Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems
• • 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
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
  • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to new organic nitrates, to their methods of preparation and to their use in the treatment of vascular diseases and in particular in the treatment of angina.
• the angina attack results from a sudden and reversible myocardial ischemia and appears when the oxygen requirements of the myocardium are greater than the intakes of the coronary circulation.
• Organic nitrates used for many years in the treatment of angina attack induce relaxation of the vascular smooth muscle fiber by increasing the level of soluble guanylate cyclase, via the nitric oxide formed during the transformation of nitrates in the presence of cysteine.
• the leader of these products is trinitrine, of very fast action; other derivatives have been developed and exhibit a slower and more prolonged action than the latter.
• organic nitrates in addition to trinitrine (nitroglycerin), the tetranitro-erythritol, hexanitroinositol, tetranitropentaerythritol, propatyl-nitrate, isosorbide 5-mononitrate (IS-5-MN), isosorbide dinitrate, isosorbide 2-mono-nitrate (IS-2 -MN), isomannide 2- nitrate, trinitrotriethanolamine, and their substituted derivatives, in particular the aminopropanol derivatives of 1,4: 3,6-dianhydrohexitol nitrates.
• the organic nitrates would act, after penetration into the smooth muscle fiber, by activating guanylate cyclase, in accordance with the scheme below:
• Intracellular depletion into thiol groups is responsible for the phenomenon of tachyphylaxis with organic nitrates, defined as the loss of activity of a substance during its repeated administration, with the need to increase the dose to obtain the same effect.
• This tachyphylaxis can take several forms:
• Patent Application EP 362 575 describes, for example, fatty acid nitrates linked to sulfur amino acids, which prevent or attenuate tachyphylaxis.
• fatty acid nitrates linked to sulfur amino acids which prevent or attenuate tachyphylaxis.
• the Applicant has therefore set itself the goal of supplying new organic nitrates which have a markedly improved activity (in particular at the level of transport and crossing of cellular barriers), do not cause any tachyphylaxis and whose toxicology and pharmacology of the products of departure is well known.
• organic nitrates characterized in that they correspond to the following formula I:
• R represents
• R 1 represents a hydrogen atom, a C 1 to C 6 alkyl group (linear, branched or cyclic), an optionally substituted phenyl or an optionally substituted benzyl
• R 2 represents a hydrogen atom, a C 1 to C 6 alkyl group (linear, branched or cyclic), an optionally substituted phenyl, an optionally substituted benzyie, a C 1 -C 6 acyl group, an optionally substituted benzoyl , an alkoxycarbonyl or a CO-X group in which X represents a C residue or a D, E, F or G residue as defined below, and m represents 1 (5-center ring) or 2 (ring with 6 centers).
• R 1 and R 2 have the same meaning as above;
• R 2 represents an OH group, an O-alkyl group at R 1 to C 6 (linear, branched or cyclic), an optionally substituted O-phenyl group, an optionally substituted O-benzyl group, a residue E as defined above next, a YB- type residue or an NH-CH (COOR 3 ) CH 2 -S- R 4 group , in which R 4 represents a hydrogen atom, an R 1 to R 6 alkyl group (linear, branched or cyclic), an optionally substituted phenyl, an optionally substituted phenyl, an optionally substituted benzyie, or one of the following groups: CH 3 - CO-NH-CH 2 , BY-CO-CH (NH-COO-C (CH 3 ) 3 ) CH 2 -S, or BY-CO- CH (NH 2 .HCl) CH 2 -S, B and Y being as defined below, and m represents 1 or 2.
• R 1 , R 3 and m have the same meaning as above.
• R 2 and R 4 have the same meaning as above
• R 5 represents a hydrogen atom, an alkyl group in R 1 to C 6 (linear, branched or cyclic), an optionally substituted phenyl, an optionally substituted S-phenyie, an optionally substituted benzyie, a CH 3 -CO- group NH-CH 2 or BY-CO-C 5 ZH 3 -S and Z represents CH or N.
