WO2003104200A1 - Derives de n-mercaptoacyl phenyalanine, leur procede de preparation et les compositions pharmaceutiques les contenant - Google Patents

Derives de n-mercaptoacyl phenyalanine, leur procede de preparation et les compositions pharmaceutiques les contenant Download PDF

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WO2003104200A1
WO2003104200A1 PCT/GB2003/002446 GB0302446W WO03104200A1 WO 2003104200 A1 WO2003104200 A1 WO 2003104200A1 GB 0302446 W GB0302446 W GB 0302446W WO 03104200 A1 WO03104200 A1 WO 03104200A1
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formula
compounds
compound
added
mixture
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PCT/GB2003/002446
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English (en)
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Anthony William James Cooper
Jacqueline Elizabeth Mordaunt
Simon Peace
Paul William Smith
Steven Smith
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Glaxo Group Limited
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Priority claimed from GB0213119A external-priority patent/GB0213119D0/en
Priority claimed from GB0216856A external-priority patent/GB0216856D0/en
Priority claimed from GB0220875A external-priority patent/GB0220875D0/en
Priority claimed from GB0302543A external-priority patent/GB0302543D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU2003232941A priority Critical patent/AU2003232941A1/en
Publication of WO2003104200A1 publication Critical patent/WO2003104200A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • N-MERCAPTOACYL PHENYLALA INE DERIVATIVES, PROCESS FOR THEIR PREPARATION, AND PH ARMACEUTICAL COMPOSITIONS CONTAINING THEM
  • the present invention relates to thiol derivatives with metalloprotease activity, more particularly N-mercaptoacyl phenylalanine derivatives with mixed ACE-NEP inhibitory activity, to pharmaceutical compositions containing them and to their use in medicine.
  • Angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) are two zinc metalloproteases involved in the metabolism of a variety of regulatory peptides and particularly those involved in the control of blood pressure and fluid homeostasis (Fournie- Zaluski et al. (1994) J. Med. Chem. 37:1070-1083).
  • ACE a zinc-containing carboxydipeptidase, converts the inactive precursor angiotensin I into angiotensin II, a peptide which promotes vasoconsthction and sodium retention and thereby leads to an increase in blood pressure.
  • Compounds with ACE inhibitory activity are useful in the treatment of hypertension, heart failure and post-infarct.
  • NEP also called 'enkephalinase'
  • NEP is a zinc-containing endopeptidase that is found in high concentration within the brush border region of the kidney. NEP inactivates the atrial natriuretic factor (ANF).
  • ANF is a hormone secreted by heart which increases the vasodilatation and, on the renal level, increases diuresis and natriuresis.
  • Compounds with inhibitory activity of the neutral endopeptidase (NEP) enzyme are useful as vasodilators. Both ACE and NEP are responsible for the degradation of the vasorelaxant peptide bradykinin at its endothelial and epithelial sites of action respectively.
  • ACE and NEP exert their action on the cardiovascular system with different mechanisms of action
  • compounds with mixed ACE-NEP inhibitory activity are generally used, alone or in combination, in the treatment of hypertension, renal failure, congestive heart failure and ischemic cardiopathologies.
  • WO 97/24342 discloses certain N-mercaptoacyl phenylalanine derivatives of formula (A) which have mixed ACE-NEP inhibitory activity and are useful in the treatment of cardiovascular diseases e.g. hypertension and congestive heart failure.
  • R is a mercapto group or a R 4 COS group convertible in an organism to a mercapto group
  • Ri is a straight or branched C 2 -C 4 alkyl group or an aryl or arylalkyl group having from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl is phenyl or a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, optionally substituted with one or more substituents, the same or different, selected from the group consisting of halogen atoms, hydroxy groups, alkoxy, alkyl, alkylthio, alkylsulphonyl or alkyloxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C C 3 alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulphon
  • R 2 is a hydrogen atom, a straight or branched C r C alkyI or a benzyl group; R is a phenyl group substituted with a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, being the phenyl and the heterocydic groups optionally substituted with one or more substituents, the same or different, as indicated for R ⁇
  • R 4 is a straight or branched C ⁇ -C 4 alkyl group or a phenyl group; the carbon atoms marked with an asterisk are stereogenic centers; and pharmaceutically acceptable salts thereof.
  • R 1 represents C ⁇ alkyl
  • R 2 represents pyrazole or pyrimidine; or a pharmaceutically acceptable derivative thereof. Further aspects of the invention are:
  • a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable carrier and/or excipient.
  • a compound of the invention for use in therapy is a compound of the invention for use in therapy.
