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WO1997038705A1 - N-formyl hydroxylamine containing compounds useful as ace inhibitors and/or nep inhibitors - Google Patents

N-formyl hydroxylamine containing compounds useful as ace inhibitors and/or nep inhibitors 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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French (fr)
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Jeffrey A. Robl
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Bristol-Myers Squibb Company
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Priority to AU26094/97A priority Critical patent/AU715451B2/en
Priority to JP09537168A priority patent/JP2000511882A/en
Priority to EP97917889A priority patent/EP0894003A4/en
Publication of WO1997038705A1 publication Critical patent/WO1997038705A1/en

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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

N-formyl hydroxylamines are provided which have structure (I) wherein R and R1 are as defined herein and A is a dipeptide derived from an amino acid or is a conformationally restricted dipeptide mimic.

Description

N-FORMYL HYDROXYLAMINE CONTAINING COMPOUNDS USEFUL AS ACE INHIBITORS AND/OR NEP INHIBITORS
Summary of the Invention 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. 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.
The compounds of this invention are those of the formula (I)
Figure imgf000003_0001
including a pharmaceutically acceptable salt thereof where: x is 0 or 1;
R is H, alkyl, alkenyl, aryl- (CH2)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; R1 is H or -COR2 where R2 is alkyl, aryl- (CH2)P-, cycloheteroalkyl- (CH2)P-, heteroaryl- (CH2)P-, alkoxy, or cycloalkyl- (CH2)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
Figure imgf000004_0001
where Rla, Rlb, R2a and R2b are independently selected from H, alkyl, aryl- (CH2)p-, cycloalkyl, cycloheteroalkyl- (CH2)P-, heteroaryl- (CH2)p-, biphenylmethyl, or
Rla and Rlb or R2a and R2b 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
Figure imgf000004_0002
optional 5 or 6 membered ring containing a single hetero atom and which may optionally include an R5 substituent (as shown) which is H, alkyl, aryl- (CH2)P or cycloalkyl- (CH2)P, cycloheteroalkyl- (CH2)P, or cycloheteroaryl- (CH2>p-;
R3 is H, alkyl or aryl -(CH2)p-; R4 is OH, Oalkyl, 0- (CH2)paryl- or NRι(R2) where Ri and R2 are independently H, alkyl, or aryl(CH2)p or heteroaryl- (CH2)p-; with the proviso that in A(l) at least one of
Figure imgf000004_0003
is other than a natural α-amino acid, and thus must be other than valine, leucine, phenylalanine, tyrosine, serine, cysteine, threonine, methionine, aspartic acid, glutamic acid, arginine, lysine or proline.
In addition, A can be a conformationally restricted dipeptide mimic which has the structure
Figure imgf000005_0001
and is a non-proteinogenic dipeptide.
Thus, the compound of formula I include
Figure imgf000005_0002
and
Figure imgf000005_0003
The term "conformationally restricted dipeptide mimic" refers to a structural skeleton which has the attributes of a conventional dipeptide
R O R O NH-C IH-CII NH-CIH-CII— but having enhanced biological properties due to additional bonds which limit the rotational freedom.
Examples of the A(2) dipeptide mimics include any of the conformationally restricted dipeptide mimics set out below. CH2 orS(O)0i2
NH
Figure imgf000006_0001
(R5 H)
, H
Figure imgf000006_0002
where Z = O or H, H where Y = O, S, CH2 orS(0)0,ι,2
Figure imgf000006_0003
where Y = O, S, CH2 )o,1>2
Figure imgf000007_0001
With respect to A(5) , R11 and R12 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 R11 and
R12 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R11 and R12 taken together with the carbon to which they are attached complete a keto substituent, i.e., \
C=0 ;
with respect to A(13) R8, R9 and R7 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-< oτ R6 and R10 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, R^ and R8 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R9 and R10 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; R4 is OH, Oalkyl, O- (CH2)m-heteroaryl,
Figure imgf000008_0001
R" or
NRι(R2); where Ri and R2 are independently H, alkyl, aryl(CH2)p, aryl or heteroaryl,-
R.14 is hydrogen, lower alkyl, cycloalkyl, or phenyl;
R1^ is hydrogen, lower alkyl, lower alkoxy or phenyl;
R16 is alkyl or ary1- (CH2)m- • anά-
R^-7 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl- (CH2)m-» aryl- (CH2)m-/ substituted aryl- (CH2)m_- or heteroaryl- (CH2)m- •
R18 is H, alkyl or alkenyl, and R18 and R17 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. R19 is H or an alkyl, and in A(4), R19 and X (which is CH2) 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. For example, 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 CH2 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 formulas A(3) and A(13) where Y is S(0)n are disclosed by Yanagisawa et al., J., Med. Chem., 30, p. 1984 - 1991 (1987) and 31, p. 422 - 428 (1988), Karanewsky in U.S. Patent 4,460,579, Cheung et al. in U.S. Patent 4,594,341, and Yanagisawa et al. in U.S. Patent 4,699,905.
The starting compounds of formula H-A(l) or H-A(2) wherein A(l) or A(2) is as defined in formula A(5) are disclosed by Karanewsky in U.S. Patents 4,460,579 and 4,711,884.
The starting compounds of formula H-A(l) or H-A(2) wherein A(l) or A(2) is as defined in formulas A(3) (Y is -CH2-, and A(21) are disclosed by Watthey et al. , J. Med. Chem., 28., p. 1511 - 1516 (1985) and Watthey in U.S. Patents 4,410,520, 4,470,988, 4,473,575, 4,537,885 and 4,575,503 and also by Parsons et al. , Biochemical & Biophysical Research Comm., 117, p. 108 - 113 (1983) and in U.S. Patent 4,873,235.
The starting compounds of formula H-A(l) or H-A(2) wherein A(l) or A(2) is as defined in formula A(3) and Y is S or 0 are disclosed by Slade et al., J. Med. Chem., 28, p. 1517 - 1521 (1985) and in U.S. Patent 4,477,464 and Itoh et al. , Chem. Pharm. Bull., 3_4, P- 1128 - 1147 (1986) and 34, P- 2078 - 2089 (1986) as well as Sugihara et al. in U.S. Patent 4,548,932 (Y is 0) and Katakami et al. in U.S. Patent 4,539,150 (Y is S) .
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) .
The starting compounds of formula H-A(l) or H-A(2) wherein A(l) or A(2) is as defined in formula A(22) are disclosed by Flynn et al in U.S.
Patent 4,973,585.
The starting compounds of formula H-A(l) or
H-A(2) wherein A(l) or A(2) is as defined in formula A(10) and Y is S, -SO, or -Sθ2 are disclosed by Harris et al. and Patchett et al. in
U.S. Patents 4,415,496 and 4,617,301.
The starting compounds of formula H-A(l) or
H-A(2) wherein A(l) or A(2) is as defined in formula A(10) and Y is CH2, and is as defined in formula A(23) where X2 is CH2 is disclosed by
Thorsett, Actual. Chim. Ther., 12, P- 257-268
(1986) .
The starting compounds of formula H-A{1) or H-A(2) wherein A(l) or A(2) is as defined in formulas A(11) and A(19) and A(20) are disclosed by
Attwood et al. , Federation of European Biochemical
Studies, 165. p. 201-206 (1984) and in U.S. Patent
4,512,994 and Natoff et al. , Drugs Of The Future, 12, p. 475-483 (1987) .
The starting compounds of formula H-A(l) or
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
H-A(2) wherein A(l) or A(2) is as defined in formula A(18) are disclosed by Bolos et al. in
Tetrahedron, 48, P- 9567-9576 (1992) .
The starting compounds of formula H-A(l) or H-A(2) wherein A(l) or A(2) is as defined in formulas A(4) and A(15) are disclosed in European
Patent Application 0629627A2.
The starting compounds of formula H-A(l) or
H-A(2) wherein A(l) or A(2) is as defined in formula A(9) are disclosed in U.S. application
Serial No. 100,408 (file HA611a) . The starting compounds of formula H-A(l) or H-A(2) wherein A(l) or A(2) is as defined in formulas A(7) and A(8) are disclosed in European Patent Application 481,522 (Flynn et al) and European Patent Application 0534363A2 (Warshawsky et al) .
The starting compounds of formula H-A(l) or H-A(2) wherein A(l) or A(2) is as defined in formula A(14) are disclosed in U.S. application Serial No. 153,854 (file HA615) .
The starting compounds of formula H-A(l) or H-A(2) wherein A(l) or A(2) is as defined in formula A(17) are disclosed in European Patent Application 0599444A1 (Barrish et al) . In addition, in accordance with the present invention, a pharmaceutical composition is provided 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.
Furthermore, in accordance with the present invention, a method is provided 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.
Detailed Description Of The Invention The term "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.
The term "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. The terms "alkoxy" or "lower alkoxy" and
"alkylthio" or "lower alkylthio" refer to such alkyl groups as defined above attached to an oxygen or sulfur.
