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SE446265B - 2-methyl-1,4-dihydropyridine - Google Patents

2-methyl-1,4-dihydropyridine

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Publication number
SE446265B
SE446265B SE7908367A SE7908367A SE446265B SE 446265 B SE446265 B SE 446265B SE 7908367 A SE7908367 A SE 7908367A SE 7908367 A SE7908367 A SE 7908367A SE 446265 B SE446265 B SE 446265B
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Sweden
Prior art keywords
methyl
dihydropyridine
carboxylic acid
compound
ester
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SE7908367A
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Swedish (sv)
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SE7908367L (en
Inventor
Y Sato
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Fujisawa Pharmaceutical Co
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Publication of SE7908367L publication Critical patent/SE7908367L/en
Publication of SE446265B publication Critical patent/SE446265B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Description

7908567-1 2 °2 A-s °z"s°°°\ ooczfls dito l NI C33 H cuzon _ N°2 A-s - °6H5cH2\Ncn ca Ooc ooc H aim CH/ 2 2 z 5 3 l" | ca, H en - c1 AJ' czssooc i ooczns ' aim .ca3 B cn2ocoæ3a Ett ändamål med föreliggande uppfinning är åstadkommande av nya uch användbara 2-metyldihydropyridinföreníngar vilka struk- turellt karakteriseras genom substituenten vid dihydropyridinkâr- nans 3-position och vilka har högre aktivitet jämfört med de kän- da föreningarna, exempelvis de ovan visade. 7908567-1 2 ° 2 A-s ° z "s °°° \ oocz fl s ditto l NI C33 H cuzon _ N ° 2 A-s - ° 6H5cH2 \ Ncn ca Ooc ooc H aim CH / 2 2 z 5 3 l" | An object of the present invention is to provide novel and useful 2-methyldihydropyridine compounds which are structurally characterized by the substituent at the 3-position of the dihydropyridine nucleus and which have a higher 3-position activity. compared with the known compounds, for example those shown above.

Z-metyldihydropyridínföreningarna enligt föreliggande upp- fínníng kan återges med följande formel: (I) 7908367-1 3 vari RI, R2, R3 och R4 är valda ur någon av följande kombina- tioner: (a) R1 är Z-trifluormetylfenyl, R2 är 2-etoxietyl, 2-fenoxi- etyl eller 2-bensyloxíetyl, RS är etyl och R4 är hydro- ximetyl eller cyano, (b) Rl är 2-trífluormetylfenyl eller 3-nítrofenyl, R2 är iso- propyl, R3 är metyl och R4 är hydroxímetyl eller cyano, eller (c) RI är z-klørfenyl, Rz är isoprvpyl, RS år metvl och F14 är cyanc. 2-metyldihydropyridínföreníngen enligt föreliggande upp- finníng är sålunda en förening vald bland: 2-fenoxietylestern av S-etoxikarbony1-4-(2-trifluormetylfenyl)- -6-hydroximetyl-2-metyl-1,4-dihydropyrídín-3-karboxylsyra; 2-etoxietylestern av 5-etoxikarbony1-4-(2-trifluormetylfenyl)- -6-hydroxímetyl-2-metyl-1,4-dihydropyridin-3-karboxylsyra; 2-bensyloxietylestern av 5-etoxíkarbony1-4-(2-trifluormety1- fenyl)-6-hydroximetyl-2-mety1-1,4-dihydropyrídín-3-karboxylsyra; ..._-Vw- --- -... isopropylestern av 6-cyano-S-metoxikarbony1-2-metyl-4-(3-nítro- fenyl)-1,4-díhydr0pyrídin-3-karboxylsyra; 2-etoxíetylestern av 6-cyano-S-etoxikarbony1~4-(2-trifluormetyl- fenyl)-2-metyl-1,4-dihydropyridín-3-karboxylsyra; 2-bensyloxíetylestern av 6-cyano-5-etoxikarbony1-4-(2-trif1uor- metylfenyll-2-metyl-1,4-díhydropyridín-3-karboxylsyra; isopropylestern av 4-(2-trifluørmetylfenyl)-6-hydroxímety1-5- metoxikarbonyl-2-metyl-1,4-dihydropyrídín-3-karboxylsyra; ísopropylestern av 4-(2-klorfenyl)-6-cyano-5-metoxíkarbonyl- ~2-metyl-1,4-dihydropyridin-3-karboxylsyra; isopropylestern av 6-cyano-4-(2-trifluormetylfenyl)-S-metoxí- karbonyl-2-metyl-1,4-díhydropyrídin-3-karboxylsyra; 2-fenoxietylestern av 6-cyano-5-etoxíkarbony1-4-(2-trífluor- metylfenyl)-2-metyl-1,4-dihydropyrídin-3-karboxylsyra;'5ÉF'"' ísopropylestern av 6-hydroxímetyl-5-metoxíkarbonyl-2-metyl-4- (3-nitrofenyl)-l,4-díhydropyrídin-3-karboxylsyra. 7908367-1 4 Med avseende på föreliggande förening och ovanstående formel (I) bör det observeras, att ett par av två optiska iso- merer kan föreligga genom den asymmetriska kolatomen i dihydro- pyridinkärnans 4-position, och denna typ av isomerer innefattas följaktligen inom ramen före föreliggande uppfinning och repre- senteras med samma formeln (I).The Z-methyldihydropyridine compounds of the present invention may be represented by the following formula: (I) wherein R 1, R 2, R 3 and R 4 are selected from any of the following combinations: (a) R 1 is Z-trifluoromethylphenyl, R 2 is 2-ethoxyethyl, 2-phenoxyethyl or 2-benzyloxyethyl, R 5 is ethyl and R 4 is hydroxymethyl or cyano, (b) R 1 is 2-trifluoromethylphenyl or 3-nitrophenyl, R 2 is isopropyl, R 3 is methyl and R 4 is hydroxymethyl or cyano, or (c) R 1 is z-chlorophenyl, R 2 is isopropyl, R 5 is methyl and F 14 is cyano. Thus, the 2-methyldihydropyridine compound of the present invention is a compound selected from: the 2-phenoxyethyl ester of S-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; 2-Ethoxyethyl ester of 5-ethoxycarbonyl- 4- (2-trifluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; 2-Benzyloxyethyl ester of 5-ethoxycarbonyl- 4- (2-trifluoromethyl-phenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; The N-isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitro-phenyl) -1,4-dihydropyridine-3-carboxylic acid; 2-Ethoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid; 2-Benzyloxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid; isopropyl ester of 4- (2-trifluoromethylphenyl) -6-hydroxymethyl] -5 methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; the isopropyl ester of 4- (2-chlorophenyl) -6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; the isopropyl ester of 6-cyano-4- (2-trifluoromethylphenyl) -S-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; 2-phenoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2 -trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid; '5EF' "'isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4 With respect to the present compound and the above formula (I), it should be noted that a pair of two optical isomers may be present through the asymmetric carbon atom in the 4-position of the dihydropyridine nucleus, and the dihydropyridine-3-carboxylic acid 7908367-1. this type of isomers is therefore included within the scope of the present invention ng and is represented by the same formula (I).

Enligt föreliggande uppfinning kan föreliggande förening- ar (I) framställas genom förfaranden såsom illustreras med föl- jande schemor. (1) Förfarande 1 2 Ria ~ Rla R ooc coon° Redaktion Rzooc coon3 CH [N I CHO IN] I 3 H g I CH3 H CHZOH (II-l) _ (I-l) vari R1a,_R2 och R" är valda ur någon av följande kombinationer: (a) _ R a år 2-trifluormetylfenyl, Rz är 2-etoxietyl, 2-fenoxi- etyl eller 2-bensyloxietyl och R3 år etyl, eller (b) Rla år 2-ttifluormetylfenyl eller 3-nitrofenyl, R2 är isopropyl och R3 år metyl. (2) Förfarande 2 1 . . 7 R _ (1) Hydroxylamin Rl rooc I coon* Uå-jiñïvßfifi SHI-ß R-zooc cooa3 ' ' > ' Af I Dehydratise” I Chs ii CHO ringsmedel CH3 H CN fil-à) (I-2 J vari Rl, R; och_R3 arïvalda ur någon av föliande kombinationer: (a) Rl är 2-trifluormetylfenyl, R2 är 2-etoxietyl, 2-fenoxi- etyl eller 2-bensyloxietyl och R3 är etyl, (b) R1 är 2-trífluormetylfenyl eller 3-nitrofenyl, R2 år ísopropyl och R3 är metyl, eller (c) R1 är 2-klorfenyl, R2 är isopropyl och R3 är metyl.According to the present invention, the present compounds (I) can be prepared by methods as illustrated by the following schemes. (1) Procedure 1 2 R 1 ~ R 1a R ooc coon ° Editing R zoooc coon 3 CH [NI CHO IN] I 3 H g I CH 3 H CH 2 OH (II-1) _ (II) wherein R 1a, _R 2 and R of the following combinations: (a) R 1a is 2-trifluoromethylphenyl, R 2 is 2-ethoxyethyl, 2-phenoxyethyl or 2-benzyloxyethyl and R 3 is ethyl, or (b) R 1a is 2-trifluoromethylphenyl or 3-nitrophenyl, R 2 is isopropyl and R 3 is methyl. (2) Process 2 1.. 7 R _ (1) Hydroxylamine R 1 rooc I coon * Ua-jiñïvß fifi SHI-ß R-zooc cooa3 ''> 'Af I Dehydratise' I Chs ii CHO ring agent CH 3 H CN fil-a) (I-2 J wherein R 1, R 2 and R 3 are selected from any of the following combinations: (a) R 1 is 2-trifluoromethylphenyl, R 2 is 2-ethoxyethyl, 2-phenoxyethyl or 2-benzyloxyethyl and R 3 is ethyl, (b) R 1 is 2-trifluoromethylphenyl or 3-nitrophenyl, R 2 is isopropyl and R 3 is methyl, or (c) R 1 is 2-chlorophenyl, R 2 is isopropyl and R 3 is methyl.

