WO1993021214A1 - Alpha-aminoboronic acid peptides and their use as elastase inhibitors - Google Patents
Alpha-aminoboronic acid peptides and their use as elastase inhibitors Download PDFInfo
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- WO1993021214A1 WO1993021214A1 PCT/GB1993/000798 GB9300798W WO9321214A1 WO 1993021214 A1 WO1993021214 A1 WO 1993021214A1 GB 9300798 W GB9300798 W GB 9300798W WO 9321214 A1 WO9321214 A1 WO 9321214A1
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- 108090000765 processed proteins & peptides Proteins 0.000 title description 4
- 239000003602 elastase inhibitor Substances 0.000 title description 3
- 102000004196 processed proteins & peptides Human genes 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
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- MODZVIMSNXSQIH-UHFFFAOYSA-N ethyl benzenecarboximidate;hydron;chloride Chemical compound Cl.CCOC(=N)C1=CC=CC=C1 MODZVIMSNXSQIH-UHFFFAOYSA-N 0.000 description 1
- XSXLCQLOFRENHC-UHFFFAOYSA-N ethyl n-benzylcarbamate Chemical compound CCOC(=O)NCC1=CC=CC=C1 XSXLCQLOFRENHC-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010265 fast atom bombardment Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229950003188 isovaleryl diethylamide Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VPKDCDLSJZCGKE-UHFFFAOYSA-N methanediimine Chemical compound N=C=N VPKDCDLSJZCGKE-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 description 1
- KDXZREBVGAGZHS-UHFFFAOYSA-M methohexital sodium Chemical compound [Na+].CCC#CC(C)C1(CC=C)C(=O)N=C([O-])N(C)C1=O KDXZREBVGAGZHS-UHFFFAOYSA-M 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical group COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- QIPHSSYCQCBJAX-UHFFFAOYSA-N propan-2-ylboronic acid Chemical compound CC(C)B(O)O QIPHSSYCQCBJAX-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003565 thiocarboxylic acid derivatives Chemical class 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 125000002114 valyl group Chemical group 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 201000002282 venous insufficiency Diseases 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- 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
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- R is an acyl group of formula A.X.CO- in which A.X-, taken together, is hydrogen, trifluoromethyl, 2,2,2-trifluoroethoxy, amino, methoxyamino, 2,2,2-trifluoroethylamino, RbRcN.O-, RaOCONH-, R S0 2 NH-, RaOCO-, RbRcNCO- or RaCO-; or
- X is a direct bond, imino, oxy or thio
- A is tetrahydropyran-4-yl, l-methylpiperid-4-yl, or 5-methyl-l,3-dioxacyclohex-5-ylmethyl;
- 17 is a direct bond, imino, carbonylimino, oxycarbonylimino or iminocarbonylimino;
- R is a group G as defined below;
- Q is oxygen or sulfur
- R is (l-5C)alkyl which has no tertiary carbon
- 1 2 Q and Q which may be the same or different, is each hydroxy or OR , or when taken together form a moiety derived from a physiologically acceptable dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or atoms which can be 0, S or N, wherein R is
- Halogeno is fluoro, chloro, bromo or iodo. Alkyl, alkoxy, etc.
- Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propenylene, trimethylene or tetramethylene diradical thereto, as well as a stable N-oxide thereof.
- the present invention encompasses a compound of formula I as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of formula I as a mixture of enantiomers, as well as in the form of an individual enantiomer.
- a compound of formula I may be viewed as a valyl (or "borovaline”) derivative.
- the compound of formula I in a form which is characterized as containing, for example, at least 95%, 98% or 99% enantiomeric excess (ee) of the (£>)-form.
- ee enantiomeric excess
- 1 2 may be preferred that the boron substituents Q and Q be chiral.
- G is (1-3C)alkyl, aryl(1-C)alkyl or heteroaryl(1-2C)alkyl which may bear one or more substituents as defined above for G or a part thereof.
