GB2196958A - Halo-homostatin peptide derivatives, their preparation and pharmaceutical compositions containing them - Google Patents
Halo-homostatin peptide derivatives, their preparation and pharmaceutical compositions containing them Download PDFInfo
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- GB2196958A GB2196958A GB08718325A GB8718325A GB2196958A GB 2196958 A GB2196958 A GB 2196958A GB 08718325 A GB08718325 A GB 08718325A GB 8718325 A GB8718325 A GB 8718325A GB 2196958 A GB2196958 A GB 2196958A
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- C—CHEMISTRY; METALLURGY
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/12—Antihypertensives
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Description
1 GB2196958A 1
SPECIFICATION
Novel peptides and peptide derivatives, their preparation and pharmaceutical compositions containing them The present invention relates to novel peptides and peptide derivatives, their preparation and pharmaceutical compositions containing them.
The invention provides a compound of formula 1, R R3 R4 10 A-HN I'AllCO-B R R Rr R 1 2 6 15 wherein A is hydrogen or a substituent, B is hydroxy or a substituent with the proviso that at least one of A and B is a peptide residue, R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or aryl, aralkyl, heteroaryl or heteroarylalkyl, the last four substituents optionally being substituted in the aryl or heteroaryl part, either R, is hydroxy, alkoxy or acyloxy and R2 is hydrogen or R, and R, together are oxo and R3 to R6 independently are hydrogen, fluorine, chlorine, alkyl, cycloalkyl, cycloalkylalkyl, or ary], aralky], heteroaryl or heteroarylalkyl, the last four substituents optionally being substituted in the aryl or heteroaryl part, with the proviso that at least one of R3 to R, is fluorine or chlorine. or an isosteric form thereof, hereinafter referred to as a -compound of the invention---. Preferred are those compounds of formula 1 wherein R, and R, are not both fluorine when R3 and R, are both other then fluorine.
A preferred group of compounds of the invention are the compounds of formula la, R R 3 R4 35 X-A a -HN O-B a-y Ia R 1 R2 R 5 6 40 wherein R and R, to R6 are as defined above, X is hydrogen or a peptide amino-end blocking group, Y is hydroxy or a peptide carboxy-end blocking group, one of A,, and B,, is a peptide residue, the other is a bond or a peptide residue, or an isosteric form thereof.
A peptide amino-end blocking group is e.g. alkoxycarbonyl of overall 2 to 10 carbon atoms, 50 alkanoyl of overall 2 to 25 carbon atoms, cycloalky1carbonyl of overall 4 to 8 carbon atoms, aroyl, or alkylsulfonyl of overall 1 to 10 carbon atoms, especially alkoxycarbonyl of overall 4 to 6 carbon atoms, particularly tert-butoxycarbonyl (BOC), or alkanoyl of overall 2 to 6 carbon atoms, particularly isovaleroyl (Iva). Cycloalkylcarbonyl preferably is of overall 4, 6 or 7 carbon atoms. Aroyl preferably is benzoyl. Alkylsulfonyl preferably is of 3 to 6 carbon atoms, it 55 preferably is branched.
A peptide carboxy-end blocking group is e.g. hydr.oxy, alkoxy of 1 to 5 carbon atoms, amino, alkylamino of 1 to 5 carbon atoms, dialkylamino of independently 1 to 5 carbon atoms in the alkyl moieties thereof, (1-benzylpiperidin-4-yl)amino or (pyridin-2- yl)methylamino, in particular al- koxy of 1 to 5 carbon atoms, amino, alkylamino of 1 to 5 carbon atoms, (1- benzylpipe,ridin-4- 60 yl)amino or (pyridin-2-yl)methylamino, especially alkoxy of 1 to 3 carbon atoms, in particular methoxy or ethoxy.
A peptide residue consists of 1 or more amino acid residues. When there is more than one amino acid residue in a peptide residue they are normally linked by peptidic carbamoyl, i.e. by -CONH-.
2 GB2196958A 2 However, a compound of the invention may optionally be in isosteric form, i.e. for example with one or more peptidic carbamoyl in isosteric form, or with one or more amino acid residues in the unnatural configuration when there is a natural counterpart.
Peptidic carbamoyl in isosteric form is e.g. -CH2NH- (reduced, -COCH2(keto), -CH(OH)CH2(hydroxy), -CH(NH2)CH2- (amino), -CH2CH2_ or -CH2CH,CH2(hydrocarbon). Preferably a compound of the invention has no peptidic carbamoyl in isosteric form overall. When it has peptidic carbamoyl in isosteric form it preferably has one or two, preferably one, peptidic carbamoyl in isosteric form.
Preferably a peptide residue consists of natural amino acid residues in their natural configura- tion. When there are amino acid residues in the unnatural configuration there preferably are only 10 one or two amino acid residues in the unnatural configuration. Amino acid residue as used herein includes imino acid residues such as proline and hydroxyproline.
A peptide residue preferably is of 1 to 7 amino acid residues.
