Novel analogs of peptidase substrates

Abstract: This invention relates to novel analogs of certain peptidase substrates in which the nitrogen atom of the scissile amide bond has been replaced with a difluoromethylene moiety and in which the carbonyl moiety of its adjacent amide bond has been replaced with a terminal amine function, said novel analogs having the property of inhibiting renin and which are useful in the treatment of hypertension.

Description: This invention relates to novel analogs of certain peptidase substrates in which the nitrogen atom of the scissile amide bond has been replaced with a difluoromethylene moiety and in which the carbonyl moiety of its adjacent amide bond has been replaced with a terminal amine function, said novel analogs having the property of inhibiting renin and which are useful in the treatment of hypertension. Document WO87/04349 relates to peptide analogs which have renin-inhibiting activity. The synthesis of α',β-diamino-α,α-difluoroketones is disclosed in Tetrahedron Letters, vol. 29, n° 30, pp 3687 - 3690, 1988. Said compounds are useful for the design of serine protease inhibitors. Document EP-A1-0 249 349 relates to difluoroketo compounds which are useful as inhibitors of human leukocyte elastase. In general, this invention relates to inhibitors of renin having the structural formula wherein R 1 is an α-amino acid or peptide, optionally bearing a protecting group on its terminal nitrogen atom, R 2 is a saturated hydrocarbyl moiety or is the residue of a characteristic α-amino acid responsible for directing the inhibitor to the active site of the enzyme, R 3 is the residue of a characteristic α-amino acid or a saturated hydrocarbyl moiety, Ra and Rb are activity-enhancing moieties. Before further defining and/or illustrating the scope of the peptidase inhibitors embraced by formula I, it may be convenient to state some of the concepts related to peptides, particularly as it may aid in the reading and understanding of this text and formulae involved herein. For example, except for proline, all of the α-amino acids found in proteins have as a common denominator a free carboxyl group and a free unsubstituted amino group on the α-carbon atom (in proline, since proline's α-amino group is substituted it is really an α-imino acid, but for convenience, it will also be spoken of as an α-amino group). Additionally, each α-amino acid has a characteristic "R-group", the R-group being the side chain, or residue, attached to the α-carbon atom of the α-amino acid. For example, the R-group side chain for glycine is hydrogen, for alanine it is methyl, for valine it would be isopropyl. Thus, throughout this specification the R 2 or R 3 moiety is the residue for each indicated α-amino acid. The specific residues of the α-amino acids are well known in the art. As a further convenience for defining the scope of the compounds embraced by the generic concept of formula I, as well as the sub-generic concepts relating to each of the individual α-amino acids involved in this invention, various α-amino acids have been classified into a variety of groups which impart similar functional characteristics. These groups (C, D, E, D, G and K) and the recognized abbreviations for the α-amino acids are set forth in Tables I and II, respectively. Alanine Ala Arginine Arg Asparagine Asn Aspartic acid Asp Asn + Asp Asx Cysteine Cys Glutamine Gln Glutamic acid Glu Gln + Glu Glx Glycine Gly Histidine His Isoleucine Ile Leucine Leu Lysine Lys Methionine Met Phenylalanine Phe Proline Pro Serine Ser Threonine Thr Tryptophan Trp Tyrosine Tyr Valine Val Norvaline n-Val Norleucine n-Leu 1-Naphthylalanine Nal(1) 2-Indolinecarboxylic acid Ind Sarcosin Sar Throughout this specification, specific compounds