CA2095671A1 - Amino acid derivatives - Google Patents
Amino acid derivativesInfo
- Publication number
- CA2095671A1 CA2095671A1 CA002095671A CA2095671A CA2095671A1 CA 2095671 A1 CA2095671 A1 CA 2095671A1 CA 002095671 A CA002095671 A CA 002095671A CA 2095671 A CA2095671 A CA 2095671A CA 2095671 A1 CA2095671 A1 CA 2095671A1
- Authority
- CA
- Canada
- Prior art keywords
- signifies
- accordance
- amino acid
- acid
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Abstract The compounds of the formula
Description
2 ~ 9 ~ 6 ~ 1 The present invention is concerned wi~h amino acid 5 derivatives. In particular, it is concerned wi~h amino acid deriva~ives of the general formula A~S(:~ N ~
0 wherein R1 signifies imidazolylme~hyl or pyridylmethyl and A signifies carboxyl, benzyloxycarbonyl, hydroxymethyl or alkylcarbonyloxymethyl, in the form of optically pure diastereomers, rnixtures of dia-stereomers, dias~ereomeric racemates or mixtures of dias~ereo-meric racemates as well as ph~rmaceutically usable salts of ~hese compounds.
:
These compounds are distinguished by valuable pharma-codynamic properties and can be used for the control or 20 prevention of illnesses. In particular, they have a renin-inhibiting activity and are accordillgly suitable for the treatment of high blood pressure and cardiac insufficiency.
,; .
- Objects of the present invention are the compounds of 25 formula I and their pharrraceutically usable sal~s per se and for use as therapeutically active substances, the manufacture of ~hese compounds, medicaments containing these and the manu-facture of such medicaments as well as the use of the compounds of formula I and their pharmaceutically usable salts in the 30 control or prevention of illnesses or in the improvemen~ of health, especially in the control or prevention of high blood pressure and cardiac insufficiency.
Kbr/1 5.2.93 ~r"
'~
The compounds of formula I above are already generically known frnrn, for example, EP-A-0,309,766 and ~P-A-0,377,139, but i~ has surprisingly been found tha~ lthey are distinguished by a pronounced oral activi~y. Of ~he compounds specifically named 5 in the two European Pa~en~ Public~tions only two are described as being orally active, namely ~he end produc~ of Example 16 of EP-A-0,309,766 and, respec~ively, the end product of Examp~e 1 Qf EP-A-0,377,139. A comparison of the oral activity of the compounds in accordance with the invention with the more active o previously described compound (Example 1 of EP-A-0,377, 1 39) shows a significantly higher oral activity for ~he compounds of formula 1, as can be coneluded readily from Figures 1-3 disoussed below.
The alkyi residues which appear in the term "alkylcarbonyl-oxymethyl" or "alkylcarbonyl" in the present description are straight-chain and branched, saturated hydrocarbon residues with 1-8, preferably 1-4, carbon atoms sueh as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyll tert-butyl, pentyl, 20 hexyl and the like.
The term "pharmaceutically usable salts" embraces salts with inorganic or organic acids such as hydrochloric acid, hydro-bromic acid, nitric acid, sulphuric acid, phosphoric acid, citric 25 acid, formic acid, maleic acid, ace~ic acid, succinic acid, tartaric acid, methanesulphonic acid, p-to5uenesulphonic acid and the like or, where A signifies carboxyl, also with inorganic or organic bases such as sodium or potassium hydroxide, ammonia, triethylamine, diisopropylethylamine, pyridine and the like. Such 30 salts ean 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 compounds of formula I have a~ least four asymmetric 35 carbon atoms and are therefore presen~ in the forrn of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereorneric racemates. The present invention embraces all forms. Mixtures of diastereomers, dia-2 ~ 7 ~
stereomeric racemates or mixtures of dias~ereomeric racerna~escan be separated according to usual methods, e.g. by column chromatography, thin-layer chroma~ography, HPLC and the like.
Those compounds of formuia I in which A signifies hydroxy-methyl or alkylcarbonyloxymethyl~ especially alkylcarbonyloxy-methyl, particularly C~ 4-alkylcarbonyloxymethyl, are preferred.
Where A does no~ have ~he foregoing significances, then those compounds of formula I in which A signifies carboxyl are o pre~erred.
From the foregoing it will be evident that those compounds of formula I in which A signifies C1 4-alkylcarbonyloxymethyl are particularly preferred.
Specially preferred compounds of formula I are:
2,2-Dimethylpropionic acid 2-[(S)- or 2-[~R)-2-[~S3-1 t(1 S~2R~3s~-1-cyclohexylmethyi-3-cyclopropyl-2~3-dihydr 20 propylcarbamoyl3-2-imidazol-4-yl-e~hylcarbamoyl]-3-phenyl-propylsulphonyl~-2-methylpropyl ester, 2,2-dimethylpropionic acid ~-~(R)- or 2-~S)-Z-[(S)-1-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-25 propylcarbamoyl~-2-pyridirl-3-yl-e~hylcarbamoyl]-3-phenyl-propylsulphonyl]-2-methylpropyl es~er and 2,2-dimethylpropionic acid 2-[~S)- or 2-~(R)-2-~(S)-1-[(1 S,2P~,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-30 propylcarbamoyl]-2-pyridin-3-yl ethylcarbamoyl]-3-phenyl-propylsulphonyl]-2-methylpropyl es~er.
Compounds of forrnula I in the form of optically pure diastereomers, mixtures of dias~ereomers, dias~ereomeric 35 racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts thereof can be manufac~ured by a) reacting a compound of the general forrnula ' :
';
2 ~ 9 ~ 6 71 2 ~ ~ 11 wherein R1 has the ~ignificance given above, 5 with an acid of the general formula Al ~SQ~i::)H lll '13 -wherein A1 signifies ben~yloxycarbonyl, hydroxymethyl or o alkylcarbonyloxymethylJ
or an activated derivative thereof, or b) reacting the compound of the ~ormula OH ~
H2N~ IV
OH
with an acid of the general formula O Rl A~ ~SO~ N ~OH V
wherein A1 and R1 have the si~nificance given above, or an ac~ivatecl derivative thereof, or 2~5Çi7~
s c) for the manufacture of a compound of formula I ;n which A
signifies carboxyl, cleaving off ~he benzyl group in a compound of formula I in which A signifies ben~yloxycarbonyi, and d) if desired, separating a rnixture of diastereomeric racemates into the diastereomeric racema~es or optically pure diastereomers, and/or 0 e) if desired, separating a mixture of dias~ereomers into the optically pure diastereomers, and/or f) if desired, conver~ing a compound obtained into a pharma-ceuticaily usable salt.
The acylation of a compound of forrnula ll with an acid of forrnula lll or an aetivated derivative thereof is effec~ed according to methods known per se in peptide chemistry. Suitable acylating agents are activated deriva~ives such as esters, mixed 20 esters, acid halides, acid anhydrides or mixed anhydrides. The reaction is carried out in an or~anic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0C and room tempera~ure. As solvents ~here some into consideration especially aromatic hydrocarbons such as 25 benzene, ~oluene or xylene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as cliethyl e~her, tetrahydrofuran or dioxan, and the like. Furthermore, the acylation can be effected in the presence of a condensation agent such as HBTU [O benzotriazolyl-N,N,N',N-tetramethyluronium 30 hexafluorophosphate, BOP [benzotrlazol-1-yloxy-bis(dimethylamino)phosphonium hexafluorophosphate], BOP~
[bis(2-oxo-2-oxazolidinyl)phosphine chloride], HOBT ~N-hydroxybenzotriazole}, DCC CdicYclohexYlcarbodilmide hydrochloridel, EDC ~N-(3-dirnethylaminopropyl)-N'-3s ethylcarbodiimide hydrochloride] and the like. The reac~ion isconveniently carried out in an organic solvent or solvent mixture which is inert under the reaction conditions at a ~ernperature between about 0 and 50C, preferably at about room tempera~ure.
~.:
2~ 671 As solvents there come into consideration especially dimethyl-forrnamide, methylene chloride, acetonitrile, tetrahydrofuran and the like.
The reaction of a compound of formula IV with an acid of formula V or an activated derivative thereof is also effected according to me~hods which are known per se in peptide chemistry, i.e. under the same conditions as given above for the acylation of a compound of formula ~I. Examples of suitable 0 activated compounds of formula V are iikewise acid halides, acid anhydrides, mixed anhydrides, esters, mixed esters and the like.
The cleavage of ~he benzyl group in accordance with process variant c) is also effected according to methods known per se, conveniently hydrogenolytically.
The starting ma~erials of formula ll are ,oartly novel and partly known. These cornpounds can be prepared by reacting the compound of formula IV with a compound of the general formula o H2N ~ Vl wherein R1 has the significance given above.
This reaction is effected according to methods which are known 2s in pep~ide chemistry, i.e. under the reaction conditions which are described above for the acylation of a compound of formula ll.
The starting material of formula IV~ i.e. 3-amino-4-cyclo-hexyl-1-cyclopropyl-1,2-blltanediol, is known.
The compounds of formuia Vl are known or can be obtained in analogy to the preparation of the known compounds.
The acids of formula lll and their activated derivatives are 35 novel and are also an object of the present invention. The prepar-ation of the acids of formula lll is presented by way or formulae ':
2 ~ 9 .~ ~ 7 1 in the following Reaction Scheme. The ac~ivated derivatives can be prepared readily by any person skilled in the art having regard to the state of the art and taking into consideration the nature of the activated deriva~ive.
The acids of formula V and ~heir activated derivatives are also novel and are an objeet of the present invention. They can be prepared readily by reacting an acid of formula lil wi~h a compound of formula Vl. The reaction is effected aecording to 0 me~hods which are known in peptide chemis~ry, i.e. under ~he reaction conditions which are described above for the aeyl~tion of a compound of formula 11. The ac~ivated derivatives o~ ~he acids of formuia V can be prepared readily by any person skilled in the art in ~he same manner as those of the acids of ~ormula 111.
The steps which are presented in the Reaction Scheme are without exeeption reactions which are usual in synthetic chemistry, all of whieh are carrie~ out according ~o methods known per se. With respect to the pr~cise reaction condi~ions for 20 the steps pr~sented in the Reaction Scheme, reference is made to the experimen$al section. In the Reac~ion Scheme the symbol R2 signKies aralkyl, especially benzyl, or alkyl, especially ~-butyl, R2l signifies alkyl, especially ~-butyl, R3 signifies benzyl and signifies alkylcarbonyl.
The starting materials of formulae Vll and Vlll used in the Reaction Scheme are known.
: :.
"
2~9~6~
Scheme H~SH ~ o ?
Vll ~lli 111~
ll l J~SOJ~R: ' ~X Xlll I
o ~ o X
_lo~5;0~0R2- --D zo~S J's Xl X~l ~; J's ZO~;OEJ~SOH
Illa Illb 2~ 671 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 blovd and there brings about the cleavage of angiotensinogen with the formation 5 of the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to the octapeptide angiotensin Il. Angiotensin ll increases the blood pressure not only directly ~y ar~crial constriction, but also indirectly by the liberation of the sodium ion-retaining hormone aldosterone from the adrenal 0 gland, with which is associated an increase in the extracelluiar fluid volume. This increase is attributed to the action of angio-tensin ll itself or to the heptapeptide angiotensin lll which is formed therefrom as a cleavage product. Inhibition of ~he en~y-ma~ic ac~ivity of renin bFings about a decrease in the formation of angiotensin I and as a consequence thereof the forma~ion of a smaller amoullt of angiotensin ll. The reduced concentration of this active peptide hormone is the actual reason for ~he blood pressure-lowering ac~ivity of renin inhibitors.
The activity of renin inhibitors can be demonstrated experimentally by means of the in vivo test described hereinaf~er:
BloQd pre~sure-lowerins~ ~tivi~y in thç a,~ mQdç~
The blood pressure-lowering effect of the compounds was measured in normotensive squirrel monkeys of both sexes (weight 400-700 g). The sodium depletion was achieved by the subcu-taneous iniection of in each case 5 mg/kg of furosemide 66, 42 and 18 hours prior to the experiment.
The compounds were administered orally ~s tlhe methane sulphonate salts in aqueous solution in a dosage of 3 mg/kg. The arterial blood pressure was measured according ~o the procedure published in Hypertension 1991; 18: 22-31.
The results obtained in this test are cornpiled in the following Figures 1-3.
