WO2000061631A1 - Antagonistes de pentapeptides modifies du recepteur de la clairance des peptides natriuretiques auriculaires - Google Patents

Antagonistes de pentapeptides modifies du recepteur de la clairance des peptides natriuretiques auriculaires Download PDF

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Publication number
WO2000061631A1
WO2000061631A1 PCT/GB2000/001319 GB0001319W WO0061631A1 WO 2000061631 A1 WO2000061631 A1 WO 2000061631A1 GB 0001319 W GB0001319 W GB 0001319W WO 0061631 A1 WO0061631 A1 WO 0061631A1
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WIPO (PCT)
Prior art keywords
phenyl
resin
secbu
para
dmf
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PCT/GB2000/001319
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English (en)
Inventor
Chris Allan Veale
Philip Duke Edwards
Robert Toms Jacobs
Timothy Wayne Davenport
Paul James Warwick
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Astrazeneca Ab
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Publication of WO2000061631A1 publication Critical patent/WO2000061631A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • ANP is a member of a family of natriuretic peptide hormones, which includes atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP).
  • the natriuretic peptides have a number of actions on the cardiovascular system, including; natriuresis, diuresis, and relaxation of vascular smooth muscle.
  • ANP is a 28-amino acid cyclic peptide which is produced in atrial myocytes in response to increases in heart rate and atrial stretch.
  • ANP receptors There are two biologically- and functionally-distinct classes of ANP receptors. The first one is linked to guanylate cyclase and is thought to mediate the physiological effects of ANP via increases in intracellular cGMP levels. These guanylate cyclase receptors are further divided into the ANP-A and ANP-B receptors according to their relative affinity for different natriuretic peptides. The second class of ANP receptors do not mediate the cardiovasculature effects of the hormone and are thought to mainly serve a clearing function of ANP from the extracellular circulation. This receptor is known as the atrial natriuretic peptide clearance receptor (ANPCR).
  • ANPCR atrial natriuretic peptide clearance receptor
  • Natriuretic peptides have a very short half life in vivo, and there are thought to be two major modes of their clearance from systemic circulation. One is via proteolytic inactivation by the enzyme neutral endopeptidase (NEP). The other is via binding to the ANP clearance receptor which is expressed on the vascular endothelium. Binding to the clearance receptor is followed by internalization and degradation of the peptide.
  • NEP neutral endopeptidase
  • the lung is thought to play a major role in ANP clearance, and studies have found over 50% of ANP is cleared in a single pass through the lungs. Approaches based on the inhibition of NEP are further complicated by the number of physiologically important peptide hormones which are substrates for this enzyme.
  • the ANPCR is thought to be primarily responsible for removal of ANP in the pulmonary vasculature, and the ANPCR is the dominate ANP receptor in lung tissue. Additionally, blockade of the clearance receptor in the lung was thought to provide a pulmonary selective approach to reduction of pulmonary blood pressure due to the presence of both the ANP-A,B and ANPCR receptors in the lung and by the proximity of these receptors to the site of ANP synthesis. For these reasons blockade of the ANPCR was chosen as the best approach to increase endogenous levels of ANP.
  • An ANPCR antagonist could have therapeutic usefulness in treating pulmonary hypertension secondary to COPD.
  • all natriuretic peptides i.e., ANP, BNP and CNP
  • an ANPCR antagonist may also be useful for protection of the transplanted heart given that plasma levels of BNP are elevated in this situation.
  • An ANPCR antagonist may have the greatest therapeutic utility in the treatment of congestive heart failure (CHF), by virtue of raising plasma concentrations of ANP and BNP.
  • CHF congestive heart failure
  • the present invention is directed to synthetic analogs of atrial peptides and more particularly o synthetic linear peptide analogs which find use as diuretics, natriuretics and/or vasodilators, or as intermediates for or modulators of such useful compounds, together with methods for their production and use.
  • lactams of the generic structure shown below were found to be blockers of the ANP clearance receptor (ANPCR).
  • lactam molecules which contained a D- amino acid or a sarcosine residue in position R7 has good metabolic stability. This is in contrast to the natural hormone ANP which has poor metabolic stability.
