IE914081A1 - Aminodiol derivatives - Google Patents
Aminodiol derivativesInfo
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- IE914081A1 IE914081A1 IE408191A IE408191A IE914081A1 IE 914081 A1 IE914081 A1 IE 914081A1 IE 408191 A IE408191 A IE 408191A IE 408191 A IE408191 A IE 408191A IE 914081 A1 IE914081 A1 IE 914081A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention relates to compounds of the formula in which W represents -CO-, -O-CO-, -SO2- or -NH-CO-, R, R<2>, R<4>, R<5>, R<6> and R<7> represent hydrogen or an organic radical and R<3> denotes alkyl, cycloalkyl or cycloalkylalkyl, processes for their preparation, intermediates and their use in the preparation of inhibitors of renin and HIV protease.
Description
HOECHST AKTIENGESELLSCHAFT HOE 90/F 353 Dr. JA/AP
Description
Aminodiol derivatives
The invention relates to compounds of the formula Ia or lb
(lb) and their salts, in which R1 is R‘-W-;
W is -CO-, -O-CO-, -SO2- or -NH-CO-;
Ra is hydrogen, (Cj-Cio) -alkyl which is optionally mono- or diunsaturated and which is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (C1-C7)-alkoxy, (Cx-C7)-alkanoyloxy, carboxyl, (C1-C7)-alkoxycarbonyl, halogen, amino, (Cx-C7)alkylamino, di-(C1-C7)-alkylamino, ((2^-C5) -alkoxycarbonyl5 amino and (C7-C15)-aralkoxycarbonylamino, (C3-C8) -cycloalkyl, (C3-C8)-cycloalkyl-(Cx-C8)-alkyl, (C6-CX4)-aryl which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cx-C7)-alkoxy, (Cx-C7)-alkyl, (Cx-C7)-alkoxy10 carbonyl, amino, and anilino and trifluoromethyl which are optionally substituted by up to two halogens, (C6-CX4)-aryl-(Cx-C6)-alkyl, in which the aryl moiety is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cx-C7)-alkoxy, (Cx-C7) -alkyl, (Cx-C7)-alkoxycarbonyl, amino, (C1-C7)-alkylamino, di-(C1-C7)-alkylamino, carboxyl, carboxyme thoxy, amino-(C1-C7)-alkyl, (Cx-C7)alkylamino- (Cx-C7) -alkyl, di- (Cx-C7) -alkylamino- (Cx-C7) alkyl, (C1-C7)-alkoxycarbonylmethoxy, carbamoyl, sulfa20 moyl, (Cx-C7)-alkoxysulfonyl and sulfo, or is the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least one carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, and which is optionally mono-, di- or trisubstituted by one or more radicals from the series comprising F, Cl, Br, hydroxyl, (Cx-C7)-alkoxy, (Cx-C7)alkyl, (Cx-C8)-alkoxycarbonyl, amino and trifluoromethyl.
R2 is H or a hydroxyl protective group, such as are described, for example, in T.W. Greene, Protective
Groups in Organic Synthesis; A. Wiley-Interscience Publications; New York-Chichester-Brisbane-TorontoSingapore, 1981. Of these, benzyl, p-methoxybenzyl, methoxymethyl, methoxyethyl, benzyloxymethyl, acetyl, trimethylsilyl, tert.-butyldimethylsilyl and tert.35 butyldiphenylsilyl are particularly suitable.
R3 is (Cx-Cx2)-alkyl, mono-, bi- or tricyclic (C3-CX8)cycloalkyl or mono-, bi- or tricyclic (C3-CX8)-cycloalkylIE 914081 (Ci-Cg)-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (Cx-C6)-alkyl.
R* and R5 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl5 (Cx-Cg)-alkyl, (C6-C14)-aryl-(Cx-Cg)-alkyl, where aryl can in each case be substituted by one, two or three identical or different radicals from the group comprising (Οχ-Cg)-alkyl and halogen, Het or Het-(Cx-Cg)-alkyl, where Het is a 5-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partially hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or different radicals from the group comprising N, 0, S, NO, SO and S02 and which can be substituted by one or two iden15 tical or different radicals from the group comprising (Ci-C6)-alkyl, (Ci~C4)-alkoxy and halogen.
