WO2002074732A2 - Inhibiteurs de la tryptase - Google Patents

Inhibiteurs de la tryptase Download PDF

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Publication number
WO2002074732A2
WO2002074732A2 PCT/EP2002/002674 EP0202674W WO02074732A2 WO 2002074732 A2 WO2002074732 A2 WO 2002074732A2 EP 0202674 W EP0202674 W EP 0202674W WO 02074732 A2 WO02074732 A2 WO 02074732A2
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Prior art keywords
different
compounds
salts
formula
alkylene
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PCT/EP2002/002674
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English (en)
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WO2002074732A3 (fr
Inventor
Thomas Martin
Wolf-Rüdiger Ulrich
Thomas Bär
Josef Stadlwieser
Stefan-Lutz Wollin
Karl Zech
Christian P. Sommerhoff
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Altana Pharma Ag
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Publication of WO2002074732A2 publication Critical patent/WO2002074732A2/fr
Publication of WO2002074732A3 publication Critical patent/WO2002074732A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • 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

Definitions

  • the invention relates to novel tryptase inhibitors which are used in the pharmaceutical industry for preparing medicaments.
  • the invention provides compounds of the formula I
  • R1 is hydrogen, 1-4C-alkyl or 1-4C-alkylcarbonyl, n is 1 or 2,
  • U1 and U2 are identical or different and are methylene [-CH 2 -], ethylene [-CH 2 -CH 2 -], trimethyl- ene [-CH 2 -CH 2 -CH 2 -], tetramethylene [-CH 2 -CH 2 -CH 2 -] or isopropylidene [-C(CH 3 ) 2 -],
  • A1 is -0-B1-A3-, -A5-B1-0-, -C(0)-N(R2) -, -N(R2)-C(0)-, -0-C(0)-N(R2)- or -N(R2)-C(0)-0-
  • A2 is -0-B2-A4-, -A6-B2-0-, -C(0)-N(R3)-, -N(R3)-C(0)-, -0-C(0)-N(R3)- or -N(R3)-C(0)-0-
  • A3 is -C(0)-N(R2) -, -N
  • R4 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or benzyl,
  • R5 and R6 are independent from each other hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or
  • B1 and B2 are identical or different and are 1-4C-alkylene
  • K 1 is -B3-X1 , -B3-Y1 or -B3-Z1 -B5-X1 ,
  • K2 is -B4-X2, -B4-Y2 or -B4-Z2-B6-X2,
  • B3 and B4 are identical or different and are a bond or 1-4C-alkylene
  • B5 and B6 are identical or different and are a bond or 1-2C-alkylene
  • X1 and X2 are identical or different and are amino, aminocarbonyl or amidino,
  • Y1 and Y2 are imidazoi-1-yl
  • Z1 and Z2 are identical or different and are 5,2-pyridinylene, 6-methyl-5,2-pyridinylene,
  • 1-4C-alkylene represents straight-chain or branched 1-4C-alkylene radicals, for example the methylene [-CH 2 -], ethylene [-CH 2 -CH 2 -], trimethylene [-CH 2 -CH 2 -CH 2 -], tetramethylene [-CH2-CH2-CH2-], 1 ,2-dimethylethylene [-CH(CH 3 )-CH(CH 3 )-], 1 ,1-dimethyIethylene [-C(CH 3 ) 2 - CH 2 -], 2,2-dimethylethy)ene [-CH 2 -C(CH 3 ) 2 -], isopropylidene [-C(CH 3 ) 2 -] or the 1-methylethylene [-CH(CH 3 )-CH 2 -] radicals.
  • 1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radicals.
  • 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
  • 3-7C-Cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals.
  • the 3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethy! may be mentioned preferably.
  • 1-4C-Alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals.
  • An example which may be mentioned is the acetyl radical.
  • the groups Z1 and Z2 are located between groups B3 and B5 (-B3-Z1-B5-) and B4 and B6 (-B4-Z2-B6-), respectively. Accordingly, in the divalent groupings mentioned by way of example (for example 3,6-indolylene), the first number indicates the point of attachment to the group B3 and B4, respectively, and the second number indicates the point of attachment to the group B5 and B6, respectively.
  • M contains chemical formulae, such as, for example,
  • the same principle has to be applied for the other chemical formulae which are part of the definition of M.
  • Suitable salts for compounds of the formula I - depending on substitution - are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids and bases customarily used in pharmacy.
  • water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toiuenesulfonic acid, methane sulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom.
  • acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, ni
  • salts with bases are also suitable.
  • examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
  • Pharmacologically unacceptable salts which can be obtained initially as process products, for example in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art. It is known to the person skilled in the art that the compounds according to the invention, and also their salts, may contain varying amounts of solvents, for example when they are isolated in crystalline form.
  • the invention therefore also embraces all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
  • n 1 or 2
  • U1 and U2 are identical or different and are methylene [-CH 2 -], ethylene [-CH 2 -CH 2 -], trimethyl- ene [-CH 2 -CH 2 -CH 2 -], tetramethylene [-CH 2 -CH 2 -CH 2 -CH 2 -] or isopropylidene [-C(CH 3 ) 2 -],
  • A1 is -0-B1 -A3-, -A5-B1 -0-, -C(0)-N(R2) -, -N(R2)-C(0)-, -0-C(0)-N(R2)- or -N(R2)-C(0)-0-,
  • A2 is -0-B2-A4-, -A6-B2-0-, -C(0)-N(R3)-, -N(R3)-C(0)-, -0-C(0)-N(R3)- or -N(R3)-C(0)-0-,
  • A3 is -C(0)-N(R2) -, -N(R2)-C(0)-, -0-C(0)-N(R2)- or -N(R2)-C(0)-0-,
  • A4 is -C(0)-N(R3)-, -N(R3)-C(0)-, -0-C(0)-N(R3)- or -N(R3)-C(0)-0-,
  • A5 is -C(0)-N(R2) -, -N(R2)-C(0)-, -0-C(0)-N(R2)- or -N(R2)-C(0)-0-,
  • A6 is -C(0)-N(R3)-, -N(R3)-C(0)-, -0-C(0)-N(R3)- or -N(R3)-C(0)-0-,
  • R2 and R3 are identical or different and are -CH 2 -C(0)OR4 or -CH 2 -C(0)N(R5)R6,
  • R4 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or benzyl,
  • R5 and R6 are independent from each other hydrogen, 1-4C-aIkyl, 3-7C-cycloalkyl or
  • B1 and B2 are identical or different and are 1-2C-alkylene, K1 !s -B3-Z1-B5-X1 ,
  • K2 is -B4-Z2-B6-X2
  • B3 and B4 are identical or different and are a bond or 1-2C-alkylene
  • B5 and B6 are identical or different and are a bond or 1-2C-alkylene
  • X1 and X2 are identical or different and are amino or amidino
  • Z1 and Z2 are identical or different and are 1 ,3-phenylene, 1 ,4-phenylene, 1 ,3-cyclohexylene or
  • n 1 or 2
  • U1 and U2 are identical are methylene [-CH 2 -], A1 is -0-B1 -A3-, -N(R2)-C(0)- or -0-C(0)-N(R2)-, A2 is -0-B2-A4-, -N(R3)-C(0)- or -0-C(0)-N(R3)-, A3 is -0-C(0)-N(R2)-, A4 is -0-C(0)-N(R3)-,
  • R2 and R3 are identical and are -CH 2 -C(0)OR4,
  • R4 is hydrogen, 1-4C-alkyl or benzyl
  • B1 and B2 are identical and are ethylene, K1 is -B3-Z1-B5-X1 , K2 is -B4-Z2-B6-X2,
  • B3 and B4 are identical and are methylene or ethylene
  • B5 and B6 are identical and are methylene
  • X1 and X2 are identical and are amino
  • Z1 and Z2 are identical and are 1 ,3-phenylene or 1 ,4-phenylene, and the salts of these compounds.
  • the compounds of the formula I are constructed from a large number of building blocks (M, A1 , A2, A3, A4, A5, A6, B1 , B2, B3, B4, B5, B6, X1 , X2, Y1, Y2, Z1 and Z2). In principle, they can be synthesized starting with any of these building blocks. If the compounds of the formula I are constructed largely symmetrically, it is favorable to start the synthesis with the central building block M, whereas in the case of predominantly asymmetrical compounds of the formula I a synthesis starting with one of the end groups K1 or K2 may be advantageous.
  • Suitable starting materials for synthesizing the compounds of the formula I according to the invention are, for example, 1 ,3-dihydoxybenzene, 1 ,3-dibromobenzene, 1 ,4-dibromobenzene, 2,5-dibromofurane, 3,4-dibromothiophen, 2,6-dibromopyridine, 2,5-dibromopyridine,
  • the compounds of the formula I can either be synthesized building block by building block, or by initially constructing relatively large fragments consisting of several individual building blocks, which can then be joined to give the complete molecule.
  • Ether bridges can be prepared, for example, by the method of Williamson.
  • ester bridges There is a large number of known methods for preparing ester bridges.
  • An example which may be mentioned here is the reaction of acids with alcohols, preferably using H 2 S0 4 or p-toluenesulfonic acid as catalyst; or with addition of a dehydrating agent, such as, for example, molecular sieve or a car- bodiimide.
  • a dehydrating agent such as, for example, molecular sieve or a car- bodiimide.
  • acyl chlorides with alcohols may be mentioned here.
