FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
The Patents Rule, 2003
COMPLETE SPECIFICATION
[See Section 10 and Rule 13]
"USE OF COMPONDS IN A DRY POWDER INHALER'
PFIZER INC., a..corporation organized under the laws of the State of Delaware, United States of America of 235 East 42nd Street, New York 10017, United States of America,
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-

WO 03/022275

PCT/IB02/03599

1
INHALATION COMPOSITIONS COMPRISING TRICYCLIC 5,6-DIHYDRO-9H-PYRAZOLO (3,4-C) -1, 2, 4-TRIAZOLO (4, 3-alpha) PYRIDINES.

The present invention relates to an inhaled formulation, comprising a compound selected from a particular class of 5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-
5 triazolo[4,3-a]pyridines, which is capable of delivering the compound as fine, solid particles to the lung and the use of such a formulation in the treatment of certain diseases such as respiratory diseases.
The compounds that are useful in the invention are the compounds of the formula 10 (I)

15
and the pharmaceutically acceptable salts thereof; wherein
R1 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C4)alkenyl, phenyl,
20 dimethylamino, (C3-C6)cycloalkyl, (C3-C6)cycloaIkyl(C1-C3)alkyl or
(C1-C6)acyl wherein the alkyl, phenyl or alkenyl groups may be substituted with up to two hydroxy, (C1-C3)alkyl, or trifluoromethyl groups, or up to three halogens;
R2 and R3 are each independently selected from the group consisting of
25 hydrogen, (C1-C14)aIkyl, (C1-C7)alkoxy(C1-C7)alkyl, (C2-C14)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C2)alkyl, a saturated or unsaturated (C4-C7)heterocyclic(CH2)n group wherein n is 0, 1 or 2, containing as the heteroatom one or two of the group consisting of oxygen, sulphur, sulphonyl, nitrogen and NR4 wherein R4 is hydrogen or (Ci-C4)alkyl; or a group of the formula

30


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wherein a is an integer from 1 to 5; b and c are 0 or 1; R5 is hydrogen, hydroxy,
(C1-G5)alkyl, (C2-C5)alkenyl, (C1-C5) alkoxy,
(C3-C6)cycloalkoxy,. halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7, N02 or
SO2NR6R7 wherein R6 and R7 are each independently hydrogen or (Ci-C4)alkyl;
5 wherein Z is oxygen, sulphur, SO2, CO or NR8 wherein R8 is hydrogen or (Cr
C4)alkyl; and Y is (C1-C5)alkylene or (C2-C6)alkenyl optionally substituted with up
to. two(C1-C7)alkyI or
(C3-C7)cycloalkyl groups; wherein each of the alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic groups may be substituted with one to fourteen of the
10 group consisting of (Ci-C2)alkyl, trifluoromethyl or halogen; and
R9 and R10 are each independently selected from the group consisting of
hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C6-C10)aryl and
(C6-C10)aryloxy.
15
These compounds/which are selective PDE4 inhibitors, are described in International Patent Application WO-A-96/39408. Conditions which may be treated by inhalation of the tricyclic 5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridines described therein include respiratory diseases such as
20 asthma and chronic obstructive airways disease (COAD, also known as chronic obstructive pulmonary disease (COPD)).
The aforementioned application refers to the optimum therapeutic dose for the compounds described therein as generally in the range (of from 0.1 to 400mg
25 daily for an average adult patient. It is indicated that a dosage for inhaler administration is generally formulated as a 0.1 to 1% (w/v) solution. Although not stated, a typical dosage form for the administration of such a solution would be a metered close inhaler (MDl).
30 On the basis of multiple dose patient studies using a solution MDl (administered via a 'spacer') to administer small amounts of said compounds at frequent intervals throughout the day, it has been calculated that a daily inhaled dose of up to 3mg of active compound would be efficacious in the treatment of both asthma and COAD. However, attempts to administer such a quantity by solution MDl

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using a more reasonable number of doses, typically not more than four per day, invariably produced an immediate cough response in most subjects. Cough severity varied but during the course of the treatment some asthma patients developed worsening of symptoms which was associated with more severe
5 cough responses. Cough responses can prevent the drug being taken on board in a quantity sufficient for the .desired therapeutic effect and, perhaps most importantly, have serious consequences for patient compliance.
It has been surprisingly found that when the active compound is administered in
10 the form of fine, solid particles, specifically using a dry powder inhaler, subjects manifest little or no cough response at doses which caused cough with the solution MDI. Subjects are able to accept the full therapeutic dose of active compound or a significant proportion thereof in a reasonable, i.e. patient-compliant, number of doses (typically not more than four per day). This is
15 unexpected since the cough response would normally be associated with the compounds per se and a powder or suspension formulation is potentially irritant.
Thus, the present invention provides an inhaled formulation comprising a compound of the formula (I), or a pharmaceutical^ acceptable salt thereof, as
20 defined above, characterised in that the formulation is capable of delivering the compound as fine, solid particles to the lung.
Further, the present invention provides the use of such an inhaled formulation in the manufacture of a medicament for the treatment of a disease treatable by the
25 inhibition of PDE4, particularly a respiratory disease such as asthma or chronic obstructive pulmonary disease.
Further, the present invention provides a method of treatment of a disease treatable by the inhibition of PDE4, particularly a respiratory disease such as
30 asthma or chronic obstructive pulmonary disease, comprising the administration of such an inhaled formulation to a mammal.
Preferred compounds for use in the invention have an aqueous solubility at physiological pH of less than' 0.15mg/ml. Compounds having an aqueous

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solubility of less than 0.05mg/ml are especially preferred. For the purposes of the invention, "physiological pH" is defined as a pH of from 6.0 to 8.0. Solubility may be measured by diluting a weighed amount of test compound with a suitable pH buffer, shaking the mixture for 24 hours, filtering the mixture and measuring the
5 saturated solubility • of the filtrate using LC-MS (liquid chromatograhy-mass spectrometry).
Preferred compounds of the formula (I) include those wherein each of the alkyl, alkenyl, cycloalkyl, alkoxyalkyl and heterocyclic groups may be substituted with 1
10 to 5 of the group consisting of (C1-G2)aIkyl, trifluoromethyl and hydrogen.
Preferably, R1 is methyl, ethyl or isopropyl.
Preferably, R3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl, (C3-
15 C7)cycloalkyl(C1-C2)alkyl or phenyl optionally substituted with 1 or 2 of the group consisting of hydrogen, hydroxy, (Ci-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7, N02 or SO2NR6R7 wherein R6 and R7 are each independently hydrogen or (C1-C4)alkyl.
20 Preferred individual compounds of the formula (I) are:
9-cyclopentyl-5,6-dihydro-7-ethyl-3-phenyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
9-cyclopenyl-5,6-dihydro-7-ethyl-3-(furan-2-yl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
25 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-pyridyl)-9H-pyrazolo[3,4-ci-1,2,4-triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(4-pyridyl)-9W-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-o:]pyridine;
9-cycIopentyl-5,6-dihydro-7-ethyl-3-(3-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-30 triazolo[4,3-a]pyridine;
' 3-benzyl-9-cyclopentyl-5,6-dihydro-7-ethyI-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-]pyridine;

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9-cyclopentyI-5,6-dihydro-7-ethyl-3-propyl-9H-pyrazolo[3l4-c]-1,2,4-triazolo[4,3-]pyridine;
3,9-dicyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3)4-c]-1,2)4-triazolo[4,3-a]pyridine;
5 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(1 -methyIcyclohex-1 -yl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
3-(tert-butyl)-9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-methylphenyl)-9H-pyrazolo[3,4-c]-1,2,4-
10 triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-methoxyphenyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9f/-pyrazolo[3,4-c]1,2,4-triazolo[4,3-a]pyridine;
15 3-(2-chlorophenyl)-9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3l4-c]-1,2,4-triazolo[4,3-a]pyridine;
9-cyclopentyl-5J6-dihydro-7-ethyl-3-(2-iodophenyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-trifluoromethylphenyl)-9W-pyrazolo[3,4-c]-
20 1,2,4-triazolo[4,3-a]pyridine; and '
5,6-dihydro-7-ethyl-9-(4-fluorophenyl)-3-(1-methylcyclohex-1-yl)-9H-pyrazolo[3,4-
c]-1,2,4-triazolo[4,3-a]pyridine;
and the pharmaceutical^ acceptable salts thereof.
25 Particularly preferred compounds of the formula (I) are 3-(tert-butyI)-9-
cyclopentyl-5)6-dihydro-7-ethyl-9/-/-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine
and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9H-pyrazolo[3,4-c]1,2,4-
triazolo[4,3-a]pyridine, and the pharmaceutical^ acceptable salts thereof.

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Most preferred are 9-cyclopentyl-5,6-dihydro-7-ethyl-3~(thien-2-yl)-9H-pyrazolo[3,4-c]1,2,4-triazolo[4,3-]pyridine, and the pharmaceutical^ acceptable salts thereof, especially the free base.
5 For the purposes of the present invention, 'fine1, solid drug particles may be taken to be those which are less than 20 micrometers in diameter. Preferably, the powdered drug used will have a particle size range wherein 90% of particles are less than 10 micrometers in diameter and 50% of particles are less than 5 micrometers in diameter. Even more preferably, the powdered drug used will
10 have a particle size range wherein 90% of particles are less than 6 micrometers in diameter and 50% of particles are less than 3 micrometers in diameter. Most preferably, the powdered drug used will have a particle size range wherein 95% of particles are less than 5 micrometers in diameter and 50% of particles are less than 2.5 micrometers in diameter.
15
A suitable particle size distribution may be obtained by micronising (milling) the bulk drug substance or by particle engineering. Examples of particle engineering are super critical fluid crystallisation and the preparation of microspheres (e.g. by spray drying).
20
Devices which are capable of delivering fine, solid particles produced by the techniques outlined above to the lung of a patient include dry powder inhalers, suspension metered dose inhalers, suspension nebulisers and suspension atomisers. Dry powder inhalers are preferred. Suitable dry powder inhalers for
25 use in the invention include capsule devices such as Spinhaler (trade mark), Rotahaler (trade mark), Handihaler (trade mark), Aerohaler (trade mark), Eclipse (trade mark), Turbospin (trade mark) and the Flowcaps (trade mark) inhaler. Other suitable dry powder inhalers for use in the invention include multidose inhalers such as Accuhaler (trade mark), Turbuhaler (trade mark), Ultrahaler
30 (trade mark), Diskhaler (trade mark), Novoliser (trade mark), Easyhaler (trade mark), Taifun (trade mark), Clickhaler (trade mark), Twisthaler (trade mark) and Aspirair (trademark).

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The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the chosen means of inhalation and standard pharmaceutical-practice.
5
In the case of an aerosol suspension spray presentation from a pressurised container, pump, spray, atomiser (e.g. an atomiser using electrohydrodynamics to produce a fine mist) or nebuliser a suitable propellant may be used such as e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a
10 hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide, a further perfluorinated hydrocarbon such as Perflubron (trade mark) or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The drug will be
15 dispersed in a suitable agent such as water or aqueous ethanol. A lubricant such as sorbitan trioleate may also be included.
Capsules, blisters and cartridges (made, for example, from gelatin or HPMC) for use in an inhaler may be formulated to contain a powder mix of a compound of
20 the formula (I), a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, trehalose or magnesium stearate. For the purposes of the present invention, a preferred dry powder formulation consists of a dry powder blend of the compound of the formula (I), or salt thereof, and lactose (preferably as lactose monohydrate). The lactose should
25 be of sufficiently fine grade that 90% of the lactose particles are less than 1000 micrometers in diameter and 50% of the lactose particles are less than 500 micrometers in diameter. Preferably, 90% of the lactose particles are less than 300 micrometers in diameter and 50% of the lactose particles are less than 100 micrometers in diameter. Most preferably, 90% of the lactose particles are less
30 than from 100 to 200 micrometers in diameter, 50% of the lactose particles are less than from 40 to 70 micrometers in diameter and 10% of the lactose particles are less than 10 micrometers in diameter. Drug loading may vary from 0.1 to 100% w/w of the dry powder blend and is preferably from 5 to 100% w/w, most preferably from 5-40% w/w.

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Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff' contains from 1 to 10000 μg of a compound of the formula (I) for delivery to the patient. The overall daily dose with an aerosol will be in the range
5 of from 1μg to 20mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
A further method of delivering fine, solid particles of drug to the lung is use of microspheres comprising polyp,( D,L-lactic-co-glycolic acid) wherein such
10 microspheres are generated in situ after delivery from a solution metered dose inhaler.
The fine, solid particles of drug to be delivered according to the invention may optionally be delivered in the; form of liposomes to modify their release
15 characteristics.
The formulations of the present invention may comprise one or more further pharmacologically active agents including:
(a) an A2a agonist such as one of the compounds generally and specifically
20 disclosed in WO-A-00/23457, WO-A-00/77018, WO-A-01/27131, WO-A-
01/27130, WO-A-01/60835, WO-A-02/00676 and WO-A-01/94368, preferably 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amind]-/V-[2-(1 -piperidinyl)ethyl]-9H-purine-2-carboxamide or a pharmaceutical^ acceptable salt or solvate thereof or 6-[(2,2-
25 diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-A/-{2-[({[1-(2-pyridinyl)-4-
piperidinyl]amino}carbonyl)amino]ethyl}-9H-purine-2-carboxamide or a
pharmaceutically acceptable salt or solvate thereof;
(b) an anticholinergic agent, such as a tiotropium, ipratropium or oxitropium
30 salt or a solvate thereof;
(c) a β2 adrenergic receptor agonist such as. salmeterol or formoterol or a pharmaceutically acceptable salt or solvate thereof;
(d) a corticosteroid; or

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(e) a dopamine D2 receptor agonist.
It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.
5
Examples
In each of Examples 1 to 3, the lactose monohydrate particle size distribution was 90% less than 190 micrometers in diameter, 50% less than 55 micrometers in
10 diameter and 10% less than 6 micrometers in diameter and the drug particle size distribution was 90% less than 5.8 micrometers in diameter, 50% less than 2.9 micrometers in diameter and 10% less than 1.0 micrometers in diameter.
Example 1 - Dry powder inhaler capsule (0.5mq)
15 %
A mixture of 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine (0.5mg, micronised by spiral air-jet milling) and lactose monohydrate (9.5mg, Pharmatose 150M (DMV) Ph.Eur) were blended by hand and filled into a size 3 opaque white capsule shell (supplied by Capsugel,
20 product code 1505).
Example 2 - Dry powder inhaler capsule (1 mq)
A mixture of 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9/-/-pyrazolo[3,4-c]-
25 1,2,4-triazolo[4,3-a]pyridine (1.0mg, micronised by spiral air-jet milling) and lactose monohydrate (19mg, Pharmatose 150M (DMV) Ph.Eur) were blended by hand and filled into a size 3 opaque white capsule shell (supplied by Capsugel, product code 1505).
30 Example 3 - Dry powder inhaler capsule (2mq)
A mixture of 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9H-pyrazolo[3,4-c]-1 T2,4-triazolo[4,3-a]pyridine (2.0mg, micronised by spiral air-jet milling) and lactose monohydrate (38mg, Pharmatose 150M (DMV) Ph.Eur) were blended by

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hand and filled into a size 3 opaque white capsule shell (supplied by Capsugel, product code 1505).
Example 4 - Dry powder inhaler
5
The capsules manufactured in accordance with Examples 1 to 3 were loaded into
a monodose inhaler (supplied by Plastiape SpA) for administration to human
subjects. _.
10 Example 5 - Clinical data
The formulations of Examples 1 to 3 were tested for tolerance and safety in a clinical trial using healthy volunteers. Volunteers were dosed using a dry powder inhaler, as described in Example 4, with capsules containing the 0.5mg, 1 mg and
15 2mg doses of Examples 1, 2 and 3, respectively, or with placebo capsules containing only lactose. A dose escalation was used and any coughs were assessed as to their number, severity, duration and quality. Some of the results are shown in Table 1.
20 Table 1 - Cough toleration

Dose Percentage of subjects coughing in the first 5 minutes following dosing

Placebo (dry powder) Active (dry powder)
1 x 0.5mg - 0 (0/9)
2 x 0.5mg - 11 (1/9)
1 x 1mg 0 (0/6) 22 (2/9)
2 x 1mg 0 (0/6) 22(2/9)
1 x 2mg 0 (0/3) 33 (3/9)
2 x 2mg 0(0/3) 11 (1/9)
3 x 2mg 0(0/3) 29 (2/7)
When a dose equivalent to the 1 x 0.5 mg dry powder dose is administered via a solution MDI, approximately 80-100% of subjects experience cough in the first 5

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minutes following dosing. Not only is the percentage of cough greatly reduced by use of the dry powder inhaler as compared with the solution metered dose inhaler but the severity of those coughs is also greatly reduced. Furthermore, with the dry powder inhaler the incidence of cough remains acceptable at doses in the
5 therapeutic range.

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Claims
1. An inhaled formulation comprising a compound of the formula (I)

10 or a pharmaceutically acceptable salt thereof; wherein
R1 is hydrogen, (Ci-C6)alkyl, (Ci.-C6)alkoxy, (C2-C4)alkenyl, phenyl,
dimethylamino, (C3-C6)cycloaIkyl, (C3-C6)cycloalkyl(Ci-C3)alkyl or
(C1-C6)acyl wherein the alkyl, phenyl or alkenyl groups may be substituted
15 with up to two hydroxy, (Ci-C3)alkyl, or trifluoromethyl groups, or up to
three halogens;
R2 and R3 are each independently selected from the group consisting of
hydrogen, (C1-C14)alkyl, (C1-C7)alkoxy(C1-C7)alkyl, (C2-C14)alkenyl, (C3-
20 C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C2)alkyl, a saturated or unsaturated
(C4-C7)heterocyclic(CH2)n group wherein n is 0, 1 or 2, containing as the
heteroatom one or two of the group consisting of oxygen, sulphur,
sulphonyl, nitrogen and NR4 wherein R4 is hydrogen 6r (C1-C4)alky!; or a
group of the formula

25

wherein a is an integer from 1 to 5; b and c are 0 or 1; R5 is hydrogen,
30 hydroxy, (C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5) alkoxy,
(C3-C6)cycloalkoxy, halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7,
N02 or SO2NR5R7 wherein R6 and R7 are each independently hydrogen or
(C1-C4)aIkyl; wherein Z is oxygen, sulphur, SO2, CO or NRB wherein R8 is

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hydrogen or (C1-C4)alkyl; and Y is (C1-C5)alkylene or (C2-C6)alkenyl optionally substututed with up to two (C1-C7)alkyl or (C3-C7)cycloalkyl groups; wherein each of the alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic groups may be substituted with one to fourteen,
5 of the group consisting of (C1-C2)alkyl, trifluoromethyl or halogen; and
R9 and R10 are each independently selected from the group consisting of
hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C6-C10)aryl and
(C6-C10)aryloxy;
10
characterised in that the formulation is capable of delivering the compound as fine, solid particles to the lung.
2. An inhaled formulation according to claim 1 wherein each of the alkyl,
15 alkenyl, cycloalkyl, alkoxyalkyl and heterocyclic groups maybe substituted with 1 to 5 of the group consisting of (C1-C2)alkyl, trifluoromethyl and hydrogen.
3. An inhaled formulation according to claim 1 or claim 2 wherein R1 is
20 methyl, ethyl or isopropyl,
4. An inhaled formulation according to any preceding claim wherein R3 is (d-C6)alkyl, (C2-C6)aIkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C2)alkyl or phenyl optionally substituted with 1 or 2 of the group consisting of
25 hydrogen, hydroxy, (C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7, N02 or SO2NR6R7 wherein R6 and R7 are each independently hydrogen or (Ci-C4)alkyl.
5. An inhaled formulation according to claim 1 wherein the compound of the
30 formula (I) is selected from:
9-cyclopentyl-5,6-dihydro-7-ethyl-3-phenyl-9W-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;

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9-cyclopenyI-5,6-dihydro-7-ethyl-3-(furan-2-yl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyI-3-(2-pyridyI)-9f/-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
5 9-cyclopentyl-5l6-dihydro-7-ethyl-3-(4-pyridyI)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
g-cyclopentyl-S.e-dihydro^-ethyl-S^S-thienyO-gH-pyrazolofS^-^-l^^-triazolo[4,3-a]pyridine;
3-benzyl-9-cycIopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,4-
10 triazolo[4,3-a]pyridine;
g-cyclopentyl-S.B-dihydro^-ethyl-S-propyl-gH-pyrazolofS^-cj-l^^-triazolo[4,3-a]pyridine;
3,9-dicyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-]pyridine;
15 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(1-methylcyclohex-1-yl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-]pyridine;
3-(tert-butyl)-9-cyclopenlyl-5,6-dihydro-7-ethyl-9W-pyrazolo[3,4-c|-1,2,4-triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-methylphenyI)-9W-pyrazolo[3,4-c]-
20 1,2,4-triazolo[4,3-o:]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-methoxyphenyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-o:]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9H-pyrazolo[3,4-c]1,2,4-triazolo[4,3-]pyridine;
25 3-(2-chlorophenyl)-9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-iodophenyl)-9/V-pyrazolo[3,4-c]-1 r2,4-triazolo[4,3-a]pyridine;

WO 03/022275 • PCT/IB02/03599
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-trifluoromethylphenyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-o:]pyridine; and
5,6-dihydro-7-ethyl-9-(4-fluorophenyl)-3-(1-methylcyclohex-1-yl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;
5 and the pharmaceutically acceptable salts thereof.
6. An inhaled formulation according to claim 1 wherein the compound of the formula (I) is 3-(tert-butyl)-9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine.
10
7. An inhaled formulation according to claim 1 wherein the compound of the formula (I) is 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9H-pyrazolo[3,4-c]1,2,4-triazolo[4,3-a]pyridine.
15 8. An inhaled formulation according to claim 1 wherein the compound of the formula (I) has an aqueous solubility at physiological pH of less than 0.15mg/ml.
9. An inhaled formulation according to claim 8 wherein the compound of the
20 formula (I) has an aqueous solubility at physiological pH of less than 0.05mg/ml.

10. An inhaled formulation according to any one of the preceding claims
wherein the fine, solid drug particles have a size distribution of 90% less
25 than 10 micrometers in diameter and 50% less than 5 micrometers in diameter.
11. An inhaled formulation according to claim 10 wherein the fine, solid drug
particles have a size distribution of 90% less than 6 micrometers in
30 diameter and 50% less than 3 micrometers in diameter.
12. An inhaled formulation according to any one of the preceding claims
. wherein the fine, solid particles are delivered to the lung by a dry powder
inhaler.

WO 03/022275

PCT/IB02/03599

16
13. An inhaled formulation according to claim 12 wherein the dry powder blend comprises lactose, preferably in its monohydrated form.
5 14. An inhaled formulation according to any one of claims 1 to 11 wherein the fine, solid particles are delivered by a suspension metered dose inhaler, a suspension atomiser or a suspension nebuliser.
15. An inhaled formulation according to" any one of claims 1 to 11 wherein the
10 fine, solid particles consist of microspheres, said microspheres comprising
poly(D,L-lactic-co-glycolic acid).
16. An inhaled formulation according to any preceding claim for use as a
medicament.
15
17. The use of an inhaled formulation according to any one of claims 1 to 15 in
the manufacture of a medicament for the treatment of a disease treatable
by the inhibition of PDE4.
20 18. The use according to claim 17, wherein the disease is a respiratory disease.
: 19. The use according to claim 18 wherein the respiratory disease is asthma or chronic obstructive pulmonary disease.

WO 03/022275 PCT/IB02/03599
17 •
20, The use of a compound of the formula (I), as defined in claim 1, having an
aqueous solubility at physiological pH of less than 0.15mg/ml in the
manufacture of a medicament for administration by inhalation,
5 characterised in that said medicament is in the form of a dry powder
inhaler or other device capable of delivering low solubility particles.
21. Use according to Claim 23 wherein said medicament is in the form of a
device other than a dry powder inhaler which is capable of delivering low
10 solubility particles, which device is a suspension metered dose inhaler or a
device capable of delivering liposomes, micronised/engineered particles, or microspheres.
22- Use according to Claim 24 wherein said device is a device capable of
15 delivering microspheres, which microspheres comprise poly(D,L-lactic-co-
glycolic acid).
23. A dry powder inhaler containing a compound of formula (I) as described in Claim 23.
20
24. A device other than a dry powder inhaler which is capable of delivering low solubility particles, which device contains a compound of formula- (I) as described in Claim 23.

Dated this 18th day of March, 2005.