WO1995012604A1 - Novel amino acid derivatives - Google Patents
Novel amino acid derivatives Download PDFInfo
- Publication number
- WO1995012604A1 WO1995012604A1 PCT/SE1993/000930 SE9300930W WO9512604A1 WO 1995012604 A1 WO1995012604 A1 WO 1995012604A1 SE 9300930 W SE9300930 W SE 9300930W WO 9512604 A1 WO9512604 A1 WO 9512604A1
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- 229960000851 pirprofen Drugs 0.000 description 1
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- PXGPLTODNUVGFL-YNNPMVKQSA-N prostaglandin F2alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O PXGPLTODNUVGFL-YNNPMVKQSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- MTIQLOQTQUBOLK-UHFFFAOYSA-N silyl dihydrogen phosphite Chemical compound OP(O)O[SiH3] MTIQLOQTQUBOLK-UHFFFAOYSA-N 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 1
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Chemical class 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- 229940035722 triiodothyronine Drugs 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- DFHAXXVZCFXGOQ-UHFFFAOYSA-K trisodium phosphonoformate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)P([O-])([O-])=O DFHAXXVZCFXGOQ-UHFFFAOYSA-K 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000010626 work up procedure 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
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4062—Esters of acids containing the structure -C(=X)-P(=X)(XR)2 or NC-P(=X)(XR)2, (X = O, S, Se)
- C07F9/4065—Esters of acids containing the structure -C(=X)-P(=X)(XR)2, (X = O, S, Se)
-
- 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)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3886—Acids containing the structure -C(=X)-P(=X)(XH)2 or NC-P(=X)(XH)2, (X = O, S, Se)
- C07F9/3891—Acids containing the structure -C(=X)-P(=X)(XH)2, (X = O, S, Se)
Definitions
- the present invention relates to the use in therapy of amino acid moieties covalently coupled to drugs which are not ⁇ -amino acids or peptides and which contain a carboxylic group thereby forming prodrugs for the parent drugs.
- the amino acid moieties function as uptake enhancers in the intestine of mammals including man.
- the present invention also relates to novel amino acid derivatives of
- the present invention relates to derivatives of phosphonoformic acid (PFA) and the use thereof as prodrugs in pharmaceutical compositions.
- PFA derivatives can be formulated for oral administration resulting in high
- bioavailability as measured by the level of PFA in the blood upon ingestion.
- the present invention also relates to processes for the preparation of the PFA derivatives.
- the present invention also relates to a method of improving the transport of pharmaceutically active compounds which are not ⁇ -amino acids or peptides and which contain a carboxyl group via the intestinal mucosa into the blood of mammals.
- the improved transport is accomplished by chemical modification of the parent drug with a bioreversible drug moiety which is disclosed in the present invention and which mediates the active uptake of the parent drug.
- PFA is a parent drug which is particularly suitable for improved transport according to this method.
- the present invention also relates to a method for the therapeutic and prophylactic control and treatment of viral infections in humans.
- CMV cytomegalovirus
- HSV-1 and HSV-2 herpes simplex virus types 1 and 2
- EBV Epstein-Barr virus
- VZV varicella zoster virus
- HHV-6 human herpesvirus 6
- HTV immunodeficiency virus
- DEPFA di-(O-ethyl)phosphonoformic acid
- DEPF-Gly stands for the derivative of DEPFA with glycine.
- foscarnet is defined herein as foscarnet sodium, the hexahydrate of the trisodium salt of phosphonoformic acid.
- bioavailability is defined herein as the fraction of an oral dose that reaches the systemic circulation.
- C max is defined herein as the peak or highest drug concentration in the systemic circulation.
- AUC is defined herein as the total integrated area under the concentration/time curve. It is an estimate of the amount of drug absorbed.
- CMV end-organ disease is defined herein as the disease associated with any organ infected by cytomegalovirus.
- F abs is the fraction of the drug absorbed which enters into the blood, i.e.
- Intravenous formulations of PFA are well known and are disclosed in U.S. Patent Nos. 4,215,113; 4,339,445; 4,665,062 and 4,771,041.
- PFA inhibits replication of all known herpesviruses in vitro including
- CMV cytomegalovirus
- HSV-2 herpes simplex virus types 1 and 2
- HHV-6 human herpesvirus 6
- EBV Epstein-Barr virus
- VZV varicella-zoster virus
- HMV Human Immunodeficiency Virus
- Treatment of CMV infections in AIDS patients and patients infected with herpesvirus with foscarnet is at present by intravenous injections. This mode of treatment is burdensome where foscarnet must be administered daily.
- the development of an oral formulation is therefore very desirable since it would offer a much more convenient method of treatment and thus result in easier, more reliable compliance. While oral formulations of PFA have been tested there is no known proven effective composition available on the market to date.
- Alkyl derivatives of PFA are known from EP 0 003 007 as are the antiviral effects in vitro and in vivo in animals of such compounds and of pharmaceutical compositions thereof. So far, however, no drug based on any of these substances has become available neither in oral nor in any other formulation.
- Amide derivatives of PFA are known from EP 0 003 008 as are the antiviral effects in vitro and in vivo in animals of such compounds and of pharmaceutical compositions thereof. So far, however, no drug based on any of these substances has become available neither in oral nor in any other formulation.
- Prodrugs of phosphorus derivatives which are designed for penetrating the blood brain barrier have been described in Eur. pat. appl. No. 91912398.4 (Glazier, A.).
- An objective of the present invention is to provide novel derivatives of PFA suitable for oral formulation which can be administered to humans and can deliver high concentrations of PFA into the blood of patients.
- Another objective of the present invention relates to the use of a chemical modification of PFA to be delivered via the intestinal mucosa into the blood as a means of improving the uptake of PFA.
- Another objective of the present invention relates to the use of an effective amount of flavoring agent to provide the level of flavor desired to mask the taste of the oral formulations of prodrugs of PFA.
- the invention comprises a compound of the formula
- the invention also comprises a pharmaceutical composition containing a compound of the general formula as an active ingredient and the use of such compositions of the compounds in the therapy of the diseases which are appropriate for treatment by the pharmaceutically active compound.
- the present invention results from the following unexpected finding: An amino acid derivative of di-(O-ethyl)phosphonoformic formulated and administered in aqueous saline solution to rats is taken up effectively and bioconverted to release high levels of PFA into the blood.
- amino acid derivatives of the present invention have the general formula I:
- R 1 and R 2 each independently are hydrogen; a branched or unbranched C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl or C 1-6 -alkoxy-C 1-6 -alkyl group which is optionally substituted with hydroxy, amino, halogen or oxo; a benzyl group; a group or a group
- R 3 is a branched or unbranched C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl or C 1-6 -alkoxy-C 1-6 -alkyl group which is optionally substituted with hydroxy, amino, halogen or oxo; and R 4 is hydrogen or a C 1-4 -alkyl group;
- R 1 and R 2 together form a group wherein R 5 is a branched or unbranched C 1-6 -alkyl or C 1-6 -alkoxy group;
- A is an amino acid residue which is selected from glycyl, alanyl, valyl, norvalyl, leucyl, isoleucyl, norleucyl, phenylalanyl, tyrosyl, seryl, homoseryl, threonyl, cysteinyl, methionyl, tryptophyl, ⁇ -aspartyl, ⁇ -glutamyl, arginyl, lysyl, histidyl, ornithyl, prolyl or 4-hydroxyprolyl, either in the L- or in the D-configuration; or physiologically acceptable salts thereof.
- the derivatives of PFA of the present invention are effective for the treatment of HIV infections and human herpesvirus infections by inhibiting the replication of the human immunodeficiency virus (HIV-1 and HIV-2), cytomegalovirus (CMV), herpes simplex virus types 1 and 2, (HSV- 1 and HSV-2), Epstein-Barr virus (EBV), varicella zoster virus (VZV) and human herpesvirus 6 (HHV-6).
- HSV-1 and HIV-2 human immunodeficiency virus
- CMV cytomegalovirus
- HSV- 1 and HSV-2 herpes simplex virus types 1 and 2
- EBV Epstein-Barr virus
- VZV varicella zoster virus
- HHV-6 human herpesvirus 6
- the present invention provides compounds which are the amino acid derivatives of pharmaceutically active compounds which are not ⁇ -amino acids or peptides and which contain a carboxyl group which can form an amide bond to an amino acid. Most preferred are derivatives of such drug molecules with glycine, L-alanine, L-proline, L-4-hydroxyproline, L-phenylalanine and L-tyrosine.
- the present invention relates to novel derivatives of PFA in which an amino acid is attached to the carboxyl group of PFA by means of an amide bond.
- the present invention also provides a method of enhancing the uptake of PFA and derivatives thereof into the blood by coupling an amino acid via an amide bond thereto.
- the present invention also provides:
- a method for treatment of diseases caused by viruses in animals including man comprising administering to an animal so infected a therapeutically effective amount of a compound of the formula I or a physiologically acceptable salt thereof.
- Particular reverse transcriptases are the reverse transcriptases of retrovirus s, such as visna, sarcoma and leucemia viruses, and human immunodeficiency virus (HTV).
- D A method for inhibiting the multiplication of virus, in particular herpesviruses, influenza virus and hepatitis B virus, and retroviruses in animals including man, by administering to an animal in need of such treatment a compound of the formula I or a physiologically acceptable salt thereof in an amount sufficient for inhibiting said multiplication.
- E A method for inhibiting the growth of virus-transformed cells in animals including man, characterized by administering to an animal in need of such treatment a compound of the formula I or a physiologically acceptable salt thereof in an amount sufficient for inhibiting said growth.
- the invention also relates to the use of a compound of the formula I or a physiologically acceptable salt thereof, in each of the above given methods A, B, C, D and E.
- the invention relates to the use of a compound of the formula I or a physiologically acceptable salt thereof, for a) inhibiting the replication of virus in animals including man, in particular herpesvirus, influenza virus, hepatitis B viruses and human immunodeficiency virus. b) for inhibiting the growth of virus-transformed cells in animals including man.
- the invention provides pharmaceutical preparations comprising as active ingredient a compound of the formula I or a physiologically acceptable salt thereof, optionally in association with a pharmaceutically acceptable carrier.
- the invention also encompasses a process for the preparation of a medicine having antiviral acitivity, characterized in that a compound of the formula I or a physiologically acceptable salt thereof is brought into an administration form suitable for therapeutical purposes, and the shaped medicine obtained by such process.
- C 1-4 -alkyl and “C 1-6 -alkyl” as a separate group or as part of a group designates alkyl groups with 1-4 or 1-6 carbon atoms which may be straight or branched such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc.
- C 2-6 -alkenyl designates mono- unsaturated alkyl groups with 2-6 carbon atoms which may be straight or branched, preferably straight, in which the double bond may be present anywhere in the chain, for example vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl etc.
- C 2-6 -alkynyl designates an alkyl group with 2-6 carbon atoms and incorporating a triple bond, e.g. ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, etc.
- C 3-8 -cycloalkyl as a group or as part of a group designates a cyclic alkyl group with 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
- C 1-6 -alkoxy designates groups comprising an oxa function substituted with an alkyl group as defined above.
- C 3-8 -cycloalkoxy designates groups comprising an oxa function substituted with a cycloalkyl group as defined above.
- halogen designates Cl, Br, I and F.
- Preferred groups of the radicals R 1 and R 2 in the formula I below are ethyl, propyl, isopropyl, acetoxymethyl, acetoxyethyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, phthalidyl and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl.
- Preferred amino acid residues A are glycyl, L-alanyl, L-phenylalanyl, L- tyrosyl, L-prolyl or L-4-hydroxyprolyl.
- R 1 , R 2 and A are as defined above are prepared by known methods for the synthesis of carbamoylphosphonates, for example as described by T. Reetz et al in J. Am. Chem. Soc. 77 (1955) 3813 and in Houben-Weyl, Methoden der
- R 1 and R 2 have the meaning given above and R 7 is an aliphatic cycloaliphatic, araliphatic, aromatic or heterocyclic leaving group, such as C 1-6 -alkoxy, C 3-8 -cycloalkoxy, benzyloxy, phenoxy, 4-nitrophenoxy, imidazolyl or succinimidoxy with an amino acid derivative H-A-OR 6 , wherein A has the meaning given above and R 6 is a suitable protecting group such as methyl, ethyl or benzyl, followed by removal of the protecting group R 6 to give a compound of the formula I.
- the carbamoylphosphonate-forming reaction is performed in a solvent, such as for example ethanol or dimethylformamide, at a temperature from 0°C to 100°C for 1 hour to 5 days.
- a solvent such as for example ethanol or dimethylformamide
- the protecting group R 6 may be removed by hydrolysis with a base such as, for example, 0.5M - 2M sodium hydroxide, lithium hydroxide or potassium hydroxide in water, methanol, ethanol or aqueous tetrahydrofuran.
- a base such as, for example, 0.5M - 2M sodium hydroxide, lithium hydroxide or potassium hydroxide in water, methanol, ethanol or aqueous tetrahydrofuran.
- the protecting group R 6 may also be removed by enzymatic hydrolysis, for example with porcine liver esterase. Examples of such methods are described, for example, by H. G. Davies et al in Best Synthetic Methods; Biotransformations in Preparative Organic
- the protecting group R 6 is benzyl, it may be removed by catalytic
- R 6 has the meaning given above and R 8 is the side chain specific for an amino acid residue A as defined in claim 1, followed by removal of the protecting group R 6 , as described above, to give a compound of the formula I.
- the carbamoylphosphonate-forming reaction is performed at 50°C to 150°C for 1 to 50 hours.
- the starting materials used in the above methods of preparation A-B are known compounds, or may be prepared by known methods commonly used for the synthesis of hydroxycarbonylphosphomc acid triesters, phosphite esters, isocyanates and esters of amino acids.
- Examples of methods for the synthesis of phosphite esters may be found in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII/2, Organische Phosphoreducationen, p. 5-78.
- Examples of methods for the synthesis of hydroxycarbonylphosphonic acid triesters are found in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII/1, Organische Phosphorberichten, p. 433-463.
- the esterification reaction is performed through the intermediary of activating agents known per se for the phosphorylation of alcohols. Examples of such methods are described for example by L. A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kössel in Progress in the Chemistry of Organic Natural Products 32 (1975) 297.
- the esterification reaction is performed through the intermediary of activating agents known per se for the phosphorylation of alcohols. Examples of such methods are described for example by L.A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kössel in Progress in the Chemistry of Organic Natural Products 32 (1975) 297. Synthesis of the phosphonic acid monoesters of formula VI are described below in methods L-N.
- R 1 -X a compound R 1 -X
- M + is a cation such as Ag + , Li + , Na + , K + , Cs + , Et 3 NH + , (i-Pr) 2 NEtH +
- the esterification reaction is carried out in a solvent, such as for example ethanol or dimethylformamide, at a temperature from 25°C to 100°C for 1 to 50 hours.
- a solvent such as for example ethanol or dimethylformamide
- the esterification reaction is carried out in a solvent, such as for example ethanol or dimethylformamide, at a temperature of 25 °C to 100°C for 1 to 50 hours.
- a solvent such as for example ethanol or dimethylformamide
- the dihalides of the formula LX are prepared from the corresponding phosphonic acids by methods known per se for the synthesis of dihalides of phosphonic acids and phosphoric acids. References for those methods are found for example in the two publications above and in Houben-Weyl, Methoden der Organishen Chemie, Auflage 4, Band XII/1, p. 386-406 and Band XII/2, p. 211-225 and p 274-292.
- the phosphonic acids are prepared by methods described in methods J and K.
- the esterification reaction is performed by methods known per se for the phosphorylation of alcohols. Examples of such methods are described for example by L.A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kössel in Progress in the Chemistry of Organic Natural Products 32 (1975) 297.
- the monoester halides of the formula X are prepared from the corresponding phosphonic acid monoesters by methods known per se for the synthesis of monohalides of phosphonic and phosphoric acids. References for those methods are found for example in the two publications above and in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII/1, p. 386-406 and Bend XII/2, p. 211-225 and p. 274-292.
- the phosphonic acid groups formed on hydrolysing the bis-silyl esters can be neutralized.
- they can be neutralized with a weak cation exchanger (M + ) or with a base such as MHCO 3 , M 2 CO 3 or MOH.
- M + is NH + 4 or a metal cation such as Li + , Na + or K + .
- the phosphonate bis-silyl esters may be obtained by reacting a compound of the formula XII
- R 6 , R 9 , A and X have the meaning given above and R 10 and R 11 have the meaning given R 1 and R 2 , R 10 and R 11 may be the same or different.
- the reaction is performed at -20°C to reflux temperatures for 1 hour to several days.
- the phosphonic acid diesters of formula XII are prepared by methods analagous to those described in A-H.
- the phosphonate bis-silyl esters may be prepared by reacting a bis-silyl phosphite with an isocyanate according to the formula
- R 6 , R 8 , R 9 and A have the meaning given above.
- the reaction is performed at 25°C to 150°C for 1 to 50 hours.
- the bis-silyl phosphites are prepared by known methods, as described for example by Sekine et al in J. Org. Chem. 46 (1981) 2097, for the preparation of
- the hydrogenation reaction may be performed with a catalyst such as palladium on charcoal.
- the phosphonic acid groups may be neutralized.
- they may be neutralized with a weak cation exchanger (M + ) or with a base such as MHCO 3 , M 2 CO 3 or MOH.
- M + is for example NH + 4 or a metal cation such as Li + , Na + or K + .
- reaction is carried out with sodium iodide in a solvent such as for example tetrahydrofuran or acetone.
- reaction is carried out at a temperature from 20°C to 100°C from 2 hours to 7 days.
- the phosphonic acid diesters of formula XIV may be prepared by methods analogous to those described in A-H.
- the phosphonic acid group formed on hydrolysing the silyl ester may be neutralized.
- it may be neutralized with a weak cation exchanger (M + ) or with a base such as MHCO 3 , M 2 CO 3 or MOH.
- M + is for example NH + 4 or a metal cation such as Li + , Na + or K + .
- the silyl esterified phosphonate group may be obtained by reacting a compound of the formula XIV
- the silylation reagents are for example bromotrimethylsilane at -20°C to 50°C for 0.5 to 20 hours, or alternatively for example chlorotrimethylsilane at 20°C to reflux temperature for several days.
- the phosphonic acid diesters of formula XIV may be prepared by methods analogous to those described in A-H.
- the silyl esterified phosphonate group may be prepared by reacting a silyl phosphite with an isocyanate according to the formula
- the esterification reaction is performed through the intermediary of activating agents known per se for the phosphorylation of alcohols. Examples of such methods are described for example by L. A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kössel in Progress in the Chemistry of Organic Natural Products 32 (1971) 297.
- the phosphonic acids of formula V are prepared by the methods described above in methods J and K. Pharmaceutical formulations
- the derivatives of PFA or salts thereof according to the invention may be used for the therapeutic and prophylactic control and treatment of herpesvirus diseases and HIV diseases.
- Oral formulations of the prodrugs of PFA or salts thereof can be used alone or with other antiviral agents such as acyclovir, ganciclovir, ddC, ddI, AZT or immunological agents such as interferon and growth factors such as granulocyte-macrophage and granulocyte-colony stimulating factors (GM-CSF and G-CSF).
- Other drags, which can be derivatized and used according to the present invention are analgesics, antirheumatics and antiphlogistics, such as acemetacin,
- acetylsalicylic acid alclofenac, diclofenac, diflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacine, ketoprofen, ketozolac, naproxen, niflumic acid, oxaprozin, pirprofen, salicylic acid, sulindac, tiaprofenic acid, tolfenamic acid and tolmetin; antibacterials and antivirals such as cinoxacin, ciprofloxacin, nalidixic acid and phosphonoacetic acid; diuretics such as etacrynic acid and canrenoic acid; hemostatics such as tranexamic acid; oncolytics such as chlorambucil;
- prostaglandins such as alprostadil, carboprost, dinoprost, dinoprostone and epoprostenol; and thyreomimetics such as levothyroxine and liothyronine.
