PT94922A - Process for the preparation of peptide derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of compounds of formula I and to the pharmaceutically acceptable salts thereof: <IMAGE> in which the Het ring has for example the formula a: <IMAGE> in which, for example, Z1 is absent and Z2, Z3, Z4, Z5 and the carbon atoms to which Z2 and Z5 are bound form a non-aromatic heterocyclic ring of 6 members; or E is absent or is for example (CH2)n, in which n varies between 1 and 4; A is for example -CONH-; p, s and q are chosen from the numbers from 0 to 4; Rz is for example hydrogen; Ra and Rb are independently for example hydrogen; R1 is for example CH2R9, in which R9 is optionally substituted aryl or heteroaryl; R2 is CHR10R11, in which R10 is for example hydrogen and R11 is for example C1-6 alkyl; R3 is CH2R12, in which R12 is for example C1-6 alkyl; R4 is for example C1-6 alkyl; and the dotted line represents an optional bond (when E is present); which are rennin inhibitors. These compounds can be prepared by the reaction of a reagent of formula III: <IMAGE> in which Het' is Het as previously defined, but in which Ra, Rb and Rc are Ra', Rb' and Rc, which are for example Ra, Rb and Rc, respectively; A1 is absent or represents an appropriate amino acid or a dipeptide unit; J is OH or a dissociable group; with a reagent of formula IV: <IMAGE> in which A2 is absent or represents for example an appropriate amino acid.

Description

ν Ύ

The present invention relates to novel compounds having pharmacological activity, processes for their preparation, the pharmaceutical preparations containing them and their use in medicine. Renin is a natural enzyme whose related disorders are the source of many cases of hypertension "is released into the blood through the kidneys and causes the separation * from a blood glycoprotein * of a deca-peptide known as angiotensin-I * Circulating angiotensin-I transforms into plasma in the lungs , in the kidneys and other tissues, in an octapeptide, angiotensin-II, which elevates blood pressure either directly by constriction of the arteries or indirectly by stimulating the release of aldosterone, a sodium-retaining hormone, from the supra- which causes an increase in the volume of extracellular fluid. "The latter effect is caused by angiotensin II itself or by angiotensin III, heptapeptide cleavage product '

Renin inhibitors have been described as being useful for the treatment of hypertension.

A group of enzyme renin inhibitor compounds has now been discovered and therefore have a potential activity relative to lowering of blood pressure, which is very useful in the treatment of hypertension. Compounds which have an associated functioning mechanism have also been described antiretroviral activity, and the present compounds may therefore be of potential use in the treatment of diseases caused by retroviral diseases, including those caused by the human immunodeficiency virus (HIV-1 and 2) and HTLV I and II. They may also use

potential ηα treatment of other cardiovascular diseases5 such as diabetes. ca ca ca ca ca car car car $ $ $ $ $ $ $ $ $ $ $? in memory and in mood raising activities. They may also be of potential use in the treatment of CN3 disorders such as Alzheimer's disease and depression. They may also have a potential use in the treatment of glaucoma. Thus, the present invention provides a compound of formula &lt; I), or a pharmaceutically acceptable salt thereof

/, ECONHCHCONHCHCONHCHCH (CH-) | (CH2) R3 '2 s 4 rY5 * (Het Zv-A / Z1 Z2

OH (i: in which the Het ring has the sub-formula Ca) or (h) s

\ *.

(b) in which one or two of. . 1 · kt, &gt;, W_j. N, N-dimethylformamide, and the like. &quot; i and M, and Y is H, and h is as hereinbefore defined, and the others are CH, CR. one of 0 ^ 5 = Q .., and:% is the other two only CH to CR both 1 L *. The compounds of formula (I) are absent and. C? -C? to which Z? and are attached form a 5-membered non-aromatic heterocyclic heterocyclic ring or are absent and the carbon atoms to which they are attached form a non-aromatic 6-membered helicalcyclic ring; -j-i &quot; v * 1 · &gt;, is. and the stereoisomers thereof, in which Z is 1-formyl. ? 1, 2, 3, 4, 5, 6, 8, 10, 11, 11, 11, 11, 11, and is absent or is Cf-L &gt; or CH &lt; CH_ &gt; . that n varies from 1 to

. n -I M4 5 (<0) - where r is θ5 1 or 2? or -COO-A is -O-, -NHCO-5 -CH2 -; Λ. p is &amp; f 1 or 2; q is 0 or 15; R is hydrogen or C1-4 alkyl or when A is hydrogen and R5 is independently selected from hydrogen and a hydrogen atom. in which R 0 is aryl or heteroaryl in a pharmaceutically acceptable salt thereof;

Râ,, is CHRâ,ƒ, Râ,, where Râ, ... is hydrogen or. methyl, and R1 is C1-4 alkyl; C 1 -C 12 cycloalkyl, aryl or optionally substituted heteroaryl 1 '' '' '' '' '' '' '' '' '' '' '' '' ' Quot; 2-oxopiperidinyl or alkoxycarbonylamino R 1 is CH 2 R 3. cycloalkyl, or cycloalkyl, or cycloalkyl, or a bonded saturated or unsaturated heterocyclic ring, through a carbon atom, hydroxy, C1-4 alkoxy alkanoyloxyamino, C3-5 alkanoylamino substituted by one or two alkyl groups

C1-6!

or C1-4 alkoxysulfonyl, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl, C1-4 alkoxycarbonyl, C1-6 alkoxycarbonyl, or a hydrogen atom (when it is between 2 and 4) is saturated or unsaturated bonded through a nitrogen atom; and the dashed line represents an optional bond (when E is present).

When the Het ring has the sub formula v-a)

Often W- ,. or W, is N or NO, usually W_, is N when E is a bond to W, is N when E is bonded to 2. * &quot; w

When the Het ring has the sub-formula <b)

Often Q, or Q "is S '1

When s Z. ~. Zn, and Zp. there is present, Z is 1 and Z is 1, ; the third A UI *

The values of Zp and s2d ?. when connected to E9 this is NP CH or C (in which optional exocyclic bond) !! the second of Z-SO, SO2, or NR1, wherein R3 is hydrogen or

is 0, 5, SQ0, 1 æl. R, CH? qu C = 0, since? one of Z is Z and Z is Z and Z5 is either C when the other is S or O, or is CH2; C, N! or. N when the other is S0 or Jjn c * _? - ^ 4 is S0? S0? or C = O when u of Z. -r a is W1 and the other is 0 S or NR5 or R6. is CO, Z, Zn, Zn, Zn, Zn, and Zn.

&gt; V

Preferably, it is C05 Σλ is N5 is CH and E is liquefied

When Z is absent;

The values of 2 are assigned to 35-α-r, and 4 Z c. When a: te is W, CH or C C wherein: iva> 1 other S 5 7 * -rr 3 ta r. B. * - * r? ? The present invention relates to a process for preparing a compound of formula G, W, S0, S0, or NR5 in which R i of? 2 and Z.T3 are one of Z7 and Z4? or S 1 '4

4-4-4-4-4-4-4- (4-

1-O

0 = 0, provided that one is CH3, CH3 or CH3. C when the other is S or 0? i.e. CH, 5 CH 5 c, NK or M when the other is SG or 80; or Z 2 is Z 1, Z or Z, or Z 1 is Z 1, Z 1, Z 2, Z 2, Z 2, is M or NR and D The other! N, N, N-dimethylaminopyridine. Cs *? * 5 is -NRCGC0N &lt; or &gt; NC0C0NR-s ου. Ζ .-, / Ζρ. U0 q £ - <-. / y is G T 7/7 ^ * λ 5 * -sr »« **> ? *** Λ. * 7 im-p are CH and CH3. i * ε. the followings are excluded from Z, s Z-- (i) some adjacent heteroaryl C03 S5 N) except M-N ' but not N-N-N 5 -i) 30, / -80 or O-S. <m e y sSo Θ - 2) §

G-C-O, S-C-Q, S-L-S '

V V

iv) CO-SO or CO-SCUi v) of heteroatoms <0, S, N) separated by a cosine C0, unless one of them is N; vi) more than two of Z and Z are CO. E &gt;. empl ua d t? Thus, &gt;

S0

I ο Νγ

I r \ s ^ /

&quot; V ο / Λ Ν t /

NR

χ Ν R Ο 9 / Ν Ο S0. / S0on / 2ν

Ν R Ο 9 9

r ΧΝ R R /

/ V »

When 5 '1' is N and the other 14 are CB, CH or CR 2, most preferably 1, 1, Z 2 is CH 2 '4

L CH 2 N 2 is L is

When lithium carbon is present at the Î ± -cycloalkyl CC = U). CT v

(C1 -C6) alkoxycarbonyl or a C1 -C4 alkoxy group, or an atom;

I 'O'

wherein X is O, S? SQ?, MH5 N-C1-4 alkyl or

Preferably E is attached to a nitrogen atom. Suitable excipients of R 1 and R 2 in the formula (a)

The compounds of formula (I) include a moiety selected from halogen, C1 -C4 alkyl, cyano, CHO, optionally substituted amino substituted alkyl or R3 R4, is a C1-4 alkyl group;

Ho &quot; R 1 is hydrogen, C 1-6 alkyl or substituted benzyl,

X * is O and R is hydrogen or C alquilo alquilo alquilo alkyl;

When one of R1 and R2 is hydrogen and the other is a halogen substituent, the substituent is preferably at the 3-position with respect to the ring nitrogen atom, when one of 14 is N or NO '

Suitable examples of Kc in the formula (b) comprise a moiety selected from the C1-6 alkyl optionally substituted by C1-6 alkyl, C1-6 alkyl optionally substituted by amino, or R7 is as defined above. hydroxyl, alkyl or benzyl optionally substituted

Suitable examples of substituents on amino groups optionally substituted in Ra / Rf and R @ 1 then comprise one or two groups independently selected from C1-6 alkyl or C1-6 alkyl substituted by carboxy or alkoxycarbonyl.

Alternatively, NR6 R6 or other amino groups substituted in Ra / Rb / Rc may be pyrrolidinyl, piperidinyl, morpholino or piperazinyl or M-substituted alkyl, or as a N-oxide thereof.

Tactile &amp;

Preferably one of R and co2h or ch2mhchpco2h '

Rh is bicyclic and the other is hydrogen preference &gt; )

King actively to the values' pC- * CT. The present invention relates to a method for the preparation of a medicament according to the invention. 1? P? P? 15? A = -COM! K ") π JL + * J. Med. Chem. 1987? 30 · .; 1-yl) -pyridine-2-carboxylic acid tert-butyl ester. 1987? Eur-lex.europa.eu eur-lex.europa.eu 701 <P s ~ * V [l q = -COO-] 4. J. Med. Chem. 1987? 31, 1839 Cp = 1? q = 1? A = -COM H-) 5. J. Med. Chem. 1987? 50, 1729, and 1771. q = 1? A = S C 0) r '6. wo 38 /? 5050 <P = 0, q = 1? A = CH-j ' R "= ΗΙ 7, EP-A-172346 Cp-5q-1Γ; A "a", R "= 14 \ A, a" here

Suitable values for R5 ', when these aryl- are phenyl or naphthyl, when those are heteroaryl; are 5- or 6-membered or 9-membered or bicyclic monocyclic groups among which 5- or 6-membered monocyclic heteroaryl is preferred. Besides that? the 5- or 6-membered monocyclic or 9- or 9-membered bicyclic heteroaryl preferably contains a " two or three heteroatoms that are selected within the oxygen class? nitrogen and sulfur and what? in case they are more than one heteroatom are the same or different. Examples of

5- or 6-membered monocyclic heteroaryl containing &quot; a &quot; three heteroatoms which are listed within the oxygen, nitrogen and sulfur class are furyl, thienyl, pyrryl, oxazolidin-4-ylthiazolyl, imidazolyl and thiadiazolyl and pyridyl, pyridazyl, pyrimidyl, pyrazolyl and triazolium. Preferred examples of these groups are furanyl, thienyl, pyrryl and pyridyl # 2 and 3-furanyl, 2- and 3-pyrryl, 2- and 3-thienyl, and 2-chloro. 3 's 4-pxrxd.i. Examples of 9- or 1-membered bicyclic heteroaryl containing one, two or three heteroatoms which are known within the class of oxygen, nitrogen and sulfur are benzofuranyl, benzo-thienyl, indolyl and indazolyl, quinolyl and isoquinolyl and quinazolyl. Examples of such groups are 2- and 3-S-3-furanyl, 2-and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolyl and, for

R 11 4-benzoimidazolyl.

Suitable examples of groups or atoms for optional substitution of R1, for benzyl and R1 and R2. include one or two substituents independently selected from haloalkylalkoxy such as fluoro, chloro or bromo), hydroxy, nitro and cyano.

