NZ625849B2 - [1,2,4]triazolopyridines and their use as phosphodiesterase inhibitors - Google Patents
[1,2,4]triazolopyridines and their use as phosphodiesterase inhibitors Download PDFInfo
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- NZ625849B2 NZ625849B2 NZ625849A NZ62584912A NZ625849B2 NZ 625849 B2 NZ625849 B2 NZ 625849B2 NZ 625849 A NZ625849 A NZ 625849A NZ 62584912 A NZ62584912 A NZ 62584912A NZ 625849 B2 NZ625849 B2 NZ 625849B2
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- New Zealand
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- compound according
- dermatitis
- compound
- triazolo
- skin
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- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
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- 229940080313 sodium starch Drugs 0.000 description 1
- YEENEYXBHNNNGV-XEHWZWQGSA-M sodium;3-acetamido-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoate;(2R,3R,4S,5S,6R)-2-[(2R,3S,4S,5R)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound [Na+].CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I.O[C@H]1[C@H](O)[C@@H](CO)O[C@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 YEENEYXBHNNNGV-XEHWZWQGSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- DRDVJQOGFWAVLH-UHFFFAOYSA-N tert-butyl N-hydroxycarbamate Chemical compound CC(C)(C)OC(=O)NO DRDVJQOGFWAVLH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
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- A61P17/08—Antiseborrheics
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- A—HUMAN NECESSITIES
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- A61P17/10—Anti-acne agents
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- A—HUMAN NECESSITIES
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- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Provided are [1,2,4]triazolopyridine compounds of general formula (I), wherein R is a branched butyl group. Examples of the compounds include [( R)-1-Methylpropyl] 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate, free base, Tert-butyl 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate, free base and [(1S)-1-methylpropyl]1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate, free base. The compounds are phosphodiesterase (PDE) 4 inhibitors. The compounds may be useful in the treatment of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing, acne, urticaria, pruritis, and eczema. xy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate, free base and [(1S)-1-methylpropyl]1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate, free base. The compounds are phosphodiesterase (PDE) 4 inhibitors. The compounds may be useful in the treatment of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing, acne, urticaria, pruritis, and eczema.
Description
[1,2,4]TRIAZOLOPYRIDINES AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates to novel [1,2,4]triazolopyridine compounds with phospho-
diesterase inhibitory activity, as well as to their use as therapeutic agents in the
treatment of inflammatory diseases and conditions.
BACKGROUND OF THE INVENTION
Phosphodiesterases are enzymes that catalyse the hydrolysis of cyclic AMP and/or cyclic
GMP in cells to 5-AMP and 5-GMP, respectively, and as such they are critical to cellular
regulation of cAMP or cGMP levels. Of the 11 phosphodiesterases identified so far,
phosphodiesterase (PDE) 4, PDE7 and PDE8 are selective for cAMP. PDE4 is the most
important modulator of cAMP expressed in immune and inflammatory cells such as
neutrophils, macrophages and T-lymphocytes (Z. Huang and J.A. Mancini, Current Med.
Chem. 13, 2006, pp. 3253-3262). As cAMP is a key second messenger in the modulation
of inflammatory responses, PDE4 has been found to regulate inflammatory responses of
inflammatory cells by modulating proinflammatory cytokines such as TNF-α, IL-2, IFN-γ,
GM-CSF and LTB4. Inhibition of PDE4 has therefore become an attractive target for the
therapy of inflammatory diseases such as asthma, chronic obstructive pulmonary
disease (COPD), rheumatoid arthritis, atopic dermatitis, inflammatory bowel disease
such as Crohn’s disease etc. (M.D. Houslay et al., Drug Discovery Today 10 (22), 2005,
pp. 1503-1519). As atopic dermatitis (AD) patients have increased PDE-activity, PDE4-
inhibition would also appear to be a viable treatment of AD (Journal of Investigative
Dermatology (1986), 87(3), 372-6).
The PDE4 gene family consists at least of four genes, A, B, C and D, which have a high
degree of homology (V. Boswell Smith and D. Spina, Curr. Opinion Investig. Drugs
6(11), 2006, pp. 1136-1141). The four PDE4 isoforms are differentially expressed in
different tissues and cell types. Thus, PDE4B is predominantly expressed in monocytes
and neutrophils, but not in cortex and epithelial cells, while PDE4D is expressed in lung,
cortex, cerebellum and T-cells (C. Kroegel and M. Foerster, Exp. Opinion Investig. Drugs
16(1), 2007, pp. 109-124). It has been speculated that inhibition of PDE4D in the brain
is associated with the adverse effects found when administering PDE4 inhibitors
clinically, primarily nausea and emesis, whereas inhibition of PDE4B is associated with
anti-inflammatory effects (B. Lipworth, Lancet 365, 2005, pp. 167-175). However, the
PDE inhibitors developed so far are not believed to be specific for any of the four PDE4
isoforms.
Numerous PDE4 inhibitors have been studied for their therapeutic effect on inflammatory
diseases, primarily asthma and COPD.
The first of these, theophylline, is a weak, non-selective phosphodiesterase inhibitor
used in the treatment of respiratory diseases such as asthma and COPD. Treatment with
theophylline may, however, give rise to both mild and severe adverse effects, e.g.
arrhythmia and convulsions, restricting the clinical utility of theophylline (Kroegel and
Foerster, supra). As phosphodiesterase has remained an attractive target for anti-
inflammatory therapy, several other, more selective PDE4 inhibitors have been
developed and investigated in a clinical setting. The clinical development of many of the
first-generation PDE4 inhibitors such as rolipram was discontinued due to dose-limiting
side effects, primarily nausea and emesis. However, Roflumilast was approved in 2010
for severe COPD associated with chronic bronchitis after dose-limiting side effects,
nausea, diarrhoea and headache were minimized. Second-generation PDE4 inhibitors
with apparently less pronounced adverse effects are currently in clinical trials (Houslay,
supra). PDE4 inhibitors are for example disclosed in EP 0771794 and EP 0943613.
, LEO Pharma A/S, discloses triazolopyridine compounds with a potent
PDE4 inhibiting activity. These compounds include a linker including a carbonyl group
between a bicyclic, heterocyclic ring system and a monocyclic ring system. It has been
shown for a related compound, piclamilast, that the linker is extremely important for the
positioning of the monocyclic ring such that it may interact with the PDE4 enzyme (Card
G.L., et al, “Structural basis for the activity of drugs that inhibit phosphodiesterases”,
Structure 2004 Dec; 12(12); 2233-47 ) to give the desired inhibitory effect.