  • Keto bridges can be introduced, for example, as a component of relatively large building blocks, such as, for example, carboxylic acid derivatives.
  • Carbamate bridges can be prepared, for example, by reacting chloroformates with amines.
  • the chlo- roformates for their part can be synthesized from alcohols and phosgene.
  • a further variant for constructing carbamate bridges is the addition of alcohols to isocyanates.
  • Carbamide bridges can be prepared, for example, by reacting isocyanates with amines.
  • reaction scheme 1 shows the preparation of some starting compounds.
  • reaction scheme 2 shows the preparation of an exemplary compound of formula I.
  • Other compounds of the formula I can be prepared analogously, or by using the abovementioned methods known per se to the person skilled in the art.
  • the N-oxidation is carried out in a manner which is likewise known to the person skilled in the art, for example using hydrogen peroxide in methanol or m-chloroperoxybenzoic acid in dichloromethane at room temperature.
  • Which reaction conditions are required in the particular case for carrying out the process is known to the person skilled in the art owing to his expert knowledge.
  • the isolation and purification of the substances according to the invention is carried out in a manner known per se, for example by distilling off the solvent under reduced pressure and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
  • Salts are obtained by dissolving the free compound in a suitable solvent (for example a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular-weight aliphatic alcohol, such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent for example a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular-weight aliphatic alcohol
  • Human tryptase is a serin protease which is the main protein in human mast cells. Tryptase comprises eight closely related enzymes ( ⁇ 1 , ⁇ 2, ⁇ 1a, ⁇ 1 b, ⁇ 2, ⁇ 3, mMCP-7-like-1 , mMCP-7-like-2; 85 to 99% sequence identity) (cf. Miller et al., J. Clin. Invest. 84 (1989) 1188-1195; Miller et al., J. Clin. Invest. 86 (1990) 864-870; Vanderslice et al., Proc. Natl.
  • tryptase Compared with other known serin proteases, such as, for example, trypsin or chymotrypsin, tryptase has some special properties (Schwartz et al., Methods Enzymol. 244, (1994), 88-100; G. H. Caughey, "Mast cell proteases in immunology and biology". Marcel Dekker, Inc., New York, 1995). Tryptase from human tissue has a noncovalently-linked tetrameric structure which has to be stabilized by heparin or other proteoglycanes to be proteolytically active.
  • tryptase is released when human mast cells are activated. Because of this, tryptase is thought to play a role in a number of disorders, in particular in allergic and inflammatory disorders, firstly because of the importance of the mast cells in such disorders and secondly since an increased tryptase concentration was observed in a number of disorders of this type.
  • tryptase is associated, inter alia, with the following diseases: acute and chronic (in particular inflammatory and allergen-induced) airway disorders of various origins (for example bronchitis, allergic bronchitis, bronchial asthma, COPD); interstitial lung disorders; disorders based on allergic reactions of the upper airways, (pharynx, nose) and the adjacent regions (for example paranasal sinuses, conjunctivae), such as, for example allergic conjunctivitis and allergic rhinitis; disorders of the arthritis type (for example rheumatoid arthritis); autoimmune disorders, such as multiple sclerosis; furthermore periodontitis, anaphylaxis, interstitial cystitis, dermatitis, psoriasis, sclerodermia/systemic sclerosis, inflammatory intestinal disorders (Crohn's disease, Ulcerative Colitis) and others.
  • acute and chronic airway disorders of various origins for example bronchitis, allergic
  • tryptase seems to be connected directly to the pathogenesis of asthma (Caughey, Am. J. Respir. Cell Mol. Biol. 16 (1997), 621-628; R. Tanaka, "The role of tryptase in allergic inflammation” in: Protease Inhibitors, IBC Library Series, 1979, Chapter 3.3.1-3.3.23).
  • a further subject of the invention relates to the compounds according to the invention for use in the treatment and/or prophylaxis of diseases, in particular the diseases mentioned.
