CA1069526A - Phosphorus esters of phosphonoacetic acid - Google Patents

Phosphorus esters of phosphonoacetic acid

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Publication number
CA1069526A
CA1069526A CA274,991A CA274991A CA1069526A CA 1069526 A CA1069526 A CA 1069526A CA 274991 A CA274991 A CA 274991A CA 1069526 A CA1069526 A CA 1069526A
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Prior art keywords
acid
mole
formula
phosphonoacetic acid
esters
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CA274,991A
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French (fr)
Inventor
Thomas R. Herrin
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Abbott Laboratories
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Abbott Laboratories
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    • 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
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

PHOSPHORUS ESTERS OF PHOSPHONOACETIC ACID

Abstract of the Disclosure A method of treating herpes simplex infection in warm-blooded animals by administering to said animals a phosphorus ester of phosphonoacetic acid of the formula

Description

P,ack&ro~nd of the Invention Herpes virus infections, though kno~lg are difficult to treat because of the lack of effective drugs.
An effective anti-herpes drug could be used in the treatment or prevention of herpes dermatitis, herpes genitalis, herpes keratitis, herpes encephalitis and as provided by the presen~
invention, herpes simplex virus. Although herpes simplex is a very common, though minor disease, the only basic treatment presently available is the application of 5-iodo-2'-deoxuridine (idoxuridine).
Detailed Description of the Invention This invention relates to a method of treating herpes simplex infections in warm-blooded animals comprising administering to such infected animal, a phosphorus ester of phosphonoacetic acid, or its inorganic salts, of the formula O O
Il 11 OH ~ (I) wherein R is an alkyl of 1 to 8 carbon atoms The ester compounds are active against herpes simplex viru~ in tissue culture. They are also active in vivo when administered either as the acid or the alkali metal salts, particularly the mono or di sodium, and calcium salts. The compounds are preferably administered topically, but can also be given by the oral or intraperitoneally (i p ) route.

~, .

~0 6~ Sz ~

Since the herpes viruses depend for replication upon a unique DNA polymerase independent from the DNA
polymerase of the mammalian host, growth of the virus may be stopped by inhibiting this necessary enzyme. These phosphorus esters of phosphonoacetic acid are potent inhibit-ors of the enzyme The present phosphorus esters of phosphonoacetic acid (PA) may be prepared by two methods. In the first method, Method (A), there is employed dimethylphenyl phosphite whereas in the second method, Method (B)~ there is employed ~-an alkylbis(trimethylsilyl)phosphite. The phosphites are reacted in each procedure with benzyl haloacetate to give tri-esters of phosphonoacetic acid which are converted by hydrolysis and hydrogenolysis to mono esters of phosphono-acetic acid. The esters are converted to crystalline ammonium salts and characterized by nmr and carbon, hydrogen and nitrogen combustion values. The two methods that may be used to produce the phosphorus esters o phosphonoacetic acid are illustrated below:

' .~ .

~o6~526 THOD (A) O

PhOP (OCH3) 2 + BrCH2C02CH2Ph , ~ Pho lpcH2co2cH2ph Pt-H2 ¦¦
HOAc >CH30 1PCH2C02H
HO

METHOD (B) Me3SiCl ROPC12 Pyridine > ROP (OH) 2 Et3N ROP (OTMS) 2 H2 Pyridine>
O O :--ClcN2co2cH2ph~ ROPCH2C02CH2Ph 1 H20 ~ ROICH2C02H
OTMS OH
: .

