GB2040291A - Trifluoromethylated dipeptides - Google Patents
Trifluoromethylated dipeptides Download PDFInfo
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- GB2040291A GB2040291A GB7944621A GB7944621A GB2040291A GB 2040291 A GB2040291 A GB 2040291A GB 7944621 A GB7944621 A GB 7944621A GB 7944621 A GB7944621 A GB 7944621A GB 2040291 A GB2040291 A GB 2040291A
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- 108010016626 Dipeptides Proteins 0.000 title 1
- -1 N, N-diethylamino Chemical group 0.000 claims abstract description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 9
- 102000015636 Oligopeptides Human genes 0.000 claims abstract description 7
- 108010038807 Oligopeptides Proteins 0.000 claims abstract description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 67
- 238000000034 method Methods 0.000 claims description 19
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 238000009833 condensation Methods 0.000 description 9
- 230000005494 condensation Effects 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 102000016387 Pancreatic elastase Human genes 0.000 description 6
- 108010067372 Pancreatic elastase Proteins 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000001527 leucocytic effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- FYFFGSSZFBZTAH-UHFFFAOYSA-N methylaminomethanetriol Chemical compound CNC(O)(O)O FYFFGSSZFBZTAH-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- LRTFPLFDLJYEKT-UHFFFAOYSA-N para-isopropylaniline Chemical compound CC(C)C1=CC=C(N)C=C1 LRTFPLFDLJYEKT-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Trifluoromethylated oligopeptides having the general formula: <IMAGE> wherein -Y- represents: - either Ala-, in which (R,n) is selected from (isobutyl, O), (cyclohexyl, O), fluoro, O), (N, N-diethylamino, O), (H, 1); - or any one of Pro-, Phe-, Val-, Leu-, in which n is 0 and R is isopropyl.
Description
SPECIFICATION
Trifluorethylated oligopeptides, a process of preparing same and their application in therapeutics
The present invention relates totrifluoromethylated oligopeptides, a process for preparing same and their application in therapeutics.
More precisely, these new compounds have the general formula:
wherein -Y- represents:
- either the motif -L-Ala, in which case the couple (R, n) assumes one of the following values: (isobutyl, 0), (cyclohexyl, 0), (fluoro, 0), (N,N-diethylamino, 0), (H, 1);
- or any one of the motifs -L-Pro-, -L-Phe-, -L-Val-, -L-Leu-, in which case n = 0 and R represents the isopropyl group.
For the sake of simplification we will represent, in what follows, the different motifs mentioned above respectively in the following way: -Ala-; -Pro-; -Phe- ; -Val-; -Leu-; it being understood that the motifs -Lys-, -Ala-, -Pro-, -Phe-, -Val- and -Leu- are of L configuration.
Finally, we also specify that the symbol -Ala- represents the group
that the symbol -Lys- represents the group
that the symbol -Pro- represents the group
that the symbol -Phe- represents the groupe
that the symbole -Val- represents the group
and that the symbol -Leu- represents the group
The invention also relates to addition salts with acids and particularly mineral acids such as hydrochloric acid.
Among the compounds of formula (I) and their salts, the preferred compounds are those in which -Yrepresents the motif -Ala- and in particular those where the couple (R, n) assumes the values (isobutyl, 0) and (fluoro, 0).
As mentioned above, the present invention also relates to the process for preparing compounds of formula (I). More precisely, this process consists in hydrogenolyzing the compounds of formula
wherein Z represents the benzyloxycarbonyl group and the set (Y, n, R) assumes any one of the following values: (Ala, 0, isobutyl), (Ala, 0, cyclohexyl), (Ala, 0, fluoro), (Ala, 0, N, N-diethylamino), (Ala, 1, H), (Pro, 0, ispropyl), (Phe, 0, ispropyl), (Val, 0, isopropyl), (Leu, 0, isopropyl).
The hydrogenolysis reaction is more particularly carried out in the presence of palladium on carbon (at 10 %) and hydrochloric acid, in methanolic solution, the hydrochloric acid being preferably in the form of a normal aqueous solution.
