NZ204536A - 1,4-dihydropyridine derivatives and pharmaceutical compositions - Google Patents

1,4-dihydropyridine derivatives and pharmaceutical compositions

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Publication number
NZ204536A
NZ204536A NZ204536A NZ20453683A NZ204536A NZ 204536 A NZ204536 A NZ 204536A NZ 204536 A NZ204536 A NZ 204536A NZ 20453683 A NZ20453683 A NZ 20453683A NZ 204536 A NZ204536 A NZ 204536A
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dihydro
compound
carboxylic acid
dimethyl
benzoxadiazol
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NZ204536A
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A Vogel
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Sandoz Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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
    • C07C255/00—Carboxylic acid nitriles
    • 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
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Description

New Zealand Paient Spedficaiion for Paient Number £04536 f / 2045 36 Priority 0 ./.$7.^.'.^ p..../.$?££■? Co :-.plci«5 Specification Fited: r 5:9.1.DMUr.a <;((<}f&k£... * 13JUNJ983 1 „ {j 0 'SE*P' 1986 Publicarcn Date: r.
P.O. Journal, 1*0: ....
B: :xT:::bs NEW ZEALAND PATENTS ACT. 1953 No.
Date: COMPLETE SPECIFICATION 1,4-DIHYDFOPYRIDINE DERIVATIVES IN OPTICALLY ACTIVE OR IN RACEMATE FORM AND THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS WWe, SANDOZ LTD, 35 Lichtstrasse, CH-4002 Basle, Switzerland, a Swiss Body Corporate | t i hereby declare the invention for which 1 / we pray that a patent may be granted tosMH/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by la) - la - 204536 1t4-0ihydropyridine derivatives, in optically active or in racemate form and their production and pharmaceutical compositions The invention relates to novel 1,4-dihydropyridine derivatives in optically active or in racemic form and their production and pharmaceutical compositions.
New Zealand Patent Specification No. 187617 discloses a broad class of 1,4-dihydropyridine derivatives. New Zealand Patent Specifications Nos. 192422 and 199437 disclose a number of further examples of this class.
He have now found that a particular group of hitherto unknown optically active and racemic 1,4-dihydropyridine derivatives, not specifically disclosed therein or suggested thereby have particularly interesting pharmacological • profiles.
The present invention provides compounds of formula I wherein one of R.j and Rg is methyl and the other is isopropyl, n-butyl, iso-butyl, cyclopentyl or iso-propoxyethyl and R3 is hydrogen or optionally substituted (C^_g)alkyl, I R 3 2045 36 either in optically active form v/hen R3 is hydrogen or in racemic or optically active form when is other than hydrogen^nd their acid addition salts hereinafter referred to as compounds of the invention.
The molecules of the compounds of formula I contain in position 4 of the 1,4-dihydropyridine ring a chiral carbon atom, due to the existence of the two different carboxylic acid ester groups COORj and COGR^. (C^_g)alkyl is, if substituted, preferably substituted by hydroxy, acetyloxy, methoxy, ethynyl, dimethyl-amir.o or morpholino. Preferred compounds are those, in which one of Rj and is methyl and the other is iso-propyl, especially those, in which additionally is (C^_g)alkyl or hydrogen,especially methyl or hydrogen,particularly methyl.
The present invention in another aspect provides a process for the production of a compound of the invention which includes the step of a) 1-N-alkylating a compound of formula la 204536 wherein and R^ are as defined above, b) exchanging the radical R^ in an optical isomer of a compound of formula II wherein R^ and are as defined above, and R^ is a leaving group by a radical OR^ wherein Rg is as defined above, and if the compound of formula I is basic, recovering it as such or in the form of an acid addition salt.
II 204536 The l-N-alkylated products of step a) may be prepared in conventional manner, using appropriate alkylating agents, for example an alkyl halide, preferably in the presence of a base e.g. sodium hydroxide. If the alkyl group is substituted and the substituent would react with the halide function, it is preferably protected and the protecting group is split off after the alkylation.
The l-N-alkylated products may be recovered in conventional manner.If the 1-N-alkyl groups contain a salt forming group, such as the dimethylamino- or the morpholino group,the l-N-alkylated products can be obtained as acid addition salts,e.g. as salts with organic acids,such as fuir.aric acid,or with inorganic acids,e.g.hydrohalic acids,such as HC1.The starting compounds in step a) are known or may be prepared by methods known per se from known compounds.The starting compounds in step a) can be prepared analogously to step b), insofar as they are optically active.