R = propyl, hexyl !

lOG!35;Z6 The phosphorus esters of phosphonoacetic acid of the present invention that may be prepared according to the Procedures (A) or (B) as illustrated above i.nclude the following: :
(II) P-Propylphosphonoacetic acid O O
Il il HO- C- CH2- P -O(CH2)2CH3 OH

(III) P-Hexylphosphonoacetic acid O O
Il 11 HO- C -CH2- P- O(CH2)sCH3 OH

(IV) P-Methylphosphonoacetic acid O O
Il 11 HO- C -CH2-,P- OCH3 OH

The following examples will further illustrate the present invention. The terms and symbols used in the examples stand for:
Ph = phenyl;
TMS = tetramethylsilane;
Pt = platinum;
MW = molecular weight;
HQAc = acetic acid, 10695~6 Example 1 P-Methylphosphonoacetic Acid A solution of 11.40 g. (0.05 mole) of benzyl bromoacetate and 10.23 g. (0,055 mole) of dimethylphenyl phosphite was heated at 130-140C. (oil bath). A stream of nitrogen was passed through the solution to remove the methyl bromide formed. The residue was evaporatively distilled and chromatographed to give 9.00 g. of benzyl methylphenyl-phosphonoacetate. Debenzylation with hydrogen on a palladium catalyst followed by hydrogenolysis with a platinum catalyst in acetic acid gave P-methylphosphonoacetic acid. This compound was treated with ammonium hydroxide and the salt crystallized from ethanol to give 2.74 g. (57% for the last three steps) of mono-ammonium salt, m.p. 183-6 (decomp).
Analysis Calcd. for C, 21.06; H, 6.31; N, 8.19 `
Found: C~ 21.13; H~ 6.03; NJ 7.85 Example 2 P~Propylphosphonoacetic Acid A solution of 80 g. (0.50 mole) of propylphosphoro-dichloridite in 60 ml. of ether was added dropwiseto a solution of 79 g. (1.00 mole) of pyridine and 18 g.
(1.00 mole) of water in 500 ml. of ether cooled in an ice bath. The mixture was allowed to warm gradually to room temperature and stirred for two hours. The mixture was filtered and the filtrate dried over MgS04 and evaporated at reduced pressure to give propyl phosphite. This compound was dissolved in 500 ml. of dry pyridine and cooled 106~5Z6 in an ice bath, To this solution was added 208 ml, (1.5 mole) of dry triethylamine followed by the dropwise addition of 189 ml, (1,5 mole) of trimethylsilyl chloride, The mixture was allowed to warm gradually to room temperature and stirred overnight. The mixture was diluted with an equal volume of ether, fil~ered and the filtrate concentrated. The residue was distilled to ~ive 50,34 g. of propyl~bis(trimethylsilyl)~
phosphite, b.p, 81,5-83,0C,/ca 20 mm, A solution of 9.2 g, ~0,05 mole) benzyl chloroacetate and 13,4 g, (0,05 mole) of propylLbis~trimethylsilyl)~phos-phite was heated at 160-5C, (oil bath) for 1 hour, The trimethylsilyl chloride formed ln the reaction was allowed to distill from the reaction mixture, The residue was evapor-atively distilled and the fraction distilling at 140-160C, (air bath temperature/0,5 mm) collected, The trimethylsilyl group was removed by hydrolysis and the resulting di-ester debenzylated with hydrogen over Pd/C catalyst, The acid was converted to the ammonium salt to give 5,35 g, (38% yield for the last three steps) of ammonium P-propylphos-phonoacetate, m,p, 155-156,5C, Analysis Calcd, for: C, 30,15; H, 7,08; N, 7,03 Found: C, 30,26; H, 7,37; N, 7,03 Ammonium P-hexylphosphonoacetate was prepared ` in a similar manner, The salt was crystallized from ethanol and had a m,p, of 178-190C.
Analysis Calcd, for: C, 39,83; H, 8,36; N, 5,81 Found: C, 39,90; H, 8.68; N, 5.78 _7_ ~695Z6 Example 3 Benzyl P-Meth~l-P-phenylphosphonoacetate A solution of 11 40 g. (0.05 mole) of benzyl bromoacetate, and 10 23 g. (0 055 mole) of dimethylphenyl phosphite was heated at 130-140C. (oil bath) for 5-1/4 hours A stream of N2 was bubbled through the mixture to help eliminate the CH3Br formed. The residue was evapor-atively distilled to remove the volatile material to give 14.82 g. of residue. This material was chromatographed on 300 g. of Florisil, and elution with 2% MeOH-PhH gave 9.00 g. of product.