Preferred examples of are phenyl and naphthyl, and preferred examples of such are aryl or. heteroaryl are phenyl, imidazol-4-yl and 2-yl, pyrazol-1-yl and 4-methylpyrazolyl,

Preferably, the amino acid residue containing

jL is Leu, D-pyrazolylalanine or His *

Abbreviations which may be used herein are as follows:

Residue of Aminino Acid

Histidine H1S Τ 1-n isoleucine leucine Leu 1-naphthylalanine MA norleucine Nysphenyls Phenols

The components of &lt; 3-amino acid are found in the (-) (or L-form) gyrase. COOTl-

According to a special aspect, the present invention provides a compound of formula (I) or is pharmaceutically acceptable; (i) the pharmaceutically acceptable salt thereof; (b) the pharmaceutically acceptable salt thereof; ) (S) (IA) in which X is Phej

V R 1 * '1

R 4

Leu or His? cyclohexylmethyl- is Câ, â, <â, † alkyl and s is 0 or s is 2 to 4 and Râ,, is carboxy; a heterocyclic ring s &lt; remaining variants in or unsaturated; are as defined by 0 to the formula

R

-t-

Suitable valences for the alkyl groups in R

R1 and R2 to R3 are each independently hydrogen. in the formulas Cl) s (ΣΑ) are methyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, n-, iso-, sac-tert- and neo-pentyl. Are cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, nal, sulphonyl. bromo-1-cycloheptyl and R5 and R5 are as defined above. when these are iodine, chlorine or

Preferably Râ, ... or Râ,, as alkyl is iso-butyl. are said to be Râ,, and Râ 'is preferably 3-pyridyl or a Câ, â, <â, "

Suitable examples of Rs such as monocyclic beyryaryl are those of the formula:

When it is a saturated heterocyclic ring, suitable examples are piperidinyl, pyrrolidinyl, piperazinyl and morpholino; optionally substituted by C 1 -C 6 alkyl groups or as an M-oxide thereof. The right-hand sequence of formula (Cl) and CIA) is preferably 4CS) -amino-5-cyclohexy-3 (S) -hydrazepentanoic acid (ACHPA), from the amino acid containing R3 or Rf. to NHCl2. &gt;

Preferably, π is 1, 2, 3 or 4,

When Z. is absent, fc is preferably attached to the 4-position in the ratio of x to n-quinazide n = 2, and to the 3-position of n- 2, Quand d Z | and 2.y are absent, and B is preferably in the 3-position with respect to Z2 when n2 is in the 2-position when n2. When Σ j and Z.-; are presents. And it is

nitrogen atom or to Z 1 carbon. E is from pr or T-sr when they represent a nitrogen atom attached to a nitrogen atom

Pharmaceutically acceptable salts include acid addition salts which may be for example salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulfuric acid, or organic acids such as, for example, . propionic acid, tartaric acid, fumaric acid, salicylic acid or acetylic acid, acetic acid, lactic acid, citric acid, roylic acid, succinic acid, salicylic acid.

The pharmaceutically acceptable salts may also comprise alkali metal salts, for example sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy lower alkylamines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tris- (2-hydroxyethylamine)

It will be appreciated that the compounds of the invention may exist as solvates, such as hydrates, and these are included whenever reference is made to a compound of formula (I) or a salt thereof,

Compounds of formula CI &gt; in which E is attached to Z 1 (when present) f Z 2 (where present) / Z 2 - Z 2 / Z 2 - where CH 2 and C 1 2 are at least one asymmetric center, in addition to those attached to R 1, (a) and (e) are those indicated in formula (IA), and are therefore capable of existing in more than one stereoisomeric form. The invention further extends to each of these forms and to mixtures thereof. the configuration in fig u. carbon atoms bearing R 2, and R 3 is hydrogen.

It will be appreciated that when the optional binding indicated in formula &lt; I &gt; is present, the compounds are able to exist in the forms E and Z (trans is the same as in the present invention). The invention extends to each of these forms and mixtures thereof.

The compounds of the invention are preferably in pharmaceutically acceptable form. By way of pharmaceutically, it is meant, inter alia, a pharmaceutically acceptable level of purity which excludes the normal pharmaceutical additives such as diluents and carriers, and also the materials considered toxic at normal dosage levels. A pharmaceutically acceptable level of purity will normally be from at least 5% by weight, excluding standard pharmaceutical additives, preferably 75%, more preferably 9% and most preferably 95%

A compound of the invention may be prepared by methods known in the art for the synthesis of compounds of analogous structure, such as peptides, and in this regard reference is made, by way of illustration, to the references of the s.R. Peitit, &quot; Synthetic Peotides &quot;, Elsevier Scientific Publishing Co. The present invention also provides a compound which has been prepared synthetically,

A compound of the present invention may, for example, be formed by the sequential linkage of the appropriate acidic amino acids or the acid of formula CIDs

Wherein Het is Het as defined in formula (I) is most commonly substituted in the following formula (I): ## STR1 ## wherein R 1 and R 2 are independently selected from the group consisting of H, and / s by Fv 'na -ub-i-uj. 1 to 1 b 1 in which R 1, H 2 and H a a bc are R 3, R 4 and R 5 are independently hydrogen or C 1-6 alkyl, ίί-ΐ. by the initial preparation and subsequent coupling of the units with the acid of form (11), the units themselves being prepared in a gradual manner in both cases chemical methods of solution analogous to those used in the peptide synthesis may be exemplified by the acid addition of the acid of the acid of the formula: ## STR4 ## with the group ## STR1 ## in the appropriate groups and the suitable reaction conditions (for the binding reactions and for the introduction and removal of the protecting groups) which preferably provide a minimum of racemization can be found in the abovementioned literature. or acid ILOD5 in cttj the appropriate target, "" t w ς (ϋΰζ η rsts)

It will be found. which when A is other than the C-terminal group is different from where the bonding is performed with a further as described in the literature above,

Thus, the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises reacting a reagent of formula (III):

ECO-A-J

(III) in which Het 'is Het as defined above, but in which R' and R ', R' and Rc are R ', R' and R ', which are R,, R e and respectively or atoms in the same groups is absent or represents an aproporyl amino acid or a dipeptide moiety? J is OH or a leaving group? and the remaining variables are as defined above with a reagent of formula (IV); R 3 H -A 2 --NHCHCH (CH 2) p / CHA (CH 2) s R 4

(IV) wherein A is absent or represents a suitable amino acid or dipeptide unit such that A * + A 2 is -NHCHR 3 CONHCH 2 R 2 CO 3, and the remaining variables are as defined above, and

then ffgasm, if desired or A ^) of the nut products. A compound according to any of the preceding claims, wherein: * J &gt; Râ, and / or W. and â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (1) or Zg in I, or Zor, R '', R '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' acceptable.

Suitable examples of J when it is a leaving group are chloro and bromo, and other suitable groups displaceable by amino nucleophile, such as C1-4 alkoxycarbonyl

It is usually preferred, especially when A1 is absent, that d is OH, and a suitable coupling reagent or a dehydration catalyst is used to effect the reaction, such as N, N-dicyclohexylcarbodiimide, as well as those described in the Descriptions and following Examples. 1 r &gt; Deprotection of A &quot; and / or A '- takes place in conventional manner, according to the protecting group (s) employed).

Acceptable pharmaceutically acceptable salts may be formed in conventional manner. 2, or Zc-, when they are in either SO or SO, respectively

S or Cou S SO, or

by conventional non-aqueous oxidation methods, such as organic peracid hydrocarbon, such as acid is preferable in a chlorinated solvent, in the presence of a chloroperoxybenzoic acid, or in the presence of a strong inorganic oxidant and soluble, as an alkali metal permanganate, or with aqueous hydrogen peroxide. A particularly suitable alternative oxidation method involves the use of magnesium monoperphthalate, as will be described in Description &lt; i &bgr; Following. : 4- V &gt;

It will be seen that the compounds of formula (I) which contain a ring Het 'in which the group R 1', R 2 'is other than R 1' Rh / Rs are useful new intermediates., Is it possible to carry out a series of these conversions? not only (I) but in the case where the final product compounds of the formula R '/ R', R '' are different from R / R / R but also in the abc abc · are R / R., R., and also to their intermediates, abc - follows; a nitro R / R substituent. to amino resin by reduction? is convertible into a sutasti- &lt; ii) an acylamino substituent is convertible to an amino substituent by deacylation;

Ciii) a hydrogen substituent in the sub-formula Ca) is convertible to a halogen substituent by halogen-

Civ &gt; an amino substituent is convertible to a corresponding substituent which is substituted by one or two alkyl groups by N-alkylation;

Cv &gt; a cyano substituent can be converted to an aminomethyl substituent by reduction?

(CVI) a bromo substituent may be converted to a cyano substituent by reaction with copper (C1) cyanide,

The conversions (i) are not exhaustive as far as the Cvi) are only exemplary and all possibilities. It is found that it is often desirable to carry out these conversions at a later stage, in the acid intermediate of formula (II). I *

Relative to (I)? the reduction is effected with a suitable reagent for reducing the nitroanisole in aminoanisole,

With respect to (ii), the deacylation is effected by treatment with a base, such as alkali metal hydroxide,

Relative to Civ) the alkylation is effected with a corresponding alkylating agent, such as chloride or bromide, under standard conditions "

Relative to C 10 reduction is effected by reaction with sodium borohydride / cobalt chloride or platinum / hydrogen oxide.

Relative to (vi), the reaction is carried out under conventional conditions. Conversion of N, N, N, or when these are M into NO can be obtained by oxidation methods similar to those used for N, When these are S or SO, in SO or SOâ,, for example by the use of 3-chloroperoxybenzoic acid. Selective oxidation can be obtained by appropriate choice of the agent and the conditions of oxidation,

Compounds of general formulas CII &gt; and (III) may themselves be prepared by standard techniques analogous to those described above.

The acids of formula (II) are either known compounds, or are prepared by methods analogous thereto and for structurally similar known compounds. The preparation of the amino acid of formula &lt; V) &gt; *

CHF-1-CHOH-CH.CO.-4H &lt; v &gt; ^ 3 ^ 2 (S) &lt; s &gt; is described in J. Med. Chem 1995, 9-1790.

With reference to the appropriate intermediates corresponding to those of formula (V), including those in which ft is other than -COMH-, a reference is made here to the references of the literature 2 to 7. mentioned above.

It will be appreciated that the protected protected forms of the present invention are novel intermediates and are an aspect of the invention.

Particularly suitable methods of preparing the compounds of the present invention are described in the Descriptions and Examples set forth below. The linkages may be carried out sequentially, starting from the attachment of the acid of formula (II) with, for example, phenylalanine or i-naphthylalanine, followed by Y-bonding, for example leucine or. histidine, and finally, the amino acid linkage of formula (V). According to a preferred aspect, however, either the acid of formula (II) is attached to a tripeptide unit formed between the amino acid of formula (I), leucine, histidine. or other R. j which contains the amino acid and phenylalanine or naphthylalanine; or alternatively the acid of formula (II) is linked to phenylalanine or naphthylalanine and these are attached to a dipeptide unit formed between the amino acid containing the amino acid and the amino acid of formula V.

As mentioned above, the compounds of the invention have been shown to be renin inhibitors and thus have a potential use in the treatment of hypertension. They may also have a potential use in the other diseases and disorders referred to above. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In particular the present invention provides an antihypertensive pharmaceutical composition comprising an effective antihypertensive amount of a compound of formula Cl) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration. However, they may be adapted to other modes of administration, for example parenteral administration to patients suffering from heart failure. Other alternative modes of administration comprise sublingual or transdermal administration, or for example eye drop compositions, for the treatment of glaucoma.

The compositions may be in the form of tablets, capsules, paddles, granules, lozenges, suppositories, reconstitutable powders or liquid preparations, such as sterile oral or parenteral solutions or suspensions. In order to achieve a certain compatibility of administration, it is preferred that the composition of the invention is in the form of a unit dose. The dosage forms for oral administration may consist of tablets and capsules and may contain conventional excipients such as For example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone filling agents, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microscrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

Solid oral compositions may be prepared by conventional blending, filling or tabletting methods. Blending operations may be employed to deliver the active agent to all compositions employing large amounts of fillers. These operations are of course conventional in the art. The tablets may be coated according to methods well known in standard pharmaceutical practice, in particular with an enteric coating.

Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or another suitable carrier prior to use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles which may comprise edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerol esters, propylene glycol and ethyl alcohol, preservatives, &quot; for example methyl or propyl oxybenzosino or propyl or sorbic acid and if desired conventional flavoring or coloring agents.

