GB1577232A - Peptide derivatives of phosphonic and phosphinic acids - Google Patents
Peptide derivatives of phosphonic and phosphinic acids Download PDFInfo
- Publication number
- GB1577232A GB1577232A GB20014/76A GB2001476A GB1577232A GB 1577232 A GB1577232 A GB 1577232A GB 20014/76 A GB20014/76 A GB 20014/76A GB 2001476 A GB2001476 A GB 2001476A GB 1577232 A GB1577232 A GB 1577232A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alanyl
- alanylamino
- group
- acid
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
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- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229950003188 isovaleryl diethylamide Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1027—Tetrapeptides containing heteroatoms different from O, S, or N
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
(54) PEPTIDE DERIVATIVES OF PHOSPHONIC
AND PHOSPHINIC ACIDS
(71) We, ROCHE PRODUCTS
LIMITED, a British Company of
Broadwater Road, Welwyn Garden City,
Hertfordshire, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to peptide derivatives. More particularly, the invention is concerned with peptide derivatives of phosphonic and phosphinic acids, a process for the manufacture thereof and pharmaceutical preparations containing same.
The peptide derivatives provided by the present invention are compounds of the general formula
wherein n is 1, 2 or 3; R', R2 and R3 each represent the characterising group of an aamino acid of the type found in proteins with the provisos that R3 represents other than a hydrogen atom and that R3 represents a methyl group when n is 1; R4 represents a hydroxy or methyl group; the configuration at the carbon atom designated as (a) is D; the configuration at the carbon atom designated as (b) is L when R2 represents other than a hydrogen atom; and the configuration at the carbon atom denoted as (c) is (R) when R' represents other than a hydrogen atom, and pharmaceutically acceptable salts thereof
As used in this specification, the expression "the characterising group of an a-amino acid of the type found in proteins" means the residue R in a natural a-amino acid of the general formula
which is of the type occurring in proteins.
Thus, for example, if the amino acid is glycine then R represents a hydrogen atom and if the amino acid is alanine then R represents the methyl group. In valine R represents the isopropyl group, in leucine represents the isobutyl group and in glutamic acid R represents the 2carboxyethyl group and in phenylalanine
R represents the benzyl group. R can also represent a residue which is linked with the amino nitrogen (with the loss of one of the hydrogen atoms attached thereto), thus forming a nitrogen-containing ring such as in proline and pyroglutamic acid.
When R1 in formula I represents other than a hydrogen atom, the configuration at the carbon atom denoted as (c) is (R); that is to say, the configuration which would be obtained by replacing the carboxyl group of a naturally occurring L a-amino acid by a phosphorus moiety.
It will be appreciated that when n in formula I hereinbefore is 2 or 3, the value of
R2 can be the same or different.
Preferred compounds of formula I hereinbefore are those in which R4 represents a hydroxy group. Also preferred are those compounds of formula I in which
R' represents a methyl group as well as those compounds of formula I in which R2 represents a methyl group and R3 represents a methyl, isopropyl or isobutyl group.
Examples of compounds of formula I are the following: (IR) - I - (D - alanyl - L alanylamino) - ethylphosphonic acid,
(IR) - 1 - (D - alanyl - L alanyl - L alanylamino) - ethylphosphonic acid,
(IR) - I - (D - valyl - L - alanyl alanylamino) - ethylphosphonic acid,
(IR) - 1 - (D - leucyl - L - alanyl - L alanylamino) - ethylphosphonic acid and (lR) - 1 - (D - alanyl - L - alanyl - L alanyl - L - alanylamino) ethylphosphonic acid.
According to the process provided by the present invention, the peptide derivatives aforesaid (i.e. the compounds of formula I and their pharmaceutically acceptable salts) are manufactured by
(a) cleaving off the protecting group(s) present in a compound of the general formula
wherein n has the significance given earlier; R'O, R20 and R30 have any of the values accorded to R1, R2 and R3 hereinbefore respectively except that any amino group or amino groups present may be in protected form and any other functional group which may be present is optionally protected; R40 represents a methyl group or R4'; R41 represents a hydroxy group or lower alkoxy protecting group; R5 represents a hydrogen atom or a protecting group; at least one protecting group is present the configuration at the carbon atom designated as (a) is D; the configuration at the carbon atom designated as (b) is L when R20 represents other than a hydrogen atom; and the configuration at the carbon atom designated as (c) is (R) when
R10 represents other than a hydrogen atom, or
(b) separating an (R,S).diastereomeric compound corresponding to formula I into its diastereomers and isolating the (R)diastereomer, and, if desired, converting an obtained compound of formula I into a pharmaceutically acceptable salt.
The compounds of general formula II also form part of the invention.
An amino group or amino groups which may be present in R'O, R20 and R30 in formula 11 can be protected with any aminoprotecting group which is well-known in peptide chemistry. Especially suitable amino-protecting groups for the purpose of the present invention are aralkoxycarbonyl groups, particularly the benzyloxycarbonyl group, and the tert-butoxycarbonyl group.
The amino-protecting group may also be a formyl, trityl or trifluoroacetyl group. Any carboxy or hydroxy group which may be present in R'O, R20 and R30 in formula 11 can be protected by a conventional carboxyprotecting or hydroxy-protecting group respectively. For example, a carboxy group may be protected by conversion into an alkyl ester (e.g. a tert-butyl ester) or an aralkyl ester (e.g. a benzyl ester). Again, for example, a hydroxy group may be protected, for example, by means of an aralkoxycarbonyl group (e.g.
benzyloxycarbonyl), an alkanoyl group (e.g.
acetyl, propionyl), an aroyl group (e.g.
benzoyl), an alkyl group (e.g. tert-butyl) or an aralkyl group (e.g. benzyl). The protection of other functional groups present in R'O, R20 and R30 may be carried out in a known manner. The protecting group denoted by R5 in formula II can be any of the amino-protecting groups mentioned earlier in connection with R'O, R20 and R30.
The cleavage of the protecting group or protecting groups present in a compound of formula 11 is carried out in accordance with methods known per se; that is to say, methods in actual use for or described in the literature on the cleavage of protecting groups. Thus, for example, an aralkoxycarbonyl group (e.g.
benzyloxycarbonyl) or a tertbutoxycarbonyl group may be cleaved off by hydrolysis (e.g. treatment with a mixture of hydrogen bromide and glacial acetic acid). An aralkoxy-carbonyl group (e.g.
benzyloxycarbonyl) can also be cleaved off by hydrogenolysis (e.g. in the presence of palladium-on-charcoal or palladium oxide).
