IE904625A1 - 2-Formylbenzylphosphonic acid derivatives, their¹preparation and their use for the treatment of diseases¹caused by viruses - Google Patents
2-Formylbenzylphosphonic acid derivatives, their¹preparation and their use for the treatment of diseases¹caused by virusesInfo
- Publication number
- IE904625A1 IE904625A1 IE462590A IE462590A IE904625A1 IE 904625 A1 IE904625 A1 IE 904625A1 IE 462590 A IE462590 A IE 462590A IE 462590 A IE462590 A IE 462590A IE 904625 A1 IE904625 A1 IE 904625A1
- Authority
- IE
- Ireland
- Prior art keywords
- carbon atoms
- group
- straight
- chain
- formula
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 16
- 241000700605 Viruses Species 0.000 title abstract description 13
- URYYOODIPZFJIN-UHFFFAOYSA-N (2-formylphenyl)methylphosphonic acid Chemical class OP(O)(=O)CC1=CC=CC=C1C=O URYYOODIPZFJIN-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 78
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 24
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 24
- -1 cyclic diester Chemical class 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 23
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 20
- 239000000651 prodrug Chemical group 0.000 claims abstract description 17
- 229940002612 prodrug Drugs 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 13
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 9
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 9
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000011575 calcium Substances 0.000 claims abstract description 9
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 9
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 9
- 239000011777 magnesium Substances 0.000 claims abstract description 9
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 9
- 239000011591 potassium Substances 0.000 claims abstract description 9
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 claims abstract description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 7
- 239000011734 sodium Substances 0.000 claims abstract description 7
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 7
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 126
- 238000000034 method Methods 0.000 claims description 16
- 150000001299 aldehydes Chemical class 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052717 sulfur Chemical group 0.000 claims description 7
- 239000011593 sulfur Chemical group 0.000 claims description 7
- 241000450599 DNA viruses Species 0.000 claims description 5
- 241001493065 dsRNA viruses Species 0.000 claims description 5
- QYMJYGVTOYLHKJ-UHFFFAOYSA-N 2-(diethoxyphosphorylmethyl)benzaldehyde Chemical compound CCOP(=O)(OCC)CC1=CC=CC=C1C=O QYMJYGVTOYLHKJ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- JBVWDICCFCRKPB-UHFFFAOYSA-N n,n-diethylethanamine;(2-formylphenyl)methylphosphonic acid Chemical compound CCN(CC)CC.CCN(CC)CC.OP(O)(=O)CC1=CC=CC=C1C=O JBVWDICCFCRKPB-UHFFFAOYSA-N 0.000 claims description 4
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- HUDIHGJNQHXFCA-UHFFFAOYSA-N [[2-(diethoxyphosphorylmethyl)phenyl]methylideneamino]thiourea Chemical compound CCOP(=O)(OCC)CC1=CC=CC=C1C=NNC(N)=S HUDIHGJNQHXFCA-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- FBPFCZMOUFCRBS-UHFFFAOYSA-N ethoxy-[(2-formylphenyl)methyl]phosphinate;triethylazanium Chemical compound CC[NH+](CC)CC.CCOP([O-])(=O)CC1=CC=CC=C1C=O FBPFCZMOUFCRBS-UHFFFAOYSA-N 0.000 claims description 3
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
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- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005070 decynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 229940042400 direct acting antivirals phosphonic acid derivative Drugs 0.000 description 1
- 229940042396 direct acting antivirals thiosemicarbazones Drugs 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- AFQIYTIJXGTIEY-UHFFFAOYSA-N hydrogen carbonate;triethylazanium Chemical compound OC(O)=O.CCN(CC)CC AFQIYTIJXGTIEY-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000005071 nonynyl group Chemical group C(#CCCCCCCC)* 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000002917 oxazolidines Chemical class 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000003007 phosphonic acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- KFUSANSHCADHNJ-UHFFFAOYSA-N pyridine-3-carbohydrazide Chemical compound NNC(=O)C1=CC=CN=C1 KFUSANSHCADHNJ-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 238000001228 spectrum Methods 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
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 150000003584 thiosemicarbazones Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000004260 weight control Methods 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
- C07F9/28—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
-
- 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
- C07F9/4056—Esters of arylalkanephosphonic acids
-
- 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
-
- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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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)
- Virology (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Communicable Diseases (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The compound of the formula I <IMAGE> in which R represents an aldehyde group or a group which can be converted into an aldehyde, R<1> and R<2> represent alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, hydrogen, sodium, potassium, calcium, magnesium, aluminium, lithium, ammonium or triethylammonium or R<1> and R<2> together form a cyclic diester, R<3> and R<4> represent alkyl, alkenyl, alkynyl, cycloalkyl, hydrogen, alkoxy or halogen, R<5> and R<8> represent alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, alkoxy, phenyl, cyanide, hydroxyl or hydrogen, X, Y or Z represent oxygen or sulphur, or prodrug forms of the compound of the formula I can be used for treatment of diseases caused by viruses. The preparation of these compounds and pharmaceutical preparations which contain them and also their use are described.
