CA2056063A1 - Aminodiol derivatives - Google Patents
Aminodiol derivativesInfo
- Publication number
- CA2056063A1 CA2056063A1 CA002056063A CA2056063A CA2056063A1 CA 2056063 A1 CA2056063 A1 CA 2056063A1 CA 002056063 A CA002056063 A CA 002056063A CA 2056063 A CA2056063 A CA 2056063A CA 2056063 A1 CA2056063 A1 CA 2056063A1
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- Prior art keywords
- alkyl
- cycloalkyl
- aryl
- radicals
- hydrogen
- 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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- 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
-
- 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
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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
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract of the disclosure Aminodiol derivatives The invention relates to compounds of the formula
Description
20a61~
HOECHST ARTIENGE5ELLSCHAFT HOE 90JF 353 Dr. JA/AP
Description Aminodiol derivatives The invention relates to compounds of the formula Ia or Ib R 3 (S) ~ R S
R - N ~ C~R
~ (Ia) 6/\
R 3 ~ R 5 R--N"" (R~--~0 R2 ~ O (Ib) ,~
and their salts, in which R1 is R -W-;
W is -CO-, -O-CO-, -SO2- or -NH-CO-;
R~ is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated and which is optionally ~ubstituted by up ; '' ' 2~5B~
to 3 identical or different radicals from the series comprising hydroxyl, (Cl-C7)-alkoxy, (C1-C7)-alkanoylo y, carboxyl, (Cl-C7)-alkoxycarbonyl, halogen, amino, (C1-C7)-alkylamino, di-(Cl-C7)-alkylamino, (C1-C5)-alko ycarbonyl-amino and (C7-CIs)-aralko ycarbonylamino, (C3-C8)-cyclo-alkyl, (C3-C8)-cycloalXyl-(Cl-C6)-alkyl, (C6-Cl~)-arylwhich is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (cl-c7)-alko y, (Cl-C7)-alkyl, (Cl-C7)-alkoxy-carbonyl, amino, and anilino and trifluoromethyl whichare optionally ~ubstituted by up to two halogens, (C6-Cl4)-aryl-(Cl-C6)-alkyl, in which the aryl moiety is optionally substituted by one or two identical or dif-ferent radicals from the series comprising F, Cl, Br, I, hydro yl, (C1-C7)-alXoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl,amino,(C1-C,)-alkylamino,di-(C1-C,)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C,)-alkyl, (Cl-C,)-alkylamino-(cl-c7)-alkyl~ di-(C1-C7)-alkylamino-(Cl-C7)-alkyl, (C1-C,)-alkoxycarbonylmethoxy, carbamoyl, sulfa-moyl, (Cl-C,)-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 nitroqen atoms and/or 1 sulfur or oxygen atom ac ring members, and which is optionally mono-, di- or trisubstituted by one or more radicals from the ~eries comprising F, Cl, Br, hydroxyl, (C1-C,)-alkoxy, (Cl-C,)-alkyl, (C1-C8)-alkoxycarbonyl, amino and trifluoromethyl.
R2 is H or a hydroxyl protective group, such as are de~cribed, for example, in T.W. Greene, ~Protective Groups in Organic Synthesis"; A. Wiley-Interscience Publications; New York-Chiche~ter-Bri~bane-Toronto-Singapore, 1981. Of these, benzyl, p-metho ybenzyl, methoxymethyl, metho yethyl, benzyloxymethyl, acetyl, trimethylsilyl, tert.-butyldimethylsilyl and tert.-butyldiphenylsilyl are particularly suitable.
R3 is (cl-cl2)-alkyl~ mono-, bi- or tricyclic (C3-Cl8)-cycloalkyl or mono-, bi- or tricyclic (c3-cl8)-cycloalkyl-:
. ~
:
, 2~G~6~
(C,-C6)-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (Cl-C6)-alkyl.
R4 and R5 are identical or different and are hydrogen, (cl-cl2)-alkyl~ (C3-C,2)-cycloalkyl, (C3-Cl2)-cycloalkyl-(cl-c6)-alkyl~ (C6-Clj)-aryl-(Cl-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (Cl-C6)-alkyl and halogen, Het or Het-(Cl-C6)-alkyl, where Het i8 a S-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partial-ly hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or dif-ferent radicals from the group comprising N, 0, S, N0, S0 and S02 and which can be substituted by one or two iden-tical or different radicals from the group comprising(Cl-C6)-alkyl, (cl-c4)-alkoxy and halogen.
R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl~ (C3-C~2)-cycloalkyl, (C3-C,2)-cycloalkyl-(C,-C6)-alkyl, (C6-C,4)-aryl-(C,-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C~-C6)-alkyl, (C,-C4)-alkoxy and halogen; or R~ and R7, together with the carbon atom carrying them, are (C3-Cl2)-cycloalkyl.
The compounds of the formulae Ia and Ib are enantiomers.