The tert-butoxycarbonyl group may also be cleaved off by means of hydrogen chloride in dioxan. A lower alkoxy group denoted by
R40 and/or R4' can be straight-chain or branched-chain alkoxy group containing from 1 to 6 carbon atoms (e.g. methoxy, ethoxy, propoxy, isoproxy, butoxy) and may be converted into a hydroxy group by treatment with a mixture of hydrogen bromide in glacial acetic acid or by means of trimethylchlorosilane followed by aqueous hydrolysis. It will be appreciated that the cleavage of the protecting groups can be carried out in a single step or in more than one step depending on the nature of the protecting groups present.
The separation of an (R,S) diastereomeric compound corresponding to formula I into its diastereomers and isolation of the (R)diastereomer can be carried out according to known methods; for example, by fractional crystallisation or by high pressure liquid chromatography.
Compounds of formula I are amphoteric in nature and form pharmaceutically acceptable salts with strong acids (e.g.
methanesulphonic acid, paratoluenesulphonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid) and with bases (e.g. sodium hydroxide).
The starting materials of formula II hereinbefore may be prepared, for example, by condensing a compound of the general formula
wherein m is zero, 1, 2 or 3; R10, R20, R40 and R41 have the significance given earlier; the configuration at the carbon atom designated as (b) is L when R20 represents other than a hydrogen atom; and the configuration at the carbon atom designated as (c) is (R) when R'O represents other than a hydrogen atom, with an appropriately protected a-amino acid, an appropriately protected dipeptide, an appropriately protected tripeptide, an appropriately protected tetrapeptide or a reactive derivative thereof as the case may require.
Thus, a compound of formula III in which m is zero can be condensed with an appropriately protected dipeptide or a reactive derivative thereof to give a compound of formula II in which n is 1, or with an appropriately protected tripeptide or a reactive derivative thereof to give a compound of formula II in which n is 2 or with an appropriately protected tetrapeptide or a reactive derivative thereof to give a compound of formula II in which n is 3.
Again, a compound of formula III in which m is 1 can be condensed with an appropriately protected a-amino acid or a reactive derivative thereof to give a compound of formula II in which n is 1, or with an appropriately protected dipeptide or a reactive derivative thereof to give a compound of formula II in which n is 2 or with an appropriately protected tripeptide or a reactive derivative thereof to give a compound of formula II in which n is 3.
Yet again, a compound of formula III in which m is 2 can be condensed with an appropriately protected a-amino acid or a reactive derivative thereof to give a compound of formula II in which n is 2 or with an appropriately protected dipeptide or a reactive derivative thereof to give a compound of formula II in which n is 3.
Finally, a compound of formula III in which m is 3 can be condensed with an appropriately protected a-amino acid or a reactive derivative thereof to give a compound of formula II in which n is 3.
Alternatively, the compounds of formula
II can be prepared by carrying out the foregoing condensation using an (R, S) compound corresponding to formula III and separating the (R) compound from the resulting (R,S) product in a manner known per se; for example, by crystallisation, chromatography or fractional crystallisation using a suitable base such as amethylbenzylamine.
The aforementioned condensation can be carried out in accordance with methods which are known per se in peptide chemistry; for example, by the mixed anhydride, azide, activated ester or acid chloride method.
In one method, an appropriate compound of formula III can be condensed with an appropriately protected a-amino acid, di-, tri- or tetrapeptide as the case may require in which the terminal carboxy function is a mixed anhydride residue formed with an organic or inorganic acid. Suitably, such an amino acid, di-, tri- or tetrapeptide carrying a free carboxy function is treated with a tertiary base such as a tri (lower (C1-C6) alkyl) amine (e.g. triethylamine) or N ethylmorpholine in an inert organic solvent (e.g. tetrahydrofuran, 1,2 - dimethoxy ethane, dichloromethane, toluene, petroleum ether or mixtures thereof) and the resulting salt is reacted with a chloroformic acid ester (e.g. the ethyl or isobutyl ester) at a low temperature. The mixed anhydride obtained is then suitably condensed in situ with the compound of formula III.
In another method, an appropriate compound of formula III can be condensed with an appropriately protected a-amino acid, di-, tri or tetrapeptide as the case may require in which the terminal carboxy group is in the form of an acid azide. This condensation is preferably carried out in an inert organic solvent such as dimethylformamide or ethyl acetate at a low temperature.
In yet another method, an appropriate compound of formula III can be condensed with an appropriately protected a-amino acid, di-, tri- or tetrapeptide as the case may require in which the terminal carboxy function is in the form of an active ester group (e.g. the p-nitrophenyl, 2,4,5 trichlorophenyl or N - hydroxysuccinimide ester group). This condensation is suitably carried out either in an inert organic solvent such as dimethylformamide or, in the case where R40 and/or R4' represents a lower alkoxy group, in an aqueous alkanol (e.g.
aqueous ethanol).
In a further method, an appropriate compound of formula III can be condensed with an appropriately protected a-amino acid, di-, tri-, or tetrapeptide as the case may require in which the terminal carboxy function is in the form of an acid chloride.
This condensation is preferably carried out in the presence of a base and at a low temperature.
The peptide derivatives provided by the present invention potentiate the activity of
D-cycloserine. In addition, they possess an antibacterial activity against organisms such as Escherichia coli, Kiebsiella aerogenes,
Streptococcus faecalis and Haemophilus in flu enzae.
The present peptide derivatives may accordingly be used as medicaments; for example, in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic carrier material suitable for enteral (e.g. oral) or parenteral administration. Examples of such carrier materials are water, lactose, starch, magnesium stearate, gum arabic, gelatin, polyalkyleneglycols and petroleum jelly.
The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragees, suppositories or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilisation and may contain adjuvants such as preservatives, stabilisers, wetting agents or salts for altering the osmotic pressure.
The peptide derivatives provided by the present invention can be administered in combination with D - cycloserine, and a pharmaceutical preparation containing a peptide derivative as set forth above, D cycloserine and a compatible carrier material also forms part of the invention.
Alternatively, the peptide derivative and
D - cycloserine can be administered separately, if necessary by different routes.
The amount of peptide derivative to be administered as well as the ratio in which the peptide derivative and D - cycloserine can be administered can vary within wide limits depending on such factors as the particular derivative chosen, the route of administration and the organism to be combatted. For example, the peptide derivative and D - cycloserine may be administered in a ratio, by weight of from ca 100:1 to 1:100.
The following Examples illustrate the process provided by the present invention; the percentages given are by weight, and "ether" means "diethyl ether".