- the compounds of the present invention are suitably admixed with excipients to be formulated into capsules, tablets, suppositories and others such as suspensions and solutions.
- oral formulations of capsules at doses of 50 mg to 1000 mg may be formulated.
- the compounds of the invention are formulated into pharmaceutical formulations for oral, prenteral and rectal administration.
- the pharmaceutical formulation contains the compound of the invention normally in combination with a pharmaceutically acceptable excipient.
- the excipient may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
- These pharmaceutical preparations are a further object of the invention.
- the amount of active compound is between 0.1-99% by weight of the preparation for oral as well as for other modes of administration.
- the compound may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium, and the like, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethyleneglycol waxes.
- the mixture is then processed into granules or pressed into tablets.
- Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalyzed degradation as long as the dosage form remains in the stomach.
- the enteric coating is chosen among pharmaceutically acceptable enteric-coating materials e.g.
- Soft gelatin capsules may be prepared with capsules containing a mixture of the active compound of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Soft gelatin capsules may also be enteric-coated as described above. Hard gelatin capsules may contain granules or enteric-coated granules of the active compound.
- Hard gelatin capsules may also contain the active compound in combination with a powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin.
- a powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin.
- the hard gelatin capsules may be enteric-coated as described above.
- Dosage units for rectal administration may be prepared in the form of suppositories with the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules, or they may be prepared in the form of a dry micro enema, or they may be reconstituted in a suitable solvent just prior to administration.
- Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g.
- liquid preparations containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol.
- such liquid preparations may contain colouring agents, flavouring agents, saccharin and carboxymethyl or other thickening agents.
- Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
- sustained release preparations at doses of 50 mg to 1000 mg, preferably 1000 mg may be formulated.
- Suitable sustained release formulations may include pharmaceutically acceptable excipients.
- the typical daily dose of the active substance will depend on various factors such as for example the individual requirement of each patient the route of
- oral dosages will be in the range of 50 to 20000 mg of active substance per day, preferably 200 mg to 15000 mg of active substance per day.
- the samples were injected onto a HPLC system consisting of an LDC analytical ConstaMetric®3200 solvent delivery system with a built-in pulse dampener (Laboratory Data Control, Riviera Beach, FI, USA), a WISP 710B autosampler, a Kratos Spectroflow 773 variable wavelength UV detector operating at 230 nm, and an ESA Coulochem®II electrochemical detector (ESA Inc, Bedford, MA, USA) with a model 5011 high sensitivity analytical cell.
- the potentials on the analytical cell were set at +0.75 and +0.95 V for channels 1 and 2, resp.
- the mobile phase (flow rate 0.7 ml/min) was a pH 5.8 phosphate buffer-methanol (75:25, v:v) mixture with 1 mM tetrahexylammonium hydrogen sulfate as ion pair creator and 0.2 mM pyrophosphoric acid to prevent peak tailing.
- the total concentration of phosphate in the mobile phase was 43 mM.
- the analytical column a Merck LiChrospher® 100 RP 18 (5 ⁇ m; E Merck
- DEPF-Gly reaches a C max of 0.18 mM as compared to C max of 0.05 mM for PFA in aqueous solution.
- the bioavailability measured as F abs is 0.64 for DEPF-Gly as compared to 0.19 for PFA in aqueous solution which corresponds to an over 3-fold increase.
- the time to reach C max was 1.5 h for DEPF-Gly and 1.25 h for PFA.
- TRIS-Ringer solution with 10 mM glucose for the mucosal to serosal side studies and Tris-Ringer solution with 10 mM mannitol for the serosal to mucosal side studies was added.
- the acceptor samples were assayed for PFA or DEPF-Gly using the HPLC assay described above.
- Fig. 2 illustrates the transport of PFA and DEPF-Gly at a donor concentration of 1 mM during a period of 210 minutes over rat jejunum.
- Di-(O-ethyl)phosphonoformylglycine was prepared in two steps in the following way:
- TMSA trimethylsilyl azide
- EMC ethyl malonyl chloride
- a sample was further purified by extraction from DCM to give a pale yellow liquid.
- DEPF-GlyOEt 0.782 g DEPF-GlyOEt was dissolved in 1 ml water. This mixture was poured into 2.0 ml 0.1 M borate-buffer (pH 8) and 70 ⁇ l (200 units) porcine liver esterase (PLE; carboxylic ester hydrolase; EC 3.1.1.1) was added conforming with Sigma PLE product information. This mixture was stirred overnight keeping the pH at 8 by adding 0.1M NaOH-solution. The reaction was stopped by adding 5.0 ml dichloromethane (DCM) to the mixture which denaturated the esterase. After filtration of the brown precipitate the aqueous layer was extracted three times with DCM. The aqueous layer was neutralised and further purified by silica gel chromatography which yielded 62% of compound DEPF-Gly as a white solid.
- DCM dichloromethane
- the active substance is preferably used in the form of a solid salt where such salts can be formed and most preferably in the form of its sodium salt.
- Each tablet contains: active substance 300.0 mg lactose 200.0 mg maize starch 25.0 mg gelatin 1.5 mg talc 12.0 mg magnesium stearate 1.5 mg
- Coated tablets Tablets according example 2 are coated with an enteric coating solution with the following composition: ethyl cellulose 120.0 g propylene glycol 30.0 g sorbitan monooleate 10.0 g water ad 1000.0 ml
- the coating is carried out by a pouring procedure in a conventional coating pan or by spraying the tablets in a pan spray tablet coater.
- Gastric juice-resistant tablets Tablets according example 2 are coated with a coating solution with the following composition: cellulose acetate phtalate 120.0 g propylene glycol 30.0 g sorbitan monooleate 10.0 g ethanol 95% 450.0 ml acetone q.s. ad 1000.0 ml
- the coating is carried out by a pouring procedure in a conventional coating pan or by spraying the tablets in a pan spray tablet coater.
- Syrup active substance 12.0 g liquid glucose 30.0 g sucrose 40.0 g ascorbic acid 0.1 g disodium edetate 10.0 mg lemon essence 25.0 mg purified water ad 100.0 g
- Each sachet contains: active substance 3.0 g citric acid anhydrous 0.5 g glucose 2.5 g
- Each capsule contains: active substance 300.0 mg microcrystalline cellulose 150.0 mg colloidal silicium oxide 5.0 mg
- Each suppository contains: active substance 500.0 mg adeps solidus q.s.
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Abstract
The use of amino acids for increasing the uptake of drugs in medicine.
Description
NOVEL AMINO ACID DERIVATIVES
Field of the invention
The present invention relates to the use in therapy of amino acid moieties covalently coupled to drugs which are not α-amino acids or peptides and which contain a carboxylic group thereby forming prodrugs for the parent drugs. Possibly the amino acid moieties function as uptake enhancers in the intestine of mammals including man.
The present invention also relates to novel amino acid derivatives of
pharmaceutically active compounds which are not α-amino acids or peptides and which contain a carboxyl group as prodrugs in pharmaceutical compositions. In particular the present invention relates to derivatives of phosphonoformic acid (PFA) and the use thereof as prodrugs in pharmaceutical compositions. The PFA derivatives can be formulated for oral administration resulting in high
bioavailability as measured by the level of PFA in the blood upon ingestion.
The present invention also relates to processes for the preparation of the PFA derivatives.
The present invention also relates to a method of improving the transport of pharmaceutically active compounds which are not α-amino acids or peptides and which contain a carboxyl group via the intestinal mucosa into the blood of mammals. The improved transport is accomplished by chemical modification of the parent drug with a bioreversible drug moiety which is disclosed in the present invention and which mediates the active uptake of the parent drug. PFA is a parent drug which is particularly suitable for improved transport according to this method. The present invention also relates to a method for the therapeutic and prophylactic
control and treatment of viral infections in humans. These include infections caused by all human herpesviruses, including cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV), varicella zoster virus (VZV), human herpesvirus 6 (HHV-6) as well as by human
immunodeficiency virus (HTV).
Definitions
The following abbreviations and definitions will be used hereinafter.
The abbreviation "i.v." stands for "intravenous".
The abbreviation "p.o." stands for "peroral". The abbreviation "PFA" stands for "phosphonoformic acid".
The abbreviation "DEPFA" stands for "di-(O-ethyl)phosphonoformic acid".
The abbreviation "DEPF-Gly" stands for the derivative of DEPFA with glycine.
The term "foscarnet" is defined herein as foscarnet sodium, the hexahydrate of the trisodium salt of phosphonoformic acid.
The term "bioavailability" is defined herein as the fraction of an oral dose that reaches the systemic circulation.
The term "Cmax" is defined herein as the peak or highest drug concentration in the systemic circulation. The term "AUC" is defined herein as the total integrated area under the
concentration/time curve. It is an estimate of the amount of drug absorbed.
The term "CMV end-organ disease" is defined herein as the disease associated with any organ infected by cytomegalovirus.
"Fabs" is the fraction of the drug absorbed which enters into the blood, i.e.
Aucoral/AuCi.v..
Background of the Invention
Intravenous formulations of PFA are well known and are disclosed in U.S. Patent Nos. 4,215,113; 4,339,445; 4,665,062 and 4,771,041.
PFA inhibits replication of all known herpesviruses in vitro including
cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV) and varicella-zoster virus (VZV) as well as certain retroviruses including the Human Immunodeficiency Virus (HIV). Treatment of CMV infections in AIDS patients and patients infected with herpesvirus with foscarnet is at present by intravenous injections. This mode of treatment is burdensome where foscarnet must be administered daily. The development of an oral formulation is therefore very desirable since it would offer a much more convenient method of treatment and thus result in easier, more reliable compliance. While oral formulations of PFA have been tested there is no known proven effective composition available on the market to date.
