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. 657,825, filed Feb. 13, 1976, now U.S. Pat. No. 4,055,645. 
    
    
     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. No. 3,462,536; U.S. Pat. No. 3,830,827 and U.S. Pat. No. 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 or 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, quanethidine, 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. No. 2,809,184; U.S. Pat. No. 2,937,169; U.S. Pat. No. 3,025,292; U.S. Pat. No. 3,164,588 and U.S. Pat. No. 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 anti-hypertensive 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 the mean arterialpressure 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                            173                               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                         138                            146                               152                                  161                                     160                                        160                                           1597   Hydralazine       1       4   180                      120                         127                            157                               157                                  178                                     176                                        177                                           1768   Hydralazine       2       5   169                      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                                           16427  Carbidopa &amp;       25      4   170                      149                         121                            114                               116                                  127                                     135                                        136                                           4228  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 HCl 
    
     The above data clearly shows the enhancement of anti-hypertensive 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.