Abstract:
Novel pharmaceutical compositions are disclosed which comprise a hypotensive agent and a phenyl hydrazino substituted propionic acid decarboxylase inhibitor. The compositions have enhanced anti-hypertensive activity.

Description:
This is a division of application Ser. No. 766,635, filed Feb. 8, 1977, now U.S. Pat. No. 4,086,354 which in turn is a division of U.S. application Ser. No. 657,825, filed Feb. 13, 1976 now U.S. Pat. No. 4,055,645, issued Oct. 25, 1977. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention is directed to novel pharmaceutical compositions containing a hypotensive agent and a decarboxylase inhibitor. 
     The hypotensive agents of the present invention comprise agents, other than phenylalanine and reserpine type compounds, which are known to be effective in treating hypertension in humans. The decarboxylase inhibitor is encompassed in the class of hydrazino phenyl propionic acid compounds disclosed in U.S. Pat. Nos. 3,462,536; 3,830,827 and 3,781,415. Combinations of this hydrazino phenylpropionic acid type decarboxylase inhibitor with reserpine or phenylalanine type hypertensive agents are disclosed in Canadian Pat. No. 737,907 and U.S. Pat. No. 3,839,585. 
     It has now been discovered that the combination of the aforesaid non-phenylalanine, non-reserpine hypotensive agents with the hydrazino-phenyl propionic acid type decarboxylase inhibitors affords enhanced anti-hypertensive activity. 
     SUMMARY OF THE INVENTION 
     Novel pharmaceutical compositions comprising (a) a non-phenylalanine, non-reserpine hypotensive agent and (b) a D,L- or L-hydrazino-phenyl propionic acid decarboxylase inhibitor and a method of treating hypertensive animals. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     An embodiment of this invention is a hypotensive pharmaceutical composition comprising 
     (a) a non-phenylalanine, non-reserpine hypotensive agent and 
     (b) the L-isomer of racemic mixture (D,L-) of a hydrazino phenylpropionic acid decarboxylase inhibitor. 
     Preferred hypotensive agents are selected from the group consisting of (1) spironolacetone, hydralazine, trimethaphan camsylate, clonidine, guanethidine, thiazide diuretics, cryptenamine, pharmaceutically acceptable salts thereof and (2) sodium nitroprusside. A more preferred group of hypotensive agents includes hydralazine, clonidine, guanethidine, the thiazide diuretics and pharmaceutically acceptable salts thereof. A most preferred group of hypotensive agents is clonidine, hydralazine, guanethidine and their pharmaceutically acceptable salts. 
     The thiazide diuretics include the benzothiadiazine class of compounds having the basic ring structure ##STR1## Representative compounds are disclosed in U.S. Pat. Nos. 2,809,184; 2,937,169; 3,025,292; 3,164,588 and 3,043,840, and are incorporated herein by references. 
     The preferred thiazide compounds are chlorothiazide, hydrochlorothiazide, trichlormethiazide, bendroflumethiazide, polythiazide, flumethiazide, and their pharmaceutically acceptable salts. Hydrochlorothiazide is a most preferred thiazide hypotensive agent. 
     Preferred decarboxylase inhibitors include the D,L-racemic mixture and the individual L-isomer of compounds having the formula: ##STR2## wherein R, R 1 , R 2  and R 3  are independently selected from hydrogen and C 1  -C 4  alkyl such as methyl, t-butyl, isopropyl and the like. A more preferred decarboxylase inhibitor is the L-isomer and most preferred is the L-isomer of ##STR3## and its pharmaceutically acceptable salts. The monohydrate of IV is known as carbidopa. 
     Pharmaceutically acceptable salts include the salts of the various compounds with suitable organic or inorganic acids. Suitable organic acids are C 2  -C 24  carboxylic acids such as acetic acid, maleic acid, pamoic acid, succinic acid, citric acid, propionic acid, isethionic acid, oxalic acid, pivalic acid and the like. Suitable inorganic acids include the hydrohalides, e.g., HCl, HI, HBr, sulfuric acid, phosphoric acid and the like. The salts may also be alkali metal salts such as the sodium or potassium salt or the ammonium salt. 
     The compositions of the present invention may contain varying amounts of the hypotensive agent and decarboxylase inhibitor. In general, the weight ratio of hypotensive agent (a) to decarboxylase inhibitor (b) will be from about 4:1 to about 1:9000. A preferred weight ratio of (a):(b) is about 1:1 to about 1:1000 and a most preferred weight ratio is about 1:5 to about 1:500. 
     In treating hypertension, a sufficient amount of the present composition is administered to the hypertensive animal to produce the desired hypotensive effect i.e. reduction in blood pressure. Effective dosages may vary and can range from about 0.2 mg/kg to about 1000 mg/kg per day. The composition may be given as a single daily dose or divided into several smaller doses during the course of the day. 
     The composition may be administered parenterally or orally. The dosage form used will depend on the mode of administration. The oral form may be a tablet, a liquid solution, dispersion, or emulsion, a capsule, or an encapsulated composition -- while the parenteral dosage form will generally be a liquid solution, suspension or emulsion. The dosage forms generally will include conventional carriers, diluents, either solid or liquid, dyes etc. and will be prepared using applicable formulation procedures. 
     The compositions of the present invention are administered to hypertensive animals to effect reduction in blood pressure. The decarboxylase inhibitors are known to have no appreciable anti-hypertensive effect. When combined with the present hypotensive agents, however, the antihypertensive effect of the hypotensive agent is unexpectedly enhanced. 
     This enhancement of anti-hypertensive activity is demonstrated in vivo in spontaneously hypertensive (SH) rats. The procedure used is as follows: 
     The test animals used were conscious, male, SH rats weighing about 290 to about 340 grams. The arterial blood pressure was measured by a direct technique involving cannulation of the caudal artery. Initial blood pressure reading was recorded. The decarboxylase inhibitor was then administered intraperitoneally (i.p.) and about 5 minutes later the hypotensive agent was given, (i.p.). The blood pressure was then continuously recorded at 1/2 hour intervals for 24 hours. 
     The effect on blood pressure of the decarboxylase inhibitor and the hypotensive agent alone was also obtained by this method. The results of these tests for representative compositions of the present invention are in the following tables: 
     
                                           Table 1__________________________________________________________________________Effects of guanethidine and hydrochlorothiazide, alone and in combinationwith carbidopa, on themean arterial pressure of conscious SH rats.          Dose     Mean Arterial Pressure, mm Hg,Group          mg/kg               No. of                   at hours after treatmentNo. Treatment  i.p. Rats                   0  1/2                         1  2  4  8  12 18 24__________________________________________________________________________1   Saline     2 ml/kg               9   168                      170                         170                            170                               166                                  164                                     166                                        166                                           1642   Carbidopa.sup.1          25   6   167                      166                         164                            166                               158                                  167                                     172                                        172                                           1623   Guanethidine.sup.2          0.078               6   179                      178                         177                            177                               174                                  180                                     180                                        177                                           1784   Guanethidine          0.312               5   174                      167                         168                            171                               171                                  174                                     170                                        170                                           1665   Guanethidine          0.625               4   176                      180                         180                            178                               172                                  179                                     173                                        174                                           1766   Guanethidine          1.25 4   171                      143                         163                            150                               150                                  154                                     147                                        155                                           1627   Guanethidine          5    4   174                      131                         133                            132                               140                                  157                                     155                                        163                                           1628   Carbidopa &amp;          25   4   173                      161                         162                            173                               166                                  172                                     171                                        172                                           170    Guanethidine          0.3129   Carbidopa &amp;          25   6   173                      157                         140                            137                               137                                  144                                     152                                        147                                           149    Guanethidine          0.62510  Carbidopa &amp;          25   4   166                      126                         133                            129                               126                                  141                                     147                                        158                                           157    Guanethidine          1.2511  Hydrochlorothiazide.sup.3          5    4   170                      179                         177                            176                               165                                  170                                     174                                        171                                           17112  Hydrochlorothiazide          20   4   164                      161                         159                            161                               159                                  163                                     152                                        151                                           14913  Hydrochlorothiazide          40   5   168                      167                         167                            164                               163                                  161                                     159                                        155                                           15514  Hydrochlorothiazide          80   5   169                      152                         160                            142                               145                                  145                                     141                                        141                                           14015  Carbidopa &amp;          25   4   170                      169                         161                            159                               156                                  158                                     152                                        154                                           152    Hydrochlorothiazide          516  Carbidopa &amp;          25   4   170                      164                         164                            163                               155                                  162                                     158                                        158                                           153    Hydrochlorothiazide          2017  Carbidopa &amp;          25   5   179                      181                         170                            162                               148                                  160                                     158                                        162                                           161    Hydrochlorothiazide          4018  Carbidopa &amp;          25   6   176                      153                         146                            146                               128                                  135                                     133                                        138                                           146    Hydrochlorothiazide          80__________________________________________________________________________ .sup.1 Dissolved in 1N HCl .sup.2 As Guanethidine sulfate dissolved in water .sup.3 Dissolved in 1N NaOH 
    
     
                                           Table 2__________________________________________________________________________Effect of hydralazine and clonidine, alone and in combination withcarbidopa, on themean arterial pressure of conscious SH rats.      Dose      Mean Arterial Pressure, mm Hg,Group      mg/kg No. of                at hours after treatmentNo. Treatment      i.p.  Rats                0  1/2                      1  2  4  8  12 18 24__________________________________________________________________________1   Saline 2 ml/kg            9   168                   170                      170                         170                            166                               164                                  166                                     166                                        1642   Carbidopa.sup.1      25    6   167                   166                      164                         166                            158                               167                                  172                                     172                                        1623   Hydralazine.sup.2      0.03  3   167                   169                      165                         172                            172                               166                                  168                                     171                                        1734   Hydralazine      0.125 4   170                   166                      165                         166                            171                               174                                  168                                     168                                        1675   Hydralazine      0.25  4   180                   159                      166                         172                            170                               172                                  175                                     176                                        1696   Hydralazine      0.5   9   164                   128                      163                         146                            152                               161                                  160                                     160                                        1597   Hydralazine      1     4   180                   120                      127                         157                            157                               178                                  176                                     177                                        1768   Hydralazine      2     5   160                   120                      126                         135                            144                               152                                  156                                     154                                        1629   Carbidopa &amp;      0.312 4   166                   158                      146                         154                            153                               166                                  164                                     163                                        157    Hydralazine      0.12510  Carbidopa &amp;      1.25  4   163                   155                      142                         145                            151                               156                                  147                                     147                                        151    Hydralazine      0.12511  Carbidopa &amp;      5     4   168                   187                      175                         166                            163                               135                                  133                                     130                                        152    Hydralazine      0.12512  Carbidopa &amp;      25    4   174                   163                      157                         144                            138                               152                                  160                                     163                                        160    Hydralazine      0.0313  Carbidopa &amp;      25    5   177                   137                      132                         149                            140                               149                                  151                                     155                                        158    Hydralazine      0.12514  Carbidopa &amp;      25    4   173                   146                      147                         158                            158                               159                                  164                                     164                                        170    Hydralazine      0.2515  Carbidopa &amp;      1.25  6   169                   143                      149                         156                            159                               161                                  157                                     165                                        166    Hydralazine      0.516  Carbidopa &amp;      5     6   172                   134                      129                         143                            150                               152                                  152                                     149                                        154    Hydralazine      0.517  Carbidopa &amp;      25    8   175                   117                      115                         130                            141                               149                                  153                                     153                                        153    Hydralazine      0.518  Clonidine.sup.3      0.00075            4   170                   171                      171                         170                            169                               166                                  172                                     161                                        17019  Clonidine      0.003 4   169                   166                      156                         165                            163                               165                                  168                                     177                                        17920  Clonidine      0.0125            4   167                   159                      167                         163                            163                               169                                  169                                     167                                        17221  Clonidine      0.025 6   168                   148                      147                         149                            151                               154                                  151                                     149                                        15022  Clonidine      0.05  7   180                   164                      159                         149                            146                               154                                  159                                     164                                        16623  Clonidine      0.2   3   173                   164                      147                         152                            150                               148                                  152                                     157                                        16224  Carbidopa &amp;      25    6   169                   153                      157                         158                            162                               175                                  169                                     163                                        171    Clonidine      0.0007525  Carbidopa &amp;      25    6   168                   134                      141                         146                            150                               148                                  151                                     152                                        162    Clonidine      0.00326  Carbidopa &amp;      25    5   166                   144                      139                         143                            154                               161                                  167                                     170                                        164    Clonidine      0.012527  Carbidopa &amp;      25    4   170                   149                      121                         114                            116                               127                                  135                                     136                                        142    Clonidine      0.0528  Carbidopa &amp;      1.25  4   180                   156                      149                         148                            151                               159                                  171                                     170                                        175    Clonidine      0.0529  Carbidopa &amp;      5     5   175                   142                      129                         128                            132                               149                                  153                                     156                                        164    Clonidine      0.05__________________________________________________________________________ .sup.1 Dissolved in 1N HCl .sup.2 As hydralazine . HCl Dissolved in water  .sup.3 As clonidine . HCl Dissolved in 1N HCl 
    
     The above data clearly shows the enhancement of antihypertensive properties of the non-reserpine, non-phenylalanine agent by the decarboxylase inhibitor. 
     Following are formulations of some representative dosage forms: 
     
         ______________________________________Tablet FormulationClonidine hydrochloride 0.1 mgCarbidopa               5.0 mgCalcium phosphate       50.0 mgLactose                 20.0 mgStarch                  10.0 mgMagnesium sulfate       0.5 mgLiquid SuspensionGuanethidine sulfate    2.5 gCarbidopa               2.5 gVeegum HV               3.0 gMethylparaben           1.0 gKaolin                  10.0 gGlycerin                250.0 gWater, q.s. → 1 literInjectable SolutionHydralazine hydrochloride                   20 mgCarbidopa . HCl         100 mgDistilled water, q.s. → 1 mlCapsule Formulation - IHydrochlorothiazide     50 mgCarbidopa               15 mgLactose                 50 mgTalc                    3 mgCapsule Formulation - IIClonidine HCl           0.2 mgCarbidopa               100.0 mgMannitol                98.0 mgStearic acid            1.0 mg______________________________________ 
    
     While the test results were obtained by i.p. administration of the two drugs of the present composition separately, the effect is demonstrative of the anti-hypertensive effect which would be obtained on administration, orally or parenterally, of the hypotensive agent and decarboxylase inhibitor either as a combination or individually and simultaneously. Another embodiment of this invention is a method of treating hypertensive animals by thus administering an anti-hypertensive amount of the aforesaid composition comprising the hypotensive agent and the decarboxylase inhibitor. 
     The term animals includes humans. 
     Claims to the invention follow: