GB2135881A - Method and pharmaceutical compositions for inhibiting or reducing gastrointestinal side effects of non-steroidal anti-inflammatory drugs - Google Patents
Method and pharmaceutical compositions for inhibiting or reducing gastrointestinal side effects of non-steroidal anti-inflammatory drugs Download PDFInfo
- Publication number
- GB2135881A GB2135881A GB08402449A GB8402449A GB2135881A GB 2135881 A GB2135881 A GB 2135881A GB 08402449 A GB08402449 A GB 08402449A GB 8402449 A GB8402449 A GB 8402449A GB 2135881 A GB2135881 A GB 2135881A
- Authority
- GB
- United Kingdom
- Prior art keywords
- methyl
- pge2
- didehydro
- alkyl
- deoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Gastrointestinal side effects in mammals during treatment with non-steroidal anti-inflammatory drugs (NSAID) are inhibited or reduced by administering concomitantly or simultaneously a NSAID and a gastrointestinal side-effect-inhibiting or reducing dose of an optically active or racemic prostaglandin or prostacyclin derivative of general formula (I> <IMAGE> wherein a) @, X and W represent, respectively, the C8-C12 substituted monocyclic or C6-C12 substituted bicyclic moiety and the alpha - and the omega - chain of the compounds disclosed in any one of the following patent documents: GB 1,425,961; GB 1,493,557; GB 1,420,338; GB 1,514,542; GB 1,483,880; GB 1,498,105; GB 1,531,567; BE 843,420; GB 1,583,263; GB 1,599,820; GB-B 2,009,145; GB-B 2,086,373; GB-B 2,805872; GB-B 2,013,661 and GB-B 2,025,972, and the pharmaceutically or veterinarily acceptable salts thereof; or b) the meanings of @, X and W are such that the general formula (I) encompasses a compound selected from the group consisting of: PGE1; PGE1, alpha -cyclodextrin clathrate; PGE2, beta -cyclodextrin clathrate; (17S)-17, 20-dimethyl-trans- DELTA <2>-PGE1; 16,16-dimethyl-trans- DELTA <2>-PGE1, methylester; 15(R)-15-methyl-PGE2; (+) (16 RS)-15-deoxy-16-hydroxy-16-methyl-PGE1, methylester; 11-deoxy-11 alpha , 16,16-trimethyl-PGE2; (+)-11 alpha , 16 alpha , beta -dihydroxy-1,9-dioxo-1-(hydroxymethyl)-16-methyl-13-trans-prostene; (+)-4,5-didehydro-16-phenoxy- omega -tetranor-PGE2, methylester; 16,16-dimethyl-PGE2; 4,5,6-trinor-3,7-inter-m-phenylene-3-oxa-PGE1; 11-deoxy-15 epsilon -methyl-PGE1; 19 beta -hydroxy-PGE1; 6 beta -PGI1; 16-phenoxy- omega -tetranor-6 beta -PGI1; 16-m-CF3-phenoxy- omega -tetranor-6 beta -PGI1 and 16-methyl-20-methoxy-PGE2 and, when appropriate, the pharmaceutically or veterinarily acceptable salts thereof.
Description
SPECIFICATION
Method and pharmaceutical compositions for inhibiting or reducing gastrointestinal side effects of non-steroidal anti-inflammatory drugs
This invention relates, in one aspect, to certain prostaglandin and prostacyclin compounds for use, by concomitant or simultaneous administration, in inhibiting or reducing the gastrointestinal side effects of non-steroidal anti-inflammatory drugs (NSAIDs).
In another aspect, the invention relates to pharmaceutical and veterinary compositions for treating inflammatory conditions comprising a combination of a gastrointestinal side-effect-inhibiting or -reducing dose of a prostaglandin or prostacyclin derivative and a therapeutic dose of a NSAID.
As is known, the therapeutic efficacy of NSAlDs, which are widely used in medicine, for example for the treatment of rheumatic and arthritic diseases, is often associated with a high incidence of gastrointestinal drawbacks, such as epigastric distress, ulceration, gastrointestinal bleeding and the like, and this is one of the most common reason for discontinuing therapy with these agents.
We have found that optically active or racemic prostaglandin or prostacyclin derivatives of general formula (I)
wherein a) 0 , X and W represent, respectively, the Cs-C12 substituted monocyclic or C6-C12 substituted bicyclic moiety and the a- and the ca-chain of the compounds disclosed in any one of the following patent documents: GB 1,425,961; GB 1,420,338; GB 1,514,542; GB 1,483,880; GB 1,498,105; GB 1,531,567; GB 1,493,557; BE 843,420; GB 1,583,263, GB 1,599,280; GB-B 2,009,145; GB-B 2,086,373; GB-B 2,085,872; GB-B 2,013,661 and GB-B 2,025,972, and the pharmaceutically or veterinarily acceptable salts thereof; or
b) the meanings of Oxy , X and Ware such that the general formula (I) encompasses a compound selected from the group consisting of:PGE1; PGEn, a-cyclodextrin clathrate; PGE2, ss-cyclodextrin clathrate; (1 7S)-1 7,20-dimethyl-trans-A2-PGE1; 16,16-dimethyl-trans-A2-PGEs, methylester; 15(R)-I 5-methyl-PGE2; ( + ) (16 RS)-15-deoxy-16-hydroxy-16-methyl-PGE1, methylester; 11-deoxy-11a, 16,16-trimethyl-PGE2; ( + )11 a, 1 6a, i3-dihydroxy-1 ,9-dioxo-1 -(hydroxymethyl)-1 6-methyl-1 3-trans-prostene; ( + )-4,5-didehydro-1 6- phenoxy--tetranor-PGE2, methyl ester; 16,1 6-dimethyl-PGE2; 4,5,6-trinor-3,7-inter-m-phenylene-3-oxa- PGE1; 11 -deoxy-1 5-methyl-PGE1; 19ss-hydroxy-PGE1; 6p-PGI1; 16-phenoxy-(o-tetranor-6ss-PGI1; 1 6-m-CF3- phenoxy-X-tetranor-6ss-PG 11 and 1 6-methyl-20-methoxy-PGE2 and, when appropriate, the pharmaceutically or veterinarily acceptable salts thereof, are able to inhibit or reduce the gastrointestinal side effects caused by administration to mammals of NSAlDs.
In particular we have found that the compounds of formula (I), in particular 1 1-deoxy-13,14-didehydro- 16(S)-methyl PGE2 methyl ester (internal code: FCE 20700); 16(S)-fluoro-13,14-didehydro-17-cyciohexyl- PGE2 methyl ester (internal code: FCE 21271); and ( + )-5-(Z,E)-13,14-didehydro-20-methyl-carbo-PGl2,the latter compound, as single geometric isomer in the optically active form and/or as racemate, are active, when administered to humans or animals, orally, parenterally or by rectal way, against the gastrointestinal side effects, e.g., gastrointestinal irritation, epigastric distress, gastrointestinal bleeding and ulcers which may be induced, for example, by the following drugs: acetylsalicylic acid (ASA), feprazone, fenbufen, zomepirac, mefenac, phenylbutazone, naproxen ibufenac, sulindac, tolmetin, ibuprofen, indomethacin, piroxicam, indoprofen, ( + )-indoprofen and ketoprofen and the pharmaceutically or veterinarily acceptable salts thereof. In this specification the term "indoprofen" means racemic indoprofen and "( + )-indoprofen" means the (S) ( + )enantiomer thereof, and the term "NSAID" refers both to a non-steroidal antiinflammatory drug and, when appropriate, to a pharmaceutically or veterinarily acceptable salt thereof.
For this purpose the compounds of formula (I) may be administered concomitantly with or simultaneously to the NSAlDs. As used in the present invention the words "concomitantly" or "concomitant" refer to the administration of a compound of formula (I) immediately, or shortly, before or after the administration of the NSAlDs. We also found that concomitant or simultaneous administration of compounds of formula (I) and
NSAIDs allows to use higher doses, therefore more effective, of the latter compounds without simultaneous enhancement of their undesirable gastrointestinal side effects. Such concomitant or simultaneous administration is therefore particularly useful in therapy, expecialiy when high doses of and/or long lasting treatments with NSAIDs are required, for example, in the therapy of patients suffering from rheumatic diseases.This important and unforeseeable property of the compounds of formula (I) allows to inhibit or reduce the gastrointestinal side effects induced by NSAlDs, at doses lower than those required for inhibiting the basal gastric acidic secretion, without causing undesirable side effects, such as diarrhea, and without antagonizing the anti-inflammatory activity of NSAlDs.
The compounds of formula (I) defined above under b) are known, e.g. they are described in Chemical and
Engineering News, Aug. 16,1982.
Examples of salts of the compounds of formula (I) with pharmaceutically orveterinarily acceptable bases are those deriving either from inorganic bases, such as sodium, potassium, calcium.and aluminium hydroxides, or organic bases, e.g. amines, such as trialkylamines. Preferred salts of the compounds of formula (I), when basic groups are present, are also acid addition salts, with inorganic, e.g., hydrochloric, hydrobromic, hydroiodic, sulphuric and nitric, acids or with organic, e.g., acetic, propionic, malic, maleic, fumaric, cinnamic and mandelic, acids or with organic sulphonic acids, e.g., methanesulphonic, ptoluenesulphonic or cyclohexylsulphonic acid.
As already stated, the present invention refers, in another aspect, to pharmaceutical or veterinary compositions for treating inflammatory conditions comprising a combination of a gastrointestinal side-effect-inhibiting or -reducing dose of a prostaglandin or prostacyclin derivative and a therapeutically effective dose of a NSAID or a pharmaceutically or veterinarily acceptable salt thereof.More exactly, the prostaglandin or prostacyclin derivative of the aforesaid pharmaceutical or veterinary compositions is one of the general formula (I), as reported above, or one of the following general formula (II)
wherein
Ra is
wherein
each of R' and R" independently is hydrogen, C1-C6 alkyl, aryl or heterocyclyl or R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic radical, or Ra is -Y-(CH2),-Z, wherein
Y is -O- or -NH-, m is an integer up to 4 and Z represents either a group
wherein
R' and R" are as defined above or a group -OR"', wherein R"' is chosen from the group consisting of C,-C6 alkyl, cycloalkyl, aryl and heteroaryl;
R'1 is hydrogen or hydroxy;
one of R'2 and R'3 is hydroxy and the other is hydrogen;;
each of R'4 and R'5 is independently hydrogen, C1-C4 alkyl or fluorine; piszero, 1,2or3; R'5 is a') C1-C4 alkyl;
b') a C3-C7 cycloalkyl ring unsubstituted or substituted by one or more substituents chosen from
halogen, trihalo-C1-C6 alkyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl and phenoxy;
c') a phenyl ring unsubstituted or substituted by one or more substituents chosen from the group
consisting of a") C1 -C6 alkyl; b") C1-C6 alkoxy; c") trihalo-C,-C6 alkyl d") halogen; e")
wherein each of Rg and R10 is independently chosen from hydrogen, phenyl, benzoyl, C1-C6 alkyl, and C1-C6 aliphatic acyl; f') phenyl unsubstituted or substituted by one or more substituents chosen from C1-C6 alkoxy and halogen; and g") phenoxy unsubstituted or substituted by one or more substituents chosen from C1 -C6 alkoxy and halogen; and d') a heterocyclic ring unsubstituted or substituted by one or more substituents chosen from halogen, trihalo-C1-C6 alkyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl and phenoxy; provided that, when Ra is a group
wherein R' and R" are as defined above, R' 6 is C1-C4 alkyl only; or a pharmaceutically or veterinarily
acceptable salt thereof.
The term C1-C6 aliphatic acyl refers to groups derived from carboxylic acids such as formyl, acetyl, propionyl, butyryl, valeryl and isovaleryl. When R"' and/or one or both of R' and Rare heterocyclyl, the heterocyclic ring is preferably chosen from pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidyl, piperazinyl and morpholinyl. An aryl group is preferably phenyl.
When R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic radical, this radical is preferably chosen from imidazolinyl, imidazolidinyi, pyrazolinyl, piperidino, piperazinyl, morpholino and pyrazolidinyl. R', R" and R" as individual heterocyclic groups can also be piperidino or morpholino.
When R"' is a cycloalkyl ring, it is preferably a C3-C7 monocycloalkyl ring, more preferably cyclopentyl, cyclohexyl or cycloheptyl.
When R'6 is a C3-C7 cycloalkyl ring unsubstituted or substituted as described above under b'), it is preferably cyclopentyl, cyclohexyl or cycloheptyl.
When R'6 is a phenyl ring unsubstituted or substituted as described above under c'), the ring is preferably substituted by one or more substituents chosen from methyl, methoxy, trifluoromethyl, fluorine, chlorine, iodine and
wherein Rg and R10 are as defined above.
When R'6 is a heterocyclic ring unsubstituted or substituted as described above under d'), it may be either a heteromonocyclic ring or a heterobicyclic ring and contains at least one heteroatom selected from N, S and
O. Examples of preferred heteromonocyclic radicals are tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl. Examples of preferred heterobicyclic radicals are 2-oxabicyclo [3.3.0] octyl, 2-oxabicyclo [3.4.0] nonyl,2-thiabicyclo [3.3.0] octyl, 2-thiabicyclo [3.4.0] nonyl and their unsaturated analogs.
Also the compounds of formula (II) own the same favourable properties as the compounds of formula (I).
In fact also the compounds of formula (II) are able to inhibit or reduce the gastrointestinal side effects of
NSAIDs, at doses lower than those required for the inhibition of the basal gastric secretion, without causing diarrhea and without antagonizing the anti-inflammatory activity of NSAIDs. The compounds of formula (II) are known compounds and are described in our published British Patent Application No. 2111986 A.
Preferred salts of the compounds of formula (II), or of the NSAlDs, when basic groups are present, are acid addition salts with inorganic, e.g., hydrochloric, hydrobromic, hydroiodic, sulphuric and nitric, acids or with organic, e.g., acetic, propionic, malic, maleic, fumaric, cinnamic and mandelic, acids or with organic sulphonic acids, e.g., methanesulphonic, p-toluenesulphonic or cyclohexylsulphonic acid.
Examples of salts of the NSAIDs with pharmaceutically or veterinarily acceptable bases, when acidic groups are present, are those deriving either from inorganic bases, such as, sodium, potassium, calcium and aluminium hydroxides, or organic bases, e.g., amines, such as, trialkylamines.
Preferred compounds of formula (I), to be used in concomitant or simultaneous administration with
NSAIDs, or, together with a therapeutically effective dose of NSAlDs, in a pharmaceutical or veterinary composition for treating inflammatory conditions, are the compounds of formula (la)
wherein
a) R is carboxy or -COOC1-C12 alkyl;
R1 is hydrogen or hydroxy; Ais-C=-C-; one of R2 and R3 is hydrogen and the other is hydroxy; R4 and R6 are independently selected from the group consisting of hydrogen, fluorine and C1 -C4 alkyl,
wherein, when one of them is C1-C4 alkyl, the other is hydrogen or fluorine and when one of them is
fluorine, the other is C1 -C4 alkyl;;
E is selected from the group consisting of -(CH2)n-, wherein n is an integer of 1 to 6, and -(CH2)n1-O-(CH2)n2-, wherein n1 and n2 are independently selected from the group consisting of zero,
1,2and3;
R6 is a member selected from the group consisting of methyl, cycloalkyl containing 3 to 7 ring carbon
atoms and optionally containing one or more ring oxygen or sulphur atoms and phenyl unsubstituted or
substituted by one or more substituents selected from the group consisting of halogen, C1 -C4 alkoxy,
phenyl and trihalomethyl; b) R is -CH2OH, carboxy or -COOC1-C4 alkyl;
R1 is hydrogen or hydroxy; Ais -CH=CH-(trans);
one of R2 and R3 is hydrogen and the other is hydroxy or C,-C4 alkoxy;; R4 and R6 are both methyl;
E is -O-(CH2)q- wherein q is zero or an integer up to 5;
R6 is C1-C6 alkyl, C3-C7 cycloalkyl or phenyl unsubstituted or substituted by halogen, C1-C4 alkoxy or
trihalomethyl; or c) R is carboxy or -COOC1-C6 alkyl;
R1 is hydrogen or C,-C6 alkyl;
Ais -CH=CH-;
one of R2 and R3 is hydrogen and the other is hydroxy or acetyloxy;
one of R4 and R5 is hydrogen or C1-C6 alkyl and the other is hydrogen, C,-C6 alkyl or fluorine;
E is -(CH2)3-;
R6 is -CH3; or the compounds of formula (Ib)
wherein
Rd is
hydrogen or C1-C12 alkyl; he symbol ------ represents a single or a double bond, wherein, when the symbol ------ is a double bond, R"3 is S hydrogen atom and R"1 and R"2 together form an oxo group, while, when the symbol ------ is a single bond, R"3 is hydroxy, and one of R"1 and R"2 is hydrogen and the other is hydroxy or acyloxy or R"1 and R"2, taken ogether, form an oxo group;
A is trans-CH=CH- or -C=C-; one of R"4 and R"5 is hydroxy and the other is hydrogen; R"6 is a member selected from the group consisting of hydrogen, methyl and fluorine;
g is zero, or an integer of 1 to 6;;
R7, when A is trans-CH=CH-, is a cycloalkyl group containing 3 to 7 ring carbon atoms, while, when A is -C""'C-, R7 is a member selected from the group consisting of methyl, cycloalkyl containing 3 to 7 ring
carbon atoms and phenyl unsubstituted or optionally substituted by one or more substituents selected
from the group consisting of halogen, C1-C6 alkoxy and trihalomethyl;
or the compounds of formula (Ic)
wherein
R8 is hydrogen, C1-C6 alkyl or fluorine; R'g is hydrogen orC1-C6 alkyl;
v is zero or an integer up to 4; and R11 is hydrogen or C1-C4 alkyl; or a pharmaceutically or veterinarily acceptable salt thereof.
More preferred compounds of formula (I) to be used in concomitant or simultaneous administration with NSAlDs, or, together with a therapeutically effective dose of NSAIDs, in a pharmaceutical or veterinary composition for treating inflammatory conditions, are the following: 1 1-deoxy-13,14-didehydro-16(R)-methyl-PGE2; 1 1-deoxy-13,14-didehydro-16(S)-methyl-PGE2; 11 -deoxy-1 3,1 4-didehydro-1 6(R)methyI-PGE2 methyl ester; 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl-PGE2 methyl ester; 1 6(S)-fluoro-1 3,1 4-didehydrn-1 7-cyclohexyl-PGE2; ( + )-5-(Z,E)-13,14-didehyd ro-20-methyl-carbo-PG 12; ( )-5(Z)- 13,1 4-didehydro-20-methyl-carbo-PGI2; + + )-5(E)-13,14-didehydro-20-methyl-carbo-PGI2; 13,1 4-didehydro-1 6(R)-methyl-PGE2; 13,14-didehydro-16(S)-methyl-PGE2; 13,14-didehydro-16(R)-methyl-PGE2 methyl ester; and 13,1 4-didehydro-1 6(S)-methyl-PGE2 methyl ester; or, when appropriate, a pharmaceutically or veterinarily acceptable salt thereof.
Preferred compounds of formula (II), to be used together with a therapeutically effective dose of NSAIDs in a pharmaceutical or veterinary composition for treating inflammatory conditions, are the compounds of formula (Ila)
wherein
Ra is -Y-(CH2)m-Z, when Y, m and Z are as defined above; one of R'2 and R'3 in hydroxy and the other is hydrogen; each of R'4 and R'5 is independently hydrogen, C1-C4 alkyl or fluorine; piszero,1,2or3; R'6 is a') C1-C4 alkyl;
b') a C3-C7 cycloalkyl ring unsubstituted or substituted by one or more substituents chosen from
halogen, trihalo-C1-C6 alkyl, C1-C4 alkyl, C1 -C4 alkoxy, phenyl and phenoxy;
c') a phenyl ring unsubstituted or substituted by one or more substituents chosen from the group
consisting of a") C1-C6 alkyl; b") C1 -C6 alkoxy; c") trihalo-C1-C6 alkyl; d") halogen; e")
wherein each of Rg and Rro is independently chosen from hydrogen, phenyl, benzoyl, C1-C6 alkyl, and C1-C6 aliphatic acyl; f") phenyl unsubstituted or substituted by one or more substituents chosen from C1-C6 alkoxy and halogen; and g") phenoxy unsubstituted or substituted by one or more substituents
chosen from C1-C6 alkoxy and halogen; and
d') a heterocyclic ring unsubstituted or substituted by one or more substituents chosen from halogen, trihalo-C1-C6 alkyl, C1 -C4 alkyl, C1 -C4 alkoxy, phenyl and phenoxy; or a pharmaceuticaily or veterinarily
acceptable salt thereof.
Preferred pharmaceutical or veterinary compositions of the invention for treating inflammatory conditions are those containing, together with a prostaglandin or prostacyclin compound of formula (I), chosen from the group consisting of 11 -deoxy-1 3,1 4-didehydro-1 6(R)-methyl-PGE2; 11 -deoxy-1 3,1 4-didehydro-1 6(S)- methyl-PGE2; 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl-PGE2, methyl ester; 11 -deoxy-1 3,1 4-didehydro-1 6(R)- methyl-PGE2, methyl ester; 16(S)-fluoro-13,14-didehydro-17-cyclohexyl-PGE2 methyl ester; ( + )-5(Z,E) 13,1 4-didehydro-20-methyl-carbo-PGl2; 13,1 4-didehydro-1 6(R)-methyl-PGE2; 13,1 4-didehydro-1 6(S)-methyl- PGE2; 13,1 4-didehydro-i 6(S)-methyl-PGE2 methyl ester; and 13,1 4-didehydro-1 6(R)-methyl-PGE2 methyl ester or a pharmaceutically or veterinarily acceptable salt thereof, when appropriate, a therapeutically effective dose of a NSAID chosen from the group consisting of: acetylsalicylic acid, fenbufen, zomepirac, mefenac, phenylbutazone, ibufenac, sulindac, tolmetin, ibuprofen, indomethacin, piroxicam, indoprofen, ( + ) indoprofen, ketoprofen, feprozone and naproxen or a pharmaceutically or veterinarily acceptable salt thereof.
More preferred pharmaceutical or veterinary compositions of the invention for treating inflammatory conditions are those containing, together with a prostaglandin or prostacyclin compound of formula (I) chosen from the group consisting of:1 1-deoxy-13,14-didehydro-16(S)-methyl-PGE2 methyl ester; 16(S) fluoro-1 3,1 4-didehydro-1 7-cyclohexyl-PGE2 methyl ester; and ( + )-5(Z,E)-1 3,1 4-didehydro-20-methyl-carbo- PGI2 or a veterinarily or pharmaceutically acceptable salt thereof, when appropriate, a NSAID chosen from: indomethacin, acetylsalicylic acid, piroxicam, indoprofen and ( + ) indoprofen or a pharmaceutically or veterinarily acceptable salt thereof.
When the prostaglandin derivatives of formula (I) are employed according to the method of this invention, they are administered, alone or in combination with a NSAID, with or without a pharmaceutical carrier or diluent. In the general embodiment of this invention the route of administration of the active agent is not critical. The prostaglandin derivative may be given orally, parenterally or by rectal route, simultaneously or concomitantly with the NSAlDs.
Analogously a pharmaceutical or veterinary composition, comprising a compound of formula (I) or (II), or a pharmaceutically or veterinarily acceptable salt thereof, and therapeutic dose of a NSAID, or a pharmaceutically or veterinarily acceptable salt thereof, may be made up with or without a pharmaceutical carrier and/or diluent. Also in this case the route of administration is not critical and the composition may be administrered by usual routes, e.g. orally, parenterally or by rectal route.
The pharmaceutical or veterinary compositions containing, as active principle, either a prostaglandin compound of formula (I) only or a compound of formula (I) or (II) together with a NSAID, or a pharmaceutically orveterinarily acceptable salt thereof, are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.For example, the solid oral forms may contain, together with the active compound(s), diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, fractionated coconut oil, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate, polyvinyl pyrrolidone cross-linked; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metaboliza ble to glucose, or metabolizable in very small amount to glucose, such as sorbitol.
The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
The suspensions or solutions for intramuscular injections may contain together with the active compound(s) a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g.
propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.
The suppositories may contain together with the active compound(s) a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethyiene sorbitan fatty acid ester surfactant or lecithin.
The proportions of the prostaglandin or prostacyclin derivatives and of the NSAlDs, if present, are determined by their solubilities, by the chosen route of administration and by standard biological practice.
For example, typical therapeutic doses of the above mentioned prostaglandin or prostacyclin substances, for the administration to adult human usually range from about 4 CLg/die to about 1000 ag/die. In particular, therapeutic doses of the above mentioned substance coded as compound FCE 20700, for the administration to adult humans usually range from about 4 pg/die to about 500 Fg/die.
Typical therapeutic compositions for adult humans, containing both the prostaglandin substance and the
NSAID comprise mixtures of these substances, e.g. compound FCE 20700 with indomethacin in a 1 :15to 1 :6,000 ratio by weight, or with indoprofen in a 1:40 to 1:20,000 ratio, or with ( + ) indoprofen in a 1:20 to 1:10,000 ratio, or with acetylsalicylicacid (ASA) in a 1:15 to 1:7,000 ratio. Preferred therapeutic compositions are those containing as prostaglandin derivative, compound FCE 20700 and, as NSAID, a compound selected from the group consisting of acetylsalicylic acid, fenbufen, zomepirac, mefenac, phenylbutazone, feprazone, ibufenac, sulindac, tolmetin, ibuprofen, naproxen, indomethacin, piroxicam, indoprofen, ( + )indoprofen and ketoprofen, or a pharmaceutically or veterinarily acceptable salt thereof.
More preferred therapeutic composition, e.g. for adult humans, is one containing compound FCE 20700 at a dose ranging from about 4 to 500 A9 and a therapeutic dose of indoprofen ranging from about 200 mg to about 800 mg or a therapeutic dose of ( + ) indoprofen ranging from about 100 mg to about 400 mg.
The following examples illustrate but do not limit this invention.
Example 1
Male rats, weighing 140 + 10 g, fasted for 16 hours but with free access to water, were given ASA (100 mg/kg orally) suspended in 0.5% Methocel in a volume of 0.5 con1/100 g b.w.. Compound FCE 20700 was orally administered (p. os) in a volume of 0.2 my/100 g b.w. 15 minutes before ASA administration. For inspection of the gastric mucosa the rats were lightly anaesthetized with ethyl ether and killed by exsanguination 2 hours after ASA. The stomachs were quickly removed, filled with saline, immersed in 0.4% formalin for 30 seconds according to Hanson and Brodie (J. Appl. Physiol. 15, 291, 1960), opened along the greater curvature and examined for lesions.Ulcers in fundus and antrum were scored on an arbitrary scale from 1 to 7 according to
Osterloh (Osterloh Von G., Lagler F., Staemmler M. and Helm F. Arzneim. Forsch. 16,901, 1966).
0 No lesions 1 Hyperemia, slight vascular engorgement 2 Massive vascular engorgement and petechiae 3 Mucosal and submucosal bleeding, slight superficial erosion, small ulcers, less than 3 in number 4 Up to 10 small ulcers ( < 3 mm) or4to 5 medium ulcers 5 Up to 15 small ulcers or 5 to 6 big ulcers (5 mm) 6 Up to 10 big ulcers, plus more small ulcers 7 More than 10 big ulcers, plus many small ulcers
The antiulcer and antisecretory activity of compound FCE 20700 is expressed in terms of ED50. For antiulcer activity this is the dose that reduces the ulcerogenic effect by 50% compared to controls.
For antisecretory activity it is the dose which reduces gastric acid accumulation after pylorus ligation by 50% compared to controls.
The ED50 was interpolated from the log dose-effect function calculated by the least squares method at the following values of the ordinate:
A) (U1 + U2)/2 for the ED50 on gastrointestinal ulcers where:
U1 = mean of ulcers induced by ulcerogenic agent in control rats
U2 = mean of spontaneous ulcers in vehicle treated control rats
B) Sc/2 for the ED50 on gastric secretion; where Sc = mean total acidity in gastric juice of control rats.
Replacing y in the general equation y = a + bx with the values A or B, resolving the equation for x (x = log (dose)) and calculating the antilog gives the ED50 for antiulcer and antisecretory activity is obtained with confidence limits for P = 0.95.
The results obtained with FCE 20700 in inhibiting the ulcer formation induced by ASA are given in the following table.
TABLE I
ED50(g/kg Dose No. of % inhibition p.os) and Compound ( g/kg p. animals of ulcers fiducial li os) mits for P= 0.95 Controls - 18 800 18 100 200 18 59 62 (FCE 20700) 50 18 35 12.5 18 10 Similar results were obtained by administering ulcerogenic doses of ketoprofen, mefenac, piroxicam,
phenylbutazone, feprazone, naproxene, tolmetin, ibufenac, fenbufen, zomepirac, sulindac, ibuprofen or
indomethacin, instead of ASA, and suitable ulcer-inhibiting doses of 11 -deoxy-13,1 4-didehydro-1 6(R)- methyl-PGE2, 11 -deoxy-1 3,1 4-didehydro-1 6(R)-methyl-PGE2, 11 -deoxy-1 3,1 4-didehydro-1 6(R)-methyl-PGE2 methyl ester,16(S)-fl uoro-13,14-didehydro-17-cyclohexyl-PGE2, or ( + )-5-(Z,E)-1 3,1 4-didehydro-20-methyl- carbo-PGI2 instead of compound FCE 20700.
Example 2
By following the same experimental procedure described in Example 1 and using compound FCE 21721 instead of compound FCE 20700 and ASA as ulcerogenic agent the following results were obtained.
TABLE II
ED50(ffi9/k9 Dose No. of % inhibition p.os) and Compound ( > g/kg p.os) animals of ulcers fiducial limits for P= 0.95 Controls - 21 FCE 21721 16 21 69 4 21 17 9.3 1 21 0 Similar results were obtained by administering ulcerogenic doses of ketoprofen, mefenac, piroxicam, phenylbutazone, ibufenac, fenbufen, zomepirac, sulindac, ibuprofen, feprazone, naproxene, tolmetin or indomethacin instead of ASA.
Example 3
Indoprofen per se is damaging very poorly rat gastric mucosa till 40 mg/kg after oral administration: in fact the score with this dose is 2.6 versus a score of 1.2 for controls.
Gastric ulcers are evident in rats only when indoprofen is associated to restraint and cold (immersion in water at 25"C for 40 minutes): in this case ulcer score is 4.10 at 40 mg/kg p. os.
Taking into account the pharmacokinetics of indoprofen in the rat as reported by G.C. Goldaniga,
E.Pianezzola, G. Valzelli in Arzneim. Forschung 24(10), 1603, 1974, where, as for indomethacin, an enterohepatic circulation probably occurs, the target organ for damage is the intestinal tract. For this reason, as model of inhibition of ulcers, intestinal ulcers were chosen.
Male rats, weighing 140+10 g, notfasted,were used at random and housed 5 per cage. Indomethacin, indoprofen or ( + ) indoprofen suspended in 0.5% Methocel was administered orally at the dose of 12,25 or 12.5 mg/kg respectively in a volume of 0.5 ml/1 00 g of body weight and, concomitantly, compound FCE 20700 was administered orally in a volume of 0.2 my/100 g b.w. 24 hours after the animals were killed by exsanguination under light chloroform anaesthesia. Median laparatomy was done and the small intestine was cut in 10 cm long segments, then cut open lengthwise and spread out for macroscopic examination of the ulcers. Ulcers were scored from 1 to 7 according to the following arbitrary scale set up in our laboratories: 0 = normal; 1 = marked vasodilation with Peyer's plaques enlarged and up to 3 small/slight ulcers; 2 = up to 10 small ulcers, up to 3-4 medium-large ulcers > 1 mm2; 3 = up to 20 small ulcers, up to 10 medium-large ulcers > 1 mm2; 4 = up to 20 medium-large ulcers > 1 mm2, plus small ulcers; stretches of ulcers along mesenteric line; 5 = up to 10 necrotic and callous ulcers or more than 20 medium-large ulcers, plus small ulcers or long stretches of ulcers along mesenteric line with necrotic and/or callous appearance; 6 = intestinal adhesions, stretches of hemorrhagic intestine; initial adhesions between adjacent loops of gut; 7 = perforated ulcers; peritonitis, intestine not examinable.
Antiulcer activity of FCE 20700 on intestinal ulcers induced by indomethacin (12 mg/kg per os):
TABLE Ill
ED50(A9/k9 Dose No. of % inhibition p.os) and Compound (ijg/kg p.os) animals of ulcers fiducial limits for P= 0.95 Control - 15 - FCE 20700 2,400 15 84 1,200 15 63 557 600 15 53 300 15 39 Antiulcer activity of FCE 20700 on intestinal ulcers induced by indoprofen 25 mg/kg p.os:
TABLE IV
ED50( Wg/kg Dose No. of % inhibition p.os) and Compound ( > g/kg p.os) animals of ulcers fiducial limits for P= 0.95 Control - 16 - FCE 20700 400 16 62 250 200 16 43 100 16 28 Antiulcer activity of FCE 20700 on intestinal ulcers induced by ( + ) indoprofen 12.5 mg/kg p.os:
TABLE V
ED50( Fg/kg Dose No. of % inhibition p.os) and Compound (ijg/kg p.os) animals of ulcers fiducial limits for P= 0.95 Control - 15 - FCE20700 400 15 50 222 200 15 48 100 15 20 Similar results were obtained by administering orally indomethacin, indoprofen or ( + )indoprofen together with a compound selected from compound FCE 20700, 11 -deoxy-1 3,1 4-didehydro-1 6(R)-methyl- PGE2,11-deoxy-13,14-didehydro-16(S)-methyl-PGE2, 11-deoxy-13,14-didehydro-16(R)-methyl-PGE2 methyl ester, 16(S)-fluoro-l 3,14-didehydro-17-cyclohexyl-PGE2 or ( + )-5-(Z,E)-1 3,14-didehydro-20-methyl-carbo- PGI2, either concomitantly or in a single pharmaceutical composition made up by mixing extemporaneously the two products in 0.5% hydroxy-propyl-methyl cellulose 400.
Example 4
Mare rats, Crl:CD (SD) Br 130-150 g b.w., fasted for 15 hours, were injected with 0.05 ml 1% carrageenin in sterile saline into the plantar tissue of the right hind paw according to the modified method of Winter: C.A.
Winter et al. (J. Pharmac. Exper. Therap. 1963, 141, 369). One hour after carrageenin injection, the test drugs, indomethacin at 1,3 and 9 mg/kg either alone or plus compound FCE 20700 at 250 llg/kg, were concomitantly administered orally in two separate suspension of 0.5% hydroxy-propyl-methyl cellulose 400.
Another group of rats was treated with 27 mg/kg of indomethacin plus 250 ug/kg of compound FCE 20700 to assess the protection against gastric ulcers, as the inhibiting effect of carrageenin oedema is already maximal at about 9 mg/kg.
The paw volume was plethysmometrically measured immediately after carrageenin injection and 4 hours later. Ulcers were evaluated following the method described in Example 1. The experiments were performed according to a factorial experimental design with two treatments, indomethacin alone and indomethacin plus compound FCE 20700, following the parallel iine bioassay method. The experiments were divided over several days according to the method of complete balanced blocks. Potency ratio (P.R.) and 95% confidence limits were calculated.
The combination tested showed the same anti-inflammatory effect as indomethacin alone: the potency ratio (P.R.) of compound FCE 20700 + indomethacin to indomethacin alone was 1.03 (0.68 - 1.57) proving the lack of interaction between the two compounds.
Moreover concomitant administration of compound FCE 20700 and indomethacin produced markedly fewer ulcerogenic gastric lesions than indomethacin alone. The ulcerogenic effect of the combination: compound FCE 20700 + indomethacin in comparison to indomethacin alone (= 1) gave a P.R. = 0.38 (0.25 0.60). This result means the dosage of indomethacin can be raised about three times without any increase in its ulcerogenic effect.
Analogous results were obtained by administering orally indomethacin, at dosages of 1,3 and 9 mg/kg, and compound FCE 20700, at 250 g/kg, in a single suspension, made up by mixing extemporaneously two separate suspensions of the two compounds in 0.5 % hydroxy-propyl-methyl cellulose 400.
Similar results were also obtained by administering orally, either concomitantly or in a single pharmaceutical composition, a NSAID chosen from acetylsalicilic acid, fenbufen, zomepirac, mefenac, phenylbutazone, feprazone, naproxene, ibufenac, sulindac, tolmetin, ibuprofen, piroxicam and ketoprofen and a prostaglandin or prostacyclin compound chosen from 1 1-deoxy-13,14-didehydro-16(R)-methyl-PGE2, 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl-PGE2, 11 -deoxy-1 3,1 4-didehydro-1 6(R)-methyl-PGE2 methyl ester, 16(S)-fluoro-13,14-didehydro-17-cyclohexyl-PGE2 and ( + )-5-(Z,E)-13,14-didehydro-20-methyl-carbo-PGI2.
Example 5
The ability to induce diarrhoea was evaluated in the rat taking into account the amount and the quality of feces over a 6 hours period after the oral treatment with compound FCE 20700 administered from 0.39 to 100 mg/kg. Up to 1.50 mg/kg feces did not show any variation in appearance and consistency; at 3.2 mg/kg feces were soft and true diarrhoea appeared at 6.4 mg/kg.
Example 6
The inhibition of basal gastric acidic secretion was evaluated as follows:
Male rats weighing 160+10 g were fasted 48 hours but given free access to water. After the first 24 hours fasting an 8% sucrose solution in 0.2% NaCI was substituted for water for 8 hours. The pylorus was ligated under light ether anaesthesia and the animals were killed after 2 hours. Total acidity in gastric juice was titrated against 0.1 N NaOH using bromothymol blue as indicator. Compound FCE 20700 was administered orally in a volume of 0.2 ml/100 g b.w. 15 minutes before pylorus ligation.
The inhibition of basal gastric secretion by FCE 20700 is given in the following table.
ED50(g/kg Dose No. of % Inhibition p.os) and Compound ( > g/kg p.os) animals of secretion fiducial limits for P= 0.95 Control - 15 FCE 20700 6.300 15 68 2,385 2.100 15 49 700 15 26 Formulation examples
Formulation 1:Tablet
Tablets, each containing 50 CLg of the active substance were manufactured by following methods well known perse in pharmaceutical technique:
Composition for 10,000 tablets:
Compound FCE 20700 50 mg
Silica gel 1.5 9 Lactose 2,000 g
Sodium starch glycolate 500 g
Cellulose microcrystalline 600 g
Magnesium lauryl sulphate 100 g
Formulation 2: Suppository
Suppositories were manufactured according to procedures known perse in pharmaceutical technique by adding a suitable amount of semi-synthetic fatty acid esters to 40 CLg of compound FCE 20700 to total 2.5 g.
Formulation 3: Tablet
Composition for 10,000 tablets:
Compound FCE 20700 50 mg ( + )Indoprofen 1,000 g
Lactose 2,000 g
Sodium starch glycolate 500 g
Cellulose microcrystalline 600 g
Magnesium lauryl sulphate 100 g
Silica gel 1.5 9 By proceeding according to methods well known perse in pharmaceutical technique, tablets, each containing 100 mg of ( + )indoprofen and 50 9 of compound FCE 20700, were obtained.
Formulation 4: Tablet
Composition for 10,000 tablets:
Compound FCE 20700 50 mg
Indoprofen 2,000 g
Lactose 2,000 g
Sodium starch glycolate 500 g
Cellulose microcrystalline 600 g
Magnesium lauryl sulphate 100 g
Silica gel 1.5 9 By proceeding according to methods well known perse in pharmaceutical technique, tablets, each containing 200 mg of Indoprofen and 50 p9 of compound 20700, were obtained.
Formulation 5: Soft gelatin capsules
Compound FCE 20700 (50 p9) was dissolved in 200 mg of fractioned coconut oil containing 0.5% lecithin
previously therein dissolved. Indoprofen (200 mg) was suspended in the obtained solution, the resulting
mixture was carefully homogenized and dosed in soft gelatin capsules.
Formulation 6: Soft gelatin capsules
Compound FCE 20700 (50,UWg) was dissolved in 200 mg of fractioned coconut oil containing 0.5 % lecithin
previously therein dissolved. ( + )Indoprofen (100 mg) was suspended in the obtained solution, the resulting
mixture was carefully homogenized and dosed in soft gelatin capsules.
Formulation 7: Suppositories
Suppositories were manufactured according to procedures known perse in pharmaceutical technique by
adding 200 mg of ( + )Indoprofen and a suitable amount of semi-synthetic fatty acid esters to 40 9 of
compound FCE 20700 to total 2.5 g.
Claims (29)
1. A method of inhibiting or reducing the incidence of gastrointestinal side effects in mammals during the treatment with a NSAID, which comprises administering concomitantly or simultaneously to said mammals a NSAID and a gastro-intestinal side-effect-inhibiting or reducing dose of an optically active or racemic prostaglandin or prostacyclin derivative of general formula (I).
wherein
a) Ov , X and W represent, respectively, the C8-C12 substituted monocyclic or C6-C12 substituted bicyclic moiety and the a- and the ca-chain of the compounds disclosed in any one of the following patent documents: GB 1,425,961; GB 1,420,338; GB 1,514,542; GB 1,483,880; GB 1,498,105; GB 1,531,567; GB 1,493,557; BE 843,420; GB 1,583,263; GB 1,599,280; GB-B 2,009,145; GB-B 2,086,373; GB-B 2,085,872; GB-B 2,013,661 and GB-B 2,025,972, and the pharmaceutically or veterinarily acceptable salts thereof; or
b) the meanings of (g, X and Ware such that the general formula (I) encompasses a compound selected from the group consisting of:PGE1; PGE1, a-cyclodextrin clathrate; PGE2, p-cyclodextrin clathrate; (17S)-17,20-dimethyl-trans-#-PGE1; 16,1 6-dimethyl-trans-A2-PGE1, methylester; 15(R)-I 5-methyl-PGE2; ( + ) (16 RS)-15-deoxy-16-hydroxy-16-methyl-PGE1, methylester; 11-deoxy-11a, 16,16-trimethyl-PGE2; ( + )- 11 α, 16α,ss-dihydroxy-1,9-dioxo-1 -(hydroxymethyl)-1 6-methyl-1 3-trans-prostene; ( + )-4,5-didehydro-1 6 phenoxy-ca-tetranor-PGE2, methylester; 16,1 6-dimethyl-PGE2; 4,5,6-trinor-3,7-inter-m-phenylene-3-oxa- PGE1; 11 -deoxy-1 5-methyI-PGE1; 1 9p-hydrnxy-PGE1; 6ss-PGI1; 16-phenoxy-#-tetranor-6ss-PGl1; 16-m-CF3 phenoxy-(o-tetranor-6ss-PG 11 and 1 6-methyl-20-methoxy-PGE2 and, when appropriate, the pharmaceutically or veterinarily acceptable salts thereof.
2. A method according to claim 1, wherein the optically active or racemic prostaglandin or prostacyclin derivative is a compound of formula (la)
wherein
a) R is carboxy or -COOC1-C12 alkyl;
R1 is hydrogen or hydroxy; Ais -C=-C-; one of R2 and R3 is hydrogen and the other is hydroxy; R4 and R5 are independently selected from the group consisting of hydrogen, fluorine and C1-C4 alkyl,
wherein, when one of them is C1-C4 alkyl, the other is hydrogen or fluorine and when one of them is
fluorine, the other is C1-C4 alkyl;;
E is selected from the group consisting of -(CH2)n-, wherein n is an integer of 1 to 6, and - (CH2)nl-O(CH2)n2-, wherein n1 and n2 are independently selected from the group consisting of zero,
1,2and3;
R6 is a member selected from the group consisting of methyl, cycloalkyl containing 3 to 7 ring carbon
atoms and optionally containing one or more ring oxygen or sulphur atoms and phenyl unsubstituted or
substituted by one or more substituents selected from the group consisting of halogen, C1-C4 alkoxy,
phenyl and trihalomethyl;
b) R is -CH2OH, carboxy or -COOC1-C4 alkyl; R1 is hydrogen or hydroxy; Ais -CH=CH-(trans); one of R2 and R3 is hydrogen and the other is hydroxy or C1 -C4 alkoxy;; R4and R5 are both methyl;
E is -O-(CH2)q-, wherein q is zero or an integer up to 5;
R6 is C1-C6 alkyl, C3-C7 cycloalkyl or phenyl unsubstituted or substituted by halogen, C1-C4 alkoxy or
trihalomethyl; or
c) R is carboxy or -COOC1-C6 alkyl;
R1 is hydrogen or C1 -C6 alkyl;
Ais -CH=CH-;
one of R2 and R3 is hydrogen and the other is hydroxy or acetyloxy; one of R4 and R5 is hydrogen or C1-C6 alkyl and the other is hydrogen, C1-C6 alkyl or fluorine;
E is -(CH2)3-;
R6 is -CH3; or a compound of formula (Ib)
wherein
Rd is hydrogen, or C1-C12 alkyl; the symbol ------ represents a single or a double bond, wherein, when the symbol ------ is a double bond, R"3 is a hydrogen atom and R"1 and R"2togetherform an oXogroup,while,whenthesymbol------isasinglebond, R"3 is hydroxy, and one of R"1 and R"2 is hydrogen and the other is hydroxy or acyloxy or R"1 and R"2, taken together, form an oxo group;
A is trans-CH=CH- or -CC-; one of R"4 and Rlb is hydroxy and the other is hydrogen;
R"6 is a member selected from the group consisting of hydrogen, methyl and fluorine;
g is zero, or an integer of 1 to 6;;
R7, when A is trans-CH=CH-, is a cycloalkyl group containing 3 to 7 ring carbon atoms, while, when A is -CC-, R7 is a member selected from the group consisting of methyl, cycloalkyl containing 3 to 7 ring
carbon atoms and phenyl unsubstituted or optionally substituted by one or more substituents selected
from the group consisting of halogen, C1 -C6 alkoxy and trihalomethyl;
or a compound of formula (Ic)
wherein
R8 is hydrogen, C1-C6 alkyl or fluorine;
R'8 is hydrogen or C1-C6 alkyl;
v is zero or an integer up to 4; and R11 is hydrogen or C1-C4 alkyl; or a pharmaceutically or veterinarily acceptable salt thereof.
3. A method according to claim 1, wherein the optically active or racemic prostaglandin or prostacyclin derivative is chosen from the group consisting of: 1 -deoxy-1 3,1 4didehydrn-1 6(R)-methyl-PGE2; 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl-PGE2; 11 -deoxy-1 3,1 4-didehydro-1 6(R)-methyl-PGE2 methyl ester; 11 -deoxy-1 3,1 4-didehydrn-1 6(S)-methyl-PGE2 methyl ester; 16(S)-fluoro-13,14-didehydro-17-cyclohexyl-PGE2; ( + )-5-(Z, E)-l 3,14-d idehyd ro-20-methyl -ca rbo-PG12; + )-5(Z)-1 3,1 Cdidehyd ro-20-methyl-ca rbo-PGlz; + + )-5(E)-13,14-didehydro-20-methyl-carbo-PGl2; 13,14-didehydro-16(R)-methyl-PGE2; 13,14-didehydro-16(S)-methyl-PGE2; 13,1 4-didehydro-1 6(R)-methyl-PGE2 methyl ester; and 13,14-didehydro-16(S)-methyl-PGE2 methyl ester; or, when appropriate, a pharmaceutically orveterinarily acceptable salt thereof.
4. A method according to any one of the preceding claims, wherein the optically active or racemic prostaglandin or prostacyclin derivative is administered to adult humans at a dosage within the range of about 4pwg/die to about 1001lg/die.
5. A method according to claim 1, wherein the optically active or racemic prostaglandin or prostacyclin derivative is the compound 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl-PGE2, methyl ester.
6. A method according to claim 5, wherein the compound 1 1-deoxy-13,14-didehydro-16(S)-methyl-PGE2, methyl ester is administered to adult humans at a dosage within the range of about 4,ag/die to about 500 ,ag/die.
7. A method according to claim 1, wherein the optically active or racemic prostaglandin or prostacyclin derivative is the compound 16(S)4I uoro-1 3,1 4-didehydro-1 7-cyclohexyl-PGE2, methyl ester.
8. A pharmaceutical or veterinary composition for treating inflammatory conditions in mammals, comprising a combination of a therapeutically effective dose of a NSAID and a gastrointestinal side-effect-inhibiting or -reducing dose of a prostaglandin or prostacyclin derivative of formula (I), as reported in claim 1, or one offormula (II)
wherein
Ra is
wherein each of R' and R" independently is hydrogen, C1-C6 alkyl, aryl or heterocyclyl or R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic radical; or Ra is -Y-(CH2)rn-Z,wherein Y is -O- or -NH-, m is an integer up to 4 and Z represents either a group
wherein
R' and R" are as defined above or a group -OR", wherein R"' is chosen from the group consisting of C1-C6 alkyl, cycloalkyl, aryl and heteroaryl;
R'1 is hydrogen or hydroxy; one of R'2 and R'3 is hydroxy and the other is hydrogen; each of R'4 and R'5 is independently hydrogen, C1-C4 alkyl or fluorine; piszero, 1,2or3; R'6 is a') C,-C4alkyl; b') a C3-C7 cycloalkyl ring unsubstituted or substituted by one or more substituents chosen from
halogen, trihalo-C-C6 alkyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl and phenoxy;
c') a phenyl ring unsubstituted or substituted by one or more substituents chosen from the group
consistng of a") C1-C6 alkyl; b") C1-C6 alkoxy; c") trihalo-C1-C6 alkyl; d") halogen; e")
wherein each of Rg and R10 is independently chosen from hydrogen, phenyl, benzoyl, C1-C6 alkyl, and C1-C6 aliphatic acyl; f") phenyl unsubstituted or substituted by one or more substituents chosen from C1-C6 alkoxy and halogen; and g") phenoxy unsubstituted or substituted by one or more substituents chosen from C1 -C6 alkoxy and halogen; and d') a heterocyclic ring unsubstituted or substituted by one or more substituents chosen from halogen, trihalo-C1-C6 alkyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl and phenoxy; provided that, when Ra is a group
wherein R' and R" are as defined above, R'6 is C1-C4 alkyl only; or a pharmaceutically or veterinarily acceptable salt thereof.
9. A pharmaceutical or veterinary composition, according to claim 8, wherein the prostaglandin or prostacyclin derivative is a compound of formula (la), (Ib), (Ic) as defined above in claim 2 or a compound of formula (Ila)
wherein
Ra is -Y-(CH2)m-Z, when Y, m and Z are as defined in claim 8; one of R'2 and R'3 is hydroxy and the other is hydrogen; each of R'4 and R'6 is independently hydrogen, C1 -C4 alkyl or fluorine; p is zero, 1,2 or3; R'6 is a') C1-C4 alkyl;
b') a C3-C7 cycloalkyl ring unsubstituted or substituted by one or more substituents chosen from
halogen, trihalo-C1-C6 alkyl, C1 -C4 alkyl, C1-C4 alkoxy, phenyl and phenoxy;
c') a phenyl ring unsubstituted or substituted by one or more substituents chosen from the group
consisting of a") C1-C6 alkyl; b") C,-C6 alkoxy; c") trihalo-C1-C6 alkyl; d") halogen; e")
wherein each of Re and R10 is independently chosen from hydrogen, phenyl, benzoyl, C1-C6 alkyl, and C1 -C6 aliphatic acyl; f") phenyl unsubstituted or substituted by one or more substituents chosen from C1 -C6 alkoxy and halogen; and g") phenoxy unsubstituted or substituted by one or more substituents
chosen from C1-C6 alkoxy and halogen; and
d') a heterocyclic ring unsubstituted or substituted by one or more substituents chosen from halogen, trihalo-C-C6 alkyl, C1-C4 alkyl, C1 -C4 alkoxy, phenyl and phenoxy; or a pharmaceutically or veterinarily
acceptable salt thereof.
10. A pharmaceutical or veterinary composition, according to claim 8, wherein the prostaglandin or prostacyclin derivative is chosen from the group consisting of 11 -deoxy-1 3,1 4-didehydro-1 6(R)-methyl-PGE2; 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl-PGE2; 11 -deoxy-1 3,1 4-didehydro-1 6(R)-methyl-PGE2 methyl ester; 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl-PGE2 methyl ester; 16(S)-fluoro-13,14-didehydro-17-cyclohexyl-PGE2; + )-5-(Z,E)-1 3,1 4-didehydro-20-methyI-ca rbo-PGlz; ( + )-5-(Z)-13,14-didehydrn-20-methyl-carbo-PGI2; ( + )-5-(E)-13,14-didehydrn-20-methyl-carbo-PGI2; 13,14-didehydro-16(R)-methyl-PGE2; 13,14-didehydro-16(S)-methyl-PGE2; 13,1 4-didehydro-1 6(R)-methyl-PGE2 methyl ester; and 13,1 4-didehydro-1 6(S)-methyl-PGE2 methyl ester; or, when appropriate, a pharmaceutically or veterinarily acceptable salt thereof.
11. A pharmaceutical or veterinary composition, according to claim 8, wherein the prostaglandin or prostacyclin derivative is chosen from the group consisting of 11 -deoxy-13,14-didehydro-16(R)-methyl-PGE2; 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl-PGE2; 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl-PGE2 methyl ester; 11 -deoxy-1 3,1 4-didehydrn-1 6(R)-methyl-PGE2 methyl ester, 1 6(S)4luoro-1 3,1 4-didehydro-1 7-cyclohexyl-PGE2 methyl ester; + + )-5-(Z,E)-13,14-didehydro-20-methyl-carbo-PGl2, 13,14-didehydro-16(R)-methyl-PGE2; 13,14-didehydro-16(S)-methyl-PGE2; 13,14-didehydro-16(S)-methyl-PGE2 methyl ester; and 13,14-didehydro-16(R)-methyl-PGE2 methyl ester or a pharmaceutically or veterinarily acceptable salt thereof, when appropriate, and the NSAID is chosen from the group consisting of acetylsalicylic acid, fenbufen, zomepirac, mefenac, phenylbutazone, ibufenac, sulindac, tolmetin, febrazone, naproxen, ibuprofen, indomethacin, piroxicam, indoprofen, ( + )indoprofen and ketoprofen or a pharmaceutically or veterinarily acceptable salt thereof.
12. A pharmaceutical or veterinary composition, according to claim 8, wherein the prostaglandin or prostacyclin derivative is chosen from the group consisting of: 11 -deoxy-1 3,1 4-didehydro-1 6(S)-methyl- PGE2 methyl ester, 16(S)4luoro-13,14-didehydro-17-cyclohexyl-PGE2 methyl ester, and ( + )-5(Z,E)-13,14 didehydro-20-methyl-carbo-PG12 or a veterina rily or pharmacQutically acceptable salt thereof, when appropriate, and the NSAID is chosen from: indomethacin, acetyl-salicylic acid, piroxicam, indoprofen and ( + ) indoprofen, or a pharmaceutically or veterinarily acceptable salt thereof.
13. A pharmaceutical composition, according to claim 8, containing the compound 11-deoxy-13,14 didehydro-1 6(S)-methyl-PGE2, methyl ester, together with indomethacin.
14. A pharmaceutical composition, according to claim 13, containing the compound 11-deoxy-13,14 didehydro-1 6(S)-methyl-PGE2, methyl ester, together with indomethacin in a 1:15 to 1 :6,000ratio ratio by weight.
15. A pharmaceutical composition for treating inflammatory conditions in mammals, comprising a combination of a therapeutically effective dose of indoprofen or a pharmaceutically acceptable salt thereof and a gastrointestinal side-effect-inhibiting or -reducing dose of the compound 11 -deoxy-13,14-didehydro- 16(S)-methyl-PGE2, methyl ester, or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition, according to claim 15, containing the compound 11-deoxy-13,14- didehydro-16(S)-methyl-PGE2, methyl ester, together withlndoprofen in a 1:40 to 1:20,000 ratio by weight.
17. A pharmaceutical composition, according to claim 16, containing the compound 11-deoxy-13,14 didehydro-16-(S)-methyl-PGE2, methyl ester, at a dosage ranging from about 4 yg to 400 g together with a therapeutic dose of indoprofen ranging from about 200 mg to about 800 mg.
18. A pharmaceutical composition for treating inflammatory conditions in mammals, comprising a combination of a therapeutically effective dose of ( + )indoprofen, or a pharmaceutically acceptable salt thereof, and a gastrointestinal side-effect-inhibiting or -reducing dose of the compound 1 1-deoxy-1 3,14- didehydro-1 6(S)-methyl-PGE2, methyl ester, or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition, according to claim 18, containing the compound 11-deoxy-13,14didehydro-16(S)-methyl PGE2, methyl ester, together with ( + ) indoprofen in a 1:20 to 1:10,000 ratio by weight.
20. A pharmaceutical composition, according to claim 19, containing the compound 1 1-deoxy-13,14- didehydro-1 6(S)-methyl-PGE2, methyl ester, at a dosage ranging from about 4,ag to 400 > 9 together with a therapeutic dose of ( + ) indoprofen ranging from about 100 mg to about 400 mg.
21. A pharmaceutical composition, according to claim 8, containing the compound 11 -deoxy-1 3,14- didehydro-1 6(S)-methyl-PGE2, methyl ester, together with acetylsaiicylic acid.
22. A pharmaceutical composition, according to claim 21, containing the compound 1 1-deoxy-13,14- didehydro-1 6(S)-methyl-PGE2, methyl ester, together with acetylsalicylic acid in a 1:15 to 1 :7,000 ratio by weight.
23. A pharmaceutical composition, according to claim 8, containing the compound 16(S)-fluoro-13,14didehydro-1 7-cyclohexyl-PGE2, methyl ester, together with indoprofen.
24. A pharmaceutical composition, according to claim 8, containing the compound 16(S)-fluoro-13,14 didehydro-17-cyclohexyl-PGE2, methyl ester, together with ( + ) indoprofen.
25. A method according to any one of claims 1-7 wherein the NSAID is one or more of the compounds set out in claim 11.
26. A two-component pack, for use in a method according to any one of claims 1-7 or 25, including a first component comprising a prostaglandin or prostacyclin as set out in any one of claims 1-3, or 5-24 and a separately packaged second component comprising a NSAID.
27. A pack according to claim 26 wherein the NSAID is a compound as set out in any one of claims 11-24.
28. A pack according to claim 26 or 27 wherein the first component and second component are packaged in unit dose form adapted for use in combination to provide dosage rates as set out in any one of claims 4, 6, 17 or 20 or in weight ratios as set out in any one of claims 14, 16, 19 or 22.
29. A composition according to claim 8 substantially as hereinbefore described with reference to any one of the Examples.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08402449A GB2135881A (en) | 1983-03-02 | 1984-01-31 | Method and pharmaceutical compositions for inhibiting or reducing gastrointestinal side effects of non-steroidal anti-inflammatory drugs |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB838305697A GB8305697D0 (en) | 1983-03-02 | 1983-03-02 | Pharmaceutical compositions |
GB08402449A GB2135881A (en) | 1983-03-02 | 1984-01-31 | Method and pharmaceutical compositions for inhibiting or reducing gastrointestinal side effects of non-steroidal anti-inflammatory drugs |
Publications (2)
Publication Number | Publication Date |
---|---|
GB8402449D0 GB8402449D0 (en) | 1984-03-07 |
GB2135881A true GB2135881A (en) | 1984-09-12 |
Family
ID=26285398
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08402449A Withdrawn GB2135881A (en) | 1983-03-02 | 1984-01-31 | Method and pharmaceutical compositions for inhibiting or reducing gastrointestinal side effects of non-steroidal anti-inflammatory drugs |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2135881A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0268388A1 (en) * | 1986-10-22 | 1988-05-25 | Glaxo Group Limited | Anti-inflammatory compositions |
WO1991016886A1 (en) * | 1990-05-03 | 1991-11-14 | G.D. Searle & Co. | Pharmaceutical composition containing ibuprofen and a prostaglandin |
WO1991016895A1 (en) * | 1990-05-03 | 1991-11-14 | G.D. Searle & Co. | Pharmaceutical composition |
WO2000025771A1 (en) * | 1998-11-04 | 2000-05-11 | Synphora Ab | Method for preventing increased iridial pigmentation during prostaglandin treatment |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1463954A (en) * | 1974-02-22 | 1977-02-09 | Upjohn Co | Compositions containing prostaglandins |
GB1463955A (en) * | 1974-01-28 | 1977-02-09 | Upjohn Co | Compositions containing prostaglandins |
GB1463953A (en) * | 1974-01-28 | 1977-02-09 | Upjohn Co | Compositions containing prostaglandins |
GB1466051A (en) * | 1974-01-28 | 1977-03-02 | Upjohn Co | Compositions containing prostaglandins |
GB2013661A (en) * | 1978-01-26 | 1979-08-15 | Erba Farmitalia | 9-deoxy-9 -methylene isosteres of pgi2 |
GB2047094A (en) * | 1979-03-21 | 1980-11-26 | Embrey M P | Controlled release compositions |
-
1984
- 1984-01-31 GB GB08402449A patent/GB2135881A/en not_active Withdrawn
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1463955A (en) * | 1974-01-28 | 1977-02-09 | Upjohn Co | Compositions containing prostaglandins |
GB1463953A (en) * | 1974-01-28 | 1977-02-09 | Upjohn Co | Compositions containing prostaglandins |
GB1466051A (en) * | 1974-01-28 | 1977-03-02 | Upjohn Co | Compositions containing prostaglandins |
GB1463954A (en) * | 1974-02-22 | 1977-02-09 | Upjohn Co | Compositions containing prostaglandins |
GB2013661A (en) * | 1978-01-26 | 1979-08-15 | Erba Farmitalia | 9-deoxy-9 -methylene isosteres of pgi2 |
GB2047094A (en) * | 1979-03-21 | 1980-11-26 | Embrey M P | Controlled release compositions |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0268388A1 (en) * | 1986-10-22 | 1988-05-25 | Glaxo Group Limited | Anti-inflammatory compositions |
AU606082B2 (en) * | 1986-10-22 | 1991-01-31 | Glaxo Group Limited | Anti-inflammatory compositions |
WO1991016886A1 (en) * | 1990-05-03 | 1991-11-14 | G.D. Searle & Co. | Pharmaceutical composition containing ibuprofen and a prostaglandin |
WO1991016895A1 (en) * | 1990-05-03 | 1991-11-14 | G.D. Searle & Co. | Pharmaceutical composition |
US5601843A (en) * | 1990-05-03 | 1997-02-11 | G. D. Searle & Co. | Pharmaceutical tablet composition |
WO2000025771A1 (en) * | 1998-11-04 | 2000-05-11 | Synphora Ab | Method for preventing increased iridial pigmentation during prostaglandin treatment |
Also Published As
Publication number | Publication date |
---|---|
GB8402449D0 (en) | 1984-03-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5312818A (en) | Method of protecting against and/or treating ulcerative gastrointestinal conditions using a thromboxane A2 receptor antagonist and combination useful in preventing and/or treating ulcers and/or inflammation | |
EP2384791B1 (en) | 13,14-dihydro-15-keto-16,16-difluoro-prostaglandin E1 or 13,14-dihydro-15-keto-16,16-difluoro-18-methyl- prostaglandin E1 for treating inflammatory bowel disease | |
EP2175861B1 (en) | Pharmaceutical combination of naproxen with 13,14-dihydro-15-keto-16,16-difluoro-18-methyl-prostaglandin E1 | |
KR101466980B1 (en) | Combined use of prostaglandin compound and proton pump inhibitor for the treatment of gastrointestinal disorders | |
US3928588A (en) | Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors | |
Konturek et al. | Prevention of ethanol and aspirin-induced gastric mucosal lesions by paracetamol and salicylate in rats: role of endogenous prostaglandins. | |
US6159983A (en) | Method and composition for treatment of inflammatory bowel disease | |
Kaminski et al. | The production of experimental cholecystitis by endotoxin | |
Brennan et al. | Prostaglandins in colonic anastomotic healing | |
GB2135881A (en) | Method and pharmaceutical compositions for inhibiting or reducing gastrointestinal side effects of non-steroidal anti-inflammatory drugs | |
US5510382A (en) | Method for composition for treatment of gastric and duodenal disorders | |
US6689788B1 (en) | Method and composition for treatment of inflammatory bowel disease | |
JPH04230326A (en) | Improved therapy for nonsteroidal anti- inflammation | |
US4081553A (en) | Cytoprotective prostaglandins for use in human intestinal diseases | |
US4228161A (en) | Anti-inflammatory combination having reduced ulcerogenicity | |
JPWO2002066030A1 (en) | Pharmaceutical composition comprising diclofenac and ornoprostil | |
US3917828A (en) | Method of reducing the undesirable gastraintestinal effects of prostaglandin synthetase inhibitors | |
EA012724B1 (en) | Use of a benzoyl derivative of 3-aminocarbazole for the treatment of a disorder associated with the production of prostaglandin e2 (pge2) | |
US5889041A (en) | Method for treating an inflammatory pathological condition | |
US4061742A (en) | Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors with PGA compounds | |
US3911124A (en) | Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors | |
Kobayashi et al. | Effect of gefarnate on endogenous prostacyclin, prostaglandin E2 and thromboxane in water-immersed rats | |
DE3404209A1 (en) | Human or veterinary pharmaceutical for the treatment of inflammatory states in humans or mammals | |
Kobayashi et al. | Role of leukotrienes in indomethacin-induced mucosal damage in rats | |
RU2445961C2 (en) | Method and composition for treating mucosal injures |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |