HK1129379A - New addition salts of angiotensin-converting enzyme inhibitors with no donor acids, a process for their preparation and pharmaceutical compositions containing them - Google Patents
New addition salts of angiotensin-converting enzyme inhibitors with no donor acids, a process for their preparation and pharmaceutical compositions containing them Download PDFInfo
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Description
Technical Field
The present invention relates to novel addition salts of angiotensin converting enzyme inhibitors carrying NO donor acids, to processes for their preparation and to pharmaceutical compositions containing them.
These compounds can be used in the areas of hypertension and cardiovascular disease.
Background
Hypertension increases the risk of vascular accidents, particularly cerebrovascular and coronary vascular accidents. It is increasingly associated with pathologies (e.g. atherosclerosis), or with metabolic diseases (e.g. obesity, diabetes or renal insufficiency), which significantly increase the risk of vasospasm and thrombosis.
Since its cardiovascular effects were discovered in 1980, Nitric Oxide (NO) has been recognized as a vasodilator and vasoprotective molecule that prevents vasospasm, atherosclerosis, and thrombosis, and thus the modulator can provide protection against cardiovascular disease. NO is essentially produced by the endothelium. NO is generally considered to have vasodilatory, anti-adhesion, anti-thrombotic, anti-inflammatory and antioxidant properties.
Angiotensin converting enzyme inhibitors (ACE), such as perindopril (Ferrari et al, 2005, Am JHP. ension, 18, 142S-154S), are therapeutic agents whose cardiovascular protective effects are well known; these products can reduce arterial pressure, myocardial infarction, cardiac insufficiency, left ventricular dysfunction, stroke and cardiovascular mortality. These beneficial effects are also found in diabetic patients with or without atherosclerosis. Recent clinical data confirm its anti-atherosclerotic and anti-inflammatory properties and its beneficial effects on endothelial dysfunction for perindopril (Ferrari et al, 2005). By blocking this converting enzyme, ACE inhibitors are able to: (1) prevention of the formation of angiotensin II, a potent vasoconstrictor associated with cardiovascular disease (Kon and Jabs, 2004, Current Opinion Nephrol Hypertens, 13, 291-297; Unger, 2002, Am J Cardiol, 89, 3A-10A; Ferrari et al, 2005), and (2) protection of bradykinin from degradation, bradykinin having beneficial effects on the cardiovascular (through anti-ischemic effects) due to endothelial production of NO (Unger 2002; Ferrari et al, 2005).
In a variety of pathological conditions (e.g. atherosclerosis, hypertension, diabetes etc.) the fact is well documented that NO production is reduced or even completely absent (Gewaltig and Kodja, 2002, Cardiovasc Res, 55, 250-. In the case of endothelial dysfunction, the beneficial effects of ACE inhibitors and the degree of inhibition of bradykinin degradation are reduced. It has been concluded that mixed products (ACE inhibitors and NO donors) are beneficial in these various pathological conditions, more particularly in cardiovascular pathologies.
Furthermore, NO donor compounds (e.g. nitroglycerin) have long been used to treat angina and cardiac insufficiency. The beneficial effects of these products are related to their ability to produce NO (either naturally or metabolically). It was also observed from their use in hypertensive patients that these NO donors were able to bring about a significant reduction in the systolic arterial pressure (Nesbit, 2005, Hypertension (Hypertension), 45, 352-. Abnormal systolic arterial pressure is a major risk factor for brain and heart accidents and is generally resistant to antihypertensive therapy. Indeed, although the antihypertensive and vasoprotective effects of products such as ACE inhibitors and other classes of antihypertensive products have been demonstrated, arterial pressure (particularly systolic arterial pressure) remains difficult to control, maintaining high morbidity and mortality in hypertensive patients.
Thus, the ability to add NO donors to ACE inhibitors such as perindopril seems to be an important strategy to combat cardiovascular diseases. Indeed, having the properties of NO donors would enhance antihypertensive, cardioprotective, and vasoprotective properties because NO is a vasodilator, antiplatelet (and therefore anti-thrombotic), anti-adhesion, and antioxidant molecule (Walford et al, 2003, J.Thromb. Haemost., 1, 2112-.
Disclosure of Invention
The compounds of the invention possess such dual pharmacological activities, thus making them important properties in the areas of hypertension and cardiovascular pathology.
More particularly, the present invention relates to salts of formula (I):
(A)m·(B)n (I)
wherein A represents an angiotensin converting enzyme inhibitor compound containing at least one salt-forming basic functional group, B represents a compound containing at least one salt-forming acidic functional group and at least one NO donor group, m represents the number of acidic functional groups in B that have been converted to a salt, n represents the number of basic functional groups in A that have been converted to a salt,
the bond between A and B is ionic.
By "salt-forming basic functional group" is understood a functional group capable of accepting a proton.
Examples of salt-forming basic functional groups may be primary, secondary or tertiary amines.
By "salt-forming acidic functional group" is understood a functional group capable of liberating a proton.
An example of a salt-forming acidic functionality may be-CO2H、-SO3H or P (O) (OH)2A group.
An NO donor group is understood to be a group capable of donating, releasing and/or transferring nitric oxide or a biologically active form thereof, and/or a group capable of stimulating the endogenous production of nitric oxide or a biologically active form thereof in vivo.
Preferably the angiotensin converting enzyme inhibitor a belongs to the following formula (II):
-R1represents a hydrogen atom or a linear or branched C1-C6An alkyl group, a carboxyl group,
-R2represents a straight or branched chain C1-C6Alkyl or aryl- (C)1-C6) An alkyl group, wherein the alkyl group is a linear or branched alkyl group,
-R3represents a straight or branched chain C1-C6Alkyl or amino- (C)1-C6) An alkyl group, wherein the alkyl group is a linear or branched alkyl group,
represents a monocyclic or bicyclic nitrogen-containing system containing from 3 to 12 carbon atoms and possibly containing one or more heteroatoms chosen additionally from N, O and S, said system being optionally substituted by one or more groups chosen from: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkoxy, oxo, carboxy, aryl, C3-C8Cycloalkyl, heteroaryl, carboxy- (C)1-C6) Alkyl (where alkyl is straight or branched) and hydroxyl,
wherein when the nitrogen-containing system is bicyclic, it may be fused, spiro or bridged.
Preferably represents pyrrolidine, perhydroindole, octahydrocyclopenta [ b ]]Pyrrole, imidazolidine or tetrahydroisoquinoline rings.
Among the angiotensin-converting enzyme inhibitors A, there may be mentioned by way of example enalapril of formula (IIa), enalaprilat of formula (IIb), lisinopril of formula (IIc), perindopril of formula (IId), perindopril of formula (IIe), ramipril of formula (IIf), spirapril of formula (IIg), trandolapril of formula (IIh), trandolaprilat of formula (IIi), imidapril of formula (IIj), moexipril of formula (IIk), moexipril of formula (IIb), trandolapril of formula (IIc), trandolaprilat of formula (IId), perindopril of formula (IIe), trandolapril of formula (,
Quinapril of formula (IIm) and ramiprilat of formula (IIn).
The following compounds are preferred compounds of formula (I):
preferably, compound B belongs to the following formula (III):
X-(Ak1)x-(Y)Y-(Ak2)z-Z (III)
wherein:
-X represents CO2H、SO3H or P (O) (OH)2，
Akl and Ak2May be the same or different and each represents a saturated or unsaturated, linear or branched C1-C8Alkylene in which one or more carbon atoms may be replaced by oxygen, sulfur or nitrogen atoms, or by SO2Alternatively, the alkylene group is optionally substituted with one or more groups selected from CO2H、SO3H. The group of the hydroxyl group and the amino group is substituted,
x, y and z, which may be identical or different, each represent 0 or 1,
-Y represents CO or CONH,
-Z represents a NO donor group.
In the compounds of formula (III), the compounds belong to one of the following formulae:
HO2C-(Ak1)x-Z (IIIa)
HO2C-CH＝CH-(Ak3)x-Z (IIIb)
wherein:
Ak1x, y, Z and Z are as defined above,
Ak3and Ak5May be the same or different and each represents a saturated straight or branched chain C1-C6Alkylene in which one or more carbon atoms may be replaced by oxygen, sulfur or nitrogen atoms, or by SO2The substitution of the radicals is carried out,
Ak4represents saturated straight-chain or branched C1-C3Alkylene in which one of the carbon atoms may be replaced by an oxygen, sulfur or nitrogen atom, or by SO2The substitution of the radicals is carried out,
Ak6represents saturated straight-chain or branched C2-C5Alkylene in which one of the carbon atoms may be replaced by an oxygen, sulfur or nitrogen atom, or by SO2The substitution of the radicals is carried out,
het represents O or NH, and is selected from the group consisting of,
and Y is1Represents a carbonyl group.
Preferably, Z is selected from the following groups:
and regioisomers thereof
And regioisomers thereof
And regioisomers thereof
Wherein:
m represents a number of 0 or 1,
R1and R2May be the same or different and each represents a straight or branched chain C1-C6Alkyl, or R1And R2Together with the nitrogen atom carrying them form a 3-to 7-membered nitrogen-containing heterocyclic ring, optionally substituted by a straight or branched chain C1-C6The substitution of the alkyl group is carried out,
R3represents a methyl group or an aminocarbonyl group,
and R is4And R'4May be the same or different and each represents a hydrogen or halogen atom or a linear or branched C1-C6Alkyl, trifluoromethyl or trifluoromethoxy.
The 3-to 7-membered nitrogen-containing heterocyclic ring mentioned above is understood to mean a saturated 3-to 7-membered monocyclic group which contains 1, 2 or 3 heteroatoms, one of these heteroatoms being a nitrogen atom and the other heteroatoms which may be present being selected from oxygen, nitrogen and sulfur.
The 3-7 membered nitrogen containing heterocycle is preferably pyrrolidinyl.
Preferred compounds of B are as follows:
preferred compounds of formula (I) are as follows:
- (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
- (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -glutaric acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
-2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -ethanesulfonic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- { [ (3- { [ 5-oxo-4-benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -methyl } -phosphonic acid (1: 1);
- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid-2, 2' - [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -imino ] -diacetic acid (1: 1);
- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- {2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -ethyl } -phosphonic acid (1: 1);
- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- (2- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -ethyl) -phosphoric acid (1: 1);
- (2S) -2- [ (4- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -butyryl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
- (2S) -2- { [3- ({4- [ (4-chlorophenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) -propionyl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
- (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) -propionyl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
- (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) -butyryl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1).
The invention also relates to a process for the synthesis of a compound of formula (I), in which compound A is reacted with compound B in an amount at least equal to an equivalent of compound A (n/m).
Compounds of the formulae (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm) and (IIn) are known.
Compound B can be obtained according to conventional organic chemical reactions.
For example, compounds B1And B2Can be obtained from crotonaldehyde which can be converted into 4-methyl-1, 2, 5-oxadiazole-5-oxide-3-carbaldehyde by reaction with sodium nitrite in acetic acid. The aldehyde thus obtained is then oxidized to obtain compound B1Or reacting with a protected triphenylphosphinomethylenecarboxylic acid compound to obtain a compound B after deprotection2。
Compound B12Can be obtained by coupling isosorbide mononitrate with succinic anhydride.
A compound B of formula (III) (wherein Z represents a group Z)9Or Z'9) Can be obtained as follows:
in the presence of a base, reacting a compound of the formula:
with alcohol compounds X- (Ak) in which the acid function is protected1)x-(Y)y-(Ak2)z-OH reaction followed by deprotection of the acid function.