The compounds of formula (II) are new and may be prepared by different methods.
In a first method, the compounds of formula (II) are obtained by condensing the compound of formula:
wherein Z has the same meaning as in formula (II), with the derivatives of formula
wherein the set (Y, n, R) has the same meaning as in formula (II), this condensation being preferably carried out in tetrahydrofuran in the presence of tetramethylguanidine and particularly at a temperature close to 000.
As for the compound of formula (III), it is obtained by condensation -for example in the presence of pyridine, in a mixture of water and ethyl acetate and by adjusting the pH of the solution to 4.5-5 by means of a 3N hydrochloric acid solution- of 7-hydroxy N-ethyl benzisoxazolinium tetrafluoroborate of formula: with the compound of formula
wherein Z has still the same meaning as in formula (II), the compound of formula (VI) resulting from the condensation of N-#-benzyloxycarbonyl lysine of formula:
wherein Z has the same meaning as in formula (II), with thioethyl trifluoroacetate of formula
CF3CO S -C2 H5 * (Vl") preferably at room temperature and in an N aqueous solution of sodium hydroxide.
As for the compounds of formula (IV), they result from the deprotection -preferably by means of a solution of hydrochloric acid in acetic acid- of the compounds of formula
wherein the set (Y, n, R) has the same meaning as in formula (II) and wherein BOC represents the tertiobutyloxycarbonyl group.
Finally, the compounds of formula (VII) are obtained
- by condensation of the compound of formula BOC - Ala - OH (VIII) with the derivatives of formula
wherein the couple (R', n) assumes the values (isobutyl, 0), (cyclohexyl, 0), (fluoro, 0), (N, N-diethylamino, 0), (H 1), and - by condensation of the compound of form
with the compounds of formula:
BOC - Y' - OH (Xl) wherein Y' represents the motifs Pro, Phe, Val and Leu, these reactions being preferably carried out according to the mixed anhydrides method.
According to a second method, the compounds of formula (II) are obtained by condensing the compound of formula:
wherein Z is the benzyloxycarbonyl group, with the derivatives of formula (IX), and by condensing the compound of formula (X) with the derivatives of formula:
wherein Z has the same meaning as in formula (XII) and wherein Y' assumes the following meanings : Pro,
Phe, Val, Leu, these two condensation reactions being preferably carried out in the same operating conditions as those used in the process for preparing the compounds of formula (II) which consisted in condensing the compound of formula (III) and the derivatives of formula (IV).
The compound of formula (XII) and those of formula (Xlil) are obtained by condensing the derivatives of formula:
wherein Z has the same meaning as in formula (II) and Y represents the motif Ala, Pro, Phe, Val or Leu, with the compound of formula (V), the operating conditions being identical to those used in the process for preparing the compounds (III).
Finally, the derivatives of formula (XIV) result from the condensation of the compounds of formula
wherein Z and Y have the same meaning as in formula (XIV), with the compound of formula (VI"), the operating conditions being identical to those used in the process for preparing the compound of formula (Vl).
The preparations hereafter are given by way of examples to illustrate the invention.
Example 1
Trifluoroacetyl-lysyl-prolyl-paraisopropyl anilide chlorhydrate (i) Code number: 60
A solution of 0.257 g of N-a-trifluoroacetyl N-E-carbobenzoxylysylprolyl p-isopropylanilide (II) (code number 69, prepared in example 2) in 20 ml of methanol and 0.5 ml of 1N hydrochloric acid was hydrogenolysed at room pressure and temperature in the presence of palladium on carbon (at 10 %). It was filtered, the solvent was evaporated, the residue was taken up in benzene and evaporation was again carried out. The residue was taken up in tetrahydrofuran, diluted with ethyl ether and the precipitate formed was filtered. 0.2 g of the desired product was obtained.
Yield :90 % Melting point: 138"C [a]25 =-54"4(C=1,DMF) Empirical formula : C22 H32 Cl F3 N4 03, H2O Molecular weight: 510.99
Elementary analysis:
C H N
Calculated (%) 51.71 6.71 10.97
Obtained (%) 51.43 6.36 11.21
By the same process, but from the corresponding reagents, the compounds of formula (I), given in table I
below, were obtained.