  • a method of treating a patient suffering from a condition susceptible to amelioration by an ACE and/or NEP inhibitor comprising administering a therapeutically effective amount of a compound of the invention.
  • the compounds of formula (I) contain chiral (asymmetric) centres (marked *).
  • the individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present invention.
  • alkyl means both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, propyl and butyl groups.
  • R 1 represents C ⁇ alkyl, more preferably C 3 . 4 alkyl, most preferably isopropyl.
  • R 2 represents pyrazole or pyrimidine.
  • the pyrimidine is C-linked to the phenyl ring.
  • the pyrazole can be N-linked or C-linked to the phenyl ring.
  • R 2 represents pyrazole.
  • R 2 represents N-linked pyrazole.
  • the compounds of the present invention exhibit improved inhibitory activity against human plasma ACE in addition to good inhibitory activity against NEP and therefore achieve greater efficacy in man.
  • mixed ACE-NEP inhibitor means a compound with both ACE and NEP inhibitory activity.
  • dual has been more commonly used in the literature. For the purposes of this patent application, the terms mixed and dual are to be considered equivalent.
  • the term "pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use.
  • pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, solvate, or prodrug e.g. ester, of a compound of formula (I), which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I), or an active metabolite or residue thereof.
  • Such derivatives are recognizable to those skilled in the art, without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5 th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.
  • Preferred pharmaceutically acceptable derivatives are salts, solvates and esters. Particularly preferred pharmaceutically acceptable derivatives are salts and solvates.
  • salts are the salts with alkali or alkali-earth metals and the salts with pharmaceutically acceptable organic bases.
  • Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
  • prodrug means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • Esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
  • Preferred compounds according to the invention include and may be selected from the following: N-[(2S)-2-(mercaptomethyl)-3-methylbutanoyl]-4-(1 H-pyrazol-1-yl)-L-phenylalanine; N-[(2S)-2-(mercaptomethyl)-3-methylbutanoyl]-4-pyrimidin-5-yl-L-phenylalanine; N-[(2S)-2-(mercaptomethyl)-4-methylpentanoyl]-4-(1 H-pyrazol-5-yl)-L-phenylalanine; N-[(2S)-2-(mercaptomethyl)-3-methylbutanoyl]-4-(1 H-pyrazol-5-yl)-L-phenylalanine; N-[(2S)-2-(mercaptomethyl)-3-methylbutanoyl]-4-(1 H-pyrazol-5-yl)-L-phenylalanine; N-[(2S)
  • Particularly preferred compounds according to the invention include and may be selected from the following: N-[(2S)-2-(mercaptomethyl)-3-methylbutanoyl]-4-(1 H-pyrazol-1 -yl)-L-pheny!alanine;
  • the compounds of the invention are mixed ACE/NEP inhibitors and are thus of use in the treatment of conditions ameliorated by an ACE and/or NEP inhibitor, e.g. cardiovascular diseases, renal disease.
  • the compounds of the invention show advantageous properties, they may be more efficacious, show greater selectivity for the target enzymes, have fewer side effects, have a longer duration of action, be more bioavailable by the preferred route, or have other more desirable properties than similar known compounds.
  • the invention therefore provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in therapy, in particular in human medicine.
  • a method for the treatment of a mammal comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in particular in the treatment of conditions susceptible to amelioration by an ACE and/or NEP inhibitor.
  • compositions of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation comprising at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, thereof in association with a pharmaceutically acceptable carrier and/or excipient.
  • the carrier and/or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deletrious to the receipient thereof.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable carrier and/or excipient for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition susceptible to amelioration by a ACE and/or NEP inhibitor.
  • a process of preparing a pharmaceutical composition comprises mixing at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable carrier and/or excipient.
  • compounds of formula (I) may be formulated for oral, buccal, parenteral, transdermal, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions or they may be presented as a dry product for constitution with water or other suitable vehicles before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • compositions for oral administration may be suitably formulated to give controlled release of the active compound.
  • buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner.
  • the compounds according to the present invention may be formulated for parenteral administration by injection, e.g. by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds according to the present invention may be formulated for topical administration by insufflation and inhalation.
  • examples of types of preparation for topical administration include sprays and aerosols for use in an inhaler or insufflator.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, lactose, talc or starch.
  • Spray compositions may be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as metered dose inhalers, with the use of a suitable propellant.
  • the compounds according to the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds according to the present invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the daily dose of the compound of formula (I) or of a pharmaceutically acceptable derivative will depend on several factors such as the seriousness of the disease, the individual response of the patient or the kind of formulation but it is usually comprised between 0.1 mg and 10 mg per kg of body weight divided into a single dose or into more daily doses.
