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WO1997038705A1 - Composes a base de n-formyl hydroxylamine convenant comme inhibiteurs de l'enzyme ace et/ou de l'endopeptidase nep - Google Patents

Composes a base de n-formyl hydroxylamine convenant comme inhibiteurs de l'enzyme ace et/ou de l'endopeptidase nep Download PDF

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Publication number
WO1997038705A1
WO1997038705A1 PCT/US1997/005744 US9705744W WO9738705A1 WO 1997038705 A1 WO1997038705 A1 WO 1997038705A1 US 9705744 W US9705744 W US 9705744W WO 9738705 A1 WO9738705 A1 WO 9738705A1
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Prior art keywords
alkyl
compound
aryl
heteroaryl
cycloalkyl
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PCT/US1997/005744
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English (en)
Inventor
Jeffrey A. Robl
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Bristol-Myers Squibb Company
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Priority to JP09537168A priority Critical patent/JP2000511882A/ja
Priority to EP97917889A priority patent/EP0894003A4/fr
Priority to AU26094/97A priority patent/AU715451B2/en
Publication of WO1997038705A1 publication Critical patent/WO1997038705A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention is directed to novel compounds possessing angiotensin converting enzyme (ACE) inhibitory activity and/or neutral endopeptidase (NEP) inhibitory activity and methods of preparing such compounds.
  • ACE angiotensin converting enzyme
  • NEP neutral endopeptidase
  • This invention is also directed to pharmaceutical compositions containing such ACE and/or NEP inhibiting compounds or pharmaceutically acceptable salts thereof and the method of using such compositions.
  • R is H, alkyl, alkenyl, aryl- (CH 2 ) p -, heteroaryl- (CH2) P -, cycloheteroalkyl- (CH2) p -, or
  • R can be joined together with the carbon to which it is attached to form a 3 to 7 membered ring which may optionally be fused to a benzene ring;
  • R 1 is H or -COR 2 where R 2 is alkyl, aryl- (CH2) P -, cycloheteroalkyl- (CH 2 ) P -, heteroaryl- (CH 2 ) P -, alkoxy, or cycloalkyl- (CH 2 ) p -;
  • p is 0 or an integer from 1 to 8; and
  • ' A is a dipeptide derived from one or two non-proteinogenic amino acid or is a conformationally restricted dipeptide mimic as described below.
  • A is a dipeptide derivative of the structure where R la , R lb , R 2a and R 2b are independently selected from H, alkyl, aryl- (CH 2 ) p -, cycloalkyl, cycloheteroalkyl- (CH 2 ) P -, heteroaryl- (CH2) p -, biphenylmethyl, or
  • R la and R lb or R 2a and R 2b may be joined together to the carbon to which they are attached to form a 3 to 7 membered ring, optionally fused to
  • a benzene optional 5 or 6 membered ring containing a single hetero atom and which may optionally include an R 5 substituent (as shown) which is H, alkyl, aryl- (CH 2 ) P or cycloalkyl- (CH 2 ) P , cycloheteroalkyl- (CH 2 ) P , or cycloheteroaryl- (CH 2 > p -;
  • R 3 is H, alkyl or aryl -(CH2)p-;
  • R 4 is OH, Oalkyl, 0- (CH 2 ) p aryl- or NR ⁇ (R 2 ) where Ri and R 2 are independently H, alkyl, or aryl(CH2) p or heteroaryl- (CH2) p -; with the proviso that in A(l) at least one of
  • ⁇ -amino acid is other than a natural ⁇ -amino acid, and thus must be other than valine, leucine, phenylalanine, tyrosine, serine, cysteine, threonine, methionine, aspartic acid, glutamic acid, arginine, lysine or proline.
  • A can be a conformationally restricted dipeptide mimic which has the structure and is a non-proteinogenic dipeptide.