• vs. R also represents, when n is other than 0 and A is a sulfur residue H or I as defined below, an OH group, an O-C 1 -C 6 alkyl group (linear, branched or cyclic), a group O -optionally substituted phenyl, an optionally substituted O-benzyl group, an E residue as defined above or a residue YB, B and Y being as defined below;
• A represents a CH 2 group, an amino acid substituted or not, with the acid function linked to Y and the amino function linked to CO or one of the following residues:
• R 2 represents a hydrogen atom, an alkyl group in R 1 to C 6 (linear, branched or cyclic), an optionally substituted phenyl, an optionally substituted benzyie, an acyl group in R 1 to R 6 , an optionally substituted benzoyl , an alkoxy-carbonyl group, or a CO-X group in which X represents one of the residues C, D, E, F or G as defined above for R,
• R 6 represents a hydrogen atom, an alkyl group in R 1 to C 6 (linear, branched or cyclic), an optionally substituted phenyl, a substituted S-phenyl, an optionally substituted benzyie or one of the following groups: CH 3 -CO-NH-CH 2 , S-CH 2 -CH- (CO-R 7 ) -NH-CH 2 -CH 2 - NH-B in which R 7 represents an OH group, an O-alkyl group in R 1 -R 6 , an optionally substituted O-phenyl group, an optionally substituted O-benzyl group killed, a residue E as defined above or a residue Y- B, B and Y being as defined below,
• n 0 or 1 or greater than 1
• Y represents an oxygen atom or an NH group.
• a group -CH 2 -C (C 2 H 5 ) (CH 2 -ONO 2 ) 2 derived from ethyltrimethylol-methane
• the compounds of formula I in accordance with the invention include their various isomers.
• the substituents from substituted phenyl and substituted benzyie groups are advantageously chosen from the following groups: NO 2 , halogen, CV 3 in which V represents a halogen or a lower alkyl.
• Organic nitrates are thus obtained which, unexpectedly, exhibit both a markedly improved activity compared to the nitrates of the prior art and do not cause tachyphylaxis.
• Such nitrates are particularly useful as vasorelaxants, in particular in the treatment of certain cardiovascular diseases and more particularly in the treatment of angina pectoris.
• the preferred compounds of formula I comprise for R, A, Y and B, respectively the following radicals:
• R represents one of the following residues:
• A represents an optionally substituted amino acid residue, when n is different from 0, and in particular glycine and its derivatives, proline and its derivatives, alanine and its derivatives, valine and its derivatives, and phenylalanine and its derivatives .
• Y represents an oxygen atom or an NH group
• the organic nitrates according to the invention comprise a thioacid R-COOH associated with an organic nitrate of the itol or dianhydro itol type, at the level of an OH or NH function of said nitrate.
• the present invention also relates to a process for the preparation of an organic nitrate in accordance with the invention, characterized in that one reacts:
• R-CO- (A) n in which R, A and n have the same meaning as above, with a derivative of formula YB, in which Y and B have the same meaning as above , in a suitable solvent and under non-epimerizing conditions.
• the solvent is, in particular and without limitation: dichloromethane, acetonitrile, dimethylformamide, ethyl acetate or tetrahydrofuran.
• the derivatives of formula II are chosen from:
• the derivative of formula III is:
• the derivatives of formula II exhibit an activity on the cardiovascular system and in particular an antigen activity.
• Both the derivatives of formula I and the derivatives of formula II find application as medicaments in the treatment of cardiovascular diseases and in particular in the treatment of angina pectoris.
• the invention also includes other arrangements which will emerge from the description which follows, which refers to examples of implementation of the process which is the subject of the present invention.
• Example 5 Glycine, N - [(t-butoxy) carbonyl] -, 5-amino, 5-deoxy, 2-O-nitro amide, 1,4: 3,6-dianhydro-L-iditol (5):
• Example 7 L-alanine, N - [(t-butoxy) carbonyl] -, 5-amino, 5-deoxy, 2-O-nitro amide, 1,4: 3,6-dianhydro-L-iditol (7 ):
• Example 10 L-phenylalanine, N - [(t-butoxy) carbonyl] -, 5-amino, 5-deoxy, 2-O-nitro amide, 1,4: 3,6-dianhydro-L-iditol (11 ):
• Example 12 L-proline, N - [(t-butoxy) carbonyl] -, 5-amino, 5-deoxy, 2-O-nitro amide, 1,4: 3,6-dianhydro-L-iditol (13 ):
• Example 13 L-proline, 5-amino, 5-deoxy, 2-O-nitro amide, 1,4: 3,6-dianhydro-L-iditol monochlorohydrate (14):
• Example 16 5 - [[2 - [[(2-pyrrolidinyl (28)) carbonyl] amino] -1-oxo ethyl] amino] -, 5-deoxy, 2-O-nitro, 1,4: 3,6 - dianhydro-L-iditol monohydrochloride (49):
• Example 17 N- [4- (3-formy 1-2,2-dimethyl-L-thiazolidine) carbonyl] -, glycine (17).