For parenteral administration, the flowable unit dosage forms are prepared by use of the compound and a sterile vehicle, and that, depending on the concentration used, can be suspended or dissolved in the vehicle. In the preparation of the solutions, the compound can be dissolved in water for injection and sterilized by filtration before being introduced into an appropriate vial or ampoule and these are closed. Advantageously, adjuvants such as a local anesthetic, a preservative and buffering agents may be dissolved in the carrier. To increase stability, the composition may be frozen after it has been introduced into the vial and the water has been withdrawn under vacuum. Suspensions parenteral compositions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and the sterilization can not be effected by filtration. The compound can be sterilized for exposure to ethylene oxide before being suspended in the carrier Advantageously, a surfactant may be included in the composition to facilitate uniform distribution of the compound.

For transdermal administration, formulations suitable for topical use, optionally comprising penetration enhancing agents, may be employed.

The compositions may contain from 1% to 99% by weight, preferably from 1% to 6% by weight, of the active material, depending on the method of administration.

The present invention further provides methods of prophylaxis or treatment of hypertension in mammals including humans, which comprises administering to the sick animal an antihypertensively effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof The effective amount will depend upon the relative efficacy of the compounds of the present invention, the severity of the hypertension to be treated, and the patient's weight. However, a unit dosage form of a composition of the invention may contain from 0.001 mg of a compound of the invention and more usually from 1 to 10 mg, for example 2 to 50 mg, for example 2, 3, 4, 5, 10, 20 or 30 mg. These compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, such that the daily dose is from 1 to 100 mg for a 70 K human adult and more especially from 5 to 5 μg © mq »Dosage not indicated above,: oxteológic those in the ranges of the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis

The following descriptions relate to the preparation of the intermediates and the following Examples are relative to the preparation of the compounds of formula (I).

The following tables show the structures prepared. The indicated abbreviations are &gt; &gt;

A Definition ACHPAA isobutylamide of 4 &lt; S) -amino-5-cyclohexyl-3- &lt; 8> -hydroespentanoic acid ACHP 4 (S) -amino-5-cyclohexyl-3- (5-hydroxy-pentanoic acid) BDC tert -butoxycarbonyl C8Z benzyloxycarbonyl (1-imidazol-1-yl) propylamino

TABLE I: Hunr H d. -R. Fig. R 1 s 1 t 1 salt /! $ 1 $ 1 soIvato! | (a) 1 (BOC) API (1 D3 (h)): CBZ-Phe-Lsu. A compound according to any of claims 1 to 4, 1 Phe-Leu API 1 D4 < a) I BOC-Pbs-Leu 1 NH "Bu I i D4 < b &gt; Phe-Leu | (A) T-CBZ-Phe-Leu | NHlBu f / e DSC b) Phe-Leu | NHâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒBu-Phe-Leu] NS-TBu 11 D9 C a) BOC-Phe-Leu | API f 1 D9C b) 1 ........ j ..... Phe-Leu j AP I f t i i 2CF_j.CGv, H θ '- J

LFADRO Z3 (CH2) CO-R n u

Desc.No. W2 W3 W4 Z2 Z3 Z4 Zs Z Ru D1 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH (A) CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH (d) A compound of the formula: wherein R 1, R 2, R 3, R 4, (B) CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 N CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 N (2) (CH2) n CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH * co 3 OEt D13 (d) N CH3 CH3 -CH2 N * co 3 OH &gt; &gt;

TABLE ibonunuscao,

Desc.No. Wx W2 W3 W4 Z2 Z3 Z4 Z5 n Ru D14 (a) N CH3 CH3 CH3 CH3 - CH 2 -C (CH 2) n CH 2 CH 2 CH 2 CH 2 CH 3 CH 2 CH CH 2 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 2 CH 3 b) CH 2 CH 2 CH 2 N 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 *

TABLE.

X

COLOR

U

Qi

Desc.No. Qi Q2 03 Z2 Z3 Z4 Z5 n Ru D18 (a) s CH CH co N * ch2 ch2 4 OEt D18 (b) s CH CH co N * ch2 ch2 4 OH V

(CH2) nC0-Phe-Leu "ACHPARt wv

Ex. No. Wx W2 W3 W4 2 2 Z3 z4 Z5 n Rt salt / solvate EI CH3 CH CH3 CH3 CH3 CH3 0 ch2 co N * 2 API 0.5CHCl3 E4a CH CH CH CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 N CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 CH2 3 API HCl E14 CH N CH CH - co N * ch2 3 API 2HC1 E15 CH CH CH N ch2 ch2 co N * 3 API HCl E16 N CH CH CH ch2 ch2 co N * 3 API HCl E19 N CH CH CH CH2 ch2 co N * 2 API E21 CH CH N CH 0 ch2 co N * 2 API

TABLE 5

Qi

COPheLeu-ACHPAR, n t

Ex.No. Q1 Q2 Q3 z2 Z3 Z4 Z5 n Rt Salt / Solvate El7a S CH CH n N ch2 ch2 4 API h2o E17b s CH CH n ch2 ch2 4 API HCl.1.5H20 E21 s CH CH co N * ch2 ch2 3 API

W? W? A. wz zz

(CH 2) CO-R 2 n u

Desc / Ex.No. W2 W3 W4 Z1 Z2 Z3 Z4 Z5 n Ru D19 (d) N CH CH2 CH2 CH2 CO N * 2 OMe D19 (e) N D CH (CH) CH CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 N

PAINTING

Desc.No. (A) NH2 CH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 N (a) H 2 n 2 D 2 (a) H 2 n 2 H 2 D 2 (a) H 2 n 2 H 2 D 2 (a) H 2 n 2 H 2 D 2 D22 (a) H-nhcoch2-

Description 1

2,5-Dihydropyrido [2,3-b] pyridin-5-yl] hexahydroic acid

Aqueous sodium hydroxide was added at -0øC &gt; ml) was added dropwise to a stirred solution of ethyl 2 - [[(3-chloro-2-hydroxyphenyl) -3- (6.32 g) in 1N ethane and the resulting mixture was stirred at room temperature for several hours. Water (50 ml) was added and the aqueous solution was washed with chloroform. The aqueous layer was neutralized with citric acid The residue was triturated with chloroform and filtered, and the filtrate was evaporated in vacuo to give the title compound (0.17 g) as a white solid (1 H NMR (DMSO-d 6) (DMSOdd): 2.1 (1H, dd), 2.6UH, dd), 3.65 (1H, m), 4.25- (1H, t), 4.8 7.05 (2H, m), 7.95 &lt; 1H, m &gt;. Tet Letts 1985, 26, 49, 6001-6004.

Description 2 (a) Methyl 3- (2,3-Bihydro-3-oxo-4 H -pyrido3,2-b3 -1,4-oxazin-4-yl) propanoate

To a stirred mixture of 2,3-dihydro-3-oxo-4 H -pyrido [2,3-b] -1,4-oxazine (0.50 g) was added dropwise ) and anhydrous potassium carbonate (0.41 g) in dry dimethylformamide (DMF) (5 ml). The reaction mixture was stirred at room temperature for 66 hours, poured into water and extracted with chloroform (3 x 10 Ml). The combined extracts were dried (Naâ,,SOâ, ") and the solvent was removed in vacuo. The crude product was purified by chromatography on 41

silica gel using ethyl acetate / petroleum ether. 60-80 ° C &gt; (&lt; -3% ethyl acetate, gradient) to provide the title compound (48g) as a white solid.1 H NMR (CDCl3): 2.75 &lt; 2H, t &gt; , 3.65 (3H, s), 0.9 (1H, dd), 7.22 (1H, dd), 8.0 (1H, dd), 4.45 (2H, 4.7 (2H, s) ) 3- (2,3-Dihydro-5-oxo-4H-pyrrole-5-propanoic acid)

10% Aqueous sodium hydroxide (0.56 ml) was added to a stirred cooled solution of 3- (2,3-dihydro-3-oxo-4H-pyrido [3,2-b] -1,4oxazin-4 -propanoate (0.047 g) in methanol (5 ml) and the resulting mixture was stirred at room temperature for 21 hours. The solvents were evaporated in vacuo and the residue was dissolved in water and adjusted to neutrality with hydrochloric acid The solution was dried under cooling, and the residue was triturated with methanol / dichloromethane (1: 5 mixture). Filtration and evaporation of the filtrate afforded the title compound (0.40 g) as a white solid.1 H NMR (CDCl3): Î'2.2 (2H, t, J = 2.2 Hz, 4) , 7 (2H, s), 7.0 (1H, m), 7.35 (1H, dd &gt;, 8.0 (1H, dd &gt;

Description 3

ACHPA

To a stirred, ice-cooled mixture of EOC-ACHPA-OH (1.2 g) and 1-hydroxybenzotriazole (HOBT) (50 g) in DMF (10 ml) was added 1- (3-chlorophenyl) -Dimethylaminopropyl) -α-ethoxy] -carbodiimide · HCl (DEC) +. G) After 10 minutes, N - (3-araapaphthyl) imidazole &lt; 0.68 ml &gt; and stirring was continued for 16 hours. Water was added and the solution was extracted with ethyl acetate &lt; 3 x 2 &amp; ml). The combined extracts were washed with water, saturated sodium hydrogen carbonate and brine, dried (Na₂SO ^) and the solvent was evaporated in vacuo, the residue was purified by chromatography on silica gel using methanol / chloroform (0-3% methanol, gradient) to provide the title compound (1.45 g), 3.0 &lt; 2H, m), 7.1 &lt; 1H, 5 &gt;, NMR (8 &gt; (24H, m), 2.15 &lt; 2H, m), 3.8 &lt; 1H, m), 3.95 &lt; 2H, t), 4.7 &lt; 1H, tn), 6.25 (1H, d), 7.6 &lt; 1H, s), 7, S &lt; 1 H, t). (b) CBZ-Phe-Leu-ACHPA 3-C1- (imidazolyl) prolylamide

To a stirred solution of BOC-ACHPA 3- (i-imidazolyl> propylamine &lt; 1.4g) in dry dichloromethane (20ml) was added ice cold trifluoroacetic acid (TFA) (20ml) and the mixture Evaporation in vacuo gave a yellow foam which was 1.8 g). This material was dissolved in dry DMF (10 ml) and triethylamine (1.37 ml) and evaporated to dryness. was added to a stirred mixture of CBΣ-αhe-Leu-OH &lt; 2.02 g &gt;, HOBT &lt; , 66 g) and DEC <0.94 g) in DMF (2 ml) at 0 DEG C. After 16 hours, water was added and the mixture was extracted with ethyl acetate <3 x 250 ml). The combined extracts were washed with water, saturated sodium hydrogen carbonate, and brine, dried (&lt; Na2 SO4) and evaporated in vacuo. The crude product was purified by silica gel chromatography, using methanol / chloroform <θ-5% methanol, gradient) to provide the title compound &lt; 1.95 g &gt; 9-4.5 &lt; 1 H, m 5, NMR &lt; $ &gt; <math> 2 <math> <math> 2 <math> math <math> math <math> math <math> math <math> math <math> E.W. et al.

Compatible with p "m =

71A &lt; c) Phe-Leu-ACHPA 3 &lt; 1-imidazolidyl) prolylamide CBZ-Phe-Leu-ACHPA 3- &lt; 1-yl) aminopropylamide (1.6 g) in ethanol (150 ml) was hydrogenated at ambient temperature and pressure in the presence of 1% palladium on charcoal for 2 hours. Filtration through kieselguhr and evaporation of the filtrate afforded the crude product which was purified by silica gel chromatography, using methanol / chloroform <0-12% methanol, gradient) to provide the title compound &lt; 0.31 g) and RHN &lt; S) C (CDCl-R) -> OD> (22H, In), 2.2 (2H, m), 2.2 (2H, m), 2.8 < 3H, m) -133 (1H, m), 3.9-4.2 (4H, 1H), 4.3 &lt; tb &gt; 1H, m), 6.9 (1H, s), 7.15 (1H, s), 7.25 &lt; 5H, m &gt; 7.7 &lt; 1H,

Description 4

(a) BQC-Phe-Leu-ACHPA isobutylamide RMM S &gt; CDCl? -R &gt; s .Js 6, 4-7.4 &lt;BH).; 3 (3H, t, J = 8 Hz); G-B. (b) a)

This material was formed from BOC-Phe-Leu-OH &lt; 1.48 g &gt; and ACHPA buffered amide (<1 g, 6 g), the procedure of Description 3 (a) was followed. The crude product was chromatographed on silica gel using methanol / chloroform &lt; 0-2% methanol, gradient). This afforded the title field &lt; 1.91 g). J. Med. Chera. 19885, 28, 1779-179®,

(b) Phe-Leu-ACHFA isobutylamine. TFA

Isobutylamide of thiooctadecanoate under stirring at RT

The solvent was removed in vacuo, and the residue, 3 g) was added after 1 hour. it was crushed with

I ether to give the title compound. NMR Î'&gt; (CDClâ,ƒOâ,ƒâ, "â, ... Câ, â, Hâ, â, â, †) â, 3 2 8 8-3n3 (4H, m), 4.44 (4H, m)

Description 5 (a) CBZ-Phe-Leu-ACHPft Issbutiiamide (4.13 g &gt; gel product, gradient)

This material was formed from CBZ-Phe-Leu-OH following the procedure of Description 4a &gt; The crude product was purified by chromatography on silica methanol / chloroform (Θ-3% methanol.

