CA1075155A - Diuretic formulations - Google Patents

Diuretic formulations

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Publication number
CA1075155A
CA1075155A CA244,829A CA244829A CA1075155A CA 1075155 A CA1075155 A CA 1075155A CA 244829 A CA244829 A CA 244829A CA 1075155 A CA1075155 A CA 1075155A
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Prior art keywords
phenoxyacetic acid
phenoxyacetic
ranges
thienyl
mole ratio
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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CA244,829A
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French (fr)
Inventor
Otto W. Woltersdorf (Jr.)
Edward J. Cragoe (Jr.)
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Merck and Co Inc
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Merck and Co Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE

The potassium conserving diuretics, N-amidino-3,5-diamino-6-chloropyrazinecarboxamide and its hydro-chloride, 2-oxygenated-6,7-methylene-2?-spirozanes; 17-a-pregnase-21-carboxylic acids and spironolactone are orally co-administered with 4-substituted carbonyl-2,3-dichloro-phenoxyacetic acid diuretics wherein the substituents are furyl, thienyl, or loweralkylthienyl as mixtures or, in the instance of N-amidino-3,5-diamino-6-chloropyrazinamide, as salts to avoid hypokalemia in patients.

Description

15~97 ~5~5 11 The present invention relates to pharmaceutical 12 formulations and particularly to preparations which have 13 advantageous diuretic and/or saluretic properties. For 14 simplicity, the word diuretic is hereafter used in a com-mon or generic sense, to apply to drugs which cause di-16 uresis (incr~ased urine excre~ion) and/or saluresis tin-17 creased electrolyte excretion). ~-18 Diuretics are valuable therapeutic agents as 19 they are useful in the treatment of cardiovascular and renal diseases. Their use is indicated in the management of all 21 types and grades of severity of congestive heart failure 22 in whi~h diuretic therapy improvement is required. Due to 23 the resultin~ loss of water and electrolyte dramatic im-24 provem$nt is noted in peripheral and pulmonary edema, 25 ~ dyspne~, orthopnea, cough, ascites and pleural effusionO
26 ` - ~ These drugs also provide effective therapy in 27 variou~ forms of renal edema; e.g., edema associated with 28 ~ephrosi~ and certain types of nephritis. Their adminis-29 tratio~ resul~s in prompt excretion of retained fluid and , ~

1~697 ~q~7S~1~i5 1 electrolytes with consequent benefit to the patient. The
2 desired electrolye to be excreted i5 sodium chloride.
3 These drugs are especially useful in the treat-
4 ment of hypertension and provide useful therapy in mild, moderate and severe forms of the disease.
6 Although diuretics are often life-saving because 7 of the above beneficial therapeutic e~fects, most of them 8 have the disadvantage of causing the excretion of appre-g ciable amounts of potassium ions. When a~ excessive los3 of potas~ium ions occurs a se~ere muscular weakness and 11 feeling of extreme physical exhaustion results. The pa-1~ tient eliminates the unwanted sodium ions due to the 13 action of the diuretic drugs but the undesired elimination 1~ of the potassium ions produces an imbalance that should not be allowed to persist.
16 In addition to their other effects, these com-17 pounds are able to maintain th~ uric acid concentration 18 in the body at pretreatment levels or to even effect a 19 decrease in the uric acid concentration. Many of the presently available diuretics and saluretics have a ten-21 dency upon administratlon to induce hyperuricemia which 22 may precipitate uric acid or sodium urate, or both, in the . .
23 body which may cause from mild to severe cases of gout.

24 The instant compounds of this invention now provide an effec ive tool to trea~ those patients requiring diuretic :: :, 6 and saluretic treatment without incurring the risk of in-27 ducing gout.

28 The invention involves co-administration of a 4-29 substituted carbonyl-2,3-dichlorophenoxyacetic acid with a :

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1 pyrazinoylguanidine as a mixture or as a salt, with a 3-2 oxygenated-6,7-m~hylene-20-spiroxane; 17-a-pregnane-21-3 carboxylic acid or with spironolactone as a mixture, to 4 thereby result in a reduction of the amount of potassium ions that are eliminated without a reduction in the amount 6 of ~odium ions that are eliminated.
7 Another advantage, in the case of the N-amidino-8 3,5-diamino 6-chloropyrazinecarboxamide salts of the 4-9 substituted carbonyl-2,3-dichlorophenoxyacetic acid diure-tics is their insolubility which makes the salts' gastroin-11 testinal absorption slower and more gradual providing a 12 chemical method of achieving the same e~fect as microencap-13 sulation.
14 The 4-substituted carbonyl 2,3-dichlorophenoxy-acetic acids useful in the present invention have the fol-16 lowing structural formula: X2 17 2 ~R

18 wherein R is furyl, thienyl, substituted thienyl wherein the . 19 substituent is lower alkyl, having from 1 to 3 carbon atoms.
~ 20 The preferred group of compounds used in thi.s 21 invention are:
22 4-(2-thienylcarbonyl)-2,3-dichlorophenoxyacetic acid;
23 4-~2-(5-methylthienyl)carbonyl]-2,3-dichlorophenoxyacetic 24 acid; and ~ ' ~ :

.. . . .. .
~,. , ' ' , ' ~75~L55 1 4-(2-furylcarbonyl)-2,3-dichlorophenoxyacetic acid.
2 The prepa.ration of these compounds is described in United 3 States Patent No. 3,758,506. Alkhough these are the pre-4 ferred ones of the 4-substituted carbonyl-2,3-dichloro-phenoxyacetic acid class of diuretics, the invention con-6 templates the use in their place of any of the related 7 compounds recited above.
8 The 3~oxygenated-6,7-methylene-20~spiroxanes 9 useful in the present invention have the fol.lowiny struc-tural formula: Z
11 0 "

wr~
f~f .

12 wherein the dashed line a~ ~he 1~2-position represents ~he 13 unsaturated embodiment characterized in that W is hydrogen 14 or methyl; Y is hydrogen, keto or ~-hydroxy; X .is hydrogen or fluoro; z is hydrogen or keto wherein the preferred 16 compound has the chemical name 6,7-methylene-20-spiroxa-1,4-17 diene-3,21-dione.

18 The 17-a-pregnane-21-carboxylic acid compounds 19 useful in the present invention have the following struc-~I -CH -COOM
20 tural ~ormula: 2 2 1 ~ , .

: - 4 ~

~ ' ' . . . . : , S
1 wherein the dashed line at the 1,2-position represents the 2 unsaturated embodiment and M represents an atom of hydrogen 3 or of an alkali or alkaline earth metal or an ammonium 4 radical whexein the preferred compound is the sodium salt of 6a, 7a-dihydro-17-hydroxy-3-oxo-3iH-cyclopropa~6,7]-17a-6 pregn-1,4,6-triene-21-carboxylic acid.
7 Spironolactone, useful in the present invention 8 has the following structural formula:
g ~F~
~X

O ~ ~-CH3 and the chemical name 17-hydroxy-7-mercapto-3-oxo-17a-11 pregn-4-ene-21-carboxylic acid r-lactone, 7-acetate.
12 To achieve the beneficial results o~ this inven-13 tion, ~he preferred pyrazinoylguanidine compound used is N-14 amidino-3,5-diamino-6-chloropyrazinecarboxamide (amiloride) which is described in the literature and patented arts.
16 However, 6,7-methylene 20-spiroxa-1,4-diene-3,21-dione, 17 the sodium salt of 6a,7a-dihydro-17-hydroxy-3-oxo-3'H-18 cyclopropa~6,7]~17a~pregn-1,4,6-triene-21-carboxylic acid 19 or spironolactone can ~e substituted in its place.
The pxesent invention contPmplates the use o~
21 both physical mixtures bf varying ratios of the 4-substi- .
22 tuted carbonyl-2,3-dichlorophenoxyacetic acid diuretics and ~ S~
:: :

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~0~5~55 1 amiloride, 3~oxygenated-6,7-methylene 20~spiroxanes, 17-~2 pregnane-21-carboxylic acids or spironolactone and khe 3 chemical salts of 4-substituted carbonyl-2,3-dichlorophen-4 oxyacetic acid and amiloride.
The N-amidino-3,5-diamino-6-chloropyrazinecar-6 boxamide salt of a 4-substituted carbonyl-2,3-dichloro-7 phenoxyacetic acid is prepared by adding the 4-substituted 8 carbonyl-2,3-dichlorophenoxyacetic acid compound to a 9 solution of N-amidino-3,5-diamino-6-chloropyrazinecar-boxamide in a suitable water miscible organic solvent such 11 as dimethylsulfoxide and then pouring the resulting solu-12 tion into water frorn which the desired amiloride salt of 13 the phenoxyacetic acid separates and is collected by 14 filtration.
The present invention embraces compositions for 16 oral administration wherein the molar ratio of the 4-substi-17 tuted carbonyl-2,3-dichlorophenoxyacetic acid to N amidino-18 3,5-diamino-6-chloropyrazinecarboxamide (amiloride) or N-19 amidino-3,5-diamino-6-chloropyrazinecarboxamide hydrochlor-ide ranges from about 100:1 to 10:1. The prefexred 21 ratios of the 4-substituted carbonyl-2,3-dichlorophenoxy-22 acetic acid to amiloride or amiloride hydrochloride ranges 23 from 50:1 to 20:1. For the case wherein the composition 24 comprises of the phenoxyacetic acid, 4-(2-thienylcar bonyl)-2,3-dichlorophenoxyacetic acid, and amiloride the 26 pre~erred absolute weights and weight ratios corresponding to the above recited molar ratios are set forth in Table 1.

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~"' ., " ' ' ' ' ' .

lS697 ~75~55 h .,, 3 ~
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a~ ~ a) u ., ~ r, I ~ S~-rl ~ ~ o ~
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.,, o R ~) h o o o u~
E~ .~: Id-l >~
.
~-rl I
.
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M
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Q o u~ u~ ~ o ~3 ~1 _ ~
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1 0~ U
~r ~ u ~

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1 The present invent.ion embraces compositions 2 for oral administration wherein the molar ra-tio of the 3 4-substituted carbonyl-2,3-dichlorophenoxyacetic acid 4 to spironolactGne ranges from about 20:1 to 2:1. For the case wherein the phenoxyacetic acid is 4-(2-thienyl-6 carbonyl)-2,3-dichlorophenoxyacetic acid the preferred 7 absolute weights and weight ratios corresponding to the 8 above recited molar ratios are set forth in Tahle 2.

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~ 8 -O
O
O ~1 .,1 ~.~
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h ~D o ~ :~
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I
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fd O ~
N ~ h : :
~ Pi ~ ~
R ~ h E~ ~ O ~1 ~,~ ~ C
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~ ~ o I o.q t) ~ d ~ u rd R. O u~ n o o U ri O ~
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tl ~q I ~ o o o o ~1 11 ~ O t)11~ o U~
I ~ N ~I ~ ~1 ~`~J ~,,0 ~
0~ 0 R O Id , : :::
--9 _ ' , ~L~7~i~55 :L The present invention embraces compositions for 2 oral administration wherein the mole rakio of the 4-substi-3 tuted carbonyl-2,3-dichlorophenoxyacetic acid to 3-oxygen-4 ated-6,7-methylene-20-spiroxanes ranges from about 5001 to 2:1. Furthermore, the present invention embrac~s cornposi-6 tions for oral administration wherein the mole ratio of the 7 4-substituted carbonyl-2,3 dichlorophenoxyacetic acid to 8 17-a pregnane-21-carboxylic acids ranges from about 50:1 g to 2:1.

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' , ~C~7~S5 1 Represerltative examples to illustrate this 2 invention are the ~ollowing:
3 EXAMPLE :l __ _ 4 Preparation of N-Amidino 3,5-diamino-6-chloropyrazinacar-boxamide Salt of 4-(2-Thienylcarbonyl)-2,3-dichl3rophenoxy-6 acetic Acid .. . . . _ . . . _ 7 To a hot solution of N-amidino-3,5-diamino-6-8 chloropyrazinecarboxamide (2.29 g., 0.01 mole) in di-g methylsulfoxide (50 ml.) is addecl 4-(2-thienylcarbonyl)-2,3-dichlorophenoxyacetic acid (3.31 g., 0.01 mole)O
11 The clear solution is poured into vigorously stirred water 12 (300 ml.). rrhe N-amidino-3,5-diamino-6-chloropyrazine-13 carboxamide salt of 4-(2-thienylcarbonyl)-2,3-dichloro-14 phenoxyacetic acid which separates melts at 200C. after recrystalliæation from ethanol.
16 Y 19 16C13N7O5S (~1/2 C2H5OH) 17 Calc.: C, 41.14; H, 3.28; N, 16.79;
18 Found: C, 40.93; El, 3.40; N, 16.81.
19 The compositions and salts of this invention can be administered in a wide variety of therapeutic 21 dosages in conventional vehicles as~ for example, by oral 22 administration in the form of a tablet. Also, the daily 23 dosage o~ the products may be varied over a wide range as, 24 for example, in the form of scored tablets containing 2.5~ 5, 10, 15, 25, 50 and 100 milligrams of the active 26 ingredients for the symp~omatic adjustment of the dosage to 27 the patient to be treated. The daily dosage is preferably 28 administered in subdivided doses spread out over a 24-hour 29 period. These dosages are well below the toxic or lethal dose of the pro~ucts.

.: . , . : .
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' 156'~7 ~75~L5~

l A suitable combined do~age form o~ the composition 2 of this invention can be administered by mixing 200 mgO of 3 a 4-substituted carbonyl-2,3~dicil1Orophenoxyacetic acid with 4 5 mg. of amiloride, or 25 mg. of spironolactone with 194 mg. or 174 mg. respectively of lactose and 1 mg. of mag-6 nesium stearate and placing the m1xture into a No. 0 7 gelatin capsule. Similarly, by employing more of the active 8 ingredient and less lactose, other dosage forms can be put 9 up in No. 0 gelatin capsules. Should it be necessary, compressed tablets, pills, or other desired combined dosages 11 can be prepared to incorporate the compositions of this 12 invention by conventional methods. An effective amount o~
13 the active ingredients of the mixture is ordinarily supplied 14 at a dosage level of ~rom about .05 m~. to about lO mg./kg.
of body weight. Pre~erably the range is from about 1 mg.
16 to 4 mg./kg. o~ body weight.
17 It is also within the scope of this invention 18 to combine the amil~ride salt o a 4-substituted carbonyl-l9 2,3-dichlorophenoxyacetic acid of structure (I) with a 4-substituted carbonyl-2,3-dichlorophenoxyacetic acid and 21 with lactose and magnesium stearate in unit dosage form. An 22 effective amount o~ the salt is ordinarily supplied at a 23 dosage level of rom about 0.05 mg. to about 0.5 mg./kg. of 24 body weight. Preferahly the range is from about 0.1 mg. to 0.3 mg./kg. of body weight. The quantity of amilor-26 ide i~ the dose can be adjusted by varying the ratio of the 27 amiloride salt of the 4-substituted carbonyl-2,3-dichloro-28 phenoxyacetic acid and the 4-substituted carbonyl-2,3-29 dichlorophenoxyacetic acid.

- 12 ~
..

'` " . ' ~ , 15~97 :1~7~S5 1 A suitable unit dosage form of the amiloride 2 salt of a 4-substituted carbonyl-2,3-dichlorophenoxyacetic 3 acid of structure tI) is composecl of 10 mg. to 20 mg. of the 4 salt mixed with 200 mg. of a 4-substituted carbonyl-2,3-dichlorophenoxy acetic acid and with 189 my. or 179 mgO re 6 spectively of lactose and 1 mg. magnesium stearate.
7 The following examples ara included to illustrate 8 the preparation of representative combined dosage forms con-9 taining a mixture of a 4-substituted carbonyl-2,3--dichloro-phenoxyacetic acid and amiloride, a 3-oxygenated-6,7-11 methylene-20-spiroxane, a 17 a-pregnane-21-carboxylic acid 12 or spironolactone.

14 Combined Dosage Form in Dry-filled Capsule Per capsule 16 4-(2-thienylcarbonyl)-2,3-dichloro-17 phenoxyacetic acid . . . ~ . . . . . . . . 250 mg.
18 N-Amidino-3,5-diamino-6-chloro~
19 pyrazinecarboxamide . . . . . . . . . . . 5 mg.
20 Lactose .................................. 144 mg.
21 Magnesium stearate O . . . . . . . . . . . 1 mg.
22 Capsule (size No. 0) 400 mg.
23 EXAMPI,E 3 24 Combined Dosa~e Form in Dry-filled Capsule Per aapsule 26 4-(2-thienylcarbonyl)-2,3-dichloro-27 phenoxyacetlc acid . ~ . . . . . . . . . . 250 mg.
28 Spironolactone . . . . . . . . . . . . . . 25 mg.
29 Lactose . . . . . . . . . . . . . . . . . 124 mg.
30 Magnesium stearate . . . . . . . . . . . . 1 mg.
; 31 Capsule (size No. 0~ 400 mg-,:
, .

~..... ' ,. ' . ', ,. ' ',: . , ''. . ~
;.~ . . : , :, .
.~ . . .. .

` ].56g7 1 The 4-(2-thienylcarbonyl)-2,3-dichlorophenoxy-2 acetic acid and N-amidino-6-chloropyrazinecarboxamide 3 or spironolactone are mixed and reduced to a No. 60 powder 4 and then lactose and magnesium st:earate are passed through a No. 60 bolting cloth onto the powder and the combined 6 ingredient~ admixed for ten minut:es and then ~illed into a 7 No. 0 dry gelatin capsule.
8 Similar combined dosaye form dry-filled capsules g are prepared by replacing the phenoxyacetic acid ingred-ient of Examples 2 and 3 by any of the other phenoxy 11 acetic acid compounds recited in this invention. If, in 12 Examples 2 and 3, one of the other mentioned phenoxy-13 acetic acid diuretics is substituted for 4-(2-thienyl-14 carbonyl)-2,3-dichlorophenoxyacetic acid, it would be used in a greater or lesser amount depending upon its known 16 relative diuretic activity with respect ~o 4-(2-thi~nyl-17 carbonyl)-2,3-dichlorophenoxyacetic acid.
The following examples are included to illustrate 19 the preparation of representative dosage forms c:ontaining an amiloride salt of a 4-substituted carbonyl-2,3-dichloro-21 phenoxyacetic acid and 4-substituted carbonyl 2,3-dichloxo-22 phenoxyacetic acid.
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2 Dry-filled C_~sule 3 Per capsule 4 N-amidino-3,5-diamino-6-chloro-pyrazinecarboxamide salt of 4-6 (2-thienylcarbonyl)-2,3-di_ 7 chlorophenoxyacetic acid . . . . . . . . . 10 mg.
8 4-(2-Thienylcarbonyl)-2,3_ g dichlorophenoxyacetic acid . . . . . . . . 240 mg.
Lactose . . . . . . . . . . . ~ . . . . . 149 mg.
11 Magnesium stearate . . . . . . . . . . . . l mg.
12 Capsule (size No. 0) 400 mg.
13 The amiloride salt of 4-(2 thienylcarbonyl)~
14 2,3-dichlorophenoxyacetic acid and the 4-(2-thienylcar-~5 bonyl)-2,3-dichlorophenoxyacetlc acid are reduced to a 16 No. 60 powder and then lactose and magnesium stearate are 17 pass~d through a No. 60 bolting cloth onto the powder and 18 the combined ingredients admixed for 10 minutes and then 19 filled into a No. 0 dry gelatin capsule~
Similar dry-fillea capsules can be prepared by : .
21 replacing the phenoxyacetic acid ingredient of t:he above 22 example by a molar equivalent amoun~ of other phenoxyacetic 23 acid compounds recited in this invention.
24 It will be apparent from the foregoing descrip~
: 25 tion that the mixtures of 3-oxygenated-6,7-me~hylene-20-26 spiroxanes, 17-a-pregnane-21-carboxylic acids or sp.irono-lactone and 4-substituted carbonyl-2,3-dichlorophenoxyacetic 28 acids o structure (I) and the salts of amiloride with the 29 4-substituted carbonyl-2,3-dichlorophenoxyacetic acids of ~ - 15 - :
`~ :

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.

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1 structure (I) of this invention constitut:e a valuable class 2 of products which have not been prepared heretofore. One 3 skilled in the art will also appreciate that the processes 4 disclosed in the above examples are merely illustrative and are capable of a wide variation and modification without 6 departing from the spirit of this invention.

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Claims (11)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:
1. A composition comprising a phenoxyacetic acid compound of the formula:

wherein R is thienyl, thienyl substituted with loweralkyl or fury1, X1 and x2 are halo and a compound selected from N-amidino-3,5-diamino-6-chloropyrazinecarboxamide, spirono-lactone or a 3-oxygenated-6,7-methylene-20-spiroxane of the formula:

wherein the dashed line at the 1,2-position represent the unsaturated embodiment, W is hydrogen or methyl; Y is hydrogen or keto, wherein the mole ratio of phenoxyacetic acid compound to N-amidino-3,5-diamino-6-chloropyrazinecarboxamide ranges from 50:1 to 10:1, the mole ratio of the phenoxyacetic acid compound to spironolactone ranges from about 15:1 to 2:1, and the mole ratio of phenoxyacetic compound to 3-oxygenated-6,7-methylene-20-spiroxane ranges from about 50:1 to 2:1.
2. A composition comprising a phenoxyacetic acid compound of the formula:

wherein R is thienyl, thienyl substituted with loweralkyl or furyl; X1 and X2 are halo and N-amidino-3,5-diamino-6-chloro-pyrazinecarboxamide or spironolactone wherein the mole ratio of the phenoxyacetic acid compound to N-amidino-3,5-diamino-6-chloropyrazinecarboxamide ranges from about 50:1 to 10:1, and the mole ratio of the phenoxyacetic acid compound to spirono-lactone ranges from about 15:1 to 2:1.
3. A composition comprising a phenoxyacetic acid compound of the formula:

wherein R is furyl, thienyl, loweralkyl thienyl, the lower-alkyl portion having from 1 to 3 carbon atoms; X1 and x2 are chloro, and N-amidino-3,5-diamino-6-chloropyrazinecarboxamide or spironolactone wherein the mole ratio of the phenoxyacetic acid compound to N-amidino-3,5-diamino-6-chloropyrazine-carboxamide ranges from about 50:1 to 10:1, and the mole ratio of the phenoxyacetic acid compound to spironolactone ranges from about 15:1 to 2:1.
4. A composition according to Claim 3, wherein the phenoxyacetic acid is 4-(2-thienylcarbonyl)-2,3-dichloro-phenoxyacetic acid.
5. A composition according to Claim 3, wherein the phenoxyacetic acid is 4-?-(5-methylthienyl)carbonyl?-2,3-dichlorophenoxyacetic acid.
6. A composition according to Claim 3, wherein the phenoxyacetic acid is 4-(2-furylcarbonyl)-2,3-dichlorophenoxy-acetic acid.
7. A composition according to Claim 3, wherein the mole ratio of phenoxyacetic acid to spironolactone is about 15:1.
8. A composition comprising a phenoxyacetic acid compound of the formula:

wherein R is thienyl, thienyl substituted with loweralkyl or furyl; X1 and x2 are halo and 3-oxygenated-6,7-methylene-20-spiroxanes of the formula:

wherein the dashed line at the 1,2-position represents the unsaturated embodiment, W is hydrogen or methyl, Y is hydro-gen, keto or .beta.-hydroxy; X is hydrogen or fluoro; Z is hydrogen or keto wherein the mole ratio of the phenoxyacetic compound to the 3-oxygenated-6,7-methylene-20-spiroxane ranges from about 50:1 to 2:1.
9. A composition according to Claim 8, wherein the 3-oxygenated-6,7-methylene-20-spiroxane is 6,7-methylene-20-spiroxa-l,4-diene-3,21-dione.
10. A composition comprising a phenoxyacetic acid compound of the formula:

wherein R is thienyl, thienyl substituted with loweralkyl or furyl; X1 and x2 are halo and 17-.alpha.-pregnane-21-carboxylic acids of the formula:

wherein the dashed line at the 1,2-position represents the unsaturated embodiment and M represents an atom of hydrogen or of an alkali or alkaline earth metal or an ammonium radical wherein the mole ratio of the phenoxyacetic compound to the 17-.alpha.-pregnane-21-carboxylic acid ranges from about 50:1 to 2:1.
11. A composition according to Claim 10, wherein the 17-.alpha.-pregnane-21-carboxylic acid is the sodium salt of 6.alpha.,7.alpha.-dihydro-17-hydroxy-3-oxo-3'?-cyclopropa?6,7?-17.alpha.-pregn-l,4,6-triene-21-carboxylic acid.
CA244,829A 1975-02-03 1976-01-27 Diuretic formulations Expired CA1075155A (en)

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ATE24997T1 (en) * 1982-01-04 1987-02-15 Karl H Beyer Jr HYPERUETIC AGENTS.
AU4777896A (en) * 1995-02-10 1996-08-27 G.D. Searle & Co. Use of low dose amount of spironolactone for treatment of cardiovascular disease

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AU507494B2 (en) 1980-02-14
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FR2299025A1 (en) 1976-08-27
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