• This compound is prepared by saponification of the corresponding ester.
• Example 20 L-cysteine, S - [(acetylamino) methyl] -N - [(tbutoxy) carbonyl] -, 5-O-nitro ester, 1,4: 3,6-dianhydroD-glucitol (20):
• the pyridine is evaporated without exceeding 40 oC and the residue is taken up in dichloromethane, washed with water, 1N hydrochloric acid, with water, with an aqueous solution of sodium bicarbonate, then with water until neutral and dried over sodium sulfate.
• F 98-99oC.
• Example 23 2-O- [2 - [(acetylamino) methyl] thio] benzoyl] -, 5-O-nitro, 1,4: 3,6-dianhydro-D-glucitol (23):
• Example 25 5-O - [(4-L-thiazolidinyl) carbonyl] -, 2-O-nitro, 1,4: 3,6-dianhydro-D-glucitol, monohydrochloride (25):
• Example 26 L-cysteine, S - [(acetylamino) methyl] -N - [(tbutoxy) carbonyl] -, 2-O-nitro ester, 1,4: 3,6-dianhydro- D-glucitol (26) :
• Example 29 Bis [5-O [(2-thio) benzoyl] -, 2-O-nitro,
• the evaporation residue is chromatographed on silica (230-400 mesh ASTM) and 10.5 g of an oil corresponding to 5 - [[3-t-butoxycarbonyl-4-L-thiazolidinyl) carbonyl] amino] are isolated - , 5-deoxy, 2-O-nitro, 1,4: 3,6-dianhydro-L-iditol (50). It has not been crystallized; it is processed directly.
• Example 34 L-cysteine, S - [(acetylamino) methy1] -, 5-amino, 5-deoxy, 2-O-nitro amide, 1,4: 3,6-dianhydro-L-iditoi, monohydrochloride (34 ):
• Example 36 L-methionine, N - [(t-butoxy) carbonyl] -, 5-amino, 5-deoxy, 2-O-nitro amide, 1,4: 3,6-dianhydro-L-iditol (37 ):
• Example 37 5 - [[2-t (phenylmethyl) thio] benzoyl] amino] -, 5-deoxy, 2-O-nitro, 1,4: 3, 6-dianhydro-L-iditol (39):
• Example 39 L-cysteine, S - [(acetylamino) methyl] -N - [(tbutoxy) carbonyl] -, 2-amino, 2-deoxy, 5-O-nitro amide, 1.4: 3.6- dianhydro-D-glucitol (41):
• Example 40 L-cysteine, S - [(acetylamino) methyl] -, 2-amino, 2-deoxy, 5-O-nitro amide, 1,4: 3,6-dianhydro-D-glucitol, monohydrochloride (42 ):
• Example 47 5 - [[(3-1-butoxycarbonyl-2-methoxycarbonyl-4- L-thiazolidinyl) carbonyl] amino] -, 5-deoxy, 2-O-nitro,
• Example 48 5 - [[3-t-butoxycarbonyl-2-phenyl-4-L-thiazolidinyl) carbonyl] amino] -, 5-deoxy, 2-O-nitro, 1,4: 3,6-dianhydro-L -iditol (56):
• Example 52 5 - [[2 - [[((3-t-butoxycarbonyl-4-L-thiazolidinyl) carbonyl] amino] 1-oxo ethyl] amino] -, 5-deoxy, 2-O-nitro, 1,4 : 3,6-dianhydro-L-iditol (60):
• Example 54 5 - [[2 - [[(3-t-butoxycarbonyl-4-L-thiazolidinyl) carbonyl] amino] 1- (2-methyl (2S)) - oxo ethyl] amino] -, 5-deoxy, 2-O-nitro, 1,4: 3,6-dianhydro-L-iditol (61):
• Example 55 5 - [[2 - [[(4-L-thiazolidinyl) carbonyl] amino] 1- (2-methyl (2S)) - oxo ethyl] amino] -, 5-deoxy, 2-O-nitro, 1,4: 3,6-dianhydro-L-iditol, monohydrochloride (62):
• Example 57 5 - [[2 - [[(4-L-thiazolidinyl) carbonyl] amino] 1- (2-isopropyl (2S)) - oxo ethyl] amino] -, 5-deoxy, 2-O-nitro, 1,4: 3, 6-dianhydro-L-iditol, monohydrochloride (64):
• Example 60 5- [[2 - [[(3-t-butoxycarbonyl-4-L-thiazolidinyl) carbonyl] amino] 1- (2- (2'-thiomethyl) ethyl (2S)) - oxo ethyl] amino] -, 5-deoxy, 2-O-nitro, 1,4: 3,6- dianhydro-L-iditol (67):