  • formationally restricted dipeptide mimic refers to a structural skeleton which has the attributes of a conventional dipeptide
  • Examples of the A(2) dipeptide mimics include any of the conformationally restricted dipeptide mimics set out below. CH 2 orS(O) 0 i 2
  • R 11 and R 12 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl -(CH2)m _ ⁇ aryl -(CH2)m _ - substituted aryl -(CH2)m-» and heteroaryl -(CH2)m _ - or R 11 and
  • R 12 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R 11 and R 12 taken together with the carbon to which they are attached complete a keto substituent, i.e., ⁇
  • R 8 , R 9 and R 7 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl -(CH2)m ⁇ - aryl- (CH2)m ⁇ substituted aryl- (CH2)m _ - and heteroaryl- (CH2)rrr;
  • RlO and R ⁇ are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl -(CH2)m-/ aryl- (CH2)rrw substituted aryl -(CH2)m ⁇ / an ⁇ 3 heteroaryl- (CH2)m- ⁇ o ⁇ R 6 and R 10 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, R ⁇ and R 8 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R 9 and R 10 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons; m is zero or an integer from 1 to 6; R 4 is OH, Oalkyl, O- (CH 2 ) m -heteroaryl,
  • Ri and R 2 are independently H, alkyl, aryl(CH 2 ) p , aryl or heteroaryl,-
  • R.14 is hydrogen, lower alkyl, cycloalkyl, or phenyl
  • R 1 ⁇ is hydrogen, lower alkyl, lower alkoxy or phenyl
  • R 16 is alkyl or ary1- (CH2)m- • an ⁇ -
  • R ⁇ - 7 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl- (CH2)m-» aryl- (CH2)m-/ substituted aryl- (CH2)m _ - or heteroaryl- ( CH2 ) m- •
  • R 18 is H, alkyl or alkenyl, and R 18 and R 17 may be taken together with the carbon and nitrogen to which they are attached to complete a saturated N-containing ring of 5 or 6 ring members.
  • R 19 is H or an alkyl, and in A(4), R 19 and X (which is CH 2 ) together with the carbons to which they are attached may form an aromatic ring of carbons (as in A(15) .
  • the starting compounds H-A(l) and H-A(2) are described in the literature or are obtained by modifications of known procedures.
  • the starting compounds of formula H-A(l) or H-A(2) wherein A(l) or A(2) is as defined in formulas A(5-), A(13), A(16), A(21), where Y (where present) is CH 2 are disclosed by Thorsett et al., J. Med. Chem., 29_, p. 251 - 260 (1988), Harris et al. in U.S. Patents 4,587,050, 4,587,238, 4,629,787 and Yanagisawa et al. in U.S. Patent 4,734,410.
  • the starting compounds of formula H-A(l) or H-A ⁇ 2) wherein A(l) or A(2) is as defined in formula A(16) can be prepared by reduction of the corresponding starting compounds wherein A(l) or A(2) is as defined in formula A(3) .
  • H-A(2) wherein A(l) or A(2) is as defined in formula A(10) and Y is S, -SO, or -S ⁇ 2 are disclosed by Harris et al. and Patchett et al. in
  • H-A(2) wherein A ⁇ 1) or A(2) is as defined in formula A(12) are disclosed by Huang et al. in U.S.
  • Patent 4,465,679. The starting compounds of formula H-A(l) or
  • a pharmaceutical composition which includes a therapeutically effective amount of compound I and a pharmaceutically acceptable carrier therefor.
  • the pharmaceutical composition as defined above will be useful in the treatment of cardiovascular diseases such as hypertension and/or congestive heart failure.
  • a method for treating a cardiovascular disease such as hypertension and/or congestive heart failure, as well as other diseases as set out hereinafter, which includes the step of administering to a mammalian species, including humans, dogs and cats, a therapeutically effective amount of a composition as defined above.
  • alkyl or “lower alkyl” refers to straight or branched chain radicals having up to and including ten carbon atoms, preferably up to and including six carbon atoms, which may optionally include one, two, or three substituents including a hydroxy, amino, alkyl, cycloalkyl, aryl, halo, trifluoromethyl, cyano, -NH(lower alkyl), -N(lower alkyl) 2 , lower alkoxy, lower alkylthio, carboxy or heteroaryl.
  • alkenyl refers to straight or branched chain radicals of 3 to 10 carbon atoms having one or two double bonds, preferably straight chain radicals of 3 to 5 carbons having one double bond, which may optionally be substituted with one, two or three substituents including alkyl, aryl, cycloalkyl, hydroxy, amino, halo, trifluoromethyl, cyano, -NH(lower alkyl), -N(lower alkyl)2, lower alkoxy, lower alkylthio, carboxy or heteroaryl.
