IE904649A1 - New amides - Google Patents
New amidesInfo
- Publication number
- IE904649A1 IE904649A1 IE464990A IE464990A IE904649A1 IE 904649 A1 IE904649 A1 IE 904649A1 IE 464990 A IE464990 A IE 464990A IE 464990 A IE464990 A IE 464990A IE 904649 A1 IE904649 A1 IE 904649A1
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- IE
- Ireland
- Prior art keywords
- acceptable salts
- physiologically acceptable
- prepared according
- optical isomers
- compound prepared
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
- C07C317/40—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/54—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Detergent Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Compounds having a renin inhibitory effect and having formula (I) wherein R<1>, R<2>, R<6> and n are as defined above with formula (I), A is a residue of an aliphatic L- alpha -amino acid, B is a residue of a lipophilic L- alpha -amino acid and D is a residue of an aliphatic L- alpha -amino acid, wherein further the hydroxy group in the link between B and D is in threo relationship with the alpha chain of B, either as such or in the form of physiologically acceptable salts and includes optical isomers unless a specific isomer is required, racemates, diastereomers, geometrical isomers and isomer mixtures whenever occurring, are disclosed. Processes for preparation and pharmaceutical preparations for such compounds and methods for treatment of heart disorders with such compounds are further disclosed.
Description
Background
Renin is a natural proteolytic enzyme, which is released into the blood from the kidney. Its only known function is to cleave circulating angiotensinogen into angiotensin I, which is a decapeptide of the following structure:
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
This in turn is further cleaved by angiotensin converting enzyme (ACE), resulting in the formation of the octapeptide angiotensin II:
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
This peptide is one of the most potent blood-pressure elevating agents known. Its biological activity in this respect is partly due to a vasoregulating effect and partly to an aldosterone-mediated antidiuretic and antisaliuretic effect.
Efforts to control hypertension by way of the reninangiotensin system has until lately been mainly directed towards inhibition of ACE. Although this principle has proved clinically useful, the non-specificity of ACE has been advocated as a reason for different side-effects. Since renin is highly specific for angiotensinogen, inhibitors of this enzyme could prove advantageous in the combat against different forms of hypertension.
The earliest efforts towards making renin inhibitors was mainly directed towards simple substrate analogues. By variations in the amino acid seguence Haber et al.
succeeded in increasing their potency. Further effectiveness was achieved by replacing the scissile dipeptide unit in the inhibitors with a non-cleavable unit such as statine (Boger et al Nature, 303, 81 (1983) or different isosteres (Szelke et al Nature, 299, 555 (1982). Compounds of this type proved very potent but had short duration of effect. This was attributed to proteolytic instability of the peptides, and thus much of the more recent work in this area has been directed towards making smaller inhibitors with reduced number of potentially scissile peptide bonds. For some recent publications on this subject see Matsuda et al, Chem. Lett. 1041 (1985), Plattner et al, 191:th ACS-meeting, New York, (1986), Hanson et al, Biochem. Biophys. Res. Comm. 132, 155 (1985) and Toda et al, Eur. J. Pharm. 129, 393 (1986). Plattner et al J. Med. Chem. 31, 2277 (1988), Luly et al J. Med.
Chem. 31, 2264 and 532 (1988), Kokubu et al Hypertension 8, suppl II, II-l (1986), Buhlmayer et al J. Med. Chem.
31, 1839 (1988), Greenlee Pharm. Res. 4, 364 (1987). Thaisrivongs et al J. Med. Chem. 31, 1369 (1988), Lizuka et al Chem. Pharm. Bull. 36.» 2278 (1988) and J. Med. Chem.
31, (1988), Hanson et al Biochem. Biophys. Res. Comm.
160, 1 (1989) and Rosenberg et al J. Med. Chem. 32, 1371 (1989). Recent patent applications relating to shorter inhibitors include EP 186977 (Sankyo), EP 190891 (Kissei), EP 172346 (Abbott), EP 189203 (Abbott), EP 172347 (Abbott), EP 181110 (Kissei), EP 273893 (Hassle).
Definitions
The following definitions apply both to the description of the invention and the claims unless otherwise specified.
1. The term ''amino acid includes amino acids of both natural and unnatural origin.
2. All ainino acids can be of either L- of D5 configuration but are preferably of the L-configuration unless otherwise stated.
3. All asymmetric centres may be of either R or S configuration unless otherwise stated.
4. Reference to carboxylic acids and amino acids should be read as the corresponding acyl residues unless it is apparent from the context that the free acid is intended.
. The term aryl means a carbocyclic or heterocyclic aromatic ring and includes phenyl, thienyl, pyridyl and naphthyl. The number of carbon atoms given for aryl includes ring heteroatoms when occurring.
Abbreviations [OH] = CH(OH)-CH2 replacing the CONH of a peptide bond [R] = CH2 replacing the carbonyl of an acyl group
Agl = Allylglycine
Ala = Alanine
Ape = 2-Aminopentanoic acid (=Nva)
Bnma = Benzyl(1-naphtylmethyl)acetic acid Boc = t-Butoxycarbonyl
Cha = Cyclohexylalanine
Dba = Dibenzylacetic acid
Dnma = Di (1-naphtylmethyl)acetic acid Dtma = Di(2-thienylmethyl)acetic acid Gly = Glycine
Tai = 2-Thienylalanine
Val = Valine
-f“ Cha-[0H]-Gly-[R]
OH CH,
-4“ Cha-[0H]-Ala-[R) -j cr
Prior art
EP-A2-0 273 893 (also mentioned above) is an earlier application by the present applicants. It discloses renin inhibiting compounds of the general formula:
containing 1-6 carbon atoms and B is phenylalaninyl; 0methyltyrosinyl; homophenylalaninyl; cyclohexylalaninyl; dibenzylacetyl and C is norvalinyl; valinyl; norleucinyl;
leucinyl; histidinyl; either as such or N - alkylated and r5 is a straight or branched alkyl group containing 1-6 carbon atoms or a cyclohexylmethyl group and R6 is H or a straight or branched alkyl group containing 1-6 carbon atoms and Y is selected from a) - SCH(CH3)2 and
b) - S(O)2CH(CH3)2· The Priority Document in said European application available as cf the publication date of said European application, i.e. a copy of SE 8605573-8, has a broader disclosure. Of the compounds disclosed in said
European application, the subclass where X-B- is dibenzylacetyl has attracted particular interest. As disclosed in EP 89850205.9, published as EP-A1-0 353 211 on January 31, 1990, said subclass has been expanded by inter alia substituting a group R6-Z-(CH2)n
X-(CH2)p-C(O)- (A)
R7-W-(CHn) it w for the dibenzylacetyl group, whereby the following definitions apply:
o is 0-2, P is 0-2, n is 0-2 X is CH or • N, Z is 0 or CH(R8) or absent, 20 W is 0 or CH(R8) or absent,
R8 is straight or branched lower alkyl (1-6 carbons) or cycloalkyl (3-7 carbons) or aryl (6-10 carbons) either as such or substituted by 1-3 substituents selected from: halogen (e.g. F,Cl), lower alkoxy (1-3 carbons e.g. methoxy), nitro, hydroxy, lower alkyl (1-3 carbons e.g. methyl) and cyano,
6
R is as defined for R and o
R is lower alkyl (1-3 carbons).