Description
2-FORMYLBENZYLPHOSPHONIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE FOR THE TREATMENT OF DISEASES CAUSED BY VIRUSES HOECHST AKTIENGESELLSCHAFT, a Joint Stock Company organized and existing under the laws of the Federal Republic of Germany, of D-6230 Frankfurt am Main 80, Federal Republic of Germany -1IE 904625 - laHOECHST AKTIENGESELLSCHAFT HOE 89/F 398 Dr. WN Description 2-Formylbenzylphosphonic acid derivatives, their preparation and their use for the treatment of diseases caused by viruses The invention relates to novel 2-formylbenzylphosphonic acid derivatives, to processes for the preparation of these compounds, to pharmaceutical agents which contain the active compounds according to the invention and to their use as medicaments, in particular for the treatment of diseases caused by viruses.
In order to treat diseases caused by viruses, various preparations have hitherto been employed, such as, for example, nucleoside analogs, amantadine, pyrophosphate analogs or immunomodulators (M.J. Wood, A.M. Geddes, The Lancet, 1987, 1189). Some phosphonic acid derivatives are known which exhibit antiviral activity. These include compounds such as phosphonoformic acid (PFA), phosphonoacetic acid (PAA), methylenediphosphonic acid (MDP) and tetrazolephosphonic acids (S.M. Roberts, NATO ASI Ser., Ser. A 143, 1988, 37; D.W. Hutchinson, M. Naylor, Nucleic Acids Res., 13, 1985, 8519). PFA has a wide antiviral spectrum, but causes some toxic side effects, which have hitherto prevented development to the antiviral medi25 cament (M.J. Wood, A.M. Geddes, The Lancet, 1987, 1189).
It is known of ortho-phosphonyloxy-acetophenone derivatives that they are especially active against picornaviruses (EP 21,000).
Diana et al. (J. Med. Chem. 27, 1984, 691; DOS 2,922,054) report on a class of compound of the type A........... in which A is an aromatic ring and C is a phosphonate or a ^-ketophosphonate in which A and C are separated from one another by means of a bridge of 3-8 methylene groups (B). From this class of compound, arylalkylphos5 phonic acids having methylene bridges of more than 5 carbon atoms showed antiviral activity against herpesviruses. However, arylalkylphosphonic acids having methylene bridges of less than 5 carbon atoms do not show antiviral activity. The substitution of the aromatic radical of these compounds is carried out, in Diana et al., essentially by means of a 2-chloro-, 4-methoxyor 4-carbethoxyphenoxy group.
Benzylphosphonic acids have hitherto not been described as active antiviral compounds (J.C.H. Mao et al., Anti15 microb. Agents Chemother. 27, 1985, 197).
Surprisingly, it has now been found that 2-formylbenzylphosphonic acid derivatives have antiviral activity.
The invention therefore relates to a compound of the formula I x R -a „ 11 1 6C(R3r4)-P-YR1 i..
S5,R6,R7,RB in which R is an aldehyde group or a group which can be converted into an aldehyde, R1 and Rz, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or 30 triethylammonium or R1 and R2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, - 3 R3 and R*, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkynyl or alkenyl group having 2 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine, R5, R6, R7 and R8, which may be identical or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula Ia • 19 C-O-R*9 I a R1S is a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and X, Y and Z, which may be identical or different, are oxygen or sulfur or a prodrug form of the compound of the formula I.
A compound of the formula I in which R1 and R2 are an alkyl group having 1 to 10 carbon atoms, an alkenyl or alkynyl group having 2 to 10 carbon atoms, hydrogen or an aralkyl group having 7 to 16 carbon atoms, R3 and R* are an alkyl group having 1 to 4 carbon atoms, an alkenyl or alkynyl group having 2 to 4 carbon atoms or hydrogen, R5, R8, R7 and R8 are chlorine, bromine, methoxy or hydrogen and - 4 X, Y and Z are oxygen, is preferred.
By the term prodrug form of the compound of the formula I, compounds are meant which are converted into a compound of the formula I in which R is an aldehyde group, en route to the site of action. In the article by H. Bundgaard (Design of Prodrugs, 1985, pp. 1 - 92, Elsevier-Verlag), the term Prodrug form is defined and illustrated by examples.
The notation alkyl group having 1 to 10 carbon atoms is to be understood as meaning, for example, the following radicals: methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, 2,2-dimethyl-l-propyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. By the notation alkenyl group having 2 to 10 carbon atoms, the following compounds, for example, are meant: ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl. By the notation alkynyl group having 2 to 10 carbon atoms, the following compounds are meant, for example: ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, nonynyl, octynyl or decynyl. An aralkyl group having 7 to 16 carbon atoms is understood as meaning the following radicals, for example: phenylmethyl, phenylethyl, phenylbutyl, phenylpropyl, phenyl25 pentyl, phenylhexyl, phenylheptyl, phenyloctyl, phenylnonyl or phenyldecyl. A cycloalkyl group having 3 to 8 carbon atoms is understood as meaning radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Alkoxy groups having 1 to 4 carbon atoms are radicals such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec.-butoxy or tert.-butoxy.
The invention furthermore relates to a process for the preparation of the compound of the formula I in which R is an aldehyde group, which comprises reacting the compound of the formula II R5,R6,R7,Re in which R3 and R*, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkynyl or alkenyl group having 2 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine, R5, R6, R7 and R8, which may be identical or different, are 10 a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula Ia li „ C-O-Rli * * * * * * * 19 la R19 is a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and T is chlorine, bromine, iodine, methylsulfonate, phenylsulfonate or tosylsulfonate, with the compound of the formula III - 6 X-R9 P^Y-R1 m ^Z-R2 in which, R1 and R2, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, eodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or R1 and R2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, R9 is a straight-chain or branched alkyl group having 1 to 4 carbon atoms and X, Y and Z, which may be identical or different, are oxygen or sulfur.