  • Figure 1 is a chart showing the dose-response effect of IV or vehicle administered orally 165 min before evaluating the change in right intraventricular peak systolic pressure
  • RVSP mean systemic arterial pressure
  • MAP mean systemic arterial pressure
  • Figure 2 is a chart showing the effect of vehicle or I (30 mg/kg, p.o.; top panel) and IV
  • the compounds of the instant invention are linear peptide compounds having the structure:
  • R 2 should be hydrogen or a C,-C 4 alkyl group, but is preferably hydrogen or methyl.
  • R 6 is a C 3 -C 5 branched or unbranched alkyl group, preferably isobutyl or sec-butyl;
  • R 8 is L-isoleucine-NH 2 , D-isoleucine-NH 2 , -CH 2 -cyclopentyl, -CH 2 -2-tetrahydrofuranyl, tert- butylglycine-NH 2 , n-butyl, NH-cyclopentyl, NHCH 2 -2-furanyl, -NHCH 2 -pyrininyl, -NHCH 2 - cyclohexyl, -NH-2-indolizidinyl, D-leucinol, -NH-isobutyl, L-allo-isoleucine-NH 2 , 1- hydroxycycloleucinol, 2-(aminomethyl)-l-ethyl-pyrrolidine, or (S)-NH-2-methylbutyl, but if R 7 is -NH-2-indolizidine, then R 8 is absent; and
  • Representative compounds according to the present invention include those of the structure:
  • Compounds of the present invention are shown to have natriuretic, diuretic and hypotensive activity in the intact mammal, and may possess vasorelaxant activity or inhibit the release of aldosterone and renin.
  • these compounds, and compositions containing them may be used as therapeutic agents in the treatment of various edematous states such as, for example, congestive heart failure, nephritic syndrome and hepatic cirrhosis, pulmonary disease, in addition to hypertension and renal failure due to ineffective renal perfusion or reduced glomerular filtration rate.
  • the present invention also provides compositions comprising an effective amount of compounds of the present invention, including the nontoxic addition salts, amides and esters thereof, which may, serve to provide the above-recited therapeutic benefits.
  • Such compositions can also be provided together with physiologically-tolerable liquid, gel or solid diluents, adjuvants and excipients.
  • the compounds of the present invention may also be combined with other compounds known to be adjuvants for, or otherwise used as, therapeutic agents for the above or related indications.
  • compositions may be administered to humans in a manner similar to other therapeutic agents and, additionally, to other mammals for veterinary use, such as with domestic animals.
  • dosage required for therapeutic efficacy will range from about 0.01 to 1000 mg/kg, more usually 0.1 to 100 mg/kg of the host body weight.
  • dosages within these ranges can be administered by constant infusion over an extended period of time until the desired therapeutic benefits have been obtained.
  • compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared.
  • the preparation may also be emulsified.
  • the active ingredient is often mixed with diluents or excipients which are physiologically tolerable and compatible with the active ingredient. Suitable diluents and excipients are, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof.
  • the compositions may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, stabilizing or pH-buffering agents, and the like.
  • compositions are conventionally administered parenterally, by injection, for example, either subcutaneously or intravenously.
  • Additional formulations which are suitable for other modes of administration include suppositories, intranasal aerosols, and, in some cases, oral formulations.
  • suppositories traditional binders and excipients may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10% preferably l%-2%.
  • Oral formulations include such normally-employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained-release formulations, or powders, and contain 10%-95% of active ingredient, preferably 25%-70%.
  • the peptide compounds may be formulated into compositions as neutral or salt forms.
  • Pharmaceutically-acceptable nontoxic salts include the acid addition salts (formed with the free amino groups) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or organic acids such as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups may be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • compounds of the present invention may also be employed as intermediates in the synthesis of such useful compounds.
  • compounds of the present invention whose activity levels are reduced or eliminated entirely can serve to modulate the activity of other diuretic, natriuretic or vasorelaxant compounds, including compounds outside the scope of the present invention, by, for example, binding to alternate receptors, stimulating receptor turnover, or providing alternate substrates for degradative enzyme or receptor activity and thus inhibiting these enzymes or receptors.
  • such compounds may be delivered as admixtures with other active compounds or may be delivered separately, for example, in their own carriers.
  • Compounds of the present invention may also be used for preparing antisera for use in immunoassays employing labeled reagents, usually antibodies.
  • the polypeptides can be conjugated to an antigenicity-conferring carrier, if necessary, by means of dialdehydes, carbodiimide or using commercially-available linkers.