A compound B of formula (III) (wherein Z represents a group Z)9Or Z'9) The novel products, which are useful as synthesis intermediates in the chemical or pharmaceutical industry, in particular in the synthesis of salts of formula (I), thus form part of the invention。
In view of their pharmacological profile, the compounds of the invention may be used in pathological processes requiring treatment with ACE inhibitors and/or NO donors, in the treatment of cardiovascular pathologies (such as arterial hypertension (in its various forms) and its vascular and renal sequelae), systolic hypertension, peripheral vascular diseases, atherosclerosis, restenosis, cardiac insufficiency, thrombosis and any thrombotic event(s), angina pectoris (stability or instability), cerebrovascular accidents (cerebrovascular accidents), coronary accidents (cardiovascular accidents), myocardial infarction, vascular remodeling, diabetes and its vascular and renal sequelae, complications associated with surgery (e.g. cardiovascular surgery) and endothelial dysfunction.
Since NO also has anti-inflammatory and antioxidant properties, the compounds of the present invention may be used to treat pathological processes associated with inflammation and oxidative stress.
The invention also relates to pharmaceutical compositions comprising as active ingredient a compound of formula (I) in association with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
Among the pharmaceutical compositions of the present invention, mention may be made in particular of compositions suitable for administration by the following routes: oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transdermal, nasal, rectal, sublingual, ocular or respiratory tract, in particular tablets or dragees, sublingual tablets, hard gelatin capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops and the like.
In addition to the compound of formula (I), the pharmaceutical compositions of the present invention may contain one or more excipients or carriers, such as diluents, lubricants, binders, disintegrants, absorbents, coloring agents, or sweetening agents.
The excipient or carrier comprises:
diluent agent: lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycerol,
lubricant: silicon dioxide, talcum powder, stearic acid and its magnesium salt and calcium salt, polyethylene glycol,
adhesive: aluminium and magnesium silicates, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,
disintegrating agent: agar, alginic acid and its sodium salt, effervescent mixture.
The percentage of the active ingredient of formula (I) in the pharmaceutical composition is preferably 5% to 50%.
The dosage which may be used depends on the age and weight of the patient, the route of administration, the nature and severity of the disease, the administration of any relevant treatment, ranging from 0.5mg to 500mg per day, one or more administrations.
Detailed Description
The following examples illustrate the invention. The structures of the compounds described in the examples can be determined according to conventional spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry).
Abbreviations:
DCC N, N' -dicyclohexylcarbodiimide
DIEA N, N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMF dimethyl formamide
EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (hydrochloride)
HOBT 1-hydroxybenzotriazole
THF tetrahydrofuran
TFA trifluoroacetic acid
Example 1: (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: 3- [ (5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl) -oxy ] -propionic acid tert-butyl ester
50% aqueous NaOH (6.4g, 80mmol) was added to a solution of 3, 4-bis (benzenesulfonyl) -1, 2, 5-oxadiazole 2-oxide (16g, 44mmol) and tert-butyl 3-hydroxypropionate (10g, 68mmol) in 200ml anhydrous THF cooled to 15 deg.C over 15 min. After stirring for 2 hours, the solvent was removed in vacuo and the residue was dissolved in 100ml of water and 100ml of ethyl acetate. The organic phase was discarded, washed with saturated NaCl solution, dried over sodium sulfate and evaporated.
The remaining oil was purified by flash chromatography eluting with a dichloromethane/ethyl acetate mixture (98/2) to afford the desired product.
And B: 3- [ (5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl) -oxy ] -propionic acid (compound B4)
14g of the compound from step A dissolved in 100ml of dichloromethane are placed under argon, 10ml of TFA are added and the mixture is stirred at room temperature for 6 hours.
The solvent was removed in vacuo. The residue was crystallized from diisopropyl ether to give the desired product.
Melting point: 138 ℃.
And C: (2S) -2- [ (3- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -succinic acid di-tert-butyl ester
A solution of the compound obtained in the above step (2.7g, 8mmol), L-aspartic acid di-tert-butyl ester hydrochloride (2.25g, 8mmol), EDCI (1.62g, 8mmol), DIEA (1.32g, 8mmol) and HOBT (1.1g, 8mmol) in 100ml anhydrous DMF was stirred at room temperature under an argon atmosphere for 72 hours. The DMF is distilled off and the residue is then dissolved in 100ml of water and 100ml of ethyl acetate. The organic phase is then treated with 5% NaHCO3The solution was washed, dried over sodium sulfate and then evaporated to dryness. The crude reaction product was purified by flash chromatography using a (90:10) dichloromethane/ethyl acetate mixture as eluent.
Step D: (2S) -2- [ (3- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl]-oxy } -propionyl) -amino]-succinic acid (Compound B)5)
A solution of the compound obtained from the above step (4g, 7.3mmol) in 100ml dichloromethane and 15ml TFA was stirred under argon atmosphere for 6 hours. The solvent was distilled off to dryness. The residue was triturated in diisopropyl ether for 2 hours until crystallization occurred. Suction filtering and drying.
Melting point: 130 ℃ and 131 ℃.
Step E: (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } propanoyl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propanoyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
A solution of perindopril or (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (368g, 1mmol) and the compound obtained from the above step (429g, 1mmol) in 50ml of water and 50ml of acetonitrile was prepared. Filtered through Whatman filter paper (filter) and lyophilized.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 51.195.948.784.02
Found value 51.495.798.803.70
Example 2: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid-4-methyl-1, 2, 5-oxadiazole-3-carboxylic acid 5-oxide (1:1)
Step A: 4-methyl-1, 2, 5-oxadiazole 5-oxide-3-carbaldehyde
A solution of crotonaldehyde (100g, 1.42mol) in 200ml of acetic acid is cooled to 0-5 ℃ and added over a period of 3 hours and 30 minutes to 400ml of an aqueous solution of sodium nitrite (340g, 4.2 mol). After stirring for 1 hour, 150ml of water are added and the mixture is extracted 6 times with 100ml of dichloromethane.
The combined organic phases are washed with 100ml of water, dried over sodium sulfate and evaporated to dryness.
The residue was purified by flash chromatography using dichloromethane as eluent.
Melting point: at 62 ℃.