This afforded the title compound (6.4 g) as light tan solid. NMR (#> <CDCl3): Î'] -, 85 (29H, m), 2.3 (2H, m), 2.9-3.15 (4H, m) 2H, m), 4.3-4.5 (2H, m), 5.04 (2H, s), 6.5-6.85 (3H, m), 7.1-7.4 (ΪΙΗ, λι). (h) Phe-Leu-ACHPA isobutyl amide. eur-lex.europa.eu eur-lex.europa.eu

This material was formed from CBΣ-Phe-ACHPA isobutylamide (6.4 g), followed by the procedure of Description 3 (c), but using ethanol / acetic acid as the solvent. This afforded the title compound (7.4 g), which further contained residual acetic acid, title (7.4

NMR δ .5 ') (CDCl3) δ 0.8-1.85 &lt; 29H, m), 2.05 (m), 2.35 &lt; 2H), 3.95 (2H, m), 4.15 (1H, m), 4.3 (1H, m), 7.25 (5H, , m &gt;, 8.0 &lt; b).

&lt; c) Phe-Leu-ACHPA Isobutylamine

(7.4 g) was dissolved in ethyl acetate and extracted into aqueous citric acid. The extract was basified with sodium carbonate and the product was isolated by extraction in chloroform (1: 1) dried (Na2 SO4) and evaporated in vacuo. This afforded the title compound &lt; 3.2 g). (CDClâ,ƒ): 0.7-1.0 (13H, m), 1.0-1.9 (1H, m), 2.3 (2H, ABX), 1.75 (1H, dd ), 3.05 (2H, m), 3.2 (1H, dd), 3.65 (1H, dd), 3.95 &lt; 2H, m &gt;, 4.35 (1H, m &gt; (1H, d &gt;, 5α &lt; 1H, t), 7.5-7.35 (1H, m), 7.7 (1H, d).

Description) methyl propanoate • thia2in-4-yl

This material was prepared from 2,3-dihydro-3-oxo-4H-pyridoC4,3-b3 -1,4-thiazine # (0.10 g), followed by the procedure of Description 2 (a ). Purification by silica gel chromatography using methanol / chloroform (0-4% methanol, gradient) afforded the title compound (0.18 g) as a colorless waxy solid.1 H NMR (1H, d), 8.45 (1H, s), 3.45 (2H, 8.45 (1H, s), 7.32 (1H, d,

{&quot; TI4 si \ ã. \ 'η,' Π jj ir- ς x J (1985) 1

Synth. Comm. (b) 5- (2,5-Dihydro &quot; 5-oxo-4H-pyrrolo4,5-c-4-thiazin-4-yl) -oranoic acid

This material was prepared from methyl 3- (2,3-dihydro-3-oxo-4 H -pyridoC4,3-h3-1,4-thiazin-4-yl) propanoate, the title compound (1), (5g) was obtained as a white solid, m.p. (DMSO-d6)? 2H), 8.1 (1H, d), 8.5 (2H. m), (2H, s), 4.5 (2H, m)

Description 7a &gt; &lt; 2-Chloro-3-nitropyridine (2 g, g), 3-amino-propanoate, ethyl HCl &lt; 1.94 g &gt; and potassium carbonate The mixture was evaporated in vacuo, partitioned between chloroform and water and partitioned. The aqueous portion was extracted with chloroform and the combined organics were washed with dichloromethane and dried (MgSO 4). water and brine, dried (Na2 SO4) and evaporated in vacuo. Chromatography on silica gel using methanol / chloroform (0-2% methanol, gradient) afforded the title compound &lt; 2.5 g) . NMR &lt; "&gt; CDCl3): 1.3 (3H, t), 2.76 (1H, dd), 8.4-8.7 (2H, m). ar. C2H, q), 4.2 &lt; kiH, q &gt;, (b) &lt; <5-Aminopyridin-2-yl) amino) propanoate

This material was formed from ethyl din-2yl) amino) propanoate &lt; 2.90 g), C &lt; 3-nitropyridine

The title compound of the description of 3 (c), This afforded the compound (2.43 g) as a red oil, <2H5bJ, 3575 (2H, m), 7.7 (1H, d). RHN &lt; S) (CDCl-ζ) s 1.3 (3H, 1), 2.7 &lt; 2Hst &gt;, 3, 4,15 &lt; 6.85 (c) 3- (2,3-Dihydro-2-oxo-1H-imidazo [4,5-b] 3-yl) propanoic acid ethyl ester (2.4 g) was stirred in dichloromethane (5 ml) as 1 After a strong reaction, the mixture was stirred for 16 hours, evaporated to dryness, dissolved in ethyl acetate, washed with water, (Naâ,,SOâ, "), Naâ,,Oâ, ) and evaporated in vacuo. Chromatography on silica (9.4%) by using methanol / methyl chloroform) afforded the title compound &lt; 2.2 g of purple solid. ) as an NMR (CDCl3): δ (b) - p (2H, t), Î'(1H, dd), 4.15 (2H, (B) (d) 3- (2,3-Dihydro-2-oxo-1H-pyrazol-4-yl) -4- ridin

-3-iH

3-oxo-4-oxo-1,2,3,4-tetrahydro- ®, 82 g utilized, ι · ί * · αΐη 95 ta

This material was formed from the title compound. -oxo-1H-imidazo [4,5-d] pyridin-3-yl) propanoate following the procedure of Description 2 (a) with ethanol as the solvent. This produced ® CuiepostO as a pink solid. NMR (S) (1H, d), (DMSOdd): δ 7.85 (1H, d) (1 H, t) (2H, t), 6.9 (1H, dd).

Description 8 (a> 2,3-Î ± -1 (ethoxycarbonylamino) pyrimidine 2,3-Biaminopyridine (2.77 g) and dry pyridine (8.1 ml) were stirred was added dropwise at 0 ° C in tetrahydrofuran (25 ml) and ethyl chloroformate (4.9 ml) was added dropwise. The mixture was stirred at 0 ° C for 15 minutes and then allowed to reach room temperature was maintained for 3 hours. It was diluted with ethyl acetate, washed with water, dried (Na2 SO4) and evaporated in vacuo. Chromatography on alumina using 1% ethyl acetate in petroleum ether &lt; p , and 60-80 ° C gave the title compound (3.db, 16 g) as an orange solid. (CDCl3): 1.35 (6H, 2xt), 4.25 (4H, 2xq), 7: 1 (1H, d), 8.2 (1H, d), 8 , 45 (1H, b), 8.8 (b). (b) 2,3-dihydro-2-oxo-1H-imidazo [1,2-a]

2,3-di (ethoxycarbonylamino) pyridine &lt; 3.16 g) was dissolved in 2M aqueous sodium hydroxide (1 ml) at 50 ° C. The solution was then acidified (5M hydrochloric acid) and neutralized with ethyl acetate hydrochloric acid, the extract was dried (Na2 SO4) and evaporated in vacuo to give the title compound , 20 g) as a brown solid. On standing, the aqueous portion produced a brown precipitate, which was filtered off and dried in vacuo, yielding a further crop of the title compound (1.14 NMR (DMSO-d6) 1H, vb) δ: 9 (1H, dd &gt;

1H, d &gt; , 8 &lt; lH, d &gt; 11.1 (c) 5-C2,5-Si-hydroxyl-1H-imidazo [4,5-b] pyridine-4-carboxylate from methyl- dihydrofur-2-one), the procedure was purified by chromatography

This material was formed at -OKQ-1 H-imidazo [3,4-c] pyridine &lt; i, 3 of Description 2a. The crude product was chromatographed using ethyl acetate / petroleum ether, gradient.) This was found to be stable at -20 ° C. C 0-1 acetate yielded the title compound (1.2 g). NMR (DMSO-d6): δH (dd) (CDCl3): 2.85 (2H, t), 7.4 (1H, d), 8.1 (1H, d) (D) 3- (2,3-Dihydro-2-oxo-1H-imidazo [4,5-b] pyrrole-1-yl) proparoic acid, the process of the Scheme 1k Zkb). This afforded the title compound (0.42 g) as a white solid. NMR (o) &lt; (1H, d), 9.9 (1H, d), 9.9 (1H, d)

This material was formed from r. 5-yl-1H-imidazo [4,5-b] pyridin-1-yl) propanoate;

a &gt; BOC-Fhe-Leu-ACHPA 3- (1-imidazolyl) propylamide

This material was formed from Boc-Phe-Leu-OH (1.60 g), (Boc-Phe-Leu-OH) (3-methyl- (b) was chromatographed on silica gel using 5% chloroform of methanol (5 g) and the crude product was treated with methanol / methanol. yielded the title compound (95 g; 1 H NMR (CDCl3, 2.2-2.0, S &lt; 2H, m)), 6.73 (s, 1H). m &gt; 1.05 2.9-3.6 (5H, m), 3.9-4.5 (1H, s), 7.05 &lt; 1H, s), 7.15 (b) 5 (1 H, m), 2.25 (6H, m), 4.25 (1H, m) To a solution of Phe-Leu-ACHPA (0.16 g, in trifluoroacetic acid <6 ml), and (b) The title compound (0.62 g) was then added and the title compound (0.62 g) was added. The title compound (0.62 g) was dissolved in dichloromethane (100 ml). The form of a BOC-acid hour and white product-solid.

Description 10 = a &gt; (2.5 g) was prepared. The title compound was prepared according to the procedure described in Example 1, except that,

This stuff. 1 was prepared as described above. c i4. 2,3-Dihydro-3- (4-pyridyl) -3,3-b-1,4-thiazine (0.36 g) butyl acrylate <0.63 m 1), sec (a) 'This produces u. the title compound (0.62 g) was obtained as a white oil (1 H NMR (CDCl 3): δ (8H, s) (2H, s), 7.33 (1H, d), 3.81 (2H, s), 3.32 (2H, t) (1H, s)

(b) 3- (2,5-Dihydro-1-iso-5-trifluoromethylphenyl) -4H-benzoimidazo [4,3- b] dihydro-3 - [(4H-pyridyl) -4,3-b] -1-propanoate (Θ, ΙΒ gs; The mixture was evaporated in vacuo from the filtrate, dried (MgSO 4), and concentrated in vacuo. ether, washed with 5% sodium hydrogen carbonate solution and brine, dried (Na2 SO4) and the residue was collected in chloroform, filtered and concentrated in vacuo. ) in vacuo to give the title compound as a colorless oil.1 H NMR (CDCl3): Î'1.4 (9H, s) (3), (7). n. (ΞΗ p "g C 2H, s), 4, β. (2H, t), 7.8 (1H, d), 8.9 (1H, d), 8.9 (1H, 4-yl) -4-thia-4-yl) propanoic acid 3- (2,3-Dihydro-1,3-dihydro- 4H-pyrido [4,3-b] -1,4-thia-sin-4-yl) propionate. was dissolved in dichloromethane (2 ml) at 0 ° C. The solution was cooled to 0 ° C overnight. The solvent was evaporated and the residue was dissolved in vacuo. The title compound (0.63 g) was obtained as a white powder (1 H NMR (CDCl 3) δ (CDCl 3) η a- r. (2H, t), 4.95 (2H, m), 1.85 (1H, t), 4.41 (2H, t), 4.95 , t)

Description 11 '' (g) 2,3-Dihydro-3-pyridin-4-yl) -5,5- b 2-1,4- 31 g), anhydrous potassium carbonate (4.02 g) and ethyl marcapioacetate (2.4 ml) were stirred in DMF (30 ml) for 1.5 hours. The mixture was diluted with ethyl acetate (3 ml), washed with water and brine, dried (Na2 SO4) and evaporated in vacuo to give a mobile oil

(4.53 g). This was dissolved in glacial acetic acid (100 ml) and stirred as iron powder (20 g) was added. The mixture was stirred at 90 ° C for 2 hours, cooled and evaporated in vacuo. The resulting brown solid was extracted twice with xylene and the extracts were evaporated to give the title compound (0.85 g), impure as a brown solid, the residue remaining, after extraction with xylene was dissolved in 10% aqueous acetic acid, filtered and extracted with 10% methanol / chloroform. This extract was dried (Na2 SO4) and evaporated in vacuo to give second crop of material (0.88 g), pure, as a yellowish solid. The starting xylene extract was purified by trituration with ether to give a total yield of 1.38 g. NMR (DMSO-d 6): 3.65 <2H, s) <1H, b). 7.2 (2H, m), 8.1 (1H, dd), 10.6 (1H), t-butyl

3-b] -1,4-thiazin-4-yl) propanoic acid

This material was prepared from 2,3-dihydro-6-oxo-4 H -pyrido [2,3-b] -1,4-thiasine (3.84 g), followed by

(a) = title C1.57 (q) in the form of

This provided the compound of a brown oil &lt; 2H, s), 4.2 &lt; 2H), 2.6 (2H, t), 7.1 (1H, d), 7.5 (1H, dd), 8.4 (9H, , 2 (1H, dd) <c> 5? -Dihydro-5-dihydro-5H-pyrido4,4-b, -1,4-thiazol-4- pro-anion and 3-ethyl-2,3-dihydro-3-t-butyl 10Cc) This is described in the following examples. 4-yl) propanoate (33 g), following the procedure of the Description afforded the title compound C 242 (a) as a powder white, C 2 H, t) NMR (DMSO-d 6): δ (DMSO-d 6): 2.55 (m) O (1H, dd), 7.65 (1H, d), 8.1 (1H, dd).