R R R 4 15 0 The -HN W part of formula 1 R 1 R 2 R 5 R 6 20 is the homostatine or a derivative of the homostatine amino acid residue. It preferably has the same configuration as natural statine at the carbon atom to which R is bound when this is asymmetrically substituted. The carbon atom to which R, and R2 are bound preferably has the R configuration when it is asymmetrically substituted.
Alkyl preferably is of 1 to 5 carbon atoms, it especially is branched, particularly isobutyl.
Cycloalkyl preferably is of 3 to 7 carbon atoms, it especially is cyclopentyl or cyclohexyl.
Cycloalkylalkyl preferably is of 3 to 7 carbon atoms in the cycloalkyl, particularly 5 or 6 carbon atoms, and of 1 to 5 carbon atoms, particularly 1 carbon atom, in the alkylene moieties thereof.
Aryl preferably is phenyl. Aralkyl preferably is phenylalkyl of 7 to 12 carbon atoms, particularly 30 benzyl. Heteroaryl preferably is pyridinyl, especially 4-pyridinyl, thienyl, especially 2-thienyl, or furyl, especially 2-furyl, preferably pyridinyl. Heteroarylalkyl preferably has 1 to 6 carbon atoms, especially 1 carbon atom in the alkylene moiety thereof. The heteroaryl moiety of heteroarylalkyl preferably has the significances indicated above as preferred for heteroaryl. The optional substi- tuents of an aryl or aralkyl moiety preferably are one or two groups alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, halogen of atomic number of from 9 to 35, hydroxy and/or amino, preferably one or two groups methyl, methoxy, chlorine, bromine, hydroxy or amino, particularly one hydroxy, amino, chlorine or bromine, optionally in protected form where appropriate.
Alkoxy preferably is of 1 to 5 carbon atoms, it especially is methoxy. Acyloxy preferably is of 40 2 to 6 carbon atoms, it especially is acetoxy.
X preferably is a peptide amino-end blocking group.
Y preferably is a peptide carboxy-end blocking group.
A preferably is a peptide residue.
B preferably is a bond or a peptide residue. B preferably is a peptide residue.
A. and B. together preferably are of at least 2 and preferably of no more than 10 amino acid residues. They preferably have significances similar to corresponding significances in known renin inhibitors, e.g.:
for A,: a bond 50 -His -Phe -Leu -Nie -Phe-Phe- 55 -Vai-Val -Phe-leu -Phe-Nie -Phe-His -Pro-Phe-His- 60 3 GB2196958A 3 and for B,,:
a bond -lie- -Leu -Val- 5 -Val-Phe -Val-Tyr -Leu-Phe -Ile-Phe- -Ile-His10 -Ala-Phe-Phe-Phe-Leu-Tyr-Leu-Val-Phe- -Val-fle-His-Ile-His-Lys-Val-Ile-His-Lys-.
R preferably is alkyl or cycloalkylalkyl. R, preferably is hydroxy or together with R2 OX01 it especially is together with R, oxo. R3 preferably is fluorine. R4 preferably is hydrogen or fluorine, 20 especially fluorine. R5 preferably is fluorine. R,; preferably is other than hydrogen, it especially is fluorine or alkyl, it preferably is alky]. Preferably three of the four substituents R3 to R6 are fluorine or chlorine and the fourth is other than hydrogen and than fluorine or chlorine, in particular R3, R, and R, are fluorine and R, is alkyl.
A preferred group of compounds of the invention is the compounds of formula laa, a R3a R 4a CO-B - Y X-Ai&7FIN aa 1 a& 30 R]a R 2a R Sa R 6a wherein X and Y are as defined above, one of Aaa and Ba is a peptide residue of 1 to 7 amino acids, the other is a bond or a peptide residue of 1 to 7 amino acids, R,, is hydrogen; alkyl of 1 to 10 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; cycloalkylal kyl of 4 to 10 carbon atoms in the cycloalkyl part and of 1 to 5 carbon atoms in the alkylene part thereof; phenyl or phenylalkyl of 7 to 12 carbon atoms optionally mono- or disubstituted in 40 the phenyl ring by alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 cabon atoms, halogen of atomic number of from 9 to 35, hydroxy or amino; pyridiny], thienyl or furyl or pyridinylalkyl of 6 to 11 carbon atoms, thienylalkyl of 5 to 10 carbon atoms or furylalkyl of 5 to 10 carbon atoms; either R,,, is hydroxy, alkoxy of 1 to 5 carbon atoms or alkanoyloxy of 1 to 5 carbon atoms and 45 R2. is hydrogen or 13, and f12a together are oxo, R,, R4a and R5a independently are fluorine or chlorine and R6. is hydrogen; fluorine; chlorine; alkyl of 1 to 5 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part. and of 1 to 5 carbon atoms in the alkylene part thereof; phenyl or 50 phenylalkyl of 7 to 12 carbon atoms optionally mono- or disubstituted in the phenyl ring by alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, halogen of atomic number of from 9 to 35, hydroxy or amino; pyridinyl, thienyl or fury] or pyridinylalkyl of 6 to 11 carbon atoms, thienylalkyl of 5 to 10 carbon atoms or furylalkyl of 5 to 10 carbon atoms, or an isosteric form thereof.
An especially preferred group of compounds of the invention is the compounds of formula laaa, X-A da -HN aa F F CO-Baa-y I aaa 60 - F R 1 aa R 2aa R6aa 4 GB2196958A 4 wherein X, Y, A.. and B.. are as defined above, R.. is alkyl of 1 to 10 carbon atoms or cycloalkylalkyl of 4 to 12 carbon atoms, R6aa is fluorine, chlorine or alkyl of 1 to 5 carbon atoms, either IR,., is hydroxy and R2aa 'S hydrogen or IR,., and R2.a together are oxo and R3aa, R4aa and R5a are fluorine, or an isosteric form thereof.
An even more preferred group of compounds of the invention is the compounds of formula 10 laaaa, R aa F F O-B aaa- Y a 15 X a- A aaa- HN aaaa R laa R 2aa R 6aa 20 wherein Raa, Ria, R2aa and IR,, are as defined above, X. is hydrogen, alkoxycarbonyl of overall 2 to 25 carbon atoms or alkanoyl of overall 2 to 25 carbon atoms, Ya is hydroxy, alkoxy of 1 to 5 carbon atoms, amino, alkylamino of 1 to 5 carbon atoms e.g. 25 isobutylamino or 2-Methylbutylamino, (1-benzylpiperidin-4-yi)amino or (pyridin-2-yi)methylamino, one of A... and B,,,,, is a peptide residue of 1 to 7 natural amino acids in their natural configuration, the other is a bond or a peptide residue of 1 to 7 natural amino acids in their natural configuration.
A... preferably is a bond, -Phe-Phe-, -Phe-His-, Phe-Nie-, Phe-leu-, -Vai, -Hid-Pro-Phe-His-, especially a bond, Phe-Phe- or -Phe-His-.
B... preferably is a bond, -Val-Phe-, -lie-His-, -Leu-Phe-, -Ala-, -Leu-, -lie-Phe- or -lie-, especially -lie-, -Leu-, or -Val-Phe-.
Glossary:
BOC =tert-butoxycarbonyl His =L-histidine 40 Iva =isovaleroyl Ile =Lisoleucine Leu =L-leucine Lys = L-lysine Phe = L-phenylalanine 45 Pro Lproline Tyr L-tyrosine Val L-valine BLY =(2S)-2-amino-(4E)-hexanoic acid statine =4-amino-3-hydroxy-6-methy[heptanoic acid statone 4-amino-3-oxo-6methyiheptanoic acid homostatine =5-amino4-hydroxy-7-methyloctanoic acid homostatone =5-amino-4-oxo-7-methyloctanoic acid ch-homostatine =5-amino6-cyclohexy]-4-hydroxy-hexanoic acid ch-homostatone =5-amino-6-cyclohexyl4-oxohexanoic acid the absolute configuration is specifically indicated in the text.
A compound of the invention may be in free form, e.g. amphoteric form, or in salt, e.g. acid addition, or anionic, salt form. A compound in free form may be converted into a salt form in known manner and vice-versa. Examples of salt forms are e.g. the trifluoroacetate, hydrochloride, 60 sodium, potassium and ammonium salt forms.
A compound of the invention may be obtained by a process comprising the step of coupling two corresponding pepticle residues or precursors thereof, and if required appropriately convert ing any resultant compound in precursor form.
The process is effected in a manner analogous to known methods. A precursor of a peptide 65 GB2196958A 5 residue is e.g a compound in protected form, e.g. having a peptide amino and/or carboxyterminal group which it is desired to split off or replace in the compound of the invention to be obtained, or some other functional group such as hydroxy which it is desired to convert into a further functional group such as oxo. A peptide residue may e.g. be a single amino acid residue 5 depending on the length of the peptide to be obtained. The above applies mutatis mutandis to isosteric forms.
The coupling step is effected by general methods well known for peptide synthesis. It is e.g. effected in an inert solvent such as dimethylformamide. Preferably a temperature of from about 0 to about 25C is used. Alkaline conditions are preferred, e.g. using N-methylmorpholin.
The optional conversion step is also effected in a manner analogous to known methods. The 10 oxydation of a. hydroxy to a keto group is e.g. effected in an inert solvent such as methylene chloride. The oxidizing agent is e.g. chromium trioxyde dipyridinium complex. The reaction temperature may be from about 0 to about 50'C, preferably room temperature.
A compound of the invention may be isolated from the reaction mixture and purified in a manner analogous to known methods. Racemic and/or diastereoisomeric mixtures may be frac- is tionated by known methods.
Insofar as the preparation of any starting material is not particularly described, this may be effected in conventional maner or in analogous manner to that described herein.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected. The purity of the compounds obtained is checked by high pressure liquid chromatography with the 20 retention times obtained using a Lichrosorb (RTM) RP8 column (diameter 4 mm, length 250 mm) and a buffered solvent gradient (acetonitrile/water, pHs) (10 to 90% in 40 minutes) at a flow rate of 1.5 ml/min.
