WO2013084199A1 - Boron heterocycles as new inhibitors of human neutrophil elastase - Google Patents

Boron heterocycles as new inhibitors of human neutrophil elastase Download PDF

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WO2013084199A1
WO2013084199A1 PCT/IB2012/057064 IB2012057064W WO2013084199A1 WO 2013084199 A1 WO2013084199 A1 WO 2013084199A1 IB 2012057064 W IB2012057064 W IB 2012057064W WO 2013084199 A1 WO2013084199 A1 WO 2013084199A1
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ring
optionally
heteroatom selected
sulphur
nitrogen
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PCT/IB2012/057064
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French (fr)
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Pedro Miguel PIMENTA GÓIS
Francesco MONTALBANO
Pedro Miguel SARAIVA DUARTE CAL
Marta Alexandra BOGALHO RODRIGUES DE CARVALHO
Lídia Maria DIOGO GONÇALVES
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Universidade De Lisboa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to the use of boron heterocycles as human neutrophil elastase (HNE) inhibitors.
  • HNE human neutrophil elastase
  • HNE human neutrophil elastase
  • HNE related diseases such as acute and chronic inflammatory diseases, lung fibrosis, pneumonia, acute respiratory distress, cystic fibrosis, pulmonary emphysema (including smoking induced emphysema) and chronic obstructive pulmonary disease (COPD) and is therefore applicable in both Pharmaceutical and Medical industries.
  • HNE related diseases such as acute and chronic inflammatory diseases, lung fibrosis, pneumonia, acute respiratory distress, cystic fibrosis, pulmonary emphysema (including smoking induced emphysema) and chronic obstructive pulmonary disease (COPD)
  • HNE Human neutrophil elastase
  • PMN polymorphonuclear neutrophils
  • 1 HNE is released from activated PMN and has been implicated in the pathogenesis of acute and chronic inflammatory diseases.1,2 HNE is believed to play a most important role in several pulmonary diseases such as: lung fibrosis, pneumonia, acute respiratory distress, cystic fibrosis, pulmonary emphysema
  • COPD chronic obstructive pulmonary disease
  • HNE l-proteinase inhibitor
  • l-antitrypsin l-antitrypsin
  • secretory leukocyte protease inhibitor l-proteinase inhibitor
  • SLPI elastase specific inhibitor - ESI - or skin-derived antileukoprotease - SKALP
  • elafin also named elastase specific inhibitor - ESI - or skin-derived antileukoprotease - SKALP
  • HNE is a valuable target and HNE inhibitors will not only protect the lungs from HNE- mediated tissue damage but also will control excessive inflammatory responses.16
  • HNE inhibition involves the nucleophilic attack of the serine residue to the inhibitor (an acylating agent for acyl-enzyme inhibitors) to form a tetrahedral intermediate which is stabilized by hydrogen bonding to the enzyme's backbone NH groups of the so-called oxyanion hole.17
  • this tetrahedral intermediate is stable enough it prevents the hydrolytic process and reversibly inhibits the enzyme transition state analogs.
  • acylating-enzyme inhibitors molecules such as: 2 -pyridin-3-yl-benzoxazinones (16-61 nM - IC50),18,19 2 -alkylthiothiazinone (3.31 ⁇ - IC50), 20 N-galloyl-4-alkylidene ⁇ -lactam (0.7 ⁇ - Ki)21 and the inhibitors derived from the natural 5 , 5-trans-fused cyclic lactone - containing euphane triterpenes (0.01 ⁇ - IC50)22 are notable examples of this class of inhibitors.
  • peptidyl trifluoromethyl ketones such as ICI- 200, 880 (0.2 nM - Ki) and FK706 (83 nM - IC50), 23, 24 pyrimidinone -keto-1, 3, 4-oxadiazole ONO-6818 (12.16 nM - Ki)25 are worth mentioned as HNE inhibitors.
  • scaffolds such as 2-pyridinyl-isothiazol-3 (2H) -one 1, 1- dioxides (0.081-23.4 ⁇ - IC50)26 are important examples of mechanism-based inhibitors of HNE.
  • boronic acids which are neutral planar trivalent compounds and isoelectronic with carbocations , were found to display very important biological properties namely as transition-state analog inhibitors.
  • aminoboronic acids were found to act as efficient inhibitors of thrombin, dipeptidyl peptidase inhibitors, proteasome inhibitors, prostate- specific antigen inhibitors, NS3 proteases or arginases .27- 29
  • Such tetravalent boron compounds, 30-40 in principle cannot act as transition-state analogs, although they have been successfully used as antifungal, antibacterial and antitumor activity .27-29
  • boronic acids against elastases there is no prior art relating to the HNE inhibitory activity of boronate heterocycles of the general formula (I) and (II) depicted in Figure 1.