  • These compounds and immunologic reagents may be labeled with a variety of labels such as chromophores; fluorophores such as, e.g., fluorescein or rhodamine; radioisotopes such as l25 1, 5 S, ,4 C, or 3 H; or magnetized particles, by means well known in the art.
  • labeled compounds and reagents can find use as, e.g., diagnostic reagents.
  • Samples derived from biological specimens may be assayed for the presence or amount of substances having a common antigenic determinant with compounds of the present invention.
  • monoclonal antibodies may be prepared by methods known in the art, which antibodies can find therapeutic use, e.g., to neutralize overproduction of immunologically -related compounds in vivo.
  • Synthesis Compounds within the scope of the present invention may be synthesized chemically by means well known in the art. One example of such a scheme may be generally depicted as:
  • the starting material is attached to a resin and the compound is constructed by the successive addition of various building blocks.
  • the resin may be attached to a starting material that will end up in a more central location of the desired compound; and through the use of commonly-known protecting groups, the compound may be extended in multiple directions. Examples
  • the resin was swelled in DMF and 250 mL of a 1 M (66.1 g diluted to 500 mL with DMF) solution of benzenethiol sodium salt in DMF was added and shaken for 1 hr. The resin was drained, washed 8X DMF and the remaining 250 mL of the 1 M solution was added and shaken for an additional hour. The resin was filtered and washed 3X DMF, 3X MeOH, 3X DMF, 3X MeOH, 8X CH 2 C1 2 , Npit test positive. Fmoc protection. To the CH 2 C1 2 swelled resin was added a solution of 12 mL DIPEA in 150 mL dry CH 2 C1 2 .
  • Fmoc-Cl (23.73 g) was dissolved in 150 mL dry CH 2 C1 2 followed by 12 mL DIPEA. This was added to the resin and reaction shaken for three hours. The resin was filtered and washed 8X CH 2 C1 2 , Npit Test, negative.
  • Boc-D-methionine (24.2 g, 97.2 mmol), L- isoleucine methyl ester hydrochloride (17.7 g, 97.2 mmol), hydroxybenztriazole hydrate (16.3 g, 117 mmol), 1 -(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.5 g, 117 mmol) and diisoproplylethylamine (35ml, 200 mmol) were dissolved in DMF (300 mL). The reaction was stirred under nitrogen for 16 hours, then it was diluted with water (1000 mL) and extracted with ethyl acetate (2 x 250 mL).
  • the second crop was determined by HPLC to be of sufficient quality to combine with the first.
  • the combined product was dried in vacuo for 30 minutes at 50 °C to yield 25.3 g white solid (89%).
  • Boc-D-freidingerlactam-L-isoleucene methyl ester t-Boc-D-methionine-L-isoleucine methyl ester (25.3 g, 67.2 mmol) was dissolved in dry methylene chloride (250 mL) under nitrogen and chilled in an ice bath.
  • Trimethyloxonium tetrafluoroborate (9.94 g, 67.2 mmol) was added in one portion. The ice bath was removed and the reaction was allowed to react for 3 hours.
  • the solids were collected by vacuum filtration and washed with hexanes (100 mL). A second crop of solids was obtained from the mother liquor and washed with hexanes (50 mL). The second crop was determined by HPLC to be of sufficient quality to combine with the first. The combined product was dried in vacuo at 50 °C for 30 minutes to yield 17.0 g white solid (77%).
  • Boc-D-zadingerlactam-L-isoluecene Boc-D-kaolin-L-isoleucene methyl ester (15.6 g, 47.5 mmol) was dissolved in THF (60 mL) and methanol (60 mL). Lithium hydroxide (4.2 g, 100 mmol) dissolved in water (60 mL) was added. After one hour, TLC analysis showed no remaining starting material. All the solvent was removed by rotary evaporation. The resulting white solid was dissolved in water (300 mL), washed with methylene chloride (50 mL), and acidified with IM HCl (105 mL). A white precipitate formed.
  • Boc-D- fingerlactam-L-isoluecene (8.86 g, 28.2 mmol) was suspended in methylene chloride and trifluoroacetic acid (30 mL) was added. After 1.5 hours the volatiles were removed by rotary evaporation. Methylene chloride (2 x 50 mL) was added and evaporated to rid remaining TFA. The residue was cooled in an ice bath and dioxane (42ml) and 10% aqueous sodium carbonate (71ml) were added. FMOC chloride (8.8 g, 33.9 mmol) was added to the resulting solution in four portions.