The term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms.
The term "halo" refers to chloro, bromo, fluoro, and iodo.
The term "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, -SO2NH2, 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.
The term "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. The term 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. Also, if the mono or bicyclic ring has an available N-atom such N atom can also be substituted by an N- protecting group such as
Figure imgf000013_0001
2, 4-dinitrophenyl, lower alkyl, benzyl, or benzhydryl.
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) .
Reaction Scheme I
VC02H PG1.0.NH PG 1-α iΛ /C02H optional chiral PG1-α /A ,C02H έ NT\ ζγ resolution Pf /χT
R . H A R .- - 3.* H " o R
3 (optically pure or
(Q is CH2, where x-1 and ennched)
Q is H, Br where x=0)
H-A(1) or H-A(2)
Hawιm '"?'
Figure imgf000014_0001
Figure imgf000014_0002
IA
As shown in Scheme I, acid 2 may be reacted with a suitably O-protected (e.g. PG1 is benzyl, p- methoxybenzyl, tetrahydropyranyl, trityl, benzhydryl, etc.) hydroxylamine to give the adduct 3. Compound 3 may be coupled directly with amine H-A(l) or H-A(2) to give a mixture of diastereomers which may be separated or preferably compound 3 may be optically enriched or purified, employing conventional techniques, to give 3*. Subsequent coupling with H-A(l) or H-A(2) gives 4 in diastereomerically enriched or pure form.
Reaction of the hydroxylamine nitrogen of 4 with a foππylating agent affords 5. At this point one or both protecting groups may be removed, either sequentially or simultaneously, to produce compound of the invention IA. For example, when PG^ is benzyl and R4 is Obenzyl, both may be removed by hydrogenolysis. When PG1 is benzyl and R4 is "Omethyl or "Oethyl, the PG1 group may be removed by hydrogenolysis and the ester group may be converted to the acid by base hydrolysis. PG1 groups such as THP or trityl may be removed by treatment with strong acid such as hydrogen chloride or trifluoro acetic acid in a protic solvent. Alternately, compounds of the invention IA may be obtained by the route depicted in Scheme II (where x is 0 or 1) .
Reaction Scheme II
Acylation
PGl-α H-CO-O-COR optional chiral
Figure imgf000015_0001
4 4aa resolution
Figure imgf000015_0002
H-A(1) or H-A(2)
Figure imgf000015_0003
As seen in Reaction Scheme II, 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. Thus, 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. For example, a calcium channel blocker, a potassium channel activator, a cholesterol reducing agent, etc.
The 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, and 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 R1 is H, x is 1, R is alkyl or arylalkyl, and A is A(l) , preferably
where
Figure imgf000018_0001
is preferably a non-proteinogenic amino acid portion wherein,
Rla and Rlb are each independently alkyl such as methyl or ethyl, or arylalkyl such as benzyl, or
Rla and Rlb together with the carbon to which they are attached form a 3-7 membered ring, preferably a 5-membered ring, or Rla and/or Rlb is biphenylmethylene and the other may be H.
Also preferred are compounds where A is
A(l) , preferably where
Figure imgf000018_0002
non- proteino-genic amino acid where R3 is H, alkyl, such as methyl or ethyl, aryl such as phenyl, or arylalkyl, such as benzyl,
R2a and R2b are independently selected from
H, alkyl, aryl, arylalkyl (with at least one of R2a and R2b being other than H) or R2a and R2b together with the carbon to which they are attached form a
3-7 membered ring, preferably 5- or 6-membered ring.
Also preferred are compounds where A is
A(2) wherein R4 is OH. The following Examples represent preferred embodiments of the present invention. Example 1
Figure imgf000019_0001
A .
Figure imgf000019_0002
A solution of BOC-L-serine (24.3 g, 0.118 mole) in dry dimethylformamide (25 ml) was added dropwise over a period of 1.0 hour to a cooled (0°, ice-salt bath) suspension of 60% NaH (10.1 g, 0.25 mole) in dry dimethylformamide (200 ml) and stirring was continued at 0° until the frothing subsided (ca. 2.0 hours) . The reaction mixture was treated dropwise with 1-fluoro-2-nitrobenzene (14.3 ml, 0.13 mole) over a period of 20 minutes, stirred at 0° under argon for 4.0 hours then poured into ice-water (750 ml) and extracted with Et2θ (2 x 100- ml) . 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 Na2Sθ4) , 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:CH3θH:HOAc (100:5:0.2) to give title compound as a thick yellow syrup (27.222 g, 70.7%) with consistent ^H-MMR and 13C-NMR spectral data. TLC: Rf 0.27 (Silica gel; CH2CI2 :CH3θH:HOAc- 100:5:0.5; UV, PMA) .
Figure imgf000020_0001
A solution of Part A(l) compound (27.1 g,
83 mmoles) in dry methanol (500 ml) was treated with 10% Pd/C (900 mg) and hydrogenated at 40 psi for 2.0 hours. The reaction mixture was filtered through a Celite® pad in a millipore unit, washing the pad well with CH3OH (5 x 100 ml) . The dark filtrate was evaporated to dryness and dried in vacuo to give a dark solid. The crude product was triturated with CH2CI2 :Hexane (1:4) to give title compound as a light tan solid (17.69 g, 71. %) with consistent iH-NMR and 13C-NMR spectral data. TLC: Rf 0.15 (Silica gel; CH2CI2 :CH3θH:HOAc- 20:1:1; UV) .
A(3)
Figure imgf000020_0002
A solution of 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 NaHCθ3 (492 ml), and the combined organic extracts were washed with H2O (3 x 492 ml) , brine (492 ml), dried (anhydrous MgSθ4), filtered, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a silica gel column (Merck) , eluting the column with EtOAc:Hexane mixtures (1:4; 1:2; 1:1) to give title compound as off-white crystals (10.5 g, 72.4%) with consistent -NMR and I^Q-I^R spectral data. TLC: Rf 0.40 (Silica gel; EtOAc:Hexane- 1:4; UV) .
H O C02Bn
A solution of Part A compound (640 mg, 2.30 mmol) in dry THF (12 mL) at 0°C was treated with LiN(TMS)2 (1.0 M in THF, 2.60 mL, 2.60 mmol) followed approximately 30 seconds later with benzyl bromoacetate (475 μL, 687 mg, 3.0 mmol) . After 25 minutes, the mixture was quenched with saturated NH4CI, diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed with H2O and brine, then dried (Na2S04), filtered and stripped to give a yellow oil. Flash chromatography (Merck Siθ2, 3/7-EtOAc/hexanes as eluant) provided title compound (967 mg, 98%) as a colorless oil/foam.
Figure imgf000021_0001
A solution of Part B compound (960 mg, 2.25 mmol) in 1,4-dioxane (4 mL) was treated with a solution of 4.0 M HCI in 1,4-dioxane (6 mL) at room temperature. After 3 hours, the mixture was concentrated in vacuo, triturated with Et2θ to give a solid and stripped to afford title compound (858 mg, 105% of theory) . m.p. 152-155°C.
Figure imgf000022_0001
D(l) .
Figure imgf000022_0002
A solution of benzylmalonic acid (23.06 g, 0.12 mole) in H2O (200 mL) was treated with 37% CH20 solution (278.4 mL) and 40% aqueous (CH3)2NH (35 mL, 0.31 mole) then stirred overnight at room temperature under argon. The clear solution was heated to an internal temperature of 90°C for 2.0 hours (at which time gas evolution had ceased) , cooled and acidified to pH 1.0 with 12 N HCI (20 mL) . The white precipitates were filtered off, washed with H2O (3 x 25 mL) and dried in vacuo to give title compound as a white solid (12.85 g, 66.6%) with consistent iH-NMR and 13C-NMR spectral data. TLC: Rf 0.63 (Silica gel; CH2Cl2:MeOH- 9:1; UV) . m.p. 66-68°C. D ( 2 ) .
Figure imgf000023_0001
(J. Med. Chem. 28, 1985, 1167)
A solution of Part D(l) compound (8.9 g,
54.9 mmoles) and O-benzylhydroxylamine (26.7 g,
0.23 mole) in absolute EtOH (9.0 ml) was refluxed for 7 days, cooled to room temperature and evaporated to dryness. The residual syrup was dissolved in 1.0 N NaOH (55 ml), stirred for 15 minutes then extracted with EtOAc (4x 18 ml) . The organic phase was washed with H2O (3 x 10 ml) and the aqueous extracts were combined and acidified to pH 2.0 with 1.0 N HCI (62 ml) . The acidic aqueous phase was then extracted with EtOAc (5 x 75 ml) and the combined organic extracts washed with H2O (2 x 30 ml), dried (anhydrous Na2Sθ4) , filtered, evaporated to dryness and dried in vacuo . The crude product (3.93 g, 25.1%) was triturated with Et2θ:Hexane (1:4; 2 x 25 ml) and all solids obtained were dissolved in CH2CI2 and filtered, washing the insoluble precipitates with CH2CI2. The clear filtrate was evaporated and dried in vacuo to give title compound as an opaque colorless solid with consistent ^H-NMR and 13C-NMR spectral data.
