CA1120400A

CA1120400A - Method of treating hypertension and medicaments therefor

Info

Publication number: CA1120400A
Application number: CA000316609A
Authority: CA
Inventors: Zola P. Horovitz; Bernard Rubin
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1977-12-27
Filing date: 1978-11-21
Publication date: 1982-03-23
Also published as: HU178747B; NL980017I1; AU4204178A; FI783991A7; IL56281A0; CH642542A5; KE3235A; SE445173B; DK578778A; LU80709A1; AR230378A1; IE782413L; DE2854316A1; NL192870C; DE2854316C3; GB2010675A; JPS647045B2; HK45483A; IT7831266A0; BE873092A

Abstract

Abstract of the Disclosure A method for reducing blood pressure comprise administering a combination of a diuretic compound and a compound having the general formula

Description

HA160a Method of Treat ng Hypertension and Medicaments Thereor ; The present invention relates to a method for reducing or alleviating hypertension with a combination comprising an effective amount of a compound of the formula (I) 4 ~1 ~
~ R~-S-(CH)n- CH- CO- N _ COR

: wherein R is hydroxy, lower alkoxy or NH2;
; Rl and R4 each is hydrogen, lower alkyl ox phenyl-lower alkyl;
R2 is hydrogen or R5-CO;
R3 is hydrogen, hydroxy or lower alkyl;
R5 is lower alkyl, phenyl or phenyl-lower alkyl; and n is 0, 1 or 2.
with an effective amount of a diuretic compound and such a combination of medicaments~

.~

l~ZV~
HA160a

2--The compounds of formula I have been reported to be angiotensin converting enzyme inhibitors which intervene in the angiotensinogen ~ renin ~
angiotensin I ~ angiotensin II mechanisn and are effective in reducing or alleviating hypertension.
See U.S. Patent 4,046,889, September 6, 1977;
Science 196, 441-443 (1977). It has been found that such compounds can be used in an oral dosaqe range of about 0.1 to 100 mg/kg per day and are most effective when provided at a total daily dosage of about 60 to 600 mg. Dosages within this range achie~e a substantial reduction in arterial blood pressure and, in most instances, little, if any significant reduction is obtained by further increasing the dosage. Although certain peptides, teprotide (SQ20,881) for example, have ~een reported to have angiotensin converting enzyme activity, they are not of practical use for such an indication because of the cost and particularly since they are ineffective when orally administered [Rubin et al., 204, Jour. Pharm.
Exper. Ther. 271-280, 1978; Laffan et al., Jour.
Pharm. Exper. Ther. 204, 281-288, 1978; Brit. Med.
Jour. 2(6141~:866, 1978].
Hypertension is also frequently treated by the administration of a diuretic. Typically, treatment with an antihypertensive agent alone results in a compensatory retention of sodium and water which concomitant administration of a diuretic prevents (Wollam et al., Drugs 14:420-460, 1977).
However, administration of a compound of formula I does not result in sodium and water HA160a retention when administered alone and, in fact, may by itself cause natriuresis and diuresis (Bengis et al, Circulation Research, Vol. 43 I-45-I-53, 1978).
Therefore, a diuretic woul~ not be expected to enhance the antihyper~ensive action of compounds o~ formula I.
However, it has been demons~rated that the administra-tion of a diuretic in combination with compounds of formula I is more effective than either drug alone.
The combination of such compounds with a diuretic as described below results in a potentiation of the reduction in blood pressure significantly beyond that level which either substance can achieve itself at a dosage within the acceptable range and also at lower dosage levels.
This invention therefore relates to a combination of a compound having formula I above and a diuretic of the group consisting of the thiazide class, e.g., chloro~hiazidel hydrochlorothiaæide, flumethiazide, hydro1umethiazide, bendroflumethiazide, methychlo-thiazide, trichlorme~hiazide, polythiazide or b~nzthiazide, as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, bumetanide, triamterene, amiloride and spironolactone, and salts of such - compounds, compositions comprising a combination of such compounds and to a method for alleviating hyper-tension with a combination of compounds.
Preferred are those compounds of formula I
wherein R is hydroxy or lower alkoxy, especially Cl~C4 lower alkoxy; Rl is hydrogen or lower alkyl, especially methyl, R2 is hydrogen or lower alkanoyl, especially C2-C4 lower alkanoyl; R3 is hydrogen '~ ~ ~A160a or hydroxy/ especially 4-hydroxy; R~ is hydrogen or lower alkyl, especially Cl-C~ lower alkyl; and n is 0 or 1. Especially pre~erred in this group are com-pounds of Eormula I wherein ~ is hydroxy; Rl is hydrogen or methyl; R2 is hydrogen or acetyl; R3 is hydrogen; ~4 is hydrogen or methyl; and n i5 0 or 1. The especially preferred embod:iment includes a compound of formula I wherein R is hydroxy; Rl is methyl; R2, R3 and R4 each is hydrogen; and n is 1, most especially tD-3~mercapto-2-methyLpropanoyl)-L
proline.
Preferred as the second component of the combination is chlorothiazide, hydrochlorothiazide, furosemide, ticrynafen or triamterene, especially 1~ hydrochlorothiazide or furosemide.
The especially preferred embodiments are compositions comprising (D-3-mercapto-2-methvl-propanoyl)-L-proline with either hydrochlorothia~ide or furosemlde.
~ ~0 The compounds of formula I can be produced as - described in U.S. Patent 4,046,889, September 6, 1977. The diuretic members of the combination are known compounds which are produced by methods described in the literatureO
According to this invention, a combination of a compound of formula I and a diuretic is administered in an effective amount which comprises a total daily dosage of about 30 to 600 mg., preferably 30 to 300 mg. of a compound of formula I and about 15 to 300 mg. preferably 15 to 200 mg. of the diuretic to a mammalian species which has elevated blood ~ ~IA160a _5_ pressure. Such total daily dosages can be used in a single administration of the total amount or in divided doses two to four times dai~y. Generally, a t.i.d. or q.i.d~ regimen is preferred. This pre 5 ferred dosage is about 10 to 100 mg. of the compound of formula I and about 5 to 75 mg. o~ the diuretic three times daily or about 5 to 125 mg. of the compound of formula I and about 2.5 to 50 mg. of the diuretic four times daily. The preferred route of admini~tration is oral.
According to one preferred embodiment, the substances can be formulated in a single pharmaceu-tical dosage form for oral administration such as tablet, capsule; solution or suspension comprising an effective lS amount of each of the active ingredients in a physiolo-gically acceptable carrier therefor.
The active substances in the dosage unit are present in a ratio of about 1:2 to about 12:1, preferably about 2.5:1 to about 10:1, of the compound of formula I with respect to the diuretic ~by weigh~).
Generally, about 10 to 200 mg. of a compound o~
formula I and about 2.5 to 100 my. of the second component can be readily formulated in the composition.
Tablets of various sizes can be prepared, e.g., 2~ of about 50 to 700 mg. in total weight, containing the active substances in the ranges described above, with the remainder being a physiologically acceptable caxrier or other materials according to accepted pharmaceutical practice. These tablets can~ o~
course, be scored to provide for fractional doses.
Gelatin capsules can be similarly formulated.