Utgångsföreningarna (II-1) och (II-2), som användes i Förfarande l och 2, kan framställas med följande metoder. 7908367-1 (A) Metod A: RI 1 4 2-»xzooc ooas R ,CH.?.CQ-Ra + CHS-(IPCH-COOR I l 3 coon NH N 4 2 CH3 H Ra (111-1) (IV-1) (11-3) vari RI, R2, R3 och R4a år valda ur någon av följande kombina- tioner: (a) RI är 2-trífluormetylfenyl, R2 ar 2-etoxíetyl, 2-fenoxi- etyl eller 2-bensyloxíetyl, R3 är etyl och R4a är dietoximetyl, eller (b) R1 är Z-trifluormetylfenyl, Z-klorfenyl eller 3-nítrofe- nyl, R2 är isopropyl, R3 är metyl och R4a är dímetoxime- tyl.The starting compounds (II-1) and (II-2) used in Methods 1 and 2 can be prepared by the following methods. 7908367-1 (A) Method A: RI 1 4 2- »xzooc ooas R, CH.?. CQ-Ra + CHS- (IPCH-COOR I l 3 coon NH N 4 2 CH3 H Ra (111-1) ( IV-1) (11-3) wherein R 1, R 2, R 3 and R 4a are selected from any of the following combinations: (a) R 1 is 2-trifluoromethylphenyl, R 2 is 2-ethoxyethyl, 2-phenoxyethyl or 2- benzyloxyethyl, R 3 is ethyl and R 4a is diethoxymethyl, or (b) R 1 is Z-trifluoromethylphenyl, Z-chlorophenyl or 3-nitrophenyl, R 2 is isopropyl, R 3 is methyl and R 4a is dimethoxymethyl.

(B) Metod B ---*- R1 nl-cH=c-cocns + R:-c-ca-cooR3-+R2ooc ooa oonz ÅHZ CH |N| 4 (111-21 c_1v_-2> 3 n a . (ïï'å) vari kombinationerna av R1, R2, R3 och R4a har ovan angiven be- _ tydelse. ' (C) Metod C al I RI Rzooc coons Hyaroiys; azooc cooxs .___---9 Nl 4 INI C53 H Ra CH3 H CHO Cï1'23 (II-3) vari kombinationerna av RI, RZ, R3 och R4a har ovan angiven be- tydelse.(B) Method B --- * - R1 nl-cH = c-cocns + R: -c-ca-cooR3- + R2ooc ooa oonz ÅHZ CH | N | 4 (111-21 c_1v_-2> 3 na. (Ïï'å) wherein the combinations of R1, R2, R3 and R4a have the meaning given above. '(C) Method C al I RI Rzooc coons Hyaroiys; azooc cooxs .___--- 9 Nl 4 INI C53 H Ra CH3 H CHO C12'23 (II-3) wherein the combinations of RI, RZ, R3 and R4a have the meaning given above.

Förfaranden för framställning av 2-metyldihydropyridín- föreningen (I) återges detaljerat nedan: (1) Förfarande 1: Föreliggande förfarande avser en metod för framställning av en förening (I~l) genom reduktion av föreningen (11-D.Processes for the preparation of the 2-methyldihydropyridine compound (I) are set forth in detail below: (1) Process 1: The present process relates to a method for the preparation of a compound (I-1) by reduction of the compound (11-D).

Reduktionen kan utföras på konventionellt sätt för tillämpning pà reduktion av en formylgrupp till en hydroximetyl- .....-,-..._.....,Ä .._...._..-.... .-..........,....--..-, 7908567-1 6 grupp, och speciellt utföres reduktionen under användning av ett reduktionsmedel, såsom en alkalimetallborhydrid (ex.vis litium- borhydrid, natriumborhydrid, kaliumborhydrid, natriumcyanobor- hydrid, etc) eller genom katalytisk reduktion, för vilken före- dragen katalysator kan vara palladium-kol, palladiumklorid eller rodium-kol och liknande. Reduktionen utföres vanligen i ett kon- ventionellt lösningsmedel, såsom vatten, metanol, etanol, iso- propanol, dimetylformamid, tetrahydrofuran, etc och liknande.The reduction can be carried out in a conventional manner for application to the reduction of a formyl group to a hydroxymethyl- .....-, -..._....., Ä .._...._..-... .-.........., .... - ..-, 7908567-1 6 group, and in particular the reduction is carried out using a reducing agent, such as an alkali metal borohydride (e.g. lithium borohydride , sodium borohydride, potassium borohydride, sodium cyanoborohydride, etc.) or by catalytic reduction, for which preferred catalyst may be palladium-carbon, palladium-chloride or rhodium-carbon and the like. The reduction is usually carried out in a conventional solvent such as water, methanol, ethanol, isopropanol, dimethylformamide, tetrahydrofuran, etc. and the like.

Reaktionstemperaturen är ej kritisk och reaktionen utföres vanligen under kylning, vid rumstemperatur eller vid något förhöjd tempe- ratur. .Reduktionsmetoden kan ev. utväljas alltefter typen av förening (II-D. (2) Förfarande 24 Föreliggande förfarande avser en metod för framställning av en förening (If2) genom omsättning av en förening (II~2) med hydroxylamin eller ett salt därav och sedan omsättning av bildad produkt med ett dehydratiseringsmedel.The reaction temperature is not critical and the reaction is usually carried out under cooling, at room temperature or at a slightly elevated temperature. .The reduction method can ev. is selected according to the type of compound (II-D. (2) Process 24 The present process relates to a method for preparing a compound (If2) by reacting a compound (II ~ 2) with hydroxylamine or a salt thereof and then reacting the product formed with a dehydrating agent.

Enligt föreliggande förfarande kan formylgruppen av ut- gångsföreningen (Ii-2) överföras till hydroxiiminometylgrupp (det första steget), och nämnda grupp kan sedan överföras till cyanogrupp (det andra steget).According to the present process, the formyl group of the starting compound (Ii-2) can be converted to hydroxyiminomethyl group (the first step), and said group can then be converted to cyano group (the second step).

Föredraget salt av hydroxylamin kan vara ett salt med en syra, såsom en oorganisk syra (ex.vis saltsyra, svavelsyra, etc) eller en organisk syra (ex.vis ättiksyra, etc). (i) Det första steget: Reaktionen i detta steg utföres på sedvanligt sätt för s.k. oximeringsreaktion, ex.vis i närvaro av en syra (såsom salt- syra, bromvätesyra, svavelsyra, myrsyra, ättiksyra, p-toluen- sulfonsyra, bortrifluorid, kiseltetraklorid eller titantetra- klorid); under basiska betingelser åstadkomna med en bas, ex.vis fri hydroxylamin; eller i sur eller basisk konventionell buffert- lösning. Reaktionen utföres vaiigen i ett lämpligt konventionellt lösningsmedel, såsom vatten, dioxan, etanol, metanol, dimetyl- formamid eller ev. en blandning därav, och om ovanstående syra är en vätska kan denna även användas som lösningsmedel.Preferred salt of hydroxylamine may be a salt with an acid, such as an inorganic acid (eg hydrochloric acid, sulfuric acid, etc.) or an organic acid (eg acetic acid, etc.). (i) The first step: The reaction in this step is carried out in the usual way for so-called oximation reaction, for example in the presence of an acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, p-toluenesulfonic acid, boron trifluoride, silicon tetrachloride or titanium tetrachloride); under basic conditions provided with a base, eg free hydroxylamine; or in acidic or basic conventional buffer solution. The reaction is carried out in a suitable conventional solvent such as water, dioxane, ethanol, methanol, dimethylformamide or optionally. a mixture thereof, and if the above acid is a liquid, it can also be used as a solvent.

Reaktionstemperaturen är ej kritisk och reaktionen ut- föres vanligen under kylning, vid rumstemperatur eller under något förhöjd temperatur. 7 7908367-1 Reaktionsprodukten från det första steget underkastas det följande andra steget med eller utan isolering och/eller rening. (ii) Det andra steget: Lämpligt denydratiseringsmedel använt vid detta steg är ett konventionellt organiskt eller oorganiskt medel, såsom en oorganisk syra (ex.vis svavelsyra, fosforsyra, polyfosforsyra, etc), en organisk syra (ex.vis myrsyra, ättiksyra, trifluorättik- syra, etansulfonsyra, p-toluensulfonsyra, etc),en organisk syra- anhydrid (ex.vis ättiksyraanhydrid, bensoesyraanhydrid, ftalsyra- anhydrid, etc),en organisk syrahalogenid (ex.vis acetylklorid, bensoylklorid, trikloracetylklorid, mesylklorid, tosylklorid, etylklorformat, fenylklorformat, etc), en oorganisk halogen- förening (ex.vls Llonylklorid, fosforpentaklorld, fosforoxiklorid, fosfortribromid, tenn(IV)klorid, titantetraklorid, etc); en karbodiimid (ex.vis N,N'-dicyklohexylkarbodiimid, N-cyklohexyl- N'-morfolinoetylkarbodiimíd, etc), N,N'~karbonyldiimidazol; pentametylenketen-N-cyklohexylimin; etoxiacetylen; 2-etyl-7- hydroxiisoxazoliumsalt; en annan fosforförening (ex.vis fosfor- pentoxid, polyfosforsyraetylester, trietylfosfat eller fenyl- fosfat) eller liknande eller ev. en blandning därav. När en syra användes som dehydratiseringsmedel kan reaktionen även utföras i närvaro av dess salt, såsom ett alkalimetallsalt (ex.vis natrium- salt eller kaliumsalt) eller liknande.The reaction temperature is not critical and the reaction is usually carried out under cooling, at room temperature or at a slightly elevated temperature. The reaction product from the first step is subjected to the following second step with or without isolation and / or purification. (ii) The second step: Suitable denydratizing agent used in this step is a conventional organic or inorganic agent, such as an inorganic acid (eg sulfuric acid, phosphoric acid, polyphosphoric acid, etc.), an organic acid (eg formic acid, acetic acid, trifluoroacetic acid). acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.), an organic acid anhydride (eg acetic anhydride, benzoic anhydride, phthalic anhydride, etc.), an organic acid halide (eg acetyl chloride, benzoyl chloride, trichloroacetyl chloride, trichloroacetyl chloride , phenyl chloroformate, etc.), an inorganic halogen compound (e.g. Llonyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, stannous chloride, titanium tetrachloride, etc.); a carbodiimide (e.g. N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, etc.), N, N '-carbonyldiimidazole; pentamethylene chain-N-cyclohexylimine; ethoxyacetylene; 2-ethyl-7-hydroxyisoxazolium salt; another phosphorus compound (e.g. phosphorus pentoxide, polyphosphoric acid ethyl ester, triethyl phosphate or phenyl phosphate) or the like or possibly a mixture thereof. When an acid is used as a dehydrating agent, the reaction may also be carried out in the presence of its salt, such as an alkali metal salt (for example, sodium salt or potassium salt) or the like.