R6 and R7 are identical or different and are hydrogen, (Cx”Cx2 )—alkyl, (C3—C12) -cycloalkyl, (C3-Cx2)-cycloalkyl(Cx-Cg)-alkyl, (C6-Ci4)-aryl-(Οχ-Cg)-alkyl, where aryl can in each case be substituted by one, two or three identical or different radicals from the group comprising (Cx-C6)-alkyl, (0χ-04)-alkoxy and halogen; or R6 and R7, together with the carbon atom carrying them, are (C3-Cx2)cycloalkyl.
The compounds of the formulae Ia and lb are enantiomers.
The invention relates both to the optically pure compounds and to their stereoisomer mixtures, such as racemates.
Alkyl can be straight-chain or branched. The same applies to radicals derived therefrom such as alkoxy.
Cycloalkyl is understood as meaning, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
A Het radical preferably has one of the following
- 4 meanings: pyridyl, thiazolyl, thienyl, pyranyl, benzofuryl, isobenzofuryl, furyl, pyrrolyl, imidazolyl, pyrazinyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, pyrimidinyl, pyrazinyl, indolizinyl, isoindolyl, indolyl, quinoxalinyl, quinazolinyl, cinnolinyl, oxazolyl, isoxazolyl or isothiazolyl. The radicals can be aromatic, partially hydrogenated or completely hydrogenated. They can be substituted by one or two identical or different radicals from the group comprising (Ci-Cg)10 alkyl, (Ci-CJ-alkoxy and halogen.
(C6-C14)-Aryl is understood as meaning, for example, phenyl, naphthyl or biphenylyl; phenyl is preferred.
Halogen is fluorine, chlorine, bromine or iodine.
Suitable salts are in particular salts with mineral 15 acids, such as HCl, H2SO4 or H3POA, into which the compounds of the formula Ia or lb are converted, for example for the purposes of storage.
Preferred compounds of the formula Ia or lb are those in which
W is as defined above,
Ra is hydrogen, (Ci-C10)-alkyl which is optionally mono- or diunsaturated, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl(Ci-Cg)-alkyl, (C6-C„)-aryl, (C6-C14)-aryl-(Cx-Cg)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 1025 membered bicyclic heterocycle additionally having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members,
R2 is as defined above,
R3 is (Ci-Cg)-alkyl, mono-, bi- or tricyclic (C3-C18)30 cycloalkyl or mono-, bi- or tricyclic (C3-C18)-cycloalkyl(C1-C3)-alkyl;
- 5 R4 and R5 are as defined above; and
R6 and R7 are identical or different and are hydrogen, (Ci-C12)-alkyl, (C3-C12)-cycloalkyl or (C3-C12)-cycloalkyl(Ci-Cg)-alkyl; or, together with the carbon atom carrying them, are (C3-C12)-cycloalkyl;
and their salts.
Particularly preferred compounds of the formula Ia or lb are those in which
W is -CO-, -0-C0- and R“ is hydrogen, ( Cx-C10) -alkyl which 10 is optionally mono- or diunsaturated, (C3-C8)-cycloalkyl, (Cs-CgJ-cycloalkyl-iCi-CgJ-alkyl, (C6-C1A)-aryl, (C6-C1A)aryl-(C1-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring members;
R2 is as defined above; and
R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl,
2-ethylbutyl, eyelopenty lmethyl, cyclohexylmethyl or cycloheptylmethyl;
R4 and R5 are as defined above; and
R6 and R7 are identical and are hydrogen or (Cx-C4)-alkyl, or, together with the carbon atom carrying them, are (C5-C7) -cycloalkyl;
and their salts.
Very particularly preferred compounds of the formula Ia or lb are those in which
R1 and R2 are as defined above.
R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl,
2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or eyeloheptylmethyl;
R* and R5 are identical or different and are hydrogen, 5 (Ci-C*)-alkyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkyl(Ci-Ca)-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thienyl, 3-thienyl, l-methylimidazol-2-yl, 1-methylimidazol4-yl or l-methylimidazol-5-yl; and
R6 and R7 are identical and are hydrogen, (Ci-CJ -alkyl or, together with the carbon atom carrying them, are a (C5-C7) -eye loalkyl, and their salts.