, LEO Pharma A/S, discloses triazolopyridine compounds, without a
carbonyl linker between the bicyclic and the monocyclic ring system. The compounds
have been found to exhibit PDE4 inhibitory activity.
There is a continued need for developing novel PDE4 inhibitors which have a more
favourable therapeutic window, i.e. fewer adverse effects, while retaining their
therapeutic anti-inflammatory effect.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission
that such documents, or such sources of information, in any jurisdiction, are prior art, or
form part of the common general knowledge in the art.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel compounds which are potent
PDE4 inhibitors having a stability profile in biological tissue that implies that only a very
low systemic exposure of the compounds will be observed upon e.g. topical
administration, and/or to at least provide the public with a useful choice. More precisely
the compounds of the present invention have high clearance in human liver microsomes.
They rapidly hydrolyse in human whole blood but do at the same time display stability
towards enzymatic hydrolyses in human keratinocytes.
In one aspect the invention provides a compound of Formula (I)
(I)
wherein R is as defined below.
In another aspect, the invention provides pharmaceutical compositions comprising a
compound of general formula (I) as defined above together with a pharmaceutically
acceptable vehicle or excipient or pharmaceutically acceptable carrier(s), optionally
together with one or more other therapeutically active compound(s).
In another aspect, the invention provides the use of a compound of the invention, for
the manufacture of pharmaceutical compositions for the prophylaxis, treatment,
prevention or amelioration of a disease, disorder or condition responsive to PDE4
inhibitory activity.
In another aspect, the invention provides a compound of the invention for use as a
medicament.
Described herein is a method for prophylaxis, treatment, prevention or alleviation of
diseases, disorders or conditions responsive to PDE4 inhibitory activity, and which
method comprises the step of administering to a living animal body a therapeutically
effective amount of the compound of formula (I) of the invention.
Other objects of the invention will be apparent to the person skilled in the art from the
following detailed description and examples.
In the description in this specification reference may be made to subject matter which is
not within the scope of the appended claims. That subject matter should be readily
identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect the invention provides a compound of Formula (I)
any of its stereoisomers or any mixture of its stereoisomers or a pharmaceutically
acceptable salt thereof,
wherein R is branched butyl.
In one embodiment of the present invention, R is 1-methylpropyl, 2-methylpropyl or
tert-butyl.
In another embodiment R is 1-methylpropyl.
In another embodiment R is 2-methylpropyl.
In another embodiment R is tert-butyl.
Specific examples of compounds of formula (I) may be selected from the group
consisting of:
[(1S)Methylpropyl] 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo-
[1,5-a]pyridinyl]cyclopropanecarboxylate;
[(1R)Methylpropyl] 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-
[1,2,4]triazolo[1,5-a]pyridinyl]cyclopropanecarboxylate;
[2-Methylpropyl] 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-
a]pyridinyl]cyclopropanecarboxylate;
Tert-butyl 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-a]pyridin-
2-yl]cyclopropanecarboxylate; or
a pharmaceutically acceptable salt thereof.
Definitions
As used throughout the present specification and appended claims, the following terms
have the indicated meaning:
The term "comprising" as used in this specification and claims means "consisting at least
in part of". When interpreting statements in this specification and claims which include
the term "comprising", other features besides the features prefaced by this term in each
statement can also be present. Related terms such as “comprise´and "comprises" are to
be interpreted in similar manner.
The term "treatment" as used herein means the management and care of a patient for
the purpose of combating a disease, disorder or condition. The term is intended to
include the delaying of the progression of the disease, disorder or condition, the
alleviation or relief of symptoms and complications, and/or the cure or elimination of the
disease, disorder or condition. The patient to be treated is preferably a mammal, in
particular a human being.
The terms "disease", "condition" and "disorder" as used herein are used interchangeably
to specify a state of a patient which is not the normal physiological state of man.
The term "medicament" as used herein means a pharmaceutical composition suitable for
administration of the pharmaceutically active compound to a patient.
The term "pharmaceutically acceptable" as used herein means suited for normal
pharmaceutical applications, i.e. giving rise to no adverse events in patients etc.
The term ”pharmaceutically acceptable salt” is intended to indicate salts prepared by
reacting a compound of formula I with a suitable inorganic or organic acid, such as
hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, 2,2-
dichloroaetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic, maleic, L-malic,
phthalic, citric, propionic, benzoic, glutaric, gluconic, D-glucuronic, methanesulfonic,
salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane-1,2-disulfonic, 2-hydroxy
ethanesulfonic acid, toluenesulfonic, sulfamic or fumaric acid.
The compounds of the invention may be obtained in crystalline form either directly by
concentration from an organic solvent or by crystallisation or recrystallisation from an
organic solvent or mixture of said solvent and a cosolvent that may be organic or
inorganic, such as water. The crystals may be isolated in essentially solvent-free form or
as a solvate, such as a hydrate. The invention covers all crystalline modifications and
forms and also mixtures thereof.
Compounds of formula (I) may or may not comprise asymmetrically substituted (chiral)
carbon atoms which give rise to the existence of isomeric forms, e.g. enantiomers. The
present invention relates to all such isomers, either in pure form or as mixtures thereof
(e.g. racemates). Pure stereoisomeric forms of the compounds and the intermediates of
this invention may be obtained by the application of procedures known in the art. The
various isomeric forms may be separated by physical separation methods such as
selective crystallization and chromatographic techniques, e.g. liquid chromatography
using chiral stationary phases. Said pure stereoisomeric forms may also be derived from
the corresponding pure stereoisomeric forms of the appropriate starting materials,
provided that the reaction occur stereoselectively or stereospecifically. Preferably, if a
specific stereoisomer is desired, said compound will be synthesized by stereoselective or
stereospecific methods of preparation. These methods will advantageously employ chiral
pure starting materials.