• Example 61 5 - [[2 - [[(4-L-thiazolidinyl) carbonyl] amino] 1- (2- (2'-thiomethyl) ethyl (2S)) - oxo ethyl] amino] -, 5- deoxy, 2-O-nitro, 1,4: 3,6-dianhydro-L-iditol, monohydrochloride (68):
• Example 62 5 - [[[N - [(3-t-butoxycarbonyl-4-L-thiazolidinyl) carbonyl] -2-pyrrolidinyl (2S)] carbonyl] amino] -, 5-deoxy, 2-O-nitro, 1,4: 3,6-dianhydro-L-iditol (69):
• Example 64 2 - [[2 - [[((4-L-thiazolidinyl) carbonyl] amino] 1-oxo ethyl] amino] -, 2-deoxy, 5-O-nitro, 1,4: 3,6-dianhydro -D-glucitol, monohydrochloride (71):
• Example 65 2-O- [2 - [[((3-t-butoxycarbonyl-4-L-thiazolidinyl) carbonyl] amino] 1-oxo ethyl] -, 5-O-nitro, 1,4: 3,6- dianhydro-D-glucitol (72):
• Example 66 2-O- [2 - [[((4-L-thiazolidinyl) carbonyl] amino] 1-oxo ethyl] -, 5-O-nitro, 1,4: 3,6-dianhydro-D-glucitol, monohydrochloride (73):
• a suspension of 6.04 g (21.21 mmol) of (3) in 200 ml of anhydrous dichloromethane is stirred at room temperature. 2.98 ml of triethylamine (21.21 mmol) are added, which causes the solid to dissolve. 4.95 g (21.21 mmol) of N-t-Boc-L-thioproline, 8.99 g (21.21 mmol) of CMC and 2.87 g (21.21 mmol) of HOBt are successively added. After 24 hours of reaction, 100 ml of dichloromethane are added and the washes are carried out as for (1). The residue obtained after evaporation is chromatographed on silica (230-400 mesh ASTM) and 7.4 g of a dry foam which has not been able to crystallize are isolated. The product is processed directly.
• Example 70 5 - [[[[2 - [(phenylmethyl) thio] benzoyl] amino] loxo ethyl] amino] -, 5-deoxy, 2-O-nitro, 1,4: 3,6-dianhydroL-iditol ( 47):
• Example 71 5 - [[2 - [[(3-formyl-2,2-dimethyl-4-L-thiazolidinyl) carbonyl] amino] 1-oxo ethyl] amino] -, 5-deoxy, 2-O-nitro , 1,4: 3,6-dianhydro-L-iditol (48):
• R 2 CO-X.
• Example A Vasorelaxing effect of the compounds in accordance with the invention on isolated vessels.
• aorta 350 g, are anesthetized by intraperitoneal injection of sodium pentobarbital (30 mg / kg).
• the thoracic aorta is quickly removed and placed in a refrigerated and oxygenated Krebs-Ringer type bicarbonate buffer solution (composition [mM]: NaCl, 118; KCl, 4.7; CaCl 2 , 2.5; MgSO 4 , 1.2; KH 2 PO 4 , 1.2; NaHCO 3 , 25.0; EDTA disodium calcium, 0.026; glucose, 11.1).
• the aorta is dissected in order to remove the connective tissue, then sectioned into 6 rings (length 5-10 mm).
• the enthothelium is removed by moderate abrasion of the intimal surface of the aortic segments using a pair of forceps. These segments are then placed between two hooks in an insulated tank filled with 25 ml of bicarbonate buffer (pH 7.4) thermostatically controlled at 37 oC and oxygenated using a 95% O 2 -5% CO 2 mixture. (pH 7.4).
• bicarbonate buffer pH 7.4
• One of the hooks is fixed at a fixed point, while the second is connected to a transducer, in order to measure the variations in isometric tension (expressed in grams).
• the segments are gradually stretched so as to reach the level of basal tension for which the contractile response to norepinephrine (10 -7 M) is maximum (optimal tension; average 2 g).