may be defined using the shorthand expression R 1 R 2 [CF 2 R 3 NRaRb]. In this formula it is quite obvious that the bracketed CF 2 R 3 NRaRb moiety is the modified α-amino acid of the P' 1 -position wherein its nitrogen atom has been replaced with a CF 2 moiety, its carbonyl moiety has been replaced by the NRaRb moiety, and R 3 represents the residue or substituent attached to the α-carbon atom (not shown) of the so-modified P′ 1 -amino acid. Of course, R 2 represents the α-amino acid in the P 1 position and the R 1 moiety represents the α-amino acid or peptide (comprised of up to 4 α-amino acids) in the P 2 or the P 2 up to P 5 positions, respectively, the terminal α-amino acid of which optionally bears an amino protecting group on its nitrogen atom. For example, the compound written as CBZ-His-β-Val-Phe-n-Leu-Leu-[CF 2 -Gly-NHCH 3 ] is a compound wherein the amino group in the α-position of the terminal α-amino acid of the R 1 moiety (i.e. histidine) has a carbobenzoxy (CBZ) protecting group, the P 4 -position α-amino acid is β-Val, the P 3 -position α-amino acid is Phe, the P 2 -position α-amino acid is n-Leu, Leu is the P 1 -position α-amino acid and the [CF 2 GlyNHCH 3 ] moiety of the P' 1 -position α-amino acid illustrates the case in which the nitrogen atom has been replaced by difluoromethylene, and the NHCH 3 is the monomethylamino moiety wherein Ra is methyl and Rb is hydrogen which has replaced the carbonyl moiety of the P' 1 -position α-amino acid, which in this instance is glycine. In the manner of the structures of Formula I the same compound would otherwise be written as Still more specifically, the novel compound capable of inhibiting renin which is embraced by this invention is the compound of the formula : R 1 -NH-CH(R 2 )-C(=O)-CF 2 -CH(R 3 )NR a R b or the pharmaceutically acceptable salts thereof, wherein R 1 is Iva-(O-methyl)Tyr-nVal-; R 2 is cyclohexylmethyl ; R 3 is H ; R a is H ; R b is H, and Iva is isovaleryl. The invention also relates to the use of the above compounds for the preparation of a medicament useful for treating renin-dependent hypertension. The compound of the invention may be in free form, e.g., amphoteric form, or in salt, e.g., acid addition, alkali metal, or anionic (e.g., ammonium) salt form. A compound in free form may be converted into a salt form in an art-known manner and vice-versa. Examples of salt forms are the trifluoroacetate, hydrochloride, sodium, potassium and ammonium forms. Unless otherwise stated, the α-amino acid building blocks of these peptidase substrate analogs are preferably in their L-configuration. The compound of Formula I inhibit renin and therefore is used as antihypertensive agent useful in treating hypertension. For their end-use application, the potency and other biochemical parameters of the enzyme inhibiting characteristics of the compound of Formula I are readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity of the disease state of the patient or animal to be treated as determined by the attending diagnostician. It is to be expected that the general end-use application dose range will be about 0.01 to 10 mg/kg per day for an effective therapeutic effect with 0.1 mg to 10 mg/kg per day being preferred. The preferred compound is : 5-Cyclohexyl-2,2-difluoro-N 4 -[N-isovaleryl-L-(O-methyl)-Tyrosyl-L-n-Valyl]-3-oxo-1,4-pentanediamine, hydrochloride, In general, the compound of formula I may be prepared by using standard chemical reactions analogously known in the art. The key intermediates required for the application of standard peptide coupling techniques may be represented by the formula Va wherein R a and R 2 are as previously defined, and P g and P g ' are each protecting groups, preferably different from each other so as to facilitate selective removal depending upon the site, nature and sequence of the reactions required to prepare the final compounds from these intermediates; the selection being according to principles well known and understood by those of ordinary skill in the art. The preparation of the required intermediate (Va) is illustrated by Reaction Scheme A. wherein P g is an amine protecting group, and R 2 and Ra are as previously defined. In effecting the steps of Reaction Scheme A it is preferred to start with the aldehyde of formula VI wherein the protecting group is a carbamate preferably wherein P g is benzyloxycarbonyl (CBZ). This so-protected aldehyde is subjected to a condensation reaction with an ester of bromodifluoroacetic acid, preferably the ethyl ester in the presence of zinc. Preferably the reaction is conducted in an anhydrous aprotic solvent, e.g., tetrahydrofuran, ether, dimethoxyethane and the like under a nitrogen or argon atmosphere. The reaction mixture is gently heated under reflux conditions, preferably to about 60°C for about 1-12 hours. The ester (VII) is converted to its amide (VIII) by treatment with the appropriate amine or liquid ammonia under anhydrous conditions, preferably using such solvents as anhydrous diethyl ether. The amidation is initiated at -78°C and following saturation with ammonia the reaction mixture is slowly allowed to rise to room temperature, or after addition of the RaNH 2 amine the mixture is refluxed in tetrahydrofuran. The so-formed amide is chemically reduced by reacting the amide with a diborane, preferably as a diborane/dimethylsulfide complex, under a nitrogen atmosphere in an anhydrous aprotic solvent (e.g., THF) under reflux conditions. The reduction yields the desired amine, in the form of an acid (e.g., HCl) salt which (after the usual work-up) by pH adjustment yields the base which may be suitably protected with an N-protecting group, e.g., P g ' is t-butoxy carbonyl using the standard reaction conditions (e.g., (BOC) 2 O, tetrahydrofuran at room temperature) for protecting the amine. Having obtained the key intermediate of formula Va standard α-amino acid or peptide coupling procedures may be conducted to prepare the individual compound of formula I. In general, this series of reactions may be depicted by Reaction Scheme C. wherein R 1 , R 2 , R 3 , R a and P g are as previously defined and R 1 OH is the equivalent to RCO 2 H, and R" b is R b or P g ' with R b and P g' being as previously defined. The cleavage of the protecting groups may be effected by any of the standard techniques known in the art, such as those illustrated in the specific hereinafter disclosed examples. Similarly, the coupling procedures after cleavage of the Pg protecting group may be effected according to standard procedures well known in the art. The oxidation may be effected via the well-known Swern oxidation procedure, or with a modified Jones reaction using pyridinium dichromate, or a chromic anhydride-pyridinium complex, or with 1,1,1-triacetoxy-2,1-benzoxiodol-3(3H)-one. Of course, if there are any protecting groups on the residues of the α-amino acid building blocks, such protecting groups may be removed after oxidation. In general the Swern oxidation is effected by reacting about 2 to 10 equivalents of dimethylsulfoxide (DMSO) with about 1 to 6 equivalents of trifluoromethylacetic anhydride [(CF 3 CO) 2 O] or oxalyl chloride [(COCl) 2 ], said reactants being dissolved in an inert solvent, e.g., methylene chloride (CH 2 Cl 2 ), said reactor being under an inert atmosphere (e.g., nitrogen or equivalently functioning gas) under anhydrous conditions at temperatures of about -80°C to -50°C to form an in situ sulfonium adduct to which is added about 1 