Medical use
As the compounds of the invention exhibit PDE4 inhibitory activity, the compounds may
be useful as therapeutic agents for inflammatory allergic diseases such as bronchial
asthma, COPD, allergic rhinitis, and nephritis; autoimmune diseases such as rheumatoid
arthritis, multiple sclerosis, Crohn's disease, and systemic lupus erythematosus; acute or
chronic cutaneous wound disorders; diseases of the central nervous system such as
depression, amnesia, and dementia; organopathy associated with ischemic reflux caused
by cardiac failure, shock, and cerebrovascular diseases, and the like; insulin-resistant
diabetes; wounds; AIDS, and the like.
In one embodiment, the compounds of the present invention are considered useful for
the treatment, prevention or alleviation of dermal diseases or conditions.
In another embodiment, the compounds of the present invention are considered useful
for the treatment, prevention or alleviation of dermal diseases or conditions selected
from the group consisting of proliferative and inflammatory skin disorders, dermatitis,
atopic dermatitis, seborrheic dermatitis, contact dermatitis, psoriasis, cancer, epidermal
inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin ageing, photo
skin ageing, acne, urticaria, pruritis, and eczema.
In another embodiment, the compounds of the present invention are considered useful
for the treatment or alleviation of atopic dermatitis.
In another embodiment, the compounds of the present invention are considered useful
for the treatment or alleviation of psoriasis.
Compounds of the invention, optionally in combination with other active compounds,
may be useful for the treatment of dermal diseases or conditions, in particular for the
treatment of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis,
seborrheic dermatitis, contact dermatitis, psoriasis, cancer, epidermal inflammation,
alopecia, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing,
acne, urticaria, pruritis, and eczema.
Besides being useful for human treatment, the compounds of the present invention may
also be useful for veterinary treatment of animals including mammals such as horses,
cattle, sheep, pigs, dogs, and cats.
For use in therapy, compounds of the present invention are typically in the form of a
pharmaceutical composition. The invention therefore relates to a pharmaceutical
composition comprising a compound of formula (I), optionally together with one or more
other therapeutically active compound(s), together with a pharmaceutically acceptable
excipient or vehicle. The excipient must be "acceptable" in the sense of being compatible
with the other ingredients of the composition and not deleterious to the recipient
thereof.
In the form of a dosage unit, the compound may be administered one or more times a
day at appropriate intervals, always depending, however, on the condition of the patient,
and in accordance with the prescription made by the medical practitioner. Conveniently,
a dosage unit of a topical formulation contain between 0.1 mg and 1000 mg, preferably
between 1 mg and 100 mg, such as 5-50 mg of a compound of formula (I).
A suitable dosage of the compound of the invention will depend, inter alia, on the age
and condition of the patient, the severity of the disease to be treated and other factors
well known to the practising physician. The compound may be administered either orally,
parenterally or topically according to different dosing schedules, e.g. daily or with weekly
intervals. In general a single dose will be in the range from 0.001 to 10 mg/kg body
weight, e.g. in the range from 0.01 to 1 mg/kg body weight. The compound may be
administered as a bolus (i.e. the entire daily dosis is administered at once) or in divided
doses two or more times a day.
In the context of topical treatment it may be more appropriate to refer to a “usage unit”,
which denotes unitary, i.e. a single dose which is capable of being administered to a
patient, and which may be readily handled and packed, remaining as a physically and
chemically stable unit dose comprising either the active material as such or a mixture of
it with solid or liquid pharmaceutical diluents or carriers. A “usage unit” is capable of
being administered topically to a patient in an application per square centimetre of the
skin of from 0.1 mg to 50 mg and preferably from 0.2 mg to 5 mg of the final
formulation in question.
It is also envisaged that in certain treatment regimes, administration with longer
intervals, e.g. every other day, every week, or even with longer intervals may be
beneficial.
If the treatment involves administration of another therapeutically active compound it is
recommended to consult Goodman & Gilman’s The Pharmacological Basis of
Therapeutics, 9 Ed., J.G. Hardman and L.E. Limbird (Eds.), McGraw-Hill 1995, for
useful dosages of said compounds.
The administration of a compound of the present invention with one or more other active
compounds may be either concomitantly or sequentially.
The formulations include e.g. those in a form suitable for oral (including sustained or
timed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramus-
cular, intraarticular and intravenous), transdermal, ophthalmic, topical, dermal, nasal or
buccal administration. Topical administration of the claimed formulation is particularly
suitable.
The formulations may conveniently be presented in dosage unit form and may be pre-
pared by any of the methods well known in the art of pharmacy, e.g. as disclosed in
Remington, The Science and Practice of Pharmacy, 20 ed., 2000. All methods include
the step of bringing the active ingredient into association with the carrier, which consti-
tutes one or more accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing the active ingredient into association with a liquid
carrier or a finely divided solid carrier or both, and then, if necessary, shaping the
product into the desired formulation.
Formulations of the present invention suitable for oral administration may be in the form
of discrete units as capsules, sachets, tablets or lozenges, each containing a prede-
termined amount of the active ingredient; in the form of a powder or granules; in the
form of a solution or a suspension in an aqueous liquid or non-aqueous liquid, such as
ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
Such oils may be edible oils, such as e.g. cottonseed oil, sesame oil, coconut oil or
peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include
synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium
carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, carbomers and polyvinylpyrrolidone. The active ingredients may
also be administered in the form of a bolus, electuary or paste.
A tablet may be made by compressing or moulding the active ingredient optionally with
one or more accessory ingredients. Compressed tablets may be prepared by compres-
sing, in a suitable machine, the active ingredient(s) in a free-flowing form such as a
powder or granules, optionally mixed by a binder, such as e.g. lactose, glucose, starch,
gelatine, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose,
methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, waxes or the like; a
lubricant such as e.g. sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride or the like; a disintegrating agent such as
e.g. starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch
glycollate, crospovidone or the like or a dispersing agent, such as polysorbate 80.
Moulded tablets may be made by moulding, in a suitable machine, a mixture of the
powdered active ingredient and suitable carrier moistened with an inert liquid diluent.
Formulations for rectal administration may be in the form of suppositories in which the
compound of the present invention is admixed with low melting water soluble or
insoluble solids such as cocoa butter, hydrogenated vegetable oils, polyethylene glycol or
fatty acids esters of polyethylene glycols, while elixirs may be prepared using myristyl
palmitate.
Formulations suitable for parenteral administration conveniently comprise a sterile oily
or aqueous preparation of the active ingredients, which is preferably isotonic with the
blood of the recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution.