The invention furthermore relates to a process for the preparation of the compound of the formula I in which R is a group which can be converted into an aldehyde, which comprises reacting the compound of the formula I in which R is an aldehyde in such a way that a group which can be converted into an aldehyde is formed.
The term group which can be converted into an aldehyde is understood as meaning radicals which are converted into an aldehyde en route to the site of action (H. Bundgaard, Design of Prodrugs, 1985, pp. 1 - 92, Elsevier-Verlag).
In particular, the aldehyde group can be derivatized in such a way that the compound of the formula I is formed in which R is a group, which can be converted into an aldehyde, of the formula lb, Ic or Id - Ί CH R14 R15 R’3-5—L-R'6 M N CH I lb Ic Id in which R10 and R11, which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 carbon atoms or R10 and Ru together form a cyclic acetal having 2 or 3 carbon atoms in the ring, R12 to R16, which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 carbon atoms or an aryl group having 6, 10 or carbon atoms, V is oxygen or sulfur, M is a hydroxyl group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or a radical of the formula Ie or If V 0 -NH-C-R17 -O-C-R1B 1. If in which R17 is a straight-chain or branched alkyl group 15 having 1 to 10 carbon atoms, an amino, pyridine, or an aryl group having 6, 10 or 14 carbon atoms and R18 is an amino group, a pyridine group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or an aralkyl group having 7 to 20 carbon atoms.
The synthesis of the compound of the formula I in which R is an aldehyde group is carried out by reacting the compound of the formula II with the compound of the formula III, expediently at temperatures between 100 and 250*C, preferably between 120 and 180’C (US 4,299,615; Houben-Weyl, Methoden der Org. Chemie (Methods of Organic Chemistry), Vol. XII/1, page 423, Thieme-Verlag, Stuttgart; Houben-Weyl, Methoden der Org. Chemie (Methods - 8 of Organic Chemistry), Vol. E2, page 300). The reaction can be carried out in a suitable solvent, such as hexamethylphosphoramide (HMPA), dimethylylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethyl-N,N'-propylene5 urea (DMPU) or N,N'-dimethyl-N,N'-ethyleneurea (DMEU).
The reaction can also be carried out without solvent. Purification is carried out by generally customary methods, preferably by chromatography on silica gel using suitable eluents, by distillation or by recrystallization from suitable solvents.
J. Schmidhauser, Purification is The compounds of the formula II and III can be prepared in a manner known per se. The conversion of the phosphonic acid diesters into their monoesters, and also into the corresponding free acids or their salts is carried out, for example, by boiling with dilute hydrochloric acid (Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Vol. XII/1, 1963), or by reaction with trimethylbromosilane (C.E. McKenna, J.C.S. Chem. Commun., 1979, 739). carried out by recrystallization in suitable solvents or by chromatographic methods, preferably by ion exchange chromatography using suitable eluents. The desired salt forms can also be obtained by ion exchange chromatography.
The synthesis of a prodrug form of the compound of the formula I can be carried out, for example, by derivatizing the aldehyde group in the compound of the formula I in such a way that compounds such as oximes, thiosemicarbazones, carboxylic acid hydrazones, Schiff's bases, oxazolidines, thiazolidines or acetals are formed. For this purpose, the compound of the formula I in which R is an aldehyde group can be reacted with the compound of the formula IVa, IVb and/or IVc, IVd or IVe OH l HO-2)-CH2 - 9 R1°-OH R11-OH Vo IVb IVc .15 R14 r13 m-nh2 HV R12-NH J Vd IV· in which R10 to R16, M and V have the meaning mentioned and n is 1 or 2.
Other prodrug forms are formed in an analogous manner by the methods described in Bundgaard. The compounds of the formula I derivatized on the aldehyde group can be converted in vitro and in vivo into the active, antiviral ly active form (aldehyde form) (H. Bundgaard, Design of Prodrugs, 1985, 1 - 92, Elsevier-Verlag). The conversion into the active form can be carried out, for ex10 ample, by hydrolysis in agueous solution or by enzymatic catalysis in or en route to the site of action.
A test for activity of chemotherapeutics for HIV infections in man causes difficulties, since no infection model in laboratory animals yet exists. Infection with other retroviruses therefore has to be resorted to for testing chemotherapeutics. In this case, the infection of the mouse with the Friend leukemia virus has been chosen. For this purpose, normal NMRI laboratory mice (NMRI = Naval Medical Research Institute) were infected by intravenous injection with mouse serum containing Friend leukemia virus. In the untreated control animals, a distinct enlargement of the spleen and liver developed as a symptom of the infection in the course of 2 weeks. Treatment was carried out over 10 days, starting 48 hours after the infection. On the 14th day of the experiment, the animals were sacrificed and dissected. The spleen was removed and weighed. As a measurement parameter of the therapeutic activity, the weight of the spleen of the treated animals was related to that of the untreated infection control.
In the case of uninfected adult laboratory mice (20 -24 g body weight), the spleen weighed about 1 % of the body weight or less, while in the case of infected animals, the spleen attained about 10 % of the body weight at the end of the experiment.