The products of step b) may also be prepared in conventional manner,using for example starting compounds of formula II in which R^.is a leaving group,e.g.OH or an azolide radical .Si:i table azolide radicals include the imidazolide radical are verv reactive and readily exchange the*v ozolyl part,e.g.the IH-imidazol-l-yl ,for an ester group,e.g.such of the type 0R2,for example by adding cn alcohol R^OH and reacting the components at an elevated temperature,e.g. 60-150°.
It is known that especially the azolide groups, such as —N 204536 Other suitable azolide radicals are e.g. the 1,2,3-triazolide, 1,2,4-triazolide, benzotriazclide, benzimidazolide and tetrazolide radicals.
The products of step b) may also be prepared in another conventional manner,by using starting compounds of formula II, wherein is a group ORg and R^ is a chiral, hydrocarbon radical substantially free from any of its epimeric form and containing one or more electron attracting groups or a hydrocarbon radical containing an amino group.
Preferred electron attracting groups include the phenyl group, the me-thoxy group or a quaternised amino group. Preferred amino groups are di(Cj ^Jalkylamino groups. Preferred quaternised amino groups are tri-(C.j ^)alkylamino groups. Preferred radicals R^ are ethyl radicals, substituted in B-position with the electron attracting groups or with the amino group, like the 2-(R)-CH30-2-phenyl-ethyl radical or the trimethylammonio-ethyl or the dimethyl amihoethyl radical The carboxylic acid ester group -C-O-R,. is, due to the presence 0 of electron attracting groups or of the amino group, easily convertible to a -c-O-Rp group for example by reaction with an alcohol R2OH, 0 preferably under basic conditions.The = OH and other compounds cf formula II may be reacted similarly.The final products can be isolated and purified by methods known per se; if desired and possible, in acid addition salt form.
Preferably in the optically active compounds II of step b) ,R^ is an azolide radical or such a group OR*,wherein R£ is a chiral hydrocarbon radical substantially free from any of its epimeric form and containing one or more electron attracting groups.
Representative starting compounds II can be prepared as indiceted by the follow'ng reaction schemes I and II, illustrating how two optically active forms lib.1.1 and lib.1.2.can be obtained by way cf a chromatographic separation or selective crystallisation respectively.
} C- C- ,9 CO Reaction Scheme i for the production of compounds ii , wherein r, = isopropy1., r. = or*, r, 9_/Di_ru ri_?_r,^«rtwi«fv>>,i ' ^ 3 H and 2-(R)-CH^O-2-phsny1 ethyl v ^n\ 0 ^ °" rr + li 11 H2it/\ VI 0-(ch2) -cn -»+f henyl u2H "CH2 och3 VIII A nh. -cm * ^ Dhenyl ' S^H 0ch„ °"^CH2^2~CN ^ \ <- T\< Q + phenyl nd-ch--/ . 2j'-H och3 chromatography ^(-)-(45) lib. 1.1 IV 1 >-0 /> III * Reaction Scheme II for the production of compounds II , wherein R-j = isopropy!, = 1-H-imidazol-l-yl andR^ = H o-(ch2)2-n /\ ' 0 VII + h2n- -(ch2)2-nc NH. o-(ch2)2-n^ 0^ C. > s s £o N/ i ^ »C . hi -(ch2)2-^ h r* © R-h= Di-0-0'-p-toluoyl-(R)resp. (L)-tartaric acid (+)-(4r) crystallisation ^(-)-(4S) lib.1.2 \x NaOH 3-oimethylaminoethylester (+)-(4R) | CH3I (-)-(4S) XI 3-Trimethyl amnion ioethyl ester (+)-(«) NaOH H--(4S) XII 3-Carboxylic acid compounds (-)-(4R) I (+H4S) XIII 3-(1H -Imidazol-l-ylcarbonyl) compounds (+)-(4R) H-(4S) lib.1.3 I I IO s 8 www**- ( 204 J o Whereas the optically active compounds lib.1.1 of reaction scheme 1 are directly prepared by chromatographic separation of the corresponding diastereoisomeric ester mixture, the optically active compounds I lb. 1.3 of reaction scheme II originate from a diastereo-isomeric salt mixture lib.1.2, the components of which can be separated by selective crystallisation.
Crystallisation is a more preferred separation method than chromatography, when carried out on an industrial scale.
After the separation the same working principle is applied to the compounds Jib.1.1 ana lib.1.2 to obtain finally compounds of formula I.
Both, the chiral ester group of the compounds I lb.1.1 and the prctonated dimethyl aminoethyl ester groups of the compounds lib.1.2 maybe converted into an ester group OR^,however in reaction scheme II in an indirect way which is a more preferred mode of production.