Föreliggande reaktion utföres vanligen i ett konven- tionellt lösningsmedel, såsom dietyleter, dimetylformamid, Dyridin, ättiksyra, myrsyra, bensen, koltetraklorid, kloroform, metylen- klorid, tetrahydrofuran, dioxan och liknande, och utföres vanligen vid rumstemperatur eller under upphettning, men reaktionstempera- s _turen är ej inskränkt till detta.The present reaction is usually carried out in a conventional solvent such as diethyl ether, dimethylformamide, dyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydrofuran, dioxane and the like, and is usually carried out at room temperature or under heating, but s _tour is not limited to this.

Enligt föreliggande uppfinning kan ifrågavarande reaktions- produkt separeras och isoleras från reaktionsblandningen och renas genom förfaranden som vanligen användes för detta ändamål, ex.vis extraktion med lämpligt lösningsmedel, kromatografi, utfällning, återkristallisation osv.According to the present invention, the reaction product can be separated and isolated from the reaction mixture and purified by methods commonly used for this purpose, for example, extraction with a suitable solvent, chromatography, precipitation, recrystallization, etc.

Metoder för framställning av mellanprodukter för fram- ställning av 2-metyldihydropyrídinföreningen (I) återges detalje- rat nedan.Methods for the preparation of intermediates for the preparation of the 2-methyldihydropyridine compound (I) are set forth in detail below.

(A) Metod A: 7908367-1 8 Detta förfarande avser en metod för framställning av en förening (II-3) genom omsättning av en förening (III-1) med en aminoförening (IV-1).(A) Method A: 7908367-18 This process relates to a method for preparing a compound (II-3) by reacting a compound (III-1) with an amino compound (IV-1).

Vardera av utgångföreningarna (III-1) och (IV-1) inne- fattar geometriska cis- och trans-isomerer genom dubbelbindningen i deras molekyler, och enligt detta förfarande kan föreningen (II-3) framställas med godtycklig ordningsföljd genom omsättning av endera geometriska isomerer av föreningen (III-1) med vilken som helst isomer av föreningen (IV-1), och följaktligen innefat- tas samtliga isomerer och optiska blandningar av isomerer av des- sa utgångsföreningar (III-1) och (IV-1) inom ramen för förelig- gæmefmfumflm Omsättningen kan utföras vid rumstemperatur eller under uppvärmning eller upphettning. Reaktionen kan företrädesvis ut- föras i frànvaro av ett lösningsmedel men kan även utföras 1 ett lämpligt lösningsmedel, såsom bensen, toluen, xylen, kloroform, koltetraklorid, metylenkloríd, etylenklorid eller något annat kon- ventionellt lösningsmedel. Reaktionen kan företrädesvis accele- reras genom närvaro av ett ämne, såsom en syra (ex.vis ättiksyra), en bas (ex.vis pyridin eller pikolin) eller i en konventionell buffertlösning. Dessa ämnen verkar som reaktionsacceleratorer och kan användas som lösningsmedel om de utgöres av vätskor.Each of the starting compounds (III-1) and (IV-1) comprises geometric cis and trans isomers by the double bond in their molecules, and according to this method, the compound (II-3) can be prepared in any order by reacting either geometric isomers of the compound (III-1) with any isomer of the compound (IV-1), and consequently all isomers and optical mixtures of isomers of these starting compounds (III-1) and (IV-1) are included within the framework for the presence of the substance fl m The reaction can be carried out at room temperature or during heating or heating. The reaction may preferably be carried out in the absence of a solvent but may also be carried out in a suitable solvent such as benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride or any other conventional solvent. The reaction can preferably be accelerated by the presence of a substance, such as an acid (eg acetic acid), a base (eg pyridine or picoline) or in a conventional buffer solution. These substances act as reaction accelerators and can be used as solvents if they are liquids.

Reaktionen kan accelereras genom uppvärmning eller upphettning.The reaction can be accelerated by heating or heating.

Reaktionsbetingelserna kan variera alltefter typen av reaktanter, lösningsmedel och/eller andra ämnen som omnämnts ovan som användes.The reaction conditions may vary according to the type of reactants, solvents and / or other substances mentioned above which are used.

(B) Metod B: Detta förfarande avser en metod för framställning av en förening (II-3) genom omsättning av en förening (III-2) med en aminoförening (IV-2).(B) Method B: This process relates to a method for the preparation of a compound (II-3) by reacting a compound (III-2) with an amino compound (IV-2).

Detta förfarande år i huvudsak detsamma som metod A och kan följaktligen utföras genom omsättning av föreningen (III-Z) med (IV~2) på samma sätt som angivits under metod A. Samma reak- tionsbetingelser (exempelvis reaktionstemperatur, lösningsmedel, accelerator, etc.) som omnämnts under metod A kan sålunda till- lämpas vid föreliggande förfarande, förutsatt att föreningen (III-2) och föreningen (IV-2) användes vid föreliggande förfa- rande istållet för föreningen (III-l)resp¿föreningen(IV-1)i metod A.This process is essentially the same as method A and can consequently be carried out by reacting the compound (III-Z) with (IV ~ 2) in the same manner as indicated under method A. The same reaction conditions (for example reaction temperature, solvent, accelerator, etc. .) mentioned under method A can thus be used in the present process, provided that the compound (III-2) and the compound (IV-2) are used in the present process instead of the compound (III-1) and the compound (IV -1) in method A.

(C) Metod C: Detta förfarande avser en metod för frasmtållning av en Z0 9 7908367-1 förening (II-2) genom hydrolys av en förening (II-3).(C) Method C: This process relates to a method for solidifying a compound (II-2) by hydrolysis of a compound (II-3).

Föreningen (II-3) kan framställas genom ovan illustrerad teknik (metoderna A och B).The compound (II-3) can be prepared by the technique illustrated above (methods A and B).

Vid föreliggande förfarande överfores dietoximetyl- eller dímetoximetylgruppen för R4a av föreningen (II-3) till en for- mylgrupp.In the present process, the diethoxymethyl or dimethoxymethyl group of R 4a of the compound (II-3) is converted to a formyl group.

Hydrolys kan utföras på konventionellt sätt som är till- lämpbart på spjälkning av en s.k. acetalfunktion till motsvarande karbonylfunktion och företrädesvis ex.vis som sur hydrolys, dvs 1 närvaro av en syra, såsom en oorganisk syra (ex.vis saltsyra, svavelsyra, etc) eller en organisk syra (ex.vis myrsyra, ättiksyra, trifluorättiksyra, p-toluensulfonsyra, etc) eller ett surt jon- bytarharts.Hydrolysis can be performed in a conventional manner which is applicable to the cleavage of a so-called acetal function to the corresponding carbonyl function and preferably eg as acid hydrolysis, ie in the presence of an acid, such as an inorganic acid (eg hydrochloric acid, sulfuric acid, etc.) or an organic acid (eg formic acid, acetic acid, trifluoroacetic acid, p- toluenesulfonic acid, etc.) or an acidic ion exchange resin.

Denna hydrolys kan utföras 1 ett lämpligt konventionellt lösningsmedel, såsom vatten, aceton, metyletylketon, dioxan, etanol, metanol, N,N-dimetylformamid eller dimetylsulfoxid, eller bland- ningar därav eller en buffertlösning därav. Reaktionstemperaturen är ej kritisk och reaktionen kan vanligen utföras under kylning, vid rumstemperatur eller under något förhöjd temperatur.This hydrolysis can be carried out in a suitable conventional solvent, such as water, acetone, methyl ethyl ketone, dioxane, ethanol, methanol, N, N-dimethylformamide or dimethyl sulfoxide, or mixtures thereof or a buffer solution thereof. The reaction temperature is not critical and the reaction can usually be carried out under cooling, at room temperature or at a slightly elevated temperature.

Den sålunda erhållna föreningen (I) innefattar ofta minst ett par optiska isomerer genom närvaron av en asymmetrisk kolatom i 4-position av 1,4-dihydropyridinkärnan och kan föreligga som enskild optisk isomer eller som en blandning därav. En racemisk förening kan upplösas 1 optiska isomerer genom konventionellt förfarande för racemisk uppdelning, såsom kemisk upplösning av salterna av diastereoisomeren med en konventionell optiskt aktiv syra (ex.vis vinsyra eller kamforsulfonsyra, etc).The compound (I) thus obtained often comprises at least a pair of optical isomers by the presence of an asymmetric carbon atom in the 4-position of the 1,4-dihydropyridine nucleus and may exist as a single optical isomer or as a mixture thereof. A racemic compound can be dissolved into optical isomers by a conventional method of racemic resolution, such as chemically dissolving the salts of the diastereoisomer with a conventional optically active acid (eg tartaric acid or camphorsulfonic acid, etc.).

Det bör observeras, att föreningen (I) besitter starka va- sodilator- och anti-hypertensívaktíviteter och är användbar för terapeutisk behandling av kardiovaskulära störningar och hyper- tension, såsom koronär insufficiens, angina pektoris eller myo- kardíal infarkt och hypertension.It should be noted that the compound (I) possesses strong vasodilator and antihypertensive activities and is useful for the therapeutic treatment of cardiovascular disorders and hypertension, such as coronary insufficiency, angina pectoris or myocardial infarction and hypertension.

För terapeutisktandamäl administreras 2-metyldihydropyri- dínföreningen (I) i en daglig dos av 0,1-S00 mg, företrädesvis 1-S0 mg.For therapeutic purposes, the 2-methyldihydropyridine compound (I) is administered in a daily dose of 0.1-00 mg, preferably 1-50 mg.

De farmaceutiska kompositionerna enligt föreliggande upp- finning innehåller som aktiv beståndsdel 2-metyldihydropyridín- föreningen (I) i en mängd av ca 0,01 mg till ca S00 mg, företrä- desvis ca 0,1 mg till ca 250 mg per dosenhet för oral och paren- .. ...Üííw-...n-a-n-v-.ffi- --- - ss 7908567-1 N teral användning.The pharmaceutical compositions of the present invention contain as active ingredient the 2-methyldihydropyridine compound (I) in an amount of about 0.01 mg to about 500 mg, preferably about 0.1 mg to about 250 mg per dosage unit for oral administration. and paren- .. ... Üííw -... nanv-.f fi- --- - ss 7908567-1 N teral use.