equivalent of the appropriate alcohols (VI). Preferably, the alcohols are dissolved in an inert solvent, e.g., CH 2 Cl 2 or minimum amounts of DMSO, and the reaction mixture is allowed to warm to about -50°C (for about 10-20 minutes) and then the reaction is completed by adding about 3 to 10 equivalents of a tertiary amine, e.g., triethylamine, N-methyl morpholine, etc. In general, the modified Jones oxidation procedure may conveniently be effected by reacting the alcohols (VI) with pyridinium dichromate in dichloromethane by contacting the reactants together in a water-trapping molecular sieve powder, e.g., a grounded 3 Angström molecular sieve), wherein said contact is in the presence of glacial acetic acid at about 0°C to 50°C, preferably at room temperature followed by isolation and then optionally removing amine protecting groups. Alternatively, 1 to 5 equivalents of a chromic anhydride-pyridine complex (i.e., a Sarett reagent prepared in situ (see Fieser and Fieser "Reagents for Organic Synthesis" Vol. 1, pp. 145 and Sarett, et al., J.A.C.S. 25, 422, (1953)) said complex being prepared in situ in an inert solvent (e.g., CH 2 Cl 2 ) in an inert atmosphere under anhydrous conditions at 0°C to 50°C to which complex is added 1 equivalent of the alcohols (VI) allowing the reactants to interact for about 1 to 15 hours, followed by isolation and optionally removing amine protecting groups. Another alternative process for converting the alcohols (VI) to the desired ketones is an oxidation reaction which employs periodinane (i.e, 1,1,1-triacetoxy-2,1-benzoxiodol- 3(3H)-one (see Dess Martin, J. Org. Chem. , 48 , 4155, (1983)). This oxidation is effected by contacting about 1 equivalent of the alcohols (VI) with 1 to 5 equivalents of periodane (preferably 1.5 equivalents), said reagent being in suspension in an inert solvent (e.g., methylene chloride) under an inert atmosphere (preferably nitrogen) under anhydrous conditions at 0°C to 50°C (preferably room temperature) and allowing the reactants to interact for about 1 to 48 hours. Optional deprotection of the amine protecting groups may be effected as desired after the ketones have been isolated. The following specific examples are given to illustrate the preparation of the compounds of this invention. EXAMPLE 1 4-Benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-6-methylheptanoic acid, ethyl ester A mixture of 2.080 g (8.3 mmol) of L-N-benzyloxycarbonyl Leucinal and 2.230 g (11 mmol) of ethyl bromodifluoroacetate in dry tetrahydrofuran (15 mL) was added dropwise to a refluxing suspension of 0.710 g of activated zinc wool in dry tetrahydrofuran (10 mL), under nitrogen. The addition rate was adjusted to maintain gentle reflux of the mixture. After the addition was complete, the solution was stirred for 3 hours at room temperature. The mixture was quenched by addition of 20 mL ethyl acetate, brine and 1M KHSO 4 (20 mL). The aqueous layer was dried over anhydrous MgSO 4 , evaporated and purified by flash chromatography (silica gel, ethylacetate/cyclohexane: 1:9). 1.130 g of the expected ester were isolated (yield: 36%) (colorless oil). Rf: 0.57 (ethyl acetate/cyclohexane, 1:1). EXAMPLE 2 4-Benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-6-methylheptanamide A stream of dry ammonia was bubbled at -78°C, through a solution of 0.820 g (2.2 mmol) of 4-benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-6-methylheptanoic acid, ethyl ester in anhydrous diethyl ether (10 mL). After saturation, the temperature was allowed to rise to room temperature with stirring. The excess ammonia was removed, and the solvent evaporated in vacuo. The residue was taken off in pentane to yield the expected amide in quantitative yield as a solid. MS(CI/NH 3 ): 