• the absence of endothelium is verified by adding a single concentration of acetylcholine (10 -6 M), after pre-contraction of the vessels by norepinephrine (10 -7 M).
• the integrity of the vascular smooth muscle is also verified by adding a single concentration of a vasodilator whose response is independent of the presence of the endothelium, SIN-1 (10 -5 M).
• FIG. 1 show more particularly the evolution over time of the effect of the compound (46) on the various hemodynamic parameters, the compound being administered po at a dose of 3 mg / kg.
• the compound (46) significantly decreases, pronounced and prolonged the systolic blood pressure (PAs) and the telediastolic pressure of the left ventricle (PTDVG).
• Figures 1 illustrate these results and show the variations ( ⁇ ) of the following hemodynamic parameters: PAs ( Figure 1a), PAd ( Figure 1b), PTDVG ( Figure 1c), FC ( Figure 1d) and vasorelaxing activity (Figure 1e).
• PAs systolic blood pressure
• PAd diastolic blood pressure
• Pigs are of the German land breed (20-26 kg) and are used after an overnight fast.
• the dogs weighing between 16 and 26 kg, are the descendants of a cross between Labrador and Harrier.
• ketamine HCI (20 mg / kg im)
• methonidate HCI (10 mg / kg im)
• xylacin HCI (3 mg / kg im)
• sodium pentobarbital 25-30 mg / kg as an iv bolus or 0.16 mg / kg / min as an iv infusion
• anesthesia is induced using sodium pentobarbital (45 mg / kg i.v.) and maintained with an i.v. infusion (flow rate 8 mg / kg / h).
• Pigs or dogs are put on artificial respiration in ambient air. Analysis of blood gases (pO 2 , pCO 2 ) is carried out at regular time intervals and oxygen can be delivered via the respirator, if necessary.
• Hemodynamic parameters recorded include left ventricular pressure (PVG; Millar PC350 Tip catheter inserted via the carotid artery), systemic blood pressure (PAs, PAd; full catheter in a femoral artery), left ventricular diastole end pressure ( PTDVG), ventricular contractility (PVGdp / dt max ) and heart rate (HR).
• PVG left ventricular pressure
• PAs systemic blood pressure
• PAd full catheter in a femoral artery
• PTDVG left ventricular diastole end pressure
• PVGdp / dt max ventricular contractility
• HR heart rate
• the compounds studied are administered intraduodenally (i.d.) or intravenously (i.v.) in several animals (1 to 4).
• the hemodynamic variables are recorded continuously for 1 to 3 hours, depending on the duration of action of the compounds.
• An antianginal activity is assessed by a decrease in PAs and PTDVG (decrease in venous return).
• Example D Measurement of the relaxing activity of the compounds in accordance with the invention on isolated guinea-pig blood vessels.
• Each compound is tested on at least four spiral vessel strips.
• the relaxation power of the compounds is measured by calculating the concentrations which give a relaxation of 50% (IC 50 ), from the concentration / effect curves.
• IC 50 concentration of 50%
• the IC 50 illustrates the relaxing effect on the isolated pulmonary vessel.
• Example E Absence of tachyphylaxis in dogs. Comparison with isosorbide mononitrate (IS-5-MN).
• the product (46) is tested in a tachyphylaxis model, in the anesthetized dog.
• IS-5-MN is used as the reference substance.
• Compound (46) is administered intraduodenally (i.d.) at a dose of 0.75 mg / kg and in a volume of 10 ml / animal, dissolved in water.
• IS-5-MN is also dissolved in water and given i.d. at a dose of 5 mg / kg in a volume of 10 ml / animal.
• the hemodynamic parameter chosen for the study of tachyphylaxis is systolic blood pressure (PAs), insofar as this parameter is very sensitive to the administration of the compounds.
• the PAs returned approximately to the control value (before the first administration).
• the IS-5-MN at 5 mg / kg and the compound (46) at 0.75 mg / kg induce, on average, a similar drop (-30 mm of Hg) in PAs.
• the maximum effect is reached 5 minutes after administration for IS-5-MN and 60 minutes after for compound (46).
• the duration of action of the compound (46) is longer, which is why the interval is 4 hours between the first and the second administration.
• the second administration of IS-5-MN causes a drop in BP which reaches its maximum at 5 min (-19 mm Hg) followed by a rapid return to the control value.
• the second administration of the compound (46) leads to a fall in BP, which reaches its maximum at 60 min (-33 mm of Hg).
• the study is stopped 120 minutes after the second administration.

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• 1991
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