- COORa is carboxy or methoxycarbonyl.
- CONRbRc is carbamoyl or N,N-dimethylcarbamoyl.
- Q and Q are, for example, hydroxy
- a pharmaceutically acceptable salt of an acidic compound of formula I is one made with a base which affords a pharmaceutically acceptable cation, which includes alkalai metal salts (especially lithium, sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from appropriate organic bases such as triethylarnine, morpholine, piperidine and triethanol amine.
- a pharmaceutically acceptable salt of a basic compound of formula I includes"anT acid-addition salt made with an acid which provides a pharmaceutically acceptable anion, including for example, a strong acid such as hydrochloric, sulfuric or phosphoric acid. It will be noted that other boronic acid derivatives have been disclosed as inhibitors of serine proteases in which the boron
- Conventional methods include, for example, removal of a benzyloxycarbonyl group by hydrogenolysis, as described in Example 2; removal of a benzyloxy ⁇ carbonyl by treatment with a strong acid, for example with trifluoromethanesulfonic acid in an inert solvent such as dichloromethane; and basic hydrolysis of a trifluoroacetyl group.
- NHRh or NHRk i.e. an amino group of formula NReRf is which Re is hydrogen and Rf is Rg, Rh or Rk
- NReRf an amino group of formula NReRf is which Re is hydrogen and Rf is Rg, Rh or Rk
- 1 2 compound of formula I in which Q and/or Q is not hydroxy into a hydroxy group by a conventinal method Conventional method include, for example, hydrogenolysis of a group in which 1 and/or 2 is benzyl
- the necessary starting materials for the above procedures may be made by procedures which are selected from standard techniques of heterocyclic chemistry and peptide chemistry, techniques which are analogous to the synthesis of known, structurally similar compounds, and techniques which are analogous to the above described procedures or the procedures described in the Examples.
- compounds herein are represented as the 6-pyrimidone, rather than the 6-hydroxypyrimidine, tautomers.
- a nitrile of formula R CN is converted into a corresponding imidic ester of formula IV wherein R is methyl or ethyl, conveniently isolated as its hydrochloride, if the imidic ester is not commercially available. Reaction of the imidic ester with an
- Transformation of R into a carboxaldehyde to afford a corresponding compound of formula X from a compound of formula IX is o the next step.
- R is a vinyl group
- the transformation may be carried out using N-methylmorpholine-N-oxide and osmium tetroxide, as o described in Example 1, part e.
- R is a dimethoxymethyl or diethoxyethyl group
- the acetal may be hydrolyzed with dilute hydrochloric acid, as described in Example 3, part f.
- a protecting group may be used during all or portions of the above described processes; the protecting group then may be removed when the final compound or a required starting material is to be formed.
- the order of steps in the sequences leading to the starting materials and products of the invention may be altered if appropriate considerations relative to coupling methods, racemization, deprotection methods, etc. are followed.
- the utility of a compound of the invention or a pharmaceutically acceptable salt thereof (hereinafter, collectively referred to as a "Compound”) may be demonstrated by standard tests and clinical studies, including those described below. Inhibition Measurements:
- the potency of a Compound to act as an inhibitor of human leukocyte elastase (HLE) on the low molecular weight peptide substrate methoxy-succinyl-alanyl-alanyl-prolyl-valine-p-nitroanilide is determined as described in U.S. Patent 4,910,190.
- the potency of an inhibitor is evaluated by obtaining a kinetic determination of the dissociation constant, K., of the complex formed from the interaction of the inhibitor with HLE. If a Compound is found to be a "slow-binding" inhibitor of HLE, special methods of analysis to accurately determine K. values for the inhibition of HLE are carried out as described in U.S. Patent 4,910,190. In general, the K. values for Compounds of the invention which were tested are generally on the order of 10 " M or much less.