The oral administration of an aqueous solution of intravenous foscarnet in animals leads to reduced and inconsistent absorption from the gastrointestinal tract (GI tract) and therefore, low bioavailabilities and low peak blood levels, e.g. in the dog
(Ritschel et al.. 1985, Meth. and Exptl. Clin. Pharmacol. 2:41-48).
One explanation of the low bioavailability might be that PFA is absorbed poorly in the GI tract because of its being charged at the pH of the GI tract.
Another explanation of the low bioavailability might be that PFA is rapidly degraded in the stomach by the inherent low pH as the drug is acid labile. This acid lability may at least in part account for the lower amount of PFA available for absorption, and therefore, the low bioavailabilities previously attained. The studies of Ritschel et al. (1985) showed that the absorption of PFA in an animal having a stomach pH close to neutral (the rabbit), is much better than in one with an acidic stomach pH (the dog), thus resulting in a higher bioavailability. Bunsgaard et al. (Int J. of Pharmaceutics, 63, 1990, 213-218) studied the decarboxylation of foscarnet in acidic solution and concluded that intragastric degradation may be of significance for the absorption of foscarnet upon peroral administration.
All attempts in the past to administer oral foscarnet to human subjects using the currently approved intravenous formulation have been suboptimal and thus, unsuccessful. (Sjövall et al., 1988, Clin. Pharm. Ther., 44:65-73 and Barditch-Croyo et al. 1991 7th Intl. Conf. on AIDS, Florence, Italy).
Alkyl derivatives of PFA are known from EP 0 003 007 as are the antiviral effects in vitro and in vivo in animals of such compounds and of pharmaceutical compositions thereof. So far, however, no drug based on any of these substances has become available neither in oral nor in any other formulation.
Amide derivatives of PFA are known from EP 0 003 008 as are the antiviral effects in vitro and in vivo in animals of such compounds and of pharmaceutical compositions thereof. So far, however, no drug based on any of these substances has become available neither in oral nor in any other formulation.
Prodrugs of phosphorus derivatives which are designed for penetrating the blood brain barrier have been described in Eur. pat. appl. No. 91912398.4 (Glazier, A.).
An objective of the present invention is to provide novel derivatives of PFA suitable for oral formulation which can be administered to humans and can deliver high concentrations of PFA into the blood of patients.
Another objective of the present invention relates to the use of a chemical modification of PFA to be delivered via the intestinal mucosa into the blood as a means of improving the uptake of PFA.
It is a further objective of the present invention to provide formulations of derivatives of PFA which exhibit acceptable absorption rates, and high and effective bioavailability.
Another objective of the present invention relates to the use of an effective amount of flavoring agent to provide the level of flavor desired to mask the taste of the oral formulations of prodrugs of PFA. Summary of the Invention
In a general aspect the invention comprises a compound of the formula
wherein is a radical of a pharmaceutically active compound D-COOH,
which is not an α-amino acid or peptide, and which is able to form an amide bond with the N-terminal group of an amino acid residue A as defined below.
The invention also comprises a pharmaceutical composition containing a compound of the general formula
as an active ingredient and the use of such compositions of the compounds in the therapy of the diseases which are appropriate for treatment by the pharmaceutically active compound.
The present invention results from the following unexpected finding: An amino acid derivative of di-(O-ethyl)phosphonoformic formulated and administered in aqueous saline solution to rats is taken up effectively and bioconverted to release high levels of PFA into the blood.
The amino acid derivatives of the present invention have the general formula I:
wherein R1 and R2 each independently are hydrogen; a branched or unbranched C1-6-alkyl, C2-6-alkenyl, C2-6alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl or C1-6-alkoxy-C1-6-alkyl group which is optionally substituted with hydroxy, amino, halogen or oxo; a benzyl group;
a group or a group
wherein R3 is a branched or unbranched C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl or C1-6-alkoxy-C1-6-alkyl group which is optionally substituted with hydroxy, amino, halogen or oxo; and R4 is hydrogen or a C1-4-alkyl group;
or wherein R1 and R2 together form a group
wherein R5 is a branched or unbranched C1-6-alkyl or C1-6-alkoxy group;
A is an amino acid residue which is selected from glycyl, alanyl, valyl, norvalyl, leucyl, isoleucyl, norleucyl, phenylalanyl, tyrosyl, seryl, homoseryl, threonyl, cysteinyl, methionyl, tryptophyl, α-aspartyl, α-glutamyl, arginyl, lysyl, histidyl, ornithyl, prolyl or 4-hydroxyprolyl, either in the L- or in the D-configuration; or physiologically acceptable salts thereof. The derivatives of PFA of the present invention are effective for the treatment of HIV infections and human herpesvirus infections by inhibiting the replication of the human immunodeficiency virus (HIV-1 and HIV-2), cytomegalovirus (CMV), herpes simplex virus types 1 and 2, (HSV- 1 and HSV-2), Epstein-Barr virus (EBV), varicella zoster virus (VZV) and human herpesvirus 6 (HHV-6).
Detailed description of the invention
The present invention provides compounds which are the amino acid derivatives of pharmaceutically active compounds which are not α-amino acids or peptides and which contain a carboxyl group which can form an amide bond to an amino acid. Most preferred are derivatives of such drug molecules with glycine, L-alanine, L-proline, L-4-hydroxyproline, L-phenylalanine and L-tyrosine. In particular the present invention relates to novel derivatives of PFA in which an amino acid is attached to the carboxyl group of PFA by means of an amide bond.
The present invention also provides a method of enhancing the uptake of PFA and derivatives thereof into the blood by coupling an amino acid via an amide bond thereto. The present invention also provides:
A. A method for treatment of diseases caused by viruses in animals including man, comprising administering to an animal so infected a therapeutically effective amount of a compound of the formula I or a physiologically acceptable salt thereof.
B. A method for the treatment of diseases caused by viruses in animals including man, by inhibiting the activity of viral polymerase, characterized by administering to an animal so infected a compound of the formula I or a physiologically acceptable salt thereof in an amount effective for inhibiting the activity of said viral polymerase.
C. A method for inhibiting the activity of reverse transcriptases of viruses in animals including man, by administration to an animal a compound of the formula I or a physiologically acceptable salt thereof in an amount sufficient for inhibiting the activity of said reverse transcriptase. Particular reverse transcriptases are the reverse transcriptases of retrovirus s, such as visna, sarcoma and leucemia viruses, and human immunodeficiency virus (HTV).
D. A method for inhibiting the multiplication of virus, in particular herpesviruses, influenza virus and hepatitis B virus, and retroviruses in animals including man, by administering to an animal in need of such treatment a compound of the formula I or a physiologically acceptable salt thereof in an amount sufficient for inhibiting said multiplication. E. A method for inhibiting the growth of virus-transformed cells in animals
including man, characterized by administering to an animal in need of such treatment a compound of the formula I or a physiologically acceptable salt thereof in an amount sufficient for inhibiting said growth. The invention also relates to the use of a compound of the formula I or a physiologically acceptable salt thereof, in each of the above given methods A, B, C, D and E. For example, the invention relates to the use of a compound of the formula I or a physiologically acceptable salt thereof, for a) inhibiting the replication of virus in animals including man, in particular herpesvirus, influenza virus, hepatitis B viruses and human immunodeficiency virus. b) for inhibiting the growth of virus-transformed cells in animals including man.
Furthermore, the invention provides pharmaceutical preparations comprising as active ingredient a compound of the formula I or a physiologically acceptable salt thereof, optionally in association with a pharmaceutically acceptable carrier. The invention also encompasses a process for the preparation of a medicine having antiviral acitivity, characterized in that a compound of the formula I or a physiologically acceptable salt thereof is brought into an administration form suitable for therapeutical purposes, and the shaped medicine obtained by such process. In the present context, the terms "C1-4-alkyl" and "C1-6-alkyl" as a separate group or as part of a group designates alkyl groups with 1-4 or 1-6 carbon atoms which may be straight or branched such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc. The term "C2-6-alkenyl" designates mono- unsaturated alkyl groups with 2-6 carbon atoms which may be straight or branched, preferably straight, in which the double bond may be present anywhere in the
chain, for example vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl etc. The term C2-6-alkynyl" designates an alkyl group with 2-6 carbon atoms and incorporating a triple bond, e.g. ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, etc. The term "C3-8-cycloalkyl" as a group or as part of a group designates a cyclic alkyl group with 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The term "C1-6-alkoxy" designates groups comprising an oxa function substituted with an alkyl group as defined above. The term "C3-8-cycloalkoxy" designates groups comprising an oxa function substituted with a cycloalkyl group as defined above. The term "halogen" designates Cl, Br, I and F.
Preferred groups of the radicals R1 and R2 in the formula I below are ethyl, propyl, isopropyl, acetoxymethyl, acetoxyethyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, phthalidyl and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl. Preferred amino acid residues A are glycyl, L-alanyl, L-phenylalanyl, L- tyrosyl, L-prolyl or L-4-hydroxyprolyl.
Preparation Reference to "meaning given above" for R1, R2 and A as used below refers to the definitions given in formula I.
Compounds of the general formula I
wherein R1, R2 and A are as defined above are prepared by known methods for the synthesis of carbamoylphosphonates, for example as described by T. Reetz et al in J. Am. Chem. Soc. 77 (1955) 3813 and in Houben-Weyl, Methoden der
Organische Chemie, Auflage 4, Band XII/1, Organische Phosphorverbindungen, p. 453-458. Examples of such methods are the following.
A. Reacting a compound of the formula II
wherein R1 and R2 have the meaning given above and R7 is an aliphatic cycloaliphatic, araliphatic, aromatic or heterocyclic leaving group, such as C1-6-alkoxy, C3-8-cycloalkoxy, benzyloxy, phenoxy, 4-nitrophenoxy, imidazolyl or succinimidoxy with an amino acid derivative H-A-OR6, wherein A has the meaning given above and R6 is a suitable protecting group such as methyl, ethyl or benzyl, followed by removal of the protecting group R6 to give a compound of the formula I.