TLC: Rf 0.33 (Silica gel; CH2Cl2:MeOH- 9:1; UV, PMA") . M.p. 69-71°C. D ( 3
Figure imgf000024_0001
A cooled (0°C, ice-salt bath) mixture of HCOOH (17.5ml) and acetic anhydride (Ac2θ) (1.75 ml) was stirred for 20 minutes, treated with Part D(2) compound (1.0 g, 3.5 mmoles) and stirring was continued at 0°C for another 3.0 hours. The reaction mixture was stripped to dryness, evaporated from Et2θ (2 x 25 ml) , toluene (20 ml) and hexane (2 x 50 ml) then dried in vacuo to give title compound as a thick syrup (1.096 g, 100% crude yield) with consistent 1H-NMR and 13C-NMR spectral data. TLC: Rf 0.23 (Silica gel; CH2Cl2:MeOH- 9:1; UV, PMA) .
D(4)
Figure imgf000024_0002
A solution of Part D(3) compound (366 mg,
1.19 mmol) in CH2C12 (9 mL) at 0°C was treated with HOBT hydrate (210 mg) followed by EDAC (230 mg,
1.20 mmol) . After 20 minutes, the mixture was treated with Part C amine hydrochloride 3 (390 mg, 1.07 mmol) followed by 4-methylmorpholine (200 μL, 184 mg, 1.8 mmol) . The mixture was stirred at 0°C for 1 hour and at room temperature for 2 hours. The reaction was partitioned between EtOAc and 5% KHSO4. The EtOAc extract was washed successively with H2O, 50% saturated NaHCθ3 and brine, then dried (Na2S04) , filtered and stripped. Flash chromatography (Merck Siθ2, 50% to 60% EtOAc in hexanes as eluant) provided title compound (550 mg, 84%) as a white foam which was shown by NMR and HPLC to be a 1:1 mixture of diastereomers.
Figure imgf000025_0001
A solution of Part D compound (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 title Isomer A and Isomer B
Figure imgf000025_0002
Trituration of a solution of the residue in MeOH with Et2θ provided 350 mg of the diastereomeric mixture. Approximately 255 mg of this mixture was separated by preparative HPLC ('YMC S5 ODS 30 x 250 mm column; flow rate 25 mL/min detecting at 220 nm; 40 to 100% B over a 30 minute linear gradient (solvent A: 90%H2θ-10% MeOH-0.1% TFA; solvent B: 10% H2O-90% MeOH-0.1% TFA); title Isomer A tR = 14.4 min; separation performed in three runs) . The desired fractions were stripped, azetroped with EtOAc, re-dissolved in EtOAc and triturated with Et2θ to give title Isomer A (105.5 mg) as an off-white solid.
MS: (M+NH4)+ 459; (M-H)~ 440
HPLC YMC S3 ODS column (6.0 x 150 mm); eluted with B:A solvent mixture, 40 to 100% B over a 20 minute linear gradient (solvent A: 90% H2O-10% MeOH-0.2% H3PO4; solvent B:0% H2O-90% MeOH-0.2% H3PO4) ; flow rate 1.5 mL/min detecting at 220 nm; tR=9.67 min (96.0%) .
Anal. Calc'd for C22H23N307»1.6H20«0.lEtOAc«0.lEt20 C, 56.29; H, 5.80; N, 8.64 Found: C, 56.21; H, 5.15; N, 8.29.
Figure imgf000027_0001
A solution of 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 Et2θ provided 350 mg of the diastereomeric mixture. Approximately 255 mg of this mixture was separated by preparative HPLC (YMC S5 ODS 30 x 250 mm column,- flow rate 25 mL/min detecting at 220 nm; 40 to 100% B over a 30 minute linear gradient (solvent A: 90%H2O-10% MeOH-0.1% TFA ; solvent B: 10% H2O-90% MeOH-0.1% TFA); Isomer B tR = 18.6 min; separation performed in three runs) . The desired fractions were stripped, azetroped with EtOAc, re-dissolved in EtOAc and triturated with Et2θ to give Isomer B (88.0 mg) as an off-white solid.
MS: (M+NH4)+ 459; (M-H) - 440
HPLC YMC S3 ODS column (6.0 x 150 mm); eluted with B:A solvent mixture, 40 to 100% B over a 20 minute linear gradient (solvent A: 90%H2O-10% MeOH-0.2% H3PO4; solvent B:0% H2O-90% MeOH-0.2% H3PO4) ; flow rate 1.5 mL/min detecting at 220 nm; tR = 13.8 min (94.0%) . Anal. Calc'd for C22H23N3θ7»l .5H2O»0.2Et2θ
C, 56.66; H, 5.84; N, 8.69 Found: C, 56.84; H, 5.22; N, 8.42.
Figure imgf000028_0001
phedriπe
Figure imgf000028_0002
A solution of Example 1 Part D(l) compound
Figure imgf000028_0003
(2.563 gm, 8.98 mmol) in CH3CN (20 mL) was treated with (IR, 2S) - (-) -ephedrine (1.522 gm, 9.2 mmol) and stirred until homogeneous. Most of the solvent was removed by rotary evaporation and the residue was dissolved in Et2θ (25 mL) and treated with hexane (16 mL) in portions until the mixture was slightly turbid. The solution was seeded and let stand overnight at room temperature. The precipitate was collected by filtration and r,insed with 1:1 Et2θ:hexanes and dried to afford 2.101 gm of white crystals ( [a_D = -16.4° (c 0.6, CH2CI2)) . The solid (2.087 gm) was dissolved in CH2CI2, concentrated and diluted with Et2θ (18 mL) and hexane (8 mL) and seeded. The precipitate was collected by filtration and washed with 1:1- Et2θ:hexanes followed by hexanes to give title compound (1.995 gm) which was diastereomerically enriched in one isomer but not diastereomerically pure ([a]D = -17.0° (c 0.6, CH2C12) ) .
mp 110-114°C
Material suitable for x-ray crystallographic analysis was obtained by repeated recrystallization of the solid from CH3CN. mp 117-119°C; ( [CC]D = -19.7° (c 0.4, CH2C12)) .
B .
Figure imgf000029_0001
COzEt
B
(Pht is phthaloyl)
Figure imgf000029_0002
To a stirred solution of L- (+) -hydroxynor- leucine (75 g, 509.6 mmole) and sodium carbonate (54 g, 509.6 mmole) in water (900 ml) at room temperature under argon was treated with N-ethoxy- carbonyl-phthalimide (111.7 g, 509.6 mmole) . After being stirred for 2.0 hours, the resulting solution was filtered through a pad of celite. The filtrate was cooled in an ice bath and carefully acidified to pH=3 with 6N HCI solution. The white solid which had precipitated was filtered and dried over P2O5 in vacuo to afford Compound 1 (124.5 g) in 88.1% yield.
M.P. 162°C
Hi-NMR (DMSO) : d = 1.32 (m, 6H) , 2.13 (m, 2H) ,
4.38 (s, OH), 5.75 (m, IH) , 7.92 (m, 4H) ppm B(2)
Figure imgf000030_0001
To a stirred slurry of Part B(l) compound
(124.5 g, 0.449 mole) and cesium carbonate (73.2 g, 0.225 mole) in DMF (1.25 L) at room temperature under argon was added benzyl bromide (98.4 g, 0.575 mole) . After 2.5 hours, the resulting solution was poured into EtOAc (3.0 L) , washed with water (3X) , 5% LiCl solution and brine, dried over anhydrous Mg2Sθ4 and evaporated in vacuo to afford title compound (142 g) as an oil in 86.1% yield.
Hi-NMR (CDC13) : d = 1.50 (m, 4H) , 2.32 (m, 2H) ,
3.62 (m, 2H) , 4.91 (dd, IH) , 5.22 (d, 2H) , 7.31 (m, 5H) , 7.77 (m, 2H) , 7.86 (m, 2H) ppm
C13-NMR (CDCI3) : 22.62, 28.46, 31.91, 52.32, 62.32, 67.46, 123.55, 128.06, 128.31, 128.53, 131.77, 134.23, 135.28, 167.76, 169.25 ppm
Figure imgf000030_0002
To a stirred and chilled (-78°C, Dry ice- IPA bath) oxalyl chloride solution (2.0 M solution in CH2CI2, 16.3 ml, 32.6 mmole) under argon was added dropwise a solution of dimethyl sulfoxide (4.64 ml, 65.32 mmole) in dry CH2CI2 (10 ml).