  • the compounds of formula (I) may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
  • each compound may differ from that when the compound is used alone.
  • the compounds of the present invention may be used in combination with other ACE and/or NEP inhibitors and the like.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions by any convenient route.
  • either the mixed ACE-NEP inhibitor or the second therapeutic agent may be administered first.
  • the combination may be administered either in the same or different pharmaceutical composition.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • each compound may differ from that when the compound is used alone.
  • Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
  • the compounds of formula (I) and pharmaceutically acceptable derivatives thereof may be prepared by the processes described hereinafter, said processes constituting a further aspect of the invention.
  • the groups are as defined above for compounds of formula (I) unless otherwise stated.
  • a process (A) for preparing a compound of formula (I) which process comprises reacting a compound of formula (II) with a compound of formula (III), followed by deprotection:
  • R 1 and R 2 have the above meanings and P 1 represents an oxygen protecting group e.g. methyl.
  • the condensation reaction is carried out using conventional techniques of peptide chemistry.
  • Deprotection reactions are carried out using conventional techniques.
  • the reaction may be carried out in the presence of a coupling agent, for example 1- [3-(dimethyIamino)propyl]-3-ethyl carbodiimide hydrochlohde, in the presence of HOBt (1- hydroxybenzotriazole), in a suitable solvent e.g. DMF (N,N-Dimethylformamide), MeCN,
  • a coupling agent for example 1- [3-(dimethyIamino)propyl]-3-ethyl carbodiimide hydrochlohde
  • HOBt 1- hydroxybenzotriazole
  • a suitable solvent e.g. DMF (N,N-Dimethylformamide), MeCN,
  • the reaction may be carried out by activation of a compound of formula (III) with thionyl chloride, followed by reaction of the activated compound of formula (III) with a compound of formula (II) in a suitable solvent e.g. DCM, ethyl acetate, preferably ethyl acetate, in the presence of a base e.g. K 2 CO 3 .
  • a suitable solvent e.g. DCM, ethyl acetate, preferably ethyl acetate
  • a base e.g. K 2 CO 3
  • the reaction is followed by deprotection under standard conditions, for example, when P 1 represents dialkyl, removal of the protecting group may be effected by NaOH in a solvent e.g. THF (tetrahydrofuran) or suspended in MeOH. Removal of the disulphide may be effected by treatment with tributyl phosphine.
  • the compound of formula (I) may then be precipitated by treatment
  • compounds of formula (III) may be prepared from compounds of formula (XI):
  • A is C h alky!, by hydrolysis of the ester groups under standard conditions e.g. using NaOH, followed by reaction with formaldehyde in the presence of a secondary amine e.g. dimethylamine (Mannich reaction), followed by neutralisation with an acid e.g. HCI.
  • P 1 is an oxygen protecting group e.g. methyl
  • B represents boron
  • P 2 is an amino protecting group, such as Boc, by treatment with pyrazole in the presence of copper acetate, pyridine and TEMPO (tetramethylpyrrolidine oxide) in an organic solvent e.g. DCM (dichloromethane); followed by deprotection of the amino group under standard conditions.
  • P 1 is an oxygen protecting group e.g. methyl
  • B represents boron
  • P 2 is an amino protecting group, such as Boc
  • P 1 is an oxygen protecting group e.g. methyl
  • SEM is 2-(thmethylsilyl)ethoxy]methyl
  • P 2 is an amino protecting group, such as Boc, by reflux in a solvent such as ethanol in the presence of an acid such as HCI.
  • SEM is 2-(trimethylsilyl)ethoxy]methyl, in the presence of a base e.g. potassium carbonate, a solvent e.g. DME, and a metal catalyst e.g. PdCI 2 , at elevated temperature.
  • a base e.g. potassium carbonate
  • a solvent e.g. DME
  • a metal catalyst e.g. PdCI 2
  • the reaction is carried out at 30-100°C, more preferably at about 70°C.
  • P 1 is an oxygen protecting group e.g. methyl
  • P 2 is an amino protecting group, such as Boc, by reaction with HCl in a solvent such as dioxane under nitrogen at room temperature.
  • Compounds of formula (VIII) may be prepared from compounds of formula (IV) by reaction with 5-bromopyridine in the presence of a base e.g. potassium carbonate, and a metal catalyst e.g. PdCI 2 .
  • the reaction is carried out at elevated temperature, preferably at 30- 100°C, more preferably at about 50°C.
  • compounds of formula (II) wherein R 2 is C4-linked pyrazole may be prepared from compounds of formula (IX):
  • reaction in the presence of a base e.g. potassium carbonate, a solvent e.g. DME, and a metal catalyst e.g. PdCI 2 , at elevated temperature and under nitrogen.
  • a base e.g. potassium carbonate
  • a solvent e.g. DME
  • a metal catalyst e.g. PdCI 2
  • the reaction is carried out at 30-100°C, more preferably at about 70°C.
  • compounds of formula (II) may be prepared from compounds of formula (XV):
  • P 2 is an amino protecting group e.g. COH, by deprotection of the amino group under standard conditions e.g. by treatment with MeOH in the presence of HCl, followed by protection of the carboxylic acid group under standard conditions e.g. by reaction with MeOH in the presence of HCl.
  • an amino protecting group e.g. COH
  • R 2 is pyrazole or pyrimidine, preferably pyrazole, in the presence of a transition metal catalyst e.g. Cul and a base e.g. Cs 2 CO 3 , K 2 CO 3 , preferably K 2 CO 3 , and a solvent e.g. NMP (n-methyl pyrrolidinone), 1 ,4-dioxane, DMF, preferably NMP.
  • a transition metal catalyst e.g. Cul and a base e.g. Cs 2 CO 3 , K 2 CO 3 , preferably K 2 CO 3
  • a solvent e.g. NMP (n-methyl pyrrolidinone), 1 ,4-dioxane, DMF, preferably NMP.
  • P 1 is an carboxylic acid protecting group e.g. methyl and P 2 is an amino protecting group e.g. COH or hydrogen, and X is a leaving group e.g. halogen, preferably iodine, by deprotection of the oxygen group under standard conditions e.g. by reaction with NaOH in a suitable solvent e.g. MeOH.
  • compounds of formula (XVI) may be prepared from compounds of formula (XIX) by by reaction with X, e.g. I 2 , in the presence of peracetic acid and an acid e.g. H 2 SO 4 and, followed by protection of the amino group under standard conditions e.g. by reaction with HCOOH in the presence of an activating group e.g. acetic anydride.
  • protecting groups used in the preparation of the compound of formula (I) may be used in a conventional manner. See for example Protective Groups in Organic Chemistry, Ed. J.F.W. McOmie, Plenum Press, London (1973) or Protective Groups in Organic Synthesis, Theodora Green, John Wiley and Sons, New York (1981 ).
  • suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g.
  • suitable oxygen protecting groups may include for example alky silyl groups, e.g. trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers e.g. tetrahydropyranyl or tert-butyl; or esters e.g. acetate.
  • the boronic acid * (1 ) (3.0g), 5-bromopyridine (1.77g), PdCI 2 [dppfj (0.39g)and potassium carbonate (5.1g) were mixed in degassed DME (45ml). The mixture was heated to 50°C for 3 hours, then cooled to room temperature. The mixture was diluted with saturated aqueous ammonium chloride (25ml) and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic portion was dried over sodium sulphate, and solvent evaporated in vacuo. Silica gel chromatography (ethyl acetate/cyclohexane 1 :10) gave the title compound (1.13g).
  • the aqueous phase was extracted with a further 2 x 200ml of chloroform then acidified with 5M HCl (200ml).
  • the product was extracted with ethyl acetate (1 x 400ml, 2 x 250ml), washed with brine (500ml), dried over Na 2 SO 4 and evaporated to give a solid (15g).
  • This was redissolved in THF (400ml), potassium hydroxide (2 equivalents) added and the mixture heated at reflux for 3 hours. The volume was reduced to 1/4, water (300ml) added and the mixture washed with chloroform (3 x 300ml). Acidification and extraction into ethyl acetate (5 x 300ml) followed by drying and solvent removal gave 8.1g (76%) of title compound.
  • the amine hydrochloride (6g) was suspended in a stirred biphasic mixture of dichloromethane ( ⁇ Oml) and water (50ml) and potassium carbonate (14.5g, 105mmol) was added at 0°C.
  • the acid chloride was added in dichloromethane (30ml) and stirring continued at 0°C for 30minut.es, then at room temperature for 1.5hours.
  • Dichloromethane (200ml) and water (100ml) were added and the aqueous phase extracted with further dichloromethane (200ml). The combined organics were washed with 2M HCl, brine (200ml) dried over Na 2 SO 4 and the solvent evaporated.
  • a mixture of diethyl isopropylmalonate (1wt) and 2M aqueous sodium hydroxide (2.2equivalents, 5.45voIumes) was heated at 80 ⁇ 5°C for 2 hours.
  • the contents were acidified with cone HCl (1.13 wt).