Specifically disclosed values for the group (A) include Dba, Dnma,Dtma, Bnma and Bpma (benzyl(4-pyridylmethyl)acetic acid).
The continued efforts of the present applicants have the purpose of providing novel therapeutically useful compounds, in particular improved renin inhibitors, and especially having increased renin inhibiting potency and/or increased bioavailability and/or less side effects.
Disclosure of the invention
This invention relates to new types of short renin inhibitors, their synthesis, pharmaceutical compositions containing the compounds as active ingredients and the use of the compounds as drugs, in particular for treatment of hypertension, congestive heart failure and other
I 10 cardiovascular disorders.
In particular the present invention relates to compounds of the general formula:
ί ι f r t
HO—-C-N-C-C-N-C-C—CH-,—C—CH?-S(O) -R° I
I I L I i. ~ >
R2_J η H 0 R η H where
R1- is an aryl group substituted with a group X, wherein X is the group
-Z m is an integer 0-2,
Z is CH or M
8
R and R are each severally hydrogen or a straight or branched lower alkyl group having 1-4 atoms, or form together with Z a 5- or 6-membered heterocyclic ring is an aryl group,
R is straight or branched alkyl or alkenyl group having 2-4 carbon atoms,
R^ is straight or branched alkyl group having 4-6 carbon 5 atoms or a cycloalkylalkyl group having 6-11 carbon atoms, r5 is hydrogen or a straight or branched alkyl having 1-3 carbon atoms, r6 is a straight or branched alkyl group having 1-5 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, an aryl group having 6-10 carbon atoms, an arylalkyl group having 7-11 carbon atoms or a cycloalkylalkyl having 4-11 carbon atoms, n is 0-2.
The main renin inhibiting activity of the compounds of formula I appears to reside in one of the optical isomers at the carbon atom marked *. Accordingly, in an embodiment of the invention, a renin inhibiting compound should comprise a substantial amount of the isomer showing renin inhibiting activity in a test therefor, known in the art, such as the test described below.
The invention provides the compounds either as such or in the form of physiologically acceptable salts and includes mixtures of optical isomers/diastereomers, unless an isomer is specified, whenever occurring.
According to a preferred embodiment of the invention R1 2 is a divalent phenyl or 1-naphthyl group and R is a phenyl or 1-naphthyl group.
According to a further preferred embodiment of the
2 invention R is a 3- or 4-substituted phenyl group and R is a phenyl group.
According to another preferred embodiment of the invention
2
R is a 3-, 4- or 5-substituted 1-naphthyl group and R is a naphthyl group.
According to a more specific embodiment of the invention
8
R and R are each severally hydrogen or a straight or branched alkyl group having 1-4 carbon atoms, or together with Z form a 5- or 6-membered heterocyclic ring, preferably piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, containing 1-2 heteroatoms (N, O or S) and optionally substituted with 1-2 alkyl groups having 1-3 carbon atoms, alkylcarbonyl groups having 1-3 carbon atoms or alkyloxycarbonyl groups having 3-6 carbon atoms, preferably Boc.
However, in a more general sense the present invention relates to compounds of the general formula
O ϋ-Ν—A—B- [ OH ] -D- (R ] -S (O) -R6
I
H
6 wherein R , R , R and n are as defined above with formula I, A is a residue of an aliphatic L-a-amino acid, B is a residue of a lipophilic L-a-amino acid and D is a residue of an aliphatic L-a-amino acid, wherein further the hydroxy group in the link between B and D is in threo relationship with the a chain of B. The main renin inhibiting activity of the compounds of formula C appears to reside in one of the optical isomers at the carbon atom marked *. Accordingly, in an embodiment of the invention, a renin inhibiting compound should comprise a substantial amount of the isomer showing renin inhibiting activity in a test therefor, such as the test described below.
Examples of the residue A are Ape and Agl. One example of the residue B is Cha. Examples of the residue D are Gly and Ala. What is stated below about compounds of formula I applies equally to compounds of formula C unless inconsistent with other requirements.
The compounds of formula I may be employed alone or in a combination for treating hypertension, congestive heart failure and other cardiovascular disorders, comprising a renin inhibitor according to formula I and one or more cardiovascular agents selected from the group comprising diuretics such as amiloride, bumetanide, chlortalidon, furosemide, gendroflumethiazide, hydrochlorothiazide and spironolactone; α-adrenergic blocking agents such as prazosin; β-adrenergic blocking agents such as atenolol, betaxolol, metoprolol, pindolol, propranolol and timolol;a- and β-adrenergic blocking agents such as labetalol; CNS-agents such as clonidine and methyldopa; vasodilators such as hydralazine, isosorbide dinitrate, isosorbide mononitrate and nitroglycerine; ACE20 inhibitors such as captopril, enalapril, lisinopril and ramipril; and Ca-antagonists such as amlodipine, diltiazem, felodipine, nifedipine, nitrendipine and verapamil.
Preferred compounds are those prepared according to the examples below.
Preparation
A further objective of the invention is the mode of preparation of the compounds of the invention. Thus the synthesis of ίο
is essentially achieved by first assembling the
S(O)n-R' portion henceforth referred to as the isostere, followed by one or two coupling reactions, optionally followed or intervened by some further manipulations of the isostere part, thus leading to structures of the formula I.
Thus the invention further relates to a process for preparation of compounds according to formula I, in which process an isostere of the formula
6 wherein R , R , R and n are as defined with formula I, is coupled to appropriate amino acids by standard peptide synthesis techniques, and in those cases where the reactions result in a mixture of diastereomers these are optionally separated by standard chromatographic or recrystallization techniques, and if desired an optical isomer is isolated.
Preferably the isostere is reacted at the N-terminal with an amino acid derivative of the formula
1 wherein R is as defined with formula I and A is as defined below and T is an activating group standardly used in peptide synthesis and preferably selected from -C(O)R^ or -CiOjOR11, wherein R11 is a straight or branched lower alkyl, N-benzotriazolyl, N-succinimidyl, nitrophenyl or azido in an inert solvent such as methylene chloride, chloroform, ethyl acetate, toluene, dimethoxyethane, DMF or THF at a temperature of -50 to 100’C, to the formation of a compound of formula I, either directly or after deprotection, or with an amino acid derivative of the formula
protecting group and T is as defined above, in an inert solvent such as methylene chloride, chloroform, ethyl acetate, toluene, dimethoxyethane, DMF or THF at a temperature of -50 to 100*C, then removing the protecting o 1 group R , and introducing a group A - T wherein A.
1 is as defined below and T is as defined above in an inert solvent such as methylene chloride, chloroform, ethyl acetate, toluene, dimethoxyethane, DMF or THF at a temperature of -50 to 100*C, to the formation of a compound of formula I, either directly or after deprotection.
I. Synthesis of isosteres 15
hereinafter referred to as the isosteres are prepared according to the following methods step 1
Method A
where an organometallic reagent 2 attacks an amino aldehyde 1 in a protected form to give compound 3 (Z1 = 0 or S)
Method B
where an appropriate carboxylic acid derivative 4 and an aliphatic aldehyde 5 react in an aldol reaction producing, after a Curtius rearrangement of the liberated carboxylic acid, an oxazolidinone 6 which can be cleaved by alkaline hydrolysis to give the desired amino alcohol 3a (Z^ = O, S)
Step 2
Conversion of = 0 into Z^ = S and of Z^ = S into
Z1 = SO or SO2
The oxygen is introduced as an ether or ester. At some step in the synthesis cleavage of the ethers and reduction of the esters respectively yield the alcohol 7
D - CH2-OR
D - CO2R
D1CH2-0H 7
The oxygen in 2 is replaced by sulphur by first transforming the primary alcohol into a leaving group, thus 8 is formed. The sulphur is then introduced by treating 8 with a thiolate. The thioether 9, either obtained in this way or directly via step 1 when Z1=S, can be oxidized to sulphoxide 10 or sulphone 11 prior to or after the coupling of the acids. (Tetr. Lett. 30, 265325 2656 (1989).)
R6^
D1-CH2-L -►
Certain precautions have to be taken when 8 is synthesized:
In these hydroxy isosteres the secondary hydroxy group has to be protected, e.g. in the form of an oxazolidinone 8a.
After the necessary transformations the oxazolidinone ring can then be cleaved to give the free amino alcohol 12.
II. Coupling of isosteres to amino acids and N-terminal groups
This is done by use of standard peptide and amide synthesis techniques such as coupling the isosteres with the hydroxybenzotriazole and hydroxysuccinimide esters of the appropriate acids either in two separate steps
or in one step
H 0
III. Separation of diastereomers
In those cases where the reactions result in a mixture of 30 diastereomers these can be separated by standard chromatographic or recrystallization techniques.
IV. Preparation of starting materials
The N-terminal acids
are either prepared by standard malonic ester alkylations of suitably substituted compounds of the following type
RX-CH2-L and R2-CH2-L followed by hydrolysis and decarboxylation, or by aromatic sulfonation of compounds of the following type
Aryl-CH2-CH
COOR
COOR followed by suitable derivatization of the corresponding 20 sulphonic acid, alkylation, hydrolysis and decarboxylation. Both these methods give racemates which could be used either as such or after separation by standard resolution techniques using salts of optically pure amines or by chromatographic techniques using chiral supports.
An alternative method for obtaining optically pure Nterminal acids is the use of the standard Evans-type of alkylation on suitable substituted chiral heterocyclic moieties
R -CH2CH2C-Het or
R1-CH2CH2C-Het followed by hydrolysis.
The amino acids used are either commercially available, or are prepared according to published methods.
The symbols used in the formulas above retain their meaning if previously defined and otherwise refer of the following:
21 = 0( S(O)n
r. = 0-2
R = lower alkyl g
R = N-protectmg group
R1^ - O-protecting group if Z1 = O and R8 if Z1 = S(0)n 15
Y = Carboxylic group or equivalent
V = H2; =0
L = Leaving group
with or without any amino acid residues attached to the nitrogen
T = an activating group
A1 = il
HC - C .2 J
Het = a chiral heterocyclic residue of the type used in Evans alkylations.
A further objective of the invention is a pharmaceutical composition containing the compounds of the invention.
Thus they can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral or rectal administration or in sterile solutions or suspensions for parenteral or nasal administration. About 0,001 to 500 mg of a compound is then compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavour etc. in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active compound in these preparations is such that a suitable dosage in the range indicated is obtained. Variations and changes which are obvious to one skilled in the art of formulations are intended to be within the scope of the invention.
A further objective of the invention is the use of the compounds as drugs for treatment of hypertension, congestive heart failure or other cardiovascular disorders. Thus for example by administration of a composition containing one of the compounds of the invention as active ingredient to a patient suffering from hypertension a reduction in blood pressure is obtained.
The substance is preferably administered orally, but parenteral, rectal and nasal routes can also be used. The dosage is preferably 0.001 to 500 mg of active ingredient and is preferably administered 1-3 times a day.
Best mode of carrying out the invention
The following examples illustrates the principles of the invention in more detail.
