GB2463883A - A pharmaceutical composition comprising an A-SMase inhibitor and an NO-donor - Google Patents

Abstract

A pharmaceutical composition comprising an A-SMase inhibitor and an NO-donor may give rise to a synergistic effect. Preferred A-SMase inhibitors are tricyclic antidepressants, most preferably amitriptyline. A preferred NO-donor is arginine. The pharmaceutical composition may be suitable for treating or preventing respiratory disorders such as chronic cough, cystic fibrosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and emphysema. Preferably the pharmaceutical composition is adnunistered by inhalation. The A-SMAse inhibitor may be a compound as per formula (I) or (II).

Description

INTELLECTUAL

. .... PROPERTY OFFICE Application No. GBO8 17585.3 RTM Date:31 March 2009 The following terms are registered trademarks and should be read as such wherever they occur in this document: Respimat Rotahaler Diskhaler Turbohaler Novolizer Aspirair Spinhaler Intellectual Property Office is an operating name of the Patent Office www.ipo.gov.uk Novel Compositions and Methods

Field of the invention

The present invention relates to a pharmaceutical composition comprising an A-SMase inhibitor and/or a NO-donor. Preferred A-SMase inhibitors are tricycic antidepressants, most preferably arnitriptyline. A preferred NO-donor is arginine. Preferably the pharmaceutical composition comprises an A-SMase inhibitor and a NO-donor, which preferably act synergistically to inhibit A-SMase. The pharmaceutical composition is suitable for treating or preventing respiratory disorders such as chronic cough, cystic fibrosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and emphysema. Preferably the pharmaceutical composition is administered by inhalation. The present invention also relates to methods of treating or preventing respiratory disorders.

Background of the invention

A wide and varied range of agents are in clinical use for the treatment of respiratory disorders. In the search for further therapies, classes of drugs first developed for other purposes have come under increasing scrutiny.

Amongst these, tricycic antidepressants such as maprotiline have surprisingly recently found application in the treatment of asthma (WO 96/37198), whilst other studies have suggested that oral doses of 10mg amitriptyine may be used to treat chronic cough (Bastian et at, Otolaryngology -Head and Neck Surgery, 2006, vol. 135, pp. 17-21). The biological effects of tricyclic antidepressants are numerous; they are believed to act for instance as norepinephrine and serotonin re-uptake inhibitors, as modulators of muscarinic and histamine HI receptors, and as inhibitors of acid sphingomyelinase (A-SMase). Thus their precise modus operandi in the treatment of respiratory disorders is not well understood. A recent study has however demonstrated that, in relation to acute neonatal Jo inflammatory lung injury at least, it is their role as A-SMase inhibitors, and hence as inhibitors of ceramide generation, that is crucial (von Bisrnarck et at, American Journal of Respiratory and Critical Care Medicine, 2008, vol. 177, pp. 1233-1241).

Another drug class of interest is represented by nitric oxide (NO) and donors of NO such as glyceryl trinitrate (nitro-glycerine). NO donors have been employed for well over 100 years to treat conditions such as angina and heart failure. They are effective due to the vasodilatory effect of NO. More recently, this effect has been employed to treat pulmonary vasoconstriction and asthma using NO or NO donors such as S-nitroso-N-acetylpenicillarnine by inhalation (WO 92/10228).

In spite of the above, however, there is a continuing need for new and improved agents and formulations.

In a separate advancement, recent studies on cell apoptosis have demonstrated that nitric oxide is also able to inhibit A-SMase (Barsacchi et at, Cell Death and Differentiation, 2002, vol. 9, pp. 1248-1255).

It has been surprisingly discovered by the present inventors that conventional A-SMase inhibitors and nitric oxide or donors thereof are able to act synergistically to inhibit A-SMase and to treat respiratory disorders such as chronic cough, cystic fibrosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis or emphysema.

Summary of the invention

A first aspect of the present invention relates to a pharmaceutical composition comprising an A-SMase inhibitor and a NO-donor, and optionally comprising one or more pharmaceutically acceptable excipients. Preferably the A-SMase inhibitor and the NO-donor act synergistically to inhibit A-SMase and/or to treat respiratory diseases.

As used herein, the term "A-SMase" refers to acid sphingomyelinase. An "A-SMase inhibitor" refers to any compound or substance that is not a NO-donor and that inhibits A-SMase. Preferably the term "A-SMase inhibitor" refers to any compound or substance that is capable of inhibiting A-SMase by disrupting its attachment to a lysosomal membrane, more preferably by disrupting its attachment to an intralysosomal membrane.

As used herein, a "NO-donor" refers to a nitric oxide donor. As used herein, a "nitric oxide donor" refers to any compound or substance that has the capacity to augment or increase the bioavailabiity of nitric oxide in vitro. The term "NO-donor group" is similarly defined as a group comprising a nitric oxide donor.

In one embodiment of the first aspect of the present invention, the A-SMase inhibitor is selected from alimema2ine, arnitriptyline, trans-I,4-bis (2-chloroben2aminomethyl) -cyclohexane (AY9944), chlorproma2ine, clomiprarnine, cocaine, cyamema2ine, desipramine, dibucaine, imiprarnine, mianserin, p erhexiine, prochlorp era2ine, propericiazine, quinacrine, tamoxifen, thioprop era2ine, thiorida2ine, trifluop era2ine, trihexyphenidyl, trimipramine, N-(6-aminohexyl)-I -naphthalenesulfonamide (W-5), N-(6-aminohexyl) -I -[5'-chloro-naphthalene-I -sulfonamide] (W-7), amlodipine, astemi2ole, ben2tropine, bepridil, camylofin, clomiphene, clop erastine, cycloben2aprine, cyproheptadine, doxepin, drofenine, pimethixene, proma2ine, protrip tyline, chlorprothixene, fendiline, fluoxetine, maprotiline, noriluoxetine, nortriptyline, paroxetine, prometha2ine, sertraline, suloctidil, terfenadine, trifiuproma2ine, 8-bromoguanosine-3',5'-cyclic monophosphate, tricyclo-decan-9-yl-xanthate, monensin, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.

As used herein, "prodrug" refers to any derivative of a drug that is metaboli2ed or otherwise converted into an active form upon introduction into the body of an animal.

Prodrugs are well known to those skilled in the art of pharmaceutical chemistry, and provide benefits such as increased absorption and halflife. Prodrugs of this invention may be formed when, for example, hydroxy groups are esterified or alkylated, or when carboxyl groups are esterified. Those skilled in the art of drug delivery will readily appreciate that the pharmacokinetic properties of the compounds of the invention may be controlled by an appropriate choice of moieties to produce prodrug derivatives.

The compounds of the present invention can be used both, in their free acid or base form and their salt form. For the purposes of this invention, a "salt" of a compound of the present invention may be an acid addition salt, or a salt formed between an acidic functionality of a compound of the present invention (e.g. a carboxylic acid group) and a

suitable cation.

Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchioric, sulphuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandeic, citric, acetic, ben2oic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulphonic acids (for example, methanesulphonic, trifiuoromethanesulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, ben2enesulphonic, toluene-p-sulphonic, naphthalene-2-sulphonic or camphorsulphonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid). The acid addition salt may be a mono-or di-acid addition salt. A preferred salt is a hydrohalogenic, sulphuric, phosphoric or organic acid addition salt. A more preferred salt is a hydrochloric acid addition salt.

Suitable cations for forming a salt with an acidic funcitonality include, but are not limited to lithium, sodium, potassium, magnesium, calcium and ammonium. The salt may be a mono-, di-or tn-salt. Preferably the salt is a mono-or di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. More preferably the salt is a mono-or di-sodium salt.

In a second embodiment of the first aspect of the present invention, the A-SMase inhibitor comprises a nitrogen atom. Preferably the A-SMase inhibitor has a P'a of at least 5, such as at least 6, at least 8 or at least 8.45. Preferably the A-SMase inhibitor has a P'a of between 5 and 20, more preferably of between 6 and 15, and most preferably of between 8 and 12.

As used herein, the P'a of an A-SMase inhibitor refers to the P'a of the conjugate acid of that inhibitor in dilute aqueous solution at 25°C.

Preferably in the second embodiment of the first aspect of the present invention, the A-SMase inhibitor has a log P of at least 0, such as at least 1, at least 2 or at least 3.61.

Preferably the A-SMase inhibitor has a log P of between 0.5 and 30, more preferably of between I and 15, and most preferably of between 2 and 8.

As used herein, the term "log P" in relation to a compound refers to the logarithm of the ratio of the compound's concentration in the octanol phase to its concentration in the aqueous phase of a two-phase octanol/water system at 25°C, i.e. log P log ([compound]octanoi/[compound]water) Preferably in the second embodiment of the first aspect of the present invention, the A-SMase inhibitor has a steric factor Ic 20, such as 15 or 10. More preferably the A-SMase inhibitor has a steric factor Ic f 6 such as 5. Most preferably the A-SMase inhibitor has a steric factor Ic 4 or 3.

The steric factor "Ic" in relation to a nitrogen-containing compound is calculated in accordance with the method outlined in Kornhuber et at, J. Med. Chem., 2008, vol. 51, pp. 219-237, as follows: (1) the most basic nitrogen atom in the compound is identified; (2) the largest substituent at the most basic nitrogen atom, as assessed by heavy atom count, is disregarded; (3) Ic is the sum of the heavy atom counts of the remaining substituents at the most basic nitrogen atom. As used herein, the term "heavy atom count" in relation to a substituent refers to the number of non-hydrogen atoms in that substituent, e.g. I for a methyl group, 3 for a -COMe group etc. Where the most basic nitrogen atom is part of a single ring and does not carry a double bond, Ic is assessed by hypothetically cleaving the nitrogen atom from the chemical structure to leave two fragments; Ic is the heavy atom count of the smaller of the two fragments (as assessed by heavy atom count); e.g. I for 1-methyl-pyrrolidine, 4 for 1-hexyl-pyrrolidine etc. Where the most basic nitrogen atom is simultaneously part of two or three rings, or is part of a single ring and carries a double bond, Ic is assigned a value of 6.

In a third embodiment of the first aspect of the present invention, the A-SMase inhibitor is selected from alimema2ine, arnitriptyline, trans-I,4-bis(2-chloroben2aminomethyl)-cyclohexane (AY9944), chlorproma2ine, clomiprarnine, cocaine, cyamema2ine, desipramine, dibucaine, imiprarnine, rnianserin, p erhexiine, prochlorpera2ine, propericiazine, quinacrine, tamoxifen, thioprop era2ine, thiorida2ine, trifluop era2ine, trihexyphenidyl, trimiprarnine, N-(6-aminohexyl) -I -naphthalenesulfonamide (W-S), N-(6-aminohexyl) -1-[5'-chloro-naphthalene-I -sulfonamide] (W-7), amlodipine, astemi2ole, ben2tropine, bepridil, camylofin, clomiphene, clop erastine, cycloben2aprine, cyprohep tadine, doxepin, drofenine, pimethixene, proma2ine, protrip tyline, chiorprothixene, fendiine, fluoxetine, maprotiline, noriluoxetine, nortriptyline, paroxetine, prometha2ine, sertraline, suloctidil, terfenadine, trifiuproma2ine, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof. Preferably the A-SMase inhibitor is selected from alimema2ine, amitriptyline, chlorproma2ine, clomipramine, desipramine, dibucaine, imipramine, prochlorpera2ine, tamoxifen, thiorida2ine, trifluopera2ine, trihexyphenidyl, trimipramine, amlodipine, ben2tropine, bepridil, clomiphene, cycloben2 aprine, cyprohep tadine, doxepin, proma2ine, protrip tyline, chlorprothixene, fluoxetine, maprotiline, nortrip tyline, paroxetine, prometha2ine, sertraline, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.

In a fourth embodiment of the first aspect of the present invention, the A-SMase inhibitor is a cationic amphiphilic drug.

In a fifth embodiment of the first aspect of the present invention, the A-SMase inhibitor is an antidepressant, such as alimema2ine, amitriptyline, chlorproma2ine, clomipramine, cocaine, cyamema2ine, desipramine, imipramine, mianserin, prochlorpera2ine, propericiazine, thiopropera2ine, thiorida2ine, trifiuopera2ine, trihexyphenidyl, trimipramine, cycloben2aprine, cyproheptadine, doxepin, pimethixene, proma2ine, protriptyline, chiorprothixene, fluoxetine, maprotiline, noriluoxetine, nortriptyline, paroxetine, prometha2ine, sertraline, trifiuproma2ine, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.

Preferably in the fifth embodiment of the first aspect of the present invention, the antidepressant is a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRII), a noradrenergic and specific serotonergic antidepressant (NASSA), a norepinephrine (noradrenaline) reuptake inhibitor (NRI), a Jo norepinephrine-dopamine reuptake inhibitor, a tricyclic antidepressant (TCAD) or a monoamine oxidase inhibitor (IMAOI). Most preferably the antidepressant is a tricyclic antidepressant TCAD).

As used herein, the term "tricycic antidepressant" refers to any antidepressant comprising at least three fused rings, such as arnitriptyline or clornipramine. Thus, the term also includes antidepressants comprising more than three rings, such as tetracyclic antidepres sants including mianserin, prochlorp era2ine and maprotiline. Optionally, the term "tricycic antidepressant" may refer to any antidepressant containing three fused rings and no other cyclic groups.

Preferably the tricyclic antidepressant is selected from aimema2ine, amitriptyine, chlorproma2ine, clornipramine, cyamema2ine, desiprarnine, irnipramine, rnianserin, prochlorpera2ine, propericia2ine, thioprop era2ine, thiorida2ine, trifiuopera2ine, trirnipramine, cycloben2aprine, cyprohep tadine, doxepin, pimethixene, proma2ine, protriptyline, chlorprothixene, maprotiline, nortriptyline, paroxetine, prometha2ine, trifiuproma2ine, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof. Most preferably the tricycic antidepressant is arnitriptyline or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.

In a sixth embodiment of the first aspect of the present invention, the A-SMase inhibitor is selected from a compound of formula (I) or (II): N(R'°)2 N(R'°)2 I (C(R9)2)m R' (C(R9)2) R8 I (II) or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, wherein at each occurrence: is independendy selected from cR", NC")2 C")2-N NR"R" R"NR" OR" CR" 0 S CR" CR" s CR" C(R")2 C(R")2 CR" C CR' or R"C C X' is independently selected from C, C, C 0 C C 0 S C C S C C(R")2 or C(R")2 C -Y-is independently selected from a chemical bond, -0-, -S-, -NR12-, -C(R12)2-, -C(R12)2-C(R12)2-, -R12CCR12-, -NR12-C(R12)2-, -C(R12)2-NR12-, -NCR12-, -R12CN-, -O-C(R12)2-, -C(R12)2-O-, -S-C(R12)2-or -C(R12)2-S-; n is independently 1, 2, 3, 4, 5 or 6; m is independently 0, 1, 2, 3, 4 or 5; R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, R11 and R12 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CF3, -Cd3, -CBr3, -CT3, -OH, -SH, -NH2, -CN, -NO2, -COOH, -R13-O-R14, -R13-S-R14, -R13-SO-R14, -R13-S02-R14, -R13-S02-0R14, -R13-O-S02-R14, -R13-NR14-S02-R14, -R13-O-S02-0R14, -R13-O-S02-N(R14)2, -R13-NR14-S02-0R14, -R13-NR14-S02-N(R14)2, -R13-N (R14)2, -R13-N(R14)3, -R13-Si(R14)3, -R13-CO-R14, -R13-CO-0R14, -R13-O-CO-R14, -R13-CO-N(R14)2, -R13-NR14-CO-R14, -R13-O-CO-0R14, -R13-O-CO-N(R14)2, -R1'-NR14-CO-0R14, -R13-NR14-CO-N(R14)2, -R13-CS-R14, -R13-CS-0R14, -R13-O-CS-R14, -R13-CS-N(R14)2, -R13-NR14-CS-R14, -R130-CS-0R14, -R13-O-CS-N(R14)2, -R13-NR14-CS-0R14, -R13-NR14-CS-N(R14)2 or -R13-is independently a chemical bond, or an optionally substituted C1-C10 alkylene, C1-C10 alkenylene or C1-C10 alkynylene group; -R14 is independently hydrogen or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 aryl, C3-C10 arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, C3-C10 alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group, each of which may optionally be substituted; and wherein any two or more R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, RH, R12, R13 or R14 may, together with the atom or atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton.

For the purposes of the present invention, an "alkyl" group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups. An alkyl group may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups. Preferably an alkyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton. Preferably an alkyl group is a C1-C12 alkyl group, which is defined as an alkyl group containing from I to 12 carbon atoms. More preferably an alkyl group is a C1-C6 alkyl group, which is defined as an alkyl group containing from I to 6 carbon atoms. An "alkylene" group is similarly defined as a divalent alkyl group.

An "alkenyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon double bond, which may be straight-chained or branched, or be or include cyclic groups. An alkenyl group may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton. Examples of alkenyl groups are vinyl, allyl, but-1-enyl and but-2-enyl groups. Preferably an alkenyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton. Preferably an alkenyl group is a C2-C12 alkenyl group, which is defined as an alkenyl group containing from 2 to 12 carbon atoms. More preferably an alkenyl group is a C2-C6 alkenyl group, which is defined as an alkenyl group containing from 2 to 6 carbon atoms. An "alkenylene" group is similarly defined as a divalent alkenyl group.

An "alkynyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon triple bond, which may be straight-chained or branched, or be or include cyclic groups. An alkynyl group may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton. Examples of alkynyl groups are ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups. Preferably an alkynyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton. Preferably an alkynyl group is a alkynyl group, which is defined as an alkynyl group containing from 2 to 12 carbon atoms.

Jo More preferably an alkynyl group is a C2-C6 alkynyl group, which is defined as an alkynyl group containing from 2 to 6 carbon atoms. An "alkynylene" group is similarly defined as a divalent alkynyl group.

-10 -A cyclic "hydrocarbyl" group includes cyclic alkyl, alkenyl, alkynyl and aryl groups.

An "aryl" group is defined as a monovalent aromatic hydrocarbon. An aryl group may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton. Examples of aryl groups are phenyl, naphthyl, anthracenyl and phenanthrenyl groups. Preferably an aryl group does not include any heteroatoms in its carbon skeleton. Preferably an aryl group is a C4-C14 aryl group, which is defined as an aryl group containing from 4 to 14 carbon atoms.

More preferably an aryl group is a C6-C10 aryl group, which is defined as an aryl group containing from 6 to 10 carbon atoms. An "arylene" group is similarly defined as a divalent aryl group.

For the purposes of the present invention, where a combination of groups is referred to as one moiety, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. A typical example of an arylalkyl group is ben2yl.

For the purposes of this invention, an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylene, alkenylene, alkynylene, arylene or hydrocarbyl group may be substituted with one or more of -F, -Cl, -Br, -I, -CF3, -CC13, -CBr3, -CT3, -OH, -SH, -NH2, -CN, -NO2, -COOH, -R-O-R, -1?-S-R, -1?-SO-R, -1?-SO2-R, -1?-SO2-OR, -RO-SO2-R, -R-SO2-N(R)2, -1?-NR-SO2-R, -1?O-SO2-OR, -1?O-S02-N (R)2, -1?-NR-SO2-OR, -1?-NR-SO2-N (R)2, -1?-N (R)2, -1?-N (R)3, -1?-P(R)2, -W-Si(R)3, -1?-CO-R, -1?-CO-OR, -1?O-CO-R, -1?-CO-N(R)2, -R-NR-CO-R, -R°O-CO-OR, -R°O-CO-N(R)2, -R-NR-CO-OR, R°LNRCON (R)2, R°LCSRP, -R°-CS-OR, -R°O-CS-R, -R°-CS-N(R)2, -R°-NR-CS-Q -R°O-CS-OR, -R°O-CS-N(R)2, -R°-NR-CS-OR, -1?-NR-CS-N(R)2, -R, a bridging substituent such as -0-, -5-, -NR-or -1?-, or a it-bonded substituent such as 0, n5 or NR. In this context, -R°-is independently a chemical bond, a C1-C10 alkylene, C1-C10 alkenylene or C1-C10 alkynylene group. -R is independently hydrogen, unsubstituted C1-C6 alkyl or Jo unsubstituted C6-C10 aryl. Optional substituent(s) are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituent(s). Preferably an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylene, alkenylene, -11 -alkynylene, arylene or hydrocarbyl group is not substituted with a bridging substituent.

Preferably an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylene, alkenylene, alkynylene, arylene or hydrocarbl group is not substituted with a 7t-bonded substituent. Preferably a substituted group comprises 1, 2 or 3 substituents, more preferably I or 2 substituents, and even more Any optional substituent may be protected. Suitable protecting groups for protecting optional substituents are known in the art, for example from "Protective Groups in Organic Synthesis" by T.W. Greene and P.G.M. Wuts (Wiley-Interscience, 4th edition, 2006).

Preferably in the sixth embodiment of the first aspect of the present invention, (a) is independently selected from -NC")2 or or (b) -X is C* Preferably, -Y-is independently selected from -5-, -C(R12)2-, -C(R12)2-C(R12)2-, -R12CCR12-, or -C(R12)2-O-. Preferably n is 2 or 3 and/or m is I or 2.

Optionally in the sixth embodiment of the first aspect of the present invention, one of R1, R2, R3, R4, R5, R6, R7 and R8 is selected from hydrogen, -F, -Cl, -Br, -I, -CF3, -Cd3, -CBr3, -CT3, -OH, -SH, -NH2, -CN, -NO2, -COOH, -R13-O-R14, -R13-S-R14, -R13-SO-R14, -R13-502-R14, -R13-502-0R14, -R13-O-502-R14, -R13-502-N(R14)2, -R13-NR14-502-R14, -R13-O-502-0R14, -R13-O-502-N(R14)2, -R13-NR14-502-0R14, -R13-NR14-502-N(R14)2, -R13-N(R14)2, -R13-N(R14)3, -R13-P(R14)2, -R13-Si(R14)3, -R13-CO-R14, -R13-CO-0R14, -R13-O-CO-R14, -R13-CO-N(R14)2, -R13-NR14-CO-R14, -R13-O-CO-0R14, -R13-O-CO-N(R14)2, -R13-NR14-CO-0R14, -R13-NR14-CO-N(R14)2, -R13-CS-R14, -R13-CS-0R14, -R13-O-CS-R14, -R13-CS-N(R14)2, -R13-NR14-CS-R14, -R130-CS-0R14, -R13-O-CS-N(R14)2, -R13-NR14-CS-0R14, -R13-NR14-CS-N(R14)2 or -R14, and all other R1, R2, R3, R4, R5, R6, R7 and R8 are hydrogen. In -12 -one alternative, R1, R2, R3, R4, R5, R6, R7 and R8 are all hydrogen. In another alternative, one of R1, R2, R3, R4, R5, R6, R7 and R8 is not hydrogen.

Preferably in the sixth embodiment of the first aspect of the present invention, at each occurrence R1, R2, R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CF3, -CC13, -CBr3, -CT3, -CN, -R13-O-R14, -R13-S-R14, -R13-SO-R14, -R13-S02-R14, -R13-S02-0R14, -R13-O-S02-R14, -R13-S02-N(R14)2, -R13-NR14-S02-R14, -R13-O-S02-0R14, -R13-O-S02-N(R14)2, -R13-NR14-S02-0R14, -R13-NR14-S02-N(R14)2, -R13-N(R14)2, or Preferably at each occurrence R9 is independently selected from hydrogen or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 aryl, C3-C10 arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, C3-C10 alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group, each of which may optionally be substituted. Most preferably at each occurrence R9 is independently selected from hydrogen or methyl.

Preferably at each occurrence R1° is independently selected from hydrogen or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 aryl, C3-C10 arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, C3-C10 alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group, each of which may optionally be substituted. Most preferably at each occurrence R1° is independently selected from hydrogen or methyl.

Optionally in the sixth embodiment of the first aspect of the present invention, at each occurrence R11 is hydrogen, and/or at each occurrence R12 is hydrogen, and/or at each occurrence -R13-is a chemical bond. Preferably at each occurrence -R14 is independently hydrogen or a C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group, each of which may Optionally in the sixth embodiment of the first aspect of the present invention, one R9 and one R10, together with the atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more additional heteroatoms N, 0 or S in its carbon skeleton.

-13 -Optionally in the sixth embodiment of the first aspect of the present invention, the two R10, together with the nitrogen atom to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more additional heteroatoms N, 0 or S in its carbon skeleton.

Optionally in the sixth embodiment of the first aspect of the present invention, one R11 and one R12, together with the atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more additional heteroatoms N, 0 or S in its carbon skeleton.

Optionally in the sixth embodiment of the first aspect of the present invention, one R1° and one R11, together with the atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more additional heteroatoms N, 0 or S in its carbon skeleton.

Preferably in the sixth embodiment of the first aspect of the present invention, an optionally substituted cyclic hydrocarbyl group is substituted with one or more of -F, -Cl, -Br, -I, -CF3, -CC13, -CBr3, -CT3, -CN, -NO2, -O-R15, -S-R15, -N-(R15)2 or -R15, or one or more it-bonded substituents such as nQ, n5 or NR15, wherein -R15 is independently hydrogen or an unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 aryl, C3-C10 arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, C3-C10 alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group. Most preferably an optionally substituted cyclic hydrocarbyl group is substituted with -OH or a methyl group.

Tn a seventh embodiment of the first aspect of the present invention, the NO-donor is nitric oxide, a NO-synthase substrate, a NO-synthase agonist, or a NO-releaser.

Preferably the NO-donor is a NO-synthase substrate such as arginine, N-cyclopropyl-N'-hydroxyguanidine, L-canavanine or N°-ben2oyl-L-arginine ethyl ester, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof. Most preferably the NO-synthase substrate is L-arginine or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof. -14-

A "NO-synthase substrate" refers to a compound or substance from which a nitric oxide synthase is capable of generating nitric oxide. Preferably it refers to a compound or substance from which endotheial nitric oxide synthase is capable of generating nitric oxide.

A "NO-synthase agonist" refers to a compound or substance which is capable of increasing the generation of nitric oxide by a nitric oxide synthase but that is not in itself a NO-synthase substrate. Such compounds include the essential co-factor tetrahydrobiopterin. Preferably the nitric oxide synthase is endothelial nitric oxide synthase.

A "NO-releaser" refers to a compound or substance that is capable of releasing nitric oxide in vivo or in vitro. The term "NO-releasing group" is similarly defined as a group comprising a moiety that is capable of releasing nitric oxide in vivo or in vitro.

Alternatively in the seventh embodiment of the first aspect of the present invention, the NO-donor is a NO-releaser. Preferably the NO-releaser is selected from: (a) Angel's salt (Na2N2O3), isonia2id, N-hydroxyben2enesulfonamide or P-nitrosophosphate; (b) an organic nitrate such as glyceryl trinitrate (GTN), [3-(nitrooxymethyl)phenyl] -2-acetyloxyben2oate (NCX-40 16), 4-nitrooxybutyl-2-acetyloxyben2oate (NCX-42 15), [3-(nitrooxymethyl)phenyl] -2-hydroxyben2oate (B-NOD), isosorbide mononitrate (ISMN), pentaerythrityl tetranitrate (PETN), isosorbide dinitrate (BiDil), nicorandil, nipradilol, nitro-pravastatin (NCX-65 SO), O-losartanyl-3-[(nitrooxy)methyl] - ben2oate (NO-Losartan A) or methyl 2-[4-[(nitrooxy)methyl] ben2oyl] thio] -ben2oate (SE 175); (c) an organic nitrite such as amyl nitrite or 2-methylbutan-2-yl nitrite; (d) a NONOate such as diethylenetriamine NONOate (DETA NO), diethylamine NONOate (DEA NO), spermine NONOate (SPER NO), dipropylenetriamine NONOate (DPTA NO), methylamine hexamethylene methylarnine NONOate (MAHMA NO), 3-propylamine-propylamine NONOate (PAPA NO), proline NONOate (PROLI NO), 1-[(ethenyloxy)-NNO-azoxy]-pyrrolidine (V-Pyrro NO), 02-(2,4-dinitrophenyl) -1-[(4-ethoxycarbonyl)pipera2in-I -yl] dha2en-I -ium-I,2-diolate (JS-JC), N-(3-aminopropyl-propan-2-ylamino)-N-hydroxynitrous amide (NOC-5), N-hydroxy-N-(methyl-(3-methylaminopropyl)-amino) -nitrous amide (NOC-7), N- -15 - ethyl-2-(1 -ethyl-2-hydroxy-2-nitrosohydra2ino) -ethanarnine (NOC-12), O--galactopyranosyl-I -(pyrrolidin-I -y1)diaen-I -ium-I,2-diolate (-Ga1-NONOate) or disodium hydroxydia2enesulfonate 1-oxide (Sulfo-NONOate); (e) a S-nitrosothiol such as S-nitroso-N-acetylpenicilarnine (SNAP), 5-nitroso-glutathione (GSNO), S-nitroso-N-valerylpenicillarnine (SNVP), S-nitrosoalbumin, 5-nitrosocysteine, N-(N-y-L-glutamyl-2-amino-2-(4-(4-5-nitrosomercapto-I- methylpiperidine) -acetyl) -glycine) (LA8 10), nitrosodiclofenac, nitrosocaptopril, N- (-D-g1ucopyranosy1) -N2-acetyl-S-nitroso-D,L-penicillarninamide (Glyco-SNAP-I), N-(2-deoxy-oç-D-g1ucopyranose-2-) -N2-acetyl-S-nitroso-D,L-penicillaminarnide (Glyco-SNAP-2), 4-phenyl-I,3,2-oxathia2olylium-5-olate, 4-(p- trifluoromethyiphenyl) -I,3,2-oxathia2olylium-5-olate, 4-(p-chlorophenyl) -1,3,2- oxathio2olylium-5-olate, 4-(p-methoxyphenyl)-I,3,2-oxathia2olyliurn-5-olate or N- (I -deoxy-oç-D-fructopyranose-I -)-N2-acetyl-S-nitroso-D,L-penicillaminarnide (Fructose-SNAP-I); (1) a N-nitrosarnine such as strepto2ocin, N,N'-dimethyl-N,N'-dinitroso-p-phenylenediamine (BNN3) or dephostatin; (g) a C-nitroso compound such as 2-nitro-2-nitrosopropane; (h) a dia2etine dioxide such as 3-bromo-3,4,4-trimethyl-3,4-dihydrodia2ete-I,2-dioxide (DD I) or 3-bromo-4-methyl-3,4-tetramethylene-3,4-dihydrodia2ete-1,2-dioxide (DD2); (i) a furoxan such as dimethyl 2,6-dimethyl-4-[2'-(3"-methylfuroxan-4"- ylmethoxy)phenyl] -I,4-dihydropyridine-3,5-dicarboxylate, dimethyl 2,6-dimethyl-4- [2'-(3"-carbamoylfuroxan-4"-ylmethoxy)phenyl] -I,4-dihydropyridine-3,5- dicarboxylate, dimethyl 2,6-dimethyl-4-[2'-(3"-cyanofuroxan-4"-ylmethoxy)phenyl] - 1,4-dihydropyridine-3,5-dicarboxylate, 4-methyl-3-phenylsulphonylfuroxan, 4- hydroxymethyl-3-furoxancarboxamide, N-(pyridin-3-yl) -3-phenyl-4-furoxancarboxarnide, 4-phenyl-3-(N',N'-dimethyl-2'-aminoethylsulphanyl)furoxan or 4-phenylsulphonyl-3-(N',N'-dimethyl-2'-aminoethylsulphanyl) furoxan; (j) a sydnonirnine such as 3-morpholinosydnonirnine (SIN-I) or molsidornine; (Ic) an oxatria2ole-5-imine such as 5-amino-3-(3',4'-dichlorophenyl)-I-oxa-2,3,4-tria2olium chloride, 5-amino-3-(3'-chloro-2'-methylphenyl) -I -oxa-2,3,4-tria2olium chloride or 5-(((cyanomethylarnino)carbonyl)amino) -(3'-chloro-2'-methylphenyl)-I -oxa-2,3,4-tria2olium chloride; -16 - (1) an oxime such as 4-(E)-methyl-2-[(E) -hydroxyimino] -5-nitro-6-methoxy-3-hexenamide (NOR-I), 4-(E) -methyl-2-ftE)-hydroxyimino] -5-nitro-3-hexenamide (NOR-2), 4-(E) -ethyl-2-[(E) -hydroxyimino] -5-nitro-3-hexenamide (NOR-3), N- ftE,2Z)-4-ethyl-2-hydroxyimino-5-nitrohex-3-enyl] pyridine-3-carboxamide (NOR- 4) or N-ftE,2Z) -4-ethyl-6-methyl-2-hydroxyimino-5-nitrohept-3-enyl] pyridine-3-carboxamide (NOR-5); or (m) a metal-NO complex such as sodium nitroprusside (SNP) or a NO 2eolite; or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.

As used herein, an "organic nitrate" refers to a compound of formula W-0N02, wherein W is an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, optionally with one or more further -0N02 groups, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton.

As used herein, an "organic nitrite" refers to a compound of formula RbONO, wherein Rb is an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, optionally with one or more further -ONO groups, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton.

As used herein, a "NONOate" refers to a compound of the formula: Rd \\ / N-0 wherein R is an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, and wherein Rd is hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, or optionally wherein RC and Rd together with the atoms to which -17 -they are attached form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more further heteroatoms N, 0 or S in its carbon skeleton.

As used herein, a "S-nitrosothiol" refers to a compound of formula W-S-NO, wherein RC is an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, optionally with one or more further -S-NO groups, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton.

As used herein, a "N-nitrosamine" refers to a compound of formula (R2N-NO, wherein each El is independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, optionally with one or more further -NO groups, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, or wherein the two R groups together with the nitrogen atom to which they are attached form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton.

As used herein, a "C-nitroso compound" refers to a compound of formula (RY)3C-NO, wherein each is independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, optionally with one or more further -NO groups, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, and wherein any two R groups together with the carbon atom to which they are attached may form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton.

As used herein, a "dia2etine dioxide" refers to a compound of the formula: + /0 -18 -wherein each Rh is independently hydrogen or an alkyl, alkenyl, alkynl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, and wherein any two R' groups together with the carbon atom or atoms to which they are attached may form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton.

As used herein, a "furoxan" refers to a compound of the formula: "I /

Z N

R

wherein each R' is independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, or wherein the two R' groups together with the carbon atoms to which they are attached form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton.

As used herein, a "sydnonirnine" refers to a compound of the formula:

I

N + 0

and an "oxatria2ole-5-imine" refers to a compound of the formula:

RN N N0

wherein each R3 is independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more -19 -heteroatoms N, 0 or S in its carbon skeleton, and wherein any two R3 groups together with the atom or atoms to which they are attached may form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton.

As used herein, an "oxime" refers to a compound of formula cRk)2CN0H wherein each Rk is independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, or wherein the two Rk groups together with the carbon atom to which they are attached form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton.

A second aspect of the present invention relates to a compound comprising an A-SMase inhibitor covalently linked to a NO-donor group, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof. Preferably the A-SMase inhibitor is as specified in any embodiment of the first aspect of the present invention.

In one embodiment of the second aspect of the present invention, the NO-donor group is a NO-releasing group. Preferably the NO-releasing group comprises or is: (a) a-0N02 group; (b) a -ONO group; (c) a group selected from: O\� o_ //N_RC Rd 1-0-N or wherein at each occurrence R and Rd are independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton; (d) a -S-NO group; -20 - (e) a -N(R15NO group, wherein El is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be subs tituted, optionally with one or more further -NO groups, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton;

RNO

(I) a -C(R2NO, or -NO group, wherein each is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, optionally with one or more further -NO groups, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, or wherein the two R groups together with the carbon atom to which they are attached form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton; (g) a group selected from:

TY

cRh)c tk\ (Rh)2C N\ + \ - 0, or Rh 0, wherein each R' is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, and wherein any two Rh groups together with the carbon atom or atoms to which they are attached may form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton; (h) a group selected from: or -21 -wherein each R' is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton; (i) a group selected from: NR NR3 f Nt NR3 N NR + ii or wherein at each occurrence R3 is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, and wherein any two R3 groups together with the atom or atoms to which they are attached may form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton; or (j) a group selected from:

NOH NOH Rk or

wherein each R' is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton.

In a second embodiment of the second aspect of the present invention, the compound further comprises a linker between the A-SMase inhibitor and the NO-donor group.

-22 -Preferably the linker comprises an alkylene, alkenylene, alkynylene, arylene, arylalkylene, arylalkenylene, arylalkynylene, alkylarylene, alkenylarylene or alkynylarylene group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton.

In a third embodiment of the second aspect of the present invention, the compound is selected from a compound of formula (III) or (IV): I (C(R9)2)m R' (C(R9)2) R8 I (III) R5 (IV) or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, wherein at each occurrence: is independently a NO-releasing group; is independently selected from CR", NC")2 C")2-N NRh1Rh1 Rh1NRh1 OR" Rh1O CRh1 or is independently selected from NR"C, CNR", CC")2 or -Y-is independently selected from a chemical bond, -0-, -5-, -NR12-, -C(R12)2-, -C(R12)2-C(R12)2-, -R12CCR12-, -NR12-C(R12)2-, -C(R12)2-NR12-, -NCR12-, -R12CN-, -O-C(R12)2-, -C(R12)2-O-, -S-C(R12)2-or n is independently 1, 2, 3, 4, 5 or 6; m is independently 0, 1, 2, 3, 4 or 5; -23 -R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, R11 and R12 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CF3, -Cd3, -CBr3, -CT3, -OH, -SH, -NH2, -CN, -NO2, -COOH, -R13-O-R14, -R13-S-R14, -R13-SO-R14, -R13-S02-R14, -R13-S02-0R14, -R13-O-S02-R14, -R13-S02-N(R14)2, -R13-NR14-S02-R14, -R13-O-S02-0R14, -R13-O-S02-N(R14)2, -R13-NR14-S02-0R14, -R13-NR14-S02-N(R14)2, -R13-N(R14)2, -R13-N(R14)3, -R13-PR14)2, -R13-Si(R14)3, -R13-CO-R14, -R13-CO-0R14, -R13-O-CO-R14, -R13-CO-N(R14)2, -R13-NR14-CO-R14, -R13-O-CO-0R14, -R13-O-CO-N(R14)2, -R1-NR14-CO-OR14, -R13-NR14-CO-N(R14)2, -R13-CS-R14, -R13-CS-0R14, -R13-O-CS-R14, -R13-CS-N(R14)2, -R13-NR14-CS-R14, -R130-CS-0R14, -R13-O-CS-N(R14)2, -R13-NR14-CS-0R14, -R13-NR14-CS-N(R14)2 or -R13-is independently a chemical bond, or an optionally substituted C1-C10 alkylene, C1-C10 alkenylene or C1-C10 alkynylene group; -R14 is independently hydrogen or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 aryl, C3-C10 arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, C3-C10 alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group, each of which may optionally be substituted; and wherein any two or more R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, R11, R12, R13 or R14 may, together with the atom or atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, O or S in its carbon skeleton.

Preferred embodiments of X, X', Y, m, n, R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, R11, R12, R13 and R14 can be found in the sixth embodiment of the first aspect of the present invention.

Preferably in the third embodiment of the second aspect of the present invention, Q is: -s-N Rd 5\\ / N-0 wherein Rd is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton. Preferably Rd is hydrogen.

A third aspect of the present invention relates to a compound selected from: -24-Me Me N+N N+N Me Me N+N N�N or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.

A fourth aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the second or third aspects of the present invention, and optionally comprising one or more pharmaceutically acceptable excipients.

In a preferred embodiment of either of the first or fourth aspects of the present invention, the pharmaceutical composition comprises two or more pharmaceutically acceptable excipients.

In another embodiment of either of the first or fourth aspects of the present invention, the pharmaceutical composition has a pH of 7 or more. Preferably the pharmaceutical composition has a pH of between 7 and 10, more preferably of between 7.5 and 9, most preferably of between 8 and 8.5.

A fifth aspect of the present invention relates to a pharmaceutical composition comprising an A-SMase inhibitor, and optionally comprising one or more pharmaceutically acceptable -25 -excipients, wherein the composition has a pH of 7 or more. Preferably the pharmaceutical composition has a pH of between 7 and 10, more preferably of between 7.5 and 9, most preferably of between 8 and 8.5. Preferably the A-SMase inhibitor is as specified in any embodiment of the first aspect of the present invention.

A sixth aspect of the present invention relates to a pharmaceutical composition comprising a NO-donor, and optionally comprising one or more pharmaceutically acceptable excipients, wherein the composition has a pH of 8 or more. Preferably the pharmaceutical composition has a pH of between 8 and 10, more preferably of between 8 and 9, most preferably of between 8 and 8.5. Preferably the NO-donor is as specified in any embodiment of the first aspect of the present invention.

In a preferred embodiment of any of the first, fourth, fifth or sixth aspects of the present invention, the composition has a pH of about 8.3.

In one embodiment of any of the first, fourth, fifth or sixth aspects of the present invention, the composition comprises a buffer.

In one embodiment of any of the first, fourth, fifth or sixth aspects of the present invention, the composition has a chloride ion concentration of between 10 and 1000 mmol/kg. Preferably, the composition has a chloride ion concentration of between 50 and 500 mmol/kg, most preferably of between 100 and 200 mmol/kg. In a particularly preferred embodiment the composition has a chloride ion concentration of about 145 mmol/kg.

The compositions employed in the present invention can be administered by oral, parental (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), transdermal, airway (aerosol), rectal, vaginal or topical (including buccal, mucosal and sublingual) administration. Preferably the compositions employed in the present invention are administered by inhalation.

-26 -For oral administration, the compounds and compositions of the invention will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lo2enges, as a powder or granules, or as an aqueous solution, suspension or dispersion.

Tablets for oral use may include the active ingredient(s) mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.

Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose. Corn starch and alginic acid are suitable disintegrating agents.

Binding agents may include starch and gelatine. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatine capsules in which the active ingredients are mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

For parenteral use, the compounds and compositions of the present invention will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride or glucose. Aqueous suspensions according to the invention may Jo include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxyben2oate. The compounds of the invention may also be presented as liposome formulations.

-27 -For topical and transdermal administration, the compounds of the invention wii generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches.

In one embodiment of any of the first, fourth, fifth or sixth aspects of the present invention, the composition is suitable for inhalation.

The efficiency of an aerosol device, such as an MDI, is a function of the dose deposited at the appropriate site in the respiratory tract. Deposition is affected by several factors, of which one of the most important is the aerodynamic particle si2e. The distribution of aerodynamic particle 52es of solid particles and/or droplets in an aerosol can be characteri2ed by their mass median aerodynamic diameter (IMMAD, the diameter around which the mass aerodynamic diameters are distributed equally) and geometric standard deviation (GSD, the measure of variability of the aerodynamic particle diameters). Aerosol particles of equivalent MMAD and GSD have similar deposition in the respiratory tract irrespective of their composition.

In order for the particles to be carried deep into the lungs, the particles must be very fine, for example having a mass median aerodynamic diameter MMAD) of less than 1Oim.

Particles having aerodynamic diameters greater than about I Oim are likely to impact the walls of the throat and generally do not reach the lung. Particles having aerodynamic diameters in the range of about 5im to about 3im will generally be deposited in the respiratory bronchioles, whereas smaller particles having aerodynamic diameters in the range of about 3 to about O.O5im are likely to be deposited in the alveoli.

Optionally in one embodiment of any of the first, fourth, fifth or sixth aspects of the present invention, the composition is suitable for use in a dry-powder inhaler.

It is favourable for unstable agglomerates of particles to be present in the powder when it is in the inhaler device. For a powder to leave an inhaler device efficiently and reproducibly, the particles of such a powder should be large, preferably ? about 4Opm. Such a powder may be in the form of individual particles having a si2e ? about 4Oprn and/or in the form -28 -of agglomerates of finer particles, the agglomerates having a si2e ? about 40tm. The agglomerates formed can have a si2e of as much as about 1000tm and, with the addition of a glidant or lubricant, those agglomerates are more likely to be broken down efficiently in the turbulent airstream created on inhalation. Therefore, the formation of unstable or "soft" agglomerates of particles in the powder may be favoured compared with a powder in which there is substantially no agglomeration. Such unstable agglomerates are stable whilst the powder is inside the device, but are then disrupted and broken up when the powder is dispensed.

Compositions suitable for use in a dry-powder inhaler may further comprise a lubricant or a glidant. Preferably the lubricant or glidant is selected from lauric acid, palrnitic acid, stearic acid, erucic acid, behenic acid, or a pharmaceutically acceptable salt or ester thereof, such as sodium stearyl fumarate, sodium stearyl lactylate, sodium lauryl sulphate, magnesium lauryl sulphate or magnesium stearate. Alternatively the lubricant or glidant may be selected from lecithin, leucine, phosphatidylcholines, phosphatidylglycerols, triglycerides, talc, titanium dioxide, aluminium dioxide, silicon dioxide or starch. Preferably the composition comprises 0.05 to 10% by weight of the lubricant or glidant, more preferably 0.1 to 5% by weight of the lubricant or glidant, more preferably 0.2 to 2% by weight, and most preferably about 0.5% by weight of the lubricant or glidant.

Preferably, where the composition is suitable for use in a dry-powder inhaler, the composition comprises a carrier material. Preferably the carrier material is selected from lactic acid, polyols such as mannitol, saccharides such as glucose or lactose, or a pharmaceutically acceptable salt thereof, such as sodium lactate, or an inorganic salt such as sodium chloride or calcium carbonate. Preferably the carrier material is present in the form of particles with a MMAD of between I and 5000im. More preferably the particles have a MMAD of between 10 and 1000im, between 20 and 500im or between 40 and 200im.

Most preferably the particles have a MMAD of between 60 and 100im. Alternatively, the carrier material may be present in the form of particles with a MMAD of between 5 and 30im, preferably between 10 and 20im.

In one embodiment where the composition is suitable for use in a dry-powder inhaler, the composition comprises up to 99% by weight of the carrier material. Preferably, the -29 -composition comprises up to 95%, more preferably up to 90%, 75%, 50%, 30% or 20% by weight of the carrier material.

The lubricant, glidant or carrier material may be in the form of particles which tend to adhere to the surfaces of the active particles, as disclosed in WO 97/03649. Alternatively, the lubricant, glidant or carrier material may be coated on the surface of the active particles by, for example, a co-milling method as disclosed in WO 02/43701. Co-spray drying is another method of producing active particles with lubricant, glidant or carrier material on their surfaces. Other possible methods of manufacturing such "coated" active particles include supercritical fluid processing, spray-free2e drying, various forms of precipitation and crystallisation from bulk solution, and other methods which would be well-known to the person skilled in the art.

Alternatively or in addition, the active particles, optionally coated with a lubricant or glidant as specified above, may adhere to the surfaces of larger carrier particles whilst in the inhaler device, but release and become dispersed upon actuation of the dispensing device and inhalation into the respiratory tract, to give a fine suspension.

In certain embodiments of the present invention, the powder composition is such that a fine particle fraction of at least 35% is generated on actuation of the inhaler device. It is particularly preferred that the fine particle fraction be greater than or equal to 45%, SO% or 6O%. Preferably, the fine particle fraction is at least ?O%, and most preferably at least 8O%.

The emitted dose (ED) is the total mass of the active agent emitted from the device following actuation. It does not include the material left inside or on the surfaces of the device. The ED is measured by collecting the total emitted mass from the device in an apparatus frequently referred to as a dose uniformity sampling apparatus (DUSA), and recovering this by a validated quantitative wet chemical assay.

The fine particle dose (FPD) is the total mass of active agent which is emitted from the device following actuation which is present in an aerodynamic particle size smaller than a defined limit. Where the term "fine particle dose" or "FPD" is used herein, the aerodynamic particle si2e is smaller than 5im. The FPD is measured using an impactor or -30 -impinger, such as a twin stage impinger (TST), multi-stage liquid impinger (MSLT), Andersen Cascade Impactor (ACT) or a Next Generation Tmpactor (NGT). Each impactor or impinger has a pre-deterrnined aerodynamic particle si2e collection cut point for each stage. The FPD value is obtained by interpretation of the stage-by-stage active agent recovery quantified by a validated quantitative wet chemical assay where either a simple stage cut is used to determine FPD or a more complex mathematical interpolation of the stage-by-stage deposition is used.

The fine particle fraction (FPF) is defined as the FPD divided by the ED and expressed as a percentage.

Preferably, the inhaler device used to dispense the powder composition is an active inhaler device, the arrangement being such that a fine particle fraction of at least 35%, preferably at least SO%, even more preferably at least 60%, even more preferably at least ?O%, and most preferably at least 80% is generated on actuation of the inhaler device. As an active device does not depend on the patient's inhalation for aerosolising the dose, the delivery of the dose is more repeatable than is observed using passive inhaler devices.

As described in WO 01/82906, an additive material may also be provided in a dose which indicates to the patient that the dose has been administered. The additive material, referred to below as indicator material, may be present in the powder as formulated for the dry powder inhaler, or be present in a separate form, such as in a separate location within the inhaler such that the additive becomes entrained in the airflow generated on inhalation simultaneously or sequentially with the powder containing the active material.

In some circumstances, for example, where any carrier particles and/or any fine excipient material present is of a material itself capable of inducing a sensation in the oropharyngeal region, the carrier particles and/or the fine excipient material can constitute the indicator material. For example, the carrier particles and/or any fine particle excipient may comprise Jo mannitol. Alternatively or in addition, where the composition is suitable for use in a dry-powder inhaler, the composition may comprise a flavouring agent such as menthol.

-31 -In one embodiment where the composition is suitable for use in a dry-powder inhaler, the composition comprises at least 50% by weight of the A-SMase inhibitor and the NO-donor. Preferably the composition comprises at least ?S%, at least 9O%, at least 95% or at least 99% by weight of the A-SMase inhibitor and the NO-donor.

Optionally in another embodiment of any of the first, fourth, fifth or sixth aspects of the present invention, the composition is suitable for use in a metered-dose inhaler (MDI).

Preferably such a composition comprises a propellant. The composition suitable for use in a MDI is preferably in the form of a solution or a suspension of the A-SMase inhibitor and/or the NO-donor in the liquefied propellant. Preferably the propellant is a hydrofluorocarbon such as 1,1,1,2-tetrafluoroethane (CF3CH2F) (HFA-I 34a), 1,1,1,2,3,3,3- heptafluoropropane (CF3CHFCF3) (HFA-227), 1,1-difluoroethane (CHF2CH3) (HFA- 152a), trifluoromethane (CHF3) (HFA-23), difluoromethane (CH2F2) (HFA-32), fluoromethane (CH3F) (HFA-41), 1,1,1,2,2-pentafluoroethane (CF3CHF2) (HFA-125), or 1,1,2,2-tetrafluoroethane (CHF2CHF (HFA-134); a perfluorocarbon such as perfluoroethane (F3CCF3), tetrafluoromethane (CF4) (PFC-14), or decafluorobutane (CF3CF2CF2CF3); a hydrochlorofluorocarbon such as monochlorodifluoromethane (C1CHF2); a chiorofluorocarbon such as Freon 11 (CC13F), Freon 12 (CC12F2), or Freon 114 (CF2C1CF2C1); a dialkyl ether such as dimethyl ether; or a low molecular weight hydrocarbon such as n-butane, i-butane, or propane; or a mixture thereof. Preferably the propellant is a blend of HFA-227 and HFA-134a, most preferably in a volume ratio of about 3:2 HFA-227 to HFA-134a.

Optionally, where the composition is suitable for use in a metered-dose inhaler, the composition comprises a lubricant, a surfactant, a polar co-solvent and/or a flavouring agent.

Particular lubricants for metered-dose inhalers that may be mentioned include polysorbates, e.g. polysorbate 80, and alkyl aryl polyether alcohols, e.g. tyloxapol. Other lubricating excipients that may be employed include high molecular weight fully halogenated chlorofluorocarbons and esters of medium chain fatty acids. The amount of lubricant in the composition will depend on the other components of the composition, the active -32 -ingredient, the nature of the valve, etc. Optionally a concentration of 0.01 to 4% w/w and more preferably 0.1 to 2% w/w of lubricant is preferred.

Surfactants are commonly added to aerosol compositions in particular solutions for metered-dose inhalers, for example to lubricate the valve components in the inhaler device and/or improve the physical stability of the aerosol compositions. Suitable surfactants include both non-fluorinated surfactants and fluorinated surfactants known in the art and disclosed, for example, in US 5,849,265 and US 4,352,789. Examples of suitable surfactants which can be used in the compositions include oleic acid; lecithins from synthetic and natural sources; sorbitan trioleate; sorbitan mono-oleate; sorbitan monolaurate; tetrahydrofurfuryl oleate; ethyl oleate; isopropyl myristate; glyceryl trioleate; glyceryl mono-oleate; glyceryl monolaurate; glyceryl monostearate; glyceryl monoricinoleate; cetyl alcohol; stearyl alcohol; and cetyl pyridinium chloride. Preferred surfactants are oleic acid, lecithin, and sorbitan trioleate. Surfactants, if used, are optionally present in amounts not exceeding 5% by weight of the total composition, though higher amounts may be used.

Flavour modifying excipients that may be added to the metered-dose inhaler composition include peppermint oil, menthol, saccharin and saccharin sodium. When the flavour modifying excipient is a solid, preferably it is microni2ed. The concentration will depend on the individual composition and the flavour modifying excipient. Typically, a concentration of 0.005 to 4% w/w, and more preferably 0.01 to 1% w/w is used.

A polar co-solvent, preferably a polar protic co-solvent such as aliphatic alcohols and polyols, e.g. ethanol, isopropanol and propylene glycol, may be included in the metered-dose inhaler composition. Preferably said polar co-solvent contains 1-6 carbon atoms, more preferably 1-4 carbon atoms, most preferably 1-3 carbon atoms. A preferred co-solvent is ethanol and typically, the aerosol composition may contain 0.01 to S% w/w of the co-solvent, preferably 0.1 to S% w/w, and most preferably 0.1 to l% w/w. For suspension compositions the amount of these polar co-solvents must be controlled so as not to dissolve the active ingredient to any significant extent.

In yet another embodiment of any of the first, fourth, fifth or sixth aspects of the present invention, the composition is suitable for use in a nebulised system. Such systems include -33 -conventional ultrasonic nebulised systems and jet nebulised systems, as well as recently introduced handheld devices such as the Respimat (available from Boehringer Ingelheim) or the AERx (available from Aradigm). In such a system, the A-SMase inhibitor and/or the NO-donor could be stabili2ed in a sterile aqueous solution, for example, with antioxidants such as sodium metabisulfite.

Preferably, in any embodiment where the composition is suitable for inhalation, the A-SMase inhibitor and/or the NO-donor are present in the form of particles with a MMAD of between 0.001 and 500im, more preferably with a MIMAD of between 0.01 and 100im. Where the composition is for delivery to the bronchioles, it is preferred that the A-SMase inhibitor and/or the NO-donor are present in the form of particles with a MMAD of between 0.1 and 50im, more preferably between 0.5 and 10im, most preferably between 2 and 5im. Where the composition is for delivery to the throat, it is preferred that the A-SMase inhibitor and/or the NO-donor are present in the form of particles with a MMAD of between 10 and 100im, more preferably between 20 and 50im.

Where the composition is for delivery to the alveoli, it is preferred that the A-SMase inhibitor and/or the NO-donor are present in the form of particles with a MMAD of between 0.05 and 3im.

A seventh aspect of the present invention relates to a pharmaceutical composition according to any of the first, fourth, fifth or sixth aspects of the present invention, or a compound according to either of the second or third aspects of the present invention, for use as a medicament, preferably for treating or preventing a respiratory disorder.

An eighth aspect of the present invention relates to a method of treating or preventing a respiratory disorder, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a pharmaceutical composition according to any of the first, fourth, fifth or sixth aspects of the present invention, or a compound according to either of the second or third aspects of the present invention.

Preferably the respiratory disorder to be treated by the pharmaceutical composition or the compound of the seventh aspect of the present invention or by the method of the eighth aspect of the present invention is: -34- (a) an acute upper respiratory infection such as acute nasopharyngitis, acute sinusitis, acute pharyngitis, acute tonsillitis, acute laryngitis, acute tracheitis, acute obstructive laryngitis, acute epiglottitis, or an acute upper respiratory infection of multiple or unspecified sites; (b) an acute lower respiratory infection such as infiuen2a, pneumonia, acute bronchitis, acute bronchiolitis, or an unspecified acute lower respiratory infection; (c) a non-infectious disorder of the upper respiratory tract such as vasomotor rhinitis, allergic rhinitis, chronic rhinitis, chronic nasopharyngitis, chronic pharyngitis, chronic sinusitis, nasal polyp, other disorders of the nose or nasal sinuses, chronic diseases of the tonsils or adenoids, peritonsillar abscess, chronic laryngitis, chronic laryngotracheitis, or other disorders of the vocal cords, larynx or upper respiratory tract; (d) a chronic lower respiratory disease such as catarrhal bronchitis, bronchitis with tracheitis, tracheobronchitis, simple chronic bronchitis, mucopurulent chronic bronchitis, unspecified chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), asthma, status asthmaticus, or bronchiectasis; (e) respiratory tuberculosis including tuberculosis of the lung, tuberculosis of the intrathoracic lymph nodes, tuberculosis of the larynx, trachea or bronchus, tuberculous pleurisy, and primary respiratory tuberculosis; (1) a lung disease due to external agents such as coal-worker's pneumoconiosis, pneumoconiosis due to asbestos or other mineral fibres, pneumoconiosis due to dust containing silica, pneumoconiosis due to other inorganic dusts, unspecified pneumoconiosis, pneumoconiosis associated with tuberculosis, airway disease due to specific organic dust, hypersensitivity pneumonitis due to organic dust, respiratory conditions due to inhalation of chemicals, gases, fumes or vapours, pneumonitis due to solids or liquids, pneumonitis due to food or vomit, or respiratory conditions due to other external agents; (g) another respiratory disease principally affecting the interstitium such as adult respiratory distress syndrome (ARDS), pulmonary oedema, pulmonary eosinophilia, or other interstitial pulmonary diseases such as alveolar or parietoalveolar conditions, other interstitial pulmonary diseases with fibrosis including idiopathic pulmonary fibrosis, other specified interstitial pulmonary diseases, or unspecified interstitial pulmonary disease; -35 - (h) a suppurative or necrotic condition of the lower respiratory tract such as abscess of the lung, abscess of the mediastinum, or pyothorax; (i) another disease of the pleura such as pleural effusion not elsewhere classified, pleural effusion in conditions classified elsewhere, pleural plaque, pneumothorax, or other pleural conditions including chylous effusion, fibrothorax and haemothorax; (j) cystic fibrosis including mucoviscidosis, cystic fibrosis with pulmonary manifestations, cystic fibrosis with intestinal manifestations, cystic fibrosis with other manifestations, and unspecified cystic fibrosis; (Ic) cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants; (1) symptoms involving the respiratory system such as haemorrhage from respiratory passages, abnormalities of breathing including dyspnoea, stridor, whee2ing, periodic breathing, hyperventilation, mouth breathing, hiccough and sneezing, pain in the throat or chest, asphyxia, pleurisy, respiratory arrest, or abnormal sputum; (m) a respiratory disorder specific to the perinatal period such as birth asphyxia, respiratory distress of newborn, congenital pneumonia, neonatal aspiration syndrome, interstitial emphysema and related conditions originating in the perinatal period, pulmonary haemorrhage originating in the perinatal period, chronic respiratory disease originating in the perinatal period, or other respiratory conditions originating in the perinatal period; or (n) another disease of the respiratory system such as post-procedural respiratory disorders not elsewhere classified, respiratory failure not elsewhere classified, diseases of the bronchus not elsewhere classified, pulmonary collapse, interstitial emphysema, compensatory emphysema, calcification of the lung, cystic lung disease (acquired), pulmolithiasis, diseases of the mediastinum not elsewhere classified, or disorders of the diaphragm.

Preferably the respiratory disorder is: (a) cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants; (b) cystic fibrosis including mucoviscidosis, cystic fibrosis with pulmonary manifestations, cystic fibrosis with intestinal manifestations, cystic fibrosis with other manifestations, and unspecified cystic fibrosis; -36 - (c) a chronic obstructive pulmonary disease including chronic asthmatic bronchitis, chronic emphysematous bronchitis, chronic bronchitis with airways obstruction, chronic bronchitis with emphysema, chronic obstructive asthma, chronic obstructive bronchitis, chronic tracheobronchitis, chronic obstructive pulmonary disease with acute lower respiratory infection, chronic obstructive pulmonary disease with acute exacerbation (unspecified), other specified chronic obstructive pulmonary diseases, and chronic obstructive pulmonary disease (unspecified); (d) an interstitial pulmonary disease with fibrosis including idiopathic pulmonary fibrosis, diffuse pulmonary fibrosis, fibro sing alveolitis (cryp togenic), Hamman-Rich syndrome, chronic pulmonary fibrosis due to inhalation of chemicals, gases, fumes or vapours, and chronic pulmonary fibrosis following radiation; or (e) emphysema including MacLeod's syndrome, panlobular emphysema, centriobular emphysema, bullous emphysema, vesicular emphysema, emphysematous bleb, compensatory emphysema, emphysema due to inhalation of chemicals, gases, fumes or vapours, interstitial emphysema, interstitial neonatal emphysema, mediastinal emphysema, surgical (subcutaneous) emphysema, traumatic subcutaneous emphysema, emphysema with chronic (obstructive) bronchitis, and emphysematous (obstructive) bronchitis.

More preferably the respiratory disorder is chronic cough, cystic fibrosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis or emphysema.

A ninth aspect of the present invention relates to an A-SMase inhibitor for treating or preventing a respiratory disorder, wherein the respiratory disorder is: (a) an interstitial pulmonary disease with fibrosis including idiopathic pulmonary fibrosis, diffuse pulmonary fibrosis, fibrosing alveolitis (cryptogenic), Hamman-Rich syndrome, chronic pulmonary fibrosis due to inhalation of chemicals, gases, fumes or vapours, and chronic pulmonary fibrosis following radiation; or (b) emphysema including MacLeod's syndrome, panlobular emphysema, centrilobular emphysema, bullous emphysema, vesicular emphysema, emphysematous bleb, compensatory emphysema, emphysema due to inhalation of chemicals, gases, fumes or vapours, interstitial emphysema, interstitial neonatal emphysema, mediastinal emphysema, surgical (subcutaneous) emphysema, traumatic subcutaneous -37 -emphysema, emphysema with chronic (obstructive) bronchitis, and emphysematous (obstructive) bronchitis.

A tenth aspect of the present invention relates to a method of treating or preventing a respiratory disorder, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of an A-SMase inhibitor, wherein the respiratory disorder is selected from: (a) an interstitial pulmonary disease with fibrosis including idiopathic pulmonary fibrosis, diffuse pulmonary fibrosis, fibrosing alveolitis (cryptogenic), Hamman-Rich syndrome, chronic pulmonary fibrosis due to inhalation of chemicals, gases, fumes or vapours, and chronic pulmonary fibrosis following radiation; or (b) emphysema including MacLeod's syndrome, panlobular emphysema, centriobular emphysema, bullous emphysema, vesicular emphysema, emphysematous bleb, compensatory emphysema, emphysema due to inhalation of chemicals, gases, fumes or vapours, interstitial emphysema, interstitial neonatal emphysema, mediastinal emphysema, surgical (subcutaneous) emphysema, traumatic subcutaneous emphysema, emphysema with chronic (obstructive) bronchitis, and emphysematous (obstructive) bronchitis.

Preferably the A-SMase inhibitor of the ninth aspect of the present invention and the method of the tenth aspect of the present invention are suitable for treating or preventing idiopathic pulmonary fibrosis or emphysema. Preferably the A-SMase inhibitor can be administered by inhalation. Preferably the A-SMase inhibitor is as specified in any embodiment of the first aspect of the present invention.

An eleventh aspect of the present invention relates to amitriptyline or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, for treating or preventing a chronic obstructive pulmonary disease such as chronic asthmatic bronchitis, chronic emphysematous bronchitis, chronic bronchitis with airways obstruction, chronic bronchitis with emphysema, chronic obstructive asthma, chronic obstructive bronchitis, chronic tracheobronchitis, chronic obstructive pulmonary disease with acute lower respiratory infection, chronic obstructive pulmonary disease with acute exacerbation (unspecified), -38 -other specified chronic obstructive pulmonary diseases, or chronic obstructive pulmonary disease (unspecified).

A twelfth aspect of the present invention relates to a method of treating or preventing a chronic obstructive pulmonary disease such as chronic asthmatic bronchitis, chronic emphysematous bronchitis, chronic bronchitis with airways obstruction, chronic bronchitis with emphysema, chronic obstructive asthma, chronic obstructive bronchitis, chronic tracheobronchitis, chronic obstructive pulmonary disease with acute lower respiratory infection, chronic obstructive pulmonary disease with acute exacerbation (unspecified), other specified chronic obstructive pulmonary diseases, or chronic obstructive pulmonary disease (unspecified), the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of amitriptyline or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.

Preferably the amitriptyline or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof of the eleventh aspect of the present invention and the amitriptyline or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof used in the method of the twelfth aspect of the present invention can be administered by inhalation.

A thirteenth aspect of the present invention relates to an A-SMase inhibitor for treating or preventing a respiratory disorder by inhalation, wherein the respiratory disorder is: (a) cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants; or (b) cystic fibrosis including mucoviscidosis, cystic fibrosis with pulmonary manifestations, cystic fibrosis with intestinal manifestations, cystic fibrosis with other manifestations, and unspecified cystic fibrosis.

A fourteenth aspect of the present invention relates to a method of treating or preventing a respiratory disorder, comprising administering to a subject in need thereof by inhalation a therapeutically or prophylactically effective amount of an A-SMase inhibitor, wherein the respiratory disorder is selected from: (a) cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants; or -39 - (b) cystic fibrosis including mucoviscidosis, cystic fibrosis with pulmonary manifestations, cystic fibrosis with intestinal manifestations, cystic fibrosis with other manifestations, and unspecified cystic fibrosis.

Preferably the A-SMase inhibitor of the thirteenth aspect of the present invention and the method of the fourteenth aspect of the present invention are suitable for treating or preventing chronic cough or cystic fibrosis. Preferably the A-SMase inhibitor is as specified in any embodiment of the first aspect of the present invention.

A fifteenth aspect of the present invention relates to a NO-donor for treating or preventing cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants.

A sixteenth aspect of the present invention relates to a method of treating or preventing cough, including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a NO-donor.

Preferably the NO-donor of the fifteenth aspect of the present invention and the method of the sixteenth aspect of the present invention are suitable for treating or preventing chronic cough. Preferably the NO-donor can be administered by inhalation. Preferably the NO-donor is as specified in any embodiment of the first aspect of the present invention.

In any of the above aspects of the present invention relating to treating or preventing a respiratory disorder, the subject to be treated is preferably a human. Preferably the human is a non-asthmatic human. Preferably the human is a non-smoking human. As used herein, a "non-smoking human" is a human who has smoked less than ten tobacco products in the last year.

A seventeenth aspect of the present invention relates to an inhaler comprising a pharmaceutical composition according to any of the first, fourth, fifth or sixth aspects of the present invention, or a compound according to either of the second or third aspects of -40 -the present invention. Preferably the inhaler is suitable for use in the treatment or prevention of a respiratory disorder. Preferably the respiratory disorder is one of the respiratory disorders mentioned above.

In one embodiment of the seventeenth aspect of the present invention, the inhaler is a dry powder inhaler. In a dry powder inhaler, the dose to be administered is stored in the form of a non-pressuri2ed dry powder and, on actuation of the inhaler, the particles of the powder are inhaled by the patient. Dry powder inhalers can be "passive" devices in which the patient's breath is the only source of gas which provides a motive force in the device.

Examples of "passive" dry powder inhaler devices include the Rotahaler and Diskhaler (GlaxoSmithKline) and the Turbohaler (Astra-Draco) and Novoli2erTM (Viatris GmbH).

Alternatively, "active" devices may be used, in which a source of compressed gas or alternative energy source is used. Examples of suitable active devices include AspirairTM (Vectura Ltd) and the active inhaler device produced by Nektar Therapeutics (as covered by US 6,257,233).

Particularly preferred "active" dry powder inhalers are referred to herein as Aspirair inhalers and are described in more detail in WO 01/00262, WO 02/07805, WO 02/89880 and WO 02/8988 1, the contents of which are hereby incorporated by reference. It should be appreciated, however, that the compositions of the present invention can be administered with either passive or active inhaler devices.

The dry powder inhaler devices in which the powder compositions of the present invention will commonly be used include "single dose" devices, for example, the RotahalerTM and the SpinhalerTM in which individual doses of the powder composition are introduced into the device in, for example, single dose capsules or blisters, and also multiple dose devices, for example, the TurbohalerTM in which, on actuation of the inhaler, one dose of the powder is removed from a reservoir of the powder material contained in the device.

In certain embodiments of the present invention, each dose is stored in a foil "blister" of a blister pack or in a single dose capsule. Accordingly, an eighteenth aspect of the present invention relates to a foil blister or a single dose capsule comprising a pharmaceutical composition according to any of the first, fourth, fifth or sixth aspects of the present -41 -invention, or a compound according to either of the second or third aspects of the present invention. Preferably the foil blister or single dose capsule is suitable for use in a dry powder inhaler.

In accordance with the embodiments of the present invention which utili2e foil blisters, exposure of the formulation to air prior to administration is reduced or prevented by storing each dose in a sealed foil blister. In some circumstances, it may be desirable to further protect the formulation by placing a plurality of blisters into a further sealed container, such as a sealed bag made, for example, of a foil such as aluminium foil. Further mechanical protection may also be desirable, to protect the sealed blisters from damage during storage and transportation, etc. The use of the sealed foil blisters (and optional sealed bags and/or other protective packaging) eliminates any need to include anti-oxidants or the like in the formulation.

The blisters which may be used in the present invention consist of a base and a lid.

Preferably, the base material is a laminate comprising a polymer layer in contact with the drug, a soft tempered aluminium layer and an external polymer layer. The aluminium provides the moisture and oxygen barrier, whilst the polymer provides a relatively inert layer in contact with the drug. Soft tempered aluminium is ductile so that it can be "cold formed" into a blister shape. It is typically 45-47jtm thick. The outer polymer layer provides additional strength to the laminate. The lid material is a laminate comprising a heat seal lacquer, a hard rolled aluminium layer (typically 2O-3Ojtm thick) and an external polymer layer. The heat seal lacquer bonds to the polymer layer of the base foil laminate during heat sealing. The aluminium layer is hard rolled to facilitate piercing. Materials for the polymer layer in contact with the drug include polyvinyl chloride (PVC), polypropylene (PP) and polyethylene (PE). The external polymer layer on the base foil is typically oriented polyamide (oPA).

In another embodiment of the seventeenth aspect of the present invention, the inhaler is a Jo metered dose inhaler (IMDI). Pressuri2ed metered dose inhalers for use in accordance with the present invention typically have two components: a canister component in which the drug particles are stored under pressure in a suspension or solution form and a receptacle component used to hold and actuate the canister. Typically, a canister will contain multiple -42 -doses of the formulation, although it is possible to have single dose canisters as well. The canister component typically includes a valved outlet from which the contents of the canister can be discharged. Aerosol medication is dispensed from the MDI by applying a force on the canister component to push it into the receptacle component thereby opening the valved outlet and causing the medication to be conveyed from the valved outlet through the receptacle component and discharged from an outlet of the receptacle component. Upon discharge from the canister, the medication is "atornised", forming an aerosol.

For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred or optional embodiment of any aspect of the present invention should also be considered as a preferred or optional embodiment of any other aspect of the present invention.

It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the present invention.

Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims (107)

1. -43 -Claims 1. A pharmaceutical composition comprising an A-SMase inhibitor and a NO-donor, and optionally comprising one or more pharmaceutically acceptable excipients.
2. 2. A pharmaceutical composition as claimed in claim 1, wherein the A-SMase inhibitor is capable of inhibiting A-SMase by disrupting its attachment to a lysosomal membrane.
3. 3. A pharmaceutical composition as claimed in claim 2, wherein the lysosomal membrane is an intralysosomal membrane.
4. 4. A pharmaceutical composition as claimed in any one of claims I to 3, wherein the A-SMase inhibitor is selected from alimema2ine, amitriptyline, trans-I,4-bis(2-chlorobenz aminomethyl) cyclohexane (AY9944), chlorproma2ine, clornipramine, cocaine, cyamema2ine, desipramine, dibucaine, imiprarnine, mianserin, perhexiine, prochlorpera2ine, propericia2ine, quinacrine, tamoxifen, thioprop era2ine, thiorida2ine, trifluoperazine, trihexyphenidyl, trimiprarnine, N-(6-aminohexyl) -I -naphthalene sulfonamide (W-5), N-(6-aminohexyl) -I-[5'-chloro-naphthalene-I -sulfonamide] (W-7), amlodipine, as temi2ole, ben2tropine, bepridil, camylofin, clomiphene, clop erastine, cycloben2aprine, cyproheptadine, doxepin, drofenine, pimethixene, proma2ine, protrip tyline, chlorprothixene, fendiine, fluoxetine, maprotiline, noriluoxetine, nortriptyline, paroxetine, prometha2ine, sertraline, suloctidil, terfenadine, trifiuprorna2ine, 8-bromoguanosine-3',S'-cyclic monophosphate, tricyclo-decan-9-yl-xanthate, monensin, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
5. 5. A pharmaceutical composition as claimed in any one of claims I to 4, wherein the A-SMase inhibitor comprises a nitrogen atom.

   Jo
6. 6. A pharmaceutical composition as claimed in claim 5, wherein the A-SMase inhibitor has: (a) a P'a of at least 5; and/or (b) a P'a of between 6 and 15; and/or -44- (c) a P1a of between 8 and 12; and/or (d) a log P of at least 0; and/or (e) a log P of between I and 15; and/or (I) a log P of between 2 and 8; and/or (g) a steric factor Ic 20; and/or (h) a steric factor Ic 10; and/or (i) a steric factor Ic 4.
7. 7. A pharmaceutical composition as claimed in any one of claims I to 6, wherein the A-SMase inhibitor is selected from alimema2ine, amitriptyline, trans-1,4-bis(2-chlorobenzaminomethyl) cyclohexane (AY9944), chlorproma2ine, clornipramine, cocaine, cyamema2ine, desiprarnine, dibucaine, imiprarnine, mianserin, perhexiine, prochlorpera2ine, propericia2ine, quinacrine, tamoxifen, thioprop era2ine, thiorida2ine, trifluoperazine, trihexyphenidyl, trimipramine, N-(6-aminohexyl) -1- naphthalenesulfonamide (W-5), N-(6-aminohexyl) -1-[5'-chloro-naphthalene-1'-sulfonamide] (W-7), amlodipine, astemi2ole, ben2tropine, bepridil, camylofin, clomiphene, clop erastine, cycloben2aprine, cyproheptadine, doxepin, drofenine, pimethixene, proma2ine, protriptyline, chiorprothixene, fendiine, fluoxetine, maprotiline, noriluoxetine, nortrip tyline, paroxetine, prometha2ine, sertraline, suloctidil, terfenadine, trifiuproma2ine, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
8. 8. A pharmaceutical composition as claimed in claim 7, wherein the A-SMase inhibitor is selected from alimema2ine, amitriptyline, chlorproma2ine, clomipramine, desipramine, dibucaine, imipramine, prochlorpera2ine, tamoxifen, thiorida2ine, trifluoperazine, trihexyphenidyl, trimipramine, amlodipine, ben2tropine, bepridil, clomiphene, cycloben2aprine, cyproheptadine, doxepin, proma2ine, protriptyline, chiorprothixene, fluoxetine, maprotiline, nortriptyline, paroxetine, prometha2ine, sertraline, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
9. 9. A pharmaceutical composition as claimed in any one of claims I to 8, wherein the A-SMase inhibitor is an antidepressant.

   -45 -
10. 10. A pharmaceutical composition as claimed in claim 9, wherein the antidepressant is selected from alimemazine, amitriptyline, chlorproma2ine, clorniprarnine, cocaine, cyamema2ine, desiprarnine, imiprarnine, mianserin, prochlorpera2ine, properlcia2ine, tlnopropera2ine, thiorida2ine, trifiuopera2ine, trihexyphenidyl, trimipramine, cycloben2aprine, cyproheptadine, doxepin, pimethixene, proma2ine, protriptyline, chiorprothixene, fluoxetine, maprotiline, noriluoxetine, nortriptyline, paroxetine, prometha2ine, sertraline, trifiuproma2ine, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
11. 11. A pharmaceutical composition as claimed in claim 9 or 10, wherein the antidepressant is a selective serotonin reuptake inhibitor (SSRII), a serotonin-norepinephrine reuptake inhibitor (SNRI), a noradrenergic and specific serotonergic antidepressant (NASSA), a norepinephrine (noradrenaline) reuptake inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor, a tricyclic antidepressant (TCAD) or a monoamine oxidase inhibitor (MAOI).
12. 12. A pharmaceutical composition as claimed in claim 11, wherein the antidepressant is a tricyclic antidepressant (TCAD).
13. 13. A pharmaceutical composition as claimed in claim 12, wherein the tricyclic antidepressant is selected from alimema2ine, amitriptyline, chlorproma2ine, clomiprarnine, cyamema2ine, desiprarnine, imiprarnine, mianserin, prochlorpera2ine, properlcia2ine, thioprop era2ine, thiorida2ine, trifluop era2ine, trirnipramine, cycloben2aprine, cyproheptadine, doxepin, pimethixene, proma2ine, protriptyline, chlorprothixene, maprotiline, nortriptyline, paroxetine, prometha2ine, trifiuproma2ine, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
14. 14. A pharmaceutical composition as claimed in claim 13, wherein the tricyclic antidepressant is amitriptyline or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
15. 15. A pharmaceutical composition as claimed in any one of claims I to 13, wherein the A-SMase inhibitor is selected from a compound of formula (I) or (II): NR% N(R1% I or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereo4 wherein at each is independently selected m 4 _1)2_, c(R11)2rk_ _NR&h1_ &h1_NRh1_ _}44_ 4= Jii_ 4R1 1s_ 1112_ 11)1 or _Rh1_, is independently selected from, t"4, 4atu1, -0-4c-, 4-s--, ---4-, -4c----, _1_..qlt11)2_ or _C(R11)24_; -Y-is independently selected from a chemical bond, -0-, -S-, -NRa-, -C(RY%-, C(R1%C(R% R12C=R% NR12C(R% 12)z-NR12-, -N=0t12, -R12C=N, -O-C(R% -C(RY-O-, -S-C(R-or -C(RY%-S-; n is independently 1,2,3,4,5 or 6; misindependentlyO,1,2,3,4or5; R1, R2, R3, R4, R5, R', R7 R8, R9, R10, R11 and R12 are independently selected from hydrogen, -P -Cl, -B; -I, -CF3, -CCI, -CBr, -Cl3, -OH, -SH, -NH, -CN, -NO2, -COOH, -R13-O-R1t -R13-S-R1t RThSORlt -R13-so2-W4, 4tSOOR1t dt1tOSOrR1t -R"-O-SON(R12, -R13-NR14-S020R14, dt1tNR14SON(R12, RN(R12, dt1tN(R14)3, R13P(R1%, -R13-Si(R14), -R13-CO-R1t -R13-CO-OR1t -R13-O-CO-R1t -R13-CO-N(R14)2, -R13-NR14-CO-R1t -R13-O-CO-OR1t -R13-O-CO-N(R1%, -R13-NR14-CO-OR1t -R13-NR14-CO-N(R1%, -R13-CS-R1t -R13-CS-OR1t -R13-O-CS-R1t RThCSN(Rl4)2, -47 - -R130-CS-0R14, -R13-O-CS-N(R14)2, -R13-NR14-CS-0R14, or -R13-is independently a chemical bond, or an optionally substituted C1-C10 alkylene, C1-C10 alkenylene or C1-C10 alkynylene group; -R14 is independently hydrogen or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 aryl, C3-C10 arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, C3-C10 alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group, each of which may optionally be substituted; and wherein any two or more R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, R11, R12, R13 or may, together with the atom or atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton.
16. 16. A pharmaceutical composition as claimed in claim 15, wherein: (a) is independently selected from Ch1)2 or or (b) -X is
17. 17. A pharmaceutical composition as claimed in claim 15 or 16, wherein -Y-is independently selected from -5-, -C(R12)2-, -C(R12)2-C(R12)2-, -R12CCR12-, -O-C(R12)2-or -C(R12)2-O-.
18. 18. A pharmaceutical composition as claimed in any one of claims 15 to 17, wherein n is 2 or 3.
19. 19. A pharmaceutical composition as claimed in any one of claims 15 to 18, wherein m is I or 2.
20. 20. A pharmaceutical composition as claimed in any one of claims 15 to 19, wherein one of R1, R2, R3, R4, R5, R6, R7 and R8 is selected from hydrogen, -F, -Cl, -Br, -I, -CF3, -CC13, -CBr3, -CT3, -OH, -SH, -NH2, -CN, -NO2, -COOH, -k'3-O-k'4, -k'3-S-k'4, -k'3-SO-R14, -k'3-S02-R'4, -k'3-S02-Ok'4, -k'3-O-S02-k'4, -k'3-S02-N(k'4)2, -48 - -R13-NR14-S02-R14, -R13-O-S02-0R14, -R13-O-S02-N(R14)2, -R13-NR14-S02-0R14, -R13-NR14-S02-N(R14)2, -R13-N(R14)2, -R13-N(R14)3, -R13-P(R14)2, -R13-Si(R14)3, -R13-CO-R14, -R13-CO-0R14, -R13-O-CO-R14, -R13-CO-N(R14)2, -R13-NR14-CO-R14, -R13-O-CO-0R14, -R13-O-CO-N(R14)2, -R13-NR14-CO-0R14, -R13-NR14-CO-N(R14)2, -R13-CS-R14, -R13-CS-0R14, -R13-O-CS-R14, -R13-CS-N(R14)2, -R13-NR14-CS-R14, -R130-CS-0R14, -R13-O-CS-N(R14)2, -R13-NR14-CS-0R14, -R13-NR14-CS-N(R14)2 or -R14, and wherein all other R1, R2, R3, R4, R5, R6, R7 and R8 are hydrogen.
21. 21. A pharmaceutical composition as claimed in claim 20, wherein R1, R2, R3, R4, R5, R6, R7 and R8 are all hydrogen.
22. 22. A pharmaceutical composition as claimed in claim 20, wherein one of R1, R2, R3, R4, R5, R6, R7 and R8 is not hydrogen.
23. 23. A pharmaceutical composition as claimed in any one of claims 15 to 22, wherein at each occurrence R1, R2, R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CF3, -Cd3, -CBr3, -CT3, -CN, -R13-O-R14, -R13-S-R14, -R13-SO-R14, -R13-S02-R14, -R13-S02-0R14, -R13-O-S02-R14, -R13-S02-N(R14)2, -R13-NR14-S02-R14, -R13-O-S02-0R14, -R13-O-S02-N(R14)2, -R13-NR14-S02-0R14, -R13-NR14-S02-N(R14)2, -R13-N(R14)2, or -R14.
24. 24. A pharmaceutical composition as claimed in any one of claims 15 to 23, wherein at each occurrence R9 is independently selected from hydrogen or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 aryl, C3-C10 arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, C3-C10 alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group, each of which may optionally
25. 25. A pharmaceutical composition as claimed in claim 24, wherein at each occurrence R9 is independently selected from hydrogen or methyl.
26. 26. A pharmaceutical composition as claimed in any one of claims 15 to 25, wherein at each occurrence R1° is independently selected from hydrogen or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 aryl, C3-C10 arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, -49 -C3-C10 alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group, each of which may optionally
27. 27. A pharmaceutical composition as claimed in claim 26, wherein at each occurrence k'° is independently selected from hydrogen or methyl.
28. 28. A pharmaceutical composition as claimed in any one of claims 15 to 27, wherein at each occurrence R11 is hydrogen.
29. 29. A pharmaceutical composition as claimed in any one of claims 15 to 28, wherein at each occurrence R12 is hydrogen.
30. 30. A pharmaceutical composition as claimed in any one of claims 15 to 29, wherein at each occurrence -R13-is a chemical bond.
31. 31. A pharmaceutical composition as claimed in any one of claims 15 to 30, wherein at each occurrence -R14 is independently hydrogen or a C1-C4 alkyl, C2-C4 alkenyl or alkynyl group, each of which may optionally be substituted.
32. 32. A pharmaceutical composition as claimed in any one of claims 15 to 31, wherein one R9 and one R10, together with the atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more additional heteroatoms N, 0 or S in its carbon skeleton.
33. 33. A pharmaceutical composition as claimed in any one of claims 15 to 32, wherein the two R10, together with the nitrogen atom to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more additional heteroatoms N, 0 or S in its carbon skeleton.Jo
34. 34. A pharmaceutical composition as claimed in any one of claims 15 to 33, wherein one R11 and one R12, together with the atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more additional heteroatoms N, 0 or S in its carbon skeleton.
35. 35. A pharmaceutical composition as dnitned in any one of dnitns 15 to 34, wherein one R1° and one R11, together with the atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more additional heteroatoms N, 0 or S in its carbon skeleton.
36. 36. A pharmaceutical composition as claimed in any one of dnitns 15 to 35, wherein an optionally substituted cyclic hydrocarbyl group is substituted with one or more of -F, -Cl, -Bc -I, -CF3, -CC3, -CBr3, -Cl3, -CN, -NO2, -O-R15, -S-R15, -N-(R1')2 or -R15, or one or more ic-bonded substituents such as 0, 5 or =NR", wherein -R15 is independently hydrogen or an unsubstituted C1-C alkyl, C2-C10 alkenyl, Q-C alkynyl, CC10 atyl, CrCrn arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, C3-C alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group.
37. 37. A pharmaceutical composition as claimed in dnitn 36 wherein an optionally substituted cyclic hydrocarbyl group is substituted with -OH or a methyl group.
38. 38. A pharmaceutical composition as claimed in any one of dnitns I to 37, wherein the NO-donor is nitric oxide, a NO-synthase substrate, a NO-synthase agonist;, or a NO-releaser.
39. 39. A pharmaceutical composition as claimed in dnitn 38, wherein the NO-donor is a NO-synthase substrate.
40. 40. A pharmaceutical composition as claimed in dnitn 39, wherein the NO-synthase substrate is srnine, N-cyclopropyl-N1-hydroxyguanidine, L-canavanine or N"-benzoyl-L-arginine -ester, or a pharmaceutically accept tautomet salt prodrug or hydrate thereof.
41. 41. A pharmaceutical composition as claimed in dnitn 40, wherein the NO-synthase substrate is L-arginine or a pharmaceutically acceptable tautomer, salt prodrug or hydrate thereof: -51 -
42. 42. A pharmaceutical composition as claimed in claim 38, wherein the NO-donor is a NO-releaser.
43. 43. A pharmaceutical composition as claimed in claim 42, wherein the NO-releaser is selected from: (a) Angel's salt (Na2N2O3), isonia2id, N-hydroxyben2enesulfonamide or P-nitrosophosphate; (b) an organic nitrate such as glyceryl trinitrate (GTN), [3-(nitrooxymethyl)phenyl] -2-acetyloxyben2oate (NCX-40 16), 4-nitrooxybutyl-2-acetyloxyben2oate (NCX-42 15), [3-(nitrooxymethyl)phenyl] -2-hydroxyben2oate (B-NOD), isosorbide mononitrate (ISMN), pentaerythrityl tetranitrate (PETN), isosorbide dinitrate (BiDil), nicorandil, nipradilol, nitro-pravastatin (NCX-6550), O-losartanyl-3-[(nitrooxy)methyl] - ben2oate (NO-Losartan A) or methyl 2-[4-[(nitrooxy)methyl] ben2oyl] thio] -ben2oate (SE 175); (c) an organic nitrite such as amyl nitrite or 2-methylbutan-2-yl nitrite; (d) a NONOate such as diethylenetriamine NONOate (DETA NO), diethylamine NONOate (DEA NO), spermine NONOate (SPER NO), dipropylenetriamine NONOate (DPTA NO), methylamine hexamefhylene methylarnine NONOate (MAHMA NO), 3-propylarnine-propylamine NONOate (PAPA NO), proline NONOate (PROLI NO), 1-[(ethenyloxy)-NNO-azoxy]-pyrrolidine (V-Pyrro NO), 02-(2,4-dinitrophenyl) -1-[(4-ethoxycarbonyl)pipera2in-I -yl] dha2en-l -ium-1,2-diolate N-(3-aminopropyl-propan-2-ylarnino) -N-hydroxynitrous arnide (NOC-5), N-hydroxy-N-(methyl-(3-methylaminopropyl) -amino)-nitrous amide (NOC-7), N-ethyl-2-(1 -ethyl-2-hydroxy-2-nitrosohydra2ino) -ethanarnine (NOC- 12), O-f3-galactopyranosyl-1-(pyrrolidin-I -yldiaen-I -ium-I,2-diolate (p-Gal-NONOate) or disodium hydroxydia2enesulfonate 1-oxide (Sulfo-NONOate); (e) a 5-nitrosothiol such as S-nitroso-N-acetylpenicillarnine (SNAP), 5-nitroso-glutathione (GSNO), S-nitroso-N-valerylpenicillarnine (SNVP), S-nitrosoalburnin, 5-nitrosocysteine, N-(N-y-L-glutamyl-2-amino-2-(4-(4-S-nitrosomercapto-1- methylpiperidine) -acetyl) -glycine) ELA8 10), nitrosodiclofenac, nitrosocaptopril, N- (-D-glucopyranosyl) -N2-acetyl-S-nitroso-D,L-penicillarninamide (Glyco-SNAP-I), N-(2-deoxy-oc,-D-glucopyranose-2-) -N2-acetyl-S-nitroso-D,L-penicillaminarnide (Glyco-SNAP-2), 4-phenyl-I,3,2-oxathia2olylium-5-olate, 4-(p- -52 - trifluoromethyiphenyl) -1,3,2-oxathia2olylium-5-olate, 4-(p-chlorophenyl) -1,3,2- oxathio2olylium-5-olate, 4-(p-methoxyphenyl) -1,3,2-oxathia2olylium-5-olate or N- (1 -deoxy-oç-D-fructopyranose-I -)-N2-acetyl-S-nitroso-D,L-penicillaminarnide (Fructose-SNAP-I); (1) a N-nitrosamine such as streptoocin, N,N'-dimethyl-N,N'-dinitroso-p-phenylenediamine (BNN3) or dephostatin; (g) a C-nitroso compound such as 2-nitro-2-nitrosopropane; (h) a dia2etine dioxide such as 3-bromo-3,4,4-trimethyl-3,4-dihydrodia2ete-1,2-dioxide (DD 1) or 3-bromo-4-methyl-3,4-tetramethylene-3,4-dihydrodia2ete-1,2-dioxide (DD2); (i) a furoxan such as dimethyl 2,6-dimethyl-4-[2'-(3"-methylfuroxan-4"- ylmethoxy)phenyl] -1,4-dihydropyridine-3,S-dicarboxylate, dimethyl 2,6-dimethyl-4- [2'-(3"-carbamoylfuroxan-4"-ylmethoxy)phenyl] -1,4-dihydropyridine-3,S- dicarboxylate, dimethyl 2,6-dimethyl-4-[2'-(3"-cyanofuroxan-4"-ylmethoxy)phenyl] - 1,4-dihydropyridine-3,S-dicarboxylate, 4-methyl-3-phenylsulphonylfuroxan, 4- hydroxymethyl-3-furoxancarboxamide, N-(pyridin-3-yl) -3-phenyl-4-furoxancarboxarnide, 4-phenyl-3-(N',N'-dimethyl-2'-aminoethylsulphanyl) furoxan or 4-phenylsulphonyl-3-(N',N'-dimethyl-2'-aminoethylsulphanyl)furoxan; (j) a sydnonimine such as 3-morpholinosydnonimine (SIN-I) or molsidornine; (Ic) an oxatria2ole-S-irnine such as S-amino-3-(3',4'-dichlorophenyl) -I -oxa-2,3,4-trla2Olium chloride, S-amino-3-(3'-chloro-2'-methylphenyl) -I -oxa-2,3,4-tria2olium chloride or 5-(((cyanomethylarnino)carbonyl)amino) -3-(3'-chloro-2'-methylphenyl)-I -oxa-2,3,4-tria2olium chloride; (1) an oxime such as 4-(E)-methyl-2-[(E)-hydroxyimino]-S-nitro-6-methoxy-3-hexenamide (NOR-I), 4-(E) -methyl-2-[(E)-hydroxyirnino] -S-nitro-3-hexenamide (NOR-2), 4-(E)-ethyl-2-[(E)-hydroxyimino] -S-nitro-3-hexenamide (NOR-3), N- [(E,2Z)-4-ethyl-2-hydroxyirnino-S-nitrohex-3-enyl] pyridine-3-carboxamide (NOR- 4) or N-[(E,2Z) -4-ethyl-6-methyl-2-hydroxyirnino-S-nitrohept-3-enyl] pyridine-3-carboxarnide (NOR-S); or Jo (m) a metal-NO complex such as sodium nitroprusside (SNP) or a NO 2eolite; or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.-53 -
44. 44. A compound comprising an A-SMase inhibitor covalently linked to a NO-donor group, or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
45. 45. A compound as claimed in claim 44, wherein the A-SMase inhibitor is as defined in any one of claims 2 to 37.
46. 46. A compound as claimed in claim 44 or 45, wherein the NO-donor group is a NO-releasing group.
47. 47. A compound as claimed in claim 46, wherein the NO-releasing group comprises or is: (a) a-0N02 group; (b) a -ONO group; (c) a group selected from: O\� o_ //N_RC Rd 1-0-N or wherein at each occurrence R and Rd are independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton; (d) a-S-NO group; (e) a -N(R15NO group, wherein El is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, optionally with one or more further -NO groups, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton;RNO(I) a -C(R2NO, or -NO group, wherein each is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally -54-be substituted, optionally with one or more further -NO groups, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, or wherein the two R groups together with the carbon atom to which they are attached form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton; (g) a group selected from: cRh)c t\ (Rh)2C N\ + \ - 0, or Rh 0, wherein each R' is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, and wherein any two Rh groups together with the carbon atom or atoms to which they are attached may form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton; (h) a group selected from: or wherein each R' is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton; (i) a group selected from: NR NR3 f Nt -55 -NR3 N NR + ii or wherein at each occurrence R3 is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton, and wherein any two R3 groups together with the atom or atoms to which they are attached may form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, 0 or S in its carbon skeleton; or (j) a group selected from:NOH NOH Rk orwherein each R' is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton.
48. 48. A compound as claimed in any one of claims 44 to 47, wherein the compound further comprises a linker between the A-SMase inhibitor and the NO-donor group.
49. 49. A compound as claimed in claim 48, wherein the linker comprises an alkylene, alkenylene, alkynylene, arylene, arylalkylene, arylalkenylene, arylalkynylene, alkylarylene, alkenylarylene or alkynylarylene group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton.
50. 50. A compound as claimed in any one of claims 44 to 47, wherein the compound is selected from a compound of formula (III) or (TV): -56 -I (C(R9)2)m R' (C(R9)2) R8 I TIxxIx (III) R5 (TV) or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, wherein at each occurrence: Q is independently a NO-releasing group; is independently selected from CR", NC")2 C")2-N NRh1Rh1 Rh1NRh1 OR" Rh1O CRh1 or is independently selected from NR"C, CNR", CC")2 or -Y-is independently selected from a chemical bond, -0-, -S-, -NR12-, -C(R12)2-, -C(R12)2-C(R12)2-, -R12CCR12-, -NR12-C(R12)2-, -C(R12)2-NR12-, -NCR12-, -R12CN-, -O-C(R12)2-, -C(R12)2-O-, -S-C(R12)2-or n is independently 1, 2, 3, 4, 5 or 6; m is independently 0, 1, 2, 3, 4 or 5; R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, R11 and R12 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CF3, -Cd3, -CBr3, -CT3, -OH, -SH, -NH2, -CN, -NO2, -COOH, -R13-O-R14, -R13-S-R14, -R13-SO-R14, -R13-S02-R14, -R13-S02-0R14, -R13-O-S02-R14, -R13-NR14-S02-R14, -R13-O-S02-0R14, -R13-O-S02-N(R14)2, -R13-NR14-S02-0R14, -R13-NR14-S02-N(R14)2, -R13-N(R14)2, -R13-N(R14)3, -R13-P(R14)2, -R13-Si(R14)3, -R13-CO-R14, -R13-CO-0R14, -R13-O-CO-R14, -R13-CO-N(R14)2, -R13-NR14-CO-R14, -R13-O-CO-0R14, -R13-O-CO-N(R14)2, -R1-NR14-CO-OR14, -57 - -R13-NR14-CO-N(R14)2, -R13-CS-R14, -R13-CS-0R14, -R13-O-CS-R14, -R13-CS-N(R14)2, -R13-NR14-CS-R14, -R130-CS-0R14, -R13-O-CS-N(R14)2, -R13-NR14-CS-0R14, -R13-NR14-CS-N(R14)2 or -R13-is independently a chemical bond, or an optionally substituted C1-C10 alkylene, C1-C10 alkenylene or C1-C10 alkynylene group; -R14 is independently hydrogen or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 aryl, C3-C10 arylalkyl, C4-C10 arylalkenyl, C4-C10 arylalkynyl, C3-C10 alkylaryl, C4-C10 alkenylaryl or C4-C10 alkynylaryl group, each of which may optionally be substituted; and wherein any two or more R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, R11, R12, R13 or R14 may, together with the atom or atoms to which they are attached, form an optionally substituted cyclic hydrocarbyl group that optionally includes one or more heteroatoms N, o or S in its carbon skeleton.
51. 51. A compound as claimed in claim 50, wherein Q is: -s-N Rd 5\\ / N-0 wherein Rd is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, 0 or S in its carbon skeleton.
52. 52. A compound as claimed in claim 51, wherein Rdis hydrogen.
53. 53. A compound selected from: Me Me N+N N+N -58 -Me Me N+N N�N or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
54. 54. A pharmaceutical composition comprising a compound as claimed in any one of claims 44 to 53, and optionally comprising one or more pharmaceutically acceptable excipients.
55. 55. A pharmaceutical composition as claimed in any one of claims I to 43 or claim 54, wherein the composition comprises two or more pharmaceutically acceptable excipients.
56. 56. A pharmaceutical composition as claimed in any one of claims I to 43 or claim 54 or 55, wherein the composition has a pH of 7 or more.
57. 57. A pharmaceutical composition comprising an A-SMase inhibitor, and optionally comprising one or more pharmaceutically acceptable excipients, wherein the composition has a pH of 7 or more.
58. 58. A pharmaceutical composition as claimed in claim 57, wherein the A-SMase inhibitor is as defined in any one of claims 2 to 37.
59. 59. A pharmaceutical composition comprising a NO-donor, and optionally comprising one or more pharmaceutically acceptable excipients, wherein the composition has a pH of 8 or more.
60. 60. A pharmaceutical composition as claimed in claim 59, wherein the NO-donor is as defined in any one of claims 38 to 43.-59 -
61. 61. A pharmaceutical composition as claimed in any one of claims I to 43 or any one of claims 54 to 60, wherein the composition has a pH of about 8.3.
62. 62. A pharmaceutical composition as claimed in any one of claims I to 43 or any one of claims 54 to 61, wherein the composition comprises a buffer.
63. 63. A pharmaceutical composition as claimed in any one of claims I to 43 or any one of claims 54 to 62, wherein the composition has a chloride ion concentration of between and 1000 mmol/kg.
64. 64. A pharmaceutical composition as claimed in claim 63, wherein the composition has a chloride ion concentration of about 145 rnmol/kg.
65. 65. A pharmaceutical composition as claimed in any one of claims I to 43 or any one of claims 54 to 64, wherein the composition is suitable for inhalation.
66. 66. A pharmaceutical composition as claimed in claim 65, wherein the composition is suitable for use in a dry-powder inhaler.
67. 67. A pharmaceutical composition as claimed in claim 66, wherein the composition comprises a lubricant or a glidant.
68. 68. A pharmaceutical composition as claimed in claim 67, wherein the lubricant or glidant is selected from lauric acid, palrnitic acid, stearic acid, erucic acid, behenic acid, or a pharmaceutically acceptable salt or ester thereof, such as sodium stearyl fumarate, sodium stearyl lactylate, sodium lauryl sulphate, magnesium lauryl sulphate or magnesium stearate.
69. 69. A pharmaceutical composition as claimed in claim 67, wherein the lubricant or glidant is selected from lecithin, leucine, phosphatidylcholines, phosphatidylglycerols, triglycerides, talc, titanium dioxide, aluminium dioxide, silicon dioxide or starch.
70. 70. A pharmaceutical composition as claimed in any one of claims 67 to 69, wherein the composition comprises 0.05 to IO% by weight of the lubricant or glidant.-60 -
71. 71. A pharmaceutical composition as claimed in any one of claims 66 to 70, wherein the composition comprises a carrier material.
72. 72. A pharmaceutical composition as claimed in claim 71, wherein the carrier material is selected from lactic acid, polyols such as mannitol, saccharides such as glucose or lactose, or a pharmaceutically acceptable salt thereof, such as sodium lactate, or an inorganic salt such as sodium chloride or calcium carbonate.
73. 73. A pharmaceutical composition as claimed in claim 71 or 72, wherein the carrier material is present in the form of particles with a MMAD of between I and 5000im.
74. 74. A pharmaceutical composition as claimed in any one of claims 71 to 73, wherein the composition comprises up to 99% by weight of the carrier material.
75. 75. A pharmaceutical composition as claimed in any one of claims 66 to 74, wherein the composition comprises a flavouring agent such as menthol.
76. 76. A pharmaceutical composition as claimed in any one of claims 66 to 75, wherein the composition comprises at least SO% by weight of the A-SMase inhibitor and the NO-donor.
77. 77. A pharmaceutical composition as claimed in claim 65, wherein the composition is suitable for use in a metered-dose inhaler.
78. 78. A pharmaceutical composition as claimed in claim 77, wherein the composition comprises a propellant.
79. 79. A pharmaceutical composition as claimed in claim 78, wherein the propellant is a so hydrofluorocarbon such as 1,1,1,2-tetrafluoroethane (CF3CH2F) (HFA-I 34a), 1,1,1,2,3,3,3- heptafluoropropane (CF3CHFCF3) (HFA-227), 1,1-difluoroethane (CHF2CH3) (HFA- 152a), trifluoromethane (CHF3) (HFA-23), difluoromethane (CH2F2) (HFA-32), fluoromethane (CH3F) (HFA-41), 1,1,1,2,2-pentafluoroethane (CF3CHF2) (HFA-125), or -61 - 1,1,2,2-tetrafluoroethane (CHF2CHF (HFA-134); a perfluorocarbon such as perfluoroethane (F3CCF3), tetrafluoromethane (CF4) (PFC-14), or decafluorobutane (CF3CF2CF2CF3); a hydrochiorofluorocarbon such as monochiorodifluoromethane (C1CHF2); a chiorofluorocarbon such as Freon 11 (CC13F), Freon 12 (CC12F2), or Freon 114 (CF2C1CF2C1); a diallcyl ether such as dimethyl ether; or a ow molecular weight hydrocarbon such as n-butane, i-butane, or propane; or a mixture thereof.
80. 80. A pharmaceutical composition as claimed in any one of claims 77 to 79, wherein the composition comprises a lubricant, a surfactant, a polar co-solvent and/or a flavouring agent.
81. 81. A pharmaceutical composition as claimed in any one of claims 66 to 80, wherein the A-SMase inhibitor and/or the NO-donor are present in the form of particles with a MMAD of between 0.001 and 500im.
82. 82. A pharmaceutical composition as claimed in any one of claims I to 43 or any one of claims 54 to 81, or a compound as claimed in any one of claims 44 to 53, for use as a medicament.
83. 83. A pharmaceutical composition or a compound as claimed in claim 82 for treating or preventing a respiratory disorder.
84. 84. A method of treating or preventing a respiratory disorder, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a pharmaceutical composition as claimed in any one of claims I to 43 or any one of claims 54 to 81, or of a compound as claimed in any one of claims 44 to 53.
85. 85. A pharmaceutical composition or a compound as claimed in claim 83, or a method as claimed in claim 84, wherein the respiratory disorder is: (a) an acute upper respiratory infection such as acute nasopharyngitis, acute sinusitis, acute pharyngitis, acute tonsillitis, acute laryngitis, acute tracheitis, acute obstructive laryngitis, acute epiglottitis, or an acute upper respiratory infection of multiple or unspecified sites; -62 - (b) an acute lower respiratory infection such as influen2a, pneumonia, acute bronchitis, acute bronchiolitis, or an unspecified acute lower respiratory infection; (c) a non-infectious disorder of the upper respiratory tract such as vasomotor rhinitis, allergic rhinitis, chronic rhinitis, chronic nasopharyngitis, chronic pharyngitis, chronic sinusitis, nasal polyp, other disorders of the nose or nasal sinuses, chronic diseases of the tonsils or adenoids, peritonsillar abscess, chronic laryngitis, chronic laryngotracheitis, or other disorders of the vocal cords, larynx or upper respiratory tract; (d) a chronic lower respiratory disease such as catarrhal bronchitis, bronchitis with tracheitis, tracheobronchitis, simple chronic bronchitis, mucopurulent chronic bronchitis, unspecified chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), asthma, status asthmaticus, or bronchiectasis; (e) respiratory tuberculosis including tuberculosis of the lung, tuberculosis of the intrathoracic lymph nodes, tuberculosis of the larynx, trachea or bronchus, tuberculous pleurisy, and primary respiratory tuberculosis; (I) a lung disease due to external agents such as coal-worker's pneumoconiosis, pneumoconiosis due to asbestos or other mineral fibres, pneumoconiosis due to dust containing silica, pneumoconiosis due to other inorganic dusts, unspecified pneumoconiosis, pneumoconiosis associated with tuberculosis, airway disease due to specific organic dust, hypersensitivity pneumonitis due to organic dust, respiratory conditions due to inhalation of chemicals, gases, fumes or vapours, pneumonitis due to solids or liquids, pneumonitis due to food or vomit, or respiratory conditions due to other external agents; (g) another respiratory disease principally affecting the interstitium such as adult respiratory distress syndrome (ARDS), pulmonary oedema, pulmonary eosinophilia, or other interstitial pulmonary diseases such as alveolar or parietoalveolar conditions, other interstitial pulmonary diseases with fibrosis including idiopathic pulmonary fibrosis, other specified interstitial pulmonary diseases, or unspecified interstitial pulmonary disease; (h) a suppurative or necrotic condition of the lower respiratory tract such as abscess of the lung, abscess of the mediastinum, or pyothorax; (i) another disease of the pleura such as pleural effusion not elsewhere classified, pleural effusion in conditions classified elsewhere, pleural plaque, pneumothorax, -63 -or other pleural conditions including chylous effusion, fibrothorax and haemothorax; (j) cystic fibrosis including mucoviscidosis, cystic fibrosis with pulmonary manifestations, cystic fibrosis with intestinal manifestations, cystic fibrosis with other manifestations, and unspecified cystic fibrosis; (Ic) cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants; (1) symptoms involving the respiratory system such as haemorrhage from respiratory passages, abnormalities of breathing including dyspnoea, stridor, whee2ing, periodic breathing, hyperventilation, mouth breathing, hiccough and sneezing, pain in the throat or chest, asphyxia, pleurisy, respiratory arrest, or abnormal sputum; (m) a respiratory disorder specific to the perinatal period such as birth asphyxia, respiratory distress of newborn, congenital pneumonia, neonatal aspiration syndrome, interstitial emphysema and related conditions originating in the perinatal period, pulmonary haemorrhage originating in the perinatal period, chronic respiratory disease originating in the perinatal period, or other respiratory conditions originating in the perinatal period; or (n) another disease of the respiratory system such as post-procedural respiratory disorders not elsewhere classified, respiratory failure not elsewhere classified, diseases of the bronchus not elsewhere classified, pulmonary collapse, interstitial emphysema, compensatory emphysema, calcification of the lung, cystic lung disease (acquired), pulmolithiasis, diseases of the mediastinum not elsewhere classified, or disorders of the diaphragm.
86. 86. A pharmaceutical composition, compound or method as claimed in claim 85, wherein the respiratory disorder is: (a) cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants; (b) cystic fibrosis including mucoviscidosis, cystic fibrosis with pulmonary so manifestations, cystic fibrosis with intestinal manifestations, cystic fibrosis with other manifestations, and unspecified cystic fibrosis; (c) a chronic obstructive pulmonary disease including chronic asthmatic bronchitis, chronic emphysematous bronchitis, chronic bronchitis with airways obstruction, -64-chronic bronchitis with emphysema, chronic obstructive asthma, chronic obstructive bronchitis, chronic tracheobronchitis, chronic obstructive pulmonary disease with acute lower respiratory infection, chronic obstructive pulmonary disease with acute exacerbation (unspecified), other specified chronic obstructive pulmonary diseases, and chronic obstructive pulmonary disease (unspecified); (d) an interstitial pulmonary disease with fibrosis including idiopathic pulmonary fibrosis, diffuse pulmonary fibrosis, fibrosing alveolitis (cryptogenic), Hamman-Rich syndrome, chronic pulmonary fibrosis due to inhalation of chemicals, gases, fumes or vapours, and chronic pulmonary fibrosis following radiation; or (e) emphysema including MacLeod's syndrome, panlobular emphysema, centriobular emphysema, bullous emphysema, vesicular emphysema, emphysematous bleb, compensatory emphysema, emphysema due to inhalation of chemicals, gases, fumes or vapours, interstitial emphysema, interstitial neonatal emphysema, mediastinal emphysema, surgical (subcutaneous) emphysema, traumatic subcutaneous emphysema, emphysema with chronic (obstructive) bronchitis, and emphysematous (obstructive) bronchitis.
87. 87. A pharmaceutical composition, compound or method as claimed in claim 86, wherein the respiratory disorder is chronic cough, cystic fibrosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis or emphysema.
88. 88. An A-SMase inhibitor for treating or preventing a respiratory disorder, wherein the respiratory disorder is: (a) an interstitial pulmonary disease with fibrosis including idiopathic pulmonary fibrosis, diffuse pulmonary fibrosis, fibrosing alveolitis (cryptogenic), Hamman-Rich syndrome, chronic pulmonary fibrosis due to inhalation of chemicals, gases, fumes or vapours, and chronic pulmonary fibrosis following radiation; or (b) emphysema including MacLeod's syndrome, panlobular emphysema, centriobular emphysema, bullous emphysema, vesicular emphysema, emphysematous bleb, compensatory emphysema, emphysema due to inhalation of chemicals, gases, fumes or vapours, interstitial emphysema, interstitial neonatal emphysema, mediastinal emphysema, surgical (subcutaneous) emphysema, traumatic -65 -subcutaneous emphysema, emphysema with chronic (obstructive) bronchitis, and emphysematous (obstructive) bronchitis.
89. 89. A method of treating or preventing a respiratory disorder, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of an A-SMase inhibitor, wherein the respiratory disorder is selected from: (a) an interstitial pulmonary disease with fibrosis including idiopathic pulmonary fibrosis, diffuse pulmonary fibrosis, fibrosing alveolitis (cryptogenic), Hamman-Rich syndrome, chronic pulmonary fibrosis due to inhalation of chemicals, gases, fumes or vapours, and chronic pulmonary fibrosis following radiation; or (b) emphysema including MacLeod's syndrome, panlobular emphysema, centriobular emphysema, bullous emphysema, vesicular emphysema, emphysematous bleb, compensatory emphysema, emphysema due to inhalation of chemicals, gases, fumes or vapours, interstitial emphysema, interstitial neonatal emphysema, mediastinal emphysema, surgical (subcutaneous) emphysema, traumatic subcutaneous emphysema, emphysema with chronic (obstructive) bronchitis, and emphysematous (obstructive) bronchitis.
90. 90. An A-SMase inhibitor as claimed in claim 88 or a method as claimed in claim 89, for treating or preventing idiopathic pulmonary fibrosis or emphysema.
91. 91. An A-SMase inhibitor or a method as claimed in any one of claims 88 to 90, wherein the A-SMase inhibitor is administerable by inhalation.
92. 92. An A-SMase inhibitor or a method as claimed in any one of claims 88 to 91, wherein the A-SMase inhibitor is as defined in any one of claims 2 to 37.
93. 93. Arnitriptyline or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof, for treating or preventing a chronic obstructive pulmonary disease such as chronic asthmatic bronchitis, chronic emphysematous bronchitis, chronic bronchitis with airways obstruction, chronic bronchitis with emphysema, chronic obstructive asthma, chronic obstructive bronchitis, chronic tracheobronchitis, chronic obstructive pulmonary disease with acute lower respiratory infection, chronic obstructive pulmonary disease with acute -66 -exacerbation (unspecified), other specified chronic obstructive pulmonary diseases, or chronic obstructive pulmonary disease (unspecified).
94. 94. A method of treating or preventing a chronic obstructive pulmonary disease such as chronic asthmatic bronchitis, chronic emphysematous bronchitis, chronic bronchitis with airways obstruction, chronic bronchitis with emphysema, chronic obstructive asthma, chronic obstructive bronchitis, chronic tracheobronchitis, chronic obstructive pulmonary disease with acute lower respiratory infection, chronic obstructive pulmonary disease with acute exacerbation (unspecified), other specified chronic obstructive pulmonary diseases, or chronic obstructive pulmonary disease (unspecified), the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of amitriptyline or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof.
95. 95. Arnitriptyline or a pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof as claimed in claim 93, or a method as claimed in claim 94, wherein the amitriptyline or pharmaceutically acceptable tautomer, salt, prodrug or hydrate thereof is administerable by inhalation.
96. 96. An A-SMase inhibitor for treating or preventing a respiratory disorder by inhalation, wherein the respiratory disorder is: (a) cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants; or (b) cystic fibrosis including mucoviscidosis, cystic fibrosis with pulmonary manifestations, cystic fibrosis with intestinal manifestations, cystic fibrosis with other manifestations, and unspecified cystic fibrosis.
97. 97. A method of treating or preventing a respiratory disorder, comprising administering to a subject in need thereof by inhalation a therapeutically or prophylactically effective amount of an A-SMase inhibitor, wherein the respiratory disorder is selected from: (a) cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants; or -67 - (b) cystic fibrosis including mucoviscidosis, cystic fibrosis with pulmonary manifestations, cystic fibrosis with intestinal manifestations, cystic fibrosis with other manifestations, and unspecified cystic fibrosis.
98. 98. An A-SMase inhibitor as claimed in claim 96, or a method as claimed in claim 97, for treating or preventing chronic cough or cystic fibrosis.
99. 99. An A-SMase inhibitor or a method as claimed in any one of claims 96 to 98, wherein the A-SMase inhibitor is as defined in any one of claims 2 to 37.
100. 100. A NO-donor for treating or preventing cough including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants.
101. 101. A method of treating or preventing cough, including chronic cough, psychogenic cough, cough with haemorrhage, and cough caused by poisoning such as with expectorants, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a NO-donor.
102. 102. A NO-donor as claimed in claim 100, or a method as claimed in claim 101, for treating or preventing chronic cough.
103. 103. A NO-donor or a method as claimed in any one of claims 100 to 102, wherein the NO-donor is administerable by inhalation.
104. 104. A NO-donor or a method as claimed in any one of claims 100 to 103, wherein the NO-donor is as defined in any one of claims 38 to 43.
105. 105. An inhaler comprising a pharmaceutical composition as claimed in any one of claims I to 43 or any one of claims 54 to 81, or comprising a compound as claimed in any one of claims 44 to 53.
106. 106. An inhnler cJafrntj jn daini 105 for use in the treatment or prevention of a resptwny dSorder.
107. 107. A foil blister or a single dose capsule compthing a pharmaceutical composition as dainied in any one of dsinis 1 to 43 or any one of dthns 54 to 81, or comprising a compound as claimed in any one of dahns 44 to 53.