The invention relates both to the optically pure com-pounds 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 exa~ple, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
A Het radical preferably has one of the following meaningss pyridyl, thiazolyl, thienyl, pyranyl, benzo-furyl, isobenzofuryl, furyl, pyrrolyl, imidazolyl, pyrazinyl, indazolyl, guinolyl, isoquinolyl, phthal-azinyl, pyrimidinyl, pyrazinyl, indolizinyl, isoindolyl, indolyl, quinoxalinyl, quinazolinyl, cinnolinyl, oxazo-ly', isoxazolyl or isothiazolyl. The radicals can be aromatic, partially hydrogenated or completely hydrogen-ated. They can be substituted by one or two identical or different radicals from the group comprising (Cl-C6)-alkyl, (C,-C4)-alkoxy and halogen.
(C6-C14)-Aryl i8 understood as meaning, for example, phenyl, naphthyl or biphenylyl; phenyl is preferred.
Halogen i8 fluorine, chlorine, bromine or iodine.
Suitable salts are in particular salts with mineral acids, such as HCl, H2S04 or H3P04, into which the com-pounds of the formula Ia or Ib are converted, for example for the purposes of storage.
Preferred compounds of the formula Ia or Ib are those in which W is as defined above, R^ is hydrogen, (C,-C10)-alkyl which is optionally mono- or diunsaturated, (C3-CB)-cycloalkyl, (C3-C8)-cycloalkyl-(C,-C6)-alkyl, (C6-C,4)-aryl, (C6-C,4)-aryl-(C,-C8)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle additionally having atleast 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 (C1-C6)-alkyl, mono-, bi- or tricyclic (C3-Cl~)-cycloalkyl or mono-, bi- or tricyclic (C3-Cla)-cycloalkyl-(C1-C3)-alkyl;
.
R4 and R5 are aY defined above; and R6 and R7 are identical or different and are hydrogen, (C1-C~z)-alkyl, (C3-Cl2)-cycloalkyl or (C3-C12)-cycloalkyl-(cl-c6)-alkyl; or, together with the carbon atom carrying them, are (C3-C12)-cycloalkyl;
and their salts.
Particularly preferred compounds of the formula Ia or Ib are those in which W is -CO-, -O-CO- and R~ is hydrogen, (cl-clo)-alkyl which is optionally mono- or diunsaturated, (C3-CB)-cycloalkyl, (c3-c8)-cycloa~ l-c6)-a~ (C6-Cl4)-aryl, (C6-Cl4)-aryl-(Cl-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least l carbon atom, l to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring member~;
R2 is as defined above; and R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R4 and R5 are as defined above; and RB and R7 are identiGal and are hydrogen or (C1-C4)-alkyl, or, together with the carbon atom carrying them, are (Cs~c7)~cYcloalkyl;
and their ~alts.
Very particularly preferred compounds of the formula Ia or Ib are those in which R1 and R2 are as defined above, 2 ~
R9 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R~ and R5 are identical or different and are hydrogen, (Cl-C~)-alkyl, (C5-C,)-cycloalkyl, (C5-C,)-cycloalkyl-(Cl-C3)-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thi-enyl, 3-thienyl, 1-methylimidazol-2-yl, l-methylimidazol-4-yl or 1-methylimidazol-5-yl; and R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C~)-cycloalkyl, and their salts.
~ he invention furthermore relates to a process for the preparation of compounds of the formula Ia or Ib, which comprises reacting a compound of the formula IIa or IIb ,, , -..
h O ~
R - N ~ ~R
~ (IIa) -~\
R CHO
R--N ~ OR
~ (IIb ~/\ ' . :
in which the radicals R1, R2, R3, R6 and R7 are as defined above, with a phosphorane of the formula III
R ~ R 4 p ~ (III) R l10 R5 in which R4 and R5 are a8 defined above and R8, R~ and Rl are identical or different aryl radical~, preferably phenyl.
To prepare a compound of the formula ITa or IIb, sultably protected amino acid dQrivativQs can be used as stsrting materials. ThesQ yield IIa or IIb as a result of double reaction with the nucleophilic formyl equivalent 2-trimethylsilylthiazole TST (Scheme 1) (A. Dondoni et al., J. Org. Chem. 1990, 55, 1439) in a solvent which is inert .
- . . .. ....
. , .. . ~. :
.
,:
~a69~
to this nucleophile such as diethyl ether, di-n-butyl ether, MTB, dichloromethane, DIP, THF, tetrahydropyran or DME at a temperature between -40C and the boiling point of the solvent, preferably between -40-C and +25-C. The first addition of TST take~ place with high syn selec-tion, 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 25C and the boiling point of the appropriate solvent.
2) Reduction using a hydride transfer reagent ~uch 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 25C, preferably between -20C and 0C.
HOECHST ARTIENGE5ELLSCHAFT HOE 90JF 353 Dr. JA/AP
Description Aminodiol derivatives The invention relates to compounds of the formula Ia or Ib R 3 (S) ~ R S
R - N ~ C~R
~ (Ia) 6/\
R 3 ~ R 5 R--N"" (R~--~0 R2 ~ O (Ib) ,~
and their salts, in which R1 is R -W-;
W is -CO-, -O-CO-, -SO2- or -NH-CO-;
R~ is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated and which is optionally ~ubstituted by up ; '' ' 2~5B~
to 3 identical or different radicals from the series comprising hydroxyl, (Cl-C7)-alkoxy, (C1-C7)-alkanoylo y, carboxyl, (Cl-C7)-alkoxycarbonyl, halogen, amino, (C1-C7)-alkylamino, di-(Cl-C7)-alkylamino, (C1-C5)-alko ycarbonyl-amino and (C7-CIs)-aralko ycarbonylamino, (C3-C8)-cyclo-alkyl, (C3-C8)-cycloalXyl-(Cl-C6)-alkyl, (C6-Cl~)-arylwhich is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (cl-c7)-alko y, (Cl-C7)-alkyl, (Cl-C7)-alkoxy-carbonyl, amino, and anilino and trifluoromethyl whichare optionally ~ubstituted by up to two halogens, (C6-Cl4)-aryl-(Cl-C6)-alkyl, in which the aryl moiety is optionally substituted by one or two identical or dif-ferent radicals from the series comprising F, Cl, Br, I, hydro yl, (C1-C7)-alXoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl,amino,(C1-C,)-alkylamino,di-(C1-C,)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C,)-alkyl, (Cl-C,)-alkylamino-(cl-c7)-alkyl~ di-(C1-C7)-alkylamino-(Cl-C7)-alkyl, (C1-C,)-alkoxycarbonylmethoxy, carbamoyl, sulfa-moyl, (Cl-C,)-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 nitroqen atoms and/or 1 sulfur or oxygen atom ac ring members, and which is optionally mono-, di- or trisubstituted by one or more radicals from the ~eries comprising F, Cl, Br, hydroxyl, (C1-C,)-alkoxy, (Cl-C,)-alkyl, (C1-C8)-alkoxycarbonyl, amino and trifluoromethyl.
R2 is H or a hydroxyl protective group, such as are de~cribed, for example, in T.W. Greene, ~Protective Groups in Organic Synthesis"; A. Wiley-Interscience Publications; New York-Chiche~ter-Bri~bane-Toronto-Singapore, 1981. Of these, benzyl, p-metho ybenzyl, methoxymethyl, metho yethyl, benzyloxymethyl, acetyl, trimethylsilyl, tert.-butyldimethylsilyl and tert.-butyldiphenylsilyl are particularly suitable.
R3 is (cl-cl2)-alkyl~ mono-, bi- or tricyclic (C3-Cl8)-cycloalkyl or mono-, bi- or tricyclic (c3-cl8)-cycloalkyl-:
. ~
:
, 2~G~6~
(C,-C6)-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (Cl-C6)-alkyl.
R4 and R5 are identical or different and are hydrogen, (cl-cl2)-alkyl~ (C3-C,2)-cycloalkyl, (C3-Cl2)-cycloalkyl-(cl-c6)-alkyl~ (C6-Clj)-aryl-(Cl-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (Cl-C6)-alkyl and halogen, Het or Het-(Cl-C6)-alkyl, where Het i8 a S-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partial-ly hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or dif-ferent radicals from the group comprising N, 0, S, N0, S0 and S02 and which can be substituted by one or two iden-tical or different radicals from the group comprising(Cl-C6)-alkyl, (cl-c4)-alkoxy and halogen.
R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl~ (C3-C~2)-cycloalkyl, (C3-C,2)-cycloalkyl-(C,-C6)-alkyl, (C6-C,4)-aryl-(C,-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C~-C6)-alkyl, (C,-C4)-alkoxy and halogen; or R~ and R7, together with the carbon atom carrying them, are (C3-Cl2)-cycloalkyl.
The compounds of the formulae Ia and Ib are enantiomers.
The invention relates both to the optically pure com-pounds 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 exa~ple, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
A Het radical preferably has one of the following meaningss pyridyl, thiazolyl, thienyl, pyranyl, benzo-furyl, isobenzofuryl, furyl, pyrrolyl, imidazolyl, pyrazinyl, indazolyl, guinolyl, isoquinolyl, phthal-azinyl, pyrimidinyl, pyrazinyl, indolizinyl, isoindolyl, indolyl, quinoxalinyl, quinazolinyl, cinnolinyl, oxazo-ly', isoxazolyl or isothiazolyl. The radicals can be aromatic, partially hydrogenated or completely hydrogen-ated. They can be substituted by one or two identical or different radicals from the group comprising (Cl-C6)-alkyl, (C,-C4)-alkoxy and halogen.
(C6-C14)-Aryl i8 understood as meaning, for example, phenyl, naphthyl or biphenylyl; phenyl is preferred.
Halogen i8 fluorine, chlorine, bromine or iodine.
Suitable salts are in particular salts with mineral acids, such as HCl, H2S04 or H3P04, into which the com-pounds of the formula Ia or Ib are converted, for example for the purposes of storage.
Preferred compounds of the formula Ia or Ib are those in which W is as defined above, R^ is hydrogen, (C,-C10)-alkyl which is optionally mono- or diunsaturated, (C3-CB)-cycloalkyl, (C3-C8)-cycloalkyl-(C,-C6)-alkyl, (C6-C,4)-aryl, (C6-C,4)-aryl-(C,-C8)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle additionally having atleast 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 (C1-C6)-alkyl, mono-, bi- or tricyclic (C3-Cl~)-cycloalkyl or mono-, bi- or tricyclic (C3-Cla)-cycloalkyl-(C1-C3)-alkyl;
.
R4 and R5 are aY defined above; and R6 and R7 are identical or different and are hydrogen, (C1-C~z)-alkyl, (C3-Cl2)-cycloalkyl or (C3-C12)-cycloalkyl-(cl-c6)-alkyl; or, together with the carbon atom carrying them, are (C3-C12)-cycloalkyl;
and their salts.
Particularly preferred compounds of the formula Ia or Ib are those in which W is -CO-, -O-CO- and R~ is hydrogen, (cl-clo)-alkyl which is optionally mono- or diunsaturated, (C3-CB)-cycloalkyl, (c3-c8)-cycloa~ l-c6)-a~ (C6-Cl4)-aryl, (C6-Cl4)-aryl-(Cl-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least l carbon atom, l to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring member~;
R2 is as defined above; and R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R4 and R5 are as defined above; and RB and R7 are identiGal and are hydrogen or (C1-C4)-alkyl, or, together with the carbon atom carrying them, are (Cs~c7)~cYcloalkyl;
and their ~alts.
Very particularly preferred compounds of the formula Ia or Ib are those in which R1 and R2 are as defined above, 2 ~
R9 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R~ and R5 are identical or different and are hydrogen, (Cl-C~)-alkyl, (C5-C,)-cycloalkyl, (C5-C,)-cycloalkyl-(Cl-C3)-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thi-enyl, 3-thienyl, 1-methylimidazol-2-yl, l-methylimidazol-4-yl or 1-methylimidazol-5-yl; and R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C~)-cycloalkyl, and their salts.
~ he invention furthermore relates to a process for the preparation of compounds of the formula Ia or Ib, which comprises reacting a compound of the formula IIa or IIb ,, , -..
h O ~
R - N ~ ~R
~ (IIa) -~\
R CHO
R--N ~ OR
~ (IIb ~/\ ' . :
in which the radicals R1, R2, R3, R6 and R7 are as defined above, with a phosphorane of the formula III
R ~ R 4 p ~ (III) R l10 R5 in which R4 and R5 are a8 defined above and R8, R~ and Rl are identical or different aryl radical~, preferably phenyl.
To prepare a compound of the formula ITa or IIb, sultably protected amino acid dQrivativQs can be used as stsrting materials. ThesQ yield IIa or IIb as a result of double reaction with the nucleophilic formyl equivalent 2-trimethylsilylthiazole TST (Scheme 1) (A. Dondoni et al., J. Org. Chem. 1990, 55, 1439) in a solvent which is inert .
- . . .. ....
. , .. . ~. :
.
,:
~a69~
to this nucleophile such as diethyl ether, di-n-butyl ether, MTB, dichloromethane, DIP, THF, tetrahydropyran or DME at a temperature between -40C and the boiling point of the solvent, preferably between -40-C and +25-C. The first addition of TST take~ place with high syn selec-tion, 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 25C and the boiling point of the appropriate solvent.
2) Reduction using a hydride transfer reagent ~uch 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 25C, preferably between -20C and 0C.
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 _ 2 3~ t~
Scheme 1 Rl N~H > R--N~S
H OH
protection 1 ,~<N 3 "Me+"
>R--N S >
\~o R 6~\R 7 3 Me Rl N~s3 R R
2~6~6t, R3 HN_ R--N~S
e.a. NBS
\~0 R \ 7 R
Rl N ~ H 3 'Me-l'' > ~b ~ 4."H ~"
R 6-\ 7 6 ~. e . g NBS
R
The Wittig reaction with a suitable phosphorane in an inert solvent such as diethyl ether, di-n-butyl ether, MTB, DIP, THF, DNE or dioxane at -30-C up to the boiling point of the solvent, preferably between 0C and 30C, yields the title compounds of the formula Ia or Ib. The aldehyde of the formula IIa or IIb 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), H~thig Verlag Heidelberg 1976, page 241).
The compoundc of the formulae Ia and Ib according to the invention are valuable intermediates for the preparation of pharmaceuticals, in particular of inhib~tors 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.
.. ; ~ . , .
