MC1793A1 - NOVEL COMPOUNDS, THEIR USE IN MEDICINE, PHARMACEUTICAL FORMULATIONS CONTAINING THEM AND PROCESS FOR THEIR PREPARATION - Google Patents

Description

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The present invention relates to new chemical compounds, their preparation, compositions containing them and their use in medicine.

Compounds exhibiting 5-beta-blocking activity, such as those described in U.S. Patent No. 3,705,907, are widely used in the therapy of hypertensive disorders. Another class of agents used to treat hypertension are angiotensin-converting enzyme (ACE) inhibitors.

10 (ECA), as described for example in the European patent

No. 0 012 401-Al. It is now accepted that compounds which are both B-blocking agents and ACE inhibitors are particularly useful in the treatment and/or prophylaxis of hypertension.

15 The Applicant has now discovered that the compounds of formula (I) (as defined below) and their physiologically acceptable salts exhibit both O-blocking and ACE-inhibiting activity.

In formula (I):

g1g2g3

I ' 1

b-(x)-a-ç-n-c-c-(y)-e (i)

Z DO

20 A is a group of formula ~Q]c-(NQ^)m~(CH2^n-/ °" k and m are independently chosen between 0 and 1 provided that m is 0 if k is 0, n is a number from 1 to 6, is hydrogen or an alkyl group in Q is chosen from -C0-/ -CH2CO- and -OCH2CO-, and any of the

25 groups -^^2^n- son^ possibly independently substituted by one or two alkyl groups in '

B is a group with the formula -R1-CQ2(OH)-C(Q3)(Q4)-NQ5-R2,

1 6 7 2

where R is a bond or -OC(Q)(Q)-, R is hydrogen

27

or an alkyl group in and Q -Q are independently

30 of hydrogen/ a C,-C4 alkyl group or a group of

8 9 1 4

formula —(C(Q)(Q)) Ph, where x is 1 or 2, Ph is a group

HAS

[P

c phenyl possibly substituted by one or more groups independently chosen from the hydroxy, alkyl groups in

8 9

C^-C^ and alkoxy in and Q and Q are independent of hydrogen or an alkyl group in '

5 E and Z are independently chosen from the carbo- groups

xyl and carboxyl derivatives, for example of the ester type;

D is hydrogen or an aliphatic substituent in C^-C^

saturated or unsaturated/ possibly substituted by an amino group;

12 3

10 G, G and G are independently chosen from hydrogen and ajkyl groups in;

(X) is a mono-, bi-, or tricyclic aromatic system possibly containing one or more heteroatoms; and

(Y) is a nitrogen mono- or bicyclic system (linked to 3

15 -CO-C(D)(G )- by the nitrogen atom in question) containing

possibly one or more other heteroatoms and possibly substituted by one or more independently chosen substituents from the aryl and alkyl groups in C^-Cg (e.g. phenyl), or (Y) is a nitrogen atom 20 directly linked to E by a bond or indirectly by an alkylene fragment in and also linked to a cycloalkyl group in C^-C^; in either case, (Y) may possibly be linked to G3 or D by an alkylene bridge in Cg-Cjj to form a closed ring;

25 provided that:

if, in the definition of A, k and m are both 0 or both 1 and Q is a -CO- group, and, in the definition

X 6 7

of B, R is a group of formula -OC(Q)(Q)- as defined

30

2

above and R is an alkyl group in

D is hydrogen or a C-Cg alkyl group, and (K) is a benzene ring or a naphthyl or indolyl cyclic system, each of them possibly substituted at any positions by one or more independently chosen substituents from among the alkyl groups (themselves possibly substituted by one or more halogen atoms), C2-C4 alkoxy halogen, nitro,

P

*

amino, carbonyl, alkoxycarbonyl and hydroxy,

then, (Y) is not a pyrrolidinyl > oxazolidinyl or thiazolidinyl ring, nor a cyclic system chosen from indolinyl, quinolinyl and tetrahydroquinolinyl.

5. Preferably, in the definition of A, n is

2

3-5, especially 4. In the definition of B, R is preferably a C1-C4 alkyl group, i.e., a methyl, ethyl, 11-propyl, isopropyl, 11-butyl, isobutyl, or 11-butyl group; the isopropyl group is preferred in particular. In the definitions of E and Z, carboxyl derivatives include esters, especially C1-C4 benzyl and alkyl esters, and hydroxymethylene and carbamoyl derivatives. Preferably, D is an alkyl group, especially a methyl group.

15 The cyclic system denoted by (X) can, for example, correspond to the formula:

where B is the point of attachment of B, a is the point of attachment of A, 1^ J4 is a pyrrole, pyridinic, or benzene ring (i.e., (X) is respectively a 20-cyclic system of indole, quinoline, or naphthalene), y and

3

z are independent integers from 0 to 3, and R and

4

R are independently chosen from halogen, alkyl (which may themselves be substituted by one or more halogen groups), and hydroxyl groups. The cyclic system 25 denoted by (X) can also be, for example,

a benzene ring possibly substituted by one or more groups as defined for R3 and R4 above. Another particularly preferred cyclic system for (X) is a carbazole system, especially when A and B are each attached to a different ring, the two

s phenyl rings possibly being substituted by 3 4

groups (R ) and (R )^, respectively, as defined above.

The cyclic system denoted by (Y) may be chosen from among the following groups: pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroli-dinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazo-lidinyl, pyrazolinyl, piperidinyl, piperidinyl, 1H-indolyl, 3H-indolyl, oxalidinyl, quinolyl, tetrahydro-10 quinolyl and morpholino, or, in general, it may be a group chosen from those of formula:

- r6

— NC 5

VR

e

5 6

where (i) R and R can together form a C2-C5 alkylene fragment to give a nitrogen ring which can itself be condensed with a C15-C15 cycloalkyl ring or with a C1-C7 aryl ring (e.g., phenyl); or (ii) R can be hydrogen or an alkyl group

en and R a cycloalkyl group in C^-C^.

As previously stated, in either 5

In case (i) or (ii), R may possibly be linked to the group

3

20 D or G of formula (i) by an alkylene bridge in C^-C,- to form a closed ring.

Suitable groups for (Y) may be any of those presented as the N-terminal group of ACE inhibitors described in J. Cardiovasc. Pharmacol., 25 Vol. 7 (Suppl. 1), 1985, page S4 (H.R. Brunmer et al.) or in European patent No. 0 159 156-A1.

Preferred compounds according to the present invention are as follows:

N-(l-carboxy-5-[5-(2-hydroxy-3-isopropylamino-30 propoxy)carbazole-3-carboxamido]pentyl)alanylproline,

N-(l-carboxy-5-[5-(2-hydroxy-3-isopropylamino-propoxy)carbazole-2-carboxamido]pentyl)alanylproline,

e

N-(l-carboxy-5-[8-(2-hydroxy-3-isopropylamino-propoxy)naphth-2-ylmethylamino]pentyl)alanylproline,

N-(1--carboxy-5-[5-(2-hydroxy-3-isopropylamino-propoxy)naphth-2-ylmethylamino]pentyl)alanylproline, 5 N-(l-carboxy-5-[4-(2-hydroxy-3-isopropylamino-

propoxy)-lH-indole~2-ylmethylamino]pentyl)alanylproline, N-(l-carboxy-5-[4-(2-hydroxy-3-isopropylamino-propoxy)-lH-indole-3-ylmethylamino]pentylalanylproline, N-(l-carboxy-5-[8-(2-hydroxy-3-isopropylamino-10) propoxy)quino3ein-2-carboxamido]pentyl)alanylproline,

N-(l-carboxy-5-[5-(2-hydroxy-3-isopropylamino-propoxy)quinoJein-2-carboxamido]pentyl)alanylproline,

N-(l-carboxy-5-[4-(2-hydroxy-3-isopropylamino-propoxy)benzylcarboxamido]pentyl)alanylproline, and 15' N-[l-carboxy-5-(2-[5-(2-hydroxy-3-isopropylamino-

propoxy)naphth-l-yloxy]acetamido)pentyl]alanylproline,

and their hemi-esters (in which Z is a C^-C^)i carbo-alkoxy group in all their individual isomeric forms, and their salts.

20 Particularly preferred isomers of corn-

1. The questions posed above are as follows:

N-(1(S,R)-carboxy-5-[5-(2(S,R)-hydroxy-3-isopropyl-aminopropoxy)carbazole-3-carboxamido]pentyl)-(S)-alanyl-(S)-proline,

25 N-(1(S,R)-carboxy-5-[5-2(S,R)-hydroxy-3-isopropyl-

aminopropoxy)carbazole-2-carboxamido]pentyl)-(S)-alany1-(S)-proline,

N-(1(S)-carboxy-5-[5-(2(S,R)-hydroxy-3-isopropyl-aminopropoxy)carbazole-3-carboxamido]pentyl)-(S)-alanyl-(S)-30 proline,

N-(l(S)-carboxy-5-[5-(2(S,R)-hydroxy-3-isopropyl-aminopropoxy)carbazole-2-carboxamido]pentyl)-(S)-alanyl-(S)-proline,

N-(1(S)-carboxy-5-[8-(2(S,R)-hydroxy-3-isopropyl-35 aminopropoxy)naphth-2-ylmethylamino]pentyl)-(S,R)-alanyl-(S)-proline,

N-(1(S)-carboxy-5-[5-(2(S,R)-hydroxy-3-isopropyl-aminopropoxy)naphth-2-ylmethylamino]pentyl)-(S)-alanyl-(S)-proline/

N-(1(S)-carboxy-5-[4-(2(S/R)-hydroxy-3-isopropyl-5 aminopropoxy)-1H-indole-2-ylmethylamino]pentyl)-(S)-alanyl-(S)-proline/

N-(1(S)-carboxy-5-[4-(2(S,R)-hydroxy-3-isopropyl-aminopropoxy)-lH-indole-3-ylmethylamino]pentyl)-(S)-alanyl-(S)-proline,

10 N-(1(S)-carboxy-5-[8-(2(S,R)-hydroxy-3-isopropyl-

aminopropoxy)quinoMine-2-carboxamido]pentyl)-(S)-alanyl-(S)-proline/

N-(1(S)-carboxy-5-[5-(2(S,R)-hydroxy-3-isopropyl-aminopropoxy)quinoline-2-carboxamido]pentyl)-(S)-alanyl-(S)~ 15 proline,

N-(1(S)-carboxy-5-[4-(2(S,R)-hydroxy-3-isopropyl-aminopropoxy)benzylcarboxamido]pentyl)-(S,R)-alanyl-(S)-proline, and

N-[1(S)-carboxy-5-(2-[5-(2(S,R)-hydroxy-3-iso-20 propylaminopropoxy)naphth-l-yloxy]acetamido)pentyl]-(S,R)-alanyl-(S)-proline.

Among these, N-(l(S)-carboxy-5-[8-(2(S,R)-hydroxy-3-isopropylaminopropoxy)napht-2-ylmethylamino]pentyl )-(S,R)-alanyl-(S)-proline, its hemi-esters (as defined ci-25 above), and their physiologically acceptable salts, are particularly preferred because of their especially advantageous combination of ACE-inhibiting and B-blocking properties.

This preferred aspect of the invention extends equally to hemi-esters (as defined above) and to physiologically acceptable salts of said compounds, and to any mixture of two or more individual isomers of one or more of the particular compounds referred to above.

Physiologically acceptable salts of compounds of formula (I) include salts derived from organic and mineral acids, as well as bases. Approximate salts

%

Examples of acid derivatives include the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, do-5 decylsulfonate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodic acid, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 10 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts formed with organic bases such as dicyclohexylamine and N-methyl-D-glucamine, and salts formed with amino acids such as arginine and lysine.

Quaternary ammonium salts can be pre-prepared, for example, by reaction with lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides, with dialkyl sulfates, with long-chain halides such as decyl, lauryl, myristyle and stearyl chlorides, bromides and iodides, and with aralkyl halides such as benzyl and phenethyl bromides.

In another aspect, the present invention provides compounds of formula (I) and their physiologically acceptable salts for use in medicine, and particularly in a method of prophylaxis or treatment of the human or animal body by therapy, or a diagnostic method. The compounds and salts can be used in all cases where an ACE inhibitor and/or an O-blocking agent is indicated. Thus, for example, compounds of formula (I) and their physiologically acceptable salts can be used for the treatment of all forms

*

for both short- and long-term hypertension (particularly forms associated with elevated serum renin levels) and, more generally, for the treatment of heart failure. Compounds of formula (I) and their physiologically acceptable salts 5 can also be used in the treatment of hyperaldosteronism.

of its physiologically acceptable salts, which is necessary to obtain the desired biological effect, is obviously a function of a number of factors, including, for example, the particular compound chosen, its intended use, the route of administration, and the recipient. In general, a daily dose is expected to be in the range of 1 ng to 100 mg, typically 50 ng to 50 mg, per 15 days and per kilogram of body weight, for example, of

500 ng to 5 mg/kg/day. An intravenous dose may, for example, be in the range of 10 ng to 1 mg/kg and be conveniently administered by infusion at a rate of 0.1 ng to 50 pg per kilogram per minute. Infusion fluids suitable for this purpose may contain, for example, 0.01 ng to 100 pg, typically 0.1 ng to 100 pg, of the active compound per milliliter. Unit dosage forms, for example, may contain 100 ng to 100 mg of the active compound; for example, ampoules for injection may contain 25 to 100 ng to 1 mg, and unit dosage forms for oral administration, such as tablets or capsules, may contain, for example, 0.001 to 50 mg, typically 0.02 to 20 mg. In the case of physiologically acceptable salts/ the weights indicated above correspond to the weight 30 of the active ion which is the ion derived from the compound of formula (I).

The compounds of formula (I) and their physiologically acceptable salts mentioned above can be used as is, but they are preferably presented with an acceptable support in the form of a pharmaceutical formulation according to the present invention. It is obviously necessary that the support

The quantity of a compound of formula (I) or of a

In the treatment or prophylaxis of conditions

10

10

15

20

25

30

be acceptable, in that it must be compatible with the other ingredients of the formulation and not be harmful to its recipient. The carrier may be a solid or a liquid, or both, and is preferably associated with the compound in a unit-dose dosage form, for example, a tablet, which may contain 0.05% to 95% by weight of the active compound. Other pharmacologically acceptable substances may also be present in the formulations of the present invention. One or more of the compounds of formula (I) and/or their physiologically acceptable salts may be incorporated into the formulations. The formulations may be prepared by any well-known pharmaceutical technique that essentially consists of combining and mixing the components.

Formulations include those suitable for oral/rectal, topical/buccal (e.g. sublingual) and parenteral (e.g. subcutaneous/intramuscular/intradermal or intravenous) administration, although the most appropriate route in any given case depends on the nature and severity of the condition being treated and the nature of the particular formula compound (I)/ or its physiologically acceptable salt, which is used.

Formulations suitable for oral administration may be presented as discrete units, such as capsules, caplets, lozenges, or tablets, each containing a predetermined amount of a compound of formula (I) or one of its physiologically acceptable salts; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. These formulations may be prepared by any suitable pharmaceutical method that includes the step of combining the active compound and the carrier (which may consist of one or more secondary ingredients). Generally, these formulations are prepared by thoroughly mixing the active compound with

H

a liquid or solid support, finely divided, or both, and then shaping the product if necessary. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally combined with one or more secondary ingredients. Tablets can be prepared by pressing the compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, and/or a dispersing/surfactant agent, in a suitable machine. Molded tablets can be prepared by molding the powdered compound moistened with an inert liquid diluent in a suitable machine.

acceptable ment, in a flavored base, usually sucrose and gum arabic or gum arabic j and lozenges containing the compound in an inert base such as gelatin and glycerin or 20 sucrose and gum arabic.

Parenteral administration advantageously consists of sterile aqueous preparations of a compound of formula (I), or of one of its physiologically acceptable salts, these preparations preferably being isotonic with respect to the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by subcutaneous, intramuscular, or intradermal injection. These preparations can be conveniently prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with respect to blood. The injectable compositions according to the invention generally contain 0.1 to 5% by weight of the active compound.

35 Formulations suitable for rectal administration are preferably presented in suppository form.

Formulations suitable for oral (sublingual) administration include lozenges containing 15 a compound of formula (i), or one of its physiological salts-

The formulations of the present invention adapted

y>-

Unit-dose formulations. These can be prepared by mixing a compound of formula (I), or one of its physiologically acceptable salts, with one or more carriers, shaping the resulting mixture. Formulations suitable for topical administration to the skin are preferably in the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these. The active compound is generally present at a concentration of 0.1 to 15% by weight of the composition, for example, 0.5 to 2%.

Logically acceptable compounds can be prepared in any conventional manner and/ according to the present invention, they can be prepared by any of the processes described below. In particular, the compounds of formula (I) and their physiologically acceptable salts can be prepared by any of the conventional processes of peptide chemistry/ which may consist of coupling, in any desired order/ the aryl portion, the amino-(hydroxy)aicoxylic side chain and the amino acids or their derivatives, which together form the compounds of formula (I). It should be noted that one can, for example, couple the aryl portion, the side chain, and the amino acids or their derivatives in any order to form two separate chemical entities, which are then coupled at a final operating stage (constituting a characteristic aspect of the present invention) to form the compound of formula (I) or a precursor of this compound, and, if necessary, the precursor is transformed (this transformation also constituting a characteristic aspect of the present invention) into the desired compound of formula (I), and optionally, if desired, the compound of formula (I) is transformed into another compound of formula (I), and possibly also, if conventional solids, for example cocoa butter, then

The compounds of formula (I) and their physico- salts

0

If desired, any compound of formula (I) thus formed is transformed into one of its physiologically acceptable salts.

is also proposed a process for preparing a compound of formula (I) or one of its physiologically acceptable salts, which consists of reacting a compound with a compound R, it being assumed that:

(a) R^ is a compound of formula (II):

Thus, in accordance with the present invention, it

B-(X)-Q-R7

(II)

and R£ is a compound of formula (III):

r -(ch.) -c-n-g-c-(y)-e 2 n 1 1 n '

Z DO

l0'« v z n 1

(m)

z or,

(b) R^ is a compound of formula (IV):

(IV)

and R2 is a compound with formula (V)

(v)

or,

(c) R^ is a compound of formula (VI);

b-(x)-a-c-n-c-c-oh

II

(VI)

Z DO

and R2 is a compound with formula (VII):

H-(Y)-E (VII)

where hydrogen H is bonded to the nitrogen atom of (Y).

In compounds of formulas (II) to (VII), A, 1 3

5 (B), D/ E/ G to G , n, X/ (Y) and Z are as defined below-

7 8 9 11 above, R / R / R and R are independently chosen from an amino group, a suitable derivative of an amino group, or a

7/9

starting group/ such that if R and/or R are a

8

amino group or a suitable amino group derivative, R and/or

11 8 10 R are a starting group> or, conversely, if R

and/or R^s are an amino group or a suitable derivative of

7 9 10

Amino group, R and/or R are a starting group" and R and

12

R are suitable carboxyl protecting groups; and then possibly carry out one or more of the following 15 optional reactions in any desired order: (i) in the event that the product of the reaction of compounds R1 and R2 is a precursor of a compound of formula (I), subject this precursor to suitable conditions and/or treat it with one or more suitable agents, to 20 cause the formation of a compound of formula (I);

(ii) transform any compound of formula (I)

thus formed into another compound of formula (I); and (iii) transform any compound of formula (I) into one of its physiologically acceptable salts. 25 In formulas (III) and (VII) above, as well as throughout this memoir, any of the ~(CH2^n~ groups forming part of the formula of an intermediate compound (for example, as appearing in formulas (III, (IV) and (XV)) are each independently substituted by one or two C^-C^ alkyl groups.

The optional reactions (i) to (iii) above constitute, separately or in any desired combinations, other characteristic aspects of the present invention.

The optional reaction (i) encompasses the case where the precursor of the compound of formula (I) is an analogue of a

10

15

20

25

30

such a compound, but where one or more of its fragments are protected by a suitable protecting group, and the reaction consists of subjecting the precursor to suitable conditions and/or treating it with one or more suitable agents, to cause the removal of the protection and, consequently, the formation of the desired compound of formula (I).

Peptides, and in particular the appropriate protecting and activating groups and the appropriate reaction conditions for the above operations, can be found in the following literature, which is given purely for illustrative purposes and in no way exhaustive or limiting:

a) Schroder and Luebke, "The Peptides" (Academic Press, 1965);

b) Bellean and Malek, J. Am. Chem. Soc., 90, 165, (1968);

(c) Tilak/Tetrahedron Letters, 849 (1970);

d) Beyerman, Helv. Chem. Acta., 56, 1729 (1973);

e) Stewart and Young, "Solid Phase Peptide Synthesis" (W.H. Freeman and Co.) (1969);

f) “Methoden der Organischen Chemie” (Houben-Weyl), 4th edition, Vol. 15, “Synthese von Peptiden”, Parts 1 and 2 (Georg Thieme Verlag, 1974);

g) "The Peptides: Analysis, Synthesis, Biology", E. Gross and J. Meienhofer editors, Vol. 1 to 4 (Academic Press, 1979);

h) “Peptides: Syntheses, Physical Data”, W. Voelter and

E. Schmid-Siegmann, Vol. 1 to 6 (Georg Thieme Verlag, 1983);

i) E. Atherton, M.J. Gait, R.C. Sheppard and B.J. Williams, Bioorganic Chem., 1979, 8, 351-370;

j) R.C. Sheppard, Chemistry in Britain, 1983, 402-414;

k) E. Atherton, E. Brown and R.C. Sheppard, J.C.S. Chem. Comm.,

1981, 1151-1152;

1) T.W. Greene, "Protective Groups in Organic Synthesis",

Wiley, New York, 1981;

m) G.C. Barrett (Ed.), "The Chemistry and Biochemistry of the Amino Acids", 1st edition, Chapman and Hall, London

Details concerning the processes of chemistry and New York, 1985.

As is common in peptide chemistry, different protecting groups can be used simultaneously on different portions of a molecule to allow for the selective removal of the protections at different reaction stages, depending on the reagents used and the reaction conditions applied. Thus, for example, the protecting groups BOC (β-butoxycarbonyl) and TBDMS (β-butyldimethylsilyl) can be removed by treatment with a strong acid such as hydrochloric acid, preferably in a suitable solvent such as methanol. The protecting group Z (benzyloxycarbonyl) can be removed by hydrogenation on palladium carbon, preferably under acidic conditions, in a suitable solvent such as methanol. When it is necessary to protect a carboxyl group as defined for the E and Z groups above, this can be conveniently achieved by forming a corresponding simple ester such as the β-butyl ester, and the subsequent removal of the protection can be carried out by acid hydrolysis.

The optional reaction (i) also encompasses the case where, in the precursor of the compound of formula (I), B represents a reactive substituent R, or a protected form of such a substituent, carried by the group (X), and the reaction consists of treating this product with one or more agents used to effect the substitution of the group B on (X).

In this case, for the preparation of compounds of

5

formula (I) in which Q is hydrogen, the reactive substituent R can be a hydroxyl group and the precursor is made to react with a compound of formula (XXIX):

0

1 / \ ^-Ph x-r -c ÇH'

7 \ N

; Q2 \ ? (XXIX)

/ \ R

Q3 Q4

Ut

2 4 1 2

in which Q to Q, R and R are as defined above,

Ph is a phenyl group and X is a suitable leaving group

such as mesyl/ and the reaction is conveniently carried out under basic conditions, and followed by an elimination of protec-

5 tion/decyclization using a suitable reagent such as trifluoracetic acid.

Alternatively, the reactive substituent R can be a group of formula (XXX):

Q6 I 0

' A 4

-0-C-C-C-Q (XXX)

I7I2I3

Q Q Q

10 in which Q2 to Q4, Q6 and Q7 are as defined above, and the reactant is a suitable amine, the reaction being conveniently carried out by heating in a suitable solvent such as dioxane.

It is to be noted that, instead of substituting group B on the ring or cyclic system (X) in the optional reaction (i), under one aspect of the present invention, an equivalent substitution can be made at any suitable stage in the entire synthesis of the compounds of formula (I) and their physiologically acceptable salts. In particular, this substitution can be carried out by following either of the procedures specified above for the compounds of formulas (XXIX) and (XXX), but using, instead of the precursor of the compound of formula (I) in which R represents a reactive substituent or a protected form of such a substituent, a suitable intermediate compound comprising said group R, where R represents a reactive substituent or a protected form of such a substituent. Examples of suitable intermediate compounds for this purpose are those defined herein by formulas (II), (IV), (VI),

(VIII), (IX), (XII), (XIII), (XIV), (XVI) and (XXVIII). These methods of operation may eventually require one or more

IS

several stages of protection and/or removal of protection, as appropriate.

The optional reaction (i) further encompasses the case where a compound of formula (I) in which Z is an ester 5 is formed by reaction of the corresponding compound of formula (I) in which Z is a carbamoyl group with the appropriate alcohol, in the presence of an acid catalyst, preferably of the ion-exchange type, for example Amberlyst 15.

The optional reaction (ii) may encompass the case where, in the compound of formula (I), E and/or Z are a carboxyl group, and consist of transforming the compound into a corresponding compound in which E and/or Z are a carboxylic acid derivative, for example by treating the compound with a suitable alcohol in the presence of a suitable acid such as sulfuric acid.

The optional reaction (ii) may also encompass the case where, in the compound of formula (I), E and/or Z are a carboxylic acid derivative, and consist of transforming the compound into a corresponding compound in which E and/or Z are a carboxyl group, for example by hydrolysis, for example under basic conditions, such as in the presence of sodium hydroxide.

The optional reaction (iii) may consist of reacting the compound of formula (I) thus formed with a 25 mineral or organic acid.

Specific subclasses of the above process according to the invention include the following:

(A) As a preferred subclass of the reaction case

(a) We can prepare compounds of formula (I) in which k is 1 and Q is something other than a methylene group by reacting a compound of formula (II) in which B, Q and (X) are as defined above

7

except that Q is not a methylene group, and R is a hydroxyl group and/or forms a carbo- group with Q

35 xyl or a carboxyl group derivative, with a compound

1 3

of formula (III) in which D, E, G to G, netZ are

5

8

as defined above and R is an amino group or an amino group derivative.

(B) As a preferred subclass of the optional reaction (i), we can present Ion compounds of formula (I) on reducing a compound of formulas (VIII), (IX) or (X):

(VIII)

(IX)

g1g2g3

I I!

b-(x)-a-c-n-c-c-(y)-e I I II

Z DO

gVg3 I I I

b-(x)-a-c-n-c-c-(y)-e

I I II

Z DO g1 g2 g3

111

b-(x)-a-c-n-c-c-(y)"e (X)

I I II

z do

1 3

in which A, B, D, E, G to G, (X), (Y) and Z are

10 as defined above/ possibly under their "

3

protected forms, and G and (Y) are respectively

3

unsaturated forms of G and (Y).

(C) As another preferred subclass of the optional reaction (i), compounds of formula (I) can be prepared

12 3

15 in which G and G are hydrogen or G

is hydrogen, by reducing respectively a compound of formulas (XI) or (XII):

q3

? (XI)

b-(x)-a-c-n-c-c-(y)-e

I I II

z do

GXG2

I

b-(x)-a-ç-n-c-c-(y)-e (xii)

z d10

G»

u

1 3

in which A, B, D/E, G to G/(X), (Y) and Z are as defined above, possibly in their protected forms, and D"*" is a group analogous to D as defined above (other than hydrogen) lacking a hydrogen atom so that it is bonded to the carbon atom of the fragment -N(G)-C- by a double bond. (D) As another preferred subclass of the optional reaction (i), compounds of formula (I) may be prepared.

in which Z is a carboxy or carbamoyl group

20 dealing with a compound of formula (XIII):

gW I I I

b - (x) - a-c-n-c-c - (y) -e (XIII)

II Ml

Z D 0

13

in which A, B, D, E, G to G, (X) and (Y) are as defined above, possibly in their protected forms,

1

and Z is a suitable carboxyl or carbamoyl precursor group, with one or more agents capable of transforming

1

15 the precursor group Z into a carboxy or carbamoyl group.

One may then, if desired, carry out one or more of the optional reactions (i) to (iii) referred to above, or, as appropriate, one or more of these other reactions

20 optional ones, in any order desired.

Reaction (a), of which reaction A is a part, is conveniently carried out using dicyclohexylcarbodiimide (DCCI) in the presence of 1-hydroxybenzotriazole (HOBT)

to eliminate racemization, in a suitable solvent

t

25 such as methylene chloride or dimethylformamide

(DMF) at a temperature, for example in the range of -15°C to 0°C, or at room temperature, as appropriate. Such a reaction protocol is hereinafter referred to as the "DCCI/HOBT" conditions.

30 f Reaction (b) is conveniently carried out at room temperature or under heating, as appropriate,

in a suitable solvent such as dichloromethane or DMF.

Reaction (c) is conveniently carried out under DCCI/HOBT conditions, or by mixed anhydride coupling, a technique well known to peptide chemists and which, for example, may consist of reacting the acid intermediate with isobutyl chloroformate and N-methylmorpholine, and then reacting it with the amine intermediate, the reaction being conveniently carried out at reduced temperatures, for example from -15°C to -25°C, to minimize racemization. Reaction (B) of the optional reaction (i)

is conveniently carried out by hydrogenation over a suitable catalyst, such as palladium on carbon, for example in a suitable solvent such as methanol. Preferred classes of compounds of formulas (IX) and (X) are those where -(Y)-È is -n'

Reaction (C) is also conveniently carried out by hydrogenation, for example by the process described in the preceding paragraph. It should be noted that, in this reaction, the intermediate compound of formula (XI) or (XII)

20 can be formed in situ (for example by a process such as described below) and that a compound of formula (XI) in the-3

what G is hydrogen can also be represented by the resonance form (XIA):

H I

b-(x)-a-c-n=c-c-(y)-E

l l II (XIA>

Z D 0

25 in which A, B, D, E, (X), (Y) and Z are as defined above. A preferred class of compounds of formula (XII) is that in which D"*" is the methylene group. It is noteworthy

2

here again a compound of formula (XII) in which G is hydrogen can also be represented by the 30 resonance form (XIIA):

r *l

22.

G1 I

b- (x) -a-c-n-c-c- (y) - e (XIIA)

I I II

Z D 0

in which A/ B, D, E/ (X), (Y) and Z are as defined above.

Reaction (D) may, for example, consist of the hydrolysis of a compound of formula (XIII) in which Z represents a cyano group. This hydrolysis is conveniently carried out by acid hydrolysis, for example, in a suitable strong mineral acid such as hydrochloric acid, in a suitable solvent such as methanol. Alternatively, reaction (D) may consist of reacting a compound of formula (XIII) in which Z is a suitable carbonyl derivative group with one or more suitable reagents capable of amined this group. For example, if Z is an activated carbonyl group such as an acid ester or chloride, the compound of formula (XIII) may be made to

react with ammonia/ preferably under aqueous conditions. If the carbonyl-derived group is the carboxyl group, the compound of formula (XIII) can be treated with a reagent capable of transforming it into a corresponding activated acid in the presence of, or by subsequently reacting with, a suitable reagent as described above in relation to reactions with acid esters and chlorides.

Suitable reagents for carrying out the formation of a corresponding activated acid may be sulfur oxychloride, a phosphorus halide such as phosphorus trichloride or phosphorus pentachloride, a phosphorus oxyhalide such as phosphorus oxychloride, trifluoroacetic anhydride, an alkyl chloroformate (e.g., ethyl), or any other suitable agent recognized by the specialist. A list of such reagents is given in Houben-Weyl's work (reference (f) above), page 29. Conveniently, the reaction may be carried out in

in a suitable solvent such as toluene, advantageously in the presence of a suitable catalyst such as dimethylformamide. Alternatively, the reaction can be carried out by reaction with a suitable weak or volatile base such as ammonia, preferably under heating. Such a reaction can be conveniently carried out using an ammonia stream or by using ammonia in situ in the presence of a dehydrating agent.

In reactions (a) and (b), and throughout this paper, unless otherwise expressly stated, the leaving group or any leaving group may be chosen from any known in chemistry, as defined e.g. in "Advanced Organic Chemistry" by J. March, 3rd edition, 1977, McGraw-Hill, New York, page 15187. These leaving groups include halogeno (preferably chloro or bromo), mesyl (i.e. methanesulfonyloxy), tosyl (i.e. toluenesulfonyloxy), and triflate (i.e. trifluoromethanesulfonyloxy) groups.

It should be noted that when any process according to the present invention does not directly lead to obtaining a desired individual isomer of a compound of formula (I) or of one of its physiologically acceptable salts, this process may include separation of isomers, either of the product itself or of any suitable intermediate compound, at any convenient stage of the reaction, for example by operating by column chromatography.

In reaction (a), the compound of formula (II) can be prepared according to the general process described in the aforementioned U.S. Patent No. 3,705,907. The compounds of formula (III) can be prepared by processes substantially similar to those described in the aforementioned European Patent No. 0,012,401 and also in European Patent No. 0,126,986-A1.

35 In reaction (b), the compounds of formula (IV)

in which, in the definition of A, Q is -C0- and k and m

are both 1, can be prepared by reacting a compound of formula (XIV):

B-(X)-R13 (XIV)

with a compound of formula (XV):

g1

r1A-<CH2VC-r15 (XV)

^ "10

co2r formulas in which B, G"'", n, R"*"^ and (X) are as defined above/ possibly in their forms 13

protected/ R is a carboxyl group or a derivative of

14

carboxyl group, R is an amino group or a derivative of

15

10 amino groups, and R is a suitably protected group,

and by treating the reaction product with one or more agents

15

suitable for eliminating R protection or trans-

9 9

form the desired group R. For example, if R is a

15

leaving group in compound of formula (IV), R can be / in compound of formula (XV), a suitably protected hydroxy group / such as β-butoxy, which can be transformed into the desired leaving group by treating the reaction product with a suitable reagent or agents, for example a methanesulfonyl halide for

9 9

20. Obtain R = mesyl. Similarly, if R is an amino group or an amino group derivative in the compound of formula 15

(IV)/ R is/ in the compound of formula (XV), a suitably protected amino group.

Compounds of formula (IV) in which, in the definition of A/k and m are both 0, can be prepared by reacting a compound of formula (XVI):

B-(X)-(CH2)n-R16 (XVI)

with a compound of formula (XVII): /"|

%(

G1

H - C - R17

co2r10

(XVII)

formulas in which B/ G"*", n, R^, R"'"0 and (X) are as defined above/ possibly in their forms

X 6 ' XV

protected, R is a departing group/ and R is a group

5 amino suitably protected/ by treating the reaction product with one or more appropriate agents to remove the 17

protection of R" and by treating the product stripped of protection with one or more suitable agents/ either to alkylate the amino group in order to obtain a compound of for-

g XX

10 mule (IV) in which R = NHQ where Q is as defined above / either to transform the amino group into a leaving group in order to obtain a compound of formula (IV) in the-

9 17

what R is a leaving group? For example, if R is

PhCH=N-/ where Ph = phenyl/ it can be stripped of its 15 protection in the reaction product by treatment with a suitable base. An optional treatment of the product to transform the amino group into a leaving group can/ for example, be carried out according to the general procedure described by E.D. Thorset/ Tet. Lett., 1982/ 2_3, 1875-6. 20 Compounds of formula (IV) in which, in the definition of A, k and m are both 0, can also be prepared by any of the procedures described in Chapter 8 (pages 246 et seq.) of the work by G.C. Barrett (Ed.) (reference (m) above). 25 Compounds of formula (V) are simple dipeptides or common derivatives thereof and can be prepared by procedures well known to specialists.

In reaction (c)/ compounds of formula (VI) in which, in the definition of A, Q is -CO- and k and m 30 are both 1/ can be prepared by reacting a compound of formula (XVI) as defined above, with a compound of formula (XVIII):

H

lî

G1 G2 G3

1A I I I 10 e -c-n-c-r (xviii)

1 3 14

in which D, G to G, R and Z are as defined below

above, possibly in their protected forms,

X 8

and R is a protected carboxyl group, and by treating the

18

reaction product so as to eliminate the protection of R

Compounds of formula (VI) in which, in the definition of A, k and m are both 0, can be prepared by reacting a compound of formula (IV) as defined above, with a compound of formula (XIX):

g3

I '

14 ' 1 fl r - c - r (XIX)

in which D, G3, R"^ and R"*"® are as defined above, possibly in their protected forms, and by treating the reaction product so as to eliminate the protection of R

The compounds of formula (VII) are simple amino acids or common derivatives thereof and they can be prepared by processes well known to specialists.

In reaction (B) of the optional reaction (i)/ compounds of formulas (VIII) to (X) in which, in the definition of A/ Q is -CO- and k and m are both 1/ can be prepared by reacting a compound of formula (XIV) as defined above, with a compound of formula (XX)/ (XXI) or (XXII) as appropriate:

12 3 G G G

14 I 1 T

R -C-N-C-C-(Y)-E (XX)

I I II

Z DO

gW

1A ^ ^

R -C-N-C-C-(Y)-E (XXI)

I I II

Z DO

gW

RU-C-N-C-C-(Y)-E (XXII)

I I II

Z DO

1 3 3 14 in which D, E, G to G, G, R, (Y) and (Y) are

5 as defined above/ possibly in their protected forms. The reaction is preferably carried out under DCCI/HOBT conditions (see above) or by mixed anhydride coupling.

The compounds of formulas (VIII) to (X) in the -10 which in the definition of A, k and m are both 0,

can be prepared by reacting a compound of formula (IV) as defined above (R9 = leaving group), with a compound of formulas (XXIII), (XXIV) or (XXV), as appropriate:

G3

rU-c-c-(y)-E (mil)

I H

D 0

G3

r141

C-(Y)-E (XXIV)

D 0 „3

R14-C-C-(I)-E 4 (XXV)

D 0

(J

f

3 3 14

in which D, E, G, G, R, (Y) and (Y) are as defined above, possibly in their protected forms.

In reaction (C) of the optional reaction (i), the compounds of formulas (XI) and (XII) can be prepared by reacting a compound of formula (XXVI):

f19

b-(x)-a-c-r20 (xxvi)

in which A, B, G*", (X) and Z are as defined above and R* and R* are either (i) G* and R** as defined above, or (ii) together form =0, with a compound of formula (XXVII):

R21

*22-C-C-(Y>-E (XXVII)

I

10

r23

in which E and (Y) are as defined above, and,

in case (i) referred to in the definition of compound (XXVI),

21 22 23

15 R is D as defined above and R and R form

21 23

together = 0, or, in case (ii), R to R are D, 3 14

G and R as defined above or else, in this same i 21 14 22 23

case (ii), R is R as defined above and R and R

form together =D^ as defined above. These reactions 20 are preferably carried out in a solvent immiscible with water such as toluene, benzene or chloroform, in the presence of a suitable acid catalyst such as β-toluenesulfonic acid.

In reaction (D) of optional reaction 25 (i)/ compounds of formula (XIII) in which Z1 is a cyano group can be prepared by reacting a compound of formula (V) as defined above with a compound of formula (XXVIII):

B-(X)-A-CHO (XXVIII)

*9

in which A/B and (X) are as defined above, in the presence of hydrocyanic acid/ formed preferably in situ, for example by mixing the reactants of formulas (V) and (XXVIII) in the presence of an alkali metal cyanide 5 such as sodium or potassium cyanide, and a suitable acid such as acetic acid, preferably in a suitable solvent such as methanol.

This reaction and the preparation of the starting materials of formulas (V) and (XXVIII) can be carried out 10 following the general methodology described in J. Med. Chem., 28, 432 (1985).

The following non-limiting examples illustrate the present invention in more particular.

Example 1

15 N-(l-carboxy-5-[4-(2-hydroxy-3-iso-propylaminopropoxy)benzylcarboxamido]pentyl)alanylproline bistrifluoroacetate

(a) 4-(2-hydroxy-3-isopropylaminopropoxy)methyl phenylacetate

16.6 g of 20-methyl 4-hydroxyphenylacetate is dissolved in 100 mL of NaOH and 20 mL of dioxane. 23.1 g (2.5 equivalents) of epichlorohydrin are added, and the mixture is stirred at 80°C for 3 hours. The mixture is cooled and extracted with 3 x 100 mL of 5:1 CHCl₂:dioxane. The organic extracts are dehydrated (MgSO₄) and evaporated under vacuum. The residue is dissolved in a mixture of 60 mL of dioxane and 60 mL of isopropylamine and heated at 65–70°C for 1 hour. The solution is evaporated under vacuum, and the residue is extracted with 5 x 50 mL of 10% citric acid. The ras-30 acid extracts are washed with ethyl acetate, then alkalized with sodium carbonate.

(b) 4-(2-hydroxy-3-isopropyl-t-butoxycarbonylaminopropoxy)-methyl phenylacetate

To a solution of 6.9 g of the ester from step (a) in 25 ml of DMF, 5.9 g of B0C20 is added.

3»

After resting overnight, 150 ml of water is added and the mixture is extracted with ethyl acetate. The organic phase is washed 5 times with water, dehydrated (MgSO₄) and evaporated.

(c) 10 g of the crude BOC-protected ester from step (b) is mixed with 920 mL (1.6 equivalents) of SVM and 20 mL of 2N NaOH, and the mixture is heated in a boiling water bath for 30 minutes. The mixture is evaporated under vacuum and the residue is dissolved in water, then thoroughly acidified with dilute HCl. The separated oil is washed several times with water by decantation. After standing for 16 hours, the oil begins to solidify. The solid is washed with water, dried, and recrystallized in ethyl acetate containing a small amount of petroleum ether (boiling point 60–80°C).

(d) 580 g of N-(l-l-t-butoxycarbonyl-5-aminopentyl)alanylproline β-butyl ester and 500 mg of the acid from step (c) are dissolved in 8 mL of DMF and 0/14 g (1.0 equivalent) of EtN is added. The mixture is cooled in an ice bath and then stirred while 0/37 g (2.0 equivalent) of 1-hydroxybenzotriazole (HOBT) is added, followed by 0/31 g (1.1 equivalent) of DCCl. After stirring for 3 hours, the mixture is placed in a refrigerator. One week later, the mixture is filtered and the residue evaporated under vacuum. Ethyl acetate is then added and washed with water, a saturated aqueous solution of NaHCO3, 10% citric acid, water, and brine. The aqueous phases are extracted with ethyl acetate and the collected organic fractions are dehydrated (MgSO^), then evaporated under vacuum to leave the product.

(e) 540 mg of the compound from step (d) is mixed with anisole and placed in a refrigerator. A mixture of 50 ml of TFA, 6.5 ml of water, and 5.5 ml of anisole is also chilled, and after 45 minutes, the reagents are mixed and left to stand for 1 week. The solution is then reduced.

3. The mixture is evaporated and ether is added, then treated again with more of the mixture containing TFA. TFA is then driven off under vacuum at room temperature, ether is added, and the mixture is thoroughly stirred to obtain a white powder. After removing the supernatant by decantation, the mixture is washed three more times in ether. It is then dried under vacuum to obtain a colorless powder. Calculated: C-48.48; H-5.849; N-7.068. Found: C-47.91; H-5.791; N-6.753. Examples 2-4

By a process analogous to that of Example 1, the following compounds according to the invention are prepared:

2. N-[1(S)-carboxy-5-(2-[5-(2(S,R)-hydroxy-3-isopropylaminopropoxy)-naphth- dihydrochloride-acetate hemihydrate

1-yloxy]acetamido)pentyl]-(S,R)-alanyl-(S)-proline.

Calculated (for 2HCl, AcOH, 0.5H2O):

C-52.84; H-6.91; N-7.25; Cl-9.17 Found: C-52.60; H-6.88; N-7.45; Cl-9.10

3. N-(l(S/R)-carboxy-5-[5-(2(S,R)-hydroxy-3-isopropylamino-propoxy)carbazole-3-carboxamido]pentyl)-(S,R)-alanyl-(S)-proline.

4. N-(1(S,R)-carboxy-5-[5-(2ÎS,R)-hydroxy-3-isopropylamino-propoxy)carbazole-2-carboxamido]pentyl)-(S;R)-alanyl-(S)-proline.

Example 5

N-(1(S)-carboxy-5-[8-(2(S,R)-hydroxy-3-isopropylaminopropoxy)naphth-2-ylmethylamino]pentyl)-(S/R)-alanyl-(S)-proline tristrifluoroacetate

(a) methyl l-hydroxy-7-naphthoate

To 50 ml of a saturated solution of hydrogen chloride in methanol, 50 g of 1-hydroxy-7-naphthoic acid is added, and the resulting mixture is heated under reflux for 2-5 hours. It is then concentrated to dryness to obtain an off-white solid. This is dissolved in 100 ml of ethyl acetate and washed successively with 30 ml of a saturated aqueous solution of sodium bicarbonate and 30 ml of water.

and 30 ml of brine. The organic phase is dehydrated (MgSO^), filtered and concentrated to dryness to obtain 5.36 g (yield: 99.7%) of an off-white solid which is homogeneous by thin layer chromatography (TLC) 5 (silica, ethyl acetate, UV/iodine); Rf = 0.38.

(b) Methylated ester of 2,3-epoxypropoxy-7-naphthoic acid

2.02 g (0.01 mol) of the naphthol from step (a) is dissolved in 20 mL of DMF and cooled to 5°C under a nitrogen atmosphere. 1.12 g (0.01 mol) of potassium 10^tbutylate is added at a rate such that the temperature of the reaction mixture does not exceed 15°C. After all the ingredients have been added, the mixture is heated to 55°C for 1 hour, and then 1.37 g (0.01 mol) of epibromhydrin is added dropwise. The mixture is heated to 100°C for 2 hours, concentrated to semi-dryness, diluted with water, and extracted in ether. The ether extracts are washed with water, then with brine, and dehydrated (MgSO₂). By filtration and concentration, 2.48 g (yield: 96.1%) of a viscous amber oil is obtained, homogeneous by TLC 20 (silica, n-hexane:ether 1:1, UV/iodine), Rf = 0.48.

(c) Methylated ester of 1(S,R)-(2-hydroxy-3-isopropyl-aminopropoxy)-7-naphthoic acid

A mixture of 15.50 g (0.0213 mol) of the epoxide from step 25(b), 100 mL of isopropylamine, and 75 mL of 1,4-dioxane is refluxed for 3 days and then concentrated to dryness to obtain an off-white solid. This is converted to its perchlorate, yielding 6.70 g (75.4%) of a white solid. TLC analysis shows that the free base contains two products that are not separable by either chromatography of the free base or recrystallization of the perchlorate. This material is used without further purification in the next step.

(d) Methylated ester of 1-[1-(3-t-butoxycarbonyl-3-isopropylamino-2(S,R)-hydroxypropoxy)]-7-naphthoic acid 35 A mixture of 6.70 g (0.0161 mol) of the amine is stirred at room temperature for 20 hours.

In step (c), in the form of perchlorate, 0.65 g (0.0162 mol) of sodium hydroxide and 3.52 g (0.0161 mol) of di-t-butyl dicarbamate are mixed in 35 ml of DMF, then concentrated to semi-dryness. The residue is diluted with water and extracted in ethyl acetate, then the organic phase is washed with water, dehydrated (MgSO4), filtered and concentrated to obtain 7.00 g (104%) of a viscous oil which solidifies at rest; P.F. 107-109°C.

Calculated for C24H34N06:

C-66.65%; H-7.92%; N-3.25%

Found: C-66.25%; H-7.61%; N-3.29%

(e) Methylated ester of 1-[1-(3-t-butoxycarbonyl-3-isopropylamino-2(S,R)-t-butyldimethylsilyloxy)propoxy]-7-naphthoic acid

To a stirred mixture of 6.70 g (0.0160 mol) of the alcohol from step (d), 0.10 g (0.8 mmol) of 4-dimethylaminopyridine, and 2.10 g (0.0163 mol) of diisopropylethylamine in 30 mL of DMF, 5.50 g (0.0365 mol) of β-butyldimethylsilyl chloride is added in a single portion. The resulting mixture is stirred for 3 days at room temperature, poured into 300 mL of water/300 mL of a saturated sodium bicarbonate solution, and extracted into ethyl acetate. The ethyl acetate phase is washed with water, then with brine, and dehydrated (MgSO4). By filtration and concentration, a mobile colorless liquid is obtained which is purified by column chromatography (silica, n-hexane:ethyl acetate at 9:1) to obtain 7.36 g (yield: 89.5%) of a colorless oil which crystallizes at rest giving a white solid; P.F. 102°C.

Calculated for C2gH45NO6:

C-65.50%; H-8.52%; N-2.63%

Found: C-65.4%; H-8.75%; N-2.59%

(f) !-[!-(3-t-butoxycarbonyl-3-isopropylamino-2(S,R)-t-butyldimethylsilylox^propoxy]-7-naphthoic acid

A solution is heated under reflux with 2.00 g (0.05 mole) of sodium hydroxide for 18 hours.

6.80 g (0.0128 mol) of the methyl ester from step (e) is reacted in 50 mL of methanol. The reaction mixture is concentrated to semi-dryness, diluted with water, and adjusted to pH 3.0 with solid citric acid. The mixture is then extracted into ethyl acetate, washed with water and then brine, and dehydrated (MgSO₄). By filtration and concentration, 5.86 g (88.5% concentration) of an off-white solid is obtained; softening point at approximately 167°C, settling point at 196°C.

10 Calculated for C2gH^2N0gSi:

C-64.96%; H-8.37%; N-2.70%

Found: C-65.37%; H-7.98%; N-2.94%

(g) 1~[1-(3-t-butoxycarbonyl-1-3-isopropylamino-2(S,R)-t-butyl-dimethylsilyloxypropoxy/-7-hydroxymethylriaphthalene]

15. To a 5.32 g (0.0103 mol) solution of the acid from step (f) in 30 mL of THF at 5°C under static anhydrous nitrogen, 18 mL of a 1 mol solution of borane-THF complex is added at a rate such that the temperature of the mixture does not exceed 10°C. After all the additions have been made, 20. the reaction mixture is stirred under cooling for 30 minutes, then at room temperature for 2 hours. Water is then added, followed by 30 mL of a saturated aqueous solution of sodium bicarbonate, and the mixture is concentrated to semi-dryness. The residue is extracted in ether, which, after 25. washing with water and brine, is filtered and concentrated to obtain 4/90 g (yield: 94.7%) of the crude alcohol in the form of a colorless gum. By silica chromatography eluting with n-hexane:ethyl acetate at 7:3, 3.53 g (yield: 68%) of pure alcohol is obtained; P.F. 81-82°C. 30 Calculated for C2gH^,-N0,-Si:

C-66.76%; H-9.00%; N-2.78%

Found: C-67.20%; H-8.90%; N-2.73%

(h) 1~ [l-(3-t-butoxycarbony l"-3-isopropylamino-2 (S,R)-t-butyl-

i dimethylsilyloxy)propoxy]-7-chloromethylnaphthalene 35 3.32 g (6.6 mmol) of the alcohol from step (g) is dissolved in 50 ml of methylene chloride and

1/10 mL (7/90 mmol) of triethylamine is added. 0/62 mL (8.0 mmol) of mesyl chloride is added, and the mixture is heated under reflux for 2 hours. TLC indicates the presence of starting material, and therefore a further 0/5 mL (3/6 mmol) of triethylamine and 0/3 mL (3/9 mmol) of mesyl chloride are added, and the mixture is heated under reflux for another 1.5 hours. The pure chloride is obtained by silica chromatography by eluting with n-hexane:ethyl acetate at a ratio of 9:1, yielding 2.63 g (yield: 76%) of a colorless, viscous oil.

(i) N-(1(S)-t-butoxycarbonyl-5-[1-(3-

t-but oxy carbony 1-3-isopropyl ami no-2-(S,. R)-t-butyldimethyl-silyloxy)propoxy]naphth-7-ylmethylamino)-(S,R)-alanyl-

(S)-proline

A mixture of 2.43 g (5.69 mmol) of N-(1(S)-t-butoxycarbonyl-5-aminopentyl)-(S,R)-alanyl-(S)-proline jt-butyl ester, 1.50 g (2.87 mmol) of 2-chloromethylnaphthalene, and 0.55 g (6.55 mmol) of sodium bicarbonate in 30 mL of acetonitrile is stirred at room temperature for 24 hours and then at 75°C for 20 hours. The reaction mixture is concentrated to near dryness, diluted with water, and extracted in ethyl acetate. The extract is washed with water, then with brine, and dehydrated (MgSO₄). By filtration and concentration, 3.40 g of a viscous oil is obtained which, by TLC (silica, CHCl3:MeOH:NH4OH at 80:20:1), proves to be a mixture of the starting materials and the product. The desired substance is obtained by column chromatography (silica) by eluting with n-hexane/n-hexane:ether at 1:1, ethyl acetate, and finally 20% methanol in ethyl acetate, giving 1.16 g (yield: 44%) of an almost colorless gum which is a mixture of diastereomers.

(j) N-(1(S)-carboxy-5-[8-(2(S,R)~ tristrifluoroacetate

hydroxy-3-isopropylaminopropoxy)naphth-2-ylmethylamino]-pentyl)-(S,R)-alanyl-(S)-proline

0.48 g (0/526 mmol) of the protected compound from

¥>

Step (i) in 0/5 ml of water and 4/5 ml of trifiluoracetic acid, then concentrate to semi-dryness. Dissolve the residue in water and wash with ether; then concentrate the aqueous phase to dryness and dry under high vacuum over phosphorus pentoxide 5 to obtain 0/40 g (yield: 82%) of a sand-colored solid; P.F. softening at approximately 120°C.

Calculated for C37H4g°i3N4F9:

C-47.90% H-5.20%; N-6.03%

Found: C-47.90%; H-5.70%; N-6.08% 10 The β-butyl ester of N-(β-β-

butoxycarbonyl-5-aminopentyl)alanylproline/ as used in step (d) of Examples 1 to 4, and the chiral t-butyl ester of N-(1(S)-t-butoxycarbonyl-5-aminopentyl)-(S,R)-alanyl-(S)-proline/ as used in step (i) of Example 5, by the following method/ using starting materials of appropriate chirality.

(a) β-Butyl ester of N-(2-bromopropionyl)proline

A solution of 1/71 g of proline β-butyl ester and 1/8 g of triethylamine 20 in 10 mL of anhydrous dichloromethane is cooled to -20°C. A solution of 2/16 g of 2-bromopropionyl bromide in 5 mL of dichloromethane at -20°C is then added to this solution in a single portion while stirring. The mixture is stirred for 30 minutes at -20°C and then allowed to cool to room temperature. Sufficient ethyl acetate is added to obtain two phases, and the upper organic phase is washed successively with 10% citric acid, a saturated aqueous solution of sodium bicarbonate, water, and finally saturated brine. The resulting solution (MgSO₄) is dehydrated and evaporated under vacuum to obtain 2/8 g of the product as an oil. The NMR spectrum in CDCl^ shows methyl protons at 1/56, butyl protons at 1.86 and proline protons at 2/0/ 3/66 and 4/446.

(b) β-Butyl ester of N-(l-β-butoxycarbonyl-5-aminopentyl)-35 alanylproline

0.93 g of powdered sodium bicarbonate is added to a solution of 3/36 g of N-benzyloxycarbonyl-lysinate

It

3t"

β-butyl and 3.08 g of the β-butyl ester of N-(2-bromopropionyl)proline from step (a) are mixed in 50 mL of anhydrous aceto-nitrile. The mixture is heated under moderate reflux for 24 hours. After cooling, the aceto-5-nitrile is driven off under vacuum, and the residue is partitioned between water and ethyl acetate. The organic phase is washed with water, 10% citric acid, a saturated aqueous solution of sodium bicarbonate, water, and saturated brine. The solution (MgSO₄) is dehydrated and evaporated to obtain 10 3/88 g of crude product. This is purified by silica gel column chromatography (Merck 5734). By elution with EtOAc:hexane at a ratio of 1:1, 3/42 g of a colorless solid is obtained. The mass and NMR spectra correspond to the β-butyl ester of N-(1-β-butoxycarbonyl-5-benzyloxy-15-carbonylaminopentyl)alanylproline. The protective coating of 4/62 g of the above benzyl compound is removed by hydrogenation in 100 mL of EtOAc:MeOH at a ratio of 1:1 over 0.53 g of a 10% w/c catalyst. Hydrogenation is complete after 4 hours. The mixture is filtered and the filtrate evaporated to dryness under 20°C vacuum. The residue is treated with 5 mL of triethylamine and 20 mL of ethyl acetate is added. The precipitate is removed by filtration and the solvent is expelled under vacuum to obtain 3/5 g of the desired t-butyl ester of N-(l-t-butoxy-carbonyl-5-aminopentyl)alanylproline. The 25 CDClg NMR spectrum corresponds to the structure.

The starting materials and reagents used in the preparation of the compounds in Examples 1 to 5 are commercially available or can be prepared by processes described in the chemical literature. 30 Pharmaceutical Formulations

In the following formulation examples, the "active compound" may be any of the compounds of formula (I)/ or a physiologically acceptable salt of such a compound.

HAS

»

Example A: TABLET

Active ingredient 500 mg

Microcrystalline cellulose 100 mg

Polyvinylpyrrolidone 10 mg

5 Starch-sodium glycolate 30 mg

Magnesium stearate 5 mg

645 mg

Mix the active compound/microcrystalline cellulose and sodium starch glycolate. Granulate with polyvinylpyrrolidone dissolved in alcohol. Dry.

Mix with magnesium stearate and compress into a tablet (645 mg). Example B: CAPSULE

Active ingredient 250 mg

Lactose 150 mg

15 Starch 25 mg

Magnesium stearate 5 mg

430 mg

Mix the active compound/lactose, starch and magnesium stearate. Fill 20 hard gelatin capsules.

Example C: SUPPOSITORY

Active ingredient 500 mg

PEG 400 800 mg

PEG 6000 1700 mg

25 3000 mg

Mix the PEG 6000. Incorporate the PEG 400, then the active compound, while mixing. Pour into a suppository mold and allow to harden.

Example D: IV INJECTION SOLUTION 30 Active ingredient 500 mg

Codex Water for Injections, up to 5.0 ml

Dissolve the active compound in approximately nine-tenths of the total volume of water for injection. Once dissolved, bring to the final volume with the remaining 35% of the water for injection.

Under aseptic conditions/sterilize the solution y

by filtration through a sterile, high-quality filter for^/

I?

*5

sterilize and package the solution in previously sterilized ampoules by purging the ampoules with nitrogen before and after filling.

Biological Examples 5 (a) Blocking of g-adrenergic receptors in vitro

In a study of the blockade of 3-adrenergic receptors in the left atrium of guinea pigs, a simple competitive blockade of responses to 11-isoprenaline gives the following results:

10. Composed of Example 2. Composed of Example 5.

pKB 5.3 PKB 7.2

(b) Inhibition of ACE in vitro

In a study of angiotensin-converting enzyme inhibition in the ileum of guinea pigs, dose-dependent inhibition of contractile responses to angiotensin I yielded the following results: Compound of Example 2 Compound of Example 5

CEçjq 13.5nM CE50 ^, 6nM

ko

10

Claims (1)

CLAIMS 1. Compound characterized in that it is a compound of formula (I): gVg3 I I I b-(x)-a-c-n-c-c-(y)-e (t ) I I II KL) Z DO in which: a is a group of formula -Q^- (NQ"'" ) - (CHp ) - / where k and m are independently chosen between 0 and 1 provided that m can only be 0 if k is 0, n is a number from 1 to 6, Q is the hydrogen or an alkyl group in Cj-CQ is chosen from -CO-, -CH2~, -CH2CO- and -OCH2CO-, and any of the groups of -(CHp)n~ are independently possibly substituted by one or two alkyl groups in C,-C. ; 12 B is a group with the formula -R -C(Q)(OH)- 15 C(Q3) (Q4)-NQ5-R2, where R"*" is a bond or -OC(Q^) (Q^)-, 2 2 7 R is hydrogen or an alkyl group in C-Cg, Q and Q are, independently of hydrogen, an alkyl group in C,-C. or 8 9 14 a group of formula -(C(Q)(Q))Ph in which x is 1 or 2, Ph is a phenyl group, possibly substituted 20 by one or more groups independently chosen from among the hydroxyl, alkyl (C-C) and alkoxy (Ci-C4') groups and are independent of hydrogen or an alkyl group in C^-C^; e and Z are independently chosen from the 25 carboxyl group and its derivatives; d is hydrogen or an aliphatic substituent in saturated or unsaturated form, possibly substituted by an amino group; 12 3 G / G and G are independently chosen from 30 hydrogen and alkyl groups in C^-C4; (X) is an aromatic mono-, bi-, or tricyclic system possibly containing one or more heteroatoms; and 1 "f (y) is a nitrogen mono- or bicyclic system (attached to -CO-C(D)(G)- by its nitrogen atom) possibly containing one or more other heteroatoms and possibly substituted by one or more substituents 5 independently chosen from the aryl and alkyl groups in or (Y) is a nitrogen atom linked to E directly by a bond or indirectly by an alkylene fragment in and also linked to a cycloalkyl group, (Y) which in either case may possibly be 3 10 linked to G or D by a C^-C^ alkylene bridge to form a closed ring; provided that : if, in the definition of A, k and m are both 0 or 1 and Q is a group -C0-, and, in the definition of B, 6 7 15 is a group of formula -OC(Q)(Q)- as defined above 2 and R is a C2-C6 alkyl group; D is: hydrogen or an alkyl group; (X) is a benzene ring or a naphthyl or indolyl cyclic system, each possibly substituted at any positions by one or more substituents independently chosen from the alkyl groups (themselves possibly substituted by one or more halogen atoms), C2-C4 alkoxy, halogeno, nitro, amino, carboxyl, C2-C4 alkoxycarbonyl, or hydroxyl groups. t 25 then (Y) is not a pyrrolidinyl, oxazolidinyl or thiazolidinyl ring, nor a cyclic system chosen from the indolinyl, quinolinyl and tetrahydroquinolinyl cyclic systems, or a physiologically acceptable salt of such a compound. 30 2. Compound according to claim 1, characterized in that, in the definition of A, Q is hydrogen and the groups of ~(CH_) - are not substituted by any group ? q alkyl in C,-C in the definition of B, Q to Q are of 2 13 hydrogen and R is an alkyl group in C2_G4' G ® G 35 are hydrogen, (X) is unsubstituted and (Y) is a pyrrolidinyl, oxazolidinyl or thizolidinyl ring or a tetraquinolinyl cyclic system. fa 3. Compound according to claim 2, characterized in that D is a C-C alkyl group, E and Z are carboxyl groups, (X) is an unsubstituted benzene ring or a naphthyl, indolyl, quinolyl or car- cyclic system 5 unsubstituted bazyle, and (Y) is a pyrrolidinyl ring. 4. N-(1(S)-carboxy-5-[8-(2(S,R)-hydroxy-3-isopropylaminopropoxy)naphth-2-ylmethylamino]pentyl-(S,R)~ alanyl-(S)-proline, N-(1(S)-carboxy-5-t4-(2-(S,R)-hydroxy 3-isopropylaminopropoxy)benzylcarboxamido]pentyl-(S,R)-alanyl 10 (S)-proline or N-[1(S)-carboxy-5-(2-[5-(2(S,R)-hydroxy-3-isopropylaminopropoxy)naphth-l-yloxy]acetamido)pentyl]-(S,R)-alanyl-(S)-proline, or a hemi-ester of any of them, or a physiologically acceptable salt of any such compound. 15.5. Compound according to claim 1, intended for to be used in medical therapy. 6. Compound according to claim 1, intended for use in the prophylaxis or treatment of a cardiovascular disorder, hyperaldosteronism, of 20 glaucoma or migraine. 7. Compound according to claim 1, intended for use in the prophylaxis or treatment of a cardiovascular disorder, namely hypertension, heart failure, myocardial infarction, or cardio- 25 ischemic pathology. 8. Compound according to claim 1, intended for use in the prophylaxis or treatment of ischemic heart disease, which is angina pectoris. 9. Compound according to claim 1, intended for 30 be used in the prophylaxis or treatment of a disease or pathological symptom as defined in any one of claims 6 to 8, this compound being N-(1(S)-carboxy-5-[8-(2(S,R)-hydroxy-3-isopropyl-aminopropoxy)naphth-2-ylmethylamino]pentyl-(S,R)-alanyl- 35 (S)-proline, N-(l(S)-carboxy-5-[4-(2(S,R)-hydroxy-3- isopropylaminopropoxy)benzylcarboxamido]pentyl-(S,R)-alanyl- M b (S)-proline or N-[1(S)-carboxy-5-(2-[5-(2(S,R)-hydroxy-3-isopropylaminopropoxy)naphth-l-yloxy]acetamido)pentyl]-(S,R)-alanyl-(S)-proline, or a hemi-ester (in which E and Z are a C2-Cg carbalcoxy group) of any of them, or a physiologically acceptable salt of any such compound. 10. Use of a compound according to claim 1 in the prophylaxis of a disease or pathological symptom as defined in any one of claims 6 to 8. 11. Use according to claim 10, characterized in that the compound according to claim 1 is N-(1(S)-carboxy-5-[8-(2(S,R)-hydroxy-3-isopropylaminopropoxy)napht-2-ylmethylamino]pentyl-(S,R)-alanyl-(S)-proline, N-(1(S)-carboxy-5-[4-(2(S,R)-hydroxy-3-isopropylaminopropoxy)benzylcarboxamido]pentyl-(S,R)-alanyl-(S)-proline or N-[1(S)-carboxy-5-(2-[5-(2(S,R)-hydroxy-3-isopropylaminopropoxy)napht-l-yloxy]acetamido)pentyl]-(S,R)-alanyl-(S)-proline, or a hemi-ester (in which E and/or Z are a carbalcoxy group in ) of 1 ' any of them, or a physiologically acceptable salt of any such compound. 12. Pharmaceutical formulation, characterized in that it comprises a compound according to claim 1 and an acceptable carrier for this compound. 13. A method for preparing a compound according to any one of claims 1 to 4, characterized in that it consists of coupling the aryl portion (X), or any precursor thereof, the amino-(hydroxy)alkoxyl side chain B, or any precursor thereof, and the amino acids or amino acid derivatives, or any precursors thereof, which together constitute the compound of formula (I) or any precursor thereof, and, if appropriate, transforming the precursor compound into the compound of formula (I) and, if desired, transforming any such compound of formula ¥f (I) into another compound of formula (I) and, if desired, to transform any compound of formula (I) thus formed into one of its physiologically acceptable salts.