Abstract:
A pharmaceutical compositions with hypotensive effects which comprise a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, ##STR1## wherein R 1  is formula (II) ##STR2## wherein R 4  and R 5  each represent hydrogen, hydroxy, nitro at the same time 
     R 2  and R 3  are hydrogen, or 
     R 1  are 3-chloro-6-pyridazinylamino, 3-methyl-6-pyridazinylamino or 3-carbamoyl-6-pyridazinylamino, and at the same time 
     R 2  and R 3  form together formula (III), ##STR3## wherein R 6  is C 1-4  alkyl group, 
     R 7  is hydrogen or a C 1-4  alkyl group, and 
     n is an integer of 1 to 3, or 
     R 2  and R 3  form together a group of the general formula (IV), 
     
       =Q-R.sup.8                                                 (IV) 
     
     wherein 
     Q is C 5-7  cycloaliphatic, and 
     R 8  is hydrogen, a C 1-4  alkoxycarbonyl or a C 2-4  alkyl, 
     and a compound of formula (V) or a pharmaceutically acceptable acid addition salt thereof, ##STR4## wherein R 9  is naphthyl, 4-indolyl or 4-morpholino-1,2,5-thiadiazol-3-yl group or ##STR5## .

Description:
FIELD OF THE INVENTION 
     This invention relates to pharmaceutical compositions with increased hypotensive effects as well as to a process for the preparation thereof. 
     BACKGROUND OF THE INVENTION 
     Compounds which exert a blocking effect on β-adrenergic receptors are have found increasingly widespread acceptance in the treatment of hypertension (Knoll J.: Gyogyszertan, Medicina, p. 282, 1971); S. Wolfson: Drugs in Cardiology Vol. I, pp. 165-179, (Stratton Intercont. Med. Book Corp., New York, 1975; R. P. Ahlquist: Progress in Drug Research 20, pp. 27-42, (Birkhauser Verlag, Basel, 1976). Their use is, however, restricted by several contraindications, such as respiratory disease (bronchial asthma), cardiovascular disease (bradycardia, heart block), renal inflammation and metabolic disorder, e.g. diabetes mellitus and liver disease (R. P. Ahlquist: Beta-Adrenergic Blocking Agents in the Management of Hypertension and Angina Pectoris, pp. 1-81, Raven Press, New York, 1974). The dosages required in the treatment of hypertension are 4 to 8 times higher than those provoking antiarrhythmic effects (A. Ablad: Drugs, 11, Suppl. 1, pp. 127-134, 1976), which may give rise to the appearance of more severe side effects, such as bronchial spasms, cardiac disorders, central nervous-system effects (hallucinations, insomnia, depression), Raynaud-syndrome and gastrointestinal disorders (D. J. Greenblatt: Drugs, 7, 118, 1974; S. A. Stephen: Am. J. Cardiol. 18, 463, 1966). A further characteristic feature of β-receptor blocking agents is that, beyond a certain limit, their therapeutic effect cannot be incresed by increasing the dosage (P. Kincaid-Smith: Beta-Adrenergic Blocking Agents in the Management of Hypertension and Angina Pectoris, pp. 9-19 (Raven Press, New York, (1974). 
     OBJECT OF THE INVENTION 
     The invention has the object of providing a novel pharmaceutical composition, free from the disadvantages discussed above, which exerts beneficial therapeutic effects in much lower dosages than the hitherto known ones and causes much weaker undesired side effects, if any, than conventional β-receptor blocking agents. 
     DESCRIPTION OF THE INVENTION 
     The invention is based on the surprising discovery that compounds of formula (I), below, which, when applied alone, exert a blocking effect on the biosynthesis of noradrenaline (decarboxylase, tyrosine hydroxylase and dopamine-β-hydroxylase blocking effects, see Zs. Huszti: Biochem. Pharm. 22, 2253 (1973) and Belgian Pat. No. 868,027), considerably potentiate the hypotensive effect of the β-adrenergic receptor blocking agents having formula (V), infra. 
     Based on the above, the invention provides pharmaceutical compositions with increased hypotensive effects, comprising a compound of formula (I), ##STR6## wherein R 1  is a group of formula (II), ##STR7##  (wherein R 4  and R 5  each can be hydrogen, hydroxy, nitro or C 1-4  alkoxycarbonyl), and at the same time 
     R 2  and R 3  are each hydrogen, or 
     R 1  is 3-chloro-6-pyridazinylamino, 3-methyl-6-pyridazinylamino or 3-carbamoyl-6-pyridazinylamino group, and at the same time 
     R 2  and R 3  form together a group of formula (III), ##STR8## wherein R 6  is C 1-4  alkyl, 
     R 7  is hydrogen or C 1-4  alkyl, and 
     n is an integer of 1 to 3, or 
     R 2  and R 3  form together a group of formula (IV), 
     
         =Q-R.sup.8                                                 (IV) 
    
     wherein 
     Q is C 5-7  cycloaliphatic group, and 
     R 8  is hydrogen, C 1-4  alkoxycarbonyl or C 2-4  alkyl, 
     and a compound of formula (V) or a salt thereof, ##STR9## wherein R 9  is naphthyl, 4-indolyl or 4-morpholino-1,2,5-thiadiazol-3-yl group or a group of formula (VI), ##STR10## wherein R 11 , R 12  and R 13  are the same or different and represent hydrogen, halogen, hydroxy, C 1-4  alkyl, C 1-4  alkoxy, C 2-4  alkenyloxy, 2-methoxyethyl or acetic amide, with the proviso that when two of R 11 , R 12  and R 13  are hydrogen, the third substituent is other than hydrogen, and when two of R 11 , R 12  and R 13  are acetic amide, the third substituent is other than acetic amide, and 
     R 10  stands for C 1-4  alkyl, in admixture with one or more conventional pharmaceutical additives. 
     The invention relates further to a process for the preparation of novel pharmaceutical compositions with increased hypotensive effects. According to the invention a compoun of formula (I) is admixed with a compound of formula (V) and the mixture is converted into pharmaceutical dosage forms, such as tablets, suppositories, etc., utilizing conventional pharmaceutical additives. 
     A preferred pharmaceutical composition according to the invention comprises 1 part by weight of 1-(4-indolyloxy)-3-isopropylamino-2-propanol hydrochloride (further: pindolol) in admixture with 20 parts by weight of 3-hydroxy-4-nitro-benzyloxyamine hydrochloride (further: compound 11,130). 
     Another preferred composition comprises 1 part by weight of pindolol in admixture with 40 parts by weight of 2-hydroxy-5-carbomethoxy-benzyloxyamine hydrochloride (further: compound 11,121). 
     Other preferred compositions according to the invention contain as β-adrenergic receptor blocking agent a compound listed in Table 1, together with a noradrenaline biosynthesis blocking compound as listed in Table 2 or a salt thereof. 
     
                       TABLE 1______________________________________                  International nameChemical name          or protected name______________________________________1-(1-Naphthyloxy)-3-isopropylamino-                  Propranolol2-propanol hydrochloride1-(2,5-Dichlorophenoxy)-3-tert.-butyl-                  Tobanumamino-2-propanol hydrochloride1-(4-[2-Methoxyethyl]-phenoxy)-3-iso-                  Metoprololpropylamino-2-propanol hydrochloride1-(4-Aminocarbonylmethyl-phenoxy)-3-iso-                  Atenololpropylamino-2-propanol hydrochloride1-(2-Allyloxy-phenoxy)-3-isopropyl-                  Oxprenololamino-2-propanol hydrochloride______________________________________ 
    
     
                       TABLE 2______________________________________                   Code No.Chemical name           (Compound)______________________________________N.sup.1 -(3-Chloro-6-pyridazinyl)-N.sup.2 -(1-carbethoxy-                   11,4732-propylidene)-hydrazineN.sup.1 -(3-Chloro-6-pyridazinyl)-N.sup.2 -(1-carbethoxy-                   11,5112-cyclohexylidene)-hydrazineN.sup.1 -(3-Chloro-6-pyridazinyl)-N.sup.2 -(2,2-methyl-                   11,5881-cyclohexylidene)-hydrazineN.sup.1 -(3-chloro-6-pyridazinyl)-N.sup.2 -(1-tert.-                   11,653carbobutoxy-2-propylidene)-hydrazineN.sup.1 -(3-Carbamoyl-6-pyridazinyl)N.sup.2 -(1-tert.-                   11,702carbobutoxy-2-propylidene)-hydrazineN.sup.1 -(3-Methyl-6-pyridazinyl)-N.sup.2 -(1-tert.-                   11,741carbobutoxy-2-propylidene)-hydrazine______________________________________ 
    
     The compositions according to the invention contain the β-receptor blocking agents in lower dosages than the conventional dosage, thus the undesired side effects of these compounds can be suppressed considerably. Another advantage of the new compositions is that the noradrenaline biosynthesis blocking compounds applied potentiate the hypotensive effects of the β-receptor blocking agents, i.e. the hypotensive effect of the composition greatly exceeds the algebraic sum of the activities of the individual constituents. 
     The favorable effects of the new hypotensive compositions according to the invention are demonostrated by the pharmaceutical test results described below. 
     (1) Determination of the hypotensive effect on awake rats suffering from genetic hypertension 
     The tests were performed according to the method of Eaton (J. C. R. Eaton: Brit. J. Pharm. 54, 282 (1975) with the modification that the blood pressure and cardiac frequency of Wistar-Okamoto rats were measured with an automatic five-channel instrument. The compounds and dosages applied, as well as the test results are listed in Tables 3 to 6. 
     The data of Tables 3 to 5 demonstrate the beneficial results obtained by administering pindolol in combination with a noradrenaline biosynthesis blocking agent. 
     
                       TABLE 3______________________________________Effect of pindolol, compound 11,130 and combinations thereof onthe blood pressure of genetically hypertensive awake rats        Blood pressure (mm Hg)  Dosage                              AfterCom-   mg/kg   No. of  Basal After  After  24pound  p.o.    animals value 2 hours                               5 hours                                      hours______________________________________Pindolol  0.25    10      182.2 180.8  164.9  183.4                  ±23.4                        ±48.2                               ±28.7                                      ±46.2Pindolol  0.25     5      161.0 140.0* 146.0  153.011,130 20              ±10.8                        ±11.7                               ±12.4                                      ±20.8Pindolol  0.5     15      165.0 161.4  160.5  150.5                  ±14.2                        ±18.6                               ±22.2                                      ±22.4Pindolol  0.5     15      173.2 128.2****                               123.6****                                      159.311,130 20              ±17.6                        ±34.7                               ±24.1                                      ±26.2Pindolol  1.0     10      164.4 135.0***                               135.0***                                      151.1                  ±13.8                        ±20.5                               ±16.9                                      ±22.2Pindolol  5.0     10      172.5 154.5***                               124.5****                                      161.0                  ±14.4                        ±8.0                               ±15.0                                      ±20.511,130 20       5      174.0 183.0  176.0  172.0                  ±12.9                        ±18.2                               ±10.2                                      ±14.4______________________________________ * = 0.05 &gt; p &gt;  0.02 ** = 0.02 &gt; p &gt; 0.01 *** = 0.01 &gt; p &gt; 0.001 **** = 0.001 &gt; p p = statistical significance (R.A. Fisher: &#34;Statistical Methods for Research Workers&#34;, Oliver and Boyd, London, 1950) ED.sub.30% p.o. ˜ 5 mg/kg of pindolol ED.sub.30% p.o. ˜ 0.5 mg/kg of pindolol + 20 mg/kg of 11,130 (ED.sub.30% is the dosage which decreases the blood pressure by 30% related to the value before treatment) 
    
     The test results listed in Table 3 indicate that the ED 30%  of pindolol (5 mg/kg) can be decreased to one-tenth upon combining this compound with 11,130. 
     
                       TABLE 4______________________________________Effect of pindolol, 11,121 and combinations thereof on theblood pressure of genetically hypertensive awake rats        Blood pressure (mmHg)  Dosage                              AfterCom-   mg/kg   No. of  Basal After  After  24pound  p.o.    animals value 2 hours                               5 hours                                      hours______________________________________Pindolol  0.25    10      184.4 181.6  168.8  188.8                  ±29.4                        ±28.8                               ±18.9                                      ±46.8Pindolol  0.25    10      199.4 151.7**                               178.8  183.311,121 5               ±41.7                        ±26.3                               ±49.2                                      ±40.3Pindolol  0.25    10      182.2 165.0  138.9***                                      175.011,121 10              ±26                        ±28.3                               ±23.2                                      ±9.7Pindolol  0.5     10      200.0 191.2  188.3  188.9                  ±31.8                        ±7.9                               ±36.4                                      ±38.4Pindolol  0.5     10      208.7 156.7* 150.4**                                      192.911,121 5               ±40.1                        ±48.8                               ±44.0                                      ±51.7Pindolol  0.5     10      160.5 112.2***                               112.7***                                      146.711,121 20              ±21.1                        ±32.1                               ±23.7                                      ±24.4Pindolol  1       10      164.4 135.0***                               135.0***                                      151.1                  ±13.8                        ±20.5                               ±16.9                                      ±22.2Pindolol  5       10      172.5 154.5***                               124.5****                                      161.0                  ±14.4                        ±8.0                               ±15.0                                      ±20.511,121 50       5      168.2 170.0  163.0  169.0                  ±10.4                        ±11.2                               ±17.8                                      ±13.4______________________________________ * = 0.05 &gt; p &gt; 0.02 ** = 0.02 &gt; p &gt; 0.01 *** = 0.01 &gt; p &gt; 0.001 **** = 0.001 &gt; p ED.sub.30% p.o. ˜ 5 mg/kg of pindolol ED.sub.30% p.o. ˜ 0.5 mg/kg of pindolol + 20 mg/kg of 11,121 
    
     The test results listed in Table 4 indicate that the combined administration of 11,121 and pindolol causes an approximately tenfold increase in the activity of pindolol. Thus the combinations of these compounds can be applied to advantage in therapy. 
     
                       TABLE 5______________________________________Effect of pindolol, 11,473 and combinations thereof on theblood pressure of genetically hypertensive awake rats        Blood pressure (mmHg)  Dosage                              AfterCom-   mg/kg   No. of  Basal After  After  24pound  p.o.    animals value 2 hours                               5 hours                                      hours______________________________________Pindolol  0.5     15      200.3 172.1* 160.8* 188.6                  ±30.5                        ±36.9                               ±46.9                                      ±30.2Pindolol  0.5     15      196.0 159.6**                               141.3**                                      179.911,473 5               ±35.3                        ±33.5                               ±48.3                                      ±28.1Pindolol  0.5     15      205.3 149.3***                               138.2****                                      191.311,473 10              ±23.3                        ±40.1                               ±32.9                                      ±42Pindolol  1       10      164.4 135.0***                               135.0***                                      151.1                  ±13.8                        ±20.5                               ±16.9                                      ±22.2Pindolol  5       10      172.5 154.5***                               124.5****                                      161.0                  ±14.4                        ±8.0                               ±15.0                                      ±20.511,473 10       5      195.0 194.0  197.0  198.0                  ±11.2                        ±8.2                               ±7.6                                      ±9.1______________________________________ * = 0.05 &gt; p &gt; 0.02 ** = 0.02 &gt; p &gt; 0.01 *** = 0.01 &gt; p &gt; 0.001  **** = 0.001 &gt; p ED.sub.30% p.o. ˜ 5 mg/kg of pindolol ED.sub.30% p.o. ˜ 0.5 mg/kg of pindolol + 10 mg/kg of 11,473 
    
     The test results listed in Table 5 indicate that the required dosage of pindolol can be decreased to about one tenth by administering it in combination with 11,473. Thus the combinations of these compounds can be applied to advantage in therapy. 
     The hypotensive effect of propranolol can also be increased by combining it with a noradrenaline biosynthesis blocking agent, such as 11,130. The test results are given in Table 6. 
     
                       TABLE 6______________________________________Effect of propranolol, 11,130 and combinations thereof onthe blood pressure of genetically hypertensive awake rats          Blood pressure (mmHg)    Dosage                            After    mg/kg   No. of  Basal After After 24Compound p.o.    animals value 2 hours                                5 hours                                      hours______________________________________Propranolol     1       5      167.5 170.0 168.7 157.5                    ±12.6                          ±12.9                                ±13.8                                      ±8.7Propranolol     1      15      169.5 161.9 146.1*                                      163.911,130   20              ±21.0                          ±26.0                                ±19.7                                      ±23.1Propranolol     5      10      186.4 178.6 175.9 181.8                    ±13.6                          ±13.4                                ±24.3                                      ±16.8Propranolol    10      15      178.0 170.0 148.3*                                      163.7                    ±16.1                          ±15.2                                ±18.6                                      ±24.711,130   20       5      174.0 183.0 176.0 172.0                    ±12.9                          ±18.2                                ±10.2                                      ±14.4______________________________________ * = 0.001 &gt; p ED.sub.15% p.o. ˜ 10 mg/kg of propranolol ED.sub.15% p.o. ˜ 1 mg/kg of propranolol + 20 mg/kg of 11,130 
    
     The test results listed in Table 6 indicate that the combined administration of propranolol and 11,130 causes an about tenfold increase in the activity of the β-receptor blocking component. 
     (2) Determination of the hypotensive effect on awake dogs suffering from renal hypertension 
     The tests were performed on dogs suffering from renal hypertension, subjected to operation as described by Grollman (A. Grollman: Proc. Soc. Exp. Biol. Med. 57, 102 (1944). The effects were determined by measuring the blood pressure on the caudal artery and the pulse rate. The test results obtained with pindolol, 11,121 and a combination thereof are listed in Table 7. 
     The data of Table 7 indicate that the hypotensive character of pindolol also changes favorably when using dogs as test animals. 
     
                                           TABLE 7__________________________________________________________________________Effect of pindolol, 11,121 and a combination thereof on the bloodpressure of awake dogswith renal hypertensionDosage        Blood pressure (mmHg) mg/kg     No. of         Basal             After                 After                     After                         After                             After                                 AfterCompound p.o.     animals         value             1 hour                 2 hours                     3 hours                         4 hours                             5 hours                                 24 hours__________________________________________________________________________Pindolol 0.1 3   156.7             133.3                 133.3                      153.0                         156.7                             160.0                                 153.3         ±15.3             ±11.5                 ±17.6                     ±5.8                         ±2.9                             ±5.0                                 ±11.511,121 5   3   165.0             170.0                 167.5                     175.0                         165.0                             172.5                                 165.0         ±5.8             ±7.6                 ±10.4                     ±5.0                         ±5.0                             ±7.6                                 ±2.9Pindolol 0.1 4   160.0             130.0                 111.2*                     143.7                         148.7                             160.0                                 157.511,121 5       ±20.9             ±30.8                 ±16.5                     ±21.4                         ±13.1                             ±8.2                                 ±15.5__________________________________________________________________________ * = 0.05 &gt; p &gt; 0.02 
    
     (3) Toxicity tests 
     Based on the data given in points 1 and 2 above it can be stated that a considerable potentiating synergism appears with respect to the hypotensive effect when applying the compounds of formula (I) in combination with those of formula (V). In the following it was investigated whether this synergism also appears with respect to the toxicity. In the first test series the LD 50  values of the individual components were determined on CFLP-mice. The compounds were administered orally, and the animals were kept under observation for one week. The LD 50  values of the individual compounds are as follows: 
     Pindolol: LD 50  =300 mg/kg p.o. 
     11,121: LD 50  =2900 mg/kg p.o. 
     11,473: LD 50  =360 mg/kg p.o. 
     To determine the toxicity values of the combinations dosages calculated on the basis of the isobole construction principle were applied. The animals were pre-treated for one hour with various dosages of 11,473 or 11,121, and then varying dosages of pindolol were administered. The results are listed in Table 8. 
     The data of Table 8 indicate that a pre-treatment with 100 or 200 mg/kg of 11,473, or with 100 or 1000 mg/kg of 11,121 hardly influences the toxicity of pindolol, thus there is no undesired potentiation of toxicity. 
     
                       TABLE 8______________________________________Toxicity values of pindolol + 11,473 and pindolol + 11,121Mortality (%)                11,121 p.o.Pindolol  Pindo-  11,473 p.o.           1000 2000mg/kg  lol     100     200   300   100   mg/  mg/p.o.   alone   mg/kg   mg/kg mg/kg mg/kg kg   kg______________________________________ 60     0       0      0     50    0      0   30 90     0       0      0     50    0      0   40135     8       0      0     70    0      0   40200    16      20      20    --    0     10   30300    46      40      70    --    50    30   40450    75      70      --    --    80    45   80______________________________________ 
    
     The test results prove unambiguously that the new combinations according to the invention enable one to use the active agents in lower amounts or in more effective forms with a high security. 
    
    
     The invention is elucidated in detail by the aid of the following non-limiting Examples. 
     EXAMPLE 1 
     Preparation of tablets 
     Composition of one tablet: 
     
         ______________________________________Pindolol                 2.5 mg11,121                   100.0 mgMicrocrystalline cellulose                    88.5 mgMagnesium stearate       2.0 mgTalc                     6.0 mgColloidal silicon dioxide                    1.0 mg______________________________________ 
    
     The tablets, weighing 200 mg in average, are provided with film coating. 
     EXAMPLE 2 
     Preparation of capsules 
     Composition of one capsule: 
     
         ______________________________________Pindolol                 2.5 mg11,473                   100.0 mgTalc                     3.0 mgMagnesium stearate       2.0 mgColloidal silicon dioxide                    0.5 mg______________________________________ 
    
     The mixture is filled into self-closing hard gelatine capsules. One capsule contains 108 mg of the above mixture in average. 
     EXAMPLE 3 
     Preparation of tablets 
     Composition of one tablet: 
     
         ______________________________________Propranolol              3.0 mg11,653                   100.0 mgMicrocrystalline cellulose                    88.5 mgMagnesium stearate       2.0 mgTalc                     6.0 mgColloidal silicon dioxide                    1.0 mg______________________________________ 
    
     EXAMPLE 4 
     Preparation of tablets 
     Composition of one tablet: 
     
         ______________________________________Atenolol                 2.5 mg11,702                   80.0 mgMicrocrystalline cellulose                    80.0 mgMagnesium stearate       2.0 mgTalc                     6.0 mgColloidal silicon dioxide                    1.0 mg______________________________________