Example 1 (A) The preparation of the starting material:
(i) 14.1 g (0.168 mol) of solid sodium bicarbonate were added to a solution of 7 g (0.056 mol) of (lR,S) - 1 - aminoethylphosphonic acid in 280 ml of water and 140 ml of ethanol while stirring at 0 C. While stirring this mixture at OOC, a solution of 17.9 g (0.056 mol) of the N hydroxysuccinimide ester of N benzyloxycarbonyl - L - alanine in 140 ml of warm ethanol was added dropwise over a period of ca 15 minutes. The latter solution was washed in with 70 ml of ethanol. The heterogeneous mixture was stirred for 1 hour at OOC and then for a further 16 hours at room temperature, the mixture becoming homogeneous. The mixture was evaporated and re-evaporated with 200 ml of water to give a gum which was dissolved in 500 ml of water. The solution was extracted firstly with 500 ml of chloroform and then twice with 250 ml of chloroform each time, acidified to pH 2 with ca 80 ml of 2N hydrochloric acid and again extracted with 500 ml of chloroform and then twice with 250 ml of chloroform each time. The aqueous layer was concentrated and passed down a column of cation exchange resin (B.D.H., Zerolit (Trade Mark) 225, SRC 13, RSO3H; 750 g; freshly regenerated in the acid cycle). The column was eluted with water and six 250 ml fractions were collected. The first four fractions were combined, evaporated and re-evaporated with water in order to remove hydrogen chloride. There was obtained a final residue of (1 R,S) - 1 - [N - benzyloxy - carbonyl
L - alanyl)amino] - ethylphosphonic acid which was separated as follows:
The latter residue was dissolved in 400 ml of water and titrated with 1M benzylamine to pH 4.5; litre 75 ml; theory 56 ml. the solution obtained was concentrated and crystallised from water to give 5.3 g of the benzylamine salt of (1S)- 1 - [(N benzyloxycarbonyl - L - alanyl)aminol - ethylphosphonic acid of melting point 21- 215"C. Concentration of the mother liquors followed by further recrystallisation from water gave the benzylamine salt of (IR) - - [(N - benzyloxycarbonyl - L - alanyl) - amino] - ethylphosphonic acid in a first crop of 0.59 g [melting point 2260--2280C (decomposition); [a]20=-32.30 (c=1 /" in acetic acid)] and a second crop of 0.825 g [melting point 2250-2270C (decomposition); [(x]D =-33 0 (c=l% in acetic acid)l. Recrystallisation of the first crop from water gave 0.333 g of pure benzylamine salt of the R-stereoisomer; melting point 2260--2280C (decomposition); [a12 =-33 I (c=1 /" in acetic acid).
1.1 g (2.5 mmol) of the benzylamine salt of ( I R) - 1 - [(N - benzyloxycarbonyl - L alanyl)amino] - ethylphosphonic acid were dissolved in 4 ml of 2N ammonium hydroxide, passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 120 g; freshly regenerated in the acid cycle) and eluted with water. There were collected 200 ml of acid eluate which was concentrated to 100 ml. To this were added successively 100 ml of methanol, 0.3 g of 5% palladium-on-charcoal catalyst and 3 drops of glacial acetic acid. The mixture was hydrogenated at room temperature and at atmospheric pressure. The catalyst was filtered off and the solvent evaporated. The gum remaining was re-evaporated with three 50 ml portions of n-propanol to yield 0.6 g of a gummy solid having a melting point of ca 2750-2800C (decomposition).
After further recrystallisation from water and ethanol, there was obtained 0.2 g of (IR) - 1 - (L - alanylamino) ethylphosphonic acid of melting point 2950-2960C (decomposition); [al020=-44.00 (c=1 /n in water).
(ii) A solution of 30 g (0.24 mol) of (IR,S) - 1 - amino - ethylphosphonic acid in 120 ml (0.48 mol) of 4N sodium hydroxide was stirred at 14"C while 180 ml (0.72 mol) of a solution of 4N sodium hydroxide and 102 g (0.60 mol) of benzyl chloroformate were added alternately in four portions. The stirring was continued and, after a further 2 hours, the temperature had risen to 200C.
The mixture was stirred for a further 16 hours at room temperature. 600 ml of ether were then added and the mixture was stirred vigorously for 2 hours in order to extract the excess benzyl chloroformate. The layers were separated and the aqueous layer was acidified to pH 2 with ca 110 ml of 5N hydrochloric acid while maintaining the temperature at below 10 C. The resulting slurry was concentrated to a low bulk in order to remove carbon dioxide. The residue was dissolved in 100 ml of 2N sodium hydroxide and 50 ml of water, passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 750 g; freshly regenerated in the acid cycle) and eluted with water. There were obtained ca 3.2 litres of acid eluate which were evaporated at room temperature and reevaporated three times with 500 ml of water each time. The residue was dissolved in water and allowed to crystalline. The crystals were filtered off, washed with icecold water and dried; yield 39.2 g; melting point 111"--113"C (decomposition).
Evaporation of the combined filtrates followed by crystallisation from 75 ml of water and 10 ml of methanol and refrigeration gave a further yield of 6.51 g; melting point 110"--1 120C (decomposition). There was obtained a total of 45.71 g of (lR,S) - 1 (benzyloxycarbonyl - amino) ethylphosphonic acid which was characterised at the monobenzylamine salt having a melting point of 1960-1970C (decomposition).
42.2 g (164 mmol) of (lR,S) - 1 - (benzyloxycarbonyl - amino) ethylphosphonic acid were dissolved in 100 ml of methanol. The solution was treated with a solution of 30.8 g (81.5 mmol) of quinine trihydrate in 100 ml of methanol and the mixture was stored for 3 hours at room temperature and then overnight at 0 C. The quinine salt of (IS) - 1 (benzyloxycarbonyl - amino) ethylphosphonic acid was filtered off and washed with methanol. The combined filtrates were evaporated and the residue was dissolved in 300 ml of 2N ammonium hydroxide. The solution was extracted three times with 300 ml of chloroform each time.
Each chloroform extract was back-washed with 150 ml of water. The aqueous extracts were combined, concentrated and then passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 750 g; freshly regenerated in the acid cycle).
Elution with water gave ca 2.3 litres of acid eluate which was evaporated. The residue was re-evaporated, initially with three 200 ml portions of water and subsequently with three 300 ml portions of methanol. There were obtained ca 24 g of a residual gum.
This gum was dissolved in 100 ml of dry methanol and treated with a solution of dehydroabietylamine [82 mmol; freshly regenerated from 28.4 g (82 mmol) of dehydroabietylamine acetate with ammonium hydroxide/petroleum ether].
The mixture was left to stand at OOC, filtered and the filtrate washed with methanol and ether. There were obtained 47.4 g of crude dehydroabietylamine salt of (lR) - R) - (benzyloxycarbonyl - amino) ethylphosphonic acid of melting point 1890-1940C (decomposition); [a]D =+16.8 (c=0.5% in methanol). Further recrystallisation from methanol and water gave 33.0 g of the pure dehydroabietylamine salt of (lR) - 1 - (benzyloxycarbonyl amino) - ethylphosphonic acid of melting point 202 0--205 0 C (decomposition); [a]D =+18.1 (c=0.5 , in methanol).
