KR19990087694A - N-[(R) -l- {3- (4-piperidyl) propionyl-3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine as a fibrinogen receptor antagonist - Google Patents

Abstract

The present invention relates to β-alanine derivatives of formula (I) which are glycoprotein IIB / IIIa antagonists, platelet aggregation inhibitors and fibrinogen binding inhibitors to platelets, methods for their preparation, pharmaceutical compositions comprising β-alanine derivatives and the humans described herein Or to a method for preventing and / or treating a disease in an animal.

Formula I

Description

N-[(R) -1- {3- (4-piperidyl) propionyl-3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine as a fibrinogen receptor antagonist

EP 512,831 A1 describes fibrinogen receptor antagonists. EP 445,796 A2 describes platelet aggregation inhibitors.

The present invention relates to β-alanine derivatives. More particularly it relates to β-alanine derivatives which are glycoprotein IIb / IIIa antagonists, platelet aggregation inhibitors and fibrinogen binding inhibitors to platelets.

The present invention relates to β-alanine derivatives. More particularly, it relates to β-alanine derivatives which are glycoprotein IIb / IIIa antagonists and platelet aggregation inhibitors, which include diseases caused by thrombus formation, namely arterial thrombosis; arteriosclerosis; Ischemic heart disease (eg, angina (eg stable angina, unstable angina including acute infarction), myocardial infarction (eg acute myocardial infarction), coronary thrombosis); Ischemic cerebral disease (e.g. cerebral infarction {e.g. cerebral thrombosis (e.g. acute cerebral thrombosis), cerebral embolism, etc.), transient cerebral anemia (e.g. temporary ischemic attack, etc.), cerebrovascular spasms after cerebral hemorrhage (e.g. subretinal bleeding) Post-cerebrovascular contraction, etc.); Pulmonary vascular disease (eg pulmonary thrombosis, pulmonary embolism, etc.); Peripheral circulatory disorders [eg arteriosclerosis occlusion, thromboivitis occlusion (eg Burger's disease), Raynaud's disease, diabetes mellitus complications (eg diabetic anemia, diabetic neuropathy), venous thrombosis (eg deep vein thrombosis) Medicaments for the prevention and / or treatment of

Recurrence after relapse stenosis and / or relapse occlusion (e.g., percutaneous transcatheter coronary angiogenesis (PTCA), after relapse stenosis and / or relapse occlusion, thrombolytic agents such as tissue plasminogen activators (TPA, etc.) Agents for the prophylaxis and / or treatment of stenosis and / or recurrent obstruction;

Agents for adjuvant therapy with thrombolytic agents (eg TPA) or anticoagulants (eg heparin);

Agents for the prevention and / or treatment of thrombosis in the case of vascular surgery, valve replacement, extracorporeal circulation (eg surgery (eg open heart surgery, pump-oxygen supply, etc.), hemodialysis, etc.), transplantation, etc .;

Agents for the prophylaxis and / or treatment of seeded intravascular aggregation (DIC), thrombotic thrombocytopenia, essential thrombocytopenia, inflammation (eg nephritis), immune diseases, etc .;

It is useful as a drug for inhibiting metastasis.

Β-alanine derivatives of the present invention are expected to be useful as inhibitors of cell adhesion and for prevention of seeded intravascular aggregation (DIC), thrombotic thrombocytopenia, essential thrombocytopenia, inflammation (e.g. nephritis, etc.), immune diseases, and / or the like. Or a medicament for treatment; It is expected to be useful as a medicament for metastasis inhibition.

Β-alanine derivatives of the present invention can be represented by the formula

Compound I can be prepared by the following method.

Method 1

Method 2

Wherein R ¹ is an amino protecting group.

Suitable salts of compounds II and III are pharmaceutically acceptable salts, such as conventional non-toxic salts, such as alkali metal salts (eg sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg calcium salts, magnesium salts, etc.) Metal salts, ammonium salts, organic base salts [eg trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt, etc.], organic acid addition salts [eg, Formate, acetate, trifluoroacetate, maleate, tartarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], inorganic acid addition salts [e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate And salts with amino acids such as arginine salts, aspartates, glutamate salts, and the like.