Example 1
Preparation of
a) Preparation of
To a stirred solution of 15.2 g (0.66 mol) of sodium in 350 ml of abs. ethanol was added 51.6 g (0.68 mol) of isopropyl mercaptan. The resulting sodium mercaptide solution was then added dropwise with stirring to an ice30 cooled solution of 103 g (0.654 mol) l-bromo-3-chloropropane in 50 ml of abs. ethanol. After the addition was completed, the ice bath was removed and after 3 h the solvent was removed by evaporation. The remainder was partitioned between water and ether, and the aqueous phase was extracted with ether. The combined organic phases were washed with water, dried (Na2SO4) and evaporated. The crude product was distilled twice to give 72.0 g (72%) of product., bp 53-58’C/4 mm Hg.
b) Preparation of
II
To a stirred mixture of 4.0 g (0.16 mol) of magnesium (Aldrich 99.95%) in 10 ml of dry tetrahydrofuran under 15 nitrogen was added a small portion of a solution of 12,6 g (0.082 mol) of X in 100 ml of dry tetrahydrofuran. When the reaction had started the mixture was brought to reflux. The rest of the solution of X was added during 30 minutes and the reflux was then continued for an additional 2.5 hours. The mixture was cooled to O’C and 7.0 g (0.027 mol) of N-Boc-cyclohexylalaninal (J. Med. Chem, 28, 1779 (1985)) in 50 ml of dry tetrahydrofuran was added rather quickly. The resulting mixture was left at room temperature for 3 hours, and was then poured into 500 ml of saturated ammonium chloride solution. The aqueous phase was separated and extracted several times with ether. The combined organic layers were dried (Na2SO4) and evaporated. The crude product was flash chromatographed on silica gel with petroleum ether/ethyl acetate (4/1). It was possible to separate the desired threo product from the corresponding erythro derivative even though they ran very close on TLC, the threo derivative eluting more rapidly. The yield was 4.4 g (44%).
III
c) Preparation of
To an ice cold solution of 7.3 g (0.020 mol) of II in 100 ml of methylene chloride was added 12.3 g (0.039 mol) of 55% meta-chloroperbenzoic acid. The mixture was stirred at room temperature for 2 h. After filtration the solution was washed with saturated aqueous sodium bicarbonate. The organic phase was washed with water, dried (Na2SO4) and evaporated, which gave 7.1 g (90%) of crude product which was used as such in the following step without further purification.
d) Preparation of
IV
To an ice cooled mixture of 46 mg (0.22 mmol) of (S)N-Boc allylglycine and 58 mg (0.43 mmol) of Nhydroxybenzotriazole in 5 ml of methylene chloride was added 104 mg (0.25 mmol) of N-cyclohexyl-N'-(2morpholinoethyl)carbodiimide-metho-p-toluenesulfonate (CME-CDI)· After 20 minutes the ice bath was removed and the mixture was then stirred for 3 hours. The solvent was then removed by evaporation, and the residue was dissolved in 5 ml of dry dimethylformamide and cooled to 0*C. Compound II, 81 mg (0.020 mmol), was dissolved in 0.17 ml of trifluoroacetic acid and 0.51 ml of methylene chloride. After 1.5 hours the mixture was evaporated and dissolved in 3 ml of dry dimethylformamide. This solution was added to the solution of the N-hydroxybenzotriazole ester described above. The pH of the mixture was adjusted to 8 by addition of N-methylmorpholine. The ice bath was removed after 30 minutes and the mixture was stirred overnight. It was then poured into water, and the resulting mixture was extracted three times with ethyl acetate. The combined organic phase was washed twice with dilute, aqueous HCl, once with saturated NaHCO^ (aq), and twice with water. Drying (NajSO^) and evaporation gave 73 mg (74%) of crude product, which was used in the next step without any further purification.
e) Preparation of (
m-Tolylsulfonyl chloride, 12 g (0.063 mol), was dissolved in 100 ml of methylene chloride and cooled to 0*C. Dimethylamine, 16.0 ml (0.126 mol) of a 40% water solution (7.9 M), was added dropwise with vigorous stirring, and the mixture was stirred for 1 hour. The organic phase was separated and washed with water. Drying (Na2SO^) and evaporation gave a crude product which was recrystallized from ethanol. Yield 8.5 g (68%), mp 69-69.5*C.
f) Preparation of
VI
A mixture of 7.8 g (0.039 mol) of V, 8.4 g (0.047 mol) of 20 N-bromosuccinimide and 50 mg of benzoylperoxide in 50 ml of carbon tetrachloride was refluxed for 4 hours. It was then allowed to cool and after filtration, evaporation and flash chromatography on silica gel, eluting with heptane/ethyl acetate (8/2), 3.2 g (25%) was obtained.
g) Preparation of
VII
Diethyl bensylmalonate, 1.0 g (4.0 mmol) was dissolved in 20 ml of dry dimethylformamide and 0.19 g (4.4 mmol) of a 55% mineral oil suspension of sodium hydride was added. After 15 minutes 1.1 g (4.0 mmol) of VI was added and the mixture was kept at 100’C for 4 hours. After cooling it was poured into water and extracted three times with ether. The combined ether phase was washed with water, dried (Na2SO^) and evaporated giving 1.2 g (67%) of the product.
h) Preparation of
VIII
The diester VII was refluxed overnight with sodium hydroxide, water and methanol. Aqueous workup with ether extraction gave the diacid, which was heated neat to effect the decarboxylation. The crude acid was used without further purification in the next step.
i) Preparation of
IX
The hydroxybenzotriazole ester of VIII was prepared by the same method as described above for the preparation of IV, from 62 mg (0.18 mmol) of VIII, 50 mg (0.37 mmol) of Nhydroxybenzotriazole and 88 mg (0.21 mmol) of CME-CDI in 3 ml of methylene chloride.
Compound IV, 84 mg (0.17 mmol), was dissolved in 0.17 ml of trifluoroacetic acid and 0.51 ml of methylene chloride. After 1.5 hours the mixture was evaporated and dissolved in 3 ml of dry dimethylformamide and added to the solution of the N-hydroxybenzotriazole ester described above in 3 ml of dry dimethylformamide at 0*C. The pH was adjusted to
8 by addition of N-methylmorpholine and the reaction mixture was then stirred at room temperature for 3 days. Workup as for IV and flash chromatography (silica gel, petroleum ether/ethyl acetate 1/9) gave 52 mg (43%) cf the title compound as a 1:1 mixture of diastereomers.