TABLE I
Code number R n -Y- Form Empirical Molecular Melting Yield 25 Elementary Analysis Formula weight point (%) ( C) [α] 546 % C H N 60 # 0 -Pro HCl+ C22H32CIF3N4O3 510.986 138 90 -54 4 (1,DMF) 1H2O +H2O Obt. 51.43 6.36 11.21 Cal. 57.51 6.31 10.32 61 " " -Phe- HCl C26H34CIF3N4O3 543.03 180 87 + 16 3 (1,MeOH) Obt. 55.34 5.88 10.06 Cal. 50.91 7.12 10.80 62 " " -Val- HCl+ C22H34CIF3N4O3 519.007 190 92 -31 7 (1,DMF) 4/3H2O +4/3 H2O Obt. 50.83 6.60 14.13 Cal. 51.82 7.31 10.51 63 " " -Leu- HCl + C22H36CIF3N4O3 533.034 132 92 -33 6 (1,DMF0 4/3H2O +4/3 H2O Obt. 51.75 6.84 10.75 Cal. 52.44 6.71 11.65 64 # 0 -Ala- HCl C21H32CIF3N4O3 480.969 124 85 -31 6 (1.1, DMF) Obt. 50.63 6.39 11.38 Cal. 53.53 6.84 10.86 65 # " " HCl + C23H34CIF3N4O3 516.005 215 91 -30 7 (1.05, MDF) 1/2 H2O +1/2 H2O Obt. 53.64 7.04 11,11 Cal. 46.11 5.23 12,65 66 -F " " HCl C17H23CIF4N4O3 442.841 180 82 -79 2 (0.5, H2O) Obt. 44.56 4.93 12.25 Cal. 45.32 6.64 12.59 67 # " " HCl + C21H33CIF3N5O3 556.456 90 90 -27 8 (1, DMF) 1/3H2O Obt. 45.22 6.42 12.31 Cal. 47.30 6.17 12.26 68 H 1 - Ala- HCl C18H26CIF3N4O3 456.894 88 88 - 22 2 (1,DMF) Obt. 47.80 6.01 12.24 Example 2 N-α-trifluoroacetyl-N-#-carbobenzoxy-lysyl-prolyl-p-isopropylanilide (II) Code number : 69
To a solution cooled to 0 C of 0.2 g of prolyl p-isopropylanilide chlorphydrate (IV) in 1.5 ml of tetrahydrofuran were added 0.105 ml of triethylamine, then 0.405 g of 3-(N-a-trifluoroacetyl-N-E- carbobenzoxylysyloxy) 2-hydroxy N-ethyl benzamide [(III), prepared in example 3], then 0.095 ml of tetramethylguanidine.It was left under stirring for 5 hours, diluted with 20 ml of water, extracted with ethyl acetate, the organic phase was washed with an aqueous solution of potassium acid sulphate, then with an aqueous solution of sodium bicarbonate. It was dried on sodium sulphate, the solvent was evaporated, the product was filtered on a neutral alumina column (elution agent: ethyl acetate) and the product obtained was crystallized in isopropylic ether. 0.31 g of the expected product was obtained.
Yield: Yield:70% Melting point ; 117 C Empirical formula: C30H37F3N405
Molecular weight: 590.64
Elementary analysis:
C H N Calculated (%) 61.01 6.31 9.49
Obtained (%) 61.02 6.31 9.67
By the same process, but from the corresponding reagents, [Compounds (III) and (lV)], the compounds of formula (II) appearing in table II below and bearing code numbers 70 - 71 - 72 and 73, were obtained.
By the same process, but by condensation of the compound of formula (XII) with those of formula (IX) and by condensation of the compounds of formula (XIII) with that of formula (X), the derivatives of formula (II) appearing in table II below and bearing code numbers 74- 75 - 76 and 77, were obtained.