  • the combined organic extracts were dried with Na 2 SO 4 , filtered through celite and concentrated.
  • the material was loaded on a silica gel flash column (5 x 20 cm) and the product was eluted off using a gradient of 10 to 30% EtOAc in hexane.
  • the FMOC-aminopyridone (15.3 g) was dissolved in 3:1 CH 2 C1 2 in TFA (100 mL). After 14 h the solvents were removed under reduced pressure. The residue was concentrated from Et,O (3 x 20 mL) to give the product (N-fluorenylmethyloxycarbonyl pyridone- isoleucine) (13.6 g) as a foam.
  • the residue was purified by silica gel flash chromatography (6 x 23 cm) using a gradient from 20 to 67% EtOAc in hexane to afford the mononitroimidazole product (8.17 g; R f of 0.33 in 30% EtOAc in hexane).
  • the obtained material and 10% Pd-C (1.4 g) were reacted in EtOH (135 mL) under 47 psi H 2 for 2 h.
  • the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure.
  • the amino-imidazole product (7.05 g) was dissolved in 10% Na 2 CO 3 (aq) (70 mL) and dioxane (42 mL) and the solution was cooled in an ice-water bath.
  • the FMOC-amino compound (5.07 g) was dissolved in 3:1 CH 2 C1 2 :TFA. After 16 h the solvents were removed under reduced pressure. The viscous oil was concentrated from Et 2 O (30 mL x 3) until a foam resulted.
  • t-Butyl ester vii (17.2 g, 60.35 mmol) was dissolved in DMSO (120 mL) and NaNO 2 (16.66 g, 4 eq.) was added in one portion followed by addition of CH 3 CO 2 H (34.55 mL, 10.0 eq.). A condenser was connected to the flask and the stirred mixture was heated to 35 °C overnight. The reaction was cooled to room temperature and quenched with water (200 mL) and allowed to stir for 15 min. The mixture was washed with Et 2 O ( 3 x 150 mL). The Et 2 O layers were combined, washed with brine, then with NaHCO 3 (sat.) (2 x 100 mL).
  • the benzoic acid derivative viii (7.57 g, 32.07 mmol) was dissolved in DMF (100 mL) and K 2 CO 3 (4.4 g, 32.07 mmol) was added as a solid and the mixture was stirred under N 2 for 15 min followed by addition of allyl bromide (2.9 mL 1.05 eq). After 2 hours, the reaction was added to ethyl acetate and washed with water (150 mL) and brine (5 x 200 mL). The organic layer was dried (MgSO 4 ), and concentrated. Silica gel chromatography (5% ethyl acetate in hexane) of the crude oil provided h as a colorless and clear oil (7.5 g, 85%).
  • N-(2-naphthoyl)-3-aminophenylacetic acid and N-(l-naphthoyl)-3- aminophenylacetic acid are examples of N-(2-naphthoyl)-3-aminophenylacetic acid and N-(l-naphthoyl)-3- aminophenylacetic acid.
  • N-(2-Naphthoyl)-3-aminophenylacetic acid A portion of the methyl 3- aminophenylacetate (1.65 g, 10 mmol) was dissolved in methylene chloride (50 mL). DIEA (3.5 mL, 20 mmol) then 2-naphthoyl chloride (2.0 g, 10.5 mmol) dissolved in methylene chloride (10 mL) were added to the resulting solution. After 16 hours the reaction was diluted with ethyl acetate (100 mL) and washed with water (50 mL), saturated ammonium chloride (50 mL), and brine (50 mL).
  • N-(2-NaphthoyI)-2-aminophenylacetic acid N-(2-NaphthoyI)-2-aminophenylacetic acid.
  • Methyl 2-aminophenylacetate 1.6 g, 10 mmol was dissolved in methylene chloride (50 mL) and DIEA (3.5 mL, 20 mmol), then 2- naphthoyl chloride (2.0 g, 10.5 mmol) dissolved in methylene chloride (10 mL) were added. After 16 hours the reaction was diluted with ethyl acetate (100 mL) and washed with saturated ammonium chloride (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate, and the solvent was removed by rotary evaporation.
  • the solvent was removed by rotary evaporation.
  • the solid was dissolved in water (1000 mL) containing a small amount of sodium carbonate. This was washed with ethyl acetate.
  • the aqueous phase was acidified with 1 M HCl and extracted with ethyl acetate (4 x 250 mL). The organics were washed with brine and dried over magnesium sulfate.
  • the solvent was removed by rotary evaporation.
  • the resulting solid was recrystallized from refluxing ethyl acetate (1000 mL) to afford N-(l-naphthoyl)-4-aminophenylacetic acid (1.16 g, 67%) as a white solid.
  • the aqueous filtrate was extracted with ethyl acetate (2 x 250 mL).
  • the solid filter cake was dissolved in ethyl acetate (1.5 L) and 0.12 N hydrochloric acid (250 mL) and the phases separated.
  • the ethyl acetate solutions were combined and concentrated in vacuo to afford an off white solid.
  • This product was suspended in ethyl acetate (100 mL), isolated by filtration and dried to afford the title compound as a white solid (18.9 g, 50.6 mmol, 76%).
  • Rink amide resin (1.5 g) was suspended in DMF (20 mL) and was gently agitated for 30 minutes. The solvent was drained from the resin, 20% (v/v) piperidine in DMF (20 mL) was added, and the suspension was gently agitated for 10 minutes. The piperidine solution was drained from the resin and the resin was washed with DMF (2 x 20 mL). The piperidine treatment was repeated.
  • the resin was suspended in DMF (5 mL) and N-fluorenylmethyloxycarbonyl-L-isoleucine (0.795 g), HATU (0.813 g) and IM N,N-diisopropylethylamine in DMF (4.3 mL) were added. The mixture was gently agitated for 3.5 h. The reaction solution was drained from the resin and the resin was washed with DMF (4 x 20 mL).
  • the resin was suspended in DMF (5 mL) and N- fluorenylmethyloxycarbonyl-L-Asp(O-t-Bu)-OH (0.88 g), HATU (0.813 g) and 1M N.N- diisopropylethylamine in DMF (4.3 mL) were added. The mixture was gently agitated for 1.75 h. The reaction solution was drained from the resin and the resin was washed with DMF (4 x 20 mL). The resin was treated with 20% (v/v) piperidine (20 mL) for 10 min, then was washed with DMF (2 x 20 mL). This treatment was repeated, and the resin was washed with additional DMF (2 x 20 mL).
  • the resin was washed with methanol (2 x 20 mL) and diethyl ether (2 x 20 mL) and was then dried in vacuo.
  • the product peptide was cleaved from the resin by treatment with trifluoroacetic acid containing 2% (v/v) thioanisole (85 mL) for 4 h.
  • the resin was removed by filtration and washed with trifluoroacetic acid (2 x 10 mL).
  • the filtrate was concentrated to afford a red oil which was triturated with diethyl ether (4 x 100 mL) to afford the crude product as a yellow solid (0.700 g).
  • the product was purified by preparative HPLC on a 45 mm i.d.
  • the peptide was assembled by a method analogous to that described in Method 1 up to the coupling of the Freidinger lactam component starting with 0.5 g of RINK amide resin. The N-terminal substituent was then appended:
  • the product peptide was cleaved from the resin by treatment with trifluoroacetic acid containing 2% (v/v) thioanisole (30 mL) for 3 h.
  • the resin was removed by filtration and washed with trifluoroacetic acid (10 mL).
  • the filtrate was concentrated to afford a red oil which was triturated with diethyl ether (3 x 100 mL) to afford the crude product as a yellow solid (0.184 g).
  • the product was purified on a C, 8 SepPak. Fractions containing the desired product were pooled and lyophilized to afford the title compound as a pale yellow solid. Yield: 0.086 g.
  • Ethyl 4-(2-quinoxaloyl)amidophenylacetate A solution of ethyl 4- aminophenylacetate (0.50 g) in dichloromethane (10 mL) was treated with 2-quinoxaloyl chloride (0.51 g) and N,N-diisopropylethylamine (0.38 g). The reaction mixture was stirred at room temperature for 2.5 h, then was diluted with ethyl acetate (50 mL) and washed sequentially with 0.1 N hydrochloric acid (2 x 50 mL), water (50 mL) and brine (50 mL). The aqueous washes were extracted with ethyl acetate (50 mL).
