AU642021B2 - Amino acid derivatives - Google Patents

Description

S F Ref: 183081

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT S R 9 0*

S.

0 0e@ *0 S S *5

S

S.

Name and Address

ORIGINAL

0 5 .15 4~e .0~S S S *5 0

U.

S. 55 S. SO 0** C. 0

S.

S.

of Applicant: Actual Inventor(s): F.Hoffmann-La Roche AG 124 Grenzache -strasse CH-4002, BaselI

SWITZERLAND

Quirico Branca, Marie-Paule Heitz, Marcel Muller, Wei-ner Noidhart, Heinz Stadler, Eric Vieir-a and Wolfgang Wosti Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Males, 2000, Australia Amino Acid Derivatives Address for Service: Invention Title: The fol loqiing statement i s a full1 descri ption of thi s i nvention i ncl udi ng the best method of performing it known to me/us:- 5845/7 RAN 4019/111 S C 9 50

S

OS4 *0 S C C 0C 9055 9 0 5* 0

S.

900 0099 95 90 S 9* 0 9 0955 So..

S

099 00 S 9 *5 The present invention is concerned with amino acid derivatives. In particular, it is concerned with -iino acid derivatives of the general formula A-B 0 R 4

NRN

15 wherein one of A and B signifies a nitrogen atom and the other signifies -CH- or both signil.y a nitrogen atom, one of X and Y signifies a nitrogen atom and the other signifies -CH- or both signify R1 signifies phenyl, pyridyl or thienyl, R 2signifies alkyl or arylalkyl. R 3signifies hydrogen, alkyl, imidazol-2-ylmethyl, imidazol-4-ylmethyl, pyridylmethyl, pyrazol-3-ylmethyl, thien-2-ylmethyl, thiazol-4--ylmethyl. alkylthiomethyl, carbamoylinethyl, carbamoylethyl or benzyl, R 4signifies cyclohexyl- 25 methyl. benzyl or isobutyl and R 5signifies one of the groups -(CH)m-R 6

P,)

and in which, R 6signifies cycloalkyl. alkyl, alkenyl or .5.91 2 arylalkyl, m signifies the number 2 or 3 and n signifies the number 3 or 4, in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts of these compounds.

These compounds are novel and are distinguished by valuable pharmacodynamic properties.

Objects of the present invention are the compounds of formula I and their pharmaceutically usable salts per se 15 and for use as therapeutically active substances, the manufacture of these compounds, medicaments containing these and the manufacture of such medicaments, as well as the use of compounds of formula I and their pharmaceuti- Scally usable salts in the control or prevention of ill- 20 nesses or in the improvement of health, especially in the control or prevention of high blood pressure and cardiac insufficiency.

The term "alkyl" used in the present description.

25 alone or in combination, signifies straight-chain and branched hydrocarbon residues with 1-8, preferably 1-4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl.

n-butyl, isobutyl, sec.-butyl. t-butyl, pentyl, hexyl and the like. The term "alkoxy" signifies alkyl ether groups in which the term "alkyl" has the above significance, such as methoxy, ethoxy, propcxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t-butoxy and the like. The term "cycloalkyl" signifies saturated, cyclic hydrocarbon residues with 3-8, preferably 3-6. carbon atoms such as cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "alkenyl" relates to straight-chain and branched, unsaturated hydrocarbon residue with 2-8, preferably 2-4, carbon atoms such as vinyl, allyl, 2- 3 -butenyl, 3-butenyl and the like. The term "alkanoyloxy" signifies the acid residue of a straight-chain or branched alkanoic acid with 1-8. preferably 1-4, carbon atoms attached via an oxygen atom, such as formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, isovaleryloxy and the like. The term "arylalkyl" denotes straight-chain or branched alkyl groups in which in which one or more hydrogen atoms have been replaced by aryl groups, whereby the term "aryl" signifies a mono- or bicyclic aromatic hydrocarbon residue with 6-14 carbon atoms which is optionally mono- or multiply-substituted by alkyl, alkoxy, alkanoyloxy. amino, alkylamino, dialkylamino, alkyl- 15 carbonylamino, hydroxy, halogen, trifluoromethyl or nitro.

such as phenyl. a- or B-naphthyl. indenyl, anthryl or phenanthryl and the like. Examples of arylalkyl groups are benzyl, diphenylmethyl. trityl, a- or B-naphthylmethyl. 2-phenylethyl, 3-phenyl-2-propyl. 4-phenyl-3- 20 -butyl, or B-naphthyl)ethyl. 3-a-naphthyl-2- -propyl. 4-a-naphthyl-3-butyl and the like, whereby the aromatic residue can in each case be mono- or multiply- -substituted as indicated above.

25 The term "pharmaceutically usable salts" embraces salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid. tartaric acid, methane- 30 sulphonic acid, p-toluenesulphonic acid and the like.

Such salts can be manufactured readily by any person skilled in the art having regard to the state of the art and taking into consideration the nature of the compound to be converted into a salt.

The ,ompounds of formula I have at least three asymmetric carbon atoms and are therefore present in the form of optically pure diastereomers, mixtures of diastereo- 4 mers, diastereomeric racemates or mixtures of Ciastereomeric racemates. The present invention embraces all forms. Mixtures of diastereomers. diastereomeric racemates or mixtures of diastereomeric racemates can be separated according to usual methods, e.g. by column chromatography, thin-layer chromatography, HPLC and the like.

Those compounds of formula I in which A and B each signify a nitrogen atom are preferred. X preferably signifies a nitrogen atom and Y preferably signifies Compounds of formula I in which R signifies 2 15 pyridyl, especially 3-pyridyl, are also preferred. R preferably signifies alkyl or phenylalkyl. especially propyl, isopropyl, isobutyl, 1-methylpropyl or benzyl.

The preferred meaning of R 3 is hydrogen, imidazol-2-yl- S" methyl, imidazol-4-ylmethyl or pyridylmethyl, especially 20 imidazol-4-ylmethyl or pyridyl-3-methyl. Cyclohexyl- 4 methyl is the preferred meaning for R R preferably signifies group The preferred meaning for m is the number 2 and the preferred meaning for R 6 is cycloalkyl.

25 From the above it follows that there are particularly preferred those compounds of formula I in which A, B and X each signify a nitrogen atom, Y signifies R signifies 3-pyridyl. R 2 signifies propyl, isopropyl. isobutyl, 1-methylpropyl or benzyl. R signifies imidazol- 30 -4-methyl or pyridyl-3-methyl, R signifies cyclohexylmethyl and R signifies group in which m signifies the number 2 and R 6 signifies cycloalkyl.

Especially preferred compounds of formula I are: (R or S)-N-[(lS,2R.3S)-l-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-propyl-a,6-bs(3-pyridyl)-striazolo[4,3-a]pyrazine-3-acetamide, (R or S)-]N-[(1S,2R.3S)---(cyclohexylmethyl)-3-cyclopropyl-2.3-dihydroxypropyl--isopropyl-a- (imidazol-4-ylmethyl)-6-(3-pyridyl)-s-triazolo[4.3-apyrazine-3-acetamide.

(R or S)-N-[(1S.2R.3S)-V-(cyclohexylmethyl)-3-cyclohexyl-2. 3-dihydroxypropyl]3-oL- (imidazol-4-ylmethyl -isobutyl-6-(3-pyridyl)-s-triazolo[4 1 ,3-apyrazine-3-acetate (R or S)-N9-[(1S.,2R.3S)-l-(cyclohexylmethyl)-2.3-dihydroxy-5-methylhexylj-8-propyl-6-(3-pyridyl)-a-(3-pyridylmethivl)-s-triazolo[4. 3-a]pyrazine-3-acetamide.

(S or R)-N-[(lS,2R.3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2.3-dihydroxypropyl]-8-[(RS)-l-methylpropyl]-a-(3- -pyridylmethyl)-6-(3-pyridyl)-s-triazolo[4.3-a]pyrazine-3- 15 -acetamide and N-[(1S.2R.3S)-l-(cyclohexylmethyl-3-cyclopropyl-2.3- -dihydroxypropyl]-B-[(RS)-l-methylpropyl]-6-(3-pyridyl)-s- -ti i.azolo[4. 3-ajpyrazine-3-carboxamide.

20 The compounds of formula I in the form of optically pure diastereomers, mixtures of diastereomers. diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmiaceutically usable salts thereof can be manufactured by a) reacting a compound of the general formula 0S50 R 4

*H

2 N R pi wherein R 4and R 5have the significance given above.

with a compound of the general formula 6 A--B 0 R2 N OH X Y R 3

III

RI

wherein A. B. X. Y, R 1

R

2 and R 3 have the significance given above.

or an activated derivative thereof, and 15 b) if desired, separating a mixture of diastereomeric racemates into the diastereomeric racemates or optically pure diastereomers. and/or c) if desired, separating a mixture of diastereomers into 20 the optically pure diastereomers, and/or d) if desired, converting a compound obtained into a pharmaceutically usable salt.

25 The acylation of a compound of formula II is effected S, according to methods known per se. Especially suitable 9 e ea" acylating agents are activated acid derivatives such as esters, mixed esters, acid halides and acid anhydrides or mixed anhydrides. The reaction is carried out in an 30 organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about O'C and room temperature. As solvents there come into consideration especially aromatic hydrocarbons such as benzene, toluene or xylene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether, tetrahydrofuran or dioxan, and the like. The reaction is effected under reaction conditions which are 7 usual in peptide chemistry, i.e. preferably in the presence of a condensation agent such as HBTU (O-benzotriazolyl-N.N.N' .N'-Letramethyluronium hexafluorophosphate). BOP (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate). BOPC (bis(2-oxo-2-oxozolidinyl)phosphine chloride), HOBT (N-hydroxybenzotriazole), DBU (1.8-diazabicyclol5.4.O]-undec-7-ene). DCC (dicyclohexylcarbodiimide). EDC (N-ethyl-N'(3-dimethylaminopropyl)carbodiimide hydrochloride). Hlnig base (ethyldiisopropylamine), and the like. The reaction is conveniently carried out in an organic solvent or solvent mixture which is inert under the reaction conditions at a temper- 15 at.ure between about 0OC and 50 0 C. preferably at about room temperature. As solvents there come into consideration especially dimethylformamide, methylene chloride, acetonitrile, tetrahydrofuran, and the like.

The starting materials of formula II in which R signifies group wherein m signifies the number 3. or group are novel and are also an object of the present invention. They can be prepared, for example, by cleaving off the amino protecting group and simultaneously also the O-protecting group in a compound of the general formulae

OH

R

4 OH R OH

R

6

(CH

2 )n B-N

B-N

30 0 OH and OH IV V wherein B sigifies an amino protecting group, prefer- 4 ably t-butoxycarbonyl or benzyloxycarbonyl, and R R6 and n have the significance given above.

8 The cleavage of the N-protecting group and O-protecting group is also effected according to methods known per se, for example in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0 C and room temperature using an acid such as hydrochloric acid, trifluoroacetic acid, and the like. Suitable solvents are ethers such as tetrahydrofuran or dioxan, alcohols such as methanol or chlorinated hydrocarbons such as methylene chloride, and the like. Under these reaction conditions the oxazolidine ring is, as already mentioned, simultaneously cleaved.

