CA1262684A - Aminoacid derivatives composition in association with diuretic agents - Google Patents

Abstract

A B S T R A C T

A solid oral dosage unit for reducing hyper-tension which comprises a combination of a carboxy-alkyl dipeptide derivative antihypertensive agent and a diuretic agent in admixture with a solid pharma-ceutically acceptable carrier.

Description

3~
- 1 - 16271~.

This is a divlsional of Canadian Serial No. 341340, filed Dece~ber 6, 1979.
The p:resent invention relates to a solid oral dosage unit for reducing hypertension whlch com-prises a cornbination of a carboxyalkyl dipeptidederivative antihypertensive agent and a diuretic agent in admixture with a solid p~larmaceutically acceptable carrier.
The carboxyalkyl dipeptide derivative corre-sponds to the general formula I:
O Rl R3 R R5 O
R -C -C -NH -CH -C -N -C -C _R6 I
wherein:
R is lower alkoxy;
Rl is a substituted lower alkyl wherein the sub-stituent is phenyl;
R~ and R7 are hydrogen;
R3 is lower alkyl;
R4 is lower alkyl;
R5 is lower alkyl;
za R4 and R5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms;
R6 is hydroxy;
and the pharmaceutically acceptable salts th~reof.
The lower alkyl groups except where noted Z5 otherwise represented by any of the variables include straight and branched chain hydrocarbon radicals from one to six carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or vinyl, allyl, butenyl and the like.
The Rl substituted lower alkyl moieties are exemplified by groups such as - Z - 1~271~

~ CH2--` R4 and R5 when joined through the carbon and nitrogen atoms to which they are attached form a 4 to 6 membered ring. Preferred ring has the formula:
rl -N ~

COOH
S Preferred are those compounds of Formula I
wherein:
R is lower alkoxy;
R6 is hydroxy;
R2 and R7 are hydrogen;
R3 is lower alkyl;
R4 and R5 are joined to form the preferred ring as defined above;
Rl is as defined previously.
Still more preferred compounds are those pre-ferred compounds of Formula I wherein further Rl is a substituted lower alkyl wherein the alkyl group has 1-4 carbon atoms and the substituent is phenyl.
Most preferred are compounds of Formula I
wherein:
R is lower alkoxy;
R6 is hydroxy;
R2 and R7 are hydrogen;
R is methyl;
R4 and R5 are joined through the carbon and nitrogen atom to form proline;
Rl is a substituted lower alkyl wherein the alkyl group has 1-4 carbon atoms and the substituent is phenyl.

~3 The preferred, more preferred and most pre-ferred compounds also include the pharmaceuticall~
acceptable salts thereof.
The products of Formula I and the preferred subgroups can be produced by one or more of the methods and subroutes depicted in the following equations:
O Rl ~ O R4 R5 O
~ 6 R -C -C -NH -CH -C -N -C -C -R

2 R7 I

The combination of compounds of formula I
with other diuretics and/or hypertensives are combi-nations whose individual per day dosages range fromone-fifth of the minimally recommended clinical dosages of the maximum recommended levels for the entities when they are given singly. To illustrate these combinations, one of the antihypertensives of this lnvention effective clinically in the range 15-200 milligrams per day can be effectively combined at levels ranging from 3-200 milligrams per day with the following antihypertensives and diuretics in dose ranges per day as indicated:

5~
~ 271Y

hydrochlorothiazide (15-200 mg), chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 ma), furosemide (5-80 mg), propanolol (20-480 mg), timolol (5-50 mq.) and methyldopa (65-2000 mg). In addition, the triple drug combinations of hydrochlorothiazide (15-200 mg) plus amiloride (5-20 mg) plus converting enzyme inhibitor o~ this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol (5-50 mg) plus the converting enzyme inhibitor of this invention (3-200 mg) are effect-ive combinations to control blood pressure in hypertensivepatients. The above dose ranges will be adjusted on a unit basis as necessary to permit divided daily dosage.
Also, the dose will vary depending on the severity of the disease, weight o~ patient and other factors which a person skilled in the art will recognize.
Typically the combinations shown above are formulated into pharmaceutical compositions as discussed below.

I

About lO to 500 mg. of a compound or mixture of compounds of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystal-line cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubri-cant such as magnesium stearate; a sweetening agent suchas sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to mate-rials of the above type, a liquid carrier such as fatty oil.
Yarious other materials may be present as coatings or to otherwise modify the physical form of the dosage unit.
~or instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active com-pound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Compounds of the formula I useful in the combination of the present application may be prepared in the following manner.

~5 - 6 - J6271'~

As will be e~ident to those skilled in the art and as demonstrated in the Exa~ples, reactive groups not involved in the condensations, such as amino, carboxy, etc., may be protected by methods standard in peptide chemistry prior to the coupling reactions and subse-quently deprotected to ob~ain the desired products.

~ethod I, Route l (R2 = H) O Rl R30 R4 R5 6 NaB~3CN
R-C-C = 0 + H2NCHC - N - C - C - R
'7 _ III

Keto acid (or ester, amide or hydroxamic acid) II is condensed with dipeptide III in aqueous solution, optimally near neutrality, or in suitable organic solvent (CH3C~ for example) in the presence of sodium cyano borohydride to give I (R = H). Alter-natively the intermediate Schiff base, enamine,or aminol may be catalytically reduced to yield produc: I, for example, by hydrogen in the presence of lO~ palladium on carbon or of Raney nickel. The ratio of dia~teriomeric products formed may be altered by choice of ~catalyst.
If R6 is a carboxy protecting group such as alkoxy or benzyloxy or the like, it can be converted by well-known methods such as hydrolysis or hydro~enation to (I), where R is hydroxy. This is true in all the following methods where the above situation exists.

~ 7 - 1~271 Alternatively II can be condensed with an amino acid IV

R3 0 Rl R3 I NaBH3CN R-C-CHNHCHCOOH
IV V

under the same conditions to yield amino acid V. Sub-sequent coupling by known methods with amino acid derivative VI gives I.
The known methods encompass rea¢tive group pro-tection during the coupling reaction, for example, by N-formyl, N-t-butoxycarbonyl and N-carbobenzyloxy groups followed by their removal to yield I. F~rther,~ore, the R
function may include removable ester groups such as benzyl, ethyl, or t-butyl. Condensing agents in this synthetic route are typically those useful in peptide chemistry such as dicyclohexvlcarbodiimide (DCC) or diphenylphosphoryl azide (DPPA) or V may be activated via the intermediacy o' active esters such as that derived from l-hydroxybenzotri-azole.

R R
6 DCC ~
R7 (DCC = Dicyclohexylcarbodiimide) or (VI) DPPA
(DPPA = Diphenylphosphoryl azide~

RQ~e, 2 O Rl ~30 R R
1~ 1 1 1~ 1 I r ~-C - C - NH2 + O=C-C - N - C ~ CO - R~

VII VIII

Amino acid (or ester, amide or hydroxamic acid) VII
is condensed with ketone VIII under conditions described for Route I to give I.
Alternatively the synthesis can be performed in a step-wise fashion by condensing VII with keto acid R3 Rl R3 VII + O = C - COOH - ~ RC - C - NHCH COOH
R
IX X

to yield amino acid X. By known methods as indicated above under Route l, X can be condensed with amino acid derivative VI to give I.
R R5 0 Rl R O R R50 X + HN - C CO - R ~ R - C- C - NHCHC-N-C-C-R

VI

In the special case of R bearing an Q-amino substituent, the carbonyl and amino groups can be convenient-ly protected as a 3-lactam function.

3~
- ~ - 16271 Method 2 Route 1 _ n I 1 6 H2N - CH - C - N - C - COR + X-C - COR
R7 ~2 I X

O Rl R O R4 R5 r R-C - C - NH - CH - C - N - C - COR

The dipeptide III is alkylated with the appropriate c-haloacid (ester or amide) or a-sulfonyloxy acid (ester or amide) XI under hasic conditions in water or an organic solvent.
X is chlorine, bromine, iodine or alkyl sulfonyl-oxy or aryl sulfonyloxy.
Alternatively the synthesis can be performed in a s~epwise fashion R3 Rl Rl R3 .
H N-CH-COOH + X~C ~ COR ~RCO ~ C ~ NH-CH ~ COOH

_ XI X

R4 R5 o Rl R3 O R4 R5 ~ ~ n ~ I n ~ I
+ HN - C - COR ~ R-C-C -NH-CH-C-N -C -COR~
R7 x2 R7 VI

X = Cl, Br, I, alkylsulfonyloxy or arylsulfonyloxy.

The aminoacid IV is alkylated by the c-halo-acid (ester or amide) or ^-sulfonyloxy acid (ester or amide) Xl under basic conditions to yield compounds X.
This is condensed by standard methods as indicated under ~oute 1 with the aminoacid (ester or amide) VI to afford I.
Reductive cleavage of a benzyl ester I ~where R6 is benzyloxy and R is alkoxy) will yield compounds of Formula I wherein R is alkoxy and R6 is hydroxy.
~0 Route 2 R-C - C -NH2 + X-CH-C-N-C -COR6 O ~2 R
VII XII

Rl R3 O R R5 O
R-C-C-NH-CH-C-N-C -CR~
o R2 R7 I
X = Cl, Br, I, alkyl sulfonyloxy or aryl sulfonyloxy.
The aminoacid or derivative VII is alkylated with the appropriately substituted c-haloacetyl or ~-sulfonyloxy acetyl aminoacià XII under basic conditions in water or other solvent to obtaln compour.ds of Formula I.
Alternatively, the synthesis can be performed in a step-wise fashion by condensing an aminoacid ester VII with a substituted -11 ~ 16271 Rl R3 ~1 R3 RCO -C-NH2 + X-CH-COOH ~ RCO-C-NH-CH-COOH

VII XIII X

X +HN-CH-COR >
Rl VI

Rl R30 R4 RS O
n ~;
R- C-C-NH- C~ C-N- C ~ CR
o R2 R7 Q-haloacetic acid or a-sulfonyloxy acetic acid ~XIII) to yield the intermediate X. By known methods described under Route 1, X can be coupled with an aminoacid VI or derivative to give I.
As desired, protecting groups may be removed by known methods.
The starting materials which are required for the above processes herein described are known in the literature or can be made by known methods from known starting materials.
In products of general Formula I, the carbon atoms to which Rl, R3 and ~ are attached may be asymmetric. The compounds accordingly exist in disastereoisomeric forms or in mixtures thereof. The above described syntheses can utilize racemates, enantiomers or dias~ereomers as starting materials. When diastereomeric products result from the synthetic procedures, the dia5tereomeric products can be separated by conventiorl21 chro~atographic or frac-5 tional crystallization methods. In general, the aminoacidpart-structures~ i.e., O Rl R3 R4R5 O
n I I I n R-C-C-NH- , -NH-CHCO -- and -N~C -C-R2 ~ R7 of Formula (I) are preferred in the S-configuration.
The compounds of this invention form salts with various inorganic and organic acids and bases which are 10 also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases e.g., dicyclohexylamine salts, N-methyl-15 D-glucamine, salts with amino acids like arqinine, lysine and the like. Also salts with organic and inorganic acids may ~e p~-epared, e.g., ~Cl, HBr, H2SO4, H3PO4, methane-sulfoni~, toluensulfonic, maleic, fumaric, camphorsulfonic.
The non-toxic physiologically acceptable salts are pre-20 ferred, although other ~alts are also useful, e.g., inisolating or purifying the product.
The salts may be formed by conventional means, as by reacting the free acid or free base forms of the produc~ with one or more equivalents of the appropriate 25 base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed ln vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchanqe resin.

~ 13 - 16271~

The following examples illustrate the prepa-ration of a combination tablet and the preparation of N-(l(S)-ethoxycarbonyl-3-phenylpropyl)~L-alanyl-L-proline.
EXAMPLE l A combination tablet with a diuretic such as hydrochlorothiazide typically contains N-(l(S)-ethoxy-carbonyl-3-phenylpropyl)-L-alanyl-L-proline (7.5 mg), hydrochlorothiazide (50 mg), pregelatinized starch USP
(82 mg), microcrystalline cellulose (82 mg) and mag-nesium stearate (l mg).

N-(l(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline _ Ethyl 2-oxo-4-phenylbutyrate (1.03 g) and L-alanyl-L-proline (0.19 g) are dissolved in a l:1 ethanol-water solvent. A solution of sodium cyanoboro~
hydride (0.19 g) in ethanol-water is added dropwise at room temperature over the course of two hours. When reaction is complete, the product is absorbed on strong acid ion-exchange xesin and eluted with 2% pyridine in water. The product-rich cuts are freeze dried to give 0.25 g of crude N-(l-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline. The mass spectrum shows a molecular ion at 448 m/e for the monosilylated species. Chroma-tography affords the desired isomer.

:

Claims (3)

WHAT IS CLAIMED IS:

1. A solid oral dosage unit for reducing hypertension comprising a combination of a diuretic and/or antihypertensive with a compound of the formula I:

I

wherein:
R is lower alkoxy;
R1 is a substituted lower alkyl wherein the sub-stituent is phenyl;
R2 and R7 are hydrogen;
R3, R4 and R5 are lower alkyl;
R4 and R5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms;
R6 is hydroxy;
in admixture with a solid pharmaceutically acceptable carrier.

2. A solid oral dosage unit for reducing hypertension comprising a combination of hydrochloro-triazide and N-(1(S)-ethoxycarbonyl-3-phenylopropyl)-L-alanine-L-proline in admixture with a solid pharmaceuti-cally acceptable carrier.

3. A solid oral dosage unit for reducing hypertension comprising a combination of 50 mg of hydro-chlorotriazide and 7.5 mg of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine-L-proline in admixture with a solid pharmaceutically acceptable carrier.