- l O ~ 2 Q 9 ~ 6 r~ 1 oo oo Il 11 11 11 11 ¢ ~ ~ ~ u s; ~
+ ~ ~ t ~ ' ~ '~
r~ " ~
r' ~ ~, ~ ~ ", ~ -~ _ H
_~ _,~
'- ~ _ a~
I ~
O O O O ~ ~
~ N ~I') (6H~W~ d~W ~ L~3a 2~9 ~ 6 ~1 n : N(lmber of tes~s A : Control B : (2S,3R,4S)-4-CL-N-~(ZS)-3-[(2S or R)-2,3-Diacetoxypropyl~sulphonyl-2 (1-naphthyl-methyi)propionyl]norleucyl]amino-5-cyclohexyl-1 -morpholino-2,3-pen~anediol ~O C : (2S,3R,4$)-4-[L-N-[~2$)-3-~2R or S)-2,3-Diace~o~ypropyl3sulphonyl-2-( 1 -naphthyl-methyl)propionyl~norleucyl~amino-5-oyclohexyl-1 -morpholino-Z,3-pentanediol D : (S or R)-2-Benzyl-N-[(S)-l-C(lS,2P~,3S)-1 cyclohexylmethyl-3-cyclQpropyl-2,3-dihyclroxy-propylcarbarnoyl~-Z-imidazol-4-y5e~hyl]-3 -(2-hydroxy-1 ,1 -dimethylethylsulphonyl)propion-amidc zo E : Acetic acid 2-~(S)- or 2-~(R)-2-L(S)-1-[~1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2 ,3-dihydroxypropylcarbamoyl]-2-imidazol-4-ylethylcarbamoyl]-3-phenylpropylsulphonyl~-2-methylpropyl ester 2~9~fi71 Il 11 11 11 11 11 + t ~ t I ~
t ~ ~
.
~"
~i ,'q~\ L
1 ~
w~
~:
[
o o ~ - ~
~ ~ t ( 6HWW) dVW ~1~3a 2~9a671 A : Control B : (2S,3R,4S)-4-[L-N-r(2S)-3-~(2S or R)-253-Diacetoxypropyl3sll1phonyl-2-( 1 -naphthyl-methyl)propionyl]norleucyl]amino-5-cyclohexyl-1 -morpholino-2, 3-pentanediol C : (2S,3R,4S)-4-EL-N-[(2S)-3-~2R or S)-2,3-Diacetoxypropyl]sulphonyl-2-1~ 1 -naphthyl-o methyl~propionyl3norleucyl]amino-5-Gyclohexyl-1 -morpholino-2,3-pentanediol F : Benzyl 2-~(S)- ur 2-~(R)-2-~(S)~ l S,ZR,~S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl~-2-imidazol-4-ylethylearba-moyl3-3-phenylpropylsulphonyl]-2-rnethyl-propionate G : 2-~S)- or 2-l[(R)-2-[~S)-1-~(1 S,2R,3S)-1 -Cyclo-hexylmethyl-3-cyclopropyi-2,3-dihydroxy-propylcarbamoyl]-2-imidazol-4 ~ylethylcarba-moyl3-3-phenylpropylsulphonyl~-2-methyl-propionic acid :`
H : 2-(R)- or 2-[(S)-2-[(S)-1-~(1 S,2R,3S)-1-Cyclo-hexylmethyl-3-cyclopropyl-2 ,3-dihydroxy-propylcarbamoyll-2-imidazol-4-ylethylcarba-rnoyl~-3-phenylpropylsulphonyl]-2-me~hyl-propionic acid 1 ~ 2 ~ .9 ~ ~ 7 1 ~ P
+ t ~ t t 4 ~aD
,~
~, 2 o H
- N
~ ' O
o 0 ~ !
(6HWul~ dYW Yl~a 209Cj6 l1 1s Q : Control B : (2S,3R,4S)-4-~L-N-~2S3-3-~(2S orR)-2,3-Diacetoxypropyl]sulphonyl-2-(1 naphthyl-methyl)propionyl]norleucyl]amino-5-cyclohexyl-1 -morpholino-2,3-pen~anediol C : (2S,3R,4S)-4-[L-N-~25)-3-1~(2R or S)-Z,3-Diacetoxypropyl}slJlphonyl-2-( 1 -naphthyl-1 o methyl)propionyl]norleucyl3ctmino-5-cyclohexyl-l -morpholino-2 9 3-pentanediol 2,2-Dimethylpropionic acid 2-[(S)- or 2-[~R)-2-~(S~ (1 S,ZR,3S)-1 -cyclohexylmethyl-3-cyciopropyl-2,3-dihydroxypropylcarbamoyl]-2-imidazol-4-yle~hylcarbamoyl]-3-phenylpropyi-sulphonyl~-~-methylpropyl ester J : 2,Z-Dirnethylpropionic acid 2-[(R~- or 2-[(S)-2-E(S)-l -E(l S,2R,3S)-l-cyclohexylmethyl-3 cyclopropyl-2,3-dihydroxypropylcarb3moyl]-2-~` pyridin-3-ylethylcarbamoyl]-3-phenylpropyl-sulphonyl3-2-methylpropyl es~er K : 2,2-Dimethylpropionic acid 2-[(S~-or2-[(R)-2-~` [(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl~-2-',: pyridin-3-ylethylcarbamoyl]-3-phenylpropyl-sulphonyl]-2-rne~hylpropyl ester 2 0 ~ 7 ~
The compounds oF formula I as well as their pharmaceuti-cally usable salts can be used as medicaments, e.g. in the form of pharmaceu~ical preparations. The pharmaceutical preparations can be administered enterally such as orally, e.g. in the form of 5 tablets, coated tablets, drag~es, hard and soft gela~ine capsules, solu~ions~ emulsions or suspensions, nasally, e.g. in the form of nasal sprays, or rec~ally, e.g. in ~he form of suppositories.
However, the administration can also be effected parenterally such as intramuscularly or intravenously, e.g. in the forrn of o injection solutions.
The compounds of formula i as well as ~heir pharmaeeuti-cally usable salts can be processed with pharmaceutically inert, inorganic or organic excipients for ~he manufacture of tablets, 5 coated tablets, dragees and hard gelatine capsules. Lac~ose, curn starch or derivatives thereof, talc, stearic acid or its salts etcO
can be used e.g. as such excipients for tabiets, dragées and hard gelatine capsules.
Sui~able excipien~s for soft gelatine capsules are e.g.
vegetable oils, waxes, fats, semi-solid and liquid polyols e~c.
~uitable excipients for ~he manufacture of solutions and syrups are e.g. water, polyols, saocharose, invert sugar, glucose 25 etc.
Suitable excipients for injec~ion solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
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 preservatives, solubilizers, viscosity-increasing substances, 35 stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxiclants. They can also contain still other therapeu~ically valuable substances.
2 0 9 ~ ~ 71 In ~ccordance with the invention the compounds of general formula I as well as their ph~rmaceutically usable salts can be used in ~he control or prevention of high blood pressure and s cardiac insufficiency. The dosage can vary within wide limits and will, of course, be fi~ted ~o the individual requirements in eaeh par~icular case. In general, in the case of oral admini-stration there should suffiee a daiiy dosage of about 3 mg to about 3 g, preferably about 10 mg to about 1 g, e.g. approxi-0 mately 300 my per person, divided in preferably 1-3 unit doses, which ean e.g. be of the same amount, whereby, however, the upper limi~ just given can also be exceeded when this is found ~o be indioa~ed. Usually, ehildren receive half of the adult dosa~e.
The following Exarnples illustra~e ~he present invention, but are not intended to be limiting in any manner. All temperatures are given in deyrees Celsius. The following abbrevia~ion~ are used:
zo His-OH = L-Histidine Fmoc = 9-Fluorenylmethoxycarbonyl DBU = 1,8-Diazabicyclo[5.4.0]undee-7-ene[1,5-5]
,~
, ~m~
2s A mixture of 2.33 9 (6.06 mmol) of (RS)-2-benzyl-3-[2 ~2,2-dimethylpropionyloxy) 1,1-dimethylethylsulphonyl]propionic aeid, 2.0 g (5.49 mmol) of (S~-2-amino-N-[(1 S,2R,3S)-1-30 cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl]-3-imidazol-4-ylpropionamide, 0.61 g (6.06 mmol) of triethyl-amine, 0.95 g (6.06 mmol) of HOBT and 2.3 9 (6.06 mmol) of HBTU in 50 ml of dimethylformamicle was stirred a~ room ~emperature overnight. Thereafter, the reaction mixture was 35 evaporated in a high vacuum. The residue was taken up in 500 ml of ethyl acetate and washed twice with 200 ml of saturated sodium hydrogen carbonate solution each time. The ethyl acetate phase was dried over sodium sulphate and subsequently evapor-2~9a~71 a~ed under reduced pressure. For purification and separation ofthe two epimeric produc~s, the residue (4.98 g) was chromato-graphed twice on 400 ~ of silica gel using a 97:3:0.1 mixture of methylene chloride, methanc~l and pyridine as the eluent. The less 5 polar 2,2-dimethylpropionic acid 2-[(S)- or 2-[~P~)-2-[(S)-l-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]-Z-imidazol-4-ylethylcarbamoyl~-3-phenyl-propylsulphonyl3-2-methylpropyl ester was precipitated from ethyl acetate/hexane and gave 1.3 9 of a colourless solid, MS:
10 731 (M~H~+. The more polar 2,2-dimethylpropionic acid Z-~(R)- or 2-[(S)-2-C~S)-l-[(1 S,2R,3S)-1-cyclohexylmethyl-3-eyclopropyl-2,3-dihydroxypropylearbamoyl]-2 -imidazol-4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-me~hylpropyl ester gave, after Iyophilization from dioxan/water, 1.08 g of a colourless powder, 15 MS: 731 (M+H)+.
The 2-amino-N-[(1S,2R,3S)-1-cyclohexylrnethyl-3-cyclo-propyl-2,3~dihydroxypropyl]-3-irnidazol-4-ylpropionamide used as ~he starting material was prepared as ~ollows:
(a) tert-Butyl ~4S,5Ps)-4-cyclohexylmethyl-5-~(S)-cyclo-propylhydroxymethyl3-2,2-dimethyl-3-oxazolidinecarboxylate and tert~butyl (4S,5R)-4-cyclohexylmethyl-5-[~R)-cyclopropyl hydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate:
A solution of 3.21 9 olF ter~-butyl (4S,5R)-4-cyclohexyl-methyl)-5-formyl-2,2-dimethyl-3-oxazolidinecarboxylate [W0 87/05302] in 25 ml of tetrahydrofuran was added dropwise at about 15 to a ~irignard compound, prepared from 3.94 ml 30 (49 mmol) of bromoeyclopropane and 1.2 g ~0.049 gram atom) of magnesium shavings in 22 ml of te~rahydrofuran, and the reaction mixture was subsequently stirred at room temperature under argon for 16 hours. Thereafter, the reaction mixture was poured into 40 ml of an ice-cold saturated ammonium c~loride 35 solution and extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate extracts were washed with 40 ml of ice-cold saturated ammonium chloride solution, then combined, dried over sodium sulphate and evaporatecl under reduced ~9;~6~1 lg pressure. For purification, the residue (4.33 9) was chromato-graphed over a column of 1 10 g of silica gel, prepared with toluene anà 1% triethylamine, using a 95:5 mixture of ~oluene and ethyl acetate as the eluen~. There were ob~ained 1.9 g of ~er~-5 butyl (4S,5R)-4-cyclohexylrnethyl-5-[(R)-cyclopropylhydroxy-methyl]-2,2-dimethyl-3-oxa~olidinecarboxylate, MS: 368 (M+H)+, and 0.5 g of tert-butyl (4S,SR)-4-cyclohexylmethyl-5-[(S3-cyclopropylhydroxymethyl]-2 ,2-dimethyl-3-oxazolidinecarboxyl-a~e, MS: 368 ~Ivl+H)+, each as a colourless oil.
(b) ~1S,2R,3S~-3-Amino-4-cyclohexyl-1-cyclopropyl-bu~ane-1 ,2-diol:
1.42 g (3.86 mmol) of ~ert-butyi (4S,5R)-4-cyclohexy!-methyl-5-[(R)-cyclopropylhytlroxyme~hyl]-2,2-dlime~hyl-3-oxazolidinecarboxyia~e dissolved in 15 ml of methanol and 10 ml of wat~r were treated wi~h 4 ml of 7.5N hydrochloric acid and s~irred a~ 50O for 3 hours. The reac~ion solution was cooled to 3O
in an ice bath, treated dropwise with 4 ml of 7.5N sodium 20 hydroxide solution and s~irred for 1 hour. The suspension obtained was evaporated under reduced pressure, water was removed azeotropically twice with 10 ml of ~oluene and the `~ residue was stirred three times with 10 ml of a 95:5 mix~ure of methylen~ chloride and methanol. The insoluble residue was 2s filtered off and ~he filtrate was ~vaporated under reduced pressure. The resulting crude produç~ (1.14 9) was suspended in 15 ml of ether and ~hen fil~ered off under suction. There was ob~ained 0.58 9 of (lS,2R,3S~-3-amino-4-cyclohexyl-1-cyclo-propylbutane-1,2-dioi as colourless crystals, rn.p. 141-142.