8.0 g (14 mmol) of the dehydroabietylamine salt of (it) - 1 benzyloxycarbonyl - amino) ethylphosphonic acid were partitioned between 100 ml of 2N ammonium hydroxide and 100 ml of petroleum ether (boiling range 600--800C). The mixture was shaken vigorously and then the layers were separated. The aqueous layer was extracted twice with 50 ml of petroleum ether each time. Each of the petroleum ether extracts was back-washed twice with 50 ml of water each time. The aqueous extracts were combined and evaporated at room temperature to give an oil. This oil was dissolved in water, passed down a column of cation exchange resin (B.D.H., Zerolit 225,
SRC 13, RSO3H; 250 g; freshly regenerated in the acid cycle) and eluted with water.
There were obtained 800 ml of an acid eluate which was concentrated to 400 ml.
To this were added successively 2.0g of 10% palladium-on-charcoal catalyst, 400 ml of methanol and 0.2 ml of glacial acetic acid.
This mixture was then hydrogenated. The catalyst was filtered off and the solvent evaporated. The residue was re-evaporated three times with 100 ml of n-propanol each time and triturated with ether to give a solid having a melting point of ca 2850-2880C (decomposition). Recrystallisation from water and ethanol gave 1.0 g of (IR) - 1 aminoethylphosphonic acid of melting point 2940-2950C (decomposition): [alD =16.9 (c=2% in IN sodium hydroxide).
0.4 g (3.2 mmol) of (IR) - I - aminoethylphosphonic acid in 14 ml of water and 7 ml of ethanol were stirred at 10 C while 0.806 g (9.6 mmol) of sodium bicarbonate were added portionwise. The mixture was subsequently stirred at 0 C while a hot solution of 1.024 R (3.2 mmol) of the N - hydroxysuccinimide ester of N benzyloxycarbonyl - L - alanine in 8 ml of ethanol was rapidly added dropwise. The mixture was stirred for 3 hours at 0 C and then for 16 hours at room temperature. The mixture was worked-up in a manner analogous to that described in the first paragraph of part (i) of this Example by passage down a column of cation exchange resin and conversion to the benzylamine salt. There were obtained 0.26 g of the benzylamine salt of ( I R) - I - [(N benzyloxycarbonyl - L alanyl)amino] ethylphosphonic acid of melting point 229 -231 C (decomposition); [a]2 =-34.2 (C=10 in glacial acetic acid).
In a manner analogous to that described in the last paragraph of part (i) of this
Example, from the benzylamine salt of ( I R) - I - [(N - benzyloxycarbonyl - L alanyl)amino] - ethyl - phosphonic acid there was obtained (IR) - 1 - (L - alanylamino) - ethylphosphonic acid of melting point 2950-2960C (decomposition); [a]0=-45.60 (c=1 /,, in water).
(iii) The N - hydroxysuccinimide ester of
N - benzyloxy - carbonyl - L - alanine was reacted with (IR) - 1 - (L - alanylamino) ethylphosphonic acid in a manner analogous to that described in the first paragraph of part (i) of this Example to give the benzylamine salt of ( I R) - I - [(N benzyloxycarbonyl - L - alanyl - L alanyl)amino] - ethylphosphonic acid of melting point 2470-2500C (decomposition); [α]D20=-45.1 (c=0.5 /" in acetic acid).
The benzylamine salt of (IR) - 1 - [(N benzyloxycarbonyl - L - alanyl - L alanyl)amino] - ethylphosphonic acid was treated in a manner analogous to that described in the third paragraph of part (i) of this Example to give (IR) - I - (L alanyl - L - alanylamino) - ethylphosphonic acid of melting point 283 - 284"C (decomposition); lal20---66.80 (c=0.5 in water).
(iv) 2.7 g (10 mmol) of (IR) - I - (L alanyl - L - alanylamino) ethylphosphonic acid were stirred in 50 ml of water at 50C while 2.0 g (20 mmol) of triethylamine followed by 50 ml of ethanol were added. The resulting clear solution was cooled to 0 C and there were added thereto 3.8 g (12 mmol) of solid N hydroxysuccinimide ester of N benzyloxycarbonyl - D - alanine in a single portion. This N - hydroxysuccinimide ester was washed in with 25 ml of ethanol. The mixture was stirred for 2 hours at 0 C and then for 16 hours at room temperature when a clear solution was obtained. The solvents were removed by evaporation and the residue was partitioned between 150 rnl of water and 100 ml of chloroform. The aqueous layer was washed with a further 100 ml of chloroform and the solvent extracts were back-washed with 50 ml of water. The aqueous extracts were combined and evaporated. The residue was taken up in a mixture of 40 ml of water and 40 ml of methanol and passed down a column of cation exchange resin (B.D.H., Zerolit 225,
SRC 13, RSO3H; freshly regenerated in the acid cycle). Elution was carried out with the same solvent system. The acid eluate obtained was ev ml of methanol and the solution treated with a solution of 3 ml of propylene oxide in 5 ml of methanol to give a white precipitate.
After standing overnight at room temperature, the precipitate was filtered off, washed successively with methanol and ether and then dried. Crystallisation from water/ethanol gave 1.96 g of ( I R) - I - (D alanyl - L - alanyl - L - alanylamino) - ethylphosphonic acid of melting point 3 180-3200C (decomposition); [α]D20=-107 (c=0.5 in IN sodium hydroxide).
Example 2 (A) The preparation of the starting material
3.8 g (15 mmol) of N benzloxycarbonyl - D - valine were stirred in 200 ml of petroleum ether (boiling point 60 -80 C), 1.5 g (15 mmol) of triethylamine were added and the mixture was cooled to -50C. 2.1 g (15 mmol) of isobutyl chloroformate were added and the mixture was maintained at 50C for 30 minutes. While stirring this mixture at -50C there was added dropwise a solution of 2.7 g (10 mmol) of (IR) - 1 - (L - alanyl - L alanylamino) - ethylphosphonic acid in a mixture of 2.0 g (20 mmol) of triethylene and 15 ml of water. This solution was washed in with 5 ml of water. The stirring was continued at -50C to 0 C for a further 2 hours and then overnight at room temperature. 150 ml of water were added and the aqueous and organic phases were separated. The aqueous phase was evaporated, the residue taken up in a mixture of 40 ml of water and 40 ml of methanol and the residue passed down a column of cation exchange resin (B.D.H.,
Zerolit 225, SRC 13, RSO3H; 150 g; freshly regenerated in the acid cycle). The column was eluted with the same solvent mixture and the acid fraction was evaporated and reevaporated with five 50 ml portions of water. The residue was triturated with 100 ml of ether and the solid filtered off. The solid was taken up in a mixture of 400 ml of methanol and 400 ml of water and the solution was tritrated to pH 4.5 with 4M aqueous benzylamine. The solution was evaporated to dryness and the resulting solid was crystallised from a mixture of 100 ml of methanol and 150 ml of ether to give 3.24 g of the benzylamine salt of (IR) - I [(N - benzyloxy - carbonyl - D - valyl
L - alanyl - L - alanyl)amino] ethylphosphonic acid of melting point 2380-2440C (decomposition).
