CA2058641A1

CA2058641A1 - Dihydropyridine amides, processes for their preparation, and their use in medicaments

Info

Publication number: CA2058641A1
Application number: CA002058641A
Authority: CA
Inventors: Juergen Stoltefuss; Claudia Hirth-Dietrich; Johannes-Peter Stasch; Dieter Neuser
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1991-01-04
Filing date: 1991-12-31
Publication date: 1992-07-05
Also published as: DE4100125A1; EP0493782A3; EP0493782A2; JPH04308575A

Abstract

ABSTRACT OF THE DISCLOSURE
Disclosed are new dihydropyridine amides of the general formula I

Description

The present nvention relates to new dihydropyridine amides, processe~ for their preparation, and their use in medicament~, in particular their use as medicaments which act on the circula~ion.

I~ ha~ already b~en disclo8ed th~t 3-aminocarbonyl-1,4-dihydropyridine-5~carboxylic acid ester derivatives have an antiarrhythmic and anti-hyperten~ive action ~cf. J
01075-467-~ and European Patent 288,758 A2].
Dihydropyridine amides which act on the circulation are lQ described in German Offenlesungs chrift 2,228,377 and also in EP-A-220,653.

It is ~lso known that the polypeptide hormone ANP (atrial natriuretic peptide) can i.nduce diuresi~, natriure~is and vasorelaxatio~ [cf. Nature ~38~ 78-83, 1989; Biochem. J.
~32, 313-321 (1985)]. This ef~ect i8 cau~ed by cyclic guanosine monopho~phate (cGNP), whose excxetion via the kidneys represen~ a ~peci~i~ marker ~or ~he aa~ivation of the ANP ystem. ~. Europ. J. Pharmacol. ~
165-168, 1986 and Am. J. Phy~iol. ~ F1220-F122~, 1988~.

20 Th~ pre~ent in~ention now relake~ to now dlhy~r~pyridlne amid~ o~ ~ho gonor~l ~ormula (I) J!~aO2C~CO ~ NHP~3 : H

Le A 27 962 - 1 -.

~b~

in which Rl - represents straight-chain or branched alkyl which has up to 6 carbon atoms ~nd which is optionally substituted by phenoxy or cyclohexyl~ or - represents hydrogen or trifluoromethyl, R2 _ represents straight-chain or branch~d alkyl which ha~ up to 4 carbon atom~ and which i~ optionally substituted by cyano, hydroxyl or acetoxy, R3 - represent~ ~traight-chain or branched alkyl having up to 5 carbon atoms, or . - represents cycloalkyl havin~-3 ~o 5 carbon a~oms.

- The compounds according to the invention exist in ~he form of sterQoisomers which either behave as image ~nd mirror image tenantiomers~ or which do not behave as image and mirror image ~diastereomer~. The invention relates to the antipodes as well as the racemic forms and also the dia tereomer mixtures. The racemic ~orm~ as well a~ the dia~t~reomer3 may be re~olved in ~ known mannor to give the ~tereo~omerically uni~orm aom~onenk~
~Gf. E.~. ~liel, Stereo~hemi~try o~ Carbon Compound~, ~cGraw Hill, 1962).

Pro~0xred ~ompound~ o~ th~ goneral ~ormula (I~ are tho~e in which Le A 27 962 - 2 -, Rl - repre~ent~ straight-chain or branched alkyl which has up to 4 carbon atom~ and which i3 optionally substituted by pheno~y or cyclohe~yl, or - represents hydrogen or trifluoromethyl, R2 _ represents straight~chain or branched alkyl which ha~ up to 3 carbon atoms and which i9 optionally ~ub~tituted by cyano, hydro~yl er acetoxy, R3 ~ repre~ent~ 3traight-ch~in or branched alkyl having up to 4 carbon atom~, or ~ lO ~ - repre ents cyclopFopyl or cyc;lopentyl.

: Particularly preferred compounds of the general formula I) are those in which : :
Rl - represent3 straigh~-chain or branched alkyl which has up to 4 carbon atoms and which is optionally substituted by cyclohexyl or phenoxy, or : - repr~sent~ hydrogen or trlfluorome~hyl, R2 _ repre~n~ m~thyl, 0~hyl or propyl, R3 - repr~o~nts methyl, ethyl, propyl~ i~opropyl, cyclopropyl or cyclepentyl.