  • alkoxy or "lower alkoxy" and
  • alkylthio or “lower alkylthio” refer to such alkyl groups as defined above attached to an oxygen or sulfur.
  • cycloalkyl refers to saturated rings of 3 to 7 carbon atoms.
  • halo refers to chloro, bromo, fluoro, and iodo.
  • aryl refers to aromatic groups containing 6 to 10 carbons, preferably phenyl, 1- naphthyl, and 2-naphthyl, which may optionally contain one, two or three substituents selected from alkyl, alkoxy, alkylthio, halo, hydroxy, trifluoromethyl, -SO 2 NH 2 , amino, -NH(lower alkyl), or -N(lower alkyl) 2 , di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl, wherein said substituents are preferably selected from methyl, methoxy, methylthio, halo, hydroxy, and amino.
  • heteroaryl refers to unsaturated rings of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the total number of hetero atoms in the ring is 4 or less, which may optionally be substituted with one, two or three substituents which include alkyl, aryl, cycloalkyl, alkoxy or halo.
  • the heteroaryl ring is attached by way of an available carbon or nitrogen atom.
  • Preferred heteroaryl groups include 2-, 3-, or 4-pyridyl, 4-imidazolyl, 4-thiazolyl, 2- and 3-thienyl, and 2- and 3-furyl.
  • heteroaryl also includes bicyclic rings wherein the five or six membered ring containing 0, S, and N atoms as defined above is fused to a benzene or pyridyl ring.
  • Preferred bicyclic rings are 2- and 3-indolyl and 4- and 5-quinolinyl .
  • the mono or bicyclic heteroaryl ring can also be additionally substituted at an available carbon atom by a lower alkyl, halo, hydroxy, benzyl, or cyclohexylmethyl.
  • the mono or bicyclic ring has an available N-atom such N atom can also be substituted by an N- protecting group such as
  • the compounds of formula I of the invention may be prepared as outlined in Reaction Scheme I set out below (where x is 0 or 1) .
  • acid 2 may be reacted with a suitably O-protected (e.g. PG 1 is benzyl, p- methoxybenzyl, tetrahydropyranyl, trityl, benzhydryl, etc.) hydroxylamine to give the adduct 3.
  • PG 1 is benzyl, p- methoxybenzyl, tetrahydropyranyl, trityl, benzhydryl, etc.
  • PG 1 is benzyl, p- methoxybenzyl, tetrahydropyranyl, trityl, benzhydryl, etc.
  • compound 3 may be formylated with an formylating agent 4a to give acid compound 7.
  • This acid may be coupled with A(l) or A(2) directly or optically resolved to give 7* and then coupled to give compound 5.
  • Compound 5 is then converted to compound of the invention IA as describedabove.
  • the compounds of formula I of the invention contain one or more asymmetric centers. Thus, these compounds can exist in diastereoisomeric forms or in mixtures thereof and all of such forms are within the scope of this invention.
  • the above described processes can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric compounds are prepared, they can be separated by conventional chromatographic or fractional crystallization methods.
  • the compounds of formula I of the invention can be isolated in the form of a pharmaceutically acceptable salt.
  • Suitable salts for this purpose are alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and salts derived from amino acids such as arginine, lysine, etc. These salts are obtained by reacting the acid form of the compound with an equivalent of base supplying the desired ion in a medium in which the salt precipitates or in aqueous medium and then lyophilizing.
  • the compounds of formula I of the invention are inhibitors of angiotensin converting enzyme and/or neutral endopeptidase.
  • the compounds of formula I including their pharmaceutically acceptable salts are useful in the treatment of physiological conditions in which either angiotensin converting enzyme inhibitors or neutral endopeptidase inhibitors have been shown to be useful.
  • Such conditions include cardiovascular diseases, particularly, hypertension, congestive heart failure, renal failure, and hepatic cirrhosis, as well as analgesic activity.