  • 60% aqueous dimethylamine (0.41 Wt) was added followed by 37%wt/wt aqueous formaldehyde (0.49 Wt) and the reaction was then stirred at 90 ⁇ 5°C for 16 hours.
  • the solution was cooled to 20+5°C and cone HCl (0.83 Wt) and MIBK (4volumes) were added. The layers were separated and the organic layer was washed with water (1 volume).
  • the MIBK layer was then concentrated under reduced pressure to about 1.4volumes.
  • Cesium carbonate (0.039wt) was then added and the mixture was heated at 40+5°C.
  • Thioacetic acid (0.36 Wt) was added and the mixture was stirred for at least 12 hours at 40 ⁇ 5°C.
  • the reaction mixture was cooled to 20 ⁇ 5°C and 20% potassium bicarbonate (2.25volumes) was added.
  • the layers were separated and the organic layer was washed with 20% potassium bicarbonate (0.9volumes).
  • the combined aqueous layers were adjusted to pH 1 with cone HCl (1.18 Wt) then the acidified layer was extracted with isopropyl acetate (2x2voIumes).
  • the combined organic layers were then washed with water (Ivolumes) and the mixture concentrated to 2volumes by vacuum distillation then isopropyl acetate (4.9volumes) was added.
  • (+)-Ephedrine hydrochlohde (0.86 Wt) was suspended in isopropyl acetate (4.2volumes) and water (0.7 volumes). 10.8M sodium hydroxide (0.58 Wt) was added and stirred to give a biphasic solution. The phases were separated and organic phase was washed with water (0.35volumes) and the solvent reduced to 3.5 volumes by vacuum distillation. 40% of the ephedrine solution (1.4volumes) was added to the racemate solution. The crystallisation was seeded and stirred for an hour at 20°C, then the remaining ephedrine was added over 2 - 3 hours. The crystallisation was cooled to 0 ⁇ 5°C and stirred for at least 2 hours. The slurry was filtered and the filter cake was washed with isopropyl acetate (2x2.8volumes) and dried in a vacuum oven at 50 ⁇ 5°C.
  • Glacial acetic acid (2.73wt, 2.62volumes) was stirred at 20°C and concentrated sulphuric acid (1.34wt, 0.73volumes) added whilst the temperature was kept below 45°C.
  • the mixture was cooled to 20°C, and iodine (0.77wt, O. ⁇ equivalents) added with stirring.
  • L- Phenylalanine (1wt) was added.
  • the mixture was heated to 55 ⁇ 5°C with pumped agitation and 40% peracetic acid (about 0.75wt) added over 2 - 4hours.
  • the reaction was then checked for completeness by HPLC ( ⁇ 5% area phenylalanine remaining, typically 0-5%).
  • the temperature of the mixture was adjusted to 40°C, and distilled under vacuum until the volume had been reduced to about 3volumes (a minimum temperature of 40°C was maintained during this operation).
  • the mixture was then diluted with toluene (1 volume), maintaining the temperature at a minimum of 30°C, followed by water (2.5volumes).
  • the mixture was cooled to 20°C and 0.880 ammonia (4volumes, 3.52wt) and toluene (1 volumes) added whilst the temperature was kept below 35°C.
  • the mixture was then allowed to settle.
  • the toluene layer was removed and the aqueous layer extracted with further toluene (1 volumes).
  • the organic layers were combined and distilled under vacuum to give a mobile oil. Toluene (O. ⁇ volumes) was added and the organic solution was used without further treatment in the next step.
  • the mixture was concentrated under reduced pressure to about 2volumes.
  • the oil was diluted with dichloromethane ( ⁇ volumes) and washed sequentially with water (4volumes) which was adjusted to pH9 by the addition of 0.880 ammonia solution and then water ( ⁇ volumes).
  • the dichloromethane solution was then diluted with toluene (4volumes) and concentrated at atmospheric pressure until a batch volume of 6 - 7volumes was achieved, typically with the solution at 65-70°C.
  • the solution was then cooled to 20°C over about 1 hour (seeded if necessary) and then to 7°C over a further 1 hour.
  • the crystallised product was aged for at least a further 1 hour and then filtered in a pressure filter. The cake was washed with cold (5-10°C) toluene (2 x 2volumes), pulled dry, and the product was then dried under vacuum at 50°C.