TABLE II
Code number R n Y Empirical Molecu- Mel- 25 Elementary Analysis formula la ting Yield weight point [α] 546 % C H N ( C) (%) Cal. 61.01 6.31 9.49 69 # 0 Pro C30H37F3N4O5 590.64 117 70 -39 9 (1,DMF) Obt. 61.02 61.02 9.67 Cal. 63.74 6.14 8.74 70 " 0 Pro C34H39F3N4O5 640.70 203 62 -23 9 (1,DMF) Obt. 63.66 5.94 8.67 Cal. 60,80 6.63 9.45 71 " 0 Val C30H39F3N4O5 592.66 216 57 +5 2 (1,DMF0 Obt. 60.70 6.67 9.61 Cal. 61.37 6.81 9.23 72 " 0 Leu C32H41F3N4O5 606.69 184 65 -6 4 (1.1, DMF) Obt. 61.07 6.85 9.27 Cal. 61.58 6.50 9.27 73 # 0 Ala C31H39F3N4O5 604.67 213 55 -11 7 (1,DMF) Obt. 61.88 6.77 9.51 Cal. 60.30 6.45 9.68 74 -i-Bu 0 " C29H37F3N4O5 578.63 180 60 -11 2 (1,DMF) Obt. 59.50 6.04 9.87 Cal. 55.55 5.22 10.36 75 -F 0 " C25H28F4N4O5 540.51 199 62 -48 3 (1, MeOH) Obt. 55.01 5.24 10.35 Cal. 58.67 6.45 11.80 76 # 0 " C29H38F3N5O5 593.65 196 58 -14 5 (1,DMF) Obt. 58.44 6.58 11.98 Cal. 58.20 5.82 10.44 77 H 1 Ala C26H31F3N4O5 563.55 190 52 15 3 (0.9, DMF) Obt. 58.10 5.97 10.28 Example 3 3-(N-a-trifluoroacetyl-N-E-carbobenzoxy-lysyi-oxy) 2-hydroxy N-ethyl benzamide (III) To a solution of 1 g of N-a-trifluoroacetyl -N-E-carbobenzoxy-lysyl (VI) in 5.32 ml of an 0.5M aqueous soluion of sodium bicarbonate and 5.32 ml of ethyl acetate was added 0.3 mi of pyridine and the solution was cooled to 0 C. The pH was then adjusted to 4.5-5 by means of 3N hydrochloric acid and 0.73 g of benzisoxazolinium tetrafluoroborate (V) was added, by small portions, in 20 min. Then it was diluted with ethyl acetate, and washed with a potassium acid sulphate solution, then with a bicarbonate solution, then with water.It was dried on sodium sulphate, the solvent evaporated and the residue was crystallized in a mixture of isopropylic ether and petroleum ether. 1.3 g of the desired product was obtained.
Yield: 90 % Melting point: 1060 C
By the same process, but from the corresponding reagents [condensation of compound (V) and compounds (XIV)], the derivatives of formulae (XII) and (XIII), which are used in the crude state, were obtained.
Example 4 N-a-trifluoroacetyl-N-E-carbobenzoxy-lysyl-alanine (XIV)
To a solution of 1.9 g of N-E-carbobenzoxy-lysyl-alanine (XV) in 10 ml of 1 N sodium hydroxide aqueous solution was added 1.9 ml of thioethyl trifluoroacetate (VI") and it was left under stirring for 20 hours at room temperature. Then it was acidified to pH = 3, by means of 1N hydrochloric acid, extracted with ethyl acetate, the solvent was evaporated and the crude product obtained was crystallized in petroleum ether. The product thus obtained was used directly in the synthesis of the compound of formula (XII).
By this same process, the other compounds of formula (XIV) were obtained.
By this process, but from N-E-carbobenzoxy-lysine (VI') and thioethyl trifluoroacetate (VI"), the compound of formula (VI) was obtained.
Compounds (XIV) and (Vl) were used directly for the synthesis of the corresponding compounds [(Xll), (Xlil)] and [(III)], respectively.