(B) The process
In a manner analogous to that described in part (B) of Example 1, from the benzylamine salt of (lR) - I - [(N benzyloxy - carbonyl - D - valyl - L alanyl - L - alanyl)aminol ethylphosphonic acid there was obtained ( I R) - I - (D - valyl - L - alanyl - L alanylamino) - ethylphosphonic acid of melting point 301 0-3040C (decomposition); [α]D20=-105 (c=0.45 /" in
IN sodium hydroxide).
Example 3 (A) The preparation of the starting material:
(i) In a manner analogous to that described in part (iv) of Example 1, from the
N - hydroxysuccinimide ester of N benzyloxy - carbonyl - L - alanine and (IR) - 1 - (L - alanyl - L - alanylamino) - ethyl - phosphonic acid there was obtained (IR) - I - [(N - benzyloxy - carbonyl - L alanyl - L - alanyl - L - alanyl)amino] ethylphosphonic acid of melting point 2550-2570C (decomposition); [a]2 =-62.0 (c=0.4 S in g!acial acetic acid).
In a manner analogous to that described in part (B) of Example 1, from (IR) - 1 [(N - benzyloxycarbonyl - L - alanyl - L alanyl - L - alanyl)amino] ethylphosphonic acid there was obtained ( I R) - 1 - (L - alanyl - L - alanyl - L alanylamino) - ethylphosphonic acid of melting point 312 -313 C (decomposition); [a]20= 101.0 (c=0.53% in 1N sodium hydroxide).
(ii) In a manner analogous to that described in part (iv) of Example 1, but with acidification to pH 2 and further solvent extraction with ether replacing passage through the resin and subsequent solvent extraction with ether, from the N hydroxysuccinimide ester of N benzyloxycarbonyi - D - alanine and (1 R) 1 - (L - alanyl - L - alanyl - L - alanylamino) - ethylphosphonic acid there was obtained the benzylamine salt of (1R) 1 - [(N - benzyloxy - carbonyl - D alanyl - L - alanyl - L - alanyl - L alanyl)amino] - ethylphosphonic acid of melting point 2720-2770C (decomposition); [(Z]D0=~ 47.00 (c=0.5% in acetic acid).
(B) The process
In a manner analogous to that described in part (B) of Example 1, from the benzylamine salt of ( I R) - 1 - [(N benzyloxy - carbonyl - D - alanyl - L alanyl - L - alanyl - L - alanyl)aminoi ethylphosphonic acid there was obtained (IR) - I -- (D - alanyl - L - alanyl - L alanyl - L - alanylamino) ethylphosphonic acid of melting point 3230-3250C (decomposition); [cu]D=-121" (c=0.48% in IN sodium hydroxide).
Example 4 (A) The preparation of the starting material:
(i) 139.7 g (0.5 mol) of dimethyl 1 benzylaminoethyl - phosphonate hydrochloride were dissolved in 1000 ml of methanol. The solution was hydrogenated at room temperature and atmospheric pressure in the presence of 15 g of 10% palladium-on-charcoal for several hours until the hydrogen uptake ceased. The catalyst was filtered off and the filtrate evaporated in vacuo. The residue of dimethyl
I - aminoethylphosphonate hydrochloride was dissolved in 500 ml of dry dimethylformamide and then treated with 160 g (0.5 mol) of the N hydroxysuccinimide ester of N benzyloxycarbonyl - L - alanine. While stirring and maintaining the temperature at below 0 C, there were added dropwise 70 ml of dry triethylamine. The mixture was then stirred overnight at room temperature.
The triethylamine hydrochloride was filtered off and washed with a small amount of dimethylformamide. The filtrate and washings were evaporated under an oilpump vacuum and at a bath temperature below 40"C. The residual oil was treated with 40 ml of water and the resulting mixture extracted with four 40 ml portions of chloroform. The combined organic phases were washed with a small volume of a strong potassium carbonate solution and then dried over sodium sulphate. The sodium sulphate was filtered off and the filtrate evaporated, firstly under a waterpump vacuum and then under an oil-pump vacuum.
The residue obtained according to the preceding paragraph was treated with 600 ml of dry ether and yielded 72.5 g of dimethyl (IS) - 1 - [(N benzyloxycarbonyl - L- alanyl)amino] ethylphosphonate of melting point 134 135"C; la10=+14.90 (c=l /n in methanol).
This material was discarded. Evaporation of the mother liquors gave ca 100 g of a gum consisting substantially of the corresponding (R)isomer.
(ii) 100 g of the foregoing gum were dissolved in 500 ml of methanol containing 0.3 mol of hydrogen chloride. The solution was hydrogenated at room temperature and atmospheric pressure in the presence of 8 g of 10% palladium-on-charcoal until the hydrogen uptake ceased. The catalyst was filtered off, the filtrate evaporated in vacuo and the residue triturated with acetone. The solid was filtered off, washed with acetone and dried in vacuo. After recrystallisation from methanol/ether, there was obtained 42 g of dimethyl (I R) - I - (L - alanyl amino) - ethylphosphonate hydrochloride of melting point l950-l980C (decomposition); [ct]2 =~51.1 (c=1 /n in water).
(iii) In a manner analogous to that described in the first paragraph of this
Example, 13 R of dimethyl (1R) - 1 - (L alanylamino) - ethylphosphonate hydrochloride and 16 g of the N - hydroxysuccinimide ester of N - benzyloxycarbonyl - L - alanine were reacted together at a temperature below 20"C in dry dimethyformamide and in the presence of triethylamine. The mixture was worked-up in the manner described in the first paragraph of this Example to give 16 g of dimethyl (IR) - I [(N - benzyloxycarbonyl - L - alanyl - L - alanyl)aminol ethylphosphonate of melting point 149"-- 151"C; [al0=-65.5" (c=1 /" in methanol).
(iv) 12.9 g (0.03 mol) of dimethyl (IR) - - (N - benzyloxy - carbonyl - L- alanyl - L - alanyl)aminol ethylphosphonate were dissolved in 150 ml of methanol containing 0.032 mol of hydrogen chloride. The solution was hydrogenated at room temperature and pressure in the presence of I g of 10% palladium-on-charcoal until the hydrogen uptake ceased. The catalyst was filtered off, the filtrate evaporated in vacuo and the oily hydrochloride evaporated twice with ethyl acetate.