  • the compounds of formula I are also inhibitors of other metalloproteases such as the matrix metalloproteases, for example, gelatinase, collagenase and stromylysin and thus are useful in the treatment of osteroarthritis, rheumatoid arthritis, metastatic tumors, and angiogenesis.
  • Diuresis, natriuresis, and blood pressure reduction are produced in a mammalian host such as man by the administration of from about 1 mg. to about 100 mg. per kg. of body weight per day, preferably from about 1 mg. to about 50 mg. per kg. of body weight per day, of one or more of the compounds of formula I or a pharmaceutically acceptable salt thereof.
  • the compounds of formula I are preferably administered orally, but parenteral routes such as subcutaneous, intramuscular, and intravenous can also be employed.
  • the daily dose can be administered singly or can be divided into two to four doses administered throughout the day.
  • the ACE and/or NEP inhibitors of formula I can be administered in combination with human ANF 99 - 126. Such combination would contain the inhibitor of formula I at from about 1 to about 100 mg. per kg. of body weight and the human ANF 99 - 126 at from about 0.001 to about 0.1 mg. per kg. of body weight.
  • the ACE and/or NEP inhibitors of formula I can be administered in combination with other classes of pharmaceutically active compounds.
  • a calcium channel blocker for example, a calcium channel blocker, a potassium channel activator, a cholesterol reducing agent, etc.
  • ACE and/or NEP inhibitors of formula I or a pharmaceutically acceptable salt thereof and other pharmaceutically acceptable ingredients can be formulated for the above described pharmacetical uses .
  • suitable compositions for oral administration include tablets, capsules, and elixirs
  • suitable compositions for parenteral administration include sterile solutions and suspensions.
  • About 10 to 500 mg. of active ingredient is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavoring, etc., in a unit dose form as called for by accepted pharmaceutical practice.
  • Preferred compounds of the invention are those of formula I wherein R 1 is H, x is 1, R is alkyl or arylalkyl, and A is A(l) , preferably
  • R la and R lb are each independently alkyl such as methyl or ethyl, or arylalkyl such as benzyl, or
  • R la and R lb together with the carbon to which they are attached form a 3-7 membered ring, preferably a 5-membered ring, or R la and/or R lb is biphenylmethylene and the other may be H.
  • A(l) preferably where non- proteino-genic amino acid where R 3 is H, alkyl, such as methyl or ethyl, aryl such as phenyl, or arylalkyl, such as benzyl,
  • R 2a and R 2b are independently selected from
  • 3-7 membered ring preferably 5- or 6-membered ring.
  • the aqueous phase was brought to pH 1.0 with 6 N_ HCI (70 ml) , extracted with EtOAc (3 x 500 ml) and the combined organic extracts were washed with brine (100 ml), dried (anhydrous Na2S ⁇ 4) , filtered, evaporated to dryness and dried in vacuo .
  • the crude product mixture was chromatographed on a silica gel column (Merck) , eluting the column with CH2Cl2:CH3 ⁇ H:HOAc (100:5:0.2) to give title compound as a thick yellow syrup (27.222 g, 70.7%) with consistent ⁇ H-MMR and 13 C-NMR spectral data.
  • TLC Rf 0.27 (Silica gel; CH2CI2 :CH3 ⁇ H:HOAc- 100:5:0.5; UV, PMA) .
  • Part A(2) compound (16.69 g, 56.3 mmoles) in dry dimethyformamide (121 ml) was treated with l-ethyl-3- (3-dimethylaminopropy1) - carbodiimide (10.64 g, 55.5 mmoles) and stirred at room temperature for 3.0 hours.
  • the reaction mixture was partitioned between EtOAc (2 x 492 ml) and 1.0 N NaHC ⁇ 3 (492 ml), and the combined organic extracts were washed with H2O (3 x 492 ml) , brine (492 ml), dried (anhydrous MgS ⁇ 4), filtered, evaporated to dryness and dried in vacuo.
  • Example 1 Part E Isomers A and B (1:1 mixture of diastereomers, 535 mg, 0.87 mmol) in MeOH (10 mL) was hydrogenated (balloon) over 10% Pd/C (123 mg) at room temperature for 2.75 hours. The solvent was filtered through Celite and the filtrate was stripped to give a diastereomeric mixture of Isomers A and B. Trituration of a solution of the residue in MeOH with Et 2 ⁇ provided 350 mg of the diastereomeric mixture.