Example 5 N-tertiobutoxycarbonyl-prolyl-p-isopropylani I ide (VII)
To a solution of N-tertiobutoxycarbonyl proline (XI) in 20 ml of tetrahydrofuran was added 0.26 g of
N-methyl morpholine and the solution was cooled to - 15 C, then 0.31 g of isobutyl chloroformiate was added and it was left under stirring at -15 C for 20 min. and 0.35 g of p-isopropylaniline (X) was added. It was left under stirring for 1 hour, then filtered, the filtrate was evaporated, the residue was taken up in ethyl acetate, it was washed with an aqueous solution of sodium bicarbonate, dried in sodium sulphate and the solvent evaporated. The residue was crystallized in a mixture of n-hexane and isopropylic ether. Thus, 0.55 g of the desired product was obtained.
Yield :70 % Melting point: 162"C Empirical formula : C1gH28N203
Molecular weight: 332.38
Elementary analysis:
C H N Calculated (%) 68.65 8.49 8.43
Obtained (%) 68.71 8.67 8.52
By the same process, but from the corresponding reagents, compounds (VII) were obtained and particularly those appearing in table Ill below and where Y = Phe, Val, Leu or Ala, these particular compounds being new.
TABLE III n = 0 Empirical Mole- Melting Yield 25 Elementary Analysis Y R formula cular point (%) α weight ( C) 546 % C H N Cal. 68.65 8.49 8.43 Pro # C19H28N2O3 332.38 162 70 -89 1 (1, MeOH) Obt. 68.71 8.67 8.52 Cal. 72.22 7.90 7.32 Phe " C23H30N2O3 382.18 128 62 +42 8 (1, MeOH) Obt. 72.05 7.97 7.23 Cal. 68.23 9.04 8.38 Val " C19H30N2O3 334.40 131 58 -30 1 (1, MeOH) Obt. 68.31 9,18 8.56 Cal. - - Leu " C20H30N2O3 348.43 Used in crude state Obt. - - Cal. 69.33 8.73 8.08 Ala # C20H30N2O3 346.41 151 68 -21 4 (1.05 ; DMF) Obt. 69.53 9.05 7.93
Example 6
Prolyl-p-isopropylanilide, chlorhydrate (IV)
A solution of 0.45 g of N-tertiobutoxycarbonyl-prolyl-p-isopropylanilide (VII) obtained in the preceding example, in 2.5 ml of a 2N solution of gaseous hydrochloric acid in acetic acid, was left at room temperature for 15 min. Then it was diluted with ether, the obtained mixture is decanted and the remaining oil is crystallized in ether. 0.25 g of the desired product was obtained.
Yield :62% Melting point: 220 Empirical formula: C14H21CIN2O
Molecularweight: 268.75 Elementary analysis:
C H N
Calculated (%) 62.56 7.87 10.42
Obtained (%) 62.52 7.81 10.58
By the same process but from the corresponding reagents, compounds (IV) were obtained and particularly those listed in table IV below and in which Y = Phe, Val, Leu or Ala, these particular compounds being new. TABLE IV
(IV) n = 0
Empirical Mole- Melting 25 Elementary Analysis Y R formula cular point Yield α weight ( C) (%) 546 % C H N Cal. 62.56 7.87 10.42 Pro # C14H21CIN2O 268.75 220 62 -37 4 (1,DMF) Obt. 62.52 7.81 10.58 Cal. - - Phe " C18H23CIN2O 318.79 185 92 +92 3 (1,DMF) Obt. - - Cal. 62.09 8.56 10.34 Val " C14H23CIN2O 270.76 235 85 +80 7 (1,DMF) Obt. 62.17 8.64 10.60 Cal. 63.25 8.25 9.83 Leu " C16H25CIN2O 284.78 225 90 +63 7 (1,dmf) Obt. 63.36 8.86 10.00 Cal. - - Ala # C16H23CIN2O 282,77 205 87 +16 (1.16 ; DMF) Obt. - - The compounds of formula (1) were tested in vitro and revealed properties as reversible inhibitors of the porcine pancreatic elastase and the human leucocytic elastse. This latter was purifiedin accordance with the method of TRAVIS (BAUGH R.J., TRAVIS J., (1976), Biochemistry, 15,4, 836). The method of investigation used was the conventional method of DIXON (DIXON M. (1953), Biochemical Journal, 55, 1970) for measuring the inhibition constants K ; of the compounds of the invention with respect to the hydrolysis reactions of succinyl-tri-L-analine-paranitroanilids catalysed by the two elastases above (BIETH J., SPIESS
B., WERMUTH C.G., (1974), Biochemical Medecine, 11,350). All the measurements were effected at 25 C in a 0.2 molar tri-hydroxymethylaminomethane solution at pH 8.