20a6~63 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 DNE 1,2-dimethoxyethane EA ethyl acetate -FAB fa~t atom bombardment Hep n-heptane ~ molecular peak MeOH methanol NS mass spectrum MTB methyl tert.-butyl ether Et20 diethyl ether R.T. room temperature m.p. melting point THF tetrahydrofuran NBS N-bromosuccinimide TST trimethylsilylthiazole 20 Red-Al sodium bis(2-methoxyethoxy)dihydroaluminate CH2Cl2 dichloromethane The examples below are used to illustrate the present invention, without restricting it theretos Example 1 (2S,lRS)-2-t-Butyloxycarbonylamino-3-cyclohexyl-1-(2-thiazolyl)propanol 3.14 g (10 mmol) of N-Boc-L-cyclohexylalanine-N,O-di-methylamide are dissolved in 30 ml of dry THF and cooled to 0C. 5.7 ml (20 mmol) of Red-Al (70 % in toluene) are added dropwise. After ~tirring at ODC for 2 hours, the mixture i8 poured into 200 ml of ice-water and extracted 3 x with ethyl acetate. The combined organic pha~es are washed with saturated NaCl solution, dried with Na2SO~
~, ~ ~ ' ' ; ,. --, - . . .
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 -30C 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 re~idue i8 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 iB
diluted with ethyl acetate and washed twice with satd.
NaCl solution. It i8 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-1).
R (EA/Hep 1:1) = 0.21; MS (DCI) = 341 (M + 1) Example la (4S,5R)-3-t-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-(2-thiazolyl)oxa~olidine 23 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 NaHC03 solution, dried with MgS04 and concentrated. The crude product is purified on SiOz using EA/cyclohexane (1 s 4).
12.5 g of the title compound are obtained.
Rr (EA/Hep 1:1) = 0.55; MS (DCI) = 381 (M + l); m.p.
= 89 - 91C, [~]DZ = -67.9 (c = 1, CH30H).
Example lb (4S,5R,lR)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-tl'-hydroxy-1'-(2-thiazolyl)methyl~oxazolidine , ~ .
- 13 _ 2~36~
12.S 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 re~idue iB dis-solved in 150 ml of methanol. 4.3 g (0.013 mol) of ~odium borohydride are added in portions with efficient cooling, during which the temperature should not rise above -lO-C.
After subsequently stirring at 0C 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 Na2S04, the solution is concentrated and the crude product is sub~ected to coarse purificstion 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 s 5) and 16.5 g of NBS are added with cooling (s 25C) in the course of 10 min. After the end of the addition, the mixture i8 strongly cooled and treated in small portions with 500 ml of satd. Na2S03 solution (s 25-C, strongly exothermic~).
After diluting with 500 ml of H20, the mixture is ex-tracted 3 x with Et20. The combined extracts are washed twice with H20 and once with saturated NaCl solution, dried with Na2S04 and concentrated. Water residues are removed by azeotropic di~tillation with toluene on a ^Rotavapor. 5.9 g of aldehyde (Compound 6, Scheme 1) are obtained, which is immediately dissolved in 80 ml of CH2Cl2 and cooled to -40C. 5.88 g (37.4 mmol) of tri-methylsilylthiazole are in~ected. The mixture is ~lowly warmed to RT overnight. After concentrating, it i~ t~ken up in 80 ml of THF nnd treated with 11.8 g (37.4 mmol) of tetrabutylammonium fluoride trihydrate. After 2 hour~, the mixture is diluted with EA, wa~hed twice with H20 and once with satd. NaCl ~olution, dried with Na2S0~ and concentrated. The crystalline crude product is recry~tal-lized from acetonitrile, 4.7 g of the title compound being obtained.
R~ (DIP) = 0.4; NS (DCI) = 411 (M + l); m.p. = 176 -178C;
1~]2 = +35.7o (c = 1, CH30H)-2 ~ 3 Example lc (4S,5R,1'R)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[1'-benzyloxy-1'-(2-thiazolyl)methyl]-oxazolidine 5.4 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 50C and 0.5 g of tetrabutylammonium iodide and 1.76 ml of benzyl bromide are added. After stirring at RT for 3 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 Na2S0~ and concentrated, 5 g of the title compound being obtained, which can be further reacted without further purification.
Rf (DIP) = 0.45; NS (DCI) = 500 (M + l); m.p. = 96C;
t~]DO = +46.3 (c = 1, CH30H).
Example ld (4S,5R,l'R)-3-t.Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-(1'-benzyloxy-l'-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 i8 concentrated to drynes#.
The crude product is dissolved in 15 ml of CH30H, and 0.5 g of NaBH4 is added in small portlon~ at -10C and the solution is concentrated. The residue is taken up in EA, and the solution is washed with satd. NaCl solution and dried with Na2S04. After concentrating, the crude product is di~solved in 23 ml of acetone/HzO (95 s 5) and added dropwi6e (15 min, -10C) to 2.25 q of NBS in 22 ml of acetone~H20 (95 s 5). 80 ml of satd. Na2S04 solution are added in small portions such that the temperature does not rise above +20C. After diluting with 100 ml of . .
- 1S ~3~3 H20, the mixture i8 extracted 3 x with Et20. The combined extracts are washed twice with H20, dried with MgSO~ and concentrated, 1.75 g (95 ~) of the title compound being obtained, which are reused a8 a crude product.
Rs (DIP) = 0.4; NS (DCI) = 446 (M + 1).
Example le (4S,SR,l'S)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-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 ld in 5 ml of THF is added dropwise (-15C) 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 trans-isomer of the title compound as an oil.
R~ (DIP) = 0.45 (ci8) 0.3 (trans);
NS (DCI) = 521 (N + l);
1~]D = +26.8 (c = 1, NeOH, trans)
. .. .
' ~ ' ` ~ , . ;
,. :. !
:- ' ~ .
_ 9 _ 2 3~ t~
Scheme 1 Rl N~H > R--N~S
H OH
protection 1 ,~<N 3 "Me+"
>R--N S >
\~o R 6~\R 7 3 Me Rl N~s3 R R
2~6~6t, R3 HN_ R--N~S
e.a. NBS
\~0 R \ 7 R
Rl N ~ H 3 'Me-l'' > ~b ~ 4."H ~"
R 6-\ 7 6 ~. e . g NBS
R
The Wittig reaction with a suitable phosphorane in an inert solvent such as diethyl ether, di-n-butyl ether, MTB, DIP, THF, DNE or dioxane at -30-C up to the boiling point of the solvent, preferably between 0C and 30C, yields the title compounds of the formula Ia or Ib. The aldehyde of the formula IIa or IIb 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), H~thig Verlag Heidelberg 1976, page 241).
The compoundc of the formulae Ia and Ib according to the invention are valuable intermediates for the preparation of pharmaceuticals, in particular of inhib~tors 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.
.. ; ~ . , .
20a6~63 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 DNE 1,2-dimethoxyethane EA ethyl acetate -FAB fa~t atom bombardment Hep n-heptane ~ molecular peak MeOH methanol NS mass spectrum MTB methyl tert.-butyl ether Et20 diethyl ether R.T. room temperature m.p. melting point THF tetrahydrofuran NBS N-bromosuccinimide TST trimethylsilylthiazole 20 Red-Al sodium bis(2-methoxyethoxy)dihydroaluminate CH2Cl2 dichloromethane The examples below are used to illustrate the present invention, without restricting it theretos Example 1 (2S,lRS)-2-t-Butyloxycarbonylamino-3-cyclohexyl-1-(2-thiazolyl)propanol 3.14 g (10 mmol) of N-Boc-L-cyclohexylalanine-N,O-di-methylamide are dissolved in 30 ml of dry THF and cooled to 0C. 5.7 ml (20 mmol) of Red-Al (70 % in toluene) are added dropwise. After ~tirring at ODC for 2 hours, the mixture i8 poured into 200 ml of ice-water and extracted 3 x with ethyl acetate. The combined organic pha~es are washed with saturated NaCl solution, dried with Na2SO~
~, ~ ~ ' ' ; ,. --, - . . .
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 -30C 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 re~idue i8 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 iB
diluted with ethyl acetate and washed twice with satd.
NaCl solution. It i8 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-1).
R (EA/Hep 1:1) = 0.21; MS (DCI) = 341 (M + 1) Example la (4S,5R)-3-t-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-(2-thiazolyl)oxa~olidine 23 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 NaHC03 solution, dried with MgS04 and concentrated. The crude product is purified on SiOz using EA/cyclohexane (1 s 4).
12.5 g of the title compound are obtained.
Rr (EA/Hep 1:1) = 0.55; MS (DCI) = 381 (M + l); m.p.
= 89 - 91C, [~]DZ = -67.9 (c = 1, CH30H).
Example lb (4S,5R,lR)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-tl'-hydroxy-1'-(2-thiazolyl)methyl~oxazolidine , ~ .
- 13 _ 2~36~
12.S 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 re~idue iB dis-solved in 150 ml of methanol. 4.3 g (0.013 mol) of ~odium borohydride are added in portions with efficient cooling, during which the temperature should not rise above -lO-C.
After subsequently stirring at 0C 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 Na2S04, the solution is concentrated and the crude product is sub~ected to coarse purificstion 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 s 5) and 16.5 g of NBS are added with cooling (s 25C) in the course of 10 min. After the end of the addition, the mixture i8 strongly cooled and treated in small portions with 500 ml of satd. Na2S03 solution (s 25-C, strongly exothermic~).
After diluting with 500 ml of H20, the mixture is ex-tracted 3 x with Et20. The combined extracts are washed twice with H20 and once with saturated NaCl solution, dried with Na2S04 and concentrated. Water residues are removed by azeotropic di~tillation with toluene on a ^Rotavapor. 5.9 g of aldehyde (Compound 6, Scheme 1) are obtained, which is immediately dissolved in 80 ml of CH2Cl2 and cooled to -40C. 5.88 g (37.4 mmol) of tri-methylsilylthiazole are in~ected. The mixture is ~lowly warmed to RT overnight. After concentrating, it i~ t~ken up in 80 ml of THF nnd treated with 11.8 g (37.4 mmol) of tetrabutylammonium fluoride trihydrate. After 2 hour~, the mixture is diluted with EA, wa~hed twice with H20 and once with satd. NaCl ~olution, dried with Na2S0~ and concentrated. The crystalline crude product is recry~tal-lized from acetonitrile, 4.7 g of the title compound being obtained.
R~ (DIP) = 0.4; NS (DCI) = 411 (M + l); m.p. = 176 -178C;
1~]2 = +35.7o (c = 1, CH30H)-2 ~ 3 Example lc (4S,5R,1'R)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[1'-benzyloxy-1'-(2-thiazolyl)methyl]-oxazolidine 5.4 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 50C and 0.5 g of tetrabutylammonium iodide and 1.76 ml of benzyl bromide are added. After stirring at RT for 3 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 Na2S0~ and concentrated, 5 g of the title compound being obtained, which can be further reacted without further purification.
Rf (DIP) = 0.45; NS (DCI) = 500 (M + l); m.p. = 96C;
t~]DO = +46.3 (c = 1, CH30H).
Example ld (4S,5R,l'R)-3-t.Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-(1'-benzyloxy-l'-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 i8 concentrated to drynes#.
The crude product is dissolved in 15 ml of CH30H, and 0.5 g of NaBH4 is added in small portlon~ at -10C and the solution is concentrated. The residue is taken up in EA, and the solution is washed with satd. NaCl solution and dried with Na2S04. After concentrating, the crude product is di~solved in 23 ml of acetone/HzO (95 s 5) and added dropwi6e (15 min, -10C) to 2.25 q of NBS in 22 ml of acetone~H20 (95 s 5). 80 ml of satd. Na2S04 solution are added in small portions such that the temperature does not rise above +20C. After diluting with 100 ml of . .
- 1S ~3~3 H20, the mixture i8 extracted 3 x with Et20. The combined extracts are washed twice with H20, dried with MgSO~ and concentrated, 1.75 g (95 ~) of the title compound being obtained, which are reused a8 a crude product.
Rs (DIP) = 0.4; NS (DCI) = 446 (M + 1).
Example le (4S,SR,l'S)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-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 ld in 5 ml of THF is added dropwise (-15C) 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 trans-isomer of the title compound as an oil.
R~ (DIP) = 0.45 (ci8) 0.3 (trans);
NS (DCI) = 521 (N + l);
1~]D = +26.8 (c = 1, NeOH, trans)
Claims (7)
1. A compound of the formula Ia or Ib (Ia) (Ib) in which R1 is R4-W-;
W is -CO-, -O-CO-, -SO2- or -NH-CO-;
Ra is hydrogen, (C1-C10)-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, (C1-C7)-alkanoyloxy, carboxyl, (C1-C7)-alkoxycarbonyl, halogen, amino, (C1-C7)-alkylamino, di-(C1-C7)-alkylamino, (C1-C5)-alkoxycarbonyl-amino and (C7-C15)-aralkoxycarbonylamino, (C3-C8)-cyclo-alkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl,(C6-C14)-aryl which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl, amino, and anilino and trifluoromethyl which are optionally substituted by up to two halogens, (C6-C14)-aryl-(C1-C6)-alkyl, in which the aryl moiety is optionally substituted by one or two identical or dif-ferent radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl,amino,(C1-C7)-alkylamino,di-(C1-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, (C1-C7)-alkoxycarbonylmethoxy, carbamoyl, sulfa-moyl, (C1-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 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, and which is optionally mono-, di- or trisub-stituted by one or more radicals from the series com-prising F, Cl, Br, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C6)-alkoxycarbonyl, amino and trifluoromethyl, R2 is H or a hydroxyl protective group;
R3 is (C1-C12)-alkyl, mono-, bi- or tricyclic (C3-C16)-cycloalkyl or mono-, bi- or tricyclic (C3-C16)-cycloalkyl-(C1-C6)-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (C1-C6)-alkyl;
R4 and R5 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12) -Cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C1-C6)-alkyl and halogen, Het or Het-(C1-C6)-alkyl, where Het is a 5-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partial-ly hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or dif-ferent radicals from the group comprising N, O, S, NO, SO
and SO2 and which can be substituted by one or two iden-tical or different radicals from the group comprising (C1-C6)-alkyl, (C1-C4)-alkoxy and halogen; and R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C1-C6)-alkyl, (C1-C4)-alkoxy and halogen; or R6 and R7, together with the carbon atom carrying them, are (C3-C12)-cycloalkyl;
and its salts.
W is -CO-, -O-CO-, -SO2- or -NH-CO-;
Ra is hydrogen, (C1-C10)-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, (C1-C7)-alkanoyloxy, carboxyl, (C1-C7)-alkoxycarbonyl, halogen, amino, (C1-C7)-alkylamino, di-(C1-C7)-alkylamino, (C1-C5)-alkoxycarbonyl-amino and (C7-C15)-aralkoxycarbonylamino, (C3-C8)-cyclo-alkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl,(C6-C14)-aryl which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl, amino, and anilino and trifluoromethyl which are optionally substituted by up to two halogens, (C6-C14)-aryl-(C1-C6)-alkyl, in which the aryl moiety is optionally substituted by one or two identical or dif-ferent radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl,amino,(C1-C7)-alkylamino,di-(C1-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, (C1-C7)-alkoxycarbonylmethoxy, carbamoyl, sulfa-moyl, (C1-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 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, and which is optionally mono-, di- or trisub-stituted by one or more radicals from the series com-prising F, Cl, Br, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C6)-alkoxycarbonyl, amino and trifluoromethyl, R2 is H or a hydroxyl protective group;
R3 is (C1-C12)-alkyl, mono-, bi- or tricyclic (C3-C16)-cycloalkyl or mono-, bi- or tricyclic (C3-C16)-cycloalkyl-(C1-C6)-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (C1-C6)-alkyl;
R4 and R5 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12) -Cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C1-C6)-alkyl and halogen, Het or Het-(C1-C6)-alkyl, where Het is a 5-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partial-ly hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or dif-ferent radicals from the group comprising N, O, S, NO, SO
and SO2 and which can be substituted by one or two iden-tical or different radicals from the group comprising (C1-C6)-alkyl, (C1-C4)-alkoxy and halogen; and R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C1-C6)-alkyl, (C1-C4)-alkoxy and halogen; or R6 and R7, together with the carbon atom carrying them, are (C3-C12)-cycloalkyl;
and its salts.
2. A compound of the formula Ia or Ib, in which Ra is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-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, R3 is (C1-C6)-alkyl, mono-, bi- or tricyclic (C3-C18)-cycloalkyl or mono-, bi- or tricyclic (C3-C12)-cycloalkyl-(C1-C3)-alkyl;
R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12)-cycloalkyl or (C3-C12)-cycloalkyl-(C1-C6)-alkyl; or, together with the carbon atom carrying them, are ( C3-C12) -cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts.
R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12)-cycloalkyl or (C3-C12)-cycloalkyl-(C1-C6)-alkyl; or, together with the carbon atom carrying them, are ( C3-C12) -cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts.
3. A compound of the formula Ia or Ib as claimed in claim 1 or 2, in which W is -CO-, -O-CO-;
Ra is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic hsterocycle having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring members;
R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C7)-cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts
Ra is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic hsterocycle having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring members;
R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C7)-cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts
4. A compound of the formula Ia or Ib as claimed in one of claims 1 to 3, in which R1 and R3 are as defined in claim 3;
R4 and R5 are identical or different and are hydrogen, (C1-C4)-alkyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkyl-(C1-C3)-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thi-enyl, 3-thienyl, 1-methylimidazol-2-yl, 1-methylimidazol-4-yl or 1-methylimidazol-5-yl;
R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C7)-cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts.
R4 and R5 are identical or different and are hydrogen, (C1-C4)-alkyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkyl-(C1-C3)-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thi-enyl, 3-thienyl, 1-methylimidazol-2-yl, 1-methylimidazol-4-yl or 1-methylimidazol-5-yl;
R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C7)-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 formula Ia or Ib as claimed in one of claims 1 to 4, which comprises reacting a compound of the formula IIa or IIb (IIa) (IIb) in which the radicals R1, R2, R3, R6 and R7 are as defined in claim 1, with a phosphorane of the formula III
(III) in which R4 and R5 are as defined in claim 1 and R8, R9 and R10 are identical or different aryl radicals;
and converting the compound obtained, if appropriate, into its salt.
(III) in which R4 and R5 are as defined in claim 1 and R8, R9 and R10 are identical or different aryl radicals;
and converting the compound obtained, if appropriate, into its salt.
6. A compound of the formula IIa or IIb (IIa) (IIb) in which R1, R2, R3, R6 and R7 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4037437.8 | 1990-11-24 | ||
| DE4037437A DE4037437A1 (en) | 1990-11-24 | 1990-11-24 | Amino diol DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2056063A1 true CA2056063A1 (en) | 1992-05-25 |
Family
ID=6418858
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002056063A Abandoned CA2056063A1 (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) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Families Citing this family (6)
| 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 |
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
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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 |
| 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 |
| IE914081A1 (en) | 1992-06-03 |
| HUT63621A (en) | 1993-09-28 |
| EP0487980A1 (en) | 1992-06-03 |
| HU208964B (en) | 1994-02-28 |
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