Preferentially the carbamoylphosphonate-forming reaction is performed in a solvent, such as for example ethanol or dimethylformamide, at a temperature from 0°C to 100°C for 1 hour to 5 days.
The protecting group R6 may be removed by hydrolysis with a base such as, for example, 0.5M - 2M sodium hydroxide, lithium hydroxide or potassium hydroxide in water, methanol, ethanol or aqueous tetrahydrofuran. The protecting group R6 may also be removed by enzymatic hydrolysis, for example with porcine liver esterase. Examples of such methods are described, for example, by H. G. Davies et
al in Best Synthetic Methods; Biotransformations in Preparative Organic
Chemistry; Academic Press; London, 1989; Chapter 2.
When the protecting group R6 is benzyl, it may be removed by catalytic
hydrogenation in the presence of a catalyst, such as palladium on charcoal.
B. Reaction of a compound of the formula III
wherein R6 has the meaning given above and R8 is the side chain specific for an amino acid residue A as defined in claim 1, followed by removal of the protecting group R6, as described above, to give a compound of the formula I. Preferentially the carbamoylphosphonate-forming reaction is performed at 50°C to 150°C for 1 to 50 hours.
The starting materials used in the above methods of preparation A-B are known compounds, or may be prepared by known methods commonly used for the synthesis of hydroxycarbonylphosphomc acid triesters, phosphite esters, isocyanates
and esters of amino acids. Examples of methods for the synthesis of phosphite esters may be found in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII/2, Organische Phosphorverbindungen, p. 5-78. Examples of methods for the synthesis of hydroxycarbonylphosphonic acid triesters are found in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII/1, Organische Phosphorverbindungen, p. 433-463.
C. Esterification of a compound of the formula V
with an alcohol R1OH, wherein A, R1 and R6 have the meaning given above, followed by removal of the protecting group R6, as described above, to give a compound of the formula I where R1=R2.
The esterification reaction is performed through the intermediary of activating agents known per se for the phosphorylation of alcohols. Examples of such methods are described for example by L. A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kössel in Progress in the Chemistry of Organic Natural Products 32 (1975) 297.
Synthesis of the phosphonic acids of the formula V are described below in methods J and K.
with an alcohol R1OH, wherein A, R1, R2 and R6 have the meaning given above, followed by removal of the protecting group R6, as described above, to give a compound of the formula I.
The esterification reaction is performed through the intermediary of activating agents known per se for the phosphorylation of alcohols. Examples of such methods are described for example by L.A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kössel in Progress in the Chemistry of Organic Natural Products 32 (1975) 297. Synthesis of the phosphonic acid monoesters of formula VI are described below in methods L-N.
E. Reaction of a compound of the formula VII
with a compound R1-X, wherein A, R1 and R6 have the meaning given above, M+ is a cation such as Ag+, Li+, Na+, K+, Cs+, Et3NH+, (i-Pr)2NEtH+ and X is a halogen such as Cl, Br or I, followed by removal of the protecting group R6, as described above, to give a compound of the formula I where R1 =R2.
Preferentially the esterification reaction is carried out in a solvent, such as for example ethanol or dimethylformamide, at a temperature from 25°C to 100°C for 1
to 50 hours.
F. Reaction of a compound of the formula VIII
with a compound R1-X, wherein A, R1 , R2, R6, M+ and X have the meaning given above, followed by removal of the protecting group R6, as described above, to give a compound of the formula I.
Preferentially the esterification reaction is carried out in a solvent, such as for example ethanol or dimethylformamide, at a temperature of 25 °C to 100°C for 1 to 50 hours.
G. Reacting a compound of the formula LX
with an alcohol R1OH, wherein A, R1, R6 and X have the meaning given above, followed by removal of the protecting group R6, as described above, to give a compound of the formula I where R1=R2. The esterification reaction is performed by methods known per se for the
phosphorylation of alcohols by phosporic and phosphonic acid halides. Examples of such methods are described for example by L.A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kossel in Progress in the Chemistry of Organic Natural Products 32 (1975) 297.
The dihalides of the formula LX are prepared from the corresponding phosphonic acids by methods known per se for the synthesis of dihalides of phosphonic acids and phosphoric acids. References for those methods are found for example in the two publications above and in Houben-Weyl, Methoden der Organishen Chemie, Auflage 4, Band XII/1, p. 386-406 and Band XII/2, p. 211-225 and p 274-292. The phosphonic acids are prepared by methods described in methods J and K.
H. Reacting a compound of the formula X
with an alcohol R1OH, wherein A, R1, R2, R6 and X have the meaning given above, followed by removal of the protecting group R6, as described above, to give a compound of the formula I.
The esterification reaction is performed by methods known per se for the phosphorylation of alcohols. Examples of such methods are described for example by L.A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kössel in Progress in the Chemistry of Organic Natural Products 32 (1975) 297.
The monoester halides of the formula X are prepared from the corresponding phosphonic acid monoesters by methods known per se for the synthesis of monohalides of phosphonic and phosphoric acids. References for those methods are found for example in the two publications above and in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII/1, p. 386-406 and Bend XII/2, p. 211-225 and p. 274-292.
The corresponding phosphonic acid monoesters are prepared by methods described below in L-N.
J. Aqueous hydrolysis of a compound of the formula XI containing two silylated phosphonate groups
wherein A and R6 have the meaning given above, and R9 is an inert organic residue, for example methyl, followed by removal of the protecting group R6, as described above, to give a compound of the formula I where R1 =R2=H.
Optionally, the phosphonic acid groups formed on hydrolysing the bis-silyl esters can be neutralized. Preferably they can be neutralized with a weak cation exchanger (M+) or with a base such as MHCO3, M2CO3 or MOH. M+ is NH+ 4 or a metal cation such as Li+, Na+ or K+.
with a compound X-Si(R9)3, wherein R6, R9, A and X have the meaning given above and R10 and R11 have the meaning given R1 and R2, R10 and R11 may be the same or different.
Preferentially, the reaction is performed at -20°C to reflux temperatures for 1 hour to several days.
The phosphonic acid diesters of formula XII are prepared by methods analagous to those described in A-H.
Alternatively, the phosphonate bis-silyl esters may be prepared by reacting a bis-silyl phosphite with an isocyanate according to the formula
where R6, R8, R9 and A have the meaning given above. Preferentially the reaction is performed at 25°C to 150°C for 1 to 50 hours.
The bis-silyl phosphites are prepared by known methods, as described for example by Sekine et al in J. Org. Chem. 46 (1981) 2097, for the preparation of
bis(trimethylsilyl) phosphite.
K. Hydrogenation of a compound of the formula XIII
wherein A and R6 have the meaning given above, followed by removal of the protecting group R6, as described above, to give a compound of the formula I where R1=R2=H. Preferably the hydrogenation reaction may be performed with a catalyst such as palladium on charcoal. Optionally the phosphonic acid groups may be neutralized. Preferably they may be neutralized with a weak cation exchanger (M+) or with a base such as MHCO3, M2CO3 or MOH. M+ is for example NH+ 4 or a metal cation such as Li+, Na+ or K+.
L. Reacting a compound of the formula XIV
with iodide or bromide anion, wherein A, R1, R6 and R10 have the meaning given above followed by removal of the protecting group R6, as described above, to give a compound of the formula I where R2=H.
Preferably the reaction is carried out with sodium iodide in a solvent such as for example tetrahydrofuran or acetone. Preferably the reaction is carried out at a temperature from 20°C to 100°C from 2 hours to 7 days.
The phosphonic acid diesters of formula XIV may be prepared by methods analogous to those described in A-H.
M. Aqueous hydrolysis of a compound of the formula XV containing one silylated phosphonate group
wherein A, R1, R6 and R9 have the meaning given above, followed by removal of the protecting group R6, as described above, to give a compound of the formula I where R2=H. Optionally the phosphonic acid group formed on hydrolysing the silyl ester may be neutralized. Preferably it may be neutralized with a weak cation exchanger (M+) or with a base such as MHCO3, M2CO3 or MOH. M+ is for example NH+ 4 or a metal cation such as Li+, Na+ or K+. The silyl esterified phosphonate group may be obtained by reacting a compound of the formula XIV
with a compound X-Si(R9)3, wherein A, R1, R6, R9, R10 and X have the meaning given above. Preferably the silylation reagents are for example bromotrimethylsilane at -20°C to 50°C for 0.5 to 20 hours, or alternatively for example chlorotrimethylsilane at 20°C to reflux temperature for several days. The phosphonic acid diesters of formula XIV may be prepared by methods analogous to those described in A-H. Alternatively, the silyl esterified phosphonate group may be prepared by reacting a silyl phosphite with an isocyanate according to the formula
where R1, R6, R8, R9 and A have the meaning given above. Preferentially, the reaction is carried out at 25°C to 150°C for 1 to 50 hours.
N. Monoesterification of a compound of the formula V
with an alcohol R1OH, wherein A, R1 and R6 have the meaning given above, followed by removal of the protecting group R6, as described above, to give a compound of the formula I where R2=H.
The esterification reaction is performed through the intermediary of activating agents known per se for the phosphorylation of alcohols. Examples of such methods are described for example by L. A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kössel in Progress in the Chemistry of Organic Natural Products 32 (1971) 297.