  • the invention likewise relates to the use of the compounds according to the invention for preparing medicaments which are employed for the treatment and/or prophylaxis of the diseases mentioned.
  • Medicaments for the treatment and/or prophylaxis of the diseases mentioned, which contain one or more of the compounds according to the invention, are furthermore a subject of the invention.
  • the medicaments are prepared by processes which are known per se and familiar to the person skilled in the art.
  • the compounds according to the invention can be also administered by inhalation in the form of an aerosol; the aerosol particles of solid, liquid or mixed composition preferably having a diameter of 0.5 to 10 ⁇ m, advantagously of 2 to 6 ⁇ m.
  • Aerosol generation can be carried out, for example, by pressure-driven jet atomizers or ultrasonic atomizers, but advantageously by propellant- driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules.
  • the administration forms additionally contain the required excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
  • propellants e.g. Frigen in the case of metered aerosols
  • surface-active substances e.g. Frigen in the case of metered aerosols
  • emulsifiers emulsifiers
  • stabilizers emulsifiers
  • preservatives e.g., emulsifiers, stabilizers, preservatives
  • flavorings e.g. lactose in the case of powder inhalers
  • fillers e.g. lactose in the case of powder inhalers
  • the compounds according to the invention are in particular used in the form of those medicaments which are suitable for topical administration.
  • suitable pharmaceutical formulations which may be mentioned are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
  • the medicaments according to the invention are prepared by processes known per se.
  • the dosage of the active compounds in the case of systemic therapy is between 0.1 and 10 mg per kilogram per day.
  • the documented pathophysiological effects of mast cell tryptase are caused directly by the enzymatic activity of the protease. Accordingly, they are reduced or blocked by inhibitors which inhibit the enzymatic activity of the tryptase.
  • a suitable measure for the affinity of a reversible inhibitor to the target protease is the equilibrium dissociation constant K ; of the enzyme-inhibitor complex. This K ⁇ value can be determined via the effect of the inhibitor on the tryptase-induced cleavage of a chromogenic peptide-p-nitroanilide substrate or a fluorogenic peptide-aminomethylcoumarin substrate.
  • the dissociation constants for the tryptase-inhibitor complexes are determined under equilibrium conditions in accordance with the general proposals of Bieth (Bieth JG, Pathophysiological Interpretation of kinetic constants of protease inhibitors, Bull. Europ. Physiopath. Resp. 16:183-195, 1980) and the methods of Sommerhoff et al. (Sommerhoff CP et al., A Kazal-type inhibitor of human mast cell tryptase: Isolation from the medical leech Hirudo medicinalis, characterization, and sequence analysis, Biol. Chem. Hoppe-Seyler 375: 685-694, 1994).
  • Human tryptase is isolated from lung tissue or prepared recombinantly; the specific activity of the protease, determined by titration, is usually greater than 85% of the theoretical value.
  • heparin 0.1-50 ⁇ g/ml
  • constant amounts of the tryptase are incubated with increasing amounts of the inhibitors.
  • the remaining enzyme activity after addition of the peptide-p-nitroanilide substrate tos-Gly- Pro-arg-pNA is determined and the cleavage of the latter is monitored at 405 nm for 3 min.
  • the remaining enzymatic activity can also be determined using fluorogenic substrates.
  • the apparent dissociation constants K iapp (i.e. in the presence of substrate) are subsequently determined by adapting the enzyme rates to the general equation for reversible inhibitors (Morrison JF, Kinetics of the reversible inhibition of enzyme-catalyzed reactions by tight-binding inhibitors, Biochim. Biophys. Acta 185, 269-286, 1969) using non-linear regression:
  • ⁇ /o 1 - ⁇ E t +l t +K iapp -[(E t +l t +K iapp ) 2 -4E t l t ] 1/2 ⁇ /2E t
  • and V 0 are the rates in the presence and absence, respectively, of the inhibitor, and E t and l t are the tryptase and inhibitor concentrations, respectively.