345 (MH + ). EXAMPLE 3 N 4 -Benzyloxycarbonyl-N 1 -tert-butoxycarbonyl-2,2-difluoro-3-hydroxy-6-methyl-1,4-heptanediamine A solution of 1M BH 3 /(CH 3 ) 2 S (1 mL) in dichloromethane was added, under nitrogen, to a mixture of 0.185 g (0.53 mmol) of 4-benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-6-methylheptanamide in anhydrous tetrahydrofuran (10 mL). The mixture was heated at reflux for 3 hours. After cooling to room temperature, methanol (3 mL) and 1N HCl in diethyl ether (6 mL) were added. The solvent was removed in vacuo. The residue was taken off in water and the aqueous layer washed with diethyl ether. The pH of the aqueous phase was adjusted to 10. Diethyl ether extraction afforded the intermediate amine which was directly converted to its N-BOC protected form [(BOC) 2 O 1.5 eq; tetrahydrofuran; room temperature]. The expected tert.-butylcarbamate was purified by chromatography (silica gel, ethyl acetate/cyclohexane, 1:1), 0.180 g (79% yield). Rf: 0.63 (ethyl acetate/cyclohexane, (1:1). Example 4 N 1 -tert-Butoxycarbonyl-2,2-difluoro-3-hydroxy-5-phenyl-1,4-pentanediamine A solution of N 4 -benzyloxycarbonyl-N 1 -tert-butoxycarbonyl-2,2-difluoro-3-hydroxy-5-phenyl-1,4-pentanediamine (0.464 g, 1 mmol) in ethanol (20 mL) was stirred at room temperature in the presence of 10% Palladium on charcoal (0.020 g) under a hydrogen atmosphere for 5 hours. The hydrogen atmosphere was then replaced by a nitrogen atmosphere and the catalyst was filtered. The solvent was removed in vacuo leaving 0.030 g of the expected product. EXAMPLE 5 4-Benzyloxycarbonylamino-5-cyclohexyl-2,2-difluoro-3-hydroxypentanoic acid, ethyl ester The title compound was prepared in 37% yield from N-benzyloxycarbonyl-3-cyclohexylalaninal, ethyl bromodifluoroacetate and zinc by the procedure described in Example 1. Rf: 0.57 (silica gel; ethyl acetate/cyclohexane 1:1). EXAMPLE 6 4-Benzyloxycarbonylamino-5-cyclohexyl-2,2-difluoro-3-hydroxypentanamide The title compound was prepared in 97% yield from the ester of Example 5 by the procedure described in Example 2. Rf: 0.53 (silica gel; ethyl acetate). MS(DCI/CI+/NH 3 ): 402(MNH + 4 , 86); 385(MH + , 13); 294(23); 169(40); 126(100). EXAMPLE 7 N 4 -Benzyloxycarbonyl-N 1 -(tert-butoxycarbonyl)-5-cyclohexyl-2,2-difluoro-3-hydroxy-1,4-pentanediamine The title compound was prepared in 51% yield from the amide of Example 6 by the procedure described in Example 3. Rf: 0.59 (silica gel; ethyl acetate/cyclohexane 1:1). EXAMPLE 8 N 1 -(tert-butoxycarbonyl)-5-cyclohexyl-2,2-difluoro-3-hydroxy-1,4-pentanediamine The title compound was prepared in 86% yield from the dicarbamate of Example 7 by the procedure described in Example 4. EXAMPLE 9 N 1 -(tert-butoxycarbonyl)-5-cyclohexyl-2,2-difluoro-3-hydroxy-N 4 -[N-isovaleryl-L-(O-methyl)tyrosyl-L-n-valyl]-1,4-pentane diamine To a stirred solution of 0.325 g (0.86 mmol) of N-isovaleryl-L-(O-methyl)tyrosyl-L-n-valine in dry acetonitrile (8 mL), under nitrogen, was added 0.090 g of N-methylmorpholine. The resulting solution was cooled to -20°C. Isobutyl chloroformate (0.117 g, 0.86 mmol) was added dropwise to the cooled reaction mixture. After 10 minutes, a solution of 0.300 g (0.89 mmol) of N 1 -(tert-butoxycarbonyl)-5-cyclohexyl-2,2-difluoro-3-hydroxy-1,4-pentanediamine in dry acetonitrile (3 mL) was added to the cooled mixture. After stirring for 4 hours at -20°C, the temperature of the mixture was allowed to rise to room temperature. Stirring was continued for 15 hours at room temperature. The solvent was then removed in vacuo and the resulting residue was chromatographed (silica gel; ethyl acetate/cyclohexane 1:1) to give the title compound in 61% yield. Rf: 0.16 (silica gel; ethyl acetate/cyclohexane 1:1). Analysis calculated for C 36 H 58 N 4 O 7 F 2 C%: 62.05; H%: 8.39; N%: 8.04 found C%: 62.06; H%: 8.30; N%: 8.00 EXAMPLE 10 N 1 -(tert-butoxycarbonyl)-5-cyclohexyl-2,2-difluoro-N 4 N-isovaleryl-L-(O-methyl)tyrosyl-L-n-valyl]-3-oxo-1,4-pentane diamine A solution of 0.330 g (0.47 mmol) of alcohol of Example 9 in methylene chloride (5 mL) was added to a mixture of pyridinium dichromate (0.314 g), 3A molecular sieves (0.573 g) and glacial acetic acid (0.010 mL) in methylene chloride (10 mL). Stirring was continued for 15 hours at room temperature. The crude mixture was purified by chromatography (silica gel: ethyl acetate/ cyclohexane 1:1) to give the title compound in 76% yield as a white solid. Rf: 0.67 (silica gel; ethyl acetate). Analysis calculated for C 36 H 56 N 4 O 7 F 2 C%: 62.23; H%: 8.12; N%: 8.06 found C%: 62.31; H%: 8.06; N%: 8.16 EXAMPLE 11 5-Cyclohexyl-2,2-difluoro-N 4 -[N-isovaleryl-L-(O-methyl)tyrosyl-L-n-valyl]-3-oxo-1,4-pentanediamine, hydrochloride A mixture of 0.207 g (0.3 mmol) of ketone of Example 10 in a saturated solution of hydrogen chloride in diethyl ether (10 mL) and tetrahydrofuran (1 mL) was stirred at room temperature for 15 hours. A white precipitate formed during that time. The solvent was removed in vacuo. The residue was taken off in diethyl ether and evaporated to dryness (three times). The residue was recrystallized from ethanol/diethyl ether, to yield 0.128 g of the title compound (68% yield). Rf: 0.65 (silica gel; AcOH/BuOH/H 2 O, 2:6:2). Analysis calculated for C 31 H 48 N 4 O 5 F 2 , HCl, (1.25 H 2 O) C%: 56.96; H%: 7.94; N%: 8.57 found C%: 56.89; H%: 7.99; N%: 8.51 By following the techniques referenced above, as well as by utilization of other known techniques, as well as by comparison with compounds known to be useful for treatment of the above-mentioned disease states, it is believed that adequate material is available to enable one of ordinary skill in the art to practice the invention. Of course, in the end-use application of the compound of this invention, the compound is preferably formulated into suitable pharmaceutical preparations such as tablets, capsules or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration. The compound of this invention can be administered to patients (animals and human) in need of such treatment in divided dosages given several times per day. As stated above, the dose will vary depending on severity of disease, weight of patient and other factors which a person skilled in the art will recognize. Typically the compound described above is formulated into pharmaceutical compositions as discussed below. The necessary amount of a compound of formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained. Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixer may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.

Claims: Claims for the following Contracting States : AT, BE, CH, LI, DE, FR, GB, IT, LU, NL, SE A compound of the formula : R 1 -NH-CH(R 2 )-C(=O)-CF 2 -CH(R 3 )NR a R b or the pharmaceutically acceptable salts thereof, wherein R 1 is Iva-(O-methyl)Tyr-nVal- ; R 2 is cyclohexylmethyl ; R 3 is H ; R a is H ; R b is H. and Iva is isovaleryl The compound according to claim 1 for the use as pharmaceutically active agent. The compound according to claim 1 for use as antihypertensive agent. The use of a compound of formula : R 1 -NH-CH(R 2 )-C(=O)-CF 2 -CH(R 3 )NR a R b or the pharmaceutically acceptable salts thereof, wherein R 1 is Iva-(O-methyl)Tyr-nVal-; R 2 is cyclohexylmethyl ; R 3 is H ; R a is H ; R b is H ; and Iva is isovaleryl, for the preparation of a medicament useful for the treatment of renin-dependent hypertension. A process for preparing a compound of the formula : R 1 -NH-CH(R 2 )-C(=O)-CF 2 -CH(R 3 )NR a R b or the pharmaceutically acceptable salts thereof, wherein R 1 is Iva-(O-methyl)Tyr-nVal-; R 2 is cyclohexylmethyl ; R 3 is H ; R a is H ; R b is ; and Iva is isovaleryl, which comprises oxidizing a compound of the formula : with R" b being R b or P' g , P' g being a protecting group, said oxidation being effected according to oxidation procedures (a), (b), (c) or (d), as follows : (a) preparing an in situ sulfonium adduct by reacting about 2 to 6 equivalents of dimethylsulfoxide with about 1 to 3 equivalents of (CF 3 CO) 2 O or (COCl) 2 ; said reaction taking place in an inert solvent, under anhydrous conditions within the temperature range of about -80°C to -50°C, contacting said sulfonium adduct with about 1 equivalent of an alcohol of Formula VI, said alcohol being dissolved in an inert solvent or minimum amounts of dimethylsulfoxide, allowing the reactants to react at about -50°C for about 10 to 30 minutes, and completing the reaction by the addition of about 3 to 10 equivalents of a tertiary amine ; (b) reacting an alcohol of Formula VI with pyridinium dichromate by contacting the reactants together in a powdered water-trapping molecular sieve in the presence of glacial acetic acid at about 0°C to 50°C ; (c) reacting an alcohol for Formula VI with about 1 to 5 equivalents of a chromic anhydride-pyridine complex, said complex being formed in situ in an inert solvent under an inert atmosphere using anhydrous conditions, said reaction of the alcohol being effected in the chromic anhydride-pyridine complex-reaction mixture for about 1 to 15 hours ; (d) reacting an alcohol of Formula VI with 1,1,1-triacetoxy-2,1-benzoxiodol-3(3H)-one, said reaction being effected in an inert solvent under anhydrous conditions in an inert atmosphere for about 1 to 48 hours, reactions (a), (b), (c) or (d) being followed by an optional deprotection of any protected amine, followed by cleavage of P' g ; (e) optionally converting the obtained compound into one of its pharmaceutically acceptable salts. Claims for the following Contracting State : ES A process for preparing a compound of the formula : R 1 -NH-CH(R 2 )-C(=O)-CF 2 -CH(R 3 )NR a R b or the pharmaceutically acceptable salts thereof, wherein R 1 is Iva-(O-methyl)Tyr-nVal-; R 2 is cyclohexylmethyl ; R 3 is H ; R a is H ; R b is H ; and Iva is isovaleryl, which comprises oxidizing a compound of the formula : with R" b being R b or P' g , P' g being a protecting group, said oxidation being effected according to oxidation procedures (a), (b), (c) or (d), as follows : (a) preparing an in situ sulfonium adduct by reacting about 2 to 6 equivalents of dimethylsulfoxide with about 1 to 3 equivalents of (CF 3 CO) 2 O or (COCl) 2 ; said reaction taking place in an inert solvent, under anhydrous conditions within the temperature range of about -80°C to -50°C, contacting said sulfonium adduct with about 1 equivalent of an alcohol of Formula VI, said alcohol being dissolved in an inert solvent or minimum amounts of dimethylsulfoxide, allowing the reactants to react at about -50°C for about 10 to 30 minutes, and completing the reaction by the addition of about 3 to 10 equivalents of a tertiary amine ; (b) reacting an alcohol of Formula VI with pyridinium dichromate by contacting the reactants together in a powdered water-trapping molecular sieve in the presence of glacial acetic acid at about 0°C to 50°C ; (c) reacting an alcohol for Formula VI with about 1 to 5 equivalents of a chromic anhydride-pyridine complex, said complex being formed in situ in an inert solvent under an inert atmosphere using anhydrous conditions, said reaction of the alcohol being effected in the chromic anhydride-pyridine complex-reaction mixture for about 1 to 15 hours ; (d) reacting an alcohol of Formula VI with 1,1,1-triacetoxy-2, 1-benzoxiodol-3(3H)-one, said reaction being effected in an inert solvent under anhydrous conditions in an inert atmosphere for about 1 to 48 hours, reactions (a), (b), (c) or (d) being followed by an optional deprotection of any protected amine, followed by cleavage of P' g ; (e) optionally converting the obtained compound into one of its pharmaceutically acceptable salts. The use of a compound of formula : R 1 -NH-CH(R 2 )-C(=O)-CF 2 -CH(R 3 )NR a R b or pharmaceutically acceptable salts thereof, wherein R 1 is Iva-(O-methyl)Tyr-nVal-; R 2 is cyclohexylmethyl ; R 3 is H ; R a is H ; R b is H ; and Iva is isovaleryl, for the preparation of a medicament useful for the treatment of renin-dependent hypertension. Claims for the following Contracting State : GR A compound of the formula : R 1 -NH-CH(R 2 )-C(=O)-CF 2 -CH(R 3 )NR a R b or the pharmaceutically acceptable salts thereof, wherein R 1 is Iva-(O-methyl)Tyr-nVal-; R 2 is cyclohexylmethyl ; R 3 is H ; R a is H ; R b is H ; and Iva is isovaleryl. The use of a compound of formula : R 1 -NH-CH(R 2 )-C(=O)-CF 2 -CH(R 3 )NR a R b or pharmaceutically acceptable salts thereof, wherein R 1 is Iva-(O-methyl)Tyr-nVal-; R 2 is cyclohexylmethyl ; R 3 is H ; R a is H ; R b is H ; and Iva is isovaleryl, for the preparation of a medicament useful for the treatment of renin-dependent hypertension. A process for preparing a compound of the formula : R 1 -NH-CH(R 2 )-C(=O)-CF 2 -CH(R 3 )NR a R b or the pharmaceutically acceptable salts thereof, wherein R 1 is Iva-(O-methyl)Tyr-nVal-; R 2 is cyclohexylmethyl ; R 3 is H ; R a is H ; R b is H ; and Iva is isovaleryl, which comprises oxidizing a compound of the formula : with R" b being R b or P' g , P' g being a protecting group, said oxidation being effected according to oxidation procedures (a), (b), (c) or (d), as follows : (a) preparing an in situ sulfonium adduct by reacting about 2 to 6 equivalents of dimethylsulfoxide with about 1 to 3 equivalents of (CF 3 CO) 2 O or (COCl) 2 ; said reaction taking place in an inert solvent, under anhydrous conditions within the temperature range of about -80°C to -50°C, contacting said sulfonium adduct with about 1 equivalent of an alcohol of Formula VI, said alcohol being dissolved in an inert solvent or minimum amounts of dimethylsulfoxide, allowing the reactants to react at about -50°C for about 10 to 30 minutes, and completing the reaction by the addition of about 3 to 10 equivalents of a tertiary amine ; (b) reacting an alcohol of Formula VI with pyridinium dichromate by contacting the reactants together in a powdered water-trapping molecular sieve in the presence of glacial acetic acid at about 0°C to 50°C ; (c) reacting an alcohol for Formula VI with about 1 to 5 equivalents of a chromic anhydride-pyridine complex, said complex being formed in situ in an inert solvent under an inert atmosphere using anhydrous conditions, said reaction of the alcohol being effected in the chromic anhydride-pyridine complex-reaction mixture for about 1 to 15 hours ; (d) reacting an alcohol of Formula VI with 1,1,1-triacetoxy-2, 1-benzoxiodol-3(3H)-one, said reaction being effected in an inert solvent under anhydrous conditions in an inert atmosphere for about 1 to 48 hours, reactions (a), (b), (c) or (d) being followed by an optional deprotection of any protected amine, followed by cleavage of P' g ; (e) optionally converting the obtained compound into one of its pharmaceutically acceptable salts.

Inventors: SCHIRLIN DANIEL, SCHIRLIN, DANIEL
Applicants: MERRELL PHARMA INC, MERRELL PHARMACEUTICALS INC.
Application year: 1989
Main classification: C07K5
IPC codes: A61K31, C07D207, C07K5, A61K38, C07K1, C07D231, C07D239, C07C271, C07D213, A61P9, A61P43, C07D295, C07K14, C12N9