(S)-Z-Amino-N-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclo-propyl-2 ,3-dihydroxypropyl]-3-imidazol-4-ylpropionamide:
A mix~ure of 343 mg (1.51 mmol) of (1 S,2R,3S)-3-amino-35 4-cyclohexyl-1-cyclopropylbutane-1,Z-diol, 995 mg (1.66 mmol) of (Fmoc)2His-OH, 0.21 ml (1.61 mmol) of 4-ethylmorpholine, 449 mg (3.22 mrnol) of HOBT ancl 347 mg (1.81 mmol) of EDC in 20 ml of dimethylformamide was left to stand at room 2 ~ 9 ~ 6 7 ~
temperature overnight. Thereafter, the reaction mixture was evapora~ed in a high vacuum, the residue was poured into a mixture of i~e and 90 ml of sodium bicarbonate solution and ex~raoted three times with 150 ml of ethyl ace~a~e each time.
s The three ethyl acetate extrac~s were washed in succession wi~h 70 ml of saturated ammonium chloride solution, 70 ml of 2N
sodium bicarbonate solution and 70 ml of satur~ted soclium chloride solution, çombined, dried over magnesium sulphate, filtered and evaporated. The crude product ob~ained was stirred o at room tempera~ure for 3 hours in 60 ml of methylene chloride and 2 ml of piperidine. Thereaf~er, the reaction mixture was evaporated and the residue was tri~urated with 50 ml of hexane and filtered off. The filtra~e was chromatoyraphed on 70 9 of silica gel using a 65:10:1 mixture o~ methylene chloride, methanol and ammonia as the eluent, whereby there were obtained 390 mg of (S)-2-amino-N-[(1 S,2R,3S)-1-cyclohexyl methyl-3-cyciopropyl-2,3-dihydroxypropyl]-3-imidazol-4 ylpropionamide as a colourless foam; MS: 365 (M+H)+.
2() The (RS)-2-benzyl-3-[2-(Z,2-dimethylpropionyloxy)-1,1-dimethylethylsulphonyl]propionie acid used as the starting rna~erial was prepared as ~ollows:
(d) (RS~-2-(2-Benzyloxycarbonyl-3-phenylpropylsulphonyl)-25 2-methylpropionic acid:
8.4 g (55.4 rnmol) of DBU were added dropwise to a solution of 3.3 9 ~27.7 mmol) of 2-rnercaptoisobutyric acid ~Can.
J. Chem. Çl (8), 1872] and 6.9 9 (27.7 mmol) of benzyl 2-benzyl-30 acrylate [EP-A 0,1 17,429~ while holding the temperature of the reaction mix~ure between 5 and 10. After completion of the addition the mixture was stirred a~ 10 for a fur~her 5 hours.
Subsequently, the reaction mixture was treated dropwise, while cooling with ice and holding the temperature below 10, with 35 Z2.5 9 (36.6 mmol) of potassium monopersulpha~e triple salt suspended in 450 ml of water. Thereafter, the mix~ure was stirred at the same temperature for one hour, then coolecl to 0 and a further Z2.5 g (36.6 mmol~ of potassium rnonopersulphate 2~3~1~7~
triple salt were added spatula-wise. The mixture was left to warm slowly to room ~emperature and stirred for a further 15 hours. For the working-wp, ~he mix~ure was diluted with 200 ml of water and extracted four times with 60 ml of ethyi 5 acetate each time. The eombined organic extracts were dried over sodium sulphate and evaporated under reducecl pressure until ~he product began to crystallize. Then, 30 ml of hexane and 20 ml of ether were added while stirring and ~he precipitated produc~ was subsequently filtered off under suction and dried.
o There were obtained 9.7 g of ~RS)-2-(2-benyloxycarbonyl-3-phenyipropylswlphonyl)-2-methylpropionic acid as a colourless solid; MS: 42~ ~M+NH4)+.
(e) (RS)-2~(2-Benzyloxycarbonyl-3-phenylpropylsulphonyl)-2-methylpropionyl chloride:
A solution of 9.0 9 (22.2 mmol~ of (RS)-2-~2-benzyloxy-carbonyl-3-phenylpropylsulphonyl)-Z-methylpropionic acid and 9.6 ml (112.3 rnmol) of oxalyl chloride in 18 ml of te~rahydro-20 furan was heated to 500 for 18 hours. Thereafter, ~he reactionsolution was evaporated under reduced pressure. The residue was ~aken up twice with 250 ml of toluene each time and evaporated under reduced pressure. The (RS)-2-(2-benzyloxycarbonyl-3-phenylpropylsulphonyl)-2-methylpropionyl chloride was obtained 25 as a yellowish oil in quanti~ative yield and was used in the next step without purification and characterization.
~ f) Benzyl (RS)-2-benzyl-3-(2-hydroxy-1 ,1 -dimethyl-ethylsulphonyl)propionate:
A solution of 9.4 9 (22.2 mmol) o~ (RS)-2-(2-benzyloxy-carbonyl-3-phenylpropylsulphonyl)-2-methylpropionyl ehloride in 45 ml of tetrahydrofuran was treated dropwise at 0 within 15 minutes with 2.3 ml ~23.3 mmol) of 1 OM borane-dimethyl 35 sulphide complex and subsequently stirred at room temperature for 3 hours. Thereafter, the mixture was cooled to oo and about 2 ml of methanol, 30 rnl of water and 30 ml of sa~urated sodium hydrogen carbonate solution were added in succession. The 2~95671 mix~ure was then extracted ~hree times with 35 ml of ether each time and the combined organic phases were subsequent3y dried over sodium sulphate and evaporated under reduced pressure. The crude product was digested in 50 ml of ether and, after suction 5 filtration and drying, there were obtained 6.7 g of benzyl (RS)-2-benzyl-3-(2-hydroxy~ dimethylethylsulphonyl~propiona~e as a colourless solid; MS: 408 (M~NH4)~.
(g) Benzyl (~S)-2-Benzyl-3-[2-(2,2-dimethylpropionyloxy)-10 1,1-dim~thylethylsulphonyÇ~propionate:
0.74 g (6.14 mmol, 1.2 mol eq.) of pivaloyl chloride were added at room tempera~ure ~o a solution of 2.0 g (5.12 mmol) of benzyl (RS)-2-benzyl-3-(2-hydroxy-1,1-dimethyle~hylsulphonyl)-propionate and 60 mg (0.5 mrnol3 of N,N'-dime~hylaminopyridine in 20 ml of dry pyridine. The reaction mix~ure was warmed ~o 40 and stirred at this temperature for a further 6 hours. For ~he working-up, the cooled reaction solution was evaporated in a wa~erjet vacuum. For purification, the residue was chromato-20 graphed on silica gel using a 99:1 mixture of methylen@ chlorideand methanol as the eluent. There were obtained 2.18 g (90% of . theory) of benzyl (RS)-2-benzyl-3-[2-(2,2-dimethylpropionyl-oxy)-1,1~ime~hyle~hylsulphonyl~propionate as colourless crystals; MS: 475 ~M+H)~.
(h) (RS)-2-Benzyl-3-[2-(2,2-dimethylpropionyloxy)~
dimethylethylsuiphonyl]propionic acid:
A solution o~ 2.17 9 (4.57 mmol) of benzyl (RS)-2-benzyl-30 3-[2-(2,2-dimethylpropionyloxy)-1 ,1-dimethylethylsulphonyl~-propionate in 100 ml of methanol was treated wi~h 0.5 9 of palladium/charcoal (5%~ and hydrogenated at room temperature under normal pressure for 90 minutes. For the working-up, the ca~alyst was filtered o ff and rinsed three times with 30 rnl of 35 methanol each time. After evaporation in a waterjet vacuum there were obtained 1.55 9 (88% of theory) of (RS)-2-ben~yl-3-[2-(2 ,Z-dirnethylpropionyloxy)-1 ,1 -dimethylethylsulphonyl3-propionic acid as colourless crystals; MS: 385 (M-~H)+.
23 2~ 671 E~
The following compound~ were manufactured in an analo-s gous manner to that described in Example l - From (RS)-2-benzyl-3-~2-(2~2-dimethylpropionyloxy) 1,1-dimethylethylsulphonyl]propionic acid and ~S)-2 amino-N-[(1 S,2R,3S)-1 -cycioh~xylme~hyl-3-cyc3Opropyl-2,3-dihydroxy-10 propyl]-3-pyridin-3-ylpropionamide ~he less polar epimer 2,2-dimethylpropionic acid 2-[(R)- or 2-[(S~-2-[~S)-1-[~ S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl]-2-pyridin-3-yle~hylcarbamoyl~-3-phenylpropylsulphonyl]-2-methylpropyl ester, MS: 742 (M~H)+, and ~he more polar epimer 2,2-dimethylpropiQnic acid 2-[(S)- or 2-~(R~-2-[(S~-1-[(l S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl]-3-phenylpropylsulphonyl~-2-methylpropyi ester, MS: 742 (M+H)~, each as a colouriess foam;
- from (RS)-3-(2-acetoxy-1,1-dimethylethylsulphonyl)-2-benzylpropionic acid and (S)-2-amino-N-[~1 S,ZR,3S)-1 -cyclo-hexylmethyl-3-cyclopropyl-2 ,3~dihydroxypropyl]-3-imidazol-4-ylpropionamide the less polar epimer ace~ic acid 2-~R)- or 2-25 [(S~-2-[(S)-1-[( 1 S,2R,3S)-1 -cyclohexylmethy3-3-cyciopropyl-2,3-dihydroxypropylcarbamoyl~-2-imidazol-4-ylethylcarbamoyl~
3-phenylpropylsulphonyl]-2-methylpropyl ester, MS: 689 (M~H~+, and the more polar epimer acetic acid 2-[(S)- or 2-[(R) 2-~(S)-l-~(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-30 propylcarbamoyl]-2-imidazol-4-ylethy3carbarr~yl]-3-phenyl-propylsulphonyl~-2-methylpropyl ester, MS: 689 ~M~H)~, each as a colourless amorphous solid;
- from (RS)-2-benzyl-3-(2-hydroxy-lJl-dirnethylethyl-3s sulphonyl)propionic acid and (S)-2-amino-N-[(1 S,2R,3S)-l-cyclo-hexylmethyl-3-cyclopropyl-2 ,3-dihydroxypropyl]-3-imidazol-4-ylpropionamide the less polar epimer ~R or S)-2-benzyl-N-~(S)-1-~(1 S,2R,3S)-l-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-209.~'71 propylcarbamoyl]-2-imidazol-4-ytethyl]-3-(2-hydroxy-1, 1-dimethylethylsulphonyl)propionamide, MS: 647 (M~H)~, and the more polar epimer (S or R)-2-benzyl-N-~($)-1-~(1 S,2R~3S~
cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylearbamoyl~
5 2-imida701-4-yle~hyl]-3-(2-hydroxy-1, 1 -dimethyle~hyl-sulphonyl)propionamide, MS: 647 (M~H)+, each as an amorphous, colourless solid.
The (S)-2-amino-N-~lS,2R,3S~-l-cyclohexylmle~hyl 3-o cyclopropyl-213-dihydroxypropyl~-3-pyridin-3-yl-propionamide used as the starting ma~erial was prepared as ~llows:
1.27 g (3.3 mmol) of HBTU ancl 0.45 ml (3.3 mmol) of trie~hylamine were added to a solution of 878 mg ~3.3 mmol) o~
15 N-(tert-butoxycarbonyl)-3-(pyridin-3-yl)-L-alanine (DE
3,640,535) and 750 mg (3.3 mmol) of (1 S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropylbutane~1,2-diol in 33 ml acetonitrile and the mixture was stirred at room temperatwre overnight. The colourless clystals obtained af~er fil~ration were dissolved in 20 30 ml of ethanol and Z3.3 ml of 1 N hydrochloric acid were added ~hereto. A~er 24 hours at 500 the solution was made basic with 2N sodium hydroxide solution, evaporated under reduced pressure and the residue was parti~ionecl between water and e~hyl acetate.
The aqueous phase was ex~raeted ~hre~ times with ethyl acetate 2s and the combined organic phases were dried over magnesiurn sulpha~e, filtered and evaporated under reduced pressure.
Chromatographic purification of the residue (silica gel, methylene chloride/methanol/ammonia 14û:10:1) yielded 436 mg of (S)-Z-amino-N-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclo-30 propyl-2,3-dihydroxypropyl~-3~pyridin-3-ylpropionamide, MS:
267 (M+H)+, as a colourless foam.
The dihydrocinnamic acid derivatives used as the starting ma~erials were prepared as follows:
3s (a) (RS)-3-(2-Acetoxy-l, l-dimethylethylsulphonyl)-2-benzylpropionic acid:
2 ~ 9 ~ 6 ~ 1 In an analogous manner to tha~ described in Example 1 (g-h), by aeylating benzyl (RS)-2-benzyl-3-(2-hydroxy-1,1~dimethyl-ethylsulphonyl)propionate with acetyl chloride in pyridine there was obtained benzyl ~RS)-3-(2-acetoxy-1,1-dimethyle~hyl-5 sulphonyl)-2-benzylpropionate, MS: 341 (M-benzyl)+, as a colour-less oil. Subsequen~ ca~alytic hyd~ogena~ion yielded (RS)-3-(2-acetoxy~ dimethylethylsulphonyl~-2-benzylpropionic acid, MS:
296 (M-l ICOOH)~, as a colourless oil.