  • Procedure B (compounds where R 8 terminates with aromatics, cvcloalkyls, and heterocvcles) 4-(2-Naphthaloylamido)phenylacetyl-3-(R)-amido-(2-oxopyrrolidine)-l- ⁇ -(l-L-(S)- methylpropyl)acetyl-L-aspartyl-N-(2-indanoyl)carboxamide
  • Polystyrene-PEG-PAC resin 50 g, 0.16 meq./gram was suspended in DMF (300 mL) and was gently agitated for 30 minutes. The solvent was drained from the resin, and the resin was washed with additional DMF (2 x 200 mL). Following the last DMF wash, N-fluorenylmethyloxycarbonyl-L-Asp- ⁇ -(allyl)-OH (15.8 g) in DMF (-30 mL), 1,3- diisopropylcarbodiimide (7.52 mL) and 0.08M of 4-dimethylaminopyridine in DMF (10 mL) were added to the resin.
  • the reaction solution was drained from the resin and the resin was washed with DMF (4 x 4 mL).
  • FT-IR analysis showed no change in intensity of the 1760 cm " ' absorption indicating that double coupling is unnecessary.
  • the resin was treated with 20% (v/v) piperidine (250 mL) for 10 min, then was washed with DMF (2 x 300 mL). This treatment was repeated, and the resin was washed with additional DMF (4 x 250 mL). Coupling of Freidinger lactam.
  • the reaction solution was drained from the resin and the resin was washed with: 5% acetic acid / 2.5% N- methylmorpholine in methylene chloride (5 x 350 mL); methylene chloride (3 x 300 mL); 0.5% sodium dietyldithiocarbamate in DMF (4 x 300 mL); DMF (5 x 300 mL); methylene chloride (4 x 300 mL); 10% acetic acid in methylene chloride (4 x 300 mL); and ether (6 x 300 mL).
  • the resin was dried under high vacuum for 18h. Yield : 45 g.
  • the mixture was gently agitated for 18 hr.
  • the reaction solution was drained from the resin and the resin was washed with DMF (5 x 20 mL), methylene chloride ( 5 x 20 mL), and diethyl ether (5 x 20 mL) and was then dried in vacuo.
  • the product peptide was cleaved from the resin by treatment with trifluoroacetic acid containing 2.5% (v/v) water (35 mL) for 1.5 h.
  • the resin was removed by filtration and washed with trifluoroacetic acid (2 x 10 mL).
  • the peptide was assembled by the method described in Procedure B, method 1. The only difference is that the amine components were synthesized on the Bohdan RAM synthesizer using low temperature conditions.
  • the resin was treated with the following solution containing: sarcosinyl-N-[(+/-)- tetrahydrofurfuryl]-carboxamide.HCl (0.125 g), HATU (0.036 g), N,N-diisopropylethylamine (0.054ml) and 1-methylimidazole (0.012 mL) in DMF (4 mL). The mixture was gently agitated for 18 hr. The reaction solution was drained from the resin and the resin was washed with DMF (5 x 20 mL), methylene chloride (5 x 20 mL), and diethyl ether (5 x 20 mL) and was then dried in vacuo.
  • DMF 5 x 20 mL
  • methylene chloride 5 x 20 mL
  • diethyl ether 5 x 20 mL
  • the product peptide was cleaved from the resin by treatment with trifluoroacetic acid containing 2.5% (v/v) water (35 mL) for 1.5 h.
  • the resin was removed by filtration and washed with trifluoroacetic acid (2 x 10 mL).
  • the filtrate was concentrated to afford a clear oil which was triturated with diethyl ether (3 x 50 mL) to afford the crude product as a white solid (0.096 g).
  • the reaction was kept at -20 °C for two hours with mixing every 30 minutes by way of nitrogen bubbling.
  • a solution containing tetrahydrofurfurylamine (0.248 mL), 1- methylimidazole (0.264 mL) in THF (4.0 mL) was added using a slow syringe speed.
  • the reaction was kept at -20 °C for four hours with mixing every 30 minutes by way of nitrogen bubbling.
  • the cooling unit was then turned off and the reaction was allowed to warm to room temperature overnight with mixing every 30 minutes by way of nitrogen bubbling.
  • the solvent was removed under vacuum.
  • the peptide was assembled using the Milligen 9050 continuous flow automated peptide synthesizer by the fmoc/t-butyl strategy on Pepsyn KA(100) resin.
  • N-fluorenylmethyloxycarbonyl-L-Asp(OBu)-OH Coupling of N-fluorenylmethyloxycarbonyl-L-Asp(OBu)-OH.
  • a solution of N- fluorenylmethyloxycarbonyl-L-Asp(OBu)-OH (0.720 g), HATU (0.660 g), and N,N- diisopropylethylamine (0.610 mL) in DMF (5.30 mL) was added to the resin using a three- hour coupling cycle.