The compound of the formula I in which R is an aldehyde group possesses useful pharmacological properties, in particular an antiviral action and in particular against diseases caused both by DNA and RNA viruses, particularly against diseases which are caused by Herpes simplex virus (HSV I), myxoviruses, Friend leukemia virus (FLV) or human immunodeficiency virus (HIV). The compounds according to the invention are therefore suitable for combating various diseases caused by viruses, such as respiratory tract disease, diseases of the skin, the eyes, the central nervous system, AIDS and AIDS-related conditions, such as AIDS-related complex (ARC), generalized lymphadenopathy (GL), AIDS-related neuralgic conditions (such as mental deficiency or trophic paraperesis), anti-HIVantibody-positive conditions, Kaposi sarcoma or thrombopenic purpura.
The compound of the formula I and/or its prodrug form can either be used as a pharmaceutical alone or mixed with physiologically tolerable auxiliaries or excipients in effective amounts. It can be administered, for example, orally in a dose of 1 to 500 mg/kg/day, preferably 5 to 50 mg/kg/day. The administration for parenteral, rectal or topical use or as an aerosol is carried out, for example in an amount of 0.5 to 500 mg/kg/day, preferably of 2 to 100 mg/kg/day. The compound of the formula I and/or its prodrug form are expediently administered in dosage units which contain at least the effective amount - 11 of the compounds according to the invention, preferably 25 to 6000 mg, particularly preferably 100 to 1000 mg. These values relate to an adult human having a weight of 75 kg. These dosage units can also be administered several times per day. The dosage can also be increased in severe cases. In many cases, however, lower amounts are also sufficient. For combating diseases which are caused by RNA or DNA viruses, the following are suitable in particular diethyl 2-formylbenzylphosphonate, 2-formylbenzylphosphonic acid di(triethylammonium) salt, monoethyl 2-formylbenzylphosphonate triethylammonium salt, diethyl 2-formylbenzylphosphonate thiosemicarbazone, diethyl 2-formylbenzylphosphonate nicotinic acid hydrazone or diethyl 2-(3,4-dimethyl-5-phenyloxazolidin-2-yl)benzylphosphonate.
The compound of the formula I according to the invention and/or its prodrug form can also be administered in combination with other substances, in particular antiviral agents and immunostimulators, such as interferons. The compound of the formula I and/or its prodrug form are referred to as the active compound in the following.
The invention furthermore includes the use of the active compound in the preparation of pharmaceuticals which are employed for the treatment and prophylaxis of the abovementioned diseases. The invention furthermore relates to pharmaceuticals which contain one or more active compounds.
The pharmaceuticals are prepared by processes which are known per se and familiar to those skilled in the art. As a pharmaceutical, the active compound is either employed as such or preferably in combination with suitable pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, - 12 emulsions, suspensions or solutions, the content of active compound being up to about 95 %, advantageously between 10 and 75 %.
In addition to solvents, gel-forming agents, suppository 5 bases, tablet auxiliaries and other active compound carriers, suitable auxiliaries or excipients for the desired pharmaceutical formulation are also, for example, antioxidants, dispersants, emulsifiers, defoaming agents, flavor modifiers, preservatives, solubilizers or colorants.
The active compound can be administered orally, parenterally, intravenously or rectally, intranasal administration as an aerosol being preferred in particular in addition to oral administration.
For a form for oral use, the active compound is mixed with the additives suitable for this purpose such as excipients, stabilizers or inert diluents and brought into a suitable form for administration, such as tablets, coated tablets, hard gelatin capsules, and aqueous or oily solutions by the customary methods. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular cornstarch. In this case, preparation can be carried out both as dry and as moist granules. Oily excipients or solvents which are suitable are, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil.
For subcutaneous or intravenous administration, the active compound is brought into solution, suspension or emulsion with the substances suitable for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Suitable solvents are, for example, physiological saline solution, alcohols, for example ethanol, propanol, glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of solvents.
The following examples serve to illustrate the invention further.
Example 1 Preparation of diethyl 2-formylbenzylphosphonate (A) 47.9 g (0.31 mol) of 2-chloromethylbenzaldehyde were heated to 160’C together with 51.5 g (0.31 mol) of triethyl phosphite. Ethyl chloride distilled off during the course of this. The product was purified by fractional distillation.
Yield: 64.5 g (81 %)? b.p.: 130*C/0.3 mm; 1H-NMR (270 MHz, CDC13/TMS): 6 = 1.23 (t, 6H, P-O-CH2CH3), 3.78 (d, 2H, CH2-P) Jp.„ = 24 Hz, 4.04 (dq,4H, P-O-CH2-CH3), 7.19 - 7.97 (m,4H,Ar-H) Example 2 Preparation of 2-formylbenzylphosphonic acid di (triethylammonium) salt (B) and monoethyl 2-formylbenzylphosphonate triethylammonium salt (C) 100 ml of 6 M HCl were added to 5.0 g (20 mmol) of diethyl 2-formylbenzylphosphonate and the mixture was boiled under reflux for 6 h. Water and HCl were distilled off in vacuo, and the residue was co-evaporated three times with toluene. The remaining brown material was chromatographed on silica gel (CH2Cl2/methanol/triethyl25 amine: 75/24/1). Compounds B and C were obtained as oily products. It was possible to separate them by chromatography on diethylaminoethyl *Sephadex A25 (Et3NH+ form, Pharmacia, Freiburg, West Germany). They differ in their elution behavior (Rf value). Elution was carried out with a triethylammonium bicarbonate gradient of from 0.3 1.0 M.
