Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/02—Monothiocarboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/02—Monothiocarboxylic acids
  • C07C327/04—Monothiocarboxylic acids having carbon atoms of thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C327/06—Monothiocarboxylic acids having carbon atoms of thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of an acyclic saturated carbon skeleton
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/02—Monothiocarboxylic acids
  • C07C327/16—Monothiocarboxylic acids having carbon atoms of thiocarboxyl groups bound to carbon atoms of six-membered aromatic rings

Definitions

• Human hypertension represents a disease of multiple etiologies. Included among these is a sodium and volume dependent low renin form of hypertension. Drugs that act to control one aspect of hypertension will not necessarily be effective in controlling another.
• mercapto-acylamino acids are known as enkephalinase inhibitors useful as analgesics and in the treatment of hypertension.
• R includes hydrogen, optionally substituted alkyl, optionally substituted phenyl, cyclohexyl and thienyl; and R 2 includes hydrogen optionally substituted alkyl, optionally substituted benzyl, phenyl, phenoxyalkyl and optionally substituted mercaptoalkyl.
• the compounds are disclosed as principally having enkephalinase activity, but also are said to be antihypertensives.
• Atrial natriuretic factors ANF which help to regulate blood pressure, blood volume and the excretion of water, sodium and potassium.
• ANF atrial natriuretic factors
• ANF were found to produce a short-term reduction in blood pressure and to be useful in the treatment of congestive heart failure. See P. Needleman et a1, "Atriopeptin: A Cardiac Hormone Intimately Involved in Fluid, Electrolyte and Blood-Pressure Homeostasis", N. Engl. J. Med . , 314, 13 (1986) pp. 828834, and M. Cantin et a1 in "The Heart as an Endocrine Gland", Scientific American, 254 (1986) pg. 76-81.
• ACE inhibitors which compounds are useful in blocking the rise in blood pressure caused by increases in vascular resistance and fluid volume due to the formation of angiotensin II from angiotensin I.
• ACE inhibitors see M. Wyvratt and A. Patchett, "Recent Developments in the Design of Angiotensin Converting Enzyme Inhibitors" in Med. Res. Rev. Vol. 5, No. 4 (1985) pp. 483-531.
• the present invention relates to mercaptoacylamino acids useful in the treatment of various types of hypertension, particularly volume expanded hypertension, and congestive heart failure.
• AAdministration of a combination of a mercaptoacylamino acid and an ACE inhibitor provides an antihypertensive effect greater than either the mercaptoacylamino acid or ACE inhibitor alone.
• Administration of a combination of a mercapto-acylamino acid of the present invention and an exogenous ANF or ACE inhibitor is therefore particularly useful in treating hypertension.
• the present invention therefore also relates to treating hypertension with a mercapto-acylamino acid or with a mercaptoacylamino acid in combination with an ANF or an ACE inhibitor, which methods comprise administering to a mammal in need of such treatment an antihypertensive effective amount of the mercapto-acylamino acid or an antihypertensive effective amount of a combination of a mercapto-acylamino acid and ANF or ACE inhibitor.
• the drug or combination of drugs is preferably administered in a pharmaceutically acceptable carrier, e.g. for oral or parenteral administration.
• the combinations of drugs may be co-administered in a single composition, or components of the combination therapy may be administered separately.
• any convenient combination of dosage forms may be used, e.g. oral mercapto-acylamino acid/oral ANF, oral mercapto-acylamino acid/parenteral ACE inhibitor, parenteral mercapto-acylamino acid/oral ANF, parenteral mercapto-acylamino acid/parenteral ACE inhibitor.
• the mercapto-acylamino acid be administered first.
• Another aspect of the invention relates to pharmaceutical compositions comprising a mercaptoacylamino acid of this invention, alone or in combination with an ANF or an ACE inhibitor, and to methods of treatment of hypertension and congestive heart failure comprising administering a mercapto-acylamino acid of this invention, alone or in combination with an ANF or an ACE inhibitor to a mammal in need of such treatment.
• Novel mercapto-acylamino acid antihypertensive compounds of the present invention are represented by the following formula:
• R 1 is Y-C 8 H 4 -, Y-C 8 H 4 S-, Y-C 6 H 4 O-,
• R 2 is R 14 (CH 2 ) k S(O) 0 _ 2 (CH 2 ) q - or R 6 OCO(CH 2 ) q -;
• R 4 is hydrogen, alkyl or ⁇ 1 -C 6 H 4 - ;
• R 14 is mono-unsaturated lower alkyl, hydroxy, alkoxy or alkylthio, provided that when R 14 is hydroxy or alkoxy, k is 2 or 3 and when R 14 is mono-unsaturated alkykl or alkylthio, k is 1, 2 or 3;
• R 6 is dihydroxyalkyl, dialkoxyalkyl, alkoxyalkoxyalkyl, haloalkyl, (haloalkoxy)alkyl or alkyl substituted with a 5-6 membered saturated ring comprising 1-2 oxygen atoms as ring members wherein the ring carbon atoms may be substituted with 0-2 alkyl substituents;
• R 7 and R 8 are independently R 6 , H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or arylalkyl, or R 7 and R 8 together with the nitrogen to which they are attached complete a 5-7 membered ring, wherein one of the 4-6 ring members comprising R 7 and R 8 may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom, and wherein the ring may be substituted on the ring carbon atoms with subst ituents chosen from alkyl and hydroxy groups;
• R 9 is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl or carbamoylalkyl; n is 0-2; m and k are independently 0-3; q is 1-4;
• X is a bond, -O-, -S-, or -CH 2 -;
• Q is hydrogen or R 10 CO-
• R 10 is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl,
• Y 2 -C 6 H 4 -alkyl alkoxy, Y 2 -C 6 H 4 -, naphthyl, furyl, thienyl or pyridyl;
• Y, Y 1 and Y 2 independently represent one or more substituents selected from H, alkyl, cycloalkyl, alkoxy, OH,
• alkyl means straight or branched alkyl chains of 1 to 6 carbon atoms
• alkoxy similarly refers to alkoxy groups having 1 to 6 carbon atoms
• Cycloalkyl means cyclic alkyl groups of 3-6 carbon atoms.
• Aryl means mono-cyclic or fused ring bi-cyclic carbocyclic aromatic groups having 6 to 10 ring members or mono-cyclic or fused ring bycyclic aromatic groups wherein 1-2 ring members may independently be nitrogen, oxygen or sulfur, wherein the carbon ring members of the aryl group are substituted by 0-3 substituents as defined above by Y.
• Examples of carbocyclic aryl groups are phenyl, ⁇ -naphthyl and 3-naphthyl, and examples of heterocyclic aryl groups are furyl, thienyl, benzofuryl, benzothienyl, indolyl and pyridyl. All positional isomers, e.g. 2-pyridyl, 3-pyridyl, are contemplated.
• Halo refers to fluorine, chlorine, bromine or iodine radicals.
• poly when used to describe substitution in a phenyl, alkylphenyl or alkoxyphenyl group, means 2 to 5 substituents. comprising the partial
• amino acids are derived from amino acids of formula Examples of such amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine.
• Preferred embodiments of compounds of formula I are compounds wherein R 1 is Y-C 6 H 4 - especially wherein Y is hydrogen. Also preferred are compounds wherein R 3 is -OR 7 or -NR 7 R 8 , wherein R 7 and R 8 are as defined above. Further preferred compounds of formula I are those wherein Q is hydrogen or R 10 CO wherein R 10 is alkyl, especially methyl, or phenyl. Also preferred are compounds wherein R 2 is R 14 (CH 2 ) k -(S(O) O _ 2 (CH)q-. Especially preferred R 14 groups are mono-unsaturated lower alkyl such as vinyl and alkylthio such as methylthio.
• Compounds of this invention may, depending on the nature of functional groups, form addition salts with various inorganic and organic acids and bases.
• Such salts include salts prepared with organic and inorganic acids, e.g. HC1, HBr, H 2 SO 4 , H 3 PO 4 , methanesulfonic acid, toluenesulfonic acid, maleic acid, furmaric acid and camphorsulfonic acid.
• Salts prepared with bases include ammonium salts, alkali metal salts, e.g. sodium and potassium salts, and alkaline earth salts, e.g. calcium and magnesium salts.
• the salts may be formed by conventional means, as by reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
• compounds of the present invention can be made by an appropriate process selected from the following process A and B, wherein Q, R 1 , R 2 , R 3 and n are as defined in claim 1, including suitable protection:
• Process B for compounds of formula I wherein R 3 is -NR 7 R 8 , condensation of a (3-thiopropionyl) amino acid of formula VI, or a reactive derivative thereof, with an amine of formula VII ,
• compounds of the present invention may be prepared by using coupling reactions well known in the peptide art to join a 3-acetylthio-2-(substituted)-propionic acid of formula 1 with an amino acid ester of formula 2.
• the following reaction Scheme 1 is an example:
• a propionic acid of formula 1 may be reacted with thionyl chloride to prepare the corresponding propionyl chloride, which may then be reacted with an amino acid ester of formula 2 or with the corresponding free acid 2a in an inert solvent such asacetonitrile in the presence of a base such as triethylamine to give isomers of formula 3, which may be separated as in Scheme 1.