Although it is in principle possible to produce starting from compounds I lb. 1.2 or,more preferably from compounds XI4the final compounds I immediately by transesterification, a more preferred route is to create (via compounds XI) a stronger electron attracting group by quaternisation (compounds XII), thus making possible a second salt crystallisation and purification.
Like the compounds lib.1.2, those of type XII can be transesteri-fied immediately into compounds of formula I. However, it is possible to hydrolyse the ester group and to convert the 3-carbo-xylic acid compounds (compounds XIII) either directly or via the 3-azolide compounds lib.1.3. into the final compounds I, 2 04C 3 6 reactions which can be carried out in conventional manner and allow the preparation of the compounds of formula I in both a good yield and a very pure state.
The invention is illustrated by the following Examples, which also describe the production of the intermediate compounds indicated in the reaction schemes 1 and II. 2045 36 Example 1: 4-(2,l,3-benzoxadiazol-4-yl)-1,4-dihydrO"5-methoxy-carbonyl-1,2,6-triniethyl-3-pyridine carboxylic acid isopropy!ester (I, Racemate process step a)) 1.5 g of solid pulverised potassium hydroxide and 0.84 ml of methyl iodide are added in a nitrogen atmosphere to a solution of 2.5 g of 4-(2,1,3-ber.zoxadiazol-4-yl )-l ,4-dihydro-5-methoxyccrbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester in 40 ml of dimethylsulphoxide. The mixture is stirred at room temperature. After 1 1/2 hours the mixture is poured into ice water and extracted with methylene chloride. The methylene chloride solution is dried with magnesium sulphate and evaporated in vacuo.
The title compound is purified by chromatography on silica gel, using methylene chloride as an eluant and is crystallised in a mixture of ether and petrolether. M.P. 125°.
Example 2: (-)-( S)- and ( + )-(R)~4~C2,l,3-benzoxadiazol-4-yl)-l,4-dihydro-5-met.hoxycarboriyl-l,2,6-trimethyl -3-pyridine carboxylic acid isopropylester (I, Antipodes). a) (+l:(?l::_dG2_l:)i(§ii4:[2,l,3-Berizox3diazoi;;4-yl);:l^4-dihydro-Ij-iSQElIQBQXYcarbonYl-^^-dimethyl-3-gyri di ne carboxylic acid-(2;[R]in)§thQxy-2-phenylethyl]ester [(+) lib.1.1 and (-) lib.1.1]. 1) A solution of 10.5 g of 4-(2,1,3-benzoxadiazol-4-yl }-l ,4-dihydro- 5-(1H-i mi dazo1 -1-y1 carbony 1) - 2,6-di methyl -3-pyridine carboxylic acid isopropylester (III) in 35.0 g of (R)-2-msthoxy-2-uhenyletnanol [prepared according to W. Kirmseet al.} Chem.Ber. 108, 7S (1975)] is heated 7 hours \ f _ . . .. _K . 2045 3 at 120°. The excess of the optically active alcohol is distilled off in high vacuum at 50-110°. The residue is dissolved in methylene chloride and the solution is washed with cold 2N hydrochloric acid, dried and evaporated to dryness _in vacuo. 2) A solution of 3.5 g of 2-acetyl-3-(2,l,3-benzoxadiazo1-4-yl)-2-propenic acid isopropylester (VII) [(Z) or (E) or a mixture of (Z) and (E) isomers] and 3.0 g 3-amino-crotonic acid (2-(R)-methoxy-2-phenylethyl )ester (VI11) in 100 ml of dioxanp is heated for 20 hours at reflux temperature and evaporated to dryness jin vacuo.
The diastereoisoneric mixture obtained according to 1) or 2) is separated by chromatography on silica gel at 5 atm. with hexane-ether (1,5:1) as the eluant.
The first compound cluted is crystallised from ethylacetate-hexane , M.P. 89C»fft^5°5 = _92° (in ethanol).
The second compound eluted is crystallised from ether-hexane or methanol-water. M.P. 127°, [oc]g^. = +77° (in ethanol). b) i+);{S}^/r-{2,]i32ben20xadia2ol;4-ylJ;lJ4;djhydro;5^riethoxy-_ ?§^§r f *a> antipods, reaction step b)] 5.3 g (-)-(S)-4-(2,1,3-benzoxadiu2ol-4-yl)-l,4-dihydro-5- I 20453 isopropoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid- (2-(R)-methoxy-2-phenylethylJester [lib.1.1 (-)] in a solution of 0.3 g sodium in 100 ml methanol are heated for 50 hours at reflux temperature under a nitrogen atmosphere.
