PH25992A - Dihydropyridine lactols process for their preparation - Google Patents

Description

SH

25992

The sub ject application is a divisional appli- cation of Serial No. 34199 filed on August 29, 1986.

The invention relates to dihydropyridine~ lactols, processes for their preparation, and their use in medicaments, in particular of medicaments which influence blood sugar.

The present invention relates to dihydropyri~ dine-lactole of the general formula I,

R20,C (1 id : rt OH in which rR represents a phenyl, naphthyl, thienyl, py- ridyl, chromonyl, thiochromonyl or thio- ’ ." chromenyl radical, the stated radicals optionally containing 1 or 2 identical or different substituents from the group com- prising fluorine, chlorine and bromine, al- kyl, alkoxy and alkylthio, each having 1 to 6 carbon atoms, and fluoroalkyl or fluoro= alkoxy, each having up to 3 carbon atoms

A

A

25999 and 3 fluorine atoms, and nitro and cyano,

Re represents a straight-chain, branched or cyclic alkyl having up to 12 carbon atoms which is optionally interrupted by 1 or 2 oxygen or sulphur atoms and which is op- tionally substituted by fluorine, chlorine, phenyl, cyano, hydroxyl, amino, C,-C5-alkyl~ amino, di-C,-C5-alkylamino or N-bengylmethyle amino, rR represents cysno or straight-chain or branched alkyl which has up to 4 carbon atoms and is optionally interrupted in the chain by N-C,=~

Cy=alkyl and/or oxygen, and g represents straight-chain, branched or cycdio alkyl which has up to 6 carbon atoms, is op= tionally interrupted by 1 or 2 oxygen atoms and is substituted by one or more radicals : from amongst fluorine, chlorine, hydroxyl, phenyl, smino, carboxyl and C,-C,~alkoxy~ carbonyl, in the form of their isomers, isomer mixtures, optical antipodes or racemates, and their physiologically acceptable salts.

Preferred compounds of the general formula I - lf

£7 25992 which may be mentioned are those in which rt represents & phenyl, naphthyl or thienyl radical, the stated radicals optionally containing 1 or 2 identical or different substituents from the group comprising fluorine, chlorine, alkoxy, alkylthio and alkyl, each of which has up to 3 carbon atoms, and trifluoromethyl, nitro and cyano, a represents straight-chain or branched alkyl which has up to 6 carbon atoms, is optionale ly interrupted by oxygen or sulphur or is substituted by fluorine or phenyl,

R’ represents straight-chain or branched alkyl having up to 3 carbon atoms, and r* represents straight-chain, branched or cy= clic alkyl which has up to 4 carbon atoms and is optionally substituted by carboxyl or C,-C-alkoxycarbonyl, in the form of their isomers, isomer mixtures, opti= cal antipodes or racemates, and their physiologically acceptable salts.

Compounds of the general formula I, in which ky represents a phenyl radical which is op= tionally substituted by nitro, chlorine, trifluoro-C,-C,-alkyl or C,-C5-alkyl,

R, represents a C,~C,-alkyl radical which is optionally substituted by Cy or C,-al= koxy,

Ry represents a C,-C5-alkyl group, : and

R, represents a C,~C,-alkyl group, may be men- tioned in particular,

The compounds according to the invention may be present in the form of their salts. The physioloe gically acceptable salts of the substances according to the invention with inorganic or organic acids are preferred. The following may be mentioned as exam- ples: hydrohalides, hydrogen sulphates, sulphates, hydrogen phosphates, acetates, maleates, citrates, fumarates, tartrates, lactates or benzoates.

The compounds according to the invention exist in stereoisomeric forms which either behave as ob- ject and image (enantiomers) or do not behave as ob=~ ject and image (diastereomers). The invention relates both to the antipodes and to the racemic forms and diastereomer mixtures. The racemic forms as well as the diastereomers can be separated into the stereo= 25% isomerically pure components in a customary manner

(see E.L. Eliel, Stereochemistry of Carbon Compounds

McGraw Hill, 1962),

The compounds according to the invention, of the general formula I, are prepared by a process in which

E7 formyl compounds of the general formula (II), 4 1 : 2 5 :

R 0,C CO,R (11) 3/ N

R CHO rt in which 1 4

R =R have the stated meaning and

R represents straight-chain or branched alkyl having up to 8 carbon atoms, in suitable solvents, are first reacted with a base . and then with acid, or

B37 dihydropyridinelactones of the general formula (111),

x 1 0 2

R°0,C (111) rR rt in which 1 4

R =R have the stated meaning, are brominated in suitable solvents, if appropriate in the presence of a base, and then hydrolyzed or di rectly hydroxylated.