- Acute Lung Injury Model Acute Lung Injury Model
- Hamsters are first lightly anesthetized with Brevital. Phosphate buffered saline (PBS) pH 7.4, either alone or containing human leukocyte elastase (HLE), is then administered directly into the trachea. Twenty-four hours later the animals are killed and the lungs removed and carefully trimmed of extraneous tissue. Following determination of wet lung weight, the lungs are lavaged with PBS and total lavagable red and white cells recovered are determined. The values for wet lung weights, total lavagable red cells and total lavagable white cells are elevated in a dose-dependent manner following administration of HLE.
- PBS Phosphate buffered saline
- HLE human leukocyte elastase
- Compounds that are effective elastase inhibitors can prevent or diminish the severity of the enzyme-induced lesion resulting in lower wet lung weight and reduced values for total lavagable cells, both red and white, relative to administration of HLE alone.
- Compounds can be evaluated by administering them intratracheally as solutions or suspensions in PBS, either with or at various times prior to the HLE challenge (400 ⁇ g), or by dosing them intravenously or orally as solutions at various times prior to the HLE challenge (100 ⁇ g) to determine their utility in preventing an HLE lesion.
- a solution of" a Compound is conveniently prepared using 10% polyethylene glycol 400/PBS or 10% polyethylene , glycol 400/water.
- HNE human neutrophil elastase
- a pharmaceutical composition comprising a pharmaceutically effective amount of a Compound and a pharmaceutically acceptable diluent or carrier.
- another feature of the invention is a method of using a Compound of the invention in the treatment of a disease or condition in a mammal, especially a human, in which HLE is implicated.
- a Compound of the present invention may be administered to a warm-blooded animal, particularly a human, in need thereof for treatment of a disease in which HLE is implicated, in the form of a conventional pharmaceutical composition, for example as generally disclosed in U.S. Patent 4,910,190.
- the preferred mode of administration may be via a powdered or liquid aerosol.
- a Compound of the invention may be administered in the same manner as cromolyn sodium via a 'Spinhaler- " (a trademark) turbo-inhaler device obtained -from Fisons Corp. of Bedford, Massachusets at a rate of about 0.1 to 50 mg per capsule, 1 to 8 capsules being administered daily for an average human.
- Each capsule to be used in the turbo-inhaler contains the required amount of a Compound of the invention with the remainder of the 20 mg capsule being a pharmaceutically acceptable carrier such as lactose.
- a Compound of the invention may be administered using a nebulizer such as, for example, a 'Retec' (trademark) nebulizer, in which the solution is nebulized with compressed air.
- the aerosol may be administered, for example, at the rate of one to about eight times per day as follows: A nebulizer is filled with a solution of a Compound, for example 3.5 mL of solution containing 10 mg/mL; the solution in the nebulizer is nebulized with compressed air; and the patient breathes normally (tidal volume) for eight minutes with the nebulizer in his mouth.
- the mode of adminstration may be oral or parenteral, including subcutaneous deposit by means of an osmotic pump.
- a compound of the invention may be conventionally formulated in an oral or parenteral dosage form by compounding about 10 to 250 mg per unit of dosage with conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice, e.g. as described in U.S. Patent 3,755,340.
- a 1 to 10 mL intravenous, intramuscular or subcutaneous injection would be given containing about 0.02 mg to 10 mg/kg of body weight of a compound of the invention 3 or 4 times daily.
- the injection would contain a compound of the invention in an aqueous isotonic sterile solution or suspension optionally with a preservative such as phenol or a solubilizing agent such as ethylenediaminetetraacetic acid (EDTA).
- EDTA ethylenediaminetetraacetic acid
- a 10 ⁇ ig/mL aqueous formulation of an acidic Compound may be prepared, for example by dissolving the Compound (10 mg), dibasic sodium phosphate heptahydrate, USP (11.97 mg), monobasic sodium phosphate, USP (0.74 mg), sodium chloride, USP (4.50 mg) and sufficient 1 N sodium hydroxide solution or 0.05 M monobasic sodium phosphate solution to achieve pH 7.0-7.5 in sufficient water for injection, USP to afford 1.0 L (1.01 g), followed by aseptic filtration, and sterile storage using standard procedures.