1H-NMR (CDC13): 0.8-2.35 (m) - thereof 1,41 (d); 2.7-3.2 (m) - thereof 2.72 (s), 2.74 (s); 3.36 (m); 3.55 (bs);
3.80 (m); 4.28 (bq); 4.8-5.0 (m); 5.3-5.4 (m); 5.91 (d);
6.06 (d); 6.19 (d)? 6.30 (s); 7.1-7.7 (m).
Examples 2-28
The preparation of these compounds is accomplished in a similar way as described above in Example 1.
Example 2.
IApe-Cha-[OH]-Ala-[R]~SO2— (Mixture of two diastereomers) 1H-NMR (CDCl3): 0.7-1.0 (m); 1.1-1.78 (m); 1.83 (s); 2.23 (m); 2.33 (m); 2.6-3.18 (m) - thereof 2.68 (d); 3.45 (m);
3.53 (d); 3.65 (m); 3.87 (d); 4.25 (m); 5.75 (d); 5.88 (d); 6.00 (d); 6.10 (d): 7.12 (d); 7.15-7.32 (m); 7.35 (d); 7.4 (d); 7.65 (d); 7.69 (d).
Example 3. 30
(Mixture of two diastereomers) 1H-NMR (CDC13): 0.75-1.0 (m); 1.08-2.08 (m) - thereof 1.4 (s); 2.2 (m); 2.62-3.2 (m); 3.49 (m); 3.75 (m); 4.2 (q);
4-76-5.0 (m); 5.32 (m); 5.60 (d); 5.82 (m); 7-08-7.39 (m);
7.69 (dd).
Example 4.
O iJ-Agl-Cha-(OH]-Gly-(R]-SO2— (Single isomer) ^H-NMR (CDClj): 0.75-0.95 (m) ; 1.07-2.02 (m) - thereof 15 1.39 (d); 2.2 (m); 2.63-3.15 (m) ; 3.49 (m); 3.72 (m); 4.18 (q); 4.90 (d); 4.91 (d); 5.35 (m) ; 5.70 (m); 7.11-7.35 (m); 7.65 (d).
Example 5.
Example 6. 30
Example 7.
(Mixture of two diastereomers) ^H-NMR (CDClj): 0.7-2.1 (m) - thereof 0.9 (dd), 1.27 (dd) 1.38 (d); 2.2 (m); 2.6-3.3 (m); 3.5 (m); 3.75 (m); 4.30 (m); 4.8 (s); 4.95 (dd); 5.35 (m); 5.70 (d); 6.0 (dd); 7.05-7.45 (m); 7.8 (dd).
Example 8.
XI
a) Preparation of
To a solution of sodium ethoxide, prepared from 1.45 g (0.0624 mol) of sodium and 40 ml of ethanol, was added
,0 g (0.0624 mol) of diethyl malonate. After stirring for 1 h at room temperature, 11,04 g (0.0624 mol) of 1chloromethylnaphtalene dissolved in 25 ml of ethanol was added. The resulting mixture was then refluxed for 2 h and then stirred at room temperature for 36 h. The resulting semi-crystalline mixture was evaporated to remove most of the ethanol, whereupon water was added. The aqueous phase was then extracted three times with ether, and the combined organic phases washed twice with NaHCO^-solution.
Drying (Na2SO4) and evaporation gave 16.9 g of crude product, which was purified by flash chromatography on silica using methylene chloride as eluent. This gave 9.0 g (48%, of the expected product.
b) Preparation of a
I
XIII
To an ice cooled, stirred solution of 3.0 ml (0.045 mol) of clSO^H in 5 ml of methylene chloride was added during
minutes 2.7 g (0.009 mol) of XII in 2.5 ml of methylene chloride. During the addition the temperature rose to +8°C. After the addition was completed the mixture was stirred at O’C for 30 minutes, and then at room temperature for 4 h. The reaction mixture was carefully washed with water. The organic phase was evaporated and ethyl acetate was added to the residue. The resulting organic phase was washed twice with water, dried (Na2SO4) and evaporated giving 3.2 g (89%, of product, which was used directly in the next step without further purification.
c) Preparation of
XIV
To an ice cooled, stirred solution of 1.0 g (0.0025 mol) of XIII in 10 ml of methylene chloride was added a 20-fold excess of ice cooled dimethylamine. The temperature of the mixture rose during the addition to about +10°C. After the addition was completed the mixture was stirred for 20 minutes at 0eC, and for 30 minutes at room temperature.
The mixture was evaporated, and the residue redissolved in methylene chloride. Washing twice with water, drying (Na2SO4) and evaporation gave 0.9 g (88%) of the product.
d) Preparation of
XV
To a suspension of toluene washed sodium hydride (0.5 g, 0.0103 mol) in 10 ml of dry toluene was added 1.4 g (0.00344 mol) of XIV dissolved in 5 ml of dry toluene. The mixture was stirred for 30 minutes at room temperature, whereupon 0.6 g (0.00344 mol) of 1-chloromethylnaphtalene in 5 ml of dry toluene was added. The resulting mixture was stirred at 75°C for 21 h. After removal of the solvent by evaporation, the residue was dissolved in ethyl acetate. Washing twice with water, drying (Na2SO4) and evaporation gave 1.9 g of crude product, which was purified further by flash chromatography on silica using hexane/ethyl acetate (2/1) as eluent. This gave 1.1 g (59%) of the product.
e) Preparation of ι
O = S=O
O
H
XVI
A mixture of 0.9 g (0.00165 mol) of XV, 0.47 g (0.0074 mol) of KOH (87%), 4.8 ml of ethanol (95%) and 1.2 ml of water was refluxed for 3.5 h. The mixture was then evaporated and 25 ml of water was added. The agueous phase was washed twice with ether and then acidified to pH 2 using 2 M HCl. The mixture was then extracted three times with ethyl acetate, whereupon the combined organic phase was washed once with water, dried (Na2SO4), and evaporated. This gave 0.7 g (95%) of the product.
f) Preparation of
o=s =o
N
H
XI
O ό
This compound was prepared in the same manner as described above in Example 1 i, starting from 107.6 mg (0.2407 mmol) of XVI, 65 mg (0.4814 mmol, of N-hydroxybenzotriazole and
115.9 mg (0.2735 mmol) of CME-CDI in 5 ml of methylene chloride and from 110 mg (0.2188 mmol) of IV, 0.33 ml of trifluoroacetic acid in 1 ml of methylene chloiide and 4 ml dimethylformamide. This gave 200 mg of crude product consisting of a 1/1 mixture of diastereomers. These were separated by flash chromatography on silica using hexane/ethyl acetate (1/5) as eluent. Thus 57 mg of the biologically less potent isomer and 35 mg of the more potent isomers were obtained. The latter had the following IH NMR- data: 0.70-2.10 (m) - thereof 0.86 (m), 1.33 (d); 2.70-3.12 (m) - thereof 2.79 (dd); 3.32-3.80 (m);
4.12 (m); 4.61 (dd), 4.75 (dd), 5.35 (m)· 5.50 (d); 5.85 (d); 7.30-7.95 (m); 8.05 (d); 8.76 (d).