Depending on the type of starting materials used, preparation of compounde according to the in- vention by processes A and B can be illustrated by the following equation:

N

CH

3

CL H,C0,C ~~ ots —

H, COC “ . 3 2 | C 2CH CH, / . , H5C " CH OH

HyC 7 CHO 3

CH,

S st 25992 67

NN ne / a,c” Z Q #3000 \ huco.s no” YT i, >“

CH

3 CH, OH

Suitable solvents for process A are water and all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols, such as methanol, ethanol, propancl or iso= propanol, ethers, such as diethyl ether, dioxane, te= trahydrofuran, glycol monomethyl ether or glycol di- methyl ether, acetonitrile, pyridine, dimethylformamide, dimethyl sulphoxide and hexamethylphosphorio acid trie amide. It is also possible to use mixtures of the stated solvents.

Suitable bases for process Aare the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, or alkali metal alcoholates, such as sodium methylate, sodium ethylate, potassium

A

25992 ethylate, potassium methylate or potassium tert.- butylate, alkali metals, such as sodium, alkali metal hydrides, such as sodium hydride or potassium hydride, and alkali metal amides, such as sodium amide or lithium diisopropylamide.

Suitable acids are the customary organic or inorganic acids. These preferably include mineral acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid, and organic car- boxylic acids, such as acetic acid.

Process A is carried out in a manner which is known per se, by first reacting the formyl compounds of the formula (II), in suitable solvents, with 100 to 5 mols, preferably from 50 to 10 mols of a base per mol of formyl compound and then treating the re- action mixture with acids. Working up is effected in a customary manner familiar to a skilled worker,

The reaction is carried out in general in temperatures from 0% to 150°C, preferably from 20°¢c. to 100°C.

The renction can be carried out under atmos- pheric pressure as well as under elevated or reduced pressure. In general, atmospheric pressure is em- ployed.

The starting compounds of the formula (II) are

WAL

25992 known or can be praparad by known processes (see DOS

German Published Specification) 2,629,892),

Process B

Bromination ie carried out in a manner which is known per se, with the customary brominating agents, such as N-bromosuccinimide or bromine, preferably with bromine,

Suitable bases are the cuatomary bases. Theme preferably include alkali metals, such as sodium or potassium, alkali metal hydrides, much as sodium hy=- dride or potassium hydride, slkal: metal anides, much a8 sodium amide or lithium,diiroprepylemide, and ore ganoretallic compounds, such as phenyllithium, ne butyllithium or tert.-butyllithium, and alcoholates, such as a ethylnte and potassium t-butylate,

Suitable solvents are custorary inert organic solvents. There preferably include ethers, such as die ethyl ether, dioxane or tetrahydrofuran, and hydrocar- bong, such as benzene, toluene, xylene, hexane, cycloe hexane or oil fractions. 1t is ulso possible to eme ploy mixtures of the stated solvents.

The bromination is carried out in a temperature range from -120°C to 100%¢. preferably from -78° ¢. to 50°C.

The bromination is carried cut in such a way - N

Pv 0 ORIGINAL n- BAD that an anion is first produced with 5 to 1 mol, pre- ferably with 2 to 1 mdl, particularly preferably with 1 mol, of base per mol of the starting compound (III), and the said anion is converted to bromide by means of bromine. The subsequent conversion of the bromine compound to the corresponding hydroxy compound of the formula (I) is advantageously carried out without isoclat- ing the bromine compound. This hydrolysis is carried out in a manner which is known per se, by means of water, if appropriate in the presence of traces of an acid, such as hydrochloric acid or sulphuric acid.

The procedure of process B can be carried out both under atmospheric pressure and under elevated or reduced pressure and is familiar to the skilled worker.

In general, atmospheric pressure is employed.

The conversion of the compounds (III) to the compounds (I) according to the invention can, however, also be carried out by other methods known from the literature and is not restricted to the stated methods.