The invention furthermore relates to a process for the preparation of compounds of the formula la or lb, which comprises reacting a compound of the formula Ila or lib
(lib) in which the radicals R1, R2, above, with a phosphorane of
R3, R6 and R7 are as defined the formula III
R4
R5 (III) in which R* and R5 are as defined above and R8, R9 and R10 are identical or different aryl radicals, preferably phenyl.
To prepare a compound of the formula Ila or lib, suitably 10 protected amino acid derivatives can be used as starting materials. These yield Ila or lib as a result of double reaction with the nucleophilic formyl equivalent 2trimethylsilylthiazole TST (Scheme 1) (A. Dondoni et al.,
J. Org. Chem. 1990, 55, 1439) in a solvent which is inert to this nucleophile such as diethyl ether, di-n-butyl ether, MTB, dichloromethane, DIP, THF, tetrahydropyran or DME at a temperature between -40 °C and the boiling point of the solvent, preferably between -40°C and +25°C. The first addition of TST takes place with high syn selection, the second with high anti selection. The resultant hydroxyl function is protected in the next reaction step using methods known from the literature. The liberation of the formyl group can be carried out by the following reaction sequence:
1) N-Alkylation with a suitable alkylating reagent such as, for example, dimethyl sulfate or methyl iodide without solvent or in a suitable inert solvent such as, for example, acetonitrile, THF, MTB, DIP or EA at temperatures between 25°C and the boiling point of the appropriate solvent.
2) Reduction using a hydride transfer reagent such as, for example, NaBH4 in a solvent suitable for these types of reaction such as, for example, methanol or ethanol at temperatures between -30C and 25 “C, preferably between -20 °C and O’C.
3) Liberation of the aldehyde group by action of reagents for the cleavage of thioacetals (see Tamura et al., Synthesis 312 (1973), Seebach et al., ibid. 357 (1977) and literature cited therein), preferably by means of N-bromosuccinimide in a mixture of acetone and water, preferably at O’C to 30’C.
- 9 Scheme 1
1. TST
2. protection
3. Me+
4. H - “
. e. g .NBS
Ha,nb
The Wittig reaction with a suitable phosphorane in an inert solvent such as diethyl ether, di-n-butyl ether, MTB, DIP, THF, DME or dioxane at -30°C up to the boiling point of the solvent, preferably between O’C and 30’C, yields the title compounds of the formula la or lb. The aldehyde of the formula Ila or lib can also be reacted with the anion of a suitable phosphine oxide with the formation of the title compound (Horner; see Krauch, Kunz, Reaktionen der Organischen Chemie (Reactions of
Organic Chemistry), Huthig Verlag Heidelberg 1976, page 2 41).
The compounds of the formulae la and lb according to the invention are valuable intermediates for the preparation of pharmaceuticals, in particular of inhibitors of renin and of HIV protease. Inhibitors in whose synthesis these compounds can advantageously be used are described, for example, in FEBS Lett. Vol. 230, 38 (1988), J. Med. Chem. Vol. 31, 2264 (1988), ibid. 2277, Biochem. Biophys. Res.
Commun. Vol. 146, 959 (1987) and EP-A-370,454.