The product obtained according to the preceding paragraph and 10.9 g (0.03 mol) of the N - hydroxysuccinimide ester of N benzyloxycarbonyl - D - leucine were stirred in the presence of 100 ml of dry dimethylformamide. While stirring and maintaining the temperature below 150C, 4.2 ml of dry triethylamine were added dropwise. The mixture was then stirred overnight at room temperature. The triethylamine hydrochloride was filtered off and washed with a small amount of dimethylformamide. The filtrate was evaporated under an oil-pump vacuum and at a bath temperature of below 40"C. The residual oil was treated with 50 ml of water and the resulting mixture extracted with four 50 ml portions of chloroform. The combined organic phases were washed with a small volume of 20% potassium carbonate solution and then dried over sodium sulphate. The sodium sulphate was filtered off and the filtrate evaporated under a waterpump vacuum. The residue was reevaporated twice with ethyl acetate.
Trituration with dry ether, filtration and vacuum drying yielded 15.5 g of dimethyl (lR) - I - (N - benzyloxycarbonyl - D leucyl - L - alanyl L - alanyl)aminol ethylphosphonate of melting point 1630-- 167"C. After recrystallisation from acetonitrile, the melting point was 1730-- 176"C; [12 =-36.6 (c=1 /,, in methanol).
(B) The process:
10.85 g of dimethyl (I R) - I - I(N benzyloxycarbonyl - D - leucyl - Lalanyl - L - alanyl)amino] ethylphosphonate were dissolved in 30 ml of a 350/" solution of hydrogen bromide in glacial acetic acid and the mixture was stirred at room temperature for 4 hours. 130 ml of ether were then added while stirring, the stirring was discontinued and the ether decanted off. This procedure was repeated twice using 80 ml of ether each time. The residue was dissolved in 70 ml of methanol and to the resulting solution were added 10 ml of propylene oxide. After refrigerating overnight, the resulting white precipitate was filtered off and washed with ethanol and ether. The product was dried in vacuo to a consant weight of 7.99 g; melting point 2930-2950C (decomposition).
Recrystallisation from 500 ml of cold water and from 700 ml of ethanol gave 6.67 g of (IR) - 1 - (D - leucyl L - lanyl - L alanylamino) - ethylphosphonic acid of melting point 3000-3020C (decomposition); [al020---l29.30 (c=10/, in water).
Example 5 (A) The preparation of the starting material:
In a manner analogous to that described in Example 4(A) from 7.82 g (0.03 mol) of dimethyl (IR) I - (L - alanylamino) ethylphosphonate hydrochloride and 9.6 g (0.03 mol) of the N - hydroxysuccinimide ester of N - benzyloxycarbonyl - D alanine there were obtained 11.1 g of dimethyl (IR) I - [(N - benzyloxy carbonyl - D alanyl - L - alanyl)amino] ethylphonate of melting point 1 15"--1 17 C; [CE]DO=28.4 (c=0.5 /" in methanol).
(B) The process
In a manner analogous to that described in Example 4(B), 9.92 g of dimethyl (IR) 1 - [(N - benzyloxycarbonyl - D - alanyl
L - alanyl)amino] - ethylphosphonate were treated with 45 ml of a 35 /n solution of hydrogen bromide in acetic acid. Workingup in the same manner as described in
Example 4(B) gave 6.16 g of crude product of melting point 2820-2850C (decomposition) which, after recrystallisation from water/ethanol, yielded 5.47 g of pure (IR) - I - (D - alanyl - L alanylamino) - ethylphosphonic acid of melting point 2920-2930C (decomposition); [a]020---l01 .20 (c=1% in water).
The following Example illustrates a typical pharmaceutical preparation containing a peptide derivative provided by the present invention:
Example A
A 1000 ml injection solution containing the following ingredients was prepared:
Per 1000 ml (IR) - I - (D - Alanyl - L
alanylamino)
ethylphosphonic acid 100.0 g
Chlorocresol 1.0 g
Acetic acid (glacial) 1.2 g
Sodium hydroxide solution (0.IN) q.s. pH 4.5
Water for injection ad 1000 ml
The (lR) - I - (D - alanyl - L alanylamino)- ethylphosphonic acid was suspended in 500 ml of water for injection.
The chlorocresol was dissolved in 200 ml of water for injection and added to the first solution. The acetic acid was then added while stirring. A 0.1N solution of sodium hydroxide in water for injection was added while stirring until a pH value of 4.5 was obtained. The solution was then made up to 1000 ml with water for injection, filtered through a sterile 0.22 micron membrane filter and filled into ampoules. The ampoules were sealed and then sterilised by autoclaving at 1210C for 20 minutes.
WHAT WE CLAIM IS:
1) Peptide derivatives of the general formula
wherein n is 1, 2 or 3; R', R2 and R3 each represent the characterising group of an aamino acid of the type found in proteins with the provisos that R3 represents other than a hydrogen atom and that R3 represents a methyl group when n is 1; R4 represents a hydroxy or methyl group; the configuration at the carbon atom designated as (a) is D; the configuration at the carbon atom designated as (b) is L when R2 represents other than a hydrogen atom; and the configuration at the carbon atom denoted as (c) is (R) when R1 represents other than a hydrogen atom, and pharmaceutically acceptable salts thereof.
2) Peptide derivatives according to claim
1, wherein R4 represents a hydroxy group.
3) Peptide derivatives according to claim 1 or claim 2, wherein R' represents a methyl group.
4) Peptide derivatives according to claim 1, claim 2 or claim 3, wherein R2 represents a methyl group and R3 represents a methyl, isopropyl or isobutyl group.
5) ( I R) - 1 - (D - Alanyl - L alanylamino) - ethylphosphonic acid.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (17)
1) Peptide derivatives of the general formula
wherein n is 1, 2 or 3; R', R2 and R3 each represent the characterising group of an aamino acid of the type found in proteins with the provisos that R3 represents other than a hydrogen atom and that R3 represents a methyl group when n is 1; R4 represents a hydroxy or methyl group; the configuration at the carbon atom designated as (a) is D; the configuration at the carbon atom designated as (b) is L when R2 represents other than a hydrogen atom; and the configuration at the carbon atom denoted as (c) is (R) when R1 represents other than a hydrogen atom, and pharmaceutically acceptable salts thereof.
2) Peptide derivatives according to claim
1, wherein R4 represents a hydroxy group.
3) Peptide derivatives according to claim 1 or claim 2, wherein R' represents a methyl group.
4) Peptide derivatives according to claim 1, claim 2 or claim 3, wherein R2 represents a methyl group and R3 represents a methyl, isopropyl or isobutyl group.
5) ( I R) - 1 - (D - Alanyl - L alanylamino) - ethylphosphonic acid.
6) (IR) - I - (D -Alanyl - L -alanyl
L - alanylamino) - ethylphosphonic acid.