After the addition was complete, the solution was stirred at -78° for 15 minutes, then treated with a solution of Part B(2) compound (lOg, 27.22 mmole) in dry CH2C12 (70 ml) , stirred at -78° for another 15 minutes and slowly treated with triethylamine (16 ml) . The resulting solution was stirred at -78° for 15 minutes, gradually warmed up to 0°, poured into 1:1 EtOAc-Et2θ (500 ml), washed with 1.0 N HCI solution, water and brine, dried over anhydrous Mg2Sθ4 and evaporated in vacuo to afford title compound (10 g) as a light yellow oil in 100% yield.
Hi-NMR (CDCI3) : d = 1.66 (m, 2H) , 2.40 (m, 4H) , 4.90 (dd, IH) , 5.18 (d, 2H) , 7.35 (m, 5H) , 7.74 (m, 2H) , 7.86 (m, 2H) , 9.72 (s, IH) ppm
C13-NMR (CDCI3) : 18.66, 27.99, 42.87, 51.83, 67.47, 123.50, 128.00,128.26, 128.44, 131.58, 134.21, 135.04, 167.55, 168.80, 201.31 ppm
B(4) .
Figure imgf000031_0001
A stirred and chilled (0°C, ice bath) solution of Part B(3) compound (10.1 g, 27.64 mmole) in dry CH2CI2 (100 ml) under argon was treated with a solution of trimethylaluminum (2.0 M solution in hexane, 23.4 ml, 46.8 mmole) . The resulting solution was stirred for 45 minutes, quenched with 100 ml of a saturated NH4CI solution (foaming) and partitioned between 1:1 Et2θ-water (400 ml) . The organic layer was separated and the aqueous layer was re-extracted with EtOAc (2x150 ml) . The organic extracts were combined, washed with brine, dried over anhydrous Mg2S04 and evaporated in vacuo to afford title compound (10.3 g) as a gum in 98.7% yield.
TLC: Silica gel, 6:4 EtOAc-hexane, Rf = 0.42, UV and PMA.
H1-NMR (CDCI3) : d = 1.12 (d, 3H) , 1.43 (m, 4H) , 3.73 (m, 2H) , 4.90 (dd, IH) , 5.19 (d, 2H) , 7.30 (m, 5H) , 7.76 (m, 2H) , 7.86 (m, 2H) ppm
C13-NMR (CDCI3) : 22.5, 23.40, 28.47, 28.59, 38.20, 38.34, 52.20.67.35, 67.51, 123.43, 127.94, 128.19, 128.41, 131.65, 134.11, 135.16, 167.62, 167.67, 169.13 ppm
B(5) .
Figure imgf000032_0001
To a stirred and chilled (-78°C, Dry ice-
IPA bath) oxalyl chloride solution (2.0 M solution in CH2CI2, 257.3 ml, 514.6 mmole) under argon was added CH2CI2 (300ml) . To this solution, a solution of dimethyl sulfoxide (80.4 g, 1.03 mole) in dry CH2CI2 (30 ml) was added dropwise. After the addition was complete, the reaction mixture was stirred at -78° for 20 minutes, treated with a solution of Part B(4) compound (151 g, 395.88 mmole) in dry CH2C12 (700 ml) , stirred at -78°C for another 20 minutes and slowly treated with triethylamine (300 ml) . The resulting solution was stirred at -78° for 15 minutes, gradually warmed up to 0°, poured into 1:1 EtOAc-Et2θ (3 L) , washed with 1.0 N HCI solution, water and brine, dried over anhydrous Mg2S04 and evaporated in vacuo to afford title compound (149.4 g) as a yellow oil in 99.5% yield.
TLC: Silica gel, 6:4 EtOAc-hexane, Rf=0.5, UV and PMA.
Hi-NMR (CDC13) : d = 1.60 (m, 2H) , 2.10 (s, 3H) , 2.26 (m, 2H) , 2.47 (m, 2H) , , 4.90 (dd, IH) , 5.19 (d, 2H) , 7.30 (m, 5H) , 7.74 (m, 2H) , 7.84 (m, 2H) ppm
C13-NMR (CDCI3) : 20.15, 27.93, 29.84, 42.47, 51.89, 67.40, 123.46, 127.97, 128.23, 128.43, 131,61, 134.17, 135.10, 167.57, 168.93, 207.80 ppm
B(6)
Figure imgf000033_0001
A chilled (-78°C, Dry ice-IPA Bath) and stirred solution of titanium(IV) chloride (112.05 g, 590.65 mmole) in CH2CI2 (1.5 L) under argon was treated with methylmagnesium chloride (3 M solution in THF, 196.9 ml, 590.65 mmole) . The black solution was allowed to warm up to -35°C and a solution of Part B(5) compound (149.4g, 393.77 mmole) was added dropwise. After the addition was complete, the resulting solution was allowed to warm up to 0°C, stirred at 0°C for 2 hours and quenched with saturated NH4CI solution. The CH2CI2 layer was separated. The aqueous layer was extracted with CH2C12 (2x700 ml) . The CH2C12 extracts were combined, washed with brine, dried over anhydrous Mg2Sθ4 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.
TLC: Silica gel, 1:1 EtOAc-hexane, Rf=0.4, UV and PMA.
Hl-NMR (CDC13) : d=1.14 (s, 6H) , 1.45 (m, 4H) , 2.30 (m, 2H) , 4.90 (dd, IH) , 5.19 (d, 2H) , 7.30 (m, 5H) , 7.74 (m, 2H) , 7.86 (m, 2H) ppm
C13-NMR (CDCI3) : 20.88, 29.00, 29.17, 42.78, 52.13, 67.35, 70.47, 123.44,127.95, 128.19, 128.41, 131.66, 134.11, 167.66, 169.14 ppm
B(7)
Figure imgf000034_0001
A stirred solution of Part B(6) compound
(44.3 g, 364.89 mmole) and azidotrimethylsilane (63.06 g, 547.34 mmole) in dry CH2C12 (2.2 L) at room temperature under argon was treated with boron trifluoride diethyl etherate (67.32 g, 474.36 mmole) . After being stirred for 5 days, the resulting solution was quenched with water (1.5 L) . The organic layer was separated, washed with saturated NaHC03 solution, water and brine, dried over anhydrous Mg2Sθ4 and evaporated in vacuo. The residue was chromatographed on a column of silica gel (E. Merck, 230-400 mesh, 700 g) eluting with EtOAc-hexane (1:3) to afford a tic-homogeneous title compound (124.9 g) as a light yellow oil in 81.3% yield. TLC: Silica gel, 3:7 EtOAc-hexane, Rf=0.5, UV and PMA.
Hi-NMR (CDC13) : d=1.20 (s, 6H) , 1.45 (m, 4H) , 2.30 (m, 2H) , 4.90 (dd, IH) , 5.19 (d, 2H) , 7.30 (m, 5H) , 7.74 (m, 2H) , 7.86 (m, 2H) ppm
C13-NMR (CDCI3) : 20.97, 25.67, 25.92, 28.80, 40.53, 52.02, 61.16, 67.40, 123.47, 127.97, 128.23, 128.43, 131.66, 134.14, 135.12, 167.60, 169.01 ppm
B(8)
Figure imgf000035_0001
A solution of 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. To this solution 1-hydroxybenzotriazole hydrate (46.74 g) was added and followed by 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. The filtrate was washed with 0.5 N HCI solution, saturated NaHCθ3 solution, and brine, dried over anhydrous Mg2S04 and evaporated in vacuo to give a gum. This was triturated with Et2θ-hexane (2:1) to afford a tic-homogeneous title compound (74.5 g) as a white solid in 87.7% yield.
TLC: Silica gel, 3:7 EtOAc-CH2Cl2, Rf=0.35, UV and PMA. Hi-NMR (CDCI3) : d=1.30 (s, 3H) , 1.45 (s, 3H) , 1.74 (m, 2H) , 1.96 (m, 3H) , 2.74 (m, IH) , 4.98 (d, IH) , 6.00 (s, IH) , 7.20 (m, 2H) , 7.85 (m, 2H) ppm
C13-NMR (CDCI3) : 23.89, 26.65, 29.58, 33.32, 40.68, 52.69, 54.51, 123.34, 123.15, 133.87, 168.06, 171.03 ppm
B(9) .
Figure imgf000036_0001
A stirred solution of Part B(8) compound (74.5 g, 260.19 mmole) in a mixture of CH3OH (900 ml) and CH2CI2 (250 ml) at room temperature under argon was treated with hydrazine monohydrate (18.24 g, 364.26 mmole) . After 48 hours, the solid was filtered off and the filtrate was evaporated in vacuo to give a solid (41 g) . To a stirred solution of the above solid
(41 g) in CH2CI2 (2 L) at room temperature under argon was added triethylamine (50 ml) and triphenylmethyl chloride (83.41 g) . After 1.5 hours, the resulting slurry was diluted with EtOAc, washed with water and brine, dried over anhydrous Mg2Sθ4 and evaporated in vacuo to give a gum. This was triturated with Et2θ-pentane to give title compound (100.1 g) as a white solid in 96.5% yield.
