WO2012004554A1 - Aldehyde compounds as inhibitors of dust mite group 1 peptidase allergen and their use - Google Patents

Aldehyde compounds as inhibitors of dust mite group 1 peptidase allergen and their use Download PDF

Info

Publication number
WO2012004554A1
WO2012004554A1 PCT/GB2011/001011 GB2011001011W WO2012004554A1 WO 2012004554 A1 WO2012004554 A1 WO 2012004554A1 GB 2011001011 W GB2011001011 W GB 2011001011W WO 2012004554 A1 WO2012004554 A1 WO 2012004554A1
Authority
WO
WIPO (PCT)
Prior art keywords
independently
compound according
asthma
present
optionally substituted
Prior art date
Application number
PCT/GB2011/001011
Other languages
French (fr)
Inventor
Clive Robinson
Jihui Zhang
David Ronald Garrod
Trevor Robert Perrior
Gary Karl Newton
Kerry Jenkins
Mark Richard Stewart
Meriel Ruth KIMBERLEY
Original Assignee
St George's Hospital Medical School
The University Of Manchester
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by St George's Hospital Medical School, The University Of Manchester filed Critical St George's Hospital Medical School
Publication of WO2012004554A1 publication Critical patent/WO2012004554A1/en

Links

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
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aldehyde compounds (for convenience, collectively referred to herein as "ALD compounds"), which, inter alia, inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ).
  • ALD compounds aldehyde compounds
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1 .
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit a dust mite Group 1 peptidase allergen, and in the treatment of diseases and disorders that are mediated by a dust mite Group 1 peptidase allergen; that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen; asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition which is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.
  • Allergic diseases such as asthma, rhinitis, conjunctivitis and eczema
  • asthma rhinitis, conjunctivitis and eczema
  • allergens Numerous sources of allergen exist, but those associated with domestic environments are especially important as disease triggers because people are exposed to them for long periods.
  • domestic allergens those derived from house dust mites (HD ) are globally the most significant cause of allergic disease. These mites are found abundantly in homes, in workplaces, in entertainment venues, and in public and private transport vehicles.
  • the allergens from the different species can be categorized into distinct groups which show immunological
  • the Group 1 allergens e.g., Der p 1 , Der f 1 , Eur m 1
  • the normal function of these cysteine peptidases in mites is as digestive enzymes that have the capability of digesting the resilient structural proteins in dried flakes of exfoliated skin which form a significant component of the HDM diet.
  • the degree of amino acid sequence conservation in HDM Group 1 cysteine peptidase allergens (>90%) is such that they may be regarded as functionally identical and, for drug discovery purposes, a single therapeutic target.
  • HDM house dust mite
  • pharmacological allergen inactivation that would mimic the effects of physical allergen avoidance. It is envisaged that the optimum means to achieve this objective would be to treat patients with such inhibitors, either topically or systemically.
  • One advantage of this approach is that pharmacological allergen inactivation would travel with the person being treated (i.e., it would be "portable") to achieve the benefits of continuous allergen avoidance, something which is not achievable with physical allergen avoidance measures.
  • inhibitors of Group 1 peptidase allergens would have additional value as acaricides applied as environmental treatments. By inactivating key enzymes involved in the digestion of food by HDM, such inhibitors would deprive mites of a source of nutrition causing them to fail to thrive. Allergens and peptidase activity
  • the first is the demonstration that the proteolytic activity of a small cadre of enzymatic allergens is vital to allergic sensitization via the airways.
  • the second is the ability of peptidases is to drive allergic sensitization to by-stander allergens that lack proteolytic activity.
  • HDM peptidase allergens therefore exert significant effects that are independent of IgE, but which have an essential bearing on IgE sensitization and allergic responses (King et al., 1998; Asokananthan et al., 2002). These actions serve to promote sensitization to the inciting peptidase allergen but, as described above, because the effects of the general mechanisms are essentially allergen non-specific, sensitization to non-enzymatic bystander allergens also occurs (Stewart et al., 2003; Wan et al., 1999).
  • Dendritic cells are the primary antigen presenting cells of the respiratory tract (Holt et al., 1990; Holt, 2002; Huh et al., 2003; Lambrecht et al conflict 2003a; Lambrecht et al., 2002; Lambrecht et al., 2003b).
  • the probability of contact with antigens must be increased (Lambrecht et al., 2003b).
  • This essential step in the detection of allergen is facilitated by the cysteine peptidase activity of Group 1 mite allergens which cleaves the transmembrane adhesion proteins of epithelial tight junctions, facilitating paracellular delivery of any allergen to dendritic cells (Wan et al., 1999; Wan et al., 2000; Winton et al., 1998).
  • Peptidase allergens are thought to contribute to innate immunity and activate a variety of cells by numerous IgE-independent mechanisms. Signalling pathways activated by cleavage of tethered ligand receptors on epithelial cells is one such mechanism contributing to the chronic release of GM-CSF and IL-6.
  • cytokines are present in increased amounts in the airways in allergic asthma and rhinitis (Broide et al., 1992; Fahy et al., 1995; Muraguchi et al., 1988; Vercelli., 1989). They promote a Th2 allergic bias via several actions. For example, IL-6 is essential to B cell maturation and in the
  • GM-CSF generates signals that cause dendritic cells to migrate from the airway epithelium to present captured antigens at regional lymph nodes (Stick et al., 2003). Proteolytic activity that cleaves tethered ligand receptors is thus associated with a chain of events central to both the initiation of allergic sensitization and its maintenance. Peptidase allergens activate mast cells by IgE-independent mechanisms and it follows, therefore, that a contribution to the acute bronchoconstriction resulting from allergen challenge must be due to this peptidase-dependent activation. This suggests that inhibitors of Group 1 peptidase allergens should attenuate acute allergic bronchoconstriction. Other
  • IgE-independent mechanisms involve a cleavage of cytokine and IgE receptors that are associated with an augmentation of allergy (Ghaemmaghami et al., 2002), cleavage of antipeptidase defences (which may already be defective in allergy) and cleavage of other protective factors such as surfactant proteins (Deb et al., 2007).
  • peptidase allergens as a target in allergy is demonstrated by the ease and directness with which they evoke IgE sensitization and by studies with generic inhibitors of cysteine peptidases in experimental animals.
  • chromosome 5q32 LETK1 e.g., chromosome 5q32 LETK1 , chromosome 7 PAI-I, chromosome 1 1 C1 esterase inhibitor, chromosome 14 serpin cluster, chromosome 18q21
  • This recent evidence supplements functional associations between allergy and protease inhibitor deficiency that have accrued over the past 25 years (Rudolph et al., 1978; Hyde et al., 1979; Eden et al., 2003; Sigsgaard et al., 2000).
  • Figure 1 is a bar graph showing the magnitude of the acute bronchoconstrictor response to house dust mite allergen following Challenge 1 (left) and Challenge 2 (right).
  • the response to Challenge 2 is expressed as a percentage of the magnitude of the mean response following Challenge 1 (data for challenge 2 shown as mean and standard error of the mean).
  • Figure 2 is a bar graph showing the percentage inhibition of the control acute
  • bronchoconstrictor response to house dust mite allergen (Challenge 1 ) following a subsequent allergen challenge (Challenge 2) administered 15, 30 and 60 minutes after treatment with compound ALD-035 (data reported as mean and standard error of the mean).
  • aldehyde compounds for convenience, collectively referred to herein as "ALD compounds"
  • ALD compounds aldehyde compounds
  • compositions e.g., a pharmaceutical composition
  • a pharmaceutical composition comprising an ALD compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • a method of preparing a composition comprising the step of admixing an ALD compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the present invention pertains to a method of inhibiting a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ), in vitro or in vivo, comprising contacting a dust mite Group 1 peptidase allergen with an effective amount of an ALD compound, as described herein.
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1
  • Another aspect of the present invention pertains to a method of inhibiting a dust mite Group 1 peptidase allergen in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an ALD compound, as described herein.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an ALD compound, as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to an ALD compound as described herein for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of an ALD compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the treatment is treatment of a disease or condition that is mediated by a dust mite Group 1 peptidase allergen.
  • the treatment is treatment of a disease or condition that is ameliorated by the inhibition of a dust mite Group 1 peptidase allergen.
  • the treatment is treatment of: asthma, for example, atopic asthma; allergic asthma; atopic bronchial IgE-mediated asthma; bronchial asthma; extrinsic asthma; allergen-induced asthma; allergic asthma exacerbated by respiratory virus infection; infective asthma; infective asthma caused by bacterial infection; infective asthma caused by fungal infection; infective asthma caused by protozoal infection; or infective asthma caused by viral infection.
  • the treatment is treatment of: bronchial hyperreactivity associated with asthma; or bronchial hyperresponsiveness associated with asthma.
  • the treatment is treatment of: airway remodelling associated with an allergic lung disease, for example, airway remodelling associated with asthma.
  • the treatment is treatment of: asthma co-presented with a chronic obstructive lung disease, for example, asthma co-presented with emphysema; or asthma co-presented with chronic bronchitis.
  • the treatment is treatment of: rhinitis, for example, allergic rhinitis; perennial rhinitis; persistent rhinitis; or IgE-mediated rhinitis.
  • rhinitis for example, allergic rhinitis; perennial rhinitis; persistent rhinitis; or IgE-mediated rhinitis.
  • the treatment is treatment of: allergic conjunctivitis, including, for example, IgE-mediated conjunctivitis.
  • the treatment is treatment of: atopic dermatitis.
  • the treatment is treatment of: an allergic condition which is triggered by dust mites.
  • the treatment is treatment of: an allergic condition which is triggered by a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1).
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1.
  • the treatment is treatment of: canine atopy.
  • the treatment further comprises treatment with one or more additional therapeutic agents, for example, one or more additional therapeutic agents selected from agents used, or likely to be used, in the treatment of a respiratory disease.
  • Another aspect of the present invention pertains to an ALD compound, as described herein, for use as an acaricide.
  • Another aspect of the present invention pertains to a composition comprising an ALD compound, as described herein, for use as an acaricide. Another aspect of the present invention pertains to an acaricide composition comprising an ALD compound, as described herein.
  • Another aspect of the present invention pertains to the use of an ALD compound, as described herein, as an acaricide.
  • Another aspect of the present invention pertains a method of killing mites (e.g., dust mites), comprising exposing said mites to an effective amount of an ALD compound, as described herein.
  • mites e.g., dust mites
  • Another aspect of the present invention pertains a method of controlling (e.g., limiting) a mite (e.g., dust mite) population comprising exposing mites to an effective amount of an ALD compound, as described herein.
  • a kit comprising (a) an ALD
  • ALD compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to an ALD compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • one aspect of the present invention pertains to compounds selected from compounds of the following formula, and salts, hydrates, and solvates thereof
  • R 1 , R 2 , R 4 , R 7 , R 8 , and R 10 are as defined herein (for convenience, collectively referred to herein as "ALD compounds"):
  • the carbon atom to which they are attached may be chiral, and if so, may independently be in the (R) or (S) configuration. Unless otherwise indicated, it is intended that both configurations are encompassed. In a preferred embodiment, the configuration is (S).
  • the carbon atom to which it is attached may be chiral, and if so, may independently be in the (R) or (S) configuration. Unless otherwise indicated, it is intended that both configurations are encompassed.
  • the configuration is (S).
  • the carbon atom to which they are attached may be chiral, and if so, may independently be in the (R) or (S) configuration. Unless otherwise indicated, it is intended that both configuations are encompassed.
  • the compound may have one or two, or three chiral centres, giving rise to enantiomers or diastereoisomers. Unless otherwise indicated, it is intended that all such enantiomers and diastereoisomers are encompassed.
  • -R 1 is independently -H or -R 1A ;
  • -R 1A is independently saturated aliphatic Ci-ealk l, phenyl, or benzyl, and is optionally substituted;
  • -R 2 is independently -H or -R 2 *;
  • -R 2 * is independently saturated aliphatic d. 3 alkyl, and is optionally substituted; or -R 1 and -R 2 , taken together with the carbon atom to which they are attached, form a saturated C 3 . 7 cycloalkyl ring or a saturated C 3 . 7 heterocyclic ring, which is optionally substituted;
  • -R 4 is independently -H or -R 4A ;
  • -R 4A is independently saturated aliphatic Ci- 3 alkyl
  • -R 7 is independently -H, -R 7A , or -R 7B ;
  • -R 7A is independently saturated aliphatic Ci- 6 alkyl, and is optionally substituted;
  • -R 7B is independently -L 7B1 -R 7BB , -R 7BB , -L 7B2 -0-R 7BB , or -
  • -R 7BB is independently -R 7BB1 , -R 7BB2 , -R 7BB3 , or -R 7SB4 ;
  • -R 7BB1 is independently phenyl or naphthyl, and is optionally substituted;
  • -R 7BB2 is independently C 5 -ioheteroaryl, and is optionally substituted;
  • R 7BB3 is independently C 3 . 7 cycloalkyl, and is optionally substituted, or is optionally fused to a benzene ring;
  • R 7BB4 is independently saturated bridged C 5 .i 0 cycloalkyl, and is optionally substituted;
  • -R 8 is independently -H or -R 8A ;
  • -R 8A is independently saturated aliphatic Chalky!, and is optionally substituted; or -R 7 and -R 8 , taken together with the carbon atom to which they are attached, form a saturated C 3 . 7 cycloalkyl ring, a saturated bridged C 5 .i 0 cycloalkyl ring, or a non-aromatic C 3 . 7 heterocyclic ring, which is optionally substituted;
  • -R 10 is independently -R 10A , -R 10B , -R 10C , or -R 10D ;
  • -R 0A is independently phenyl or naphthyl, and is optionally substituted;
  • -R 10B is independently C 5 .i 0 heteroaryl, and is optionally substituted;
  • R 10C is independently saturated C 3 . 7 cycloalkyl, and is optionally substituted;
  • -R 0D is independently non-aromatic C 3 .i 0 heterocyclyl, and is optionally substituted.
  • aliphatic alkyl refers to linear and branched alkyl groups, but not alicyclic alkyl (e.g., cycloalkyl) groups.
  • -nBu is an example of a linear C 4 alkyl group
  • -iBu is an example of a branched C 4 alkyl group; in this way, both -nBu and -iBu are examples are aliphatic C 4 alkyl groups.
  • C 3-7 heterocyclic ring refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S).
  • pyridyl is an example of a C 6 heteroaryl group
  • piperidino is an example of a C 6 heterocycyl group.
  • C 3 . 7 heterocyclic ring refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S).
  • heteroaryl refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, and which has one or more heteroatoms (e.g., N, O, S) forming part of the aromatic ring system.
  • heteroatoms e.g., N, O, S
  • pyridyl is an example of a C 6 heteroaryl group
  • quinolyl is an example of a
  • heterocyclyl refers to a group that is attached to the rest of the molecule by a ring atom that is not part of an aromatic ring (i.e., the ring is fully or partially saturated), and the ring system contains one or more heteroatoms (e.g. , N, O, S).
  • heteroatoms e.g. , N, O, S.
  • piperidino is an example of a C s heterocycyl group.
  • -R is independently -H or -R 1A ;
  • -R 2 is independently -H or -R 2 *
  • -R 1 is independently -H or -R A ;
  • -R 2 is independently -H.
  • -R 1 is independently -R 1A ;
  • -R 2 is independently -H.
  • -R 1 is independently -H
  • -R 2 is independently -H.
  • -R 1A if present, is independently saturated aliphatic C 1-4 alkyl.
  • -R 7A is independently saturated aliphatic C 3- 4alkyl.
  • (81) A compound according to any one of (1) to (73), wherein -R 7BB1 , if present, is independently naphthyl, and is optionally substituted, for example, with one or more substituents independently selected from -F, -CI, -Br, -I, -Me, and -Ph.
  • the Group -R 8 (109) A compound according to any one of (1 ) to (108), wherein -R is independently -H.
  • (1 10) A compound according to any one of (1) to (108), wherein -R 8 is independently The Group -R 8A
  • (120) A compound according to any one of (1 ) to (44), wherein -R 7 and -R 8 , taken together with the carbon atom to which they are attached, form a saturated C 3-7 cycloalkyl ring.
  • (121 ) A compound according to any one of (1) to (44), wherein -R 7 and -R 8 , taken together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted, for example, with one or more substituents -R X2 .
  • (122) A compound according to any one of (1) to (44), wherein -R 7 and -R 8 , taken together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (123) A compound according to any one of (1) to (44), wherein -R 7 and -R 8 , taken together with the carbon atom to which they are attached, form cyclohexyl.
  • (145) A compound according to any one of (137) to (141 ), wherein -R 1 is -iPr, -R 4 is -Me, and -R 7 is -CH 2 -R 7BB ; for example, as shown below: (146) A compound according to any one of (137) to (141), wherein -R is -nBu, -R is -Me, and -R 7 is -CH 2 -R 7BB ; for example, as shown below:
  • (150) A compound according to any one of (137) to (141 ), wherein R 1 is -iPr, -R 4 is -Me, and -R 7 is -R 7A ; for example, as shown below: (151) A compound according to any one of (137) to (141), wherein R 1 is -nBu, -R 4 is -Me, and -R 7 is -R 7A ; for exampl
  • the Group -R 10 (154) A compound according to any one of (1) to (153), wherein -R is independently
  • -R 10A if present, is independently phenyl or naphthyl, and is optionally substituted, for example, with one or more substituents independently selected from:
  • -R 10B if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl (e.g., 1 H-[1 ,2,3]triazolyl, 2H-[1 ,2,3]triazolyl, 4H-[1 ,2,4]triazolyl, 1 H-[1 ,2,4]triazolyl), oxadiazolyl (e.g. , [1 ,2,3]oxadiazolyl, furazanyl, [1 ,2,4]triazolyl), oxadiazolyl (e.
  • -R 0B if present, is independently pyridyl, pyrimidinyl, or pyrazinyl, and is optionally substituted, for example, with one or more substituents -R X3 .
  • the Group -R 10C (187) A compound according to any one of (1) to (186), wherein -R 0C , if present, is independently saturated C 3 - 7 cycloalkyl, and is optionally substituted, for example, with one or more substituents -R X2 .
  • -R 10C if present, is independently cyclopentyl or cyclohexyl.
  • the Group -R 10D (192) A compound according to any one of (1 ) to (191 ), wherein -R 10D , if present, is independently non-aromatic C 3 . 10 heterocyclyl t and is optionally substituted, for example, with one or more substituents -R X2 .
  • (200) A compound according to any one of (1 ) to (191 ), wherein -R 10D is independently pyrrolidinyl, piperidinyl, morpholinyl, piperizinyl, tetrahydrofuranyl, tetrahydropyranyl, dixoanyl, azepanyl, or diazepanyl.
  • -R 10D is independently pyrrolidinyl, piperidinyl, morpholinyl, piperizinyl, tetrahydrofuranyl, tetrahydropyranyl, or dixoanyl.
  • each -R s is independently saturated aliphatic Ci. 6 alkyl, phenyl, or -CH 2 -phenyl;
  • each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R ss , -CF 3 , -OH, -OR ss , or -OCF 3 , wherein each -R ss is
  • each -R T is independently saturated aliphatic C h alky!, phenyl, or
  • each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R " " " , -CF 3 , -OH, -OR n , or -OCF 3 , wherein each -R 77 is independently saturated aliphatic C 1-4 alkyl.
  • -CH CH 2 , -C ⁇ CH, cyclopropyl
  • each -L v - is independently saturated aliphatic C 2-4 alkylene
  • each -R v is independently saturated aliphatic Ci. 6 alkyl, phenyl,
  • each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R w , -CF 3 , -OH, -OR w , or -OCF 3 ;
  • each C 5 . 6 heteroaryl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R w , -CF 3 , -OH, -OR w , or -OCF 3 ;
  • each -R w is independently saturated aliphatic C ⁇ alkyl
  • two adjacent groups -R X3 may together form -OCH 2 0-, -0CH 2 CH 2 0-, -CH 2 0CH 2 - or -OCH 2 CH 2 -;
  • two adjacent groups -R X3 may, together with the ring atoms to which they are attached, form a C s . 7 carbocyclic ring or a C 5 . heterocyclic ring.
  • -CH CH 2 , -C ⁇ CH, cyclopropyl
  • two adjacent groups -R X3 may together form -OCH 2 0-, -OCH 2 CH 2 0-, -CH 2 OCH 2 - or -OCH 2 CH 2 -.
  • (231 ) A compound according to any one of (1 ) to (230), wherein the compound has a molecular weight of from 241 to 1200.
  • One aspect of the present invention pertains to ALD compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
  • the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g. , at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g. , at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • substantially purified form refers to the compound in any
  • the substantially purified form refers to a mixture of stereoisomers, i.e. , purified with respect to other compounds. In one embodiment, the substantially purified form refers to one
  • the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g. , no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1 % by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • 60% optically pure i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer
  • at least 70% optically pure e.g., at least 80% optically pure, e.g., at least 90% optically pure, e
  • a cyclic acetal may be formed if a diol is used, for example, ethylene glycol, to produce the corresponding 1 ,3-dioxolane.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C -7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • C -7 alkyl includes n-propyl and iso-propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • reference to a specifc group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space.
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,
  • 1H-pyridin-2-one-5-yl and 2-hydroxyl-pyridin-5-yl are tautomers of one another.
  • a reference herein to one is intended to encompass both. See, for example, ALD-068.
  • H may be in any isotopic form, including H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 2 C, 13 C, and 1 C; O may be in any isotopic form, including 6 0 and 18 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation e.g., asymmetric synthesis
  • separation e.g., fractional crystallisation and chromatographic means
  • isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K ⁇ alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as ⁇ 3 .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from:
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + . If the compound is cationic, or has a functional group which upon protonation may become cationic (e.g., -NH 2 may become -NH 3 + ), then a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • Suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • a reference to a particular compound also includes salt forms thereof.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g. , compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a hydroxy group may be protected as an ether (-OR) or an ester
  • the aldehyde or ketone group is readily regenerated, for example, by hydrolysis using water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc),
  • a carboxylic acid group may be protected as an ester for example, as: an Ci. 7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C -7 haloalkyl ester (e.g., a
  • Ci. 7 trihaloalkyl ester a triC 1-7 alkylsilyl-Ci. 7 alkyl ester; or a Cs ⁇ oaryl-C ⁇ alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • prodrug refers to a compound which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), lipid directed enzyme prodrug therapy (LIDEPT), etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • Compounds of Formula (I) may be prepared, for example, by reacting an alcohol of Formula (II) with an appropriate oxidising agent, as illustrated in the following scheme.
  • Suitable oxidising agents include, but are not limited to, Dess-Martin periodinane, pyridinium chlorochromate (PCC), tetrapropylammonium perruthenate (TPAP), and the use of Swern or modified Swern conditions, which use DMSO in conjunction with an activating agent such as oxalyl chloride.
  • Alcohols of Formula (II) can be prepared by several different routes which are well known in the art.
  • One such method involves reacting a compound of Formula (III) with a compound of Formula (IV) using standard acid-amine coupling conditions, as illustrated in the following scheme.
  • Such conditions are known in the art.
  • a potential side reaction under such conditions can be the epimerisation of the R 4 chiral centre. It is common to avoid such side reactions by carrying out low temperature coupling reactions using a mixed anhydride derived from Formula (III).
  • Mixed anhydrides are commonly generated in situ using, for example, isobutylchloroformate or ethylchloroformate and a mild base, such as N-methylmorpholine. Such methods are in the art.
  • the alcohol group of compound (IV) may also be protected with for example a silyl protecting group in order to prevent side reactions during the coupling process.
  • Compound (II) can then be generated following removal of the protecting group.
  • Suitable alcohol protecting groups and conditions for their removal can be found for example in Protective Groups in Organic Synthesis, 3rd Ed., (T. Green and P. Wuts; 4th Edition; Wiley-lnterscience, 1999), pp. 17-245.
  • Dipeptide and tripeptide derivatives may be synthesised on a polymeric
  • the first Fmoc protected amino acid is generally coupled to Wang or 2-chloro-trityl resin.
  • Suitable conditions include the use of hydroxybenzotriazole (HOBt) with
  • ⁇ , ⁇ '-diisopropylcarbodiimide DIC
  • 2-(1 H-7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium HATU
  • TBTU 0-(Benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate
  • HBTU 0-Benzotriazole-N,N,N',N'-tetramethyl- uronium-hexafluoro-phosphate
  • PyBop benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • peptide derivatives can be built up in a sequential fashion using solution chemistry with appropriately protected amino acids using methods known in the art.
  • suitable nitrogen protecting groups include, but are not limited to, carboxybenzyl (CBz), t-butoxycarbonyl (Boc), and fluorenylmethyloxycarbonyl (Fmoc).
  • CBz carboxybenzyl
  • Boc t-butoxycarbonyl
  • Fmoc fluorenylmethyloxycarbonyl
  • ALD compounds of Formula (I) may be generated by the selective reduction of a carboxylic acid or a carboxylic acid derivative.
  • One carboxylic acid derivative used for such purposes which is well known to the art is a Weinreb amide.
  • Weinreb amides can be converted to aldehydes using reducing agents such as but not limited to, lithium aluminium hydride and diisobutylaluminium hydride. cheme 3
  • Weinreb amides of Formula (V) may be prepared from the corresponding carboxylic acid using methods well known in the art.
  • an Fmoc-protected amino acid can be coupled to a N-methylhydroxylamine modified resin such as Weinreb AM resin purchasable from Novabiochem. This can then be used to synthesise a resin bound Weinreb amide of formula (V) using standard resin- based Fmoc coupling methods.
  • ALD compounds of formula (I) can subsequently be generated following treatment of the resin with a suitable reducing agent such as lithium aluminium hydride in an appropriate solvent such as tetrahydrofuran (see, for example, Fehrentz et al., 1995).
  • ALD compounds of formula (I) may be prepared from a derivative which contains a masked aldehyde unit, one such example would be a dimethyl acetal.
  • aldehyde protecting groups can be found, for example, Protective Groups in Organic Synthesis, 3rd Ed., (T. Green and P. Wuts; 4th Edition; Wiley-lnterscience, 1999), pp. 293-368.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising an ALD compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the composition is in the form of a dry powder, for example, suitable for delivery (e.g., administration) using a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • sutable DPIs are well-known in the art.
  • DPI administration may be used to deliver the drug to the lung or the nose.
  • the composition is in the form of a suspension, for example, suitable for delivery (e.g., administration) using a nebuliser. This may be used to deliver the drug to the lung or the nose.
  • the composition is in the form of a solution or suspension in a liquid propellant, for example, suitable for delivery (e.g., administration) as an aerosol, for example, using a pressurised metered dose inhaler (pMDI).
  • pMDI pressurised metered dose inhaler
  • Suitable propellants are well-known in the art, and include, for example, dichlorodifluoromethane (CFC-12), trichlorofluoromethane,
  • dichoro-tetrafluoroethane HFA-134a, HFA-227, HCFC-22, HFA-152, isobutene, and carbon dioxide. This may be used to deliver the drug to the lung or the nose, and may additionally be used to delivery the drug to the skin.
  • the composition is in the form of an aqueous solution, for example, suitable for delivery (e.g., administration) using a dropper, syringe, metered dose spray pump or atomiser.
  • a dropper e.g., syringe, metered dose spray pump or atomiser.
  • This may be used to deliver the drug to the nose, to the skin, to the eye, and additionally may be used for injection.
  • the composition further comprises one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing an ALD compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing an ALD compound, as described herein; one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein; and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the compounds described herein are useful, for example, in the treatment of diseases and disorders that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1), such as, for example, asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition that is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m
  • One aspect of the present invention pertains to a method of inhibiting a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1), in vitro or in vivo, comprising contacting a dust mite Group 1 peptidase allergen with an effective amount of an ALD compound, as described herein.
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1
  • One aspect of the present invention pertains to a method of inhibiting a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an ALD compound, as described herein.
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1
  • Suitable assays for determining inhibition of a dust mite Group 1 peptidase allergen are described herein and/or are known in the art. Use in Methods of Therapy
  • Another aspect of the present invention pertains to an ALD compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to an ALD compound, as described herein, in combination with one or more (e.g.; 1 , 2, 3, 4) additional therapeutic agents, as described herein, for use in a method of treatment of the human or animal body by therapy.
  • one or more e.g.; 1 , 2, 3, 4
  • additional therapeutic agents as described herein, for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of an ALD compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the medicament comprises the ALD compound.
  • Another aspect of the present invention pertains to use of an ALD compound, as described herein, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, in the manufacture of a medicament for use in treatment.
  • the medicament comprises the ALD compound and the one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of an ALD compound, as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of an ALD compound, as described herein, preferably in the form of a pharmaceutical composition, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, preferably in the form of a pharmaceutical composition.
  • an ALD compound as described herein, preferably in the form of a pharmaceutical composition
  • additional therapeutic agents as described herein, preferably in the form of a pharmaceutical composition.
  • the treatment is treatment of a disease or disorder that is mediated by a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ).
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1 .
  • the treatment is treatment of. a disease or condition that is ameliorated by the inhibition of a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ).
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1 .
  • the treatment is treatment of: asthma, for example, atopic asthma; allergic asthma; atopic bronchial IgE-mediated asthma;
  • bronchial asthma extrinsic asthma; allergen-induced asthma; allergic asthma
  • infective asthma exacerbated by respiratory virus infection; infective asthma; infective asthma caused by bacterial infection; infective asthma caused by fungal infection; infective asthma caused by protozoal infection; or infective asthma caused by viral infection.
  • the treatment is treatment of: bronchial hyper-reactivity associated with asthma; or bronchial hyper-responsiveness associated with asthma.
  • the treatment is treatment of: airway remodelling associated with an allergic lung disease, for example, airway remodelling associated with asthma.
  • the treatment is treatment of: asthma
  • the treatment is treatment of: rhinitis, for example, allergic rhinitis; perennial rhinitis; persistent rhinitis; or IgE-mediated rhinitis.
  • the treatment is treatment of: allergic
  • conjunctivitis for example, IgE-mediated conjunctivitis.
  • the treatment is treatment of: atopic dermatitis.
  • the treatment is treatment of: an allergic condition which is triggered by dust mites.
  • the treatment is treatment of: an allergic condition which is triggered by dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1).
  • an allergic condition which is triggered by dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1).
  • the treatment is treatment of: canine atopy.
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure
  • treatment i.e., prophylaxis
  • treatment includes the prophylaxis of asthma, reducing the incidence of asthma, reducing the severity of asthma, alleviating the symptoms of asthma, etc.
  • terapéuticaally-effective amount refers to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents.
  • Typical examples of combinations for inhaled use in treatment of respiratory disease are fixed combinations of glucocorticoid receptor agonists and beta 2 adrenoceptor agonists.
  • Such a combination product is "Advair” (also known as “Seretide”), which is a fixed combination of fluticasone propionate and salmeterol.
  • Such combinations may be used in dry powder devices, pressurised metered dose inhalers and nebulisers.
  • Many other respiratory agents may be used in fixed combinations in such devices. They may also be adminstered separately from different devices in different relative doses.
  • An inhaled combination product will be a fixed combination of a compound described herein with one or more additional agents (in which the ratios are decided on the merits of the individual components and selected from a suitable range by experiment) together with appropriate excipients.
  • one aspect of the present invention pertains to a compound as described herein, in combination with one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents.
  • the agents i.e., the compound described herein, plus one or more other agents
  • the precise dosage regimen of either combination or sequential treatment will be
  • ALD compounds described herein may be used in combination with one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, for example, in combination therapy as described herein.
  • the one or more additional therapeutic agents are selected from agents used, or likely to be used, in the treatment of a respiratory disease. ln one embodiment, the one or more additional therapeutic agents are selected from: an anti-asthma agent and an anti-allergy agent.
  • the one or more additional therapeutic agents are selected from: a beta 2 -adrenergic agonist;
  • glucocorticoid receptor agonist a glucocorticoid receptor agonist
  • an immune response modifier e.g., an agonist of one or more Toll-Like Receptors (e.g., TLR2, TLR4, TLR7, TLR8, TLR9) or a vaccine;
  • an immune response modifier e.g., an agonist of one or more Toll-Like Receptors (e.g., TLR2, TLR4, TLR7, TLR8, TLR9) or a vaccine;
  • a selective phoshodiesterase (PDE) isoenzyme inhibitor e.g., an inhibitor of PDE4 and/or PDE5;
  • MAP mitogen-activated protein
  • IKK2 IkappaB kinase 2
  • Syk tyrosine-protein kinase
  • PI3Kgamma phosphoinositide-3 kinase gamma
  • a lung surfactant protein especially SP-A, SP-D;
  • the ALD compounds described herein may also be used as an acaricide, e.g., to control the population of, or to kill, mites, e.g., dust mites.
  • Another aspect of the present invention pertains to an ALD compound, as described herein, for use as an acaricide.
  • Another aspect of the present invention pertains to a composition comprising an ALD compound, as described herein, for use as an acaricide.
  • Another aspect of the present invention pertains to an acaricide composition comprising an ALD compound, as described herein.
  • Another aspect of the present invention pertains to the use of an ALD compound, as described herein, as an acaricide.
  • Another aspect of the present invention pertains a method of killing mites (e.g., dust mites), comprising exposing said mites to an effective amount of an ALD compound, as described herein.
  • Another aspect of the present invention pertains a method of controlling (e.g., limiting) a mite (e.g., dust mite) population comprising exposing mites to an effective amount of an ALD compound, as described herein.
  • the ALD compounds described herein may also be used as cell culture additives to inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ).
  • a dust mite Group 1 peptidase allergen e.g., Der p 1 , Der f 1 , Eur m 1 .
  • the ALD compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • the ALD compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other dust mite Group 1 peptidase allergen inhibitors, other anti-asthma agents, etc.
  • kits comprising (a) an ALD compound as described herein, or a composition comprising an ALD compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
  • the kit further comprises one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein.
  • the written instructions may also include a list of indications for which the active ingredient is a suitable treatment. Routes of Administration
  • the ALD compound or pharmaceutical composition comprising the ALD compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray, drops or from an atomiser or dry powder delivery device); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital,
  • the subject/patient may be a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey
  • a rodent e.g., a guinea pig, a hamster, a rat, a mouse
  • murine e.g., a mouse
  • a lagomorph e.g., a rabbit
  • ape e.g., gorilla, chimpanzee, orangutang, gibbon
  • a human e.g., gorilla, chimpanzee, orangutang, gibbon
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • the subject/patient is a dog.
  • the ALD compound While it is possible for the ALD compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one ALD compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one ALD compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 8th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
  • Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • solutions e.g., aqueous, nonaqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions
  • Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
  • the compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients.
  • the compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
  • Formulations suitable for administration to the lung include those presented as a solution or suspension for delivery from a nebuliser; a dry powder for use in an appropriate inhaler device; and an aerosol spray for delivery from a pressurised pack with the use of a suitable propellant, such as dichlorodifluoromethane (CFC-12),
  • Formulations intended for nasal delivery can be adminsitered as aqueous solutions or suspensions, as solutions or suspensions in suitable propellants or as dry powders.
  • Nasal droppers, nebulisers, atomisers, pressurised metered dose inhalers and dry powder inhalers for nasal delivery are available.
  • the active compound is preferably in the form of microparticles.
  • Suitable microparticles may be prepared by a variety of techniques, including spray-drying, freeze-drying and micronisation.
  • microparticles may be formulated with excipients that aid delivery and release.
  • microparticles may be formulated with large carrier particles that aid the flow, for example, from a dry powder inhaler (DPI) into the lung.
  • DPI dry powder inhaler
  • Suitable carrier particles are well-known in the art, and include lactose particles; they may have a mass median aerodynamic diameter of > 90 ⁇
  • the active compound may be administered in a manner compatible with the inhaler system used.
  • Suitable aerosol formulation may include, in addition to the active compound, excipients such as, for example, propellant (e.g., Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavourings, fillers (e.g., lactose in the case of powder inhalers) and, if appropriate, one or more additional active compounds.
  • propellant e.g., Frigen in the case of metered aerosols
  • surface-active substances e.g., emulsifiers, stabilizers, preservatives, flavourings
  • fillers e.g., lactose in the case of powder inhalers
  • a large number of systems are known with which aerosols of optimum particle size can be generated and administered, using an inhalation technique appropriate for the patient.
  • adaptors spacers, expanders
  • pear-shaped containers e.g., NebulatorTM, VolumaticTM
  • automatic devices emitting a puffer spray e.g., AutohalerTM
  • metered aerosols in particular in the case of powdered inhalers
  • a number of technical solutions are available (e.g., DiskhalerTM, RotadiskTM, TurbohalerTM).
  • the active compound may be delivered in a multi-chamber device, thus allowing for delivery of combination agents.
  • the active compound may also be used when formulated as an aqueous dispersion of nanoparticulates, or as a dry powder
  • nanoparticulate aerosol formulation or as a propellant-based aerosol formulation.
  • Suitable nanoparticles may be prepared by spray-drying or freeze-drying aqueous nanoparticulate dispersions of drugs.
  • Methods for the preparation of nanoparticulate dispersions of drugs, the preparation of aqueous, dry powder and propellant-based formulations of nanoparticulate drugs and their use in aerosol delivery systems are known (see, e.g., Bosch et al., 2009).
  • Formulations suitable for oral administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • mouthwashes e.g., losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • suppositories e.g., pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
  • Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. , magnesium stearate, talc, silica); disintegrants (e.g.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
  • Creams are typically prepared from the compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e. , an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier also known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for intranasal administration where the carrier is a liquid and the drug can be administered as an aqueous solution or suspension in a suitable vehicle or propellant, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, by pressurised metered dose inhaler or atomiser, include aqueous or oily preparations of the compound.
  • Formulations suitable for intranasal administration, where the carrier is a solid include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 micrometres which is administered in the manner in which snuff is taken, i.e. , by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g. , solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • sterile liquids e.g. , solutions, suspensions
  • Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • the concentration of the compound in the liquid is from about 1 ng/mL to about 10 pg/mL.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried
  • appropriate dosages of the ALD compounds, and compositions comprising the ALD compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular ALD compound, the route of administration, the time of administration, the rate of excretion of the ALD compound, the duration of the treatment, other drugs,
  • ALD compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • a suitable dose of the ALD compound is in the range of about 0.5 pg to about 20 mg per kilogram body weight of the subject per day.
  • the upper limit will be set by the chosen device for delivery.
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • DIPEA N,N-diisopropylethylamine
  • HATU 2-(7-Aza-1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
  • PS-Tosyl chloride polystyrene supported tosyl chloride
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TIPS triisopropylsilane
  • Reverse-Phase Preparative LC-MS Mass-directed purification preparative LC-MS using a preparative C-18 column (Phenomenex Luna C18 (2), 100 x 21.2 mm, 5 pm).
  • Peptides were synthesised on Wang resin using standard amide coupling procedures (see., e.g., Chan, W. C. and White, P. D., Fmoc Solid Phase Peptide Synthesis A Practical Approach, Oxford University Press, 2000).
  • Fmoc-amino acids were purchased from commercial suppliers (e.g., Advanced Chemtech, Bachem, NovaBiochem or Polypeptide).
  • Peptide grade DMF which is free of dimethylamine, was used for peptide couplings to prevent any unwanted removal of Fmoc groups. Kaiser tests were used to indicate successful coupling of Fmoc-amino acids.
  • Step 1 Coupling of First Amino Acid to Wang Resin: Wang resin was swollen with an appropriate volume of DMF then drained under vacuum. The Fmoc-amino acid (6 equiv.) was added followed by an appropriate volume of DMF (5 mLJg of resin), sufficient to cover the resin and peptide, and this mixture was shaken for 30 min. After that time, DIC (3 equiv.) and DMAP (catalytic) were added and the mixture was shaken for 4-5 h. The resin was drained under vacuum, washed with DCM and MeOH then re-swollen with DCM.
  • step 2 Successful coupling could be indicated by carrying out step 2 on a small portion of the resin and performing a Kaiser test to indicate the presence of a free NH 2 group.
  • the exact amount of amino acid attached to the resin was not quantified and subsequent reactions were performed on the basis of the maximum loading as indicated from the supplier.
  • approximate loadings are supplied by the supplier and these were used for calculating amounts of reagent for subsequent steps.
  • the resin was shaken with an appropriate volume of 20% v/v piperidine in DMF (5 mL/g resin) for 1 h then washed with DMF, DCM, MeOH and re-swollen with DCM.
  • a positive Kaiser Test (blue colour) indicates the presence of a free NH 2 group.
  • Step 3 Amide Coupling: The resin was shaken in an appropriate volume of DMF ( ⁇ 5 mL/g resin) with the appropriate Fmoc-amino acid (2 equiv.) or capping group R 10 CO 2 H (2 equiv.), TBTU (2 equiv.) and DIPEA (4 equiv. or 6 equiv. if, e.g., HCI salt is used) for 4-5 h. After that time, the resin was drained under vacuum, washed with DMF, DCM, MeOH and re-swollen with DCM. A negative Kaiser test (no colour change) indicates that all of the free amino sites have coupled. If the solution remained blue, step 3 was repeated.
  • DMF ⁇ 5 mL/g resin
  • Steps 2 and 3 were repeated for the coupling of additional amino acids and capping groups as necessary.
  • Step 4 Resin Cleavage:
  • the resin was shaken with the cleavage solution consisting of 95% TFA, 2.5% TIPS and 2.5% water (10 mlJg of resin) for 90 min, and then drained into an appropriate vessel.
  • the resin was washed with DCM under vacuum filtration.
  • the solvent was subsequently evaporated under vacuum, then azeotroped with toluene to remove any residual water or triturated with /so-hexane and diethyl ether or MTBE to leave the crude product residue.
  • the resulting peptide (A) was either used crude or further purified by trituration with ether, flash column chromatography or reverse-phase preparative HPLC.
  • Step 1 Synthesis of BOC-Amino Dipeptide Ethyl Esters (10): A solution of compound (8) (10 g, 1 equiv.) in THF (100 mL) was treated with /so-butyl chloroformate (1.05 equiv.) at -40°C, and NMM (1 equiv.), and stirred at -40°C for 30 min. A solution of compound (9) (1.1 equiv.) in a DMF and THF (40 mL, 1 : 1) mixture was added to the above reaction mixture at -40°C followed by addition of NMM (1 equiv.). The resulting mixture was stirred at -40°C for 2 h.
  • the reaction was stirred at -40°C for approximately 1 h until complete as measured by LC-MS. Additional amino alcohol could be added if required.
  • the reaction mixture was allowed to warm to ambient temperature.
  • the resulting mixture was diluted with EtOAc (10 volumes) and sat. aq. NaHC0 3 (10 volumes).
  • the layers were separated and the aqueous layer extracted with EtOAc (2 x 10 volumes).
  • the combined organic phases were washed with water (3 x 10 volumes) and brine (10 volumes) and concentrated under vacuum.
  • the resulting alcohol (3) was either used directly or purified by flash column chromatography.
  • Step 1 Deprotecting the Fmoc-Weinreb-AM Resin: Fmoc-Weinreb-AM resin was swollen with an appropriate volume of DMF then drained under vacuum, washed twice with DCM then drained under vacuum. The resin was shaken with an appropriate volume of 20% v/v piperidine in DMF (8 ml_/g resin) for 1 h then washed with DMF, DCM, MeOH and re-swollen with DCM. A positive chloranil test (orange/red colour) indicates the presence of a free NH group.
  • Step 2 Coupling of First Amino Acid to H-Weinreb-AM Resin:
  • the resin was swollen with an appropriate volume of DCM then drained under vacuum, washed twice with DMF then drained under vacuum.
  • the resin was shaken with an appropriate volume of 20% v/v piperidine in DMF (15 mlJg resin) for 0.5 - 1 h, then washed with DMF, DCM, MeOH and re-swollen with DCM.
  • a positive Kaiser test (blue colour) indicates the presence of a free NH 2 group.
  • Step 4 Coupling of Subsequent Amino Acids / Capping Groups to H-AA-Weinreb-AM Resin:
  • the resin was shaken with the appropriate Fmoc-amino acid (2 equiv.) or capping group R 10 CO 2 H (3 equiv.), TBTU (2 equiv.) and DIPEA (4 equiv. or 6 equiv. if, e.g., HCI salt is used) in an appropriate volume of DMF ( ⁇ 3 - 5 mL/g resin) for 4 - 5 h.
  • DMF ⁇ 3 - 5 mL/g resin
  • the resin was drained under vacuum, washed with DMF, DCM, MeOH and re-swollen with DCM.
  • a negative Kaiser test (no colour change) indicates that all of the free amino sites have coupled. If the solution remained blue, step 4 was repeated.
  • Steps 3 and 4 were repeated for the coupling of additional amino acids or capping groups as necessary.
  • Step 5 Resin Cleavage:
  • the resin was swollen in anhydrous THF (4 mL/g resin) and was gently stirred at 0°C under an inert atmosphere (e.g. nitrogen).
  • a solution of LiAIH 4 (4 equiv.) in THF ( ⁇ 2.5M) was added to the resin and the mixture was gently stirred for 1 h. After this time the mixture was quenched at 0°C by dropwise addition of a sat. aq. solution of KHS0 4 ( ⁇ 1.5 mL/g resin) followed by a solution of aq. Rochelle salt (sodium potassium tartrate; 1.2M, 4 equiv.). The quenched mixture was allowed to warm to ambient temperature and was diluted with water (4 mL/g resin).
  • ALD- 3 (Gemini)_1 Rt 9 mg, 033 (A21) 7.38 min; m/z 506 46%
  • ALD- 3 (Gemini)_ Rt 4mg, 038 (A31 ) 5.56 min; m/z 432 7%
  • Derp 1 enzyme activity assay The fluorogenic substrate used for measuring Der p 1 proteolytic activity was
  • Test compounds were dissolved in dry D SO and maintained at 4°C as stock solutions until being diluted for use in screening assays. Final concentration of DMSO in all enzymatic assays was 0.5% v/v.
  • Reaction mixtures were assembled in a 96-well plate format (Perkin Elmer Optiplate 96F, Perkin Elmer LAS, Seer Green, Buckinghamshire, UK) using a Perkin Elmer MultiPROBE II Plus HTS EX robot with Gripper attachment. Plates were pre-formatted with serial dilutions (10 plJwell) of test compound or appropriate control in reaction buffer
  • composition potassium phosphate buffer pH 8.25 containing 1 mM EDTA
  • DTT dithiothreitol
  • reaction buffer pH 8.25 containing 1 mM EDTA
  • Dithiothreitol DTT, 10 plJwell, 1 mM final concentration
  • 10 ⁇ of Der p 1 dissolved at 2.5 g/mL in reaction buffer supplemented with 1 mM DTT.
  • Reaction mixtures were then incubated at room temperature for 20 minutes before initiating the reaction by the addition of 10 pL of substrate (12.5 ⁇ final concentration).
  • the plate was immediately transferred to a fluorescence plate reader (Perkin Elmer Fusion Alpha-FP or Perkin Elmer Envision) equipped with a temperature-controlled carrier set at 30°C and the reaction followed by excitation/emission at 330/420 nm.
  • Fractional activity (Initial rate at inhibitor concentration [X] / Initial rate at inhibitor concentration zero) * 100
  • Equation 2 Equation 2:
  • V V min + [ V - V min ] / [ 1 + ( X / ICso ) Hillslope ]
  • Vmin is the minimum of Y observed at high inhibitor concentration
  • V max is the maximum of Y observed at zero inhibitor concentration
  • ALD-001 ALD-002, ALD-005, ALD-007, ALD-008, ALD-010, ALD-011 , ALD-012, ALD-013, ALD-015, ALD-016, ALD-018, ALD-022, ALD-026, ALD-029, ALD-030, ALD-032, ALD-034, ALD-035, ALD-037, ALD-039, ALD-040, ALD-042, ALD-043, ALD-045, ALD-051 , ALD-052, ALD-053, ALD-055, ALD-058, ALD-060, ALD-062, ALD-063, ALD-064, ALD-065, ALD-071.
  • HDM allergens were harvested from a laboratory culture of
  • Freeze-dried stocks of HDM allergen mixture stored at -20°C were reconstituted in their original volumes of 0.22 pm filter-sterilised de-ionised water containing 5 mM L-cysteine and 0.05% v/v Tween 20 and diluted to working concentration using sterile Dulbecco's phosphate buffered saline containing 5 mM L-cysteine and 0.05% v/v Tween 20. Animals were sensitized to a mixture of all HDM allergens on Days 0, 7, and 14 by intraperitoneal injection (0.5 mL) of the mixture formulated as described above.
  • Physiological recordings On Day 21 of the sensitization and challenge protocol, rats were anaesthetised with pentobarbitone (100 mg/kg, i.p.) and ventilated via a tracheal cannula (approximately 7 mlJkg, 1 Hz) with a mixture of air and oxygen (50:50). The anaesthetised, ventilated animals were paralysed with norcuron (4 mg/kg, i.m.). Ventilation was monitored by a flow transducer (Fleisch, type 0000) in-line with the respiratory pump.
  • pentobarbitone 100 mg/kg, i.p.
  • a tracheal cannula approximately 7 mlJkg, 1 Hz
  • norcuron 4 mg/kg, i.m.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aldehyde compounds of the following formula (A) (for convenience, collectively referred to herein as "ALD compounds"), which, inter alia, inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1, Der f 1, Eur m 1 ). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit a dust mite Group 1 peptidase allergen, and in the treatment of diseases and disorders that are mediated by a dust mite Group 1 peptidase allergen; that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen; asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition which is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.

Description

ALDEHYDE COMPOUNDS AS INHIBITORS OF DUST MITE GROUP 1 PEPTIDASE ALLERGEN AND THEIR USE
RELATED APPLICATION
This application is related to United Kingdom patent application number 101 141 1.4 filed 06 July 2010, the contents of which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aldehyde compounds (for convenience, collectively referred to herein as "ALD compounds"), which, inter alia, inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit a dust mite Group 1 peptidase allergen, and in the treatment of diseases and disorders that are mediated by a dust mite Group 1 peptidase allergen; that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen; asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition which is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.
BACKGROUND A number of patents and publications are cited herein in order to describe and disclose the invention more fully and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims that follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like. Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Allergic Diseases
Allergic diseases, such as asthma, rhinitis, conjunctivitis and eczema, are escalating global healthcare problems that have not been contained by existing medications. These clinical conditions are initiated and triggered in genetically susceptible individuals by exposure to a diverse range of substances known as allergens. Numerous sources of allergen exist, but those associated with domestic environments are especially important as disease triggers because people are exposed to them for long periods. Amongst domestic allergens, those derived from house dust mites (HD ) are globally the most significant cause of allergic disease. These mites are found abundantly in homes, in workplaces, in entertainment venues, and in public and private transport vehicles.
Chronic sensitization to HDM allergens can occur at any time of life and subsequent exacerbations triggered by repeated allergen exposure increase the probability that minor conditions such as allergic rhinitis will escalate into asthma, which is more serious. In addition, house dust mites create health problems for animals that co-habit with humans. For example, the condition of canine atopy is an inherited condition that gives rise to a miscellany of allergic conditions of the skin, nose and eyes (Sture et al., 1995). Perennial symptoms are commonly associated with sensitization and subsequent re-exposure to dust mite allergens. It is well-described with house dust mites recognised as significant triggers of perennial allergic symptoms in dogs, resulting in a need for veterinary treatment to alleviate disease symptoms. The symptoms seen in dogs largely resemble those seen in human atopic dermatitis and conjunctivitis. The pre-eminence of house dust mite allergens as triggers of allergic conditions has resulted in a need to understand why they are allergenic. Studies into the molecular basis of allergenicity have revealed that the HDM allergen of greatest clinical significance is a cysteine peptidase. Surprisingly, this peptidase activity contributes decisively to the development of allergy to HDM allergens generally and to other by-stander allergens unrelated to HDM. Several species of dust mite are known (e.g., Dermatophagoides pteronyssinus,
Dermatophagoides farinae, Dermatophagoides siboney and Euroglyphus maynei) and each of these produce numerous allergenic proteins. The allergens from the different species can be categorized into distinct groups which show immunological
cross-reactivity because they are extremely similar proteins with highly conserved amino acid sequences. In the case of HDM, the Group 1 allergens (e.g., Der p 1 , Der f 1 , Eur m 1 ) underlie > 95% of HDM allergy and are a highly conserved family of cysteine peptidases. The normal function of these cysteine peptidases in mites is as digestive enzymes that have the capability of digesting the resilient structural proteins in dried flakes of exfoliated skin which form a significant component of the HDM diet. The degree of amino acid sequence conservation in HDM Group 1 cysteine peptidase allergens (>90%) is such that they may be regarded as functionally identical and, for drug discovery purposes, a single therapeutic target. It is also now known that a clinically significant allergen from another mite, Blomia tropicalis, of more restricted geographical distribution is a related cysteine peptidase and shows immunological reactivity with the Group 1 allergens from house dust mites. This suggests that an inhibitor of Gropup 1 HDM allergens may be more generally applicable as inhibitors of related molecules in all species of mite that cause allergy. The Group 1 HDM allergens are major triggers of asthma and other allergic conditions. When inhaled, their peptidase activity cleaves proteins and thus (i) increases the permeability of the airway epithelium allowing access for them and other, non-peptidase allergens to dendritic antigen presenting cells, and (ii) triggers signalling events that skew immunological responses to the Th2 phenotype. Both of these events initiate allergy and must be recapitulated to maintain it. Blocking these essential, initial steps in allergic sensitization by inhibiting the cysteine peptidase activity of the Group 1 allergens could therefore provide the basis for a unique approach to the treatment and prevention of allergy. Group 1 HDM allergens as a therapeutic target
People are exposed to house dust mite (HDM) allergens for up to 23 hours each day; consequently these allergens are of major significance in a range of clinical conditions that share elevated IgE as a molecular marker of disease. Population-based
cross-sectional and longitudinal studies demonstrate that a positive skin test reaction for IgE antibody to HDM allergens is associated with asthma, persistent rhinitis, allergic conjunctivitis or atopic dermatitis (Arruda et al., 1991; Gelber et al., 1993; Miyamoto et al., 1968; Peat et al., 1996; Peat et al., 1991 ; Pollart et al.,1989; Smith et al., 1969; Sporik et al., 1990) In genetically predisposed individuals, first encounters with these allergens can trigger the onset of disease at any time and, with repeated exposures through life, minor conditions can evolve into serious disease. Thus, the probability of developing asthma is increased 10-20 fold after rhinitis has been established. Furthermore, the largest ever study of adult-onset asthma demonstrated, contrary to previous beliefs, that HDM allergy is as important to adults as children (Jaakkola et al., 2006). Allergy risk and severity both show dose-response relationships with allergen exposure. This increases the attraction of pharmacological intervention aimed at Group 1 HDM allergens. Clinical evidence strongly supports a threshold level of exposure above which sensitization of at-risk individuals becomes probable. Furthermore, a dose-response relationship exists between concentrations of these allergens in homes (and thus human exposure) and the importance of this sensitization to asthma (Gelber et al., 1993; Peat et al., 1991 ; Platts-Mills et al., 1997; Platts-Mills et al., 1987; Dowse et al., 1985; Charpin et al., 1991). These observations imply that avoidance or inactivation of these key allergens (i.e., by reducing the dose of functional allergen to which an individual is exposed) is likely to decrease sensitization, causing symptoms to wane and clinical prognosis to improve. Reducing exposure to these allergens is the basis of physical allergen avoidance strategies which have been investigated as a means of controlling allergy. The benefits of physical allergen avoidance are supported by controlled trials in which people have been moved to environments (e.g., alpine sanatoria) where allergen avoidance can be managed rigorously (Dowse et al., 1985; Platts-Mills et al., 2000; Vervloet et al., 1982; Peroni et al., 1994). The effect of a strict regime of allergen avoidance is rapid in onset, with patients showing a significant decrease in markers of inflammation or medicine usage within 2 to 4 weeks (van Velzen et al., 1996; Schultze-Werninghaus, 2006; Bodini et al., 2004; Gourgoulianis et al., 2001; Piacentini et al., 1999; Piacentini et al., 1998). However, such physical avoidance measures are generally impractical and the benefits wane upon a return to everyday life.
Given the contribution of proteolytic activity to allergic sensitization, the development of a means to inhibit the peptidase activity of Group 1 allergens would provide
pharmacological allergen inactivation that would mimic the effects of physical allergen avoidance. It is envisaged that the optimum means to achieve this objective would be to treat patients with such inhibitors, either topically or systemically. One advantage of this approach is that pharmacological allergen inactivation would travel with the person being treated (i.e., it would be "portable") to achieve the benefits of continuous allergen avoidance, something which is not achievable with physical allergen avoidance measures. In addition to their use as medicines, it is likely that inhibitors of Group 1 peptidase allergens would have additional value as acaricides applied as environmental treatments. By inactivating key enzymes involved in the digestion of food by HDM, such inhibitors would deprive mites of a source of nutrition causing them to fail to thrive. Allergens and peptidase activity
Two observations are relevant to an appreciation of the contribution of peptidase activity to allergic sensitization. The first is the demonstration that the proteolytic activity of a small cadre of enzymatic allergens is vital to allergic sensitization via the airways. The second is the ability of peptidases is to drive allergic sensitization to by-stander allergens that lack proteolytic activity. When administered alone and without adjuvants, such non-enzymatic bystanders fail to evoke responses, induce tolerance or show only weak IgG-mediated reactions, even with systemic immunisation (Seymour et al., 1998; van Halteren et al., 1997; McMillan et al., 2004; McCusker et al., 2002; Hellings et al., 2001). Since the majority of allergens are non-proteolytic, the ability of individual peptidases to exert a marked influence on the development of sensitization to by-stander allergens creates an interesting therapeutic opportunity which inhibitors of Group 1 mite allergens could exploit.
Previous studies have shown that the proteolytic activity of Group 1 HDM allergens makes an essential contribution to allergy through two general mechanisms that are central to the initiation and maintenance of the allergic state. These are: · Facilitating allergen delivery across mucosal surfaces, thus gaining access to antigen presenting cells (e.g., in the lungs, dendritic cells) (Holt et al., 1990; Holt, 2002; Huh et al., 2003; Lambrecht et al., 2003a; Lambrecht et al., 2002; Lambrecht et al., 2003b; Wan et al., 2000).
• Activating signal transduction pathways that favour development of allergy in the genetically predisposed (Hellings et al., 2001 ; Comoy et al., 1998; Stewart et al., 2003).
HDM peptidase allergens therefore exert significant effects that are independent of IgE, but which have an essential bearing on IgE sensitization and allergic responses (King et al., 1998; Asokananthan et al., 2002). These actions serve to promote sensitization to the inciting peptidase allergen but, as described above, because the effects of the general mechanisms are essentially allergen non-specific, sensitization to non-enzymatic bystander allergens also occurs (Stewart et al., 2003; Wan et al., 1999).
Allergen delivery
Dendritic cells are the primary antigen presenting cells of the respiratory tract (Holt et al., 1990; Holt, 2002; Huh et al., 2003; Lambrecht et al„ 2003a; Lambrecht et al., 2002; Lambrecht et al., 2003b). However, for effective IgE responses to develop and be maintained, the probability of contact with antigens must be increased (Lambrecht et al., 2003b). This essential step in the detection of allergen is facilitated by the cysteine peptidase activity of Group 1 mite allergens which cleaves the transmembrane adhesion proteins of epithelial tight junctions, facilitating paracellular delivery of any allergen to dendritic cells (Wan et al., 1999; Wan et al., 2000; Winton et al., 1998).
IqE-independent cell activation
Peptidase allergens are thought to contribute to innate immunity and activate a variety of cells by numerous IgE-independent mechanisms. Signalling pathways activated by cleavage of tethered ligand receptors on epithelial cells is one such mechanism contributing to the chronic release of GM-CSF and IL-6. These cytokines are present in increased amounts in the airways in allergic asthma and rhinitis (Broide et al., 1992; Fahy et al., 1995; Muraguchi et al., 1988; Vercelli., 1989). They promote a Th2 allergic bias via several actions. For example, IL-6 is essential to B cell maturation and in the
IL-4-dependent synthesis of IgE (Muraguchi et al., 1988; Vercelli., 1989). GM-CSF generates signals that cause dendritic cells to migrate from the airway epithelium to present captured antigens at regional lymph nodes (Stick et al., 2003). Proteolytic activity that cleaves tethered ligand receptors is thus associated with a chain of events central to both the initiation of allergic sensitization and its maintenance. Peptidase allergens activate mast cells by IgE-independent mechanisms and it follows, therefore, that a contribution to the acute bronchoconstriction resulting from allergen challenge must be due to this peptidase-dependent activation. This suggests that inhibitors of Group 1 peptidase allergens should attenuate acute allergic bronchoconstriction. Other
IgE-independent mechanisms involve a cleavage of cytokine and IgE receptors that are associated with an augmentation of allergy (Ghaemmaghami et al., 2002), cleavage of antipeptidase defences (which may already be defective in allergy) and cleavage of other protective factors such as surfactant proteins (Deb et al., 2007).
Demonstrations of proteolytic allergen contributions to allergy
The potential importance of peptidase allergens as a target in allergy is demonstrated by the ease and directness with which they evoke IgE sensitization and by studies with generic inhibitors of cysteine peptidases in experimental animals.
Strong allergen-specific IgE sensitization can be achieved by non-invasive exposure of mice to Der p 1 of high specific proteolytic activity in the absence of adjuvants (Zhang et al., 2009). In Brown Norway rats, development of Der p 1 -specific IgE and allergic responsiveness also occurs without the need for additional adjuvants. In contrast, the difficulties in raising high titre antibodies to recombinant Der p 1 that lacks high enzyme activity (and which therefore behaves like a by-stander allergen) are well known. The proteolytic nature of Der p 1 also augments the sensitization to non-peptidase by-stander allergens from HDM and other sources (Gough et al., 2001). The promotion of allergen delivery by peptidase allergens may be augmented by their inactivation of antipeptidase defences (Kalsheker et al., 1996). Of related significance is that the loss of functional polymorphisms in endogenous enzyme inhibitors
(e.g., chromosome 5q32 LETK1 , chromosome 7 PAI-I, chromosome 1 1 C1 esterase inhibitor, chromosome 14 serpin cluster, chromosome 18q21) predisposes the subject to allergic disease. This recent evidence supplements functional associations between allergy and protease inhibitor deficiency that have accrued over the past 25 years (Rudolph et al., 1978; Hyde et al., 1979; Eden et al., 2003; Sigsgaard et al., 2000).
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a bar graph showing the magnitude of the acute bronchoconstrictor response to house dust mite allergen following Challenge 1 (left) and Challenge 2 (right). The response to Challenge 2 is expressed as a percentage of the magnitude of the mean response following Challenge 1 (data for challenge 2 shown as mean and standard error of the mean).
Figure 2 is a bar graph showing the percentage inhibition of the control acute
bronchoconstrictor response to house dust mite allergen (Challenge 1 ) following a subsequent allergen challenge (Challenge 2) administered 15, 30 and 60 minutes after treatment with compound ALD-035 (data reported as mean and standard error of the mean).
SUMMARY OF THE INVENTION
One aspect of the invention pertains to certain aldehyde compounds (for convenience, collectively referred to herein as "ALD compounds"), as described herein.
Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising an ALD compound, as described herein, and a pharmaceutically acceptable carrier or diluent. Another aspect of the invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of admixing an ALD compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
Another aspect of the present invention pertains to a method of inhibiting a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ), in vitro or in vivo, comprising contacting a dust mite Group 1 peptidase allergen with an effective amount of an ALD compound, as described herein.
Another aspect of the present invention pertains to a method of inhibiting a dust mite Group 1 peptidase allergen in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an ALD compound, as described herein.
Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an ALD compound, as described herein, preferably in the form of a pharmaceutical composition.
Another aspect of the present invention pertains to an ALD compound as described herein for use in a method of treatment of the human or animal body by therapy.
Another aspect of the present invention pertains to use of an ALD compound, as described herein, in the manufacture of a medicament for use in treatment.
In one embodiment, the treatment is treatment of a disease or condition that is mediated by a dust mite Group 1 peptidase allergen.
In one embodiment, the treatment is treatment of a disease or condition that is ameliorated by the inhibition of a dust mite Group 1 peptidase allergen. In one embodiment, the treatment is treatment of: asthma, for example, atopic asthma; allergic asthma; atopic bronchial IgE-mediated asthma; bronchial asthma; extrinsic asthma; allergen-induced asthma; allergic asthma exacerbated by respiratory virus infection; infective asthma; infective asthma caused by bacterial infection; infective asthma caused by fungal infection; infective asthma caused by protozoal infection; or infective asthma caused by viral infection.
In one embodiment, the treatment is treatment of: bronchial hyperreactivity associated with asthma; or bronchial hyperresponsiveness associated with asthma.
In one embodiment, the treatment is treatment of: airway remodelling associated with an allergic lung disease, for example, airway remodelling associated with asthma.
In one embodiment, the treatment is treatment of: asthma co-presented with a chronic obstructive lung disease, for example, asthma co-presented with emphysema; or asthma co-presented with chronic bronchitis.
In one embodiment, the treatment is treatment of: rhinitis, for example, allergic rhinitis; perennial rhinitis; persistent rhinitis; or IgE-mediated rhinitis.
In one embodiment, the treatment is treatment of: allergic conjunctivitis, including, for example, IgE-mediated conjunctivitis.
In one embodiment, the treatment is treatment of: atopic dermatitis.
In one embodiment, the treatment is treatment of: an allergic condition which is triggered by dust mites.
In one embodiment, the treatment is treatment of: an allergic condition which is triggered by a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1). In one embodiment, the treatment is treatment of: canine atopy.
In one embodiment, the treatment further comprises treatment with one or more additional therapeutic agents, for example, one or more additional therapeutic agents selected from agents used, or likely to be used, in the treatment of a respiratory disease.
Another aspect of the present invention pertains to an ALD compound, as described herein, for use as an acaricide.
Another aspect of the present invention pertains to a composition comprising an ALD compound, as described herein, for use as an acaricide. Another aspect of the present invention pertains to an acaricide composition comprising an ALD compound, as described herein.
Another aspect of the present invention pertains to the use of an ALD compound, as described herein, as an acaricide.
Another aspect of the present invention pertains a method of killing mites (e.g., dust mites), comprising exposing said mites to an effective amount of an ALD compound, as described herein.
Another aspect of the present invention pertains a method of controlling (e.g., limiting) a mite (e.g., dust mite) population comprising exposing mites to an effective amount of an ALD compound, as described herein. Another aspect of the present invention pertains to a kit comprising (a) an ALD
compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound. Another aspect of the present invention pertains to an ALD compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
Another aspect of the present invention pertains to an ALD compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION
Compounds One aspect of the present invention relates to certain aldehyde compounds which are related to N-({[(2-Oxo-ethylcarbamoyl)-methyl]-carbamoyl}-methyl)-acylamide:
Figure imgf000013_0001
All of the compounds of the present invention have a terminal aldehyde moiety
(i.e., -C(-O)H). terminal
aldehyde
moiety
Figure imgf000013_0002
Thus, one aspect of the present invention pertains to compounds selected from compounds of the following formula, and salts, hydrates, and solvates thereof
(e.g., pharmaceutically acceptable salts, hydrates, and solvates thereof), wherein R1, R2, R4, R7, R8, and R10 are as defined herein (for convenience, collectively referred to herein as "ALD compounds"):
Figure imgf000013_0003
Depending upon the values of -R1 and -R2, the carbon atom to which they are attached may be chiral, and if so, may independently be in the (R) or (S) configuration. Unless otherwise indicated, it is intended that both configurations are encompassed. In a preferred embodiment, the configuration is (S).
Depending upon the values of -R4, the carbon atom to which it is attached may be chiral, and if so, may independently be in the (R) or (S) configuration. Unless otherwise indicated, it is intended that both configurations are encompassed. In a preferred embodiment, the configuration is (S). Depending upon the values of -R7 and -R8, the carbon atom to which they are attached may be chiral, and if so, may independently be in the (R) or (S) configuration. Unless otherwise indicated, it is intended that both configuations are encompassed. Depending upon the values of -R1, -R2, -R4, -R7, and -R8, the compound may have one or two, or three chiral centres, giving rise to enantiomers or diastereoisomers. Unless otherwise indicated, it is intended that all such enantiomers and diastereoisomers are encompassed. Some embodiments of the invention include the following:
(1) A compound selected from compounds of the following formulae, and
pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000014_0001
wherein:
-R1 is independently -H or -R1A;
-R1A is independently saturated aliphatic Ci-ealk l, phenyl, or benzyl, and is optionally substituted;
-R2 is independently -H or -R2*;
-R2* is independently saturated aliphatic d.3alkyl, and is optionally substituted; or -R1 and -R2, taken together with the carbon atom to which they are attached, form a saturated C3.7cycloalkyl ring or a saturated C3.7heterocyclic ring, which is optionally substituted;
-R4 is independently -H or -R4A;
-R4A is independently saturated aliphatic Ci-3alkyl;
-R7 is independently -H, -R7A, or -R7B;
-R7A is independently saturated aliphatic Ci-6alkyl, and is optionally substituted; -R7B is independently -L7B1-R7BB, -R7BB, -L7B2-0-R7BB, or -|_7B2-0-L7B1-R7BB;
-L7B1- is independently saturated aliphatic C1-3alkylene;
-L7BZ- is independently saturated aliphatic C1-3alkylene;
-R7BB is independently -R7BB1, -R7BB2, -R7BB3, or -R7SB4;
-R7BB1 is independently phenyl or naphthyl, and is optionally substituted; -R7BB2 is independently C5-ioheteroaryl, and is optionally substituted;
-R7BB3 is independently C3.7cycloalkyl, and is optionally substituted, or is optionally fused to a benzene ring;
-R7BB4 is independently saturated bridged C5.i0cycloalkyl, and is optionally substituted;
-R8 is independently -H or -R8A;
-R8A is independently saturated aliphatic Chalky!, and is optionally substituted; or -R7 and -R8, taken together with the carbon atom to which they are attached, form a saturated C3.7cycloalkyl ring, a saturated bridged C5.i0cycloalkyl ring, or a non-aromatic C3.7heterocyclic ring, which is optionally substituted;
-R10 is independently -R10A, -R10B, -R10C, or -R10D;
-R 0A is independently phenyl or naphthyl, and is optionally substituted;
-R10B is independently C5.i0heteroaryl, and is optionally substituted;
-R10C is independently saturated C3.7cycloalkyl, and is optionally substituted; and
-R 0D is independently non-aromatic C3.i0heterocyclyl, and is optionally substituted.
For the avoidance of doubt, the term "aliphatic alkyl" refers to linear and branched alkyl groups, but not alicyclic alkyl (e.g., cycloalkyl) groups. For example, -nBu is an example of a linear C4alkyl group, and -iBu is an example of a branched C4alkyl group; in this way, both -nBu and -iBu are examples are aliphatic C4alkyl groups.
For the avoidance of doubt, the index "Cx.y" in terms such as "C5-ioheteroaryl",
"C3-7heterocyclic ring", "C3.7heterocyclyl", and the like, refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S). For example, pyridyl is an example of a C6heteroaryl group, and piperidino is an example of a C6heterocycyl group.
For the avoidance of doubt, the index "Cx.y" in terms such as "C5-ioheteroaryl",
"C3.7heterocyclic ring", "C3.7heterocyclyl", and the like, refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S).
For the avoidance of doubt, "heteroaryl" refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, and which has one or more heteroatoms (e.g., N, O, S) forming part of the aromatic ring system. For example, pyridyl is an example of a C6heteroaryl group, and quinolyl is an example of a
C10heteroaryl group. In contrast, "heterocyclyl" refers to a group that is attached to the rest of the molecule by a ring atom that is not part of an aromatic ring (i.e., the ring is fully or partially saturated), and the ring system contains one or more heteroatoms (e.g. , N, O, S). For example, piperidino is an example of a Csheterocycyl group. The Group -R1
(2) A compound according to (1), wherein -R1 is independently -H or -R A. (3) A compound according to (1), wherein -R1 is independently -R A.
(4) A compound according to (1), wherein -R1 is independently -H. The Group -R2
(5) A compound according to any one of (1) to (4), wherein -R2 is independently -H or -R2*
(6) A compound according to any one of (1) to (4), wherein -R2 is independently -R2
(7) A compound according to any one of (1) to (4), wherein -R2 is independently -H.
The Groups -R1 and -R2 (8) A compound according to (1), wherein:
-R is independently -H or -R1A; and
-R2 is independently -H or -R2*
(9) A compound according to (1), wherein:
-R1 is independently -H or -R A; and
-R2 is independently -H.
(10) A compound according to (1 ), wherein:
-R1 is independently -R1A; and
-R2 is independently -H.
(11) A compound according to (1), wherein:
-R1 is independently -H; and
-R2 is independently -H.
The Group -R1A
(12) A compound according to any one of (1) to (11), wherein -R1A is independently saturated aliphatic C -6alkyl, phenyl, or benzyl, and is optionally substituted, for example, with one or more substituents -RX1. (13) A compound according to any one of (1 ) to (1 ), wherein -R1A, if present, is independently saturated aliphatic C^alkyl, phenyl, or benzyl.
(14) A compound according to any one of (1) to (11), wherein -R1A, if present, is independently saturated aliphatic C1-6alkyl, and is optionally substituted, for example, with one or more substituents -RX1.
(15) A compound according to any one of (1) to (11), wherein -R1A, if present, is independently saturated aliphatic Chalky!.
(16) A compound according to any one of (1) to (11), wherein -R A, if present, is independently saturated aliphatic Chalky!, and is optionally substituted, for example, with one or more substituents -RX1. (17) A compound according to any one of (1) to (11), wherein -R1A, if present, is independently saturated aliphatic C1-4alkyl.
(18) A compound according to any one of (1) to (11), wherein -R A, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
(19) A compound according to any one of (1) to (11), wherein -R A, if present, is independently saturated aliphatic C3-4alkyl.
(20) A compound according to any one of (1) to (11), wherein -R A, if present, is independently -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
(21) A compound according to any one of (1) to (11), wherein -R1A, if present, is independently -iPr, -nBu, -iBu, or -tBu. (22) A compound according to any one of (1) to (11), wherein -R1A, if present, is independently -nPr, -iPr, -nBu, -iBu, or -sBu.
(23) A compound according to any one of (1) to (11), wherein -R1A, if present, is independently -iPr or -nBu.
(24) A compound according to any one of (1) to (11), wherein -R1A, if present, is independently -iPr.
(25) A compound according to any one of (1) to (11), wherein -R A, if present, is independently -nBu. The Group -R
(26) A compound according to any one of (1) to (25), wherein -R , if present, is independently saturated aliphatic d.3alkyl, and is optionally substituted, for example, with one or more substituents -RX1.
(27) A compound according to any one of (1) to (25), wherein -R2*, if present, is independently saturated aliphatic Ci.3alkyl. (28) A compound according to any one of (1) to (25), wherein -R2*, if present, is independently -Me, -Et, -nPr, or -iPr.
(29) A compound according to any one of (1) to (25), wherein -R2*, if present, is independently -Me or -Et.
(30) A compound according to any one of (1) to (25), wherein -R¾, if present, is independently -Me.
The Group -C(R )(R2)-
(31) A compound according to (1), wherein -R1 and -R2, taken together with the carbon atom to which they are attached, form a saturated C3.7cycloalkyl ring or a non-aromatic C3.7heterocyclic ring, which is optionally substituted, for example, with one or more substituents -RX2.
(32) A compound according to (1 ), wherein -R1 and -R2, taken together with the carbon atom to which they are attached, form a saturated C3-7cycloalkyl ring or a non-aromatic C3.7heterocyclic ring. (33) A compound according to (1), wherein -R1 and -R2, taken together with the carbon atom to which they are attached, form a saturated C3.7cycloalkyl ring, which is optionally substituted, for example, with one or more substituents -RX2.
(34) A compound according to (1 ), wherein -R1 and -R2, taken together with the carbon atom to which they are attached, form a saturated C3-7cycloalkyl ring.
(35) A compound according to (1 ), wherein -R1 and -R2, taken together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted, for example, with one or more substituents -RX2. (36) A compound according to (1 ), wherein -R1 and -R2, taken together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
(37) A compound according to (1 ), wherein -R1 and -R2, taken together with the carbon atom to which they are attached, form cyclopentyl.
(38) A compound according to (1 ), wherein -R and -R2, taken together with the carbon atom to which they are attached, form a non-aromatic C3.7heterocyclic ring, which is optionally substituted, for example, with one or more substituents -RX2.
(39) A compound according to (1 ), wherein -R1 and -R2, taken together with the carbon atom to which they are attached, form a non-aromatic C3.7heterocyclic ring.
The Group -R4
(40) A compound according to any one of (1) to (39), wherein -R4 is independently -R A.
(41 ) A compound according to any one of (1) to (39), wherein -R4 is independently -H. The Group -R4A
(42) A compound according to any one of (1) to (41 ), wherein -R A, if present, is independently -Me, -Et, -nPr, or -iPr. (43) A compound according to any one of (1) to (41 ), wherein -R4A, if present, is independently -Me or -nPr.
(44) A compound according to any one of (1) to (41 ), wherein -R4A, if present, is independently -Me.
The Group -R7
(45) A compound according to any one of (1) to (44), wherein -R7 is independently -R7A or -R7B.
(46) A compound according to any one of (1) to (44), wherein -R7 is independently -R7A
(47) A compound according to any one of (1) to (44), wherein -R7 is independently -R
(48) A compound according to any one of (1) to (44), wherein -R7 is independently -H. The Group -R
(49) A compound according to any one of (1) to (48), wherein -R , if present, is independently saturated aliphatic Ci.6alkyl, and is optionally substituted, for example, with one or more substituents -RX1.
(50) A compound according to any one of (1) to (48), wherein -R7A, if present, is independently saturated aliphatic d-6alkyl. (51 ) A compound according to any one of (1) to (48), wherein -R7A, if present, is independently saturated aliphatic Chalky!, and is optionally substituted, for example, with one or more substituents -RX1.
(52) A compound according to any one of (1) to (48), wherein -R7A, if present, is independently saturated aliphatic C alkyI.
(53) A compound according to any one of (1) to (48), wherein -R7A, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu. (54) A compound according to any one of (1) to (48), wherein -R7A, if present, is independently saturated aliphatic C3-4alkyl.
(55) A compound according to any one of (1) to (48), wherein -R7A, if present, is independently -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.
(56) A compound according to any one of (1) to (48), wherein -R , if present, is independently -tBu.
The Group -R 78
(57) A compound according to any one of (1) to (56), wherein -R7B, if present, is independently -L7B1-R7BB, -L7B2-0-R7BB, or -|_7B2-0-L7B1-R7BB.
(58) A compound according to any one of (1 ) to (56), wherein -R7B, if present, is independently -L7B1-R7BB or -L7B2-0-L7B1-R BB
(59) A compound according to any one of (1 ) to (56), wherein -R7B, if present, is independently -L7B1-R7BB. (60) A compound according to any one of (1 ) to (56), wherein -R7B, if present, is independently -L7B2-0-L7B1-R7BB. (61 ) A compound according to any one of (1) to (56), wherein -R7B, if present, independently -L7B2-0-R7BB.
(62) A compound according to any one of (1) to (56), wherein -R7B, if present, independently -R7BB
The Group -L 7B1
(63) A compound according to any one of (1) to (62), wherein -L7B1-, if present, independently -CHr, -CH(Me)-, -C(Me) , -CH2CH2-, or -CH2CH2CH .
(64) A compound according to any one of (1) to (62), wherein -L7B1-, if present, independently -CH2- or -CH2CH2-.
(65) A compound according to any one of (1) to (62), wherein -L781-, if present, is independently -CH2-.
The Group -L 7B2
(66) A compound according to any one of (1) to (65), wherein -L -, if present, is independently -CH2-, -CH(Me)-, -C(Me)2-, -CH2CH2-, or -CH2CH2CH2-.
(67) A compound according to any one of (1) to (65), wherein -L7B2-, if present, is independently -CH2- or -CH2CH2-.
(68) A compound according to any one of (1) to (65), wherein -L7B2-, if present, is independently -CH2-. The Group -R7BB
(69) A compound according to any one of (1) to (68), wherein -R7BB, if present, is independently -R7BB1, -R7BB2, or -R7BB3. (70) A compound according to any one of (1) to (68), wherein -R7BB, if present, is independently -R7BB1.
(71) A compound according to any one of (1) to (68), wherein -R7BB, if present, is independently -R7BB2. (72) A compound according to any one of (1) to (68), wherein -R , if present, is independently -R7BB3.
(73) A compound according to any one of (1) to (68), wherein -R7BB, if present, is independently -R7BB4.
The Group -R7BB1
(74) A compound according to any one of (1) to (73), wherein -R7BB , if present, is independently phenyl or naphthyl, and is optionally substituted, for example, with one or more substituents -RX3.
(75) A compound according to any one of (1) to (73), wherein -R7BB1, if present, is independently phenyl or naphthyl, and is optionally substituted, for example, with one or more substituents independently selected from -F, -CI, -Br, -I, -Me, and -Ph.
(76) A compound according to any one of (1) to (73), wherein -R7BB , if present, is independently phenyl or naphthyl. (77) A compound according to any one of (1) to (73), wherein -R7BB1, if present, is independently phenyl, and is optionally substituted, for example, with one or more substituents -RX3.
(78) A compound according to any one of (1) to (73), wherein -R7BB1, if present, is independently phenyl, and is optionally substituted, for example, with one or more substituents independently selected from -F, -CI, -Br, -I, -Me, and -Ph.
(79) A compound according to any one of (1) to (73), wherein -R7BB , if present, is independently phenyl.
(80) A compound according to any one of (1) to (73), wherein -R7BB1, if present, is independently naphthyl, and is optionally substituted, for example, with one or more substituents -RX3. (81) A compound according to any one of (1) to (73), wherein -R7BB1, if present, is independently naphthyl, and is optionally substituted, for example, with one or more substituents independently selected from -F, -CI, -Br, -I, -Me, and -Ph.
(82) A compound according to any one of (1) to (73), wherein -R7BB1, if present, is independently naphthyl. The Group -R
(83) A compound according to any one of (1 ) to (82), wherein -R7BB2, if present, is independently C5.ioheteroaryl, and is optionally substituted, for example, with one or more substituents -RX3.
(84) A compound according to any one of (1 ) to (82), wherein -R7BB2, if present, is independently Cs-ioheteroaryl. (85) A compound according to any one of (1 ) to (82), wherein -R7BB2, if present, is independently C5.6heteroaryl, and is optionally substituted, for example, with one or more substituents -RX3.
(86) A compound according to any one of (1 ) to (82), wherein -R7BB2, if present, is independently C5-6heteroaryl.
(87) A compound according to any one of (1 ) to (82), wherein -R7BB2, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl (e.g., 1 H-[1 ,2,3]triazolyl, 2H-[1 ,2,3]triazolyl, 4H-[1 ,2,4]triazolyl, 1 H-[1 ,2,4]triazolyl), oxadiazolyl (e.g., [1 ,2,3]oxadiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl), thiadiazolyl (e.g., [1 ,2,3]thiadiazolyl, [1 ,2,5]thiadiazolyl,
[1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl), pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl (e.g., [1 ,3,5]-triazinyl), and is optionally substituted, for example, with one or more substituents -RX3.
(88) A compound according to any one of (1) to (82), wherein -R7BB2, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted, for example, with one or more substituents -RX3.
(89) A compound according to any one of (1 ) to (82), wherein -R7BB2, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. (90) A compound according to any one of (1 ) to (82), wherein -R7BB2, if present, is independently pyridyl, and is optionally substituted, for example, with one or more substituents -Rx3.
(91 ) A compound according to any one of (1) to (82), wherein -R7BB2, if present, is independently pyridyl. (92) A compound according to any one of (1) to (82), wherein -R7BB2, if present, is independently C9.i0heteroaryl, and is optionally substituted, for example, with one or more substituents -RX3. (93) A compound according to any one of (1) to (82), wherein -R7BB2, if present, is independently C9.i0heteroaryl.
(94) A compound according to any one of (1) to (82), wherein -R BB2, if present, is independently quinolinyl, isoquinolinyl, or indolyl, and is optionally substituted, for example, with one or more substituents -R 3.
(95) A compound according to any one of (1) to (82), wherein -R7BB2, if present, is independently quinolinyl, isoquinolinyl, or indolyl. The Group -R7BB3
(96) A compound according to any one of (1) to (95), wherein -R7BB3, if present, is independently C3.7cycloalkyl, and is optionally substituted, for example, with one or more substituents -RX2, or is optionally fused to a benzene ring.
(97) A compound according to any one of (1) to (95), wherein -R7BB3, if present, is independently C3.7cycloalkyl, and is optionally substituted, for example, with one or more substituents -RX2. (98) A compound according to any one of (1) to (95), wherein -R7BB3, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally substituted, for example, with one or more substituents -RX2.
(99) A compound according to any one of (1) to (95), wherein -R7BB3, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
(100) A compound according to any one of (1) to (95), wherein -R7BB3, if present, is independently cyclohexyl. (101 ) A compound according to any one of (1 ) to (95), wherein -R7BB3, if present, is independently C3-6cycloalkyl, and is optionally fused to a benzene ring.
(102) A compound according to any one of (1) to (95), wherein -R7BB3, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and is optionally fused to a benzene ring. (103) A compound according to any one of (1 ) to (95), wherein -R , if present, is independently cyclopentyl fused to a benzene ring; as in, for example, indan-2-yl:
(indan-2-yl)
Figure imgf000025_0001
The Group -R
(104) A compound according to any one of (1) to (103), wherein -R7 , if present, is independently saturated bridged Cs-^cycloalkyl, and is optionally substituted, for example, with one or more substituents -RX2.
(105) A compound according to any one of (1) to (103), wherein -R7BB4, if present, is independently saturated bridged C5-i0cycloalkyl.
(106) A compound according to any one of (1) to (103), wherein -R7BB4, if present, is independently bicyclo[1.1.1]pentyl or adamantyl, and is optionally substituted, for example, with one or more substituents -RX2.
(107) A compound according to any one of (1) to (103), wherein -R7BEM, if present, is independently bicyclo[1.1.1]pentyl (an example of a saturated bridged C5cycloalkyl group) or adamantyl (an example of a saturated bridged Ciocycloalkyl group).
Figure imgf000025_0002
(108) A compound according to any one of (1) to (103), wherein -R7BB4, if present, is independently adamantyl.
The Group -R8 (109) A compound according to any one of (1 ) to (108), wherein -R is independently -H. (1 10) A compound according to any one of (1) to (108), wherein -R8 is independently The Group -R8A
(1 1 1) A compound according to any one of (1) to (1 10), wherein -R8A, if present, is independently saturated aliphatic Ci.6alkyl, and is optionally substituted, for example, with one or more substituents -RX1.
(1 12) A compound according to any one of (1 ) to (1 10), wherein -R8A, if present, is independently saturated aliphatic d-6alkyl. (1 13) A compound according to any one of (1) to (1 10), wherein -R8A, if present, is independently saturated aliphatic
Figure imgf000026_0001
and is optionally substituted, for example, with one or more substituents -RX1.
( 14) A compound according to any one of (1) to (110), wherein -R8A, if present, is independently saturated aliphatic d^alkyl.
(1 15) A compound according to any one of (1) to (1 10), wherein -R8A, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu. (1 16) A compound according to any one of (1 ) to (1 10), wherein -R8A, if present, is independently -Me, -Et, -nPr, or -iPr.
(117) A compound according to any one of (1) to (110), wherein -R , if present, is independently -Me.
The Group -C(R7)(R8)-
(118) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a saturated C3.7cycloalkyl ring, a saturated bridged C5.10cycloalkyl ring, or a non-aromatic C3-7heterocyclic ring, which is optionally substituted, for example, with one or more substituents -RX2.
(1 19) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a saturated C3.7cycloalkyl ring, which is optionally substituted, for example, with one or more substituents -R*2.
(120) A compound according to any one of (1 ) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a saturated C3-7cycloalkyl ring. (121 ) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted, for example, with one or more substituents -RX2.
(122) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (123) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form cyclohexyl.
(124) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a saturated bridged C5. 0cycloalkyl ring, which is optionally substituted, for example, with one or more substituents -RX2.
(125) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a saturated bridged C5.10cycloalkyl ring.
(126) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a non-aromatic C3.7heterocyclic ring, which is optionally substituted, for example, with one or more substituents -RX2.
(127) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a non-aromatic C3.7heterocyclic ring.
(128) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a non-aromatic Cs.7heterocyclic ring, which is optionally substituted, for example, with one or more substituents -RX2.
(129) A compound according to any one of (1) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a non-aromatic C5.7heterocydic ring.
(130) A compound according to any one of (1 ) to (44), wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form a non-aromatic Ceheterocyclic ring, which is optionally substituted, for example, with one or more substituents -RX2.
(131) A compound according to any one of (1) to (44), wherein -R7 and -RB, taken together with the carbon atom to which they are attached, form a non-aromatic
Cgheterocyclic ring.
Some Preferred Combinations (132) A compound accordi mple, as shown below:
Figure imgf000028_0001
(133) A compound according to (132), wherein the carbon atom to which -R4 is attached has the configuration shown in the following formula:
Figure imgf000028_0002
(134) A compound according to (132), wherein the carbon atom to which -R4 is attached, and the carbon atom to which -R and -R2 is attached, have the configurations shown in the following formula:
Figure imgf000028_0003
(135) A compound according to any one of (132) to (134), wherein: -R1 is -iPr and -R4 is -Me; for example, as shown below:
Figure imgf000028_0004
(136) A compound according to any one of (130) to (132), wherein: -R1 is -nBu and -R4 is -Me; for example, as shown below:
Figure imgf000029_0001
(137) A compound according to (1), wherein: -R2 is -H; and -R8 is -H; for example, as shown below:
Figure imgf000029_0002
(138) A compound according to (137), wherein the carbon atom to which -R4 is attached has the configuration shown in the following formula:
Figure imgf000029_0003
(139) A compound according to (137), wherein the carbon atom to which -R4 is attached, and the carbon atom to which -R1 and -R2 is attached, have the configurations shown in the following formula:
Figure imgf000029_0004
(140) A compound according to (137), wherein the carbon atom to which -R4 is attached, the carbon atom to which -R1 and -R2 is attached, and the carbon atom to which -R7 and -R8 are attached, have the configurations shown in the following formula:
O R4 O (141) A compound according to (137), wherein the carbon atom to which -R4 is attached, the carbon atom to which -R and -R2 is attached, and the carbon atom to which -R7 and -R8 are attached, have the configurations shown in the following formula:
Figure imgf000030_0001
(142) A compound according to any one of (137) to (141), wherein: -R1 is -iPr and -R4 is -Me; for example, as shown below:
Figure imgf000030_0002
(143) A compound according to any one of (137) to (141 ), wherein: -R1 is -nBu and -R4 is -Me; for example, as shown below:
Figure imgf000030_0003
(144) A compound according to any one of (137) to (141), wherein -R7 is -CH2-R for example, as shown below:
Figure imgf000030_0004
(145) A compound according to any one of (137) to (141 ), wherein -R1 is -iPr, -R4 is -Me, and -R7 is -CH2-R7BB; for example, as shown below:
Figure imgf000030_0005
(146) A compound according to any one of (137) to (141), wherein -R is -nBu, -R is -Me, and -R7 is -CH2-R7BB; for example, as shown below:
Figure imgf000031_0001
(147) A compound according to any one of (137) to (141), wherein -R1 is -iPr, -R4 is -Me, and -R7 is -CH2-Ph; for example, as shown below:
Figure imgf000031_0002
(148) A compound according to any one of (137) to (141), wherein -R1 is -nBu, -R4 is -Me, and -R7 is -CH2-Ph; for example, as shown below:
Figure imgf000031_0003
(149) A compound according to any one of (137) to (141), wherein -R7 is -R
for example, as shown bel
Figure imgf000031_0004
(150) A compound according to any one of (137) to (141 ), wherein R1 is -iPr, -R4 is -Me, and -R7 is -R7A; for example, as shown below:
Figure imgf000031_0005
(151) A compound according to any one of (137) to (141), wherein R1 is -nBu, -R4 is -Me, and -R7 is -R7A; for exampl
Figure imgf000032_0001
(152) A compound according to any one of (137) to (141), wherein R1 is -iPr, -R4 is -Me, and -R7 is -tBu; for example, as shown below:
Figure imgf000032_0002
(153) A compound according to any one of (137) to (141), wherein R1 is -nBu, -R4 is -Me, and -R7 is -tBu; for exampl
Figure imgf000032_0003
The Group -R 10 (154) A compound according to any one of (1) to (153), wherein -R is independently
Figure imgf000032_0004
(155) A compound according to any one of (1) to (153), wherein -R10 is independently
-R10A or -R10B.
(156) A compound according to any one of (1) to (153), wherein -R10 is independently -R10A
(157) A compound according to any one of (1) to (153), wherein -R is independently -R10B
(158) A compound according to any one of (1) to (153), wherein -R is independently -R10C (159) A compound according to any one of (1) to (153), wherein -R 0 is independently -R10D
The Group -R10A
(160) A compound according to any one of (1) to (159), wherein -R 0A, if present, is independently phenyl or naphthyl, and is optionally substituted, for example, with one or more substituents -RX3. (161) A compound according to any one of (1) to (159), wherein -R10A, if present, is independently phenyl or naphthyl, and is optionally substituted, for example, with one or more substituents independently selected from:
-F, -CI, -Br, -I,
Ci-4alkyl, -O-C^alkyl,
-CF3, -OCF3,
phenyl, -O-phenyl,
-NH2, -NH(C1-4alkyl), -NiC^alkyl);,,
Figure imgf000033_0001
pyrrolidine, piperidino, morpholino, piperizino, N-iC^alky -piperizino,
-0-CH2CH2-NH2, -0-CH2CH2-NH(Ci.4alkyl), -O-CHzCHz-NiC^alkyl);,,
-0-CH2CH2-pyrrolidino, -0-CH2CH2-piperidino, -0-CH2CH2-morpholino,
-0-CH2CH2-piperizino, -0-CH2CH2-{N-(Ci-4alkyl)-piperizino},
-0-CH2-imidazol-2-yl, -O-CH iN-tCi^alky -imidazol^-yl}, and
=0.
(162) A compound according to any one of (1) to (159), wherein -R 0A, if present, is independently phenyl or naphthyl, and is optionally substituted, for example, with one or more substituents independently selected from:
phenyl, -O-phenyl,
-NH2, -NH(C alkyl), -N(C1-4alkyl)2,
pyrrolidino, piperidino, morpholino, piperizino, N-iC^alkyO-piperizino,
-0-CH2CH2-NH2, -O-CH^HrNhKC^alkyl), -0-CH2CH2-N(C1-4alkyl)2,
-0-CH2CH2-pyrrolidino, -0-CH2CH2-piperidino, -0-CH2CH2-morpholino,
-0-CH2CH2-piperizino, -0-CH2CH2-{N-(C alkyl)-piperizino},
-0-CH2-imidazol-2-yl, and -0-CH2-{N-(C1-4alkyl)-irnidazol-2-yl}.
(163) A compound according to any one of (1) to (159), wherein -R10A, if present, is independently phenyl, and is optionally substituted, for example, with one or more substituents -RX3. (164) A compound according to any one of (1) to (159), wherein -R 0A, if present, is independently phenyl, and is optionally substituted, for example, with one or more substituents independently selected from:
-F, -CI, -Br, -I,
Ci-4alkyl, -0-C1-4alkyl,
-CF3, -OCF3,
phenyl, -O-phenyl,
-NH2, -NH(C1-4alkyl), -N(d.4alkyl)2,
-NH(C=0)(C alkyl),
pyrrolidino, piperidino, morpholino, piperizino,
Figure imgf000034_0001
-0-CH2CH2-NH2, -0-CH2CH2-NH(Ci-4alkyl), -0-CH2CH2-N(C1-4alkyl)2,
-0-CH2CH2-pyrrolidino, -0-CH2CH2-piperidino, -0-CH2CH2-morpholino,
-0-CH2CH2-piperizino, -0-CH2CH2-{N-(Ci-4alkyl)-piperizino},
-0-CH2-imidazol-2-yl, and -O-CHHN- C^alkylHmidazol^-yl}.
(165) A compound according to any one of (1) to (159), wherein -R10A, if present, is independently phenyl, and is optionally substituted, for example, with one or more substituents independently selected from:
phenyl, -O-phenyl,
-NH2, -NHiC^alkyl), -N(C1.4alkyl)2,
pyrrolidino, piperidino, morpholino, piperizino, N-(C1.4alkyl)-piperizino,
-0-CH2CH2-NH2, -0-CH2CH2-NH(Ci-4alkyl), -0-CH2CH2-N(C1-4alkyl)2,
-0-CH2CH2-pyrrolidino, -0-CH2CH2-piperidino, -0-CH2CH2-morpholino,
-0-CH2CH2-piperizino, -0-CH2CH2-{N-(C alkyl)-piperizino},
-0-CH2-imidazol-2-yl, and -0-CH2-{N-(C1-4alkyl)-imidazol-2-yl}.
(166) A compound according to any one of (1) to (159), wherein -R 0A, if present, is independently phenyl. (167) A compound according to any one of (1) to (159), wherein -R10A, if present, is independently naphthyl, and is optionally substituted, for example, with one or more substituents -RX3.
(168) A compound according to any one of (1) to (159), wherein -R10A, if present, is independently naphthyl.
The Group -R 0B
(169) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently C5.10heteroaryl, and is optionally substituted, for example, with one or more substituents -RX3. (170) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl (e.g., 1 H-[1 ,2,3]triazolyl, 2H-[1 ,2,3]triazolyl, 4H-[1 ,2,4]triazolyl, 1 H-[1 ,2,4]triazolyl), oxadiazolyl (e.g. , [1 ,2,3]oxadiazolyl, furazanyl, [1 ,3,4]oxadiazolyl,
[1 ,2,4]oxadiazolyl), thiadiazolyl (e.g. , [1 ,2,3]thiadiazolyl, [1 ,2,5]thiadiazolyl,
[1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl), pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl (e.g. , [1 ,3,5]-triazinyl), indolyl, isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,
benzoisoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, phthalazinyl, or quinoxalinyl, and is optionally substituted, for example, with one or more substituents -RX3.
(171 ) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently C5.6heteroaryl, and is optionally substituted, for example, with one or more substituents -RX3.
(172) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently C5-6heteroaryl, and is optionally substituted, for example, with one or more substituents independently selected from:
-NH2, -NH(C1-4alkyl), - iC^alky a,
pyrrolidine piperidino, morpholino, piperizino, N-iC^alky -piperizino,
Figure imgf000035_0001
=0.
(173) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted, for example, with one or more substituents -RX3.
(174) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted, for example, with one or more substituents -RX3. (175) A compound according to any one of (1) to (168), wherein -R 0B, if present, is independently pyridyl, pyrimidinyl, or pyrazinyl, and is optionally substituted, for example, with one or more substituents -RX3.
(176) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently pyridyl, pyrimidinyl, or pyrazinyl, and is optionally substituted, for example, with one or more substituents independently selected from: -NH2, -NH(C^alkyl), -N(C alkyl)2l
pyrrolidino, piperidino, morpholino, piperizino, N-id^alky -piperizino,
-NHC(=0)(C alkyl), and
=0.
(177) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently pyridyl, and is optionally substituted, for example, with one or more substituents -RX3. (178) A compound according to any one of (1) to (168), wherein -R 0B, if present, is independently pyridyl, and is optionally substituted, for example, with one or more substituents independently selected from:
-NH2, -NH(Ci.4alkyl), -N(C1-4alkyl)2,
pyrrolidino, piperidino, morpholino, piperizino, N-iC^alkylJ-piperizino,
Figure imgf000036_0001
=0.
(179) A compound according to any one of (1 ) to (168), wherein -R108, if present, is independently C9- 0heteroaryl, and is optionally substituted, for example, with one or more substituents -RX3.
(180) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently indolyl, isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, phthalazinyl, or quinoxalinyl, and is optionally substituted, for example, with one or more substituents -R 3.
(181) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently benzothiazolyl, quinolinyl, or isoquinolinyl, and is optionally substituted, for example, with one or more substituents -RX3.
(182) A compound according to any one of (1) to (168), wherein -R 0B, if present, is independently benzothiazolyl, quinolinyl, or isoquinolinyl. (183) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently benzothiazolyl, and is optionally substituted, for example, with one or more substituents -RX3.
(184) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently benzothiazolyl. (185) A compound according to any one of (1 ) to (168), wherein -R10B, if present, is independently quinolinyl or isoquinolinyl, and is optionally substituted, for example, with one or more substituents -RX3. (186) A compound according to any one of (1) to (168), wherein -R10B, if present, is independently quinolinyl or isoquinolinyl.
The Group -R10C (187) A compound according to any one of (1) to (186), wherein -R 0C, if present, is independently saturated C3-7cycloalkyl, and is optionally substituted, for example, with one or more substituents -RX2.
( 88) A compound according to any one of (1) to (186), wherein -R 0C, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted, for example, with one or more substituents -RX2.
(189) A compound according to any one of (1 ) to (186), wherein -R10C, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
(190) A compound according to any one of (1) to (186), wherein -R10C, if present, is independently cyclopentyl or cyclohexyl, and is optionally substituted, for example, with one or more substituents -RX2. ( 91) A compound according to any one of (1) to (186), wherein -R10C, if present, is independently cyclopentyl or cyclohexyl.
The Group -R10D (192) A compound according to any one of (1 ) to (191 ), wherein -R10D, if present, is independently non-aromatic C3.10heterocyclylt and is optionally substituted, for example, with one or more substituents -RX2.
(193) A compound according to any one of (1) to (191 ), wherein -R10D, if present, is independently non-aromatic C3.10heterocyclyl, and is optionally substituted, for example, with one or more substituents independently selected from d.4alkyl.
(194) A compound according to any one of (1) to (191), wherein -R10D, if present, is independently non-aromatic C3.i0heterocyclyl. (195) A compound according to any one of (1 ) to (191 ), wherein -R , if present, is independently non-aromatic C5.7heterocyclyl, and is optionally substituted, for example, with one or more substituents -RX2. (196) A compound according to any one of (1 ) to (191 ), wherein -R 0D, if present, is independently non-aromatic C5.7heterocyclyl, and is optionally substituted, for example, with one or more substituents independently selected from Ci-4alkyl.
(197) A compound according to any one of (1 ) to (191 ), wherein -R10 , if present, is independently non-aromatic C5.7heterocyclyl.
(198) A compound according to any one of (1 ) to (191 ), wherein -R10D is independently pyrrolidinyl, piperidinyl, morpholinyl, piperizinyl, tetrahydrofuranyl, tetrahydropyranyl, dixoanyl, azepanyl, or diazepanyl, and is optionally substituted, for example, with one or more substituents -RX2.
(199) A compound according to any one of (1 ) to (191 ), wherein -R10D is independently pyrrolidinyl, piperidinyl, morpholinyl, piperizinyl, tetrahydrofuranyl, tetrahydropyranyl, dixoanyl, azepanyl, or diazepanyl, and is optionally substituted, for example, with one or more substituents independently selected from C -4alkyl.
(200) A compound according to any one of (1 ) to (191 ), wherein -R10D is independently pyrrolidinyl, piperidinyl, morpholinyl, piperizinyl, tetrahydrofuranyl, tetrahydropyranyl, dixoanyl, azepanyl, or diazepanyl.
(201) A compound according to any one of (1 ) to (191 ), wherein -R10D is independently pyrrolidinyl, piperidinyl, morpholinyl, piperizinyl, tetrahydrofuranyl, tetrahydropyranyl, or dixoanyl, and is optionally substituted, for example, with one or more substituents -RX2. (202) A compound according to any one of (1 ) to (191), wherein -R 0 is independently pyrrolidinyl, piperidinyl, morpholinyl, piperizinyl, tetrahydrofuranyl, tetrahydropyranyl, or dixoanyl, and is optionally substituted, for example, with one or more substituents independently selected from d^alkyl. (203) A compound according to any one of (1 ) to (191), wherein -R10D is independently pyrrolidinyl, piperidinyl, morpholinyl, piperizinyl, tetrahydrofuranyl, tetrahydropyranyl, or dixoanyl.
(204) A compound according to any one of (1 ) to (191 ), wherein -R10D is independently piperidinyl, morpholinyl, or piperizinyl, and is optionally substituted, for example, with one or more substituents -RX2. (205) A compound according to any one of (1) to (191), wherein -R10D is independently piperidinyl, morpholinyl, or piperizinyl, and is optionally substituted, for example, with one or more subsituents independently selected from d.4alkyl.
(206) A compound according to any one of (1) to (191), wherein -R10D is independently piperidinyl, morpholinyl, or piperizinyl.
(207) A compound according to any one of (1) to (191), wherein -R 0D is independently piperidinyl, and is optionally substituted, for example, with one or more substituents -RX2.
(208) A compound according to any one of (1) to (191), wherein -R10D is independently piperidinyl, and is optionally substituted, for example, with one or more substituents independently selected from Ci.4alkyl.
(209) A compound according to any one of (1) to (191), wherein -R10D is independently piperidin-4-yl, and is optionally substituted, for example, with one or more substituents -RX2. (210) A compound according to any one of (1) to (191), wherein -R 0D is independently piperidin-4-yl, and is optionally substituted, for example, with one or more substituents independently selected from
Figure imgf000039_0001
The Optional Substituents -RX1
(211) A compound according to any one of (1) to (210), wherein each -RX , if present, is independently selected from:
-F, -CI, -Br, -I, phenyl, -CF3, -OH, -ORs, -OCF3, -NH2, -NHRS, -NRS 2, pyrrolidino, piperidino, morpholino, piperizino, N-(C1-4alkyl)-piperizino, -NHC(=0)Rs, -NRsC(=0)Rs, -C(=0)Rs, -C(=0)OH, -C(=0)ORs, -C(=0)NH2, -C(=0)NHRs, -C(=0)NRs 2,
-C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino,
-C(=0)-{N-(C alkyl)-piperizino}-, -SRS, -S(=0)Rs, and -S(=0)2Rs;
wherein each -Rs is independently saturated aliphatic Ci.6alkyl, phenyl, or -CH2-phenyl;
wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -Rss, -CF3, -OH, -ORss, or -OCF3, wherein each -Rss is
independently saturated aliphatic C1-4alkyl.
(212) A compound according to (211), wherein each -RX1, if present, is independently selected from: -F, -CI, -Br, -I, -OH, >ORs, -NH2, -NHRS, -NRS 2, pyrrolidino, piperidino, morpholino, piperizino, N-(C1-4alkyl)-piperizino, -NHC(=0)Rs, -NRsC(=0)Rs, -C(=0)NH2, -C(=0)NHRs,
Figure imgf000040_0001
and -C(=0)-{N-(C1.4alkyl)-piperizino}-.
(213) A compound according to (211 ), wherein each -RX1, if present, is independently selected from:
-OH, -ORs, -NH2, -NHRS, -NRS 2, pyrrolidino, piperidino, morpholino, piperizino, N-(C alkyl)-piperizino, -NHC(=0)Rs, -NRsC(=0)Rs, -C(=0)NH2, -C(=0)NHRs,
Figure imgf000040_0002
-C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, and -C(=0)-{N-(C1-4alkyl)-piperizino}-.
(214) A compound according to any one of (211) to (213), wherein each -Rs is
independently saturated aliphatic C1-6alkyl.
(215) A compound according to any one of (211) to (213), wherein each -Rs is
independently saturated aliphatic C -4alkyl.
The Optional Substituents -R*2
(216) A compound according to any one of (1) to (210), wherein each -RX2, if present, is independently selected from:
-F, -CI, -Br, -I, -RT, phenyl, -OH, -ORT, -C(=0)RT, -NH2, -NHRT, -NRT 2, pyrrolidino, piperidino, morpholino, piperizino,
Figure imgf000040_0003
and
-NRTC(=0)RT;
wherein each -RT is independently saturated aliphatic Chalky!, phenyl, or
-CH2-phenyl;
wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R""", -CF3, -OH, -ORn, or -OCF3, wherein each -R77 is independently saturated aliphatic C1-4alkyl.
(217) A compound according to (216), wherein each -R , if present, is independently selected from:
-RT, -OH, -ORT, -C(=0)RT, -NH2, -NHRT, -NRT 2, pyrrolidino, piperidino, morpholino, piperizino, N- C^alky -piperizino, -NHC(=0)RT, and -NRTC(=0)RT.
(218) A compound according to (216), wherein each -Rx2, if present, is independently selected from:
-RT, -C(=0)RT, -NH2, -NHRT, -NRT 2, pyrrolidino, piperidino, morpholino, piperizino, N-(C alkyl)-piperizino, -NHC(=0)RT, and -NRTC(=0)RT. (219) A compound according to (216), wherein each -R , if present, is independently selected from:
-RT, -NH2, -NHRT, -NRT2, pyrrolidine piperidino, morpholino, piperizino,
N-(C alkyl)-piperizino, -NHC(=0)RT, and -NRTC(=0)RT.
(220) A compound according to (216), wherein each -RX2, if present, is independently selected from:
-RT, -NH2, -NHRT, -NRT2, pyrrolidine piperidino, morpholino, piperizino, and N-(C alkyl)-piperizino.
(221 ) A compound according to (216), wherein each -RX2, if present, is independently -RT.
(222) A compound according to any one of (216) to (221), wherein each -RT is
independently saturated aliphatic d^alkyl.
(223) A compound according to any one of (216) to (221), wherein each -RT is
independently saturated aliphatic C1-4alkyl.
The Optional Substituents -RX3
(224) A compound according to any one of (1) to (223), wherein each -RX3, if present, is independently selected from:
-F, -CI, -Br, -I,
-Rv,
-CH=CH2, -C≡CH, cyclopropyl,
-CF3, -CHF2, -OCF3, -OCHF2,
-CN,
-N02,
-OH, -ORv,
-Lv-OH, -L -ORv,
-0-Lv-OH, -0-Lv-OR ,
Figure imgf000041_0001
pyrrolidino, piperidino, morpholino,
piperizino, N-(C1-4alkyl)-piperizino,
-LV-NH2, -LV-NHRV, -L -NRV 2,
-L -pyrrolidino, -Lv-piperidino, -L -morpholino,
-Lv-piperizino, -.^-{N-iC^alky -piperizino},
-Lv-imidazol-2-yl, -Lv-{N-(C alkyl)-imidazol-2-yl},
-0-Lv-NH2, -0-L -NHRv, -0-L -NRv 2,
-0-Lv-pyrrolidino, -0-Lv-piperidino, -0-Lv-morpholino,
-0-L -piperizino, -O-L^N-iC^alky -piperizino}, -0-Lv-imidazol-2-yl, -0-Lv-{N-(Ci.4alkyl)-imidazol-2-yl},
-NHC(=0)Rv, -NRvC(=0)Rv,
-C(=0)Rv,
-C(=0)OH, -C(=0)ORv,
-C(=0)NH2, -C(=0)NHRv, -C(=0)NRv 2,
-C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino,
-C(=0)-piperizino, -C(=0)-{N-(Ci-4alkyl)-piperizino}-,
-NHC(=0)NH2, -NHC(=0)NHR , -NHC(=0)NRv 2,
-NHC(=0)-pyrrolidino, -NHC(=0)-piperidino, -NHC(=0)-morpholino,
-NHC(=0)-piperizino, -NHC(=0)-{N-(C^alkyl)-piperizino}-,
-S(=0)2Rv,
-S(=0)2NH2, -S(=0)2NHRv, -S(=0)2NRv 2, and
=0;
wherein each -Lv- is independently saturated aliphatic C2-4alkylene;
wherein each -Rv is independently saturated aliphatic Ci.6alkyl, phenyl,
-CH2-phenyl, C5.6heteroaryl, or -CH2-C5.6heteroaryl;
wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -Rw, -CF3, -OH, -ORw, or -OCF3;
wherein each C5.6heteroaryl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -Rw, -CF3, -OH, -ORw, or -OCF3;
wherein each -Rw is independently saturated aliphatic C^alkyl;
and additionally, two adjacent groups -RX3 may together form -OCH20-, -0CH2CH20-, -CH20CH2- or -OCH2CH2-;
and additionally, two adjacent groups -RX3 may, together with the ring atoms to which they are attached, form a Cs.7carbocyclic ring or a C5. heterocyclic ring.
(225) A compound according to (224), wherein each -RX3, if present, is independently selected from:
-F, -CI, -Br, -I,
-Rv,
-CH=CH2, -C≡CH, cyclopropyl,
-CF3, -CHF2, -OCF3, -OCHF2l
-CN,
-N02,
-OH, -ORv,
-Lv-OH, -Lv-ORv,
-0-L -OH, -0-L -ORv,
Figure imgf000042_0001
pyrrolidinp, piperidino, morpholino,
piperizino, N-(C,_,alkyl)-piperizino,
-LV-NH2, -LV-NHRV, -LV-NRV 2, -Lv-pyrrolidino, -Lv-piperidino, -Lv-morpholino,
-Lv-piperizino, -Lv-{N-(Ci^alkyl)-piperizino},
-Lv-imidazol-2-yl, -Lv-{N-(C alkyl)-imidazol-2-yl},
-0-L -NH2, -0-Lv-NHRv, -0-Lv-NRv 2,
-0-Lv-pyrrolidino, -0-Lv-piperidino, -0-Lv-morpholino,
-0-L -piperizino, -0-Lv-{N-(C1-4alkyl)-piperizino},
-0-Lv-imidazol-2-yl, -0-Lv-{N-(C^alkyl)-imidazol-2-yl},
-NHC(=0)Rv, -NRvC(=0)Rv,
-C(=0)Rv,
-C(=0)OH, -C(=0)ORv,
-C(=0)NH2, -C(=0)NHRv, -C(=0)NR 2,
-C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino,
-C(=0)-piperizino, -C(=0)-{N-(C -4alkyl)-piperizino}-,
-NHC(=0)NH2l -NHC(=0)NHRv, -NHC(=0)NRv 2,
-NHC(=0)-pyrrolidino, -NHC(=0)-piperidino, -NHC(=0)-morpholino,
-NHC(=0)-piperizino, -NHC(=0)-{N-(C alkyl)-piperizino}-,
-S(=0)2Rv,
-S(=0)2NH2, -S(=0)2NHRv, -S(=0)2NRv 2, and
=0;
and additionally, two adjacent groups -RX3 may together form -OCH20-, -OCH2CH20-, -CH2OCH2- or -OCH2CH2-.
(226) A compound according to (224), wherein each -R 3, if present, is independently selected from:
-F, -CI, -Br, -I,
-Rv,
-OH, -ORv,
Figure imgf000043_0001
pyrrolidino, piperidino, morpholino,
piperizino, and
Figure imgf000043_0002
(227) A compound according to (224), wherein each -RX3, if present, is independently selected from:
-F, -CI, -Br, -I,
-Rv,
-OH, -ORv,
-NH2, -NHRV, and -NRV 2.
(228) A compound according to any one of (224) to (226), wherein each -Lv- is independently -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. (229) A compound according to any one of (224) to (228), wherein each -R is
independently saturated aliphatic d.6alkyl.
(230) A compound according to any one of (224) to (228), wherein each -Rv is
independently saturated aliphatic Ci.4alkyl.
Molecular Weight
(231 ) A compound according to any one of (1 ) to (230), wherein the compound has a molecular weight of from 241 to 1200.
(232) A compound according to (231 ), wherein the bottom of range is 250, 275, 300, 325, 350, 375, 400, or 500. (233) A compound according to (231 ) or (232), wherein the top of range is 100, 1000, 900, 800, 700, or 600.
(234) A compound according to any one of (1) to (230), wherein the compound has a molecular weight of range from 375 to 700.
Specific Compounds
(235) A compound according to (1 ), selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Code Compound
ALD-032
ALD-033
ALD-034
ALD-035
ALD-036
ALD-037
ALD-038
ALD-039
0
Figure imgf000050_0001
Code Compound
ALD-047
ALD-048
ALD-049
ALD-050
ALD-051
ALD-052
ALD-053
Figure imgf000052_0001
Code Compound
ALD-063
o H o
ALD-064
ALD-065
o \ H o ^
ALD-066
ALD-067
ALD-068
ALD-069
ALD-070
ALD-071 Combinations
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., -R1 , -R2, -R4, -R7, -R8, -R 0, -R A, -R2*,
R4A
Figure imgf000054_0001
-R10D, -R , -RX2, -RX3, etc.) are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e. , compounds that can be isolated, characterised, and tested for biological activity). In addition, all sub-combinations of the chemical groups listed in the
embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.
Substantially Purified Forms
One aspect of the present invention pertains to ALD compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g. , at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g. , at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
Unless specified, the substantially purified form refers to the compound in any
stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e. , purified with respect to other compounds. In one embodiment, the substantially purified form refers to one
stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
In one embodiment, the contaminants represent no more than 50% by weight, e.g. , no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1 % by weight.
Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
Geminal Diols, Hemiacetals, and Acetals
It is anticipated that the aldehyde (-C(=0)H) group of the ALD compounds may deliberately or inadvertently be converted entirely or partially to the corresponding geminal diol, hemi-acetal, or acetal upon contact with water, an alcohol, or a mixture of water and an alcohol. Such a transformation may occur, for example during purification (e.g., during recrystallisation from an aqueous or alcoholic solvent). This is illustrated below wherein, for example, each -RA is independently Ci-4alkyl, for example, -Me.
Furthermore, a cyclic acetal may be formed if a diol is used, for example, ethylene glycol, to produce the corresponding 1 ,3-dioxolane.
Figure imgf000055_0001
hemiacetal acetal It is anticipated that in aqueous solution any such geminal diols, hemiacetals, and acetals would be present in equilibrium with the parent compound. For the avoidance of doubt, it is intended that, unless otherwise specified, references herein to the ALD compounds also encompass such geminal diol, hemi-acetal, and acetal forms.
geminal diol hemiacetal acetal
Figure imgf000056_0001
Isomers
Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
A reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C -7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). However, reference to a specifc group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space. For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a
hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,
thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
Figure imgf000057_0001
keto enol enolate
For example, 1H-pyridin-2-one-5-yl and 2-hydroxyl-pyridin-5-yl (shown below) are tautomers of one another. A reference herein to one is intended to encompass both. See, for example, ALD-068.
Figure imgf000057_0002
1 H-pyridin-2-one-5-yl 2- ydroxyl-pyridin-5-yl
Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including H, 2H (D), and 3H (T); C may be in any isotopic form, including 2C, 13C, and 1 C; O may be in any isotopic form, including 60 and 180; and the like.
Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Salts
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of
pharmaceutically acceptable salts are discussed in Berge er a/., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO"), then a salt may be formed with a suitable cation.
Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K\ alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Α 3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from:
ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 +. If the compound is cationic, or has a functional group which upon protonation may become cationic (e.g., -NH2 may become -NH3 +), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.
Solvates and Hydrates
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g. , compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof. Chemicallv Protected Forms
It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.
For example, a hydroxy group may be protected as an ether (-OR) or an ester
(-OC(=0)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=0)CH3, -OAc).
For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=0) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated, for example, by hydrolysis using water in the presence of acid.
For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>Ν-0·).
For example, a carboxylic acid group may be protected as an ester for example, as: an Ci.7alkyl ester (e.g., a methyl ester; a t-butyl ester); a C -7haloalkyl ester (e.g., a
Ci.7trihaloalkyl ester); a triC1-7alkylsilyl-Ci.7alkyl ester; or a Cs^oaryl-C^alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=0)CH3).
Prodrugs
It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=0)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=0)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
Another form of prodrug of the ALD compounds may be one wherein the aldehyde (-C(=0)H) group of the ALD compound is protected, for example, as an acetal or hemiacetal, which is converted, in vivo, to the corresponding aldehyde.
Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), lipid directed enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. Chemical Synthesis
Several methods for the chemical synthesis of ALD compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
Compounds of Formula (I) may be prepared, for example, by reacting an alcohol of Formula (II) with an appropriate oxidising agent, as illustrated in the following scheme. Suitable oxidising agents include, but are not limited to, Dess-Martin periodinane, pyridinium chlorochromate (PCC), tetrapropylammonium perruthenate (TPAP), and the use of Swern or modified Swern conditions, which use DMSO in conjunction with an activating agent such as oxalyl chloride.
Scheme 1
Figure imgf000061_0001
(it) (I)
Alcohols of Formula (II) can be prepared by several different routes which are well known in the art. One such method involves reacting a compound of Formula (III) with a compound of Formula (IV) using standard acid-amine coupling conditions, as illustrated in the following scheme. Such conditions are known in the art. A potential side reaction under such conditions can be the epimerisation of the R4 chiral centre. It is common to avoid such side reactions by carrying out low temperature coupling reactions using a mixed anhydride derived from Formula (III). Mixed anhydrides are commonly generated in situ using, for example, isobutylchloroformate or ethylchloroformate and a mild base, such as N-methylmorpholine. Such methods are in the art.
Scheme 2
Figure imgf000061_0002
The alcohol group of compound (IV) may also be protected with for example a silyl protecting group in order to prevent side reactions during the coupling process.
Compound (II) can then be generated following removal of the protecting group. Suitable alcohol protecting groups and conditions for their removal can be found for example in Protective Groups in Organic Synthesis, 3rd Ed., (T. Green and P. Wuts; 4th Edition; Wiley-lnterscience, 1999), pp. 17-245.
Dipeptide and tripeptide derivatives may be synthesised on a polymeric
(e.g., polystyrene) resin using standard resin-based Fmoc coupling methods. The first Fmoc protected amino acid is generally coupled to Wang or 2-chloro-trityl resin.
Subsequent amino acids are coupled using standard acid-amine coupling conditions. Suitable conditions include the use of hydroxybenzotriazole (HOBt) with
Ν,Ν'-diisopropylcarbodiimide (DIC) or 2-(1 H-7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU), 0-(Benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), 0-Benzotriazole-N,N,N',N'-tetramethyl- uronium-hexafluoro-phosphate (HBTU), or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop), with a suitable base such as N,N-diisopropylethylamine (DIPEA). Further information on the synthesis of peptides on resin may be found, for example, in: Chan and White, Fmoc Solid Phase Peptide Synthesis: A Practical Approach (Oxford University Press, 2000).
Alternatively, peptide derivatives can be built up in a sequential fashion using solution chemistry with appropriately protected amino acids using methods known in the art. The use of suitable nitrogen protecting groups coupled with low temperature mixed-anhydride coupling conditions is commonly used for this purpose. Suitable nitrogen protecting groups include, but are not limited to, carboxybenzyl (CBz), t-butoxycarbonyl (Boc), and fluorenylmethyloxycarbonyl (Fmoc). A review of amine protecting groups can be found, for example, Protective Groups in Organic Synthesis, 3rd Ed., (T. Green and P. Wuts; 4th Edition; Wiley-lnterscience, 1999), pp. 494-653.
Alternatively ALD compounds of Formula (I) may be generated by the selective reduction of a carboxylic acid or a carboxylic acid derivative. One carboxylic acid derivative used for such purposes which is well known to the art is a Weinreb amide. Weinreb amides can be converted to aldehydes using reducing agents such as but not limited to, lithium aluminium hydride and diisobutylaluminium hydride. cheme 3
Figure imgf000062_0001
(V) (I)
Weinreb amides of Formula (V) may be prepared from the corresponding carboxylic acid using methods well known in the art. Alternatively an Fmoc-protected amino acid can be coupled to a N-methylhydroxylamine modified resin such as Weinreb AM resin purchasable from Novabiochem. This can then be used to synthesise a resin bound Weinreb amide of formula (V) using standard resin- based Fmoc coupling methods. ALD compounds of formula (I) can subsequently be generated following treatment of the resin with a suitable reducing agent such as lithium aluminium hydride in an appropriate solvent such as tetrahydrofuran (see, for example, Fehrentz et al., 1995).
Alternatively ALD compounds of formula (I) may be prepared from a derivative which contains a masked aldehyde unit, one such example would be a dimethyl acetal. A review of aldehyde protecting groups can be found, for example, Protective Groups in Organic Synthesis, 3rd Ed., (T. Green and P. Wuts; 4th Edition; Wiley-lnterscience, 1999), pp. 293-368. Compositions
One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising an ALD compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
In one embodiment, the composition is in the form of a dry powder, for example, suitable for delivery (e.g., administration) using a dry powder inhaler (DPI). Examples of sutable DPIs are well-known in the art. DPI administration may be used to deliver the drug to the lung or the nose.
In one embodiment, the composition is in the form of a suspension, for example, suitable for delivery (e.g., administration) using a nebuliser. This may be used to deliver the drug to the lung or the nose. In one embodiment, the composition is in the form of a solution or suspension in a liquid propellant, for example, suitable for delivery (e.g., administration) as an aerosol, for example, using a pressurised metered dose inhaler (pMDI). Examples of sutable pMDIs are well-known in the art. Suitable propellants are well-known in the art, and include, for example, dichlorodifluoromethane (CFC-12), trichlorofluoromethane,
dichoro-tetrafluoroethane, HFA-134a, HFA-227, HCFC-22, HFA-152, isobutene, and carbon dioxide. This may be used to deliver the drug to the lung or the nose, and may additionally be used to delivery the drug to the skin.
In one embodiment, the composition is in the form of an aqueous solution, for example, suitable for delivery (e.g., administration) using a dropper, syringe, metered dose spray pump or atomiser. This may be used to deliver the drug to the nose, to the skin, to the eye, and additionally may be used for injection.
In one embodiment, the composition further comprises one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein.
Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing an ALD compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing an ALD compound, as described herein; one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein; and a pharmaceutically acceptable carrier, diluent, or excipient.
Uses
The compounds described herein are useful, for example, in the treatment of diseases and disorders that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1), such as, for example, asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition that is triggered by a dust mite Group 1 peptidase allergen; and canine atopy. Use in Methods of Inhibiting a Dust Mite Group 1 Peptidase Allergen
One aspect of the present invention pertains to a method of inhibiting a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1), in vitro or in vivo, comprising contacting a dust mite Group 1 peptidase allergen with an effective amount of an ALD compound, as described herein.
One aspect of the present invention pertains to a method of inhibiting a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an ALD compound, as described herein.
Suitable assays for determining inhibition of a dust mite Group 1 peptidase allergen are described herein and/or are known in the art. Use in Methods of Therapy
Another aspect of the present invention pertains to an ALD compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
Another aspect of the present invention pertains to an ALD compound, as described herein, in combination with one or more (e.g.; 1 , 2, 3, 4) additional therapeutic agents, as described herein, for use in a method of treatment of the human or animal body by therapy.
Use in the Manufacture of Medicaments
Another aspect of the present invention pertains to use of an ALD compound, as described herein, in the manufacture of a medicament for use in treatment.
In one embodiment, the medicament comprises the ALD compound.
Another aspect of the present invention pertains to use of an ALD compound, as described herein, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, in the manufacture of a medicament for use in treatment.
In one embodiment, the medicament comprises the ALD compound and the one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents. Methods of Treatment
Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of an ALD compound, as described herein, preferably in the form of a pharmaceutical composition.
Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of an ALD compound, as described herein, preferably in the form of a pharmaceutical composition, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, preferably in the form of a pharmaceutical composition. Conditions Treated: Diseases and Disorders Mediated by a Dust Mite Group 1 Peptidase Allergen
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disease or disorder that is mediated by a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ).
Conditions Treated: Diseases and Disorders Ameliorated by the Inhibition of a Dust Mite Group 1 Peptidase Allergen
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of. a disease or condition that is ameliorated by the inhibition of a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ).
Conditions Treated: Particular Diseases and Disorders
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: asthma, for example, atopic asthma; allergic asthma; atopic bronchial IgE-mediated asthma;
bronchial asthma; extrinsic asthma; allergen-induced asthma; allergic asthma
exacerbated by respiratory virus infection; infective asthma; infective asthma caused by bacterial infection; infective asthma caused by fungal infection; infective asthma caused by protozoal infection; or infective asthma caused by viral infection.
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: bronchial hyper-reactivity associated with asthma; or bronchial hyper-responsiveness associated with asthma.
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: airway remodelling associated with an allergic lung disease, for example, airway remodelling associated with asthma.
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: asthma
co-presented with a chronic obstructive lung disease, for example, asthma co-presented with emphysema; or asthma co-presented with chronic bronchitis. ln one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: rhinitis, for example, allergic rhinitis; perennial rhinitis; persistent rhinitis; or IgE-mediated rhinitis. In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: allergic
conjunctivitis, for example, IgE-mediated conjunctivitis.
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: atopic dermatitis.
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: an allergic condition which is triggered by dust mites.
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: an allergic condition which is triggered by dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1).
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: canine atopy.
Treatment
The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure
(i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment."
For example, treatment includes the prophylaxis of asthma, reducing the incidence of asthma, reducing the severity of asthma, alleviating the symptoms of asthma, etc.
The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
Combination Therapies
The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents.
Typical examples of combinations for inhaled use in treatment of respiratory disease are fixed combinations of glucocorticoid receptor agonists and beta 2 adrenoceptor agonists. Such a combination product is "Advair" (also known as "Seretide"), which is a fixed combination of fluticasone propionate and salmeterol. Such combinations may be used in dry powder devices, pressurised metered dose inhalers and nebulisers. Many other respiratory agents may be used in fixed combinations in such devices. They may also be adminstered separately from different devices in different relative doses.
An inhaled combination product will be a fixed combination of a compound described herein with one or more additional agents (in which the ratios are decided on the merits of the individual components and selected from a suitable range by experiment) together with appropriate excipients.
For example, one aspect of the present invention pertains to a compound as described herein, in combination with one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents.
Thus, the agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously in fixed combination or at different times by individually varying dose schedules from a similar or different inhalation device. The precise dosage regimen of either combination or sequential treatment will be
commensurate with the properties of the therapeutic agent(s).
Additional Therapeutic Agents The ALD compounds described herein may be used in combination with one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, for example, in combination therapy as described herein.
In one embodiment, the one or more additional therapeutic agents are selected from agents used, or likely to be used, in the treatment of a respiratory disease. ln one embodiment, the one or more additional therapeutic agents are selected from: an anti-asthma agent and an anti-allergy agent.
In one embodiment, the one or more additional therapeutic agents are selected from: a beta2-adrenergic agonist;
an antagonist of the M3 muscarinic receptor;
a dual beta2 adrenoceptor agonist - M3 muscarinic antagonist;
a glucocorticoid receptor agonist;
a leukotriene antagonist;
a 5-lipoxygenase inhibitor;
a cromone;
an immunosuppressant;
an immune response modifier, e.g., an agonist of one or more Toll-Like Receptors (e.g., TLR2, TLR4, TLR7, TLR8, TLR9) or a vaccine;
a xanthine derivative;
a selective phoshodiesterase (PDE) isoenzyme inhibitor, e.g., an inhibitor of PDE4 and/or PDE5;
an inhibitor of certain kinase enzymes, e.g., p38 mitogen-activated protein (MAP) kinase,
IkappaB kinase 2 (IKK2), tyrosine-protein kinase (Syk), and phosphoinositide-3 kinase gamma (PI3Kgamma);
a histamine type 1 receptor antagonist;
a alpha adrenoceptor agonist vasoconstrictor sympathomimetic;
an inhibitor of a matrix metalloprotease;
a modulator of chemokine receptor function;
a cytokine;
a modulator of cytokine function;
an agent which act on a cytokine signalling pathway;
an immunoglobulin;
an immunoglobulin preparation;
an antagonist that modulates immunoglobulin function;
an antibody that modulates immunoglobulin function;
a lung surfactant protein, especially SP-A, SP-D;
an inhibitor of Der p 3, an inhibitor of Der p 6, and an inhibitor of Der p 9. Use as an Acaricide
The ALD compounds described herein may also be used as an acaricide, e.g., to control the population of, or to kill, mites, e.g., dust mites. Another aspect of the present invention pertains to an ALD compound, as described herein, for use as an acaricide. Another aspect of the present invention pertains to a composition comprising an ALD compound, as described herein, for use as an acaricide. Another aspect of the present invention pertains to an acaricide composition comprising an ALD compound, as described herein.
Another aspect of the present invention pertains to the use of an ALD compound, as described herein, as an acaricide.
Another aspect of the present invention pertains a method of killing mites (e.g., dust mites), comprising exposing said mites to an effective amount of an ALD compound, as described herein. Another aspect of the present invention pertains a method of controlling (e.g., limiting) a mite (e.g., dust mite) population comprising exposing mites to an effective amount of an ALD compound, as described herein.
Other Uses
The ALD compounds described herein may also be used as cell culture additives to inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ).
The ALD compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
The ALD compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other dust mite Group 1 peptidase allergen inhibitors, other anti-asthma agents, etc.
Kits
One aspect of the invention pertains to a kit comprising (a) an ALD compound as described herein, or a composition comprising an ALD compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
In one embodiment, the kit further comprises one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein. The written instructions may also include a list of indications for which the active ingredient is a suitable treatment. Routes of Administration
The ALD compound or pharmaceutical composition comprising the ALD compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray, drops or from an atomiser or dry powder delivery device); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital,
intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
The Subject/Patient
The subject/patient may be a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey
(e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.
In one preferred embodiment, the subject/patient is a human.
In one preferred embodiment, the subject/patient is a dog.
Formulations
While it is possible for the ALD compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one ALD compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one ALD compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound. The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 8th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary. The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols. Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
The compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
Formulations suitable for administration to the lung (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth) include those presented as a solution or suspension for delivery from a nebuliser; a dry powder for use in an appropriate inhaler device; and an aerosol spray for delivery from a pressurised pack with the use of a suitable propellant, such as dichlorodifluoromethane (CFC-12),
trichlorofluoromethane, dichoro-tetrafluoroethane, HFA-134a, HFA-227, HCFC-22, HFA- 152, isobutene, carbon dioxide, or other suitable gases. Devices for these methods of delivery are available. Formulations intended for nasal delivery can be adminsitered as aqueous solutions or suspensions, as solutions or suspensions in suitable propellants or as dry powders. Nasal droppers, nebulisers, atomisers, pressurised metered dose inhalers and dry powder inhalers for nasal delivery are available.
For administration by inhalation, the active compound is preferably in the form of microparticles. Suitable microparticles may be prepared by a variety of techniques, including spray-drying, freeze-drying and micronisation.
The microparticles may be formulated with excipients that aid delivery and release. For example, in a dry powder formulation, microparticles may be formulated with large carrier particles that aid the flow, for example, from a dry powder inhaler (DPI) into the lung. Suitable carrier particles are well-known in the art, and include lactose particles; they may have a mass median aerodynamic diameter of > 90 μητ
For administration using an aerosol, the active compound may be administered in a manner compatible with the inhaler system used. Suitable aerosol formulation may include, in addition to the active compound, excipients such as, for example, propellant (e.g., Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavourings, fillers (e.g., lactose in the case of powder inhalers) and, if appropriate, one or more additional active compounds.
For the purposes of inhalation of microparticulate formulations, a large number of systems are known with which aerosols of optimum particle size can be generated and administered, using an inhalation technique appropriate for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g., Nebulator™, Volumatic™), and automatic devices emitting a puffer spray (e.g., Autohaler™), for metered aerosols, in particular in the case of powdered inhalers, a number of technical solutions are available (e.g., Diskhaler™, Rotadisk™, Turbohaler™). Additionally, the active compound may be delivered in a multi-chamber device, thus allowing for delivery of combination agents.
For administration to the nose or lung, the active compound may also be used when formulated as an aqueous dispersion of nanoparticulates, or as a dry powder
nanoparticulate aerosol formulation, or as a propellant-based aerosol formulation.
Suitable nanoparticles may be prepared by spray-drying or freeze-drying aqueous nanoparticulate dispersions of drugs. Methods for the preparation of nanoparticulate dispersions of drugs, the preparation of aqueous, dry powder and propellant-based formulations of nanoparticulate drugs and their use in aerosol delivery systems are known (see, e.g., Bosch et al., 2009).
Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier. Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. , magnesium stearate, talc, silica); disintegrants (e.g. , sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g. , sodium lauryl sulfate); preservatives (e.g. , methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e. , an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues. Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for intranasal administration, where the carrier is a liquid and the drug can be administered as an aqueous solution or suspension in a suitable vehicle or propellant, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, by pressurised metered dose inhaler or atomiser, include aqueous or oily preparations of the compound. Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 micrometres which is administered in the manner in which snuff is taken, i.e. , by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound. Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g. , solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
Typically, the concentration of the compound in the liquid is from about 1 ng/mL to about 10 pg/mL. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried
(lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Dosage
It will be appreciated by one of skill in the art that appropriate dosages of the ALD compounds, and compositions comprising the ALD compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular ALD compound, the route of administration, the time of administration, the rate of excretion of the ALD compound, the duration of the treatment, other drugs,
compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of ALD compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
In general, a suitable dose of the ALD compound is in the range of about 0.5 pg to about 20 mg per kilogram body weight of the subject per day. In practice, for an inhaled agent, the upper limit will be set by the chosen device for delivery. Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
EXAMPLES
The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.
Chemical Synthesis Abbreviations Aq., aqueous;
Boc, ferf-butoxycarbonyl;
Cone, concentrated;
DCM, dichloromethane;
DIC, diisopropylcarbodiimide;
DIPEA, N,N-diisopropylethylamine;
DMAP, 4-dimethylaminopyridine;
DMF, dimethylformamide;
DMSO, dimethylsulfoxide;
EDC, 1 -Ethyl-3-[3-dimethylaminopropyl]carbodiimide;
ELSD, evaporative light scattering detection;
equiv., equivalents;
Et20, diethyl ether;
EtOAc, ethyl acetate;
Fmoc, fluorenylmethyloxycarbonyl;
h, hours;
HATU, 2-(7-Aza-1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate;
HOAT, 1-Hydroxy-7-Azabenzotriazole;
HOBt, N-Hydroxybenzotriazole;
HPLC, high performance liquid chromatography;
LC-MS, liquid chromatography mass spectrometry;
LDA, lithium diisopropylamide;
min, minutes;
MeOH, methanol;
MTBE, methyl-terf-butylether;
NMM, N-methylmorpholine;
NMR, nuclear magnetic resonance;
pet. ether, petroleum ether;
PS-Tosyl chloride, polystyrene supported tosyl chloride;
Rt, retention time;
Sat., saturated;
TFA, trifluoroacetic acid; THF, tetrahydrofuran;
TIPS, triisopropylsilane;
TMS, tri-methylsilane;
TBTU, 0-(ben2otriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate;
UPLC, ultra high performance liquid chromatography;
% v/v, percentage volume to volume;
% w/v percentage weight to volume.
Analytical Methods
Reverse-Phase Preparative LC-MS: Mass-directed purification preparative LC-MS using a preparative C-18 column (Phenomenex Luna C18 (2), 100 x 21.2 mm, 5 pm).
Analysis of products and intermediates has been carried using reverse-phase analytical HPLC-MS or UPLC-MS, using the parameters set out below. Purity was typically assessed by diode array at 210-400 nm.
HPLC Analytical Methods:
AnalpH2_45C: Phenomenex Luna C18(2) 5 pm, 100 x 4.6mm; A = water + 0.1% TFA; B= MeCN + 0.1% TFA; 45°C; %B: Omin 5%, 4.4min 95%, 5.3min 95%, 5.31 min 5%, 6.5min 5%; 2.5ml/min. AnalpH2: Phenomenex Luna C18 (2) 5 pm, 100 x 4.6 mm; A = water + 0.1% formic acid; B = MeCN + 0.1% formic acid; 35°C; % B: 0 min 5%, 4.4 min 95%, 5.3 min 95%, 5.31 min 5%, 6.5 min 5%; 2.5 mL/min.
AnalpH2_MeOH: Phenomenex Luna C18 (2) 3 pm, 50 x 3.0 mm; A = water + 0.1% formic acid; B = MeOH; 45°C; % B: 0 min 5%, 4.4 min 95%, 5.2 min 95%, 5.21 min 5%, 6.5 min 5%; 1.1 mL/min.
AnalpH2_MeOH_4min: Phenomenex Luna C18 (2) 3 pm, 50 x 4.6 mm; A = water + 0.1% formic acid; B = MeOH; 45°C; % B: 0 min 5%, 1 min 37.5%, 3 min 95%, 3.5 min 95%, 3.51 min 5%, 4.5 min 5%; 2.25 mL/min.
Aldehyde_QC_1 : Phenomenex Luna C18 (2) 5 pm, 150 x 4.6 mm; A = water + 0.1% TFA; B = MeCN + 0.1% TFA; 55°C; % B: 0 min 5%, 0.5 min 5%, 7.5 min 95%, 10min 95%, 10.1 min 5%, 13min 5%; 1.5 mL/min. Aldehyde_QC_2: Phenomenex Luna C18 (2) 5 pm, 150 x 4.6 mm; A = water + 0.1 % TFA; B = MeCN + 0.1 % TFA; 50°C; % B: 0 min 5%, 0.1 min 5%, 8 min 95%, 10.5 min 95%, 10.55 min 5%, 13.5 min 5%; 1.5 mL/min. Aldehyde_QC_3: Phenomenex Luna C 8 (2) 5 pm, 150 x 4.6 mm; A = water + 0.1 % TFA; B = MeCN + 0.1 % TFA; 55°C; % B: 0 min 5%, 1 min 5%, 7 min 95%, 10min 95%, 10.15 min 5%, 13 min 5%; 1.5 mUmin.
Aldehyde_QC (Gemini)_1 : Phenomenex Gemini C18 (2) 5 pm, 150 x 4.6 mm; A = water + 0.1% TFA; B = MeCN + 0.1 % TFA; 55°C; % B: 0 min 5%, 0.5 min 5%, 7.5 min 95%, 10 min 95%, 10.1 min 5%, 13 min 5%; 1.5 mlJmin.
Aldehyde_QC (Gemini)_2: Phenomenex Gemini C18 (2) 5 pm, 150 x 4.6 mm; A = water + 0.1 % TFA; B = MeCN + 0.1 % TFA; 55°C; % B: 0 min 5%, 0.5 min 5%, 7.5 min 95%, 10 min 95%, 10.1 min 5%, 13 min 5%; 2 mL min.
UPLC Analytical Methods: Method_2_Bic: Acquity UPLC BEH C-8, 1.7 pm, 100 x 2.1 mm; 40°C; A = 0.005 M ammonium bicarbonate (aq.); B = acetonitrile; % B: 0 min 30%, 4 min 80%, 6 min 80%, 6.1 min 30%; 0.3 mUmin.
Method_2_TFA_UPLC_2: Acquity UPLC BEH C18 1.7 pm, 100 x 2.1 mm; 25°C; A = water + 0.025% TFA; B = acetonitrile + 0.025% TFA; % B: 0 min 30%, 4 min 80%, 6 min 80%, 6.1 min 30%; 0.4 mL/min.
Method_4_TFA_UPLC_2: Acquity UPLC BEH C18 1.7 pm, 100 x 2.1 mm; 25°C A = water + 0.025% TFA; B = acetonitrile + 0.025% TFA; % B: 0 min 10%, 4 min 80%, 6 min 80%, 6.1 min 10%; 0.3 mL/min.
UPLC Analytical Methods:
Method_2_Bic: Acquity UPLC BEH C-8, 1.7 pm, 100 x 2.1 mm; 40°C; A = 0.005 M ammonium bicarbonate (aq.); B = acetonitrile; % B: 0 min 30%, 4 min 80%, 6 min 80%, 6.1 min 30%; 0.3 mL/min.
Method_2_TFA_UPLC_2: Acquity UPLC BEH C18 1.7 pm, 100 x 2.1 mm; 25°C; A = water + 0.025% TFA; B = acetonitrile + 0.025% TFA; % B: 0 min 30%, 4 min 80%, 6 min 80%, 6.1 min 30%; 0.4 mL/min. Method_4_TFA_UPLC_2: Acquity UPLC BEH C18 1.7 pm, 100 x 2.1 mm; 25°C A = water + 0.025% TFA; B = acetonitrile + 0.025% TFA; % B: 0 min 10%, 4 min 80%, 6 min 80%, 6.1 min 10%; 0.3 mUmin.
A General Approach for the Synthesis of ALD Compounds (I)
Some general methods used for the synthesis of ALD compounds of the present invention are illustrated in the following scheme.
Scheme 5
Solid Phase
Synthesis
Route 1
Figure imgf000082_0001
Dipeptide Acids (A)
Route 3
Route 2
Solution
Phase
Synthesis
Figure imgf000082_0002
ALD (I)
Route 4
Figure imgf000082_0003
Synthesis Synthesis of Dipeptide Intermediates (A) Route 1 : Dipeptide Intermediates (A) via Solid Phase Peptide Synthesis
Scheme 6
Figure imgf000083_0001
(A)
Peptides were synthesised on Wang resin using standard amide coupling procedures (see., e.g., Chan, W. C. and White, P. D., Fmoc Solid Phase Peptide Synthesis A Practical Approach, Oxford University Press, 2000). Fmoc-amino acids were purchased from commercial suppliers (e.g., Advanced Chemtech, Bachem, NovaBiochem or Polypeptide). Peptide grade DMF, which is free of dimethylamine, was used for peptide couplings to prevent any unwanted removal of Fmoc groups. Kaiser tests were used to indicate successful coupling of Fmoc-amino acids.
Typical Procedure
Step 1 - Coupling of First Amino Acid to Wang Resin: Wang resin was swollen with an appropriate volume of DMF then drained under vacuum. The Fmoc-amino acid (6 equiv.) was added followed by an appropriate volume of DMF (5 mLJg of resin), sufficient to cover the resin and peptide, and this mixture was shaken for 30 min. After that time, DIC (3 equiv.) and DMAP (catalytic) were added and the mixture was shaken for 4-5 h. The resin was drained under vacuum, washed with DCM and MeOH then re-swollen with DCM. Successful coupling could be indicated by carrying out step 2 on a small portion of the resin and performing a Kaiser test to indicate the presence of a free NH2 group. In general, the exact amount of amino acid attached to the resin was not quantified and subsequent reactions were performed on the basis of the maximum loading as indicated from the supplier. For amino acids that were purchased pre-attached to Wang resin, approximate loadings are supplied by the supplier and these were used for calculating amounts of reagent for subsequent steps. Step 2 - Fmoc-Deprotection:
The resin was shaken with an appropriate volume of 20% v/v piperidine in DMF (5 mL/g resin) for 1 h then washed with DMF, DCM, MeOH and re-swollen with DCM. A positive Kaiser Test (blue colour) indicates the presence of a free NH2 group.
Step 3 - Amide Coupling: The resin was shaken in an appropriate volume of DMF (~5 mL/g resin) with the appropriate Fmoc-amino acid (2 equiv.) or capping group R10CO2H (2 equiv.), TBTU (2 equiv.) and DIPEA (4 equiv. or 6 equiv. if, e.g., HCI salt is used) for 4-5 h. After that time, the resin was drained under vacuum, washed with DMF, DCM, MeOH and re-swollen with DCM. A negative Kaiser test (no colour change) indicates that all of the free amino sites have coupled. If the solution remained blue, step 3 was repeated.
Steps 2 and 3 were repeated for the coupling of additional amino acids and capping groups as necessary. Step 4 - Resin Cleavage:
The resin was shaken with the cleavage solution consisting of 95% TFA, 2.5% TIPS and 2.5% water (10 mlJg of resin) for 90 min, and then drained into an appropriate vessel. The resin was washed with DCM under vacuum filtration. The solvent was subsequently evaporated under vacuum, then azeotroped with toluene to remove any residual water or triturated with /so-hexane and diethyl ether or MTBE to leave the crude product residue. The resulting peptide (A) was either used crude or further purified by trituration with ether, flash column chromatography or reverse-phase preparative HPLC.
Dipeptide Intermediates (A) Prepared by Route 1
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Route 2: Dipeptide Intermediates (A) via Solution Phase Peptide Synthesis
Scheme 7
Figure imgf000090_0001
Figure imgf000090_0002
(11)
Figure imgf000090_0003
(12)
Figure imgf000090_0004
(A)
Typical Procedure
Step 1 - Synthesis of BOC-Amino Dipeptide Ethyl Esters (10): A solution of compound (8) (10 g, 1 equiv.) in THF (100 mL) was treated with /so-butyl chloroformate (1.05 equiv.) at -40°C, and NMM (1 equiv.), and stirred at -40°C for 30 min. A solution of compound (9) (1.1 equiv.) in a DMF and THF (40 mL, 1 : 1) mixture was added to the above reaction mixture at -40°C followed by addition of NMM (1 equiv.). The resulting mixture was stirred at -40°C for 2 h. The precipitated salts were filtered and washed with EtOAc (200 mL). The combined filtrate was washed with 10% w/v citric acid solution (2 x 50 mL), 5% w/v NaHC03 solution (2 x 50 mL), brine solution (50 mL), dried over Na2S04, filtered and concentrated in vacuo to give a crude residue. This was stirred with pet. ether (100 mL) for 30 min. The desired product (10) was isolated by filtration. (If necessary, the product was further washed with a 1 : 1 mixture of pentane-Et20 to remove additional impurities.) Step 2 - Synthesis of Amino Dipeptide Ethyl Esters (11):
A solution of compound (10) (5g, 1 equiv.) in DCM (50 mL) was treated with TFA
(5 equiv.) at 0°C and stirred at room temperature for 16 h. The volatiles were
concentrated and the residue was stirred with Et20 (150 mL) for 10 min and then filtered to collect the precipitated solid which was washed with n-pentane (50 mL) to obtain compound (11).
Step 3a - Synthesis ofAmido Dipeptide Ethyl Esters (12):
To a solution of compound (11) (10 g, 1 equiv.) and DIPEA (3 equiv.) in DCM (100 mL) at -20°C was added the appropriate acid chloride (R10COCI, 0.9 equiv.) and the reaction mixture was stirred at -20oC for 1 h. The reaction mixture was filtered to remove salts and the filtrate washed with 10% w/v citric acid solution (2 x 50 mL), 5% NaHC03 solution (2 x 50 mL) and brine solution (50 mL), dried over Na2S04, filtered and concentrated in vacuo to give a crude residue. This was further purified by trituration to give compound (12).
Step 3b - Synthesis ofAmido Dipeptide Ethyl Esters (12):
To a stirred mixture of carboxylic acid (R10CO2H, 1.8 g, 1 equiv.) in THF (100 mL) at -40°C was added /so-butyl chloroformate (1.05 equiv.) followed by NMM (2.5 equiv.). After 30 min, a solution of compound (11) (1 equiv.) in THF (20 mL) was added to the above reaction mixture at -40°C and stirred for 1 h. After that time, the THF was evaporated from the reaction mixture and the residue dissolved in EtOAc (200 mL), washed with (aq.) 10% w/v NaHC03 solution (2 x 100 mL), brine solution (100 mL), dried (Na2S04) and concentrated to obtain a crude residue. This was dissolved in CHCI3 (20 mL) and n-pentane was added to precipitate crude (12) which was collected by filtration. The solid was washed with n-pentane to give the desired compound (12).
Step 3c - Synthesis ofAmido Dipeptide Ethyl Esters (12):
To a solution of carboxylic acid (R10CO2H, 360 mg, 2.87 mmol, 1 equiv.) in DMF (10 mL) at 0°C was added EDC.HCI (1.2 equiv.), HOBt.HzO (1.2 equiv.) and DIPEA (2.5 equiv.) followed compound (11) (1 equiv.). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and the resulting residue was dissolved in EtOAc (50 mL), washed with brine (2 x 10 mL), dried (Na2S04) and concentrated in vacuo. Purification by column chromatography (typically neutral alumina, 1 % MeOH/CHCI3) afforded the desired compound ( 2). Step 4 - Synthesis of Capped Dipeptides (A):
To a solution of compound (12) (1 equiv.) in THF (6 volumes) and H20 (6 volumes) was added LiOH.H20 (4 equiv.) at 0°C. The reaction mixture was stirred for 2 h. The volatiles (THF) were removed from the reaction mixture, the aqueous was adjusted to pH ~7 with (aq.) 10% w/v citric acid solution. The precipitated solid was collected by filtration, washed with H20 (50mL), /7-pentane (50mL) and dried to obtain the corresponding capped dipeptide intermediate (A).
Dipeptide Intermediates (A) Prepared by Route 2
Figure imgf000092_0001
Compound Code Analytical Data Yield
AnalpH2_MeOH_4min;
Used
A43 Rt = 1.49mins; m/z 417
VN 0 ^ M 0 crude
(MH+); white solid
AnalpH2_MeOH_4min;
Rt = 1.42mins; m/z 417 Used
A44
(MH+); transleucent crude ^ solid
R,: 0.4 (50%
1.6g,
A47 MeOH/CHCI3); white
o 42% solid
Route 3: Synthesis of ALP Compounds via Tri-Petide Alcohol
Scheme 8
Figure imgf000093_0001
Typical Procedure
Step 1 - Synthesis of Peptidyl Alcohols (3):
To a solution of acid (A) (1 equiv.) in THF (25-50 mg/mL) and optionally DMF (0.05-0.25 volumes) at -40°C was added NM (3.1 equiv.) and /so-butyl chloroformate (1.1 equiv.). The reaction mixture was stirred at -40°C for approximately 30 min (extent of formation of the mixed anhydride can be monitored by quenching an aliquot of the reaction mixture in, e.g., excess pyrrolidine and analysing extent of amide formation by LC-MS). A solution of the amino alcohol (1.1 equiv.) in THF or DMF (0.1 volumes) was added dropwise. The reaction was stirred at -40°C for approximately 1 h until complete as measured by LC-MS. Additional amino alcohol could be added if required. The reaction mixture was allowed to warm to ambient temperature. The resulting mixture was diluted with EtOAc (10 volumes) and sat. aq. NaHC03 (10 volumes). The layers were separated and the aqueous layer extracted with EtOAc (2 x 10 volumes). The combined organic phases were washed with water (3 x 10 volumes) and brine (10 volumes) and concentrated under vacuum. The resulting alcohol (3) was either used directly or purified by flash column chromatography.
Step 2 - Synthesis of Peptidyl Aldehydes (4):
To a stirred solution of the corresponding alcohol (3) (1 equiv.) in dry DCM (1 mL/15-200 mg of alcohol) and optionally dry DMF (10-100% v/v depending upon solubility) at ambient temperature was added Dess-Martin periodinane (2 equiv.) in portions. The reaction mixture was stirred at ambient temperature and monitored by LC-MS until full conversion to product aldehyde had occurred (typically 1 h to 1 day). Where necessary, more Dess-Martin periodinane was added to complete the oxidation. The reaction mixture was quenched by addition of sat. (aq.) NaHC03 (1 volume) and (aq.) Na2S203 (10% w/v). The mixture was stirred for approximately 30 min, diluted with EtOAc (10 volumes) and washed with sat. (aq.) NaHC03 (2 x 5 volumes), deionised water (5 volumes) and brine (5 volumes). The organic layer was subsequently dried over MgS04 and evaporated to give the desired compound which was either triturated with ether or purified by reverse-phase preparative HPLC (a H20 + 0.1% TFA:MeCN + 0.1 % TFA gradient at 50°C was used for preparative HPLC) followed by lyophilisation to give the desired compound (4).
Route 4: Synthesis of ALP compounds using Weinreb Resin
Typical Procedure
Step 1 - Deprotecting the Fmoc-Weinreb-AM Resin: Fmoc-Weinreb-AM resin was swollen with an appropriate volume of DMF then drained under vacuum, washed twice with DCM then drained under vacuum. The resin was shaken with an appropriate volume of 20% v/v piperidine in DMF (8 ml_/g resin) for 1 h then washed with DMF, DCM, MeOH and re-swollen with DCM. A positive chloranil test (orange/red colour) indicates the presence of a free NH group.
Step 2 - Coupling of First Amino Acid to H-Weinreb-AM Resin:
To the resin was added the appropriate Fmoc-amino acid (2 equiv.), HATU (2 equiv.) and DIPEA (4 equiv.) in an appropriate volume of DMF (3 mU g of resin), sufficient to cover the resin dissolve the reagents, and this mixture was shaken for 5 h. After that time the resin was drained under vacuum, washed with DMF, DCM and MeOH then re-swollen with DC . Successful coupling could be indicated by performing a chloranil test to demonstrate the absence of a free NH group (lack of orange/red colour). In general, the exact amount of amino acid attached to the resin was not quantified and subsequent reactions were performed on the basis of the maximum loading as indicated from the supplier. For amino acids that were purchased pre-attached to Wang resin, approximate loadings are supplied by the supplier and these were used for calculating amounts of reagent for subsequent steps.
Step 3 - Fmoc-Deprotection:
The resin was swollen with an appropriate volume of DCM then drained under vacuum, washed twice with DMF then drained under vacuum. The resin was shaken with an appropriate volume of 20% v/v piperidine in DMF (15 mlJg resin) for 0.5 - 1 h, then washed with DMF, DCM, MeOH and re-swollen with DCM. A positive Kaiser test (blue colour) indicates the presence of a free NH2 group.
Step 4 - Coupling of Subsequent Amino Acids / Capping Groups to H-AA-Weinreb-AM Resin: The resin was shaken with the appropriate Fmoc-amino acid (2 equiv.) or capping group R10CO2H (3 equiv.), TBTU (2 equiv.) and DIPEA (4 equiv. or 6 equiv. if, e.g., HCI salt is used) in an appropriate volume of DMF (~3 - 5 mL/g resin) for 4 - 5 h. After that time, the resin was drained under vacuum, washed with DMF, DCM, MeOH and re-swollen with DCM. A negative Kaiser test (no colour change) indicates that all of the free amino sites have coupled. If the solution remained blue, step 4 was repeated.
Steps 3 and 4 were repeated for the coupling of additional amino acids or capping groups as necessary. Step 5 - Resin Cleavage:
The resin was swollen in anhydrous THF (4 mL/g resin) and was gently stirred at 0°C under an inert atmosphere (e.g. nitrogen). A solution of LiAIH4 (4 equiv.) in THF (~2.5M) was added to the resin and the mixture was gently stirred for 1 h. After this time the mixture was quenched at 0°C by dropwise addition of a sat. aq. solution of KHS04 (~1.5 mL/g resin) followed by a solution of aq. Rochelle salt (sodium potassium tartrate; 1.2M, 4 equiv.). The quenched mixture was allowed to warm to ambient temperature and was diluted with water (4 mL/g resin). The mixture was extracted with DCM (3 x 5 mL/g resin) using a hydrophobic frit to retain the aqueous phase, residual resin and insoluble salts. The combined DCM phase was dried over Na2S04. Svnthesized ALP Compounds
For aldehydes synthesised by route 3 the corresponding dipeptide acids are shown in brackets. Yields are quoted from these dipeptide acids for route 3 and based upon theoretical resin loadings for route 4.
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Code Compound Route Analytical Data Yield
Aldehyde_QC
15
ALD- 3 (Gemini)_1 ; Rt
mg, 032 (A32) 6.51 min; m/z 430
60% (MH+); white solid.
Aldehyde_QC
ALD- 3 (Gemini)_1 ; Rt 9 mg, 033 (A21) 7.38 min; m/z 506 46%
(MH+); white solid.
Figure imgf000100_0001
Aldehyde_QC
21
ALD- 3 (Gemini)_1 ; Rt
mg, 034 (A45) 4.73 min; m/z 431
32% (MH+); white solid.
Aldehyde_QC
30
ALD- (Gemini)_1 ; Rt
3 (A6) mg, 035 5.79 min; m/z 390
X o ^ 28%
(MH+); white solid.
Aldehyde_QC
50.4
ALD- 3 (Gemini)_1 ; Rt
mg, 036 (A34) 6.84 min; m/z 466
35% o H o ^ (MH+); white solid.
Aldehyde_QC
(Gemini)_1 ; Rt 11
ALD- 3
3.97 min; m/z 391 mg, 037 (A16)
o X H o ^ (Mhf ); colourless 17% amorphous solid.
Aldehyde_QC
ALD- 3 (Gemini)_ ; Rt 4mg, 038 (A31 ) 5.56 min; m/z 432 7%
(MH+); white solid.
Aldehyde_QC_1;
88
ALD- Rt 6.22 min; m/z
3 (A7) mg, 039 442 (MH+); white
50% XF solid.
Figure imgf000101_0001
Code Compound Route Analytical Data Yield
Aldehyde_QC_2;
135
ALD- 3 Rt 6.65 min; m/z
mg, 047 (A35) 452 (MH+); white
72% amorphous solid.
Aldehyde_QC
ALD- 3 (Gemini)_2; Rt 1 mg, 048 (A24) 3.41 min; m/z 425 1 %
(MH+); white solid.
Aldehyde_QC
32
ALD- 3 (Gemini)_2; Rt
mg, 049 0 j ° (A14) 5.93 min; m/z 474
42% (MH+); white solid.
Aldehyde_QC
3 mg,
ALD- 3 (Gemini)_2; Rt
4% 050 (A38) 5.57 min; m/z 454
(MH+); white solid.
Aldehyde_QC_2;
84
ALD- 3 Rt 4.30 min; m/z
mg, 051 (A16) 405 ( H+); white
42% solid.
Aldehyde_QC_2;
23
ALD- 3 Rt 4.74 min; m/z
mg, 052 (A17) 536 (MH+);
13% colourless solid.
Aldehyde_QC_2;
139
ALD- Rt 6.30 min; m/z
3 (A6) mg, 053 404 (MH+); white
43% solid.
Figure imgf000103_0001
Figure imgf000104_0001
solid. H NMR data for some of the above compounds is shown below.
Figure imgf000105_0001
Additional Synthesis Details
Described below are the syntheses of materials and reagents that may not be readily commercially available, and synthetic sequences outside the scope of those outlined above.
Synthesis of Ether Linked Benzoic Acid Intermediates - General Procedure:
Figure imgf000105_0002
Synthesis of 1~Methyl-1H-imidazole-2-carbaldehyde (BB5):
Figure imgf000105_0003
To a solution of 1 -methyl imidazole (57 g, 0.7 mmol) in THF (250 mL) was added LDA (2 M solution in THF, 348 mL) at -60°C and the stirred for 3 h. The reaction mixture was cooled -78'C, DMF (75 mL) was added rapidly, and the reaction mixture was slowly allowed to warm to room temperature and stirred at ambient temperature overnight. The reaction mixture was cooled to 0°C, a solution of NaH2P04 (100 g in 350 mL H20) was added and the resulting mixture was stirred for 30 min. The mixture was filtered to remove insoluble material and the filtrate was extracted with DCM (4 x 400 mL). The combined organic extracts were concentrated in vacuo and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 30% EtOAc/pet. ether) to provide (BB5) (41g, 53%) as a yellow solid. Rf: 0.3 (15% MeOH/CHCI3). H NMR (400 MHz, CDCI3): δ 9.82 (1 H, s), 7.28 (1 H, app d), 7.13 (1 H, app d), 4.04 (3H, s); m/z 111 (MH)+.
Synthesis of (1-Methyl-1 -imidazol-2-yl)methanol (BB6):
Figure imgf000106_0001
(BB5) (BB6)
To a solution of compound (BB5) (40.5 g, 368 mmol) in MeOH (300 mL) at 0°C was added NaBH (20.89 g, 551 mmol) portion wise. The reaction mixture was slowly warmed to room temperature and stirred for 5 h. The reaction mixture was cooled to 0°C, H20 (150 mL) was added and the mixture was stirred for 30 min at room temperature then concentrated in vacuo. The crude residue was dissolved in H20 (150 mL) and extracted with CHCI3 (4 x 200mL). The combined organic layers were dried over Na2S04 and concentrated. The residue was stirred with Et20 (150 mL) and filtered to afford
(BB6) (36 g, 87%) as a white solid. Rf: 0.4 (15% MeOH/CHCI3). H NMR (400 MHz, CDCI3): δ 6.89 (1 H, app d), 6.83 (1 H, ap d), 4.66 (2H, s), 3.72 (3H, s); m/z 1 13 ( H)+.
Synthesis of 2-(Chloromethyl)-1-methyl-1 H-imidazole Hydrochloride (BB7):
Figure imgf000106_0002
(BB6) (BB7)
To a solution of (BB6) (35.5 g, 316.96 mmol) in DCM (1500 mL) was added SOCI2 (330 mL, 4436 mmol) at 0°C, warmed to room temperature and stirred for 5 h. The reaction mixture was concentrated, the residue was washed with DCM (2 x 500 mL), followed by Et20 (2 x 200 mL) to obtain (BB7) (50 g, 95%) as an off-white solid. Rf: 0.4 (EtOAc). 1H NMR (400 MHz, DMSO-cfe): δ 7.76 (1 H, app d), 7.70 (1 H, app d), 5.17 (2H, s), 3.87 (3H, s); m/z 131 (MH)+.
Figure imgf000107_0001
A suspension of 4-hydroxy benzoic acid methyl ester (18 g, 1 18.42 mmol) and powdered anhydrous K2C03 (40.85 g, 296 mmol) in dry DMF (150 mL) was heated to 100°C. To the stirred reaction mixture was added (BB7) (25.5 g, 153.6 mmol) in six portions. The reaction mixture was stirred for 6 h and then cooled to room temperature and filtered. The filtrate was dissolved in H20 (200 mL), extracted with EtOAc (2 x 250mL), the combined organics were washed with brine solution (3 x 100mL), dried over Na2S04, concentrated in vacuo. The resulting crude compound was purified by column
chromatography (100-200 mesh silica gel, eluted with 2% MeOH-CHCI3) to provide (BB8) (17.1g, 52%) as an off-white solid. R,: 0.2 (50% EtOAc/pet. ether). H NMR (400 MHz, CDCI3): δ 8.0 (2H, d, J = 8.8 Hz), 7.33 (2H, d, J = 8.8 Hz), 7.02 (1 H, app d), 6.91 (1 H, app d), 5.22 (2H, s), 3.88 (3H, s), 3.73 (3H, s); m/z 247 (MH)+.
Synthesis of 4-(1-Methyl-1H-imidazol-2-yl)methoxybenzoic Acid Hydrochloride (BB9):
Figure imgf000107_0002
To a solution of (BB8) (24.1 g, 97.96 mmol) in MeOH (180 mL) was added aq. 5 N NaOH (70 mL) solution at room temperature. The reaction mixture was stirred at room temperature for 8 h and concentrated in vacuo. The residue was dissolved in H20 (100 mL) and washed with Et20 (2 x 100 mL), the aqueous layer was cooled in an ice bath and acidified with 6 N aq. HCI (pH ~6). The precipitated solid was collected by filtration and washed with pet ether (200 mL) and dried to provide (BB9) (20.7 g, 76%) as a white solid. Rf: 0.6 (5% MeOH/CHCI3). 1H NMR (400 MHz, DMSO-cfe): δ 7.92 (2H, d, J = 8.8 Hz), 7.42 (1 H, s), 7.21-7.19 (3H, m), 5.36 (2H, s), 3.76 (3H, s); mlz 233 (MH)+. Synthesis of Methyl-3-(1-methyl-1 H-imidazol-2-yl)methoxy Benzoate (BB10):
Figure imgf000108_0001
(BB7) (BB10)
A suspension of 3-hydroxy benzoic acid methyl ester (18 g, 1 18.42 mmol) and powdered anhydrous K2C03 (40.85 g, 296 mmol) in dry DMF (150 mL) was heated to 100°C. To the reaction mixture was added (BB7) (25.5 g, 153.6 mmol) in six portions. The reaction mixture was stirred for 6 h and then was cooled to room temperature and filtered. The filtrate was dissolved in H20 (200 mL), extracted with EtOAc (2 x 250 mL), and the combined organics were washed with brine solution (3x100mL), dried (Na2S04) and concentrated in vacuo. The resulting crude compound was purified by column chromatography (100-200 mesh silica gel, 2% eOH-CHCI3) to provide (BB10) (15.3 g, 52%) as an off-white solid. R,: 0.2 (50% EtOAc/pet. ether). 1H NMR (400 MHz, CDCI3): δ 7.67-7.55 (2H, m), 7.36 (1 H, t, J = 7.6 Hz), 7.25 (1 H, app d), 7.02 (1H, app d), 6.91 (1 H, app d), 5.19 (2H, s), 3.92 (3H, s), 3.74 (3H, s); m/z 247 (MH+).
Synthesis of Methyl-3-(1-methyl-1H-imidazol-2-yl)methoxy Benzoic Acid Hydrochloride (BB11):
Figure imgf000108_0002
(BB10) (BB11) To a solution of (BB10) (15.1 g, 61.38 mmol) in MeOH (150 mL) was added 5 N aq. NaOH (40 mL) solution at room temperature. The reaction mixture was stirred at room temperature for 5 h and concentrated in vacuo. The residue was dissolved in H20 (150 mL) and washed with Et20 (2 x 100mL), the aqueous layer was cooled in an ice bath and acidified with 6 N aq. HCI (pH ~6). The precipitated solid was collected by filtration, washed with chilled H20 (50 mL) and pet. ether (200 mL) and dried to provide (BB11) (7.8g, 46%) as an off-white solid. Rf: 0.6 (15% MeOH/CHCfe). 1H NMR (400 MHz, DMSO-d6): δ 7.65-7.56 (2H, m), 7.43 (1 H, t, J = 8 Hz), 7.35-7.30 (1 H, m), 7.26-7.20 (m, 1 H), 6.92-6.90 (m, 1 H), 5.21 (2H, s), 3.7 (3H, s); mlz 233 (MH+). Synthesis of Pyrimidine-4-carboxylic Acid (BB12);
Figure imgf000109_0001
To a solution of 4-methylpyrimidine (4g, 46.5 mmol) in pyridine (20 mL) was added Se02 (8.7 g, 79.06 mmol) at room temperature. The reaction mixture was then heated to 60°C for 2 h, and then stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (50 mL) and filtered to remove selenium waste. The filtrate was concentrated to give a residue that was stirred with H20 (20 mL), the precipitated solid was filtered and washed with acetone (2 x 20 mL) and dried to provide (BB12) (3.1g, 58%) as a brown solid. Rf: 0.2 (40%MeOH/CHCI3). 1H NMR (400MHz, DMSO-d6): δ 13.8 (1 H, br s), 9.37 (1 H, s), 9.07 (1 H, d, J = 5.2 Hz), 8.01 (1 H, d, J = 4 Hz); m/z 123 (M-H)\
Biological Methods- Enzyme Assays Many of the compounds contain a centre which is sufficiently basic, and were purified in such a way, that it is likely that they were obtained as the corresponding trifluoroacetic acid (TFA) salt. Consequently, in the biological studies described herein, it is believed that the following compounds were studied in the form of the corresponding TFA salt: ALD-026, ALD-029, ALD-031 , ALD-034, ALD-037, ALD-051 , ALD-052, ALD-054, ALD-056, ALD-057, ALD-059, ALD-060, ALD-062, ALD-063, ALD-064, ALD-065, ALD-067, ALD-070.
Assay for Per p 1 Der p 1 purification:
House dust mites of the species Dermatophagoides pteronyssinus were cultured as described (see Zhang et al., 2007). Der p 1 was purified chromatographically and its identity confirmed by SDS-PAGE and MALDI-TOF mass spectrometry (see Zhang et al., 2007). Its concentration in solution was determined in a quartz cuvette by absorbance at 280 nm using an extinction coefficient of 47,705 M'1 cm'1.
Derp 1 enzyme activity assay: The fluorogenic substrate used for measuring Der p 1 proteolytic activity was
2-aminobenzoylvalylalanylnorleucylseryl-(3-nitro)tyrosinyl aspartamide. This compound is internally quenched by fluorescence resonance energy transfer (FRET), but upon cleavage its emission at 420 nm increases when the substrate is excited at 330 nm (see Zhang et al., 2007).
Test compounds were dissolved in dry D SO and maintained at 4°C as stock solutions until being diluted for use in screening assays. Final concentration of DMSO in all enzymatic assays was 0.5% v/v.
Reaction mixtures were assembled in a 96-well plate format (Perkin Elmer Optiplate 96F, Perkin Elmer LAS, Seer Green, Buckinghamshire, UK) using a Perkin Elmer MultiPROBE II Plus HTS EX robot with Gripper attachment. Plates were pre-formatted with serial dilutions (10 plJwell) of test compound or appropriate control in reaction buffer
(composition: potassium phosphate buffer pH 8.25 containing 1 mM EDTA), to which a further 60 pL of reaction buffer was added. Dithiothreitol (DTT, 10 plJwell, 1 mM final concentration) was then added together with 10 ί of Der p 1 dissolved at 2.5 g/mL in reaction buffer supplemented with 1 mM DTT. Reaction mixtures were then incubated at room temperature for 20 minutes before initiating the reaction by the addition of 10 pL of substrate (12.5 μΜ final concentration). The plate was immediately transferred to a fluorescence plate reader (Perkin Elmer Fusion Alpha-FP or Perkin Elmer Envision) equipped with a temperature-controlled carrier set at 30°C and the reaction followed by excitation/emission at 330/420 nm.
Enzyme assay data analysis
Inhibitory activity was analysed from progress curves of reactions in the presence of a range of inhibitor concentrations. Initial reaction velocities were calculated by
computational non-linear regression and the degree of inhibition produced by compounds determined, from which the concentration required to inhibit the reaction by 50% (IC50) was calculated according to the scheme below: Initial velocity in each well was converted to fractional activity by Equation 1 :
Equation 1 :
Fractional activity = (Initial rate at inhibitor concentration [X] / Initial rate at inhibitor concentration zero) * 100
Then, IC50 was determined by fitting the data of fractional activity and inhibitor concentration to a 4-parameter logistic curve, using Equation 2: Equation 2:
V = Vmin + [ V - Vmin ] / [ 1 + ( X / ICso ) Hillslope ] where:
V is the fractional activity of the enzyme in the presence of inhibitor at concentration [X]; [X] is the inhibitor concentration;
Vmin is the minimum of Y observed at high inhibitor concentration;
Vmax is the maximum of Y observed at zero inhibitor concentration; and
Hillslope is the slope of the dose-response (inhibition) curve.
Biological Data - Per p 1 Enzyme Assay
The following compounds were studied using the Der p 1 assay described above:
ALD-001 to ALD-073.
All of the compounds were found to have a Der p 1 IC50 of less than 20 μΜ.
The following compounds were found to have a Der p 1 IC50 of less than 2 μΜ:
ALD-001 , ALD-002, ALD-003, ALD-005, ALD-006, ALD-007, ALD-008, ALD-009, ALD-010, ALD-01 1 , ALD-012, ALD-013, ALD-014, ALD-015, ALD-016, ALD-017, ALD-018, ALD-0 9, ALD-021 , ALD-022, ALD-023, ALD-024, ALD-026, ALD-027, ALD-028, ALD-029, ALD-030, ALD-031 , ALD-032, ALD-033, ALD-034, ALD-035, ALD-036, ALD-037, ALD-038, ALD-039, ALD-040, ALD-041 , ALD-042, ALD-043, ALD-044, ALD-045, ALD-046, ALD-047, ALD-048, ALD-049, ALD-050, ALD-051 , ALD-052, ALD-053, ALD-054, ALD-055, ALD-056, ALD-057, ALD-058, ALD-059, ALD-060, ALD-061 , ALD-062, ALD-063, ALD-064, ALD-065, ALD-066, ALD-067, ALD-068, ALD-069, ALD-070, ALD-071.
The following compounds were found to have a Der p 1 IC50 of less than 200 nM:
ALD-001 , ALD-002, ALD-005, ALD-006, ALD-007, ALD-008, ALD-010, ALD-01 1 , ALD-012, ALD-013, ALD-014, ALD-015, ALD-016, ALD-017, ALD-018, ALD-019, ALD-022, ALD-023, ALD-024, ALD-026, ALD-027, ALD-029, ALD-030, ALD-031 , ALD-032, ALD-033, ALD-034, ALD-035, ALD-036, ALD-037, ALD-039, ALD-040, ALD-041 , ALD-042, ALD-043, ALD-044, ALD-045, ALD-046, ALD-047, ALD-048, ALD-049, ALD-050, ALD-051 , ALD-052, ALD-053, ALD-054, ALD-055, ALD-056, ALD-057, ALD-058, ALD-059, ALD-060, ALD-061 , ALD-062, ALD-063, ALD-064, ALD-065, ALD-066, ALD-067, ALD-068, ALD-069, ALD-070, ALD-071. The following compounds were found to have a Der p 1 IC50 of less than 20 nM:
ALD-001 , ALD-002, ALD-005, ALD-007, ALD-008, ALD-010, ALD-011 , ALD-012, ALD-013, ALD-015, ALD-016, ALD-018, ALD-022, ALD-026, ALD-029, ALD-030, ALD-032, ALD-034, ALD-035, ALD-037, ALD-039, ALD-040, ALD-042, ALD-043, ALD-045, ALD-051 , ALD-052, ALD-053, ALD-055, ALD-058, ALD-060, ALD-062, ALD-063, ALD-064, ALD-065, ALD-071.
Data for several ALD compounds are shown in the following table.
Figure imgf000112_0001
Biological Methods - Allergen challenge studies in vivo
Animal identification and randomisation:
The studies were performed in male Brown Norway rats (approximate weight 350 g at time of allergen challenge) obtained from Harlan UK Ltd. Each animal was allocated a unique identification number after sensitisation, identified by a waterproof tail mark, and randomly assigned to a treatment group. All studies were conducted in accordance with the Animals (Scientific Procedures) Act 1986, with UK Home Office Guidance on the implementation of the Act and with all applicable Codes of Practice for the care and housing of laboratory animals.
Housing and environment:
Animals were initially housed within an air-conditioned colony room within the animal house until being transferred to a procedure room. Animals were caged in groups of up to 5. During the study, the rooms and cages were cleaned at regular intervals to maintain hygiene. The rooms were illuminated by fluorescent lights set to give a 12 hour light-dark cycle (on 07.00, off 19.00), as recommended in the Home Office Animals (Scientific Procedures) Act 1986. Air temperature (target temperature 21 °C ± 2°C) and relative humidity (which was not controlled) was measured during acclimatisation and the in-life phase. A diet of RM-1 (Special Diets Services, Witham, UK) and mains tap water was offered ad libitum.
Sensitization procedure to House Dust Mite (HDM) allergen:
A mixture of HDM allergens was harvested from a laboratory culture of
Dermatophagoides pteronyssinus. Allergen dose was standardized according to the Der p 1 content of the mixture as determined by an ELISA measurement referenced against the IUIS standard for Der p 1. The allergen sensitization dose for each animal on each day contained 10 pg Der p 1. Freeze-dried stocks of HDM allergen mixture stored at -20°C were reconstituted in their original volumes of 0.22 pm filter-sterilised de-ionised water containing 5 mM L-cysteine and 0.05% v/v Tween 20 and diluted to working concentration using sterile Dulbecco's phosphate buffered saline containing 5 mM L-cysteine and 0.05% v/v Tween 20. Animals were sensitized to a mixture of all HDM allergens on Days 0, 7, and 14 by intraperitoneal injection (0.5 mL) of the mixture formulated as described above.
Physiological recordings: On Day 21 of the sensitization and challenge protocol, rats were anaesthetised with pentobarbitone (100 mg/kg, i.p.) and ventilated via a tracheal cannula (approximately 7 mlJkg, 1 Hz) with a mixture of air and oxygen (50:50). The anaesthetised, ventilated animals were paralysed with norcuron (4 mg/kg, i.m.). Ventilation was monitored by a flow transducer (Fleisch, type 0000) in-line with the respiratory pump. Coincident pressure changes within the thorax were monitored directly via an intrathoracic cannula, so that the pressure difference between the trachea and thorax could be measured and displayed. From these measurements of flow and differential pressure, both airways resistance (RL) and dynamic compliance (Cdyn) were calculated for each respiratory cycle on a digital electronic respiratory analyser (PMS, Mumed Ltd, UK). Blood pressure and heart rate were recorded from the carotid artery by means of a transducer.
Drug delivery and allergen challenge:
Drugs were dissolved in DMSO as 10 mM stock solutions and then diluted in sterile saline (Baxter Healthcare, Berkshire, UK) for use in treatment. Drug solutions (100 pL of a 40 μΜ solution) were administered by the intra-tracheal (i.t.) route using a Penn Century IA-1 C sapphire orifice aerosoliser fitted to an FMJ-250 high pressure syringe (Penn Century, Philadelphia, PA, USA). For these studies, the tip of the IA-1 C aerosoliser was inserted inside the tracheal cannula and the volume of drug delivered regulated by means of volumetric stops on the syringe plunger. This combination of aerosoliser and syringe generates a plume of liquid with droplets 16-22 pm in mass median aerodynamic diameter.
Allergen challenge was with a mixture of HDM allergens containing a 10 μg dose of Der p 1. Freeze-dried stocks of HDM allergen mixture stored at -20°C were reconstituted in their original volumes of 0.22 pm filter-sterilised deionised water containing 5 mM L-cysteine and 0.05% v/v Tween 20 and diluted to working concentration using sterile Dulbecco's phosphate buffered saline containing 5 mM L-cysteine and 0.05% v/v
Tween 20. Allergen challenge (100 μί) was performed by the intratracheal (i.t.) route using a Penn Century aerosoliser as described above.
Study Design:
The study design comprised groups of 12 animals which had been actively sensitized to HDM allergens as described above. On day 21 of the study, the groups received two separate challenges with HDM allergens by the intratracheal (i.t.) route. In all cases, the effect of challenge 1 had fully resolved before the second challenge was made. At an interval of 2 hours before the second allergen challenge, animals received a dose of test compounds. Data analysis:
To evaluate the effect of allergen challenge and its modification by test compounds, lung function parameters were measured prior to allergen delivery (baseline) and at the peak response. The numerical difference in the lung function parameter (e.g., change in airway resistance) was recorded as the magnitude of the allergen challenge. This process was repeated after the animals had been dosed with test compound. Statistical analysis of the responses before and after administration of the test compound was used to determine if the compound exerted a significant effect. It was found by experiment to be equally valid to conduct these statistical comparisons either by comparing the change in the lung function parameter per se before and after treatment with test compound, or by expressing the magnitude of the second allergen challenge as a percentage of the first challenge and performing the statistical evaluation using the transformed data.
Biological Data - Allergen challenge studies in vivo Validation of study design
Figure 1 is a bar graph of the magnitude of response following Challenge 1 (left) and Challenge 2 (right), expressed as a percentage of the magnitude of the response following Challenge 1.
Figure 1 illustrates the results obtained when a group of rats sensitized to HDM allergens were subjected to two successive challenges with the same allergen mixture by the intratracheal (i.t.) route on Day 21 after sensitization was commenced. The average median response for challenge 1 was determined and defined as 100%. In each rat, the magnitude of the second response was then determined and expressed as the percentage of the response to challenge 1 . For the purposes of illustration of the second challenge response, the data are shown as the median and interquartile range
determined in 12 animals.
These data indicate that the magnitude of the second challenge is similar to that seen in the first challenge, enabling the modulating effect of a drug administered between the two treatments to be determined.
Effects of compounds on acute allergic bronchoconstriction:
Compound ALD-035 was studied using in vivo allergen challenge methods described above.
Code Structure
ALD-035 Figure 2 is a bar graph showing the percentage inhibition of the acute bronchoconstrictor response to allergen following administration of Compound ALD-035 at 15, 30 and 60 minutes prior to allergen challenge. Groups of 8-9 rats were challenged by the i.t. route with a mixture of house dust mite allergens (Challenge 1 ) and the acute bronchoconstrictor response in each animal declared as 100%. Compound ALD-035 was dosed by the i.t. route 15, 30 or 60 min prior to a second allergen challenge. The resulting acute bronchoconstrictor response was measured and the percentage inhibition of Challenge 1 calculated for each animal. Data show the mean percentage inhibition of the control allergen response (open columns), with error bars indicating the standard error of the mean. Statistical significance was evaluated by one-way ANOVA and pairwise multiple comparisons made using the Student-Newman-Keuls procedure. Asterisks denote significant inhibition (P<0.05) compared to the control allergen challenge. For skilled persons, inhibition of acute bronchoconstriction following allergen provocation in experimental models such as this is known to be indicative of a clinically beneficial effect in asthma.
The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.
REFERENCES
A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below.
Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Arruda et al., 1991 , "Exposure and sensitization to dust mite allergens among asthmatic children in Sao Paulo, Brazil", Clin. Exp. Allergy, Vol. 21 , pp. 433-439.
Asokananthan et al., 2002, "House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1 , activates protease-activated receptor (PAR)-2 and inactivates PAR-1", J. Immunol.,
Vol. 169, pp. 4572-4578.
Badalamente et al., 1984, "A method of enhancing neurofiber regrowth", European patent publication number EP 0100673 published 15 February 1984.
Barrett et al., 2005, "P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K", Biorq. Med. Chem. Lett.. Vol. 15, pp. 3540-3546.
Bodini et al., 2004, "Exhaled breath condensate eicosanoids and sputum eosinophils in asthmatic children: a pilot study", Pediatr. Allergy Immunol., Vol. 15, pp. 26-31. Bosch et al., 2009, "Dry powder aerosols of nanoparticulate drugs", US Patent No.
7,521 ,068, granted 21 April 2009.
Broide et al., 1992, "Cytokines in symptomatic asthma airways", J. Allergy Clin. Immunol.,
Vol. 89, pp. 958-967.
Charpin et al., 1991 , "Altitude and allergy to house-dust mites. A paradigm of the
influence of environmental exposure on allergic sensitization",
Am. Rev. Respir. Pis., Vol. 143, pp. 983-986.
Ciapetti et al., 1994, "CrCI2 mediated allylation of N-protected alpha-amino aldehydes.
A versatile synthesis of polypeptides containing an hydroxyethylene isostere",
Tetra. Lett.. Vol. 35, No. 19, pp. 3183-3186.
Comoy et al., 1998, "The house dust mite allergen, Dermatophagoides pteronyssinus, promotes type 2 responses by modulating the balance between IL-4 and IFN- gamma", J. Immunol.. Vol. 160, pp. 2456-2462.
Deb et al., 2007, "Major house dust mite allergens Dermatophagoides pteronyssinus 1 and Dermatophagoides farinae 1 degrade and inactivate lung surfactant proteins
A and D", J. Biol. Chem.. Vol. 282, pp. 36808-36819. Dowse et al., 1985, "The association between Dermatophagoides mites and the increasing prevalence of asthma in village communities within the Papua New Guinea highlands", J. Allergy Clin. Immunol., Vol. 75, pp. 75-83.
Eden et al., 2003, "Asthma features in severe alphal -antitrypsin deficiency: experience of the National Heart, Lung, and Blood Institute Registry", Chest, Vol. 123, pp. 765-771.
Fahy et al., 1995, "Comparison of samples collected by sputum induction and
bronchoscopy from asthmatic and healthy subjects", Am. J. Respir. Crit. Care
Med.. Vol. 152, pp. 53-58.
Fehrentz et al., 1995, "Improved solid phase synthesis of C-treminal peptide aldehydes"
Tetrahedron Lett.. Vol. 36, pp 7871-7874.
Fukuda et al., 1996, "Cysteine Protease Inhibitor", International patent publication number
WO 96/30395 A2 (Takeda Chemical Industries, Ltd.) published 03 October 1996. Fusetani et al., 1999, "Tokaramide A, a new cathepsin B inhibitor from the Marine Sponge Theonella aff. mirabilis", Bioorq. & Med. Chem., Vol. 9, pp. 3397-3402.
Gelber et al., 1993, "Sensitization and exposure to indoor allergens as risk factors for asthma among patients presenting to hospital", Am. Rev. Respir. Pis.. Vol. 147, pp. 573-578.
Ghaemmaghami et al., 2002, "The proteolytic activity of the major dust mite allergen Der p 1 conditions dendritic cells to produce less interleukin-12: allergen-induced Th2 bias determined at the dendritic cell level", Clin. Exp. Allergy. Vol. 32,
pp. 1468-1475.
Gough et al., 2001. "The proteolytic activity of the major dust mite allergen Der p 1
enhances the IgE antibody response to a bystander antigen", Clin. Exp. Allergy. Vol. 31 , pp. 1594 1598.
Gourgoulianis et al., 2001 , "The influence of altitude in bronchial asthma", Arch. Med.
Res.. Vol. 32, pp. 429-431.
Grootendorst et al.,2001, "Benefits of high altitude allergen avoidance in atopic
adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids", Clin. Exp. Allergy. Vol. 31 , pp. 400-408.
Habich et al., 1997, "Valine-containing pseudopeptides with antiviral activity", US patent number 5,633,231 (Bayer Akteingesellschaft) granted 27 May 1997.
Hellings et al., 2001 , "Eosinophilic rhinitis accompanies the development of lower airway inflammation and hyper-reactivity in sensitized mice exposed to aerosolized allergen", Clin. Exp. Allergy. Vol. 31 , pp. 782-790.
Holt et al., 1990, "A contiguous network of dendritic antigen-presenting cells within the respiratory epithelium", Int. Arch. Allergy Appl. Immunol., Vol. 91 , pp. 155- 59. Holt, 2002, "The role of airway dendritic cell populations in regulation of T-cell responses to inhaled antigens: atopic asthma as a paradigm", J .Aerosol Med.. Vol. 15, pp. 161-168. Huh et al., 2003, "Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung
parenchyma", J.Exp.Med.. Vol. 198, pp. 19-30.
Hyde et al., 1979, "Protease inhibitor variants in children and young adults with chronic asthma", Ann. Allergy. Vol. 43, pp. 8-13.
Jaakkola et al., 2006, "Are atopy and specific IgE to mites and molds important for adult asthma?", J. Allergy Clin. Immunol., Vol. 7, pp. 642-648.
Kalsheker et al., 1996, "The house dust mite allergen Der p1 catalytically inactivates alpha 1- antitrypsin by specific reactive centre loop cleavage: a mechanism that promotes airway inflammation and asthma", Biochem. Biophys. Res. Commun..
Vol. 221, pp. 59-61.
King et al., 1998, "Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium", J. Immunol., Vol. 161 , pp. 3645-3651.
Lambrecht et al., 2002, "Myeloid dendritic cells make it to the top", Clin. Exp. Allergy, Vol. 32, pp. 805-810.
Lambrecht et al., 2003a, "Taking our breath away: dendritic cells in the pathogenesis of asthma", Nat. Rev. Immunol.. Vol. 3, pp. 994-1003.
Lambrecht et al., 2003b, "The other cells in asthma: dendritic cell and epithelial cell
crosstalk", Current Opinion in Pulmonary Medicine. Vol. 9, pp. 34-41.
McCusker et al., 2002, "Site-specific sensitization in a murine model of allergic rhinitis: role of the upper airway in lower airways disease", J. Allergy Clin. Immunol.,
Vol.110, pp. 891-898.
McMillan et al., 2004, "Prolonged allergen challenge in mice leads to persistent airway remodelling", Clin. Exp. Allergy. Vol. 34, pp. 497-507.
Miyamoto et al., 1968, "Allergenic identity between the common floor mite
(Dermatophagoides farinae Hughes, 1961) and house dust as a causative antigen in bronchial asthma", J. Allergy. Vol. 42, pp. 14-28.
Mullersman et al., 1991, "Conjugation of N-acylated amino sugars to protein by reductive alkylation using sodium cyanoborohydride: application to an azo derivative of alpha-amanitin", Biochem. Cell Biol.. Vol. 69, pp. 418-427.
Muraguchi et al., 1988, "The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells", J. Exp. Med. Vol. 167, pp. 332-344.
Orlowski et al., 1996, "Substrate-relatd peptidyl-aldehyde inhibitors of the proteolytic activity of the multicatalytic proteinase complex", US patent number 5,580,854 granted 03 December 1996.
Peat et al., 1991 , "Sensitivity to common allergens: relation to respiratory symptoms and bronchial hyper-responsiveness in children from three different climatic areas of
Australia", Clin. Exp. Allergy. Vol. 21 , pp. 573-581.
Peat et al., 1996, "House dust mite allergens. A major risk factor for childhood asthma in
Australia", Am. J. Resoir. Crit. Care Med.. Vol. 153, pp. 141-146. Peroni et al., 1994, "Effective allergen avoidance at high altitude reduces allergen- induced bronchial hyperresponsiveness", Am. J. Respir. Crit. Care Med., Vol. 149, pp. 1442-1446.
Piacentini et al., 1998, "Mite-antigen avoidance can reduce bronchial epithelial shedding in allergic asthmatic children", Clin. Exp. Allergy, Vol. 28, pp. 561-567.
Piacentini et al., 1999, "Allergen avoidance at high altitude and urinary eosinophil protein
X", J. Allergy Clin. Immunol. Vol. 104, pp. 243-244.
Platts-Mills et al., 1987, "Seasonal variation in dust mite and grass-pollen allergens in dust from the houses of patients with asthma", J. Allergy Clin.lmmunol., Vol. 79, pp. 781-791.
Platts-Mills et al., 1997, "Indoor allergens and asthma: report of the Third International
Workshop", J. Allergy Clin. Immunol., Vol. 100, pp. S2-24.
Platts-Mills et al., 2000, "The role of intervention in established allergy: avoidance of indoor allergens in the treatment of chronic allergic disease", J. Allergy Clin.
Immunol.. Vol. 106, pp. 787-804.
Pollart et al.,1989, "Epidemiology of acute asthma: IgE antibodies to common inhalant allergens as a risk factor for emergency room visits", J. Allergy Clin. Immunol.,
Vol 83, pp. 875-882.
Raddatz et al., 1997, "Oxime- and nitron-substituted pseudopeptides with an anti-viral action", International patent publication number WO 97/30075 A1 (Bayer
Akteingesellschaft) published 21 August 1997.
Rudolph et al., 1978, "The significance of nasal protease inhibitor concentrations in house dust allergy", Allergy, Vol. 33, pp. 310-315.
Schultze-Werninghaus, 2006, "Should asthma management include sojourns at high altitude?", Chem. Immunol. Allergy, Vol. 91 , pp. 16-29.
Seymour et al., 1998, "Aerosol-induced immunoglobulin (Ig)-E unresponsiveness to
ovalbumin does not require CD8+ or T cell receptor (TCR)-gamma/delta+ T cells or interferon (IFN)-gamma in a murine model of allergen sensitization", J. Exp. Med.. Vol. 187, pp. 721-731.
Siev et al., 2000, "Novel hydrazino-carbonyl-amino-methylated polystyrene (HCAM) resin methodology for the synthesis of P1 -aldehyde protease inhbitor candidates", Org. Lett.. Vol. 2, No. 1 , pp. 19-22.
Sigsgaard et al., 2000, "S and Z alphal -antitrypsin alleles are risk factors for bronchial hyperresponsiveness in young farmers: an example of gene/environment interaction", Eur. Respir. J, Vol. 16, pp. 50-55.
Smith et al., 1969, "Clinical significance of skin reactions to mite extracts in children with asthma", Br. Med. J, Vol. 1 , pp. 723-726.
Sporik et al., 1990, "Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study", N. Engl. J. Med., Vol. 323, pp. 502-507. Stewart et al., 2003, "Allergen structure and function", in: Middleton's Allergy. Principles and Practice. (Eds. Adkinson et al.; Publisher: Mosby, Philadelphia), pp. 585-609. Stick et al., 2003, "The airway epithelium as immune modulator: the LARC ascending",
Am. J. Respir. Cell Mol. Biol, Vol. 28, pp. 641-644.
Sture et al., 1995, "Canine atopic dermatitis: the prevalence of psoitive intradermal skin tests at two sites in the north and south of Great Britain", Vet. Immunol.
Immunopathol., Vol. 44, pp. 293-308.
van Halteren et al., 1997, "Regulation of antigen-specific IgE, lgG1 , and mast cell
responses to ingested allergen by mucosal tolerance induction", J. Immunol., Vol. 159, pp. 3009-3015.
van Velzen et al., 1996., "Effect of allergen avoidance at high altitude on direct and
indirect bronchial hyperresponsiveness and markers of inflammation in children with allergic asthma", Thorax, Vol. 51, pp. 582-584.
Vercelli., 1989, "Endogenous interleukin 6 plays an obligatory role in interleukin 4- dependent human IgE synthesis", Eur. J. Immunol., Vol. 19, pp. 1419-1424.
Vervloet et al., 1982, "Altitude and house dust mites", J. Allergy Clin. Immunol., Vol. 69, pp. 290-296.
Wan et al., 1999, "Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions", J. Clin. Invest., Vol. 104, pp. 123-133.
Wan et al., 2000, "Tight junction properties of the immortalized human bronchial epithelial cell lines Calu-3 and 16HB", Eur. Respir. J., Vol. 15, pp. 1058-1068.
Wannamaker et al., 1999, "Inhibitors of Caspases", International patent publication
number WO 99/47545 A2 (Vertex Pharmaceuticals Inc.) published 23 September
1999.
Winton et al., 1998, "Cell lines of pulmonary and non-pulmonary origin as tools to study the effects of house dust mite proteinases on the regulation of epithelial permeability", Clin. Exp. Allergy, Vol. 28, pp. 1273-1285.
Zhang et al., 2007, "Interactions between mature Der p 1 and its free prodomain indicate membership of a new family of C1 peptidases," Allergy, Vol. 62, pp. 1302-1309. Zhang et al., 2009, "Novel Der p 1 inhibitors attenuate HDM sensitization in mice", Amer.
J. Respir. Crit. Care Med., Vol. 179, p. A4249.

Claims

A compound selected from compounds of the following formula, and
pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000122_0001
wherein:
-R1 is independently -H or -R1A;
-R1A is independently saturated aliphatic d-6alkyl, phenyl, or benzyl;
-R2 is independently -H; -R4 is independently -Me; -R7 is independently -R7A or -R7B;
-R7A is independently saturated aliphatic Ci-ealkyl;
-R7B is independently -L7B1-R7BB, -R7BB, -L7B -0-R7BB, or -L7B2-0-L7B1-R7BB;
-L7B1- is independently saturated aliphatic Ci_3alkylene;
-L782- is independently saturated aliphatic Ci.3alkylene;
-R7BB is independently -R7BB1, -R7BB2, -R7BB3, or -R BB4;
-R7BB1 is independently phenyl or naphthyl, and is optionally substituted;
-R7BB2 is independently C5-ioheteroaryl, and is optionally substituted;
-R7BB3 is independently C3.7cycloalkyl, and is optionally substituted, or is optionally fused to a benzene ring;
-R7BB4 is independently saturated bridged C5.iocycloalkyl, and is optionally substituted; -R8 is independently -H or -R8A;
-R8* is independently saturated aliphatic Ci.6alkyl; or -R7 and -R8, taken together with the carbon atom to which they are attached, form a saturated C3.7cycloalkyl ring, a saturated bridged C5.iocycloalkyl ring, or a non-aromatic C3.7heterocyclic ring, which is optionally substituted; -R10 is independently -R10A, -R10B, -R10C, or -R 0D;
-R 0A is independently phenyl or naphthyl, and is optionally substituted;
-R 0B is independently C5.i0heteroaryl, and is optionally substituted;
-R10C is independently saturated C3-7cycloalkyl, and is optionally substituted; and
-R 0D is independently non-aromatic C3-ioheterocyclyl, and is optionally substituted.
A compound according to claim 1 , wherein -R1 is independently -R1A.
A compound according to claim 1 or 2, wherein -R , if present, is independently saturated aliphatic Chalky!.
A compound according to claim 1 or 2, wherein -R , if present, is independently saturated aliphatic C^alkyl.
A compound according to claim 1 or 2, wherein -R , if present, is independently -iPr.
A compound according to claim 1 or 2, wherein -R , if present, is independently -nBu.
7. A compound according to any one of claims 1 to 6, wherein -R7 is independently -R7A. 8. A compound according to any one of claims 1 to 6, wherein -R7 is independently -R7B.
9. A compound according to any one of claims 1 to 8, wherein -R7A, if present, is independently saturated aliphatic C3-4alkyl.
10. A compound according to any one of claims 1 to 8, wherein -R7A, if present, is independently -tBu.
1 1. A compound according to any one of claims 1 to 10, wherein -R7B, if present, is independently -L7B1-R7BB.
12. A compound according to any one of claims 1 to 11 , wherein -L7B1-, if present, is independently -CH2-. 13. A compound according to any one of claims 1 to 12, wherein -R7BB, if present, is independently -R7BB1.
14. A compound according to any one of claims 1 to 12, wherein -R78B, if present, is independently -R7BB2. 15. A compound according to any one of claims 1 to 12, wherein -R7BB, if present, is independently -R7BB3.
16. A compound according to any one of claims 1 to 12, wherein -R7BB, if present, is independently -R7BB4.
17. A compound according to any one of claims 1 to 16, wherein -R7BB1, if present, is independently phenyl or naphthyl, and is optionally substituted with one or more substituents -RX3. 18. A compound according to any one of claims 1 to 16, wherein -R7BB1, if present, is independently phenyl or naphthyl, and is optionally substituted with one or more substituents independently selected from -F, -CI, -Br, -I, -Me, and -Ph.
19. A compound according to any one of claims 1 to 16, wherein -R7BB1, if present, is independently phenyl.
20. A compound according to any one of claims 1 to 16, wherein -R7BB1, if present, is independently naphthyl. 21. A compound according to any one of claims 1 to 20, wherein -R7BB2, if present, is independently C5.10heteroaryl, and is optionally substituted with one or more substituents -RX3.
22. A compound according to any one of claims 1 to 20, wherein -R7BBZ, if present, is independently C5.6heteroaryl.
23. A compound according to any one of claims 1 to 20, wherein -R7BB2, if present, is independently pyridyl, and is optionally substituted with one or more substituents -RX3.
24. A compound according to any one of claims 1 to 20, wherein -R7BB2, if present, is independently pyridyl.
25. A compound according to any one of claims 1 to 24, wherein -R7BB3, if present, is independently C3.7cycloalkyl, and is optionally substituted with one or more substituents -RX2, or is optionally fused to a benzene ring.
26. A compound according to any one of claims 1 to 24, wherein -R , if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
27. A compound according to any one of claims 1 to 24, wherein -R7BB3, if present, is independently cyclohexyl.
28. A compound according to any one of claims 1 to 27, wherein -R7BB4, if present, is independently saturated bridged C5-ioCycloalkyl, and is optionally substituted with one or more substituents -Rxz.
29. A compound according to any one of claims 1 to 27, wherein -R7BB4, if present, is independently adamantyl.
30. A compound according to any one of claims 1 to 29, wherein -R8 is independently
-H.
31. A compound according to any one of claims 1 to 29, wherein -R is independently
-R 8A
32. A compound according to any one of claims 1 to 31 , wherein -R , if present, is independently -Me.
33. A compound according to any one of claims 1 to 6, wherein -R7 and -R8, taken together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
34. A compound according to any one of claims 1 to 33, wherein the carbon atom to which -R" is attached, and the carbon atom to which -R1 and -R2 is attached, have the configurations shown in the following formula:
Figure imgf000125_0001
A compound according to any one of claims 1 to 30, wherein -R8 is -H, and wherein the carbon atom to which -R" is attached, the carbon atom to which -R1 and -R2 is attached, and the carbon atom to which -R7 and -R8 are attached, have the configurations shown in the following formula:
Figure imgf000126_0001
A compound according to any one of claims 1 to 30, wherein -R is -H, and wherein the carbon atom to which -R4 is attached, the carbon atom to which -R1 and -R2 is attached, and the carbon atom to which -R7 and -R8 are attached, have the configurations shown in the following formula:
Figure imgf000126_0002
A compound according to any one of claims 1 to 36, wherein -R10 is independently
_R10A
A compound according to any one of claims 1 to 36, wherein -R10 is independently
_R10B
A compound according to any one of claims 1 to 36, wherein -R10 is independently
_R10D
A compound according to any one of claims 1 to 39, wherein -R10A, if present, is independently phenyl or naphthyl, and is optionally substituted with one or more substituents -RX3.
A compound according to any one of claims 1 to 39, wherein -R10A, if present, is independently phenyl, and is optionally substituted with one or more substituents X3 A compound according to any one of claims 1 to 39, wherein -R1 , if present, is independently phenyl, and is optionally substituted with one or more substituents independently selected from:
-F, -CI, -Br, -I,
Ci-4alkyl, -0-C1-4alkyl,
Figure imgf000127_0001
phenyl, -O-phenyl,
-NH2, -NH(C^alkyl), - d^alky z,
-NH(C=0)(CMalkyl),
pyrrolidino, piperidino, morpholino, piperizino, N-iC^alky -piperizino,
-0-CH2CH2-NH2l -0-CH2CH2-NH(C,.4alkyl), -0-CH2CH2-N(C1.4alkyl)2,
-0-CH2CH2-pyrrolidino, -0-CH2CH2-piperidino, -0-CH2CH2-morpholino,
-0-CH2CH2-piperizino, -0-CH2CH2-{N-(Ci.4alkyl)-piperizino},
-0-CH2-imidazol-2-yl, and -O-CHHN-iCi^alky -imidazol^-yl}.
A compound according to any one of claims 1 to 39, wherein -R10A, if present, is independently phenyl.
A compound according to any one of claims 1 to 43, wherein -R10B, if present, is independently C5.10heteroaryl, and is optionally substituted with one or more substituents -RX3.
A compound according to any one of claims 1 to 43, wherein -R10B, if present, is independently C5.6heteroaryl, and is optionally substituted with one or more substituents -RX3.
A compound according to any one of claims 1 to 43, wherein -R10B, if present, is independently pyridyl, and is optionally substituted with one or more substituents -RX3.
A compound according to any one of claims 1 to 43, wherein -R10B, if present, is independently pyridyl, and is optionally substituted with one or more substituents independently selected from:
-NH2, -NH(C alkyl), -N(C,.4alkyl)2,
pyrrolidino, piperidino, morpholino, piperizino, N-(C1-4alkyl)-piperizino,
Figure imgf000127_0002
=0.
A compound according to any one of claims 1 to 43, wherein -R10B, if present, is independently benzothiazolyl, quinolinyl, or isoquinolinyl. A compound according to any one of claims 1 to 48, wherein -R , if present, is independently saturated C3-7cycloalkyl, and is optionally substituted with one or more substituents -RX2.
A compound according to any one of claims 1 to 48, wherein -R10C, if present, is independently cyclopentyl or cyclohexyl.
A compound according to any one of claims 1 to 50, wherein -R10D, if present, is independently non-aromatic C3.10heterocyclyl, and is optionally substituted with one or more substituents -RX2.
A compound according to any one of claims 1 to 50, wherein -R10D is
independently piperidin-4-yl, and is optionally substituted with one or more substituents independently selected from Chalky!.
A compound according to any one of claims 1 to 52, wherein each -RX2, if present, is independently selected from:
-F, -CI, -Br, -I, -RT, phenyl, -OH, -ORT, -C(=0)RT, -NH2, -NHRT, -NRT 2, pyrrolidine piperidino, morpholino, piperizino, N-(Ci.4alkyl)-piperizino,
-NHC(=0)RT, and -NRTC(=0)RT;
wherein each -RT is independently saturated aliphatic Chalky!, phenyl, or -CH2-phenyl;
wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R17, -CF3, -OH, -OR71, or -OCF3, wherein each -R™ is independently saturated aliphatic C1-4alkyl.
A compound according to claim 53, wherein each -RT is independently saturated aliphatic C1-4alkyl.
A compound according to any one of claims 1 to 54, wherein each -RX3, if present, is independently selected from:
-F, -CI, -Br, -I,
-Rv,
-CH=CH2, -C≡CH, cyclopropyl,
-CF3, -CHF2, -OCF3, -OCHF2,
-CN,
-N02,
-OH, -ORv,
-L -OH, -Lv-ORv,
-0-Lv-OH, -0-Lv-ORv,
-NH2, -NHRV, -NRV2, pyrrolidino, piperidino, morpholino,
piperizino, N-(C alkyl)-piperizino,
-LV-NH2, -LV-NHRV, -LV-NRV 2,
-Lv-pyrrolidino, -Lv-piperidino, -Lv-morpholino,
-Lv-piperizino, -Lv-{N-(C1-4alkyl)-piperizino},
-Lv-imidazol-2-yl, -Lv-{N-(C1-4alkyl)-imidazol-2-yl},
-0-Lv-NH2, -0-Lv-NHRv, -0-L -NRv 2,
-0-Lv-pyrrolidino, -0-L -piperidino, -0-Lv-morpholino,
-0-Lv-piperizino, -0-Lv-{N-(C1J(alkyl)-piperizino},
-0-L -imidazol-2-yl, -0-L -{N-(C^alkyl)-imidazol-2-yl},
-NHC(=0)R , -NRvC(=0)Rv,
-C(=0)Rv,
-C(=0)OH, -C(=0)ORv,
-C(=0)NH2, -C(=0)NHRv, -C(=0)NRv 2l
-C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino,
-C(=0)-piperizino, -C(=0)-{N-(Ci- alkyl)-piperizino}-,
-NHC(=0)NH2, -NHC(=0)NHRv, -NHC(=0)NRv 2t
-NHC(=0)-pyrrolidino, -NHC(=0)-piperidino, -NHC(=0)-morpholino,
-NHC(=0)-piperizino, -NHC(=0)-{N-(Ci-4alkyl)-piperizino}-,
-S(=0)2Rv,
-S(=0)2NH2, -S(=0)2NHRv, -S(=0)2NRv 2, and
=0;
wherein each -Lv- is independently saturated aliphatic C2. alkylene;
wherein each -Rv is independently saturated aliphatic d.6alkyl, phenyl, -CHrphenyl, C5-6heteroaryl, or -CH2-C5.6heteroaryl;
wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -Rw, -CF3, -OH, -ORw, or -OCF3;
wherein each C5.6heteroaryl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -Rw, -CF3, -OH, -ORw, or -OCF3;
wherein each -Rw is independently saturated aliphatic C1-4alkyl;
and additionally, two adjacent groups -RX3 may together form -OCH20-, -OCH2CH20-, -CH2OCH2- or -OCH2CH2-;
and additionally, two adjacent groups -R 3 may, together with the ring atoms to which they are attached, form a C5.7carbocyclic ring or a C5.7heterocyclic ring. A compound according to claim 55, wherein each -R , if present, is independently selected from:
-F, -CI, -Br, -I
-Rv,
-OH, -ORv,
Figure imgf000130_0001
pyrrolidino, piperidino, morpholino,
piperizino, and N-(Ci.-ialkyl)-piperizino.
57. A compound according to claim 55 or 56, wherein each -Rv is independently
saturated aliphatic Chalky!.
A compound according to claim 1 , selected from the following compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000130_0002
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
A composition comprising a compound according to any one of claims 1 to 58, and a pharmaceutically acceptable carrier, diluent, or excipient.
A method of preparing a composition comprising admixing a compound according to any one of claims 1 to 58 and a pharmaceutically acceptable carrier, diluent, or excipient.
61. A compound according to claim 1 , for use in a method of treatment of the human or animal body by therapy.
62. A compound according to any one of claims 1 to 58, for use in a method of
treatment of:
asthma, for example, atopic asthma; allergic asthma; atopic bronchial IgE-mediated asthma; bronchial asthma; extrinsic asthma; allergen-induced asthma; allergic asthma exacerbated by respiratory virus infection; infective asthma; infective asthma caused by bacterial infection; infective asthma caused by fungal infection; infective asthma caused by protozoal infection; or infective asthma caused by viral infection;
bronchial hyperreactivity associated with asthma; or bronchial
hyperresponsiveness associated with asthma; airway remodelling associated with an allergic lung disease, for example, airway remodelling associated with asthma;
asthma co-presented with a chronic obstructive lung disease, for example, asthma co-presented with emphysema; or asthma co-presented with chronic bronchitis;
rhinitis, for example, allergic rhinitis; perennial rhinitis; persistent rhinitis; or IgE-mediated rhinitis;
allergic conjunctivitis, for example, IgE-mediated conjunctivitis;
atopic dermatitis;
an allergic condition which is triggered by dust mites;
an allergic condition which is triggered by dust mite Group 1 peptidase allergen (e.g. , Der p 1 , Der f 1 , Eur m 1 ); or
canine atopy. 63. Use of a compound according to any one of claims 1 to 58, in the manufacture of a medicament for the treatment of:
asthma, for example, atopic asthma; allergic asthma; atopic bronchial
IgE-mediated asthma; bronchial asthma; extrinsic asthma; allergen-induced asthma; allergic asthma exacerbated by respiratory virus infection; infective asthma; infective asthma caused by bacterial infection; infective asthma caused by fungal infection; infective asthma caused by protozoal infection; or infective asthma caused by viral infection;
bronchial hyperreactivity associated with asthma; or bronchial hyperresponsiveness associated with asthma;
airway remodelling associated with an allergic lung disease, for example, airway remodelling associated with asthma;
asthma co-presented with a chronic obstructive lung disease, for example, asthma co-presented with emphysema; or asthma co-presented with chronic bronchitis;
rhinitis, for example, allergic rhinitis; perennial rhinitis; persistent rhinitis; or
IgE-mediated rhinitis;
allergic conjunctivitis, for example, IgE-mediated conjunctivitis;
atopic dermatitis;
an allergic condition which is triggered by dust mites;
an allergic condition which is triggered by dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1 ); or
canine atopy. A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 58, wherin the treatment of treatment of:
asthma, for example, atopic asthma; allergic asthma; atopic bronchial IgE-mediated asthma; bronchial asthma; extrinsic asthma; allergen-induced asthma; allergic asthma exacerbated by respiratory virus infection; infective asthma; infective asthma caused by bacterial infection; infective asthma caused by fungal infection; infective asthma caused by protozoal infection; or infective asthma caused by viral infection;
bronchial hyperreactivity associated with asthma; or bronchial
hyperresponsiveness associated with asthma;
airway remodelling associated with an allergic lung disease, for example, airway remodelling associated with asthma;
asthma co-presented with a chronic obstructive lung disease, for example, asthma co-presented with emphysema; or asthma co-presented with chronic bronchitis;
rhinitis, for example, allergic rhinitis; perennial rhinitis; persistent rhinitis; or IgE-mediated rhinitis;
allergic conjunctivitis, for example, IgE-mediated conjunctivitis;
atopic dermatitis;
an allergic condition which is triggered by dust mites;
an allergic condition which is triggered by dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1); or
canine atopy.
A compound according to claim 62, use according to claim 63, or a method according to claim 64, wherein the treatment further comprises treatment with one or more additional therapeutic agents selected from agents used, or likely to be used, in the treatment of a respiratory disease.
A method of inhibiting a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1), in vitro or in vivo, comprising contacting a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1) with an effective amount of a compound according to any one of claims 1 to 58.
A method of inhibiting a dust mite Group 1 peptidase allergen (e.g., Der p 1 , Der f 1 , Eur m 1) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 58. A compound according any one of claims 1 to 58, for use as an acaricide.
A composition comprising a compound according to any one of claims 1 to 58, for use as an acaricide.
An acaricide composition comprising a compound according to any one of claims 1 to 58.
Use of a compound according to any one of claims 1 to 58 as an acaricide.
A method of killing mites (e.g., dust mites), comprising exposing said mites to an effective amount of a compound according to any one of claims 1 to 58.
A method of controlling (e.g., limiting) a mite (e.g., dust mite) population comprising exposing mites to an effective amount of a compound according to any one of claims 1 to 58.
PCT/GB2011/001011 2010-07-06 2011-07-04 Aldehyde compounds as inhibitors of dust mite group 1 peptidase allergen and their use WO2012004554A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1011411.4 2010-07-06
GBGB1011411.4A GB201011411D0 (en) 2010-07-06 2010-07-06 Therapeutic compounds and their use

Publications (1)

Publication Number Publication Date
WO2012004554A1 true WO2012004554A1 (en) 2012-01-12

Family

ID=42669292

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2011/001011 WO2012004554A1 (en) 2010-07-06 2011-07-04 Aldehyde compounds as inhibitors of dust mite group 1 peptidase allergen and their use

Country Status (2)

Country Link
GB (1) GB201011411D0 (en)
WO (1) WO2012004554A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8541363B2 (en) 2010-01-22 2013-09-24 St George's Hosptial Medical School Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
CN103655557A (en) * 2012-09-11 2014-03-26 北京大学 Use of CD38 enzyme inhibitor in treating bronchial hyperresponsiveness diseases
WO2017049206A1 (en) * 2015-09-17 2017-03-23 City Of Hope Pcna inhibitors
US10829440B2 (en) 2015-06-12 2020-11-10 Brown University Antibacterial compounds and methods of making and using same
WO2021060048A1 (en) 2019-09-25 2021-04-01 日産化学株式会社 Method for producing peptide compound
US11555010B2 (en) 2019-07-25 2023-01-17 Brown University Diamide antimicrobial agents
WO2024028417A1 (en) 2022-08-03 2024-02-08 Institut National de la Santé et de la Recherche Médicale New composition for the treatment and/or prevention of vitiligo

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1011411A (en) 1960-11-13 1965-12-01 B C M Plastic Developments Ltd Improvements in the production of tube bends of reinforced thermo-setting plastic
EP0100673A2 (en) 1982-08-02 1984-02-15 The Research Foundation Of State University Of New York A method of enhancing neurofiber regrowth
WO1996030395A2 (en) 1995-03-31 1996-10-03 Takeda Chemical Industries, Ltd. Cysteine protease inhibitor
US5580854A (en) 1994-03-04 1996-12-03 Mount Sinai School Of Medicine Of The City University Of New York Substrate-related peptidyl-aldehyde inhibitors of the proteolytic activity of the multicatalytic proteinase complex
WO1997004004A1 (en) * 1995-07-17 1997-02-06 Peptide Therapeutics Limited CYSTEINE PROTEASE INHIBITORS FOR USE IN TREATMENT OF IgE MEDIATED ALLERGIC DISEASES
US5633231A (en) 1993-09-14 1997-05-27 Bayer Aktiengesellschaft Valine-containing pseudopeptides with antiviral activity
WO1997030075A1 (en) 1996-02-16 1997-08-21 Bayer Aktiengesellschaft Oxime- and nitron-substituted pseudopeptides with an anti-viral action
WO1999047545A2 (en) 1998-03-19 1999-09-23 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US7521068B2 (en) 1998-11-12 2009-04-21 Elan Pharma International Ltd. Dry powder aerosols of nanoparticulate drugs

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1011411A (en) 1960-11-13 1965-12-01 B C M Plastic Developments Ltd Improvements in the production of tube bends of reinforced thermo-setting plastic
EP0100673A2 (en) 1982-08-02 1984-02-15 The Research Foundation Of State University Of New York A method of enhancing neurofiber regrowth
US5633231A (en) 1993-09-14 1997-05-27 Bayer Aktiengesellschaft Valine-containing pseudopeptides with antiviral activity
US5580854A (en) 1994-03-04 1996-12-03 Mount Sinai School Of Medicine Of The City University Of New York Substrate-related peptidyl-aldehyde inhibitors of the proteolytic activity of the multicatalytic proteinase complex
WO1996030395A2 (en) 1995-03-31 1996-10-03 Takeda Chemical Industries, Ltd. Cysteine protease inhibitor
WO1997004004A1 (en) * 1995-07-17 1997-02-06 Peptide Therapeutics Limited CYSTEINE PROTEASE INHIBITORS FOR USE IN TREATMENT OF IgE MEDIATED ALLERGIC DISEASES
WO1997030075A1 (en) 1996-02-16 1997-08-21 Bayer Aktiengesellschaft Oxime- and nitron-substituted pseudopeptides with an anti-viral action
WO1999047545A2 (en) 1998-03-19 1999-09-23 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US7521068B2 (en) 1998-11-12 2009-04-21 Elan Pharma International Ltd. Dry powder aerosols of nanoparticulate drugs

Non-Patent Citations (73)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients", 2005
"Reminqton's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY
ARRUDA ET AL.: "Exposure and sensitization to dust mite allergens among asthmatic children in Sao Paulo, Brazil", CLIN. EXP. ALLERQY, vol. 21, 1991, pages 433 - 439
ASOKANANTHAN ET AL.: "House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1", J. IMMUNOL., vol. 169, 2002, pages 4572 - 4578
BARRETT ET AL.: "P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K", BIORQ. MED. CHEM. LETT., vol. 15, 2005, pages 3540 - 3546, XP025313772, DOI: doi:10.1016/j.bmcl.2005.05.062
BERGE ET AL.: "Pharmaceutically Acceptable Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
BODINI ET AL.: "Exhaled breath condensate eicosanoids and sputum eosinophils in asthmatic children: a pilot study", PEDIATR. ALLERGY IMMUNOL., vol. 15, 2004, pages 26 - 31
BROIDE ET AL.: "Cytokines in symptomatic asthma airways", J. ALLERQY CLIN. IMMUNOL.L, vol. 89, 1992, pages 958 - 967
CHAN, W. C., WHITE, P. D.: "Fmoc Solid Phase Peptide Synthesis A Practical Approach", 2000, OXFORD UNIVERSITY PRESS
CHAN, WHITE: "Fmoc Solid Phase Peptide Synthesis: A Practical Approach", 2000, OXFORD UNIVERSITY PRESS
CHARPIN ET AL.: "Altitude and allergy to house-dust mites. A paradigm of the influence of environmental exposure on allergic sensitization", AM. REV. RESPIR. DIS., vol. 143, 1991, pages 983 - 986
CIAPETTI ET AL.: "CrC12 mediated allylation of N-protected alpha-amino aldehydes. A versatile synthesis of polypeptides containing an hydroxyethylene isostere", TETRA. LETT., vol. 35, no. 19, 1994, pages 3183 - 3186, XP002005180, DOI: doi:10.1016/S0040-4039(00)76862-6
COMOY ET AL.: "The house dust mite allergen, Dermatophagoides pteronyssinus, promotes type 2 responses by modulating the balance between IL-4 and IFN-gamma", J. IMMUNOL., vol. 160, 1998, pages 2456 - 2462
DEB ET AL.: "Major house dust mite allergens Dermatophagoides pteronyssinus 1 and Dermatophagoides farinae 1 degrade and inactivate lung surfactant proteins A and D", J. BIOL. CHEM., vol. 282, 2007, pages 36808 - 36819
DOWSE ET AL.: "The association between Dermatophagoides mites and the increasing prevalence of asthma in village communities within the Papua New Guinea highlands", J. ALLERQV CLIN. IMMUNOL., vol. 75, 1985, pages 75 - 83
EDEN ET AL.: "Asthma features in severe alpha1-antitrypsin deficiency: experience of the National Heart, Lung, and Blood Institute Registry", CHEST, vol. 123, 2003, pages 765 - 771
FAHY ET AL.: "Comparison of samples collected by sputum induction and bronchoscopy from asthmatic and healthy subjects", AM. J. RESPIR. CRIT. CARE MED., vol. 152, 1995, pages 53 - 58
FEHRENTZ ET AL.: "Improved solid phase synthesis of C-treminal peptide aldehydes", TETRAHEDRON LETT., vol. 36, 1995, pages 7871 - 7874
FUSETANI ET AL.: "Tokaramide A, a new cathepsin B inhibitor from the Marine Sponge Theonella aff. mirabilis", BIOORQ. & MED. CHEM., vol. 9, 1999, pages 3397 - 3402, XP004185522, DOI: doi:10.1016/S0960-894X(99)00618-6
GELBER ET AL.: "Sensitization and exposure to indoor allergens as risk factors for asthma among patients presenting to hospital", AM. REV. RESPIR. DIS., vol. 147, 1993, pages 573 - 578
GHAEMMAGHAMI ET AL.: "The proteolytic activity of the major dust mite allergen Der p 1 conditions dendritic cells to produce less interleukin-12: allergen-induced Th2 bias determined at the dendritic cell level", CLIN. EXP. ALLERGY, vol. 32, 2002, pages 1468 - 1475
GOUGH ET AL.: "The proteolytic activity of the major dust mite allergen Der p 1 enhances the IgE antibody response to a bystander antigen", CLIN. EXP. ALLERGY, vol. 31, 2001, pages 1594 1598
GOURGOULIANIS ET AL.: "The influence of altitude in bronchial asthma", ARCH. MED. RES., vol. 32, 2001, pages 429 - 431
GROOTENDORST ET AL.: "Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids", CLIN. EXP. ALLERQY, vol. 31, 2001, pages 400 - 408
HELLINGS ET AL.: "Eosinophilic rhinitis accompanies the development of lower airway inflammation and hyper-reactivity in sensitized mice exposed to aerosolized allergen", CLIN. EXP. ALLERGY, vol. 31, 2001, pages 782 - 790
HOLT ET AL.: "A contiguous network of dendritic antigen-presenting cells within the respiratory epithelium", INT. ARCH. ALLERQY APPL. IMMUNOL., vol. 91, 1990, pages 155 - 159
HOLT: "The role of airway dendritic cell populations in regulation of T-cell responses to inhaled antigens: atopic asthma as a paradigm", J.AEROSOL MED., vol. 15, 2002, pages 161 - 168
HUH ET AL.: "Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma", J.EXP.MED., vol. 198, 2003, pages 19 - 30
HYDE ET AL.: "Protease inhibitor variants in children and young adults with chronic asthma", ANN. ALLERGY, vol. 43, 1979, pages 8 - 13
JAAKKOLA ET AL.: "Are atopy and specific IgE to mites and molds important for adult asthma?"", J. ALLERQV CLIN. IMMUNOL., vol. 117, 2006, pages 642 - 648, XP005396914, DOI: doi:10.1016/j.jaci.2005.11.003
KALSHEKER ET AL.: "The house dust mite allergen Der p1 catalytically inactivates alpha 1- antitrypsin by specific reactive centre loop cleavage: a mechanism that promotes airway inflammation and asthma", BIOCHEM. BIOPHVS. RES. COMMUN., vol. 221, 1996, pages 59 - 61
KING ET AL.: "Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium", J. IMMUNOL., vol. 161, 1998, pages 3645 - 3651
LAMBRECHT ET AL.: "Myeloid dendritic cells make it to the top", CLIN. EXP. ALLERQV, vol. 32, 2002, pages 805 - 810
LAMBRECHT ET AL.: "Taking our breath away: dendritic cells in the pathogenesis of asthma", NAT. REV. LMMUNOL., vol. 3, 2003, pages 994 - 1003
LAMBRECHT ET AL.: "The other cells in asthma: dendritic cell and epithelial cell crosstalk", CURRENT OPINION IN PULMONARY MEDICINE, vol. 9, 2003, pages 34 - 41
MARTIN J. O'DONNELL ET AL: "UPS on Weinreb Resin: A Facile Solid-Phase Route to Aldehyde and Ketone Derivatives of "Unnatural" Amino Acids and Peptides", JOURNAL OF COMBINATORIAL CHEMISTRY, vol. 2, no. 2, 1 March 2000 (2000-03-01), pages 172 - 181, XP055005944, ISSN: 1520-4766, DOI: 10.1021/cc990071y *
MCCUSKER ET AL.: "Site-specific sensitization in a murine model of allergic rhinitis: role of the upper airway in lower airways disease", J. ALLERQV CLIN. IMMUNOL., vol. 110, 2002, pages 891 - 898
MCMILLAN ET AL.: "Prolonged allergen challenge in mice leads to persistent airway remodelling", CLIN. EXP. ALLERPV, vol. 34, 2004, pages 497 - 507
MIYAMOTO ET AL.: "Allergenic identity between the common floor mite (Dermatophagoides farinae Hughes, 1961) and house dust as a causative antigen in bronchial asthma", J. ALLERGY, vol. 42, 1968, pages 14 - 28
MULLERSMAN ET AL.: "Conjugation of N-acylated amino sugars to protein by reductive alkylation using sodium cyanoborohydride: application to an azo derivative of alpha-amanitin", BIOCHEM. CELL BIOL., vol. 69, 1991, pages 418 - 427, XP009180419
MURAGUCHI ET AL.: "The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells", J. EXP. MED, vol. 167, 1988, pages 332 - 344
PEAT ET AL.: "House dust mite allergens. A major risk factor for childhood asthma in Australia", AM. J. RESPIR. CRIT. CARE MED., vol. 153, 1996, pages 141 - 146
PEAT ET AL.: "Sensitivity to common allergens: relation to respiratory symptoms and bronchial hyper-responsiveness in children from three different climatic areas of Australia", CLIN. EXP. ALLERGY, vol. 21, 1991, pages 573 - 581
PERONI ET AL.: "Effective allergen avoidance at high altitude reduces allergen-induced bronchial hyperresponsiveness", AM. J. RESPIR. CRIT. CARE MED., vol. 149, 1994, pages 1442 - 1446
PIACENTINI ET AL.: "Allergen avoidance at high altitude and urinary eosinophil protein X", J. ALLERQV CLIN. IMMUNOL, vol. 104, 1999, pages 243 - 244, XP027487221, DOI: doi:10.1016/S0091-6749(99)70145-4
PIACENTINI ET AL.: "Mite-antigen avoidance can reduce bronchial epithelial shedding in allergic asthmatic children", CLIN. EXP. ALLERQV, vol. 28, 1998, pages 561 - 567
PLATTS-MILLS ET AL.: "Indoor allergens and asthma: report of the Third International Workshop", J. ALLERQV CLIN. IMMUNOL., vol. 100, 1997, pages 2 - 24
PLATTS-MILLS ET AL.: "Seasonal variation in dust mite and grass-pollen allergens in dust from the houses of patients with asthma", J. ALLERQV CLIN.LMMUNOL., vol. 79, 1987, pages 781 - 791
PLATTS-MILLS ET AL.: "The role of intervention in established allergy: avoidance of indoor allergens in the treatment of chronic allergic disease", J. ALLERGY CLIN. IMMUNOL., vol. 106, 2000, pages 787 - 804
POLLART ET AL.: "Epidemiology of acute asthma: IgE antibodies to common inhalant allergens as a risk factor for emergency room visits", J. ALLEROV CLIN. IMMUNOL., vol. 83, 1989, pages 875 - 882
RUDOLPH ET AL.: "The significance of nasal protease inhibitor concentrations in house dust allergy", ALLERGY, vol. 33, 1978, pages 310 - 315
SCHULTZE-WERNINGHAUS: "Should asthma management include sojourns at high altitude?", CHEM. IMMUNOL. ALLERGY, vol. 91, 2006, pages 16 - 29
SEYMOUR ET AL.: "Aerosol-induced immunoglobulin (1g)-E unresponsiveness to ovalbumin does not require CD8+ or T cell receptor (TCR)-gamma/delta+ T cells or interferon (IFN)-gamma in a murine model of allergen sensitization", J. EXP. MED., vol. 187, 1998, pages 721 - 731
SIEV ET AL.: "Novel hydrazino-carbonyl-amino-methylated polystyrene (HCAM) resin methodology for the synthesis of P1-aldehyde protease inhbitor candidates", ORG. LETT., vol. 2, no. 1, 2000, pages 19 - 22
SIGSGAARD ET AL.: "S and Z alpha1-antitrypsin alleles are risk factors for bronchial hyperresponsiveness in young farmers: an example of gene/environment interaction", EUR. RESPIR. J, vol. 16, 2000, pages 50 - 55
SMITH ET AL.: "Clinical significance of skin reactions to mite extracts in children with asthma", BR. MED. J, vol. 1, 1969, pages 723 - 726
SPORIK ET AL.: "Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study", N. ENGL. J. MED., vol. 323, 1990, pages 502 - 507
STEWART ET AL.: "Middleton's Alleray. Principles and Practice", 2003, MOSBY, article "Allergen structure and function", pages: 585 - 609
STICK ET AL.: "The airway epithelium as immune modulator: the LARC ascending", AM. J. RESPIR. CELL MOL. BIOL, vol. 28, 2003, pages 641 - 644
STURE ET AL.: "Canine atopic dermatitis: the prevalence of psoitive intradermal skin tests at two sites in the north and south of Great Britain", VET. LMMUNOL. LMMUNOPATHOL., vol. 44, 1995, pages 293 - 308
T. GREEN, P. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE, pages: 494 - 653
T. GREEN, P. WUTS: "Protective Groups in Orqanic Synthesis", 1999, WILEY-INTERSCIENCE, pages: 17 - 245
T. GREEN, P. WUTS: "Protective Groups in Orqanic Synthesis", 1999, WILEY-INTERSCIENCE, pages: 293 - 368
T. GREEN, P. WUTS: "Protective Groups in Orqanic Synthesis", 2006, JOHN WILEY AND SONS
VAN HALTEREN ET AL.: "Regulation of antigen-specific IgE, IgG1, and mast cell responses to ingested allergen by mucosal tolerance induction", J. IMMUNOL., vol. 159, 1997, pages 3009 - 3015
VAN VELZEN ET AL.: "Effect of allergen avoidance at high altitude on direct and indirect bronchial hyperresponsiveness and markers of inflammation in children with allergic asthma", THORAX, vol. 51, pages 582 - 584
VERCELLI.: "Endogenous interleukin 6 plays an obligatory role in interleukin 4-dependent human IgE synthesis", EUR. J. LMMUNOL., vol. 19, 1989, pages 1419 - 1424
VERVLOET ET AL.: "Altitude and house dust mites", J. ALLERQV CLIN. IMMUNOL., vol. 69, 1982, pages 290 - 296
WAN ET AL.: "Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions", J. CLIN. INVEST., vol. 104, 1999, pages 123 - 133
WAN ET AL.: "Tight junction properties of the immortalized human bronchial epithelial cell lines Calu-3 and 16HB", EUR. RESPIR. J., vol. 15, 2000, pages 1058 - 1068
WINTON ET AL.: "Cell lines of pulmonary and non-pulmonary origin as tools to study the effects of house dust mite proteinases on the regulation of epithelial permeability", CLIN. EXP. ALLERQV, vol. 28, 1998, pages 1273 - 1285
ZHANG ET AL.: "Interactions between mature Der p 1 and its free prodomain indicate membership of a new family of C1 peptidases", ALLERGY, vol. 62, 2007, pages 1302 - 1309
ZHANG ET AL.: "Novel Der p 1 inhibitors attenuate HDM sensitization in mice", AMER. J. RESPIR. CRIT. CARE MED., vol. 179, 2009, pages A4249

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8541363B2 (en) 2010-01-22 2013-09-24 St George's Hosptial Medical School Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
US8637453B2 (en) 2010-01-22 2014-01-28 St George's Hospital Medical School Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
CN103655557A (en) * 2012-09-11 2014-03-26 北京大学 Use of CD38 enzyme inhibitor in treating bronchial hyperresponsiveness diseases
CN103655557B (en) * 2012-09-11 2018-03-30 北京大学 Purposes of the CD38 enzyme inhibitors in airway hyperreactivity disease is treated
US10829440B2 (en) 2015-06-12 2020-11-10 Brown University Antibacterial compounds and methods of making and using same
WO2017049206A1 (en) * 2015-09-17 2017-03-23 City Of Hope Pcna inhibitors
US10550070B2 (en) 2015-09-17 2020-02-04 City Of Hope PCNA inhibitors
US10913706B2 (en) 2015-09-17 2021-02-09 City Of Hope PCNA inhibitors
US11345656B2 (en) 2015-09-17 2022-05-31 City Of Hope PCNA inhibitors
US11555010B2 (en) 2019-07-25 2023-01-17 Brown University Diamide antimicrobial agents
WO2021060048A1 (en) 2019-09-25 2021-04-01 日産化学株式会社 Method for producing peptide compound
WO2024028417A1 (en) 2022-08-03 2024-02-08 Institut National de la Santé et de la Recherche Médicale New composition for the treatment and/or prevention of vitiligo

Also Published As

Publication number Publication date
GB201011411D0 (en) 2010-08-18

Similar Documents

Publication Publication Date Title
US8541363B2 (en) Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
WO2012004554A1 (en) Aldehyde compounds as inhibitors of dust mite group 1 peptidase allergen and their use
FI112943B (en) Pyrimidinyl derivatives and their use in the preparation of a drug for inhibiting interleukin protease activity
US5552400A (en) Fused-bicyclic lactams as interleukin-1β converting enzyme inhibitors
JP4009320B2 (en) Inhibitor of interleukin-1β converting enzyme
EP0942925B1 (en) Inhibitors of interleukin-1 beta converting enzyme
EP0611375A1 (en) Peptides inhibiting il-1 beta release
JPH07179414A (en) Urethanes and ureas which induce formation of cytokine
KR100622709B1 (en) Heterocyclic compounds, intermediates thereof and elastase inhibitors
EP3262028B1 (en) N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and n-(-4hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use
CN1234229A (en) Apparatus for treatment of immunomediated inflammatory disorders
US20030195141A1 (en) Anti-inflammatory peptides
ES2259812T3 (en) DERIVATIVES OF (3R) -3-AMINO-4-CARBOXIBUTIRALDEHIDO INHIBITORS OF THE LIBERATION OF INTERLEUQUINA-1 / BETA.
JPH10511362A (en) Anti-herpes peptidomimetic compound
MXPA96006192A (en) Inhibitors of lactama biciclica de la enzima queconvierte la interleucina-1-b

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11736436

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11736436

Country of ref document: EP

Kind code of ref document: A1