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