WO2004035042A1

WO2004035042A1 - New use of no donating nsaids

Info

Publication number: WO2004035042A1
Application number: PCT/SE2003/001603
Authority: WO
Inventors: Bror Jonzon; Janet Hoogstraate
Original assignee: Astrazeneca Uk Limited
Priority date: 2002-10-18
Filing date: 2003-10-15
Publication date: 2004-04-29
Also published as: SE0203093D0; AU2003269774A1

Abstract

The present invention relates to the use of NO-donating Non Steroidal Antiinflammatory Drugs in the treatment of conditions associated with gastrointestinal motility, to method of treatment of such conditions and to the use of pharmaceutical compositions comprising one or more NO-donating NSAID(s) in the treatment of said conditions. More particularly, the invention is directed to the use of one or more NO-donating NSAID(s) for the manufacture of a medicament for the treatment of conditions associated with disturbed gastrointestinal motility.

Description

NEW USE OF NO DONATING NSAIDS

FIELD OF THE INVENTION

The present invention relates to the use of Nitrix Oxide (NO) donating Non Steroidal Antiinflammatory Drugs (NS AID(s)) in the treatment of conditions associated with gastrointestinal motility, to a method of treatment of such conditions and to the use of pharmaceutical compositions comprising one or more NO-donating_NSAID(s) in the treatment of said conditions.

More particularly, the invention relates to the use of one or more NO-donating NSAID(s) for the manufacture of a medicament for the treatment of conditions associated with inappropriate gastrointestinal motility.

BACKGROUND OF THE INVENTION

Gastrointestinal (GI) motility and perception of GI motility such as satiety may influence both general and drug related GI symptoms, as well as feeding behaviour affecting weight control. Early satiety (early satisfied feeling after food intake) is a factor limiting food intake in anorectic patients. Disturbed satiety can promote increased food intake in overweight subjects. Nitric Oxide (NO) is an important mediator for the control of GI motility and perception of GI motility. NO donators may influence these conditions both by increasing or decreasing these effects depending on the type of disorder and dosing. One common reason for disturbances of GI function including motility and GI symptoms is treatment with NSAIDs. Non-steroidal anti-inflammatory drugs (NSAIDs), commonly and hereafter abbreviated as NSAIDs, are well-known drugs for the treatment of pain and inflammation. Surprisingly, the addition of of the NO donating moiety to NSAIDs, resulting in NO- NSAIDs does not give rise to disturbed GI motility abd GI symptoms. This implies that NO-NS AIDs can be used for the treatment of anorexia, weigth reduction and motility related symptoms. Nitric oxide donating NSAID compounds, commonly and hereinafter abbreviated as NO- donating NSAIDs, are compounds whereby the NO is linked to the NSAID molecule. The NO is released during absorption in the GI tract after administration of the NO-donating NSAID as well as during distribution of the compound in the body. Examples of these compounds as well as the preparation thereof are described in WO 94/04484, WO 94/12463, WO 95/09831 and WO 95/30641.

Nitric oxide synthase (NOS) is present in the gastrointestinal tract .

In diabetics, systemic NO (glyceryl trinitrate) influences GI motility (by decreasing the antral area) and improves the meal distribution. (Undeland, K. A. et al., European Journal of Gastroenterology &Heρatology, vol 10, no 8, 677-681, (1998)), Gilja O.H. et al., Digestive Diseases and Sciences, vol 42, No 10, 2124-2131, (1997) describe the relation between functional dyspepsia and impaired function of the proximal stomach. Glyceryl trinitrate prior to a standardized meal improves the accommodation of the proximal stomach and the somptom score in patients with functional dyspepsia..

Inhibition of NOS impairs accommodation (Tack, J., et al., Gut 2002,; 51: 219-224) work with L-NMMA, an NO inhibitor, showed that NO is involved in nausea, satiety and motility (Kuiken, S.D. et al., Gut 2002; 51:212-218)).

It is known from the literature that NO acts as a neurotransmitter on the smooth muscles, for example on the sphincter of the stomach. NO inhibits nitric oxidase synthesase (NOS). Therefore it is believed that nitric oxide may be involved in the satiety perception after food intake.

NO-donating compounds may thus affect the gastrointestinal motility and perception and may thus be involved in satiety perception.

DETAILED DESCRIPTION OF THE INVENTION Use

It has now surprisingly been found that NO-donating NSAIDs have an effect on the gastrointestinal (GI) motility. Nitric oxide released from the NO-donating NSAID has the ability to modulate and normalize the GI motility, e.g. GI symptoms and weight control.

NO-donating NSAIDs may thus be used to normalize satiety compared to NSAIDs. Individuals with disturbed gastric motility and/or individuals with early satiety may benefit from treatment with one or more NO-donating NSAID(s). The compounds may for example be able to facilitate weight reduction and reduce GI motility disturbance, including counteracting NSAIDs related GI symptoms.

NO-donating NSAIDs are suggested to normalize or facilitate normal food intake, i.e. improve digestion, compared to NSAIDs. It is therefore believed that NO-donating NSAIDs may be useful in the treatment of individuals suffering from disturbed motility in the GI tract. This is for example the case in patients with anorexia.

One embodiment of the invention relates to the use of one or more NO-donating NSAID(s) in the manufacture of a medicament for the treatment of conditions associated with disturbed gastrointestinal motility.

Another embodiment of the invention relates to the use of one or more NO-donating NS AID(s) in the manufacture of a medicament for the treatment of conditions of disturbed motility in the gastrointestinal tract.

A further embodiment of the invention relates to the use of one or more NO-donating NS AID(s) in the manufacture of a medicament for the treatment of conditions associated with early satiety.

Yet another embodiment of the invention relates to the use of one or more NO-donating

NSAID(s) in the manufacture of a medicament for the treatment of anorexia. Yet a further embodiment of the invention relates to the use of one or more NO-donating NSAID(s) in the manufacture of a medicament for the treatment of weight reduction.

One embodiment of the invention relates to the use of one or more NO-donating NSAID(s) in the manufacture of a medicament to normalize or facilitate food intake.

Another embodiment of the invention relates to the use of one or more NO-donating NSAID(s) in the manufacture of a medicament to counteract NSAIDs' related GI symptoms.

The invention further relates to a method of treatment of conditions associated with disturbed gastrointestinal motility and/or any other disorder and/or condition mentioned above, comprising administrering to a mammal, including man in need of such treatment, a therapeutically effective amount of one or more NO-donating NSAID(s).

The term "NSAID" is defined as a non-steroidal anti-inflammatory drug, i.e. any drug having an anti-inflammatory effect, but which compound does not belong to the compound class "steroids". The term "NSAID" includes COX 1 and/or COX 2 inhibitors.

The term "NO-donating NSAID" is contemplated to include any non-steroidal anti- inflammatory drug (NSAID), a salt or an enantiomer thereof, which has the capability to release nitrogen oxide. The term "NO-donating NSAID" includes any salts, solvates and enantiomers thereof.

In the context of the present specification, the term "therapy" and "treatment" includes prevention and prophylaxis, unless there are specific indications to the contrary. The terms "treat", "therapeutic" and "therapeutically" should be construed accordingly. Pharmaceutical composition

One embodiment of the invention relates to a pharmaceutical composition for use in the treatment of conditions associated with disturbed gastrointestinal motility and/or any other disorder and/or condition mentioned above, comprising one or more NO-donating NSAID(s) optionally in admixture with one or more pharmaceutically acceptable adjuvant(s), diluent(s) and/or carrier(s).

The composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment, patch or cream or for rectal administration as a suppository. In general the above compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical diluents and/or inert carriers.

Suitable daily doses of the NO donating NSAID(s) in the treatment of a mammal, including man may be between 50 and 1500 mg per unit dose.

The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.

One possible pharmaceutical composition is a Self Emulsifying Drug Delivery System, commonly known as SEDDS, as described in WO 01/66087. The SEDDS is a pharmaceutical composition suitable for oral administration, in the form of an emulsion pre-concentrate, comprising one or more NO-donating NSAID(s); one or more surfactants; and optionally together with an oil or semi-solid fat. The composition forms in-situ oil-in- water emulsion upon contact with aqueous media such as gastrointestinal fluids. The pre- concentrate emulsion is usually filled into conventional capsules.

In one embodiment of the invention the pharmaceutical composition is a Self Emulsifying Drug Delivery System.

The term "unit dose" is defined as the amount of active drug administered in one dosage form, e.g. one tablet, one single capsule, one suppository, one patch or one sachet. Compounds

Any NO-donating NSAID will be appropriate for the use according to the present invention.

Examples of NSAIDs are naproxen, diclofenac, aceclofenac, indomethacine, ketorolac, sulindac, meloxicam, piroxicam, tenoxicam, ibuprofen, ketoprofen, naproxen, azapropazon, nabumetone, carprofen, tiaprofenic acid, suprofen, indoprofen, etodolac, fenoprofen, fenbufen, flurbiprofen, bermoprofen, pirazolac, zaltoprofen, nabumetone, bromfenac, ampiroxicam, and lornoxicam.

Examples of COX 1 and/or 2 inhibitor(s) are rofecoxib, celecoxib, etodolac, etoricoxib, loxoprofen, lumiracoxib, nimesulide, meloxicam, valdecoxib, tilmacoxib, parecoxib sodium, flosulide, darbufelone mesylate, 2-benzyl-4-isopropoxy-5-(4- methanesulfonylphenyl)pyridazin-3-one and 1,2-diarylcyclopentenes, as salts and or enantiomers thereof, or mixtures thereof.

These list should however not be considered as exhaustive in any way.

As stated above the term "NSAID" inclused COX 1 and/or COX 2 inhibitors.

In one embodiment of the invention the NO-donating NSAIDs suitable for the uses according to the present invention are compounds of formula I; ML_TιA_T2-COO-X-ONO_m (I) wherein:

M is a radical of a physiologically active compound;

L is O, S, (CO)O, (CO)NH, (CO)NR¹, NH, NR¹, wherein R¹ is a linear or branched alkyl group, or

wherein R^b is H, Cj.ι₂alkyl or C₂-ι₂alkenyl;

R² is (CO)NH, (CO)NR¹, (CO)O, or CR¹ and a and b are independently 0 or 1; A is a substituted or unsubstituted straight or branched alkyl chain; τι and τ₂ are each independently 0, 1, 2 or 3; X is a carbon linker; and m is 1 or 2.

M may be any radical of any physiologically active compound.

In one embodiment of the invention the group M is part of the molecule of an NSAID, COX 1 and/or COX 2 inhibitor.

In another embodiment of the invention the NO-donating NSAIDs are selected from compounds disclosed in WO 94/04484, WO 94/12463, WO 95/09831 and WO 95/30641, which are hereby incorporated by reference.

In a further embodiment of the invention the group M is selected from the group consisting of

s described in US 3,641,127, and

as described in WO 96/32946 , and cycloalkyls as described in WO 98/25918 such as 2,2-dimethyl-cyclopropane-l-methanol, and

-OCOCH, as described in CN 1144092 , and

or

as described in WO 95/09831, and

as described in WO 02/30866, and

as described in US 6,297260.

In yet another embodiment of the invention L is selected from the group consisting of O, S, NH, NR¹, wherein R¹ is a linear or branched alkyl group, as described in WO 95/09831, and

(CO) or (CO)O as described in WO 95/30641, and

b

wherein Rb is H, Cι-ι₂alkyl or C₂__]2alkenyl and a and b are independently 0 or 1, as described in WO 02/053188,

and

wherein R_b, a and b are defined as above; and R² is (CO)NH, (CO)NR¹, (CO)O, or CR¹. In yet a further embodiment of the invention A is selected from the group consisting of -(CH₂)_n-, whereby n is 0, 1, 2, 3 or 4,

wherein dl is 1, 2 or 3.

In one embodiment of the invention the group ML_TιAτ₂ is selected from the group consisting of

In another embodiment of the invention the carbon linker X is selected from the group consisting of

A' wherein A' and B are chosen among hydrogen, linear or branched or

I cyclic substituted or non substituted alkyl group, and vl is comprised -(C)_v1- between 1 and 10

B as described in WO 95/09831, and

-(CH₂-CH₂-O)₂- . or a cycloalkyl having 5 to 7 carbon atoms optionally substituted, and

wherein ml is comprised between 0 and 3, and

0), and

p is comprised between 0 and 6, as described in WO 95/30641 and WO 02/92072, and

-(CH₂)_q-OCO-(CH₂)_r, wherein q and r each independently comprise between 0 and 6. wherein Z is O, SO, S or a saturated, unsaturated or

A' A' aromatic 5 or 6 membered ring or 5 or 6 membered heterocyclic ring

-₍C₎ -Z —₍C₎ - containing one or more heteroatoms selected independently from

>v3 N, O and S,

B B wherein said ring may optionally be substituted, and v2 and v3 are independently comprised between 0 and 4.

In a further embodiment of the invention the carbon linker X is selected from the group consisting of linear, branched or cyclic -(CH₂)-_Wι wherein wl is an integer from 2 to 10; - (CH₂)_w2-O-(CH₂)_w3- wherein w2 and w3 are integers from 2 to 10; and -CH₂-C₆H₄-CH2-.

In yet another embodiment of the invention the carbon linker X is selected from the group consisting of linear -(CH₂)_wr wherein wl is an integer from 2 to 6; -(CH₂)₂-O-(CH₂)₂- and -CH CόH-t-CH .

In yet a further embodiment of the invention the NO-donating NSAIDs are selected from the group consisting of

In one embodiment of the invention the NO-donating NSAID is 4-(nitrooxy)butyl-(S)-2-(9- methoxy-2-naphtyl)-propanoate. In another embodiment of the invention the NO-donating NSAID is 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid 4-(nitrooxy)-butyI ester.

Examples

The invention is described in more detail by the following non-limiting examples.

The examples below support that NO-donating NSAIDs have an effect on the gastric motility.

Example

In this study, 3 groups of eight male Sprague-Dawley rats fasted overnight and received 300 Qmol/kg of 4-(nitrooxy)butyl-(S)-2-(9-methoxy-2-naphtyl)-propanoate (compound la), 300 Dmol/kg naproxen or vehicle by gavage. 15 minutes later a semisolid meal, containing charcoal as a non-absorbable marker, was administered by gavage in a volume of 10 ml/kg. 15 min after the semisolid meal had been given, the rats were anaesthetised with isoflurane and the small intestine and stomach were removed. The distance travelled from the pyloric sphincter towards the caecum was measured and expressed as a percentage of the total length of the small intestine. The stomach and its contents were weighed in order to obtain a rough estimate of stomach emptying.

The mean intestinal transit was 55.6D2.8% in the group treated with 300 Dmol/kg of 4-(nitrooxy)butyl-(S)-2-(9-methoxy-2-naphtyl)-propanoate and 59.6D 1.7% in the group treated with the vehicle. There was no statistical difference between the groups. Furthermore, no statistical difference in mean stomach weight was found between the compound la-treated and vehicle-treated groups (5.46D0.21 g and 5.60D0.15 g, respectively).

However, the stomach weight was decreased and the intestinal transit time prolonged in the group treated with naproxen, suggesting that the gastrointestinal motility is enhanced by COX inhibition or as a result of a direct effect of the naproxen moiety. The results are shown in Figures 1 and 2. Short description of Figures 1 and 2

Figure 1 shows the effect of compound la, naproxen and the vehicle on gastric emptying of a semisolid meal in the rat, expressed in weight of the stomach (g)

Figure 2 shows the effect of compound la, naproxen and the vehicle on intestinal propulsion of a semisolid meal in the rat, expressed in relative length of the gastrointestinal tract (transit %).

Claims

1. Use of one or more NO-donating Non Steroidal Antiinflammatory Drug(s) (NO- donating NS AID(s)) in the manufacture of a medicament for the treatment of conditions associated with disturbed gastrointestinal motility.

2. Use of one or more NO-donating NSAID(s) in the manufacture of a medicament for the treatment of conditions associated with early satiety.

3. Use of one or more NO-donating NSAID(s) in the manufacture of a medicament for the treatment of anorexia.

4. Use of one or more NO-donating NS AID(s) in the manufacture of a medicament for the treatment of weight reduction.

5. Use of one or more NO-donating NSAID(s) in the manufacture of a medicament to normalize or facilitate food intake.

6. Use of one or more NO-donating NSAID(s) in the manufacture of a medicament to counteract NSAIDs' related GI symptoms.

7. A pharmaceutical composition for use in the treatment of conditions associated with disturbed gastrointestinal motility, comprising one or more NO-donating NSAID(s) optionally in admixture with one or more pharmaceutically acceptable adjuvant(s), diluent(s) and/or carrier(s).

8. A method of treatment of conditions associated with disturbed gastrointestinal motility, comprising administrering to a mammal, including man in need of such treatment, a therapeutically effective amount of one or more NO-donating NSAID(s).

9. The use according to any one of claims 1 to 6 wherein the NO-donating NSAID is a compounds of formula I;

ML_TιAτ₂-COO-X-ONO_m (I) wherein:

M is a radical of a physiologically active compound;

b b FT

or

wherein R is H, Cι.ι₂alkyl or C₂__.2alkenyl;

R² is (CO)NH, (CO)NR¹, (CO)O, or CR¹ and a and b are independently 0 or 1; A is a substituted or unsubstituted straight or branched alkyl chain; τι and χ are each independently 0, 1, 2 or 3; X is a carbon linker; and m is 1 or 2.

10. The use according to claim 9 wherein group M is part of the molecule of an NSAID, COX 1 and/or COX 2 inhibitor.

11. The use according to claim 9 wherein the group MLπAτ₂ is selected from the group consisting of

12. The use according to claim 9 wherein the carbon linker X the carbon linker X is selected from the group consisting of A' wherein A' and B are chosen among hydrogen, linear or branched or

I cyclic substituted or non substituted alkyl group, and vl is comprised

-(C)*- between 1 and 10, and

B

— (CH₂-CH₂-O)₂- . or ^a cycloalkyl having 5 to 7 carbon atoms optionally substituted, and

wherein ml is comprised between 0 and 3, and

0)_p and

p is comprised between 0 and 6, and

-(CH₂)_q-OCO-(CH₂)_r, wherein q and r each independently comprise between 0 and 6, and wherein Z is O, SO, S or a saturated, unsaturated or

A' A' aromatic 5 or 6 membered ring or 5 or 6 membered heterocyclic ring _z i_Q) containing one or more heteroatoms selected independently from

I i ^" N, O and S,

□ g wherein said ring may optionally be substituted, and v2 and v3 are independently comprised between 0 and 4.

13. The use according to any one of claims 1 to 6 wherein the NO-donating NSAID is 4- (nitrooxy)butyl-(S)-2-(9-methoxy-2-naphtyl)-propanoate.

14. The use according to any one of claims 1 to 6 wherein the NO-donating NS AID is 2- [(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(nitrooxy)-butyl ester.