List of the abbreviations used:
TLC thin-layer chromatography DCI desorption chemical ionization DIP diisopropyl ether DME 1,2-dimethoxyethane EA ethyl acetate FAB fast atom bombardment Hep n-heptane M molecular peak MeOH methanol MS mass spectrum MTB methyl tert.-butyl ether Et2O diethyl ether R.T. room temperature m.p. melting point THF tetrahydrofuran NBS N-bromosuccinimide TST trimethylsilylthiazole Red-Al sodium bis (2-methoxyethoxy) dihydroaluminate CH2C12 dichloromethane
The examples below are used to illustrate the present invention, without restricting it thereto:
Example 1 (2S, IRS) -2-t-Butyloxycarbonylamino-3-cyclohexyl-l- (2thiazolyl)propanol
3.14 g (10 mmol) of N-Boc-L-cyclohexylalanine-N,0-diraethylamide are dissolved in 30 ml of dry THF and cooled to 0°C. 5.7 ml (20 mmol) of Red-Al (70 % in toluene) are added dropwise. After stirring at O’C for 2 hours, the mixture is poured into 200 ml of ice-water and extracted 3 x with ethyl acetate. The combined organic phases are washed with saturated NaCI solution, dried with Na2SO4 and concentrated. 2.6 g of N-Boc-L-cyclohexylalaninal are obtained, which is dissolved as the crude product in 30 ml of dry CH2C12 and treated dropwise at -30°C with 3.13 g (20 mmol) of 2-trimethylsilylthiazole. The mixture is kept in a deep-freeze at -25 °C for 14 hours. After concentrating, the residue is dissolved in 30 ml of THF/5 ml of H20 and treated with 3 g (20 mmol) of cesium fluoride. After refluxing for 7 hours, the mixture is diluted with ethyl acetate and washed twice with satd.
NaCl solution. It is concentrated after drying over Na2SO4.
The product is separated from small amounts of unreacted aldehyde on silica gel (eluent EA/Hep 1:2). 1.83 g (54 %) of the title compound are obtained. According to
NMR, it is a 5 : 1 mixture (R- or S-configuration on carbon C-l).
R£ (EA/Hep 1:1) = 0.21; MS (DCI) = 341 (M + 1)
Example la ( 4S,5R)-3-t-Butyloxycarbonyl-4-cyclohexylmethyl-2,220 dimethyl-5-(2-thiazolyl)oxazolidine g of the title compound 1 (67.6 mmol) in 250 ml of toluene are heated to reflux for 48 hours with 40 ml of
2,2-dimethoxypropane and 2.5 g of p-toluenesulfonic acid. After cooling, the mixture is washed with 1 N NaHCO3 solution, dried with MgSO4 and concentrated. The crude product is purified on SiO2 using EA/cyclohexane (1 : 4).
12.5 g of the title compound are obtained.
Rf (EA/Hep 1:1) = 0.55; MS (DCI) = 381 (M + 1); m.p.
= 89 - 91eC, [a]o2 = -67.9° (c = 1, CH3OH) .
Example lb (4S,5R,IR)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2dimethyl-5- [ 1' -hydroxy-l' - (2-thiazolyl) methyl ] oxazolidine
- 13 12.5 g (32.8 mmol) of the title compound la are dissolved in 70 ml of acetonitrile. 3.9 ml (1.25 equivalents) of dimethyl sulfate are added and the mixture is heated to boiling for 7 hours. After standing overnight at RT, it is concentrated to dryness. The solid residue is dissolved in 150 ml of methanol. 4.3 g (0.013 mol) of sodium borohydride are added in portions with efficient cooling, during which the temperature should not rise above -10’C. After subsequently stirring at O’C for 30 minutes, 40 ml of acetone are added. After concentrating, the residue is taken up in 500 ml of EA and washed with 200 ml of satd. NaCl solution. After drying with Na2SOA, the solution is concentrated and the crude product is subjected to coarse purification by filtration through a little silica gel,
14 g being obtained (Compound 5, Scheme 1). This product is dissolved in 250 ml of acetone/H20 (95 : 5) and 16.5 g of NBS are added with cooling (< 25°C) in the course of 10 min. After the end of the addition, the mixture is strongly cooled and treated in small portions with 500 ml of satd. Na2SO3 solution (< 25eC, strongly exothermic!).
After diluting with 500 ml of H20, the mixture is extracted 3 x with Et2O. The combined extracts are washed twice with H20 and once with saturated NaCl solution, dried with Na2SO4 and concentrated. Water residues are removed by azeotropic distillation with toluene on a *Rotavapor. 5.9 g of aldehyde (Compound 6, Scheme 1) are obtained, which is immediately dissolved in 80 ml of CH2C12 and cooled to -40°C. 5.88 g (37.4 mmol) of trimethylsilylthiazole are injected. The mixture is slowly warmed to RT overnight. After concentrating, it is taken up in 80 ml of THF and treated with 11.8 g (37.4 mmol) of tetrabutylammonium fluoride trihydrate. After 2 hours, the mixture is diluted with EA, washed twice with H20 and once with satd. NaCl solution, dried with Na2SO4 and concentrated. The crystalline crude product is recrystallized from acetonitrile, 4.7 g of the title compound being obtained.