Hydroxylation can also be carried out by means of 2-sulphonyloxaziridine, with molybdenum peroxide/ pyridine/phesphite or with oxygen/phosphite, in each case in the presence of bases, in inert organic s0l= vents, as described, for example, By E. Vede Js in J.

Am. Chem. Soc. 96, 5944 (1974) or J. Org. Chem. 43, -l1l2 =

ANT

25992 188 (1978), or by J. M. Billmers, J. Finn in J. Org.

Chem, 49, 3243 (1984) or by H. H. Wassermann, B.H.

Lipschuts in Tetrahedron Letters 1975, 1731.

The compounds according to the invention, of the formula I, possess a valuable pharmacological action spectrum.

These compounds reduce the blood sugar level and can therefore be employed for the treatment of diabetes,

The blood glucose-reducing action of the substances to be investigated was tested on male

Wistar rats weighing between 140 and 190 g. For this purpose, the rats were weighed 18 hours before admi-~ nistration of the substances, divided into groups of 6 animals and made to fast, The substances to be in vestigated were suspended in aqueous 0,75% strength tragacanth suspension using an Ultra-Turrax directly before administration. Administration of the traga- canth suspension (control animals) or of the substances suspended in tragacanth was effected by means of a gavage,

For each rat, blood was withdrawn from the re- troorbital venous plexus 30, 60 and 120 minutes after administration. In each case, 30 Pp of blood were withdrawn using an automatic dilutor, and were deproteinized with 0.3 ml of uranyl acetate (0.16%). After cen- trifuging, the glucose in the supernatant liquid was determined photometrically by the glucose oxidase method in a Gemsaec solids analyser, using boamino~- phenazone as the color reagent. The results were eva- luated using the Student t-test, p ( 0.05 being chosen aa the significance limit,

Substances which at some time produced a signie ficant reduction in the blood glucose concentration of rats, by at least 10%, compared with the control group, which received only tragacanth suspension, were stated to be effective.

Table 1 below contains the changes found in the blood glucose concentrations, as a percentage of the control.

Table 1 eee

Substance Decrease in blood glucose concentration as a 1% of the (Example No.) control 10 mg/kg PeOe ee ——————————————— 1 29 2 3h ee

The present invention includes pharmaceutical formulations which, in addition to non-toxic, inert - 1h = iV 25992 pharmaceutically suitable excipients, contain one or more active compounds according to the invention, or which consist of one or more active compounds accord- ing to the invention, as well as processes for the

S preparation of these formulations,

The present invention also includes pharma- ceutical formulations in dosage units. This means that the formulations are in the form of individual parts, for example tablets, dragees, capsules, pills, suppositories and ampules of which the content of active compound correspond to a fraction or a multi ple of an individual dose. The dosage units can con- tain, for example 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the amount of active compound which is given in one administration and which usual- ly corresponds to a whole, a half, a third or a quarter of a daily dose.

By non-toxic, inert pharmaceutically suitable excipients there are to be understood solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of every kind.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions » may be mentioned as preferred pharmaceutical formula-

A

25992 tions.

Tablets, dragees, capsules, pills and granules can contain the active compound or compounds alonge side the customary excipients, such as (a) fillers and extenders, for example starch, lactose, sucrose, glucose, mannitol and silica, (b) binders, for example carboxymethylcellulose, alginates, gelatine and poly- vinylpyrrolidone, (c) humectants, for example glycerol, (d) disintegrating agents, for example agar-agar, cale cium carbonate and sodium bicarbonate, (e) solution retarders, for example paraffin, and (f) resorption accelerators, for example quaternary ammonium come pounds, (g) wetting agents, for example cetyl alcohol and glycerol monostearate, (h) adsorbents, for example kaolin and betonite, and (i) lubricants, for example talc, calcium stearate and magnesium stearate and solid polyethylene glycols, or mixtures of the com- pounds listed under (a) to (i).

The tablets, dragees, capsules, pills and gra- nules can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of such composition that they release the active compound or compounds only, or preferential- 4 ly, in a certain part of the intestinal tract, op- tionally in a delayed manner, examples of embedding ww 16 = ed! 25992 compositions which can be used being polymeric subse tances and waxes.

The active compound or compounds, optionally together with one or more of the abovementioned ex~ cipients, can also be in a micro-encapsulated form,

Suppositories can contain, in addition to the active compound or compounds, the customary water-soe= luble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat, and higher esters (for example Cy -8leohol with C6" fatty acid), or mixtures of thease substances,

Solutions and emulsions can contain, in addi- tion to the active compound or compounds, the customary excipients, such as solvents, solubilizing agents and emulsifiers, for example water, ethyl alcohol, iso- propyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1l,3-buty=- lene glycol, dimethylformamide, oils, especially cote tonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol-formal, tetrahydrofurfuryl alcchol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in a sterile form which is

AVY

25992 isotonic with blood.

Suspensions can contain, in addition to the active compound or compounds, the customary excipients, such as liquid diluents, for example water, ethyl al- cohol or propylene glycol, suspending mgents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and sorbitan esters, micro=crystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

The formulation forms mentioned can also con=- tain colorents, preservatives and additives which im=- prove the odor and flavor, for example peppermint oil and eucalyptus oil, and sweeteners, for example sac=- charin,

The therapeutically active compounds should preferably be present in the abovementioned pharma- ceutical formulations in a concentration of about O.1 to 99.5, preferably of about 0.5 to 95, % by weight of the total mixture.

The abovementioned pharmaceutical formulations can also contain other pharmaceutical active compounds in addition to the active compounds according to the invention.

The abovementioned pharmaceutical formulations are prepared in the customary manner according to

2A 25992 known methods, for example by mixing the active compound or compounds with the excipient or exci- plents,

The present invention also includes the use of the compounds of the formula I and/or their salts, and of pharmaceutical formulations which contain the compounds of the formula 1 and/or their salts, in human and veterinary medicine, for the prevention, alleviae . tion and/or cure of the abovementioned diseases. cn In general, tt has proved advantageous, both in human medicine and in veterinary medicine, to adminis- ter the active compound or compounds according to the invention in total amounts of about 0.01 to about 200 mg/kg, preferably O,1 to SO mg/kg, of body weight every 2h hours, optionally in the form of several individual administrations, in order to achieve the desired results.

However, it can be necessary to deviate from the dosages mentioned, and in particular to do so as a function of the species and the body weight of the sub ject to be treated, the nature and severity of the disease, the nature of the formulation and of the ad~- ministration of the medicament and the time or interval over which the administration takes place. Thus it cen in some cases suffice to manage with less than the abovementioned amount of active compound, while in

AL

25992 other cases the abovementioned amount of active come pound must be exceeded. The particular optimum dos- age required and the type of administration of the active compounds can easily be determined by anyone skilled in the art on the basis of his expert knowledge.

Example 1 (Process B)

Isopropyl h-(2-chlorophenyl)-l-ethyl-7-hydroxy- 2-methyl-5-o0x0=1,4,5,7-tetrahydrofuro/2,4-b/pyridine- 3=carboxylate 3° c1

HCOOC 0 tye ©)

Co no”

L,

CH

60 mmol of diisopropylamina in 100 ml of analytical grade tetrahydrofuran are initially taken. 50 mmol of butyllithium are added at a temperature of 0°, under a stream of N>. Thereafter, the mixture is cooled to =78°C and a solution of 50 mmol of isopropyl l~(2=-chlorophenyl)=l-ethyl=2-methyl-5-oxo=l,4,5,7= ~w 20 =

IA

» 25992 tetrahydro/3,4-b/pyridine-3~carboxylate (dissolved in

THF) is added dropwise. The mixture is stirred for 15 minutes at -78°C, and this solution is pumped, with the aid of nitrogen, into a solution of 50 mmol of Br, 8 and 50 ml of THF, and immediately thereafter 50 mmol of Br, and 50 ml of THF, and immediately thereafter 50 mmol of cyclohexene are added and the mixture ia allowed to warm up to room temperature and is evaporated down, the residue is dissolved in DMSO, and H,0 is added until the mixture starts to become cloudy. The mixture is left to stand for 12 hours, and the product is preci- pitated with H,04 filtered off under suction and sepa= rated with 9:1 CH C1,/MeOH over silica gel,

Yield: 30% of theory mepes 145-147°C. . The following was prepared analogously to Example 1:

Example 2 - ’ Ethyl 4=(2-0hlorophenyl)=1-ethyl-7-hydroxy-2- methyl 5=0x0-1,4,5,7~tetrahydrofuro/3, 4=b7pyridine-3- oarboxylate oo 2) »

0

Haslliu Co A og nye Sw > ln UH 3

Cig

Yield: 13% of theory (amorphous)

MS: 377 (10%, M"); 348 (20%); 304 (10%) 266 (100%); 29 (40%) kxanple 5 lsopropyl les thy l-7-hydroxy-s-methyl-'t-(2-methylphenyl)-

Seoxe-1,4,5,7-tat1 shycrofuro/ f 4~b/pyridine-3-carboxylate ® / Z C

H.C (H,0) JHCOGE ~~ m7 3°70

Hor 1 VAS 7 el / i, CG Br 3 > LH

Cts

Yield: 30% of theory

MS: 371 (15%, M'); 328 (25%): 280 (80..); 278 (100%); —————— -P2 w BAD ORIGINAL 9

192 (20%); 164 (20%); 42 (50%); 29 (35%).

Example 4

Isopropyl l-ethyl=-7-hydroxy-2-methyl-5-oxo=4=(2=-tri- fluoromethylphenyl)-1,4,5,7-tetrahydrofuro/3,4=b/- pyridine<3«carboxylate ) ne” Z 0 (HAC) JHCO0C — . 0° we 7 YY . OH

Coll

Yield: 35% of theory

L4-nMR (GCL): = 0.8 (dy 3H); 1.1 (dy 3H)3 1.3 (ty 3H); 23 (8s, IH); 3.5=3.9 (s, broad, 2H) 4,8 (hepte., 1H); 5.3 (=, 1H); 5.9 (s, 1H) 6.1 (8s, broad, 1H); 7e2= 7.6 (m, LH);

Example 5 (Process A)

Isopropyl l-ethyl-7-hydroxy=-2-methyl-lt-(3-nitrophenyl)= 5-0x0=1,k4,5,7-tetrahydrofuro/3,4-b/~pyridine-3~carboxy=- late

0 KAN 25992 3 No, . - >

Le 0 (Hy )Hooog | EN

Li i,c © ) | OH

Cols ce 5 mmol of 3-methyl 5-isopropyl-l-ethyl-2- formyl-6-methyl=h=(3=nitrophenyl)=l,4=dihydropyridine~ 3,5=dicarboxylate in 40 mmol of 2 N KOH are initially taken and heated for a short time at 50°¢ in a water bath, after which stirring is continued for 1 hour at room temperature. The solution is clarified with active carbon and acidified with hydrochloric acid, and the precipitate is filtered off under suction.

Yield: 25% of theory 1ganmr (CDCl) = 0.8 (d, 3H); 1.1 (d, 3H); 1.3 (t, 3H)3 2.3 (8, 3H; 3.4=4.0 (m, broad, 2H); 4.7 (m, 1H); 5.1 (8s, 1H)} 5.9 (as, 1H); 6.2 (s, broad, 1H)} 7.3=8.3 (m, 4H)

It is understcod that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.

Claims (1)

Hr CLAIMS:

1. A process for the preparation of a dihydro~ pyridinelactol of the formula rt 0 2 - TY 2 ne ~ pt OH in which rt represents phenyl which is optionally substi- tuted by 1 or 2 identical or different substituents selected from the group consisting of halogen, Cy-Ce= alkyl, fluoroalkyl with up to 3 carbon atoms and 3e fluorine atoms and nitro Rr? represents a straight or branched alkyl have ing up to 12 carbon atomsj rR represents straight or branched alkyl with adh up to 4 carbon atoms; and Rt represents straight or branched alkyl with up to 6 carbon atoms} comprising brominating a dihydropyridinelactone of the formula

We oo #o,c N - at 1 2 3 Lh wherein Ry Ry, RZ and R are as defined above in the . presence of a suitable solvent and then converting the bromine compound to the corresponding hydroxy compound fe. s by hydrolysis. SIEGRRIED GOLDMANN HANS JURGEN AHR WALTER PULS KLAUS SCHDOBMANN FRIEDRICH BOSSERT HILMAR BISCHOFF DIETER PETZINNA : JOACHIM BENDER inventors Lr