Table V below gives the results obtained for the compounds of formula (1) as well as for reference compounds (A). acetyl-L-prolyl-L-alanyl-L-prolyl-L-alaninal for the pancreatic elastase [THOMPSON R.C.,
Bicohemistry (1973), 12, 1,47) and (B), oleic acid, for the leucocytic elastase (ASHE B.M. and ZIMMERMAN
M., (1977), Bioch. Biophys. Res. Comm. 75, 1974).
TABLE V (Values of the inhibition constants K on the pancreatic elastase and the leucocytic elastase)
Compound K1 (a) xK1(a) tested pancreatic leucocytic
(M) (M) 60 2.2 x 10-7 2 x10-6 61 4.5 x 10-7 2 x10-6 62 3.6 x 10-7 3.8 x 10-s 63 3.3 x 10-7 3 x10-7 64 7 x10-8 1 x 10-6 65 1 x 10-7 5 x 1037 66 4.5 x 10-8 1.8x10-5 67 1.5 x 10-7 4.5 x 10-7
A 8 x B 9 x 10-6 (a) The values were obtained in the absence of any solvent.
Furthermore the toxicity of the compounds of the invention was studied intravenously on mice. More precisely, the compounds were tested in solution form in physiological serum containing 10 % of DMF.
Thus, by way of example, no case of mortality was observed following administration of 20, 40 and 80 mg/kg respectively of the compound of code number 63.
Because of their pharmacological properties, the compounds of the invention find their application as a therapeutical agent, for example in the treatment of emphysema.
Claims (11)
1. Trifluoromethylated oligopeptides having the general formula
wherein -Y- represents:
- either the motif -L-Ala-, in which case the couple (R, n) assumes one of the following values: (isobutyl, 0), (cyclohexyl, 0), (fluoro, 0), (N, N-diethylamino, 0), (H, 1);
- or any one of the motifs -L-Pro-, -L-Phe-, -L-Val-, -L-Leu-, in which case n = 0 and R represents the isopropyl group.
2. Trifluoromethylated oligopeptides of formula (I) in which Y represents the motif -Ala-.
3. Trifluoromethylated oligopeptide of formula (I) in which Y represents the motif -Ala- and the couple (R, n) assumes the value (isobutyl, 0).
4. Trifluoromethylated oligopeptides of formula (I) in which Y represents the motif -Ala- and the couple (R, n) assumes the value (fluoro, 0).
5. A pharmaceutical composition characterized in that it contains, as active constituent, at least one compound according to any one of the preceding claims.
6. A process for preparing compounds of formula (I), characterized in that it consists in hydrogenolyzing the compounds of formula:
wherein Z represents the benzyloxycarbonyl group, and the set (Y, n, R) assumes any one of the following values: (Ala, 0, isobutyl), (Ala, 0, cyclohexyl), (Ala, 0, fluoro), (Ala, 0, N, N-diethylamino), (Ala, 1, H), (Pro, 0, isopropyl), (Phe, 0, isopropyl), (Val, 0, isopropyl), (Leu, 0, isopropyl).
7. A process for preparing the compounds of formula (II) used in the process forming the subject matter of claim 6, characterized in that it consists in condensing the compound of formula
wherein Z has the same meaning as in formula (II) with the derivatives of formula
wherein the set (Y, n, R) has the same meaning as in formula (II).
8. A process for preparing the compounds of formula (IV) used in the process forming the subject matter of claim 7, characterized in that it consists in the deprotection of compounds of formula
wherein the set (Y, n, R) has the same meaning as in formula (II) and wherein BOC represents the tertiobutyloxycarbonyl group.