- a Compound of the invention will be administered to humans at a daily dose in the range of, for example, 5 to 100 mg of the Compound by aerosol or 50 to 1000 mg intravenously, or a combination of the two.
- a daily dose in the range of, for example, 5 to 100 mg of the Compound by aerosol or 50 to 1000 mg intravenously, or a combination of the two.
- generally equivalent amounts of a pharmaceutically acceptable salt of the Compound also may be used.
- Protocols for the administration of the HLE inhibitor and evaluation of the patients are described in the European Patent Applications with Publication Numbers 458535, 458536, 458537, and 463811 for the treatment or prevention of cystic fibrosis, ARDS, bronchitis, and hemorrhage associated with acute non-lymphocytic leukemia or its therapy, respectively; and a Compound of the invention may be used similarly for the treatment of those diseases and conditions either alone or in combination with another therapeutic agent customarily indicated for the treatment of the particular condition.
- a Compound of the invention may conveniently be administered by a parenteral route, either alone or simultaneously or sequentially with other therapeutically active agents customarily administered for the condition.
- temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 °C;
- reversed phase chromatography means flash chromatography over octadecylsilane (ODS) coated support having a particle diameter of 32-74 ⁇ , know as ⁇ PREP-40-0DS" (Art 731740-100 from Bodman Chemicals, Aston, PA, USA); thin layer chromatography (TLC) was carried out on 0.25 mm silica gel GHLF plates (Art 21521 from Analtech, Newark, DE, USA); reversed phase-TLC (RP-TLC) was carried out Whatman MKC 18 F plates (Art 4803-110 from Bodman Chemicals);
- melting points are uncorrected and (dec) indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations;
- NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, • determined at 250 MHz using DMSO-d, as solvent; conventional abbreviations for signal shape are used; for AB spectra the directly observed shifts are reported;
- the mixture was stirred at a bath temperature of -30 to -25 °C for 30 minutes and 4-methyl- morpholine (0.16 mL) and 2-methyl-l-(4,4,5,5-tetramethyl-l,3,2- dioxaborolidin-2-yl)propylammonium trifluoroacetate (0.43 g) were added. Stirring was continued at -25 °C for 15 minutes, before allowing the mixture to warm to room temperature overnight. The white precipitate was removed by filtration through a medium fritted glass funnel and the filtrate was concentrated to a pink foam.
- N-allylbenzamidine hydrochloride was generated by dissolving N-allylbenzamidine hydrochloride (79.7 g) in 1 N sodium hydroxide. The free base was then extracted into dichloromethane, which was dried and evaporated to provide N-allylbenzamidine (65.2 g). This was added to diethyl ethoxymethylenemalonate (78 mL) in ethanol (50 mL). The resulting solution was heated at 120 °C for 2 hours.
- This material was dissolved in ethyl acetate (1 mL)and the solution was placed in a 3 L, 3-necked flask equipped with a mechanical stirrer and a nitrogen inlet. To the solution was added 2,3-dimethyl-2,3-butanediol (378 g) and anhydrous magnesium sulfate (200 g). The mixture was allowed to stir for 70 hours, the solids were removed by filtration, and the filtrate was evaporated to yield an amber oil. The oil was purified by two fractional distillations at reduced pressure.
- Example 2 To a solution of the product from Example 1 (2.55 g) in tetrahydrofuran (50 mL) was added 10% (w/w) palladium on carbon (0.53 g) and the suspension was stirred under hydrogen overnight. The mixture was filtered through diatomaceous earth and evaporated to give a pale grey foam (2.10 g).
- N-(2,2-Diethoxyethyl)-4-fluorobenzamidine N-(2,2-Diethoxyethyl)-4-fluorobenzamidine.