The formulation may be conveniently sterilised by for instance filtration through a
bacteria retaining filter, addition of sterilising agent to the formulation, irradiation of the
formulation or heating of the formulation. Liposomal formulations as disclosed in e.g.
Encyclopedia of Pharmaceutical Technology, vol.9, 1994, are also suitable for parenteral
administration.
Alternatively, the compounds of formula (I) may be presented as a sterile, solid prepa-
ration, e.g. a freeze-dried powder, which is readily dissolved in a sterile solvent
immediately prior to use.
Transdermal formulations may be in the form of a plaster or a patch.
Formulations suitable for ophthalmic administration may be in the form of a sterile aque-
ous preparation of the active ingredients, which may be in microcrystalline form, for
example, in the form of an aqueous microcrystalline suspension. Liposomal formulations
or biodegradable polymer systems e.g. as disclosed in Encyclopedia of Pharmaceutical
Technology, vol.2, 1989, may also be used to present the active ingredient for ophthal-
mic administration.
Formulations suitable for topical or ophthalmic administration include liquid or
semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or
water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions
such as drops. Compositions for ophthalmic treatment may preferably additionally
contain a cyclodextrin.
For topical administration, the compound of formula (I) may typically be present in an
amount of from 0.01 to 5% by weight of the composition, e.g. from 0.01% to 1% by
weight of the composition.
Formulations suitable for nasal or buccal administration include powder, self-propelling
and spray formulations, such as aerosols and atomisers. Such formulations are disclosed
in greater detail in e.g. Modern Pharmaceutics, 2 ed., G.S. Banker and C.T. Rhodes
(Eds.), page 427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3 ed., G.S.
Banker and C.T. Rhodes (Eds.), page 618-619 and 718-721, Marcel Dekker, New York
and Encyclopedia of Pharmaceutical Technology, vol. 10, J. Swarbrick and J.C. Boylan
(Eds), page 191-221, Marcel Dekker, New York.
In addition to the aforementioned ingredients, the formulations of a compound of
formula (I) may include one or more additional ingredients such as diluents, buffers,
flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g.
methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
The pharmaceutical composition may additionally comprise one or more other active
components conventionally used in the treatment of dermal disease or conditions, e.g.
selected from the group consisting of glucocorticoids, vitamin D and vitamin D
analogues, antihistamines, platelet activating factor (PAF) antagonists, anticholinergic
agents, methylxanthines, β-adrenergic agents, COX-2 inhibitors, salicylates, indo-
methacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum
cholesterol lowering agents, retinoids, zinc salts, salicylazosulfapyridine and calcineurin
inhibitors.
METHODS OF PREPARATION
The compounds of the present invention can be prepared in a number of ways well
known to those skilled in the art of synthesis. The compounds of formula (I) may for
example be prepared using the reactions and techniques outlined below together with
methods known in the art of synthetic organic chemistry, or variations thereof as
appreciated by those skilled in the art. Preferred methods include, but are not limited to,
those described below. The reactions are carried out in solvents appropriate to the
reagents and materials employed and suitable for the transformations being effected.
Also, in the synthetic methods described below, it is to be understood that all proposed
reaction conditions, including choice of solvent, reaction atmosphere, reaction
temperature, duration of experiment and work-up procedures, are chosen to be
conditions of standard for that reaction, which should be readily recognized by one
skilled in the art of organic synthesis. Not all compounds falling into a given class may
be compatible with some of the reaction conditions required in some of the methods
described. Such restrictions to the substituents which are compatible with the reaction
conditions will be readily apparent to one skilled in the art and alternative methods can
be used.
Starting materials are either known or commercially available compounds or can be
prepared by routine synthetic methods well known to a person skilled in the art.
LCMS Method "XE Metode 7 CM"
A quality check was performed on a Waters LCT Premier MS instrument and a Waters
Aquity UPLC.
Column: Waters Aquity UPLC HSS T3 1.8 µm, 2.1 x 50 mm, at 40°C.
Solvents: A = 10 mM ammonium acetate + 0.1% HCOOH, B = MeCN + 0.1% HCOOH.
Flow: 0.7 ml/min. Injection volume 2 µl. UV detection range 240 - 400 nm.
Gradient: Time % A % B
0.00 min 99 1
0.50 min 94 6
1.00 min 94 6
2.60 min 5 95
3.80 min 5 95
3.81 min 99 1
4.80 min 99 1
The MW confirmation and purity was extracted and checked with OpenLynx.
H Nuclear magnetic resonance (NMR) spectra were recorded at 400 or 600 MHz.
Chemical shift values ( , in ppm) are quoted in the specified solvent relative to internal
tetramethylsilane ( = 0.00) or chloroform ( = 7.25) standards. The value of a
multiplet, either defined (doublet (d), triplet (t), quartet (q)) or not (m) at the
approximate midpoint is given unless a range is quoted. (bs) indicates a broad singlet.
The organic solvents used were usually anhydrous. Chromatography was performed on
Merck silica gel 60 (0.040 - 0-063 mm). The solvent ratios indicated refer to v:v unless
otherwise noted.
The following abbreviations have been used throughout:
DBU 1,8-diazabicyclo[5.4.0]undecene
DCE 1,2-dichloroethane
DCM dichloromethane
DIAD diisopropyl azodicarboxylate
DMAP N,N-dimethylpyridinamine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
EDCI (3-dimethylamino-propyl)-ethyl-carbodiimide
EtOH ethanol
MeOH methanol
EtOAc ethyl acetate
L litre
Me methyl
NMR nuclear magnetic resonance
RT room temperature
THF tetrahydrofuran
Pet. petroleum
General Methods
The compounds of the invention may for example be prepared according to the following
non-limiting general methods and examples. R is as previously defined for the
compounds of Formula (I):
Preparation 1
Tert-Butyl hydroxycarbamate
To a stirred suspension of hydroxylamine·HCl (150 g, 2.17 mol) and K CO (150 g, 1.09
mol) in diethyl ether (940 mL) and water (30 mL) at 0°C, a solution of di-tert-butyl
dicarbonate (308 g, 1.41 mmol) in diethyl ether (600 mL) was added slowly for 15 min.