Example 4 P-Methyl-P-phenYlphosphonoacetic Acid Benzyl P-methyl-P-phenylphosphonoacetate, 9,00 g.
(0.0281 mole), was debenzylated with hydrogen on a palladium catalyst to give 6.168 g. (0.0268 mole, 95% of theory) of P-methyl-P-phenylphosphonoacetic acid.

Example 5 P-Methylphosphonoacetic Acid P-Methyl-P-phenylphosphonoacetic acid, 6.168 g.
(0 268 mole), was dephenylated with PtO2-HOAC-H2 The residue was azeotroped with toluene to remove the HOAc The residue was dissolved in H20, made basic with concentrated NH40H The solvent was evaporated and the residue crystallized from 95% EtOH to give 2.74 g. (60%) of product, m p. 183-6~C (decomposed, bubbles formed) 1c)69~'~6 Analysis Calcd. for C3HloN05P: C, 21 06; H, 6.31; N, 8.19 Found: C, 21.13; H, 6.03; N, 7.85 Example 6 Hexylbis(trimethylsilyl~ Phosphite Hexylphosphorodichloridite, 40.40 g. (0.20 mole), in 50 ml. of (C2Hs)2O was added dropwise to a mixture of 34.76 g. (0.44 mole) of H20 in 300 ml of (C2Hs)20, cooled in an ice bath. The mixture was allowed to warm to room temperature, filtered and the filtrate dried over MgSO4, and evaporated to give 31 0 g. of a clear colorless liquid.
This material, CH3(CH2)50P(OH)2, was dissolved in 250 ml. of dry pyridine and 83 ml. (0.60 mole) of dry (C2Hs)3N was added and the solution was cooled in an ice bath. Chlorotrimethylsilane, 26 ml. (0.60 mole) was added ~ ~
dropwise. After the addition was complete, the mixture was ;-allowed to war~ to room temperature and stirred overnight.
The mixture was dilutéd with (C2H5)20, filtered, and the filtrate concentrated on a rotary evaporator. The residue was distilled to 38.24 g. of product, b.p. 85-8C.I'0.5 mm.

Example 7 BenzYl P-Hexyl-P-trimethYlsilylphosphonoacetate A solution of 16.80 g. (.0541 mole) of hexylbis-(trimethylsilyl) phosphite and 11.04 g. (0.06 mole) of benzyl chloroacetate was heated in a 165-170 oil bath for 1,5 hours, Chlorotrimethylsilane be~an to distill at 165. The _g_ `

106~5Z6 volatile material was evaporatively distilled at temperatures up to 150 at 0.5 mm. The product was distilled at 175/0 5 mm to give 13.88 g (66% yield, 0.036 mole).

Example 8 P-HexYlphosphonoacetic Acid Monoammonium Salt Benzyl P-hexyl-P-trimethylsilylphosphonoacetate, 13.0 g., was hydrolyzed with NH40H, and the diester debenzyl-ated with H2-Pd. The product was crystallized from EtOH-EtOAc to give 4 07 g. (50%) of product, m.p. 178-190.
Analysis Calcd. for C8H20NO5P: C, 39.83; H, 8.36; N, 5.81 Found: C, 39.90; H, 8.68; N, 5.78 Example 9 PropYlbis(trimethylsilyl) Phosphite A solution of 80 g (0.50 mole) of propylphosphoro-dichloridite in 60 ml. of (C2H5)2O was added dropwise to a solution of 79 g. (1 00 mole) of pyridine and 18 g. (1.00 mole)of H2O in 500 ml. of (C2Hs)2O, and cooled in an ice bath.
After the addition was complete, the mixture was stirred at room temperature for approximately 2 hours. The mixture was filtered, and the filtrate dried over MgSO4 and evaporated to give a clear colorless liquid.
The liquid was dissolved in 500 ml. of dry pyridine and the solution was cooled in an ice bath. Dry (C2H5)3N, 208 ml. (1.5 mole) was added to the solution followed by the dropwise addition of 189 ml. (1.5 mole) of chlorotrimethyl-silane. The mixture was stirred overnight at room temperature, diluted with (C2H5)2O, filtered and concentrated at reduced :., : . , ~,. :. . .

695~Z6 pressure. The mixture was refiltered and the residue distilled to give 50.34 g (37%) of product, b.p. 81.5-83.0/
10 mm.

Example 10 Benzyl-P-Propyl-P-trimethylsilylphosphonoacetate A solution of 13.4 g. (0.05 mole) of propylbis- -(trimethylsilyl) phosphite and 9.2 g. (0.05 mole) of benzyl chloroacetate was heated at 160-5C for 1 hour. The yellow-green residue was evaporatively distilled. The fraction distilling up to 130/0.5 mm was discarded. The fraction, temperature 140-160C/0.5 mm was collected;
yield 12,77 g. (74%).

Example 11 P-Propylphosphonoacetic Acid Monoammonium Salt Benzyl P-(propyl)-P-(trimethylsilyl)phosphono-acetate, 24.20 g. (0.0703 mole), was hydrolyzed with H20 and concentrated at reduced pressure. The solution was chilled in an ice bath and made basic with concentrated NH40H. Hydrogenolysis with H2-Pd gave the desired product.
; 20 The product was crystallized from C2H5OH to give 5 35 g (38%) of the title compound, m.p. 155-156.5.
Analysis Calcd. for: C5H14NO5P: C, 30.15; H, 7.08; N, 7.03 Found: C, 30.26; H, 7.37; N, 7.03 ~o695Z6 .

In Table I below, there is listed the characteristic nuclear magnetic resonance (NMR) signals of compounds II, III and IV as illustrated and defined above. Table I
~ncluc1es the solvent in which each compound was dissolved in order to record the NMR spectra. The NMR spectra given :~
in Table I are for the ammonium salts of II, III and IV.

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X
V~ C~
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:~
~n aJ c~ a) cn ,1.~/~ ~ ~ ~ ~':
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¢~4 ~ ~ ~ C~
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o ex, ~ : .
U~ C~ O ~ .
a) U ~:
Z
V~ ~ ~ _l ~ V~ Oc~ 0~ c~
E~ a~ ~
U~ ~ V

~0695Z6 Example 12 Herpes Sim~lex Viruses Isolation and Purification of Herpes Simplex Type 2 _ _ Deoxyribonucleic Acid (DNA~ PolYmerase Herpes virus infected Wi-38 cells were grown and harvested when 25% of the cells showed cytopathic effect of the virus. The DNA polymerase was isolated according to the procedure of Smith and Gallo (1972) which involved column chromatography on DEAE-cellulose and phosphocellulose, However, buffer connaining 20% glyceryl instead of 10% was used. The final enzyme preparation has a specific activity of 313 units/mg. for herpes simplex virus type 2.

Viral Deoxyribonucleic Acid (DNA) Polymerase Assay The reaction mixture (0,2 ml.) contains 10 ~M
of 2'-deoxyadenosine-5'-triphosphate~2'-deoxycytidine-5'-triphosphateJ 2'-deoxyguanosine-5'-triphosphate~and 2,5 tritium labeled thymidine-5'-triphosphate which was appropriately diluted with unlabeled dTTP to give 880 counts per minute per pico-mole, 10 ~g of activated calf thymus DNA
50 mM Tris-HCl buffer (pH 8,0), 3mM MgC12, 100 mM KCl and 1 mM dithiothritol, The amounts of enzyme used in each r~action was chosen to give a linear rate for at least 30 minutes at 37C, The reaction was terminated by the addition of 3 ml, of cold 5% trichloroacetic acid - 0,01 M sodium pyrophosphate, ; 25 The acid-insoluble material was collected, washed twice on glass filter discs (Reeve Angel 984-H) and the incorporated 3H-dTMP was determined by a liquid scintillation counter, ., . ~