TLC-: Silica gel, 6:4 EtOAc-hexane, Rf=0.53, UV and PMA.
H!-NMR (CDCI3) : d=1.00 (s, 3H) , 1.10 (s, 3H) , 1.46 (m, 6H) , 3.36 (m, IH) , 4.03 (m, IH) , 5.20 (d, IH) , 6.00 (s, IH) , 7.20 (m, 2H) , 7.85 (m, 2H) ppm C13-NMR (CDCI3) : 22.86, 25.81, 33.50, 34.23, 40.16, 51.97, 55.60, 71.89, 126.22, 127.61, 128.96, 146.48, 176.71 ppm
B(10]
Figure imgf000037_0001
To a stirred solution of Part B(9) compound (50 g, 125 mmole) in dry THF (1020 ml) at room temperature under argon was added simultaneously (at same rate) a solution of lithium bis (trimethylsily)amide (1.0 M solution in THF, 627.3 ml, 627.3 mmole) and a solution of ethyl bromoacetate (104.8 g, 627.3 mmole) in THF (523 ml) over the period of 1.0 hour. After the addition was complete, the solution was stirred for 30 hours, quenched with saturated NH4CI solution (1.0 liter) and extracted with EtOAc (3x700 ml) . The EtOAc extracts were combined, washed with saturated NaHC03 solution and brine, dried over anhydrous Mg2S04 and evaporated in vacuo to afford a black oil. The experiment was repeated on the same scale to give a similar result. The combined black oils was chromatographed on a column of silica gel (E. Merck, 230-400 mesh, 1.6 kg) eluting with EtOAc- hexane (1:4) to give a light yellow oil. This was dissolved in dry CH2CI2 (2 L) and treated with trifluoroacetic acid (78 ml) . The solution was stirred at room temperature under argon for 1.0 hour and then evaporated in vacuo at 30°. The residue was diluted with 1.0 N HCI solution (400 ml) and washed with Et2θ (2x400 ml) . The aqueous was carefully neutralized to pH=7-8 with solid NaHC03 (foaming) and extracted with CH2CI2 (3x1.2 L) . The CH2CI2 extracts were combined, dried over anhydrous Na2S04 and evaporated in vacuo to afford a tic homogeneous title compound (51.5 g) as a light brown oil in 84.7% yield.
TLC: Silica gel, 8:1:1 CH2CI2-CH3OH-ACOH, Rf=0.3, PMA and Ninhydrin.
H!-NMR (CDCI3) : d=1.28 (t, 3H) , 1.36 (s, 3H) , 1.38 (s, 3H) 1.60 (m, IH) , 1.90 (m, 5H) , 3.75 (m, IH) , 4.00 (d, IH) , 4.22 (q, 2H) , 4.28 (d, 2H) ppm
C13-NMR (CDCI3) : 14.00, 20.06, 28.19, 30.07, 32.29, 39.98, 46.87, 53.20, 58.38, 60.73, 170.35, 177,06 ppm
C.
Figure imgf000038_0001
Part A compound (641 mg, 1.42 mmol) was partitioned between EtOAc and 5% KH2PO4 (adjusted to pH 2.5 with H3PO4) . The layers were separated and the aqueous layer was back-extracted with EtOAc. The pooled EtOAc extracts were washed with brine, dried (Na2Sθ4) , filtered and stripped to give an oil (assume 1.42 mg) . The oil was dissolved in CH2CI2 (10 mL) and the resulting solution was treated with Part B amine (364 mg, 1.50 mmol) in CH2C12 (2 mL) and cooled to 0°C. The mixture was subsequently treated with HOBT hydrate (195 mg) followed by EDAC (285 mg, 1.48 mmol) . After stirring at 0°C for 45 minutes and at room temperature for 45 minutes, the mixture was partitioned between EtOAc and 5% KH2PO4 (adjusted to pH 2.5 with H3PO4) . The EtOAc extract was washed successively with H2O, 50% saturated NaHC03 and brine, then dried (Na2Sθ4), filtered and stripped. The residue was flash chromatographed
(Merck Siθ2, 7/3-EtOAc/hexanes as eluant) to obtain title compound (427 mg, 59%, TLC Rf 0.37 (8/2- EtOAc/hexanes) ) as a diastereomerically pure compound. In addition, the minor diastereomer was isolated from the column (66 mg, 9%, TLC Rf 0.27 (8/2-EtOAc/hexanes) ) . NMR of this material was consistant with an isomer of the title compound.
Figure imgf000039_0001
Acetic anhydride (500 μL) 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 NaHC03. The EtOAc extract was washed with brine, dried (Na2Sθ4) , 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.
TLC Rf 0.37 (EtOAc)
HPLC YMC S3 ODS column (6.0 x 150 mm); eluted with
B:A solvent mixture, 40 to 100% B over a 20 minute linear gradient ( solvent A : 90%H2O- 10% MeOH-0 .2% H3PO4 ; solvent B : 0% H2O-90% MeOH-0 .2 % H3PO4 ) ; f low rate 1 . 5 mL/min detecting at 220 nm; tR = 17 . 2 min ( 100% ) .
Figure imgf000040_0001
A solution of Part D compound (216 mg, 0.402 mmol) in absolute EtOH (5 mL) was hydrogenated (balloon) over 10% Pd/C (33 mg) at room temperature for 2 hours. The mixture was filtered through Celite, stripped, and azeotroped twice with EtOAc/Et2θ/hexanes to give title compound (174 mg, 97%) as an off-white foam.
TLC Rf 0.33 (5/95-HOAc/EtOAc)
HPLC YMC S3 ODS column (6.0 x 150 mm); eluted with B:A solvent mixture, 40 to 100% B over a 20 minute linear gradient (solvent A: 90%H2O-10% MeOH-0.2% H3PO4; solvent B:0% H2O-90% MeOH-0.2% H3PO4) ; flow rate 1.5 mL/min detecting at 220 nm; tR = 12.8 min ( 100%) .
Figure imgf000040_0002
A stirred solution of Part E compound (168 mg, 0.376 mmol) in MeOH (3 mL) at room temperature was treated with aqueous 1 N NaOH (3 mL) . An additional portion of aqueous 1 N NaOH (3 mL) was added after 3.5 hours. After a total of 6 hours, the mixture was made acidic with 5% KHSO4 and extracted twice with EtOAc. The EtOAc extract was washed with brine, dried (Na2Sθ4) , filtered and stripped. The residue was dissolved in a small amount of MeOH and EtOAc and triturated with
Et2θ/hexanes to give title compound (134 mg, 86%) as an off-white solid/foam ([a]D = +18.0° (c 0.5, CH2C12)) •
TLC Rf 0.10 (5/95-HOAc/EtOAc)
HPLC YMC S3 ODS column (6.0 x 150 mm); eluted with B:A solvent mixture, 40 to 100% B over a 20 minute linear gradient (solvent A: 90%H2O-10% MeOH-0.2% H3PO4; solvent B:0% H2θ-90% MeOH-0.2% H3PO4) ; flow rate 1.5 mL/min detecting at 220 nm; tR = 9.00 min (>97.4%) .
Anal. Calc'd for C21H29N3O6O.75H2O»0.3Et20 C, 58.57; H, 7.42; N, 9.23 Found C, 58.31; H, 7.20; N, 8.99.
Example 4 [S-(R*,R*) ]-3- [ [3- (Formylhydroxyamino) -l-oxo-2- (phenylmethyl)propyl]amino] -2,3,4, 5-tetrahydro-2- oxo-lH-benzazepine-1-acetic acid
Figure imgf000041_0001
A .
Figure imgf000042_0001
A ( l ) .
Figure imgf000042_0002
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. The solution was then extracted with EtOAc (3 x 250 ml) and the combined organic extracts were washed with brine (100 ml) , dried (anhydrous MgSθ4) , filtered, evaporated to dryness and dried in vacuo . The crude product (17.819 g) was recrystallized from CH2CI2 (70 ml) and Hexane (400 ml) to give title compound as off-white precipitates (10.017 g, m. pt. 138-140°C) with consistent l-H-NMR and 13c_NMR spectral data. The mother liquor was chromatographed on a silica gel column (Merck, 240 g) , eluting the column with EtOAc:Hexane (1:4) to give an additional amount of 5.058 g (total yield= 15.075 g, 85.6 %) . TLC: Rf 0.37 (Silica gel; EtOAc:Hexane-l:1; UV) .