• Scheme 2 is an example:
• n, Ac, R p , R r and R t are as defined above, and wherein R t may also be hydrogen.
• R 3 esters of compounds of formula I are prepared by standard esterification techniques, for example N-(t-butoxycarbonyl)-S-allyl-(R)-cysteine is reacted with 2- (2-chloroethoxy)ethanol in the presence of a coupling agent such as DEC and a base such as 4-dimethylaminopyridine, the amino function is deprotected and the resultant amino acid ester is reacted with a compound of formula 1 in a manner similar to that described in Scheme 2.
• a coupling agent such as DEC
• a base such as 4-dimethylaminopyridine
• N-(t-butoxycarbonyl)-S-methylthiomethyl-(R)-cysteine is reacted with N,N-diethylbromoacetamide and a reagent such a cesium carbonate, the resultant ester is deprotected at the amino function and a reaction similar to that described in
• compounds of formula I wherein R 3 is -NR 7 R 8 may be prepared by coupling a propionyl chloride of formula 8 with an amino acid of formula 2a in the presence of a base and then coupling the desired -NR 7 R 8 group to the carboxylic group using a typical peptidecoupling reaction.
• Scheme 4 shows an example of such a procedure:
• R 3 is -NR 7 R 8 comprises reacting a propionic acid of formula 1 with an amino acid t-butyl ester of formula: 1, removing the t-butyl ester and coupling the -NR 7 R 8 group to the carboxylic acid group as above.
• Q is R 10 CO-
• R 10 CO- may be prepared by known methods, for example by adding a mercaptoacid of formula R 10 COSH to an acrylic acid to obtain a thiosubstituted propionic acid analogous to compounds, of formula 1.
• an amide of formula I wherein Q is -SH may be reacted with a compound of formulae R 10 COC1 in the presence of a base to obtain the desired sulfur substituted derivative.
• R 2 is R 14 (CH 2 ) k -S(O) 1 _ 2 -(CH 2 )q are prepared by oxidizing with hydrogen peroxide the corresponding substituted alkylthioalkyl compound of formula I (e.g. those wherein R 2 is, e.g. R 14 (CH 2 ) k -S-(CH 2 q-).
• a second aspect of the invention is the administration of a combination of a compound of formula I and an ANF.
• ANF As indicated by Needleman et al., a number of ANF have been isolated so far, all having the same core sequence of 17 amino acids within a cysteine disulf ide bridge, but having different N-termini lengths. These peptides represent N-terminal truncated fragments (21-48 amino acids) of a common preprohormone (151 and 152 amino acids for man and rats, respectively).
• Human, porcine and bovine carboxyterminal 28-amino acid peptides are identical and differ from similar peptides in rats and mice in that the former contain a methionine group at position 12 while the latter contain isoleucine.
• ANFs contemplated for use in this invention are ⁇ human AP 21 (atriopeptin I), ⁇ human AP 28, ⁇ human AP 23 (atriopeptin II or APII), ⁇ human AP 24, ⁇ human AP 25, ⁇ human AP 26, ⁇ human AP 33, and the corresponding rat sequence of each of the above wherein Met 12 is IIe. See Table 1 for a comparison of the peptides.
• a third aspect of the invention in the administration of a combination of an ACE, inhibitor and a compound of formula I.
• ACE inhibitors are those disclosed in the article by Wyvratt et a1., cited above, and in the following publications: U.S. Patents 4,105,776, 4,468,519, 4,555,506, 4,374,829, 4,462,943, 4,470,973, 4,470,972, 4,350,704, 4,256,761, 4,344,949, 4,508,729, 4,512,924, 4,410,520 and 4,374,847; and the following foreign patents or published patent applications: GB 2,095,682, EPA 50,800, EPA 79,522, EPA 79,022 and EPA 46,953.
• ACE inhibitors for use in the combination of this invention: spirapril, enalapril, ramipril, perindopril, indolapril, lysinopril, pentopril, cilazapril, captopril, zofenopril, pivalopril, fosinopril and L- (5)-2- [N- [ 1- (ethoxycarbonyl)-3-phenylpropyl]alanyl]-1,2,3, 4-tetrahydro-6, 7-dimethoxyisoquinoline-3-carboxylic acid monohydrochloride.
• mice are dosed subcutaneously (1 ml/kg) with vehicle (methylcellulose, hereinafter MC) or mercapto-acylamino acid and blood pressure is monitored for the next 4 hours.
• vehicle methylcellulose, hereinafter MC
• mercapto-acylamino acid mercapto-acylamino acid
• the animals first undergo a challenge with an ANF such as atriopeptin II (AP II) or AP28 30 ⁇ g/kg iv and at the end of 60 min. are treated with drug vehicle or a mercapto-acylamino acid subcutaneously.
• a second ANF challenge is administered 15 min. later and blood pressure is monitored for the next 90 min.
• the antihypertensive effect in SHR of mercaptoacylamino acids and ACE inhibitors, alone and in combination, is determined as follows: Animals are prepared for blood pressure measurement as described above. After stabilization, animals are dosed subcutaneously or orally with test drugs or placebo and blood pressure is monitored for the next 4 hr.
• compositions of this invention comprise a mercapto-acylamino acid or a mercapto-acylamino acid and an ANF or a mercapto-acylamino acid and an ACE inhibitor in combination with a pharmaceutically acceptable carrier, for administration to mammals.
• a pharmaceutically acceptable carrier for administration to mammals.
• a variety of pharmaceutical forms is suitable, preferably for oral or parenteral administration, although mechanical delivery systems such as transdermal dosage forms are also contemplated.
• the daily antihypertensive dose of the compound or combinations of this invention is as follows: for mercapto-acylamino acids alone the typical dosage is 1 to 100 mg/kg of mammalian weight per day administered in single or divided dosages; for the combination of mercapto-acylamino acid and an ANF, the typical dosage is 1 to 100 mg of mercapto-acylamino acid/kg mammalian weight per day in single or divided dosages plus 0.001 to 0.1 mg ANF/kg of mammalian weight per day, in single or divided dosages, and for the combination of mercaptoacylamino acid and an ACE inhibitor, the typical dosage, is 1 to 100 mg of mercapto-acylamino acid/kg mammalian weight per day in single or divided dosages plus 0.1 to 30 mg ACE inhibitor/kg of mammalian weight per day in single or divided dosages.
• any component or combination to be administered is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
• Compounds of this invention are not toxic at the therapeutically effective dose.
• the compounds or combinations of this invention may be administered to patients in a dosage range as follows: for treatment with mercapto-acylamino acids alone, about 10 to about 500 mg per dose given 1 to 4 times a day, giving a total daily dose of about 10 to 2000 mg per day; for the combination of mercapto-acylamino acid and ANF, about 10 to about 500 mg mercapto-acylamino acid per dose given 1 to 4 times a day and about 0.001 to about 1 mg ANF given 1 to 6 times a day (total daily dosage range of 10 to 2000 mg day and .001 to 6 mg/day, respectively); and for the combination of a mercapto-acylamino acid and an ACE inhibitor, about 10 to about 500 mg mercaptoacylamino acid and an ACE inhibitor
• Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions.
• Typical injectable formulations include solutions and suspensions.
• Typical pharmaceutically acceptable carriers may be used in said formulations.
• Drug refers to any mercapto-acylamino acid of the present invention.
• ACE inhibitor refers to any of the ACE inhibitors listed on page 14, especially those in the list of preferred ACE inhibitors.
• Anrial peptide refers to any antihypertensive atrial peptide, especially those listed in Table 1.
• Drug for Injection (per vial) g/vial g/vial
• Methylparaben 1.8 Propylparaben 0.2 0.2 Sodium Bisulfite 3.2 3.2 Disodium Edetate 0.1 0.1
• pH is adjusted to 6.2 using 0.1N citric acid solution.
• Step 1 N-t-Butyloxycarbonyl-S-allyl-(R)-cysteine: Treat S-allyl-(R)-cysteine (1.42g) in THF (20 ml) and MeOH (5 ml) with di-t-butyl dicarbonate (2.1g) and triethylamine (2.5 ml) and stir the resulting mixture at room temperature for 20 hr. Concentrate the mixture in vacuo, dilute with water, and extract with hexane. Acidify the aqueous solution with KHSO 4 solution and extract with EtOAc. Concentrate the dried (MgSO 4 ) EtOAc solution in vacuo to give the title compound, a clear oil.
• Step 2 N-t-Butyloxycarbonyl-S-allyl-(R)-cysteinamide : React N-t-butyloxycarbonyl-S-allyl-(R)-cysteinamide (2.02g) with triethylamine (2.5 ml) in THF (25 ml). Cool the mixture to 0-5 °C. Add ethyl chloroformate (1.4 ml) in THF (5 ml) dropwise over 5 min. and stir the reaction mixture for 15 min. Add ammonium: hydroxide (29%, 0.8,ml) in THF (5 ml) dropwise. Allow the reaction mixture to warm to room temperature and stir for 18 hr. Filter the reaction mixture and concentrate the filtrate in vacuo.

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