Example 1: N-BOC-(4R,5S)-2-isobutyl-2,3,3-trifluorohomostatinValOCH3 (coupling peptide units) mg of a diastereoisomeric mixture of N-BOC-(4R,5S)-2-isobuty]-2,3,3- trifluoro-hoffiostatin0C2H5 are mixed with 80 mg of valine methyl ester and heated at 80' for 24 hours. The mixture is allowed to cool, poured onto potassium bisulfate solution, extracted with ether, the organic phase dried and evaporated. The residue is chromatographed over silicagel using methylene chloride/ether 50:1 as an eluent. Two diastereoisomeric compounds are obtained:
-isomer A:[UJ20=-32' (c=0.88 in D CHIC12) ?5 retention time 38 minutes 35 [a120= isomer B., -29' (c0.85 in CH,C12) retention time 37.5 minutes.
1; The starting material is obtained as follows:
a) 0.85 g sodium are dissolved in 15 ml ethanol and successively 5 ml fluoromalonic acid diethyl ester and 4.5 ml isobutyl iodide added. The mixture is agitated 15 hours at 60, then extracted with ether. 2-Fluoro-2isobutyl-malonic acid diethyl ester (B.P.j,mm=155') is obtained.
b) 5.5 g of the above diethyl ester are dissolved in 100 ml dioxan and a solution of 0.95 g sodium hydroxide in 60 ml water added. After 15 hours the solution is concentrated under reduced pressure, the residue dissolved in water and extracted with ether. The aqueous phase is acidified with phosphoric acid and reextracted with ether. The organic phase is evaporated at room temperature. 2-Fluoro-2-isobutylmalonic acid mon-ethyl ester (crude) is obtained.
c) 4.05 g of the above monoethyl ester and 3 g N-BOC-(4S,3R)-2,2difluorostatine are dissolved in 25 ml methanol and neutralised with 4 ml triethylamine. The mixture is electrolyzed 50 for 6 hours at 15-20' using a current of about 1 A. The reaction mixture is diluted with ether, washed with.potassium bisulfate and sodium bicarbonate solution and evaporated to dryness.
The residue is chromatographed over silicagel using hexan/ether 1:2 as an eluent.
N-BOC-(4R,5S)-2-isobutyl-2,3,3-trifluorohomostatin-OC2H5 is obtained as a diastereoisomeric mix ture with an Rf of about 0.35 (silicagel, ether/hexan 1:1) The N-BOC-(4S,3R)-2,2-difluorostatine used in step c) is obtained as follows:
a') 1.45 g zinc powder are suspended in 30 ml tetrahydrofuran and heated to reflux tempera ture. 4.4 g ethylbromodifluoroacetate are added at once and as soon as a vigorous reaction is initiated 2 g of N-BOC-L-leucinal dissolved in 5 ml tetrahydrofuran are added dropwise. After 30 minutes the reaction mixture is allowed to tool, then taken up in ethyl acetate and washed 60 with 2N tartaric acid. The organic phase is dried over magnesium sulfate, evaporated to dryness and chromatographed over silicagel using ether/hexane 2:8 as an eluent. N- BOC-(4S,3R)-2,2 difluorostatine -ethyl ester is obtained ([a]20= - 12.2% c=0.29 in ethanol).
D b') 1 g N-BOC-(4S,3R)-2,2-difluorostatine ethyl ester is dissolved in methanol/water and reacted with 0.25 g of concentrated aqueous sodium hydroxide, After 2 hours the mixture is 65 6 GB2196958A 6 made acidic with 2N tartaric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. N-BOC-(4S,3R)-2,2-difluorostatine is obtained (crude).
Example 2: N-BOC-Phe-Phe-(5S)-2-isobutyl-2,3,3-trifluorohomostaton-ValOCH, (precursor conversion by oxidation) mg of isomer A of the title compound of Example 6 are added to a solution of 200 mg chromium trioxyde dipyridinium complex in 2 mi methylene chloride. After 24 hours at room temperature the reaction mixture is filtered over silicagel and the filtrate is evaporated to dryn ess. The residue is chromatographed over silicagel using ether/methylene chloride as an eluent. 10 Isomer A of the title compound is obtained (retention time 23.1 minutes).
Isomer B of the title compound is obtained in analogous manner starting from isomer B of the title compound of Example 6.
Example 3: (4R,5S)-2-isobutyl-2,3,3-trifluorohomostatin-ValOCH, (precursor conversion by splitting off a protecting group) mg of isomer A of the title compound of Example 1 are dissolved in 1 mI methylene chloride, cooled to 0-5' and 1 mi trifluoroacetic acid is added. After 2 hours at O-W the solvent is evaporated, the residue dissolved in ethyl acetate and extracted with sodium bicarbo nate solution. The organic phase is dried and the solvent evaporated. Isomer A of the title 20 compound is obtained.
Isomer B of the title compound is obtained in analogous manner, starting from isomer B of the title compound of Example 1.