And B: 4-methyl-1, 2, 5-oxadiazole 5-oxide-3-carboxylic acid (Compound B)1)
14.2g KMnO were added at 20 ℃ over a period of 1 hour and 30 minutes4(90mmol) were added portionwise to 400ml of an aqueous solution of 7g of the compound obtained in step A. 100ml of 1M NaOH are then added and filtered through 200g of Celite. The filtrate was acidified with 100ml of 1M HCl and concentrated to 100ml using a rotary evaporator. Extraction with dichloromethane was carried out 8 times with 100ml each time, and the organic fraction was dried over sodium sulfate and evaporated to give the title compound.
Melting point: 92 deg.C.
And C: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid-4-methyl-1, 2, 5-oxadiazole-3-carboxylic acid 5-oxide (1:1)
This compound was obtained according to the procedure described in step E of example 1, starting from perindopril and the compound obtained in the above step.
Elemental microanalysis:
％C ％H ％N
calculated value 53.907.0810.93
Found value 54.107.0711.28
Example 3: (2R, 3R) -2-hydroxy-3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -succinic acid- (2S, 3aS, 7sS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: (2R, 3R) -2-hydroxy-3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -succinic acid di-tert-butyl ester
A50% NaOH solution (1.2g, 30mmol) was added to 3, 4-bis (benzenesulfonyl) -1, 2, 5-oxadiazole 2-oxide (7g, 19mmol) and di-tert-butyl tartrate (5g, 19mmol) in 100ml of anhydrous THF over 0.5 h. After stirring for 5 hours, the solvent was evaporated to dryness and the residue was dissolved in water and ethyl acetate. The organic fraction was dried over sodium sulfate, evaporated to dryness and then purified by flash chromatography using (98:2) dichloromethane/ethanol mixture as eluent to give the desired product as a colorless oil.
And B: (2R, 3R) -2-hydroxy-3- { [ 5-oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl]Oxy) -succinic acid (Compound B)3)
The compound obtained in the above step was stirred in 50ml dichloromethane and 10ml TFA for 4 hours.
The solvent was removed in vacuo and the residue was crystallized from diisopropyl ether.
Melting point: 198-200 ℃.
And C: (2R, 3R) -2-hydroxy-3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained in the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 50.135.707.544.32
Found value 49.685.307.744.17
Example 4: (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -glutaric acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -glutaric acid di-tert-butyl ester
Compound B obtained from step B of example 14A solution of the prepared solution (2.5g, 8mmol), L-glutamic acid di-tert-butyl ester hydrochloride (2.36g, 8mmol), EDCI (1.62g, 8mmol), DIEA (1.32ml, 8mmol) and HOBT (1.1g, 8mmol) in 100ml anhydrous DMF was stirred at room temperature for 72 h. DMF was distilled off and the residue was dissolved in 100mlWater and 100ml ethyl acetate. The organic phase was washed with 5% NaHCO3The solution was washed then with water, dried over sodium sulphate and evaporated to dryness. Purification by flash chromatography using a (90:10) dichloromethane/ethyl acetate mixture as eluent gave the title product as a colorless oil.
And B: (2S) -2- [ (3- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl]-oxy } -propionyl) -amino]Glutaric acid (Compound B)6)
A solution of the compound from step A (3g, 5.5mmol) in 100ml dichloromethane and 15ml TFA was stirred under argon for 6 hours. The solvent was removed by distillation in vacuo. The residue was triturated in diisopropyl ether, filtered off with suction and then dried in vacuo to give the desired product as white crystals.
Melting point: 157 ℃ and 158 ℃.
And C: (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -glutaric acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained in the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 51.786.088.633.95
Found value 51.215.938.693.68
Example 5: (2E) -3- (4-methyl-5-oxo-1, 2, 5-oxadiazol-3-yl) -acrylic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: (2E) -3- (4-methyl-5-oxo-1, 2, 5-oxadiazol-3-yl) -acrylic acid-tert-butyl ester
A solution prepared from the compound obtained in step A of example 2 (3.9g, 30mmol) and a solution of tert-butyl triphenylphosphinomethylenecarboxylate (13.1g, 35mmol) in 100ml anhydrous THF was stirred at room temperature for 1 hour.
The solvent was removed in vacuo and the residue was purified by flash chromatography using dichloromethane as eluent to give the desired product as white crystals.
Melting point: 72-74 ℃.
And B: (2E) -3- (4-methyl-5-oxo-1, 2, 5-oxadiazol-3-yl) -acrylic acid (compound B)2)
A solution of the compound obtained from the above step (6.2g, 27mmol) in 100ml dichloromethane and 10ml TFA was stirred at room temperature for 8 h. The solvent was then evaporated in vacuo and the residue was crystallized from diethyl ether, subsequently filtered off with suction and dried to give the desired product as white crystals.
Melting point: 160 ℃.
And C: (2E) -3- (4-methyl-5-oxo-1, 2, 5-oxadiazol-3-yl) -acrylic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N
calculated values: 55.757.1110.40
Measured value: 55.907.0610.25
Example 6: 2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -ethanesulfonic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: n- {2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -oxy ] } -5-norbornene-2, 3-dicarboximide
Compound B obtained in step B of example 14A solution of (2.5g, 5.4mmol), N-hydroxy-5-norbornene-2, 3-dicarboximide (1.03g, 5.4mmol) and DCC (1.17g, 5.4mmol) in 100ml of anhydrous THF was stirred at room temperature for 20 hours. The dicyclohexylurea formed was removed by filtration and the THF was removed by vacuum distillation.
The crude product is dissolved in 80ml of ethyl acetate, filtered off again and evaporated to dryness. The active ester obtained can be used directly in step B without purification.
And B: 2- [ (3- { [ 5-oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl)]-oxy } -propionyl) -amino]-ethanesulfonic acid (compound B)11)
The activated ester obtained in the above step (2.56g, 5.4mmol), aminoethanesulfonic acid (0.81g, 6.5mmol) and NaHCO3A solution of (0.54g, 6.5mmol) in 80ml of water was stirred at room temperature for 48 hours. The solvent was removed by distillation in vacuo. The residue is dissolved in 100ml of water and 100ml of ethyl acetate. After extraction and slow decanting of the supernatant, the aqueous phase was eluted on a DOWEX50WX8 cation exchange resin. The solvent was evaporated in vacuo. The residue was purified by reverse phase preparative HPLC column eluting with (650:350:1) water-acetonitrile-TFA mixture. The pure components were freeze-dried.
