Pharmaceutical compositions comprising a quinazolinone derivative and a myotonolytic agent

a The present invention relates to analgesically and myotonolytically active preparations as well as to methods for inducing analgesia and of treating myotonic conditions, in a subject other than man. Various proposals have been made for the combination of analgesic and myotonolytic agents and a number of such preparations for use e.g. in the treatment of pain are available.

In accordance with the present invention it has now surprisingly been found that co-administration of an analgesically active quinazolinone and a centrally acting myotonolytic results in enhanced and advantageous analgesic as well as myotonolytic activity.

More particularly it has been found that coadministration of an analgesically active quinazolinone and a centrally acting myotonolytic unexpectedly provides greater analgesic potency than the sum of the individual components (super-additive synergism). Equally surprisingly it has also been found that the administration of an analgesically active quinazolinone will potentiate ־ 2

500-5510 the activity of a co-administered centrally acting myotonolytic. 'Moreover, it has been found that e.g. in the dog, co-administration of a guinazolinone and a myotonolytic as aforesaid results in an unexpected and significant raising of the level of the myotonolytic in the blood plasma (increase in bio-availability) compared with the results obtained on administration of the myotonolytic alone.

The co-administration of an analgesically active guinazolinone and a centrally acting myotonolytic, as well as of pharmaceutical preparations containing these components as active agents in combination, is accordingly indicated as being of particular and unforeseen advantage in inducing analgesia, e.g. for the treatment of pain, and also for the treatment of myotonic conditions, e.g. for the treatment of muscle spasm and for muscle relaxation. Co-administration of said components will be seen as being of especial potential in the treatment of conditions in which both analgesic and myotonolytic treatment are simultaneously indicated.

Accordingly in one aspect the present invention provides a pharmaceutical preparation comprising as active agents, a) an analgesically active guinazolinone and b) a centrally acting myotonolytic.

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It will be appreciated that the analgesic and myotonolytic components employed in accordance with this invention may each be known as possessing other pharmacological activity of greater or lesser degree.

Suitable analgesically active quinazolinones for use in the preparations of theinvention are those of formula I,

<img file="IL59786A_D0001.tif" />

wherein is alkyl, ^c₃_g cycloalkyl,.

alkyl substituted by cycloalkyl, ^Cl-5 P°lyhaloalkyl, allyl or propargyl, either R₂ and R^ are the same or different and each is hydrogen, fluorine, chlorine, bromine, C-j_j-alkyl, -alkylthio or -alkoxy, nitro or trifluoromethyl, with the proviso that one only of R₂ and is alkylthio, nitro or trifluoromethyl, or R₂ and R^ together are 6,7-methylenedioxy, and signifies a radical of formula Q,

<img file="IL59786A_D0002.tif" />

־ 4 -

2־59786

500-5510 wherein and Y₂^maY be the same or different and each is hydrogen, fluorine, chlorine, bromine, C₁_₃־alkyl or -alkoxy, or trifluoromethyl, with the proviso that one only of Y^ and Y₂ is trifluoromethyl.

The compounds of the formula I are in general known e.g. from U.K. Patent Specifications No . 1,379,677, Israeli Patent Specification No.31683 and DOS 20 58 722 and have been described as analgesic and anti-inflammatory agents.

In one group of compounds of formula I is C^_^alkyl excluding tertiary alkyl attached to the ring nitrogen atom directly via the tertiary carbon atom or is allyl, propargyl or C^-cycloalkyl.

Preferred compounds of formula I are those wherein is alkyl, particularly isopropyl, either R₂ is hydrogen, chlorine, alkyl particularly methyl, or alkoxy particularly methoxy and most preferably is alkyl, especially 7-alkyl and R₃ is hydrogen, or R₂ and R₃ together are 6,7-methylenedioxy, and is phenyl or halophenyl, especially fluorophenyl and preferably 4-fluorophenyl.

Especially preferred compounds of formula I are.

1-Isopropyl-4-(4-fluorophenyl)-7-methyl2־(IH)-quinaz1) olinone;

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2) l-Isopropyl-4-phenyl-7-methyl-2(1H)-quinazolinone;

3) l-Isopropyl-4-(4-fluorophenyl)-6,7-methylenedioxy-2(1H)quinazolinone;

4) l-Isopropyl-4-phenyl-6,7-inethylenedioxy-2(1H)-quinazol- inone; ־

5) l-Cyclopropylmethyl-4-phenyl-6-methoxy-2 (1H) -quinazolinone; and

6) 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)quinazolinone, compound 1) being the most preferred.

Suitable centrally acting myotonolytics for use in the preparations of the invention are those of formula II,

<img file="IL59786A_D0003.tif" />

wherein X is oxygen; sulphur or imino, n is 1 or 2, is hydrogen, halogen, C^-alkyl, -alkylthio or -alkoxy, trifluoromethyl or hydroxy,

A is a five-membered heterocyclic ring containing at least one heteroatom chosen from nitrogen, oxygen and sulphur and having 2 adjacent carbon atoms common with the benzene ring, with the proviso that the nucleus is other than benzo-2,l,3-thiadiazole, and

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R₂ and R^ are substituents which may be present in ring A, wherein

R2 is attached to a ring carbon atom and is hydrogen, halogen, C^-alkyl, -a-lkoxy or ' “alkylthio,. tri fluoromethyl or hydroxy and ^R3 is attached to a ring nitrogen atom and is hydrogen or C^-alkyl, with the proviso that when A is [c]pyrrole the nitrogen atom of A is substituted by C, .1-4 alkyl.

The compounds of formula II are in general known, e.g. from DOS 2800062, DOS 2653005 and DOS 2416024. The compounds have been stated to have diverse pharmacological activities, e.g. myotonolytic activity.

In the compounds of formula II, A is, for example, [b] or [cjpyrrole, [d]imidazole, [d]pyrazole, [d]triazole, [bj or [c]furan, [c] or [d]isoxazole, [d]oxazole, [c]furazan, [bl or [c]thiophene, [c] or [d]isothiazole, [d]thiazole,

[d] (1,2,3)-thiadiazole, [b] or [c]pyrroline, [b] or [c]dihydrofuran or [b]dihydrothiophene. Preferably A is [b]furan, [b]thiophene, [d]oxazole or [d]triazole, especially [b]furan. Halogen means fluorine, chlorine, bromine or iodine, preferably bromine or chlorine. Alkyl, alkoxy or alkylthio preferably contains 2 carbon atoms, especially 1 carbon atom. R| is preferably other than hydroxy and is

- ר 500-5510 preferably hydrogen, chlorine or methyl. is preferably ortho to the heterocyclic-amino moiety. is preferably alkyl, hydrogen or halogen, especially chlorine. The heterocyclic-amino residue is preferably attached to position 4 or 7 of the bicyclic moiety. When the heterocyclic amino moiety is attached to the 4 position of the bicyclic moiety, then R^, when present, is preferably in the 3 position. RJ,, when present, is preferably alkyl, n is preferably 1.

In the compounds of formula II any carbon containing substituent has preferably 1 carbon atom.

A further group of suitable centrally acting myotonolytics comprises those of formula III,

<img file="IL59786A_D0004.tif" />

wherein each of R, R and R, independently, is

XX *J hydrogen, halogen, C^_^-alkyl, -alkoxy or -alkylthio, nitro, cyano or hydroxy.

The compounds of the formula III are also in general known e.g. from Belgian Patent No. 844532 and DOS 2636309 and have been described as myotonolytics and as anti-tremor and anti-rigor agents.

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In the compounds of formula III halogen is preferably fluorine, bromine or chlorine.

Preferred compounds of formula III are those wherein one of the substituents R£, R^ and R^ signifies hydro5 gen and especially wherein R^ is hydrogen. Preferably one of the substituents RJ, R£ and R^ is other than hydrogen.

is preferably chlorine.

Preferred compounds of formula III are those of formula Illa,

<img file="IL59786A_D0005.tif" />

wherein R£, R^ and have the meanings given above.

Especially preferred compounds of the formula Illa are:1) 5-Chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole; and

2) 5-Chloro-7-methyl-4-(2-imidazolin-2-ylamino)-2,l,3benzothiadiazole.

compound 1) being the most preferred.

A further centrally acting myotonolytic of special use in the preparations of the invention is Y-amino-β-(p9

5510־500 chlorophenyl)-butyric acid, known as baclofen.

The centrally acting myotonolytic, and in particular the compounds of the formula II and III above as well as the compound ץ-amino-β-(p-chlorophenyl)-butyric acid may be employed in free base form or in pharmaceutically acceptable salt form e.g., acid addition salt_farm.Such.salt forms are...

known and include for example the hydrochloride. The activity of any pharmaceutically acceptable salt form will generally be of the same order as that of the respective free base form. As used herein all amounts of such compounds referred to in relation to the compositions of the invention refer to the amount of free base form. Similar considerations apply to weight ratios.

Especially preferred pharmaceutical preparations in accordance with the present invention comprise

a) as analgesically active quinazolinone - l-isopropyl-4(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone, and

b) as centrally acting myotonolytic,'either 5-chloro4־־(2-imidazolin-2-ylamino)-2,1,3-benzothiadazole, or K-amino-β-(p-chlorophenyl)-butyric acid. .

The preparations according to the invention may be prepared in conventional manner using conventional galenical techniques. For example compositions may be prepared by mixing together of the active agents

a) (analgesically active quinazolinone) and b) (centrally acting myotonolytic). They may optionally be admixed with

500-5510 conventional pharmaceutical excipients such as fillers, granulating agents, disintegrating agents, binding agents, lubricating agents, dispersing agents, wetting agents, stabilising agents, dyestuffs and preservatives.

The preparations of the invention are suitably put up in solid form e.g. as tablets, powder, granules and capsules or as suspensions or emulsions. Preferably they are put up in unit dosage form particularly in unit dosage form for oral administration. Such unit dosage forms may contain active, agents a) and b) separately, e.g. in separate layers in a layer or mantle tablet or in split capsules.

Accordingly, in a further aspect the present invention provides a process for the production of a pharmaceutical preparation which comprises formulating an active agent a) as stated above with an active agent b) as stated above and optionally putting up the preparation in unit dosage form.

In yet a further aspect the present invention provides a pack or dispenser-device adapted for the concomitant presentation or administration of an active agent a) and an active agent b) as stated above, said active agents being contained in said pack or dispenser-device apart. Conveniently the active agents a) and b) are contained in the pack or dispenser-device in separated unit dosage forms. Preferably the pack or dispenser-device bears directions

- 500-5510 for the concomitant administration of a pre-determined amount of active agents a) and b). The directions may for example be printed directly on the pack or device.

As already mentioned the combination of a) an analgesically active quinazolinone and b) a centrally acting myotonolytic exhibits an enhanced analgesic activity, which is surprisingly more potent than the sum of the activities of the individual components. This effect may be demonstrated in standard, tests with animals, e.g.

employing the adjuvans arthritis pain test on the rat [A.W. Pircio et al. Europ. J. of Pharmacology 31, 207-215 (1975)]. On oral administration of an agent a) such as l-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)quinazolinone and an agent b) such as 5-chloro-4-(2-imid15 azolin-2-ylamino)-2,l,3-benzothiadiazole in combination at doses of from 1.6 to 4.9 mg/kg and 2.7 to 0.9 mg/kg respectively, a dose dependent synergism is evidenced.

Clinical investigation of the acute analgesic effects of single oral doses also indicates that active agents a) and b) when administered in combination have markedly superior activity than the single component alone.

In one such trial unit doses comprising (i) 1 mg of a centrally acting myotonolytic such as 5-chloro-4-(2imidazolin-2-ylamino)-2,l,3-benzothiadiazole, (ii) 25 mg and (iii) 100 mg of an analgesically active quinazolinone such as l-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)

5510־500 quinazolinone and (iv) 1 and 25 mg of the myotonolytic and the quinazolinone respectively were administered to 48 otherwise healthy subjects with a history of non-migrainous headache [mostly muscle-contraction (tension) headache: some of combined vascular and tension headache] using a double blind, randomised, partial cross-over design. Subjects with classical migraine, known allergy to drugs, disturbances of the gastro-intestinal tract, cardio-vascular, hepatic and renal system, a history of ulcers or drug dependence and those having ingested analgesics, sedatives or other psychotropic drugs within the previous 4 hours were excluded.

Each subject received two of the four identically appearing test doses (partial cross-over design) and the order of administration was randomised. The subjects were instructed to swallow each dose following the onset of headache of moderate or severe but not mild or unbearable intensity at least 1 hour after meals. The second dose was handed out at least 24 hours after administration of the first.

Each subject was required to classify pain intensity (i) with the aid of. a verbal rating and (ii) on a horizontai line (visual analogue scale), 1, 2 and 3 hours after administration of the test dose. Side effects thought to be attributable to the test treatment were also recorded.

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Estimation of analgesia based upon analysis of the returns from the trial in accordance with standard techniques indicate that dose (iv) comprising the combination of active agents a) and b) was a far more effective medication than doses Ci), (ii) or (iii) containing the agents individually. All medications were well tolerated, side effect incidence being very low and randomly distributed among all four doses.

The enhanced myotonolytic activity of active agents a) and b) (e.g. l-isopropyl-4-(4-fluorophenyl)-7-methyl2(1H)-quinazolinone and 5-chloro-4-(2-imidazolin-2-ylamino)2,1,3-benzothiadiazole) in combination as compared with the activity of agent b) alone can also be demonstrated in standard animal tests, for example in the Thalaraonal rigor test in the rat, in which the effectiveness of preadministered oral doses in inhibiting rigidity induced by injection of 7.5 mg of Thalamonal is objectively rated by a trained observer employing an Offner-Dynograph. In this test enhancement of activity in dose dependent manner using e.g. doses of 0.25 mg/kg body weight of agent b) as above in combination with agent a) at weight ratios of from 1:10 to 1:50 [b):a)] is shown for the agents in combination.

The co-administration of active agents a) and b) is accordingly indicated for use in the induction of analgesia e.g. in the treatment of inflammatory or painful conditions such as post-operative pain and headache, as well

500-5510 as in the treatment of myotonic conditions, e.g. in the treatment of muscle spasm and for muscle relaxation.

Co-administration of active agents a) and b) is especially indicated for use in the treatment of painful conditions associated with muscular spasm and acute painful musculo-skeletal conditions e.g. in the treatment of tension or muscle contraction headache, post-operative pain and of rheumatological conditions.

Accordingly in a yet further aspect of the present invention provides a method of inducing analgesia and/or other than man of treating myotonic conditions in a subject^in need of such treatment, which method comprises concomitantly administering to said subject an effective amount of an active agent a) and an active agent b) as stated above. Preferably agents a) and b) are administered orally.

The exact daily dosages of active agents a) and b) for use in the method of the invention will of course depend upon the particular analgesically active quinazolinone and centrally acting myotonolytic employed, as well as upon the mode of administration and the condition to be treated.

I

In general the indicated daily dosage of the analgesic will be of the order of from 40-90% of the standard daily dosage used for inducing analgesia. For the myotonolytic component the daily dosage will be of the order of from 209.0%־ of the standard daily dosage used in treating

- 500-5510 myotonic conditions.

A suitable indicated daily dosage is in the range of from about 25 to about 600 mg, and preferably from about 25 to about 400 mg of active agent a).

A preferred daily dosage using the preferred active agent l-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone is from about 25 to 200 mg.

Conveniently the active agents are administered in sustained release form or alternatively in divided doses 2 to 4 times a day containing e.g. 25, 50, 100 or 200 mg of active agent a), or in a single dose once a day containing e.g. 25 or 50 mg of active agent a).

An indicated weight ratio of active agent a) to active agent b) is from about 5:1 to about 100:1 preferably from 25:1 to 100:1. For the preferred active agent 1-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone a particularly suitable ratio is from about 10:1, preferably about 20:1 and more preferably about 25:1 to about 50:1. A further suitable ratio is from about 10:1 preferably about 20:1 to about 30:1. The most preferred ratio is about 25:1.

The following Examples are illustrative of compositions for use in the invention.

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EXAMPLE 1: Tablet suitable for oral administration

Tablets containing the ingredients indicated below may be prepared by conventional techniques and are useful for oral administration once or twice a day in the treatment of pain and/or muscle spasm.

<td> Ingredient</td><td> Weight (mg)</td>

<td> l-isopropyl-4-(4-fluorophenyl)7-methyl-2(1H)-guinazolinone</td><td> 100.00</td>

<td> l-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole</td><td> 2.288</td>

<td> hydrochloride</td><td> (= 2.0 mg base)</td>

<td> Polyoxyethylenepolypropylenepolymer (Pluronic® F68)</td><td> 8.00</td>

<td> Corn Starch</td><td> 20.00</td>

<td> Gelatine</td><td> 12.00</td>

<td> Cross-linked polyvinylpyrrolidon</td><td> 30.00</td>

<td> Lactose</td><td> 65.712</td>

<td> Magnesium stearate</td><td> 2.00</td>

<td></td><td> 240.000</td>

If desired the tablet may be shaped so that it may be easily divided into two.

־ 17

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EXAMPLE 2: Tablet suitable for oral administration

Tablets containing the ingredients indicated below may be prepared by conventional techniques and are useful for oral administration once or twice a day in the treatment of pain and/or muscle spasm.

<td> Ingredient</td><td> Weight (mg)</td>

<td> l-isopropyl-4-(4־fluorophenyl)7-methyl-2(1H)-quinazolinone</td><td> 50.00</td>

<td> 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole hydrochloride</td><td> 2.288 (= 2.0 mg base)</td>

<td> Tartaric acid</td><td> 2.00</td>

<td> Hydroxypropylcellulose</td><td> 1.70</td>

<td> Polyoxyethylenepolypropylenepolymer (Pluronic® F 68)</td><td> 4.00</td>

<td> Sodium carboxymethyl cellulose</td><td> 11.00</td>

<td> Anhydrous lactose</td><td> 40.10</td>

<td> Microcrystalline cellulose</td><td> 53.012</td>

<td> Magnesium stearate</td><td> .0.9 .0 165.00 mg</td>

If desired the tablet may be shaped so that it may be easily divided into two.