Example 4: N-BOC-Phe-Phe-(4R,5S)-2-isobutyl-2,3,3-trifluorohomostatinValOCH3 (coupling peptide units) 56 mg N-BOC-Phe-Phe-01-1 are dissolved in 1 mi of tetra hydrofu ran, 56 mg of the title compound of Example 3 (isomer A), 37 mg hydroxybenzotriazol and 29 mg dicyclohexylcarbodi imid are added at 0'. The reaction mixture is concentrated under reduced pressure. After 24 hours the product is chromatographed over silicagel using a solvent gradient of ether in methy- 30 lene chloride (0 to 20%) as an eluent. Isomer A of the title compound is obtained:
[a]20=-26.2' (c=0.805 in CH2C12); retention time 34.0 minutes. Diastereoisomer B is obtained D using the same procedure, starting from isomer B of the title compound of Example 3:
[a]20=-32.8' (c=0.53 in CH2C12); retention time 34.0 minutes.
D Example 5: N-BOC-Pho-Phe-(4R,5S)2-isobutyl-2,3,3-trifluorohomostatin-Val- OH 68 mg of isomer A of the title compound of Example 4 are dissolved in 3 mi dioxan and 0.5 mi water and treated with 14 mg aqueous NaOH solution at room temperature for 1 hour, The mixture is acidified with 2N tartaric acid and extracted with ethyl acetate. Isomer A of the title compound is obtained:
[a120 -29.1'(c=0.82 in CH2C12); retention tirne 23.1 minutes. Diastereoisomer B is obtained in D analogous manner, starting from isomer B of the title compound of Example 4:
(a]20-26.2' (c= 1.05 in CH2C12).
D Example 6:N-BOC-Phe-Phe-(4R,5S)-2-isobutyl-2,3,3-trifluorohomostatinValPhe-OCH, 48 mg of isomer A of the title compound of Example 5, 15 mg Lphenylalanine methylester, 16 mg hydroxybenzotriazol and 13 mg dicyclohexylcarboddimid are dissolved in 1 mi tetrahydrofurane at 0' and concentrated under reduced pressure. After 15 hours at room temperature the crude product is purified by chromatography over silicagel using a solvent gradient of ether in 50 methylene chloride (0-20%). Isomer A of the title compound is obtained. [a120=-45.2' (c=0.79 in CH2C12); retention time 36.1 minutes. Isomer B is obtained in analo- D gous manner, starting from isomer B of the title compound of Example 5.
Example 7: N-(Bis-(1-Naphthylmethyl)acetyl)-Nle-(4R,5S)-2,2,3,3tetrafluoro-ch-homostat in-buty55 lamid 76 mg of N-(Bis-(1-Naphthyimethyi)acetyl)-Nie-OH are mixed with 60 mg 2,2, 3,3-Tetrafluoro-chhomostatin-butylamide, and 46 mg Hydroxybenzotriazol in 1.5 m] of Tetra hydrofura n. At 0' 36 mg N,N'-Dicyclohexylcarbodiimid are added and the mixture is stirred for 15 hours. The crude product is purified on silica, using a solvent gradient of ether in methylene chloride (0 to 10%) 60 as an eluent. The title compound is obtained as a colorless solid.
-42.0' (c= in CH2C1A' Example 8: N-(Bis-(l-Naphthylmethyl)acetyl)-Nle-(4R)-2,2,3,3-tetrafluoroch-homostaton-b utylamide 28 mg of the compound of Example 7 are treated with 170 mg Collin's reagent as described 65 in Example 2.
7 GB 2.196 958A 7 [20=-31.6' (c=0.2 in CH ID 2C12) Example 9: N-BOC-Phe-Nie-(4R,5S)-2,2,3,3-tetrafluoro-ch-homostatin- butylamide 143 mg of BOC-Phe-Nie-OH, 135 mg Tetrafluoro-ch-homostatinbutyla mid, 104 mg Hydroxy5 benzotriazol and 81 mg N,N'-Dicyclohexylcarbodiimid are reacted as in Example 7. [a]2,0=-42.3' (c=0.18 in CH,Cl,).
Example 10: N-BOC-Phe-Nle-(5S)-2,2,3,3-tetrafluoro-chhomostatonbutylamide 23 mg of the title compound of Example 9 are oxidised with 230 mg Collins's reagent as in 10 Example 2.
[a]DO=-51.3' (c=0.26 in CH2Cl2), Example 11: N-BOC-Phe-Nie-(4R,5S)-3,3-difluoro-ch-homostatinbutylamide 97 mg BOC-Phe-Nie-OH, 83 mg Difluoro-ch-homostatin-butylamide, 70 mg Hydroxybenzotria15 zol and 55 mg N,N'-Dicyclohexylcarbodiimide are reacted as in Example 7. [a]20=-19.4' (c=0.3 in CH,Ci,).
Example 12: N-BOC-Phe-Nie-(4R)-3,3-difluoro-ch-homostaton-butylamide mg of the title compound of Example 11 are oxidised with 150 mg Collin's reagent using 20 the procedure as in Example 2.
[a120=-42.3' (c=0.17 in CH2C12). The obtained title compound is in equilibrium with the corre0 sponding enolform i.e. N-BOC-Phe-Nie-(4R)-3,3-difluoro-ch-homostatin- butylamid.
Example 13: N-BOC-Phe-Bly-(4R,5S)-2,2,3,3-tetrafluoro-ch-homostatin-Leu-apicoline 25 163 mg BOC-Phe-Bly-OH, 218 mg H-tetrafluoro-ch-homostatin-Leua-picoline, 116 mg Hydroxybenzotriazol and 92 mg N, Wd icyclohexylcarbodii mid are reacted together in 2 m] methylenechloride - during 15 hours at room temperature. After chromatography over silicagel using a solvent gradient of methanol in methylene chloride (0,1-5%) the title compound is obtained. [a120=-50.51 (c=0,3 in CH2C12). D Example 14: N-BOC-Phe-Bly-(5S)-2,2,3,3-tetrafluoro-ch-homostaton-Leu-a- picoline mg of the title compound of example 13 are dissolved in 1 m] methylenechloride and oxidised with 150 mg Collin's reagent as in example 2.
I20=_19.4' (c=0,17 in CH alD 2C12).
00 The following compounds are obtained in analogous manner to Examples 1 to 14:
Example No.
16 17 18 19 20 21 22 23 24 25 26 27 28 Compound N-BOC-Phe-His(4R,5S)-2-isObutYI-2,3,3-trifluoro - homostatin-Val-Phe- OCH 3 N-BOC-Phe-His- (SS)-2-isObutY]-2,3.3-trifluoro -homostaton-Val-Phe- OCH 3 N-BOC-Phe-His- (4R,SS)-2-isobuty]-2,3,3-trifluoro -homostatin-lle- His-OCH 3 H-BOC-Phe-His- (55)-2-isobuty]-2,3,3-trifluoro -homostaton-lle- His-OCH 3 N-BOC-Phe-His- (4R.5S)-2-isobutyl-2,3.3-trifluoro -chhomostatin-Val-Phe-OCH N-BOC-Phe-His- (SS)-2-isobuty]-2,3,3-trifluoro -chhoinostaton-Val-Phe-OCH 3 N-BOC-Phe-His, ('4R,SS)-2-isobuty]-2,3,3trifluoro -ch-homostatin-lle-His-OCH N-BOC-Phe-His- ( 55)-2-isQbijtyl-2.3. 3-trifluoro -ch-homostaton-lle-His-OCH 3 N-DOC-Phe-His-(4R.5S)-2,2,3,3tetrafluoro-ch-honiostatin-lle-His-OCH 3 N-DOC-Phe-His-(5S)-2,2,3,3tetrafluoro-ch-homostaton-lle-His-OCH 3 H-BOC-Phe-His-(4R,SS)-2,2,3,3tetrafluoro-ch-homostatin-Val-Phe-OCi 3 N-BOC-Pbe-His-(55)-2,2,3,3tetrafluoro-ch-homostaton-Val-Phe-OC[ 3 N-BOC-Phe-His-(5S)-2,2,3,3tetrafluoro-ch-hoinostaton-2-methylbutylamin N-BOC-Phe-(5S)-2,2,3,3tetrafluoro-ch-honjostaton-2-methylbutylaniin X 1 3 G) m m (0 0) co 01 m co 9 GB2196958A 9 The compounds of the invention are useful because they possess pharmacological activity.
In particular they exhibit effects typical of renin inhibitors. This appears from standard tests. Thus, they exhibit a 50% inhibition of mouse submaxillary gland renin activity on the synthetic octapeptide substrate at a concentration from 10-5M to 10-11M in the test method of K. Murakami et al., Analyt. Biochem. 110 (1981) 232-239 (with the modification that the concentration of synthetic substrate is lowered from 20 yM to 7 #M), in the method of P. Corvol et al., Biochem. Biophys. Acta 523 (1978) 485493, and pure human renin activity according to Corvol et al., BBA in press.
In the antibody trapping method of K. Poulsen and J. J4rgensen, J. Clin. Endocrin. Metab. 39 (1974) 816-825 they prevent human plasma renin activity at a concentration ranging from 10 10-5M to 10-11M.
The compounds of the invention are therefore useful for the prevention and treatment of hypertension and congestive heart failure.
Preferred for the prevention and treatment of hypertension and congestive heart failure. are the title compounds of Examples 13 and 14, particularly of Example 14.
As indicated daily dosage is from about 1 mg to about 500 mg, suitably administered e.g.
orally, in divided dosages of from about 0.25 mg to about 250 mg of the compounds, or in sustained release form.
The compounds of the invention may be administered in free form or in pharmaceutically acceptable salt form. Such salt forms exhibit the same order of activity as the free forms and 20 are readily prepared in conventional manner. The present invention also provides a pharmaceuti cal composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated to be used for enteral, preferably oral, administration, e.g. tablets, or paren teral. administration, e.g. injectable solutions or suspensions.