And C: 2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -ethanesulfonic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in step E of example 1, starting from perindopril and the compound obtained in the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 48.666.008.878.12
Found value 48.326.328.668.08
Example 7: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- { [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -methyl } -phosphonic acid (1:1)
Step A: { [ (3- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl]-oxy } -propionyl) -amino]-methyl } -phosphonic acid (Compound B)9)
The solution prepared from the compound obtained in step A of example 6 (2.14g, 4.5mmol), aminomethylphosphonic acid (0.7g, 6mmol) and NaHCO3A solution of (1g, 12mmol) in 50ml dioxane and 50ml water was stirred at room temperature for 72 hours. The solvent was then evaporated to dryness and the residue was dissolved in 100ml of water and 100ml of ethyl acetate and stirred for 1 hour. The supernatant was discarded and the aqueous phase was purified on a DOWEX50WX8 cation exchange resin column. The residue obtained after evaporation of the water was crystallized in acetonitrile, filtered off with suction and then dried in vacuo to give the desired product.
Melting point: 171 ℃ and 172 ℃.
And B: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- { [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -methyl } -phosphonic acid (1:1)
The compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 48.005.989.034.13
Found value 47.386.059.073.97
Example 8: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid-2, 2' - [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -imino ] -diacetic acid (1:1)
Step A: 2, 2' - [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -diacetic acid tert-butyl ester
A solution of the compound obtained from example 1 step B (3.5g, 11mmol), tert-butyl iminodiacetate (2.74g, 11mmol), HOBT (1.5g, 11mmol) and EDCI (2.4g, 12mmol) in 100ml anhydrous DMF was stirred at room temperature for 72 h.
DMF was distilled off in vacuo. The residue is dissolved in 100ml of water and 100ml of ethyl acetate. The organic phase was washed with 5% NaHCO3The aqueous solution was washed, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography using a (95:5) dichloromethane-ethyl acetate mixture as eluent to give the desired product as a colorless oil.
And B: 2, 2' - [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl)]-oxy } -propionyl) -amino]-twoAcetic acid (Compound B)8)
A solution of the compound obtained from the above step (800mg, 1.5mmol) in 50ml dichloromethane and 5ml TFA was stirred at room temperature for 6 hours. The solvent was then evaporated in vacuo. The residue was crystallized from diisopropyl ether, filtered off with suction and then dried using a vacuum pump to give the desired product as white crystals.
Melting point: 154 deg.C (decomposition).
And C: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid-2, 2' - [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -imino ] -diacetic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 51.195.948.784.02
Found value 51.415.938.793.56
Example 9: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- {2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -ethyl } -phosphoric acid (1:1)
Step A: { [ (3- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl]-oxy } -propionyl) -amino]-ethyl } -phosphoric acid (Compound B)7)
This compound was obtained according to the procedure described in step a of example 7, using aminoethyl phosphate instead of aminomethyl phosphate.
Melting point: 162 ℃.
And B: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- {2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -ethyl } -phosphoric acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 48.666.138.874.06
Found value 48.816.068.904.42
Example 10: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- (2- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -ethyl) -phosphoric acid (1:1)
Step A: (2- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -ethyl) phosphonic acid dimethyl ester
A50% aqueous NaOH solution (1.5g, 32mmol) was added to a solution of 3, 4-bis (benzenesulfonyl) -1, 2, 5-oxadiazole 2-oxide (7.5g, 20.7mmol) and dimethyl 2-hydroxyethylphosphonate (4.5g, 31mmol) in 100ml THF over 0.5 h. After stirring for 1 hour, the solvent was removed in vacuo and the residue was dissolved in water (100ml) and ethyl acetate (100 ml). The organic phase is dried over sodium sulfate and then evaporated to dryness. The residue was purified by flash chromatography using a (95:5) dichloromethane/ethanol mixture as eluent to give the desired product as a colorless oil.
And B: (2- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl]-oxy } -ethyl) -phosphoric acid (Compound B)10)
2.9ml of trimethylsilyl bromide (4eq.) were added to a solution of the compound obtained from the above step (1.8g, 4mmol) in 50ml of dioxane, and the reaction mixture was then heated at 60 ℃ for 4 hours.
The solvent was evaporated to dryness. The residue was purified on a Biogel column using a (1:1) water/acetonitrile mixture as eluent. The fractions containing the pure product were freeze-dried.
And C: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- (2- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -ethyl) -phosphoric acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 48.466.037.804.46
Found value 48.535.977.954.61
Example 11: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid-mono- (6-nitrooxy-hexahydro-furo [3, 2-b ] furan-3-yl) succinate (1:1)
Step A: mono- (6-nitrooxy-hexahydro-furan [3, 2-b ]]Furan-3-succinate (Compound B)12)
A solution of isosorbide mononitrate (5.73g, 30mmol), succinic anhydride (3.0g, 30mmol) and 100mg of DMAP in 100ml of acetonitrile was heated at reflux for 20 hours.
The solvent was then removed by evaporation. The product was purified by flash chromatography using a (98:2) dichloromethane/ethanol mixture as eluent.
The product obtained was recrystallized from diisopropyl ether to give the desired product as a white solid.
Melting point: and 65 ℃.
And B: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid-mono- (6-nitrooxy-hexahydro-furo [3, 2-b ] furan-3-yl) succinate (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N
calculated value 52.806.886.37
Found value 52.666.876.65
Example 12: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid N- (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -glycine (1:1)
Step A: n- (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -glycine tert-butyl ester
The compound obtained in step B of example 1 (1.5g, 4mmol), tert-butyl glycinate (0.6g, 4mmol), EDCI was added at room temperature under argonA solution of (0.81g, 4mmol) and HOBT (0.57g, 4mmol) in 100ml of anhydrous DMF was stirred for 24 h. The DMF is then distilled off and the residue is dissolved in 100ml of water and 100ml of ethyl acetate. The organic phase was washed with 5% NaHCO3The aqueous solution was washed, dried over sodium sulfate and then evaporated to dryness. Purification by flash chromatography using a (95:5) dichloromethane/ethyl acetate mixture as eluent gave the title product as a colorless oil.
And B: n- (3- { [ 5-oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl]-oxy } -propionyl) -glycine (Compound B)13)
A solution of the compound obtained in the above step (1.7g, 4mmol) in 100ml dichloromethane and 10ml TFA was stirred at room temperature for 6 hours.
The solvent was then removed in vacuo and the residue was triturated in ether for 2 hours until crystallisation occurred. Suction filtration and vacuum pump drying.
Melting point: 177 ℃.
And C: (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid N- (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -glycine (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Example 13: (2S) -2- [ (4- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -butyryl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: 4- [ (5-oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl) -oxy]-butyric acid (Compound B)16)
This compound was obtained according to the method described in example 1 steps a and B, but using tert-butyl 4-hydroxybutyrate instead of tert-butyl 3-hydroxypropionate in step a.
Melting point: 130 ℃ and 131 ℃.
And B: (2S) -2- [ (4- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl)]-oxy } -butyryl) -amino]-succinic acid (Compound B)14)
This compound was obtained according to the method described in example 1, steps C and D, but starting from the compound obtained in the above step.
And C: (2S) -2- [ (4- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -butyryl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 51.786.088.633.95
Found value 52.526.058.823.47
Example 14: { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -acetic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } acetic acid (Compound B15)
This compound was obtained according to the method described in example 1, steps a and B, but using tert-butyl hydroxyacetate instead of tert-butyl 3-hydroxypropionate in step a.
And B: { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -acetic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 52.096.038.384.80
Found value 51.765.848.504.97
Example 15: 3- [ (5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl) -oxy ] -propionic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from example 1, step B.
Example 16: 4- [ (5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl) -oxy ] -butyric acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from example 13, step a.
Example 17: 3- ({4- [ (4-chlorophenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) -propionic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: 3- ({4- [ (4-chlorophenyl) sulfonyl group]-5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) -propionic acid (compound B)17)
This compound was obtained according to the method described in example 1, steps a and B, but using 3, 4-bis [ (4-chlorophenyl) -sulfonyl ] -1, 2, 5-oxadiazole 2-oxide instead of 3, 4-bis (benzenesulfonyl) -1, 2, 5-oxadiazole 2-oxide in step a.
And B: 3- ({4- [ (4-chlorophenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) -propionic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Example 18: (2S) -2- { [3- ({4- [ (4-chlorophenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) propanoyl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propanoyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: (2S) -2- { [3- ({4- [ (4-chlorophenyl) sulfonyl group]-5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) propanoyl]Amino succinic acid (Compound B)18)
This compound was obtained according to the method described in steps C and D of example 1, but starting from the compound obtained in step a of example 17.
And B: (2S) -2- { [3- ({4- [ (4-chlorophenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) propanoyl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propanoyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S ％Cl
calculated value 49.075.578.413.854.26
Found value 49.125.828.273.704.12
Example 19: (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -acetyl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: (2S) -2- [ (3- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl]-oxy } -acetyl) -amino]-succinic acid (Compound B)24).
The title compound was obtained according to the method described in example 1, steps a-D, but using tert-butyl hydroxyacetate instead of tert-butyl 3-hydroxypropionate in step a.
And B: (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -acetyl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 50.575.798.944.09
Found value 50.715.799.043.82
Example 20: (2S) -2- [ (2- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] oxy } ethyl) amino ] succinic acid: (2S, 3aS, 7aS) -1- [ (1S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: (2S) -2- [ (2-hydroxyethyl) amino ] succinic acid di-tert-butyl ester
Di-tert-butyl L-aspartate (5.62g, 20mmol), 2-bromoethanol (2.84ml, 40mmol) and K2CO3A solution of (5.6g, 40mmol) in 100ml of acetonitrile was heated at reflux for 16 h. The inorganic salts are filtered off and the solvent is removed by distillation in vacuo. The crude product obtained is purified by flash chromatography on silica gel using a (95:5) dichloromethane/ethanol mixture as eluent. The desired product was obtained as a colorless oil.
And B: (2S) -2- [ (2- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl]Oxy } ethyl) amino]Succinic acid (Compound B)25)
This compound was obtained according to the method described in example 1, steps a and B, but using the compound obtained in the above step instead of tert-butyl 3-hydroxypropionate.
Melting point: 160 ℃ and 161 ℃.
And C: (2S) -2- [ (2- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] oxy } ethyl) amino ] succinic acid- (2S, 3aS, 7aS) -1- [ (1S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 51.496.159.104.17
Found value 51.055.949.204.06
Example 21: (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) propanoyl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propanoyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl group]-5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) propanoyl]Amino succinic acid (Compound B)21)
This compound was obtained according to the method described in example 1, steps a-D, but using 3, 4-bis [ (4-methylphenyl) sulfonyl ] -1, 2, 5-oxadiazole 2-oxide in place of 3, 4-bis (benzenesulfonyl) -1, 2, 5-oxadiazole 2-oxide in step a.
Melting point: 167 ℃ and 168 ℃.
And B: (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) propanoyl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propanoyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 51.786.088.633.95
Found value 51.925.968.453.96
Example 22: (2S) -2- { [3- ({4- [ (4-chlorophenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) butyryl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: (2S) -2- { [3- ({4- [ (4-chlorophenyl) sulfonyl group]-5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) butanoyl]Amino succinic acid (Compound B)26)
This compound was obtained according to the method described in example 1, steps a-D, but using tert-butyl 4-hydroxybutyrate instead of tert-butyl 3-hydroxypropionate and 3, 4-bis [ (4-chlorophenyl) -sulfonyl ] -1, 2, 5-oxadiazole 2-oxide instead of 3, 4-bis (benzenesulfonyl) -1, 2, 5-oxadiazole 2-oxide in step a.
Melting point: 145-146 ℃.
And B: (2S) -2- { [3- ({4- [ (4-chlorophenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) butyryl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S ％Cl
calculated value 49.675.728.283.794.19
Found value 49.445.788.203.704.10
Example 23: (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) butyryl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl group]-5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) butanoyl]Amino succinic acid (Compound B)27)
This compound was obtained according to the method described in example 1, steps a-D, but using tert-butyl 4-hydroxybutyrate instead of tert-butyl 3-hydroxypropionate and 3, 4-bis [ (4-methylphenyl) -sulfonyl ] -1, 2, 5-oxadiazole 2-oxide instead of 3, 4-bis (benzenesulfonyl) -1, 2, 5-oxadiazole 2-oxide in step a.
Melting point: 147 ℃ and 148 ℃.
And B: (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) butyryl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 52.366.228.483.88
Found value 52.666.158.674.16
Example 24: 2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -butyryl) -amino ] -ethanesulfonic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: 2- [ (3- { [ 5-oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl)]-oxy } -butyryl) -amino]-ethanesulfonic acid (compound B)28)
This compound was obtained according to the method described in example 6, steps a and B, but in step a compound B obtained from example 13, step a was used16In place of the compound B4。
Melting point: 131 ℃ and 132 ℃.
And B: 2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -butyryl) -amino ] -ethanesulfonic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Elemental microanalysis:
％C ％H ％N ％S
calculated value 49.306.148.717.98
Found value 49.156.128.828.22
Example 25: n, N-bis (2-sulfo) ethyl) -4- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] oxy } butanamide- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
Step A: n- {2- [ (3- { [ 5-Oxo-4- (phenylsulfonyl) -1, 2, 5-oxadiazol-3-yl ] oxy } -butyryl) -oxy ] } -5-norbornene-2, 3-dicarboximide
This compound was obtained according to the procedure described in step A, example 6, but using in step A the compound B obtained from step A, example 1316In place of the compound B4。
And B: n, N-bis (2-sulfoethyl) -4- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl]Oxy } butanamide (Compound B)29)
This compound was obtained according to the procedure described in step B of example 6, using diaminoethanesulfonic acid (prepared according to DE 10033580) and the compound obtained in the above step as starting materials.
And C: n, N-bis (2-sulfoethyl) -4- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] oxy } butanamide- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
This compound was obtained according to the procedure described in example 1, step E, starting from perindopril and the compound obtained from the above step.
Pharmacological investigation of the products of the invention
Example 26: NO Donor Activity
In vitro study
An endothelial-free aortic ring was used. Initial contraction was first induced with 60mM KCl to demonstrate sensitivity of the loop, washed, and stable contraction induced with norepinephrine (0.1-0.3. mu.M) in the presence or absence of guanylate cyclase inhibitor (ODQ (10. mu.M)). Using cumulative concentration series, by IC5(dose for maximum effect of 50% inhibition) the activity of the experimental product was calculated.
As a result: the compounds of the invention have very significant relaxant actionUsing; for example, IC of the Compounds of examples 1 and 750The values were 0.048 and 0.047. mu.M, respectively.
Example 27: inhibiting angiotensin I-converting enzyme activity
In vivo experiments
Rats were anesthetized with pentobarbital, placed under artificial respiration, and mean arterial pressure was measured through a catheter previously placed in the femoral artery and connected to a pressure transducer. The vagus nerve was divided into multiple sections and mecamylamine (sympathetic ganglion blocking agent) was injected intravenously at 1.5mg per kg. After stabilization, angiotensin I was injected intravenously in an amount of 1.5 μ g per kg.
The maximal hypertensive response to angiotensin I was determined in rats that received acacia gum (Senegal gum) alone, or the test compound in acacia gum, by the oral route 60 minutes prior to anesthesia (control group). Inhibition was determined as the percentage of response to angiotensin I compared to the control group response.
As a result: the compound has obvious inhibition effect; for example, injection of the compounds of examples 1 and 7 at a dose of 0.1mg/kg resulted in inhibition of angiotensin I by 85 and 88%, respectively.
Example 28: pharmaceutical composition
1000 tablets are prepared, each tablet containing a dose of 100mg
The
The
The
The
The one
The.
Claims (17)
1. A compound of formula (I):
(A)m·(B)n (I)
wherein A represents an angiotensin converting enzyme inhibitor compound containing at least one salt-forming basic functional group, B represents a compound containing at least one salt-forming acidic functional group and at least one NO donor group, m represents the number of acidic functional groups in B that have been converted to a salt, n represents the number of basic functional groups in A that have been converted to a salt,
the bond between A and B is ionic.
2. The compound of formula (I) according to claim 1, wherein a belongs to formula II:
wherein:
-R1represents a hydrogen atom or a linear or branched C1-C6An alkyl group, a carboxyl group,
-R2represents a straight or branched chain C1-C6Alkyl or aryl- (C)1-C6) An alkyl group, wherein the alkyl group is a linear or branched alkyl group,
-R3represents a straight or branched chain C1-C6Alkyl or amino- (C)1-C6) An alkyl group, wherein the alkyl group is a linear or branched alkyl group,
represents a monocyclic or bicyclic nitrogen-containing system containing from 3 to 12 carbon atoms and capable of containing one or more further heteroatoms selected from N, O and S, said system being optionally substituted by one or more groups selected from: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkoxy, oxo, carboxy, aryl, C3-C8Cycloalkyl, heteroaryl, carboxy- (C) wherein the alkyl is linear or branched1-C6) An alkyl group and a hydroxyl group, and a carboxyl group,
wherein when the nitrogen-containing system is bicyclic, it may be fused, spiro or bridged.
3. A compound of formula (I) according to claim 2, whereinRepresents pyrrolidine, perhydroindole, octahydrocyclopenta [ b ]]Pyrrole, imidazolidine or tetrahydroisoquinoline rings.