  • the resin was then treated with 20% (v/v) piperidine / DMF using a 10 min cycle.
  • the product peptide was cleaved from the resin by treatment with trifluoroacetic acid containing 2.5% (v/v) water (35 mL) for 1.5 h.
  • the resin was removed by filtration and washed with trifluoroacetic acid (2 x 10 mL).
  • the filtrate was concentrated to afford a clear oil which was triturated with diethyl ether (3 x 50 mL) to afford the crude product as a white solid (0.410 g).
  • the product was purified by preparative HPLC on a 25 mm i.d. x 20 cm Waters 300 A column using an acetonitrile/water (+0.1% (v/v) trifluoroacetic acid) gradient at a flow rate of 12 mL/min.
  • the mixture was stirred with an overhead stirrer for two hours, then transferred to a fritted glass funnel and was washed with a one to one mixture of methanol and DMF (3 x 300 mL), DMF (3 x 300 mL), methylene chloride (5 x 300 mL) and methanol (5 x 300 mL).
  • the resin was dried in vacuo at 40 °C for 16 hours. MAS-NMR showed disappearance of the aldehyde proton.
  • the resin was treated with a second batch of the reaction cocktail (4.2 g N-fluorenylmethyloxycarbonyl- D-Arg(Pbf)-OH, 2.3 g HATU, and 2.7 mL DIEA in 50 mL DMF) for an additional hour.
  • the liquid was drained and the resin was washed with DMF (10 x 50 mL).
  • NPIT test showed the reaction was complete.
  • the resin was treated with 20% piperidine in DMF (2 x 50 mL) then washed with DMF (10 x 50 mL).
  • the liquid was drained and the resin was washed with DMF (10 x 20 mL), methylene chloride (5 x 20 mL) and ether (5 x 20 mL) then dried in vacuo at 40 °C for 30 minutes.
  • the resin was treated with a solution of TFA (50 mL), water (1 mL), thioanisole (1 mL), and TIS (0.5 mL) for one hour.
  • the liquid was filtered from the resin and reduced to about 5 mL by rotary evaporation. Ether (200 mL) was added to precipitate the crude product.

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Abstract

L'invention concerne un composé présentant la formule générale (A). L'invention traite aussi de procédés utilisant des composés pour traiter des maladies et une composition pharmaceutique comprenant ces composés.
PCT/GB2000/001319 1999-04-12 2000-04-07 Antagonistes de pentapeptides modifies du recepteur de la clairance des peptides natriuretiques auriculaires WO2000061631A1 (fr)

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US12889099P 1999-04-12 1999-04-12
US60/128,890 1999-04-12

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WO2000061631A1 true WO2000061631A1 (fr) 2000-10-19

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068047A2 (fr) * 2000-03-17 2001-09-20 Merck Patent Gmbh Preparation contenant des derives de chinoxaline
EP1189881A1 (fr) * 1999-05-07 2002-03-27 Texas Biotechnology Corporation Derives de l'acide propanoique inhibant la liaison des integrines a leurs recepteurs
US6723711B2 (en) 1999-05-07 2004-04-20 Texas Biotechnology Corporation Propanoic acid derivatives that inhibit the binding of integrins to their receptors
US6972296B2 (en) 1999-05-07 2005-12-06 Encysive Pharmaceuticals Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
US7276481B2 (en) 2001-03-20 2007-10-02 Prochon Biotech Ltd. Method and composition for treatment of skeletal dysplasias
WO2010135541A2 (fr) 2009-05-20 2010-11-25 Biomarin Pharmaceutical Inc. Variants du peptide natriurétique de type c
US7879544B2 (en) 2002-07-29 2011-02-01 Hmgene Inc. Methods of identifying adipocyte specific genes, the genes identified, and their uses
WO2012003145A3 (fr) * 2010-07-02 2012-05-03 Allergan, Inc. Agents thérapeutiques pour l'hypertension oculaire
US8377884B2 (en) 2007-11-21 2013-02-19 Biomarin Pharmaceutical Inc. Variants of C-type natriuretic peptides