  • the aqueous layer was extracted with CH 2 C1 2 (2x700 ml) .
  • the CH 2 C1 2 extracts were combined, washed with brine, dried over anhydrous Mg 2 S ⁇ 4 and evaporated in vacuo.
  • the black residue was passed through a pad of silica gel (E. Merck, 230-400 mesh, 900 g) eluting with EtOAc-hexane (1:1) to afford a tic-homogeneous title compound (144.8 g) as a yellow oil in 93% in yield.
  • Part B(7) compound (124.8 g, 296.81 mmole) and 10% Pd/C (32g) in dry DMF (2.0 L) was hydrogenated for 24 hours. After completion, argon was bubbled through the reaction mixture to remove excess hydrogen and methyl sulfide (2.6 ml) was added to poison the palladium.
  • 1-hydroxybenzotriazole hydrate 46.74 g
  • ethyl-3 (3-dimethylamino) - propylcarbodiimide hydrochloride salt (68.74 g) .
  • the resulting solution was stirred at room temperature under argon for 3.5 hours, diluted with EtOAc (2 L) and filtered through a pad of celite.
  • Part A compound (641 mg, 1.42 mmol) was partitioned between EtOAc and 5% KH 2 PO 4 (adjusted to pH 2.5 with H 3 PO 4 ) . The layers were separated and the aqueous layer was back-extracted with EtOAc. The pooled EtOAc extracts were washed with brine, dried (Na 2 S ⁇ 4) , filtered and stripped to give an oil (assume 1.42 mg) . The oil was dissolved in CH 2 CI 2 (10 mL) and the resulting solution was treated with Part B amine (364 mg, 1.50 mmol) in CH 2 C1 2 (2 mL) and cooled to 0°C.
  • Acetic anhydride 500 ⁇ L was added to formic acid (5.0 mL) at 0°C and the mixture was stirred for 30 minutes. Approximately 2.6 mL of this solution was added to a solution of Part C compound (208 mg, 0.413 mmol) in THF (1.1 mL) at 0°C. After 30 minutes, most of the solvent was removed by rotary evaporation and the residue was partitioned between EtOAc and saturated NaHC0 3 . The EtOAc extract was washed with brine, dried (Na 2 S ⁇ 4 ) , filtered and stripped to give title compound (216 mg, 97%) as an oily foam which was used directly in the next reaction without futher purification.
  • Part D compound 216 mg, 0.402 mmol
  • absolute EtOH 5 mL
  • Pd/C 33 mg
  • the mixture was filtered through Celite, stripped, and azeotroped twice with EtOAc/Et 2 ⁇ /hexanes to give title compound (174 mg, 97%) as an off-white foam.
  • Solid sodium azide (26.0 g., 0.2 mole) was introduced into a 3-neck round-bottom flask with an overhead stirrer, made into a paste with warm water (26 ml), layered with chloroform (160 ml) and cooled down to 0° (ice-salt bath) .
  • the mixture was treated dropwise with concentrated sulfuric acid (11.2 ml, 0.5 eq.) over a period of 10 minutes, stirred for an additional 10 minutes then decanted into a flask containing anhydrous sodium sulfate.
  • the dried solution was filtered through a glass wool plug in a funnel into a 500-ml round-bottom flask. Titration of an aliquot (1.0 ml) with 1.0 N NaOH using phenolphthalein as an indicator gave a normalitity of 1.7 N for the hydrazoic acid.
  • Tetralone (15.94 g, 0.108 mole) was added to the hydrazoic acid solution (0.136 mole or 1.25 eq. ) , heated to 40-45° (oil bath) then treated dropwise with 36.0 N H2SO4 (28.7 ml, 5 eq. ) over a period of 1.0 hour. (Intense bubbling took place with each drop added for the first 30 minutes) . The reaction mixture was cooled down to room temperature, poured into H2O (720 ml) and stirred for 5 minutes.
  • Part A(3) compound (10.858 g, 53.7 mmoles) in dry tetrahydrofuran (100 ml) was treated with Bu4NBr (1.791 g, 5.56 mmoles) and powdered KOH (3.937 g, 70.2 mmoles) followed by ethyl bromoacetate (6.8 ml, 61.3 mmoles).