4. A compound of formula (I) according to claim 1, wherein a represents enalapril, enalaprilat, lisinopril, perindopril lat, ramipril, spirapril, trandolapril, trandolaprilat, imidapril, moexipril, quinapril or ramiprilat.
5. A compound of formula (I) according to claim 1, selected from the following compounds:
wherein formula B is as defined in claim 1.
6. A compound of formula (I) according to any one of claims 1 to 5, wherein B belongs to the following formula (III):
X-(Ak1)x-(Y)Y-(Ak2)z-Z (III)
wherein:
-X represents CO2H、SO3H or P (O) (OH)2，
Akl and Ak2May be the same or different and each represents a saturated or unsaturated, linear or branched C1-C8Alkylene in which one or more carbon atoms may be replaced by oxygen, sulfur or nitrogen atoms, or by SO2Alternatively, the alkylene group is optionally substituted with one or more groups selected from CO2H、SO3H. Of hydroxy and amino groupsThe substitution of the group(s),
x, y and z, which may be identical or different, each represent 0 or 1,
-Y represents CO or CONH,
-Z represents a NO donor group.
7. The compound of formula (I) according to claim 6, wherein the compound of formula (III) is selected from the compounds of the following formulae:
wherein:
Ak1x, y, Z and Z are as defined in claim 6,
Ak3and Ak5May be the same or different and each represents a saturated straight or branched chain C1-C6Alkylene in which one or more carbon atoms may be replaced by oxygen, sulfur or nitrogen atoms, or by SO2The substitution of the radicals is carried out,
Ak4represents saturated straight-chain or branched C1-C3Alkylene in which one of the carbon atoms may be replaced by an oxygen, sulfur or nitrogen atom, or by SO2The substitution of the radicals is carried out,
Ak6represents saturated straight-chain or branched C2-C5Alkylene in which one of the carbon atoms may be replaced by an oxygen, sulfur or nitrogen atom, or by SO2The substitution of the radicals is carried out,
het represents O or NH, and is selected from the group consisting of,
and Y is1Represents a carbonyl group.
8. The compound of formula (I) according to claim 6 or 7, wherein Z is selected from the group consisting of:
and regioisomers thereof
And regioisomers thereof
And regioisomers thereof
Wherein:
m represents a number of 0 or 1,
R1and R2May be the same or different and each represents a straight or branched chain C1-C6Alkyl, or R1And R2Together with the nitrogen atom carrying them form a 3-to 7-membered nitrogen-containing heterocyclic ring, optionally substituted by a straight or branched chain C1-C6The substitution of the alkyl group is carried out,
R3represents a methyl group or an aminocarbonyl group,
R4and R'4May be the same or different and each represents a hydrogen or halogen atom or a linear or branched C1-C6Alkyl, trifluoromethyl or trifluoromethoxy.
9. The compound of formula (I) according to any one of claims 1 to 5, wherein B is selected from the following compounds:
10. a compound of formula (I) according to claim 1, selected from the following compounds:
- (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
- (2S) -2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -glutaric acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
-2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -ethanesulfonic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- { [ (3- { [ 5-oxo-4-benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -methyl } -phosphonic acid (1: 1);
- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid-2, 2' - [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -imino ] -diacetic acid (1: 1);
- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- {2- [ (3- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -propionyl) -amino ] -ethyl } -phosphonic acid (1: 1);
- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid- (2- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -ethyl) -phosphoric acid (1: 1);
- (2S) -2- [ (4- { [ 5-oxo-4- (benzenesulfonyl) -1, 2, 5-oxadiazol-3-yl ] -oxy } -butyryl) -amino ] -succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1:1)
- (2S) -2- { [3- ({4- [ (4-chlorophenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) -propionyl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
- (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) -propionyl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1);
- (2S) -2- { [3- ({4- [ (4-methylphenyl) sulfonyl ] -5-oxo-1, 2, 5-oxadiazol-3-yl } oxy) -butyryl ] amino } succinic acid- (2S, 3aS, 7aS) -1- [ (2S) -2- { [ (1S) -1- (ethoxycarbonyl) -butyl ] -amino } -propionyl ] -octahydro-1H-indole-2-carboxylic acid (1: 1).
11. A compound of formula (III):
X-(Ak1)x-(Y)Y-(Ak2)z-Z (III)
wherein
-X represents CO2H、SO3H or P (O) (OH)2，
Akl and Ak2May be identical or different and each represents a saturated or unsaturated, linear or branched C1-C8Alkylene in which one or more carbon atoms may be replaced by oxygen, sulfur or nitrogen atoms, or by SO2Alternatively, the alkylene group is optionally substituted with one or more groups selected from carboxyl, SO3H. The group of the hydroxyl group and the amino group is substituted,
x, y and z, which may be identical or different, each represent 0 or 1,
-Y represents CO or CONH,
-Z represents a group Z9Or Z'9：
Wherein R is4And R'4May be the same or different and each represents a hydrogen or halogen atom or a linear or branched C1-C6Alkyl, trifluoromethyl or trifluoromethoxy.
12. A process for the synthesis of a compound of formula (I) according to claim 1, wherein compound a is reacted with compound B in an amount at least equal to (n/m) equivalents of compound a.
13. A pharmaceutical composition comprising as active ingredient a compound of formula (I) according to any one of claims 1 to 10 together with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
14. The pharmaceutical composition of claim 13 for use in the treatment of cardiovascular pathologies.
15. The pharmaceutical composition of claim 14 for the treatment of arterial hypertension and its vascular and renal sequelae, systolic hypertension, peripheral vascular disease, atherosclerosis, restenosis, cardiac insufficiency, thrombosis and any thrombotic event, stable or unstable angina, cerebrovascular accidents, coronary accidents, myocardial infarction, vascular remodeling, diabetes and its vascular and renal sequelae, complications associated with cardiovascular surgery or endothelial dysfunction.
16. The pharmaceutical composition of claim 13, for use in the treatment of inflammatory pathologies and oxidative stress pathologies.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR07.06629 | 2007-09-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1129379A true HK1129379A (en) | 2009-11-27 |
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