~A160a Liquid formula~ions can also be prepared by dissolving or suspending khe combination of active substances in a conventional liquid vehicle acceptable Eor pharmaceutical administration so as ~o provide the desired dosage in one to four teaspoonsful.
Such dosage forms can be administered to the patient on a regimen of one to four doses per day.
According to another modifica-tion, in order to more finely regulate the dosage schedule, the substances may be administered separately in individual dosage uni~s at the same time or carefully coordinated times.
Since blood levels are built up and maintained by a regulated schedule of administration, the same result is achieved by the simultaneous presence o~ the two substances. The respective substances can be individually formulated in separate unit dosage forms in a mannex similar to that described above.
~ ixed combinations of the compound o~ formula I
and the diuretic are more convenient and are preferred, expecially in tablet or capsule form for oral administration.
In formulating the compositions of this invention the active substances, in the amounts described above, are compounded according to accep~ed pharmaceutical practice with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in the particular type o~ unit dosage form.
Illustrative of the adjuvants which may be incorporated in tablets are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin;

HA160a an excipient such as dicalcium phosphate or cellulose;
a disintegra-ting agent such as corn starch, potato starch, alginic acid or the like; a lubricant such as stearic acid or magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavor-ing agent such as orange, peppermint, oil of wintergreen or cherry. ~hen the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil.
Various o-ther materials may be present as coatings or to otherwise modify the physical orm o the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, water, alcohol or the like as the carrier, glycerol as solubilizer, sucrose as sweetening agent, methyl and propyl parabens as preservatives, a dye and a 1avoring such as cherry or orange.
Many of the active substances described above 2V form commonly known, pharmaceutically acceptable salts such as alkali metal and other common basic salts or acid addition salts, etc. References to the base substances are therefore intended to include those common salts known to be substantially equivalent to the parent compound.
The following examples are illustrative of the invention and constitute especially preferred embodiments. They also serve as models for the preparation of ~ther members o the group which can be produced by suitable substitution of lngredients as described above.

HA160a Example 1 6000 tablets each containing the following ingredients:
(D-3-mercapto-2-methylpropanoyl)-L-proline 100 mg.
*Avicel (microcrystalline cellulose) 100 mg.
Hydrochlorothiazide 12.5 mg.
Lactose U.S.P. 113 mg.
Corn starch U.S.P. 17.5 mg.
Stearic acid U.S.P. 7 mg.
350 mg.
are produced (from sufficient bulk quantities) by slugging the (D-3-mercapto-2-methylpropanoyl)-L-~ proline,*Avicel and a portion of the stearic acid.
- 15 The slugs are ground and passed through a ~2 screen, - then mixed with the hydrochlorothiazide, lactose, corn starch and remainder of the stearic acid. The mixture is compressed into 350 ~g. capsule shaped tablets in a tablet press. The table~s are scored for dividing in half.
Example 2 10,000 tablets each containing the following ingredients:
(D-3-mercapto 2-methylpropanoyl)-25 L-proline 200 mg.
Corn starch U.S.P. 17.5 mg.
Lactose U.S.P. 215.4 mg.
Acacia U.S.P. 10.6 mg.
Water qs (ca. 0.03 ml.~
30 Hydrochlorothiazide 25 mg.
Corn starch U.S.P. 17.5 mg.

* Trade Mark HA160a _g_ Avicel 200 mg.
Stearic Acid 14 mg.
700 mg.
are produced from sufficient bulk quantities as follows:
The acacia is dissolved in wa-terO 17.5 mg.
of corn starch~ the (D-3-mercapto-2-methylpropanoyl)-L-proline and lactose are mixed thoroughly. The dry mixture is granulated using ~he aqueous solution of acacia. The granulation is wet screened, dried at 120F~ and reduced. Th~ reduced, dry granulation is mixed with the hydrochlorothiazide and the remaining excipients are then added and mixed. The mixture i5 compressed into tablets of 700 mg. each.
Example 3 Tablets each containing the following ingredients are made as descrlbed in Example 2:
(D-3-mercapto-2-methylpropanoyl)~
L-proline 75 mg.
Corn starch U.S.P. 8 mg.
Lactose U.S.P. 120 mg.
Acacia U.S~P. 6 mg.
Water qs. (ca. 0.03 ml.
Chlorothiazide 50 mg.
Corn starch U.S.P. 8 mg.
Avicel 75 mg.
Stearic acid 8 mg.
350 mg.
Exam~le ~
1000 capsules, each containing the following ingredients:

HA160a (D-3-mercapto-2-methylpropanoyl)-L-proline lO0 mg.
Lac~ose U.S.P. 211.8 mgO
Magnesium stearate 3.2 mg.
Hydrochlorothiazide 10 mg.
325 mg.
are produced by dry blending the hulk materials (except the magnesium stearate) in a Hobart mixer, then passing the blend through a #20 screen. The materials are mixed again in the Hobart mixer with the magnesium stearate. The mixture is then filled into #2 two-piece gelatin capsules.
Example 5 By substituting 10 mg. of furosemide for the hydrochlorothiazide in Example 4, capsules containing furosemide and (~-3-mercapto-2-methylpropanoyl)-L-proline are similarly produced.
Example 6 By following the proceudre of Example 2 but substituting 20 mg. of furo~emide for the hydrochloro-thiazide and using 220.4 mg. of lactose, 700 mg.
tablets each containing 20 mg. of furosemide and 200 mg. of (D-3-mercapto-2-methylpropanoyl)-L-proline are similarly produced.
Example 7 By substituting 10 mg. of furosemide for the hydrochlorothiazide and using 115.5 mg.iof lactose in the procedure of ~xample 1, 350 mg. scored tablats each containing 10 mg. of furosemide and 100 mg. of (D-3-mercapto-2-methylpropanoyl)-~-proline are similarly produced.

3~ Oa Exam~
6000 ~cored ~ablets of 400 mg. each and containing the following ingredients:
(D 3-mercapto-2~methylpropanoyl)-L-praline 125 mg.
; Corn starch 8 mg.
Lactose U.S.P. 95 mg.
Acacia 7 mg.
Water qs. (ca. 0.03 ml.
; 10 Triamterene 50 mg.
Corn starch U.S.P. 8 mg.
A~icel 100 mg.
Stearic acid 7 mg.
400 mg.
are produced as described in Example 2.

6000 scored tablets of 350 mg. each and containing the following ingredients:
(D-3-mercapto-2-methylpropanoyl)-L-proline 100 mg.
~vicel 100 mg.
Triamterene 25 mg.
Lactose U.S.PO 100 mg.
Corn starch U.S.P. 17 mg.
Stearic acid 8 mg.
350 mg.
are produced as described in Example 1.
Example 10 5000 scored tablets of 180 mg. each and containing the following ingredients:
~D-3-mercapto-2-methylpropanoyl)-L-proline 10 mg.

.. ~

HA160a -12=

Avicel 50 mg.
HydrochlQrothiazide 5 mg.
Lactose U.S.P. 101 mg.
Corn starch U.S.P. 10 mg.
Stearic acid 4 mg.
180 mg.
are produced as described in Example 1.
Example 11 By substituting the same amount of ticrynafen ~or the hydrochloro~hiazide in Example 1, tablets containing 100 mg. of (D-3-mercapto-2-methylpropanoyl)-L-proline and 12.5 mg. of ticrynafen are similarly obtained.
Representative of the results obtained with combinations of agents of this invention are data obtained from studies in spontaneously hypertensive ra-ts and two kidney renal hypertensive rats.
A) In an acute study with spontaneously hypertensive rats, ten to fourteen week old male Wistar-Kyoto spontaneously hypextensive rats (190-210 gm.) of the Okamoto-Aoki strain (obtained from Taconic Farms, Germantown, N.Y.) were given food and water ad libitum and intubated according to the method of Weeks and Jones, Proc. Soc. Exp.
Biol. Med. 104, 646-648 ~1960), to prepare them for blood pressure and heart rate determination by implanting indwelling abdominal aortic ca~heters under sodium pentobarbital anesthesia.
Three weeks later their direct blood pressure and heart rate were recorded by the method of Laffan et al., Cardiovasc. Res. 6, 319-324 (1972), modified HA160a as follows. The signal from the transducer was digiti~ed in a 10 bit A/D con~erter and input to a PDP 11/05 computer~ The computer was programmed to sense and store samples at a rate of 125/sec for each rat, as well as the number of pressure pulses ~uring 10 sec. of each scan on each rat. These parameters were averaged and stored as the MBP
(mean blood pressure, mm Hg) and heart rate (beats/min.) for that time. Data were acquired from each rat every five minutes. Six such sets o~ data were averaged to give a mean value repxesenting a 30 minute sample and this 30 minute figure was stored for subsequent analysis. Each time a 48 hour cycle was compleked (or sooner if demanded) the data were transferred serially to a host computer (PDP 11/40) for further analysis and the data were printed out on a Versatec Printer/Plotter ~or at least 16 hours after each dose.
The spontaneously hypertensive rats were segregated into four groups of five rats each (except group 3 which included six rats). The ~ollowing was adminis-tered to the rats in the respective group~:
1. (Control) Agar - 5 ml./kg + agar - 5 ml./kg 2. Water - 5 ml./kg + Compound A - 30 mg./kg 3. Compound F - 50 mg./kg + Agar - 5 ml./kg ** *

4. Compound F 50 mg./kg + Compound A
30 mg./kg * Compound A = (D-3-mercapto-2-methylpropanoyl)-L-proline ** Compound F = Furosemide S~ HA160a Compound F was suspended in 0.25% agar and Compound A was in aqueous solution. All substances were administered by gavage and there was a one hour interval between drugs. Test resul-ts were evaluated 2.5 hours after single oral doses.
The followiny resulks were obtained;
TABLE I
Mean Blood Pressure (mm/Hg) Before 2.5 hours after sinc~le oral dose (1) 173 169 (2) 175 158 (3) 184 172 (4) 177 128 15 ^ In thase studies Compound F alone, 50 mg./kg.
p.o., produced a 9.7% decrease in SHR blood pressure.
Compound A alone, 30 mg~/kg., produced 6.5~ decrease ; in blood pressure. The combination of Compound A, 30 mg.~kg., p.o., + Compound B, 50 mg./kg., p.o., reduced blood pressure in SHR rats by 27~7~o B) In chronic studies with renal hypertensive rats, male rats (]15-150 g.) of the Charles River Sprague Dawley (COBS-CO) s~rain were anesthPtized with ether and a silver clip (0.22 m~ i.d.) was placed on the left renal artery through a flank incision. The contralateral kidney was left intact (two-kidney Goldblatt model: 2-K RHR). Each rat was fitted with a tail cuff for air inflation and a Korotkoff sound microphone for the detection of arterial pulsa~ion.
An oscilloscope was used for a visual appearance and disappearance of ~he pulse. Blood pressure measurements IA16Oa were determined after a minimum of six inflations withsystolic pressures observed on a Narco physiograph manome~er. Blood pressures were determined initially just prior to dosing and twice weekly at 4 hours after S dosing.
The number of rats in each group was 15. Single daily treatments were made by gavage with crossover treatments as indicated in the table below. The c~ntrol gro~p received distilled water. Compo~md was administered in distilled water, 30 mg./kg~
Compound H was administered in 0.25% methylcellulose.
The mean blood pressure ~mm/Hg.) for each group before dosing and on day 119 (4 hours after dosing) and the number of survivors on day 120 is shown in the table~

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.

HA160a The foregoing data show that on long term treatment compound ~I shows no significant decrease in blood pressure. Compound A alone shows approximately a 10 to 15~ reduction in blood pressure. The combination dosing with Compound A and Compound H shows approximately a 30~ reduction in bloocl pre~sure.
~oreover, the combination is the only one howing a 100~ survivor rate.

~0 :~0

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. An oral antihypertensive composition comprising about 30 to 600 mg. of a compound of the formula wherein R is hydroxy, lower alkoxy or NH2;
Rl and R4 each is hydrogen, lower alkyl or phenyl-lower alkyl;
R2 is hydrogen or R5-CO;
R3 is hydrogen, hydroxy or lower alkyl, R5 is lower alkyl, phenyl or phenyl-lower alkyl; and n is 0, 1 or 2, about 15 to 300 mg. of a diuretic selected from the group consisting of chlorothiazide, hydrochlorothiazide, amiloride, flumethiazide, hydro-flumethiazide, bendroflumethiazide, methylclothiazide, trichlormethiazide, polythiazide, benz-thiazide, ethacrynic acid, ticrynafen, chlorthalidone, furo-semide, bumetanide, triamterene, spironolactone and salts thereof, and a physiologically acceptable carrier therefor.

2. A composition as in claim 1 comprising about 30 to 300 mg. of the compound of the formula and about 15 to 200 mg. of the diuretic.

3. A composition as in claim 1 wherein the compound of the formula has R as hydroxy or lower alkoxy; Rl as hydro-gen or lower alkyl; R2 as hydrogen or lower alkanoyl; R3 as hydrogen or hydroxy; R4 as hydrogen or lower alkyl; and n as 0 or 1.

4. A composition as in claim 1 wherein the compound of the formula has R as hydroxy; R1 as hydrogen or methyl; R2 as hydrogen or acetyl; R3 as hydrogen; R4 as hydrogen or methyl; and n as 0 or 1.

5. A composition as in claim 1 wherein the diuretic is chlorothiazide, hydrochlorothiazide, furosemide, ticryna-fen or triamterene.

6. A composition as in claim l wherein the diuretic is hydrochlorothiazide or furosemide.

7. A composition as in claim 1 wherein the compound of the formula has R as hydrogen or lower alkoxy; R1 as hydrogen or lower alkyl; R2 as hydrogen or lower alkanoyl; R3 as hy-drogen or hydroxy; R4 as hydrogen or lower alkyl; and n as 0 or l; and the diuretic is chlorothiazide, hydrochlorothia-zide, furosemide, ticrynafen or triamterene.

8. A composition as in claim 1 wherein the compound of the formula is (D-3-mercapto-2-methylpropanoyl)-L-proline and the diuretic is hydrochlorothiazide or furosemide.

9. A composition as in claim 1 comprising about 30 to 300 mg. of (D-3-mercapto-2-methylpropanoyl)-L-proline and about 15 to 200 mg. of hydrochlorothiazide.

10. A composition as in claim 1 comprising about 30 to 300 mg. of (D-3-mercapto-2-methylpropanoyl)-L-proline and about 15 to 200 mg. of furosemide.

11. A composition as in claim 1 comprislng about 5 to 125 mg. of (D-3-mercapto-2-methylpropanoyl)-L-proline and about 2.5 to 50 mg. of hydrochlorothiazide.

12. A composition as in claim 1 comprising about 5 to 125 mg. of (D-3-mercapto-2-methylpropanoyl)-L-prollne and about 2.5 to 50 mg. of furosemide.

13. A composition as in claim 1 comprising about 5 to 125 mg. of (D-3-mercapto-2-methylpropanoyl)-L-proline and about 5 to 75 mg. of triamterene.