0(b) (RS)-2-Benzyl-3-~2-hydroxy-1 ,1-dimethylethyl-sulphonyl~propionic acid:
In an analogous manner to that describedl in Example 1 ~h), by catalytically hydrogenating the benzyl (RS)-2-benzyl-3-(2-15 hydroxy-1,1-dimethylethylsulphonyl)propionate described in Example 1 (f) over palladium/eharcoal ~5%~ the~ was ob~ained (RS)-2-benzyl-3-(2-hydroxy-1 ,1 -dimethylethylsulphonyl)-propionic acid as a eolourless solid; MS: 300 (M)+.
20~e~
In an analogous manner to that described in Example 1, by condensing (RS)-2-benzyl-3-(1-benzyloxycarbonyl-1-methyl-ethylsulphonyl)propionic aoid with (S)-2-amino-N-[(1 S,2R,3S)-1-zs cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl]-3-imidazol-4-yipropionamide there were obtained the less polar epimer benzyl 2-[(S)- or 2-[(R)-2-~(S)-1-[(1 S,2R,3S)-1 cyclo-hexylme~hyl-3-cyclopropyl-2 ,3-dihydroxypropylcarbamoyl]-2-imidazol 4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-30 methylpropionate, MS: 751 (M+tl)+, and the more polar epimerbenzyl 2-~(R)- or 2-[(S)-2-~(S)-1 [(1 S,2R,3S)-1-cyclohexyl-methyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl3-2-imidazol-4-ylethylcarbamoyl3-3-phenylpropylsulphonyl]-2 -methylpropionate, MS: 751 (M~H)~, each as a colourless foam.
3s The (RS)-2-benzyl~3-~1-benzyloxycarbonyi-1-methylethyl-sulphonyl)propionic acid used as the starting rnaterial was prepared as follows:
2 ~ 9 5 6 r~ L
2~
~ a~ (RS)-2-~2-tert-Bu~oxycarbonyl-2-benzylethyl-sulphonyl)-Z-methylpropionic acid:
In an analogous manner ~o that described in Examp!e 1 (d~, by the addition of 2-mercaptoisobutyric acid to tert-butyl 2-benzylacrylate, prepared according to a generally known proeedure from 2-benzylacrylic acid and N,N-dimethylformamide di~tert-butyl acetal [Tetrahedron 1979, ~5, 1675)], there was 10 obtai~ed (RS)-2-(2-tert-butoxycarbonyl-2-benzylethyl-sulphonyl)-2-methylpropionic acid as a yellowish oil; MS: 282 ~M-H2C-C(CH3)2]+-(b) Benzyl (RS~-2-~2-tert-butoxycarbonyl-2-benzylethyl-sulphonyl)-2-methylpropionate:
A solution of 500 mg (1.3 mmol) of (RS)-2-(Z-ter~-butoxycarbonyi-2-benzylethyisulphonyl)-2-methylpropionic acid in 5 ml of acetonitrile was treated with 197 mg (1.3 mmol) of 20 DBU and 222 mg (1.3 mmol) of benzyl bromide were added dropwise thereto a~ room temperature. The yellowish reaction solution was stirred for a fur~her 3 hours, ~hen treated with 10 ml of water and extracted twi~e with 10 ml of ethyl ace~ate each time. The combined ethyl ace~ate phases were washed twice 25 with S ml of water each time, subsequently dried over sodium sulphate and evaporated under reduced pressure. The thus-obtained benzyl ester was used in the following oxidation step in the form o~ a yellow oil (580 mg) without further purification and characteriza~ion.
The oxidation with potassium monopersulphate triple salt was effected analogously ~o Example 1 (d) and gave benzyl (RS)-2-~2-tert-butoxyoarbonyl-2-benzylethylsulphonyl)-2-methyl-propionate as a colourless oil; MS: 461 ~M~H)~.
(c) (RS)-2-Benzyl-3-(1-benzyloxycarbonyl-1-methylethyl-sulphonyl)propionic acid:
2 7 2 ~ ~ ~ 6 7 1 A mixture of 401 mg (0.87 mmol) of benzyl (RS)-2~(2-tert-butoxycarbonyl-2-benzyie~hylsulphonyl)-2-methyl-propionate and 5 ml of anhydrous formic acid was s~irred at room temperature. After 6 hours the initially turbid solution 5 became clear. This solution was evaporated at 40 under recluced pressure and ~he residue was ~aken up in 10 ml of ethyl ~cetate and washed with 3 ml of water. After drying over sodium sulphate and evaporation in a waterjet vacuum there were obtained 340 mg of (RS)~2-benzyl-3-(1-benzyloxycarbonyl-1-o methylethylsulphonyl)propionic acid, MS: 313 (M-benzyl)~, as a colourless oil which was used in the followin~ step without ~urther purification.
~m~
The foilowing compounds were rnanufactured by cataly~ic hydrogena~ion in an analogous manner to tha~ described in Example 1 (h):
- From benzyl 2~[(S)- or 2-~(R)-2-[(S~-l-[(lS,2R,3S)-1-cyclohexylmethyJ-3-cyclopropy5-2,3-dihydroxypropylcarbamoyl]-~-imidazol-4-ylethylcarbamoyl~-3 -phenylpropylsulphonyl~-2-methylpropionate the 2-~(S)- or Z-~(R~-2~[(S)-1 -[(l S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl-25 carbamoylJ-2~imidazol-4-ylethylcarbamoyl]-3-phenylpropyl-sulphonyl]-2-methylpropionic acid as a colourless, amorphous solid; MS: 661 (M+H)'~, and - from benzyl 2-[(R)- or 2-[~S)-2-[(S)-l -[(1 S,ZR,3S)-1-30 cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl]-2-imidazol-4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-methylpropionate the 2-~(R)- or 2-~(S)-2-[~S)-1-[(1 S/2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl-carbamoyl]-2-imidazol-4-ylethylcarbamoyl]-3-phenylpropyl-35 sulphonyl]-Z-methylpropionic acid as a colourless, amorphous solid; MS: 661 (M+H)+.
2 1~ ' 7 ~
~m~
~Q~e~
5 CQmp~.siti~;
2,2-Dimethylpropionic acid 2-~(S~- or 2-L(R)-2-~(S)-l-[~1 S,ZR,3S)-1 -cyclohexyimethyl-3-cyclopropyl-7,3-dihydroxypropylcarbamoyl~-2-imidazol-4-ylethyl-o carbamoyl~-3-phenylpropylsulphonyl]-Z-snethylpropyl es~r, micronized 5.0 g Polysorba~e 80 0.3 g Hydro)(ypropylmethylcellulose 1.0 g Flavour q.s.
Methylparaben 0.2 g Propylparaben 0~04 g Water ad 100.0 ml Ex~m~le B
Qral.~Leous solll~ion Com~ition 2,2-Dimethylpropionic acid 2-[(S)- or 2-[(R)-2-[(S)-1-[(1S,2R,3S)-l-cyclohexylmethyl-3 eyclopropyl-2,3-dihydroxypropylcarbamoyl]-2-imidazol-4 -ylethyl-carbamoyl~-3-phenylpropylsulphonyl] ~2-methylpropyl 35 ester, 1.0 g Methylparaben 0.2 g 2 ~3 9 i ) & r~ ~L
Propylparaben o 04 g Flavour q.s.
5 Water ad 100.0 ml .~m~
ÇQmQQ~;
1 ) 2,2-Dirne~hylpropionic acid Z-[(S) or 2-~(R)-2-[(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyelopropyl-2,3-dihydroxypropylearbamoyl]-2-imidazol-4-ylethylcarbamoyl~3-phenylpropyi-sulphonylll~2-methylpropyl es~er 200 mg 2) Anhydrous lactose 160 mg 3) Hydroxypropylme~hylcellulose 18 mg 4) Sodium carboxymethylcellulose 20 mg 2s 5) Magnesium stearate ~mg Tablet weight 400 mg 1 ) and 2) are mixed in~ensively. The mixture is thereafter moistened with an aqueous solution of 3) and kneaded, and the resul~ing mass is granulated, dried and sieved. The granula~e is mixed with 4) and 5) and pressed to tablets of suitable size.
3s 2~9~7 ~
E~am~
C~mp~ n 1 ) Z~2-Dlmetnylpropionic aeid 2-[(S)- or 2-[(R)-20[(S)-l -[~1 S,2R,3S)-1 -cyc~ohexylmethyl-3-cyolopropyl-2,3-dihydroxypropylcarbamoyl]-2-imidazol-4-ylethyl-o carbamoyl]-3-phenylpropylsulphonyl~-2-methyl-propyl ester 200 mg 2) Anhydrous lactose 160 mg 33 Hydroxypropylmethylcellulose 18 mg 4) Sodiumcarboxymethyicellulose 20 mg 5) Magnesiumstearate 2 Capsule fill weigh~ 400 mg Manuf~[j~LQr~ res 1 ) and 2) are mixed intensively. The mixture is thereafter moistened with an aqueous solution of 3~ and kneaded, and the resulting mass is granulated, dried and sieved. The granula~e is mixed with 4) and 5) and the mixtur~ is Fiiled into capsules of suitable size.
~mQIQ~
Inieçtion sql~ion 35 ~m~i~
2,~-Dimethylpropionic acid 2-[(S)- or 2-[(R) 2-~(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyclo-2~9~7~
propyl-2,3 dihydroxypropylcarbamoyl~-2-imidazol-4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-methylpropyl ester 20 mg 5 Pyrogen-free D-mannitol 10 mg Water ~r injection ad 1.0 ml The active substance and the mannitol are dissolved in nitrogen-gassed water and subse~uently Iyophilized according to a conventional procedure.
~E
When the procedures described in Examples A-E are ~ollowed, corresponding galenical preparations can be manufactured fr~m the following, likewise preferred comp~unds zo and their pharmaceutically usable salts:
2,2-Dime~hylpropionic acid 2-r(R)- or Z-[(5)-2-[(S)-1-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]-2-pyridin-3-ylethylc3rbamoyl]-3-phenyl-25 propylsulphonyl~-2-methylpropyl ester and 2,2-dimethylpropionic acid 2-~(S)- or 2-[(R)-Z-[(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl]-3~phenyl-30 propylsulphonyl~-2-methylpropyl ester.
0 wherein R1 signifies imidazolylme~hyl or pyridylmethyl and A signifies carboxyl, benzyloxycarbonyl, hydroxymethyl or alkylcarbonyloxymethyl, in the form of optically pure diastereomers, rnixtures of dia-stereomers, dias~ereomeric racemates or mixtures of dias~ereo-meric racemates as well as ph~rmaceutically usable salts of ~hese compounds.
:
These compounds are distinguished by valuable pharma-codynamic properties and can be used for the control or 20 prevention of illnesses. In particular, they have a renin-inhibiting activity and are accordillgly suitable for the treatment of high blood pressure and cardiac insufficiency.
,; .
- Objects of the present invention are the compounds of 25 formula I and their pharrraceutically usable sal~s per se and for use as therapeutically active substances, the manufacture of ~hese compounds, medicaments containing these and the manu-facture of such medicaments as well as the use of the compounds of formula I and their pharmaceutically usable salts in the 30 control or prevention of illnesses or in the improvemen~ of health, especially in the control or prevention of high blood pressure and cardiac insufficiency.
Kbr/1 5.2.93 ~r"
'~
The compounds of formula I above are already generically known frnrn, for example, EP-A-0,309,766 and ~P-A-0,377,139, but i~ has surprisingly been found tha~ lthey are distinguished by a pronounced oral activi~y. Of ~he compounds specifically named 5 in the two European Pa~en~ Public~tions only two are described as being orally active, namely ~he end produc~ of Example 16 of EP-A-0,309,766 and, respec~ively, the end product of Examp~e 1 Qf EP-A-0,377,139. A comparison of the oral activity of the compounds in accordance with the invention with the more active o previously described compound (Example 1 of EP-A-0,377, 1 39) shows a significantly higher oral activity for ~he compounds of formula 1, as can be coneluded readily from Figures 1-3 disoussed below.
The alkyi residues which appear in the term "alkylcarbonyl-oxymethyl" or "alkylcarbonyl" in the present description are straight-chain and branched, saturated hydrocarbon residues with 1-8, preferably 1-4, carbon atoms sueh as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyll tert-butyl, pentyl, 20 hexyl and the like.
The term "pharmaceutically usable salts" embraces salts with inorganic or organic acids such as hydrochloric acid, hydro-bromic acid, nitric acid, sulphuric acid, phosphoric acid, citric 25 acid, formic acid, maleic acid, ace~ic acid, succinic acid, tartaric acid, methanesulphonic acid, p-to5uenesulphonic acid and the like or, where A signifies carboxyl, also with inorganic or organic bases such as sodium or potassium hydroxide, ammonia, triethylamine, diisopropylethylamine, pyridine and the like. Such 30 salts ean 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 compounds of formula I have a~ least four asymmetric 35 carbon atoms and are therefore presen~ in the forrn of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereorneric racemates. The present invention embraces all forms. Mixtures of diastereomers, dia-2 ~ 7 ~
stereomeric racemates or mixtures of dias~ereomeric racerna~escan be separated according to usual methods, e.g. by column chromatography, thin-layer chroma~ography, HPLC and the like.