Claims (8)
- CLAIMS 1. A compound of formula 1,R R3 R4 A-HIN 1100 CO-B R R Rg; R 1
- 2. 6 wherein A is hydrogen or a substituent, B is hydroxy or a substituent, 40 with the proviso that at last one of A and B is a I 14;18 IJU[JL t; lz;o UU, R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or aryl, aralkyl, heteroaryl or heteroarylalkyl, the last four substituents optionally being substituted in the aryl or heteroaryl part, either R, is hydroxy, alkoxy or acyloxy and R, is hydrogen or R, and R, together are oxo and R, to R, independently are hydrogen, fluorine, chlorine, alkyl, cycloalkyl, cycloalkylalkyl, or aryl, 45 aralkyl, heteroary] or heteroarylalkyl, the last four substituents optionally being substituted in the aryl or heteroaryl part, with the proviso that at least one of R, to R, is fluorine or chlorine, or an isosteric form thereof, 2. A compound of claim 1 of formula]a R R 3 R 4 X-A,-HN 0-8a-Y X R. R - 1 2AS 6 wherein IA R and R, to R6 are as defined in claim 1, X is hydrogen or a peptide amino-end-blocking group, Y is hydroxy or a peptide carboxy-end blocking group, one of Aa and B,, is a peptide residue, the other is a bond or a peptide residue, GB 2 196 958A 10 or an iscisteric form thereof.
- 3. A compound of claim 1 selected from N-BOC-(4R,5S)-2-isobutyl-2,3,3trifluoro-homostatin-ValOCH, N-BOC-Phe-Phe-(5S)-2-isobutyl-2,3,3-trif luorohomostaton-ValOCH3 5 (413, 5S)-2-isobutyl-2,3,3-trif luorohomostatinValOCH3 N-BOC-Phe-Phe-(4R,5S)-2-isobutyl-2,3,3-trif luorohomostatinValOCH3 N-BOC-Phe-Phe-(4R,5S)-2-isobutyl-2,3,3-trifluorohomostatin-ValOCH N-BOC-Ph e-Phe-(4R, 5 S)-2-iso butyl-2,3,3 -trifl uo rohom ostati nVal-Phe-OCH3 N-(Bis-(l -Naphthylmethyl)acetyl)-Nle-(4R,5S)-2,2,3,3tetrafluoro-ch-homostatin-butyla mid N-(Bis-(l -Naphthylmethyl)acetyl)-Nle-(4R)-2,2,3,3-tetrafluoro-chhomostaton-butylamid e N-BOC-Phe-Nle-(4R,5S)-2,2,3,3-tetrafluoro-chhomostatin-butylamide N-BOC-Phe-Nle-(5S)-2,2,3,3-tetrafluoro-chhomostaton-butylamide N-BOC-Phe-Nle-(4R,5S)-3,3-difluoro-ch-hoostatinbutylamide N-BOC-Phe-N le-(4R)-3,3-d if I uoro-ch-hom ostati n-butyla mid e 15 N-BOC-Phe-His-(4R,5S)-2-isobutyl-2,3,3-trifluoro-homostatin-Val-PheOCH3 N-BOC-PHe-His-(5S)-2-isobutyl-2,3,3,-trifluoro-homostaton-Val-PheOCH3 N-BOC-Phe-His-(4R,5S)-2-isobutyl-2,3,3-trifluoro-homostatin-Ile-HisOCH, N-BOC-Phe-His-(5S)-2-isobutyl-2,3,3-trifluoro-homostaton-Ile-HisOCH3 N-BOC-Phe-His-(4R,5S)-2-isobutyl-2,3,3-trifluoro-ch-homostatin-ValPhe-OCH3 20 N-BOC-Phe-His-(5S)-2-isobutyl-2,3,3-trifluoro-ch-homostatonVal-Phe-OCH3 N-BOC-Phe-His-(4R,5S)-2-isobutyl-2,3,3-trifluoro-chhomostatin-Ile-His-OCH3 N-B OC-Phe-His-(5S) -2-i sob utyl-2,3,3-triflu o ro-c h-hom ostaton-I I e-H i s-OCH, N-BOC-Phe-His-(4R,5S)-2,2,3,3tetrafluoro-ch-homostatin-Ile-His-OCH3 N-BOC-Phe-His-(5S)-2,2,3,3tetrafluoro-ch-homostaton-Ile-His-OCH3 25 N-BOC-Phe-His-(4R,5S)-2,2,3,3tetrafluoro-ch-homostatin-Val-Phe-OC13 N-BOC-Phe-His-(5S)-2,2,3,3tetrafluoro-ch-homostaton-Val-Phe-OC'3 N-BOC-Phe-His-(5S)-2,2,3,3tetrafluoro-ch-homostaton-2-methylbutylamin N-BOC-Phe-(5S)-2,2,3,3tetrafluoro-ch-homostaton-2-methylbutylamin N-BOC-Phe-Bly-(4R,5S)-2,2,3,3tetrafluoro-ch-homostatin-Leu-d-picolin N-BOC-Phe-Bly-(5S)-2,2,3,3-tetrafluoro-ch-homostaton-Leu-d-picolin.
- 4. A compound according to any one of claims 1 to 3 in free form.
- 5. A compound according to any one of claims 1 to 3 in pharmaceutically acceptable salt form.
- 6. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 in pharmaceutically acceptable form in association with a pharmaceutical carrier or diluent.
- 7. A compound of any one of claims 1 to 3 for use as a pharmaceutical.