Rf (DIP) = 0.4; MS (DCI) = 411 (M + 1); m.p. = 176 -178eC;
[a]o° = +35.7° (C = 1, CH3OH).
- 14 Example lc (4S,5R,1'R) -3-t. -Butyloxycarbonyl-4-cyclohexylmethyl-2,2dimethyl-5-[1' -benzyloxy-1'-(2-thiazolyl)methyl]oxazolidine
.4 g (13.2 mmol) of the title compound lb are dissolved in 100 ml of THF and added dropwise to 0.7 g of sodium hydride (50 % in oil, washed twice with Hep) in 20 ml of THF. After 20 min at reflux, the mixture is cooled to 50°C and 0.5 g of tetrabutylammonium iodide and 1.76 ml of benzyl bromide are added. After stirring at RT for hours, the mixture is taken up in about 500 ml of satd. NaCl solution. After extracting twice with ethyl acetate, the extract is dried with Na2SO4 and concentrated, 5 g of the title compound being obtained, which can be further reacted without further purification.
Rf (DIP) = 0.45; MS (DCI) = 500 (M + 1); m.p. = 96’C;
[a]g° = +46.3° (c = 1, CH3OH) .
Example Id (4S,5R,l'R)-3-t.Butyloxycarbonyl-4-cyclohexylmethyl-2,220 dimethyl-5-(1'-benzyloxy-1'-formyl)oxazolidine
2.1 g (4.2 mmol) of the title compound lc are dissolved in 10 ml of acetonitrile and 0.55 ml of dimethyl sulfate are added. After refluxing for 8 hours and standing overnight at RT, the mixture is concentrated to dryness.
The crude product is dissolved in 15 ml of CH3OH, and 0.5 g of NaBH4 is added in small portions at -10eC and the solution is concentrated. The residue is taken up in EA, and the solution is washed with satd. NaCl solution and dried with Na2S0A. After concentrating, the crude product is dissolved in 23 ml of acetone/H20 (95 : 5) and added dropwise (15 min, -10°C) to 2.25 g of NBS in 22 ml of acetone/H20 (95 : 5). 80 ml of satd. Na2SO<, solution are added in small portions such that the temperature does not rise above +20°C. After diluting with 100 ml of
- 15 H2O, the mixture is extracted 3 x with Et2O. The combined extracts are washed twice with H20, dried with MgSO4 and concentrated, 1.75 g (95 %) of the title compound being obtained, which are reused as a crude product.
Rf (DIP) = 0.4; MS (DCI) = 446 (M + 1).
Example le (4S, 5R, 1' S) -3-t. -Butyloxycarbonyl-4-cyclohexylmethyl-2,2dimethyl-5-[1'-benzyloxy-3'-(2-pyridyl)-prop-2'-enyl]oxazolidine
1.72 g (4 mmol) of 2-picolyltriphenylphosphonium chloride are suspended in 30 ml of dry THF. 0.43 g of potassium t.-butylate are added under argon. After 2 hours at RT, 0.85 g of the title compound Id in 5 ml of THF is added dropwise (-15 °C) to the lemon-yellow solution. After standing at RT overnight, the mixture is diluted with H20, extracted (3 x) with EA, washed with satd. NaCl solution, dried (Na2SO4) and concentrated. Chromatography on SiO2 yields 0.11 g of cis-isomer and 0.4 g of transisomer of the title compound as an oil.
Rf (DIP) = 0.45 (cis)
0.3 (trans);
MS (DCI) = 521 (M + 1);
[q]d° = +26.8° (c = 1, MeOH, trans)
Claims (11)
1. A compound of the formula Ia or lb (lb) in which R 1 is R a -W-; W is -CO-, -O-CO-, —SO 2 — or -NH-CO-; R a is hydrogen, (Οχ-Οχ 0 )-alkyl which is optionally mono- or 10 diunsaturated and which is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (0χ-0 7 )-alkoxy, (Ci-C 7 )-alkanoyloxy, carboxyl, (Cx-C 7 )-alkoxycarbonyl, halogen, amino, (0χ-0 7 )17 alkylamino, di-(C x -C 7 )-alkylamino, (C x -C 3 )-alkoxycarbonylamino and (C 7 -C 15 )-aralkoxycarbonylamino, (C 3 -C e )-cycloalkyl, (C 3 -C 8 )-cycloalkyl-(C x -C 6 )-alkyl, (C 6 -C X4 )-aryl which is optionally substituted by one or two identical or 5 different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C x -C 7 )-alkoxy, (C x -C 7 )-alkyl, (C x -C 7 )-alkoxycarbonyl, amino, and anilino and trifluoromethyl which are optionally substituted by up to two halogens, (C 6 -C X4 )-aryl-(C x -C 6 )-alkyl, in which the aryl moiety is 10 optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C x -C 7 )-alkoxy, (C x -C 7 )-alkyl, (C x -C 7 )-alkoxycarbonyl, amino, (C x -C 7 )-alkylamino, di-(C x -C 7 )-alkylamino, carboxyl, carboxyme thoxy, amino-(C x -C 7 )-alkyl, (C x -C 7 )15 alkylamino-(C x -C 7 )-alkyl, di- (C x -C 7 ) -alkylamino- (C x -C 7 )alkyl, (C x -C 7 )-alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (C x -C 7 )-alkoxysulfonyl and sulfo, or is the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least 1 carbon atom, 1 to 20 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, and which is optionally mono-, di- or trisubstituted by one or more radicals from the series comprising F, Cl, Br, hydroxyl, (C x —C 7 )-alkoxy, (C x -C 7 )-alkyl, (C x -C 8 )-alkoxycarbonyl, amino and trifluoromethyl, 25 R 2 is H or a hydroxyl protective group; R 3 is (C x -C x2 )-alkyl, mono-, bi- or tricyclic (C 3 -C X8 )cycloalkyl or mono-, bi- or tricyclic (C 3 -C x8 )-cycloalkyl (C x -C 8 )-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (C x -C 8 )-alkyl; 30 R 4 and R 5 are identical or different and are hydrogen, (C X -C X2 )-alkyl, (C 3 -C X2 )-cycloalkyl, (C 3 -C X2 )-cycloalkyl (C x -C 6 )-alkyl, (C 8 -C X4 )-aryl-(C x -C 6 )-alkyl, where aryl can in each case be substituted by one, two or three identical or different radicals from the group comprising 35 (C x -C 8 )-alkyl and halogen, Het or Het-(C x -C 6 )-alkyl, where Het is a 5-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partially hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or different radicals from the group comprising N, 0, S, NO, SO 5 and S0 2 and which can be substituted by one or two identical or different radicals from the group comprising (Cx-Cg)-alkyl, (Cx-C 4 )-alkoxy and halogen; and R 6 and R 7 are identical or different and are hydrogen, (Cx-Cx 2 )-alkyl, (C 3 -Cx 2 )-cycloalkyl, (C 3 -Cx 2 )-cycloalkyl10 (Οχ—C 6 )—alkyl, (C 6 —Οχ^) -aryl-(Ci-C 6 )-alkyl, where aryl can in each case be substituted by one, two or three identical or different radicals from the group comprising (Cx-Cg)-alkyl, (Cx-CJ-alkoxy and halogen; or R 6 and R 7 , together with the carbon atom carrying them, are (C 3 -C 12 )15 cycloalkyl; and its salts.
2. A compound of the formula Ia or lb, in which R“ is hydrogen, (Cx-C 10 )-alkyl which is optionally mono- or diunsaturated, (C 3 -C e )-cycloalkyl, (C 3 -C 8 )-cycloalkyl20 (Cx-Cg)-alkyl, (C 6 -Cx 4 )-aryl, (C 6 -C u )-aryl-(Cx-C 6 )-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10membered bicyclic heterocycle additionally having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, 25 R 3 is (Cx-C 6 )-alkyl, mono-, bi- or tricyclic (C 3 -Cx 8 )cycloalkyl or mono-, bi- or tricyclic (C 3 -Cx 8 )-cycloalkyl(Cx-C 3 )-alkyl; R 6 and R 7 are identical or different and are hydrogen, (Cx-Cx 2 )-alkyl, (C 3 -C 12 )-cycloalkyl or (C 3 -C 12 )-cycloalkyl30 (Cx-Cg)-alkyl; or, together with the carbon atom carrying them, are (C 3 -C 12 )-cycloalkyl; and the other radicals are as defined in claim 1; IE and its salts.
3. A compound of the formula la or lb as claimed in claim 1 or 2, in which 5 W is -CO-, -0-C0-; R“ is hydrogen, (Ci-C 10 )-alkyl which is optionally mono- or diunsaturated, (C 3 -C e )-cycloalkyl, (C 3 -C 8 )-cycloalkyl(Ci-Ce)-alkyl, (C 6 -C 14 )-aryl, (C 6 -C 14 )-aryl-(0χ-0 6 )-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 1010 membered bicyclic heterocycle having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring members; R 3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or 15 eyeloheptylmethyl; R 6 and R 7 are identical and are hydrogen, (Cx-C 4 )-alkyl or, together with the carbon atom carrying them, are a (C 5 -C 7 ) -cycloalkyl; and the other radicals are as defined in claim 1; 20 and its salts
4. A compound of the formula la or lb as claimed in one of claims 1 to 3, in which R 1 and R 3 are as defined in claim 3; 25 R 4 and R 5 are identical or different and are hydrogen, (Οχ—C 4 )—alkyl, (C 5 -C 7 )-cycloalkyl, (C 5 -C 7 )-eye loalkyl (Cx-C 3 )-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4IE 914081 - 20 pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thienyl, 3-thienyl, l-methylimidazol-2-yl, 1-methylimidazol4-yl or l-methylimidazol-5-yl; R 6 and R 7 are identical and are hydrogen, (Cj-CJ -alkyl or, 5 together with the carbon atom carrying them, are a (C 5 -C 7 ) -cycloalkyl; and the other radicals are as defined in claim 1; and its salts.
5. A process for the preparation of a compound of the 10 formula Ia or lb as claimed in one of claims 1 to 4, which comprises reacting a compound of the formula Ila or lib (lib) 15 in which the radicals R 1 , R 2 , R 3 , R 6 and R 7 are as defined in claim 1, with a phosphorane of the formula III R 8 R 4 in which R 4 and R 5 are as defined in claim 1 and R 8 , R 9 and R 10 are identical or different aryl radicals; and converting the compound obtained, if appropriate, into its salt.
6. A compound of the formula Ila or lib (Ila) in which R 1 , R 2 , R 3 , R 6 and R 7 are as defined in claim 1.
7. The use of a compound as claimed in one of claims 1 to 4 for the preparation of inhibitors of renin and of HIV protease.
8. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
9. A process for the preparation of a compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
10. A compound as claimed in claim 1, whenever prepared by a process claimed in a preceding claim.
11. A compound as claimed in claim 6, substantially as hereinbefore described and exemplified.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4037437A DE4037437A1 (en) | 1990-11-24 | 1990-11-24 | Amino diol DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE914081A1 true IE914081A1 (en) | 1992-06-03 |
Family
ID=6418858
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE408191A IE914081A1 (en) | 1990-11-24 | 1991-11-22 | Aminodiol derivatives |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0487980A1 (en) |
| JP (1) | JPH04266877A (en) |
| KR (1) | KR920009806A (en) |
| CN (1) | CN1061778A (en) |
| AU (1) | AU8808691A (en) |
| CA (1) | CA2056063A1 (en) |
| CS (1) | CS354591A3 (en) |
| DE (1) | DE4037437A1 (en) |
| FI (1) | FI915495A (en) |
| HU (1) | HU208964B (en) |
| IE (1) | IE914081A1 (en) |
| MX (1) | MX9102186A (en) |
| NO (1) | NO914584L (en) |
| NZ (1) | NZ240693A (en) |
| PL (1) | PL292498A1 (en) |
| PT (1) | PT99585A (en) |
| TW (1) | TW206218B (en) |
| ZA (1) | ZA919245B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA93002392A (en) | 1992-03-11 | 2005-02-04 | Narhex Ltd | Amine derivatives of oxo- and hydroxy-substitued hydrocarbons. |
| US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
| US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
| NZ249789A (en) * | 1992-03-11 | 1997-07-27 | Narhex Ltd | Hydrazine, carbazate and 1,2-diazacyclic derivatives and pharmaceutical compositions |
| US5691368A (en) * | 1995-01-11 | 1997-11-25 | Hoechst Marion Roussel, Inc. | Substituted oxazolidine calpain and/or cathepsin B inhibitors |
| KR100709257B1 (en) * | 2005-08-30 | 2007-04-19 | 삼성에스디아이 주식회사 | Fuel supply apparatus and fuel cell system with the same |
| CN102822152A (en) * | 2009-11-09 | 2012-12-12 | 诺瓦德克斯制药股份有限公司 | Novel 1,3-oxazolidine compounds and their use as renin inhibitors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0397779A1 (en) * | 1988-02-01 | 1990-11-22 | The Upjohn Company | Renin inhibiting peptides with polar end groups |
-
1990
- 1990-11-24 DE DE4037437A patent/DE4037437A1/en not_active Withdrawn
-
1991
- 1991-06-29 TW TW080105058A patent/TW206218B/zh active
- 1991-11-14 EP EP91119397A patent/EP0487980A1/en not_active Withdrawn
- 1991-11-21 FI FI915495A patent/FI915495A/en unknown
- 1991-11-22 PT PT99585A patent/PT99585A/en not_active Application Discontinuation
- 1991-11-22 HU HU913654A patent/HU208964B/en not_active IP Right Cessation
- 1991-11-22 MX MX9102186A patent/MX9102186A/en unknown
- 1991-11-22 ZA ZA919245A patent/ZA919245B/en unknown
- 1991-11-22 PL PL29249891A patent/PL292498A1/en unknown
- 1991-11-22 CA CA002056063A patent/CA2056063A1/en not_active Abandoned
- 1991-11-22 AU AU88086/91A patent/AU8808691A/en not_active Abandoned
- 1991-11-22 NZ NZ240693A patent/NZ240693A/en unknown
- 1991-11-22 JP JP3307398A patent/JPH04266877A/en active Pending
- 1991-11-22 IE IE408191A patent/IE914081A1/en not_active Application Discontinuation
- 1991-11-22 CS CS913545A patent/CS354591A3/en unknown
- 1991-11-22 NO NO91914584A patent/NO914584L/en unknown
- 1991-11-22 KR KR1019910020895A patent/KR920009806A/en not_active Application Discontinuation
- 1991-11-22 CN CN91110931A patent/CN1061778A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| NZ240693A (en) | 1993-07-27 |
| ZA919245B (en) | 1992-07-29 |
| HU913654D0 (en) | 1992-02-28 |
| CN1061778A (en) | 1992-06-10 |
| DE4037437A1 (en) | 1992-05-27 |
| AU8808691A (en) | 1992-05-28 |
| TW206218B (en) | 1993-05-21 |
| JPH04266877A (en) | 1992-09-22 |
| CA2056063A1 (en) | 1992-05-25 |
| PT99585A (en) | 1992-10-30 |
| FI915495A (en) | 1992-05-25 |
| KR920009806A (en) | 1992-06-25 |
| FI915495A0 (en) | 1991-11-21 |
| NO914584L (en) | 1992-05-25 |
| PL292498A1 (en) | 1992-11-16 |
| CS354591A3 (en) | 1992-06-17 |
| MX9102186A (en) | 1992-07-08 |
| NO914584D0 (en) | 1991-11-22 |
| HUT63621A (en) | 1993-09-28 |
| EP0487980A1 (en) | 1992-06-03 |
| HU208964B (en) | 1994-02-28 |
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