The phosphonic acids of formula V are prepared by the methods described above in methods J and K. Pharmaceutical formulations
The derivatives of PFA or salts thereof according to the invention may be used for the therapeutic and prophylactic control and treatment of herpesvirus diseases and HIV diseases. Oral formulations of the prodrugs of PFA or salts thereof can be used alone or with other antiviral agents such as acyclovir, ganciclovir, ddC, ddI, AZT or immunological agents such as interferon and growth factors such as granulocyte-macrophage and granulocyte-colony stimulating factors (GM-CSF and G-CSF). Other drags, which can be derivatized and used according to the present invention
are analgesics, antirheumatics and antiphlogistics, such as acemetacin,
acetylsalicylic acid, alclofenac, diclofenac, diflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacine, ketoprofen, ketozolac, naproxen, niflumic acid, oxaprozin, pirprofen, salicylic acid, sulindac, tiaprofenic acid, tolfenamic acid and tolmetin; antibacterials and antivirals such as cinoxacin, ciprofloxacin, nalidixic acid and phosphonoacetic acid; diuretics such as etacrynic acid and canrenoic acid; hemostatics such as tranexamic acid; oncolytics such as chlorambucil;
prostaglandins, such as alprostadil, carboprost, dinoprost, dinoprostone and epoprostenol; and thyreomimetics such as levothyroxine and liothyronine.
The compounds of the present invention are suitably admixed with excipients to be formulated into capsules, tablets, suppositories and others such as suspensions and solutions. Using known pharmaceutical procedures oral formulations of capsules at doses of 50 mg to 1000 mg may be formulated.
For clinical use the compounds of the invention are formulated into pharmaceutical formulations for oral, prenteral and rectal administration. The pharmaceutical formulation contains the compound of the invention normally in combination with a pharmaceutically acceptable excipient. The excipient may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compound is between 0.1-99% by weight of the preparation for oral as well as for other modes of administration. In the preparation of pharmaceutical formulations containing the compounds of the present invention in the form of dosage units for oral administration the compound may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium, and the like, as
well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethyleneglycol waxes. The mixture is then processed into granules or pressed into tablets. Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalyzed degradation as long as the dosage form remains in the stomach. The enteric coating is chosen among pharmaceutically acceptable enteric-coating materials e.g.
beeswax, shellac or anionic film-forming polymers and the like, if preferred in combination with a suitable plasticizer. To the coating various dyes may be added in order to distinguish among tablets or granules with different active compounds or with different amounts of the active compound present
Soft gelatin capsules may be prepared with capsules containing a mixture of the active compound of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Soft gelatin capsules may also be enteric-coated as described above. Hard gelatin capsules may contain granules or enteric-coated granules of the active compound.
Hard gelatin capsules may also contain the active compound in combination with a powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. The hard gelatin capsules may be enteric-coated as described above.
Dosage units for rectal administration may be prepared in the form of suppositories with the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules, or they may be prepared in the form of a dry micro enema, or they may be reconstituted in a suitable solvent just prior to administration. Liquid preparations for oral administration may be prepared in the form of syrups
or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharin and carboxymethyl or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
In addition, using known pharmaceutical procedures, sustained release preparations at doses of 50 mg to 1000 mg, preferably 1000 mg may be formulated. Suitable sustained release formulations may include pharmaceutically acceptable excipients.
The typical daily dose of the active substance will depend on various factors such as for example the individual requirement of each patient the route of
administration and the disease. In general, oral dosages will be in the range of 50 to 20000 mg of active substance per day, preferably 200 mg to 15000 mg of active substance per day.
Experiments Bioavailability studies
In vivo experiments were performed using male Wistar rats, breed U:WU rats. Phosphonoformic acid or a prodrug according to the present invention was administered orally or intravenously to the rat and whole blood samples (200 μl) were collected from the canulated jugular vein and stored in heparinised cups. Oral absorption of DEPF-Gly and PFA were calculated relative to an intravenous dose of PFA in a cross-over design in 4 animals. The obtained figures of results were treated statistically to determine the standard deviation. After centrifugation, 20.0 μl plasma samples were taken and diluted with 180 μl 1 mM pyrophosphoric acid and
treated with about 20 mg activated charcoal. After intensive vortexing the samples were centrifuged for 15 min at 2000 g and the supernatant was brought into vials for a sample processor (Waters WISP 710B). Phosphonoformic acid plasma standards (ranging from 0.5 μM to 1 mM) prepared with rat plasma, were used to quantify the concentration of phosphonoformic acid in the samples.
Immediately after the workup procedure the samples were injected onto a HPLC system consisting of an LDC analytical ConstaMetric®3200 solvent delivery system with a built-in pulse dampener (Laboratory Data Control, Riviera Beach, FI, USA), a WISP 710B autosampler, a Kratos Spectroflow 773 variable wavelength UV detector operating at 230 nm, and an ESA Coulochem®II electrochemical detector (ESA Inc, Bedford, MA, USA) with a model 5011 high sensitivity analytical cell. The potentials on the analytical cell were set at +0.75 and +0.95 V for channels 1 and 2, resp. The mobile phase (flow rate 0.7 ml/min) was a pH 5.8 phosphate buffer-methanol (75:25, v:v) mixture with 1 mM tetrahexylammonium hydrogen sulfate as ion pair creator and 0.2 mM pyrophosphoric acid to prevent peak tailing. The total concentration of phosphate in the mobile phase was 43 mM. The analytical column, a Merck LiChrospher® 100 RP 18 (5μm; E Merck
Nederland BV, Amsterdam, NL) was held at a constant temperature of 37°C.
Under these conditions phosphonoformic acid showed a retention time of 8.5 min.
The oral absorption of the derivative of PFA was tested compared to the oral absorption of PFA in an aqueous solution. Both oral administrations were compared to an intravenous dose of PFA to calculate the absolute bioavailability
(Fabs). All doses were equimolar (180 μmol/kg). Solutions for i.v. and p.a.
administration were 120 mM in sterile normal saline with respect to PFA or DEPF- Gly. From Fig. 1 it can be seen that the plasma concentration after oral
administration of DEPF-Gly reaches a Cmax of 0.18 mM as compared to Cmax of
0.05 mM for PFA in aqueous solution. The bioavailability measured as Fabs is 0.64 for DEPF-Gly as compared to 0.19 for PFA in aqueous solution which corresponds to an over 3-fold increase. The time to reach Cmax was 1.5 h for DEPF-Gly and 1.25 h for PFA. For a compilation of results see Table 1.
Table 1
Dose AUC
Compound (umol/kg) Route (mM•h) Fabs
PFA 180 i.v. 0.58 ± 0.05 -
PFA 180 p.o. 0.10 ± 0.02 0.19 ± 0.04
DEPF-Gly 180 p.o. 0.37 ± 0.05 0.64 ± 0.12
In vitro intestinal transport study Transport of DEPF-Gly across living intestinal tissue was performed in Ussing chambers (Ussing, H.H. and Zehran, K., Acta Physiol. Scand. 23:110-127(1951)) in the following way: Rat intestine (Wistar rats, breed U:WU) was stripped of its underlying muscle layer, placed between two Lucite® chambers and bathed on both sides with a TRIS-Ringer solution with a pH of 7.4 containing 10 mM glucose at the serosal side and 10 mM mannitol on the mucosal side. During transport studies tissue integrity was monitored using fluorescein as a fluorescent transport marker. The viability was monitored measuring potential difference and short-circuited current of the tissue. After equilibration during 45 min, PFA or DEPF-Gly was added to the donor side of the membrane at a concentration of 1 mM. For studies of the transport from the mucosal to the serosal side (m-to-s) the substance to be tested was added on the mucosal side and for transport in the opposite direction (s-to-m) it was added on the serosal side. At intervals of 30 min samples were taken from the acceptor phase up to 210 minutes. In order to maintain a constant volume, TRIS-Ringer solution
with 10 mM glucose for the mucosal to serosal side studies and Tris-Ringer solution with 10 mM mannitol for the serosal to mucosal side studies was added. The acceptor samples were assayed for PFA or DEPF-Gly using the HPLC assay described above.
Fig. 2 illustrates the transport of PFA and DEPF-Gly at a donor concentration of 1 mM during a period of 210 minutes over rat jejunum. A higher m-to-s (closed symbols) transport rate than s-to-m (open symbols) transport rate was observed. This suggests that in transport from the mucosal to serosal side another mechanism is involved in addition to passive diffusion.
Example 1
Di-(O-ethyl)phosphonoformylglycine was prepared in two steps in the following way:
Step 1
Preparation of di-(0-ethyl)phosphonoformylglycine-ethyl ester (DEPF-Gly-OEt; Mw 267).
Dioxane was refluxed overnight over cuprous chloride (CuCl) and freshly distilled before use. 6.3 ml (47.9 mmol: 1.2 eq) trimethylsilyl azide (TMSA) was slowly added to 50 ml dioxane under an argon atmosphere. 5 ml (39.7 mmol; 1 eq) ethyl malonyl chloride (EMC) was slowly added to this mixture under continuous stirring. After 15 minutes the temperature was raised to 90-100°C. Vigorous stirring of the yellow solution resulted in the escape of nitrogen bubbles, which stopped after 3 hours. Trimethylsilyl chloride (TMSC; b.p. 56-57°C) formed during the reaction destilled off. Then 6.2 ml (48.1 mmol; 1.2 eq) diethylphosphite (DEP) was added dropwise to the resulting reaction mixture and was refluxed for 1.5 hrs.
Dioxane was removed under reduced pressure to give a thick yellow liquid (78% yield).
A sample was further purified by extraction from DCM to give a pale yellow liquid.
Bp 172°C;
n=1.398;
1H-NMR (300 MHz, DMSO-d6) δ(ppm) 1.1 (t, 6H), 1.3 (t, 3H), 4.45 (m,
6H), 3.6 (m, 2H); EI-MS; 267 (M/Z);
FAB-MS: 268 (M+l);
FT-IR (cm- 1): 3271 (m, NH), 3000 (s, CH2/CH3), 1752 (s, C=O aliphatic ester), 1662 (s, NHCO), 1520 (m, NHCO), 1250 (s, P=O), 1200 (s, P-O),
875 (s, CH2/CH3).
Step 2
Preparation of di-(0-ethyl)phosphonoformylglycine(DEPF-Gly; Mw 239).
0.782 g DEPF-GlyOEt was dissolved in 1 ml water. This mixture was poured into 2.0 ml 0.1 M borate-buffer (pH 8) and 70 μl (200 units) porcine liver esterase (PLE; carboxylic ester hydrolase; EC 3.1.1.1) was added conforming with Sigma PLE product information. This mixture was stirred overnight keeping the pH at 8 by adding 0.1M NaOH-solution. The reaction was stopped by adding 5.0 ml dichloromethane (DCM) to the mixture which denaturated the esterase. After filtration of the brown precipitate the aqueous layer was extracted three times with DCM. The aqueous layer was neutralised and further purified by silica gel chromatography which yielded 62% of compound DEPF-Gly as a white solid.
UV:λmax=208.3 nm;
Mp 160-162°C;
1H-NMR (300 MHz, DMSO-d6) δ(ppm) 1.2 (t, 6H), 4.1 (d, 4H), 3.85 (d, 2H), 8.7 (s, 1H);
FAB-MS: 240 (M+1);
FT-IR (cm-1): 3520 (w, OH), 3271 (m, NH), 3000 (s, CH2/CH3, 1662 (s,
NHCO), 1520 (m, NHCO), 1250 (s, P=O), 1200 (s, P-O), 875 (s, CH2/CH3).
The following examples illustrate the preparation of pharmaceutical compositions of the invention. The active substance is preferably used in the form of a solid salt where such salts can be formed and most preferably in the form of its sodium salt.
Example 2
Tablets Each tablet contains: active substance 300.0 mg lactose 200.0 mg maize starch 25.0 mg gelatin 1.5 mg talc 12.0 mg magnesium stearate 1.5 mg
Example 3
Coated tablets Tablets according example 2 are coated with an enteric coating solution with the following composition: ethyl cellulose 120.0 g propylene glycol 30.0 g sorbitan monooleate 10.0 g water ad 1000.0 ml
The coating is carried out by a pouring procedure in a conventional coating pan or by spraying the tablets in a pan spray tablet coater.
Example 4
Gastric juice-resistant tablets Tablets according example 2 are coated with a coating solution with the following composition: cellulose acetate phtalate 120.0 g propylene glycol 30.0 g sorbitan monooleate 10.0 g ethanol 95% 450.0 ml acetone q.s. ad 1000.0 ml
The coating is carried out by a pouring procedure in a conventional coating pan or by spraying the tablets in a pan spray tablet coater.
Example 5
Syrup active substance 12.0 g liquid glucose 30.0 g sucrose 40.0 g ascorbic acid 0.1 g disodium edetate 10.0 mg lemon essence 25.0 mg purified water ad 100.0 g
Example 6 Powder for suspension (Sachet)
Each sachet contains: active substance 3.0 g citric acid anhydrous 0.5 g glucose 2.5 g
Example 7
Capsules
Each capsule contains: active substance 300.0 mg microcrystalline cellulose 150.0 mg colloidal silicium oxide 5.0 mg
Example 8
Solution for injection active substance 5.0 g disodium edetate 2.5 mg sodium chloride for isotonia q.s. hydrochloric acid to pH 6.5-7
sterile water for injection ad 100.0 ml
Example 9
Suppositories Each suppository contains: active substance 500.0 mg adeps solidus q.s.
Claims
Claims
1. A compound of the formula I
wherein R1 and R2 each independently are hydrogen; a branched or unbranched C1-6-alkyl, C2-6-alkenyl, C2-6alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl or C1-6-alkoxy-C1-6-alkyl group which is optionally substituted with hydroxy, amino, halogen or oxo; a benzyl group; a group or a group
wherein R3 is a branched or unbranched C1-6- alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl or C1-6-alkoxy-C1-6- alkyl group which is optionally substituted with hydroxy, amino, halogen or oxo; and R4 is hydrogen or a C1-4-alkyl group;
or wherein R1 and R2 together form a group
A is an amino acid residue which is selected from glycyl, alanyl, valyl, morvalyl, leucyl, isoleucyl, norleucyl, phenylalenyl, tyrosyl, seryl, homoseryl, threonyl, cysteinyl, methionyl, tryptophyl, α-aspartyl, α-glutamyl, arginyl, lysyl, histidyl omithyl, prolyl or 4-hydroxyprolyl either in the L- or in the D-configuration; or physiologically acceptable salts thereof.
2. A compound according to claim 1 wherein A is a glycyl residue.
3. A compound according to claim 1 wherein A is a L-alanyl residue.
4. A compound according to claim 1 wherein A is a L-phenylalanyl residue.
5. A compound according to claim 1 wherein A is a L-prolyl residue.
6. A compound according to claim 1 wherein A is a L-4-hydroxyprolyl residue.
7. A compound according to claim 1 wherein A is a L-tyrosyl residue. 8. A compound according to claim 1 wherein R1 and R2 are ethyl.
9. A process for the preparation of a compound of the formula I as defined in claim 1, characterized by A. reaction of a compound of the formula II
wherein R1 and R2 have the meaning given above and R7 is an aliphatic cycloaliphatic, araliphatic, aromatic or heterocyclic leaving group, such as C1-6-alkoxy, C3-8-cycloalkoxy, benzyloxy, phenoxy, 4-nitrophenoxy, imidazolyl or succinimidoxy with an amino acid derivative H-A-OR6, wherein A has the meaning given above and R6 is a suitable protecting group such as methyl, ethyl or benzyl, followed by removal of the protecting group R6 to give a compound of the formula I, or B. reaction of a compound of the formula III
wherein R6 has the meaning given above and R8 is the side chain specific for an amino acid residue A as defined in claim 1, followed by removal of the protecting group R6 to give a compound of the formula I, or
C. esterification of a compound of the formula V
with an alcohol R1OH, wherein A, R1 and R6 have the meaning given above, followed by removal of the protecting group R6 to give a compound of the formula I where R1=R2, or
D. esterification of a compound of the formula VI
with an alcohol R1OH, wherein A, R1, R2 and R6 have the meaning given above, followed by removal of the protecting group R6 to give a compound of the formula
I, or
E. reaction of a compound of the formula VII
with a compound R1-X, wherein A, R1 and R6 have the meaning given above, M+ is a cation such as Ag+, Li+, Na+, K+, Cs+, Et3NH+, (i-Pr)2NEtH+ and X is a halogen such as Cl, Br or I, followed by removal of the protecting group R6 to give a compound of the formula I where R1=R2, or
F. reaction of a compound of the formula VIII
with a compound R1-X, wherein A, R1 , R2, R6, M+ and X have the meaning given above, followed by removal of the protecting group R6 to give a compound of the formula I, or G. reacting a compound of the formula IX
with an alcohol R1OH, wherein A, R1, R6 and X have the meaning given above, followed by removal of the protecting group R6 to give a compound of the formula I where R1=R2, or
H. reacting a compound of the formula X
with an alcohol R1OH, wherein A, R1, R2, R6 and X have the meaning given above, followed by removal of the protecting group R6 to give a compound of the formula I, or
J. aqueous hydrolysis of a compound of the formula XI containing two silylated phosphonate groups
wherein A and R6 have the meaning given above, and R9 is an inert organic residue, for example methyl, followed by removal of the protecting group R6 to give a compound of the formula I where R1=R2=H, or
K. hydrogenation of a compound of the formula XIII
wherein A and R6 have the meaning given above, followed by removal of the protecting group R6 to give a compound of the formula I where R1=R2=H, or
L. reacting a compound of the formula XIV
with iodide or bromide anion, wherein A, R1 and R6 have the meaning given above, and R10 has the meaning given R1 and R2, followed by removal of the protecting group R6 to give a compound of the formula I where R2=H, or M. aqueous hydrolysis of a compound of the formula XV containing one silylated phosphonate group
wherein A, R1 , R6 and R9 have the meaning given above, followed by removal of the protecting group R6 to give a compound of the formula I where R2=H, or
N. monoesterification of a compound of the formula V
with an alcohol R1OH, wherein A, R1 and R6 have the meaning given above, followed by removal of the protecting group R6 to give a compound of the formula I where R2=H.
10. A compound according to the formula
acid or a peptide, and which is able to form an amide bond with an amino acid, and A is defined as in claim 1.
11. A compound according to any of claims 1 to 8 or 10 for use in therapy.
12. A compound according to any of claims 1 to 8 for use in the treatment of viral infections.
12. A compound according to any of claims 1 to 8 for use in the treatment of herpesvirus infections.
13. A compound according to any of claims 1 to 8 for use in the treatment of HIV infections including the state of AIDS.
14. A compound according to claim 10, wherein D-COOH is an antibacterial drag for use in the treatment of bacterial infections. 15. A compound according to claim 10 wherein D-COOH is an analgesic drug for use in the treatment of pain.
16. A compound according to claim 10 wherein D-COOH is an antirheumatic drug for use in the treatment of arthritis.
17. A compound according to claim 10, wherein D-COOH is an antiphlogistic drag for use in the treatment of inflammatory diseases.
18. A compound according to claim 10, wherein D-COOH is an oncolytic drag for use in the treatment of tumors.
19. A compound according to claim 10, wherein D-COOH is a drag of the prostaglandin group for use in the control of acid secretion in the stomach. 20. A compound according to claim 10, wherein D-COOH is a drag of the prostaglandin group for use in the control of smooth muscle contractions in the uterus.
21. A compound according to claim 10, wherein D-COOH is a diuretic drag for use in increasing diuresis.
22. The use of a compound according to any of claims 1 to 8 in the manufacture of a formulation for the treatment of viral infections.
23. The use of a compound according to any of claims 1 to 8 in the manufacture of a formulation for the treatment of herpesvirus infections.
24. The use of a compoud according to any of claims 1 to 8 in the manufacture of a formulation for the treatment of HIV including the state of AIDS. 25. The use of a compound according claim 10, wherein D-COOH is an
antibacterial drag in the manufacture of a formulation for the treatment of bacterial infections.