(B): Rf - 0.1; yield: 2.4 g (30 %); m.p.: 1H-NMR (270 MHz, DMSO/TMS): 6 = 1.07 (t, 18H,N-CH2-CH3), 2.86 (q, 12H,N-CH2-CH3), 3.23 (d,2H,CH2-P) JP.H = 23 Hz, 7.24 - 7.78 (m,4H,Ar-H), 10.31 (S,1H,CHO).
(C): Rf = 0.3; yield: 1.4 g (21 %); 1H-NMR (270 MHz, DMSO/TMS): δ = 1.01 - 1.17 (m,12H, N-CH2-CH3 & P-O-CH2-CH3), 2.88 (q, 6H,N-CH2-CH3), 3.27 (d,2H,CH2-P) Jp_H = 23 Hz, 3.68 ((dq,2H, P-O-CH2-CH3), 7.18 - 7.78 (m,4H,Ar-H), 10.31 (S,1H,CHO).
Example 3 Preparation of 2-formylbenzylphosphonic acid di(triethylammonium) salt (B) 3.2 g (21 mmol) of trimethylsilyl bromide were added dropwise to 2.0 g (8 mmol) of the compound A in 10 ml of absolute dioxane, and the reaction mixture was heated to 50°C and stirred at this temperature for 6 h. The mixture was evaporated, water was added several times and the solution was lyophilized. The crude product was purified by chromatography as in Example 2.
Yield: 1.98 g (62 %).
Example 4 Diethyl 2-formylbenzylphosphonate thiosemicarbazone (D) 2.0 g (8 mmol) of the compound A and 0.73 g of thiosemicarbazide were dissolved or suspended in 200 ml of absolute ethanol. 2 ml of acetic acid were added and the mixture was boiled under reflux for 3 h. In the course of the slow cooling, the product D precipitated in crystal25 line form.
Yield: 1.8 g (68 %); m.p.: 195 to 197*C; ^-NMR (270 MHz, CDC13/TMS): δ = 1.16 (t,6H,CH2-CH3), 3.38 (d,2H,CH2-P, Jp-H = 23 Hz), 3.94 (dq,4H, CH2-CH3), 7.23 - 7.39 (m,3H,Ar-H), 8.40 (s,lH,Ar-H), 11.37 (s,lH,Ar-CH=N).
Example 5 Diethyl 2-formylbenzylphosphonate nicotinic acid hydrazone (E) 2.0 g (8 mmol) of the compound A and 1.07 g (8 mmol) of 5 nicotinic acid hydrazide were dissolved in 30 ml of absolute ethanol. After adding 1 ml of acetic acid, the mixture was boiled under reflux for 8 h. The solvent was removed by rotary evaporation and the residue was chromatographed on silica gel (eluent CH2Cl2/EtOH 9.5/0.5; Rf - 0.45). The product E was obtained in crystalline form.
Yield: 2.2 g (73 %); m.p.: 136 to 140*C; hl-NMR 270 MHz, CDC13/TMS): 6 - 1.14 - 1.37 (m,6H,CH3), 3.61 - 3.79 (d,2H,CH2-P), Jp.H = 24 Hz, 3.87 - 4.16 (m,4H,CH2-CH3), 7.11 - 7.49 (m,4H,Ar-H), 7.70 - 9.23 (m,5H,Py-H), 10.17 & 11.25 (each s, ratio 1:3, ΙΗ,ΝΗ).
Example 6 Diethyl 2-(3,4-dimethyl-5-phenyloxazolidin-2-yl)benzylphosphonate (F) 2.0 g (8 mmol) of the compound A and 1.32 g (8 mmol) of (-)-ephedrine were dissolved in 100 ml of benzene and heated under reflux in a water separator for 24 h. The solvent was then removed by rotary evaporation and the residue was chromatographed on silica gel (eluent CH2Cl2/ethanol 9.5/0.5; Rf = 0.55). The product F was obtained as an oil.
Yield: 2.4 g (75 %); 1H-NMR (270 MHz, CDC13/TMS); S = 0.80, (d,3H,CH-CH3), 1.25 (m,6H,O-CH2-CH3), 2.27 (s,3H,N-CH3), 3.18 (dq, 1H,CH-CH3), 3.20 & 3.28 (dd,lH,Ph-CH-CH), 3.59 - 3.76 (m,2H,CH2-P); 4.01 (m,4H,O-CH2-CH3), 5.19 (s,lH,Ar-CH(O-)(N-), 7.16 7.45 (m,8H,Ar-H), 7.89 - 7.98 (m,lH,Ar-H).
Example 7 Pathogen-free NMRI mice having a weight of about 15 g were infected intraperitoneally with Herpes simplex Type 1 and then treated intraperitoneally, orally or subcutaneously with the compounds mentioned in Table 1. The treatment was carried out twice daily over the course of 2.5 days, starting after infection. The result of treatment was determined on the basis of the course of the disease and the survival rate compared to the untreated infection controls. The controls received a water-soluble methylhydroxyethylcellulose (viscosity 300 Pa.s, administered in 2 % strength solution) instead of the compounds to be tested. The experiments were carried out using groups of 5 mice each per preparation.