The volume of the solution is reduced 50% in vacuc and 100 ml of ice water are added. The mixture is extracted with methylene chloride. The methylene chloride solution is dried with magnesium sulphate and evaporated in vacuo. The residue is purified by chromatography on silica gel at low pressure (flash) Hexane-other (1:4) is used as an eluant. M.p. of the pure ( + )-(4S)-eriantionser [(Ia)-( + )] after crystallisation from ether- hexane: 142°. [a]^6 = +9»9° (ethanol, c - 1,5 g/dl). - +6,7° (ethanol, c = 1,5 g/dl). c) J^benzcxadiazol-^yl}-]. >4-dihydro2§-methoxy-_ £3rb9D)f]:l2?25l£rI[:l®i!}yIl32!?yrid2!]§_!:§Ll?2*£llc..§£1'd_isoprogyI-ester [I, antipode, reaction step a)] To a solution of 0.7 g (+)-(4S)-(2,l,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxy-lic acid isopropylester in 10 ml dimethyl-sulphoxide are added 0.43 g pulverised potassium hydroxide. After addition of 0.23 ml methyl iodide the mixture is stirred 1 hour under nitrogen.
Then the mixture is poured into ice water and extracted with methylene chloride. The methylene chloride solution is dried with magnesium sulphate and evaporated in vacuo. The residue is purified by chromatography on silica gel at low pressure (flash). Methylene chloride-ether (49:1) was used as an eluant m 2C453 The title compound was crystallised from ether-hexane. M.p. 92°. [crtj^g = -3°jfethanol, c = 0,67 g/dl),£^545 = "25°» (chloroforiTi, c = "1,0 g/dl). d) (il:{^iiii2jl23;benzoxadiazol34-yl}-1,4-dihydro;^methoxy- Siir^Uyll^^zdill^^ll^pyridine^arboxyl ic_acid 252Ei22^~ ester [ la, antipode, reaction step b)] This compound is prepared from the enantiomer (+)-(4R) under a) in a manner analogous to that described in b). M.p. 140° (crystallised in ether-hexane). = -10,1° (ethanol, c = 1,67 g/dlj. [a]*°= _6j7° (ethanol, c » 1,67 g/dl). e) £+}-(5H^2,li^benzoxadiazol^^yl};]^I^i hydro; 5^methoxy-£2r!?2Py2l]i?2§I^rl!P?£hy2;3;;pyridine_carboxyl ic_acid_isopropv}; ester [I, antipode, reaction step a)] This compound is prepared from the enantiomer (-)-(4R) under d) in a manner analogous to that described in c). M.p. 93° (crystallised in ether-hexane). [a]gj6 = +3.1° (ethanol, c =0,83 g/dl). [a]^g = + 23° (chloroform, c = 1,1 g/dl) The imidazolide (III), used in a)l) has a m.p. 166° and is prepared from 4-(2,l,3-benzoxadiazol-4-yl)-l,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid (IV), which is reacted with a small excess of 1,1'-carbonyldiimidazole at in dicxane. 204536 The acid (IV) has a m.p. 213° and is obtained from 4-(2,l,3-benzoxadiazol -4-yl)-l,4-dihydro-5-isopropoxycarbonyl-2,6-di-methyl-3-pyridine carboxylic acid -(2-cyanoethylJester (V) which is hydrolysed at room temperature with 3 mol NaOH in water-1,2-dimethcxyethane (2:1).
The ester (V) m.p. 125° is prepared by reaction of the amino-crotonic-acid-(2-cyanoethyl)ester (VI) with 2-acetyl-3-(2,l,3-benzoxadiazol-4-yl)-2-propenic acid isopropylester (VII) in dioxane.
The ester (VI), m.p. 88°, is obtained from the corresponding acetoacetic acid-(2-cyanoethyl)ester by reaction in benzene solution with gaseous ammonia, The ester (VII) is obtained by condensation of 2,1,3-benzoxa-diazol-4-aldehyds with the corresponding acetoacetic acid ester in boiling benzene in the presence of catalytic amounts of piperidine and acctic acid.
The ester (VII) crystallises as a mixture and can be separated into the E-isomer, m.p. 75° and the Z-isomer, m.p. 55°. 204536 Example 3: (+)-(S)-4-(2,l .3-benzoxadiazol-''>-yl )-l ,4-dihyriro- S-methoxycarbonyl-2,6-dimeth\'l-3-pyridi ne carboxylic acid isopropylester (I) [I,reaction step b)] a) 1 _j3;benzox3dia2ol;4;Y]};l24;dihvdro;5;isogrogoxycarbonyl; 2 »6-dimethylcc!T^2x^2l£_^£:3?-dimeaminoeth^l]- estcr_£IX) a.1 5.0 g of 4-(2,l ,3-benzoxadiazol-4-yl)-l>4-dihydro-5-(1H -imidazol-l-ylcarboriyl)-2,6-dimethyl-3-pyridine carboxylic acid isopropylester (111) and 24.5 ml of 10 2-dimethylanu'noethanol in 20 ml of riioxane are heated hours to boiling temperature. The mixture is extracted with ice water and ethyl acetate. The organic phase is dried with magnesium sulphate, evaporated to dryness -in vacuo and the residue is purified by chromatography 15 on silica gel. Methylenechloride-ether (4:1) is used as an eluant. The hydrochloride salt of the product is crystallised from ethanol-ether. M.p. 150°. a.2 182.6 g of 2-acetyl-3-(2,l,3-benzoxadiazol-4-yl)-2-propenic acid isopropylester (VII) (Z,E-isomer mixture) and 114.7 g 20 of 3-aminocrotonic acid-(2-dimcthylaminoethyl)ester in 1 1 of dioxane are heated 16 hours to boiling temperature. The mixture is evaporated to dryness in vacuo, the residue is converted into the hydrochloride salt and crystallised from ethanol-ether. 2 045 3 6 - 16 b) 1 j3;bonzoxadiazol;4;vl};1 hydro;5;i?ogropoxy- £^1^20^11 §i __ ~ aminoethyl}ester_£XI] 52.6 g of the title compound under a) (IX) and 49.6 g of 5 (-)-di-0,0'-p-toluoyl-(L)-tartaric acid dissolved in 200 ml of hot isopropanol and allowed to stand. The di-G,0'-p-toluoyl-(L)-tartaric acid salt (X) is formed . After cooling to room temperature the formed crystals are filtered and recrystallised twice from isopropanol.The product, the di-0,O'-p-toluoyl-(L)-tartaric acid salt, is dried in high vacuum at 90°. M.p. 146°, [«Jn = -122° (ethanol, ?fi c = 1 g/dl), [<0545 = -156° (ethanol, c = 1 g/dl). The salt is converted into the title compound (XI) by addition of diluted sodium hydroxide and is extracted with ether. It is an ?n ?n oily substance, [a]p = -45° (ethanol, c = 1 g/dl), [01^45 " -58° (ethanol, c = 1 g/dl). c) {;}:lSH-{2J1^3:benzpxadiazol:4;vl);]i4:dih^dro::5;iso9ro9ox^: ca rbony 1 - 2,6-d_i methyl-3-pyridine carboxylic acid-£2-triiT«3thyl- amnionioethvUester-^iodi de_(Xl I) 12.4 g of the title compound under b) (XI) are dissolved in 120 ml of methanol. After adding 2.34 ml of methyl iodide,the solution is allowed to stand 15 hours at room teniae ratu re.
The formed crystals are filtered and recrystal1ised from methanol-ether. M.p. 222°, Ta]^0 = -75° . (ethanol, c = 1 g/dl) Ca:!546 = (ethanol> c = 1 S/dl).
J 2 045 3 6 d) j3;benzoxadiazoi;i^]);i j^dihydrg^s^isoprogox^-cjirkpDylifL'^idi^sthyi^pYridiRe^arboxyii^a^^ A solution of 15 g of the iodo methyl ate under c.) (XII) in 150 ml of dioxane and 300 nil 2n aqueous sodium hydroxide is allowed to stand 16 hours at room temperature. While stirring and cooling,the solution is acidified by dropv/ise addition of concentrated hydrochloric acid. After stirring 30 minutes in an ice oath, the formed crystals are filtered, washed with ice water and dried in high vacuum at 80°.
M.p. 163°, [a]p° = +17° (ethanol, c = 1 g/dl), Ca]^6 = (ethanol, c = 1 g/dl). e) i;];^)_".^ri2,l23;benzoxadia2ol;4;^l];]J4;dihvdro;5[lH ^imidazol; 1 -yl carbonyl ^ :2_,5-d inie th^l~ 3-gy r\di rie_ carboxj^l i c^aci d_i sogrog^l-S'§ter £I lb. 1. 3}__ A mixture of 8.6 g of the acid under d) (XIII) and 9.75 g of 1,1'-carbonyldiimidazole in 190 ml of dioxane are stirred 2 hours at 50° bath temperature. The solution is evaporated to dryness in vacuo and the residue is purified by chromatography on silica gel under slight pressure, using methylene chloride-20 ethanol (19:1) as an eluant. The product is crystallised from methylene chloride-ether.
M.p. 182°, [ajp° = -50° (ethanol, c = 1 g/dl). ^546 = "*71° (ethano1» c = 1 g/dl) - 2 0453 f) itizi^ltt^li^benzoxadiazol^yl];! ,4-dihvdro-5 -rnethox^-ester (I) A solution of 5 g of the imidazolide under s) (II b.1.3) in 50 ml of methanol is heated 16 hours at reflux temperature and is evaporated to dryness in vacuo. The residue is purified by chromatography on silica gel under slight pressure, using hexane-ether (1:3) as the eluant.
The product is crystallised from ether-hexane. M.p. 141°, [a]*0 = +8° (ethanol, c = 1 g/dl), CcO^jg = +12° (ethanol, c = 1 g/dl). 204536 - 19 - IUU SU4I In an analogous manner as described in Example 1 the following compounds are prepared. The starting compounds are known or may be prepared by methods known per se from known compounds: Example 9 11 12 13 14 1 CH, CH.
CH, CH.
CH.
CH.
R.
Racemate or anti pcde 4 CH^ n-butyl CHj11 + M.p. 117° ch3 i-butyl chj1' + M.p. 133° C ch3 eye1opentyl CHj1' + M.p. 143° 7 ch3 -(CH2)2-0-i-propyl CH + M.p. 136° 8 ch3 i-propyl (c!!2)2-0h2) + oil i-propyl i-propyl i-propyl i-propyl i-propyl i-propyl 0 !l -(CH2)2-0-C-CH3 -(CH2)2-0-CH3 3} 4) -CH2-csch5^ CH,, -(CH ) > 3 6) 7) -(CH2)2-N v_/ CH 8) CH. + oi 1 + M.p. 106c + M.p. 100c M.p. 179° (hydrogenfumarate) M.p. 162° (hydrogenfumarate) M.p. 92° [a^°-+15o,Ca^°5=+20c (methanol,c=l g/dl) HBr-salt: M.p.243° (methanol,c=0,6 g/dl) 204536 1IMJ LJJ I Example n-| Racemate or Antipode CH. i-propyl rH 9) (CH2)2-N^'M3 CH.
M.p. 92° [O]g°-)5«,[«]|S6=-20- (methanol, c=l g/dl) HBr-salt: M.p.243° (methanol, c=0,6 g/dl) I •>,« ! 2) alkylation with CH^ I alkylation with Br-(CH2)2~0- 3) 4) ) and ether splitting with HC1 from the compound of Example 8 by reaction with acetanhydride alkylation with I-(CH^-O-CH^ 6) alkylation with Br-CI^-CSCH alkylation with CI-(CH^-N- (CH^)^ 7\ A~\ ^alkylation with ^^(CH^)^-^^ p 8) alkylation of the compound of Example 3f according to Example 12 9) " If II II 2d " 20453 The compounds of the invention possess pharmacological activi ty.
The compounds exhibit effects typical of calcium antagonists.
They exhibit a pronounced muscle-relaxing effect, particularly on smooth muscle, as indicated by vasodilating and blood pressure lowering activity in standard tests. For example in the anaesthetized cat test using tracer microspheres (R. Hof et al., Basic Res.Cardiol. Z5 [1980] 747-756 and 76 [1981] 630-638", R. Hof et al. , J .Cardiovasc. Pharmacol. 4_ [19823 352-362) coronary vasodilation is observed upon administration of from about 5 to about 200 /ug/kg i.v. or from about 5 to about 400 /ug/kg i.d. of l-N-alkylated compounds of formula I and from about 5 to about 50 /ig/kg i.v. cr from about 10 to about 200 /ug/kg i.d. of compounds ir. which = H and a fall in blood pressure is observed upon administration of from about 5 to about 250^ug/kg i.v. for l-N-alkylated compounds and from about 5 to about 50 /ug/kg i.v. for compounds in which R. = H.
A fall in blood pressure is also observed in the conscious spontaneously hypertensive rat (method of Ceroid and Tschirki, Arzneimittelforsch. 18_[1968] 1285) upon administration of from about 0.1 to about 50 /ug/kg s.c. of the l-N-alkylated compounds and of about 0.1 to about 10 mg/kg s.c. of the compounds in which R^ = H. 2 045 3 6 The compounds are therefore indicated for use as calcium antagonists for the prevention and treatment of - coronary insufficiency, e.g. Angina pectoris", - cerebrovascular insufficiency, such as cerebrovascular insults, e.g. stroke, and cerebrovascul ar spasms', - disturbances in peripheral circulation e.g. in limbs such as intermittent claudication and spasms, e.g. colic! - asthma, e.g. exertion-related asthma', and - hypertension.
An indicated daily dose is from about 5 to about 400 mg for l-N-alkylated compounds and from about 5 mg to about 200 mg for compounds in which = H, suitably administered, e.g. orally, in divided dosages of from about 1.25 mg to about 200 mg of the l-N-alkylated compounds and from about 1.25 mg to about 100 mg of the compounds in which = H, two to four times daily, or in retard form. An example of a daily dosage is from about 5 mg to about 200 mg, preferably from about 10 to about 50 mg of the compound of Example 2c.
Preferred are the title compounds of Examples 2b and 2c.
The compound of formula I which are l-N-alkylated,especially the compound of Example 2c, have, when i.v. administered, an advantageous slow onset and longer duration of activity, compared with intraduodenal administration.
They are approximately equipotent when administered i.d.oti.v.

Claims (37)

2W536 The slow onset and long duration of the activity render these substances, due to less side effects, safer than other 1,4-dihydro-pyridines for intravenous use. The compounds with S-configuration, e.g. the compounds of Examples 2b and 2c have, related to their activity a better pharmacological profile than the corresponding R- and the racemic forms. The compounds of the invention are administered in free form or if possible and appropriate, in pharmaceutical^ acceptable acid addition salt form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of the invention in free form or where possible and appropriate in pharmaceutical^ acceptable salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet. 20453 6 _ 24 - Hwy" 'jl.U-1 WHAT AlWE CLAIM IS:
1. A process for the production of a compound of formula I wherein one of and is methyl and the other is isopropyl, n-butyl, iso-butyl, cyclopentyl or iso-propoxyethyl and Rj is hydrogen or optionally substituted (C^ g)alkyl either in optically active form when R^ is hydrogen or in racemic or optically active form when is other than hydrogen, ar.d their acid addition salts, which includes the step of a) 1-N-alkylating a compound of formula la 20453 - 25 - wherein R^ and R2 are as defined above or b) exchanging the radical in an optical isomer of a compound of formula II RjOOC \ ^-COR ^ 'J H,C ^ I R \ 'CH. II wherein R^ and R^ are as defined above, and R^ is a leaving group, by a radical OR^, wherein R^ is as defined above, and if the compound of formula I is basic, recovering it as such or in the form of an acid addition salt.
2. A process of claim 1,defined in step b),in which the compound of formula II has a substituent R^ which is an azolide radical or a group 0R| wherein RjS is a chiral .hydrocarbon radical substantially free from any of its epimeric form and containing one or more electron attracting groups.
3.A process of claim 2 in which the compound of formula II = OR* and R, is methyl or isoprcpyl.;0 I;- 26 -;304536;v * t
4. A process for the production of a compound of formula I or its acid addition salts defined in claim 1 substantially as hereinbefore described with reference to any one of the Examples.
5. A compound of formula I and its addition salts,whenever produced by a process of claim 1.
6. A compound of formula I and its addition salts as defined in claim 1.
7. A compound of claim 6 wherein one of R-j and is methyl and the other is isoprcpyl.
8. A compound of claim 7, wherein R^ is (f^_g)alkyl.
9. A compound of claim 7, wherein R^ is methyl.
10. A compound of claim 7, wherein R^ is hydrogen.
11. 4-(2.1,3-ben?oxadiazol~4-yl )-l ,4-dihydro-5-methoxy-carbcnyl-1,2,6-trimethyl-3-pyridine carboxylic acid isopropylester.
12. (-)-(S)-4-(2,l>3-benzoxadiazol-4-yl)-l,4-dihydro-5-methaxy-carbonyl-1,2,6-trimethyl-3-pyridine carboxylic acid isopropylester.
13. (+)-(R)-4-(2,l ,3-ben20xadiaz0l-4-yl)-l ,4-rfihydro-5-methoxy-carbonyl-l,2,6-triniethyl-3-pyridine carboxylic acid isopropylester.
14. (•i-)-(S)-4-(2,1,3-beniox?.diazol-4-yl )-l ,4-dihydro-5-methoxy-carbonyl-2,6-diniethyl-3-pyridine carboxylic acid isopropylester. 20453 _ 27 - 'JUU-WJ <
15. (-)-(R)-4-(2,l,3-benzoxadiazol-4-yl)-l,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester.
16. 4-(2,1,3-benzoxadiazol-4-yl)-l,4-dihydro-5-methoxy-carbonyl-1,2,6-trimethyl-3-pyridir,e carboxylic acid n-butylester.
17. 4-(2»1>3-benzoxadiazol-4-yl)-l,4-dihydro-5-methoxy-carbonyl-1,2,6-trime thy1-3-pyridine carboxylic acid isobutylester.
18. 4-(2,1,3-benzoxadiazol-4-yl )-l,4-dihydro-5-methoxy-carbonyl-1,2,6-trimethyl-3-pyridine carboxylic acid cyclopentyl-ester.
15. 4-(2,l ,3-berizoxadiazol-4-yl )-l ,4-dihydro-5-methoxy- carbonyl-1,2,6-trimethy1-3-pyridine carboxylic ccid-2-isopropoxy-ethyTester.
20. 4-(2,l,3-bsn20xadia2ol-4-yl )-l ,4-dihydro-l-(2-hydroxyethyl)-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester.
21. l-(2-acetoxyethyl)-4-(2,l ,3-benzoxadiazol-4-yl)-l,4-dihydro-5-methoxycarbony1-2,6-dimethyl-3-pyridine carboxylic acid isopropylester.
22. 4-(2,l,3-benzoxadiazol-4-yl)-l,4-dihydro-5-methoxy-carbonyl -1 - (2-methoxyethyl)-2,6-dimethyl --3-pyri di ne carboxyl ic acid isopropylester. - 28 - 204536 I UIM J JJ- J
23. <-(2,1,3-benzoxadia2ol-4-yl)-l,4-dihydro-5- methoxycarbonyl-2,6-dimethyl-l-(?-propinyl)-3-pyridine carboxylic acid isopropylester.
24. 4- (2,1,3-benzoxadiazo!-4-yl) -1 - (2-d i niethy 1 ami no-ethyl)- 1,4-di hydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester and its acid addition salts.
25. 4-(2,1,3-benzoxadiazol-4-yl)-l,4-dihydro-5-methoxy carbonyl-2,6-dimethyl-l-[2-(4-morpholinyl)ethyl]-3-pyridine carboxylic acid isopropylester and its scid addition salts.
26. (+)-(S)-4-(2,1 ,3-benzoxadia:?ol-4-yl )-l-(2-dimethyl-aminoethyl)-l,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester and its acid addition salts.
27. (-)-(R)-4-(2»1,3-benzoxadiazol-4-yl)-l-(2-dimethyl-aminoethyl)-l,4-dihydro-5-methoxycarbonyl-2,6-aimethyl-3-pyridine carboxylic acid isopropylester and its acid addition salts.
28. A compound of formula II, as defined in claim 1.
29. A compound of formula II, as defined in claim 3.
30. (-)-($)-4-(2,1,3-benzoxadiazol-4-yl)-l.4-dihydros' i sopropoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid-(2-(R)-niethoxy-2-phonylethyl )ester. 204536 r
31. (+)-(R)-4-(2,l,3-benzoxadiazol-4-yl)-l,4-dihydro-5-isopropoxycarbony1-2,6-dimethyl-3-pyridine carboxylic acid-(2-(R)-methoxy-2-phenylethyl)ester.
32. 4-(2,1,3-benzoxadiazol-4-yl)-l,4-dihydro-5-(1H -iraidazol-1-ylcarbony1)-2,6-dimethyl-3-pyri di ne carboxyli c aci d isopropylester.
33. (-)-(S)-4-(2,l,3-benzoxadiazol-4-yl)-l,4-dihydro-5-(1H -imidazol-l-ylcarbonyl)-2,5-dimethyl-3-pyridine carboxylic acid isopropylester.
34. ( + )-(R)-4-(2,l ,3-benzoxadiazol-4-yl )-l ,4-dinydro-5-(1H -imidazol-l-ylcarfcenyl)-2,6-dimethyl-3-pyridine carboxyl ic acid isopropyl ester.
35. A compound of any one of claims 5 to 27 for use as a pharmaceutical.
36. A compound of any one of claims 5 to 27 f0r use -in the treatment of coronary insufficiency, cerebrovascular insufficiency, peripheral circulation disturbances, hypertension or asthma.
37. A pharmaceutical composition, which comprises a compound of any one of claims 5 to 27.in association with a pharmaceutical carrier or diluent. 'AT^ -II .IC? pAvOF " - ; AS
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