  • N-Formyl-4-iodo-L-phenylalanine methyl ester (1wt) was suspended in methanol ( ⁇ volumes) and water ( ⁇ volumes) and treated with 2M sodium hydroxide (1.73 Wt) at 22 ⁇ 3°C. This 5 mixture was stirred for about 4hours until complete by HPLC. The reaction mixture was heated to 31 ⁇ 2°C then 2M hydrochloric acid (0.41 Wt) was added at 31 ⁇ 2°C over 20 - 30 minutes, then N-formyl-4-iodo-L-phenylalanine seed (0.001 wt) was added as a slurry in 1 :1 Methano water.
  • N-Formyl-4-(1 H-pyrazol-1-yl)-L-phenylalanine (1wt) was suspended in methanol (lOvolumes) and stirred at 22 ⁇ 3°C.
  • Acetyl chloride (0.94 wt, 3equivalents) was added ⁇ dropwise at 20- ⁇ O°C over about I ⁇ minutes.
  • the resulting solution was warmed to ⁇ O ⁇ ⁇ °C and held for at least 14hours. The mixture was analysed. When complete (ie. ⁇ 3% amino acid) the solution was cooled to 22 ⁇ 3°C and concentrated in vacuo to about ⁇ volumes at ⁇ 30°C.
  • Methyl 4-(1 H-pyrazol-1-yl)-L-phenylalanine hydrochloride (1wt) was suspended in ethyl acetate ( ⁇ volumes) and treated with 2M K 2 CO 3 (10 volumes) then stirred at 20-2 ⁇ ° until all ⁇ the solids had dissolved (up to one hour). The phases were separated and the lower aqueous layer extracted with ethyl acetate ( ⁇ volumes). The combined organic layers were treated with charcoal (0.2 ⁇ wt) for about 2 hours at 20-2 ⁇ °C. The charcoal was removed by filtration and ethyl acetate (3 volumes) was used to wash through the charcoal bed.
  • the filtrate was treated with potassium carbonate (2M, 10 volumes) and the rapidly stirred 0 biphasic solution was treated with the toluene solution of the acid chloride (prepared above) over 20minut.es keeping the temperature below 2 ⁇ °C.
  • the acid chloride was rinsed in with toluene (0.1 volumes).
  • the solution was stirred rapidly for 30minut.es and the phases separated.
  • the upper organic layer was washed with water ( ⁇ volumes) and concentrated to about ⁇ volumes by atmospheric distillation.
  • Methyl 4-(1 H-pyrazol-1-yl)-L-phenylalanine hydrochloride ( ⁇ .Og) was suspended in ethyl ⁇ acetate (7 ⁇ ml) and treated with 2M K 2 CO 3 (33ml) then stirred at 20-2 ⁇ °C until all the solids had dissolved.
  • the rapidly stirred biphasic solution was treated with the solution of the acid chloride (prepared above) over 20 minutes keeping the temperature below 2 ⁇ °C.
  • the solution was stirred rapidly for 30 minutes and the phases separated.
  • the upper organic layer was washed with 1 M HCl (33ml) and water (33ml) then concentrated to approximately 0 3 ⁇ ml by atmospheric distillation.
  • the slurry was acidified to pH 1.2 by addition of 36%w/w (11.6M) HCl (1.9equivalents, 0.39 volumes, 13ml).
  • the slurry was cooled to 0- ⁇ °C and aged for 30 minutes then the solid collected by filtration, washed with cold (0- ⁇ °C) 1 :1 MeOH/water (2 x 3 volumes, 100ml) and dried in a vacuum oven at ⁇ 0°C to give the title compound as a pale yellow to brown powder. 28.04g, 96.7% yield. 0
  • Example 3 0 N-F(2S)-2-(mercaptomethyl)-4-methylpentanovn-4-(1 H-pyrazol- ⁇ -yl)-L-phenylalanine from Methyl ⁇ /- ⁇ (2S)-2-[(acetylthio)methyl]-4-methyIpentanoyl ⁇ -4-(1 H-pyrazol-5-yI)-L- phenylalaninate
  • Methyl ⁇ /- ⁇ (2S)-2-[(acetyIthio)methyl]-3-methylbutanoyl ⁇ -4-(1 H-pyrazol-1 -yl)-L- phenylalaninate (1wt) was charged to the vessel and de-oxygenated by 3 vacuum/nitrogen cycles.
  • the solid was suspended in a mixture of water (3volumes) and MeOH ( ⁇ volumes) 0 and stirred at 20°C under nitrogen. 32%w/w (10. ⁇ M) NaOH (3. ⁇ equivalents, 0.73volumes) was added over ⁇ minutes and the mixture stirred at 20°C for ⁇ Ominutes.
  • tributylphosphine (0.02eq, 0.012volumes) was added and the solution stirred for 30-60minutes. A sample was analysed by HPLC to ⁇ confirm most of the disulfide was reduced back to starting material.