A(2)
Figure imgf000043_0001
A solution of Part A(l) compound (1.0 g,
6.20 mmoles) in dry CHCI3 (15 ml) was cooled down to 0°C (ice-salt bath), treated with PCI5 (1.5 g, 7.20 mmoles) followed by 12 (15 mg) then stirred at 0°C under argon for 30 minutes. The yellow solution was treated with Br2 (0.39 ml or 1.2 g, 7.51 mmoles), warmed up to room temperature and refluxed under argon for 4.0 hours . The mixture was then poured into ice-water (20 g) , stirred and the phases were separated, washing the aqueous phase with CHCI3 (25 ml) . The combined organic extracts were washed with H2O (5.0 ml), dried (anhydrous MgS04) , filtered, evaporated to dryness and dried in vacuo. The crude product mixture was chromatographed on a silica gel column (Merck, 70 g),- eluting the column with EtOAc:Hexane (1:9) to give title compound as off-white precipitates (1.137 g., m.pt. 170-172°, 70.1 %) with consistent ^-NMR and 13C-NMR spectral data. TLC: Rf 0.13 (Silica gel; EtOAc:Hexane -1:4; UV) . A(3) .
Figure imgf000044_0001
A solution of Part A(2) compound (936 mg, 3.9 mmoles) and NaN3 (300 mg, 4.6 mmoles) in dry dimethylsulfoxide (20 ml) was stirred at 60° (oil bath) under argon for 6.0 hours. The reaction mixture was cooled down to room temperature, poured into cold water (125 ml) , stirred for 15 minutes and filtered, washing the solids formed with water. The crude product was dried in vacuo at 60° over drierite for 24 hours to give title compound (725 mg, m.pt. 150-152°, 91.9 %) as an off-white solid with consistent ^H-NMR and l3c-NMR spectral data. TLC: Rf 0.58 (Silica gel; EtOAc:Hexane- 1:4 then 1:1; UV) .
A(4;
Figure imgf000044_0002
A solution of 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) . The combined organic extracts were washed with H2O (2 x 196 ml) and brine (100 ml) , dried (anhydrous Na2S04) , filtered, evaporated to dryness and dried in vacuo . The crude product was combined with the crude product mixture from a previous run (2.936 g, 12.86 mmole scale) and chromatographed on a silica gel column (Merck) , eluting the column with Toluene:EtOAc (98.2) and EtOAc:Hexane (1:9) to give title compound as a solid (15.48 g, 93.5%)1 with consistent 1-H-NMR and 13C-NMR spectral data.
TLC: Rf 0.63 (Silica gel; EtOAc:Hexane- 1:2; UV) .
A(5) .
Figure imgf000045_0001
A solution of 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 1H-NMR and 13C-NMR spectral data. TLC: Rf 0.45 (Silica gel; CH2CI2 :CH3θH- 9:1; UV) .
A(6) .
Figure imgf000045_0002
A solution of Part A(5) compound (14.8 g, 56.4 mmoles) and L-tartaric acid (8.50 g) in hot absolute ethanol (118 ml) was kept overnight at 0°, at room temperature for 3 days and then at 0° for another 2 days. The solid that formed was recrystallized from absolute ethanol (118 ml) two more times until a consistent specific rotation was obtained. The precipitates (6.319 g) from the second recrystallization was then suspended in EtOAc (100 ml), treated with 10% NH4OH (12 ml) and stirred for 5 minutes. The organic phase was separated, washed with 10% NH4OH (10 ml) and brine (15 ml) , dried (anhydrous Na2Sθ4) , filtered, evaporated to dryness and dried in vacuo to give title compound as a white solid (3.927 g, m.pt. 105-107°, 26.5%) with consistent iH-NMR and 13C-NMR spectral data.
[a]D = -277° (c 0.99, EtOH) . TLC : Rf 0.45 (Silica gel; CH2Cl2:CH3θH- 9:1; UV) .
B.
Figure imgf000046_0001
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 Na2Sθ4) , 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) .
A solution of the above free acid (286.6 πtg,"0.93 mmole) in dry CH2CI2 (6.0 ml) was cooled to 0°C (ice-salt bath) and treated sequentially with a solution of the above free amine (271 mg) in dry CH2CI2, HOBT.H2O (126.1 mg, 0.93 mmole) and
EDAC (185.4 mg, 0.97 mmole) . The reaction mixture was stirred at 0°C for 1.0 hour, at room temperature for 2.0 hours, then partitioned between EtOAc (2 x 20 ml) and H2O (4.0 ml) . The organic extracts were washed with 5% KH2PO4 (adjusted to pH 2.5; 4.0 ml) , H2O (4.0 ml), saturated NaHCθ3 (4.0 ml) and brine (4.0 ml), dried (anhydrous Na2Sθ4), filtered, evaporated to dryness and dried in vacuo . The crude product was chromatographed on a silica gel column (Merck, 70 g.) , eluting the column with EtOAc:Hexane mixtures (1:3; 1:1) to give pure title compound (202 mg) and impure product. A second chromatography gave title compound as a syrup (total of 292.1 mg, 59.3%) with consistent iH-NMR and 13C-NMR spectral data. TLC: Rf 0.32 (Silica gel; EtOAc:Hexane -1:1; UV) .
Figure imgf000047_0001
A cooled solution of HCOOH (5.0 ml) was treated with acetic anhydride (AC2O) (0.5 ml) and stirred at 0°C for 30 minutes. A solution of Part B compound (288 mg, 0.54 mmole) in dry THF (1.5 ml) was cooled to 0°C (ice-salt bath) , treated with the above AC20/HCOOH mixture (3.4 ml) and stirred at 0°C for 1.0 hour. The reaction mixture was evaporated to dryness and the residual syrup was dissolved in EtOAc (40 ml) , washed with saturated NaHC03 (5.0 ml) and brine (5.0 ml) , dried (anhydrous Na2Sθ4) , filtered, evaporated to dryness, evaporated from toluene and dried in vacuo to give title compound as a syrup (311.3 mg, 100 % crude) with consistent iH-NMR and 13C-NMR spectral data. TLC: Rf 0.18 (Silica gel; EtOAc:Hexane (1:1; UV) .
D.
Figure imgf000048_0001
A solution of Part C compound (311 mg) in CH3OH (10 ml) was treated with 10% Pd/C (53 mg) and hydrogenated (balloon) at room temperature for 2.0 hours. The reaction mixture was diluted with CH3OH (10 ml) and filtered through a Celite® pad in a millipore unit, washing the pad well with CH3OH (3 x 10 ml) . The clear filtrate was evaporated to dryness and dried in vacuo to give title compound as a syrup (256.7 mg, 100% crude) with consistent 1H-NMR and 13C-NMR data. TLC: Rf 0.25 (Silica gel; CH2Cl2:MeOH- 9:1; UV) .
E. [S-(R*,R*) ]-3-[ [3-(Formylhydroxyamino)- l-oxo-2- (phenylmethyl)propyl]amino] - 2,3,4, 5-tetrahydro-2-oxo-lH-benzazepine-l- acetic acid
A solution of Part D compound (256.7 mg) in CH3OH (3.5 ml) was treated with 1.0 N NaOH (2.17 ml, 4 eq) and stirred at room temperature for 1.0 hour under argon. 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 Na2Sθ4) , filtered, evaporated to dryness and dried in vacuo . The crude product was triturated with CH2CI2 :Hexane (1:4-25 ml) and hexane (20 ml) then dried in vacuo to give title compound as an amorphous off-white solid (215.6 mg, 90.4%) with consistent MS, IR, 1H- NMR and analytical data. TLC: Rf 0.30 (Silica gel; EtOAc:HOAc- 95:5; UV) .
[α]D = -332.8° (c 0.558, CH3OH)
HPLC: tR= 5.21 min (95.8% R isomer) ; tR =9.58 min (3.59% S isomer); YMC S3 ODS-A 150 x 6 mm; 220 nm, flow rate = 1.5 ml/min; 56% (10% H2O- 90% CH3OH- 0.2% H3P04)/44% (90% H2O- 10% CH3θH-0.2% H3PO4), isocratic.
Anal. Calc'd for C23H25N3θ6: C, 62.86; H, 5.73; N, 9.56
Found: C, 62.88; H, 5.98; N, 9.20.
Figure imgf000049_0001
A.
Figure imgf000049_0002
COOCH3
A solution of L-hydroxynorleucine (2.0 g, 13.6 mmoles) in dry methanol (70 ml) was saturated with HCI gas until a clear yellow solution was obtained. The reaction mixture was cooled to room temperature, stirred for 2.0 hours, evaporated to dryness, evaporating the syrup once from toluene (100 ml) then evaporated in vacuo to give the ester as a yellow oil. The crude ester was dissolved in dry CH2CI2 (50 ml) and dry DMF (15 ml), treated with NMM (2.5 ml, 22.7 mmoles) and cooled to 0°C (ice-salt bath) . The mixture was treated with N- phthaloyl-L-phenylalanine (4.0 g, 13.6 mmoles), HOBt»H2θ (1.89 g, 13.99 mmoles) and EDAC (2.87 g, 14.98 mmoles), stirred at 0°C for 25 minutes and at room temperature for 2.0 hours.
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) . An additional 321 mg was obtained on re-chromatography of the impure fractions to give title compound (4.32 g, 73%) with consistent 1H-NMR and 13C-NMR spectral data. TLC: Rf 0.43 (Silica gel; EtOAc; UV) .