9. A process for preparing the compounds of formula (II), characterized in that it consists in condensing the compound ottormula:
wherein Z is the benzyloxycarbonyl group, with the derivatives of formula:
wherein the couple (R', n) assumes the values (isobutyl, 0), (cyclohexyl, 0), (fluoro, 0), (N, N-diethylamino, 0), (H, 1), and in condensing the compound of formula
with the compounds of formula
wherein Z has the same meaning as in formula (XII) and wherein Y' assumes the following meanings : Pro,
Phe, Val, Leu.
10. A process for preparing the compounds of formulae (XII) and (XIII) used in the process forming the subject matter of claim 9, characterized in that it consists in condensing the derivatives of formula
wherein Z has the same meaning as in formula (II) and Y represents the motif Ala, Pro, Phe, Val or Leu, with the compounds of formula
11. As synthesis intermediates the compounds of formulae (it), (IV), (VII), (XII), (XIII) and (XIV).
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7901410A FR2416883A2 (en) | 1977-02-18 | 1979-01-19 | Tri:fluoro:acetyl oligopeptide derivs. - useful as elastase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2040291A true GB2040291A (en) | 1980-08-28 |
Family
ID=9220984
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7944621A Withdrawn GB2040291A (en) | 1979-01-19 | 1979-12-31 | Trifluoromethylated dipeptides |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS55100347A (en) |
| AU (1) | AU5474980A (en) |
| ES (1) | ES487622A0 (en) |
| GB (1) | GB2040291A (en) |
| GR (1) | GR73130B (en) |
| IT (1) | IT1149281B (en) |
| NL (1) | NL8000345A (en) |
| ZA (1) | ZA8079B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4499082A (en) * | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
| EP0168769A3 (en) * | 1984-07-16 | 1989-02-08 | Merck & Co. Inc. | Process for preparing carboxyalkyl dipeptides |
| US5693617A (en) * | 1994-03-15 | 1997-12-02 | Proscript, Inc. | Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein |
| CN113861240A (en) * | 2021-10-20 | 2021-12-31 | 中国科学院大学 | A kind of trifluoromethyl reagent and its synthetic method and application |
-
1979
- 1979-12-27 GR GR60859A patent/GR73130B/el unknown
- 1979-12-31 GB GB7944621A patent/GB2040291A/en not_active Withdrawn
-
1980
- 1980-01-07 ZA ZA00800079A patent/ZA8079B/en unknown
- 1980-01-08 IT IT19070/80A patent/IT1149281B/en active
- 1980-01-11 ES ES487622A patent/ES487622A0/en active Granted
- 1980-01-18 NL NL8000345A patent/NL8000345A/en not_active Application Discontinuation
- 1980-01-18 AU AU54749/80A patent/AU5474980A/en not_active Abandoned
- 1980-01-18 JP JP447080A patent/JPS55100347A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4499082A (en) * | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
| EP0168769A3 (en) * | 1984-07-16 | 1989-02-08 | Merck & Co. Inc. | Process for preparing carboxyalkyl dipeptides |
| US5693617A (en) * | 1994-03-15 | 1997-12-02 | Proscript, Inc. | Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein |
| CN113861240A (en) * | 2021-10-20 | 2021-12-31 | 中国科学院大学 | A kind of trifluoromethyl reagent and its synthetic method and application |
| CN113861240B (en) * | 2021-10-20 | 2023-10-31 | 中国科学院大学 | A trifluoromethyl reagent and its synthesis method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| NL8000345A (en) | 1980-07-22 |
| ES8202786A1 (en) | 1980-12-16 |
| IT8019070A0 (en) | 1980-01-08 |
| ES487622A0 (en) | 1980-12-16 |
| ZA8079B (en) | 1981-01-28 |
| JPS55100347A (en) | 1980-07-31 |
| IT1149281B (en) | 1986-12-03 |
| GR73130B (en) | 1984-02-07 |
| AU5474980A (en) | 1980-07-24 |
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| Date | Code | Title | Description |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |