Pharmaceutical compositions comprising a quinazolinone derivative and a myotonolytic agent

(54) Name Pharmaceutical preparation containing a quinazolinone and 5-chloro-4- (2-imidazolin-2-yl-amino) -2,1,3-benzothiadiazole (56) Published publications: --- (57) Summary:

Composition with improved analgesic and myotonolytic activity containing as active substances

a) an analgesically active quinazolinone and

b) a centrally acting myotonolytic agent.

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The invention relates to analgesically and myotonolytically active preparations.

Various combinations of analgesic and myotonolytic agents are known and are available for the treatment of pain.

It has now surprisingly been found that the concomitant administration of an analgesically active quinazolinone and a centrally active myotonolytic agent results in both an enhanced and beneficial analgesic effect as well as a myotonolytic effect.

In particular, it has been found that the concomitant administration of an analgesically active quinazolinone and a centrally active myotonolytic drug surprisingly produces a stronger analgesic effect than the sum of the effects of the individual components (superadditive synergism). Similarly, it has surprisingly been found that the administration of an analgesically active quinazolinone potentiates the action of a co-administered centrally active myotonolytic drug. In addition, it has been found that, for example, in dogs, the concomitant administration of a quinazolinone and a myotonolytic agent, as stated above, results in an unexpected and significant increase in the level of the myotonolytic agent in blood plasma (enhancement of bioavailability) relative to the administration of myotolone alone.

Thereby, the concomitant administration of analgesically active quinazolinone and a centrally active myotonolytic drug, as well as administration of pharmaceutical preparations containing these components as active substances in combination, leads to a special and unpredictable benefit in the onset of analgesia, for example in the treatment of pain and likewise the treatment of myotonic conditions, for example in the treatment of muscle spasms and for muscle relaxation. The simultaneous administration of said components is attributed to a special potential in the treatment of conditions which require simultaneous analgesic and myotonolytic treatment.

The present invention thus relates to a pharmaceutical composition which contains as active substances

(a) an analgesically active quinazolinone; and

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b) a centrally active myotonolytic agent.

It is believed that the analgesic and myotonolytic components used in the present invention may exhibit other pharmacological effects.

Suitable analgesically active quinazolinones are compounds of formula I:

<img file="SE445708B_D0001.tif" />

wherein R- is C - ^ alkyl alkyl, Cjg cyk cycloalkyl, C - alkyl alkyl substituted by Cgg cycloalkyl, C C₁- polyhaloalkyl, allyl or propargyl,

R₂ and R 2 are the same or different and each is hydrogen, fluoro, chloro, bromo, C 1-6 alkyl, alkylthio or alkoxy, nitro or trifluoromethyl with the proviso that only one of the substituents R₂ and R 2 is alkylthio, nitro or trifluoromethyl, or

R₂ and R 2 together are 6,7-methylenedioxy, and

Rjj is a residue of the formula Q:

<img file="SE445708B_D0002.tif" />

wherein Y ^ and Y.₂ are the same or different and each is hydrogen, fluorine, chlorine, bromine, C1-4 alkyl or alkoxy or trifluoromethyl, however, at most one of the substituents and Y₂ is trifluoromethyl.

The compounds of formula I are generally known, for example from British Patent Specifications 1,248,450 and 1,579,677, DOS 1,248,450 and 2,058,722. They have an analgesic and anti-inflammatory effect.

In a group of compounds of formula I, R 1 is C 1-6 alkyl except for tert, alkyl, in which the tertiary carbon atom is bonded directly to the ring nitrogen atom, or -allyl, propargyl or C 1-4 cycloalkyl.

Preferred compounds of formula I are those compounds wherein:

Is alkyl, especially isopropyl,

R₂ is hydrogen, chlorine, alkyl, especially methyl, or alkoxy, especially

8002642-0 methoxy, especially alkyl, especially 7-alkyl, and

R 2 is hydrogen or

R₂ and R 1 together are 6,7-methylenedioxy and

Is phenyl or halophenyl, especially fluorophenyl and especially 4-fluorophenyl.

Preferred compounds of this group are:

1) 1-isopropyl-4- (4-fluorophenyl) -7-methyl-2 (1H) -quinazolinone;

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

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

4) 1-isopropyl-4-phenyl-6,7-methylenedioxy-2 (1H) -quinazolinone;

5) 1-cyclopropylmethyl-4-phenyl-6-methoxy-2 (1H) -quinazolinone and

6) 1- (2,2,2-trifluoroethyl) -4-phenyl-6-chloro-2 (1H) -quinazolinone.

Compound 1) is particularly preferred.

As centrally active myotonolytics come compounds of formula II

<img file="SE445708B_D0003.tif" />

considering, wherein

X is acid, sulfur or imino group, n is 1 or 2 and

R₁ is hydrogen, halogen, C · ^alk alkyl, C₁__in)-alkoxy, C-_L__in)-alkylthio, trifluoromethyl or hydroxy, and

A is a 5-membered heterocycle which has two adjacent carbon atoms in common with the benzene ring and contains oxygen, nitrogen or sulfur together with the condensed benzene ring, but which is not, however, benzo-2, 1,3 ~ thiadiazole,

R? ' and R 2 'are bonded to a substitutable ring A, wherein R' 'bonded to a ring carbon is hydrogen, halogen, C 1-6 alkyl, alkoxy, C_in)-alkylthio, trifluoromethyl or hydroxy or R^{i * * * * * * * * x}bonded to a ring nitrogen atom is hydrogen or C₁__ij-alkyl, with the proviso that when A is / cpyrrole its nitrogen atom is substituted against C-_L__J)alkyl.

The compounds of formula II are generally known, for example, from DOS 2,800,062, 2,653,005 and 2,416,024. The compounds possess pharmacological action of various types, for example, they are myo8002642-0 tonolytically active.

For example, in the compounds of formula II, A may mean Δ7 or / cjpyrrole, fdj imidazole, / cijpyrazole, / d / triazole, Zb7 or / cjfuran, [c] or / aisoxazole, / jdjoxazole, , / Vtiazole, / α7 (1,2,3-thiadiazole), / b / or / c / pyrroline, / bell / cdihydrofuran or / b / dihydrotiophene. A is preferably / b7furan, / Vtiophene, / d / oxazole or Z37triazole, especially Zb7furan. Halogen can mean fluorine, chlorine, bromine and iodine, preferably bromine or chlorine. Alkyl, alkoxy or alkylthio preferably contain 2 carbon atoms, especially 1 carbon atom. Preferably, R 2 / does not mean hydroxy and is more particularly hydrogen, chlorine or methyl. is preferably in ortho position relative to the heterocyclylamine residue. Rg 'preferably means alkyl, hydrogen or halogen, especially chlorine. The heterocyclylamine residue is preferably in the 4 or 7 position of the ring system. If the heterocyclylamine residue is in the 4 position, R 6 'is preferably in the 3 position. Presently is preferably alkyl, n is preferably 1.

A further group of suitable centrally acting myotonolytics comprises compounds of formula III:

<img file="SE445708B_D0004.tif" />

hrs

<img file="SE445708B_D0005.tif" />

III wherein

Ri, ^R2 ^ocil 3 ° depending on each other are hydrogen, halogen, alkyl, alkoxy or alkylthio, nitro, cyano or hydroxy. The compounds of formula III are generally known, for example, from Belgian Patent 844,532 and DOS 2,636,309. They act as myotonolytics, antitremor and anti-rigor agents.

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

The preferred compounds of formula III are those wherein one of the substituents R R, R R ^och R 2 is hydrogen and in particular

Rg hydrogen. Preferably, one of the substituents R ^, Rg and R ^ has a different meaning from hydrogen. R 2 is preferably chlorine.

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Preferred compounds of formula III are compounds of formula IIIa:

<img file="SE445708B_D0006.tif" />

N ^^ NH

Illa wherein R 2, R 2 and R 2 are as defined above.

Particularly preferred compounds of formula IIla are:

I) 5-Chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole and

2) S-Chloro-T-methyl-1- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole.

Compound 1) is particularly preferred.

A further centrally active myotonolytic agent is β-amino- (p-chlorophenyl) butyric acid, known by the name Baclofen.

The centrally active myotonolytic, and especially the compounds of formulas II and III, as well as the / -amino- / 5- (p-chlorophenyl) butyric acid, can be used in the form of the free bases or in the form of pharmaceutically acceptable salts, for example acid addition salts. Such salt forms are known and include, for example, the hydrochloride. The pharmaceutically acceptable salts generally have on the order of magnitude the same activities as the corresponding free bases. All amounts of these compounds refer to the amount of free base hereinafter. The same is true for the weight20 conditions.

Particularly preferred are pre-pharmaceutical preparations which are

a) Analgesically active quinazolinone contains 1-isopropyl-4

- (4-fluorophenyl) -7-methyl-2 (1H) -quinazolinone and

(b) containing either centrally active mynotonolytic either

5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole, or β-amino-β- (p-chlorophenyl) butyric acid.

The compositions of the invention can be prepared in a manner known per se using the customary procedure in gal1 eti in various processes. For example, the preparations may be prepared by one

8002642-0 mixes the active substance a) (analgesically active quinazolinone) and b) (centrally active myotonolytic drug). In addition, conventional pharmaceutical additives such as fillers, granulating agents, disintegrating agents, binders, lubricants, suspending agents, crosslinking agents, stabilizers, dyes and preservatives may be involved.

The compositions of the invention are preferably in solid form, for example as tablets, powders, granules and capsules, or as suspensions or emulsions. They are preferably in the form of a unit dose, especially a unit dose for oral administration. This unit dose may comprise the active substances a) and b) spaced apart, for example in spaced layers in a layered or sheathed tablet.

Accordingly, the invention has for its object to provide a process for the preparation of a pharmaceutical preparation, characterized in that it combines an active substance a) as indicated above with an active substance b) as mentioned above and optionally transfers the preparation into a pharmaceutical composition. unit dose.

A further aspect of the invention consists in a package or dosing device suitable for simultaneously providing or dosing an active substance a) and an active substance b) as stated above, these active substances being separated in this package or dosing device. Preferably, the active substances a) and b) are present in the package or dosing device in separate unit doses. The package or dosing device preferably has instructions for the simultaneous administration of a specified amount of the active substances a) and b). For example, the instructions may be printed directly on the package or dosing device.

As already mentioned, the combination of an a) analgesically active quinazolinone and b) a centrally active mynotonolytic exhibits an enhanced analgesic effect which surprisingly substantially exceeds the sum of the effects of the individual components. This effect can be demonstrated in standard animal tests, for example in rat adjuvant arthritis pain test. Pircio et al., Europ. J. of Pharmacology 51, 207-215 (1975) J- After oral administration of a combination of an active substance a), for example, 1-isopropyl-4- (4-fluorophenyl) -7-methyl-2 (1H) -quinazolinone, and an active substance b), for example 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,1-benzothiadiazole, in doses of 1.6 to 4.9 mg / kg

8002642-0 respectively 2.7 to 0.9 mg / kg a dose-dependent synergism can be established.

Clinical examination of the acute analgesic effect of oral unit doses also shows that the administration of the active substances a) and b) in combination gives a stronger effect than the individual components.

In such an experiment unit doses were tested which consisted of: i) 1 mg of a centrally active myotonolytic, for example 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole, ii) 25 mg iii) 100 g of an analgesically active quinazolinone, for example 1-isopropyl-4- (4-fluorophenyl) -7-methyl-2 (1H) -quinazolinone and iv) 1 mg of the myotonolytic and 25 mg of the quinazolinone, of 48 healthy individuals with headaches not caused by migraines / mostly muscle contraction (tension) headaches; some with combined vascular and tension headaches ^ with double-blind specimens and in randomized and partially crossed device. Individuals with classic migraine, known drug allergy, disorders of the digestive organs, cardiovascular, hepatic and renal systems with a history of abscesses or drug dependence and those who had taken analgesics, sedatives or other psychotropic agents within the previous four hours were excluded from the trials.

Each test subject received 2 of the 4 identical test doses (partially crossing device), and the order of administration was changed at random. After onset of moderate or stronger headache but not mild or incurable intensity, patients swallowed the first dose for at least 1 hour after meals. The second dose was not less than 30 hours after the first dose.

Each subject rated their pain intensity using:

i) a verbal evaluation scale and ii) a horizontal line (visual analogue scale)

1, 2 and 3 hours after taking the test dose. Adverse reactions that could be attributed to the trial were also recorded.

The evaluation of analgesia, using standard methods, shows that the dose iv) containing the combination of the active substance a) and the active substance b) resulted in a significantly more effective treatment than the doses i), ii) or iii) which contained the individual components. All treatments are tole

8002642-0 ₈ was well managed, the occurrence of side effects was small and arbitrarily distributed over the four doses.

The enhanced myotonolytic action of the combination of the active substances a) and b), for example, 1-isopropyl-4- (4-fluorophenyl) -7-methyl-2 (1H) -quinazolinone and 5-chloro-4- (2- Imidazolin-2-ylamino-2,1,3-benzothiadiazole in relation to the action of the active substance alone can also be shown in standard animal tests. Thus, for example, in the rat thalamonal stiffness test, the effect of pre-orally administered doses on inhibition of stiffness induced by 7 mg / kg ip talamonal, objectively assessed by trained observers with the help of the Offner dynographer. In this test, for the combination of active substances, a dose-dependent enhancement of efficacy is determined, for example, at doses of 0.25 mg / kg body weight of the active substance b) as mentioned above in combination with the active substance a) in a weight ratio of 1:10 to 1:50 fb): a) 7.

The concomitant administration of the active substances a) and b) is similarly suitable for the generation of analgesia, for example in the treatment of inflammatory and painful conditions such as post-operative pain and headache, such as in the treatment of myotonic conditions, for example in the treatment of muscle spasms and for muscle relaxation.

The concomitant administration of the active substances a) and b) is particularly useful in the treatment of pain conditions associated with muscle spasms and acute painful musculoskeletal conditions, for example in the treatment of tension or muscle contraction headaches, postoperative pain and rheumatological conditions.

According to a further aspect of the present invention, there is thus provided a method for generating analgesia and / or treating myotonic conditions, which is characterized by simultaneously administering effective doses of the above defined active substances a) and b). Preferably, the substances a) and b) are administered orally.

The daily doses of the active substances a) and b) for the above uses will, of course, depend on the nature of the used analgesically active quinazolinone and the centrally active myotonolytic, as well as on the mode of administration and the type of treatment. In general, the daily administered dose of the analgesic is 40 -90 $ of the usual daily dose for the analgesic indication. For the myotonolytic component, the daily dose amounts to $ 20-90 of the usual daily dose provided for the myotonic indication.

A suitable daily dose of the active substance a) is about 25 to 5,600 mg, preferably about 25 to about 400 mg.

A preferred daily dose of the preferred active substance 1-isopropyl-4- (4-fluorophenyl) ~ 7 ~ methyl-2 (1H) -quinazolinone is about 25 to 200 mg.

Preferably, the active substances are administered in a delayed or in aliquots 2-4 times daily in amounts of Examples 10, 25, 50, 100 or 200 mg of the active substance a) or in a unit dose once daily in amounts of, for example, 25 or 50 mg of the active substance.

The weight ratio of the active substances a) to b) is between about 5: 1 and about 100: 1, preferably between 25: 1 and 100: 1.

A particular weight ratio of the preferred active substance 1-isopropyl-4- (4-fluorophenyl) -7-methyl-2 (1H) -quinazolinone is between about 10: 1, preferably about 20: 1, especially about 25: 1 and about 50: 1. Another suitable weight ratio is between about 10: 1, preferably about 20: 1 and about 30: 1. Particularly preferred is the weight ratio of 25: 1.

The following examples illustrate the invention.

Example 1: Tablets for oral administration

Tablets containing the ingredients listed below may be prepared in a manner known per se, and may be taken once or twice daily to treat pain and / or muscle spasms.

Composition 1-isopropyl-4- (4-fluorophenyl) -7-methyl-2 (1H) -quinazolinone

5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole hydrochloride

Polyoxyethylene-polyoxypropylene polymer (Pluronic ® F 68)

cornstarch

Gelatine

Polyvinylpyrrolidone, cross-linked

Lactose

Magnesium

Weight (mg)

100,0

2,288 (= 2.0 mg base)

8,0

20,0

12,0

30,0

65,712

2,0

240,0

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The tablets may have a breaking instruction, which allows for division.

EXAMPLE 2: Tablets for oral administration

Tablets containing the ingredients listed below may be prepared in a manner known per se, and may be taken once or twice daily to treat pain and / or muscle spasms.

Composition Weight (mg)

1-isopropyl¹1- (4-Fluorophenyl) -7-methyl2 (1H) -quinazolinone

5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole hydrochloride

TA

Hydroxipropyleellulosa

Polyoxyethylene-polyoxypropylene polymer (Pluronic © F 68)

Sodium carb oxime tulle starch

Lactose, anhydrous

Cellulose, microcrystalline

Magnesium t earate

100,0

2,288 (= 2.0 mg base)

2,00

1,7

4,0

11,0

40,10

53,012 __θχ9 ____

165.00 mg

The tablets may have a breaking instruction, which allows for division.

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