Those compounds of formuia I in which A signifies hydroxy-methyl or alkylcarbonyloxymethyl~ especially alkylcarbonyloxy-methyl, particularly C~ 4-alkylcarbonyloxymethyl, are preferred.
Where A does no~ have ~he foregoing significances, then those compounds of formula I in which A signifies carboxyl are o pre~erred.
From the foregoing it will be evident that those compounds of formula I in which A signifies C1 4-alkylcarbonyloxymethyl are particularly preferred.
Specially preferred compounds of formula I are:
2,2-Dimethylpropionic acid 2-[(S)- or 2-[~R)-2-[~S3-1 t(1 S~2R~3s~-1-cyclohexylmethyi-3-cyclopropyl-2~3-dihydr 20 propylcarbamoyl3-2-imidazol-4-yl-e~hylcarbamoyl]-3-phenyl-propylsulphonyl~-2-methylpropyl ester, 2,2-dimethylpropionic acid ~-~(R)- or 2-~S)-Z-[(S)-1-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-25 propylcarbamoyl~-2-pyridirl-3-yl-e~hylcarbamoyl]-3-phenyl-propylsulphonyl]-2-methylpropyl es~er and 2,2-dimethylpropionic acid 2-[~S)- or 2-~(R)-2-~(S)-1-[(1 S,2P~,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-30 propylcarbamoyl]-2-pyridin-3-yl ethylcarbamoyl]-3-phenyl-propylsulphonyl]-2-methylpropyl es~er.
Compounds of forrnula I in the form of optically pure diastereomers, mixtures of dias~ereomers, dias~ereomeric 35 racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts thereof can be manufac~ured by a) reacting a compound of the general forrnula ' :
';
2 ~ 9 ~ 6 71 2 ~ ~ 11 wherein R1 has the ~ignificance given above, 5 with an acid of the general formula Al ~SQ~i::)H lll '13 -wherein A1 signifies ben~yloxycarbonyl, hydroxymethyl or o alkylcarbonyloxymethylJ
or an activated derivative thereof, or b) reacting the compound of the ~ormula OH ~
H2N~ IV
OH
with an acid of the general formula O Rl A~ ~SO~ N ~OH V
wherein A1 and R1 have the si~nificance given above, or an ac~ivatecl derivative thereof, or 2~5Çi7~
s c) for the manufacture of a compound of formula I ;n which A
signifies carboxyl, cleaving off ~he benzyl group in a compound of formula I in which A signifies ben~yloxycarbonyi, and d) if desired, separating a rnixture of diastereomeric racemates into the diastereomeric racema~es or optically pure diastereomers, and/or 0 e) if desired, separating a mixture of dias~ereomers into the optically pure diastereomers, and/or f) if desired, conver~ing a compound obtained into a pharma-ceuticaily usable salt.
The acylation of a compound of forrnula ll with an acid of forrnula lll or an aetivated derivative thereof is effec~ed according to methods known per se in peptide chemistry. Suitable acylating agents are activated deriva~ives such as esters, mixed 20 esters, acid halides, acid anhydrides or mixed anhydrides. The reaction is carried out in an or~anic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0C and room tempera~ure. As solvents ~here some into consideration especially aromatic hydrocarbons such as 25 benzene, ~oluene or xylene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as cliethyl e~her, tetrahydrofuran or dioxan, and the like. Furthermore, the acylation can be effected in the presence of a condensation agent such as HBTU [O benzotriazolyl-N,N,N',N-tetramethyluronium 30 hexafluorophosphate, BOP [benzotrlazol-1-yloxy-bis(dimethylamino)phosphonium hexafluorophosphate], BOP~
[bis(2-oxo-2-oxazolidinyl)phosphine chloride], HOBT ~N-hydroxybenzotriazole}, DCC CdicYclohexYlcarbodilmide hydrochloridel, EDC ~N-(3-dirnethylaminopropyl)-N'-3s ethylcarbodiimide hydrochloride] and the like. The reac~ion isconveniently carried out in an organic solvent or solvent mixture which is inert under the reaction conditions at a ~ernperature between about 0 and 50C, preferably at about room tempera~ure.
~.:
2~ 671 As solvents there come into consideration especially dimethyl-forrnamide, methylene chloride, acetonitrile, tetrahydrofuran and the like.
The reaction of a compound of formula IV with an acid of formula V or an activated derivative thereof is also effected according to me~hods which are known per se in peptide chemistry, i.e. under the same conditions as given above for the acylation of a compound of formula ~I. Examples of suitable 0 activated compounds of formula V are iikewise acid halides, acid anhydrides, mixed anhydrides, esters, mixed esters and the like.
The cleavage of ~he benzyl group in accordance with process variant c) is also effected according to methods known per se, conveniently hydrogenolytically.
The starting ma~erials of formula ll are ,oartly novel and partly known. These cornpounds can be prepared by reacting the compound of formula IV with a compound of the general formula o H2N ~ Vl wherein R1 has the significance given above.
This reaction is effected according to methods which are known 2s in pep~ide chemistry, i.e. under the reaction conditions which are described above for the acylation of a compound of formula ll.
The starting material of formula IV~ i.e. 3-amino-4-cyclo-hexyl-1-cyclopropyl-1,2-blltanediol, is known.
The compounds of formuia Vl are known or can be obtained in analogy to the preparation of the known compounds.
The acids of formula lll and their activated derivatives are 35 novel and are also an object of the present invention. The prepar-ation of the acids of formula lll is presented by way or formulae ':
2 ~ 9 .~ ~ 7 1 in the following Reaction Scheme. The ac~ivated derivatives can be prepared readily by any person skilled in the art having regard to the state of the art and taking into consideration the nature of the activated deriva~ive.
The acids of formula V and ~heir activated derivatives are also novel and are an objeet of the present invention. They can be prepared readily by reacting an acid of formula lil wi~h a compound of formula Vl. The reaction is effected aecording to 0 me~hods which are known in peptide chemis~ry, i.e. under ~he reaction conditions which are described above for the aeyl~tion of a compound of formula 11. The ac~ivated derivatives o~ ~he acids of formuia V can be prepared readily by any person skilled in the art in ~he same manner as those of the acids of ~ormula 111.
The steps which are presented in the Reaction Scheme are without exeeption reactions which are usual in synthetic chemistry, all of whieh are carrie~ out according ~o methods known per se. With respect to the pr~cise reaction condi~ions for 20 the steps pr~sented in the Reaction Scheme, reference is made to the experimen$al section. In the Reac~ion Scheme the symbol R2 signKies aralkyl, especially benzyl, or alkyl, especially ~-butyl, R2l signifies alkyl, especially ~-butyl, R3 signifies benzyl and signifies alkylcarbonyl.
The starting materials of formulae Vll and Vlll used in the Reaction Scheme are known.
: :.
"
2~9~6~
Scheme H~SH ~ o ?
Vll ~lli 111~
ll l J~SOJ~R: ' ~X Xlll I
o ~ o X
_lo~5;0~0R2- --D zo~S J's Xl X~l ~; J's ZO~;OEJ~SOH
Illa Illb 2~ 671 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 blovd and there brings about the cleavage of angiotensinogen with the formation 5 of the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to the octapeptide angiotensin Il. Angiotensin ll increases the blood pressure not only directly ~y ar~crial constriction, but also indirectly by the liberation of the sodium ion-retaining hormone aldosterone from the adrenal 0 gland, with which is associated an increase in the extracelluiar fluid volume. This increase is attributed to the action of angio-tensin ll itself or to the heptapeptide angiotensin lll which is formed therefrom as a cleavage product. Inhibition of ~he en~y-ma~ic ac~ivity of renin bFings about a decrease in the formation of angiotensin I and as a consequence thereof the forma~ion of a smaller amoullt of angiotensin ll. The reduced concentration of this active peptide hormone is the actual reason for ~he blood pressure-lowering ac~ivity of renin inhibitors.
The activity of renin inhibitors can be demonstrated experimentally by means of the in vivo test described hereinaf~er:
BloQd pre~sure-lowerins~ ~tivi~y in thç a,~ mQdç~
The blood pressure-lowering effect of the compounds was measured in normotensive squirrel monkeys of both sexes (weight 400-700 g). The sodium depletion was achieved by the subcu-taneous iniection of in each case 5 mg/kg of furosemide 66, 42 and 18 hours prior to the experiment.
The compounds were administered orally ~s tlhe methane sulphonate salts in aqueous solution in a dosage of 3 mg/kg. The arterial blood pressure was measured according ~o the procedure published in Hypertension 1991; 18: 22-31.
The results obtained in this test are cornpiled in the following Figures 1-3.
- l O ~ 2 Q 9 ~ 6 r~ 1 oo oo Il 11 11 11 11 ¢ ~ ~ ~ u s; ~
+ ~ ~ t ~ ' ~ '~
r~ " ~
r' ~ ~, ~ ~ ", ~ -~ _ H
_~ _,~
'- ~ _ a~
I ~
O O O O ~ ~
~ N ~I') (6H~W~ d~W ~ L~3a 2~9 ~ 6 ~1 n : N(lmber of tes~s A : Control B : (2S,3R,4S)-4-CL-N-~(ZS)-3-[(2S or R)-2,3-Diacetoxypropyl~sulphonyl-2 (1-naphthyl-methyi)propionyl]norleucyl]amino-5-cyclohexyl-1 -morpholino-2,3-pen~anediol ~O C : (2S,3R,4$)-4-[L-N-[~2$)-3-~2R or S)-2,3-Diace~o~ypropyl3sulphonyl-2-( 1 -naphthyl-methyl)propionyl~norleucyl~amino-5-oyclohexyl-1 -morpholino-Z,3-pentanediol D : (S or R)-2-Benzyl-N-[(S)-l-C(lS,2P~,3S)-1 cyclohexylmethyl-3-cyclQpropyl-2,3-dihyclroxy-propylcarbarnoyl~-Z-imidazol-4-y5e~hyl]-3 -(2-hydroxy-1 ,1 -dimethylethylsulphonyl)propion-amidc zo E : Acetic acid 2-~(S)- or 2-~(R)-2-L(S)-1-[~1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2 ,3-dihydroxypropylcarbamoyl]-2-imidazol-4-ylethylcarbamoyl]-3-phenylpropylsulphonyl~-2-methylpropyl ester 2~9~fi71 Il 11 11 11 11 11 + t ~ t I ~
t ~ ~
.
~"
~i ,'q~\ L
1 ~
w~
~:
[
o o ~ - ~
~ ~ t ( 6HWW) dVW ~1~3a 2~9a671 A : Control B : (2S,3R,4S)-4-[L-N-r(2S)-3-~(2S or R)-253-Diacetoxypropyl3sll1phonyl-2-( 1 -naphthyl-methyl)propionyl]norleucyl]amino-5-cyclohexyl-1 -morpholino-2, 3-pentanediol C : (2S,3R,4S)-4-EL-N-[(2S)-3-~2R or S)-2,3-Diacetoxypropyl]sulphonyl-2-1~ 1 -naphthyl-o methyl~propionyl3norleucyl]amino-5-Gyclohexyl-1 -morpholino-2,3-pentanediol F : Benzyl 2-~(S)- ur 2-~(R)-2-~(S)~ l S,ZR,~S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl~-2-imidazol-4-ylethylearba-moyl3-3-phenylpropylsulphonyl]-2-rnethyl-propionate G : 2-~S)- or 2-l[(R)-2-[~S)-1-~(1 S,2R,3S)-1 -Cyclo-hexylmethyl-3-cyclopropyi-2,3-dihydroxy-propylcarbamoyl]-2-imidazol-4 ~ylethylcarba-moyl3-3-phenylpropylsulphonyl~-2-methyl-propionic acid :`
H : 2-(R)- or 2-[(S)-2-[(S)-1-~(1 S,2R,3S)-1-Cyclo-hexylmethyl-3-cyclopropyl-2 ,3-dihydroxy-propylcarbamoyll-2-imidazol-4-ylethylcarba-rnoyl~-3-phenylpropylsulphonyl]-2-me~hyl-propionic acid 1 ~ 2 ~ .9 ~ ~ 7 1 ~ P
+ t ~ t t 4 ~aD
,~
~, 2 o H
- N
~ ' O
o 0 ~ !