26. The use of a compound according to claim 10, wherein D-COOH is an analgesic drug in the manufacture of a formulation for the treatment of pain.
27. The use of a compound according to claim 10, wherein D-COOH is an antirheumatic drag in the manufacture of a formulation for the treatment of arthritis.
28. The use of a compound according to claim 10, wherein D-COOH is an antiphlogistic drag in the manufacture of a formulation for the treatment of inflammatory diseases. 29. The use of a compound according claim 10, wherein D-COOH is an oncolytic drug in the manufacture of a formulation for the treatment of tumors.
30. The use of a compound according to claim 10, wherein D-COOH is a drag of the prostaglandin group in the manufacture of a formulation for the control of acid secretion in the stomach.
31. The use of a compound according to claim 10, wherein D-COOH is a drag of the prostaglandin group in the manufacture of a formulation for the control of smooth muscle contraction in the uterus. 32. The use of a compound according to claim 10, wherein D-COOH is a diuretic drag in the manufacture of a formulation for the increasing diuresis.
33. A method for the treatment of herpesvirus infection wherein a therapeutically active amount of a compound according to any of claims 1 to 8 is administered to a mammal in the need of such treatment.
34. A method for the treatment of HIV infections including AIDS wherein a therapeutically active amount of a compound according to any of claims 1 to 8 is administered to a mammal in the need of such treatment
35. A method for the treatment of bacterial infections wherein a therapeutically active amount of a compound according to claim 10, wherein D-COOH is an antibacterial drug is administered to a mammal in the need of such. 36. A method for the treatment of pain wherein a therapeutically active amount of a compound according to claims 10, wherein D-COOH is an analgesic drag is administered to a mammal in the need of such treatment
38. A method for the treatment of arthritis wherein a therapeutically active amount of a compound according to claim 10, wherein D-COOH is an antireeumatic drag is administered to a mammal in the need of such treatment.
39. A method for the treatment of inflammatory diseases wherein a therapeutically active amount of a compound according to claim 10, wherein D-COOH is an antiphlogistic drug is administered to a mammal in the need of such treatment
40. A method for the treatment of tumors wherein a therapeutically active amount of a compound according to claim 10, wherein D-COOH is an oncolytic drag is administered to a mammal in the need of such treatment. 41. A method for the control of acid secretion in the stomach wherein a therapeutically active amount of a compound according to claim 10, wherein D-COOH is a drag of the prostaglandin group is administered to a mammal in the need of such treatment. 42. A method for the control of contractions in the uterus wherein a therapeutically active amount of a compound according to claim 10, wherein D-COOH is a drug of the prostaglandin group is administered to a mammal in the need of such treatment. 43. A method for increasing diuresis wherein a therapeutically active amount of a compound according to claim 10, wherein D-COOH is a diuretic drag is administered to a mammal in the need of such treatment.
44. The use of an amino acid moiety A-OH in the preparation of prodrugs of the general formula
45. The use of an amino acid as agent to be linked by an amide bond to form a compound of the general formula
wherein is defined as in claim 10
for increasing the uptake via the gastrointestine into the blood of the parent drag D-COOH.
46. A compound of the formula
wherein R1, R2, R6 and A have the meaning given in claims 1 and 9.
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AU57226/94A AU5722694A (en) | 1993-11-05 | 1993-11-05 | Novel amino acid derivatives |
PCT/SE1993/000930 WO1995012604A1 (en) | 1993-11-05 | 1993-11-05 | Novel amino acid derivatives |
AU58251/94A AU5825194A (en) | 1993-11-05 | 1993-11-19 | Novel amino acid derivatives |
PCT/SE1993/000998 WO1995012605A1 (en) | 1993-11-05 | 1993-11-19 | Novel amino acid derivatives |
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PCT/SE1993/000930 WO1995012604A1 (en) | 1993-11-05 | 1993-11-05 | Novel amino acid derivatives |
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PCT/SE1993/000998 WO1995012605A1 (en) | 1993-11-05 | 1993-11-19 | Novel amino acid derivatives |
Country Status (2)
Country | Link |
---|---|
AU (2) | AU5722694A (en) |
WO (2) | WO1995012604A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000030653A2 (en) * | 1998-11-25 | 2000-06-02 | Jomaa Pharmaka Gmbh | Use of phosphonoformic acid derivatives for treating infections |
WO2001026661A1 (en) * | 1999-10-11 | 2001-04-19 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions comprising oxophosphonate-based metalloproteinase inhibitors |
US6458772B1 (en) | 1909-10-07 | 2002-10-01 | Medivir Ab | Prodrugs |
WO2002078714A1 (en) * | 2001-03-30 | 2002-10-10 | Jomaa Pharmaka Gmbh | Formulations which are resistant to gastric juice and are used to apply anti-infective compounds inhibiting the 2-c-methylerythrose-4 metabolic pathway, and the salts and esters of the same |
Families Citing this family (9)
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US7018654B2 (en) | 1999-03-05 | 2006-03-28 | New River Pharmaceuticals Inc. | Pharmaceutical composition containing an active agent in an amino acid copolymer structure |
US6716452B1 (en) | 2000-08-22 | 2004-04-06 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
US7060708B2 (en) | 1999-03-10 | 2006-06-13 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
US7375082B2 (en) | 2002-02-22 | 2008-05-20 | Shire Llc | Abuse-resistant hydrocodone compounds |
US7338939B2 (en) | 2003-09-30 | 2008-03-04 | New River Pharmaceuticals Inc. | Abuse-resistant hydrocodone compounds |
US7105486B2 (en) | 2002-02-22 | 2006-09-12 | New River Pharmaceuticals Inc. | Abuse-resistant amphetamine compounds |
KR100822498B1 (en) | 2002-02-22 | 2008-04-16 | 샤이어 엘엘씨 | Novel Sustained Release Pharmaceutical Compounds to Prevent Abuse of Controlled Substances |
NZ544162A (en) | 2003-05-29 | 2008-09-26 | Shire Llc | Abuse resistant amphetamine compounds |
KR100915284B1 (en) | 2003-09-30 | 2009-09-03 | 샤이어 엘엘씨 | Pharmaceutical compositions for prevention of overdose or abuse |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0003008A1 (en) * | 1977-12-22 | 1979-07-11 | Astra Läkemedel Aktiebolag | Amide derivatives of phosphonoformic acid, pharmaceutical compositions and methods for combating virus infections |
US4357329A (en) * | 1980-07-11 | 1982-11-02 | Bayer Aktiengesellschaft | Combating pests with N-phosphonylcarbonyl-carbamates |
DD242811A1 (en) * | 1985-11-21 | 1987-02-11 | Univ Halle Wittenberg | METHOD FOR PRODUCING N-SUBSTITUTED N-PHOSPHONOFORMYLAMINOSAURES AND THEIR DERIVATIVES |
-
1993
- 1993-11-05 AU AU57226/94A patent/AU5722694A/en not_active Abandoned
- 1993-11-05 WO PCT/SE1993/000930 patent/WO1995012604A1/en unknown
- 1993-11-19 AU AU58251/94A patent/AU5825194A/en not_active Abandoned
- 1993-11-19 WO PCT/SE1993/000998 patent/WO1995012605A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0003008A1 (en) * | 1977-12-22 | 1979-07-11 | Astra Läkemedel Aktiebolag | Amide derivatives of phosphonoformic acid, pharmaceutical compositions and methods for combating virus infections |
US4357329A (en) * | 1980-07-11 | 1982-11-02 | Bayer Aktiengesellschaft | Combating pests with N-phosphonylcarbonyl-carbamates |
DD242811A1 (en) * | 1985-11-21 | 1987-02-11 | Univ Halle Wittenberg | METHOD FOR PRODUCING N-SUBSTITUTED N-PHOSPHONOFORMYLAMINOSAURES AND THEIR DERIVATIVES |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6458772B1 (en) | 1909-10-07 | 2002-10-01 | Medivir Ab | Prodrugs |
US6974802B2 (en) | 1998-02-13 | 2005-12-13 | Medivir Ab | Treatment of viral infections using prodrugs of 2′,3-dideoxy,3′-fluoroguanosine |
US7071173B2 (en) | 1998-02-13 | 2006-07-04 | Medivir Ab | Antiviral methods employing double esters of 2′, 3′-dideoxy-3′-fluoroguanosine |
US7825238B2 (en) | 1998-02-13 | 2010-11-02 | Medivir Ab | Antiviral methods employing double esters of 2′, 3′-dideoxy-3′-fluoroguanosine |
WO2000030653A2 (en) * | 1998-11-25 | 2000-06-02 | Jomaa Pharmaka Gmbh | Use of phosphonoformic acid derivatives for treating infections |
WO2000030653A3 (en) * | 1998-11-25 | 2000-11-16 | Hassan Jomaa | Use of phosphonoformic acid derivatives for treating infections |
WO2001026661A1 (en) * | 1999-10-11 | 2001-04-19 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions comprising oxophosphonate-based metalloproteinase inhibitors |
JP2003511418A (en) * | 1999-10-11 | 2003-03-25 | イサム・リサーチ・デベロツプメント・カンパニー・オブ・ザ・ヘブルー・ユニバーシテイ・オブ・エルサレム | Compositions comprising oxophosphonate-based metalloproteinase inhibitors |
US7468359B2 (en) | 1999-10-11 | 2008-12-23 | Yissum Research Develpment Company Of The Hebrew University Of Jerusalem | Compositions comprising oxophosphonate-based metalloproteinase inhibitors |
WO2002078714A1 (en) * | 2001-03-30 | 2002-10-10 | Jomaa Pharmaka Gmbh | Formulations which are resistant to gastric juice and are used to apply anti-infective compounds inhibiting the 2-c-methylerythrose-4 metabolic pathway, and the salts and esters of the same |
Also Published As
Publication number | Publication date |
---|---|
WO1995012605A1 (en) | 1995-05-11 |
AU5825194A (en) | 1995-05-23 |
AU5722694A (en) | 1995-05-23 |
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