After addition the reaction mixture was stirred at RT for 2 hours. The reaction mixture
was filtered and the filtrate was dried over anhydrous Na SO and concentrated. The
obtained crude was washed with cyclohexane (50 mL × 3) and dried to afford the title
compound (150 g, 52%, white solid). H NMR (400 MHz, CDCl ): δ = 7.18 (br, 2H), 1.47
(s, 9H) ppm.
Preparation 2
Tert-Butyl 4-nitrobenzoyloxycarbamate
To a stirred solution of tert-butyl hydroxyl carbamate (150 g, 1.128 mol) in dichloro-
methane (2 L) at 0 °C, triethylamine (174 mL, 1.24 mol) was added followed by 4-
nitrobenzoyl chloride (205 g, 1.105 mol) in equal portions. After the addition was
completed the reaction mixture was stirred at RT for 1 hour. The reaction mixture was
quenched with water (500 mL) and extracted. The separated dichloromethane layer was
washed with brine (200 mL), dried over anhydrous Na SO and concentrated. The
obtained crude was washed with hexane (100 mL x 2) and dried to afford the title
compound (300 g, 94%, yellow solid). H NMR (400 MHz, CDCl ): δ = 8.34-8.27 (m,
4H), 2.97-2.92 (m, 1H), 1.53 (s, 9H) ppm.
Preparation 3
O-(4-Nitrobenzoyl) hydroxylamine
To a stirred solution of tert-butyl 4-nitrobenzoyloxy carbamate (300 g, 1.06 mol) in
dichloromethane (2 L) at 0 °C, methanesulphonic acid (69 mL, 1.06 mol) was added
slowly. After the addition was completed, the reaction mixture was allowed to stir at RT
for 16 hours. The reaction mixture was diluted with dichloromethane (1 L), washed with
% aq NaHCO (300 mL), water (200 mL), brine (200 mL), dried over anhydrous
Na SO and concentrated. The obtained crude was washed with hexane (100 mL x 2)
and dried to afford the title compound (150 g, 77%, pale yellow solid). H NMR (400
MHz, CDCl ): δ = 8.33-8.30 (m, 2H), 8.22-8.19 (m, 2H), 6.73 (brs, 2H) ppm.
Preparation 4
1-Hydroxmethyl-cyclopropanecarboxylic acid ethyl ester
To a stirred solution of diethyl cyclopropane-1, 1-dicarboxylate (2.13 g, 11.4 mmol) in
THF (80 mL) at RT, lithium aluminum tri-tert-butoxyhydride (38.76 mL, 38.76 mmol, 1.0
M solution in THF) was added slowly. After the addition was completed, the reaction
mixture was stirred at RT for 18 hours. The reaction mixture was diluted with ethyl
acetate (100 mL), washed with 1N aq HCl (20 mL), water (20 mL), 5% aq. NaHCO (25
mL), brine (20 mL), dried over anhydrous Na SO , filtered and concentrated to afford
the title compound (1.3 g, 79%, yellow oil). H NMR (400 MHz, CDCl ): δ = 4.20-
4.13(m, 2H), 3.62 (m, 2H), 2.61 (m, 1H), 1.29-1.24 (m, 5H), 0.88-0.85 (m, 2H) ppm.
Preparation 5
1-Formyl-cyclopropanecarboxylic acid ethyl ester
To a stirred solution of 1-hydroxmethyl-cyclopropanecarboxylic acid ethyl ester (1.1 g,
7.63 mmol) in dichloromethane (45 mL), NaHCO (2.5 g, 29.76 mmol) and Dess-Martin
periodinane (6.46 g, 15.23 mmol) were added. The suspension was then stirred at RT
for 30 min. The reaction mixture was quenched with a 1:1 solution of 10% aq. Na S O
2 2 3
and 10% aq. NaHCO (20 mL) maintain the temperature below 20°C, stirred for 30 min.
The reaction mixture was then diluted with dichloromethane (100 mL) and extracted.
The organic layer was washed with brine (30 mL), dried over anhydrous Na SO , filtered
and concentrated. The crude was purified by silica gel column chromatography (0 to
% EtOAc in pet. ether as eluent) to afford the title compound (800 mg, 76%, yellow
oil). H NMR (400 MHz, CDCl ): δ = 10.40 (s, 1H), 4.25 (m, 2H), 1.68-1.65 (m, 2H),
1.62-1.59 (m, 2H), 1.33-1.26 (m, 3H) ppm.
Preparation 6
3-Methoxy-pyridinylamine
A suspension of 3-methoxynitropyridin (30 g, 194.8 mmol) and 10% Pd/C (10 g) in
ethanol (1 L) was hydrogenated in a par hydrogenator (H , 40 psi pressure) at RT for 4
hours. The reaction mixture was filtered through celite and the filtrate was concentrated
to afford the title compound (22 g, 91%, brown solid). H NMR (400 MHz, CDCl ): δ =
7.66 (d, J=5.2Hz; 1H), 6.91 (d, J=7.6Hz, 1H), 6.63-6.60 (m, 1H), 4.65 (br, 2H), 3.84
(s, 3H) ppm.
Preparation 7
1, 2-Diaminomethoxy-pyridinium salt of 4-nitrobenzoic acid
To a stirred solution of 3-methoxy-pyridinylamine (30 g, 164.8 mmol) in dichloro-
methane (400 mL), O-(4-nitrobenzoyl) hydroxylamine (13.2 g, 214.2 mmol) was added
at 10 °C. After addition the reaction mixture was stirred at RT for 16 hours. The resulted
precipitate was filtered, washed with dichloromethane (25 mL × 2) and dried to afford
the title compound (40 g, 91%, brown solid) (CAUTION: The salt is thermally unstable).
H NMR (400 MHz, DMSO): δ = 8.53 (br, 2H), 8.12 (d, J=8Hz; 2H), 8.01 (d, J=8.8Hz;
2H), 7.73 (d, J=6.4Hz; 1H), 7.33 (d, J=7.2Hz; 1H), 7.17 (br, 2H), 6.77 (t, J=6.8Hz;
1H), 3.93 (s, 3H) ppm.
Preparation 8
1-(8-Methoxy-[1, 2, 4]triazolo[1,5-a]pyridineyl)-cyclopropanecarboxylic acid ethyl
ester
To a stirred solution of diaminomethoxy-pyridinium salt of 4-nitrobenzoic acid (1 g,
7.14 mmol) in ethanol (10 mL) at 0 °C, DBU (2.1 mL) was added followed by 1-formyl-
cyclopropanecarboxylic acid ethyl ester (1.5 g, 10.71 mmol). After addition the reaction
mixture was stirred at RT for 2 hours. The reaction mixture was concentrated, the
obtained residue was diluted with EtOAc (100 mL), washed with water (20 mL x 2),
brine (20 mL), dried over anhydrous Na SO , filtered and concentrated. The crude was
purified by silica gel column chromatography (using 0 to 15% EtOAc in CH Cl as eluent)
to afford the title compound (800 mg, 53%, white solid). H NMR (400 MHz, CDCl ): δ =
8.18-8.16 (d, J=6.4Hz; 1H), 6.89 (t, J=7.2Hz, 1H), 6.76 (d, J=8Hz; 1H), 4.20-4.14 (m,
2H), 4.03 (s, 3H), 1.73-1.70 (m, 2H), 1.59-1.56 (m, 2H), 1.20 (t, J=6.8Hz; 3H) ppm.
Preparation 9
1-(5-Bromomethoxy-[1, 2, 4]triazolo[1,5-a]pyridinyl)-cyclopropanecarboxylic acid
ethyl ester
To a stirred solution of 1-(8-methoxy-[1, 2, 4]triazolo[1,5-a]pyridineyl)-cyclo-
propanecarboxylic acid ethyl ester (25 g, 95.7 mmol) in acetonitrile (300 mL) at RT, N-
bromosuccinimide (34 g, 191.5 mmol) was added portion wise. After addition the
reaction mixture was stirred at RT for 6 hours. The reaction mixture was diluted with
EtOAc (600 mL), washed with water (100 mL x 2), brine (50 mL), dried over anhydrous
Na SO , filtered and concentrated. The crude was purified by silica gel column
chromatography (0 to10% EtOAc in dichloromethane as eluent) to afford the title
compound (25 g, 77%, colorless solid). H NMR (400 MHz, DMSO): δ = 7.44 (d,
J=8.4Hz; 1H), 7.07 (d, J=8Hz; 1H), 4.13-4.08 (m, 2H), 3.97 (s, 3H), 1.60-1.57 (m,
2H), 1.48-1.45 (m, 2H), 1.13 (t, J=7.4Hz; 3H) ppm.
Preparation 10
1-(5-Bromomethoxy-[1,2,4]triazolo[1,5-a]pyridinyl)cyclopropanecarboxylic acid
To a solution of ethyl 1-(5-bromomethoxy-[1,2,4]triazolo[1,5-a]pyridinyl)cyclo-
propanecarboxylate (3.00 g, 8.82 mmol) in THF (25 mL) was added an aqueous 1 M
solution of LiOH (25 mL). The mixture was stirred at 80 °C for 30 minutes, cooled to
room temperature and diluted with EtOAc (50 mL) and water (50 mL). The organic
phase was extracted with an aqueous 0.1 M solution of NaOH (25 mL) and the combined
aqueous phases were acidified with conc. HCl to pH 0-1, and extracted four times with
DCM (30 mL). Evaporation to dryness of the combined organic phases yielded the title
compound (2.54 g, 94%). H NMR (DMSO, 400 MHz): δ = 12.61 (s, 1H), 7.42 (d, 1H,
J=8.3 Hz), 7.06 (d, 1H, J=8.3 Hz), 3.97 (s, 3H), 1.53 (q, 2H, J=3.9 Hz), 1.40 (q, 2H,
J=3.9 Hz) ppm.
Preparation 11
1-[8-Methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-a]pyridin
yl]cyclopropanecarboxylic acid
1-(5-Bromomethoxy-[1,2,4]triazolo[1,5-a]pyridinyl)cyclopropanecarboxylic acid
(1.00 g, 3.20 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3H-isobenzo-
furanone (preparation of the boronate was described in WO2011/134468) (1.67 g,
6.40 mmol) were dissolved in degassed dioxane (16 mL). Pd (dba) (29 mg, 32 mol),
PCy (18 mg, 64 mol) and K PO (2.38 g, 11.2 mmol) were mixed in degassed water
3 3 4
(10 mL). The two solutions were mixed and subsequently heated in a micro wave oven
to 110 °C for 10 minutes, cooled to room temperature and diluted with EtOAc (40 mL).
The organic phase was extracted with water (25 mL) and an aqueous 0.1 M solution of
NaOH (25 mL) and the combined aqueous phases were acidified with conc. HCl to pH 0-
1, and extracted with DCM (30 mL x 4). Upon evaporation of the combined organic
phases the title compound crystalized out (746 mg, 64%). HPLC-Retention time (XE
Metode 7 CM): 1.97 minutes. Detected “M+1”-mass: 366.11. Calculated “M+1”-mass:
366.11. H NMR (DMSO, 300 MHz): δ = 8.25 – 8.20 (m, 1H), 8.13 (dd, 1H, J=8.2, 1.4
Hz), 8.00 (d, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.2 Hz), 7.24 (d, 1H, J=8.3 Hz), 5.51 (s,
2H), 4.04 (s, 3H), 1.58 – 1.48 (m, 2H), 1.48 – 1.39 (m, 2H) ppm.
Example 1
[(1S)Methylpropyl] 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo-
[1,5-a]pyridinyl]cyclopropanecarboxylate (Compound 1)
A mixture of 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-
a]pyridinyl]cyclopropanecarboxylic acid (10 mg, 27 mol), (1S)methylpropanol (10
L, 108 mol), DMAP (6.7 mg, 54 mol) and EDCI·HCl (10.5 mg, 54 mol) in DCM (0.5
mL) was stirred in a sealed vial at RT overnight before more (1S)methylpropanol (10
L,108 mol) and DMAP (6.7 mg, 54 mol) was added and the mixture was heated to 50
°C for 3 hours. Evaporated to dryness and acidic prepHPLC purification afforded the title
compound. HPLC-Retention time (XE Metode 7 CM): 2.35 minutes. Detected “M+1”-
mass: 422.16. Calculated “M+1”-mass: 422.17. H NMR (DMSO, 600 MHz): δ = 8.25 –
8.21 (m, 1H), 8.14 (dd, 1H, J=8.0, 1.2 Hz), 8.01 – 7.97 (m, 1H), 7.41 (d, 1H, J=8.2
Hz), 7.23 (d, 1H, J=8.2 Hz), 5.51 (s, 2H), 4.78 (h, 1H, J=6.3 Hz), 4.04 (s, 3H), 1.61 –
1.40 (m, 6H), 1.13 (d, 3H, J=6.2 Hz), 0.78 (t, 3H, J=7.4 Hz) ppm.
Example 2
[(1R)Methylpropyl] 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo-
[1,5-a]pyridinyl]cyclopropanecarboxylate (Compound 2)
A mixture of 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-
a]pyridinyl]cyclopropanecarboxylic acid (400 mg, 1.095 mmol), (2R)-butanol
(122 mg, 1.64 mmol), DMAP (147 mg, 1.20 mmol) and EDCI·HCl (231 mg, 1.20 mmol)
in DCM (10 mL) was stirred at RT overnight before it was evaporated to dryness. Column
chromatography (gradient MeOH 0 to 5% in DCM) followed by recrystallization in EtOH
and freezedrying afforded the title compound as colorless powder (138 mg, 30%). HPLC-
Retention time (XE Metode 7 CM): 2.33 minutes. Detected “M+1”-mass: 422.15.
Calculated “M+1”-mass: 422.17. H NMR (DMSO, 400 MHz): δ = 8.23 (br s, 1H), 8.14
(dd, 1H, J=8.0, 1.6 Hz), 7.99 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.2 Hz), 7.24 (d, 1H,
J=8.2 Hz), 5.51 (s, 2H), 4.78 (h, 1H, J=6.3 Hz), 4.04 (s, 3H), 1.62 – 1.38 (m, 6H), 1.13
(d, 3H, J=6.3 Hz), 0.78 (t, 3H, J=7.4 Hz) ppm.
Example 3
[2-Methylpropyl] 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-
a]pyridinyl]cyclopropanecarboxylate (Compound 3)
A mixture of 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-
a]pyridinyl]cyclopropanecarboxylic acid (250 mg, 685 mol), isobutanol (100 µL, 1.37
mmol), DMAP (250 mg, 2.05 mmol) and EDCI·HCl (262 mg, 1.37 mmol) in DCM (14 mL)
was stirred at 50 °C for 2 hours in a sealed vial, before it was diluted with DCM (80 mL),
washed with an aqueous 1 M solution of HCl (40 mL) and evaporated to dryness. The
crude mixture was redissolved in MeCN (~2 mL) and the crude product was crystalized
upon addition of water (~2 mL). Column chromatography (gradient EtOAc 20 to 100% in
pet. ether) and subsequent recrystallization in MeCN and water afforded the title
compound as colorless crystals (178 mg, 62%). HPLC-Retention time (XE Metode 7 CM):
2.34 minutes. Detected “M+1”-mass: 422.16. Calculated “M+1”-mass: 422.17. H NMR
(DMSO, 600 MHz): δ = 8.22 (br s, 1H), 8.13 (dd, 1H, J=8.1 Hz, 1.5 Hz), 8.00 (d, 1H,
J=8.0 Hz), 7.40 (d, 1H, J=8.2 Hz), 7.24 (d, 1H, J=8.2 Hz), 5.51 (s, 2H), 4.04 (s, 3H),
3.84 (d, 2H, J=6.5 Hz), 1.79 (m, 1H), 1.61 – 1.54 (m, 2H), 1.54 – 1.46 (m, 2H), 0.78
(d, 6H, J=6.7 Hz) ppm.
Example 4
Tert-butyl 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-a]pyridin-
2-yl]cyclopropanecarboxylate (Compound 4)
A suspension of 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-
a]pyridinyl]cyclopropanecarboxylic acid (30 mg, 83 mol) and benzyltriethyl-
ammonium chloride (19 mg, 83 mol) in DMF (1.0 mL) was gently heated until it
became a solution. Tert-butyl bromide (297 L, 2.64 mmol) and K CO (171 mg, 1.24
mmol) were added and the mixture was stirred at 55 °C for three days. Additional tert-
butyl bromide (139 L, 1.24 mmol) and K CO (171 mg, 1.24 mmol) were added and the
mixture was stirred at 55 °C for one more day. PrepHPLC purification afforded the title
compound. HPLC-Retention time (XE Metode 7 CM): 2.29 minutes. Detected “M+1”-
mass: 422.18. Calculated “M+1”-mass: 422.17. H NMR (DMSO, 300 MHz): δ = 8.27 –
8.22 (m, 1H), 8.16 (dd, 1H, J=8.0, 1.5 Hz), 8.00 (d, 1H, J=8.2 Hz), 7.40 (d, 1H, J=8.2
Hz), 7.22 (d, 1H, J=8.3 Hz), 5.51 (s, 2H), 4.04 (s, 3H), 1.54 – 1.40 (m, 4H), 1.38 (s,
9H) ppm.
ASSAYES
PDE4 assay
Human recombinant PDE4 (Genbank accession no NM_006203) was incubated for 1 hour
with the test compound at concentrations up to 10 μM, with cAMP (1x10-5M), and with a
low amount (0.021 MBq) of radioactively labelled cAMP. At the end of the incubation, the
cleavage of the substrate was evaluated by the binding of the AMP product to SPA
beads, which generate chemoluminescence when bound to the radioactive tracer. The
AMP product inhibited the binding of the radioactive tracer to the beads, and the
luminescent signal was competed.
The results were calculated as the molar concentrations resulting in 50% inhibition of
the substrate cleavage compared to controls samples, and are expressed as a range of
IC (nM).
The compounds of the present invention were tested in the PDE4 assay, IC (nM):
Compound 1, 10.6 nM; Compound 2, 13.0 nM; Compound 3, 12.3 nM; Compound 4,
.7 nM (based on an average value of from 2 to 5 tests for each compound).
TNF-α release
Human peripheral blood mononuclear cells (PBMC) were isolated from buffy coats. The
blood is mixed with saline at a ratio of 1:1, and the PBMC were isolated using
Lymphoprep tubesTM (Nycomed, Norway). The PBMC were suspended in RPMI1640 with
0.5% human serum albumin, pen/strep and 2 mM L-glutamine at a concentration of 5 x
105 c/ml. The cells were pre-incubated for 30 minutes with the test compounds in 96
well tissue culture plates and stimulated for 18 hours with lipopolysaccharide 1 mg/ml
(Sigma). TNF-α concentration in the supernatants was measured using homogeneous
time-resolved fluorescence resonance (TR-FRET). The assay is quantified by measuring
fluorescence at 665 nm (proportional to TNF-a concentration) and 620 nm (control).