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  • Chemical & Material Sciences (AREA)
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Abstract

L'invention concerne des composés de la formule I. Dans cette dernière, M, A1, A2, K1 et K2 ont des significations telles que décrites dans le descriptif et constituent de nouveaux inhibiteurs de la tryptase efficaces.
PCT/EP2002/002674 2001-03-15 2002-03-12 Inhibiteurs de la tryptase WO2002074732A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP01106540.6 2001-03-15
EP01106540 2001-03-15

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WO2002074732A2 true WO2002074732A2 (fr) 2002-09-26
WO2002074732A3 WO2002074732A3 (fr) 2003-10-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2305639A3 (fr) * 2005-04-14 2011-06-29 Novartis AG Composes organiques

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009297A1 (fr) * 1994-09-23 1996-03-28 Arris Pharmaceutical Corporation Compositions et procedes de traitement de maladies inflammatoires provoquees par les mastocytes
WO1998004537A1 (fr) * 1996-07-30 1998-02-05 Arris Pharmaceutical Corporation Nouveaux composes et compositions servant a traiter des maladies associees a l'activite de tryptase
DE19944066A1 (de) * 1999-09-14 2001-03-15 Byk Gulden Lomberg Chem Fab Inhibitoren der Tryptase
WO2001019809A1 (fr) * 1999-09-14 2001-03-22 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de la tryptase
WO2001046168A1 (fr) * 1999-12-20 2001-06-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de tryptase
WO2001046128A2 (fr) * 1999-12-20 2001-06-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de tryptase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009297A1 (fr) * 1994-09-23 1996-03-28 Arris Pharmaceutical Corporation Compositions et procedes de traitement de maladies inflammatoires provoquees par les mastocytes
WO1998004537A1 (fr) * 1996-07-30 1998-02-05 Arris Pharmaceutical Corporation Nouveaux composes et compositions servant a traiter des maladies associees a l'activite de tryptase
DE19944066A1 (de) * 1999-09-14 2001-03-15 Byk Gulden Lomberg Chem Fab Inhibitoren der Tryptase
WO2001019809A1 (fr) * 1999-09-14 2001-03-22 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de la tryptase
WO2001046168A1 (fr) * 1999-12-20 2001-06-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de tryptase
WO2001046128A2 (fr) * 1999-12-20 2001-06-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de tryptase

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2305639A3 (fr) * 2005-04-14 2011-06-29 Novartis AG Composes organiques

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