7)(lR) -l -(D alkyl - L - alanyl - L alanylamino) - ethylphosphonic acid.
8) (IR) - I - (D - Leucyl - L -alanyl L - alanylamino) - ethylphosphonic acid.
9) 9) (IR) - 1 -(D -Alanyl - L - alanyl - L - alanyl - L - alanylamino)
ethylphosphonic acid.
10) A process for the preparation of the
peptide derivatives set forth in claim 1,
which process comprises
(a) cleaving off the protecting group(s)
present in a compound of the general
formula
wherein n is as defined in claim 1; R10, R20 and R30 have any of the values accorded to R', R2 and R3 in claim 1 except that any amino group or amino groups present may be in protected form and any other functional group which may be present is in protected form where required; R40 represents a methyl group or R41; R41 represents a hydroxy group or lower alkoxy protecting group; R5 represents a hydrogen atom or a protecting group; at least one protecting group is present; the configuration at the carbon atom designated as (a) is D; the configuration at the carbon atom designated as (b) is L when R20 represents other than a hydrogen atom; and the configuration at the carbon atom designated as (c) is (R) when R10 represents other than a hydrogen atom, or
(b) separating an (R,S)-diastereomeric compound corresponding to formula I into its diastereomers and isolating the (R)diastereomer, and, if desired, converting an obtained compound of formula I into a pharmaceutically acceptable salt.
11) A process according to claim 10, wherein there is prepared a peptide derivative in which R4 represents a hydroxy group.
12) A process according to claim 10 or claim 11, wherein there is prepared a peptide derivative in which R1 represents a methyl group.
13) A process according to claim 10, claim 11 or claim 12, wherein there is prepared a peptide derivative in which R2 represents a methyl group and R3 represents a methyl, isopropyl or isobutyl group.
14) A process according to claim 10, wherein ( I R) - I - (D - alanyl - L alanylamino) - ethylphosphonic acid is prepared.
15) A process according to claim 10, wherein ( I R) - I - (D - alanyl - L alanyl - L - alanylamino) ethylphosphonic acid is prepared.
16) A process according to claim 10, wherein (IR) - 1 - (D - valyl - L - alanyl - L - alanylamino) - ethylphosphonic acid is prepared.
17. A process according to claim 10, wherein ( I R) - I - (D - leucyl - L alanyl - L - alanylamino) ethylphosphonic acid is prepared.
18) A process according to claim 10, wherein (I R) - I - (D - alanyl - L alanyl - L - alanyl - L - alanylamino) - ethylphosphonic acid is prepared.
19) A process according to claim 10, wherein a compound of formula II is obtained by condensing a compound of the general formula
wherein m is zero, 1, 2 or 3; R10, R20, R40 and
R41 have the significance given in claim 10; the configuration at the carbon atom designated as (b) is L when R20 represents other than a hydrogen atom; and the configuration at the carbon atom designated as (c) is (R) when R10 represents other than a hydrogen atom, with an appropriately protected a-amino acid, an appropriately protected dipeptide, an appropriately protected tripeptide, an appropriately protected tetrapeptide or a reactive derivative thereof as the case may require.
20) A process for the preparation of the peptide derivatives set forth in claim 1, substantially as hereinbefore described with reference to part (B) of any one of Examples
I to 5.
21) A peptide derivative as set forth in claim 1, when prepared by the process claimed in any one of claims 10 to 20 or by an obvious chemical equivalent thereof.
22) A pharmaceutical preparation containing a peptide derivative as set forth in claim I in association with a compatible pharmaceutical carrier material.
23) A pharmaceutical preparation containing a peptide derivative as set forth in claim 1, D - cycloserine and a compatible pharmaceutical carrier material.
24) A compound of the general formula
wherein n is as defined in claim 1; R10, R20
and R30 have any of the values accorded to
R1, R2 and R3 in claim I except that any
amino group or amino groups present may
be in protected form and any other
functional group which may be present is
optionally protected; R40 represents a
methyl group or R41; R41 represents a
hydroxy group or lower alkoxy protecting group; R5 represents a hydrogen atom or a protecting group; at least one protecting group is present; the configuration at the carbon atom designated as (a) is D; the configuration at the carbon atom designated as (b) is L when R20 represents other than a hydrogen atom; and the configuration at the carbon atom designated as (c) is (R) when
R10 represents other than a hydrogen atom.
Priority Applications (23)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB20014/76A GB1577232A (en) | 1976-05-14 | 1976-05-14 | Peptide derivatives of phosphonic and phosphinic acids |
NL7704370A NL7704370A (en) | 1976-05-14 | 1977-04-21 | PROCESS FOR PREPARING PEPTID DERIVATIVES. |
IT23054/77A IT1075484B (en) | 1976-05-14 | 1977-04-29 | PEPTIDE DERIVATIVES AND PROCEDURE FOR THEIR PREPARATION |
ZA00772732A ZA772732B (en) | 1976-05-14 | 1977-05-06 | Peptide derivatives and process for the preparation thereof |
IL52040A IL52040A (en) | 1976-05-14 | 1977-05-06 | Peptidyl derivatives of phosphonic acids,their manufacture and pharmaceutical compositions containing them |
AU25008/77A AU511452B2 (en) | 1976-05-14 | 1977-05-09 | Peptide derivatives |
NZ184047A NZ184047A (en) | 1976-05-14 | 1977-05-09 | Peptide derivatives of phosohonic and phosphinic acides and pharmaceutical compositions |
PH19754A PH14715A (en) | 1976-05-14 | 1977-05-10 | Peptide derivatives and compositions containing same |
LU77319A LU77319A1 (en) | 1976-05-14 | 1977-05-12 | |
CA278,276A CA1090785A (en) | 1976-05-14 | 1977-05-12 | Peptide derivatives and process for the preparation thereof |
FI771518A FI771518A (en) | 1976-05-14 | 1977-05-12 | |