- 8. A compound according to any one of claims 1 to 3 wherein R5 and R, are not both fluorine when R3 and R, are both other than fluorine.Published 1988 at The Patent Office, State House, 66/71 High Holborn, London WC1R 4TP Further copies maybe obtained from The Patent Office, Sales Branch, St Mary Cray, Orpington, Kent BR5 3RD Printed by Burgess & Son (Abingdon) Ltd. Con 1/87.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB868619182A GB8619182D0 (en) | 1986-08-06 | 1986-08-06 | Peptides & derivatives |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8718325D0 GB8718325D0 (en) | 1987-09-09 |
GB2196958A true GB2196958A (en) | 1988-05-11 |
GB2196958B GB2196958B (en) | 1990-07-04 |
Family
ID=10602311
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB868619182A Pending GB8619182D0 (en) | 1986-08-06 | 1986-08-06 | Peptides & derivatives |
GB8718325A Expired - Lifetime GB2196958B (en) | 1986-08-06 | 1987-08-03 | Halo-homostatin peptide derivatives ,their preparation and pharmaceutical compositions containing them |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
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GB868619182A Pending GB8619182D0 (en) | 1986-08-06 | 1986-08-06 | Peptides & derivatives |
Country Status (7)
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JP (1) | JPS6348295A (en) |
BE (1) | BE1001618A4 (en) |
CH (1) | CH673655A5 (en) |
DE (1) | DE3725137A1 (en) |
FR (1) | FR2602511A1 (en) |
GB (2) | GB8619182D0 (en) |
IT (1) | IT1211681B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5071837A (en) * | 1990-11-28 | 1991-12-10 | Warner-Lambert Company | Novel renin inhibiting peptides |
US5717093A (en) * | 1993-07-08 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
US5716973A (en) * | 1991-01-02 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Anti-viral compounds |
US5831094A (en) * | 1993-09-09 | 1998-11-03 | Merrell Pharamceuticals Inc. | Difluoro statone antiviral analogs |
US6114380A (en) * | 1995-12-18 | 2000-09-05 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0195212A2 (en) * | 1985-02-04 | 1986-09-24 | Merrell Dow Pharmaceuticals Inc. | Novel peptidase inhibitors |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0486478A3 (en) * | 1984-08-06 | 1992-08-12 | The Upjohn Company | Renin-inhibiting peptides |
CH672792A5 (en) * | 1985-02-19 | 1989-12-29 | Sandoz Ag | |
DE3674131D1 (en) * | 1985-04-19 | 1990-10-18 | Upjohn Co | SUBSTITUTED DIHALO-STATIN INHIBITORS. |
WO1987002675A1 (en) * | 1985-11-01 | 1987-05-07 | Pfizer Inc. | Difluorocyclostatine containing polypeptides |
ATE109157T1 (en) * | 1987-07-01 | 1994-08-15 | Pfizer | FLUORINE-CONTAINING RENIN INHIBITORS. |
JPH10183253A (en) * | 1996-12-24 | 1998-07-14 | Nisshin Steel Co Ltd | Production of cold rolled steel sheet or hot dip plated steel sheet excellent in surface property and workability |
-
1986
- 1986-08-06 GB GB868619182A patent/GB8619182D0/en active Pending
-
1987
- 1987-07-27 BE BE8700830A patent/BE1001618A4/en not_active IP Right Cessation
- 1987-07-27 FR FR8710662A patent/FR2602511A1/en not_active Withdrawn
- 1987-07-28 IT IT8748235A patent/IT1211681B/en active
- 1987-07-29 DE DE19873725137 patent/DE3725137A1/en not_active Withdrawn
- 1987-07-31 CH CH2936/87A patent/CH673655A5/de not_active IP Right Cessation
- 1987-08-03 GB GB8718325A patent/GB2196958B/en not_active Expired - Lifetime
- 1987-08-05 JP JP62196151A patent/JPS6348295A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0195212A2 (en) * | 1985-02-04 | 1986-09-24 | Merrell Dow Pharmaceuticals Inc. | Novel peptidase inhibitors |
Non-Patent Citations (1)
Title |
---|
JP A2 61/183253 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5071837A (en) * | 1990-11-28 | 1991-12-10 | Warner-Lambert Company | Novel renin inhibiting peptides |
US5716973A (en) * | 1991-01-02 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Anti-viral compounds |
US5717093A (en) * | 1993-07-08 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
US5831094A (en) * | 1993-09-09 | 1998-11-03 | Merrell Pharamceuticals Inc. | Difluoro statone antiviral analogs |
US5948778A (en) * | 1993-09-09 | 1999-09-07 | Merrel Pharmaceuticals Inc. | Difluoro statone antiviral analogs |
US6114380A (en) * | 1995-12-18 | 2000-09-05 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
Also Published As
Publication number | Publication date |
---|---|
GB8619182D0 (en) | 1986-09-17 |
DE3725137A1 (en) | 1988-02-11 |
IT8748235A0 (en) | 1987-07-28 |
BE1001618A4 (en) | 1989-12-19 |
CH673655A5 (en) | 1990-03-30 |
GB2196958B (en) | 1990-07-04 |
IT1211681B (en) | 1989-11-03 |
GB8718325D0 (en) | 1987-09-09 |
FR2602511A1 (en) | 1988-02-12 |
JPS6348295A (en) | 1988-02-29 |
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Legal Events
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PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19920803 |