The chemotherapeutic action of the compound A can be seen from Table 1.
Table 1 Preparation Herpes simplex 1 Average survival time (days) Dosage (mg/kg) Surviving animals Control sc 0 1 6.7 A sc 2.5 2 9.0 20 A sc 25 0 7.2 A sc 250 0 8.4 Control po 0 1 8.0 A po 2.5 4 8.0 A po 25 5 — 25 A po 250 4 8.0 Control sc 0 1 8.3 C sc 3 1 8.5 C sc 10 3 8.0 C sc 30 4 10.0 30 Control po 0 1 7.8 C po 3 4 9.0 C PO 10 3 8.0 C PO 30 1 8.3 Control sc 0 1 8.3 35 B sc 3 2 7.8 B sc 10 3 7.0 B sc 30 3 6.5 Table 1, continuation Herpes simplex 1 Surviving animals Average survival time (days) Preparation Dosage (mg/kg) Control Ρθ 0 1 7.8 B po 3 3 7.0 B po 10 2 8.3 B Po 30 3 6.0 Control ip 0 1 8.3 A ip 3 0 8.0 A ip 10 4 9.0 A ip 30 3 8.5 po = orally sc = subcutaneously ip = intraperitoneally Example 8 Cell cultures of Hela and Vero cells were inoculated into microtitre plates and infected with myxoviruses (influenza A2). 2 Hours after infection, the compounds B and C were added to the infected cell cultures in various dilutions. 48 to 72 hours after infection, the result of treatment was determined microscopically and photometric25 ally by neutral red absorption (color test according to Finter) (Finter, N.B. Interferons, 1966) on the basis of the cytopathogenic effect. The minimum concentration at which about half the infected cells do not show a cytopathogenic effect is regarded as the minimum inhibitory concentration (MIC). The results are summarized in Table 2.
Influenza A2 MIC (pg/ml) MTD (pg/ml) Table 2 Substance 44.4 4.94 > 400 > 400 MIC = minimum inhibitory concentration MTD = maximum tolerated dose Example 9 Pathogen-free NMRI mice having a weight of about 16 g were infected intranasally with influenza A2 and then treated subcutaneously and orally with the compounds mentioned in Table 3. The compounds were administered to the animals under slight ether anesthesia using one drop of virus suspension in each of the nostrils. The treatment was carried out twice daily over the course of 2.5 days, starting after infection. Amantadine was always used as the comparison. The success of the treatment was determined on the basis of the course of the disease and the survival rate compared to the untreated infection controls. The controls received a water-soluble methylhydroxyethylcellulose (viscosity 300 Pa.s, administered in 2 % strength solution) instead of the compounds to be tested. The experiments were carried out using groups of 5 mice each per preparation.
The chemotherapeutic action is shown in Table 3. - 19 Table 3 Influenza A2 Preparation Dosage (mg/kg) Number of surviving animals Average survival time (days) Control P° 0 2 7.5 Amantadine po 80 5 — A po 2.5 4 9.0 A po 3 4 8.0 10 A po 10 4 7.0 A po 25 2 6.3 A po 30 2 7.3 Control sc 0 0 6.6 Amantadine sc 80 5 — 15 A sc 2.5 2 6.7 A sc 25 3 7.0 Control sc 0 2 6.7 Amantadine sc 80 5 — B sc 1.5 1 8.5 20 B sc 15 4 8.0 Control po 0 1 6.5 Amantadine po 80 4 8.0 B po 1.5 3 8.5 B po 15 5 — 25 B po 150 3 7.0 Control sc 0 0 6.8 C sc 0.25 5 — C sc 2.5 5 — C sc 25 3 7.5 30 Control po 0 0 7.2 C po 0.25 5 — C PO 2.5 2 6.0 C po 25 5 — Control po 0 0 6.6 35 D po 0.25 4 8.0 D po 2.5 1 7.0 D PO 25 2 7.3 - 20 Table 3, continuation Influenza A2 Preparation Dosage (mg/kg) Number of Surviving animals Average time (days) Control PO 0 0 6.6 E PO 0.25 4 8.0 E PO 2.5 3 6.7 E PO 25 3 6.0 Control po 0 1 7.0 F po 0.25 3 6.5 F po 2.5 3 6.5 F PO 25 2 7.0 sc = subcutaneously po = orally Example 10 Laboratory mice (NMRI, female, weight 20 - 24 g) were infected intravenously with Friend leukemia virus (FLV)20 containing mouse serum. The treatment was started 48 h after infection. The mice were treated over the course of 10 days with the substances indicated in Table 4. The substances indicated were administered orally or intraperitoneally once a day. 14 days after infection, the animals were sacrificed by dislocation and the spleens were removed. The weight of the spleens was determined. As a measurement parameter of the therapeutic activity, the weight of the spleen of the animals which had been treated with compounds A and D was related to that of the untreated infection control.
Suramin and azidothymidine (AZT) were used as standard substances. The action of the preparations is shown in Table 4.
Table 4 Preparation Friend leukemia virus Dosage Survival rate % Relative weight of the spleen % of body weight Control po 0 100 12.36 AZT po 15.5 100 3.26 A po 17.5 100 7.74 A po 81 100 5.67 Control ip 0 100 10.64 AZT ip 50.0 100 7.60 D ip 50.0 100 7.60 Control ip 0 100 12.36 Suramin ip 50 70 6.06 A ip 25 90 6.27 A ip 50 100 6.52 ip = intraperitoneally po = orally
Claims (9)
1. Patent claims 1. A compound of the formula (I) x R -a λ 11 1 &C(R 3 R 4 )-P-YR 1 rS, R 6, R 7, r B in which R is an aldehyde group or a group which can be converted into an aldehyde, R 1 and R 2 , which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, eodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or R 1 and R 2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, R 3 and R 4 , which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkynyl or alkenyl group having 2 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine, R 5 , R 6 , R 7 and R 8 , which may be identical or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula Ia - 23 Ο Η C-O-R 19 I* R 1S is a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and X, Y and Z, which may be identical or different, are oxygen or sulfur or a prodrug form of the compound of the formula I.
2. A compound of the formula I as claimed in claim 1, in which R 1 and R 2 are an alkyl group having 1 to 10 carbon atoms, an alkenyl or alkynyl group having 2 to 10 carbon atoms, hydrogen or an aralkyl group having 7 to 16 carbon atoms, R 3 and R* are an alkyl group having 1 to 4 carbon atoms, an alkenyl or alkynyl group having 2 to 4 carbon atoms or hydrogen, R 5 , R 6 , R 7 and R® are chlorine, bromine, methoxy or hydrogen and X, Y and Z are oxygen.
3. A compound as claimed in claim 1, in which R is a group, which can be converted into an aldehyde, of the formula Ib, Ic or Id RH R15 ι M N CH ι lb lc Id in which R 10 and R 11 , which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 carbon atoms or R 10 and R 11 together form a cyclic acetal having 2 or 3 carbon atoms in the ring, R 12 to R 16 , which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 carbon atoms or an aryl group having 6, 10 or 14 carbon atoms, V is oxygen or sulfur, M is a hydroxyl group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or a radical of the formula Ie or If I· -O-C-R 1 ® If 7. 8. 8. in which R 17 is a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an amino, pyridine, or aryl group having 6, 10 or 14 carbon atoms and R 18 is an amino group, a pyridine group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or an aralkyl group having 7 to 20 carbon atoms. Diethyl 2-formylbenzylphosphonate. 2-Formylbenzylphosphonic acid di(triethylammonium) salt. Monoethyl 2-formylbenzylphosphonate triethylammonium salt. Diethyl 2-formylbenzylphosphonate thiosemicarbazone. A process for the preparation of the compound of the formula I as claimed in claim 1, in which R is an aldehyde group, which comprises reacting the compound of the formula II R 3 z C-7 X R 4 in which R 3 and R*, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkynyl or alkenyl group having 2 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine, R 5 , R 6 , R 7 and R 8 , which may be identical or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula Ia II -C-O-R 19 la R 19 is a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and T is chlorine, bromine, iodine, methylsulfonate, phenylsulfonate or tosylsulfonate, with the compound of the formula Il’I x-R 9 p'-Y-R 1 111 ^Z-R2 in which, R 1 and R 2 , which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or R 1 and R 2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, R 8 is a straight-chain or branched alkyl group having 1 to 4 carbon atoms and X, Y and Z, which may be identical or different, are oxygen or sulfur. 9. The process for the preparation of the compound of the formula I as claimed in claim 1, in which R is a group which can be converted into an aldehyde, which comprises reacting the compound of the formula I in which R is an aldehyde in such a way that a group which can be converted into an aldehyde is formed. 10. The process for the preparation of the compound of the formula I as claimed in claim 3, which comprises reacting the compound of the formula I in which R is an aldehyde group with the compound of the formula IVa, IVb and/or IVc, IVd or IVe HO-(CH 2 )-CH 2 RlO-OH R 11 “OH IVb 1 Vc 1 Vo HV R 12 -NH r1 6 m-nh 2 IVd IV. in which R 10 and R n are a straight-chain or branched alkyl 11. 11. 12. 12. 13. 13. 1
4. 14. group having 1 to 10 carbon atoms, R 12 to R 16 , which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 carbon atoms or an aryl group having 6, 10 or 14.carbon atoms, V is oxygen or sulfur, K is a hydroxyl group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or a radical of the formula Ie or If I· ii . Q -O-C-R 1B IF in which R 17 is a straight-chain or branched alkyl group having 1 to 10 carbon atoms, or an amino, pyridine, or an aryl group having 6, 10 or 14 carbon atoms and R 18 is an amino group, a pyridine group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or an aralkyl group having 7 to 20 carbon atoms. The use of the compound of the formula I as claimed in claim 1 for the production of a pharmaceutical for the treatment of diseases which are caused by RNA or DNA viruses . The use of the compound of the formula I as claimed in claim 2 for the production of a pharmaceutical for the treatment of diseases which are caused by RNA or DNA viruses. The use of the compound of the formula I as claimed in claim 3 for the production of a pharmaceutical for the treatment of diseases which are caused by RNA or DNA viruses. A pharmaceutical preparation containing an effective amount of the compound as claimed in claim 1. 1
