FR2641972A1 - NEW THERAPEUTIC USE OF (ALPHA) -AMINOFLUOROCETONES - Google Patents

Abstract

The present invention relates to the use of alpha-aminofluoroketones, especially benzyloxycarbonyl-1-phenylalanylalanylfluoromethylketone, for the preparation of medicaments having cardiovascular and antihypertensive activity.

Description

The subject of the present invention is a

  new therapeutic use of "-aminofluoro-

  ketones, especially for the treatment of disorders

  cardiovascular and high blood pressure.

  American patent 4518528 describes the = -aminofluoroketones of formula: o

X-N - N CHF-R2

R1 I (a) R or

X- N CH CHF-R2

  (CH2) I (b) or o0 X_ Y_N i / - CHF - R2 I (c) R%

X-Y- N CHF-R2 ()

or

X- Y- N (CH2) CH CHF- R2

\ (CH2) n I (d)

  in which R1 and R2 each signify, independently

  in each case, hydrogen or an optionally substituted C1-C6 alkyl group, aryl or alkylaryl o the alkyl group contains i to 4 carbon atoms; n means an integer from i to 4; Y

2641-972

  means an amino acid or a peptide chain containing

  from 2 to 6 amino acids and X signifies a group

terminal protector of peptides.

  The substituted alkyl group means an alkyl group substituted by a hydroxy, amino group,

guanidino, carboxy or mercapto.

  In said US patent, the α-amino-

  fluoroc6tones are described as having irreversible inhibitory activity on serine protease and cysteine protease, including cathepsin B, H, C, G, R, elastase, trypsin, plasma kallikrein, glandular kallikrein, plasmin , the plasminogen activator etc ... In this document it is suggested

  that the compounds can be used for processing

  emphysema, but no mention is made

  that these compounds can have a cardiovascular effect

  laire. The Applicant has now surprisingly found that the aaminofluoroketones of formula I (a) -I (d) have antihypertensive properties such as

  it appears from the tests carried out in the spontaneous rat -

  hypertensive according to the protocol described for example by Fozard et al., in J. Cardiovasc. Pharmacol. 9, 328-347 (1987). In this test, the compounds of formula I (a) -I (d) exert antihypertensive activity after oral administration at a dose of between and 50 mg / kg. In contrast, the compounds do not lower blood pressure in normotensive rats, even at doses up to 60 mg / kg administered orally

  oral. It has also been found that the potentia-

  read and prolong the drop in blood pressure

  produced by the auriferous natriuretic factor

  cular (ANF) in anesthetized rabbit and open chest, according to the protocol described by Hof in Brit. J.

Pharmacol. 78, 375-394 (1983).

  Due to their anti-hypertensive effects

  The compounds are also indicated for use.

  prophylaxis or treatment of

  cardiovascular disorders, for example

  heart failure, left ventricular hypertrophy and stroke, such as

cerebrovascular attacks.

  The present invention therefore relates to the use of

  sation of the compounds of formula I (a) -I (d) for the preparation

  ration of drugs with cardiovascular activity

  anti and hypertensive. The preferred compounds are those of formula I (a) and I (c), more preferably those of formula I (c), in particular those in which Y signifies a single amino acid, preferably phenylalanine. R2 preferably means hydrogen and RI preferably means a methyl group. The compound

  especially preferred is benzyloxy-carbonyl-1-

  phenylalanyl-alanyl-fluoromethyl-ketone corresponding to the formula CHrH2o {t,, 0, C N "'/v.dC' 0 NH.11 'C w'H CH2F

0 CH3

  This compound can be obtained in the form of the racemic mixture of the Z- (L) -Phe- (L) Ala-CH2F isomers and

  Z- (L) Phe- (D) Ala-CH2F, where Z signifies a benzyl-

  oxycarbonyl, or in pure (L, L) form. The mixture and

  the pure form (L, L) have identical activity.

  The antihypertensive effect starts slowly and lasts a long time, the maximum effect being reached approximately 5 hours after administration, and

  persists for approximately 24 hours after administration

  tration. For use as an antihypertensive agent and for other cardiovascular indications, the appropriate dose of active substance naturally varies depending on the compound of formula I (a) -I (d) used, the patient, the mode of administration and the nature and severity of the condition to be treated. A suitable daily dose is between approximately 700 and approximately 3.5 g administered advantageously by

  example in divided doses, up to 4 times a day.

  The compounds of formula I (a) -I (d) can be administered by any usual route, for example by enteral route, preferably by oral route, for example in the form of tablets or capsules, or by parenteral route , for example under

  form of injectable solutions or suspensions.

  The compound of formula II is the preferred compound. It was determined, for example, that this compound had an ED50 of 15 mg / kg in the spontaneously hypertensive rat as described above. The compound of formula II can therefore be administered orally to

  a daily dose of between 700 mg and 2.5 g.

  The invention also relates to the compounds

  pharmaceuticals with cardiovascular activity

  cellular and anti-hypertensive and comprising the compounds of formula I (a) I (d) in combination with at least one pharmaceutical carrier or diluent, for example hydroxypropylcellulose, corn starch, lactose, silica gel, magnesium stearate etc ... Such compositions can be prepared according to the usual methods. Unit dosage forms contain, for example, from about 175 mg to about

1.75 g of active substance.

  The following example illustrates this

  invention without in any way limiting its scope.

EXAMPLE

  Tablets having the composition are prepared

  Next tion: Components Weight (mg) Compound of formula II 250 Lactose 58 Corn starch 90 Methylhydroxypropylcellulose 14 Amorphous silica 3 Magnesium stearate 5

TOTAL 420

Claims (6)

  1. The use of a-aminofluoroketones of formula o H X-N CHF-R2 R I (a) or 0 X N'C X- * (N- CH \ CHF-R2 2) n \ (CH2) 5   I (b) or on H X_- .. Y- N / CHF- R2 I (c) or R X- Y- N CH CHF- R2 I (d) (CH2).   in which R1 and R2 each signify, independently   in each other, hydrogen or an optionally substituted C1-C6 alkyl group, aryl or alkylaryl o the alkyl group contains i & 4 carbon atoms; n means an integer from i to 4; Y   means an amino acid or a peptide chain containing   from 2 to 6 amino acids and X signifies a terminal protecting group for peptides, for the preparation of medicaments having cardiovascular and anti-hypertensive activity.   2. The use of benzyloxy-carbonyl-   l-phenylalanyl-alanyl-fluoromethyl ketone of formula II xCH 2 0 h   a CH U c NHN C C H2 / NH / c / N C CH2F II O CH3   for the preparation of a drug having activity   cardiovascular and anti-hypertensive.   3. The use according to claim 1,   characterized in that α-aminofluoroketone is administered   administered orally at a daily dose of between 700 mg and 3.5 g at one time or in divided doses. 4. The use according to claim 2, characterized in that the compound of formula II is administered orally at a daily dose of between 700 mg and 2.5 g in one go or in divided doses.   5. A pharmaceutical composition having cardiovascular and anti-hypertensive activity, and comprising a compound of formula Ia, Ib or Ic as specified in claim 1, in combination with a   pharmaceutically acceptable diluent or vehicle.   6. A pharmaceutical composition having cardiovascular and anti-hypertensive activity, and comprising the compound of formula II specified in claim 2, in combination with a diluent or   pharmaceutically acceptable vehicle.