In the above and subsequent description herein, suitable examples for various term definitions are described in detail as follows.

The term "lower" means 1 to 6 carbon atoms, unless stated otherwise.

The term "advanced" means a group having from 7 to 20 carbon atoms unless otherwise stated.

Suitable "lower alkyl" may be straight or branched chains such as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, secondary-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

Suitable “amino protecting groups” are ar (lower) alkyls such as benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl, which may have from 1 to 3 suitable substituent (s) as described below. Etc.), 5- (lower) alkyl-2-oxo-1,3-dioxol-4-yl] (lower) alkyl [eg, (5-methyl-2-oxo-1,3-dioxol-4- 1) methyl, etc.], and the like.

Suitable "acyl groups" and "acyl" may include aliphatic acyls, aromatic acyls, arylaliphatic acyls and heterocyclic-aliphatic acyls derived from carboxylic acids, carboxylic acids, carbamic acids and sulfonic acids.

Suitable examples of such "acyl groups" can be described as follows:

Lower or higher alkanoyls such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonano Day, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, isocanoyl, etc.); Lower or higher alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, heptyloxycarbonyl, etc.); Lower or higher alkylsulfonyl (eg methylsulfonyl, ethylsulfonyl, etc.); Aliphatic acyl such as lower or higher alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.); Aroyl (eg benzoyl, toluroyl, naphthoyl, etc.); Ar (lower) alkanoyl [eg phenyl (C ₁ -C ₆ ) alkanoyl (eg phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naph Til (C ₁ -C ₆ ) alkanoyl (eg, naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.); Ar (lower) alkenoyl [eg phenyl (C ₃ -C ₆ ) alkenoyl (eg phenylpropenyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl ( C ₃ -C ₆ ) alkenoyl (eg, naphthylpropenoyl, naphthylbutenoyl, etc.); Ar (lower) alkoxycarbonyl [eg phenyl (C ₁ -C ₆ ) alkoxycarbonyl (eg benzyloxycarbonyl etc.), etc.]; Aryloxycarbonyl (eg, phenoxycarbonyl, naphthyloxycarbonyl, etc.); Aryloxy (lower) alkanoyl (eg, phenoxyacetyl, phenoxypropionyl, etc.); Arylcarbamoyl (eg phenylcarbamoyl, etc.); Arylthiocarbamoyl (eg phenylthiocarbamoyl, etc.); Arylglyoxyl oils (eg phenylglyoxyl oil, naphthylglyoxyl oil, etc.); Aromatic acyls such as arylsulfonyl (eg phenylsulfonyl, p-tolylsulfonyl, etc.) which may have 1 to 4 lower alkyl;

Heterocyclic carbonyl; Heterocyclic (lower) alkanoyl (eg, heterocyclic acetyl, heterocyclic propanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclic hexanoyl, etc.); Heterocyclic (lower) alkenoyl (eg, heterocyclic propenoyl, heterocyclic butenoyl, heterocyclicpentenoyl, heterocyclic hexenoyl, etc.); Heterocyclic acyl such as heterocyclicglyoxyl oil and the like.