10695Z~

The effect of each of the compounds in the inhibition of Herpes simplex type 2 deoxyribonucleic acid (DNA) is recorded below in Table II

Table II

Percent Compound Concentration (u~L~l) Inhibition II' 8.0 50%
III 166 0 50%
IV 19 9 50%

Example 13 The effectiveness of the phosphorus ester of phosphonoacetic acid against herpes simplex infections in mice was determined as follows: -' 15 Mice were infected with herpes simplex virus, type 2 and treated with a phosphorus ester of phosphonoacetic ;
acid two hours post infection and each of the five days thereafter. Virus inoculation was accomplished by plucking the fur from the flank and back of anesthetized mice and 'placing a drop (0.05 ml.) of herpes virus on the surface of the pluc'ked s'kin. Using a needle, the skin of the mouse was pricked through a drop of virus. The mice utilized for control purposes were not treated in any manner.
In Table III below, there is listed the survival time of untreated, infected mice and infected mice treated with compounds of the present invention, The treated mice had topically applied to them~ 2% aqueous solutions of compounds II and III.

Table III
Average Survival Average Survival Time of Untreated Time of Treated Compound Mice (days) Mice (days) II 9,1 11.8 (P = 0.05)*
III 8.7 9.5 (P = 0.05)*

*Statistical analysis using the Mann-Whitney U test.

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of producing a phosphorous ester of phosphonoacetic acid of the formula (I) wherein R is an alkyl of 1 to 8 carbon atoms, or its inorganic salts, which method comprises the steps of:

(a) reacting dimethylphenyl phosphite or an alkylbis(trimethylsilyl)phosphite with a benzyl haloacetate of the formula XCH2CO2CH2Ph where X is Cl, Br or F; to provide the tri-esters of phosphonoacetic acid; and (b) converting said tri-esters by hydrolysis and hydrogenolysis to mono esters of phosphonoacetic acid.
2. The process defined in claim 1 including the step of preparing an inorganic salt of the acid thus obtained.
3. A method according to Claim 1, wherein R is (-CH3).
4. A method according to Claim 1 wherein R
is CH3(CH2)2-.
5. A method according to Claim 1 wherein R
is CH3(CH2)5-.
6. A phosphorus ester of phosphonoacetic acid of the formula wherein R is an alkyl of 1-8 carbon atoms, or its inorganic salts, whenever prepared by the process defined in Claim 1 or 2 or by the obvious chemical equivalent.
7. A phosphorus ester of the formula , whenever prepared by the process defined in Claim 3 or by the obvious chemical equivalent.
8. A phosphorus ester of the formula , whenever prepared by the process defined in Claim 4 or by the obvious chemical equivalent.
9. A phosphorus ester of the formula , whenever prepared by the process defined in Claim 5 or by the obvious chemical equivalent.
CA274,991A 1976-04-30 1977-03-29 Phosphorus esters of phosphonoacetic acid Expired CA1069526A (en)

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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1144937A (en) * 1977-12-22 1983-04-19 Dke J.E. Helgstrand Aromatic derivatives, pharmaceutical compositions and methods for combatting virus infections
HU190449B (en) * 1983-05-17 1986-09-29 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara,Hu Process for production of derivatives of acetid acid substituated by phosphorus

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3767795A (en) * 1971-02-25 1973-10-23 Abbott Lab Method for combating certain virus infection

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JPS52133925A (en) 1977-11-09
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FR2349596B1 (en) 1980-03-14

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