The starting materials of formula II in which R signifies group wherein m signifies the number 2, are 15 known or can be obtained in analogy to the preparation of r the known compounds.

S S o The compounds of formulae IV and V are also novel and are objects of the present invention. They can be prepared according to different methods known per se starting from compounds of formula VI. These preparative S procedures are compiled in Scheme I hereinafter. In this Scheme Met signifies a metal such as lithium or magnesium 4 6 S* and L, R R and n have the significance as given 25 above. With respect to the precise reaction conditions reference is made to the experimental section.

*S

9- Scheme I B-HN

K

1 1

H

0

I

4b

B

B.

B.

B

eBB

C

a

B.

C C C BB

B.

B

B*B

B

BB.* Ca 'a B B B. 0 R4 B-Ni 20 oVill 25 A-0I

R

4 O H B-N CN A- xIv 4

S

BBO

B. B B C

B.

IR

4

OH

R

4 OH A BN/K<KR6

XV

AT -o

OH

IV

The starting materials of formula III in which A. B and X each signify a nitrogen atom and Y signifies -CH- are known from EP-A 0.369.743 or can be obtained in analogy to the preparation of the known compounds.

The remaining compounds of formula III are also novel and are an object of the present invention. They can be prepared starting from corresponding pyrazinones. pyridazinones and pyridinones according to various methods which are known per se and which are in part analogous to the process described in EP-A 0.369.743. These preparative procedures as well as the process according to EP-A 15 0.369.743 are compiled in Schemes II-IV hereinafter. In S1 2 these Schemes R signifies alkyl and A. B, R R and 3 R have the significance given above. The pyrazinones of formula XVI in Scheme IT and the pyridazinones of formula XXIV in Scheme III as well as their preparation 20 are described in part in EPA 0.369.743 or Chim. Ther.. 6, 109 (1971) or can be obtained in analogy to the preparation of the known compounds. The pyridinones of formula XXXII in Scheme IV are novel, but belong to a known class of substance. They can be prepared in analogy to the preparation of the compounds described in Tetrahedron 25 Letters 1974. 1183 and Arch. Pharm.. 317. 183 (1984).

N *e t*oo 11 Scheme II 0

R

2 Y,111

NH

RIM

R

2

N

xN 00 *9 C 9O

S.

A..

S. A

S

Ct ,g S.

eq SS 6 0O 0&

HN-NH

2 R2

N

CN

P

2

N

XIX

NH

2

R,

S

COO*S

0 S*S

OS

LI S 59 Ce C vgl. EPA 0. 369. 743 A1I

SOSO

C

~S 0*

S.

H

2 N COOR -N N1R

R

2 COOH nan

N~R

N R3 12 Scheme III 0 R2

NH

AXXIV

S S

SS

S.

El *ee

S

5 0 S 56 S S S. S

S.

S.

OS*

CI

R

2

N

N I

N,

xxv

HN-NH

2 2I

N

R, xxvi

ON

R

2 N

NH

2

R

2

I>N

N

1

~I

NH

2 R2

N

11

N

1

XI

0 0S@S 0O 65 S

S.

5 0 5556 5505

S

S

5 0 R2 N

COCH/

RiMb

N

R2 N COOR N R, /xx J3 Scheme IV 7 6 6 66 66.

6 6@ 66 6666 S 6 6* 0 06 6 6*0 xxxiII

HN-NH

2 ON

R

2 N

IN

XXXIV R 1 yol 6 60600* 6

S..

OS

66 q~ *0 6 6 6606 6606 666 66 6 0 6 66

R

2 Uxv R

NH

2

R

2

N

I-

RXXXVIII

f

R

2

,OOR

k, XXXIX 14 The compounds of formula I and their pharmaceutically usable salts have an inhibitory activity on the natural enzyme renin. The latter passes from the kidneys into the blood and there brings about the cleavage of angiotensinogen with the formation of the decapeptide angiotensin I which is then cleaved in the lungs, the kidney, and other organs to the octapeptide angiotensin II. Angiotensin II increases the blood pressure not only directly by arterial constriction, but also indirectly by the liberation of the sodium ion-retaining hormone aldosterone from the adrenal gland, with which is associated an increase in the extracellular fluid volume. This increase is attributed to the 15 action of angiotensin II itself or to the heptapeptide angiotensin III which is formed therefrom as a cleavage product. Inhibition of the enzymatic activity of renin brings about a decrease in the formation of angiotensin I and as a consequence thereof zhe formation of a smaller 0eo amount of angiotensin II. The reduced concentration of this active peptide hormone is the actual reason for the blood pressure-lowering activity of renin inhibitors.

The activity of renin inhibitors can be demonstrated experimentally by means of the in vitro test described hereinafter: In vitro test with pure human renin The test is carried out in Eppendorf test tubes. The incubation mixture consists of 100 u1 of human renin 0 30 in buffer A (0.1M sodium phosphate solution. pH 7.4, containing 0.1% bovine serum albumin. 0.1% sodium azide and 1 mM ethylenediaminetetraacetic acid), sufficient for a renin activity of 2-3 ng of angiotensin I/ml/hr.; (2) 145 ul of buffer A; 30 .1 of 10 PM human tetradecapeptide renin substrate (hTD) in 10 mM hydrochloric acid; 15 Il of dimethyl sulphoxide with or without inhibitor and 10 Ll of a 0.03 molar solution of 15 hydroxyquinoline sulphate in water.

The samples are incubated for three hours at 37 0 C or 4 0 C in triplicate. 2 x 100 ±l samples per experimental test tube are used in order to measure the production of angiotensin I via RIA (standard radioimmunoassay; clinical assay solid phase kit). Cross reactivities of the antibody used in the RIA are: angiotensin I 100%; angiotensin II 0.0013%; hTD (angiotensin I-Val-

T

le-His-Ser-OH) 0.09%. The production of angiotensin I is determined by the difference between the experiment at 37 0 C and that at 4 0

C.

CS

15 The following controls are carried out: 0 Incubation of hTD samples without renin and without inhibitor at 37 0 C and 4°C. The difference between these two values gives the base value of the angiotensin I production.

Incubation of hTD samples with renin, but without inhibitor at 37°C arl 4 0 C. The difference between these f, 0 .c 0: values gives the maximal value of angiotensin I production.

*9 In each sample the base value of the angiotensin I production is subtracted from the angiotensin I production which is determined. The difference between the maximal 'value and the base value gives the value of the maximal substrate hydrolysis 100%) by renin.

The results are given as IC values which denote that concentration of the inhibitor at which the enzymatic activity is inhibited by 50%. The ICSO values are determined from a linear regression curve from a logit-log plot.

The results obtained in this test are compiled in the following Table: 16 Tabl1e Compound IC 50value in nmol/lt

A

B

C

D

E

F

:0.

0 to A (R cr S)-N-[(lS,2R.3S)-l-(Cyclohexylmethyl)-3-cyclopropyl-2. 3-dihydroxypropyl)-8-propyl-i. 6-bis (3- -pyridyl)-s-triazolo[4.3-a)pyrazine-3-acetamide.

B or S)-N-[(lS,2R,3S)-l-(Cyclohexylmethyl)-3-cyclopropyl-2. 3-dihydroxypropyl]--8-isopropyl-ct-(imidazol-4- -ylmethyl)-6-(3-pyridyl)-s-triazolo[4.3-a]-pyrazine-3- -acetamide.

C (R or S)-N-U1lS.2R,3S)-l-(Cyclohexylmethyl)-3-cyclohexyl-2.3-iyrxpoy c-imdzl4ymty)8 -isobutyl-6-(3--pyridyl)-s-triazolor4,3-a~pyrazine-3- -acetate.

55

S

.SSS

S S S. S D (R or S)-N-[(lS,2R,3S)-l-(Cyclohexylmethyl)-2.3-dihydroxy-5-methylhexyl]-8-propyl-6-(3-pyridyl)-a-(3- -pyridylmethyl)-s-triazolo[l",3-alpyrazine-3-acetamide.

E (S or R)-N-[(S,2R.3S -l-(CyclohexyluieLhiyl)-3-cyclopropyl-2.3-dihydroxypropyl]-8-( (RS)-l-methylpropyl)- -iL-(3-pyridylmethyl)-6-(3)-pyridyl)-s-triazolo[4. 3-a)pyrazine-3-acetamide.

17 F N-[(1S,2R,3S)-l-(Cyclohexylmethyl)-3-cyclopropyl-2,3- -dihydroxypropyl]-8-[(RS)-l-methylpropyl]-6-(3-pyridyl)s-triazolo[4,3-a]pyrazine-3-carboxamide.

The compounds of formula I as well as their pharmaceutically usable salts can be used as medicaments, e.g.

in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered enterally such as orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft qelatine capsules, solutions.

emulsions or suspensions, nasally, e.g. in the form of nasal sprays, or rectal'y, e.g. in the form of suppositories. However, the administration can also be effected 15 parenterally such as intramuscularly or intravenously, e.g. in the form of injection solutions.

For the manufacture of tablets, coated tablets, dragees and hard gelatine capsules the compounds of formula I as well as their pharmaceutically usable salts can be processed with pharmaceutically inert, inorganic or organic excipients. Lactose, maize starch or derivatives o; thereof, talc, stearic acid or its ialts etc can be used as such excipients for e.g. tablets, dragees and hard 25 gelatine capsules.

Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.

Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.

Suitable excipients for injection solutions are e.g.

water, alcohols, polyols, glycerol, vegetable oils etc 18 -Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.

Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers, viscosity-increasing substances, stabilizing agents, wetting agents, emvlsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.

15 In accordance with the invention the compounds of general formula I as well as their pharmaceutically usable 4* salts can be used in the control or prevention of high blood pressure and cardiac insufficiency. The dosage can vary within wide limits and will, of course, be fitted to the individuial requirements in each particular case. In general, in the case of oral administration there should suffice a daily dosage of about 3 mg to about 3 g, preferably about 10 mg to about 1 g. e.g. approximately 300 mg per person, divided in preferably 1-3 unit doses, which can e.g. be of the same amount, whereby, however, the upper limit just given can also be exceeded when this is found to be indicated. Usually, children receive half of the adult dosage.

1 30 The following Examples are intended to illustrate the present invention, but are not intended to be limiting in any manner. All temperatures are gi-ren in degrees Celsius.

Example 1 218 mg (0.56 mmol) of rac-B-propyl-6-(3-pyridyl)-a- -(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid. 127 mg (0.56 mmol) of (1S,2R,3S)-3-amino-4-cyclo- 19 -hexyl-l-cyclopropyl-1.2-butaned&ol (EP-A 0.332.008) and 248 mg of (0.56 mmol) of benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP) are dissolved in 20 ml of methylene chloride (CH 2 Cl 2 0.192 ml (1.12 mmol) of Hilnig base is added thereto and the solution is stirred at room temperature for 12 hours.

Subsequently it is partitioned between CH C12 and saturated ammoniuru chloride solution, the organic phase is dried over sodium sulphate and finally the solvent is removed under reduced pressure.

The crude product (600 mg of yellow oil), which contains the desired product as a 1:1 mixture of two epimezs.

Is purified and separated into the two epimers by chromatography on silica gel using a 10:1 mixture of CH2 C1 and methanol. There are thus obtained 33 mg of the more polar epimer (R or S)-N-[(lS.2R.3S)-l-.Ccyclohexylmethyl)-3-cyclopropyl-2.3dihydroxylpropyl-propyla.6- -bis(3-pyridyl)-s-triazolo[4,3a]pyrazine-3-acetamide as yellow crystals. MS: 598 (M4H)+ 76 mg of the pure, less polar epimer (S or R)-N-[(1S.2R.3S)-l-(cyclohexylmethy.)-3-cyclopropyl-2.3-dihyroxypropylJ-8-propyl- 6-bis(I-pyrr dl)ys-tiazolo4.3-alprazine3-acet 2 mide. MS: 598 and 166 mg of a mixture *coo of both epimers. i.e. (RS)-N-[(lS.2R.3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2.3-dihydroxypropyl]-B-propyl-a.6- -bis(3-pyridyl)-s-triazolo[4. 3-a pyrazine-3-acetamide, MS: 598 The rac-B-propyl-6-(3-pyridyl)-a-(3-pyridylmethyl)- -s-triazolo[4.3-a]pyrazine-3-acetic acid used as the starting material was prepared as follows: 3.31 g (11.7 mmol) of 3-(2-amino-1.1-diethoxyethyl)pyridine (Org. Synthesis 64. 19(1986)] and 1.17 ml (11.7 mmol) of 2-oxo-n-valeric acid are dissolved in 20 150 ml of dimethylformamide, 2.63 ml (23.4 mmol) of N- -methylmorpholine and 4.85 g (12.8 mmol) of TBTU [2-(1H- -benzotriazol-l-yl)-1.l,3.3-tetramethyluronium tetrafluoroborate] are added thereto and the solution is stirred at room temperature under argon for 14 hours. The mixture is partitioned between ethyl acetate and water and there are obtained, after the usual working-up of the organic phase, 2.6 g of crude product as a brown oil which is purified by chromatography on silica gel (eluent: 95:5 mixture of CH2Cl 2 and ether, yield: 1.42 g of N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-2-oxovaleramide,

MS:

309 500 mg (1.62 mmol) of N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-2-oxovaleramide are treated with 20 ml of 2N hydrochloric acid and subsequently stirred at 30° for 22 hours. Thereafter the solvent is removed in a high vacuum and the residue is treated twice with toluene, which is again removed each time under reduced pressure.

The desired product is thus obtained as beige cryetals, yield: 420 mg Recrystallization from methanol/ether yields N-(nicotinoylmeth-l)-2-oxo-valeramide, melting point 80-82°.

150 mg (0.55 mmol) of N-(nicotinoylmethyl)-2-oxovaleramide and 1.5 g (19.3 ramol) of ammonium acetate are dissolved in 10 ml of ethanol aaid the solution is heated 30 to reflux for 90 minutes. Then, the mixture is poured on to 50 ml of ice/water, extracted three times with 20 ml of ethyl acetate each time, the organic phase is washed with ml of water, dried over sodium sulphate and the solvent is then removed under reduced pressure, crude yield: 195 mg of yellow crystals. Recrystallization from ethyl acetate yields 3-propyl-5-(3-pyridyl)-2(1H)-pyrazinedione, melting point 188-189° (dec.).

21 430 mg (2 mmol) of 3-propyl-5-(3-pyridyl)-2(IH)-pyrazinedione are treated with 2 ml of phosphorus oxychloride and the mixture is subsequently heated to reflux for hours. Then, the phosphorus oxychloride is removed under reduced pressure, the residue is evaporated once with toluene and "he crude product is dissolved in 20 ml of CH2C12 and washed with 10 ml of ice-water. The aqueous phase is extracted once with 10 ml of CH2C1 2 and the combined organic phases are dried over sodium sulphate. The solvent is removed under reduced pressure and the desired 2-chloro-3-propyl-5-(3-pyridyl)pyrazine is obtained as beige crystals, yield: 468 mg melting S" 15 point 207-209° (from CH 2 C1 2 /ether).

:2.5 ml of pyridine are treated with 2.5 ml (51.4 mmol) of hydrazine hydrate, 500 mg (1.85 mmol) of 2-chloro-3- -propyl-5-(3-pyridyl)pyrazine are added thereto and the o 20 mixture is subsequently heated to reflux for 90 minutes.

Thereafter, the reaction solution is left to cool, 10 ml of water are added, the mixture is cooled at 50 for minutes and finally the crystallized-out product is filtered off under suction.

25 The crude product is dried over potassium hydroxide at 400 under reduced pressure and recrystallized from alcohol/water whereby there are obtained 270 mg of 2-hydrazino-3-propyl-5-(3-pyridyl)pyrazine as S. 0 beige needles, melting point 162-163°.

30 340 mg (1.35 mmol) of diethyl (3-pyridyl)malonate (Arch. Pharm. 308, (1975) 663), 311 mg (1.35 mmol) of 2-hydrazino-3-propyl-5-(3-pyridyl)pyrazine and 257 mg (1.35 mmol) of p-toluenesulphonic acid are treated with 150 ml of xylene and the mixture Is subsequently heated to reflux on a water separator for 12 hours. Thereafter, the xylene is distilled off, the residue is dissolvud in 22 CH 2 Cl 2 washed with sodium bicarbonate solution, the organic3 phase is dried over sodium sulphate and the solvent is removed u~nder reduced pressure. The residue is chromatographed on silica gel using a 10:1 mixture of CH 2Cl and methanol, whereby there are obtained 300 mg of ethyl rac-8-propyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[4. 3-ajpyrazine-3-acetate. MS: 416 300 mg (0.72 mmol) of ethyl rac-8-propyl-6-(3-pyridyl)-cL-(3-pyridylmethyl)-striazoo..apyrazine3.

-acetate are dissolved in 50 ml of ethanol. treated with 1.44 ml of 1N sodium hydroxide solution (1.44 mmol) and the solution .s subsequently heated at 500 for 2 hours.

0. It is neutralized by adding 1.44 ml of 1N hydrochloric acid (pH 5) and evaporated to dryness under reduced pressure. The residue is then partitioned between water (5 ml) and a 10:1 mixture of CH 2 C1 2 and methanol ml). The organic phase is c'ried over sodium sulphate and the solvent is removed under reduced pressure. There are thus obtained 300 mg of rac-8-propyl-6-(3-pyridyl)-ac-(3-pyridylmethyl)-s-triazolo[4.3-alpyrazine-3acid as a yellow amorphous powder. R,:0.l *(CH Cl /MeOH; 5:1).

Soo* 2 2 Example 2 30 The following compounds were manufactured in an S analogous manner to that described in Example 1: From rae-cL-(imidazol-4-ylmethyl)-B-propyl-6-(3- -pyridyl)-s-triazolo(4.3-a~pyrazine-3-acetic acid and 35(1S.2R.3S)-3-amino-4-cyclohexyl-l-,iyclopropyl-1.2-butanediol the two epimers (R or S)-N-[(S.2R.3S)-l-.(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydrnxypropyl]-a-(imidazol-4- -ylmethyl-B3-propyl-6-(3-pyridyl)-s-triazolo[4.3-a~pyrazine- 23 -3-acetamide and (Ri or S)-N-((lS.2R.3S)-l-(cyclohexylmethyl) -3-cyclopropyl-2. 3-dihydroxypropyl]J-x- imidazol-4- -ylmethyl)-8-propyl-6-(3-pyridyl)-s-triazolo[4. 3-a]-pyrazine -3-acetamide. each as a pale yellow solid, MS: 587 from B-propyl-6-(3-pyridyl)-s-triazolo[4.3-ajpyrazine- -3-acetic acid and (lS.2R.3S)-3-amino-4-cyclohexyl-l- -cyclopropyl-1.2-butanediol the N-[(lS,2R.3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2. 3-dihydroxypropylj-8-propyl-6- -(3-pyridyl)-s-triazolo(4.3-a~pyrazine-3-acetamide as a solid. MS: 507 00 *000 from rac-8-isopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[4. 3-a]pyrazine-3-acetic acid and 0,0(lS.2R,3S)-3-amino-4-cyclohexyl--cyclopropyl12-butane- V. diol the (RS)-N-[(1S.2R.3S)-l-(cyclohexylmethyl)-3-.cyclo- -(3-pyridylmethyl).-s-triazolo[4.3-a~pyrazine-3-acetaaide as a 1:1 epimer mixture. MS: 598 from rac-8-isopropyl-a-(imidazol-1-ylmethyl)-6-(3pyridyl)-s-triazolo[4.3-a~pyrazine-3-acetic acid and (lS.2R.3S)-3-amino-4-cyclohexyl--cyclopropyl1.2-buitanedio1 the two epimers (S or R)-N-[(lS.2R.3S)-l-(cyclohexyliethyl)-3-cyclopropyl-2. 3-dihydroxypropylj-B-isopropyl-a- -pyrazine-3-acetamide and (R or S)-N-[(lS.2R.3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2.3-dihydroxypropyl]-Bisopropyl.

a-(imidazol-4-ylmethyl)-6-(3-pyridyl)-s-triazolo(4.3-a]- -pyrazine-3-acetamide, each aL a pale yellow solid, M7- 587 -from rac-8-isobutyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[4.3-a]pyrazine-3-acetic acid and (31S.2R.3S)-3-amino-4-cyclohexyl-l-cyclopropyl-1.2-butanediol 24 the 3:1-epimer mixture (RS)-N-[((1S,2R.3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2. 3-dihydroxypropyl]-B-isobutyl-cx- -(3-pyridylmethy1)-6-(3-pyridyl)-s-triazoloL4. 3-alpyrazine- -3-acetamide and the less polar. pure epimer (S or R)-N- -[(iS.2R.3S)--(cyclohexylmethyl)3cyclopopyl23dihydroxypropyl]-B-isobutyl-a(3pyridylmethyl)6-(3.pyridyl)-s-triazoloE'4.3-a~pyrazine-3-acetamide. each as a pale yellow solid. ?4S: 612 from rac-8-isobutyl-a-(imidazol-1-ylmehyl6...(3 -pyridyl)-s-triazolo[4.3-apyrazine-3..acetic acid and (lS.

2

R.

3 S)-3-amino-4-cyclohexyl.1.cyclopropyl...2-butanediol the two epimers (S or R)-N-[(S,2R.3S).-l-(cyclohexyl- 0 o methyl)-3--cyclohexyl2.3-dihydroxypropJ..-..(imidazol4zine-3-acetate and (R or S)-N-[(lS.2R.3S)-1-(cyclohexylmethyl)-3-cyclohexyl-2. 3-dihydroxypropyl]-cz-(imidazol-4- -ylmethyl)-8-isobutyl-6-(3-pyridy).s-.triazolo[4. 3-a]pyrazine-3-acetate. each as a solid. MS: 601 from 8-isobutyl-6-(3-pyridyl)-s-triazolo[4.3-alpyra- '6604,zine-3-acetic acid and (1S.2R.3S)-3--amino-4-cyclohexyl--- 66 4 25 cyclopropyl-1.2-butanediol the N-[(lS.2R.3S)-1--(cyclohexylmethyl)-s-cyclopropyl-.2,3-dihydroxypr. qylJ-8-*isobutyl- -6-(3-pyridyl)-s-triazolo[4.3-ajpyrazine-3-acetamide as a solid, MS: 521 0:6 30o from rac-6-(4-pyridyl)-a-(3-pyridyllmethyl)-B-propyl- -s-triazolo[4.3-apyrazine-3-acetic acid and (lS.2R.3S)-3- -amino-4-cyclohexyl-l-cyclopropyl-1.2-butanediol the 1:1 epimer mixture (RS)-N-I(1S.2R.3S)-1-(cyclohexylmethyl)-3- -cyclopropyl-2. 3-dihydroxypropylj-8-propyl-6-(4-pyridyl)a-(3-pyridylmethyl)-s-triazolo[4.3-a~pyrazirie-3-acetamide as a solid, MS: 598 from rac-a-(imidazol-4-ylmethyl)-s-propyl-6-(4- 25 -pyridyl)-s--triazolo[4. 3-a]pyrazine-3-acetic acid and (1S.2R,3S)-3-amino-4-c~ clohexyl-1-cyclopropyl-1. 2-butanediol the (RS)-N-[(1S.2R.3S)-1-(cyclohexylmethyl)-3--cyclopropyl-2.3-dihydroxypropyl]-x-(imidazol-4-yllethyl)-8- ~-propyl-6- (4-pyridyl)-.s-triazolo[4. 3-a~pyrazine-3-acetanlide as a 1:1 epimer mixture, MS: 587 (M+H) from 8-propyl-6-(4-pyridyl)-s-triazolo[4.3-alpyrazine-3-acetic acid and (lS.2R.3S)-3-amino-4-cyclohexyl-1- -cyclopropyl-1.2-butanediol the N-[(1S,2R.3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2. 3-dihydroxypropyl]-B-propyl-6- -(4-pyridyl)-s-triazolo[4.3-a~pyrazine-3-carboxamide as a pale yellow solid, MS: 507 from 6-phenyl-8-propyl-s-triazolof4.3-b]-pyridazine-3alp" -acetic acid and (lS.2R.3S)-3-amino-4-cyclohaxyl-l-cyclopropyl-1.2-butanediol the N--(1S.2R.36)-1-(cyclohexylmethyl)-3-cyclopropyl-2.3-dihydroxypropyl]-6-phenyl-8- -propyl-s-triazolo[4.3-b]pyridazine-3-acetamide as a solid, MS: 508 (M+HNO from rac-6-phenyl-8-oropyl-ax-(3-pyridylmethyl)-s- Ob 6 25 -triazolo[4.c3-blpyridazine-3-acetic acid and (1S.2R,3S)- -3-amino-4-cyclohexyl-l-cyclopropyl-1.2-butanediol the 1.000 2R.3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2.3- -dihydroxypropylJ-6-phenyl-8-propyl-a- (3-pyrridylmethyl 0:00 -triazolo[4.3-b~pyridazine-3-carboxamide as a solid.

9044 MS:598 -from B-benzyl-6-phenyl-s-triazoloE4.3-blpyridazine-3- -acetic acid and (1S.2R.3S)-3-amino-4-cyclohexyl-l-cyclopropyl-1.2-butanediol the 8-benzyl-N-j(lS.2R.3S)-1-(cyclo- 35hexylmethyl)-3-cyclopropyl-2.3-dihydroxypropyl]j-6-phenyl-striazolo[4,3-blpyridazine-3-acetamide, MS: 482 (M-C 4 H 7 0) 26 from (RS)-8-benzyl-6-phenyl--(3-pyridylmethyl).s- -triazolo[4,3-b]pyrjdazine-3-acetic acid and (lS,2R,3S)-3- -amino-4--cyclohexyl-l-cyclopropyl..i.2-butanediol the (RS)-B-benzy1-N-[(lS.2R.3S)...(cycohexymethy)3 -cyclopropyl-2,3-dihydroxypropyl>6-phenyl(3..3pyridyl.

methyl)-s-triazolo[4. 3-b]pyridazinE-3-acetamide, MS: 645 from rac-8-propyl-6-(3-pyridyl)-.(3.pyridylmethyl)- -s-triazoloE4.3-alpyrazine-3-acetic acid and (2S.3R,4S)-2- -amino-l-cyclohexyl-6-methyl3.4.heptanediol (J.Med.Chem.

31 2277. 1988) the two epimers (S or 2 R.,3S)-l-(cyclohexylmethyl)2,3dihydroxy-5methyl.

hexyl]J-8-propyl-6-(C3-pyridyl) (3-pyridylmethyl 15 -triazolo[4,3-alpyrazine-3-acetamide and (R or S)-N- -[(1S.2R.3S)-1-(cyclohexylmethyl)-23-dihydroxy-5-.methyl.

hexyl]-8-propyl-6-(3-pyridyl)a(3pyridylmethyl).s- -triazolo[4,3-ajpyrazine-3-acetamide, MS: in each case 614 from rac-8-propyl-6-(3-pyridyl)-t- (3-pyridylmethyl)- -s-triazoloj4.3-ajpyrazine-3-acetic acid and (lS,2R,3S)-3- -amino-l-cyclopropyl-4-phenyl-1,2-butanediol the 1:1 epimer mixture (RS)-N-[(lS,2R.,3S)-1-(cyclohexylmethyl)-3- -cyclopropy1-2,3-dihydroxypropy1J-B-propyl-a-(3-pyridyl- -methy1.)-6-(3-pyridy1)-s-triazolo[4,3-alpyrazine-3- -acetamide,M"Z: 592 from rac-8-benzyl-6--(3-pyridyl)--a-(3-pyridylmethyl)- -s-triazolo(4.3-ajpyrazine-3-acetic acid and (lS,2R.3S)-3- -amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol the 1:1 epimer mixture (RS)-8-benzyl-N-[(1S,2R.3S)-l-(cyclohexylmethyl) -3-cyclopropyl-2. 3-dihydroxypropy. J-6- (3- -pyridyl)-aL-(3-pyridylmethyl)-s-triazolo(4.3-a]-pyrazine- -3-acetamide, MS: 646 CM+H): 27 from rac-B-benzyl-cL-(imidazo-4-ymethy)-6-(3pyri dyl)-s-triazolo[4.3-apyrazine-3-.acetic acid and (lS.2R.3S)-3-amino-4-cyclohexyl-..cyclopropyl-1.2..butanediol the 1:1 epimer mixture (RS)-8-benzyl-N-[(1S.2R,3S)-l- -(cyclohexylmethyl)-3-cycopropy2.3-dihydroxypropyl...- -(imidazol-4-ylmethyl)-6-(3-pyridyl)striazolo[43a]-.

pyrazine-3-acetamide. MS: 635 (Mi-H)+ from 8-benzyl-6-(3-pyridy1)-s-triazolo(4,3-a~pyrazine- -3-acetic acid and (lS.2R.3S)-3-amino-4-cyclohexyl-l- -cyclopropyl-l.2-butanediol the 8-benzyl-N--[()'S,2R.3S)-l- -(cyclohexylmethyl)-3-cyclopropyl-2. 3-dihydroxypropylJ-6-(3- -pyridyl)-s-triazolo[4.3-a~pyrazine-3-acetamide as a S @0solid. MS: 555 (M+H) 4 from rac-8-propyl-6-(3-pyridyl)-a-(3-pyridymethyl).

-s-triazolo(4.3-a~pyrazine-3-acetic acid and (2S.3R,4S)-2- S 20 -amino-1-cyclohexyl-5-methyl-3,4-hexanediol (EP-A 0.332.008) the two epimers (R or S)-N-[(1S,2R.3S)-l- -(cyclohexylmethyl)-2.3-dihydroxy..methylpentyl8..oxo.

propyl-6- (3-pyridyl)-a- (3-pyridylmethyl).-s-triazolo- -[4,3-alpyrazine-3-acetamide and (S or R)-N-[(lS,2R.3S)-lsee%* 25 -(cyclohexylmethy1)-2,3-dihydroxy-4-methylpentyl-Boxo- '06 propyl-6-(3-pyridyl)-z- (3-pyridylmethyl)-s-triazolo- (4.3-a]pyrazine-3-acetamide, MS: in each case 600 from rac-1--(imidazol-4-ylmethyl)-8-propyl-6(3.

pyridyl)-s-triazolo(4.3-a~pyrazjne-3-acetic acid and (lS,2R.3S)-3-amino-1-cyclopropyl-4-phenyl-1.2.but~nediol the 2:1 epimer mixture (RS)-N-U1lS.2R.3S)-l-(cyclohexylmethyl )-3-cyclopropyl--2. 3-dihydroxypropyl]-c.- (imidazol-4- -ylmethyl)-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetamide as a solid, MS: 580(M+ from rac-cx-(imidazol-4-ylmethyl)--propyl.-6-(3- -pyridyl)-s-triazolo[4. 3-ajpyrazine-3--acetic acid and 28 (2S.3R,4S)-2-amino-1-cyclohexy-6methy.-3.4-.heptanediol 'the two epimers (R or S)-N-((1S.2R.3S)-l-(cyclohexylmethyl)-2.3-dihydroxy-4-methylhexyl]jc-(imidazol-4-ylmethyl)-8-propyl-6-(3-pyridyl)-s-triazolo[4.3-a~pyrazine-3- -acetamide and (S or R)-IN-[(lS,2R,3S)-l-(cyclohexrylmethyl)-2.3-dihydroxy-4-methylhexyJ-.-(imidazol-4-ylmethyl)-B-propyl-6-(3-pyridy)s-triazoo[4.3-a]pyrazine-3- -acetamide. MS: in each case 603 from rac-a.-(imidazol-4-ylmethyl).-8-propyl-6-(3- -pyridyl)-s-triazolo[4.3-a]pyrazine-3-acetjc acid and (2S. 3R.4S)-2-ainino-l-cyclohexcyl-5-methyl-3 .4-hexanediol the two epimers (R or S)-N-[((S.2R.3S)-1-(cyclohexylmethyl) 3-dihydroxy-4--methylpentyl3-a.- (imidazol-4- -ylmethyl)-B-propyl-6-(3-pyridyl)-s-triazolo[4. 3-a)pyrazine-3-acetamide and (S or R)-N-[(lS,2R.3S)-l-(cyclo- ~hexylmethyl 3-d ihydroxy-4-methylpentyl 3-a.-(Cimidazol-4- 20 -ylmethyl)-8-propyl-6-(3-pyri~y1)-s-triazolo[4. 3-alpyrazinae- -3-acetamide. MS: in each case 589 (M+H) from rac-8-propyl-a-(3-pyridylmethyl)-6-(3-pyridyl)- -6-triazolo[4.3-b~pyridazine-3-acetic acid and (1S.2R.3S)- 3-amino-4-cyclohexyl-l-cyclopropyl-1.2-butanediol the (RS)-N-[(lS.2R.3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2.3- -dihydroxypropyl ]-B-propyl-.- (3-pyridylmethyl (3- B. -pyridyl)-s-triazoloE4.3-bjpyridazine-3-acetamide as a 1:1 epimer mixture. MS: 598 from rac-8-propyl-a-(3-pyridylmethy1)-6-(2-thienyl)- S. 6:-s-triazolo[4,3-b~pyridazine-3-acetic acid and (1S.2R.3S)- -3-amino-4-cyclohexyl-l-cyclopropyl-l. 2-butanediol the two epimers (S or R)-N-[(lS.2R.3S)-l-(cyclohexylmethyl)-3cyclopropyl-2.3-dihydroxypropyl]--propyl-.-(3-pyridylmethyl)-6-(2-thienyl)-s-triazolo[4.3-bjpyridazine-3- -acetamide and (R or S).--KlS1.2R,3S)-l-(cyclohexylmethyl) -3-cyclopropyl-2. 3-dihydroxypropyl 3-B-propyl-i- (3- 29 -pyridylmethyl)-6-(2-thienyl)-s-triazolo[4 1 'ab]-pyridazine- -3-acetamide. each as a solid. MS: 603 from 8-propyl-6-(2-thienyl)-s-triazolo[4.3-bJ-pyridazine-3-aceti.c acid and (IS.2R,3S)-3-amino-4-cyclohexyl- -1-cyclopropyl-1.2-butanediol the N-[U1S.2R.3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2.3..dilyroxypropyl]8..propyl.6- -(2-thienyl)-s-triazolo[4.3-b]pyridazine3-.acetamide as a solid. MS: 511. from rac-8-propyl-6-C3-pyridyl)-a-(3-pyridylmethyl).

-s-trlazolot4.3-ajpyrazine-3-acetic acid and (lR or S.2R S)-l-[(lR.2S)-1-amino-3-cycohexy..1..hydroxypropyl].

-1.2-cyclohexanediol the two epimers (R or -i-(cyclohexylmethyl)-2-~i'Ur.,',y-2-[(lR or S,2R or S)-1.2- :-dihydroxyphienyl~ethyl]-8-propyl a(3..pyridylmethyl)-.- -propyl,-s-triazolo(4.3-a~pyrazine-3-acetamide and (S or 20 R)-N-[(1S.2R)-l-(cyclohexylmethyl)-2-hyaroxy-2-[C1R or S.2R or S)-1.2-dihydroxyphenyl3ethyl]-B-proyl..-(3- -pyridylmethyl)-B-propyl-s-triazolo(4. 3-a]pyrazine-3-acetamide. each as a solid. MS: 642 age**- from (RS)-8-[(RS)-]-methylpropylj--a-(3-pyridylmethyl)-6-(3-tv'A~dyl)-s-riazolo[4.3a~pyrazineB..acetic acid and (lS.2R.3S)-3-amino--4-cyclohexyl-1-cyclopropyl- .*-1.2-butanediol the two epimer mixtures (S or R)-N- -[(lS,2R.3S)-l-Ccyclohexylmethyl)-3.-cyclopropyl-2.3-dihydroxypropyl]-B-[(RS)-l-methylpropyl]-cz-(3-pyridylsee:methyl)-6-(3-pyridyl).-s-triazolo[4.3-a]pyrazine-3-acetamide and (RS)-N--((S.2R.3S)--(cyclohexylmethyl)-3-cyclopropy1- -2.3-dihydroxypropyl]-B-[(RS)-l-methylpropyl]-.-(3- -pyridylmethyl)-6-(3-pyridyl)-s-triazolo[4.3-a~pyrazine-3acetamide. eacli as a pale yellow solid, MS: 612 from rac-B-(l-methylpropyl)-6-(3-pyridyl)-s-triazolo- [4.3-ajpyrazine-3-acetic acid and (IS.2R.3S)-3-amino-4- 30 -cyclohexyl-1-cyclopropyl-1.2-butanediol the N- -U1S.2R3S)---(cyclohexylmethyl)-3-cyclopropyl-2.3-djhydroxypropyl--(RS)--methylpropyl.6-.3pyridyl)s- -triazolo(4.3-a~pyrazine-3-carboxamide as a solid, MS: 520. from rac-Gx-(imidazo-4-ylmethy)-B-(RS)--methy..

propy1J-6-(3-pyridyl)-s-trii zolo[4. 3-a]pyrazine-3-acetic acid and (lS,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl- -1,2-butanediol the two 1:1 epimer mixtures (S or R)-8- -E(RS)-1-methylpropy1J]-N-u(lS.2R.3S)-l-(cyclohexylmethyl)- ,yclopropyl-2. 3-dihydroxypLOPY)-I-( imidazol-4-ylrctfyl)-6-(3-pyridyl)-s-trazolo4.3-a]pyrazine....acetamide and (R or S)-8-[(RS)--methylpropyl-N-[(lS.2R.3S..1-.

-(cyclohexylmethyl)-3cycopropyl2.3-dihydroxypropyl..a..

-(imidazol-4-ylmethyl)-6-(3-pyridyl)-striazolo[4.3.ajpyra- 00* zine-3-acetamide. each as a pale yellow solid, MS: 601 from~ rac-a-methyl-e-propyl-6-(3-pyridyl)-s-triazolo- [4.3-ajpyrazine-3-acetic acid and (lS.2R.3S)-3-amino-4- -cyclohexyl-1-cyclopropyl-1.2-butanediol the (RS)-N- 25 -r(lS.2R.3S)-l1(cyclohexylmethyl)3cyclopropyl23-dihydroxyprcpyl]-cx-methyl-8-propyl-6- (3-pyridyl)-s-triazolo[4.3-a]pyrazine-3-acetamide as a 1:1 epimer mixture.

*MS: 521 and from rac-a-methyl-B-[(RS)-l-methylpropylJ-6-(3- -pyridyl)-s-triazolo[4.3-a~pyrazine-3-acetic acid and (lS.2R.3S).--3-amino-4-cyclohexyl-1-cyclopropyl-1.2-butanediol the (RS)-8-[(RS)-l-methylpropylJ-N-[(lS.2R.3S)-1- -(cyclohexylmethyl)-3-cyclopropy1-2.3-dihydroxypropyl]-a- -methyl-6-(3-pyridyl)-s-triazolo[4.3-a~pyrazine-3-acetamide a mixture of diastereomers, MS: 535 The acids and arl~ne diols used as the starting 31 materials were prepared as follows: rac-ax-(Imidazol-4-lmethl)- Boy-provl6-(.. piyrid...s -triazoloF4.3-apVyrazine-3-acetic acid In an analogous manner to that described in Example 1.

by condensing 2-hydrazino-3-propyl-5-c3-pyridyl)pyrazine with diethyl (imidazol-4--yl-methyl)malonate (J.Chem.Soc.

a9. (1911) 1390) there is obtained ethyl rac-a-(imidazol-4-ylmethyl)-8-propyl-6-(3-pyridyl) -s-triazolo(4. 3-a)pyrazine-3-acetate. MS: 405 which is converted into the above acid by saponification analogously to Example 1.

8-Propyl-6--(3-pyridvl)-s.-triazolor4,3-alpyrazine-3-acetic acid 20 In an analogous manner to that described in Example 1, by condensing 2-hydrazino-3- propyl-5-(3--pyridyl)pyrazine with diethyl malonate i~n toluene in place of xylene there is obtained ethyl 8-propyl-6.-(3-pyridyl)-s-triazolo- [4.3-a]pyrazine-3-acetate. MS: 325 and by corresponding basic saponification there is obtained the 25desired acid. MS: 269 CM-C H).

4* rac-8-Isopropyl-6- (3-Dyr idyl idylmethyl )-s-triazolof4.3-alpyrazine-3-acetic acid In an analogot's manner to Example 1. by condensing 0***3-(2-amino-1.1-diethoxycthyl)pyridine with 3-methyl-2-oxobutanoic acid there obtained N-[2.2-diethoxy-2-(3-pyridyl)ethylJ-3.3-dimett~yi-2-oxobutyranide. Acidic hydrolto 3-methyl-h- (nicotinoylmethyl)-2-oxobutyramide and subsequent ring c'lvture gives 3-isopropyl-5-(3-pyridyl)- -2(1H)-pyrazinone s a yellow. crystalline solid, melting point 200-2020 (from ethyl acetate). The converrion into 32 the cortesponding chloride, 2-chloro-3-isopropyl-5-(3- -pyridyl)pyrazine. is effected analogously to Example 1.

Hydrazinolysis yields 2-hydrazino-3-isopropyl-5-(3- -pyridyl)pyrazine as beige crystals, melting point 164-1650 (from ethanol/water), and subsequent condensation with diethyl (3-pyridyl),,aalonate yields ethyl rac-8--isopropyrl-6-(3-pyridyl)-aL-(3-pyridylmethyl)-s-triazolo- [4,3-a]pyrazine-3-acetate as a pale yellow solid, MS: 416 which is converted into the above acid by basic saponification.

-triazolor4,3-anRvrazin-a-3-acetic acid In an analogous manner to Example 1. by condensing see 2-hydrazino-3--isopropyl-5-(3-pyridyl)pyrazine with diethyl 00:0 (imidazol-4-ylmethyl)malonate there is obtained ethyl rac- 20-8-isopropyl-a- CLtidazol-4-ylmethyl) 3-pyridyl 2-tr:,Iazolo'ij.3-ajpyrazine-3-acetate, MS: 405 which is converted into the above acid by alkalitie saponiification.

6 rac-B-Isobutyl-cL- (3-pyridylmethyl (3-pyridvl -triazolor4,3- lpyrazine-3-acetic acid 96*0In an analogou.. manner to Example 1. by condensing 3-(2-amino-1. l-diethoxyethyl)pyridine with 4-methyl-2-oxopentanoic acid1 there is obtained N-(2.2-diethoxy-2-(3- -pyridyl)ethyl]-4-methyl-2-oxovaleramide as a colourless.

amorphous solid. Acidic hydrolysis yields 4-methyl-14- -(nicotinoylmte'Jayl)-2-oxovaleramide and subsequent ring closure yields 3-isobutyl-5-(3-pyridyl)-2(lH)-pyrazinone as a crystalline solid, melting point 195-1960 (from ethyl acetate). The conversion Into the corresponding chloride, 2-chloro-3-isobutyl-5- (3-pyridyl)pyrazine. is also 33 effected analogously to Example 1.

Hydrazinolysis of the chloride yields 2-hydrazino-3- -isobutyl-5-(3-pyridyl)pyrazine as beige crystals. melting point 154-1550 (from ethanol/water) and subsequent condensation with diethyl C3-pyridyl)malonate yields ethyl rac- -8-isobuatyl-a-(3-pyridylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-a)pyrazine-3-acetate, MS: 430 which is converted into the above acid by basic saponification.

rac-aL-(Imidazol--4-ylmethyl)-8-isobutyl-6-(3-pyridyl)-s- -triazolor4. 3-a lpvrazine-3-acetic acid In an analogous manner to Example 1. by condensing 2- 15 -hydrazino-3-isobutyl-5.-(3-pyridyl)pyrazine with diethyl Vo Cimidazol-4-ylmethyl)malonate ti-ere is obtained ethyl rac- Cimidazol-4-ylmethyl isobutyl-6- (3-pyridyl -triazolo[4,3-slpyrazine-3-acetate, MS: 419 which is converted into the above acid by alkaline saponification.

8-Isobutvl-6-(3-pyridvl)-s-triazolo[4.3-slpvrazine-3-acetic acid In an analogous manner to Example 1. by condensing 2-hydrazino-3-isobutyl-5-(3-pyridyl)pyrazine with diethyl 0006 malonate there is obtained ethyl 8-isobutyl-6-(3-pyridyl)- -s.-triazolo[4.3-a]pyrazine-3-acetate. MS: 339 which is converted by saponification into the above acid: MS 267 CM-CO2)+ rac-8-Benzvl.- -(3-pyridyl)-a-(3-pyridylmethvl)-s-triazolo- [4.3-alpyrazine-3-acetic acid In an analogous manner to Example 1. by condensing 3-(2-amino-1.1-diethoxyethyl)pridile with phenylpyruvic 34 acid there is obtained N-[2.2-diethoxy-2-(3-pyridyl)ethyl]-3-phenylpyruvamide as an amorphous, yellow solid.

Subsequent acidic hydrolysis to 3-phenyl-N-[[(3-pyridyl)carbonyljmethyl~pyruvaide and ring closure gives 3- -benzyl-5-(3-pyridyl)-2(lH)-pyrazinone as a solid, melting point 188-1900 (from ethyl acetate).

Chlorination to 2-benzyl-3-chloro-6-(3-pyridyl)pyrazine and hydrazinolysis yields 2-benzyl-3-hydrazino-6- -(3-pyridyl)pyrazine as a beige, crystalline solid.

Melting point 183-1840 (from methanol/water).

Condensation with diethyl (3-pyridyl)malonate finally gives ethyl rac-8-benzyl-a-(3-pyridylmethyl)-6-(3t 15 -pyridyl)-s-triazolo[4.3-apyrazine-3-acetate, MS: 464 which is converted into the above acid by basic r saponification.

06.5 0. r ac-8-Benzvl-c- imidazol-4-ylmethyl) 3-pyridyl -s- 20 -triazolof4,3-alpVrazine-3-acetic acid In an analogous manner to that described in Example 1, by condensing 2-benzyl-3-hydrazino-6-(3-pyridyl)pyrazine 406600 with diethyl (imldazol-4-ylmethyl)malonate there is 0SSS 25 obtained ethyl rac-8-benzyl-a-(imidazol-4-ylmethyl)-6- -(3-pyridyl)-s-triazolo[4.3-a]pyrazine-3-acetate. MS: 453 which is converted into the above acid by alkaline saponification.

8-Benzvl-6-(3.-pyridvl)-s-triazolor4. 3-a2praz-ine-3-acetic 6e acid In an analogous manner to Example 1, by condensing 2-benzyl-3-hydrazino-6-(3-pyridyl)pyrazine with diethyl malonate there is obtained ethyl B-benzyl-6-(3-pyridyl)-s- -tria:zolo[4,3-apyrazine-3-acetate, which is converted by 35 basic saponification into the above acid, MS: 301 (M-C0 2 rac-6-(4-Pvridyl)-aL-(3-pvridyl)-8-propyl-s-triazolj-.

rq~.3-aprazine-3-acetic acid In ark analogous manner to Example 1, by condensing 4-(2-amino-1,1-diethoxyethyl)pyrimidine (Org. Synthesis 64, 19 (1986)] with 2-oxopentanoic acid there is obtained N-(2.2-diethoxy-2-C4-pyridyl)ethyl]-2-oxovaleramide as a white solid, melting point 95-960. Subsequent acidic hydrolysis to N-(isonicotinoylmethyl)-2-oxovaleramide arid ring closure gives 3-propyl-5--(4-pyridyl)-2-pyrazinone as yellow crystals, melting point 237-2380 (dec.).

Chlorination to 2-chloro-3-propyl-5-(4-pyri-dyl)- -pyrazine and hydrazinolysis yields 2-hydrazino-3-propyl- -5-(4-pyridyl)pyrazine as a red, crystalline solid, melting point 216-2170 (from ethanol/water).

condensation with diethyl (3-pyridyl)malonate analogously to Example I. fir 4 dlly gives ethyl rac-6-(4-pyridyl)- -a-(3-pyridyl)-8-propyl-s-triazolo(4. 3-alpyrazine- 00.00.+ OI -3-acetate. MS: 416 CM which is converted into the above acid by basic saponification.

rac-u.- C midazol-4-vlmethyl )-8-Propyl-6- (4-pyridv),)-s- -triazoloC4.3-ahpyraZine-3-acetic acid Analogously to Example 1. by condensing 2-hydrazino-3- I. -propyl-5-(4-pyridyl)pyrazine with diethyl (imidazol-4-ylmethyl)malonate there is obtained ethyl rac-a-(imidazol- -4-ylmethyl)-8-propyl-6-(4-pyridyl)-s-triazolo[4. pyrazine-3-acetate. MS: 405 which is converted into the above acid by basic saponification.

36 8-Propvl-6-(4-vridl-s-triazoor4.3aprazin.3.acetic acid Analogously to Example 1, by condensing 2-hydrazino-3- -propy!-S-(4-pyr-idyl)pyrazine with diethyl malonate there is obtained ethyl 8-propyl-6--(4-pyridyl)-s-triazolo- (4,3-alpyrazine-3-acetate, MS: 325 which is 1o converted into the above acid by basic saponification.

6-Phenvl-8-prO2Vl-s-triazoo4.3b~liriazine-3.acetic acid In an analogous manner to Example 1. by chlorinating 6-phienyl-4-propyl-3(2H)-pyridazinone (Chim. Ther. 6. 109 there is obtained 3-chloro-6-phenyl-4-propylpyridazine. MS: 232 which is converted by hydrazinolysis into 3-hydrazino-6-phenyl-4-propylpyridazine.

US: 228 Subsequent ring condensation with diethyl malonate to ethyl 6-phenyl-8-propyl-s-triazolo[4.3-b]pyridazine-3-acetate. MS: 324 followed by basic saponification gives the above acid an~ a solid. MS: 252 (M-C0 2 25rac-6-Phenvl-8-Dropvl-cx-(3-Dyridylmethvl)-s-triazolo- 4,3-blpyridazine-3-acetic acid In an analogous manner to Example 1, by condensing 3-hydrazino-6-phenyl-4.-propylpyridazine with diethyl (3-pyridyl)malonate there is obtained ethyl rac-6-phenyl- -8-propyl-ci-(3-pyridylmethyl)-s-triazolo[4.3-b]pyridazine-3-acetate. which is converted by basic saponification into the above acid. MS: 398 (Mdl) 8-Denzvl-6-phenyl-s-triazolof4.3-bhw.ridazine-3-acetic acid In an analogous manner to that described in Example 1.

by the ring condensation of 4-benzyl-3-hydrazino-6-phenyl- 37 pyridazine [Indian J.Chem., 15B. 352 (1977)] with diethyl malonate there is obtained ethyl 8-benzyl-6-phenyl-s-.

-triazolo[4,3-blpyridazine-3-acetate, MS: 372 (M) which is saponified with a base to the above acid, MS: 316

(M-CO)

(RS)--8-Benzyl-6-phenl-a-3-yri dvlmethyl).s-triazolo r4.3-blpyridazine-3-acetic acid In an analogous manner, by the ring condensation of 4- -benzyl-3-hydrazino-6-phenylpyridazine with diethyl (3- -pyridyl)malonate there is obtained ethyl rac-B-benzyl-6- -phenyl-dL-(3-pyridylmethyl)--triazolo[4.3-b)pyridazine- -3-acetate, which is converted by basic saponification into the above acid, MS: 436 (M+H) rac-8-(1-Methylpro yl)-6-(3-pyridyl)-s-triazolor4, 3-al- Pyrazine-3-acetic acid In an analogous manner to Example 1. by condensing 3-(2-amino-1.J-diethoxyethyl)pyridine with 3-methyl-2-oxopentanoic acid there is obtained rac- -[2.2-diethoxy-2-(3- -pyridyl)ethyl]-3-methyl-2-oxovaleramide as an amorphous.

nolourless solid. Subsequent acidic hydrolysis to rac-3- -methyl-2-oxo-N-[(3-pyridylcarbonyl)methyljvaleramide e* hydrochloride (beige, crystalline solid, melting point 158-1590) and ring closure gives -(3-pyridyl)-2(1H)-pyrazinone as a yellow solid, '-elting point 146-1480 (from acetonitrile). The conversion into rac-2-chloro-3- (1-methylpropyl)-5-(3-pyridyl)pyrazine is also effected analogously to Example 1. Hydrazinolysis to rac-2-!,,drazino-3-(l-methylpropyl)-5-(3-pyridyl)p'razine in the form of beige crystals, melting point 166-1670 (from ethanol/water) and subsequent condensation with diethyl malonate gives ethyl rac-8-(l-methylpropyl)-6-(3- -pyridyl)-s-triazolo[4.3-a]pyrazine-3-acetate, MS: 335 38 which is converted by saponification into the above acid, MS: 267 (M-C0 2 (RS)-8-[(RS)-1-Methylpropvll-a-(3-pyridylmethy]A-6-(3- -pvridl)-s- triazolo[4. 3-alpyrazine-3-acetic acid In an analogous manner to Example 1, by condensing rac-2-hydrazino-3-(l-methylpropyl)-5-(3-pyridyl)pyrazine with diethyl C3-pyridyl)malonate there is obtained ethyl (RS)-8-C(RS)-1-methylpropyl]-i-(3-pyridylmethyl)-6-(3- -pyridyl)-s-triazolo[4.3-a]pyrazine-3-acetate, MS: 430 which is converted into the above acid by alkaline saponification.

15 rac-a-Clmidazol-4-vlmethyl)-8-r(RS)-l-methylpropyll- -6-(3-pvridvl)-s-triazolor4, 3-a lpyrazine-3-acetic acid In an analogous manner to Example 1. by condensing rac-2-hydrazino-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine 20 with diethyl (imidazol-4-ylmethyl)malonate there is obtained ethyl (RS)-8--(RS)-1-methylpropylj-i-(imidazol- -'-ylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-ajpyrazine-3- -acetate. MS: 419 which is converted into the 6069*5 abcve acid by alkaline saponification.

8-Propyl-6-(2-thienyl)-s-triazolor4.3-blpvridazine-3-acetic soft acid 3000 11.2 g (200 mmol) of potassium hydroxide in 75 il of 601% 30 water are added at 00 dropwise to a suspension of 11.6 g (100 mmol) of 2-oxo-n-valeric acid and 12.6 g (100 mmol) of 2-acetylthiophene in 75 ml of ethanol and the suspension is held at 00 for 48 hours. After evaporation of the ethanol the residue is made acid with 25% hydrochloric acid and extracted three times with ethyl acetate. The combineO ethyl acetate extracts are dried, 39 filtered and evaporated. After chromatography on silica gel using a 5:1 mixture of methylene chloride and methanol as the eluent and crystallisation from ether there are obtained 10.0 g of rac-m-hydroxy-m-propyl-y- -oxo-2--thiophenebutyric acid as a colourless powder.

melting point 128-1310, MS: 197 (M-COOH).

A solution of 10 i of rac-ci-hydroxy-a-propyl-y- -oxo-2-thiophenebutyric acid and 25 ml of hydrazine 1o hydrate in 250 ml of ethanol is heated to reflux for 3 hours. The solution is evaporated to about 40 ml and the separated crystals are filtered off under suction.

There are thus obtained 5.1 g of 4-propyl-6-(2- -thienyl)-3(2H)-pyridazinone as a colourless powder.

Melting point 171-1740, MS: 220 :Chlorination to 3-chloro-4-propyl-6-(2-thienyl)pyrida.

zine. MS: 238 and hydrazinolysis yields 3-hydrazino-4-propyl-6-(2-thienyl)pyridazine. melting point 20 129-1320, analogously to Example 1.

Subsequent ring condensation with diethyl malonate yields ethyl 8-propyl-6- (2-thienyl)-s-triazolo[4. 3-b]pyridazin-3.-acetate, which is converted by basic saponification into the desired B-propyl-6-(2-thienyl)-s-tria- **zolo[4.3-b]pyridazine-3-acetic acid, MS: 258 (M-CO 2 rac-8B.Prcpyl-c-(3-pyridvlmethyl)-6-(2-thienyl)-s-triazoo.

r4,3-blpyridazine-3-acetic acid In an analogous manner to Example 1. by condensing the above-described 3-hydrazino--4-propyl-6-(2-thienyl)pyridazine with diethyl (3-pyridyl)malonate there is obtained ethyl rac-8-propyl-ax-(3-pyridylmethyl)-6-(2-thienyl)- -s-triazolo--[4,3-b]pyridazine-3-acetate. which is converted by alkaline saponification into the above acid, MS: 349 (M-C0 2 40 rac-8-Propl-z-(3-pridylmethl)-6-(3pridyl)..s.triazolo.

[4.3-blpvridazine-3-acetic acid In an analogous manner to that described above, by an aldol condensation of 2-oxo-n--valeric acid with 3-acetylpyridine there is obtained y-oxco-c-[(E)-propylidene]- -3--pyridinebutyric acid, MS: 219 Ring closure with hydrazine yields 4-propyl-6--(3-pyridyl)-3(2H)- -pyridazinone, MS: 215 which is converted into the 1o corresponding chloride, 3-chloro-4-propyl-6-(3- -pyridyl)pyridazine, MS: 233 Hydrazinolysis to 3-hydrazino-4-propyl-6-C3-pyridyl)pyridazine, MS: 229 and condensation with diethyl C3-pyridyl)malonate yields ethyl rac-8-propyl-a-C3-pyridylmethyl)-6-3-pyridyl)-s-triazolo4,3-b]pyridazine.3-acetate, which is converted by basic saponification into the above acid, MS: 388 Crac-a-Methvl-8-Dropyl-6-(3-pvridvl)-s-triazolor4,3-alpyra ine-3-acetic acid In an analogous manner to that described in Example 1, by condensing 2-hydrazino-3--propyl-5-(3-pyridyl)pyrazine with diethyl methylmalonate there is obtained ethyl e, 25 rac-cL-methyl--propyl-6-(3-pyridyl)-s-triazoio[4,3-aJpyrazine-3-acetate. MS: 339 ,which by saponification analogously to Example 1 is converted into the above acid which is used directly in the next step.

rac-a-Methvl-8-r(RS)-l-methvlpropvll-6-(3-pyridvl)-s- -triazolor4..3-alpvrazine-3-acetic acid in analogous manner to that described in Example 1. by condensing 2-hydrazino-3--((RS)-l-methylpropyl]-5-(3- 41 -pyridyl)pyrazine with diethyl methylmalonate there is obtained ethyl rac-a-methyl-8-[(RS)-l-methylpropyl]-6- -(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate. MS: 353 which by saponification analogously to Example 1 is converted into the above acid which is used directly in the next step.

(1S.2R.3S)-3-Amino-1-cyclopropyl-4-phenyl-1.2-butanediol 9.96 ml (124.5 mmol) of bromocyclopropane in ether (100 ml) are added dropwise within 30 minutes under slight reflux to 3.03 g (124.5 mmol) of magnesium in absolute ether (10 ml) and the mixture is subsequently heated to reflux for 2 1/2 hours. Subsequently, 6.25 g (22.63 mmol) 6* 15 of tert.-butyl [1S,2R)-l-benzyl-2-cyano-2-hydroxyethyl]- 0. carbamate (EP-A 0.266.950) are added dropwise within 45 minutes under reflux and the mixture is heated at reflux for a further 2 1/2 hours. The mixture is then left to cool to 100, 10% citric acid (100 ml) is added *0 20 dropwise thereto and the mixture is extracted twice with 250 ml of ether each time. After usual working-up of the organic phase the crude product is purified by flash S chromatography on silica gel using a 9:1 mixture of toluene and ethyl acetate as the eluent. In this manner 25 there are obtained 2.83 g of tert.-butyl [(1S,2R)-1- -benzyl-2-(cyclopropylcarbonyl)-2-hydroxyethyl]carbamate, MS:246 (M-C 3

H

9 0).

,c 2.83 g (8.77 mmol) of tert.-butyl [(1S.2R)-1-benzyl-2- 30 -(cyclopropylcarbonyl)-2-hydroxyethyl]carbamate are dissolved in methylene chloride (130 ml), acetic acid (3 ml) is added thereto and the mixture is then treated portionwise at 0-100 with 332 mg (8.78 mmol) of sodium borohydride. The reaction solution is stirred at 5" for a further 2 hours and then partitioned between 2N sodium bicarbonate solution and methylene chloride. After the 42 usual working-up of the organic phase the residue is crystallized from ether/hexane, whereby there are obtained 2.1 g of tert-butyl [(1S,2R,3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydrroxypropyl]carbamate melting point 83-85°.

g (6.23 mmol) of tert-butyl ((1S,2R,3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamate are dissolved in methanol (20 ml), 2N hydrochloric acid (20 ml) is added thereto and the solution is heated to 500 for 90 minutes.

The solution is neutralized by adding lN sodium hydroxide solution (40 ml) and concentrated to dryness S**e Ne.. 15 under reduced pressure. The residue is partitioned •between water and methylene chloride and the organic phase o is worked-up as usual. There is thus obtained the desired o (lS,2R,3S)-3-amino-l-cyclopropyl-4-phenyl-1,2-butanediol as a white, crystalline solid, yield 0.7 g MS: 20 150 (M-C 4

H

8 O) (1R or S,2R or S)-l-r(IR.,2S)-l-Amino-3-cyclohexyl-l- S -hydruxypropyll-1.2-cyclohexanediol 25 1.28 g (5 mmol) of tert-butyl (lS)-(2-cyclohexyl-l- -formylethyl)carbamate (EP-A 0.332.008) are dissolved in 25 ml of ether and there are added dropwise thereto at -78° 70 ml (7 molar eq.) of a 0.5 molar l-lithium-l- -cyclohexene solution 1950, 2014) in ether.

S 30 Thereafter, the reaction solution is left to react at -78° for 1 1/2 hours and is subsequently heated to reflux for a further 48 hours. After the usual aqueous working-up the desired product is obtained as an epimer mixture which is separated into the individual components by chromatography on silica gel (eluent: 9:1 mixture of toluene and ethyl acetate). In this manner there obtained 270 mg of 43 tert-butyl E(lS.2S)-2-(l-cyclohexen-1-yl)-l-cyclohexylmethyl)ethyljcarbamate as crystals and 800 mg of tert-butyl [(lS.2R)-2-(l-cyclohexen-1-yl)-1--(cyclohexylmethyl)ethyl~carbamate as an oil, R :0.4 and, respectively. 0.35I (4:1 mixture of toluene and ethyl acetate as the eluent).

260 mg of tert-butyl [(1S.2S)-2-(1l-cyclohexen-1-yl)-l- -(cyclohexylmethyl)ethyl~carbamate (or the epimeric tert- -butyl [(lS.2R)-2-(1-cyclohexen-1-yl)-l-(cyclohexylmethyl)ethyl]carbamate) are dissolved in 2.2-dimethoxypropane (10 ml). 15 mg of p-toluenesulphonic acid monohydrate are added thereto and the solution is stirred at room temperature for 3 hours. After the usual aqueous working-up the residue is chromatographed on silica gel (ethyl acetate/toluene; 9:1) and there are obtained 270 mg of tert-butyl (4S.5S)-5--(1-cyclohexen--1-yl)-4- 20-(cycioheylmethyl)-2.2-dimethyl-3-oxazolidinecarboxylate.

as an oil. RF: 0.4 (9:1 mixture of ethyl acetate anid 0* 0 *6 toluene as the eluent).

340 mg (0.9 mmol) of tert-butyl (4S.5S)-5--(l-cyclohexen-1-yl)-4-(cycloheylmethyl)-2.2-dimethyl-3-oxazolidinecarboxylate in 36 m! of a 3:1 mixture of acetone and water are treated with 2.27 mmol of 4-methylmorpholine 4-oxide S monohydrate and subsequently with 3.4 ml of osmium tetroxide solution (1 g of osmium tetroxide in 199 ml of see* 30 t-butanol and 1 ml of t-butyl hydroperoxide. 70% in water) and the solution is stirred at room temperature for 4 hours. Subsequently. it is treated with 3.4 ml of 38% sodium bisuiphite solution, concentrated under reduced pressure, extracted with ethyl acetate and there is after the usual working-up the desired product as a diastereomer mixture which is separated by chromatography. Yield: 30 mg of the less polar epimer of tert-butyl (4S.SR)-4-(cyclohexylmethyl)-5-E(lS or R.2S 44 or R)-l.2-dihydroxycyclohexyl..2.2dimethyl3.oxazolidine carboxylate as an oil, R :0.3 (4:1 mixture of toluene and ethyl acetate as the eluent) and 330 mg of the more polar epimer tert-butyl (4S.SR)-4-(cyclohexylmethyl)- -5-U1lR or S.2R or S)-1.2-dihydroxycyclohexyl]-2.2-dimethyl-3--oxazolidine carboxylate as a foam, R F 0.28 (4:1 mixture of toluene and ethyl acetate as the eluent).

310 mg (0.753 mmol) of tert-butyl (4S.SR)-4-(cycloor R.2S or R)-1,2-dihydroxycyclohexylJ-2.2-dimethyl-3-oxazolidinecarboxylate (or tert- -butyl (4S.5R)-4-Ccyclohexylmethyl)-5-[(lR or S.2R or S)- -1.2-dihydroxycyclohexyl-22methyl..3...oxazolidinecar boxylate) are dissolved in 8 ml of methanol, 4 ml of 2N hydrochloric acid are added thereto and the mixture is stirred at room temperature for 22 hours. The reaction 0 mixture is then evaporated under reduced pressure. toluene is added thereto twice and evaporation under reduced pressure is carried out each time. In this manner there is 0 :00 obtained (lR or S.2R or S)-l-[U1R2S)-1-amino-3-cyclo- 0 *aohexyl-1-hydroxypropyl]-1.2-cyclohexanediol as an amorphous solid. RF:O.15 (65:10:1 mixture of methylene chloride.

methanol and ammonia as the eluent).

to* Example A A sterile filtered. aqueous solution of (R or S)-N- (lS.2R.3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2.3-dihydroxypropyl]-B-propyl-L. 6-bis(3-pyridyl)-s-triazolo- (4.3-ajpyrazine-3-acetamide is mixed while warming with a :sterile gelatine solution. which contains phenol as a 9. a.:preserving agent, under aseptic conditions so that 1.0 ml of so~lution has the following composition: 45 CR or S)-N-,lS.2R.3S)-1-(Cyclohexylmethyl)-3-cyclopropyl- -2.3-dihydrcoxypropyl]-8-propyl-.6-bis(3-pyridy] -triazolo[4,3-a]pyrazine-3-acetamide 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Dist. Water ad 1.0 ml The mixture is filled into 1.0 ml vials under aseptic conditions.

Example B mg of (R or S)-N-((lS.2R,3S)-l-(cyclohexylmethyl)-3- -cyclopropyl-2.3-dihydroxyprop l-8-propyl-o. 6-bis(3- -pyridyl)-s-triazolo[4. 3-ajpyrazine--3-acetamide are 00 dissolved in 1 ml of an aqueous solution with 20 mg of mannitol. The solution is filtered sterile and filled under aseptic conditions into a 2 ml ampoule, cooled to a low temperature and lyophilized. Prior to administration the lyophilizate is dissolved in 1 ml of distilled water or 1 ml of physiological saline. The solution is used intramuscularly or intravenously. This formulation can also be filled into double chamber injection ampoules.

000 25 Example C 500 mg of finely milled (R or -1-(cyclohexylmethyl)-3-cyclopropyl-2.3-dihydroxypropyl]- -8-propyl-a.6-bis(3-pyridyl)-s-.triazolo[4.3-a~pyrazine- -3-acetamide are suspended in a mixture of 3.5 ml of SOSMyglyol 812 and 0.08 g of benzyl alcohol. This suspension is filled into a container having a dosage valve. 5.0 g of Freon 12 are filled under pressure into the container through the valve. The Freon is dissolved in the Myglyol-benzyl alcohol mixture by shaking. This spray container contains about 100 single doses which can be applied individually.

46 Example D 3 When the procedures described in Examples A-C are followed, corresponding galenical preparations can be manufactured fromn the following, likewise preferred.

compounds: (R or S)-N-4(iS.2R.3S)-l-(Cyclohexylmethyl)-3-cyclopropyl-2. 3-dihydroxypropyl]-8-isopropyl-ax-(imidazol-4- -ylmethyl)-6-(3-pyridyl)-s-triazolo[4.3-apyraze..3- -ace tamide; (II or S)-N-[(lS.2R.3S)--(cyclohexylmethy..3cyclohexyl-2.3-dihydroxypropyl]-z-(imidazol-4.ylmethyl)-8 -isobutyl-6-(3-lpyridyl)-s-triazolo[4.3-a~pyrazine-3-acetate; or S)-N,-[2.S.2R.3S)-l-(cyclohexylmethyl)-2.3-di- 20 hydroxy-5-methyllexyl-B-propyl-6-(3-pyridyl)-..(3- -pyridylmethyl)-s-triazolo[4.3-apyrazine-3-acetamide; (S or R)-N-[(lS.2R.3S)-1-(cyclohexylmethyl)-3-cyclopropy1-2.3-dihydroxypropyl-8-[(RS)--methroylropl]..(3pyridylmethyl)-6-(3-pyridyl)-s. triazolo[4.3-ajpyrazine-3- -acetamide and (1S.2R. 3S)-l- (cyclohexylmethyl-3-cyclopropyl-2. 3- -dihydroxypropyl]-8-[(RS)-l-methylpropyl]-6-(3-pyridyl)-s- -triakzolO[4.3-a]pyrazine-3-carboxamide.

Claims (2)

1. 47- The ckdams, defining the Invention are as follows, 1. Amino acid derivatives of the general formula A-B 0 R R2 I j x R 3 o* 2 *to 25*5 sees~ wherein one of A and B signifies a nitrogen atom and the other signifies or bo .h signify a nitrogen atom, one of X and Y signifies a nitrogen atom and the other signifies -CH- or both signify -CH-.R1 signifies phenyl. pyridyl or thienyl. R 2signifies alkyl or arylpilkyl, R 3signifies hydrogen, alkyl, imidazol- -ylmethyl. imidazol-4-ylimethyl, pyridylmetkiyl, pyrazol-?3-ylmethyl, thien-2-ylmethyl, thiazol-4-ylmethyl, alkylthiomethyl. carbamoylmethyl. carbamoylethyl or benzyl. R 4signifies cyclohexyl- methyl, benzyl or isobutyl and R 5signifies one of the groups (OH 2 n -(CH)m-R 6 and
2. 55.5 S 555 S. S a *5 in which R 6 signifies cycloalkyl. alkyl. alkenyl or arylalkyl, m signifies the number 2 or 3 and n signi- fies the number 3 or 4, in the form of optically pure diastereomers. mixcures of diastereomers, diastereomeric racemates or mixtures of 48 diastereomeric racemates as well as pharmaceutically usable salts of these compounds. 2. Compounds according to claim 1, wherein A and B each si, zy a nitrogen atom. 3. Compounds according to claim 1 or 2, wherein X signifies a nitrogen atom and Y signifies -CH-. 4. Compounds according to any one of claims 1-3, wherein R 1 signifies pyridyl. preferably 3-pyridyl. Compounds according to any one of claims 1-4, wherein R 2 signifies alkyl or phenylalkyl, preferably propyl, isopropyl, isobutyl, 1-methylpropyl or benzyl. 6. Compounds according to any one of claims S" wherein R signifies hydrogen, imidazol-2-ylmethyl, imidazol-4-ylmethyl or pyridylmethyl. preferably 20 imidazol-4-ylmethyl or pyridyl-3-methyl. *o 7. Compounds according to any one of claims 1-6, wherein R 4 signifies cyclohexylrithyl. 25 8. Compounds according to any one of claims 1-7, wherein R signifies group 9. Compounds according to claim 8, wherein m signifies the number 2 and R 6 signifies cycloalkyl. 10. Compounds according to any one of claims 1-9, wherein A, B and X each signify a nitrogen atom, Y CS 1 2 signifies R signifies 3-pyridyl R 2 signifies propyl, isopropyl, isobutyl, 1-methylpropyl or benzyl, R 3 signifies imidazol-4-ylmethyl or pyridyl-3-methyl, R 4 signifies cyclohexylmethyl and R 5 signifies 49 group in which m signifies the number 2 and R 6 signifies cycloalkyl. 11. (R or S)-N-CC1S,2R,3S)-l-(2 yclohexylmethyl)-3- -cyclopropyl-2,3-dihydroxypropyl-8-propyla,6bis3- -pyridyl)-s-triazolo[4,3-a]pyrazinc-3-acetamide. 12. CR or S)-N--[(lS,2R,3S)-l-(Cyclohexylmethyl)-3- -cyclopropyl-2. 3-dilaydroxypropyl-8-isopropyl-c.-imidazol. -4-ylmethyl)-6-C3-pyridyl)-s-triazolo[4. 3-alpyrazine-3- -acetamide. 13. CR or S)-N-[(CS.2R,3S)-l-CCyclohexylmethyl)-3- -cyclohexyl-2. 3-dihydroxypropyl 2-a-C Imidazol-4-ylmethyl) -8-isobutyl-6-(3-pyridyl)-s-triazolc(4. 3-a]pyrazine-3- -acetate. :*Got 14. CR or S)-N-C(CS,2R.3S)-l-CCyclohexylmethyl)-2.3- -py. idylmethyl)-s-triazoloC4,3-alpyrazine-3-acetamide. CS or R)-N-[(1S.2R.3S)-l-Cyc.ohexylmethyl)-3- -cyclopropyl-2, 3-dihydroxypropyl3-8- [(RS)-l-methylpropyl]- -aL--3-pyridylmethyl)-6-(3-pyridyl)-s-triazolo(4, 3-a]- 25 pyrazine-3-acetamide. 16. N-[(CS.2R.3S)-l-(Cyclohexylmethyl-3-cyclopropyl- *~.-2,3-dihydroxypropyli]-8-(tS)-1-methylpropyl]-6-(3-pyridyl)- -s-triazolo[4,3-a~pyrazine-3-carboxamide. 17. Compounds of the formula A' B' 0 N2 OH ii X Y R 3 Yl wherein one of A' and B' signifies a nitrogen atom and the other signifies -CH- or both signify a nitrogen atom and one of X and Y signifies a nitrogen atom and the other signifies -CH- or both signify with the proviso that X signifies -CH- when A' and s B' each signify a nitrogen atomi, R, signifies phenyl, pyridyl or thienyl, R 2 signifies alkyl or arylalkyt, and R 3 signifies hydroge, alkyl, imidazol-2-ylmethyl, imidazol-4-ylmethyl, pyridylmethyl, pyrazol-3-yl methyl, thien-2-yinmethyl, thliazol-4-ylrnethyl, alkyithiomethyl, carbamnoylmnethyl, carbamnoylethyl or benzyl. SO of 2 51 18. Amino acid derivatives according to any o claims 1-16 for use as therapeutically ac I substances. 19. Amino acid de ives according to any one of claims 1-16 use in the control or prevention of high bl ressure and cardiac insufficiency. A process for the manufacture of a compound according to any one of claims 1-16. which process comprises a) reacting a compound of the general formula R4 I II H 2 N R SS wherein R and R have the significance given in claim 1, with a compound of the general formula 25 S 25 A-B 0 R 2 N: x N OH X Y R3 Ri 1 2 3 wherein A, B, X, Y, R R and R have the significance given in claim 1, S or an activated derivative thereof, and db 52 b) if desired, separating a mixture of diastereomiric racemates into the diastereomeric racemates or optically pure diastereomers, and/or c) if desired, separating a mixture of diastereomers into the optically pure diastereomers, and/or s d) if desired, converting a compound obtained into a pharmaceutically usable salt. 19. Amino acid derivatives according to any one of claims 1 to 16, whenever prepared according to the process as claimed in claim 18 or by an obvious chemical equivalent thereof. Amino acid derivatives of the formula I as ;et out in claim 1, substantially as hereinbefore described with reference to any one of the Examples. 21. A process for the preparation of amino acid derivatives of the formula I as set out in claim 1, substantially as hereinbefore described with reference to any one of the Examples. 22. A pharmaceutical composition for the control or prevention of high blood pressure and/or cardiac insufficiency comprising a compound according to any one of claims 1 to 16, 19 or 20 together with a pharmaceutically acceptable carrier, diluent and/or excipient. 23. A method for the treatment or prophylaxis of high blood pressure and/or cardiac insufficiency in a patient requiring said treatment or prophylaxis, which method comprises administering to said patient an effective amount of at least one compound according to any one of claims 1 to 16, 19 or 20, or of a composition according to claim 22. Dated 26 July, 1993 F. Hoffmann-La Roche AG 25 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON S S 52 of 2 RAN 4019/111 Abstract The compounds of the formula A--B 0 R4 R2 N NH Rs X Y R 3 R1 a d. w 1 2 3 4 wherein A, B, X, Y, R, R 2 R 3 R and R have the significance given in claim 1, 15 in the form of optically pure diastereomers, mixtures of V. diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts thereof inhibit the activity of the natural enzyme renin and can accordingly be used in the form of 20 20 pharmaceutical preparations in the control or prevention r of high blood pressure and cardiac insufficiency. They can be manufactured according to various methods which are known per se.