EP0756590A1 - Synthese des prototypes des inhibiteurs de la renine - Google Patents

Synthese des prototypes des inhibiteurs de la renine

Info

Publication number
EP0756590A1
EP0756590A1 EP95913311A EP95913311A EP0756590A1 EP 0756590 A1 EP0756590 A1 EP 0756590A1 EP 95913311 A EP95913311 A EP 95913311A EP 95913311 A EP95913311 A EP 95913311A EP 0756590 A1 EP0756590 A1 EP 0756590A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
alkyl
compound
mmol
methyl
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.)
Withdrawn
Application number
EP95913311A
Other languages
German (de)
English (en)
Inventor
Stephen Hanessian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
Novartis AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ciba Geigy AG, Novartis AG filed Critical Ciba Geigy AG
Publication of EP0756590A1 publication Critical patent/EP0756590A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/02—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from isocyanates with formation of carbamate groups

Definitions

  • This invention relates to the field of biological activity relating to enzymatic and similar specific chemical breakdown of angiotensinogen by scission to angiotensin-l, then to angiotensin-ll, which engages receptors initiating biological activity as is well known.
  • Renin inhibitors prevent the production of angiotensin-ll, a potent vasoconstrictor and therefore are potent antihypertensives.
  • angiotensinogen is first cleaved to provide a specific fragment (angiotensin I), then subcleaved to a second specific fragment (angiotensin II), which engages the appropriate receptor to initiate biological activity:
  • the present invention contemplates novel stereoselective chemical synthensis of compounds as of the general formula I
  • the background is that of stereospecific synthetic organic chemistry, a voluminous and ever expanding field, in which it is a full time occupation to keep abreast of general trends, especially in areas relating to human medical application.
  • a principal object of the invention is to develop novel compounds suitable as prototypes for renin inhibitors. It is a related principal object to synthesize said novel compounds by novel chemical processes. It is a subsidiary object to devise practical synthetic schemes to prepare the novel compounds. It is a further subsidiary object to prepare the novel com ⁇ pounds as stereoisomerically pure as practicable. It is a further object to characterize all the compounds so prepared as fully as possible. Other objects would be readily apparent to skilled practitioners in the art, from the following specification, appended claims, and accompanying schemes and figures.
  • the invention is directed to a chemical compound having the structure
  • R . is hydrogen, or hydrocarbylcarboxy wherein the hydrocarbyl entity is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R 2 and R 3 or independently alkyl of 1 to 4 carbon atoms, R 4 is alkyl of 1 to 6 carbon atoms or a substituent of aliphatic character, R 5 is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms and alkoxy derivatives , primary and secondary amides and alkyl derivatives. Alkyl derivatives of primary and secondary amides are, for example, primary and secondary carbamoylalkyl groups.
  • Substituents of aliphatic character are, for example, butyl, 2-morpholinoethyl or 2- carbamoyl-2-methyl-propyl.
  • Alkoxy derivatives are, for example, alkoxyalkoxy groups such as 3-methoxy-propyloxy.
  • R is preferably alkylcarboxy and the alkyl group has 1 to 6 carbon atoms.
  • a preferred compound is (1 'S,2S,3R,3'R,5S)-5-[(3'-Butylcarbamoyl)-1 'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine- 1 -carboxylic acid tert-butyl ester.
  • Another preferred compound is (1'S,2S,3R,3'R,5S)-5-[(3'- Butylcarbamoyl)-1 'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine.
  • R ⁇ is preferably aralkylcarboxy and the aralkyl group has 7 to 10 carbon atoms.
  • a preferred compound is (1 'S,2S,3R,3'R,5S)-5-[(3'-Butylcarbamoyl)- 1'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine-1 -carboxylic acid benzyl ester.
  • Both A may be hydrogen, when R ⁇ is preferably alkylcarboxy and the aralkyl group has 1 to 7 carbon atoms.
  • a preferred compound is (2R,4S,5S,7R)-5-[[1 ,1-Dimethylethoxy)car- bonyl]amino]-4-hydroxy 2,7-dimethyl-8-phenyl octanioic acid butyl amide.
  • Another preferred compound is (2R,4S,5S,7R)-5-amino-4-hydroxy-2,7-dimethyl-8-phenyl octanoic acid butyl amide.
  • the invention is directed to processes of preparation of a first chemical compound of structure
  • n is 0-3 inclusive
  • A are either both hydrogen atoms or form a single carbon-nitrogen bond
  • Ri is hydrogen, or hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms
  • R 2 and R 3 are independently alkyl of 1 to 4 carbon atoms
  • R is alkyl of 1 to 6 carbon atoms or a substituent of aliphatic character such as, for example, butyl, 2-morpholinoethyl or 2- carbamoyl-2-methyi-propyl
  • R 5 is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy or 3 to 10 carbon atoms and alkoxy derivatives such as 3- ethoxy-propyl
  • the processes include a step selected from the group consisting of (a) hydrogenolysis of a second compound of the above formula wherein both A together form a single carbon nitrogen bond and Ri is alkylcarboxy wherein said alkyl has 1 to 6 carbon atoms, in the presence of Pd(OH)2/C; (b) hydrogenolysis of a third compound of the above formula wherein both A together form a single carbon nitrogen bond and R is aralkylcarboxy wherein said aralkyl has 7 to 10 carbon atoms, in the presence of Pd(PH) 2 /C, and dialkyl dicarbonate wherein both said dicarbonate alkyl groups are identical and have 1 to 6 carbon atoms; and (c) treating a fourth compound having the structure
  • Ri is hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R 2 and R 3 are independently alkyl of 1 to 4 carbon atoms, with R 4 NHAIMe 2 where R 4 is alkyl of 1 to 6 carbon atoms.
  • n is zero, in both formulae.
  • a preferred process of claim 14, comprises the step of hydrogenolysis of said second compound.
  • Another preferred process comprises the step of hydrogenolysis of said third compound.
  • a further preferred process comprises the step of treating said fourth compound, where in a preferred step Ri is alkyl ⁇ carboxy, said alkyl group having 1 to 6 carbon atoms.
  • Ri may be aralkylcar ⁇ boxy, said aralkyl having 7 to 10 carbon atoms.
  • Scheme 1 indicates a first synthetic route of the invention
  • 17a was hydrogenated saturating the double furan/lactone bond to give 93 % yield of 18a as a mixture of two rotamers.
  • the saturated lactone ring of 18a was methylated, 67 % of the desired mono- methyl 19a, and 15 % of the dimethyl lactone were obtained.
  • Crystalline 19a was X-ray analyzed.
  • the lactone ring was opened by formation of the butyl amide to give 2a in 76 % yield. Then the pyrrolodine ring was hydrogenolyzed to give 3a in 73 % yield.
  • This route is generally analogous to scheme 2, starting with cyclized imine 14, and protecting the imino nitrogen with a carboxybenzyl group rather than a carboxybutyl group, to yield 67 % (from 13) of 15b as a mixture of anomers and rotamers. Thereafter the steps are closely similar giving 89 % of 16b, 78 % of 17b, as 5:1 threo:erythro isomeric ratio. Pure erythro 17b was crystallized as a mixture of rotamers. Crystalline 17b was X-ray analyzed. Continuing gave 90 % of 18b, 56 % of 19b, 52 % of 2b, which was directly converted to 3a, in 46 % yield.
  • the reaction was stirred at -78°C for 2 h and then quenched with 15 mL of 1 :15 % aqueous NH 4 OH and saturated aqueous NH CI solution. The cooling bath was removed and the reaction allowed to warm to room temperature. Aqueous 10 % NH 4 OH (50 mL) and ether (300 mL) were then added and the resulting mixture was stirred until a homogenous organic phase and a dark blue aqueous phase were obtained.
  • Triphenylphosphine (5.33 g, 20.3 mmol) was added to the solution of 2.82 g (13.56 mmol) of the hydroxyester 9 in 70 mL of anhydrous THF and cooled to 0°C. DEAD was added dropwise followed by the dropwise addition of (PhO) 2 P(O)N 3 . The reaction was gradually allowed to warm to room temperature overnight.
  • reaction mixture was quenched with a solution of AcOH (0.15 mL) in 0.4 mL anhydrous THF and allowed to warm to temperature, then diluted with EtOAc, washed with water, brine, dried over MgSO 4 and concentrated. Purification of the residue by column chromatography (silica gel.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Prototypes d'inhibiteurs de la rénine ayant la structure générale (I) dans laquelle n vaut de 0 à 3 inclus, A représente soit deux atomes d'hydrogène, soit une liaison simple carbone-azote; R1 représente hydrogène ou hydrocarbylcarboxy où l'entité hydrocarbyle est sélectionnée dans le groupe comprenant alkyle de 1 à 6 atomes de carbone ou aralkyle de 7 à 10 atomes de carbone, R2 et R3 représentent, indépendamment, alkyle de 1 à 4 atomes de carbone, R4 représente alkyle de 1 à 6 atomes de carbone ou un substituant de caractère aliphatique tel que, par exemple, butyle, 2-morpholinoéthyle ou 2-carbamoyle-2-méthyle-propyle, R5 est sélectionné parmi des composés aromatiques, des composés aromatiques et hétéroaromatiques substitués, des cycloalkyles substitués ou non substitués, des cycloalcènes possédant de 3 à 8 atomes de carbone, lesdits substituants étant sélectionnés entre alkyle, alcoxy de 3 à 10 atomes de carbone, et des dérivés d'alcoxy, tels que 3-méthoxy-propyloxy, des amides primaires et secondaires et des dérivés d'alkyle. Ces prototypes sont préparés à l'aide d'une nouvelle synthèse à plusieurs étapes. Ces composés sont des produits intermédiaires précieux utilisés dans la fabrication de produits pharmaceutiques, tels que des inhibiteurs de la rénine et des inhibiteurs de la protéase du VIH.
EP95913311A 1994-04-21 1995-04-12 Synthese des prototypes des inhibiteurs de la renine Withdrawn EP0756590A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CA002121898A CA2121898A1 (fr) 1994-04-21 1994-04-21 Synthese de prototypes d'inhibiteurs de la renine
CA2121898 1994-04-21
PCT/IB1995/000257 WO1995029150A1 (fr) 1994-04-21 1995-04-12 Synthese des prototypes des inhibiteurs de la renine

Publications (1)

Publication Number Publication Date
EP0756590A1 true EP0756590A1 (fr) 1997-02-05

Family

ID=4153433

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95913311A Withdrawn EP0756590A1 (fr) 1994-04-21 1995-04-12 Synthese des prototypes des inhibiteurs de la renine

Country Status (12)

Country Link
EP (1) EP0756590A1 (fr)
JP (1) JPH09512266A (fr)
CN (1) CN1147810A (fr)
AU (1) AU2082395A (fr)
CA (1) CA2121898A1 (fr)
CZ (1) CZ306596A3 (fr)
FI (1) FI963743A (fr)
HU (1) HUT74743A (fr)
IL (1) IL113401A0 (fr)
PL (1) PL316677A1 (fr)
WO (1) WO1995029150A1 (fr)
ZA (1) ZA953187B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10205862A1 (de) * 2002-02-13 2003-08-21 Bayer Cropscience Ag DELTA1-Pyrroline
GB0511686D0 (en) * 2005-06-08 2005-07-13 Novartis Ag Organic compounds
CN109422664B (zh) * 2017-08-23 2022-02-18 中国科学院福建物质结构研究所 一类干扰素调节剂及其制备方法和用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9529150A1 *

Also Published As

Publication number Publication date
CA2121898A1 (fr) 1995-10-22
AU2082395A (en) 1995-11-16
IL113401A0 (en) 1995-07-31
JPH09512266A (ja) 1997-12-09
HUT74743A (en) 1997-02-28
FI963743A0 (fi) 1996-09-20
CN1147810A (zh) 1997-04-16
WO1995029150A1 (fr) 1995-11-02
PL316677A1 (en) 1997-02-03
ZA953187B (en) 1995-10-23
FI963743A (fi) 1996-09-20
CZ306596A3 (en) 1997-01-15
HU9602892D0 (en) 1996-12-30

Similar Documents

Publication Publication Date Title
JP5792139B2 (ja) レニン阻害剤の合成中間体としての３−アルキル−５−（４−アルキル−５−オキソ−テトラヒドロフラン−２−イル）ピロリジン−２−オン誘導体
ES2354986T3 (es) Síntesis alternativa de inhibiodores de renina e intermedios de los mismos.
US5618966A (en) Method forming protease inhibitor synthetic intermediates
AU2008234834B2 (en) New methods
JP6944473B2 (ja) 初期サクビトリル中間体のための新規な方法
RU2730006C1 (ru) Способ получения 5r-[(бензилокси)амино]пиперидин-2s-карбоновой кислоты или её производного
Jayaraman et al. Application of (+)-(1S, 2S)-2-amino-1-phenylpropan-1, 3-diol in the formal total synthesis of carbapenems, novel 4-cyano-β-lactams and β-hydroxy aspartates
EP0756590A1 (fr) Synthese des prototypes des inhibiteurs de la renine
EP0959070B1 (fr) Procédé de préparation de 3-amino-2-oxopyrrolidines, nouveaux produits intermédiaires et leur utilisation
MXPA96003967A (en) Synthesis of prototypes for ren inhibitors
JP4084855B2 (ja) 環式化合物の製法
Fernández et al. Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo [2.2. 1] heptanes. IV: Synthesis of enantiopure methyl (1S, 2R, 3R, 4R, 5S)-5-benzyloxycarbonylamino-2, 3-isopropylidenedioxy-4-methoxycyclopentanecarboxylate
MX2014011419A (es) Clorhidrato de (3,4-dicloro-fenil)-((s)-3-propil-pirrolidin-3-il)- metanona y procesos de manufacturacion.
WO2002048095A1 (fr) Procede de production de derives d'$g(a)-aminohalomethyle cetone
JP2008184388A (ja) 四置換ピロリジン類の製造法
WO2004099136A1 (fr) Procede de production de derives de pyrrolidine
CA2188294A1 (fr) Synthese des prototypes des inhibiteurs de la renine
JP2000026408A (ja) 対掌体的に純粋なピロリジン誘導体、その塩、それらの製造方法
JPS60109561A (ja) β−ラクタム化合物の製法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19960729

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NOVARTIS AG

17Q First examination report despatched

Effective date: 19971021

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19980103