~ In addikion, proce~ses for the preparation of ~he com-: pound~ ~ccording to the invention of the general formula ::

~L~L~LZ~ 3 -~ 3~/1ç~

(I) were found, which procesaea are characteri~ed in khat [A] aldehydes of the general formula (II) 1 (I~3 C~O
in which S R1 is as defined above, are reacted~either with ~-ketocarboxylic acid esters of the general formula~(III) R20 2C~
(III~
3 '~
in which 0 R2 i8 ~8 deined above, and ~-ketocarboxamidee o~? the general ~rmula (IV) ONHR~
(IV) i~ which ~ ~3 i ~ a- detined abovo, :
?

~'' ~'' ' and ammonia, or the compounds of the ~eneral formulae (II) and (III) are reacted directly with enaminocarboxamides of the general formula (V) ,¢~oNHR3 (V) in which R3 is a~ defined above, if appropriate in the presence of an inert solvent, or compounds of the general formula (VI) ~OR 1 F1200t::~H
I (VI) H3C~o ln whiah R1 and R2 are as defined above are prepared first a~ intermediatas and then reacted Le A 27 962 - 5 _ with compound~ o~ the goneral foxmula (V) or EB~ ylidene-~-ketocarboxamides of khe general formula (VII) ~E:tl ' H~CoNHR3 ~ H3 (VII) .
in which Rl and R3 are a~ defined above, are prepared first and reacted with compounds of the general formula (VIII), ~202C~
H3C ~ NHz ~VIII) in which RZ :Ls ~ de~in~d aJ~ove, in inert ~olvents, or Le A 2?~9~2 - 6 --. ., ' ~ ,~' ; .
, ~:: . . .
'. - : ' , " ' :

~C] dlhydropyridinemonocaxboxylic aaid~ o~ the gener~l formula (IX) R202C~OOH
H (IX) in which R' and R2 are ~ deflned above, are reacted, if appropriate via a reactive acid deri~ative, wlth amlnes o~ tho general formula (X) ~I2N-R3 (X) in which R3 i~ as de~ined above, 1~ ~ppropri~te in the ~re~ena~ o~ an inerk organi~
~olv~

The proce~es accordin~ to the invention can be illus~ra-ted by way o~ exampl~ by the following aquation:

.

LI~ Z-25~ - 7 -t A ~
H3COZC ~CO-NHCH3 OCF3 t `1 ~ ~ NH3 H 3 C--~o o~~C H 3 CHO

~CF3 H3C02C~CCO-NH-CH3 tB]

[~0- ( t:H2 ) 3-(~ H3C02C
H~C O - NH <¦ --~
H ~C~NH2 o~CH3 CH~ ) 3-~
H3C02C~O-NH~
~3C N H3 lC~ ~
~ Cf~2{>
H3GOOC~OOH
~3C H3 ~N 1 I NJ

L~3 A 2 7 9 6 2 - 8 -.
,, , . , .. . , ~ ,, . : , .' , - ' : . ' ' ' :

,: .

.J J; .i, ~ J ; .~.

~o-CH2{~
f5N

H3COOC~O-N~5 H3C H~
H

H2N -C~H5 ~o-cHz-c6Hl 1 H3COOC~O-NH-C2H5 H3C H H~

Proces~ variants A and B

Suitable ~,olvents are water or all inert organic 301vent~
which do not undergo change~ under the rea~ion condi~
tions. r~hese preferahly inalude alcohols 0uch a~
mekhanol, ethanQl, propanol, i~opropanol, ethora ~uch a0 di~th~l 0th~r, dioxano, tet.rahydro~uran, qly~r~ol mono-m~thyl ether or glyaol dimethyl 2ther, or ,~mide~ such as dimethyl~ormamide, dimethylacet,~mide or hex,~methylphos phoric ~riamide, or glacial ace~ic acid, dimethyl ~ul-phoxide, acetonitrile or pyridine.

e~A 27 962 - 9 _ .

The reaction temperature~ can be varied withln a sub~ta~-tial range. In general, th~ proces~ is carried out b~tween +10C and +150C, preferably between +20C and +100C, in particular at the boiling point of the solvent S in que~tion.

The reaction can be carried out under atmo~pheric pxe~
sure, bu~ also under increa~ed or reduced pres~ure. I~
iæ ganerally carried out under atmospheric pres6ure.

When carrying out process variant.~ A and B according to the invention, the ~ubstance involved in the reac~ion can be used in any dQsired ratio. In general, however, the reactant~ are used in molar amounts. The ~ubstances according to the invention are preferably isolated and purified in such a manner that the solvent i8 distilled off in vacuo and the residue, which may be obtained in cry~talline ~orm aft~r ice-cooling, i~ recrystalli ed from a fiuitable golvent. In some ca~es, purification of the compound~ acaording to the in~ention may have to be carried out by mean~ o~ chromatography.

The aldehyde~ o the general o~nula ( II ~, whleh a~e employed a~ ~kar~ing ~ub~kanG~, are lcnown or can bo pre~?~r~d by known method~ ~G~rman O~enlegunS~chri~t 2,165,260; 2,401,66g; T.D. ~rri~, ~;.P. }~oth, ~J. Org.
Ch~am. ~, 2004 (1979); W.J. Dale, ~.E. Henni~, J. Arn.
Chem. Soc. ~,2543(1956); Chem. ~bstr. ~, 13929 (1963)~.

The ~-ketocarboxylic acld esters of the general formula Le A 27~ 962 - 10 -', ~
'-.

~ 3;~.~. 3.

(III), which are employed as s~arting sub~tancas, are known or can be prepared by known methods ~D. Borrmann in Houben Weyl's "Methoden der organischen Chemie" C"Methods in Organic Chemistry"] Vol. VII/4, 230 (1968); Y. Oikawa, R. Sugano, O. Yonemit~u, J. Org. Chem. 43, 2087 (1978)].

The ~-ketocarboxamides of the general formula (IV~, which are employed as st~rting sub~tances, are known or can be prepared by knewn methods tGerman Qffenlegungs chrift 1,142,859~.

The enaminocarboxamides of the general formula (V), which are Pmployed a~ starting substances, are known or can be prepared by known methods [German Offenlegungsschrift 2,228,377].

The enaminocarboxylic acid esters of the general formula (VIII), which are employed as starting ~ubstances, are known or can be prepared by known methods [F.A. Glichman, A.C. Cope, J. Am. Chem. Soc. 67, 1017 (1945)].

The ylidene-~-ketocarboxamide~ o~ the general ~ormula (VII), which ~re employed a~ ~tartlng ~ub~tanc~, and the ~lideno-~koto~arboxyli~ ~cld ~er~ o~ the general ~ormula (V~), which ~re ~mployed a8 ~arting substanca~, are know~l or can be prepared by known methods ~G. Jones "The Rnoevena~el Conden~ation" in Organic Reactions Vol.
XV, 204 (1967)].

The way in which proces~ variant C according to the invention i~ carried out i~ ba~ed on the mekhodology known ~rom the literature fo.r converting carboxylic acid~
into carboxamides. In this method, the carboxylic acid is fir~t converted into an activated form such as, for example, the acid chloride or the Lmidazolide, and these are either isolated a~ such or reacted in a ~econd reaction step, or amidated directly in-situ ke give the compounds according to the invention. Example~ of activating reagents which may be mentioned apart from the inorganic halides such as thionyl chloride, phosphoru~-trichloride or phosphoruR pentachloride, or carbo~yldiimida201e, are carbodiimides such as cyclohexylrarbodiimide or l-cyclohexyl-3-[2-(N-methyl-morpholino)-ethyl]car~odiimide p-toluenesulphonate or N~
hydroxyphthalLmide or N-hydroxybenzo~riazole in the presence of dicyclohe~ylcarbodiimide. Nakurally, it is also possible fox the dihydropyridinemonocarboxylic acids to be employed in th~ form of their salts. [The methodology of the amidation is described, for example, by: Fieser & Fieser, Reagents for Organic Synthesis, John Wiley & Son~ Inc. (1967), page 231 - 236; J,C. Shihan and G.P. Hess, J. ~m~ Chem. SocO 77, 1067 (1955); V. Goodm~n, G.W. Xennex, Adv. ln Protein Chem. ~, 488 ~1957); W.A.
Bonner, P.I. McNamee~ ~. Org. Chem. ~, 254 (19S1); H.A.
Sta~b/ ~ngew. Chemi0 Int. Ed. 1l 351 ~1962); Fie~er Fieser, ~ea~nt~ ~or Organlc Synthe~i~, John Wiley & Sons Inc. ~ , 116, 114; H.C. Beyerman, U.O. van d~r Brink, Re. Trav. ~Q, 1372 (1961); C.A~ Buehlex, D.~. Pear~on, ~ohn Wiley & Sons, Volume I (1970), page 895 o~ward~, Volume II, (1977)].

Le A 27 962 - 12 -Suitable solvents for proves variant C are, besides water, all inert organic solvents which do not undergo changes under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetra-hydrofuran, glycol dimethyl ether, or halogenated hydro-carbons such as dichloromethane, trichloromethane or tetrachloromethane, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or hydrocarbons, such as benzene, toluene or xylene, or acetonitrile, nitromethane, pyridine, dimehtyl sulphoxide or ethyl acetate. Mixtures of the solvents mentioned can also be used. If the activated intermediates of the dihydrpopyridinemonocarboxylic acids are isolated, it is also possible to ue the amines of the formula (X) on their own as diluents.
The reaction temperatures can be varied within a wide range. In general, the reaction is carried out in a range from -70°C to +140°C, preferably from -20°C to +100°C.
The reaction can be carried out at atmospheric pressure, but also under increased or reduced pressure. It is generallyc arried out under atomospheric pressure.
When carrying out process variant C according to the invention, the substances involved int he reaction may be used in any desired ratio. However, the reactants are generally employed in molar amounts, However, it has proven advantageous to employ the amine in 5- to 10-fold molar excess. It is particularly expedient to employ a large excess o~ the amine directly as the solv0nt.

The dihydxopyridlnemonocarboxylic acids of the general formula ~IX), which are employed a~ starting ~ubstance3, are known or can be prepared by known me~hods [German Offenlegungsschrift ~,847,236; 3,20~,671; 2,962,241], ~he amines o~ the general ~ormula (X), which are employed a~ starting substance~, are known or can be prepared by known methods [Houben Weyl~ Methoden der organischen-Chemie~ Methods in Organic Chemistry") Vol. XI/l;
Paulsen, Angewande Chemie 78t 501 566 (1966~].

The compound~ according to the invention which were selected ~ow a valuable pharmacological spectrum of action which could no~ have been anticipated. Compared with Xnown dihydropyridines which have a similar struc-ture, ~uch a~, for example, representative~ de~cribed inGerman Offenlegunys~chrift 2,228,377, the compound~
according to the invantion ~how a dlfferent spectrum of action, both quantitatively and from the point of view o~
~uality~ Apart rom acting a~ calcium antagoni~t~, thoy increa~0 the ~NP-dependen~ na~riure~l~ when ~he ANP
~y3te~ i~ ~timulated by ~olume stre~. Thi~ addltlonal componen~ o~ ac~ion w~ d~tect0d in r~t~ ln a model o~
acute hypexvol~mi~t the te~t sub~tance~ were admini~terod or~lly in a tylo~e suspen~ion. ~n acute volume ~tre~3 was triggered by in~ectin~ 15 ml/kg o~
phy~iological sodium ¢hloride 801ution into the caudal vein, and tha urine was ~ub~equently collected over one : ' .

I,e A ?7 ~2 - 14 -, hour. The compound~ according ko the invention unexpectedly increase the excretion o~ ~odium, see ~rable I. At the s.ame time, the excretion of cGMP, whic~ is a specific marker for the activation of the ANP ~ystem, is increased (for example i~ Example l9 by 100%).

Table I:

EEm~le Dosage rate in mg/~g, Inc~ in Na+
Nb. pex oral ~L~istration . e~ion in %

~ 10 80 11 10 gS
19 lO lO0 The compound~ according to the invention can therefore be employed in medicament3 for treating pathologically changed blood pressure and cardiac insufficiency, and 15 al50 as substances for use in coronary ~herapy.

In addition, they can be employed for treating cardiac arrhykhmias, renal in~u~iciancy, cirrho~i~ o the li~e~, a~clte~, oedema o~ the lun~s, oedema o~ ~he b~ain, oedema o px~nancy, ~lauaoma o~ diabe~e~ mellitu~.

~he new aative compQunda can be aonr~r~ed in a known manner into the cu~toma~ fonmulations, ~uch a~ tablets, coated tablet~, pill~, granules, aexosols, ~yrup~, emul~ions, su~pen~ion~ and 801ution8, with the use of iner~, non-toxic, pharmaceutically acceptable excipients L~ A 27 962 - 15 -f)~3~

or solvent~. In ~hi~ CQn~eXt, the therapeutlcally actlve compound should in each case be pre~ent ln the ~l~al mixture in a ~oncentration of approximat01y 0.5 to 90% by weight, that is to say, in amounts which su~fice to obtain the do~age range indicated.

For example, the formulations are prepared by ex*ending the active oompound~ with ~olvents and/or excipients, if appropriate wikh the use of emulsifiers and/or disper-~ants, it being po~sible ~or organic solvents to be used as auxiliary solvents if appropriate, for example in casQs when wster i3 used as the diluent.

Administration is carried out in the cu~tomary manner, preferably orally or parenterally, in particularly perlingually or intravenously.

In the ca~e of parenteral administration, solutions of the actiYe compounds can be employed while ~uitable liquid excipients are being used.

To obtain af~eckive result~ ha~ generally proven advantageou~ to adminisker amounks o~ approxlm~kely 0.001 to 1 mg/kg, preerably appro~imately 0.01 ~o 0.5 mg/kg o~
body wel~ht when adminl0t~xed in~r~enou~ly, ~nd, ln the a~e o~ orAl ~dmini~r~i.on, khe do~a~e r~ke 1~ approxl-mat~ly 0.01 ko 20 mg/kg, pre~erably 0.1 to 10 mg/kg of body weight.

~owever, it may be nece~a~y to deviate from the amoun~

Le A 27 g62 - 16 -, mentioned, n~mely a~ a function o~ the body weight or the nature of the route of administration~ on the individual behaviour towards the medicament, the nature o its formulation, and the point in time or interval of admini-stration. For ex~mple, in some sase~ it may 8uf f ice tomake do with le8s than the abovementioned minimum amount, whila the abovementioned upper limit must be exceeded i~
other cases. I~ larger amounts are administered, i~ may be expedient to spacQ several individual dosages over one day.

Preparation ~xample~

!3E~L

Methyl 1,4~dihydro-2,6-dimethyl-4-[2-(2-phensxy-ethoxy)]-phenyl-3-cyclopropyl-carbamoylpyridine-5-carboxylate ¢ ~ o-(CH2)2-0-C6H5 H3C02C ~ O-MH- a H3C N H~

~.8 g (14.1 mmol) o~ methyl 2-(2-phenoxy-ekho~)-benx~ ene-~cotonae~Ate ~nd 1.97 g (14.1 mmol) of N-cyclopropyl-3-aminocarboxamide are bolled overnlght in 40 ml of i~opropnnol. ~he mixture iB concentrated and purified over a ~ilica gel col~mn u~ing toluene/ethyl acetate mixture~. The purified fraction3 are collected h~ A 27 962 - 17 -3 ~

and ~oncentrated. 'rhe product crystallises ~rom iso-propanol. 3.0 g o~ colourless crystals o~ melting poink 151C axe obtained.

The examples listed in Table 1 were prepared analogously S to the procedure of Example 1:

R l H3Co2C~o-NHR3 Example No. Rl R3 m.p.(C) 2 -~CH2)3-0-c6HS ~ 178 3 ~C~2)2-0 C6H5 -C2H5 135 4 -CH~ ~ b 165 H ~ 1a~

6 C~3 ~ 257 Le A 27 962 - 18 ~ 3li Example No. Rl R3 m.p.(C) 8 CF3 -CH? 236 ~ .

12 -CH~2 ~ ~ 169 13 -~2 ~ -C3H7 145 14 CH2 ~ -C2HS 150 : ' :
~S -CH3 -CH3 186 16 -CH2 ~ -CH~ llO

17 -CH3 ~ 1~2 ~: 19 CF3 ~ 243-245 ~@LJL~ k~ - 19 -:: ~ . ,; ', ' ' .' ' '' .
, ',

Claims

1. Dihydropyridine amides of the general formula (I) in which R1 _ represents straight-chain or branched alkyl which h s up to 6 carbon atoms and which is optionally substituted by phenoxy or cyclohexyl, or - represents hydrogen or trifluoromethyl, R2 - represents straight-chain or branched alkyl which has up to 4 carbon atoms and which is optionally substituted by cyano, hydroxyl or acetoxy, R3 - represents straight-chain or branched alkyl having up to 5 carbon atoms, or - represents cycloalkyl having 3 to 5 carbon atoms, in racemic form and in the form of their optical antipodes.

2. Compounds of the general formula (I) according to Claim 1, in which R1 - represents straight-chain or branched alkyl which has up to 4 carbon atoms and which is optionally substituted by phenoxy or cyclohexyl, or - represents hydrogen or trifluoromethyl, R2 - represents straight-chain or branched alkyl which has up to 3 carbon atoms and which is optionally substituted by cyano, hydroxyl or acetoxy, R3 - represents straight-chain or branched alkyl having up to 4 carbon atoms, or - represents cyclopropyl or cyclopentyl.

3. Compounds of the general formula (I) according to Claim 1, in which R1 - represents straight-chain or branched alkyl which has up to 4 carbon atoms and which is optionally substituted by cyclohexyl or phenoxy, or - represents hydrogen or trifluoromethyl, R2 - represents methyl, ethyl or propyl, R3 - represents methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclopentyl.

4. Process for the preparation of compounds of the general formula (I) in which R1 - represents straight-chain or branched alkyl which has up to 6 carbon atoms and which is optionally substituted by phenoxy or cyclohexyl, or represents hydrogen or trifluoromethyl, R2 - represents straight-chain or branched alkyl which has up to 4 carbon atoms and which is optionally substituted by cyano, hydroxyl or acetoxy, R3 - represents straight-chain or branched alkyl having up to 5 carbon atoms, or - represents cycloalkyl having 3 to 5 carbon atoms, characterized in that [A] aldehydes of the general formula (II) (II) in which R1 is as defined above, are reacted either with .beta.-ketocarboxylic acid esters of the general formula (III) (III) in which R2 is as defined above, and .beta.-ketocarboxamides of the general formula (IV) (IV) in which R3 is as defined above, and ammonia, or the compounds of the general formulae (II) and (III) are reacted directly with enaminocarboxamides of the general formula (V) (V) in which R3 is as defined above, is appropriate in the presence of an inert solvent, or compounds of the general formula (VI) (VI) in which R1 and R2 are as defined above are prepared first as intermediates and then reacted with compounds of the general formula (V) or ylidene-.beta.-kekocarboxamides of the general formula (VII) (VII) in which R1 and R3 are as defined above, are prepared first and reacted with compounds of the general formula (VIII), (VIII) in which R2 is as defined above, in inert solvents, or [C] dihydropyridinemonocarboxylic acids of the general formula (IX) (IX) in which R1 and R2 are as defined above, are reacted, if appropriate via a reactive acid derivative, with amines of the general formula (X) H2N-R3 (X) in which R3 is as defined above, if appropriate in the presence of an inert organic solvent.

5. The compound methyl 1,4-dihydro-2,6-dimethyl-4-[2-(3-phenoxypropoxy]phenyl-3-cyclopropylcarbamoylpyridine-5-carboxylate of the formula:

.

6. The compound methyl 1,4-dihydro-2,6-dimethyl-4-(2-methoxy)phenyl-3-cyclopentylcarbamoylpyridine-5-carboxylate of the formula:

.

7. The compound methyl 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethoxy)phenyl-3-cyclopropylcarbamoylpyridine-5-carboxylate of the formula:

.

8. A medicament for treating a disease relating to blood circulation, which comprises an effective amount of the compound as defined in claim 1, 2, 3, 5, 6 or 7 in admixture with a pharmaceutically acceptable excipient or solvent.

9. Use of the compound as defined in claim 1, 2, 3, 5, or 7 for the preparation of a medicament for treating pathologically changed blood pressure or cardiac insufficiency or for use in coronary therapy.