Results are expressed as IC values (nM) calculated from inhibition curves using as
positive controls the secretion in LPS stimulated wells and as negative controls the
secretion in unstimulated cells.
The compounds of the present invention were tested in the TNF-α release assay, IC
(nM): Compound 1, 12.8 nM; Compound 2, 15.7 nM; Compound 3, 14.6 nM;
Compound 4, 15.3 nM (based on an average value of from 2 to 5 tests for each
compound).
HLM (human liver microsomes) assay
Incubations of test compounds in DMSO, diluted with phosphate buffer, pH 7.4, at 0.5
μM were carried out with human liver microsomes (0.5 mg/mL). The percentage of
organic solvent in the incubations was 1%. The human liver microsomal suspension in
phosphate buffer was mixed with NADPH (1 mM) and preheated to 37 °C before test
compound was added. Aliquots were taken at 0, 5, 10, 20 and 30 minutes, and reactions
were terminated by addition of methanol containing analytical internal standard (IS).
The results were expressed as apparent clearance (Cl ) (mL/min/kg) and hepatic
extraction ratio (E ) (%) calculated from the rate constant (k) (min ) of test compound
depletion.
The compounds of the present invention were tested in the HLM assay, E (%):
Compound 1, >91%; Compound 2, >91%; Compound 3, >91%; Compound 4, >91%
(based on an average value of from 2 to 3 tests for each compound).
Human whole blood (WB) assay
Incubations of test compounds in DMSO, diluted with phosphate buffer, pH 7.4, at 1 μM
were carried out with human whole blood. The percentage of organic solvent in the
incubations was 1%. The incubations were performed at 37°C with aliquots taken at 0,
, 30, 60 and 120 minutes, and reactions were terminated by addition of methanol
containing analytical internal standard (IS).
The results were expressed as half-life (T½) in minutes calculated from the rate constant
(k) (min ) of test compound depletion.
The examples of the present invention were tested in the WB assay, T½ (minutes):
Compound 1, 10.7 minutes; Compound 2, 12.6 minutes; Compound 3, 16.6 minutes;
Compound 4, <11.2 minutes (based on an average value of from 2 to 4 tests for each
compound).
Keratinocyte stability (KC) assay
Incubations of test compounds in DMSO, diluted with growing medium, pH ~7.4, at 1 μM
were carried out with plated human keratinocytes. The percentage of organic solvent in
the incubations was 0.5%. The incubations were performed at 37°C with aliquots taken
at 0, 60, 120, 240 and 1440 minutes, and reactions were terminated by addition of
methanol containing analytical internal standard (IS).
The results were expressed as half-life (T½) in minutes calculated from the rate constant
(k) (min ) of test compound depletion.
The examples of the present invention were tested in the KC assay, T½ (minutes):
Compound 1, >720 minutes; Compound 2, >720 minutes; Compound 3, >720
minutes; Compound 4, >720 minutes (based on an average value of from 2 to 4 tests
for each compound).
Claims (20)
1. A compound of general formula (I) 5 (I) any of its stereoisomers or any mixture of its stereoisomers or a pharmaceutically acceptable salt thereof, wherein R is branched butyl.
2. The compound according to claim 1, any of its stereoisomers or any mixture of its stereoisomers or a pharmaceutically acceptable salt thereof, wherein R is 1- methylpropyl, 2-methylpropyl, or tert-butyl. 15
3. The compound according to claim 1, which is [(1S)methylpropyl] 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo- [1,5-a]pyridinyl]cyclopropanecarboxylate, free base.
4. The compound according to claim 1, which is 20 [(1R)Methylpropyl] 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)- [1,2,4]triazolo[1,5-a]pyridinyl]cyclopropanecarboxylate, free base.
5. The compound according to claim 1, which is [2-Methylpropyl] 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5- 25 a]pyridinyl]cyclopropanecarboxylate, free base.
6. The compound according to claim 1, which is Tert-butyl 1-[8-methoxy(1-oxo-3H-isobenzofuranyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-yl]cyclopropanecarboxylate, free base.
7. A pharmaceutical composition comprising a compound according to any one of claims 1-6 together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s). 5
8. The pharmaceutical composition according to claim 7 further comprising one or more other therapeutically active compound(s).
9. A use of the compound according to any of the claims 1-6, for the manufacture of a pharmaceutical composition.
10. The use of a compound according to claim 9 in the manufacture of a pharmaceutical composition for the treatment or amelioration of a disease, disorder or condition responsive to PDE4 inhibitory activity. 15
11. The use according to claim 10, wherein the disease, disorder or condition is dermal diseases or conditions.
12. The use according to claim 11, wherein the disease, disorder or condition is proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic 20 dermatitis, contact dermatitis, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing, acne, urticaria, pruritis, and eczema.
13. The compound according to any of the claims 1-6, for use as a medicament.
14. The compound according to claim 13 for use in the treatment or amelioration of a disease, disorder or condition responsive to PDE4 inhibitory activity.
15. The compound according to claim 13 for use in the treatment or amelioration of 30 dermal diseases or conditions.
16. The compound according to claim 13 for use in the treatment of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid 35 induced skin atrophy, skin ageing, photo skin ageing, acne, urticaria, pruritis, and eczema.
17. A compound according to any one of claims 1-6 substantially as herein described with reference to any example thereof.
18. A pharmaceutical composition of claim 7 or 8 substantially as herein described 5 with reference to any example thereof.
19. A use of any one of claims 9-12 substantially as herein described with reference to any example thereof. 10
20. The compound according to any one of claims 1-6 for use according to any one of claims 13-16 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161578677P | 2011-12-21 | 2011-12-21 | |
US61/578,677 | 2011-12-21 | ||
US201261666430P | 2012-06-29 | 2012-06-29 | |
US61/666,430 | 2012-06-29 | ||
PCT/EP2012/076191 WO2013092739A1 (en) | 2011-12-21 | 2012-12-19 | [1,2,4]triazolopyridines and their use as phospodiesterase inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ625849A NZ625849A (en) | 2016-06-24 |
NZ625849B2 true NZ625849B2 (en) | 2016-09-27 |
Family
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