Example 9.
Example 10.
o ’() \-C-Agl-Cha-(OH)-Gly-[Rj-SO2—<
(Mixture of two diastereomers) 1H-NMR (CDC13):
0.70- -2.111 Im) - thereof 0.84 (m), 1.35 (dd); 2.75-3 .20 (m); 3.30- -3.51 (m); 3.58-3.75 (m); 4.02-4.18 (m); 4.46 (d) / 4.63 (d); 4.70 (d);4.79 (d); 5.12 (m); 5.21 (d); 5.48 (d); 5.70 (d); 5.76 (d)il.30-7.93 (m); 8.08 (d); 8.12 (d); 8.78 (d); 8.82 (d) .
Example 11.
ϋ-Agi-Cha-ίOH)-Gly-1R]-SO2 —<
(Mixture of two diastereomers) 1H-NMR (CDC13):
0.6-2.2 (m)-thereof 0.8 (m), 1.1 (m), 1.3 (d); 2.73 (d);
2.9 (m); 3.1(dd); 3.25-3.8 (m); 4.1 (dd); 4.6 (d); 4.75 (dd); 5.2 (m);5.4-5.6 (dd); 6.05-6.3 (dd); 7.2-8.1 (m); 8.25 (d).
Example 12.
Ο ϋ-Agl-Cha-(OH]-Gly- (R] -SOj—ζ
Example 14.
$-Agl-Cha-[OH)-Gly-[R]-SO2—ζ (Mixture of two diastereomers) 1H-NMR (CDC13):
0.76-0.94(m)? 1.05-2.1 (m) - thereof 1.32 (d); 2.8 (d);
2.84-3.08(m); 3.27-3.5 (m); 3.59 (m); 3.79 (m); 4.2 (m); 4.6 (m);4.74 (d); 5.14 (m); 5.59 (d); 5.67 (d); 6.12 (d); 6.17 (d) ,-7.26-7.62 (m); 7.76 (m); 7.85 (d); 7.89 (d); 8.03 (d); 8.1(d); 8.15 (d); 8.67 (m).
Example 15,
V
C-Agl-Cha-(OH]-Gly-(R]-SO2—<
Example 16
V
C-Agl-Cha-[OH]-Gly-[R)-SO2—<
(Mixture of two diastereomers) 1H-NMR (CDC13):
0.75-0.98(m); 1.05-1.5 (m) - thereof 1.32 (d); 1.53-2.1 (m)? 2.4-2.54(m); 2.8-3.75 (m); 4.1 (m); 4.55 (m); 4.75 (d); 5.13 (m);5.37 (d); 5.5 (d); 5.78 (m); 7.28-7.6 (m); 7.68 (m); 7.78 (m); 7.9 (m); 8.07 (m); 8.18 (m); 8.6 (m)
Example 18.
Example 19.
Example 20
u
C-Agl-Cha-(OH) -Gly- (R] -SOj—ζ
V
C-Agl-Cha-[OH)-Gly-(R)-SO2—<
Example 22
v
Ϊ-Agl-Cha-[OH ]-Gly-[ R J-SO2-\
O
V
Ϊ-Agl-Cha-[OH]-Gly-[ R]-SOj—ζ
Example 24
-Agl-Cha-[OH]-Gly-[R]-SO2-^(
Example 25.
Boc
!!-Agl-Cha-[OHj-Gly-iR]-SO2—ζ
Example 27.
Boc-θ— J ο
ο !!-Agl-Cha-[OH]-Gly-[R]-SO2—ζ
Ο ϋ-Agl-Cha-[OH)-Gly-1 RI-SO2—<
Example 29
Solution for injection.
A solution is prepared from the following ingredients:
Renin inhibitor 1 g Ethanol 100 ml Polyethylene glycol 400 400 ml Water for inj. up to 1000 ml
The active constituent is dissolved in the ethanol/polyethylene glycol mixture. Water is added to final volume, whereafter the solution is filtered through a sterile 0.2 pm filter and aseptically filled into sterile ampoules (5 ml).
Example 30
Solution for injection.
A solution is prepared from the following ingredients:
Renin inhibitor 1 g
Sodium chloride 9 g
Methyl p-hydroxybenzoate 0.5 g Propyl p-hydroxybenzoate 0.2 g Water for inj. up to 1000 ml
The active constituent, sodium are dissolved in the main part chloride and preservatives of the water, whereafter the volume is adjusted to 1000 ml. The solution is filtered through a sterile 0.2 pm filter and aseptically filled into sterile ampoules (5 ml).
Example 31
Solution for nasal administration
A solution is prepared from the following ingredients:
Renin inhibitor 10 g
Glycerol 200 g
Methyl p-hydroxybenzoate 1 g Propyl p-hydroxybenzoate 0.2 g Water for inj. up to 1000 ml
The active constituent and the preservatives were dissolved in glycerol and the main part of the water. The volume is then adjusted to 1000 ml and the solution is filled into sterile polyethylene containers.
Example 32
Tablets for oral administration
1000 tablets are prepared from the following ingredients:
Renin inhibitor 10 g 25 Lactose 100 g
Polyvinyl pyrrolidone 20 g Avicel 20 g Magnesium stearate 2 g
The active constituent and lactose are mixed with an aqueous solution of polyvinyl pyrrolidone. The mixture is dried and milled to form granules. The Avicel and then the magnesium stearate are then admixed. The mixture is then compressed in a tablet machine giving 1000 tablets, each containing 10 mg of active constituent.