B.
Figure imgf000050_0001
A solution of oxalyl chloride (1.02 ml, 11.7 mmoles) in dry CH2CI2 (56 ml) , was cooled to -78°C (dry-ice-acetone bath) , treated with a solution of dry DMSO (1.67 ml, 21.6 mmoles) in CH2CI2 (2.0 ml) and stirred at -78°C for 20 minutes. The mixture was treated with a solution of Part A compound (4.29 g, 9.78 mmoles) in dry CH2CI2 (22 ml), stirred at -78°C for another 15 minutes, then treated with triethyl-amine (8.4 ml) . The 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
Na2S04) , filtered, evaporated to dryness and dried in vacuo to give title compound as a thick syrup (4.428 g, 100% crude yield) , with consistent ^-NMR and 13C-NMR spectral data. TLC: Rf 0.73 (Silica gel; EtOAc; UV) .
Figure imgf000051_0001
A mixture of Part B compound (4.428 g, 9.78 mmoles) and TFA (0.20 ml, 2.6 mmoles) in dry CH2CI2 (62 ml) was refluxed under argon for 2.0 hours. The reaction mixture was cooled to room temperature, washed with 1/2 saturated NaHCθ3 (20 ml) and brine (20 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 CH2CI2 :EtOAc (9:1) to give the desired product as a syrup. The syrup was triturated with Et2θ:Hexane (2:1-60 ml) to give title compound as a white precipitate (2.92 g, 72%; m.p. 141-143°C) with consistent ^H-NMR and 13C-NMR spectral data. TLC: Rf 0.67 (Silica gel; CH2CI2 :EtOAc-9: 1; UV) .
D.
Figure imgf000052_0001
A solution of Part C compound (2.923 g, 6.99 mmoles) in dry CH2CI2 (14 ml) was treated with triflie acid (4.15 ml, 6.7 eq) and the resulting yellow solution was stirred at room temperature for 20 hours. The reaction mixture was then poured into ice-water (100 ml) , extracted with EtOAc (3 x 100 ml) and the combined organic extracts washed with H2O (2 x 25 ml) and brine (25 ml), dried (anhydrous Na2Sθ4) , filtered, evaporated to dryness and dried in vacuo . The crude product mixture was chromatographed on a silica gel column (Merck) , eluting the column with EtOAc:Hexane mixtures (1:1; 2:1) and EtOAc:HOAc (100:1) . The desired fractions were combined, evaporated to dryness and dried in vacuo to give impure title compound as a solid foam (1.238 g, 42%) with consistent ^-H-NMR and 13C- NMR spectral data. TLC : Rf 0.73 (Silica gel; EtOAc:HOAc-95:5; UV) .
Figure imgf000052_0002
A solution of Part D compound (1.238 g, 3.06 mmoles) in dry DMF (3.5 ml) was treated sequentially with benzyl bromide (0.35 ml, 2.94 mmoles) and CS2CO3 (450 mg, 1.38 mmoles) then stirred at room temperature for 3.0 hours. 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≤θ4) , filtered, evaporated to dryness and dried in vacuo . The crude product (1.63 g) was chromatographed on a silica gel column (Merck), eluting the column with EtOAc:Hexane (1:3) to give title compound as a syrup (586.4 mg, 39%) with consistent ^-NMR and 13C-NMR spectral data. TLC: Rf 0.45 (Silica gel; EtOAc:Hexane-l:1; UV) .
F.
Figure imgf000053_0001
A solution of Part E compound (586 mg, 1.18 mmoles) in dry methanol (15 ml) was treated with NH2NH2»H2θ (66 μl, 1.2 eq) and stirred at room temperature for 48 hours. The reaction mixture was diluted with Et2θ (50 ml) and filtered through a millipore unit, washing the solids well with Et2θ (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) . The combined organic extracts were washed with brine (15 ml) , dried (anhydrous Na2Sθ4) , filtered, evaporated to dryness and dried in vacuo to give title compound as a thick syrup (351 mg, 82 %) with a consistent ^H-NMR spectrum. TLC: Rf 0.42 (CH2CI2 :MeOH-9 :1; UV, Ninhydrin)
Figure imgf000054_0001
Example 3 Part A ephedrine salt (538 mg, 1.2 mmoles), was partitioned between 5% KH2PO4
(adjusted to pH 2.5; 5.4 ml) and EtOAc (2 x 22 ml) and the combined organic extracts were washed with brine (5.4 ml), dried (anhydrous Na2Sθ4) , filtered, evaporated to dryness and dried in vacuo to give the free acid of the ephedrine salt as a clear syrup (323 mg, 100% crude yield) .
A solution of the free acid in dry CH2CI2 (8.0 ml) was cooled to 0°C (ice-salt bath) and treated sequentially with a solution of Part F compound (351 mg, 0.96 mmole) in dry CH2CI2 (2.0 ml), HOBT-H20 (163 mg, 1.2 mmoles) and EDAC ( 240 mg, 1.25 mmoles) . The reaction mixture was stirred at 0°C for 1.0 hour, at room temperature for 1.5 hours, then partitioned between EtOAc (40 ml) and H2O (5.0 ml) . The organic extracts were washed with 5 % KH2PO4 (adjusted to pH 2.5; 5.0 ml), H2O (5.0 ml) , saturated NaHCθ3 (5.0 ml) and brine (5.0 ml) , dried (anhydrous Na2Sθ4) , filtered, evaporated to dryness and dried in vacuo. The crude product (810 mg) was chromato-graphed on a silica gel column (Merck) , eluting the column with EtOAc:Hexane (1:3) to give pure title compound (494 mg, 65%) as a solid foam with consistent ^H- NMR and 13C-NMR spectral data. TLC: Rf 0.45 (Silica gel; EtOAc:Hexane -1:1; UV) . H .
Figure imgf000055_0001
A cooled solution (0°C, ice-salt bath) of HCOOH (5.0 ml) was treated with Ac2θ (0.5 ml) and stirred at 0°C for 30 minutes. A solution of Part G compound (493 mg, 0.78 mmole) in dry THF (2.2 ml) was cooled to 0°C (ice-salt bath) , treated with the above AC20/HCOOH mixture (4.9 ml) and stirred at 0°C for 1.5 hours. The reaction mixture was evaporated to dryness, evaporated from Et2θ (50 ml) and the residual syrup was dissolved in EtOAc (60 ml), washed with saturated NaHCθ3 (7.0 ml) and brine (7.0 ml), dried (anhydrous Na2S04), filtered, evaporated to dryness, evaporated from toluene and dried in vacuo to give title compound as a syrup (558.3 mg, 100 % crude) with consistent 1H-NMR and 13C-NMR spectral data. TLC: Rf 0.2 (Silica gel; EtOAc:Hexane-l: 1; UV) .
Figure imgf000055_0002
A solution of Part H compound (535 mg, 0.78 mmole) in CH3OH (15 ml) was treated with 10 % Pd/C
(83 mg) and hydrogenated (balloon) at room temperature for 4.0 hours . The reaction mixture was diluted with CH3OH (15 ml) and filtered through a celite pad in a millipore unit, washing the pad well with CH3OH (3 x 15 ml) . The clear filtrate was evaporated to dryness and dried in vacuo to give a syrup (354.8 mg) which was triturated with CH2CI2 :Hexane (1:5-30 ml) and hexane (25 ml) then dried in vacuo . Title compound was obtained as an off-white solid foam (348.5 mg, 90%) .
TLC: Rf 0.38 (Silica gel; CH2Cl2:MeOH- 9:1; UV) .
MS (M+H)+ = 480 [α]D = +44.6° (c 0.52, CH3OH)
HPLC : tR= 11.72 min (95.9% ) ; YMC S3 ODS-A 150 x 6 mm; 220 nm, flow rate = 1.5 ml/min; 55% (10% H2O- 90% CH3OH- 0.2% H3PO4)/ 45% (90% H2O- 10% CH3OH- 0.2% H3PO4) , isocratic.
Anal. Calc'd for C26H29N3θ6»0.4 H2θ»0.14 Hexane (Eff. Mol. Wt. = 497.08) :
C, 64.63; H, 6.83; N, 8.46 Found: C, 64.24; H, 6.43; N, 8.12
The following are examples of additional compounds of the invention which may be prepared employing procedures set out hereinbefore and in the working Examples.
Figure imgf000057_0001
Figure imgf000058_0001

Claims

What is claimed is:
1. A compound of the formula
Figure imgf000059_0001
including a pharmaceutically acceptable salt thereof wherein x is 0 or 1,
R is H, alkyl, alkenyl, aryl- (CH2)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; R1 is H or -COR2 where R2 is alkyl, aryl- (CH2)P-, cycloheteroalkyl- (CH2)P-, heteroaryl- (CH2)P-, alkoxy or cycloalkyl- (CH2)p-; p is 0 or an integer from 1 to 8; and A is a dipeptide derived from one or two non-proteinogenic amino acids or is a conformationally restricted dipeptide mimic.
2. The compound as defined in Claim 1 wherein A is a dipeptide derivative of the structure
Figure imgf000059_0002
wherein Rla, Rlb, R2a and R2b are independently selected from H, alkyl, aryl- (CH2)p-, cycloalkyl, cycloheteroalkyl- (CH2)p-, heteroaryl- (CH2)p-, biphenylmethyl, or
Rla and Rlb or R2a and R2b may be joined together to the carbon to which it is attached to form a 3 to 7 memebered ring, optionally fused to a benzene ring; and
Figure imgf000060_0001
refers to an optional 5 or 6 membered ring containing a single hetero atom and which may optionally include an R5 substituent which is H, alkyl, aryl-(CH2)p, cycloalkyl- (CH2)P, cycloheteroalkyl- (CH2)P or cycloheteroaryl- (CH2)p-;
R3 is H, alkyl or aryl -(CH2)p-;
R4 is OH, Oalkyl, Oaryl- (CH2)p- or NRι(R2) where Ri and R2 are independently H, alkyl, aryl, aryl(CH2)p or heteroaryl (CH2)p; with the proviso that in A(l) at least one of
Figure imgf000060_0002
is other than a natural α-amino acid.
3. The compound as defined in Claim 1 wherein A is a conformationally restricted dipeptide mimic.
4. The compound as defined in Claim 3 wherein the conformationally restricted dipeptide mimic has the structure
Figure imgf000060_0003
, -
5. The compound as defined in Claim 3 wherein A has the formula S, CH2
Figure imgf000061_0001
Figure imgf000061_0002
where Z = O or H, H where Y = O, S, CH2 or S(O)0,1>2
Figure imgf000061_0003
where Y = O, S, NH or 8(0) .2
Figure imgf000062_0001
where Y = O, S, CH2
Figure imgf000062_0002
Λ or S(O)0,ι,2 CH2
Figure imgf000062_0003
with respect to A(5) , R11 and R12 are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl -(CH2)p-, aryl -(CH2)p-, and heteroaryl -(CH2)p-, or R11 and R12 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R11 and R12 taken together with the carbon to which they are attached complete a keto substituent, with respect to A(13), R8, R9 and R7 are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl -(CH2)ιrr> aryl- (CH2)m~# and heteroaryl- (CH2)m-;
R1(^ and R6 are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl -(CH2)p-, aryl-(CH2)p, and heteroaryl- (CH2)p-, or R6 and R10 taken together with the carbons to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, R6 and R8 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R9 and R10 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons;
R4 is OH, Oalkyl, 0- (CH2)p-heteroaryl,
Figure imgf000063_0001
NRχ(R2) where Ri and R2 are independently H, alkyl, aryl, aryl-(CH2)p or heteroaryl;
R!4 is hydrogen, alkyl, cycloalkyl, or phenyl;
R15 is hydrogen, alkyl, alkoxy or phenyl; R16 is alkyl or aryl- (CH2)m-; and R17 is hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl- (CH2)m- > aryl- (CH2)m-/ or heteroaryl- (CH2)m~■
R18 is H or alkyl or alkenyl, and R18 and R17 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. Rl9 is H or an alkyl, and in A(4), Rl9 and X
(which is CH2) together with the carbons to which they are attached may form an aromatic ring of carbons (as in A(15) .
6. The compound as defined in Claim 1 wherein A is
Figure imgf000063_0002
l
Figure imgf000063_0003
where X1 = H, Ph, NHS02R5 ^ 2 (where R5 H)
Figure imgf000063_0004
Figure imgf000064_0001
where Y = O, S, NH, S(O)0Λ2
Figure imgf000064_0002
7. The compound as defined in Claim 6 wherein A is
Figure imgf000064_0003
where Y = O, S, CH2lS(O)0|ι,2 where Y = O, S, CH2, S(O)0ι1 ,2
Figure imgf000064_0004
where Y = O, S, CH2,S(O)0,ι,2
8. The compound as defined in Claim 1 wherein R1 is H, R is alkyl or arylalkyl, R4 is OH.
9. The compound as defined in Claim 2 where in A(l)
R1' R">
O is a non-proteinogenic amino acid portion.
10. The compound as defined in Claim 9 wherein Rla and Rlb are independently alkyl or arylalkyl, or Rla and Rlb together with the carbon to which they are attached form a 3 to 7 membered ring; or one of Rla and Rlb is biphenylmethylene and the other is biphenylmethylene or H.
11. The compound as defined in Claim 9 where in A(l) ,
Figure imgf000065_0001
is a non-proteinogenic amino acid where R3 is H, alkyl or arylalkyl,
R2a and R2b are independently selected from
H, alkyl, aryl or arylalkyl, with at least one of
R2a and R2b being other than H, or R2a and R2b together with the carbon to which they are attached form a 3 to 7 membered ring.
12. A pharmaeutical composition comprising a therapeutically effective amount of a compound as defined in Claim 1 and a pharmaceutically acceptable carrier therefor.
13. The pharmaceutical composition as defined in Claim 12 useful in the treatment of cardiovascular diseases such as hypertension and/or congestive heart failure.
14. A method of treating a cardivascular disease such as hypertension and/or congestive heart failure, which comprises administering to a mammalian species a therapeutically effective amount of a composition as defined in Claim 12.
15. The compound as defined in Claim 1 which is
Figure imgf000066_0001
10 or a pharmaceutically acceptable salt thereof
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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 (en) * 2015-05-22 2016-12-01 Biotheryx, Inc. 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 (en) * 2017-03-16 2020-01-10 西建卡尔有限责任公司 Forms and compositions of MK2 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4539150A (en) * 1983-06-29 1985-09-03 Mitsui Toatsu Chemicals, Inc. Benzothiazepine derivatives and their methods of preparation
US5552400A (en) * 1994-06-08 1996-09-03 Sterling Winthrop Inc. Fused-bicyclic lactams as interleukin-1β converting enzyme inhibitors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK77487A (en) * 1986-03-11 1987-09-12 Hoffmann La Roche hydroxylamine
FR2679564A1 (en) * 1991-07-23 1993-01-29 Inst Nat Sante Rech Med NOVEL ACYLMERCAPTOALCANOLDIPEPTIDES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM.
RU2124503C1 (en) * 1992-05-18 1999-01-10 И.Р.Сквибб энд Санз, Инк. Heterocyclic nitrogen-containing derivatives of carboxylic acid, method of their synthesis, pharmaceutical composition
DE69424846T2 (en) * 1993-11-16 2000-11-16 Novartis Ag, Basel Cyclic amino acid derivatives with ACE and NEP inhibitory activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4539150A (en) * 1983-06-29 1985-09-03 Mitsui Toatsu Chemicals, Inc. Benzothiazepine derivatives and their methods of preparation
US5552400A (en) * 1994-06-08 1996-09-03 Sterling Winthrop Inc. Fused-bicyclic lactams as interleukin-1β converting enzyme inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0894003A4 *

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US7323448B2 (en) 1998-02-07 2008-01-29 British Biotech Pharmaceuticals Ltd. Antibacterial agents
US6423690B1 (en) 1998-02-07 2002-07-23 British Biotech Pharmaceuticals Ltd. Antibacterial agents
WO1999039704A1 (en) * 1998-02-07 1999-08-12 British Biotech Pharmaceuticals Limited Antibacterial agents
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 (en) * 1998-12-16 2000-06-22 British Biotech Pharmaceuticals Limited N-formyl hydroxylamine derivatives as antibacterial agents
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 (en) * 1999-03-29 2000-10-05 British Biotech Pharmaceuticals Limited Antibacterial agents
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 (en) * 2000-04-28 2002-02-21 Degussa 2,6-diamino-6-methyl-heptanoic acid and derivatives, process for the preparation thereof and use thereof
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 (en) * 2015-05-22 2016-12-01 Biotheryx, Inc. Compounds targeting proteins, compositions, methods, and uses thereof
US9822098B2 (en) 2015-05-22 2017-11-21 Biotheryx, Inc. Compounds targeting proteins, compositions, methods, and uses thereof
CN107787320A (en) * 2015-05-22 2018-03-09 拜欧赛里克斯公司 Compound, its composition, method and the purposes of targeting protein
CN107787320B (en) * 2015-05-22 2020-12-04 拜欧赛里克斯公司 Protein-targeting compounds, compositions, methods and uses thereof
RU2694895C2 (en) * 2015-05-22 2019-07-18 Биотерикс, Инк. Protein-targeted compounds, their compositions, methods and applications
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 (en) * 2017-03-16 2020-01-10 西建卡尔有限责任公司 Forms and compositions of MK2 inhibitors
CN110678178B (en) * 2017-03-16 2023-10-03 百时美施贵宝公司 Forms and compositions of MK2 inhibitors

Also Published As

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

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