US9714238B2 (en) 2010-07-02 2017-07-25 Allergan, Inc. Therapeutic agents for ocular hypertension

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0323740A2 (fr) * 1987-12-24 1989-07-12 California Biotechnology, Inc. Analogues linéaires de peptides atrio-natriurétiques
EP0356124A2 (fr) * 1988-08-18 1990-02-28 California Biotechnology, Inc. Inhibiteurs d'élimination de peptide atrial-natriurétique
DE4242946A1 (de) * 1992-12-18 1994-06-23 Bayer Ag Neue acyclische Peptide, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323740A2 (fr) * 1987-12-24 1989-07-12 California Biotechnology, Inc. Analogues linéaires de peptides atrio-natriurétiques
EP0356124A2 (fr) * 1988-08-18 1990-02-28 California Biotechnology, Inc. Inhibiteurs d'élimination de peptide atrial-natriurétique
DE4242946A1 (de) * 1992-12-18 1994-06-23 Bayer Ag Neue acyclische Peptide, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KOYAMA S ET AL: "AP-811, A NOVEL ANP-C RECEPTOR SELECTIVE AGONIST", INTERNATIONAL JOURNAL OF PEPTIDE AND PROTEIN RESEARCH,DK,MUNKSGAARD, COPENHAGEN, vol. 43, no. 4, 1 April 1994 (1994-04-01), pages 332 - 336, XP000434523, ISSN: 0367-8377 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1189881A1 (fr) * 1999-05-07 2002-03-27 Texas Biotechnology Corporation Derives de l'acide propanoique inhibant la liaison des integrines a leurs recepteurs
EP1189881A4 (fr) * 1999-05-07 2002-11-27 Texas Biotechnology Corp Derives de l'acide propanoique inhibant la liaison des integrines a leurs recepteurs
US6723711B2 (en) 1999-05-07 2004-04-20 Texas Biotechnology Corporation Propanoic acid derivatives that inhibit the binding of integrins to their receptors
US6972296B2 (en) 1999-05-07 2005-12-06 Encysive Pharmaceuticals Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
US7812038B2 (en) 1999-05-07 2010-10-12 Encysive Pharmaceuticals, Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
WO2001068047A2 (fr) * 2000-03-17 2001-09-20 Merck Patent Gmbh Preparation contenant des derives de chinoxaline
WO2001068047A3 (fr) * 2000-03-17 2002-03-07 Merck Patent Gmbh Preparation contenant des derives de chinoxaline
US7276481B2 (en) 2001-03-20 2007-10-02 Prochon Biotech Ltd. Method and composition for treatment of skeletal dysplasias
US8211853B2 (en) 2002-07-29 2012-07-03 Hmgene Inc. Method of promoting apoptosis of differentiated adipocytes and increasing endogenous expression of SFRP-5 peptide by administration of SFRP-5 peptide
US7879544B2 (en) 2002-07-29 2011-02-01 Hmgene Inc. Methods of identifying adipocyte specific genes, the genes identified, and their uses
US8377884B2 (en) 2007-11-21 2013-02-19 Biomarin Pharmaceutical Inc. Variants of C-type natriuretic peptides
WO2010135541A2 (fr) 2009-05-20 2010-11-25 Biomarin Pharmaceutical Inc. Variants du peptide natriurétique de type c
US8198242B2 (en) 2009-05-20 2012-06-12 Biomarin Pharmaceutical Inc. Variants of C-type natriuretic peptide
USRE46707E1 (en) 2009-05-20 2018-02-13 Biomarin Pharmaceutical Inc. Variants of C-type natriuretic peptide
US8598121B2 (en) 2009-05-20 2013-12-03 Biomarin Pharmaceutical Inc. Variants of C-type natriuretic peptide
EP4029512A1 (fr) 2009-05-20 2022-07-20 BioMarin Pharmaceutical Inc. Variantes du peptide natriurétique de type c
EP3175863A1 (fr) 2009-05-20 2017-06-07 BioMarin Pharmaceutical Inc. Variantes du peptide natriurétique de type c
USRE48267E1 (en) 2009-05-20 2020-10-20 Biomarin Pharmaceutical Inc. Variants of C-type natriuretic peptide
WO2012003145A3 (fr) * 2010-07-02 2012-05-03 Allergan, Inc. Agents thérapeutiques pour l'hypertension oculaire
US9714238B2 (en) 2010-07-02 2017-07-25 Allergan, Inc. Therapeutic agents for ocular hypertension
US8633220B2 (en) 2010-07-02 2014-01-21 Allergan, Inc. Therapeutic agents for ocular hypertension

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