Example 33
Gelatine capsules for oral administration Gelatine capsules are filled with a mixture of the following ingredients:
Renin inhibitor 10 mg Magnesium stearate 2 mg Lactose 188 mg
Biological data
The potencies of the compounds of the invention as renin inhibitors were determined in vitro at pH 6.0 and at 7.2 using a human renin/angiotensinogen reaction. The assay is based on the method of Ikeda et al (J.Clin.Endocrinal
Metab. 54, 423 (1982), and relies on a radioimmunometric determination of the amount of angiotensin I released from angiotensinogen by renin in a human plasma pool.
For determination at pH 6.0 the compounds of the invention were dissolved in 0.1 M acetic acid (10 microliter) and then added to human plasma (200 microliter) containing
EDTA and 0.6 M citrate buffer (20 microliter). After 125 incubation for 60 minutes at 37°C, I-labelled angiotensin I containing 0.5 mg/ml pepstatine A was added.
Antibody coated spheres were added and the resulting mixture incubated for 3 hours at room temperature. 2 ml of distilled water was then added, whereafter the liquid was removed with an aspirator. The radioactivity of the spheres was then determined using a gamma scintillation technique. For determination at pH 7.2 a similar procedure was used using an imidazolbased buffert instead of a citrate buffert.
The potencies of the compounds thus obtained (see table 1) 35 are given as means of at least four experiments and are expressed as ρΙΟ^θ, i.e. the negative logarithm of the molar concentration required to cause 50% inhibition.
Table 1
Example No 5 _
7
16 pIC5Q(pH 6.0) pIC5Q(pH 7.2)
0 j
*
8.
*
8.
8.4
7.4 8.8 8.6
7.6
8.6
8.4 *
* *
*
Tested as a mixture of diastereomers.
Most of these compounds were also tested for oral activity 20 in rats using 10 micromol/kg. Samples were taken after
0-25 h from the tail vein and analyzed in a human plasma pool, and the plasma levels were compared with plasma levels of a reference compound (EP 273893, Example 1). Of the compounds tested in this way compounds no 8 and 11 showed an oral activity comparable to that of the reference compound.
Claims (47)
1. Compounds of the general formula o ? 5 HC—C-N-C-C-N R 4 H H 2 -C—CH 2 -S(O) n -R' ii where R 1 is an aryl group substituted with a group X, wherein X is the group -S(O)_ -Z_ \ r 8 m is an integer 0-2, 20 Z is CH or N 7 8 R and R are each severally hydrogen or a straight or branched lower alkyl group having 1-4 atoms, or form together with Z a 5- or 6-membered heterocyclic 25 ring R is an aryl group, R 3 is straight or branched alkyl or alkenyl group having 30 2-4 carbon atoms, R 4 is straight or branched alkyl group having 4-6 carbon atoms or a cycloalkylalkyl group having 6-11 carbon atoms, 35 r5 is hydrogen or a straight or branched alkyl having 1-3 carbon atoms, r6 is a straight or branched alkyl group having 1-5 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, an aryl group having 6-10 carbon atoms, an arylalkyl group having 7-11 carbon atoms or a cycloalkylalkyl having 4-11 carbon atoms, n is 0-2, either as such or in the form of physiologically acceptable salts and including mixtures of optical 10 isomers/diastereomers, unless an isomer is specified, whenever occurring.
2. A renin inhibiting compound as claimed in claim 1, comprising a substantial amount of the isomer at the 15 carbon atom marked * showing renin inhibiting activity in a test therefor.
3. Compounds according to one or more of the preceding 20 claims wherein is a divalent phenyl or 1-naphthyl group 2 and R is a phenyl or naphthyl group.
4. Compounds according to one or more of the preceding claims wherein R^ is a 3- or 4-substituted phenyl group 2 25 and R is a phenyl group.
5. Compounds according to one or more of claims 1-3 wherein R 1 is a 3-, 4- or 5-substituted 1-naphthyl group 2 and R is a naphthyl group.
6. Compounds according to one or more of the preceding
7. 8 claims wherein R and R are each severally hydrogen or a straight or branched alkyl group having 1-4 carbon atoms, or together with Z form a 5- or 6-membered heterocyclic 35 ring, preferably piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, containing 1-2 heteroatoms (N, O or S) and optionally substituted with 1-2 alkyl groups having 1-3 carbon atoms, alkylcarbonyl groups having 1-3 carbon atoms or alkyloxycarbonyl groups having 3-6 carbon atoms, preferably Boc. 5 7. Compounds of the general formula | C-N—A—B-[OH]-D-[R]-S(O) -R 6 I H 12 6 wherein R , R , R and n are as defined above with formula I, A is a residue of an aliphatic L-a-amino acid, B is a residue of a lipophilic L-a-amino acid and D is a residue 15 of an aliphatic L-a-amino acid, wherein further the hydroxy group in the link between B and D is in threo relationship with the a chain of B, either as such or in the form of physiologically acceptable salts and including mixtures of optical isomers/diastereomers, unless an 20 isomer is specified, whenever occurring.
8. A renin inhibiting compound as claimed in claim 7, comprising a substantial amount of the isomer at the carbon atom marked * showing renin inhibiting activity in 25 a test therefor.
9. The compound prepared according to Example 1 cither as such or in the form of physiologically acceptable salts and including optical isomers.
10. The compound prepared according to Example 2 either as such or in the form of physiologically acceptable salts and including optical isomers. 35
11. The compound prepared according to Example 3 either as such or in the form of physiologically acceptable salts and including optical isomers.
12. The compound prepared according to Example 4 either as such or in the form of physiologically acceptable salts and including optical isomers.
13. The compound prepared according to Example 5 either as such or in the form of physiologically acceptable salts and including optical isomers. 10
14. The compound prepared according to Example 6 either as such or in the form of physiologically acceptable salts and including optical isomers.
15. The compound prepared according to Example 7 either as 15 such or in the form of physiologically acceptable salts and including optical isomers.
16. The compound prepared according to Example 8 either as such or in the form of physiologically acceptable salts 20 and including optical isomers.
17. The compound prepared according to Example 9 either as such or in the form of physiologically acceptable salts and including optical isomers.
18. The compound prepared according to Example 10 either as such or in the form of physiologically acceptable salts and including optical isomers. 30
19. The compound prepared according to Example 11 either as such or in the form of physiologically acceptable salts and including optical isomers.