- ethyl 4-fluorobenzimidate hydrochloride 18.5 g
- aminoacetaldehyde diethyl acetal 14.5 mL
- the solvent was evaporated, the resulting oil dissolved in 1 N NaOH (200 L) , and the solution extracted several times with dichloromethane.
- Example 3.g. by replacing 4-fluorobenzonitrile with the required nitrile in the step corresponding to Example 3.a.
- Example 18 2-[2-(4-Fluorophenyl)-5-(2,6-dimethylpyrid-4-ylmethoxy- carbonylamino)-6-oxo-l,6-dihydro-l-pyrimidinyl]-N-[2-methyl-l- (4,4,5,5-tetramethyl-l,3,2-dioxaborolidin-2-yl)propyl]acetamide.
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- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5518141A JPH07505877A (en) | 1992-04-16 | 1993-04-15 | α-aminoboronic acid peptides and their use as elastase inhibitors |
EP93909050A EP0636143B1 (en) | 1992-04-16 | 1993-04-15 | Alpha-aminoboronic acid peptides and their use as elastase inhibitors |
DE69314169T DE69314169T2 (en) | 1992-04-16 | 1993-04-15 | PEPTIDES WITH AN ALPHAAMINOBORONAIRE GROUP AND THEIR USE AS AN ELASTASE INHIBITOR |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB929208382A GB9208382D0 (en) | 1992-04-16 | 1992-04-16 | Substituted derivatives |
GB9208382.3 | 1992-04-16 | ||
GB929217301A GB9217301D0 (en) | 1992-08-14 | 1992-08-14 | Substituted derivatives |
GB9217301.2 | 1992-08-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993021214A1 true WO1993021214A1 (en) | 1993-10-28 |
Family
ID=26300735
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1993/000798 WO1993021214A1 (en) | 1992-04-16 | 1993-04-15 | Alpha-aminoboronic acid peptides and their use as elastase inhibitors |
Country Status (8)
Country | Link |
---|---|
US (1) | US5736535A (en) |
EP (1) | EP0636143B1 (en) |
JP (1) | JPH07505877A (en) |
AT (1) | ATE158588T1 (en) |
AU (1) | AU3959693A (en) |
CA (1) | CA2133657A1 (en) |
DE (1) | DE69314169T2 (en) |
WO (1) | WO1993021214A1 (en) |
Cited By (28)
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US5693617A (en) * | 1994-03-15 | 1997-12-02 | Proscript, Inc. | Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein |
WO1998009949A1 (en) * | 1996-09-06 | 1998-03-12 | Nippon Kayaku Kabushiki Kaisha | Novel acetamide derivatives and protease inhibitors |
US5780454A (en) * | 1994-10-28 | 1998-07-14 | Proscript, Inc. | Boronic ester and acid compounds |
WO2001007407A1 (en) * | 1999-07-26 | 2001-02-01 | Bristol-Myers Squibb Pharma Company | Lactam inhibitors of hepatitis c virus ns3 protease |
WO2001087851A1 (en) * | 2000-05-18 | 2001-11-22 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
WO2002006242A2 (en) * | 2000-07-18 | 2002-01-24 | Neurogen Corporation | 5-substituted 2-aryl-4-pyrimidinones |
US6458952B1 (en) | 1999-05-19 | 2002-10-01 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
US6624180B2 (en) | 2000-11-20 | 2003-09-23 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade |
US6653316B1 (en) | 1999-05-19 | 2003-11-25 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6660885B2 (en) | 2000-03-13 | 2003-12-09 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
US6664255B1 (en) | 1999-05-19 | 2003-12-16 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
US6686484B2 (en) | 2000-04-17 | 2004-02-03 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade |
US6693121B2 (en) | 2000-04-05 | 2004-02-17 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade |
US6716838B1 (en) | 1999-05-19 | 2004-04-06 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
US6750342B1 (en) | 1999-05-19 | 2004-06-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6867217B1 (en) | 1999-05-19 | 2005-03-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
US6875791B2 (en) | 2000-04-05 | 2005-04-05 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
US6969715B2 (en) | 2001-10-03 | 2005-11-29 | Pharmacia Corporation | 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade |
US7015223B1 (en) | 2000-11-20 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade |
US7015230B1 (en) | 1999-05-19 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
US7105559B2 (en) | 2001-10-03 | 2006-09-12 | Pharmacia Corporation | Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade |
US7119094B1 (en) | 2000-11-20 | 2006-10-10 | Warner-Lambert Company | Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade |
US7122627B2 (en) | 1999-07-26 | 2006-10-17 | Bristol-Myers Squibb Company | Lactam inhibitors of Hepatitis C virus NS3 protease |
EP2562174A1 (en) | 2011-08-24 | 2013-02-27 | Bayer Cropscience AG | Herbicidal 6-Oxo-1,6-dihydropyrimidin-5-carboxamides and 2-Oxo-1,2-dihydropyridin-3-carboxamides |
WO2013084199A1 (en) * | 2011-12-07 | 2013-06-13 | Universidade De Lisboa | Boron heterocycles as new inhibitors of human neutrophil elastase |
WO2021053058A1 (en) | 2019-09-17 | 2021-03-25 | Mereo Biopharma 4 Limited | Alvelestat for use in the treatment of graft rejection, bronchiolitis obliterans syndrome and graft versus host disease |
WO2021209740A1 (en) | 2020-04-16 | 2021-10-21 | Mereo Biopharma 4 Limited | Methods involving neutrophil elastase inhibitor alvelestat for treating coronavirus infection |
WO2023067103A1 (en) | 2021-10-20 | 2023-04-27 | Mereo Biopharma 4 Limited | Neutrophil elastase inhibitors for use in the treatment of fibrosis |
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US7025813B2 (en) * | 2001-10-25 | 2006-04-11 | Agfa-Gevaert | Ink composition containing a particular type of dye, and corresponding ink-jet printing process |
US6803447B2 (en) * | 2002-08-16 | 2004-10-12 | Eutechpark Mmp1.28 | Preparation of supramolecular polymers by copolymerization of monomers containing quadruple hydrogen bonding units with regular monomers |
AU2003279611A1 (en) * | 2003-11-04 | 2005-05-19 | Suprapolix B.V. | Preparation of supramolecular polymers containing quadruple hydrogen bonding units in the polymer backbone |
EP1773903B1 (en) * | 2004-07-12 | 2017-08-09 | SupraPolix B.V. | Supramolecular ionomers |
ATE532540T1 (en) | 2005-05-04 | 2011-11-15 | Suprapolix Bv | MODULAR BIORESORBABLE OR BIOMEDICAL BIOLOGICALLY ACTIVE SUPRAMOLECULAR SUBSTANCES |
EP2087027B1 (en) | 2006-11-20 | 2011-10-05 | SupraPolix B.V. | Supramolecular polymers from low-melting, easily processable building blocks |
US8628789B2 (en) | 2007-03-23 | 2014-01-14 | Suprapolix, B.V. | Strong reversible hydrogels |
WO2010002262A1 (en) * | 2008-07-04 | 2010-01-07 | Suprapolix B.V. | High flow supramolecular compounds |
EP2450394B1 (en) | 2010-11-05 | 2017-06-07 | SupraPolix B.V. | A process for the preparation of a supramolecular polymer |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0315574A2 (en) * | 1987-11-05 | 1989-05-10 | Hoechst Aktiengesellschaft | Renin inhibitors |
US4963655A (en) * | 1988-05-27 | 1990-10-16 | Mayo Foundation For Medical Education And Research | Boron analogs of amino acid/peptide protease inhibitors |
EP0528633A1 (en) * | 1991-08-15 | 1993-02-24 | Zeneca Limited | Pyrimidinyl acetamides as elastase inhibitors |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4537773A (en) * | 1983-12-05 | 1985-08-27 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid derivatives |