FR7714549A FR2351124A1 (en) | 1976-05-14 | 1977-05-12 | PEPTIDIC DERIVATIVES AND PROCESS FOR THEIR PREPARATION |
GR53459A GR73010B (en) | 1976-05-14 | 1977-05-13 | |
NO771717A NO771717L (en) | 1976-05-14 | 1977-05-13 | PEPTIDE DERIVATIVES AND PROCEDURES FOR THE MANUFACTURE OF THESE |
SE7705628A SE7705628L (en) | 1976-05-14 | 1977-05-13 | PEPTIDE DERIVATIVES AND PROCEDURES FOR THE PREPARATION THEREOF |
PT66544A PT66544B (en) | 1976-05-14 | 1977-05-13 | Process for preparing peptide derivatives |
DE19772721760 DE2721760A1 (en) | 1976-05-14 | 1977-05-13 | PEPTIDE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
BE177536A BE854591A (en) | 1976-05-14 | 1977-05-13 | PEPTIDIC DERIVATIVES AND PROCESS FOR THEIR PREPARATION |
DK209877A DK209877A (en) | 1976-05-14 | 1977-05-13 | PROCEDURE FOR PREPARING PEPTIDE DERIVATIVES |
JP5447577A JPS52139023A (en) | 1976-05-14 | 1977-05-13 | Peptide derivative |
AT345877A AT355740B (en) | 1976-05-14 | 1977-05-13 | METHOD FOR PRODUCING NEW PEPTIDE DERIVATIVES |
MC771242A MC1146A1 (en) | 1976-05-14 | 1977-05-13 | PEPTIDIC DERIVATIVES AND PROCESS FOR THEIR PREPARATION |
ES458748A ES458748A1 (en) | 1976-05-14 | 1977-05-13 | Peptide derivatives of phosphonic and phosphinic acids |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB20014/76A GB1577232A (en) | 1976-05-14 | 1976-05-14 | Peptide derivatives of phosphonic and phosphinic acids |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1577232A true GB1577232A (en) | 1980-10-22 |
Family
ID=10138919
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB20014/76A Expired GB1577232A (en) | 1976-05-14 | 1976-05-14 | Peptide derivatives of phosphonic and phosphinic acids |
Country Status (23)
Country | Link |
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JP (1) | JPS52139023A (en) |
AT (1) | AT355740B (en) |
AU (1) | AU511452B2 (en) |
BE (1) | BE854591A (en) |
CA (1) | CA1090785A (en) |
DE (1) | DE2721760A1 (en) |
DK (1) | DK209877A (en) |
ES (1) | ES458748A1 (en) |
FI (1) | FI771518A (en) |
FR (1) | FR2351124A1 (en) |
GB (1) | GB1577232A (en) |
GR (1) | GR73010B (en) |
IL (1) | IL52040A (en) |
IT (1) | IT1075484B (en) |
LU (1) | LU77319A1 (en) |
MC (1) | MC1146A1 (en) |
NL (1) | NL7704370A (en) |
NO (1) | NO771717L (en) |
NZ (1) | NZ184047A (en) |
PH (1) | PH14715A (en) |
PT (1) | PT66544B (en) |
SE (1) | SE7705628L (en) |
ZA (1) | ZA772732B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0103867A1 (en) * | 1982-09-17 | 1984-03-28 | Kyowa Hakko Kogyo Co., Ltd. | Phosphorus-containing peptide derivative |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0002039A1 (en) * | 1977-11-19 | 1979-05-30 | Ciba-Geigy Ag | Phosphonous acid derivatives, processes for their preparation and their use in combating microorganisms |
DE2966111D1 (en) * | 1978-10-05 | 1983-10-06 | Ciba Geigy Ag | Process for influencing plant growth |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS51639B1 (en) * | 1971-07-28 | 1976-01-09 | ||
IL48835A (en) * | 1975-01-27 | 1979-05-31 | Sparamedica Ag | Amino acyl and peptidyl derivatives of phophonic acids, their preparation and pharmaceutical compositions containingthem |
-
1976
- 1976-05-14 GB GB20014/76A patent/GB1577232A/en not_active Expired
-
1977
- 1977-04-21 NL NL7704370A patent/NL7704370A/en not_active Application Discontinuation
- 1977-04-29 IT IT23054/77A patent/IT1075484B/en active
- 1977-05-06 IL IL52040A patent/IL52040A/en unknown
- 1977-05-06 ZA ZA00772732A patent/ZA772732B/en unknown
- 1977-05-09 AU AU25008/77A patent/AU511452B2/en not_active Expired
- 1977-05-09 NZ NZ184047A patent/NZ184047A/en unknown
- 1977-05-10 PH PH19754A patent/PH14715A/en unknown
- 1977-05-12 CA CA278,276A patent/CA1090785A/en not_active Expired
- 1977-05-12 FI FI771518A patent/FI771518A/fi not_active Application Discontinuation
- 1977-05-12 FR FR7714549A patent/FR2351124A1/en active Granted
- 1977-05-12 LU LU77319A patent/LU77319A1/xx unknown
- 1977-05-13 GR GR53459A patent/GR73010B/el unknown
- 1977-05-13 MC MC771242A patent/MC1146A1/en unknown
- 1977-05-13 JP JP5447577A patent/JPS52139023A/en active Pending
- 1977-05-13 NO NO771717A patent/NO771717L/en unknown
- 1977-05-13 PT PT66544A patent/PT66544B/en unknown
- 1977-05-13 DK DK209877A patent/DK209877A/en unknown
- 1977-05-13 SE SE7705628A patent/SE7705628L/en unknown
- 1977-05-13 ES ES458748A patent/ES458748A1/en not_active Expired
- 1977-05-13 BE BE177536A patent/BE854591A/en unknown
- 1977-05-13 DE DE19772721760 patent/DE2721760A1/en not_active Withdrawn
- 1977-05-13 AT AT345877A patent/AT355740B/en not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0103867A1 (en) * | 1982-09-17 | 1984-03-28 | Kyowa Hakko Kogyo Co., Ltd. | Phosphorus-containing peptide derivative |
US4677125A (en) * | 1982-09-17 | 1987-06-30 | Kyowa Hakko Kogyo Co., Ltd. | Phosphorus-containing peptide derivatives |
Also Published As
Publication number | Publication date |
---|---|
PT66544B (en) | 1979-04-12 |
GR73010B (en) | 1984-01-24 |
BE854591A (en) | 1977-11-14 |
NL7704370A (en) | 1977-11-16 |
IT1075484B (en) | 1985-04-22 |
MC1146A1 (en) | 1978-01-30 |
CA1090785A (en) | 1980-12-02 |
NO771717L (en) | 1977-11-15 |
JPS52139023A (en) | 1977-11-19 |
IL52040A (en) | 1979-11-30 |
AT355740B (en) | 1980-03-25 |
SE7705628L (en) | 1977-11-15 |
ES458748A1 (en) | 1978-03-01 |
FI771518A (en) | 1977-11-15 |
AU2500877A (en) | 1978-11-16 |
PT66544A (en) | 1977-06-01 |
FR2351124B1 (en) | 1981-02-13 |
PH14715A (en) | 1981-11-13 |
ZA772732B (en) | 1978-04-26 |
ATA345877A (en) | 1979-08-15 |
AU511452B2 (en) | 1980-08-21 |
LU77319A1 (en) | 1978-06-26 |
DK209877A (en) | 1977-11-15 |
DE2721760A1 (en) | 1977-12-01 |
IL52040A0 (en) | 1977-07-31 |
FR2351124A1 (en) | 1977-12-09 |
NZ184047A (en) | 1980-04-28 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed [section 19, patents act 1949] | ||
PCNP | Patent ceased through non-payment of renewal fee |