  • the solution was line-filtered into a new reaction vessel and line-washed with water (3volumes).
  • the clarified solution was acidified to pH 3.0-3.6 by addition of 36%w/w (11.6M) HCl (3.4equivalents, 0.70volumes) and aged for lOminutes to allow crystallisation to 0 develop.
  • the slurry was acidified to pH 1 by addition of 36%w/w (1 1.6M) HCl (1.2equivalents, 0.24volumes).
  • UV Detection Range 215 to 330nm
  • Solvents A: 0.1% Formic Acid + 10mMolar Ammonium Acetate.
  • Inhibitory activity against ACE was determined via the following protocol, following the rate of cleavage of the substrate MCA-Ala-Ser-Asp-Lys-Dpa-OH, resulting in an increase in ⁇ fluorescence at 320nm excitation/400nm emission.
  • Human ACE refers to human kidney ACE.
  • the assay used was identical to that described above except that human/rat plasma was substituted for the buffered human ACE.
  • Tables (i) and (ii) represent values obtained upon repeat testing.
  • the Compounds of the invention (1-5) show increased Human ACE pKi, Human plasma ACE pKi and Rat plasma ACE pKi compared to Compound X. This surprising potency indicates improved ACE-NEP inhibitory activity.
  • Compounds may be tested for ACE inhibitory activity using tests for inhibition of Angiotensin I conversion. The conversion of Angiotensin I to Angiotensin II mediated by ACE is measured using purified human ACE enzyme. The ability of the compounds of the invention to inhibit this conversion is calculated from the altered ratio of Angiotensin I to Angiotensin II.

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Abstract

L'invention se rapporte à des composés de formule (I), dans laquelle R1 représente alkyle C1-6; R2 représente pyrazole ou pyrimidine; ou leur dérivé pharmaceutiquement acceptable. L'invention se rapporte également à des compositions pharmaceutiques contenant les composés de formule (I) et à leur utilisation dans le domaine de la médecine, plus particulièrement dans l'amélioration d'un état clinique, auquel cas un inhibiteur ACE et/ou NEP est indiqué.
PCT/GB2003/002446 2002-06-07 2003-06-05 Derives de n-mercaptoacyl phenyalanine, leur procede de preparation et les compositions pharmaceutiques les contenant WO2003104200A1 (fr)

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GB0220875A GB0220875D0 (en) 2002-09-09 2002-09-09 Compounds
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Cited By (15)

* Cited by examiner, † Cited by third party
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US7723345B2 (en) 2005-12-29 2010-05-25 Lexicon Pharmaceuticals, Inc. Multicyclic amino acid derivatives and methods of their use
US7786119B2 (en) 2004-04-01 2010-08-31 Cardiome Pharma Corp. Drug conjugates of ion channel modulating compounds
US7855291B2 (en) 2005-12-29 2010-12-21 Lexicon Pharmaceuticals, Inc. Process for the preparation of substituted phenylalanines
US7897763B2 (en) 2005-12-29 2011-03-01 Lexicon Pharmaceuticals, Inc. Process for the preparation of substituted phenylalanines
US7968729B2 (en) 2007-08-24 2011-06-28 Lexicon Pharmaceuticals, Inc. 1-phenyl-1H-pyrazole-based compounds
WO2012065958A1 (fr) 2010-11-16 2012-05-24 Novartis Ag Procédé de traitement d'une néphropathie induite par les produits de contraste
EP2543368A1 (fr) 2007-12-11 2013-01-09 Viamet Pharmaceuticals, Inc. Inhibiteurs de métalloenzymes utilisant des fractions de liaison à un métal en combinaison avec des fractions de ciblage
WO2014081702A2 (fr) 2012-11-20 2014-05-30 Novartis Ag Mimétiques d'apéline linéaire synthétique pour le traitement d'une insuffisance cardiaque
WO2015013169A2 (fr) 2013-07-25 2015-01-29 Novartis Ag Bioconjugués de polypeptides d'apeline synthétiques
WO2015013168A1 (fr) 2013-07-25 2015-01-29 Novartis Ag Polypeptides cycliques pour le traitement de l'insuffisance cardiaque
WO2016116842A1 (fr) 2015-01-23 2016-07-28 Novartis Ag Conjugués d'acides gras de l'apeline synthétique présentant une demi-vie améliorée