  • the reaction mixture was stirred at room temperature under argon for 1.5 hours then partitioned between H20 (196 ml) and CH2CI2 (2 x 375 ml) .
  • Part A(4) compound (8.95 g, 31.0 mmoles) in absolute ethanol (50 ml) was treated with 10% Pd/C (443 mg) and hydrogenated at 45 psi for 3.5 hours, venting the Parr bottle every 30 minutes for the first 1.5 hours.
  • the mixture was filtered through a Celite ® pad in a millipore unit, washing the pad well with absolute ethanol (3 x 50 ml) .
  • the clear filtrate was evaporated to dryness and dried in vacuo to give title compound as a thick yellow syrup (7.929 g, 97.5%) with consistent 1 H-NMR and 13 C-NMR spectral data.
  • TLC Rf 0.45 (Silica gel; CH2CI2 :CH3 ⁇ H- 9:1; UV) .
  • Example 3 Part A ephedrine salt (414 mg, 0.93 mmole), was partitioned between 5 % KH2PO4 (adjusted to pH 2.5; 4.0 ml) and EtOAc ( 2 x 20 ml) and the combined organic extracts were washed with brine (4.0 ml), dried (anhydrous Na2S ⁇ 4) , filtered, evaporated to dryness and dried in vacuo to give the free acid of the Example 4 Part A compound as a clear syrup (286.6 mg, 100 % crude yield) .
  • Part D compound 256.7 mg
  • CH3OH 3.5 ml
  • 1.0 N NaOH 2.17 ml, 4 eq
  • the reaction mixture was brought to pH 1.0 with 5% KHSO4 (9.45 ml), extracted with EtOAc (40 ml) and the organic extract washed with brine (5.0 ml), dried (anhydrous Na2S ⁇ 4) , filtered, evaporated to dryness and dried in vacuo .
  • the reaction mixture was partitioned between EtOAc (2 x 200 ml) and H2O (60 ml) and the combined organic extracts were washed sequentially with 0.5 N. HCI (60 ml), H2O (60 ml), 1/2 saturated NaHC03 (60 ml) and brine (60 ml), dried (anhydrous Na2S04), filtered, evaporated to dryness and dried in vacuo .
  • the crude product mixture was chromatographed on a silica gel column (Merck, 200 g) , eluting the column with EtOAc to give the desired product as a syrup (4.0 g) .
  • reaction mixture was stirred at -78°C for 5.0 minutes, allowed to come to room temperature over a period of 45 minutes, then partitioned between EtOAc (200 ml) and 0.5 N HCI (2 x 20 ml) . The organic phase was washed with brine (40 ml) , dried (anhydrous
  • Part D compound 1.238 g, 3.06 mmoles
  • dry DMF 3.5 ml
  • benzyl bromide 0.35 ml, 2.94 mmoles
  • CS2CO3 450 mg, 1.38 mmoles
  • the mixture was diluted with EtOAc (50 ml) , washed with H2O (5.0 ml), 0.5 N HCI (5.0 ml) and brine (5.0 ml) , dried (anhydrous Na2 ⁇ 4) , filtered, evaporated to dryness and dried in vacuo .
  • Part E compound (586 mg, 1.18 mmoles) in dry methanol (15 ml) was treated with NH2NH2»H2 ⁇ (66 ⁇ l, 1.2 eq) and stirred at room temperature for 48 hours.
  • the reaction mixture was diluted with Et2 ⁇ (50 ml) and filtered through a millipore unit, washing the solids well with Et2 ⁇ (40 ml) .
  • the clear solution was evaporated to dryness and the solids obtained were suspended in CH2CI2 (90 ml) and the solution filtered through a millipore unit, washing the solids well with CH2CI2 (40 ml) .
  • Example 3 Part A ephedrine salt (538 mg, 1.2 mmoles), was partitioned between 5% KH2PO4
  • Part H compound (535 mg, 0.78 mmole) in CH3OH (15 ml) was treated with 10 % Pd/C
  • TLC Rf 0.38 (Silica gel; CH2Cl2:MeOH- 9:1; UV) .