US4499082A (en) * | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
GB8600263D0 (en) * | 1985-01-22 | 1986-02-12 | Ici America Inc | Peptide derivatives |
GB9017694D0 (en) * | 1990-08-13 | 1990-09-26 | Sandoz Ltd | Improvements in or relating to organic chemistry |
GB9207145D0 (en) * | 1991-04-18 | 1992-05-13 | Ici Plc | Heterocyclic amides |
-
1993
- 1993-04-15 DE DE69314169T patent/DE69314169T2/en not_active Expired - Fee Related
- 1993-04-15 JP JP5518141A patent/JPH07505877A/en not_active Ceased
- 1993-04-15 CA CA002133657A patent/CA2133657A1/en not_active Abandoned
- 1993-04-15 WO PCT/GB1993/000798 patent/WO1993021214A1/en active IP Right Grant
- 1993-04-15 AT AT93909050T patent/ATE158588T1/en active
- 1993-04-15 AU AU39596/93A patent/AU3959693A/en not_active Abandoned
- 1993-04-15 EP EP93909050A patent/EP0636143B1/en not_active Expired - Lifetime
-
1995
- 1995-01-19 US US08/375,136 patent/US5736535A/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0315574A2 (en) * | 1987-11-05 | 1989-05-10 | Hoechst Aktiengesellschaft | Renin inhibitors |
US4963655A (en) * | 1988-05-27 | 1990-10-16 | Mayo Foundation For Medical Education And Research | Boron analogs of amino acid/peptide protease inhibitors |
EP0528633A1 (en) * | 1991-08-15 | 1993-02-24 | Zeneca Limited | Pyrimidinyl acetamides as elastase inhibitors |
Cited By (46)
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US5693617A (en) * | 1994-03-15 | 1997-12-02 | Proscript, Inc. | Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein |
US6297217B1 (en) | 1994-10-28 | 2001-10-02 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
US5780454A (en) * | 1994-10-28 | 1998-07-14 | Proscript, Inc. | Boronic ester and acid compounds |
US6066730A (en) * | 1994-10-28 | 2000-05-23 | Proscript, Inc. | Boronic ester and acid compounds, synthesis and uses |
US8378099B2 (en) | 1994-10-28 | 2013-02-19 | Millennium Pharmacueticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
US6747150B2 (en) | 1994-10-28 | 2004-06-08 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
US8003791B2 (en) | 1994-10-28 | 2011-08-23 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
US7531526B2 (en) | 1994-10-28 | 2009-05-12 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
US7119080B2 (en) | 1994-10-28 | 2006-10-10 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
US6465433B1 (en) | 1994-10-28 | 2002-10-15 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
US6548668B2 (en) | 1994-10-28 | 2003-04-15 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
US6617317B1 (en) | 1994-10-28 | 2003-09-09 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compositions |
US6271238B1 (en) | 1996-09-06 | 2001-08-07 | Nippon Kayaku Kabushiki Kaisha | Acetamide derivatives and protease inhibitors |
WO1998009949A1 (en) * | 1996-09-06 | 1998-03-12 | Nippon Kayaku Kabushiki Kaisha | Novel acetamide derivatives and protease inhibitors |
US6750342B1 (en) | 1999-05-19 | 2004-06-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6458952B1 (en) | 1999-05-19 | 2002-10-01 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
US6653316B1 (en) | 1999-05-19 | 2003-11-25 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6664255B1 (en) | 1999-05-19 | 2003-12-16 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
US7015230B1 (en) | 1999-05-19 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
US6870056B1 (en) | 1999-05-19 | 2005-03-22 | Pharmacia Corporation | Substitituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
US6716838B1 (en) | 1999-05-19 | 2004-04-06 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
US6867217B1 (en) | 1999-05-19 | 2005-03-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
US7122627B2 (en) | 1999-07-26 | 2006-10-17 | Bristol-Myers Squibb Company | Lactam inhibitors of Hepatitis C virus NS3 protease |
WO2001007407A1 (en) * | 1999-07-26 | 2001-02-01 | Bristol-Myers Squibb Pharma Company | Lactam inhibitors of hepatitis c virus ns3 protease |
US6852761B2 (en) | 2000-03-13 | 2005-02-08 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
US6660885B2 (en) | 2000-03-13 | 2003-12-09 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
US6693121B2 (en) | 2000-04-05 | 2004-02-17 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade |
US6875791B2 (en) | 2000-04-05 | 2005-04-05 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
US6916847B2 (en) | 2000-04-05 | 2005-07-12 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
US6686484B2 (en) | 2000-04-17 | 2004-02-03 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade |
WO2001087851A1 (en) * | 2000-05-18 | 2001-11-22 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
WO2002006242A2 (en) * | 2000-07-18 | 2002-01-24 | Neurogen Corporation | 5-substituted 2-aryl-4-pyrimidinones |
US7169790B2 (en) | 2000-07-18 | 2007-01-30 | Neurogen Corporation | 5-substituted 2-aryl-4-pyrimidinones |
US6943173B2 (en) | 2000-07-18 | 2005-09-13 | Neurogen Corporation | 5-substituted 2-aryl-4-pyrimidinones |
WO2002006242A3 (en) * | 2000-07-18 | 2002-07-18 | Neurogen Corp | 5-substituted 2-aryl-4-pyrimidinones |
US6828338B2 (en) | 2000-11-20 | 2004-12-07 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade |
US7119094B1 (en) | 2000-11-20 | 2006-10-10 | Warner-Lambert Company | Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade |
US7015223B1 (en) | 2000-11-20 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade |
US6624180B2 (en) | 2000-11-20 | 2003-09-23 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade |
US6969715B2 (en) | 2001-10-03 | 2005-11-29 | Pharmacia Corporation | 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade |
US7105559B2 (en) | 2001-10-03 | 2006-09-12 | Pharmacia Corporation | Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade |
EP2562174A1 (en) | 2011-08-24 | 2013-02-27 | Bayer Cropscience AG | Herbicidal 6-Oxo-1,6-dihydropyrimidin-5-carboxamides and 2-Oxo-1,2-dihydropyridin-3-carboxamides |
WO2013084199A1 (en) * | 2011-12-07 | 2013-06-13 | Universidade De Lisboa | Boron heterocycles as new inhibitors of human neutrophil elastase |
WO2021053058A1 (en) | 2019-09-17 | 2021-03-25 | Mereo Biopharma 4 Limited | Alvelestat for use in the treatment of graft rejection, bronchiolitis obliterans syndrome and graft versus host disease |
WO2021209740A1 (en) | 2020-04-16 | 2021-10-21 | Mereo Biopharma 4 Limited | Methods involving neutrophil elastase inhibitor alvelestat for treating coronavirus infection |
WO2023067103A1 (en) | 2021-10-20 | 2023-04-27 | Mereo Biopharma 4 Limited | Neutrophil elastase inhibitors for use in the treatment of fibrosis |
Also Published As
Publication number | Publication date |
---|---|
CA2133657A1 (en) | 1993-10-28 |
DE69314169D1 (en) | 1997-10-30 |
US5736535A (en) | 1998-04-07 |
DE69314169T2 (en) | 1998-01-15 |
AU3959693A (en) | 1993-11-18 |
ATE158588T1 (en) | 1997-10-15 |
JPH07505877A (en) | 1995-06-29 |
EP0636143B1 (en) | 1997-09-24 |
EP0636143A1 (en) | 1995-02-01 |
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