Suitable "heterocyclic moieties" in "heterocycliccarbonyl", heterocyclic (lower) alkyl "," heterocyclic (lower) alkenoyl "and" heterocyclicglyoxyl oils "as mentioned above and "Heterocyclic group" means a saturated or unsaturated monocyclic or polycyclic heterocyclic group comprising one or more hetero atoms such as oxygen, sulfur, nitrogen atoms and the like, wherein the preferred heterocyclic groups are 1 to Unsaturated 3-8 membered (more preferably 5- or 6-membered) heteromonocyclic groups containing four nitrogen atoms, for example pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, di Hydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-tria Zolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetra Zolyl, etc.); saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1-4 nitrogen atoms, for example pyrrolidinyl, imidazolidinyl, piperi Dill, piperazinyl, and the like; unsaturated condensed heterocyclic groups containing 1 to 4 nitrogen atoms, for example indolyl, isoindoleyl, indolinyl, indolinyl, benzimidazolyl, quinolyl , Dihydroquinolyl, isoquinolyl, indazolyl, quinoxalinyl, dihydroquinoxalinyl, benzotriazole and the like; comprising 1 to 2 oxygen atom (s) and 1 to 3 nitrogen atom (s) Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups such as oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4-oxadiazolyl, 1 , 3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) 1 to 2 oxygen atom (s) and 1 to 3 nitrogen atoms Saturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups including (s) such as morpholinyl, cydnonyl and the like; 1 to 2 oxygen atom (s) and Unsaturated condensed heterocyclic groups comprising unsaturated condensed heterocyclic groups containing 1 to 3 nitrogen atom (s), for example benzoxazolyl, benzoxadiazolyl, and the like; Unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), for example thiazolyl, Isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc. ), Dihydrothiazinyl and the like; Saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), for example thiazolidinyl Etc; Unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1 to 2 sulfur atom (s), for example thienyl, dihydrodithiinyl, dihydrodithionyl and the like ; Unsaturated condensed heterocyclic groups comprising 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atoms such as benzothiazolyl, benzothiadiazolyl and the like; Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing oxygen atoms such as furyl and the like; Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing an oxygen atom and 1 to 2 sulfur atom (s) such as dihydrooxatiinyl and the like; Unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atom (s) such as benzothienyl, benzodithiyl, and the like; It may be an unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom (s), for example a heterocyclic group such as benzoxathynyl and the like.

Acyl moieties as mentioned above may be selected from 1 to 10 identical or different suitable substituents such as lower alkyl (eg methyl, ethyl, propyl, etc.); Lower alkoxy (eg methoxy, ethoxy, propoxy, etc.); Lower alkylthio (eg methylthio, ethylthio, etc.); Lower alkylamino (eg methylamino, ethylamino, propylamino, etc.); Cyclo (lower) alkyl [eg cyclo (C ₃ -C ₆ ) alkyl (eg cyclopentyl, cyclohexyl, etc.)]; Cyclo (lower) alkenyls such as cyclo (C ₃ -C ₆ ) alkenyls (eg cyclohexenyl, cyclohexadienyl, etc.); Halogen (eg fluorine, chlorine, bromine, iodine); Amino; Amino protecting groups as mentioned above; Hydroxy; Protected hydroxy as mentioned below; Cyano; Nitro; Carboxyl; Protected carboxy; Sulfo; Sulfamoyl; Imino; Oxo; Amino (lower) alkyl (eg aminomethyl, aminoethyl, etc.); Carbamoyloxy; Hydroxy (lower) alkyl) such as hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3-hydroxypropyl, and the like.

Suitable "protected hydroxy" are acyl as mentioned above, phenyl (lower) alkyl which may have one or more suitable substituents (eg benzyl, 4-methoxybenzyl, trityl etc.), trisubstituted silyls [eg Tri (lower) alkylsilyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.); and tetrahydropyranyl.

More preferred "amino protecting groups" may be lower alkoxycarbonyl or ar (lower) alkoxycarbonyl and most preferred may be tert-butoxycarbonyl or benzyloxycarbonyl.

Method 1

Compound I can be prepared by removing the amino protecting group of Compound II or a salt thereof.

The reaction is carried out according to conventional methods such as hydrolysis and reduction.

Preferably the hydrolysis is carried out in the presence of an acid such as base or Lewis acid.

Suitable bases are inorganic and organic bases, ie alkali metals [e.g. sodium, potassium, etc.], alkaline earth metals [e.g. magnesium, calcium, etc.], hydroxides or carbonates or bicarbonates thereof, trialkylamines [e.g. trimethylamines] , Triethylamine, etc.], picoline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [ 5.4.0] undec-7-ene and the like.

Suitable acids may include organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid and the like and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and the like.

Removal reactions using Lewis acids, such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid and the like] are preferably carried out in the presence of a cationic adsorbent [e.g. anisol, phenol and the like].

Typically the reaction is carried out in the presence of a solvent such as water, an alcohol such as methanol, ethanol, methylene chloride, tetrahydrofuran, mixtures thereof or any other solvent which does not adversely affect the reaction. Liquid bases or acids can also be used as solvents. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Reduction methods that may be applied for the removal reaction may include chemical reduction and catalytic reduction may be performed with metals (eg, tin, zinc, iron, etc.) or metallic compounds (eg, chromium chloride, chromium acetate, etc.) and organic or inorganic acids (eg, Formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, and the like.

Suitable catalysts used for catalytic reduction include platinum catalysts (eg platinum plates, sponge platinum, platinum black, colloidal platinum, platinum oxides, platinum wires, etc.), palladium catalysts (eg sponge palladium, palladium black, palladium oxide, carbon phase). Palladium, colloidal palladium, palladium on barium, sulfate, palladium on barium carbonate, etc.], nickel catalysts (eg, reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (eg, reduced cobalt, Rani cobalt, etc.), Conventional catalysts such as iron catalysts (eg, reduced iron, Raney iron, etc.), copper catalysts (eg, reduced copper, Rani copper, Ulman copper, etc.).

Reduction is carried out in conventional solvents which do not adversely affect the reaction, such as water, methanol, ethanol, propanol, N, N-dimethylformamide or mixtures thereof. In addition, they can also be used as solvents when the above-mentioned acids to be used for chemical reduction are liquids. In addition, suitable solvents to be used for catalytic reduction may be the solvents mentioned above and other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran or the like or mixtures thereof.

The reaction temperature of the reduction is not critical and the reaction is usually carried out under cooling to warming.

Thus when the compound I obtained is in salt form it can be converted to the free form by conventional means.

Method 2

Compound I can be prepared by desalting compound III.

The reaction is carried out according to conventional methods such as neutralization, recrystallization, desalting resin column chromatography.

The compounds obtained by the above methods 1 and 2 can be separated and purified by conventional methods such as powdering, recrystallization, column chromatography, reprecipitation and the like.

Compound I may include solvated compounds such as hydrates and the like.

Compound I is a crystal that is stable and easy to handle.

The pharmacological test data of compound I of the present invention to show the use of compound I are shown below.

Test 1: Fibrinogen Binding to Platelets

Test compound

Compound of Example 1

Test Methods

Washed human platelets are prepared from platelet rich plasma by gel filtration. Washed platelets are activated with 20 μM ADP for 10 minutes and fixed with 0.8% paraformaldehyde for 30 minutes. Platelets are then washed by centrifugation and suspended in Hepes Tyrodes containing ₂ mM CaCl ₂ and 1 mM MgCl ₂ .

30ul of platelets are incubated at a final concentration of 2 × 10 ⁸ / ml with 10 μg / ml FITC-fibrinogen and test compound. The reaction is left for 30 minutes at room temperature. FITC fluorescence of bound fibrinogen is measured using FACS, a flow cytometer.

Specific binding is calculated by subtracting the binding in the presence of a 50-fold excess of unlabeled fibrinogen. The results are expressed as IC ₅₀ values (amount required to inhibit 50% binding).

Test result

Test Compound (I) IC ₅₀

1.6 x 10 ^-8

Pharmaceutical compositions of the present invention include pharmaceutical formulation forms, such as rectal, lung (nasal or oral inhalation), nasal, ocular, external (local), oral or parenteral (subcutaneous, intravenous and intramuscular). ) In solid, semisolid or liquid form comprising Compound I as active ingredient in admixture with organic or inorganic carriers or excipients suitable for administration or inhalation.

The active ingredient may be used, for example, in tablets, pellets, troches, capsules, suppositories, creams, ointments, sprays, inhalable powders, solvents, emulsions, suspensions and the use together with conventional pharmaceutically acceptable non-toxic carriers. It may be formulated in another suitable form and optionally further adjuvants, stabilizers, thickeners and coloring agents and flavorings may be used.

Compound I is included in the pharmaceutical composition in an amount sufficient to produce the desired effect according to the progression or symptom of the disease.

The pharmaceutical compositions of the present invention may be prepared according to conventional methods in the art. In some cases, techniques commonly used in the art for improving the bioavailability of a medicament may be applied to the pharmaceutical compositions of the present invention.

For application of the composition to humans or animals it is to be applied by inhalation, including intravenous (including intravenous infusion), intramuscular, pulmonary or oral administration or by spraying from a metered amount of inhaler, nebulizer or dry powder nebulizer. desirable.

In general, the dosage of a therapeutically effective amount of Compound I given for the prophylaxis and / or treatment of the disease in a human or animal varies depending on the age and symptoms of the patient to be treated and the daily dosage of Compound I for intravenous administration. Is 0.001 to 100 mg / kg body weight of the human or animal, and for intramuscular administration, the daily dose of Compound I is 0.001 to 100 mg / kg body weight of the human or animal, and the daily dose of Compound I for oral administration Is between 0.001 and 200 mg / kg body weight of human or animal.

The following examples are provided for the purpose of illustrating the invention in more detail.

Example 1

N-[(R) -1- {3- (1-benzyloxycarbonyl-4-piperidyl) propionyl} -3-piperidylcarbonyl] -2 (S) in 1N HCl (0.94 ml) A mixture of 10% Pd-C (0.1 g) in acetylamino-β-alanine (0.5 g) and tetrahydrofuran (5 ml) is hydrogenated under atmospheric pressure for 2 hours. The filtrate is concentrated in vacuo after the catalyst is filtered off. The residue was redissolved in water, neutralized with saturated NaHCO ₃ solution and eluted with a resin of HP-20 eluted with isopropanol: H ₂ O = (1: 1) followed by freeze drying and recrystallization from ethanol to give white crystals. As N-[(R) -1- {3- (4-piperidyl) propionyl-3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine (0.34 g, 91.0%) To obtain.

IR (KBr pellet): 2943, 2862, 1608 cm ^-1

NMR (D ₂ O, δ): 1.31-1.88 (8H, m), 1.94-2.03 (4H, m), 2.03 (3H, s), 2.39-2.54 (3H, m), 2.80-3.05 (3H, m ), 3.19-3.48 (5H, m), 3.63-3.74 (1H, m), 3.81-3.95 (1H, m), 4.18-4.34 (1H, m), 4.35-4.41 (1H, m)

Elemental analysis for C ₁₉ H ₃₂ N ₄ O ₅ · 1.6H ₂ O:

Calculated: C 53.66, H 8.34, N 13.17

Found: C 53.63, H 8.56, N 13.03

Claims (6)

Compounds of formula (I). Formula I (i) removing the amino protecting group of the compound of formula II or a salt thereof to give a compound of formula I, or (ii) desalting a salt of a compound of formula (I) to obtain a compound of formula (I). Formula I Formula II In the above formula, R ¹ is an amino protecting group. A pharmaceutical composition comprising the compound of claim 1 in admixture with a pharmaceutically acceptable carrier or excipient as an active ingredient. Use of the compound of claim 1 for the manufacture of a drug. The compound of claim 1 for use as a drug. Diseases caused by thrombus formation, comprising administering the compound of claim 1 to a human or animal; Recurrent stenosis or reoccurrence; Thrombus formation that occurs in the case of vascular surgery, valve replacement, extracorporeal circulation or transplantation; Seeded intravascular aggregation; Thrombotic thrombocytopenia; Essential thrombosis; Inflammation; Immune diseases; Or for the prophylaxis and / or treatment of metastasis or for adjuvant therapy with thrombolytic agents or anticoagulants.