5. A method for the production of a pharmaceutical, wherein an effective amount of a compound as claimed in claim 1 is converted into a suitable form for administration. 1
6. A compound of the formula (I) given and defined in claim 1 or a prodrug thereof, substantially as hereinbefore described and exemplified. 1
7. A process for the preparation of a compound of the formula (I) given and defined in claim 1 or a prodrug thereof, substantially as hereinbefore described and exemplified. 1
8. A compound of the formula (I) given and defined in claim 1 or a prodrug thereof, whenever prepared by a process claimed in any one of claims 8-10 or 17. 1
9. Use according to claim 11, substantially as hereinbefore described. 20. A pharmaceutical preparation according to claim 14, substantially as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3942318A DE3942318A1 (en) | 1989-12-21 | 1989-12-21 | 2-FORMYLBENZYLPHOSPHONIC ACID DERIVATIVES, THEIR PRODUCTION AND THE USE THEREOF FOR THE TREATMENT OF DISEASES CAUSED BY VIRUSES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE904625A1 true IE904625A1 (en) | 1991-07-17 |
| IE67439B1 IE67439B1 (en) | 1996-04-03 |
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| Application Number | Title | Priority Date | Filing Date |
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| IE462590A IE67439B1 (en) | 1989-12-21 | 1990-12-20 | 2-Formylbenzylphosphonic acid derivatives their preparation and their use for the treatment of diseases caused by viruses |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0433928B1 (en) |
| JP (1) | JP2997552B2 (en) |
| KR (1) | KR100191087B1 (en) |
| AT (1) | ATE119908T1 (en) |
| AU (1) | AU640723B2 (en) |
| CA (1) | CA2032772C (en) |
| DE (2) | DE3942318A1 (en) |
| FI (1) | FI102280B (en) |
| HU (1) | HU208144B (en) |
| IE (1) | IE67439B1 (en) |
| IL (1) | IL96730A (en) |
| NO (1) | NO179614C (en) |
| NZ (1) | NZ236554A (en) |
| PL (1) | PL288361A1 (en) |
| PT (1) | PT96287B (en) |
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| JP2006335737A (en) * | 2005-06-03 | 2006-12-14 | Ihara Nikkei Kagaku Kogyo Kk | METHOD FOR PRODUCING BENZO[c]HETEROCYCLIC 5-MEMBERED RING COMPOUND |
| AU2006272521A1 (en) * | 2005-07-27 | 2007-02-01 | Gilead Sciences, Inc. | Antiviral phosphonate conjugates for inhibition of HIV |
| JP5789430B2 (en) | 2011-06-27 | 2015-10-07 | イハラニッケイ化学工業株式会社 | Method for producing 2-chloromethylbenzaldehyde, 2-chloromethylbenzaldehyde-containing composition and storage method thereof |
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1989
- 1989-12-21 DE DE3942318A patent/DE3942318A1/en not_active Withdrawn
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1990
- 1990-12-15 AT AT90124305T patent/ATE119908T1/en not_active IP Right Cessation
- 1990-12-15 DE DE59008715T patent/DE59008715D1/en not_active Expired - Fee Related
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- 1990-12-20 JP JP2417963A patent/JP2997552B2/en not_active Expired - Fee Related
- 1990-12-20 AU AU68304/90A patent/AU640723B2/en not_active Ceased
- 1990-12-20 PL PL28836190A patent/PL288361A1/en unknown
- 1990-12-20 ZA ZA9010269A patent/ZA9010269B/en unknown
- 1990-12-20 NO NO905521A patent/NO179614C/en unknown
- 1990-12-20 IE IE462590A patent/IE67439B1/en not_active IP Right Cessation
- 1990-12-20 CA CA002032772A patent/CA2032772C/en not_active Expired - Fee Related
- 1990-12-20 PT PT96287A patent/PT96287B/en not_active IP Right Cessation
- 1990-12-21 HU HU908412A patent/HU208144B/en not_active IP Right Cessation
- 1990-12-21 KR KR1019900021297A patent/KR100191087B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0616685A (en) | 1994-01-25 |
| NO179614B (en) | 1996-08-05 |
| CA2032772A1 (en) | 1991-06-22 |
| HU208144B (en) | 1993-08-30 |
| CA2032772C (en) | 2001-10-23 |
| FI906268A (en) | 1991-06-22 |
| HUT56111A (en) | 1991-07-29 |
| RU2039063C1 (en) | 1995-07-09 |
| AU6830490A (en) | 1991-06-27 |
| DE59008715D1 (en) | 1995-04-20 |
| AU640723B2 (en) | 1993-09-02 |
| KR100191087B1 (en) | 1999-06-15 |
| IL96730A0 (en) | 1991-09-16 |
| ATE119908T1 (en) | 1995-04-15 |
| KR910011874A (en) | 1991-08-07 |
| EP0433928B1 (en) | 1995-03-15 |
| FI906268A0 (en) | 1990-12-19 |
| EP0433928A1 (en) | 1991-06-26 |
| NO905521L (en) | 1991-06-24 |
| NO179614C (en) | 1996-11-13 |
| IE67439B1 (en) | 1996-04-03 |
| NO905521D0 (en) | 1990-12-20 |
| NZ236554A (en) | 1992-12-23 |
| PL288361A1 (en) | 1992-07-13 |
| IL96730A (en) | 1996-10-31 |
| FI102280B1 (en) | 1998-11-13 |
| PT96287B (en) | 1998-06-30 |
| JP2997552B2 (en) | 2000-01-11 |
| DE3942318A1 (en) | 1991-06-27 |
| ZA9010269B (en) | 1991-09-25 |
| FI102280B (en) | 1998-11-13 |
| PT96287A (en) | 1991-09-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |