DD263052A5 - PROCESS FOR PREPARING NEW COMPOUNDS - Google Patents

Abstract

The invention relates to the preparation of compounds of the formula (I) and of physiologically acceptable salts thereof. In formula (I): Q and Q exp 1 to Q exp 8 are hydrogen; A is a group of formula CONQ exp 9 (CH ind 2) ind n-, wherein n is 4 and Q exp 9 is hydrogen; B of an isopropyl group; E is a carboxyl group; Z is a carboxyl or C 2-5 carboalkoxy group; D is a methyl group; (X) a naphthyl or indolyl ring system; and - NY is a pyrrolidinyl ring; and physiologically acceptable salts thereof; Restrictive conditions are given. New compounds are: N- (1 (S) -carboxy-5- (5- (2 (R, s) -hydroxy-3-isopropylaminopropoxy) naphth-2-ylcarboxamido) pentyl) - (R, S) -proline, N- (1 (S) -carboxy-5- (8- (2 (R, S) -hydroxy-3-isopropylaminopropoxy) naphth-2-ylcarboxamido) pentyl) - (R, S) -alanyl- (S) - proline, N- (1 (S) -carboxy-5- (4- (2 (S) -hydroxy-3-isopropylaminopropoxy) -1H-indol-2-ylcarboxamido) pentyl) - (S) -alanyl- (S) proline. Formula (I) {Process, Preparation, Compounds, N- (1 (S) -carboxy-5- (5- (R, S) -hydroxy-3-isopropylaminopropoxy) naphth-2-ylcarboxamido) pentyl) - (R, S) -alanyl- (S) -proline}

Description

wherein R, (X), A, D, E, Q ⁶ to Q ⁸ and NY are as defined above, or if appropriate, protected forms thereof, and Q ^{10 is} a corresponding carboxyl or carbamoyl precursor, having a Means or agents that will cause the conversion of precursor group Q ¹⁰ into a carboxyl or carbamoyl group; and, if desired, one or more of the optional reactions (i) to (iii) of claim 2, or, where appropriate, one or more further optional reactions in any order.

4. The method according to claim 3 (A), characterized in that the reaction using dicyclohexylcarbodiimide (DCCI) in the presence of 1-hydroxybenzotriazole (HOBT) to suppress the racemization in a suitable solvent and at between -15 ⁰ C and room temperature lying temperature is made.

5. The method according to claim 3 (B), characterized in that the reaction is carried out at room temperature or under heating, as appropriate, in a suitable solvent.

6. The method according to claim 3 (C), characterized in that the reaction is carried out under the conditions defined in claim 4 DCCI / HOBT conditions or by mixed anhydride coupling.

7. The method of claim 3 (D) to (E), characterized in that the reaction is carried out by hydrogenation over a suitable catalyst.

8. The method of claim 3 (F), characterized in that the reaction is the hydrolysis of a compound of formula (XIX), wherein Q ^{10 is} cyano, or the reaction of a compound of formula (XIX), wherein Q ^{10 is} a corresponding carbonyl derivative , with one or more suitable agents which cause the conversion of the carbonyl derivative into a carboxyl group.

A process according to any one of claims 1 to 8, characterized in that the compound of formula (I) or a physiologically acceptable salt thereof prepared in this way is:

N- (1 (S) -casboxy-5- [5- (2 (R, S) -hydroxy-3-isopropylaminopropoxy) naphth-2-ylcarboxamido] pentyl) - (R, S) -alanyl- (S) proline,

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

N- (1 (S) -carboxy-5- [4- (2 (S) -hydroxy-3-isopropylaminopropoxy) -1H-indol-2-ylcarboxaymido] pentyl) - (S) -alanyl- (S) -proline .

or a half ester (as defined above) of each

or a physiologically acceptable salt of any such compound.

Field of application of the invention

The invention relates to a process for the preparation of new hypotensive compounds.

Characteristic of the known state of the art

Compounds which exhibit a β-adrenergic blocking effect, for example as described in US Pat. No. 3,705,907, are widely used in the therapy of hypertonic conditions. Another class of agents used to treat hypertension are inhibitors of angiotensin converting enzyme (ACE), as described, for example, in European Patent 0,012,401. It is believed that compounds which are simultaneously beta-receptor blockers and ACE inhibitors are particularly useful for the treatment and prophylaxis of hypertension and other conditions.

In EP-A-85306144.8, novel compounds of formula (I) (as defined below) and their physiologically acceptable salts are described as having both beta-blocking and ACE inhibitory activities. In formula (I) represent:

QQ ¹ Q ³ Q ⁴ ζ Q ⁷ ρ

i Γ I i ill ~ ο)

B-N-C-C-C-O- (X) -A-C-N-C-C-NY

___C; OH (f Q ° QO^fc

Q and Q ¹ to Q ^{8 are} atoms or groups independently selected from hydrogen and C 1-4 alkyl; A is a group of the formula - (CO) iHNQ ⁹ ) _m - (CH 2) _n - in which k and m are either both O or both 1, η is 1 to 6, Q ^{9 is selected} from hydrogen and C 1 to C 4 alkyl, and each of the - (CH ₂ ) _n groups is independently optionally substituted by one or two C _w alkyl groups;

B is a C 1-4 alkyl group;

E and Z are independently selected from carboxyl and carboxyl derivatives, e.g. For example, esters; D is hydrogen or a C 1-4 alkyl group optionally substituted by an amino group;

(X) a benzene ring or a naphthyl or indoryl ring system, each of which is optionally substituted in any position by one or more substituents independently selected from C _{1 to} C ₁ alkyl (which itself is optionally substituted by one or more halogen atoms ), C _M alkoxy, halogen, nitro, amino, carboxy, C 1-4 -alkoxycarbonyl and

hydroxy; and -N Y is a pyrrolidinyl, oxazolidinyl or thiazolidinyl ring or an indolinyl, quinolinyl and

Tetrahydroquinolinyl selected ring system,

and the formula (I) also includes the physiologically acceptable salts thereof.

Object of the invention

With the invention, compounds of the above type are to be provided, which are characterized by particularly favorable properties.

Explanation of the essence of the invention

It has now been discovered that certain individual compounds of formula (I) and their physiologically acceptable salts are particularly advantageous beta-receptor blockers and ACE inhibitors.

The invention therefore provides a process for the preparation of the following three individual compounds, namely:

N- (1 (S) -carboxy-5- [5- (2 (R, S) -hydroxy-3-isopropylaminopropoxy) -naphth-2-ylcarboxamido] pentyl- (R, S) -alanyl- (S) -proline , N- (1 (S) -carboxy-5- [8- (2 (R, S) -hydroxy-3-isopropylaminopropoxy) -naphth-2-ylcarboxamido] -pentyl) - (R, S) -alanyl- (S) -proline, and N- (1 (S) -carboxy-5- [4- (2- (S) -hydroxy-3-isopropylaminopropoxy) -1H-indol-2-ylcarboxamido] pentyl) - (S) -alanyl- (S) -proline, and its half-esters (in which Z is C ₂ -S-carboalkoxy),

which are hereinafter referred to as the compounds of the invention, and provided by their physiologically acceptable salts.

Of these, N- (1 (S) -carboxy-5- [4- (2- (S) -hydroxy-3-isopropylaminopropoxy) -1H-indol-2-ylcarboxamido] -pentyl- (S) -alanyl- (S. ) -proline, its half-esters (as defined above) and their pharmaceutically-acceptable salts are most particularly preferred because of their particularly advantageous combination of ACE inhibition and β-blocking effects.

The term N- (1 (S) -carboxy-5-] 4- (2- (S) -hydroxy-3-isopropylaminopropoxy) -1H-indol-2-ylcarboxamido] pentyl- (S) -alanyl- (S) -proline is used herein to describe the (S), (S), (S), (S) isomer of N- (1-carboxy-5- [4- (2-hydroxy-3-isopropylaminopropoxy) -1H-indole 2-ylcarboxamido] pentyl-alanyl-proline when it is substantially free of other optical isomers or any mixture of these isomers with other optical isomers, which is advantageously at least 50 mass% / mass, preferably at least 90 mass% / mass and most preferably at least 95Ma .-% / mass of the former contains isomers.

The invention also extends to the preparation of the non-physiologically acceptable salts of the compounds of the invention, such as may be used as precursors in the preparation of the compounds of formula (I) and their physiologically acceptable salts.

The physiologically acceptable salts of compounds of the invention include salts derived from organic and inorganic acids as well as from bases. Acid-derived salts are acetate, adipate. Alginate, aspartate, benzoate, benzenesulfonate, hydrogensulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanopropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate , Lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, 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 with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine and salts with amino acids such as arginine and lysine.

Quaternary ammonium salts can be formed when a nitrogen-containing group is present, for example by reaction with lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; Dialkyl sulfates, long-chain halides such as decyl, layryl, myristyl and stearyl chlorides, bromides and iodides, Arakylhalogeniden such as benzyl and phenethyl bromides.

The compounds of the formula I and their salts can always be used where an ACE inhibitor and / or β-blocker is appropriate. For example, the compounds of formula (I) and their physiologically acceptable salts can be used in the therapy of cardiovascular disorders, especially for the treatment of all forms of hypertension, both in the long and short term (especially in those with high serum -Reninmengen associated) and in general for the treatment and prophylaxis of congestive heart disease. Compounds of formula (I) and their physiologically acceptable salts may also find use in the treatment of hyperaldosteronism, angina pectoris, glaucoma and migraine.

The amount needed by a compound of the invention or a physiologically acceptable salt thereof to achieve the desired biological effect will, of course, depend on a number of factors, for example the specific compound chosen, the purpose for which it is intended, the mode of administration and the recipient. In general, it is believed that a daily dose is in the range of 1 ng to 100 mg per day, per kilogram of body weight, e.g. B. 50 ng to 50 mg and especially 500 ng to 5 mg / kg / day. For example, an intravenous dose is in the range of 10 ng to 1 mg / kg, which can be administered as an infusion of 0.1 ng to 50 micrograms per kilogram per minute. For this purpose suitable infusion liquids contain, for example, from 0.01 ng to 100 .mu.g, especially from 0.1 ng to 100pg per milliliter. For example, unit doses contain 100ng to 100mg of the active ingredient, for example, vials for injection contain 100ng to 1mg, and orally administrable unit dose formulations such as tablets or capsules contain from 0.001 to 50, especially 0.02 to 20mg. In the preceding section, the masses indicated in the case of physiologically acceptable salts refer to the mass of the active substance ion, that is to the ion derived from the compound of the formula (I).

Although the compounds of the present invention and their physiologically acceptable salts can be used as the compound per se, they are preferably provided for use in the treatment or prophylaxis of the above-noted conditions as a formulation of the invention having an acceptable carrier. The carrier must of course be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not harmful to the recipient The carrier may be a solid or a liquid and is preferably compounded with the compound as a unit dose. Formulated, for example, as a tablet, which may contain 0.05 to 95% by mass of compound Other pharmacologically active substances may also be present in the formulations according to the invention as described above The compounds according to the invention and their physiologically acceptable salts may be incorporated into the formulations either in the form of an acid, salt or ester thereof, and the formulations may be prepared according to one of the well known techniques of pharmacy consisting essentially of mixing the ingredients of the formulations.

The formulations include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, with the most suitable dosage form being used in each case The nature and severity of the condition to be treated and the nature of the subject compound or a physiologically acceptable salt thereof will depend. Formulations suitable for oral administration may be in the form of discrete units, such as capsules, cachets, troches, or tablets, each containing a certain amount of the compound of the invention or a physiologically acceptable salt thereof; of powder or granules; a solution or suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water emulsion; or a water-in-oil fluid emulsion. Such formulations may be prepared by any pharmacy method, but all methods include the step of bringing the compound together with the carrier agent which is one or more additional ingredients. In general, they are prepared by uniformly and intimately admixing the compound with the liquid or finely divided solid carriers or both, and then, if necessary, shaping the product into the required preparation. For example, a tablet may be prepared by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients. Compressed tablets may be prepared by pressing in a suitable machine the compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent (s). Molded tablets may be prepared by moistening the powdered compound with an inert liquid diluent and shaping it in a suitable machine. ι

Formulations suitable for buccal (sub-lingual) administration are candies containing a compound of the invention or a physiologically acceptable salt thereof in a seasoned base, usually sucrose and acacia or tragacanth; and lozenges containing the compound in an inert base such as gelatin and glycerin or sucrose and gum acacia.

Formulations of the invention suitable for parenteral administration are generally sterile aqueous preparations of a compound of the invention or a physiologically acceptable salt thereof, which preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be by subcutaneous or intramuscular or intradermal injections. Such preparations are generally prepared by mixing the compound with water, making the product sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain 0.1 to 5% by mass / mass of active ingredient.

Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These can be prepared by mixing the compound of the invention or a physiologically acceptable salt thereof with one or more of the usual solid carriers, for example cocoa butter, and molding the resulting mixture. Formulations suitable for topical application to the skin are preferably presented in the form of an ointment, cream, lotion, paste, gel, spray, aerosol or oil. Possible carriers are petrolatum, lanolin, polyethylene glycols, alcohols and combinations thereof. The active ingredient is generally present at a concentration of 0.1 to 15 mass% / mass of the composition, for example from about 0.5 to about 2%.

The compounds of the invention and their physiologically acceptable salts may be prepared in any conventional manner, and in accordance with the invention may be prepared, for example, by any of the methods described hereinafter. The compounds of the invention and their physiologically acceptable salts can be prepared by any conventional method in peptide chemistry, and can include the coupling of the aryl moiety, the amino (hydroxy) alkoxy side chain and the amino acids or their derivatives, which together form the compounds of the invention, in any order. It will be appreciated, for example, that the aryl moiety, side chain and amino acids or their derivatives may be coupled in any order to form two discrete chemically unified substances which then form as the final processing step (which may be claimed as aspect of the invention) compound of the invention or a precursor thereof, and if desired, the precursor is converted into the claimed compound of the invention (which transformation can also be claimed as one aspect of the invention), and optionally the compound of the invention, if desired, to another compound of the invention, and also optionally, if desired, each compound of the invention thus formed is converted to a physiologically acceptable salt thereof.

Therefore, according to the present invention, there is provided a process for producing a compound of the invention or a physiologically acceptable salt thereof by a production method of compounds of the formula (I) and their physiologically acceptable salts as defined in the above-mentioned EP-A 85306144.8 It is that a compound R ^{1 is} reacted with a compound R ² , wherein

(a) R ^{1 is} a reactive derivative of a compound of the formula (II)

R- (X) (II)

and R ^{2 is} a compound of the formula (III)

ZQ ⁷ D

HQ ^y N - (CH ₂ ) _n -CNCC-NY _(III)

Q ⁶ QOE

or a reactive derivative thereof; or

(b) R ^{1 is} a reactive derivative of a compound of formula (IV)

R- (X) -A-CH '(IV)

Q ⁶

and R ^{2 is} a reactive derivative of a compound of the formula (V)

HN - C - C - NY ^(V)

QOE

represents; or

(c) R ^{1 is} a compound of the formula (VI)

ZQD

ι ι ι

R- (X) -A-C-N-C-C-OH Μ)

or a reactive derivative thereof and R ^{2 is} a compound of the formula (VII) HN Y

° S

(VII)

or a reactive derivative thereof;

(in which R in the compounds of the formulas (II) to (VII) R is a group of the formula (VIII)

QQ ¹ Q ³ Q ⁴ S - I - C - C - C - O - ^IVI "'

Q ² OH Q ⁵

or R is a reactive substituent on group (X) ₉ , and in formulas (II) to (VIII) η, Q, Q ¹ to Q ⁹ , A, B, D, E, -NY, (X) and Z are as defined above and, if appropriate, each of the compounds of

Formula (II) to (VII) and the group of formula (VIII) includes protected forms thereof; and then, if desired, one or more of the optional reactions are performed in any order;

(i) When the product of the reaction of compound R ¹ and R ² is a precursor for a compound of formula (I), this precursor is exposed to such conditions and / or treated with a suitable agent or agents, that thereby the consequent formation of a compound of formula (I) takes place;

(ii) each compound of formula (I) thus formed is converted into another compound of formula (I); (iii) any compound of formula (I) formed is converted into a physiologically acceptable salt thereof. In formulas (II) to (VIII), reference to a reactive derivative of a compound having such a formula refers to such compounds when substituted by one or more reactive moieties, and / or to such compounds, if any of them or more components are replaced by one or more reactive components.

In the above formula (III) and throughout the specification, each of the - (CH ₂ ) _n groups forming part of a formula of an intermediate compound (for example, as shown in the following formulas (XII), (XX), (XXI), (XXIII) and (XXV), each independently independently substituted by one or two C 1-4 alkyl groups.

The above-mentioned optional reactions (i) to (iii) are further aspects of the invention and may be claimed herein individually or in any combination. The optional reaction (i) includes the situation in which the precursor for the compound of the formula (I) is an analog of such a compound, but wherein one or more components thereof are protected with a suitable protecting group, and the reaction therein in that the precursor is exposed to such conditions and / or treated with an agent or agents to thereby deprotect with subsequent formation of the desired compound of formula (I).

Details of the methods of peptide chemistry, and especially of suitable activating and protecting groups, and suitable reaction conditions for the above-mentioned methods are given in the following references, which are given by way of example only and are not intended to be exhaustive or restrictive: Schroder and Luebke, "The Peptides" (Academic Press (1965).

c) Tilak, Tetrahedron Letters, 849 (1970).

d) Beyerman, HeIv. Chim. Acta., 56, 1729 (1973).

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

f) "Methods of Organic Chemistry" (Houben-Weyl), 4th ed., Vol. 15, "Synthesis of peptides", parts 1 and 2 (Georg Thieme Verlag, 1974).

g) "The Peptides: Analysis, Synthesis, Biology", Gross, F. and Meienhofer, J. Hsg., Vol 1 to 4 (Academic Press, 1979) h) "Peptides: Syntheses, Physical Data", Voelter, W and Schmid-Siegmann, F., Vol. 1 to 6 (Georg Thieme Verlag, 1983). i) F.Atherton, M.J. Gait, R.C. Sheppard and B.J. Williams, Bioorganic Chem., 1979, 8, 351-370.

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

k) F.Atherton, F. Brown and R.C. Sheppard, J.C.S. Chem. Comm. 1981.1151-1152.

I) T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1981.

m) G.C.Barrett (Ed.), The Chemistry and BiochemistryoftheAminoAcids, 1st Edition, Chapman and Hall, London and New York,

As is common in peptide chemistry, various protecting groups can be used simultaneously on different components of a molecule to facilitate selective deprotection at various reaction stages, depending on the reactants and reaction conditions employed. For example, the protecting groups BOC (t-butoxycarbonyl) and TBDMS (t-butyldimethylsilyl) may 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) may be removed by hydrogenation over palladium-carbon, preferably under acidic conditions, in a suitable solvent such as methanol. When it is necessary to protect a carboxy group as defined above for groups E and Z, this can best be accomplished by the formation of a corresponding simple ester such as the t-butyl ester, and removal of the protecting group can be accomplished by acid hydrolysis. The optional reaction (i) also relates to the case where in the precursor for the compound of the formula (I) represents a reactive substituent (or a protected form thereof) on the group (X), and the reaction comprises treating this product with an agent or with agents which serve to aid the substitution of the group of formulas (VIII) and (X).

In this case, the reactive substituent may be for the preparation of compounds of formula (I) wherein Q is hydrogen. Be hydroxy and the precursor with a compound of formula (IX)

,1

, 4

ί / ⁰ ^ CH

cf " . Ph

tr - ο - G - α ι (ix »

Q ⁵ 3 / \ ^ 3

^Q Q ² Q ¹

(wherein Q ¹ to Q ⁵ and B are as defined above, Ph is phenyl and X ^{1 is} a corresponding leaving group such as mesyl), and the reaction is generally carried out under basic conditions followed by deprotection / decyclization with a corresponding Reactants such as trifluoroacetic follows. Alternatively, the reactive substituent may be a group of formula (X) ₁

OQ ⁴

C-O- (X)

* is

• Λ

Q ³ Q

(wherein Q ¹ to Q ⁵ are as defined above), and the reactant is a corresponding amine, the reaction being best carried out by heating in a suitable solvent such as dioxane. It will be appreciated that instead of substituting the group of formula (VIII) on the ring or ring system (X) as part of the optional reaction (i), which is an aspect of the present invention, equivalent substitution at any convenient stage throughout the procedure for the synthesis of compounds of formula (I) and their physiologically acceptable salts. This substitution can be carried out primarily by applying the procedures specified above with respect to the compounds of the formulas (IX) and (X), but replacing the precursor for the compound of the formula (I) in which R is a reactive substituent (or its protected form), then an appropriate intermediate including this group R is used when R represents a reactive substituent (or its protected form). Examples of intermediates suitable for this purpose are those subsequently defined by the formulas (XI), (XIII), (XV), (XVI), (XIX), (XXI), (XXVII) and (XXIX). Optionally, such methods may optionally require one or more steps for protection and / or guard removal, as dictated by Bedaf.

The optional reaction (i) further includes the case where a compound of the formula (I) wherein Z is an ester by the reaction of the corresponding compound of the formula (I) wherein Z is carbamoyl with the corresponding alcohol in Presence of an acid catalyst, preferably of the ion exchange type such as Amberlyst 15, is formed. The optional reaction (ii) may also have the case where when in the compound of the formula (I) E and / or Z represents a carboxy group, the compound is converted to a corresponding compound wherein E and / or Z is a carboxylic acid derivative for example, by treating the compound with an appropriate alcohol in the presence of a suitable acid such as sulfuric acid.

The optional reaction (ii) may also include the case where, in the compound of the formula (I), E and / or (Z) is a carboxylic acid derivative, the compound becomes a corresponding compound wherein E and / or Z is a carboxy group represents, for example, by hydrolysis, for. B. under basic conditions, for example in the presence of sodium hydroxide is converted.

The optional reaction (iii) may comprise reacting the compound of formula (I) so formed with a suitable mineral or organic acid.

Specific subclasses of the above process for the preparation of a compound of the invention or a physiologically acceptable salt thereof, according to the method of preparation of compounds of formula (I) and their physiologically acceptable salts, may comprise the following:

(A) as a preferred subclass of the above reaction variant (a) for the preparation of compounds of the formula (I) in which k and m are both 1, the reaction of a compound of the formula (XI)

R- (X) -R ³ ₍ (XI)

(wherein R and [X] are independently as defined above, or as appropriate, protected forms thereof, and R ^{3 is} carboxy or a carboxylic acid derivative) with a compound of formula (XII)

ZQ ⁷ D

i '^ n

- (CH ₂ ) _n --C - N - C ^ - C - N ^ Y _{(X ||)}

(wherein n, D, E, Z, Q ⁶ to Q ⁸ and -NY are independently as defined above, or as appropriate

are protected forms thereof, and R ^{4 represents} a group of the formula -NHQ ⁹ in which Q ^{9 has} the meaning defined above); (B) as a preferred subclass of the above reaction variant (b) Reaction of a compound of the formula (XIII) ₁

-10- Z63 05Z

Κ. (χ) - A - C - R ^{5 (XIII)}

(wherein R, [X], A, Q ⁶ and Z are independently as defined above, or, as appropriate, protected forms thereof, and R ⁵ corresponds to the following definition of formula (XIV)) with a compound of formula (XIV)

D.

, R ⁶ - C - C - n "~ \

, Q ⁸ o

(wherein D, E, Q ⁸ and NY are independently as defined above, or, if appropriate, protected

Forms thereof are and one of R ⁵ (in formula (XIII) above) and R ^{6 is} a group of formula -NHQ ⁷ and the other is an outgoing group);

(C) as a preferred subclass of reaction variant (c) above. Reacting a compound of the formula (VI) as defined above with a compound of the formula (VII) as defined above.

(D) as a preferred subclass of the optional above reaction (i), reducing a compound of formula \ XV)

ZQ ⁷ R ⁷

R 1 - (X) - A - C - N - C - C - N G (XV)

I ₆ 's H ^

Q. (Τ 0 E

(wherein R, (X), A, E and Q ⁶ to Q ^{8 are} independently as defined above, or where appropriate, protected forms thereof, and R ⁷ and NQ are independently defined above for D and fvj Y, respectively Groups and unsaturated forms thereof are selected, provided that at least one in such an unsaturated form

consists; and -

(E) as another preferred subclass of the optional above reaction (i) for the preparation of compounds of formula (I) wherein Q ⁶ and Q ⁷ or Q ^{8 are} hydrogen, reducing a compound of formula (XVI)

R - (X) - A - R - - Cj - N ^ Y _(χνι)

OE (wherein R, (X), A, E, and N j Y are independently as defined above, or, if appropriate, protected

Forms thereof, and R ^{8 represents} a group of formula (XVII)

z o

| l

-C = N-C- (XVIII)

Q ^S

(wherein Z, D and Q ⁸ are as defined above) or a group of the formula (XVIII) ZQ ⁷ R ⁹

Iiii

- C - N - C - < ^XVI ">

(wherein Z, Q ⁶ and Q ⁷ are as defined above and R ^{9 is} an analogue of the group D defined above (but not hydrogen) and has the same formula as D except that it lacks a hydrogen atom and is thereby replaced by a Double bond is bound to the -NQ ⁷ -C -r moiety »;

(F) and as still another preferred subclass of the above optional reaction (i) for the preparation of compounds of formula (I) wherein Z is carboxyl or carbamoyl, the treatment of a compound of formula (XIX)

«10 R - (χ) -AGNCG- N ^ Y ^(XIX)

<| ° Q ⁸ 0 E

(wherein R, (X), A, D, E, Q ⁶ to Q ⁸ and N γ are independently as defined above, or as appropriate

"^ - ^/ is protected forms thereof, and Q ^{10 is} a corresponding carboxyl or carbamoyl precursor) with a

Means or agents that serve to effect the conversion of the precursor group Q ¹⁰ to a carboxyl or carbamoyl group;

and optionally, if required, one or more of the above optional reactions (i) to (iii), or if

it is appropriate to carry out one or more of the optional reactions in any order. Reaction (A) is generally carried out using dicyclohexylcarbodiimide (DCCI) in the presence of 1-hydroxybenzotriazole (HOBT) to suppress racemization in a suitable solvent such as methylene chloride or DMF at a reduced temperature, e.g. Example in the range of -15 ° C to 0 ⁰ C or up to room temperature, as appropriate made. Such reaction protocol is hereinafter referred to as "DCCI / HOBT." Reaction (B) is best carried out at room temperature or under heating, as appropriate, in a suitable solvent such as dichloromethane or DMF.

Reaction (C) is best carried out under DCCI / HOBT conditions or by mixed anhydride coupling, which is a technique well known to those skilled in the art of peptide chemistry, but may, for example, involve the reaction of the acid intermediates Isobutyl chloroformate and N-methylmorpholine and subsequent reaction with the amine intermediate, the reaction being most conveniently at a reduced temperature, e.g. B. from -15 ⁰ C to -25 ° C, is performed in order to limit the racemization to a minimum.

Reaction (D) is best carried out by hydrogenation over a suitable catalyst such as palladium on carbon, for example in a suitable solvent such as methanol.

In reaction (D), a preferred class of compounds of formula (XV) are the compounds of formula (XVI) wherein R ^{8 is} a group of formula (XVIII) wherein R ^{9 is} CH ₂ . Another preferred class of compounds of formula (XV) are

those in which -N, G represents a ring of formula - ^ J.

° ^ Y

Reaction (E) is also best carried out by hydrogenation, for example by the method described in the previous section. It will be appreciated that the intermediate compound of formula (XVI) can be formed in situ in this reaction (for example, by a subsequently described method) and when the group R ⁸ in the compound of formula (XVI) has formula (XVII) in which Q ^{8 is} hydrogen, then the group of formula (XVII) may also have the resonance form (XVIIA),

    , I (XV) IA)

- CH - N = C -

(wherein D and Z are independently as defined above or, if appropriate, protected forms thereof), and when the group R ^{8 has} the formula (XVIII) in which Q ^{7 is} hydrogen, then the group (XVIII) may be the Resonant form (XVIIIA)

Z D. '

C-N = C- (XVIIIA)

(wherein D, Z and Q ^{6 are} independently as defined above or, if appropriate, protected forms thereof). The reaction (F) may include, for example, the hydrolysis of a compound of formula (XIX) wherein Q ^{10 is} cyano. This hydrolysis is best described as acid hydrolysis, e.g. B. in a suitable strong mineral acid such as hydrochloric acid, made in a suitable solvent such as methanol.

Alternatively, the reaction (E) may also comprise the reaction of a compound of formula (XIX) wherein Q ^{10 is} a corresponding carbonyl derivative with one or more suitable reactant (s) serving to initiate the amination of the carbonyl derivative ). Thus, for example, when Q ^{1C is} an activated carbonyl group such as an ester or an acid chloride, the compound of formula (XIX) may be reacted with ammonia, preferably under aqueous conditions. When the carbonyl derivative is carboxy, the compound of formula (XIX) may be treated with a reactant which promotes the formation of a corresponding activated acid in the presence of or by subsequent reaction with a corresponding reagent as described above Reactions with esters and acid chlorides has been described.

The reactant which serves to initiate the formation of a corresponding activated acid may be sulfur oxychloride, a phosphorus halide such as phosphorus tri- or pentachloride, a phosphorous oxyhalide such as oxychloride, trifluoroacetic anhydride, an alkyl (ζ B ethyl) chloroformate, or any other suitable agent which will be known to the person skilled in the art. A compilation of such reagents can be found in Houben-Weyl (Ref. [F] supra), Part 1, p. 29. In general, the reaction may be carried out in a suitable solvent such as toluene, if possible in the presence of a corresponding catalyst such as dimethylformamide. Alternatively, the reaction may be by reaction with a suitable weak or volatile base such as ammonia, preferably by heating. Such a reaction can best be carried out using an ammonia stream or by the use of ammonia in situ in the presence of a dehydrating agent.

In reaction (B) and elsewhere in this specification, unless expressly stated otherwise, the or each leaving group may be selected from any known in the art of chemistry, for example as described in J. March, Advanced Organic Chemistry, 3. 1977, McGraw Hill, NY, p. 187. Such leaving groups include halo (preferably chloro or bromo) mesyl (i.e., methanesulfonyloxy) tosyl (i.e., toluenesulfonyloxy) and triflate (i.e., trifluoromethanesulfonyloxy).

It is to be emphasized that if any process of the invention does not result in any case in the preparation of a required single isomer of a compound of formula (I) or a physiologically acceptable salt thereof, this process entails the separation of isomers, either from the final product itself or of any intermediate compound at an appropriate stage of the reaction, for example, by means of column chromatography. In process (A) supra, the compound of formula (XI) can be prepared by the general method described in the above-cited U.S. Patent 3,705,907. The compounds of the formula (XII) can be prepared by methods which are generally analogous to those mentioned in the above-mentioned EU patent 0.012.401 and also EU-PS 0.126.986 A1. In process (B) compounds of formula (XIII) wherein in the definition of A k and m are both 1 by reacting a compound of formula (XI) as defined above with a compound of formula (XX),

Z ₁

) - G - R ¹¹

l ·

(wherein R ⁴ , n, Z and Q ^{6 are} independently as defined above or, if appropriate, protected forms thereof, and when in the required compound of formula (XIII) R ^{5 is} a group of formula -NHQ ⁷ as above R ^{11 is} a protected analogue of the group of the formula -NHQ ⁷ , and when in the required compound of the formula (XIII) R ^{5 represents} an outgoing group then R ^{11 represents} a supported hydroxy group, for example an alkoxy group such as t-butoxy), and if R ^{11 represents} a protected hydroxy group, the reaction product is treated with an agent or agent which results in the conversion of the protected hydroxy group to the desired leaving group (s). For example, when the leaving group is mesyl, the reaction product may be treated with a methanesulfonyl halide such as the chloride.

Compounds of the formula (XIII) in which, in the definition of A, both are 0 can be prepared by reacting a compound of the formula (XXI)

R- (X) - (CH ₂ ) _n -R ¹² ₍ (XXI)

(wherein R, [X] and η are independently as defined above, or where appropriate, are protected forms thereof, and R ^{12 is} a corresponding leaving group) with a compound of formula (XXII)

H- H - R ¹³ (XXIl)

(wherein Z and Q ⁶ and R ^{11 are} independently as defined above, or where appropriate, protected forms thereof, and R ^{13 is} an appropriately protected amino group), and the reaction product is reacted with an agent or agent which ( which) is treated to remove the protection from the protected amino group, and when in the required compound of the formula (XIII) R ^{5 represents} a group of the formula NHQ ⁷ in which Q ^{7 is} a C 1-4 alkyl group, the deprotected product is reacted with a corresponding alkylating agent or agents, and when in the desired compound of formula (XIII) R ^{6 represents} an leaving group, the deprotected product with an agent or agents which converts the amino group is brought into the leaving group (s), is reacted. For example, when the protected amino group R ¹³ is a group of the formula PhCH = N (where Ph is phenyl), deprotection can be carried out by treatment with a suitable base. The optional treatment of the deprotected product to convert the amino group into an outgoing group may be carried out, for example, according to the general procedure described in EDThorset, Tet. Lett., 1982,23,1875-6 method described.

The compounds of the formula (XIII) in which both are 0 in the definition of A can likewise be obtained by one of the methods described in Chapter 8 (p. 246ff.) Of the publication of GC Barett (Hsg.) (Designated m) supra, be prepared method described.

The compounds of formula (XIV) are simple dipeptides or minor derivatives thereof and can be prepared by methods well known to those skilled in the art.

263

In process (C), compounds of formula (VI) wherein in the definition of A k and m are both 1 may be prepared by the reaction of a compound of formula (XI) as defined above with a compound of formula (XXIII)

2 O ⁷ D

R ⁴ - (CHJ _n -CNC- R ¹⁴

2'n, i (XXIlI)

Q ⁶ Q ⁸

(wherein R ⁴ , η, D, Z and Q ⁶ to Q ^{8 are} independently as defined above, or where appropriate, protected forms thereof, and R ^{14 is} a protected carboxy group) and then deprotecting Group R ¹⁴ getting produced. ι.

Alternatively, compounds of formula (VI) wherein in the definition of A k and m are both 0 by the reaction of a compound of formula (XIII) as defined above and wherein in the definition of A k and m are both 0, can a compound of the formula (XXIV) ₁

R ⁶ - O - R ¹⁴ ,

, (XXIV)

Q ³

(wherein R ⁶ , D and Q ^{8 are} independently as defined above, or as appropriate, protected forms thereof, and R ¹⁴ is as defined above) and subsequent removal of the protection from the group R ¹⁴ .

The compounds of formula (VII) are simple amino acids or insignificant derivatives thereof and can be prepared by methods well known to those skilled in the art.

In process (D) the compounds of formula (XV) wherein in the definition of A are both known as 1 can be prepared by the reaction of a compound of formula (XI) as defined above with a compound of formula (XXV)

ZQ ⁷ R ⁷

- (CH ₉ J _n -CNCCN 2 η

₍ ^ (XXV,

Q ⁶ Q ⁸ OE

(wherein n, E, R ⁴ , R ⁷ , Q ⁶ to Q ⁸ and | \ | * Q are independently as defined above, or if it is

is appropriate, protected forms thereof), preferably under DCCI / HOBT conditions or by mixed anhydride coupling.

The compounds of formula (XV) wherein in the definition of A k and m are both 0 can be prepared by reacting a compound of formula (XIII) as defined above with a compound of formula (XXVI)

R ⁷

6 ^{l of} R ⁶ - C - C - NG

ι! j ^x - ⁱ \ (XXVl)

Q ⁸ 0 E

(wherein E, Q ⁸ , R ⁶ , R ⁷ and NG are independently as defined above, or if so

is appropriate, protected forms thereof are) produced.

In process (E), the compounds of formula (XVI) may be prepared by the reaction of a compound of formula (XXVII) ₁

R ¹⁵

¹ 16

R- (X) -A-C-R (XXVII)

(wherein R, [X], A, and Z are independently as defined above, or, as appropriate, protected forms thereof, and either [i] one of R ¹⁵ and R ^{16 is} a group Q ⁶ as defined above; another is a group of the formula -NHQ ⁷ as defined above or [ii] R ¹⁵ and R ¹⁶ together form = 0) with a compound of the formula (XXVIII)

R ¹⁹

13 '

R -CQH Y

II N-V (XXVIII)

-14- 263 053

(wherein D, E and jig γ are independently as defined above, or, if appropriate, protected

Forms thereof are, and in the case given in the definition of formula [XXVII] [i] R ¹⁷ and R ¹⁸ both represent = 0 and R ^{19 is} a group D as defined above, or in case [ii] R ¹⁸ a group of the formula NHQ ⁷ as defined above and either R ^{17 is} a group Q ⁸ as defined above and R ^{19 is} a group D as defined above or R ¹⁷ and R ¹⁹ together represent a group = R ⁹ as defined above) , This reaction is preferably carried out in a water-immiscible solvent such as toluene, benzene or chloroform in the presence of a corresponding acid catalyst such as p-toluenesulfonic acid.

In process (F), the compounds of formula (XIX) wherein Q ^{10 is} cyano can be prepared by the reaction of a compound of formula (XXIX)

R- (X) -A-CHO ₍ (XXIX)

(wherein R, [X] and A are as defined above, or where appropriate, are protected forms thereof) with a compound of formula (V) as defined above in the presence of preferably in situ generated hydrocyanic acid, for example by mixing the reactants of formula (XXIX) and (V) in the presence of an alkali metal cyanide (such as sodium or potassium cyanide) and a corresponding acid such as acetic acid, preferably in a suitable solvent such as methanol. This reaction, as well as the preparation of the intermediates of formulas (XXIX) and (V), can be carried out according to the general methodology described in J. Med. Chem., 1985, 28434-442.

embodiments

The invention will now be described in more detail by way of the following illustrative examples.

Example 1 N- (1 (S) -carboxy-5- [4- (2- (S) -hydroxy-3-isopropylaminopropoxy) -1H-indol-2-ylcarboxamido] pentyl) - (S) -alanyl- (S. ) proline

(a) 2-Benzyloxybenzaldehyde

A mixture of salicylaldehyde (24.5 g), benzyl bromide (34 g), anhydrous potassium carbonate (15 g) and acetone was refluxed for 5 hours with stirring. The solvent was removed in vacuo and the residue was partitioned between dilute caustic and ether. The ether layer was washed with water, dried (MgSO ₄ ) and evaporated to afford the product as a viscous oil which slowly crystallized on standing. The solid thus obtained had a melting point of 46 ° C.

(b) ethyl azidoacetate

Ethyl bromoacetate (167g) and then tetrabutylammonium bromide (0.5g) were added to a solution of sodium azide (78g) in water (200ml). The mixture was stirred vigorously for 1 hour and then steam distilled. The oily product was separated and dried over anhydrous calcium chloride, yield 126g (97%).

(c) Methyl ^ -benzyloxyindole ^ -carboxylate

Sodium (9.2g) was dissolved in dry methanol (270ml) and the solution was cooled to 0 ° C. A mixture of 2-benzyloxybenzaldehyde from step (a) (42.4g) and ethyl azidoacetate from step (b) (51.6g) was then added. After a stirring time of 5 hours at 0 to 5 ° C, the mixture was poured onto ice and ammonium chloride (20 g). The mixture was extracted with ether (600 ml). The organic phase was washed with water, dried (MgSO ₄ ) and evaporated under vacuum at 25 ° C. The yellow solid was dissolved in xylene (400 ml) and the resulting solution was added dropwise to the refluxing xylene (25 ml) over 2 hours. The solution was refluxed for an additional hour, then allowed to stand overnight. 19 g of methyl 4-benzyloxyindole-2-carboxylate, mp 193-194 ° C was recovered. A sample recrystallized from methanol had a melting point of 195.5 ° C.

(d) Methyl 4-hydroxyindole-2-carboxylate

Methyl 4-benzyloxyindole-2-carboxylate from step (c) (4.2g) and 10% palladium on charcoal (0.5g) in methanol (100ml) was shaken with hydrogen for one hour. The catalyst was removed and the solvent evaporated. The residue was recrystallized from methanol / trichlorethylene (charcoal) to give 2.5 g of methyl 4-hydroxyindole-2-carboxylate (87%) as colorless needles, mp 192-193 ° C.

(e) Methyl 4- (2 (S) -oxiranylmethoxy) -1H-indole-2-carboxylate

A solution of methyl 4-hydroxyindole-2-carboxylate from step (d) (3.35g) in DMF (7ml) was added to a suspension of 60% sodium hydride oil dispersion (704mg) in DMF (10ml) and the mixture was stirred in an ice bath until foaming ceased. A solution of 2S-glycidyl tosylate (J. Org. Chem., 51, 3710 [1986]) (4.0 g) in DMF (7 ml) was added at 0 ° C; the mixture was kept wurde3 hours at 50 ⁰ C, then cooled, and the solvent was removed under vacuum. The residue was chromatographed on a 10χ 15 cm silica column using 2% MeOH-CH ₂ Cl ₂ as the eluent; About 100 ml fractions were collected. The fractions containing the product were taken together and evaporated to leave a white solid (3.6 g) which was recrystallized from isopropanol. Yield 2.5 g, m.p. 141-144 ° C, [α] _D = + 8.75 ° (1.0, CHCl ₃ ).

263

(f) Methyl 4- [2 (S) -hydroxy-3-isopropylamino] -1H-indole-2-carboxylate

The epoxide of step (e) (0.56 g) was added (1 ml) maintained in a mixture of DMF (5ml), isopropylamine (5ml) and water for 2 hours at 50 ⁰ C. The solvents were evaporated under vacuum and the residue was stirred with EtOAc for 48 hours at 5 ⁰ C. The product was collected by filtration, yield 278 mg. Additional product was recovered from the mother liquor by chromatography on silica using MeOH-CH ₂ Cl ₂ - "880" NH ₃ (90: 10: 1), yield 300 mg. Chiral rearrangement NMR showed that the product was> 93% of a single enantiomer. Melting point 124-125 ° C, [α] _D = -9.3 ° (1.0, 1 M, HCl)

Analysis: C ₁₆ H ₂₂ N ₂ O ₄ : required C, 62.73; H, 7.24; N, 9.14%

found C, 62.48; H, 7.41; N, 9.17%.

(g) Methyl 4- [3- (N-t-butoxycarbonyl-N-isopropylamino) -2 (S) -hydroxypropoxy] -1H-indole-2-carboxylate

The product from step (f) (0.64g) was dissolved in dry DMF (5ml), a solution of di-t-butylpyrocarbonate (Fluka, 0.46g) in DMF (3ml) was added and the solution was cooled to ambient temperature 2 Stirred for 5 hours. TLC showed that the reaction was complete (SiO ₂ , CHCl ₃ -MeOH, 8: 1). The solvent was evaporated and the residue was subjected to chromatography on silica using EtOAc (40-60) gasoline (1: 2) as eluent. The fractions containing the product were taken together and evaporated and the residue was crystallized from petrol. Yield 0.64g, m.p. 87-88 ° C, [α] _D = + 5.31 ° (1.0, MeOH). Analysis: C ₂₁ H ₃₀ N ₂ O ₆ required C, 62.05; H, 7:44; N, 6.89%

found C, 62.08; H, 7.49; N, 6.77%.

(h) 4- [3- (Nt-butoxycarbonyl-IM-isopropylamino) -2 (S) -hydroxypropoxy] -1H-indole-2-carboxylic acid The ester from step (g) (0.57g) was dissolved in MeOH ( 6 mL) and 2M NaOH (2.1 mL) was added; The mixture was refluxed on a steam bath for 30 minutes, cooled, diluted with water (5 ml), and MeOH was evaporated in vacuo. The aqueous residue was filtered and the pH was adjusted to 5 by the dropwise addition of 10% citric acid. After a stirring time of 30 minutes, the white precipitate was collected by filtration, washed with water and dried under vacuum over P ₂ O ₅ , yield 0.42 g, melting point 170-172 ° C (decomposition). [a] _D = + 4.9 ° (1.0, MeOH).

Analysis: C ₂₀ H ₂₈ N ₂ O ₆ requires C, 61.21; H, 7.19; N, 7.14%;

found C, 61.34; H, 6.97; N, 7.07%

(i) Methyl O-trifluoromethanesulfonyl-Fl-lactate

This compound was prepared according to the method described by Effenberger, et al., Angew. Chem. Int. Ausg., 1983, 95, 50, described methodology. Thus, a solution of methyl R-lactate (Aldrich, 4.16 g) and pyridine (2 mL) in CH ₂ Cl ₂ (10 mL) was added dropwise to a stirred solution of trifluoromethanesulfonic anhydride (Aldrich, 7.86 mL) in CH ₂ Cl ₂ (40 mL ) at <0 ° C. The reaction mixture was stirred and allowed to stand at about 10 ^° C. for 2 hours to warm. The mixture was washed with water and brine, then dried over MgSO 4. The solvent was evaporated and the residue chromatographed on silica using CH ₂ Cl ₂ as eluent. The product-containing fractions were evaporated to obtain a mobile colorless oil, 8.7 g (containing solvent). This material was stored in a freezer and used directly in the next step.

(j) Methyl [N-1 (S) -t-butoxycarbonyl-5-N-benzyloxycarbonylaminopentyl] - (S) -alaninate.

The triflate from step (i) was dissolved in CH ₂ Cl ₂ (15 ml) and added dropwise over about 20 minutes to a solution of t-butyl N ^E -benzyloxycarbonyl-S-lysinate (J. Org. Chem., 28, 1251). 1963]) (8,05g) and triethylamine (5,6ml) in CH ₂ Cl ₂ (40ml) at <-5 ⁰ C. The solution was stirred at 0 ^° C for 1 hour, then allowed to warm to room temperature. The solvent was evaporated and the residue chromatographed on silica with EtOAc as eluent. Product fractions were concentrated to give a gum, yield 5g. NMR and mass spectra were consistent with the structure, [a] _D = -24.96 ° (1.0, EtOAc).

(k) N- [1 (S) -t-Butoxycarbonyl-5-N-benzyloxycarbonylaminopentyl] - (S) -alanine The ester from step (j) (5g) was dissolved in MeOH (15ml) and a solution of NaOH (0.66 g) in water (7 ml) was added dropwise. The mixture was stirred at ambient temperature for 5 hours, then diluted with water, and MeOH was removed in vacuo. The residual aqueous solution was washed with ether (2x) and acidified by the dropwise addition of 1 M HCl (16.5 ml). The resulting white precipitate was collected by filtration, washed with water and dried over P ₂ O ₅ . Yield 3.78g. This material was converted to the HCl salt as follows: The solid was dissolved in warm dioxane (50 ml), filtered, and 3.4 M HCl-dioxane (3.47 ml) was added; after the addition of ether, an oil was precipitated. The solvents were evaporated, the residue was taken up in water and the remaining dioxane removed by evaporation. The white precipitate was collected and dried. Yield 2g; Another 1.4 g were obtained by freeze-drying the mother liquor. Melting point 140 to 141 ° C, [a] _D = -7.5 ° (1.0, dioxane).

(I) t -butyl-N-II-fSJ-t-butoxycarbonyl-BN-benzyloxycarbonylaminopentyl-tSJ-alanyl-fSJ-prolinate The acid from step (k) (3.4g) was dissolved in DMF (20ml) and N- Methylmorpholine (0.46 ml) was added. The solution was cooled in an ice-bath and 1-hydroxybenzotriazole (1.06g) added, followed by dicyclohexylcarbodimide (1.79g). The mixture was stirred for 1 hour at 0 ° C, then a solution of t-butyl-S-prolineate (J.Amer.Chem.Soc, 82, 3559 [1960]) (1.35g) in DMF was added. The reaction mixture was stirred at 4 ° C for 18 hours, then filtered and concentrated in vacuo. The residue was taken up in EtOAc, filtered and the filtrate was washed successively with 5% citric acid (3x), 5% NaHCO ₃ Ox) and brine (1 χ) and dried over MgSO ₄ . and the residue was chromatographed on silica with EtOAc-MeOH (99.5: 0.5) as the eluent, and product fractions were combined and evaporated to give 2.2 g, [α] _D = -57.8 ° (1.03, CHCl ₃ ).

-16- 263 053

(m) t -butyl-NfKSI-t-butoxycarbonyl-S-aminopentyl-iSJ-alanyl-f Si-proline

The compound from Step (I) (5.19g) was dissolved in MeOH (50ml) under nitrogen and 10% Pd-C catalyst (0.5g) was added. Hydrogen was bubbled through the stirred suspension for 2.5 hours whereupon TLC indicated that the reaction was complete. Nitrogen was bubbled through the mixture and the catalyst was removed with the aid of

Filtration through celite removed. The filtrate was evaporated to give the product as a colorless oil, 3.6g, [a] _D = -74.4 ° (1.0, CHCl ₃ ).

(n) t -butyl-N-fHSl-t-butoxycarbonyl-S - ^ - IS -fN-t-butoxycarbonyl-N-isopropylaminol ^ isl-hydroxypropoxyl-IH-indole-2-carboxamido] pentyl] - (S) - alanyl (S) -prolinate

The indolecarboxylic acid of step (h) (2g) was dissolved in DMF (20ml) and cooled in an ice bath; 1-Hydroxybenzotriazole (0.69g) was added followed by a solution of dicyclohexylcarbodiimide (1.05g) in DMF (5ml). After stirring for 45 minutes at 0 ⁰ C a solution of the amine of step (i) (2,18g) in DMF (10 ml) was added, and the mixture was stirred at ambient temperature for 18 hours. It was then filtered and concentrated under vacuum. The residue was taken up in EtOAc, filtered, and the filtrate was washed successively with 5% citric acid (3x), 5% NaHCO ₃ (3x), brine (1x), and dried over MgSO ₄ . The solvent was removed under vacuum and the residue (3.9 g) was chromatographed on silica with CH ₂ Cl ₂ -MeOH (92: 8) as eluent chromatographies. Product fractions were taken together and evaporated to give an off-white solid, 2.95 g, [a] _D = -46.7 ° (0.9 MeOHK

AnSIySeIC ₄₂ H ₆₇ N ₅ O ₁₀ : required C, 62.90; H, 8:42; N, 0.74%

found ^, 63,16; H, 8.49; N, 8.63%

(o) S) -Carboxy-5- [4- (2 (S) -hydroxy-3-isopropylaminopropoxy) -1H-indol-2-ylcarboxamido] pentyl- (S) -alanyl- (S) -proline The compound of Step (s) (2.9g) was dissolved in a mixture of trifluoroacetic acid-water-ethyl methyl sulfide (9: 1: 1.2ml) and stirred overnight at ambient temperature. The solvents were evaporated and the residue was taken up in water, washed with ether (2x) and then freeze-dried. The residue was chromatographed on a column of DE 52 cellulose (5 x 50 cm) pre-equilibrated in 0.005 M NH ₄ HCO ₃ , pH 8 and eluted with a linear gradient of 31.0.005-0.2 M NH ₄ HCO ₃ , pH Eluent fractions were monitored by HPLC (Zor'bax C8.0.2% TFA in 25% H ₂ O-MeCN). The pure product-containing fractions were taken together and freeze-dried. The residue was desalted by adsorption on a column of Zorbax C18, washing with water and subsequent elution with MeOH. The eluent was evaporated and the residue was dissolved in water, filtered and freeze-dried to recover the required product as a fluffy white solid. Yield 1.75g, [α] _D = -30.2 ° (1.0, MeOH). Analysis: C ₂₉ H ₄₃ N ₅ O ₈ -S ^ H ₂ O requires C, 53.73; H, 7.70; N, 10.80%

found C, 53.87; H, 7.75; N, 10.66%.

Example 2 and 3

The following compounds according to the invention were prepared in a manner analogous to the method in Example 1:

2. N- (1 (S) -carboxy-5- [5- (2 (R, S) -hydroxy-3-isopropylaminopropoxy) naphth-2-ylcarboxamido] pentyl) - (R, S) -alanyl- (S. ) -prolinbistrifluoracetat

3. N- (1 (S) -carboxy-5- [8- (2 (R, S) -hydroxy-3-isopropylaminopropoxy) naphth-2-ylcarboxamido] pentyl) - (R, S) -alanyl- (S. ). proinobis trifluoroacetate ·

The materials and reactants used in the preparation of the compounds of Examples 1 to 3 are commercially available and can be obtained by methods described in the chemical literature. Biological examples

(a) beta-blocking in vitro

In an analysis of β-adrenoceptor blockade in the left atrial heart aorta, a simple competitive blocking of isoprenaline gave the following results:

pK _B

Compound of Example 1 7.0

Compound of Example 2 5.4

Compound of Example 3 5.3

(b) ACE inhibition in vitro

In an analysis of angiotensin converting enzyme inhibition in the guinea pig ileum, the dose-dependent inhibition of contractile responses to angiotensin I produced the following results:

EC ₅₀

Compound of Example 1 1.4nM

Compound of Example 2 13.5 nM

Compound of Example 3 10.3 nM

Claims (2)

¹ II R- (X) -A-C-N-C-C-OH (VI) Q ⁵ Q ⁸ O and R ^{2 is} a compound of the formula (VII) ^HI ^ ^Y n / in n \ _ (VII) in which in the formulas (II) to (VII) R is a group of the formula (VIII) QQ ¹ Q ³ Q ⁴ tilt B-N- -C-C-O (VIII) I ₂ i I ₅ Ο; OH Q or R is a reactive substituent on group (X), and in formulas (II) to (VIII) n, Q, Q ¹ to Q ⁹ , A, B, D, E, - | \ j γ (X) and Z have the meaning defined above, and if so appropriate, each of the compounds of formulas (II) to (VII) and the group of formula (VIII) protected f_o mn en "include; and then, if requested, one or more of the following optional conversions may be made in any desired order: (i) when the product of the reaction of compounds R ¹ and R ^{2 is} a precursor of a compound of formula (I), the precursor is exposed to such conditions and / or treated with an appropriate agent or agents such that the consequent formation of a Compound of formula (I) takes place;
(ii) each compound of the formula (I) thus formed is converted into another compound of the Converted formula (I); and
(iii) any compound of formula (I) is converted into a physiologically acceptable salt thereof transformed. 3. The method according to claim 1 or 2, characterized in that it consists in that: (A) a compound of formula (Xl) R- (X) -R ³ (XI) wherein R and (X) are as defined above, or where appropriate, are protected forms thereof, and R ^{3 is} a carboxyl or a carboxyl derivative, with a compound of formula (XII) ZQ ⁷ D R ⁴ - (CH ₂ ) _n - G - Ii - c - c - Q (Χ ") 1. Process for the preparation of novel hypotensive compounds of the formula (I) QQ ¹ Q ³ Q ⁴ ζ Q ⁷ D (D. 3-NCCCO- (X) -AGNCC-InPy
12 '· 5 lc j ρII <<><γ- Q OHC; C ⁶ Q ⁸ O ^Ε in which mean: Q and Q ¹ to Q ^{8 are} hydrogen; A is a group of formula CONQ ⁹ (CH ₂ ) _n -, where n is 4 and Q ^{9 is} hydrogen; B is an isopropyl group; E is a carboxyl group; Z is a carboxyl or C ₂ _ _5-carboxy; D is a methyl group; (X) a naphthyl or indolyl ring system; and ^on and physiologically acceptable salts thereof; with the proviso that when (X) is a naphthyl ring system, the compound of formula (I): N- (1 (S) -carboxy-5- [5- (2 (R, S) -hydroxy-3-isopropylaminopropoxy) naphth-2-ylcarboxamido] pentyl) - (R, S) -alanyl- (S) - proline, or N- (1 (S) -carboxy-5- [8- (2 (R, S) -hydroxy-3-isopropylaminopropoxy) naphth-2-ylcarboxamido] pentyl] - (R, S) -alanyl- ( S) -proline, or a half-ester (wherein ZC _{2 is} -5-carboalkoxy) of either, and when (X) is an indolyl ring system, the compound of formula (I) N- (1 (S) -carboxy-5- [4- (2 (S) -hydroxy-3-isopropylaminopropoxy) -1H-indol-2-ylcarboxamido] pentyl) - (S) -alanyl- (S) -proline or a Halbester (wherein Z is C ₂ _ ₅ carboalkoxy is) thereof; characterized in that the method comprises combining the aryl moiety (X), or any precursor thereof, the amino (hydroxy) alkoxy side chain, or any precursor thereof, and the amino acids or amino acid derivatives, or any precursor thereof the compound of formula (I) or a precursor thereof, and, if appropriate, the precursor compound is converted to the compound of formula (J), and if so required, any such compound of formula (I) in another compound of the formula (I) is converted, and if desired, each compound of the formula (I) thus formed is converted to a physiologically acceptable salt thereof. Process according to claim 1, characterized in that the process comprises reacting a compound R ¹ with a compound R ² , wherein: (a) R ^{1 is} a compound of the formula (II) R- (X) (II) and R ^{2 is} a compound of the formula (III) ZQ ⁷ D HQ ⁹ N - (CH) - C - N - C - C - N - Y ^(III) 16 18 Il Q Q 0 is, or (b) R ^{1 is} a compound of the formula (VI) ^(IV) is, or (c) R ^{1 is} a compound of the formula (VI) ZQ ⁷ D. ₂ ) _n i ⁶ Q ³ 0 ^Ξ wherein η, D, E, Z, Q ⁶ to Q ⁸ and -f-.j γ have the meaning as defined above, or if it is appropriate, protected forms thereof, and R ^{4 represents} a group of the formula -NHQ ⁹ , wherein Q ^{9 has} the meaning explained later, is reacted; or (B) a compound of the formula (XIII) R - (X) -A-C-R wherein R, (X), A, Q ⁶ and Z are as defined above or, if appropriate, protected forms thereof, and R ^{5 is} as defined in the following definition for formula (XIV), with a compound of Formula (XIV) D Q ^o O wherein D, E, Q ⁸ and NY are as defined above, or when appropriate, protected forms thereof, and one of R ⁵ (in the above formula [XIII]) and R ^{6 is} a group of the formula -NHQ ⁷ and the other is an outgoing group; or (C) reacting a compound of formula (VI) as defined above with a compound of formula (VII) as defined above; or (D) a compound of the formula (XV) ₁ ZQ ⁷ R ⁷ ι- ι ' R- (X) -ACNCC-NG _(XV \ II!> *% ^(XV) I _{6 3} ! % wherein R, (X), A, E and Q ⁶ to Q ⁸ are as defined above, or where appropriate, protected forms thereof, and R ⁷ and ν Q are independently from above for D and NY, respectively defined groups and unsaturated forms thereof are selected, provided that at least one such unsaturated form is reduced; or (E) a compound of the formula (XVI) _{1 R} _ (χ) _ A - R ⁸ · - C - N> ^ p- (XVI) ~ o wherein R, (X), A, E and -N Y have the meaning defined above, or if it is appropriate, protected forms thereof, and R ^{8 is} a group of formula (XVII) ZD i ι -C = NQ- _{(XV ||)} Q ⁸ in which Z, D and Q ^{8 have} the meaning defined above, or a group of the formula (XVIII) ZQ ⁷ R ⁹ -i I ii, - υ - N - G. - (XViIi) A ⁶ wherein Z, Q ⁶ and Q ⁷ are as defined above and R ^{9 is} an analogue of group D as defined above (but not hydrogen), which has the same formula as D except that it lacks a hydrogen atom and attaches to it NQ ⁷ -C component bound by means of a double bond is reduced; or
(F) a compound of the formula (XIX) Q ¹⁰ Q ⁷ D ι ι ι ^ R - (χ) - A - C - N - C - C - N Y (XIX)