Fackmannen på området vet, att mängden aktiv beståndsdel 1 enhetsdosformen kan bestämmas genom hänsyn tagen till bestånds- delens aktivitet såväl som storleken av den patient som behandlas.Those skilled in the art know that the amount of active ingredient in the unit dosage form can be determined by considering the activity of the ingredient as well as the size of the patient being treated.

Den aktiva bestàndsdelen kan vanligen tillhandahållas i fast form, såsom tablett, granul, pulver, kapsel, dragé, pastill eller suppositorium, eller 1 form av suspension eller lösning, såsom sírup, injoktionsïönning. emuïslon, lemonnd, etc och liknande.The active ingredient may generally be provided in solid form, such as tablet, granule, powder, capsule, dragee, lozenge or suppository, or in the form of a suspension or solution, such as syrup, solution for injection. emuïslon, lemonnd, etc and the like.

Som farmaceutisk bärare eller utspädningsmedel kan användas fasta eller flytande, ogiftiga, farmaceutiskt acceptabla ämnen. Ex. på fasta eller flytande bärare eller utspädningsmedel är laktos, magnesiumstearat, terra alba, sukros, majsstärkelse, talk, stearin- syra, gelatin, agar, pektin, akacia, jordnötolja, olivolja eller sesamolja, kakaosmör, etylenglykol eller andra konventionella ämnen. Bäraren eller utspädningsmedlet kan även innehålla för- 'dröjningsmaterial} såsom glycerylmonostearat, glyceryldistearat, ett vax eller liknande.As pharmaceutical carrier or diluent, solid or liquid, non-toxic, pharmaceutically acceptable substances can be used. Ex. on solid or liquid carriers or diluents are lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive or sesame oil, cocoa butter, ethylene glycol or other conventional substances. The carrier or diluent may also contain retardant materials such as glyceryl monostearate, glyceryl distearate, a wax or the like.

I ändamål att visa användbarheten av föreningen (I) redo- visas nedan farmakologiska testresultat av vissa representativa föreningar.In order to demonstrate the usefulness of the compound (I), pharmacological test results of certain representative compounds are reported below.

Testföreningar: Förening A-l: Nifedipine (referensförening).Test compounds: Compound A-1: Nifedipine (reference compound).

Förening A-2: (referensförening) Förening A-4: (referensföreníng) Förening A-S: (referensförening) Förening A-6: (referensföreníng) Förening A-7: (referensföreníng) Isopropylester av 6-cyano-5-metoxikarbonyl-2-metyl- 4'(3~nitrofeny1)-1,4-dihydropyridin-3-karboxylsyra.Compound A-2: (reference compound) Compound A-4: (reference compound) Compound AS: (reference compound) Compound A-6: (reference compound) Compound A-7: (reference compound) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2- methyl 4 '(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid.

Isopropylester av 4-(2-klorfenyl)-6-cyano-5-mefi0Xi_ karbonyl-2-metyl-1,4-dihydropyridin-3-karboxylsyra.Isopropyl ester of 4- (2-chlorophenyl) -6-cyano-5-methoxy-carbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

Isopropylester av 6-cyano-4-(2-trifluormetylfenyl)- -m@t0Xikarb0nyl-2-metyl-1,4-dihydropyridin-3- karboxylsyra. 2-fenoxietylester av 6-cyano-4-(2-trifluormety1_ fenyl)-5-etoxíkarbonyl-2-metyl-l,4-dihydropyridin- 3-karboxylsyra.Isopropyl ester of 6-cyano-4- (2-trifluoromethylphenyl) -m-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. 2-Phenoxyethyl ester of 6-cyano-4- (2-trifluoromethylphenyl) -5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

Isopropylester av 4-(2-trifluormetylfenyl)_6_ hYdT0Ximetyl-5-metoxikarbonyl-2-metyl-1,4-dihydro- pyridin-3-karboxylsyra.Isopropyl ester of 4- (2-trifluoromethylphenyl) -6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

“Förening B: Förening C: Förening D; Förening E; Förening F: 7908367-1 ll Förening G: 2-fenoxietylester av 4-(2-trifluormetylfenyl)-5- etoxikarbonyl-6-hydroximetyl-2-metyl-1,4-dihydro- pyridin-3-karboxylsyra.Compound B: Compound C: Compound D; Compound E; Compound F: 7908367-1 11 Compound G: 2-phenoxyethyl ester of 4- (2-trifluoromethylphenyl) -5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

Förening H: isoprppylestern av 6-hydroximetyl-5-metøx1karbonyl- 2-metyl-Ä-(3-nitrofenyl)-1,4-dihydropyridin-3-karboxylsyra- Förening I: 2-etoxietylestern av 5-etoxikarbony1-4-(2-tr1f1uormety1- fenyl)-6-hydroximetyl-2-metyl-l,4-d1hydropyr1din-3- karboxylsyra Förening J: 2-bensyloxietylestern av 5-etoxikarbonyl-4-(2-trifluor- metylfenyl)-6-hydroxïmetyl-2-metyl-1,4-d1hydropyr1d1n-3- karboxylsyrae Förening K:2-etoxietylestern av 6-cyano-5-etoxikarbonyl-Ä-(2-tri- fluormetylfenyl)-2-metyl-1,4-dihydropyridin-3-karboxyl- syra e Förening L:2-bensyloxietylestern av 6-cyano-5-etoxikarbonyl-4-(2- trifluormetylfenyl)-2-metyl-1,Ä-d1hydropyrid1n~3-karboxyl syra Hxgctensiv effekt Testmetod: Wistar-råttor användes per grupp. Varje djur immobili- serades 1 en efter kroppsstorleken anpassad bur. Blodtrycket upp- mättes på femurartären medelst en trycktransduktor och registre- rades som elektriskt integrerade värden av medelartärtrycket, øch hjärtrytmen bestämdes med en pulsvågdetektor. Operation för katetisering utfördes under lätt anestesi med eter. Testföreningen administrerades oralt 5 timmar efter operationens fullbordande.Compound H: the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-N- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid Compound I: 2-ethoxyethyl ester of 5-ethoxycarbonyl- 4- (2 -Trifluoromethyl-phenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid Compound J: 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-hydroxymethyl-2- Methyl K-2-ethoxyethyl ester of 6-cyano-5-ethoxycarbonyl-N- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid Acid e Compound L: The 2-benzyloxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,1-dihydropyridine-3-carboxylic acid Hxgctensive effect Test method: Wistar rats were used per group. Each animal was immobilized in a cage adapted to body size. Blood pressure was measured on the femoral artery by means of a pressure transducer and recorded as electrically integrated values of the mean artery pressure, and the heart rhythm was determined with a pulse wave detector. Catheterization surgery was performed under light anesthesia with ether. The test compound was administered orally 5 hours after completion of the operation.

Testresultatz Medelvärden avACÄ-maxímisänkníng av blodtrycket (mmHg) visas i följande tabell. _.-_-.._.-.--~.-.~._.,.._...-...-.-n-.ww.. 7908367-1 1, TABELL 1 Dos 1 mg/kg 10 mg/kg Förening A-1 -2s,sT 1,5 -44,6 T 1,2 A-6 -11,0 ej testad A-7 -10,2 ej testad B -44,eT 1,7 -50,0 T 1,3 c -29,2 T 3,0 -40,6 T 2,2 D -34,6 T 0,9 -47,4 T 1,3 E -22,8 T 2,1 44,2 T 1,5 F g -18,0 T 1,9 -46,6 T 2,1 G -13,2 T 3,5 -47,8 T 2,4 Effekt av koronarblodflóde: Testmetod: Mongrel-hundar, vägande 8-15 kg, anestetíserades med en intrapektoneal dos av pentobarbitalnatrium 35 mg/kg. Därefter öppnades thorax under artíficíell respiration, en flödesmåtarsond infördes i vänstra circumflexgrenen av koronárartären. Blodtryck- et uppmättes i femurartåren och föreningen enligt föreliggande uppfinning injícerades intravenöst. Vården av toppblodflödet uppmättes.Testresultatz Mean values of ACÄ maximum decrease in blood pressure (mmHg) are shown in the following table. _.-_-.._.-.-- ~ .-. ~ ._., .._...-...-.- n-.ww .. 7908367-1 1, TABLE 1 Dos 1 mg / kg 10 mg / kg Compound A-1 -2s, sT 1.5 -44.6 T 1.2 A-6 -11.0 not tested A-7 -10.2 not tested B -44, eT 1 .7 -50.0 T 1.3 c -29.2 T 3.0 -40.6 T 2.2 D -34.6 T 0.9 -47.4 T 1.3 E -22.8 T 2.1 44.2 T 1.5 F g -18.0 T 1.9 -46.6 T 2.1 G -13.2 T 3.5 -47.8 T 2.4 Effect of coronary blood flow: Test method : Mongrel dogs, weighing 8-15 kg, were anesthetized with an intrapectoneal dose of pentobarbital sodium 35 mg / kg. Thereafter, the thorax was opened under artificial respiration, a flow meter probe was inserted into the left circumflex branch of the coronary artery. Blood pressure was measured in the femoral veins and the compound of the present invention was injected intravenously. The care of the top blood flow was measured.

Testresultat: TABELL Z Ökning av koronârblodflöde (%). Angivna värden anger procenttal jämfört med kontroll.Test results: TABLE Z Increase in coronary blood flow (%). Stated values indicate percentages compared to control.

Dos ug/kg , 10 100 Testéöreningar A-1 89 72 A-5 ej testad g 109 B 181 219 H ej testad 144 Vasodilaterande effekt på den isolerade artâren: Testmetod: "_ Den stora koronârartåren med 2 mmisavtterdíameter av- lâgsnades från en pentobarbitalanesticerad hund. En spiralfor- mig remsa med en ungefärlig längd av 15 mm skars ut från den sto- ra artären och suspenderades i ett organbad innehållande Tyrods lösning vid 37°C, som luftades med en gasblandning av 95% syre U 7908367"1 och 5% koldioxid. Remsans tonus registrerades under användning av en kraftfórskjutande transduktor och en polygraf. Efter det att begynnelsevilopåkánníngen justerats till 1,0 g för den stora artären, sattes kaliumklorid (2,61 mg/ml, 35 mmol) till organ- badet för att öka påkänningstonus på remsorna från den stora ar- tären till l,4~l,6 g. De kumulativa koncentrationerna för test- föreningarna adderades sedan, och slutligen tillsattes papaverin (3,8 x 10'5g/ml, 10_4mol) för bestämning av den maximala relaxa- tionen.Dose ug / kg, 10 100 Testing compounds A-1 89 72 A-5 not tested g 109 B 181 219 H not tested 144 Vasodilating effect on the isolated artery: Test method: "_ The large coronary artery with a diameter of 2 mm was removed from a pentobarbital anesthetized A helical strip with an approximate length of 15 mm was excised from the great artery and suspended in an organ bath containing Tyrod's solution at 37 ° C, which was aerated with a gas mixture of 95% oxygen U 7908367 "1 and 5 % carbon dioxide. The tone of the strip was recorded using a force-shifting transducer and a polygraph. After adjusting the initial resting strain to 1.0 g for the great artery, potassium chloride (2.61 mg / ml, 35 mmol) was added to the organ bath to increase the stress tone on the strips from the great artery to 1.4 ~ l. The cumulative concentrations of the test compounds were then added, and finally papaverine (3.8 x 10.5 g / ml, 10 -4 mol) was added to determine the maximum relaxation.

Testreultat: Värdena i följande tabell anger den maximala relaxation, som förorsakas av administrering av testföreningarna (1 x 10'9g/ml), i procent (medelvärde) i förhållande till det fall att den maxima- la relaxationen, som förorsakas av administrering av l0'4mol pa- paverin, sättes till 100%.Test results: The values in the following table indicate the maximum relaxation, which is caused by administration of the test compounds (1 x 10'9g / ml), in percent (mean) in relation to the case of the maximum relaxation, which is caused by administration of 10 4 mol paverine, set to 100%.

TABELL 3 Testfórening Testresultat A-2 18% A-4 13 A-5 20 B 85 G 60 I 44 J 76 K 56 L 71 Följande exempel återges i ändamål att illustrera före- liggande uppfinning.TABLE 3 Test Compound Test Results A-2 18% A-4 13 A-5 20 B 85 G 60 I 44 J 76 K 56 L 71 The following examples are set forth to illustrate the present invention.

Framstållning av utgångfóreníngarna för metoderna A och B Framställning l 1) Till en lösning av 3-nitrobensoaldehyd (7,56 g) och metyl- 4,4-dimetoxlacetoncetat (7,93 g) 1 torkad bensen (30 ml) sattes ättiksyra (0,l8 g) och plperidin (0,l7 5), och blandningen upp- hettades under ñterflöde i 3.5 timmar under det att vattnet azeo- tropiskt avlägsnades. ßfter tillsats av bensen till reaktions- blandningen tvättades lösningen 1 tur och ordning med vatten, utspädd vattenlösning av natriumvätekarbonat, vatten och en mättad ll zs vattenlösning av natriumklorid och torkades sedan. 7908367-1 14 Avlägsnande av lösningsmedlet under reducerat tryck gav en cljeartat återstod (l5,74 g), som kromatograferades över silikagel (470 g) med en blandning av bensen och etylacetat (25:l på volymen) som elue- ringsmedel till bildning av en gul olja (8,06 g) av metyl-4,4- dimetoxi-2-(3-nifirobensyliden)acetoacetat (en blandning av cis- och trans-isomerer).Preparation of the starting compounds for methods A and B Preparation 1 1) To a solution of 3-nitrobenzoaldehyde (7.56 g) and methyl 4,4-dimethoxlacetone acetate (7.93 g) in dried benzene (30 ml) was added acetic acid (0 , 18 g) and plperidine (0, 17 5), and the mixture was heated under reflux for 3.5 hours while the water was azeotropically removed. After adding benzene to the reaction mixture, the solution was washed successively with water, dilute aqueous sodium bicarbonate, water and a saturated aqueous sodium chloride solution, and then dried. Removal of the solvent under reduced pressure gave a clear residue (1.544 g) which was chromatographed on silica gel (470 g) with a mixture of benzene and ethyl acetate (25: 1 by volume) as eluent to give a yellow oil (8.06 g) of methyl 4,4-dimethoxy-2- (3-nitrobenzylidene) acetoacetate (a mixture of cis and trans isomers).

NMR 6 ppm (CDCl5): 2) NMR 6 ppm (CDCI _3) NMR å ppm (CDCl3): 4) ) 6) NMR 6 ppm (coin), 3:45 (5: 6H): 3,91 (S, 5H), ,43 (S, ÖH), 4:90 (S: 1H): _ 7:25'8:4 (SH: m)' Följande föreningar erhölls på i huvudsak samma sätt som enligt framställning l -1).NMR δ ppm (CDCl 5): 2) NMR δ ppm (CDCl 3) NMR δ ppm (CDCl 3): 4) 6) NMR δ ppm (coin), 3:45 (5: 6H): 3.91 (S, 5H),, 43 (S, ÖH), 4:90 (S: 1H): _ 7: 25'8: 4 (SH: m) 'The following compounds were obtained in essentially the same manner as in Preparation l -1).

Metyl-2-(2-k blandning av 3)* 3,28 (s, 6H), 3,81 (S, 3H), 7°7)5 (4H: m), 3188 (5: 3H): ,08 (S, IH), lorbensyliden)-#,4-dimetoxiacetoacetat (en cis- och trans-isomerer). 3,41 (S, 6H), 4,68 (s,.1H), 8,02 (s, ia), 3:71 (S, 3H), ,08 (s, IH), 8,12 (s, IH).Methyl 2- (2-k mixture of 3) * 3.28 (s, 6H), 3.81 (S, 3H), 7 ° 7) 5 (4H: m), 3188 (5: 3H): 08 (S, 1H), lorbenzylidene) - #, 4-dimethoxyacetoacetate (a cis and trans isomers). 3.41 (S, 6H), 4.68 (s, 1H), 8.02 (s, 1a), 3:71 (S, 3H), 08 (s, 1H), 8.12 (s , 1H).

Metyl-2-(2-trifluormetylbensyliden)-4,4-dimetoxiaceto- acetat (en blandning av cis- och trans-isomerer). 3,28 (S, ÖH), 3,84 (S, 3H), 7:2'7:8 (ÄH: m)1 3,42 (s, 6H), 4,62 (s, 1H), 3,61 (S, BH), :06 (sl lH): 8,0-8,14 (lH, m). 2-fenoxietylestern av 2-(2-trifluormetylbensyliden)aceto- ättiksyra (en blandning av cis- och trans-isomerer).Methyl 2- (2-trifluoromethylbenzylidene) -4,4-dimethoxyacetoacetate (a mixture of cis and trans isomers). 3.28 (S, ÖH), 3.84 (S, 3H), 7: 2.7: 8 (HH: m) 1 3.42 (s, 6H), 4.62 (s, 1H), 3 61 (S, BH),: 06 (sl 1H): 8.0-8.14 (1H, m). The 2-phenoxyethyl ester of 2- (2-trifluoromethylbenzylidene) acetoacetic acid (a mixture of cis and trans isomers).

NMR 6 ppm (CDCl3): 2:18 (5: 3H): 2:a? (S: 3H): 6,8-8,2 (IOH, m). 319“#:9 (ÄH: m): 2-ctoxlctylestern av 2-(2-trifluunuetyibensyliden)aceto- ättíksyra (eu blandning av cis- och trans-isumerer).NMR δ ppm (CDCl 3): 2:18 (5: 3H): 2: a? (S: 3H): 6.8-8.2 (10H, m). 319 #: 9 (AH: m): The 2-ethoxyethyl ester of the 2- (2-trifluoromethylbenzylidene) acetoacetic acid (a mixture of cis- and trans-isomers).

NMR Ö ppn (CCl4): 2,10 (S, 53), ëøl-us? (m: 1,10 (u, J=7nz, 3n), 2,11 (S, BH), 2,38 (S, 3H), 1,18 (c, ==7IIZ, }II),' 4,l-4,5 m), 7,3-3,0 (SH, m), 3,1-3,8 (än, m). 2-bensyloxietylestern av 2-(2-trifluonnetylbensyliden)- acetoättiksyra (en blandning av cis- och trans-isomerer. 2,37 (S, BH), ?,2-8,0 (lOH. må. 4,57 (S, 4H), 3:4”3:9 (EH: m): 4,53 (S, 4H), í 7908367-1 Framställníng av mellanprodukterna Framstállníng 1 1) En blandning av metyl-4,4-dimetoxi-2-(3-nitrobenayliden)- acetoacetat (8,0 g) oçh isopropyl-3-aminokrotonat (4,07 g) upp- hettades vid 70°C 1 1 timme under omröflng, och omröring utfördes vid 1oo°c under 1 timme och vid 12o°C under ytterligare 2,5 timmar.NMR δ ppn (CCl 4): 2.10 (S, 53), ëøl-us? (m: 1.10 (u, J = 7nz, 3n), 2.11 (S, BH), 2.38 (S, 3H), 1.18 (c, == 7IIZ,} II), , l-4.5 m), 7.3-3.0 (SH, m), 3.1-3.8 (than, m). The 2-benzyloxyethyl ester of the 2- (2-trifluoromethylbenzylidene) acetoacetic acid (a mixture of cis- and trans-isomers. 2.37 (S, BH),?, 2-8.0 ( , 4H), 3: 4 ”3: 9 (EH: m): 4.53 (S, 4H), í 7908367-1 Preparation of the intermediates Preparation 1 1) A mixture of methyl-4,4-dimethoxy-2- (3-Nitrobenaylidene) acetoacetate (8.0 g) and isopropyl 3-aminocrotonate (4.07 g) were heated at 70 ° C for 1 hour with stirring, and stirring was carried out at 100 ° C for 1 hour and at 120 ° C for a further 2.5 hours.

Efter upplösning av reaktionsblandningen 1 etylacetat tvättades lösningen med vatten och en vattenlösning av natriumklorid, torka- des över magnesiumsulfat och indunstades sedan till torrhet under reducerat tryck till bildning av en gulorange olja (ll,05 S) av isopropylestern av 5-metoxikarbonyl-6-dimetoximetyl-2-metyl-4-(3- nitrofenyl)-l,4-dihydropyridin-3-karboxylsyra.After dissolving the reaction mixture in ethyl acetate, the solution was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated to dryness under reduced pressure to give a yellow-orange oil (11.05 S) of the isopropyl ester of 5-methoxycarbonyl-6- dimethoxymethyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid.

NMB 6 ppm (CDCl3): 1,13 (d, J=7,0Hz, 6H), 1,27 (d, J=7,0Hz, 6H), 2:40 (35: 5): 3:47 (51 6H): 3:50 (5: 6H)» 3,69 (3H, s), 5,0 (1H, hepbec, J=7,oHz), ,17 (lH, s), 6,04 (1H, s), 6,92 (IH, bred s), 7,2-8,2 (4H, m).NMB δ ppm (CDCl 3): 1.13 (d, J = 7.0Hz, 6H), 1.27 (d, J = 7.0Hz, 6H), 2:40 (35: 5): 3:47 ( 51 6H): 3:50 (5: 6H), 3.69 (3H, s), 5.0 (1H, hepbec, J = 7, 0Hz),, 17 (1H, s), 6.04 (1H , s), 6.92 (1H, broad s), 7.2-8.2 (4H, m).

Följande föreningar erhölls på i huvudsak samma sätt som enligt framställning l-1). 2) Isopropylestern av 4-(2-klorfenyl)-5-metoxikarbonyl-6- dimetoxímetyl-2-metyl-1,4-dihydropyridin-3-karboxylsyra, . amp. 86-87,5°c. ' 3) Isopropylestern av 4-(2-trifluormetylfenyl)-5-metoxiæ _ karbonyl-6-dimetoximetyl-2-metyl-1,4-dihydropyridin-3- karbøxylsyra, smp. 92-9400. I 4) 2-fenoxietylestern av 5-etoxikarbonyl-6-dietoximetyl-4-(2- fiPiflu°rmetylfeny1)-2-meeyl-1,4-ainyaropyriain-3-karboxyl- syra.The following compounds were obtained in substantially the same manner as in Preparations 1-1). 2) The isopropyl ester of 4- (2-chlorophenyl) -5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid,. amp. 86-87.5 ° C. 3) The isopropyl ester of 4- (2-trifluoromethylphenyl) -5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, m.p. 92-9400. In 4) the 2-phenoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-pifluoromethylphenyl) -2-methyl-1,4-aminopyramine-3-carboxylic acid.

NMR Ö ppm (CDCI-jh 1104-15 (9H: 177): 2:37 (BH, S), },5~4,6 (IOH, m), 5,67 (IH, s), 7,12 (ln, s), 6,7-7,8 (1oH, m). ) 2'°t°XieÜYlestern av 5-etoxikarbonyl-6-d1etox1metyl-4- (2-triflußrmefiylfenyl)-2-mecyl-1,4-a1nyaropyr1a1n-3- karboxylsyra.NMR δ ppm (CDCl 3 δ 1104-15 (9H: 177): 2:37 (BH, S),}, δ ~ 4.6 (10H, m), 5.67 (1H, s), 7.12 (1n, s), 6.7-7.8 (10H, m).) 2 '° t ° Xylethyl ester of 5-ethoxycarbonyl-6-diethoxylmethyl-4- (2-trifluoromethylphenyl) -2-mecyl-1,4 -a1nyaropyr1a1n-3-carboxylic acid.

NMR 6 ppm (cc14)= 1,0-1,4 (125, m), 2,33 (3H, S), (12H. m), 5,s-s.7 (m, m), 6,47 (ln, 5), 3»3-4,3 6:10 S), 7l2"7:7 (hu, m).NMR δ ppm (cc14) = 1.0-1.4 (125, m), 2.33 (3H, S), (12H, m), δ, ss.7 (m, m), 6.47 ( ln, 5), 3 »3-4,3 6:10 S), 7l2" 7: 7 (hu, m).

A20 7908367-1 2-beusyloxiebylestern av 5-etuxíkurbonyl-G-dietuximety1- Ä-(2-trtfluonnetylfenyl)-2-metyl-1.4-d1hydropyridin-3-_ 16 fi) karboxylsyra.A20 7908367-1 The 2-beusyloxybyl ester of the 5-ethoxycarbonyl-G-dietuximethyl-N- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-1616 fi) carboxylic acid.

NMR ß ppm (cnc13)= 1,0-1,6 (9fl, m), 5,4-4,4 2,32 (3H, S), (lon, m), 4,n7 (2H, s), 5,6-5,7 (lfl, m), 6,11 (1H, s), 6,6-6,8 (IH, bred S), 7,2-7,7 (su, m).NMR δ ppm (cnc13) = 1.0-1.6 (9fl, m), 5.4-4.4 2.32 (3H, S), (lon, m), 4, n7 (2H, s) , 5.6-5.7 (1fl, m), 6.11 (1H, s), 6.6-6.8 (1H, broad S), 7.2-7.7 (su, m).

Framställning Z l) En blandning av 2-fenoxietylestern av 2-(2-trifluormetyl- bensyliden)acétoacetat (19,62 g) och etyl-2-amino-4,4-dietoxi- krotonat (ll,95 g) upphettades 1 20 timmar vid 100-l10°C och under ytterligare 12 timmar vid 120-13000. Erhàllen blandning upplöstes i etylacetat och tvättades med vatten och torkades sedan över vattenfritt magnesiumsulfat. Lösningsmedlet avlägsnades genom destillation till bildning av en råolja (27,7 g), som kromatogra- ferades över silikagel med en blandning av bensen och etylacetat (50:l, räknat på volymen) som elueringsmedel till bildning av 2-fenoxíetylestern av 5-etoxi-6-dietoximetyl-4-(2-trif1uormetyl- fenyl)-2-metyl-1,4-dihydropyridin-3-karboxylsyra (l9,34 g).Preparation Z 1) A mixture of the 2-phenoxyethyl ester of 2- (2-trifluoromethylbenzylidene) acetoacetate (19.62 g) and ethyl 2-amino-4,4-diethoxycrotonate (11, 95 g) was heated. hours at 100-110 ° C and for a further 12 hours at 120-13000. The resulting mixture was dissolved in ethyl acetate and washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give a crude oil (27.7 g), which was chromatographed on silica gel with a mixture of benzene and ethyl acetate (50: 1 by volume) as eluent to give the 2-phenoxyethyl ester of 5-ethoxy. -6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid (19.34 g).

NMR a ppm (cnc13)= 1,0-1,5 (9H, m), 2.57 (BH, s), 3,5-4,6 (1oH, m), 5,67 (ln, S), 7,12 (ln, s), 6,7-7,8 (1oH, m).NMR δ ppm (cnc13) = 1.0-1.5 (9H, m), 2.57 (BH, s), 3.5-4.6 (10H, m), 5.67 (ln, S), δ 12 (ln, s), 6.7-7.8 (10H, m).

Följande föreningar erhölls på i huvudsak samma sätt som enligt~framställning 2-1). 3) 2-etoxietylestern av 5-etoxikarbonyl?6-dietoximetyl-4- (2-trifluormetylfenyl)>2-metyl-1,4-dihydropyridin-3- karboxylsyra.The following compounds were obtained in essentially the same manner as in Preparation 2-1). 3) The 2-ethoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl)> 2-methyl-1,4-dihydropyridine-3-carboxylic acid.

NMR 6 ppm (cc14)= 1,0-1,4 (12H, m), 2,38 (33, S), 3,3-4,3 (12H, m), 5,5-5,7 (ln, m), 6,10 (ln, s), 6,47 (lH, s), 7,2-7,7 (4H, m). 2-bensyloxiebylestern av 5-etoxikarbonyl-6-dietoximetyl- 4-(2-trifluormetylfenyl)-2-metyl-1,4-dihydropyridin-3- karboxylsyra.NMR δ ppm (cc14) = 1.0-1.4 (12H, m), 2.38 (33, S), 3.3-4.3 (12H, m), 5.5-5.7 ( 1n, m), 6.10 (1n, s), 6.47 (1H, s), 7.2-7.7 (4H, m). The 2-benzyloxybyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

NMH ö ppm (CDcl3): |.o-|,6 (9H, m), 2,32 (3H_ S), 3,q-q,q (IUH. m), 4,h1 (au. s), 5,6-5,7 (1H, m) 6.11 (xn. s), 6.6-6,8 (JH, bred s), 7,2- 7s7 (ÜH, m). ' Isopropylestern av 5-metoxikarbonyl-6-dimetoximetyl-2- meÜY1'4*(3-DibP0fenyl)-1,4-dihydropyridin-3-karboxylsyra. 3) 4) smed vatten och torkades sedan. 17 7908367-1 1,13 (d, J=7,øuz; óx), 1,27 (d, J=7.0Hz, ön). 2,40 (BH, s), },Ä7 (s, 6H), 3,50 (s, 6H), 3,69 (BH, s), 5,0 (IH, heptet, J=7,0Hz), ,17 (ln, s), 6,04 (ln, S), 6,92 (ln, bred s), 7,2-8,2 (45, m).NMH δ ppm (CDCl 3): δ-δ, δ (9H, m), 2.32 (3H-S), δ, qq, q (IUH. M), 4.1 h1 (au. S), 6-5.7 (1H, m) 6.11 (xn. S), 6.6-6.8 (JH, broad s), 7.2-7s7 (ÜH, m). The isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4 * (3-DibPophenyl) -1,4-dihydropyridine-3-carboxylic acid. 3) 4) forged water and then dried. 17 7908367-1 1.13 (d, J = 7, øuz; óx), 1.27 (d, J = 7.0Hz, ön). 2.40 (BH, s),}, 77 (s, 6H), 3.50 (s, 6H), 3.69 (BH, s), 5.0 (1H, heptet, J = 7.0Hz) ,, 17 (ln, s), 6.04 (ln, S), 6.92 (ln, broad s), 7.2-8.2 (45, m).

) Isopropylestern av 4-(2-klorfenyl)-5-metox1karbonyl-6- dimetoximetyl-2-metyl-1,4-dihydropyridln-5-karboxylsyra, smp. 86-87,5°C.The isopropyl ester of 4- (2-chlorophenyl) -5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-5-carboxylic acid, m.p. 86-87.5 ° C.

NMR 6 ppm (CDC15): _ 6) Isopropylestern av Ä-(2-trifluormetylfenyl)-5-metoxi- knrbunyl~6-dlmetuxlmetyl-?-metyl-1,N-dihydvopyr1dln-3- karbuxylsyru. nw äfiffl: anno. 1720. 1510, l278, 768 cm'1. 1h93. 1035. 1319, 951, 1653. 1095, 1690. 1206, Framställning 3 1) Till en lösning av 2-fenoxíetylestern av 5-etoxíkarbonyl- 6-dietoximetyl-4-(2-trifluormetylfenyl)-2-metyl-1,Ä-dihydropyridin- 3-karboxylsyra (l5,85 g) i acetqn (159 ml) sattes 6N saltsyra (l5,85 ml) vid rumstemperatur under omröring, øch omröringen upp- rätthölls 1 1,5 timmar. Reaktionsblandníngen neutrallserades med en mättad vattenlösning av natriumvätekarbonat och acetonet av- Återstoden upplöstes 1 etylacetat, tvättades Avlägsnande av lösningsmedlet gav en olja (l3,56 g) av 2-fenoxietylestern av 5-etoxikarbonyl-4- (2-trifluormetylfenyl)-6-formyl-2-metyl-1,4-dihydropyrldin-3- lägsnades 1 vakuum. karboxylsyra.NMR δ ppm (CDCl 3): δ) The isopropyl ester of Ä- (2-trifluoromethylphenyl) -5-methoxycarbonyl-6-dimethoxymethyl-β-methyl-1,1-dihydopyridine-3-carboxylic acid. nw ä fi ffl: anno. 1720. 1510, l278, 768 cm'1. 1h93. 1035. 1319, 951, 1653. 1095, 1690. 1206, Preparation 3 1) To a solution of the 2-phenoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,1- Dihydropyridine-3-carboxylic acid (1.55 g) in acetone (159 ml) was added 6N hydrochloric acid (1.55 ml) at room temperature with stirring, and stirring was maintained for 1.5 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and the acetone was dissolved. The residue was dissolved in ethyl acetate, washed. -2-methyl-1,4-dihydropyridine-3 was removed in vacuo. carboxylic acid.

NMR 6 ppm (CDCl3): 2,40 (BH, s), 4,0- 6:7"7:7 (Zl-OH: 79): 1,22 (BH, t, J=7,5Hz), 4,6 (ófl, m), 5,71 (ln, s), ,26 (IH, s).NMR δ ppm (CDCl 3): 2.40 (BH, s), 4.0-6: 7 "7: 7 (Z1-OH: 79): 1.22 (BH, t, J = 7.5Hz), 4.6 (fl, m), 5.71 (ln, s), 26 (1H, s).

Följande föreningar erhölls på i huvudsak samma satt som enligt framställning 3-1). 2) Isopropylestern av 4-(2-klorfenyl)-6-formyl-5-metoxi- karbonyl-2-metyl-1,4-dihydropyridin-3-karboxylsyra, smp. 102-lo3°c. 3) Isopropylestern av 4-(2-trifluormetylfenyl)-6-formyl-5- metoxlkarbonyl-2-metyl-1,4-dihydropyridln-)~karboxylsyra, smp. 85-85°C. '4 ) 2-etoxietylestern av 5-etoxikarbonyl-6-formyl-4-(2-tri- fluormetylfenyl)-2-metyl-1,4-dihydropyridin-5-karboxylsyra. 1 omrördes vid rumstemperatur 1 4 timmar. 79Û8367~1 N una 6 ppm (cnc13)= 1,114 (u, J=7Hz, en), 1,26 (u, Jam, 6:a), 2,43 (BH, S), 3,3-3,3 (ÄH, m), 4,0-4.5 (4n, m), 5,7-5,8 (ln, m), 6,8-7.0 (ln, m), 7,1-7,8 (4H, m), 10,27 (lH, S). ) 2-bensyloxietylestern av 5-etoxikarbonyl-6-formy1-4-(2- trifluormetylfenyl)-2-metyl-1,4-dihydropyridín-3- karboxylsyra.The following compounds were obtained in essentially the same manner as in Preparation 3-1). 2) The isopropyl ester of 4- (2-chlorophenyl) -6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, m.p. 102 ° C. 3) The isopropyl ester of 4- (2-trifluoromethylphenyl) -6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-) carboxylic acid, m.p. 85-85 ° C. 4) The 2-ethoxyethyl ester of 5-ethoxycarbonyl-6-formyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-5-carboxylic acid. 1 was stirred at room temperature for 1 4 hours. 79Û8367 ~ 1 N una 6 ppm (cnc13) = 1.114 (u, J = 7Hz, en), 1.26 (u, Jam, 6: a), 2.43 (BH, S), 3.3-3, 3 (1H, m), 4.0-4.5 (4n, m), 5.7-5.8 (1n, m), 6.8-7.0 (1n, m), 7.1-7.8 ( 4H, m), 10.27 (1H, S). ) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-6-formyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

NMR 6 ppm (CCl¿): 2,40 (BH, s), 3,4- ,7-5,8 (ln, m), ,28 1,23 (BH, t, J=7,5Hz), 4,5 (6H, m), 4,41 (2H, s), 6,8-6.9 (IH, m), 7.2-7.8 (9H, m)- (IH. s).NMR δ ppm (CCl 3): 2.40 (BH, s), 3.4-, 7-5.8 (ln, m), δ 1.23 (BH, t, J = 7.5Hz), 4.5 (6H, m), 4.41 (2H, s), 6.8-6.9 (1H, m), 7.2-7.8 (9H, m) - (1H, s).

Framställníñ§_Z__ En blandning av isopropylestern av 5-metoxikarbony1-6- dimetoximetyl-2-metyl-4-(5-nitrofenyl)-1,4-dihydropyridin-}- karboxylsyra (ll,0 g) och 6N saltsyra (ll ml) i aceton (110 ml) Efter avlägsnande av acetonet sattes vatten till reaktionsblandningen och justerades till pH 7,5 med en mättad vattenlösning av natriumvätekarbonat.Preparation A mixture of the isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4- (5-nitrophenyl) -1,4-dihydropyridine-} -carboxylic acid (11, 0 g) and 6N hydrochloric acid (11 ml) in acetone (110 ml) After removal of the acetone, water was added to the reaction mixture and adjusted to pH 7.5 with a saturated aqueous solution of sodium hydrogencarbonate.

Den bildade vattenlösningen extraherades med etylacetat, extraktet tvättades med vatten och torkades över vattenfritt magnesiumsulfat.The resulting aqueous solution was extracted with ethyl acetate, the extract was washed with water and dried over anhydrous magnesium sulfate.

Avlägsnande av lösningsmedlet gav en oljig återstod, som omedel* bart stelnade till bildning av gulorange râkristaller av isopropyl- estern av 6-formyl-5-metoxikarbonyl-2-metyl-4-(3-nitrofenyl)-l,4- dihydropyridin-3-karboxylsyra.Removal of the solvent gave an oily residue which immediately solidified to form yellow-orange crude crystals of the isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3 -carboxylic acid.

NMR 6 ppm (CDCl3): 1,13 (3H, d, J=7Hz), 1,28 (BH, d, J=7Hz), 1,79 (3H,sl3,8o (än, s), 5,02 (ln, nepcet, J=7Hz), ,27 (lH, s), 7,11 (1H, bred s), 7,4-8,2 Exempel 1 (4H, m), 10,60 (lH, s). 1) Till en lösning av isopropylestern av 6-formyl-5-metoxi- karbony1-2-metyl-4-(3-nitrofenyl)-1,4-dihydropyridin-3-karboxylat (4,2 g) 1 etanol (85 ml) sattes successivt portionsvis natríum- borhydrid (0,409 g) under en tidsperiod av 35 min. under kylning under 0°C med omröring. Därefter surgjordes reaktionsblandningen med en 50% vattenlösning av ättiksyra och etanolen avlägsnades under reducerat tryck. Den erhållna vattensuspensionen utspäddes med vatten och det utfällda blekgula pulvret uppsamlades genom filtrering och tvättades med vatten och torkades. Pulvret (3,89 g) återkristalliserades med etanol till bildning av ett gult pulver (3,05 g) av isopropylestern av 6-hydroximetyl-5-metoxikarbonyl- 79Û8367~1 19 2-metyl-4-(3-nitrofenyl)-1,4-dihydropyr1din-}-karboxylsyra, smp. 16u-166°c.NMR δ ppm (CDCl 3): 1.13 (3H, d, J = 7Hz), 1.28 (BH, d, J = 7Hz), 1.79 (3H, s13.8o (than, s), δ, O 2 (1n, nepcet, J = 7Hz),, 27 (1H, s), 7.11 (1H, broad s), 7.4-8.2 Example 1 (4H, m), 10.60 (1H, s) 1) To a solution of the isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (4.2 g) 1 ethanol (85 ml) was successively added portionwise sodium borohydride (0.409 g) over a period of 35 minutes. while cooling below 0 ° C with stirring. Then the reaction mixture was acidified with a 50% aqueous solution of acetic acid and the ethanol was removed under reduced pressure. The resulting aqueous suspension was diluted with water and the precipitated pale yellow powder was collected by filtration and washed with water and dried. The powder (3.89 g) was recrystallized from ethanol to give a yellow powder (3.05 g) of the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1 , 4-dihydropyridine -} - carboxylic acid, m.p. 16u-166 ° C.

Följande Förenin¿nr erhölls på i huvudsak snmmn sätt som enligt ex. 1~l)- 2) Isopropylestern av 4-(2-trifluormetylfenyl)-6-hydroxi- metyl-5-metoxikarbonyl-2-metyl-l,4-dihydropyridin~3- karboxylsyra, smp. 123-12500. m 3.) 2-fenoxietylestern av 5-etoxikarbonyl-4-(2-trif1uormetyl- fenyl)-6-hydroximetyl-2-metyl-1,ü-dihydropyridin-3- karbokylsyra, smp. 148-l49°C. 4 ) 2-etoxietylestern av 5-etoxikarbonyl-4-(2-trifluormety1- fenyl)-6-hydroxlmetyl-2-metyl-l,4-dihydropyridin-3- karboxylsyra, smp. 65-66,506. _ ) 2-bensyloxietylestern av 5-etoxikarbonyl-4-(2-trifluor- metylfenyl)-6-hydroximetyl-2-metyl-1,4-dihydropyridin-3- karboxylsyra, smp. 1014-10600. _ Exemgel 2 - 1) Till en lösning av isopropylestern av 6-formyl-5-metoxi- _karbonyl-2-metyl*§-(3-nitrofenyl)-1,4-dihydropyrídin-3-karboxyl- syra (4,5 g) 1 ättiksyra (35 ml) sattes hydroxylaminhydroklorid (O,97 g) och natriumacetat (1,43 g), och blandningen omrördes vid rumstemperatur i 2,5 timmar. Därefter sattes till reaktionsbland- ningen ättiksyraanhydrid (4,l4 g) och blandningen omrördes vid rumstemperatur i 1,5 timmar och vid 95-l00°C 1 ytterligare 4 timmar. Ättiksyran och överskottet ättiksyraanhydrid avlägsnades i vakuum, varefter till återstoden sattes vatten och neutralise- rades med mättad vattenlösning av natriumvätekarbonat. Den er- hållna vattensuspensionen extraherades 2 ggr med etylacetat, och de sammanslagna extrakten tvättades med vatten, torkades över vattenfritt magnesiumsulfat och indunstades till torrhet under reducerat tryck till bildning av en rödbrun olja (4,88 g), som kromatograferades över silikagel (150 g) med en blandning av bensen och etylacetat (l0íl räknat på volymen) som elueringsmedel till bildning av ràkristaller (2,99 g). Dessa àterkristalliserades ur etanol till bildning av gula prismor (l,89 g) av isopropylestern av 6-cyano-5-metoxikarbonyl-2-metyl-4-(5-nitrofenyl)-l,4-dihydro- pyridin-3-karboxylsyra, smp. 148-15000.The following compounds were obtained in essentially the same manner as according to e.g. 1 - 1) - 2) The isopropyl ester of 4- (2-trifluoromethylphenyl) -6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, m.p. 123-12500. m.) The 2-phenoxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,1-dihydropyridine-3-carboxylic acid, m.p. 148-149 ° C. 4) The 2-ethoxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethyl-phenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, m.p. 65-66,506. _) The 2-benzyloxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, m.p. 1014-10600. Example 2 - 1) To a solution of the isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl * §- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (4.5 g To acetic acid (35 ml) was added hydroxylamine hydrochloride (0.97 g) and sodium acetate (1.43 g), and the mixture was stirred at room temperature for 2.5 hours. Then, acetic anhydride (4.4 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours and at 95-100 ° C for a further 4 hours. The acetic acid and excess acetic anhydride were removed in vacuo, then water was added to the residue and neutralized with saturated aqueous sodium bicarbonate solution. The resulting aqueous suspension was extracted twice with ethyl acetate, and the combined extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a red-brown oil (4.88 g) which was chromatographed on silica gel (150 g). ) with a mixture of benzene and ethyl acetate (10 l by volume) as eluent to give crude crystals (2.99 g). These were recrystallized from ethanol to give yellow prisms (1.89 g) of the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (5-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid. m.p. 148-15000.

Följande föreningar erhölls på som enligt ex. 2-1). i huvudsak samma sätt 79Q8367-1 20 2) 3) 4> s) 6) Isopropyléšfiern av 4-(2-klorfenyl)-6-cyano-5-metøxi- karbonyl-2-metyl-l,4-dihydropyridin-3-karboxylsyra, smp. 176-177°c.The following compounds were obtained as according to ex. 2-1). essentially the same way 79Q8367-1 20 2) 3) 4> s) 6) Isopropylene of 4- (2-chlorophenyl) -6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3- carboxylic acid, m.p. 176-177 ° C.

Isopropylestern av 6-cyano-4-(2-trifluormetylfenyl)-5- metoxikarbonyl-2-metyl-1,Ä-dihydropyridin-3-karboxyl- syra, smp. 172-173°c. 2-fenoxietylestern av 6-cyano-5-etoxikarbonyl-#-(2- trifluormetyltenyl)-2-metyl-l,4-dihydropyridin-3-karboxyl- syra, smp. 118-119°c. 2-etoxietylestern av 6-cyano-5-etoxikarbonyl-4-(2-tri- fluormetylfenyl)-2-metyl-1,4-dihydropyridin-5-karboxyl- syra, smp. 104-l05°C. 2-bensyloxietylestern av 6-cyano-5-etoxikarbonyl-4-(2- trifluormetylfenyl)-2-metyl-1,4-dihydropyridin-3-karboxyl- syra., smp. 146-l47,5°C.The isopropyl ester of 6-cyano-4- (2-trifluoromethylphenyl) -5-methoxycarbonyl-2-methyl-1,1-dihydropyridine-3-carboxylic acid, m.p. 172-173 ° C. The 2-phenoxyethyl ester of 6-cyano-5-ethoxycarbonyl-# - (2-trifluoromethyltenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, m.p. 118-119 ° C. The 2-ethoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-5-carboxylic acid, m.p. 104-105 ° C. The 2-benzyloxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, m.p. 146-147.5 ° C.

Claims (2)

21 7908367-1 PATENTKRAV21 7908367-1 PATENT REQUIREMENTS 1. Díhydropyridinföreningar kännetecknade därav att de utgöres av: 2-fenoxíetylestcrn av 5-etoxíkarbony1-4-(2-trífluormetylfenyl)- -6-hydroximety1-2-metyl-1,4-dihydropyridin-3-karboxylsyra; 2-etoxíetylestern av S-etoxikarbony1-4-(2-trífluormetylfenyll- -6-hydroxímetyl-2-metyl-1,4-dihydropyrídin-3-karboxylsyra; 2-bensyloxietylestern av S-etoxikarbony1-4-(2-trif1uormetyl~ fenyll-6-hydroximety1-2-metyl-1,4-díhydropyridin-3-knrboxylsyru; ísopropylestern av 6-cyano-5-metoxikarbony1-2-metyl-4-(3-nítro- fenyl)-1,4-dihydropyridin-3-karboxylsyra; 2-etoxietylestern av 6-cyano-5-etoxikarbony1-4-(2-trif1uormetyl- fenyll~2-metyl-l,4-díhydropyrídin-3-karboxylsyra; 2-bensyloxietylestern av 6-cyano-S-etoxíkarbony1-4-(2-trif1uor- metylfenyl)-2-metyl-1,4-dihydropyridin-3-karboxylsyra; isopropylesfern av 4-(2-trifluormctylfenyll-6-hydroxímety1-S- metoxikarbonyl-2-metyl-1,4-dihydropyridin-3-karboxylsyra; ísopropylestern av 4-(2-klorfenyl)-6-cyano-S-metoxíkarbonyl- -2-metyl-1,4-dihydropyridin-3-karboxylsyra; isopropylestern av 6-cyano-4-(2-trifluormetylfenyl)-5-metoxi- karbonyl-2-mctyl-1,4-dihydropyridín-3-kurboxylsyra; 2-fenoxietylestern av 6-cyano-S-etoxikarbony1-4-(2-trif1uor- metylfcnyl)-2-mctyl-1,4-díhydropyridín-3-karboxylsyra; och¶ ísopropylestern av 6-hydroximetyl-S-metoxikarbonyl-2-mety1-4- (3-nitrofenyl)-1,4-dihydropyridin-3-karboxylsyra.Dihydropyridine compounds characterized in that they are: 2-phenoxyethyl ester of 5-ethoxycarbonyl- 4- (2-trifluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; 2-Ethoxyethyl ester of S-ethoxycarbonyl- 4- (2-trifluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; 2-Benzyloxyethyl ester of S-ethoxycarbonyl-4- (2-triphylmethyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3 -carboxylic acid; 2-ethoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid; 2-benzyloxyethyl ester of 6-cyano-5-ethoxycarbonyl 4- (2-Trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid; -3-carboxylic acid; the isopropyl ester of 4- (2-chlorophenyl) -6-cyano-5-methoxycarbonyl--2-methyl-1,4-dihydropyridine-3-carboxylic acid; isopropyl ester of 6-cyano-4- (2-trifluoromethylphenyl) ) -5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-curboxylic acid; 2-phenoxyethyl ester of 6-cyano-5-ethoxycarbonyl- 4- (2-trifluoromethylphenyl) - 2-methyl-1,4-dihydropyridine-3-carboxylic acid; and the isopropyl ester of 6-hydroxymethyl-S-methoxycarbonyl-2-methyl- 4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid. 2. Förening enligt krav 1, vilken är isopropylestern av 6-cyano-5-metoxíkarbony1-2-metyl-4-(3-nitro- fenyl)-1,4-dihydropyridín-3-karboxylsyra.A compound according to claim 1, which is the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid.
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GB1552911A (en) * 1975-07-02 1979-09-19 Fujisawa Pharmaceutical Co 1,4 dihydropyridine derivatives and the preparation thereof
GB1591089A (en) * 1976-12-17 1981-06-10 Fujisawa Pharmaceutical Co 1,4-dihydropyridine derivatives and process for preparation thereof
DE2658183A1 (en) * 1976-12-22 1978-07-06 Bayer Ag 2-POSITION SUBSTITUTED 1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS A MEDICINAL PRODUCT

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NL7907482A (en) 1980-04-14
SE8400689D0 (en) 1984-02-09
GB2036722A (en) 1980-07-02
JPS61118366A (en) 1986-06-05
SE7908367L (en) 1980-04-11
BE879263A (en) 1980-04-08
GB2036722B (en) 1982-12-01
FR2438654A1 (en) 1980-05-09
IT1125469B (en) 1986-05-14
JPS6143343B2 (en) 1986-09-26
SE446096B (en) 1986-08-11
JPS6125711B2 (en) 1986-06-17
CA1117117A (en) 1982-01-26
DE2940833C2 (en) 1989-01-26
IT7926362A0 (en) 1979-10-09
FR2438654B1 (en) 1983-01-14
DE2940833A1 (en) 1980-04-30
CH642353A5 (en) 1984-04-13
SE8400689L (en) 1984-02-09
JPS5562065A (en) 1980-05-10

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