Description 12 (a) t-Butyl 3- (2,3-dihydro-1,1,3-triPKO-4 H -pyrido [2,3-b] -1,4-thiazin-4-yl) propanoate

This material was formed from t-butyl 3- (2,3-dihydro-3-oxo-4 H -pyrido [2,3-b] -1,4-thiazin-4-yl) propanoate (Description ll (b> ) (0.4 g), following the procedure of Description 10 (h). This afforded the title compound &lt; 0.29 g) as a clear oil but contaminated with about 2% of an unidentified impurity &lt; RMM &gt; = NMR (8) (2H, s),: CDCl3): 0.55 (1H, dd)

(2H, t), 4.35 (1H, d), 8.55 (1H, dd)

(b) 5- (2,3-Dihydro-1,1,1-trio-4H-pyrido [2,3-b] -1,4-thiazin-4-yl) proanoic acid

This material was formed from ie 3- (2,3-dihydro-1 H -1,3-dihydro-4 H -purine. 3-yl) -1,2,3 -b i -1,4-a] pyrimidin-4-yl) propanoate; followed by the processing of the

This afforded the pure title compound (0.16 g) as a gray solid.1 H NMR (DMSOd 6): 2.55 (2H, t), 4.2 (2H, t), 4.95 (2H, s), 7.8 (3H, m, 1H), 8.2 (1H, d), 8.5 (1H, d).

(A) 4- (57-Dihydro-5,7-dihydro-6H-pyrrolo1,3,4-bpyridin-6-yl) butanoate

A mixture of pyridine-2,3-dicarboxylic acid (15 g) and urea (6.65 g) was heated at 18 ° C for 30 minutes. After cooling to room temperature the residue was triturated with ethyl acetate and water to give crude dicerboximide intermediate α.

This crude intermediate was alkylated with ethyl 4-bromo-butyrate and the procedure of Description 2 (a>) was followed to provide the title compound (3.75 g). NMR (DMSO-d6):? 1.3 (3H, t &gt;, &lt; 2H, t), 4.1 (2H, q), 7.6 &lt; (1H, d), 2.0 (2H, quin), 2.4-8.1 (1H, d), 9.0 (1H, d), 3.38

&lt; b) 4- (6,7-Dihydroxy-7-hydroxy-5-oxo-5H-indole-3,4-b1yl) butanoate To a stirred solution of (5,7- ethyl ester (95 ml of methanol (55 ml) at 0 ° C was added sodium hydroxide &lt; Î', 2â € ²â € ƒâ € ƒâ € ƒAfter 2 minutes, the reaction was quenched with 5M hydrochloric acid and the reaction mixture was evaporated, the residue partitioned between chloroform (50 ml) and aqueous sodium hydrogen carbonate (2 ml), then the organic phase was dried and evaporated to dryness on silica using Et2 O acetate afforded the title compound (0.68 g &gt;, RHN &lt; S) <CDC17) s 1.2 <3H, t> 2.0-2.2 (2H, m), 2.4-2.5-3.6-3.7 (2H, m), 4.1 (2H, q), 7.5H, dd> 8.1H, d &gt;; 8.8 (1H, d); (c) 4- (6,7-Dihydro-5-β-5Î ± -pyrrolo1,5c-3apos;

A solution of ethyl 4- (6,7-dihydro-7-hydroxy-5-oko-5 H -pyrrolo3,3-bpyridin-6-yl) butanoate (0.33 g) acetic acid (8 ml) was kept under The reaction mixture was filtered and evaporated, then the title compound (0.24 g) was obtained by chromatography on silica using acetate (2H, t), 3.78 (1H, d), 8.9 (1 H, m) t> 4.0 (2H, q &gt;, 4.8 (2H, s &gt;, (Ti-Lfas),

(d) 4- (6,7-Dihydro-5-oxo-1H-pyrrolo [3,4-b] pyridin-1-yl) butanoic acid To a solution of 4- (6,7- 5-pyridin-6-yl) ethyl] butanoate &lt; / RTI &gt; in ethanol (7 ml) was added water (7 ml) and potassium carbonate (Θ2 g). This mixture was stirred at room temperature for 3 days and then evaporated. Chromatography on silica by use of 50% methanol / chloroform afforded the title compound (0.18 g:. NMR (DMSO-d6): δ (2H-s), 7.5 &lt; (2H, s), 8.1 (d), 2.25 (2H, t), 1.60 (1H, d). 4.5

Description 14 (a) 4-C amp,, 7 Di Dihydro-5-hydroxy; -OKD-5H-pyrrolo3,3-biorgiridin-6yl) butanoate The title compound &lt; 0,

Tox obtained as a slower by-product of the synthesis of ethyl 4- (6,7-dihydro-7 "-hydroxy-5-DKO-5 H -pyrrolo3,3-bpyridin-6-yl) butanoate (Description 13 B)). (CDCl3): 1.3 (3H, t), 1.9-2.1 (2H, m), 3.3-3.3 (2H, m). &lt; IH.d). H-> K? , q &gt; s. (1H, d) (b-4-yl) -7-Dihydro-7- (5H-pyrrolo [3,2-b] pyridin-4-yl)

A solution of pyrrolo-3,4-bipyridin-6-yl) -4 &lt; Ethyl D-5H-butanoate (â † ', 23 g) in &gt; *

ethanol (25 ml) was acidified with 1M hydrochloric acid and then &lt; 2H, t &gt;, 4.0 &lt; 2H, q); The title compound was obtained as a pale yellow oil (10% yield) and the filtrate was concentrated to give 17 g. (3H, m), 1.8-i, 9 &lt; 2H, m), 7 &lt; 2 &gt; 2H, t &gt;, 3.6-4.5 &lt;; 2H), 7.1 (1H, d), R7 - (c) 4- [7-Dihydro-7-ok -5H-pyrrolo5,4-bpyridin-6-11) butanoic acid 4 &lt; 6,7-dihydro-7-ethyl &lt; 917 g &gt; , This provides

This material was formed from 5-amino-5H-pyrrolo [4,4-b] pyridin-6-yl) butanoate. Description 13Cd), or the title compound &lt; 0.12 g &gt; NMR (DMSO-d6):? ): 1.8-1.9 (2H, m) &amp; 2.2-2.3 (2H, t), 3.6 (2H, t); <H4, d, 8.7 &lt; 1H, d &gt;

(A) 4- (5,7-Dihydro-6H-pyrrolo1,5,4-c3-pyridin-6-yl) -butanoate ethyl

This material was formed from β-ridin Î ±-3,4-tri-carboximide (2.5 g) and ethyl 4-bromobutyrate (2.0 ml), following the procedure of Description 2 ( a) =. This provided the title compound &lt; 3.13 therein. NMR (S) (CDClâ,ƒ): 1.25 (3H, t), 1.78 (1H, d), 2.0 &lt; 2H, quinoline, 2.4 &lt; 2H, t), 9.05 (1H, d), 9.15 (1H, s). 8

4-fluoro-6- butanoate &lt; b) Ethyl 4- (6,7-dihydro-5H-7-e-pyrroloyl)

This material was formed from -5,7-dioxo-5H-pyrrolo3,5-cpyridin-6-yl) butanoate - b) and 13 (c), except for the chromatography of the 5-hydroxy intermediate. Chromatography on silica by the use of acetate (2H, t), 7.20 (2H, t, J = 8 Hz), 7.40 (1H, s) 51), 4505 (2H, q), 4.45 &lt; 2H, s &gt;, 7.45 (1H, d), 8.75 (1H, d), 9.1 (1H, s). C c) Ac 4 - &lt; 6,7-dihydro-5H-7-oxo-pyrrole-1-ol 34-c] pyridin-6-yl) -butanamide.

This material was formed from ethyl 4- (6,7-dihydro-5H-7-oxo-pyrrolo [3,4-c] pyridin-6-yl) butanoate (0.030 g) The title compound (0.2 g), (DMSO-d6): 1.8 (s, 3H) &lt; 2H, * quin), -? - &quot; 31 &quot; &lt; 2H, t),? 5 '/ 5' '- 4' '-' '' '' '' '' | (1), (1), (1), (1), (1) and (2) W-; . Fig.

EXAMPLE 16 (a) 4- (7H-Dihydro-6-oxo-1-naphthyridin-8-one

A mixture of 1,8-naphthyridine (2.5 g) and ethyl (13.7 ml) in ethanol (100 ml) was 4-bromobutyl

After stirring for 6 days, the mixture was evaporated and the mixture stirred in an ice bath as a solution of potassium ferrocyanide (38 g) in water (1.25 ml) was added dropwise was added dropwise over ½ hour followed by the dropwise addition of a solution of potassium hydroxide (17.5 g) in water (25 ml). Stirring was continued for 24 hours, during which time the reaction mixture was allowed to warm to room temperature. Water was added to dissolve the remaining solid and the solution was washed with chloroform. The aqueous layer was acidified with 5M hydrochloric acid and extracted with chloroform. The combined chloroform extracts were dried (Na 2 SO 4) and evaporated in vacuo. The residue was recrystallised from methanol to provide the title compound &lt; 25 g). NMR (δ): DHSOd, δ = 1.8, 2.2 (2H, m), 4.4 (2H, m), 6.7. (1H, dd), 7.9 (1H, d), 8.2 (1H, dd), 8.61, 12.5 (1H, b). * Chem. Pharm. Bull. 19 (9) 1857-62 (1971), &lt; b) 4- (7-Oko-5,6,7,8-tetrahydro-1-naphthyridine-B-yl) -butyric acid, nitrogen was added To a solution of (11) butanoic acid (0.04 mole) in two portions, stirred at ambient temperature to give acid (g) ), followed by 4 &lt; 7,8-dihydro-7-oxo-1,8-naphthyridine-8-formic acid S / 1 / methanol (24 ml) after 1 hour of reaction. The mixture was filtered, the filtrate was concentrated in vacuo, filtered, and evaporated in vacuo. The residue was purified on silica gel by the use of methanol / chloroform (methanol, gradient) to provide the title compound (Θ).

NMR (qs): CCDC1. 9.8 &lt; 1H, b). \ 251 = 1 H, d5

Description 17a

AC 1 d D

6-oxo-1,5-naphthyridin-5-yl) butanoic acid

This material was formed from 1,5-naphthyridine * <1, g) followed by the procedure described in Description 1. By evaporation of the chloroform excretes the solid produced was filtered from the residual liquid to give the title compound Câ,2 g ) NMR (S) &lt; 1H, dd);  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (1H, dd), 8.1 (1H, d), V.45 Pharm. Buli, 1V (V)? 1B5 / -62 (1971). (b) 4- (6-Oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-5-yl) butane-3-carboxylic acid

This material was formed from hydro-6-oxo-1,5-naphthyridin-5-yl) butanoic acid (Φ, 12 g) in the course of the procedure described in Example 1 (b). The title compound, obtained by filtration in vacuo yielded which was used without further purification, the title compound &lt; 0, NMR (CDCl3) (CD3 OD) Î'1.9 (2H, m), 254 (2H, t), 2.75 (2H, t) 3.1 &lt; 2H, t &gt; 4.0 C2H. * 7 τε =:.

Γ; B &gt; ,, CW \ JL

Description 18

Ca) 5- (7-Oko-4,5,6,7-tetrahydro-1-naphthyl, 6-pyridin-6-yl)

This material was formed from 435-dihydrothymidine in 2-methyl-3 H -pyrid-7 (R) -cyclohexylcarbamate and ethyl S-bromovalerate (1.44 ml), followed by The crude product was purified by silica gel chromatography, using ethyl acetate / petroleum ether (bp 60-8 ° C &gt; 0-3% ethyl acetate, gradient) to give the title compound &lt; δ935 g &gt;, NMR (CDCl3): 1.2 (3H, m), 7.3 (3H, m), 2.3 &lt; 2H, ns &gt; 3.4-3.7 &lt; 4H, m), 4.1 (2H, q), 6.9 (1H, d), 7.466 &lt; 1966). Chem., &Lt; b) 5-Tetrahydro-1ieno2,5-cpyridin-6-yl) -oenoic acid

This material was formed from ethyl 5- [7-chloro-4,5,6,7,7-tetrahydro-thieno [2,3-c] pyridin-6-ylpentanoate (0.32 g), followed by the procedure of Description 7, Compound of title), 27 g) was isolated as a slightly colorless oil. NMR (8) CDMSO6? s

3H), 3.63 (3H, t, J = 7.0 Hz) 7.1 2.2 &lt; 2H, m &gt; ClH, d) (C2 H, t)

Description 19 &lt; a) 5- (3-Nitro-pyridin-2-yl) thio) propanoic acid

3-Mercaptopropionic acid (5.0 ml), 2-chloro-3-pyridine (9.11 g) and anhydrous potassium carbonate (19.8 g) in DMF (10 ml) were stirred for 5.5 hours. The solids were then dissolved by addition of water (2 ml), the mixture was stirred for 16 hours, diluted with water (<500 ml), washed with ethyl acetate and acidified with concentrated hydrochloric acid. was then extracted into ethyl acetate and the extract was dried (Naâ,,SOâ, ") and evaporated in vacuo to give the title compound (1.3 g) as a yellow solid (2H, t) (1 H, dd), 8.8) -thio) propanoic acid &lt; b) -3- [15-Aminopyridin-3-yl]

Ethyl (2-chloro-3-nitro-pyridin-2-yl) thio) propanoic acid (28 g) was hydrogenated over 1% palladium on charcoal Cpasta aq. , 4.4 g) for 24 hours. An additional 4.1 g of the catalyst was added and the hydrogenation continued for a further 64 hours. Filtration through kieselguhr and evaporation in vacuo gave the title compound as a white solid. a solid yellow orange (C₂çH₂;): δ: 9.9 (2H, m); (2H, t)

(c) 23-Dihydro-5H-pyrazole-2,5-b] -1,5-triazepin-4-one

3 - (<3-Aminopyridin-2-yl) thio) propanoic acid (7.54 g) and 1,3-dicyclohexylcarbodiimide <7.84 g) were combined together in DMF (75 ml) for 4.5 hours, this mixture was evaporated in vacuo, collected in ethyl acetate, filtered and evaporated to give a yellow / brown solid. This was purified by chromatography on silica gel using ethyl acetate / petroleum ether (ρ â ¤ 60-80Â ° C) (50-100% ethyl acetate, gradient) to give the title compound &lt; 100 Q). NMR (CDCl3): 2.70 (d), 8.05 (b), 8 (d) 3- (4-Oxo-2 ', 3,4'

Methyl) -1H-b] -1,5-thiazepin-1-yl) orphoate

This material was formed from 1,2-dihydro-5 H -pyrido [2,3-b] -1,5-thiazepin-4-one (0.55 g), the procedure of Description 2 (a) being, This afforded the title compound as the title compound as the title compound as a white solid.1 H NMR (CDCl3): δ (2H, t), 2.75 (2H, m), 3.4-3.0 (5H, m) (1H, dd), 7.65 (1H, dd), 8.0 (1H, dd)

(e) 5 - [[4 - [[2,3,4,5-Tetrahydro-pyrido [2,3-b] -1,5-thiaze-5β) -propanoic acid

This material is formed from 3- [4-oxo-2,3,4,5-tetrahydropyrido [2,3-b] [3 S, 5-thiazepin-5-yl] propanoate, followed by the process of Scissors 7 (d),

Description? 2 &lt; a &gt; (3-pyrrolidin-2-yloxyacetyl)

Sodium hydride (100% dispersion in mineral oil, 0.31 g) under nitrogen in BMP Cl (ml) was added dropwise while ethyl glycollate (1.0 ml) was added dropwise. After 1 min, 2-chloro-3-nitropyridine, 3 g) was added. After a further 15 minutes, the mixture was partitioned between ethyl acetate and water and partitioned. The organic portion was washed with water and brine, dried (Na2 SO4) and evaporated in vacuo to give the title compound (2.1 g) as a brown oil.1H NMR. 2% contamination by the pyridine starting material (the peaks are not indicated in the following). NMR (S) (CDCl3) .delta.HCl, m), 8.35 (2H, m), 1.3 (3H, t). , 4.25 (2H, q), 5.05 &lt; 2H, s), 7.1 &lt; h) (3-Amino-pyridin-2-yl) oxyacetate

This material was formed from ethyl (3-nitropyridin-2-yl) oxyacetate (2 g, 9 g), and the procedure of Description 3 (c) was followed. This provided the title compound &lt; 1.76 g &gt; as a yellow oil.1 H NMR (Î ±) (CDClâ,ƒ): Î'13.2 &lt; 2H, q), (1H, dd), A &lt; ΙΗ, -dd &gt; , 7.5 (1H, dd), 4.9 (2H, s), 6.7 (c), 2,3-Dihydro-3-oxo-4-oxopyrido [1,2,4] oxadiazine (1.75 g) was stirred at reflux in dry xylene (5 ml) for 3 hours, evaporated to dryness, and the residue was taken up in 10% methanol / c The filtrate was concentrated and purified by silica gel chromatography using methanol / chloroform (Θ-i &% gradient methanol). This afforded the title compound &lt; 0.73 g) as a brown solid. m), 8 (CDMSOd)): 4.75 &lt; 2H, s &gt; 7.0 (lK, ddd), 7.2 or ... .... . 1 € *? Β5 <IH? h &gt; . (d)

5- (2,5-Dihydro-4-oxo-4-hydroxy-4-fluorobenzoic acid)

This material is formed from 2-4B-pyridoE2,3-h3-1,4-oxasin- followed by Descriptions 2Ca &gt; and 7 (d).

Description 21: o

Ca) 5- [ C3-nitrooiridin-4-yl) thio) propanes

This material was formed from 4-chloro-3-nitropyridine (4.33 g), following the procedure of Description 19C). Some amount of solid precipitated from the ethyl acetate extract? Why this extract? which still contained residual brine? was evaporated to dryness? This was afforded the title compound (83.8 g) as a brown powder.1 H NMR (DMSO-d6): νmax DMSO-d6: 9.25 (1H) (d) tb Het, Chem. 32 (a): wherein R H is as defined for formula (I). 11) 2477 (1989) 2,5-Dihydrobenzofuran-5 H -pyrrolo [3,4-b] -1,3-thiazole-4-one This material is formed from pyridin- 1-yl) thio) propanoic acid following the procedures of 19 (b) and 19C (11): 5- (4-oxo-6Î ±, 4,5Î ± -tetrahydro-4H-pyrrole- (1) propanoic acid (b)

This material is formed from 2,3-dihydro-5H- (1R) -C4,3-b3-1,5-phyzepin-4-one; following the processes of Descriptions 2 (a) and 7 (d).

Description 22 &lt; a) 23-Si-hydroxymethyl-5-pyridin-4-yl) -4- 4-Qaazine

This material is formed from 4-chloro-3-nitropyridine, following the procedures of Descriptions 20 (a) - (c 5. <b) 3- (2,3-Dihydro-3-oxo -4H-pyrido [3,4-b] -4-oxazin-4-yl) propanoic acid of the orocess

This material is formed from 253-dihydro-3-o-o-4H-pyridotri 4,3-b3-1,4-DMasine; followed by Descriptions 2 (a &gt; and 7Cd &gt; = Εκmple 1

(2,5-tetriothiofuro [5,2-b] pyridin-3-yl) acetyl-Phe-Leu-ACHPA.O.SI-UO

This material was formed from 2,3-dihydroxyfuro [3,2-b] pyridine-3-acetic acid (Description 1) C, 74 g) and Phe-Leu-ACHPA isobutylamide (Description 5Cc) C, 15 g &gt;, following the procedure of Description 3a &gt;. The crude product was purified by silica gel chromatography using methanol / chloroform (-4 -4% methanol, gradient) to provide the title compound C13 (13 g) as a cream solid. NMR (DMSO): δ 0.7-1.9 (29H, m); , 2.2-2.5 (3H, m), 2.7-3.25 (5H, m), 3.6-4.1 (4H, m), 4.2-4.45 (2H, n), 4.5-4.75 (2H, m), 7.1-7.35 (7H, m), 7.9 &lt; 1H, m).

Analyzes © --Η- ^ Μ-Ο. .Delta. = 5H2 O requires C, 66.8; H, 8.38%, 10%. Found: C, 66.85; H, 8.45; N, 9.7%. E.M. (m / z) <FAB) = 692 (consistent with m.p. = 691).

Example 2

Dihydro-4-oxo-furo [5,2-b] pyridin-3-yl] acetic acid,

To a stirred solution of 2,3-dihydro-furo [3,2-b] pyridine-3-acetyl-Phe-Leu-ACHPft isobutylamide (Example 1) (0.064 g) in dry dichloromethane (1 ml) at C was added 8% to 3% chloro-5-hydroxyacetic acid (AMCPBA) (0.2 g) in three portions over 5 minutes. After stirring at room temperature for 18 hours, additional 80% AMCPBA (10 g, 2 g) was added and stirring was continued

The residue was purified using methanol / hexane to give the white solid compound, MS (m / z) (FAB) = 708 ° C. The solvent was evaporated in vacuo and the residue chromatographed on silica gel (0.6% methanol, gradient) of the title t, q as a solid (dl = 70%).

Example 5

5- (2,5-dihydro-zin-4-yl) propanoyl-Phe-Leu-ACHPA-O-5-O-O-4H-imidazole-2-carboxylic acid A solution of the compound of formula (I) The solid is obtained from 2,3-dihydro-4-o-tocopherol in the same manner as in Example 1 (a). (a) The product in: Ratio of (a) to (b) and (b) to (g) 1% methanolic gradient): tb______________________________________ tb tb______________________________________ tb tb______________________________________ tb tb______________________________________ tb tb______________________________________ &quot; T 1 (6H, m), 3.8 (2H, fam> 3.95 &lt; 2H, t), 4.10 &lt; 2H, bm), 4.3-4.0H, bm &gt; 4.7 &lt; 2H, s), 4.9 6.9 (1H, s), 7, &lt; 1H, q), 7.1-7.5 (8H, m), 7.6 (1H, s) ), 7.8 (1H, t), 8.0 8.1-8.3 (2H, m), 8.3 (0.5H, s).

Analyzes -0 = SCHU1-4 requires C, 09.6.3 Η, 7, β? N,

Found: C, 60.0; Η, 7.Θ? M, 13.2%. E * M «(m / 2) (FAB) = 787 (consistent with p * m« = 786)

Example 4a 5- (2,5-Dihydro-5-oxo-4H-pyridine-5-carboxylic acid 5- (1-imidazolyl)

C4,5-b3-1,4-thiazin-4-yl) proparalyne &lt; RTI ID = 0.0 &gt; Phe-Leu-ACHPA *

This material was prepared from 2,3-dihydro-3-oxo-4H-pyrido [4,1-b] -1,4-thiazine-4-propanoic acid 6 (b) &gt; ΦΦ, ϋ g)? followed by the procedure of Example 3. Purification by silica gel chromatography using methanol / chloroform (? -left% gradient methanol) afforded the title compound &gt; Λ »s | / ilsH, s) and (DMSO-d6): Î'3 / '-1.9 < 24H? m)? jL. 1 H-NMR (CDCl3): δ (3H, m), 7.4 (1H, m) &lt; 2H, s), 3.8-4.1 / 1H, m) (1H, d), 6.9>, 7.1-7.3 (7H, m), 5.43 (1H, d) 1H, s), 7.75 (1H, t) ώ. (2H, m), 8.14 (1H, d), 8.7 (1H, s), where: &quot; 4 H and R2 = 58; 2H requires C, 53.5; N, λ X O j i 4%, ./¾ · | a U * T i n M | ......... 3 * s / «· · · · s · $ s s -w *? '" .*B

(E.M., <m / z) CF 3) -SO 3 (consistent with the p-value of the free base 02)

Example 4b zin-4-yl) propanoic acid 5- (1-imidazolo [4,3-b] -1,4-

Phe-Leu H * | 'H * 5 HI · - * V-' V Ui! The corresponding free base (Example 4Ca> Compound 3g) was dissolved in methanol (1 ml), acidified with 5% hydrochloric acid diluted with water <25 ml) and was by freezing. This afforded the title compound &lt; Î'03 g) as a white powder, &lt; / RTI &gt; NMR (CDCl3):? (S, 1H)

(2H, m), 1.51 (2H, m), 2.01 (2H, m) (3H, m), 3.85 (m), 4.05 (m &gt;, 4.2 &lt; 2H, t) , 4.3 (1H, q &gt;, 4.55 (1H, m), 1.33 (1H, m). j (1H, d), 7.7 (1H, s), 7.8 (1H, s), 7.85 (1H, , 8.2 (2H, m), 8.35 (1H, d), 8.6 (1H, s), 8.1 (1H, s), 14.4 (b). M.S. (m / z) (FAB) = = SO3. the p 'm' of the free base - 802)

Example 5

The material was prepared from 2,3-dihydro-furo [2,3-b] pyridine-5-yl) -acetic acid-2-carboxylic acid [ 3-acetic acid (Description Ia) &gt; <0.14 g &gt;, following the procedure of Example 3 = This provided the title compound (0.25 g). NMR (DMSO-d6):? (b), 6.8 (1H, s), 7, &gt; -8 = &lt; tb &gt; 2H, m), (48.0), (14H, bs), 2.1 (2H, m), 2. 4.15-4.6 (3H, m), 1.32 (1H, m). FAB) = / 44 (consistent with pcI = = 743).

Example 6

5- (2,3-dihydro-2-oxo-1H-indol-4-yl) -5,5-bpyridin-3-yl] propanoyl-Phe-Leu-ACHPA

This material was formed from 2,2'-

3-propionic acid (Description 7 (d) (1051 g) and 3-C (imidazol-1-yl) propyl] amide (2: 1). Phe-Leu-ACHPA (Description 9 (b)) &lt; 0.40 g), followed by the binding procedure of Description 3b), but substituting N, N-diisopropylethylamine ( The crude product was purified by chromatography on silica gel using methanol / chloroform (0-103 (methanol, gradient) to give the title compound free base. This was dissolved in methanol &lt; 2 ml) a slight excess of 5M hydrochloric acid was added and the mixture was diluted with water (30 ml) and dried by freezing to give the title compound (0.19 g). NMR (DMSO-d6): Î'0.7-1.0 (8H, bs), 1.01 (1H, (2H, m), 2.15 (2H, m), 1.27 (2H, m), 2.15 (2H, m) * -? (1H, m), 4.5 (1H, m) = 7, θ (1H, dd), 7.1-7.4 (m, 1H), 7.7 (1H, d), 8.3 (1H, m), 7.7 (1H, s) (1H, m), 7.15 (1H, s), 11.15 (1H, s), 14.55 (1H, b) op * m * of the free base = 771>

EXAMPLE 7 3- (1-Imidazolyl) propyl] amino] -5- (3,4,5-biorgiridin-1-yl) oropanoyl-Phe · HCl

(2%) 3-hydroxy-Leu-ACHPA: o-1H-imi-

This material was formed from 2,3-dihydro-2-oxo-1H-imidazo [4,5-b] pyridine-1-propanoic acid (Description 8 <d)) (0.10 g), followed by of Example 6 This afforded the title compound &lt; 0.2 g) as a white powder.1 H NMR (DMSO): δ (m), 2.7 (1H, dd), Î' , 7.1 (2H, m), 2.1 (2H, m), 3.0 (3H, m), 3.85 (4H, m), 4.2 1 H-NMR (DMSO-d 6): δ 7.8 (1H, m), 7.1 (1H, m) (1H, s), (2H, m), 8.2-8.4 (2H, m), 9.1 (1H, s), 11.5 (1H, b), 14.55 &lt; 1H, b & gt , MS (m / z> (FAB) 771), 2 (consistent with oo, m, free bass

Exemplary 8

5-t-1-imidazolyl) propamide hydrochloride (5,5-dihydro-4-oxo-5,2-hrpyridin-5-yl) acetyl-Phe -Leu-ACHPA

This material was formed from 2,3-dihydro-4-oxofuro [3,2-b] pyridine-3-acetic acid-Phe-Leu-ACHPA (Example 5) (0.31 g), followed by the procedure of Example 2. After purification by chromatography, acidification and freeze-drying was effected in the manner described

in Example 6. C () K

(affords the title compound (0.12 to &lt; 2H, m +, 2H, m), 3.8-4.1 (3H, m), (12H, m), 8.2-8.5 (3H, m), 4.55 (2H, m), 2.75 (1H, m), 6.9 (1H, m), 7.17 (2H, m), 9.15 (1H, s), 14.7 (1H, b). E.M., m / 759). :) (FAB) with the free bass p.m.

Example 9

5- (2,3-Dihydro-1, 1,3-trioxo-4H-pyrido [3,4-b] -1,4-thiazin-4-yl) propanoic acid 5- (1-imidazolyl) -Phe-Leu-ACHPA

This material was formed from the acid,

2,3-dihydroxy-1,3-thyridyl; o-4H-pyrazolo [4,3-b] pyrid-4-yl] (0.053 g), following the procedure of Example 6. This afforded the title compound (0.098 g) as a white, off-white solid EMN CS) &lt; DMSOd 6); tJ 0.7-1.0 &lt; 8H, m), 1.0-1.5 (7H, m), 1.5-1.8 (7H, m &gt; 1.9 (2H, m) and 45 C 2H, m), 2.7 (1H, dd), 3.05 (3H, m), 3.85 &lt; 2H, bs &gt; (4H, m), 4.5 (2H, m), 7.14 (1H, m), 7.5 (1H, 35, 1H, d &gt; , 7.7 (1H, s), 7.8 (1H, s), 7.85-8.25 (1H, d), 8.4 (1H, d), 8.65-8.95 (1H, s). 9.1 &lt; 1H, s), 14.45 (1H, b). (FAB) = 834), 835 (consistent with the free base m.p. =

Example 10 3- (1-Imidazolyl) prooylamide HCl and 3- (2 = 3-hydroxythio-3-pko-4 H-

3-yl) propanoyl-Phe-Leu-ACHPft 6 ': 1 H-NMR (DMSO-d 6):? , m), 1.5 (7H, m), 1.5-1.8 (7H, m), 2.4 (2H, m), 2.7 (1H, dd) (1H, m), 3.65 (2H, m), 3.65 (2H, m), 3.65 (3H, m) 2H, t), 4.3

This material was formed from 2,3-dihydro-3-β-4-pyrido [2,3- b] -1 H -thiazine-4-propanoic acid (D- The procedure of Example 6 was repeated as a white solid (0.21 g). The title compound was obtained as a white solid (0.21 g). form a white solid, â € ƒâ € ƒâ € ƒ1-7.3 (6H, m), 7.45 (1H, d), 7.8 (1H, s), 7.9 (1H, m), 8.15 &lt; 1H , 7.65 (1H, d), 8.4 (1H, d), 9.15 (1H, s), 14.65 (1H, b)

^ ϋιτ ^ Ε.Μ. (FAB) = 3 Θ 3 (consistent with δ ρ of the free base 802).

Example 1 (a) HCl.1.5-4- (4-thiasin-4-yl) -3- (1-imidazolyl) prooylamid-4-yl) -4H-pyrido [2,3- b]

d and 3- (5 ', 3'-dlyhydro-1-1,3') oropanoyl-Phe-Leu-ACHPA

This material was formed from 2,3-dihydro-1,1,3-trioxo-4H-pyrido2,3-b3-i4-thiazir-4-propanoic acid (Description 12 <b> , 15 g), followed by the procedure of Example 6. This afforded the title compound (1.23 g) as a white solid.1 H NMR (DMSO-d6): Î'10.7-1 (8H, m), 1.0-1.9 HW (7H, m), 1.9 (2H, m), 2.15 (2H, m); (1H, dd), 3.83 (2H, bs), 3.95 (1H, t, J = 4.0 Hz) 4 '"? (2H, t), 4.54-5.59 (1H, m), 7.3-7.3 (6H, m), 3.74 (1H, d, 7.9 (3H, m), 8.05 (1H, m), 8.25 (1H, d), 8.4 (1H, d), 9.1 (1H, 1H, d): 30 =

Analysis 42 58 88 «HCl» 1 H 5 O requires 5-1.8 C 7 H, m), 3.05 (3H, m), 4.3 (1H, q), 7.7 &lt; 1H, s), (IH, d i, C i η 0 ', 0 5 N, • f · -> iC, q τ-3 in a

Found: 56.0 (s, 1H, H, (m / z) δ-AB) = 835 (consistent with the free base p =

Sc »4 5«

EXAMPLE 12 3- (1-Imidazolyl) propyl] imidazolidin-1-yl) -biphenyl-6-i-1 This material

(6β-dihydroxy) butanoyl-Pbe-Leu-ACHPA-OKO-5H · was formed from 6,7-dihydro-5α-5α-5β-pyrrolo [ 4-ph-3-pyridine-6-butanoic acid &lt; (15 g), following the procedure of Example 6 This afforded the title compound (0.14 g) (NMR (DMSO-d 6): δ (DMSO-d 6): δ (3H, m), 1.5-1.8 (8H, m), 2.7-3.3 (1H, m), 1.5-1.8 (8H, m) 3.4 (1H, m), 3.8 (2H, m) 4.1-4.5 &lt; oH, m), 4.5-5.4 (m), /, 1-7.6 &lt; / H, m &gt; &lt; 1H, d), 9.1 (1H, s), 14.6 (1H, b). . (FAB) = 785 (consistent with free base salt = 784), m.p.

Example 13

3- (6,7-dihydro-7-oxo-5H-pyrrolo1,5,5-bipyridin-6-yl) butan-1-ylhexane

This material was formed from 6,7-dihydro-7-oxo-5H-pyrrolo3,3-bpyridine-6-butyric acid (Description 14Cc)) &lt; 0.12 g), followed by Example 6 This afforded a title compound &lt; 0.09 g, &lt; 3 &gt; NMR (DMSOd6): 0.7-1.0 (is> H, m), 1.0-1.4 &lt; 6H, m), 1.4-1.8 (8H, m), o '..... . 1.9 (2H, t), 2.0-2.1 <3H, m), 2.7 (1H, t), 2.9-3.1 (3H, m), 3.4-3 , M), 3.6 (2H, m), 4.1-4.6, 4.6-5.1 (m), 7.1-7.4 &lt; 6H, m), &lt; / RTI &gt; 7.7 (1H, s), 7.8 (1H, s), 7.9 (1H, t), 8.05 (1H, d), 8.2 (2H, m), 8.7 &lt; (M / z) (FAB) 784), 85 85 (consistent with m.p. of the free base -

Î'-Methoxy-5- (1-imidazolyl) propylamide.SH- [6,7-dihydro-7-oxo-

1-ol-5-ol-6-yl) -butanoyl-Phe-Leu-hCHPA

This material was formed from 6,7-dihydro-5H-7-aza-pyrrolo [3,4-c] pyridine-6-fauanoic acid (Description 15 (c>) (0.19 g), followed by The title compound was obtained in a similar manner to that described in Example 6. This afforded the title compound (1.28g). NMR (DMSOdd): 2.03 (m, 2H) EXAMPLE 15 3- (1-Imidazolyl) -8H-1,8-naphthyridin-8 (1H, bs). -yl) butanoyl-Phe-Leu-ACHPft

This material was formed from 7-oko-5,6,7,8-tetrahydro-1H-1,8-naphthyridine-8-butanoic acid (Description 16 (b)) (0.66 g) (0.1 g, 8.3 mmol), and 4.5 (S) (DMSO-d6): δ 0.65-1.02 (4H, m) m), 2.6 (2H, dd), 7.0 (1H, m), 7.2 (ΒΗ, ιτ?), Ι, Θ -1.5 C16H, m &gt; 3.8 (2H, m), 7.3-7.55 (1H, m), 1.32 (2H, m) 4H, m), 7.6 (1H, d)

14.5 (1H, b). (FAB) = 799 (consistent with δ p "m" free base = 798). E κ is f 16

3-yl-1H-1,5-naphthyridin-5-yl) butanoyl-Phe-3-carboxylic acid (3-chlorophenyl) Leu-ACHFA isomerase was formed from 7Î ± -tetrahydro-5H-1,5-naphthyridine-5-hutanoic acid (Description 17b)) (Θ, 12 g), following the procedure of Example 6. This afforded the title compound (Î', 23 g â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ2 H-NMR (300 MHz, , m), 7.4-7.6 (11H, m), 8.15-8.38 (1H, m), 7.45 (1H, d) m), 1.8-2.8 (16B, m), 1.9 (2H, m, 2.1 (4Hsm), 2.8 (2H, .6 (1H, m), 7.65 (1H, s), 9.15 (1H, the pm of the base free = 798).

Example 17a "DHD-

• Imidazolyl) propylantide »H * -, U

3-pyridyl-6-yl) -pentanoic acid-Phe-Leu-oxo-4,5,6,7-tetrahydroisoquinoline 0 .t xa -1. iJ d &quot; column on

This material was formed from 6β-tetrahydro-6β-thieno [2,3-c] pyridine-6β-18β (fa)), followed by the crude product by purity chromatography

X X s i 1 i CS gel, taking ut. Methanol / 1.6 g of methanol / chloroform, gradient). δΓδ SB oht er the ta compound. NMR (DMSO-d 6): δ 0.7-1.9 (29H, m), Î'-C-Î ± and <4H, m) or (6H, m), 3.5 &lt; (1H, m), 4.5 (1H, m), 4.0-4.9 (2H, m), 3.8 (2H, m) 1H), 6.9 (1H, d), 1H, di (d), 2H), 7.2-7.3 (5H, m), 7.5 (1H, 1 H-NMR (CDCl3): Î'0.8 (2H, m), 2.85 (2H, m) EXAMPLE 1: Preparation of the compound of the general formula: ## STR1 ## in which the compound of the formula ## STR4 ## is replaced by the following: Found: C, 63.2; N, 11 RV to L '1ib to E &gt;; 17b of

3-yl-imidazolyl) -amide:

(2-chloro-2,3-dihydro-1H-imidazol-1-yl) -piperazin-1-one;

This material was formed from the corresponding free base (Example 17 (3)), following the procedure of Example 4 < b) &quot; 1 H-NMR (DMSO-d 6): δ (5H, m), 7.9 (1H, m), 7.9 (1H, M), 2.1-2.3 (5H, m), 2.7-3.1 3.5 (2H, q &gt;, 3.9 M), 7.2-7.3 &lt; 5H, m), 7.4 (1H, d), 7.6 &lt; 1H, d &gt; , 7.7-7.8 (2H, m), 7.9 (1H, s), δ, β-8.3 (2H, &lt; n), 9.1 (1H, s), 14.5 (1H, bs).

The title compound was prepared from the title compound as a colorless oil, mp Found: C, 59.88; H, 59.9; N, 11.1%.

Example 5 5- t-imidazolyl) propylamide, 4-pko-5 ', 3', 4 ', 5-tetrahydro-

(5-Bromo-5-furan-5-yl) propanoic acid PhH-Leu ACHPA

This material was formed from 3S4-dihydro-4-o-2H-pyrrole-3-yl-4-thiazepine-5-propanoic acid (Description 19)) s followed by the procedure of Example 3 =

Example 19

Imidazolyl) propylamide of 3-C2-C3-C6-C4-oxazin-4-yl) propanoyl-Phe-Leu

dihydro-ACHPA ΌΧΟ-

Jt! "I1! ρχτ

Hr) -

This material was formed from 3-oxo-4 H -pyrido [2,3-b] -4,4-oxazine-4-propanoic acid following the procedure of Example 3: 2- [3-

Example 2: 3-Cyclohexyl) propylamide pyrido [4,3-b] -1,5-thiazepin-5-ol 3- (4-oxo-2,3,4,5-tetrahydro-4-oxo) nj

This material was formed as a white solid. 2 H-pyrido [3,4-b] -1,4-diazepine. The process of Example 3 is followed by the procedure of Example 3.

Example 21 5- (1-Imidazolyl) propylamide of C₂₂, δ-d ihyd r o · k or β-H or

14,5-h3-1-a4-oxazin-4-yl) Dropanoyl-Phe-Leu-AuHPA acid

This material was formed 1

1a-Fhe- &quot; Leu ~ ACHPA ψ

2,3-b] -1,4-oxazin-4-propanoic acid methyl ester (Description 22 <b> g), followed by The title compound was prepared as in Example 3.

Biological Data

In vitro inhibition of human renin The renin inhibitory activity was estimated as the percentage change in renin activity in human plasma in the presence and absence of the compound. The source of plasma was blood drawn from healthy volunteers. defined by the difference in angiotensin I levels between two halves of a sample, one incubated at 37 ° C and the other at 4 ° C for 2 hours. Angiotensin I levels were measured by the use of a radioimmunoassay- The results were calculated as the mean of the last two, where the duplicate determinations and the IC values were calculated by linear regression analysis of hair at least three concentrations of compound

The results were as follows:

Compound E2 E3 4 Ε1Θ Eli Ei4 6 12 14

Claims (3)

A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof; Θ / 5'1 n /, ECONHCHCONHCHCONHCHCH (CH) ZC4 4 | In which the ring Hei has the formula (a) or (b); (b) in which one or two of W3 and W3 is N or NO (such that if two are NO, then these are and W2>, and the others are CH3, Q., 0-¾ and Q- * is S and the other two are CH 2 and CR 2 are both Z 1 and Z 1 are absent and Z 1 and Z 2 are the I and Z atoms. Carbon atoms which form a 5-membered non-aromatic heterocyclic ring or Z is absent and Z 1, Z 2, Z 2, Z 2, are in the form of a non-aromatic heterocyclic ring of &quot; membered &quot; or &quot; Z, Z, Z &quot; to the carbon atoms to which Z 1 and Z are - Linked heterocyclic ring form a 7-membered non-aromatic heterocyclic ring E is absent or is &lt; Ct-L) or &lt; / RTI &gt; , wherein n ranges from 1 to 2, wherein r is 1 or 2, or -CH 2 - p is 1 or 2 is 1, 2, 3, or 4, which is 0 or 1, R is hydrogen, C1-4 alkyl, or when A is -CH2 -, hydroxy, are independently selected from hydrogen and a b substituent: in which R3 is optionally substituted aryl or heteroaryl is wherein R3 is hydrogen or methyl and R2 is C1-4 alkyl; C _ ciclo ciclo cycloalkyl, optionally substituted aryl or heteroaryl, or [k S S S] alkanoylamino 2-O-isopyrrolidinyl, 2-o-piperidinyl or alkoxycarbonylamino, wherein R 2 is C 1-6 cycloalkyl or phenyl; is C1-6 alkyl, cycloalkyl a saturated or unsaturated heterocyclic ring bonded through a carbon atom, hydroxy, C1-6 alkoxy, C1-6 alkanoyl, C1-4 alkanoylamino, amino substituted by one or two groups C? alkylsulfanyl carboxy, alkoxycarbonyl, C1 -C4 alkoxycarbonyl, aminocarbanyl or CH <NHR <R <R <R <R <R <R <R < Ra is a saturated or unsaturated hetero-cyclic ring attached through a nitrogen atom and the dotted line represents an optional bond (when E is present) which comprises reacting a reactant of formula (III) (III) in which H '' is Het as hereinbefore defined but wherein R 'and R' are R '' and R '' are R 'and R' '' '' '' '' '' ha is absent or represents an aproporyl amino acid or a dipeptide unit J is OH or a leaving group and the remaining variables are as defined above with a reagent of formula &lt; A V &gt; s (IV) in which A 'is absent or represents a suitable aromatic acid or a 1' dipeptide unit such that A 'is an amino acid or a pharmaceutically acceptable salt thereof; and the variables VaaScentss are as defined above and then, if desired or necessary, the deprotection (within A 2 or 3 of the products) and / or the conversion of Î ±: Z R 2, R 3, R 4 and R 5 are independently selected from the group consisting of halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, The present invention relates to a pharmaceutically acceptable salt thereof. 21. A process according to claim 19 characterized in that Z "and Z" are absent, Z is CO, Z "is M, Z, and X is Z-linked. A process according to claim 1, characterized by the Het ring having the formula &lt; a &gt; 5 W-j. be N and W1 * W "and W" are CH, CR2 or CR2 Z2 are absent. Z0 is S = Z-, C4, Process according to any one of claims 1 to 3, which is characterized by one of Ra and Rh in the sub-formula tb> R4 is hydrogen and the other is CH3 W3 -L-> COâ,,H or CHâ,ƒNHCHâ,,COâ,,H; or R1. in the sub-formula (b) is hydrogen, ψ The title compound was prepared according to the procedure described in Example 1 for the preparation of the title compound. The reaction is carried out in a manner similar to that described in Example 1, in which R 2 is as defined above. 0, [3], [4] and [5]. U Liil walks out of this way. X-S. &lt; I A) Or. (S) - (S) - (S) - (S) - (S) -N- (IA) in QU.S. X X is Phe Y is Leu R, 1 '- · 1 ·! is C V is -0. _ , _ 1 . w or s is; at 4 and K "e; carboxy or unsubstituted and unsaturated quaternary ammonium salts are as defined in any one of claims 1 to 4, in which: of Claims 1 and 2 wherein E is C ^)) s alkyl, Frog 1 4 or 1. A process according to any one of claims 1 to 3 characterized in that the sequence from R- which contains the acidic acid or K_. A process as claimed in any one of claims 1 to 8, characterized in that s is 0 and is isobutyl or is 4, 3 or 4, or is unsubstituted or substituted or unsubstituted. . 4 and R "is imidazolyl, 2-imidazolyl, 4-morpholinyl, 2-oxopyrrolidin-1-yl, 2-pyridyl, 2-pyridyl, N-oxido, 3-pyridyl, hydroxyethyl acrylamide? A process according to any one of the preceding claims, characterized in that a compound selected from the group consisting of 2'-dihydrofuro [3, 4, 5, 6, 2,3-dihydro-4-oxofuro [3,5-b] pyridine-3-acetyl-Phe-Leu-AACHPs 3- &lt; 1-imidazolyl) propylamide of 253-dihydro-3-oxo-4H-pyrido- Γ. 3,2-b] -1,3,4-oxadiazol-4-propanoyl-Phe-Leu-AACHP; (1-imidazolidin-1-yl) propionamide of 2â € ²-2,3-dihydro-5-3- (4-thiazine-4-propanoyl-Phe-Leu-AACHP if-β-4H-pyrido3-C1-imidazolyl) propylamide. 2,3-dihydro-2,3-dihydro-2-oxo-1H-imidazo [4,5-b] pyridine-3-carboxylic acid [3- pyridin-3-propanoyl-Phe-Leu-AACHP, 3-propoxy-1H-imidazole-3-carboxylic acid 3-propoxy- AACHP 3- &lt; 2,3-dihydro-4-oxo-3,4-dihydro-3-acetyl-3-acetyl-β-Lys-AACHP (3- (1-pyridazolidinyl) 3-trio-4H-pyrrolo [3,4-c] [1,4] thiazine-4-propanoyl-Phe-Leu-AACHP; 3 <&lt; 1-yl] isoxazol-1 &gt; 3-oxo-4H-pyrido [2,3-a] pyrimidin-4-yl] -propionamide; Methyl-3- (1-imidazolyl) -2,3-dihydro-1H-pyrrolo [2,3-b] [1,4] diazabicyclo [ propanoyl-β-Phe-Leu-AACHP 9 3- (1-imidazolyl) propyl ester of α-7-dihydro-5-oxo-5H-pyrrolo [3,4-b] pyridine- 6-butanoyl-Phe-Leu-AACHP 6β-Dihydro-7-O-O-5H-pyrrolo [3,4-b] pyridine-6-carboxylic acid 1-Phe-Leu-AACHP 3 657-dihydro-5H-7 &quot; -OKO-pyrrolo [3,4-c] pyridazine-6-butanoyl-Ph s-Leu-AACHP5 3-C 1-imidazolyl) propylamide 7-O-O- -6-Amino-5,6,7,8,7-tetrahydro-5 H -pyrazolo [1,5-a] pyrimidine-4-carboxylic acid [ 1,5-naphthyridine a-5-butoxy-Phe-Leu-AACHP 3 3-C-imidazolyl} propylamide of 7-amino-5 s and 3,7,8-tetrahydra- thieno [3,2-c] pyridine-6-carboxylic acid-1-hep-AACHP, 3- (4-azahydro-4-oxo-2H-pyridyl) -3- L2 is hydrogen; 4-thiazepine-5-prooanoyl) -Phs-Leu-AACHP, 2,3- (1-imidazolyl) propylamide of 2- [4-oxazin-4-propanecar-Phe-Leu. 4H-pyrrolo [3,2-c] imidazolyl) propylamide as a white solid. 1-imidazol-1-yl) propylamide-b 3-13-dihydro-Leu-AACHP and 2-methyl- 4-c? A method for the treatment of hypertension, characterized by administering a composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, which contains the compound obtained according to any one of claims 1 to 10, for example in unit doses from 1 to 6 times per day such that the dosage is from 1 to 1 mg for an adult of 70 kg, preferably from 5 to 5 € 10 mg »Lisbon, August 6, 1990 JL PEREIRA DA CRUZ Official Agent of Proprietee Industrial fftUA VICTOR CORDON, 10-A 3 "1200 USBOA