(6HWul~ dYW Yl~a 209Cj6 l1 1s Q : Control B : (2S,3R,4S)-4-~L-N-~2S3-3-~(2S orR)-2,3-Diacetoxypropyl]sulphonyl-2-(1 naphthyl-methyl)propionyl]norleucyl]amino-5-cyclohexyl-1 -morpholino-2,3-pen~anediol C : (2S,3R,4S)-4-[L-N-~25)-3-1~(2R or S)-Z,3-Diacetoxypropyl}slJlphonyl-2-( 1 -naphthyl-1 o methyl)propionyl]norleucyl3ctmino-5-cyclohexyl-l -morpholino-2 9 3-pentanediol 2,2-Dimethylpropionic acid 2-[(S)- or 2-[~R)-2-~(S~ (1 S,ZR,3S)-1 -cyclohexylmethyl-3-cyciopropyl-2,3-dihydroxypropylcarbamoyl]-2-imidazol-4-yle~hylcarbamoyl]-3-phenylpropyi-sulphonyl~-~-methylpropyl ester J : 2,Z-Dirnethylpropionic acid 2-[(R~- or 2-[(S)-2-E(S)-l -E(l S,2R,3S)-l-cyclohexylmethyl-3 cyclopropyl-2,3-dihydroxypropylcarb3moyl]-2-~` pyridin-3-ylethylcarbamoyl]-3-phenylpropyl-sulphonyl3-2-methylpropyl es~er K : 2,2-Dimethylpropionic acid 2-[(S~-or2-[(R)-2-~` [(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl~-2-',: pyridin-3-ylethylcarbamoyl]-3-phenylpropyl-sulphonyl]-2-rne~hylpropyl ester 2 0 ~ 7 ~
The compounds oF formula I as well as their pharmaceuti-cally usable salts can be used as medicaments, e.g. in the form of pharmaceu~ical preparations. The pharmaceutical preparations can be administered enterally such as orally, e.g. in the form of 5 tablets, coated tablets, drag~es, hard and soft gela~ine capsules, solu~ions~ emulsions or suspensions, nasally, e.g. in the form of nasal sprays, or rec~ally, e.g. in ~he form of suppositories.
However, the administration can also be effected parenterally such as intramuscularly or intravenously, e.g. in the forrn of o injection solutions.
The compounds of formula i as well as ~heir pharmaeeuti-cally usable salts can be processed with pharmaceutically inert, inorganic or organic excipients for ~he manufacture of tablets, 5 coated tablets, dragees and hard gelatine capsules. Lac~ose, curn starch or derivatives thereof, talc, stearic acid or its salts etcO
can be used e.g. as such excipients for tabiets, dragées and hard gelatine capsules.
Sui~able excipien~s for soft gelatine capsules are e.g.
vegetable oils, waxes, fats, semi-solid and liquid polyols e~c.
~uitable excipients for ~he manufacture of solutions and syrups are e.g. water, polyols, saocharose, invert sugar, glucose 25 etc.
Suitable excipients for injec~ion solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
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 preservatives, solubilizers, viscosity-increasing substances, 35 stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxiclants. They can also contain still other therapeu~ically valuable substances.
2 0 9 ~ ~ 71 In ~ccordance with the invention the compounds of general formula I as well as their ph~rmaceutically usable salts can be used in ~he control or prevention of high blood pressure and s cardiac insufficiency. The dosage can vary within wide limits and will, of course, be fi~ted ~o the individual requirements in eaeh par~icular case. In general, in the case of oral admini-stration there should suffiee a daiiy dosage of about 3 mg to about 3 g, preferably about 10 mg to about 1 g, e.g. approxi-0 mately 300 my per person, divided in preferably 1-3 unit doses, which ean e.g. be of the same amount, whereby, however, the upper limi~ just given can also be exceeded when this is found ~o be indioa~ed. Usually, ehildren receive half of the adult dosa~e.
The following Exarnples illustra~e ~he present invention, but are not intended to be limiting in any manner. All temperatures are given in deyrees Celsius. The following abbrevia~ion~ are used:
zo His-OH = L-Histidine Fmoc = 9-Fluorenylmethoxycarbonyl DBU = 1,8-Diazabicyclo[5.4.0]undee-7-ene[1,5-5]
,~
, ~m~
2s A mixture of 2.33 9 (6.06 mmol) of (RS)-2-benzyl-3-[2 ~2,2-dimethylpropionyloxy) 1,1-dimethylethylsulphonyl]propionic aeid, 2.0 g (5.49 mmol) of (S~-2-amino-N-[(1 S,2R,3S)-1-30 cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl]-3-imidazol-4-ylpropionamide, 0.61 g (6.06 mmol) of triethyl-amine, 0.95 g (6.06 mmol) of HOBT and 2.3 9 (6.06 mmol) of HBTU in 50 ml of dimethylformamicle was stirred a~ room ~emperature overnight. Thereafter, the reaction mixture was 35 evaporated in a high vacuum. The residue was taken up in 500 ml of ethyl acetate and washed twice with 200 ml of saturated sodium hydrogen carbonate solution each time. The ethyl acetate phase was dried over sodium sulphate and subsequently evapor-2~9a~71 a~ed under reduced pressure. For purification and separation ofthe two epimeric produc~s, the residue (4.98 g) was chromato-graphed twice on 400 ~ of silica gel using a 97:3:0.1 mixture of methylene chloride, methanc~l and pyridine as the eluent. The less 5 polar 2,2-dimethylpropionic acid 2-[(S)- or 2-[~P~)-2-[(S)-l-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]-Z-imidazol-4-ylethylcarbamoyl~-3-phenyl-propylsulphonyl3-2-methylpropyl ester was precipitated from ethyl acetate/hexane and gave 1.3 9 of a colourless solid, MS:
10 731 (M~H~+. The more polar 2,2-dimethylpropionic acid Z-~(R)- or 2-[(S)-2-C~S)-l-[(1 S,2R,3S)-1-cyclohexylmethyl-3-eyclopropyl-2,3-dihydroxypropylearbamoyl]-2 -imidazol-4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-me~hylpropyl ester gave, after Iyophilization from dioxan/water, 1.08 g of a colourless powder, 15 MS: 731 (M+H)+.
The 2-amino-N-[(1S,2R,3S)-1-cyclohexylrnethyl-3-cyclo-propyl-2,3~dihydroxypropyl]-3-irnidazol-4-ylpropionamide used as ~he starting material was prepared as ~ollows:
(a) tert-Butyl ~4S,5Ps)-4-cyclohexylmethyl-5-~(S)-cyclo-propylhydroxymethyl3-2,2-dimethyl-3-oxazolidinecarboxylate and tert~butyl (4S,5R)-4-cyclohexylmethyl-5-[~R)-cyclopropyl hydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate:
A solution of 3.21 9 olF ter~-butyl (4S,5R)-4-cyclohexyl-methyl)-5-formyl-2,2-dimethyl-3-oxazolidinecarboxylate [W0 87/05302] in 25 ml of tetrahydrofuran was added dropwise at about 15 to a ~irignard compound, prepared from 3.94 ml 30 (49 mmol) of bromoeyclopropane and 1.2 g ~0.049 gram atom) of magnesium shavings in 22 ml of te~rahydrofuran, and the reaction mixture was subsequently stirred at room temperature under argon for 16 hours. Thereafter, the reaction mixture was poured into 40 ml of an ice-cold saturated ammonium c~loride 35 solution and extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate extracts were washed with 40 ml of ice-cold saturated ammonium chloride solution, then combined, dried over sodium sulphate and evaporatecl under reduced ~9;~6~1 lg pressure. For purification, the residue (4.33 9) was chromato-graphed over a column of 1 10 g of silica gel, prepared with toluene anà 1% triethylamine, using a 95:5 mixture of ~oluene and ethyl acetate as the eluen~. There were ob~ained 1.9 g of ~er~-5 butyl (4S,5R)-4-cyclohexylrnethyl-5-[(R)-cyclopropylhydroxy-methyl]-2,2-dimethyl-3-oxa~olidinecarboxylate, MS: 368 (M+H)+, and 0.5 g of tert-butyl (4S,SR)-4-cyclohexylmethyl-5-[(S3-cyclopropylhydroxymethyl]-2 ,2-dimethyl-3-oxazolidinecarboxyl-a~e, MS: 368 ~Ivl+H)+, each as a colourless oil.
(b) ~1S,2R,3S~-3-Amino-4-cyclohexyl-1-cyclopropyl-bu~ane-1 ,2-diol:
1.42 g (3.86 mmol) of ~ert-butyi (4S,5R)-4-cyclohexy!-methyl-5-[(R)-cyclopropylhytlroxyme~hyl]-2,2-dlime~hyl-3-oxazolidinecarboxyia~e dissolved in 15 ml of methanol and 10 ml of wat~r were treated wi~h 4 ml of 7.5N hydrochloric acid and s~irred a~ 50O for 3 hours. The reac~ion solution was cooled to 3O
in an ice bath, treated dropwise with 4 ml of 7.5N sodium 20 hydroxide solution and s~irred for 1 hour. The suspension obtained was evaporated under reduced pressure, water was removed azeotropically twice with 10 ml of ~oluene and the `~ residue was stirred three times with 10 ml of a 95:5 mix~ure of methylen~ chloride and methanol. The insoluble residue was 2s filtered off and ~he filtrate was ~vaporated under reduced pressure. The resulting crude produç~ (1.14 9) was suspended in 15 ml of ether and ~hen fil~ered off under suction. There was ob~ained 0.58 9 of (lS,2R,3S~-3-amino-4-cyclohexyl-1-cyclo-propylbutane-1,2-dioi as colourless crystals, rn.p. 141-142.
(S)-Z-Amino-N-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclo-propyl-2 ,3-dihydroxypropyl]-3-imidazol-4-ylpropionamide:
A mix~ure of 343 mg (1.51 mmol) of (1 S,2R,3S)-3-amino-35 4-cyclohexyl-1-cyclopropylbutane-1,Z-diol, 995 mg (1.66 mmol) of (Fmoc)2His-OH, 0.21 ml (1.61 mmol) of 4-ethylmorpholine, 449 mg (3.22 mrnol) of HOBT ancl 347 mg (1.81 mmol) of EDC in 20 ml of dimethylformamide was left to stand at room 2 ~ 9 ~ 6 7 ~
temperature overnight. Thereafter, the reaction mixture was evapora~ed in a high vacuum, the residue was poured into a mixture of i~e and 90 ml of sodium bicarbonate solution and ex~raoted three times with 150 ml of ethyl ace~a~e each time.
s The three ethyl acetate extrac~s were washed in succession wi~h 70 ml of saturated ammonium chloride solution, 70 ml of 2N
sodium bicarbonate solution and 70 ml of satur~ted soclium chloride solution, çombined, dried over magnesium sulphate, filtered and evaporated. The crude product ob~ained was stirred o at room tempera~ure for 3 hours in 60 ml of methylene chloride and 2 ml of piperidine. Thereaf~er, the reaction mixture was evaporated and the residue was tri~urated with 50 ml of hexane and filtered off. The filtra~e was chromatoyraphed on 70 9 of silica gel using a 65:10:1 mixture o~ methylene chloride, methanol and ammonia as the eluent, whereby there were obtained 390 mg of (S)-2-amino-N-[(1 S,2R,3S)-1-cyclohexyl methyl-3-cyciopropyl-2,3-dihydroxypropyl]-3-imidazol-4 ylpropionamide as a colourless foam; MS: 365 (M+H)+.
2() The (RS)-2-benzyl-3-[2-(Z,2-dimethylpropionyloxy)-1,1-dimethylethylsulphonyl]propionie acid used as the starting rna~erial was prepared as ~ollows:
(d) (RS~-2-(2-Benzyloxycarbonyl-3-phenylpropylsulphonyl)-25 2-methylpropionic acid:
8.4 g (55.4 rnmol) of DBU were added dropwise to a solution of 3.3 9 ~27.7 mmol) of 2-rnercaptoisobutyric acid ~Can.
J. Chem. Çl (8), 1872] and 6.9 9 (27.7 mmol) of benzyl 2-benzyl-30 acrylate [EP-A 0,1 17,429~ while holding the temperature of the reaction mix~ure between 5 and 10. After completion of the addition the mixture was stirred a~ 10 for a fur~her 5 hours.
Subsequently, the reaction mixture was treated dropwise, while cooling with ice and holding the temperature below 10, with 35 Z2.5 9 (36.6 mmol) of potassium monopersulpha~e triple salt suspended in 450 ml of water. Thereafter, the mix~ure was stirred at the same temperature for one hour, then coolecl to 0 and a further Z2.5 g (36.6 mmol~ of potassium rnonopersulphate 2~3~1~7~
triple salt were added spatula-wise. The mixture was left to warm slowly to room ~emperature and stirred for a further 15 hours. For the working-wp, ~he mix~ure was diluted with 200 ml of water and extracted four times with 60 ml of ethyi 5 acetate each time. The eombined organic extracts were dried over sodium sulphate and evaporated under reducecl pressure until ~he product began to crystallize. Then, 30 ml of hexane and 20 ml of ether were added while stirring and ~he precipitated produc~ was subsequently filtered off under suction and dried.
o There were obtained 9.7 g of ~RS)-2-(2-benyloxycarbonyl-3-phenyipropylswlphonyl)-2-methylpropionic acid as a colourless solid; MS: 42~ ~M+NH4)+.
(e) (RS)-2~(2-Benzyloxycarbonyl-3-phenylpropylsulphonyl)-2-methylpropionyl chloride:
A solution of 9.0 9 (22.2 mmol~ of (RS)-2-~2-benzyloxy-carbonyl-3-phenylpropylsulphonyl)-Z-methylpropionic acid and 9.6 ml (112.3 rnmol) of oxalyl chloride in 18 ml of te~rahydro-20 furan was heated to 500 for 18 hours. Thereafter, ~he reactionsolution was evaporated under reduced pressure. The residue was ~aken up twice with 250 ml of toluene each time and evaporated under reduced pressure. The (RS)-2-(2-benzyloxycarbonyl-3-phenylpropylsulphonyl)-2-methylpropionyl chloride was obtained 25 as a yellowish oil in quanti~ative yield and was used in the next step without purification and characterization.
~ f) Benzyl (RS)-2-benzyl-3-(2-hydroxy-1 ,1 -dimethyl-ethylsulphonyl)propionate:
A solution of 9.4 9 (22.2 mmol) o~ (RS)-2-(2-benzyloxy-carbonyl-3-phenylpropylsulphonyl)-2-methylpropionyl ehloride in 45 ml of tetrahydrofuran was treated dropwise at 0 within 15 minutes with 2.3 ml ~23.3 mmol) of 1 OM borane-dimethyl 35 sulphide complex and subsequently stirred at room temperature for 3 hours. Thereafter, the mixture was cooled to oo and about 2 ml of methanol, 30 rnl of water and 30 ml of sa~urated sodium hydrogen carbonate solution were added in succession. The 2~95671 mix~ure was then extracted ~hree times with 35 ml of ether each time and the combined organic phases were subsequent3y dried over sodium sulphate and evaporated under reduced pressure. The crude product was digested in 50 ml of ether and, after suction 5 filtration and drying, there were obtained 6.7 g of benzyl (RS)-2-benzyl-3-(2-hydroxy~ dimethylethylsulphonyl~propiona~e as a colourless solid; MS: 408 (M~NH4)~.
(g) Benzyl (~S)-2-Benzyl-3-[2-(2,2-dimethylpropionyloxy)-10 1,1-dim~thylethylsulphonyÇ~propionate:
0.74 g (6.14 mmol, 1.2 mol eq.) of pivaloyl chloride were added at room tempera~ure ~o a solution of 2.0 g (5.12 mmol) of benzyl (RS)-2-benzyl-3-(2-hydroxy-1,1-dimethyle~hylsulphonyl)-propionate and 60 mg (0.5 mrnol3 of N,N'-dime~hylaminopyridine in 20 ml of dry pyridine. The reaction mix~ure was warmed ~o 40 and stirred at this temperature for a further 6 hours. For ~he working-up, the cooled reaction solution was evaporated in a wa~erjet vacuum. For purification, the residue was chromato-20 graphed on silica gel using a 99:1 mixture of methylen@ chlorideand methanol as the eluent. There were obtained 2.18 g (90% of . theory) of benzyl (RS)-2-benzyl-3-[2-(2,2-dimethylpropionyl-oxy)-1,1~ime~hyle~hylsulphonyl~propionate as colourless crystals; MS: 475 ~M+H)~.
(h) (RS)-2-Benzyl-3-[2-(2,2-dimethylpropionyloxy)~
dimethylethylsuiphonyl]propionic acid:
A solution o~ 2.17 9 (4.57 mmol) of benzyl (RS)-2-benzyl-30 3-[2-(2,2-dimethylpropionyloxy)-1 ,1-dimethylethylsulphonyl~-propionate in 100 ml of methanol was treated wi~h 0.5 9 of palladium/charcoal (5%~ and hydrogenated at room temperature under normal pressure for 90 minutes. For the working-up, the ca~alyst was filtered o ff and rinsed three times with 30 rnl of 35 methanol each time. After evaporation in a waterjet vacuum there were obtained 1.55 9 (88% of theory) of (RS)-2-ben~yl-3-[2-(2 ,Z-dirnethylpropionyloxy)-1 ,1 -dimethylethylsulphonyl3-propionic acid as colourless crystals; MS: 385 (M-~H)+.
23 2~ 671 E~
The following compound~ were manufactured in an analo-s gous manner to that described in Example l - From (RS)-2-benzyl-3-~2-(2~2-dimethylpropionyloxy) 1,1-dimethylethylsulphonyl]propionic acid and ~S)-2 amino-N-[(1 S,2R,3S)-1 -cycioh~xylme~hyl-3-cyc3Opropyl-2,3-dihydroxy-10 propyl]-3-pyridin-3-ylpropionamide ~he less polar epimer 2,2-dimethylpropionic acid 2-[(R)- or 2-[(S~-2-[~S)-1-[~ S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl]-2-pyridin-3-yle~hylcarbamoyl~-3-phenylpropylsulphonyl]-2-methylpropyl ester, MS: 742 (M~H)+, and ~he more polar epimer 2,2-dimethylpropiQnic acid 2-[(S)- or 2-~(R~-2-[(S~-1-[(l S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl]-3-phenylpropylsulphonyl~-2-methylpropyi ester, MS: 742 (M+H)~, each as a colouriess foam;
- from (RS)-3-(2-acetoxy-1,1-dimethylethylsulphonyl)-2-benzylpropionic acid and (S)-2-amino-N-[~1 S,ZR,3S)-1 -cyclo-hexylmethyl-3-cyclopropyl-2 ,3~dihydroxypropyl]-3-imidazol-4-ylpropionamide the less polar epimer ace~ic acid 2-~R)- or 2-25 [(S~-2-[(S)-1-[( 1 S,2R,3S)-1 -cyclohexylmethy3-3-cyciopropyl-2,3-dihydroxypropylcarbamoyl~-2-imidazol-4-ylethylcarbamoyl~
3-phenylpropylsulphonyl]-2-methylpropyl ester, MS: 689 (M~H~+, and the more polar epimer acetic acid 2-[(S)- or 2-[(R) 2-~(S)-l-~(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-30 propylcarbamoyl]-2-imidazol-4-ylethy3carbarr~yl]-3-phenyl-propylsulphonyl~-2-methylpropyl ester, MS: 689 ~M~H)~, each as a colourless amorphous solid;
- from (RS)-2-benzyl-3-(2-hydroxy-lJl-dirnethylethyl-3s sulphonyl)propionic acid and (S)-2-amino-N-[(1 S,2R,3S)-l-cyclo-hexylmethyl-3-cyclopropyl-2 ,3-dihydroxypropyl]-3-imidazol-4-ylpropionamide the less polar epimer ~R or S)-2-benzyl-N-~(S)-1-~(1 S,2R,3S)-l-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-209.~'71 propylcarbamoyl]-2-imidazol-4-ytethyl]-3-(2-hydroxy-1, 1-dimethylethylsulphonyl)propionamide, MS: 647 (M~H)~, and the more polar epimer (S or R)-2-benzyl-N-~($)-1-~(1 S,2R~3S~
cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylearbamoyl~
5 2-imida701-4-yle~hyl]-3-(2-hydroxy-1, 1 -dimethyle~hyl-sulphonyl)propionamide, MS: 647 (M~H)+, each as an amorphous, colourless solid.
The (S)-2-amino-N-~lS,2R,3S~-l-cyclohexylmle~hyl 3-o cyclopropyl-213-dihydroxypropyl~-3-pyridin-3-yl-propionamide used as the starting ma~erial was prepared as ~llows:
1.27 g (3.3 mmol) of HBTU ancl 0.45 ml (3.3 mmol) of trie~hylamine were added to a solution of 878 mg ~3.3 mmol) o~
15 N-(tert-butoxycarbonyl)-3-(pyridin-3-yl)-L-alanine (DE
3,640,535) and 750 mg (3.3 mmol) of (1 S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropylbutane~1,2-diol in 33 ml acetonitrile and the mixture was stirred at room temperatwre overnight. The colourless clystals obtained af~er fil~ration were dissolved in 20 30 ml of ethanol and Z3.3 ml of 1 N hydrochloric acid were added ~hereto. A~er 24 hours at 500 the solution was made basic with 2N sodium hydroxide solution, evaporated under reduced pressure and the residue was parti~ionecl between water and e~hyl acetate.
The aqueous phase was ex~raeted ~hre~ times with ethyl acetate 2s and the combined organic phases were dried over magnesiurn sulpha~e, filtered and evaporated under reduced pressure.
Chromatographic purification of the residue (silica gel, methylene chloride/methanol/ammonia 14û:10:1) yielded 436 mg of (S)-Z-amino-N-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclo-30 propyl-2,3-dihydroxypropyl~-3~pyridin-3-ylpropionamide, MS:
267 (M+H)+, as a colourless foam.
The dihydrocinnamic acid derivatives used as the starting ma~erials were prepared as follows:
3s (a) (RS)-3-(2-Acetoxy-l, l-dimethylethylsulphonyl)-2-benzylpropionic acid:
2 ~ 9 ~ 6 ~ 1 In an analogous manner to tha~ described in Example 1 (g-h), by aeylating benzyl (RS)-2-benzyl-3-(2-hydroxy-1,1~dimethyl-ethylsulphonyl)propionate with acetyl chloride in pyridine there was obtained benzyl ~RS)-3-(2-acetoxy-1,1-dimethyle~hyl-5 sulphonyl)-2-benzylpropionate, MS: 341 (M-benzyl)+, as a colour-less oil. Subsequen~ ca~alytic hyd~ogena~ion yielded (RS)-3-(2-acetoxy~ dimethylethylsulphonyl~-2-benzylpropionic acid, MS:
296 (M-l ICOOH)~, as a colourless oil.
0(b) (RS)-2-Benzyl-3-~2-hydroxy-1 ,1-dimethylethyl-sulphonyl~propionic acid:
In an analogous manner to that describedl in Example 1 ~h), by catalytically hydrogenating the benzyl (RS)-2-benzyl-3-(2-15 hydroxy-1,1-dimethylethylsulphonyl)propionate described in Example 1 (f) over palladium/eharcoal ~5%~ the~ was ob~ained (RS)-2-benzyl-3-(2-hydroxy-1 ,1 -dimethylethylsulphonyl)-propionic acid as a eolourless solid; MS: 300 (M)+.
20~e~
In an analogous manner to that described in Example 1, by condensing (RS)-2-benzyl-3-(1-benzyloxycarbonyl-1-methyl-ethylsulphonyl)propionic aoid with (S)-2-amino-N-[(1 S,2R,3S)-1-zs cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl]-3-imidazol-4-yipropionamide there were obtained the less polar epimer benzyl 2-[(S)- or 2-[(R)-2-~(S)-1-[(1 S,2R,3S)-1 cyclo-hexylme~hyl-3-cyclopropyl-2 ,3-dihydroxypropylcarbamoyl]-2-imidazol 4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-30 methylpropionate, MS: 751 (M+tl)+, and the more polar epimerbenzyl 2-~(R)- or 2-[(S)-2-~(S)-1 [(1 S,2R,3S)-1-cyclohexyl-methyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl3-2-imidazol-4-ylethylcarbamoyl3-3-phenylpropylsulphonyl]-2 -methylpropionate, MS: 751 (M~H)~, each as a colourless foam.
3s The (RS)-2-benzyl~3-~1-benzyloxycarbonyi-1-methylethyl-sulphonyl)propionic acid used as the starting rnaterial was prepared as follows:
2 ~ 9 5 6 r~ L
2~
~ a~ (RS)-2-~2-tert-Bu~oxycarbonyl-2-benzylethyl-sulphonyl)-Z-methylpropionic acid:
In an analogous manner ~o that described in Examp!e 1 (d~, by the addition of 2-mercaptoisobutyric acid to tert-butyl 2-benzylacrylate, prepared according to a generally known proeedure from 2-benzylacrylic acid and N,N-dimethylformamide di~tert-butyl acetal [Tetrahedron 1979, ~5, 1675)], there was 10 obtai~ed (RS)-2-(2-tert-butoxycarbonyl-2-benzylethyl-sulphonyl)-2-methylpropionic acid as a yellowish oil; MS: 282 ~M-H2C-C(CH3)2]+-(b) Benzyl (RS~-2-~2-tert-butoxycarbonyl-2-benzylethyl-sulphonyl)-2-methylpropionate:
A solution of 500 mg (1.3 mmol) of (RS)-2-(Z-ter~-butoxycarbonyi-2-benzylethyisulphonyl)-2-methylpropionic acid in 5 ml of acetonitrile was treated with 197 mg (1.3 mmol) of 20 DBU and 222 mg (1.3 mmol) of benzyl bromide were added dropwise thereto a~ room temperature. The yellowish reaction solution was stirred for a fur~her 3 hours, ~hen treated with 10 ml of water and extracted twi~e with 10 ml of ethyl ace~ate each time. The combined ethyl ace~ate phases were washed twice 25 with S ml of water each time, subsequently dried over sodium sulphate and evaporated under reduced pressure. The thus-obtained benzyl ester was used in the following oxidation step in the form o~ a yellow oil (580 mg) without further purification and characteriza~ion.
The oxidation with potassium monopersulphate triple salt was effected analogously ~o Example 1 (d) and gave benzyl (RS)-2-~2-tert-butoxyoarbonyl-2-benzylethylsulphonyl)-2-methyl-propionate as a colourless oil; MS: 461 ~M~H)~.
(c) (RS)-2-Benzyl-3-(1-benzyloxycarbonyl-1-methylethyl-sulphonyl)propionic acid:
2 7 2 ~ ~ ~ 6 7 1 A mixture of 401 mg (0.87 mmol) of benzyl (RS)-2~(2-tert-butoxycarbonyl-2-benzyie~hylsulphonyl)-2-methyl-propionate and 5 ml of anhydrous formic acid was s~irred at room temperature. After 6 hours the initially turbid solution 5 became clear. This solution was evaporated at 40 under recluced pressure and ~he residue was ~aken up in 10 ml of ethyl ~cetate and washed with 3 ml of water. After drying over sodium sulphate and evaporation in a waterjet vacuum there were obtained 340 mg of (RS)~2-benzyl-3-(1-benzyloxycarbonyl-1-o methylethylsulphonyl)propionic acid, MS: 313 (M-benzyl)~, as a colourless oil which was used in the followin~ step without ~urther purification.
~m~
The foilowing compounds were rnanufactured by cataly~ic hydrogena~ion in an analogous manner to tha~ described in Example 1 (h):
- From benzyl 2~[(S)- or 2-~(R)-2-[(S~-l-[(lS,2R,3S)-1-cyclohexylmethyJ-3-cyclopropy5-2,3-dihydroxypropylcarbamoyl]-~-imidazol-4-ylethylcarbamoyl~-3 -phenylpropylsulphonyl~-2-methylpropionate the 2-~(S)- or Z-~(R~-2~[(S)-1 -[(l S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl-25 carbamoylJ-2~imidazol-4-ylethylcarbamoyl]-3-phenylpropyl-sulphonyl]-2-methylpropionic acid as a colourless, amorphous solid; MS: 661 (M+H)'~, and - from benzyl 2-[(R)- or 2-[~S)-2-[(S)-l -[(1 S,ZR,3S)-1-30 cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl]-2-imidazol-4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-methylpropionate the 2-~(R)- or 2-~(S)-2-[~S)-1-[(1 S/2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl-carbamoyl]-2-imidazol-4-ylethylcarbamoyl]-3-phenylpropyl-35 sulphonyl]-Z-methylpropionic acid as a colourless, amorphous solid; MS: 661 (M+H)+.
2 1~ ' 7 ~
~m~
~Q~e~
5 CQmp~.siti~;
2,2-Dimethylpropionic acid 2-~(S~- or 2-L(R)-2-~(S)-l-[~1 S,ZR,3S)-1 -cyclohexyimethyl-3-cyclopropyl-7,3-dihydroxypropylcarbamoyl~-2-imidazol-4-ylethyl-o carbamoyl~-3-phenylpropylsulphonyl]-Z-snethylpropyl es~r, micronized 5.0 g Polysorba~e 80 0.3 g Hydro)(ypropylmethylcellulose 1.0 g Flavour q.s.
Methylparaben 0.2 g Propylparaben 0~04 g Water ad 100.0 ml Ex~m~le B
Qral.~Leous solll~ion Com~ition 2,2-Dimethylpropionic acid 2-[(S)- or 2-[(R)-2-[(S)-1-[(1S,2R,3S)-l-cyclohexylmethyl-3 eyclopropyl-2,3-dihydroxypropylcarbamoyl]-2-imidazol-4 -ylethyl-carbamoyl~-3-phenylpropylsulphonyl] ~2-methylpropyl 35 ester, 1.0 g Methylparaben 0.2 g 2 ~3 9 i ) & r~ ~L
Propylparaben o 04 g Flavour q.s.
5 Water ad 100.0 ml .~m~
ÇQmQQ~;
1 ) 2,2-Dirne~hylpropionic acid Z-[(S) or 2-~(R)-2-[(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyelopropyl-2,3-dihydroxypropylearbamoyl]-2-imidazol-4-ylethylcarbamoyl~3-phenylpropyi-sulphonylll~2-methylpropyl es~er 200 mg 2) Anhydrous lactose 160 mg 3) Hydroxypropylme~hylcellulose 18 mg 4) Sodium carboxymethylcellulose 20 mg 2s 5) Magnesium stearate ~mg Tablet weight 400 mg 1 ) and 2) are mixed in~ensively. The mixture is thereafter moistened with an aqueous solution of 3) and kneaded, and the resul~ing mass is granulated, dried and sieved. The granula~e is mixed with 4) and 5) and pressed to tablets of suitable size.
3s 2~9~7 ~
E~am~
C~mp~ n 1 ) Z~2-Dlmetnylpropionic aeid 2-[(S)- or 2-[(R)-20[(S)-l -[~1 S,2R,3S)-1 -cyc~ohexylmethyl-3-cyolopropyl-2,3-dihydroxypropylcarbamoyl]-2-imidazol-4-ylethyl-o carbamoyl]-3-phenylpropylsulphonyl~-2-methyl-propyl ester 200 mg 2) Anhydrous lactose 160 mg 33 Hydroxypropylmethylcellulose 18 mg 4) Sodiumcarboxymethyicellulose 20 mg 5) Magnesiumstearate 2 Capsule fill weigh~ 400 mg Manuf~[j~LQr~ res 1 ) and 2) are mixed intensively. The mixture is thereafter moistened with an aqueous solution of 3~ and kneaded, and the resulting mass is granulated, dried and sieved. The granula~e is mixed with 4) and 5) and the mixtur~ is Fiiled into capsules of suitable size.
~mQIQ~
Inieçtion sql~ion 35 ~m~i~
2,~-Dimethylpropionic acid 2-[(S)- or 2-[(R) 2-~(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyclo-2~9~7~
propyl-2,3 dihydroxypropylcarbamoyl~-2-imidazol-4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-methylpropyl ester 20 mg 5 Pyrogen-free D-mannitol 10 mg Water ~r injection ad 1.0 ml The active substance and the mannitol are dissolved in nitrogen-gassed water and subse~uently Iyophilized according to a conventional procedure.
~E
When the procedures described in Examples A-E are ~ollowed, corresponding galenical preparations can be manufactured fr~m the following, likewise preferred comp~unds zo and their pharmaceutically usable salts:
2,2-Dime~hylpropionic acid 2-r(R)- or Z-[(5)-2-[(S)-1-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]-2-pyridin-3-ylethylc3rbamoyl]-3-phenyl-25 propylsulphonyl~-2-methylpropyl ester and 2,2-dimethylpropionic acid 2-~(S)- or 2-[(R)-Z-[(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl]-3~phenyl-30 propylsulphonyl~-2-methylpropyl ester.
Claims (16)
1. Amino acid derivatives of the general formula l wherein R1 signifies imidazolylmethyl or pyridylmethyl and A signifies carboxyl, benzyloxycarbonyl, hydroxymethyl or alkylcarbonyloxymethyl, 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.
2. Compounds in accordance with claim 1, wherein A
siynifies hydroxymethyl or alkylcarbonyloxymethyl, especially alkylcarbonyloxymethyl, particularly C1-4-alkylcarbonyloxy-methyl.
siynifies hydroxymethyl or alkylcarbonyloxymethyl, especially alkylcarbonyloxymethyl, particularly C1-4-alkylcarbonyloxy-methyl.
3. Compounds in accordance with claim 1, wherein A
signifies carboxyl.
signifies carboxyl.
4. 2,2-Dimethylpropionic acid 2-[(S)- or 2-{(R)-2-[(S))-1-[(1S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]-2-imidzol-4-ylethylcarbamoyl]-3 -phenyl-propylsulphonyl]-2-methylpropyl ester.
5. 2,2-Dimethylpropionic acid 2-[(R)- or 2-[(S)-2-[(S)-1-[(1S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl]-3-phenyl-propylsulphonyl]-2-methylpropyl ester.
6. 2,2-Dimethylpropionic acid 2-[(S)- or 2-[(R)-2-[(S)-1-[(1S,2R,3S)-l-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl]-3-phenyl-propylsulphonyl]-2-methylpropyl ester.
7. Compounds of the general formulae III V
and wherein R1 signifies imidazolylmethyl or pyridylmethyl and A1 signifies benzyloxycarbonyl, hydroxymethyl or alkylcarbonyloxymethyl.
and wherein R1 signifies imidazolylmethyl or pyridylmethyl and A1 signifies benzyloxycarbonyl, hydroxymethyl or alkylcarbonyloxymethyl.
8. Amino acid derivatives in accordance with any one of claims 1-6 for use as therapeutically active substances.
9. Amino acid derivatives in accordance with any one of claims 1-6 for use in the control or prevention of high blood pressure and cardiac insufficiency.
10. A process for the manufacture of a compound in accordance with any one of claims 1-6, which process comprises a) reacting a compound of the general formula II
wherein R1 has the significance given in claim 1, with an acid of the general formula III
wherein A1 signifies benzyloxycarbonyl, hyroxymethyl or alkylcarbonyloxymethyl, or an activated derivative thereof, or b) reacting the compound of the formula IV
with an acid of the general formula V
wherein A1 has the significance given earlier in this claim and R1 has the significance given in claim 1, or an activated derivative thereof, or c) for the rnanufaçture of a compound of formula I in which A
signifies carboxyl, cleaving off the benzyl group in a compound of formula I in which A signifies benzyloxycarbonyl, and d) if desired, separating a mixture of diastereomeric racemates into the diastereomeric racemates or optically pure diastereomers, and/or e) if desired. separating a mixture of diastereomers into the optically pure diastereomers, and/or f) if desired, converting a compound obtained into a pharmaceutically usable salt.
wherein R1 has the significance given in claim 1, with an acid of the general formula III
wherein A1 signifies benzyloxycarbonyl, hyroxymethyl or alkylcarbonyloxymethyl, or an activated derivative thereof, or b) reacting the compound of the formula IV
with an acid of the general formula V
wherein A1 has the significance given earlier in this claim and R1 has the significance given in claim 1, or an activated derivative thereof, or c) for the rnanufaçture of a compound of formula I in which A
signifies carboxyl, cleaving off the benzyl group in a compound of formula I in which A signifies benzyloxycarbonyl, and d) if desired, separating a mixture of diastereomeric racemates into the diastereomeric racemates or optically pure diastereomers, and/or e) if desired. separating a mixture of diastereomers into the optically pure diastereomers, and/or f) if desired, converting a compound obtained into a pharmaceutically usable salt.
11. A medicament containing an amino acid derivative in accordance with any one of claims 1-6 and a therapeutically inert excipient.
12. A medicament for the control or prevention of high blood pressure and cardiac insufficiency, containing an amino acid derivative in accordance with any one of claims 1-6 and a therapeutically inert excipient.
13. The use of an amino acid derivative in accordance with any one of claims 1-6 for the manufacture of medicaments against high blood pressure and/or cardiac insufficiency.
14. Amino acid derivatives in accordance with any one of claims 1-6, whenever prepared according to the process as claimed in claim 10 or by an obvious chemical equivalent thereof.
15. The invention as hereinbefore described.
16. A method of treating or preventing high blood pressure and/or cardiac insufficiency which comprises administering to a patient requiring such treatment an effective amount of an amino acid derivative in accordance with any one of claims 1-6.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH179592 | 1992-06-04 | ||
| CH1795/92 | 1992-06-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2095671A1 true CA2095671A1 (en) | 1993-12-05 |
Family
ID=4218776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002095671A Abandoned CA2095671A1 (en) | 1992-06-04 | 1993-05-06 | Amino acid derivatives |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0572909A1 (en) |
| JP (1) | JPH0656781A (en) |
| CN (1) | CN1081446A (en) |
| AU (1) | AU3995393A (en) |
| CA (1) | CA2095671A1 (en) |
| ZA (1) | ZA933795B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3856166T2 (en) * | 1987-09-29 | 1998-08-06 | Banyu Pharma Co Ltd | N-acylamino acid derivatives and their use |
| CA2004846A1 (en) * | 1988-12-19 | 1990-06-19 | Yutaka Koike | N-substituted acylamino acid compounds, process for their production and their use |
| CA2023099A1 (en) * | 1989-09-04 | 1991-03-05 | Quirico Branca | Amino acid derivatives |
-
1993
- 1993-05-06 CA CA002095671A patent/CA2095671A1/en not_active Abandoned
- 1993-05-26 EP EP93108471A patent/EP0572909A1/en not_active Withdrawn
- 1993-05-28 ZA ZA933795A patent/ZA933795B/en unknown
- 1993-06-01 AU AU39953/93A patent/AU3995393A/en not_active Abandoned
- 1993-06-03 JP JP5156321A patent/JPH0656781A/en active Pending
- 1993-06-03 CN CN93106671A patent/CN1081446A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ZA933795B (en) | 1993-12-06 |
| AU3995393A (en) | 1993-12-09 |
| JPH0656781A (en) | 1994-03-01 |
| CN1081446A (en) | 1994-02-02 |
| EP0572909A1 (en) | 1993-12-08 |
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