20. The compound prepared according to Example 12 either 35 as such or in the form of physiologically acceptable salts and including optical isomers.
21. The compound prepared according tc Example 13 either as such or in the form of physiologically acceptable salts and including optical isomers.
22. The compound prepared according to Example 14 either 5 as such or in the form of physiologically acceptable salts and including optical isomers.
23. The compound prepared according to Example 15 either as such or in the form of physiologically acceptable salts 10 and including optical isomers.
24. The compound prepared according to Example 16 either as such or in the form of physiologically acceptable salts and including optical isomers.
25. The compound prepared according to Example 17 either as such or in the form of physiologically acceptable salts and including optical isomers. 20
26. The compound prepared according to Example 18 either as such or in the form of physiologically acceptable salts and including optical isomers.
27. The compound prepared according to Example 19 either 25 as such or in the form of physiologically acceptable salts and including optica? isomers.
28. The compound prepared according to Example 20 either as such or in the form of physiologically acceptable salts 30 and including optical isomers.
29. The compound prepared according to Example 21 either as such or in the form of physiologically acceptable salts and including optical isomers.
30. The compound prepared according to Example 22 either as such or in the form of physiologically acceptable salts and including optical isomers.
31. The compound prepared according to Example 23 either as such or in the form of physiologically acceptable salts and including optical isomers.
32. The compound prepared according to Example 24 either as such or in the form of physiologically acceptable salts and including optical isomers. 10
33. The compound prepared according to Example 25 either as such or in the form of physiologically acceptable salts and including optical isomers.
34. The compound prepared according to Example 26 either 15 as such or in the form of physiologically acceptable salts and including optical isomers.
35. The compound prepared according to Example 27 either as such or in the form of physiologically acceptable salts 20 and including optical isomers.
36. The compound prepared according to Example 28 either as such or in the form of physiologically acceptable salts and including optical isomers.
37. A process for preparation of compound according to any of claims 1-36, wherein an isostere of the formula wherein R 4 , R 3 and R 8 are as defined in claim 1, is coupled to an appropriate amino acid and appropriate acyl 35 compounds by standard peptide synthesis technigues, and in those cases where the reactions result in a mixture of diastereomers these are optionally separated by standard chromatographic or recrystallization techniques, and if desired an optical isomer is isolated.
38. A compound according to any of the claims 1-36 for use 5 as a renin inhibitor.
39. A compound according to any of claims 1-36 for use as a drug for treatment of hypertension, congestive heart failure and other cardiovascular disorders. 1C
40. A pharmaceutical preparation for treatment of hypertension, congestive heart failure and other cardiovascular disorders comprising a therapeutically effective amount of any of the compounds outlined in claims 1-36, and further15 more comprising a pharmaceutical carrier.
41. A pharmaceutical preparation as claimed in claim 40 further comprising one or more cardiovascular agents selected from the group comprising diuretics, a-adrenergic 20 blocking agents, β-adrenergic blocking agents, a and 8adrenergic blocking agents, CNS-agents, vasodilators, ACEinhibitors and Ca-antagonists.
42. Use of compound according to any of claims 1-36 as an 25 active ingredient for manufacture of a pharmaceutical preparation for obtaining inhibition of renin in a human or animal organism.
43. Use of compound according to any of the claims 1-36 as 30 an active ingredient for manufacture of a pharmaceutical preparation for treatment of hypertension, congestive • heart failure and other cardiovascular disorders. - 54
44. A compound as defined in claim 1 or claim 7 hereinbefore specifically mentioned.
45. A process according to claim 37 substantially as hereinbefore described with reference to any one of Examples 1-28.
46. A compound obtained by a process according to claim 37 or 45.
47. A pharmaceutical preparation according to claim 40 substantially as hereinbefore described with reference to any one of Examples 29-33. Dated this 21st day of December, 1990 ANNE RYAN & CO.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8904350A SE8904350D0 (en) | 1989-12-22 | 1989-12-22 | NEW AMIDES |
SE9002439A SE9002439D0 (en) | 1990-07-16 | 1990-07-16 | NEW AMIDES II |
Publications (1)
Publication Number | Publication Date |
---|---|
IE904649A1 true IE904649A1 (en) | 1991-07-17 |
Family
ID=26660673
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE464990A IE904649A1 (en) | 1989-12-22 | 1990-12-21 | New amides |
Country Status (6)
Country | Link |
---|---|
CN (1) | CN1052679A (en) |
AU (1) | AU7032391A (en) |
IE (1) | IE904649A1 (en) |
IL (1) | IL96713A0 (en) |
PT (1) | PT96325A (en) |
WO (1) | WO1991009838A1 (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4645759A (en) * | 1984-06-22 | 1987-02-24 | Abbott Laboratories | Renin inhibiting compounds |
SE8605573D0 (en) * | 1986-12-29 | 1986-12-29 | Haessle Ab | NOVEL COMPOUNDS |
DE3733296A1 (en) * | 1987-10-02 | 1989-04-20 | Merck Patent Gmbh | AMINOSAEUREDERIVATE |
SE8802428D0 (en) * | 1988-06-28 | 1988-06-28 | Haessle Ab | NEW COMPOUNDS |
CA2004846A1 (en) * | 1988-12-19 | 1990-06-19 | Yutaka Koike | N-substituted acylamino acid compounds, process for their production and their use |
-
1990
- 1990-12-18 AU AU70323/91A patent/AU7032391A/en not_active Abandoned
- 1990-12-18 WO PCT/SE1990/000847 patent/WO1991009838A1/en unknown
- 1990-12-18 IL IL96713A patent/IL96713A0/en unknown
- 1990-12-21 PT PT96325A patent/PT96325A/en not_active Application Discontinuation
- 1990-12-21 IE IE464990A patent/IE904649A1/en unknown
- 1990-12-21 CN CN90110070A patent/CN1052679A/en active Pending
Also Published As
Publication number | Publication date |
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IL96713A0 (en) | 1991-09-16 |
AU7032391A (en) | 1991-07-24 |
PT96325A (en) | 1991-09-30 |
WO1991009838A1 (en) | 1991-07-11 |
CN1052679A (en) | 1991-07-03 |
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