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Abstract

La présente invention concerne des n-formyl hydroxylamines représentés par la structure (I). R et R1 sont conformes à la description qui en est donnée dans la demande, et A est un dipeptide dérivé d'un acide aminé ou est un dipeptide mimique à conformation restreinte.
PCT/US1997/005744 1996-04-12 1997-04-07 Composes a base de n-formyl hydroxylamine convenant comme inhibiteurs de l'enzyme ace et/ou de l'endopeptidase nep WO1997038705A1 (fr)

Priority Applications (3)

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JP09537168A JP2000511882A (ja) 1996-04-12 1997-04-07 Ａｃｅ阻害剤及び／またはｎｅｐ阻害剤として有用なｎ―ホルミルヒドロキシルアミン化合物
EP97917889A EP0894003A4 (fr) 1996-04-12 1997-04-07 Composes a base de n-formyl hydroxylamine convenant comme inhibiteurs de l'enzyme ace et/ou de l'endopeptidase nep
AU26094/97A AU715451B2 (en) 1996-04-12 1997-04-07 N-formyl hydroxylamine containing compounds useful as ace inhibitors and/or NEP inhibitors

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US60/016,295 1996-04-12

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WO1999039704A1 (fr) * 1998-02-07 1999-08-12 British Biotech Pharmaceuticals Limited Agents antibacteriens
WO2000035440A1 (fr) * 1998-12-16 2000-06-22 British Biotech Pharmaceuticals Limited Derives d'hydroxylamine n-formyle utilises comme agents antibacteriens
WO2000058294A1 (fr) * 1999-03-29 2000-10-05 British Biotech Pharmaceuticals Limited Agents antibacteriens
WO2001083423A3 (fr) * 2000-04-28 2002-02-21 Degussa Acide 2,6-diamino-6-methyl-heptanoique et derives, procede de preparation et utilisation correspondants
US6509330B2 (en) 2000-02-17 2003-01-21 Bristol-Myers Squibb Company Hydroxamic acid containing compounds useful as ACE inhibitors and/or NEP inhibotors
US6509331B1 (en) 1998-06-22 2003-01-21 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6528505B1 (en) 1998-06-22 2003-03-04 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6635632B1 (en) 1996-12-23 2003-10-21 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6774125B2 (en) 1998-06-22 2004-08-10 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6838455B2 (en) 1998-06-22 2005-01-04 Athena Neurosciences, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
US6906056B2 (en) 1998-06-22 2005-06-14 Elan Pharmaceuticals, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6908911B1 (en) * 1999-08-10 2005-06-21 British Biotech Pharmaceuticals Limited Antibacterial agents
US6958330B1 (en) 1998-06-22 2005-10-25 Elan Pharmaceuticals, Inc. Polycyclic α-amino-ε-caprolactams and related compounds
WO2016191178A1 (fr) * 2015-05-22 2016-12-01 Biotheryx, Inc. Protéines de ciblage de composés, compositions, méthodes, et leurs utilisations
US9938302B2 (en) 2016-05-18 2018-04-10 Biotheryx, Inc. Chimeric compounds targeting proteins, compositions, methods, and uses thereof
CN110678178A (zh) * 2017-03-16 2020-01-10 西建卡尔有限责任公司 Mk2抑制剂的形式和组合物

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US7390801B2 (en) 1996-12-23 2008-06-24 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6951854B1 (en) 1996-12-23 2005-10-04 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US7153847B2 (en) 1996-12-23 2006-12-26 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6635632B1 (en) 1996-12-23 2003-10-21 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6787522B2 (en) 1998-02-07 2004-09-07 British Biotech Pharmaceuticals Antibacterial agents
GB2349884A (en) * 1998-02-07 2000-11-15 British Biotech Pharm Antibacterial agents
US7148198B2 (en) 1998-02-07 2006-12-12 British Biotech Pharmaceuticals, Ltd. Antibacterial agents
US6423690B1 (en) 1998-02-07 2002-07-23 British Biotech Pharmaceuticals Ltd. Antibacterial agents
US7323448B2 (en) 1998-02-07 2008-01-29 British Biotech Pharmaceuticals Ltd. Antibacterial agents
WO1999039704A1 (fr) * 1998-02-07 1999-08-12 British Biotech Pharmaceuticals Limited Agents antibacteriens
US6696438B2 (en) 1998-06-22 2004-02-24 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6528505B1 (en) 1998-06-22 2003-03-04 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6509331B1 (en) 1998-06-22 2003-01-21 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6774125B2 (en) 1998-06-22 2004-08-10 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6838455B2 (en) 1998-06-22 2005-01-04 Athena Neurosciences, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
US6906056B2 (en) 1998-06-22 2005-06-14 Elan Pharmaceuticals, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6958330B1 (en) 1998-06-22 2005-10-25 Elan Pharmaceuticals, Inc. Polycyclic α-amino-ε-caprolactams and related compounds
WO2000035440A1 (fr) * 1998-12-16 2000-06-22 British Biotech Pharmaceuticals Limited Derives d'hydroxylamine n-formyle utilises comme agents antibacteriens
US6476067B1 (en) 1998-12-16 2002-11-05 British Biotech N-formyl hydroxylamine derivatives as antibacterial agents
US6503897B1 (en) 1999-03-29 2003-01-07 British Biotech Pharmaceuticals Ltd. Antibacterial agents
WO2000058294A1 (fr) * 1999-03-29 2000-10-05 British Biotech Pharmaceuticals Limited Agents antibacteriens
US6908911B1 (en) * 1999-08-10 2005-06-21 British Biotech Pharmaceuticals Limited Antibacterial agents
US6509330B2 (en) 2000-02-17 2003-01-21 Bristol-Myers Squibb Company Hydroxamic acid containing compounds useful as ACE inhibitors and/or NEP inhibotors
WO2001083423A3 (fr) * 2000-04-28 2002-02-21 Degussa Acide 2,6-diamino-6-methyl-heptanoique et derives, procede de preparation et utilisation correspondants
US6504047B2 (en) 2000-04-28 2003-01-07 Degussa Ag 2,6-diamino-6-methyl-heptanoic acid and derivatives, process for the preparation thereof and use thereof
US10669260B2 (en) 2015-05-22 2020-06-02 Biotheryx, Inc. Compounds targeting proteins, compositions, methods, and uses thereof
WO2016191178A1 (fr) * 2015-05-22 2016-12-01 Biotheryx, Inc. Protéines de ciblage de composés, compositions, méthodes, et leurs utilisations
US9822098B2 (en) 2015-05-22 2017-11-21 Biotheryx, Inc. Compounds targeting proteins, compositions, methods, and uses thereof
CN107787320A (zh) * 2015-05-22 2018-03-09 拜欧赛里克斯公司 靶向蛋白质的化合物、其组合物、方法和用途
CN107787320B (zh) * 2015-05-22 2020-12-04 拜欧赛里克斯公司 靶向蛋白质的化合物、其组合物、方法和用途
RU2694895C2 (ru) * 2015-05-22 2019-07-18 Биотерикс, Инк. Нацеленные на белки соединения, их композиции, способы и применения
US10144745B2 (en) 2016-05-18 2018-12-04 Biotheryx, Inc. Chimeric compounds targeting proteins, compositions, methods, and uses thereof
US10562917B2 (en) 2016-05-18 2020-02-18 Biotheryx, Inc. Chimeric compounds targeting proteins, compositions, methods, and uses thereof
US9938302B2 (en) 2016-05-18 2018-04-10 Biotheryx, Inc. Chimeric compounds targeting proteins, compositions, methods, and uses thereof
CN110678178A (zh) * 2017-03-16 2020-01-10 西建卡尔有限责任公司 Mk2抑制剂的形式和组合物
CN110678178B (zh) * 2017-03-16 2023-10-03 百时美施贵宝公司 Mk2抑制剂的形式和组合物

Also Published As

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AU2609497A (en) 1997-11-07
EP0894003A1 (fr) 1999-02-03
CA2251292A1 (fr) 1997-10-23
EP0894003A4 (fr) 2000-10-04
JP2000511882A (ja) 2000-09-12
AU715451B2 (en) 2000-02-03

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