WO2020110011A1 (fr) 2018-11-27 2020-06-04 Novartis Ag Peptides cycliques servant d'inhibiteurs de proprotéine convertase subtilisine/kexine de type 9 (pcsk9) pour le traitement de troubles métaboliques
WO2020110008A1 (fr) 2018-11-27 2020-06-04 Novartis Ag Composés pentamères cycliques servant d'inhibiteurs de proprotéine convertase subtilisine/kexine de type 9 (pcsk9) pour le traitement d'un trouble métabolique
WO2020110009A1 (fr) 2018-11-27 2020-06-04 Novartis Ag Composés tétramères cycliques servant d'inhibiteurs de proprotéine convertase subtilisine/kexine de type 9 (pcsk9) pour le traitement de troubles métaboliques
WO2023084449A1 (fr) 2021-11-12 2023-05-19 Novartis Ag Dérivés diaminocyclopentylpyridines pour le traitement d'une maladie ou d'un trouble

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US5760241A (en) * 1995-12-28 1998-06-02 Zambon Group S.P.A. Thiol derivatives with metallopeptidase inhibitory activity

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WO1997024342A1 (fr) * 1995-12-28 1997-07-10 Zambon Group S.P.A. Derives thiol presentant une activite inhibitrice de metallopeptidase
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DEPREZ P ET AL: "THIOL INHIBITORS OF ENDOTHELIN-CONVERTING ENZYME", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 6, no. 19, 1996, pages 2317 - 2322, XP000653094, ISSN: 0960-894X *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7786119B2 (en) 2004-04-01 2010-08-31 Cardiome Pharma Corp. Drug conjugates of ion channel modulating compounds
US7723345B2 (en) 2005-12-29 2010-05-25 Lexicon Pharmaceuticals, Inc. Multicyclic amino acid derivatives and methods of their use
US7855291B2 (en) 2005-12-29 2010-12-21 Lexicon Pharmaceuticals, Inc. Process for the preparation of substituted phenylalanines
US7897763B2 (en) 2005-12-29 2011-03-01 Lexicon Pharmaceuticals, Inc. Process for the preparation of substituted phenylalanines
US8629156B2 (en) 2005-12-29 2014-01-14 Lexicon Pharmaceuticals, Inc. Tryptophan hydroxylase inhibitors
US8063057B2 (en) 2005-12-29 2011-11-22 Lexicon Pharmaceuticals, Inc. Multicyclic amino acid derivatives and methods of their use
US8575362B2 (en) 2007-08-24 2013-11-05 Lexicon Pharmaceuticals, Inc. Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds
US7968729B2 (en) 2007-08-24 2011-06-28 Lexicon Pharmaceuticals, Inc. 1-phenyl-1H-pyrazole-based compounds
EP2543368A1 (fr) 2007-12-11 2013-01-09 Viamet Pharmaceuticals, Inc. Inhibiteurs de métalloenzymes utilisant des fractions de liaison à un métal en combinaison avec des fractions de ciblage
WO2012065958A1 (fr) 2010-11-16 2012-05-24 Novartis Ag Procédé de traitement d'une néphropathie induite par les produits de contraste
WO2014081702A2 (fr) 2012-11-20 2014-05-30 Novartis Ag Mimétiques d'apéline linéaire synthétique pour le traitement d'une insuffisance cardiaque
WO2015013169A2 (fr) 2013-07-25 2015-01-29 Novartis Ag Bioconjugués de polypeptides d'apeline synthétiques
WO2015013168A1 (fr) 2013-07-25 2015-01-29 Novartis Ag Polypeptides cycliques pour le traitement de l'insuffisance cardiaque
WO2016116842A1 (fr) 2015-01-23 2016-07-28 Novartis Ag Conjugués d'acides gras de l'apeline synthétique présentant une demi-vie améliorée
WO2020110011A1 (fr) 2018-11-27 2020-06-04 Novartis Ag Peptides cycliques servant d'inhibiteurs de proprotéine convertase subtilisine/kexine de type 9 (pcsk9) pour le traitement de troubles métaboliques
WO2020110008A1 (fr) 2018-11-27 2020-06-04 Novartis Ag Composés pentamères cycliques servant d'inhibiteurs de proprotéine convertase subtilisine/kexine de type 9 (pcsk9) pour le traitement d'un trouble métabolique
WO2020110009A1 (fr) 2018-11-27 2020-06-04 Novartis Ag Composés tétramères cycliques servant d'inhibiteurs de proprotéine convertase subtilisine/kexine de type 9 (pcsk9) pour le traitement de troubles métaboliques
WO2023084449A1 (fr) 2021-11-12 2023-05-19 Novartis Ag Dérivés diaminocyclopentylpyridines pour le traitement d'une maladie ou d'un trouble

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