  • HNE human neutrophil elastase
  • R 1 represents in compound ( I ) and ( II ) : H, C3 ⁇ 4, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, CH 2 Ar or CH 2 CH 3 Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
  • R 3 , R 5 , R 6 represents in compound (I) and (II) : H, CH 3 , C 1 -C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C 2 -C6 alkanoyl, C3 ⁇ 4Ar or C3 ⁇ 4CH 3 Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
  • R 4 represents in compound (I) and (II) : H, CH 3 , C 1 -C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C 2 -C6 alkanoyl, C3 ⁇ 4Ar or CH 2 C3 ⁇ 4Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, OH, OCH 3 , OCH 2 CH 3 , OCHCH 3 CH 3 , OCH 2 CHCH 3 CH 3 , OPh, CCH, CCPh, CN, NH 2 , NHR 1 or N R 2 R X in which the R 1 and R 2 group may be optionally a phenyl or a substituted phenyl, a 5 or 6 member azacyclic ring, CH
  • R represents in compound (I) and (II) : H, CH 3 , C 1 -C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C 2 -C6 alkanoyl, C3 ⁇ 4Ar or CH 2 C3 ⁇ 4Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
  • R 8 represents in compound (II) : H, CH 3 , C 1 -C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C 2 -C6 alkanoyl, C3 ⁇ 4Ar or CH 2 C3 ⁇ 4Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
  • X represents in compound (I) and (II) : A double bond with 0, or a simple bond with a H, CH 3 , C 1 -C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C 2 -C6 alkanoyl, C3 ⁇ 4Ar or CH 2 C3 ⁇ 4Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
  • HNE related diseases such as acute and chronic inflammatory diseases, lung fibrosis, pneumonia, acute respiratory distress, cystic fibrosis, pulmonary emphysema (including smoking induced emphysema) and chronic obstructive pulmonary disease (COPD) .
  • HNE related diseases such as acute and chronic inflammatory diseases, lung fibrosis, pneumonia, acute respiratory distress, cystic fibrosis, pulmonary emphysema (including smoking induced emphysema) and chronic obstructive pulmonary disease (COPD) .
  • COPD chronic obstructive pulmonary disease
  • Figure 1 General formula of boron heterocycles with human neutrophil elastase (HNE) inhibitory activity.
  • a round bottom flask equipped with a magnetic stirrer was charged with an amino acid or amino alcohol (2.0 eq.), salycilaldehyde (1.5 eq.) and distilled water (2.0 mL) .
  • This suspension was stirred at 90 °C for 1 hour, after which the boronic acid (0.41 mmol) was added.
  • the mixture was stirred at 90 °C for 20 h and the product was filtered and washed with water, hexane and was recovered with dichloromethane .
  • Fluorometric assays for the human neutrophil elastase (HNE) (Merck, Germany) inhibition activity were carried out in 200 yL assay buffer (0.1 M HEPES pH 7.5 at 25 ° C) containing 20 yL of 0.17 ⁇ HNE in assay buffer (stock solution 1.7 ⁇ in 0.05 M acetate buffer, pH 5.5), and 5 yL of each concentration of tested inhibitors.
  • HNE human neutrophil elastase
  • Reaction was initiated by the addition of 175 yL of fluorogenic substrate to final concentration of 200 yM (MeO-Suc-Ala- Ala-Pro-Val-AMC, Merck, Germany) and activity was monitored (excitation 380 nm; emission 460 nm) for 30 min, at 25°C on a Fluorescence Microplate Reader Tecan infinite M200

Abstract

The invention described herein provides a new family of human neutrophil elastase (HNE) inhibitors. These are boron heterocycles of the general formula shown in (I) and (II), wherein R1, R2, R3, R4, R5, R6, R7, R8 and X are as defined in the specification section as well as their isomers and racemates and their use as HNE inhibitors. The use of these compounds and also of the pharmaceutical compositions and medicaments containing them is useful in treating human HNE related diseases and is therefore applicable in both Pharmaceutical and Medical industries.

Description

DESCRIPTION
"BORON HETEROCYCLES AS NEW INHIBITORS OF HUMAN NEUTROPHIL
ELASTASE"
Field of the Invention
The present invention relates to the use of boron heterocycles as human neutrophil elastase (HNE) inhibitors.
Summary of the Invention
The invention described herein provides a new family of human neutrophil elastase (HNE) inhibitors. These are boron heterocycles of the general formula shown in Figure 1, wherein R1, R2, R3, R4, R5, R6, R7, R8 and X are as defined in the specification section below, as well as their isomers and racemates and their use as HNE inhibitors. The use of these compounds and also of pharmaceutical compositions and medicaments containing them is useful in treating HNE related diseases, such as acute and chronic inflammatory diseases, lung fibrosis, pneumonia, acute respiratory distress, cystic fibrosis, pulmonary emphysema (including smoking induced emphysema) and chronic obstructive pulmonary disease (COPD) and is therefore applicable in both Pharmaceutical and Medical industries.
State of the art
Human neutrophil elastase (HNE - EC 3.4.21.37), is a serine protease of the chymotrypsin superfamily that is stored in the primary azurophilic granules of polymorphonuclear neutrophils (PMN) . HNE comprises 218 amino acids and its molecular weight is 29-33 kDa . As a serine protease, its activity depends on a catalytic triad composed by aspartate, histidine, and serine residues. 1 HNE is released from activated PMN and has been implicated in the pathogenesis of acute and chronic inflammatory diseases.1,2 HNE is believed to play a most important role in several pulmonary diseases such as: lung fibrosis, pneumonia, acute respiratory distress, cystic fibrosis, pulmonary emphysema
(including smoking induced emphysema) and chronic obstructive pulmonary disease (COPD).3-12 Importantly, COPD, an escalating health problem, refers to a condition of inflammation and progressive deterioration of the structure of the lung as well as irreversible narrowing of the airways. The World Health Organization (WHO) estimates that 210 million people have COPD worldwide .13, 14
Usually, an interplay between HNE and its natural endogenous inhibitors, such as l-proteinase inhibitor (Al- PI, l-antitrypsin) , secretory leukocyte protease inhibitor
(SLPI), and elafin (also named elastase specific inhibitor - ESI - or skin-derived antileukoprotease - SKALP) , avoids the potential damaging effects of extracellular HNE.6, 15 Nevertheless, an imbalance between protease and antiprotease may lead to tissue damage. The excess of HNE resulting from this disproportion, hydrolyses elastin, the structural protein which gives the lungs their elasticity. Cleavage of other matrix proteins as well as inflammatory mediators, cell receptors, and lung surfactant is also potentiated by the excess of extracellular HNE. Furthermore, it may set off other proteases and induce the expression of neutrophil cytokines and chemokines leading to polymorphonuclear neutrophil-dominated airway inflammation. Hence, HNE is a valuable target and HNE inhibitors will not only protect the lungs from HNE- mediated tissue damage but also will control excessive inflammatory responses.16
HNE inhibition involves the nucleophilic attack of the serine residue to the inhibitor (an acylating agent for acyl-enzyme inhibitors) to form a tetrahedral intermediate which is stabilized by hydrogen bonding to the enzyme's backbone NH groups of the so-called oxyanion hole.17 When this tetrahedral intermediate is stable enough it prevents the hydrolytic process and reversibly inhibits the enzyme transition state analogs. Regarding the acylating-enzyme inhibitors molecules such as: 2 -pyridin-3-yl-benzoxazinones (16-61 nM - IC50),18,19 2 -alkylthiothiazinone (3.31 μΜ - IC50), 20 N-galloyl-4-alkylidene^-lactam (0.7 μΜ - Ki)21 and the inhibitors derived from the natural 5 , 5-trans-fused cyclic lactone - containing euphane triterpenes (0.01 μΜ - IC50)22 are notable examples of this class of inhibitors. Considering the family of transition state analogs, peptidyl trifluoromethyl ketones (TFMKs) such as ICI- 200, 880 (0.2 nM - Ki) and FK706 (83 nM - IC50), 23, 24 pyrimidinone -keto-1, 3, 4-oxadiazole ONO-6818 (12.16 nM - Ki)25 are worth mentioned as HNE inhibitors. Furthermore, scaffolds such as 2-pyridinyl-isothiazol-3 (2H) -one 1, 1- dioxides (0.081-23.4 μΜ - IC50)26 are important examples of mechanism-based inhibitors of HNE.
Boron compounds have played a significant role as synthetic building blocks. More recently, boronic acids, which are neutral planar trivalent compounds and isoelectronic with carbocations , were found to display very important biological properties namely as transition-state analog inhibitors. For example aminoboronic acids were found to act as efficient inhibitors of thrombin, dipeptidyl peptidase inhibitors, proteasome inhibitors, prostate- specific antigen inhibitors, NS3 proteases or arginases .27- 29 Such tetravalent boron compounds, 30-40 in principle, cannot act as transition-state analogs, although they have been successfully used as antifungal, antibacterial and antitumor activity .27-29 Despite the reported biological activity of boronic acids against elastases, there is no prior art relating to the HNE inhibitory activity of boronate heterocycles of the general formula (I) and (II) depicted in Figure 1. Based on the aforementioned, despite HNE has been identified as a therapeutic target for COPD more than 30 years ago, only Sivelestat (ONO-5046), an HNE inhibitor from Ono Pharmaceutical, has been approved for clinical use. Nevertheless, Sivelestat is only approved in Japan and its development in the USA terminated in 2003. Other inhibitors in pre-clinical or phase I trials were discontinued for various reasons. Hence, there is an urgent need for low-molecular-weight synthetic elastase inhibitors .
DESCRIPTION OF THE INVENTION
The invention described herein provides a new family of human neutrophil elastase (HNE) inhibitors. These are boron heterocycles of the following general formula:
Figure imgf000005_0001
According to the present invention, there is therefore a compound of the formula (I) -(II) wherein:
R1 represents in compound ( I ) and ( II ) : H, C¾, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, CH2Ar or CH2CH3Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur. R2 represents in compound ( I ) and ( II ) : H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, a vinyl group of the general formula CH=CHR in which the R represents a H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from 0, S and N, a vinyl group of the general formula CH=CHAr in which the Ar represents optionally a phenyl, a substituted phenyl ring, a heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, an Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a CI, Br or F substituted phenyl ring in the o- or p- or o- and p- positions, a naphthyl, a monocyclic or bicyclic heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur. Ar
R3, R5, R6, represents in compound (I) and (II) : H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, C¾Ar or C¾CH3Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
R4 represents in compound (I) and (II) : H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, C¾Ar or CH2C¾Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, OH, OCH3, OCH2CH3, OCHCH3CH3, OCH2CHCH3CH3, OPh, CCH, CCPh, CN, NH2, NHR1 or N R2RX in which the R1 and R2 group may be optionally a phenyl or a substituted phenyl, a 5 or 6 member azacyclic ring, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from 0, S and N. R represents in compound (I) and (II) : H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, C¾Ar or CH2C¾Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur. R8 represents in compound (II) : H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, C¾Ar or CH2C¾Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur. X represents in compound (I) and (II) : A double bond with 0, or a simple bond with a H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, C¾Ar or CH2C¾Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
The use of these compounds and also of pharmaceutical compositions and medicaments containing them is useful in treating HNE related diseases, such as acute and chronic inflammatory diseases, lung fibrosis, pneumonia, acute respiratory distress, cystic fibrosis, pulmonary emphysema (including smoking induced emphysema) and chronic obstructive pulmonary disease (COPD) .
Some embodiments of the present invention are further detailed below, which are not to be considered as limitative of the scope of this invention. BRIEF DESCRIPTION OF DRAWINGS
Figure 1. General formula of boron heterocycles with human neutrophil elastase (HNE) inhibitory activity.
Figure 2. Compound 1 - Example of a boron heterocycle
Figure 3. Compound 2 - Example of a boron heterocycle
Figure 4. Compound 3 - Example of a boron heterocycle
Figure 5. Compound 4 - Example of a boron heterocycle
Figure 6. Compound 5 - Example of a boron heterocycle
Figure 7. Compound 6 - Example of a boron heterocycle
Figure 8. Compound 7 - Example of a boron heterocycle
Figure 9. Compound 8 - Example of a boron heterocycle
Figure 10 . Compound 9 - - Example of a boron heterocycle
Figure 11 . Compound 10 - Example of a boron heterocycle
Figure 12 . Compound 11 - Example of a boron heterocycle
Figure 13 . Compound 12 - Example of a boron heterocycle
Figure 14 . Compound 13 - Example of a boron heterocycle
DETAILED DESCRIPTION OF THE INVENTION
Experimental procedure for the preparation of boron heterocycles :
A round bottom flask equipped with a magnetic stirrer was charged with an amino acid or amino alcohol (2.0 eq.), salycilaldehyde (1.5 eq.) and distilled water (2.0 mL) . This suspension was stirred at 90 °C for 1 hour, after which the boronic acid (0.41 mmol) was added. The mixture was stirred at 90 °C for 20 h and the product was filtered and washed with water, hexane and was recovered with dichloromethane .
Compound 1 was obtained in 50% after 20 h at 90 °C (0.067 g) ; 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 1.05 (dd, J = 12.9, 6.4 Hz, 6H, -CHCH2CH (C¾) 2) , 1.77 - 1.96 (m, 1H, -CHCH2CH-) , 2.03 - 2.27 (m, 2H, -NCHC¾-), 4.53 (td, J = 5.7, 2.3 Hz, 1H, -NCHCO-), 6.96 - 7.07 (m, 1H, Ar) , 7.16 (d, J = 8.4 Hz, 1H, Ar) , 7.21 - 7.35 (m, 3H, Ar) , 7.39 (dd, J = 7.5, 1.8 Hz, 2H, Ar) , 7.44 (dd, J = 7.8, 1.6 Hz, 1H, Ar) , 7.62 (td, J = 8.7, 7.4, 1.7 Hz, 1H, Ar) , 8.21 (d, J = 2.2 Hz, 1H, Ar) ; 13C-NMR (400MHz, CDC13, 25°C, TMS): δ 22.50, 22.93 ( -CHCH2 ( CH3) 2 ) , 25.16 ( -NCHCH2CH- ) , 37.16 (-NCHCH2-), 60.64 (-NCHCH2 -), 117.49, 120.27, 127.83, 128.43, 130.89, 131.65 (Ar) , 139.02 ( -NCHAr- ) , 156.70, 159.70 (Ar, quaternary), 170.79 (-CHCOO-) . (Figure 2)
Compound 2 was obtained in 52 % after 20 h at 90 °C (0.059 g) ; 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 1.73 (d, J = 6.8 Hz, 1H, -CHC¾) , 4.62 (qd, J = 6.7, 2.3 Hz, 1H, -CHC¾) , 6.93 - 7.08 (m, 1H, Ar) , 7.16 (d, J = 8.4 Hz, 1H, Ar) , 7.20 - 7.33 (m, 2H, Ar) , 7.40 (dd, J = 7.5, 1.7 Hz, 1H, Ar) , 7.45 (dd, J = 7.8, 1.6 Hz, 1H, Ar) , 7.55 - 7.71 (m, 1H, Ar) , 8.17 (d, J = 2.2 Hz, 1H, Ar) ; 13C-NMR (400MHz, CDC13,
25°C, TMS): δ 12.98 (-CHCH3), 58.59 (-NCHCH3-), 117.30, 120.22, 120.35, 125.83, 127.83, 128.48, 130.74, 131.60, 139.07 (Ar) , 156.61 (Ar, quaternary), 159.79 (ArCHN-) , 170.66 (-CHCOO-) . (Figure 3)
Compound 3 was obtained in 86"6 after 20 h at 90 °C (0.125 g) ; 1H-NMR (400 MHz, CDC13, 25°C, TMS): d 2.71 (t, 1H, JH: 13.2 Hz, -CHC¾Ph) , 3.41 (dd, 1H, JH: 3.6, 14.0 Hz, -CHC¾Ph) , 4.34 (dd, 1H, JH: 3.6 Hz, 12.4, -NCHCH2-) , 6.87- 6.95 (m, 3H, Ar) , 7.02-7.05 (m, 1H, Ar) , 7.11- 7.16 (m, 2H, Ar) , 7.27-7.34 (m, 6H, Ar) , 7.43-7.55 (m, 3H, Ar) ; 13C-NMR
(400 MHz, CDCI3, 25°C, TMS): δ 37.73 (-CHCH2Ph), 66.92 (-NCHCO-), 117.57, 120.19, 120.32, 127.79, 127.90, 128.58, 129.16, 129.21, 130.55, 131.45, 135.11, 139.04 (Ar) , 159.95 (-NCHAr-), 160.43 (Ar, quaternary), 170.22 (-CHCOO-) . HMRS (EI): m/z calcd [M+1H] 356.1458, found [M+1H] 356.1466. (Figure 4)
Compound 4 was obtained in 80 % after 20 h at 90 °C (0.122 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 2.68 (t, 1H, JH: 13.2 Hz, -CHC¾Ph) , 3.45 (dd, 1H, JH: 3.4, 13.8 Hz, -CHC¾Ph) , 4.36 (dd, 1H, JH: 3.2, 12.4 Hz, -NCHCO-), 6.80
- 7.71 (m, 14H, Ar) ; 13C-NMR (400 MHz, CDC13, 25°C, TMS): δ 37.79 (-CHCH2Ph), 66.87 (-NCHCH2-), 114.74, 114.94, 117.47, 120.32, 120.38, 127.91, 129.16, 129.24, 131.53, 132.34, 132.41, 134.97, 139.23 (Ar) , 159.84 (Ar, quaternary), 160.56 (Ar, quaternary), 170.13 (-CHCOO-) . (Figure 5)
Compound 5 was obtained in 31 % after 20 h at 90 °C (0.048 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 2.72 (t, 1H, JH: 13.0 Hz, -CHC¾Ph) , 3.42 (dd, 1H, JH: 3.2, 13.6 Hz, -CHC¾Ph) , 3.81 (s, 3H, -ArOC¾) , 4.34 (dd, 1H, JH: 3.2, 12.4 Hz, -NCHCO-), 6.80 - 7.35 (m, 14H, Ar) ; 13C-NMR (400 MHz, CDCI3, 25°C, TMS): δ 37.87 (-CHCH2Ph), 55.04 (-ArOCH3), 66.82 (-NCHCO-), 113.42, 117.55, 120.15, 120.27, 127.80, 129.16, 129.28, 131.48, 131.96, 135.14, 138,92 (Ar) , 159.94 (ArCHN-), 159.98, 160.22 (Ar, quaternary), 170.42 (-CHCOO- ) . (Figure 6)
Compound 6 was obtained in 74 % after 20 h at 90 °C (0.111 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 2.34 (s, 3H, -ArC¾) , 2.73 (t, 1H, JH: 12.0 Hz, -CHC¾Ph) , 3.42 (dd, 1H, JH: 4.0, 14.0 Hz, -CHC¾Ph) , 4.35 (dd, 1H, JH: 4.0, 12.0 Hz, -NCHCO-), 6.91 (t, 1H, JH: 8.0 Hz, Ar) , 6.99 - 7.04 (m, 3H, Ar) , 7.12 - 7.16 (m, 4H, Ar) , 7.28 - 7.38 (m, 5H, Ar) , 7.50
- 7.56 (m, 1H, Ar) ; 13C-NMR (400 MHz, CDC13, 25°C, TMS): δ 21.44 ( -Ar H3) , 37.78 (-CHCH2Ph), 66.90 (-NCHCO-), 117.62, 120.14, 120.32, 127.80, 128.67, 129.16, 129.28, 130.61, 131.46, 135.21, 138.19, 138.94 (Ar) , 159.94 (Ar, quaternary), 160.35 (ArCHN-) , 170.35 (-CHCOO-) . (Figure 7)
Compound 7 was obtained in 63 % after 20 h at 90 °C (0.095 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 2.35 (s, 3H, -ArC¾) , 2.70 (t, 1H, JH: 12.0 Hz, -CHC¾Ph) , 3.41 (dd, 1H, JH: 2.0, 14.0 Hz, -CHC¾Ph) , 4.34 (dd, 1H, JH: 4.0, 12.0 Hz, -NCHCO-), 6.73 (d, 1H, JH: 8.0 Hz, Ar) , 6.85 (s, 1H, Ar) , 6.97 - 7.03 (m, 3H, Ar) , 7.12 (s, 1H, Ar) , 7.28 - 7.38 (m, 6H, Ar) , 7.45 - 7.47 (m, 2H, Ar) ; 13C-NMR (400 MHz, CDC13, 25°C, TMS): δ 22.50 ( -Ar H3) , 37.75 (-CHCH2Ph), 66.75 (-NCHCO-), 115.41, 120.38, 121.74, 127.74, 127.88, 128.48, 129.14, 129.24, 130.58, 131.23, 135.28 (Ar) , 151.41 (Ar, quaternary), 159.95 (Ar, quaternary), 159.99 (ArCHN-), 170.58 (-CHCOO-) . (Figure 8)
Compound 8 was obtained in 88 "6 after 20 h at 90 °C (0.133 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 2.69 (t, 1H, JH: 13.0 Hz, -CHC¾Ph) , 3.39 (dd, 1H, JH: 3.6, 14.0 Hz, -CHC¾Ph) , 3.84 (s, 3H, -ArOC¾) , 4.31 (dd, 1H, JH: 3.2, 12.4 Hz, -NCHCO-), 6.45 - 6.50 (m, 2H, Ar) , 6.97 - 7.09 (m, 4H, Ar) , 7.28 - 7.48 (m, 6H, Ar) , 7.49-7.50 (m, 2H, Ar) ;
13C-NMR (400 MHz, CDC13, 25°C, TMS): δ 37.78 (-CHCH2Ph), 55.87 (-ArOCH3), 66.54 (-NCHCO-), 102.62, 110.12, 111.47, 127.65, 127.88, 128.42, 129.10, 129.24, 130.57, 132.88, 135.47 (Ar) , 158.98 (ArCHN-), 162.65 (Ar, quaternary), 168.80 (Ar, quaternary), 170.91 (-CHCOO-) . (Figure 9)
Compound 9 was obtained in 78 % after 20 h at 90 °C (0.125 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 2.73 (t, 1H, JH: 13.0 Hz, -CHC¾Ph) , 3.44 (dd, 1H. JH: 3.6, 14.0 Hz, -CHC¾Ph) , 3.85 (s, 3H, -ArOC¾) , 4.31 (dd, 1H, JH: 3.4, 12.2 Hz, -NCHCO-), 6.47 - 6.52 (m, 2H, Ar) , 6.95 - 7.04 (m, 5H, Ar) , 7.28 - 7.40 (m, 5H, Ar) ; 1JC-NMR (400 MHz, CDC13, 25°C, TMS) : δ 38.22 (-CHCH2Ph), 55.89 (-ArOCH3), 66.02 (-NCHCO-), 102.72, 110.19, 111.50, 125.71, 127.70, 127.75, 129.11, 129.34, 129.80, 132.82, 135.32 (Ar) , 158.24 (ArCHN- ), 162.34 (Ar, quaternary), 168.70 (Ar, quaternary), 171.05 (-CHCOO-) . HMRS (EI): m/ z calcd. [M+1H] 392.1128, found [M+1H] 392.1138. (Figure 10)
Compound 10 was obtained in 50 % after 20 h at 90 °C (0.08 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 2.54 (dd, J = 14.1, 12.3 Hz, 1H, -CHC¾Ph) , 3.23 (dd, J = 14.2, 3.0 Hz, 1H, -CHC¾Ph) , 3.83 (s, 3H, -OCH3) , 4.32 (dd, J = 12.2, 3.1 Hz, 1H, -NCHCO-), 6.39 - 6.46 (m, 2H, Ar) , 7.07 - 7.39 (m, 6H, Ar) , 7.61 (dd, J = 1.9, 0.9 Hz, 1H, Ar) , 7.68 (dd, J = 7.5, 1.7 Hz, 1H, Ar) ; 13C-NMR (400 MHz, CDC13, 25°C, TMS): δ 37.82 (-CHCH2Ph), 55.89 (-OCH3), 66.49 (-NCHCO-) , 102.60, 110.27, 114.76, 127.73, 129.15, 129.5, 132.34, 132.89, 135.32 (Ar) , 158.99 (Ar, quaternary), 162.57 (-CHCOO-) . (Figure 11)
Compound 11 was obtained in 66 % after 20 h at 90 °C (0.12 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 2.59 - 2.69 (m, 1H, - CHC¾Ph) , 3.40 (dd, 1H, JH: 13.8, 3.2 Hz, -CHC¾Ph) , 3.84 (s, 3H, -OC¾) , 4.34 (dd, 1H, JH: 12.3, 3.3 Hz, -NCHCO-), 6.17 - 6.51 (m, 2H, Ar) , 6.92 - 7.07 (m, 3H, Ar) , 7.19 - 7.50 (m, 7H, Ar) ; 13C-NMR (400 MHz, CDC13, 25°C, TMS): δ 38.1 (-CHCH2Ph), 56.2 (-OCH3), 66.8 (-NCHCO-), 103.0, 110.7, 111.7, 123.1, 129.5, 131.3, 132.7, 133.3, 135.6 (Ar) , 159.5 (Ar, quaternary), 162.8 (Ar, quaternary), 169.4 (Ar, quaternary), 169.3 (-CHCOO-) . (Figure 12)
Compound 12 was obtained in 50 % after 20 h at 90 °C (0.09 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 2.54 (dd, J = 14.1, 12.4 Hz, 4H, -CHC¾Ph) , 3.24 (dd, J = 14.1, 2.9 Hz, 5H, -CHC¾Ph) , 3.84 (s, 3H, -OCH3) , 4.30 (dd, 1H, JH: 12.3, 3.3 Hz, -NCHCO-), 6.43 - 6.46 (m, 2H, Ar) , 7.07 - 7.30 (m, 3H, Ar) , 7.28 - 7.40 (m, 5H, Ar) , 7.61 (dd, J = 7.9, 1.0 Hz, 1H, Ar) , 7.70 (dd, J = 7.5, 1.7 Hz, 1H, Ar) ; 13C-NMR (400 MHz, CDC13, 25°C, TMS): δ 37.26 (-CHCH2Ph), 55.9 (-OCH3), 68.38 (-NCHCO-), 101.78, 110.33, 112.6, 126.8, 127.8, 129.0, 129.3, 129.86, 133.0, 134.2, 133.5, 135.6, 161.7 (Ar) , 169.41 (Ar, quaternary), 162.8 (Ar, quaternary), 169.7 (Ar, quaternary), 170.4 (-CHCOO-) . (Figure 13)
Compound 13 was obtained in 66 % after 20 h at 90 °C (0.111 g) , 1H-NMR (400 MHz, CDC13, 25°C, TMS): δ 3.08 - 3.18 (m, 1H, - CHC¾Ph) , 3.55 (dt, 1H, JH: 8.6, 4.3 Hz, -CHC¾Ph) , 3.85 (s, 3H, -OC¾) , 4.34 (dd, 1H, JH: 11.9, 3.7 Hz, -NCHCO-), 6.71 - 7.46 (m, 16H); 13C-NMR (400 MHz, CDC13, 25°C, TMS): δ 38.8 (-CHCH2Ph) , 56.2 (-OCH3), 66.0 (-NCHCO- ), 103.0, 110.3, 112.0, 126.8, 127.8, 128.1, 128.7, 129.5, 129.7, 133.2, 135.7, 138.9, 158.6 (Ar, quaternary), 162.8 (Ar, quaternary), 168.9 (Ar, quaternary), 171.4 (-CHCOO-) . (Figure 14)
Human neutrophil elastase activity with fluorogenic peptide substrate
Fluorometric assays for the human neutrophil elastase (HNE) (Merck, Germany) inhibition activity were carried out in 200 yL assay buffer (0.1 M HEPES pH 7.5 at 25 °C) containing 20 yL of 0.17 μΜ HNE in assay buffer (stock solution 1.7 μΜ in 0.05 M acetate buffer, pH 5.5), and 5 yL of each concentration of tested inhibitors. Reaction was initiated by the addition of 175 yL of fluorogenic substrate to final concentration of 200 yM (MeO-Suc-Ala- Ala-Pro-Val-AMC, Merck, Germany) and activity was monitored (excitation 380 nm; emission 460 nm) for 30 min, at 25°C on a Fluorescence Microplate Reader Tecan infinite M200
(Tecan, Switzerland) . The Km of this substrate of HNE was previously determined to be 185 μΜ (data not shown) . For all assays, saturated substrate concentration was used, throughout, in order to obtain linear fluorescence curves. Inhibitors stock solutions were prepared in DMSO, and serial dilutions were made in DMSO. Controls were performed using enzyme alone, substrate alone, enzyme with DMSO and a positive control (MeOSuc-Ala-Ala-Pro-Ala-CMK, Calbiochem, Germany) . By computing the log of inhibitors concentrations versus the percentage of activity and using the GrafPad program the IC50 values were determined by non-linear regression analysis. Assays were performed in triplicate and data presented as the mean and the standard deviation.
(Table 1) :
Table 1. HNE assays with several boron heterocycles , in which A= IC50 (μΜ) , B= SD, C(F)= Compound ( Figure )
C (F) A B
1 (2) 90.99 1.1
2 (3) >100 -
3 (4) 20.27 1.5
4 (5) 16.06 1.7
5 (6) 40.03 1.5
6 (7) 19.61 1.9
7 (8) 15.39 1.3
8 (9) 9.3 1.3
9 (10) 19.05 1.6
10 (11) 17.0 4.7
11 (12) 2.3 0.2
12 (13) 2.0 0.6
13 (14) 54.3 13.2 The boron heterocycles of the general formula (I) and (II) shown in fig. 1, wherein R1, R2, R3, R4, R5, R6, R7, R8 and X are as defined in the specification section as well as their isomers and racemates, were tested in the above described assay and the compounds of the examples 3,4 and 6-12 gave IC50 values for inhibition of human neutrophil elastase of less than 30 μΜ (micromolar) , indicating that this family of compounds is expected to have therapeutic utility .
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Claims

1. Boron heterocyclic compounds of the general formula (I) and (II), isomers and racemates thereof characterized in that they are for use as inhibitors of human neutrophil elastase: HNE, in the treatment of HNE related diseases,
Figure imgf000019_0001
wherein :
R1 represents in compound (I) and (II) : H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, CH2Ar or CH2CH3Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R2 represents in compound (I) and (II) : H, CH3, Ci-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, a vinyl group of the general formula CH=CHR in which the R represents a H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from 0, S and N, a vinyl group of the general formula CH=CHAr in which the Ar represents optionally a phenyl, a substituted phenyl ring, a heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, an Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a CI, Br or F substituted phenyl ring in the o- or p- or o- and p- positions, a naphthyl, a monocyclic or bicyclic heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R3, R5, R6, represents in compound
(I) and (II) : H, C¾, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, CH2Ar or CH2CH3Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R4 represents in compound (I) and (II) : H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, C¾Ar or CH2C¾Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, OH, OCH3 , OCH2CH3 , OCHCH3CH3 , OCH2CHCH3CH3 , OPh, CCH, CCPh, CN, NH2, NHR1 or N R2RX in which the R1 and R2 group may be optionally a phenyl or a substituted phenyl, a 5 or 6 member azacyclic ring, CH3 , C1-C6 alkyl which optionally may incorporate one further heteroatom selected from 0, S and N; R7 represents in compound
(I) and (II) : H, C¾, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, CH2Ar or CH2CH3Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R8 represents in compound (II) : H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, C¾Ar or CH2C¾Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur; X represents in compound (I) and (II) : A double bond with 0, or a simple bond with a H, CH3, C1-C6 alkyl which optionally may incorporate one further heteroatom selected from nitrogen, oxygen and sulphur, formyl or C2-C6 alkanoyl, C¾Ar or CH2C¾Ar in which the Ar group may be optionally a phenyl, a substituted phenyl ring, a naphthyl, a heteroaromatic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
2. Pharmaceutical composition characterized in that it comprises at least one compound according to Claim 1, and/or a pharmaceutically suitable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluents or carriers.
3. Compound of the general formula (I) and (II) or a pharmaceutically suitable salt thereof, according to claim 1 characterized in that it is for use in the manufacture of a medicament for the treatment of human HNE related diseases or conditions.
4. Compound of the general formula (I) and (II) or a pharmaceutically suitable salt thereof according to claim 1 characterized in that it is for use in the manufacture of a medicament for the treatment of lung fibrosis, pneumonia, acute respiratory distress, cystic fibrosis, pulmonary emphysema, including smoking induced emphysema, bronchietasis, bronchitis including chronic bronchitis, and obstructive pulmonary disease, COPD.
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