DE2316881A1 - BIOLOGICALLY ACTIVE COMPOUNDS, THE PROCESS FOR THEIR PRODUCTION AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

Priority A- April 1972, Great Britain, ITr. 15 280/72

The invention "relates to compounds which beiiitzen. Hypofilyl-cärnische activity and for the treatment of hyporglykäni-specific-n states vie Dlabetcc mellitus, · are suitable, a method to her ei * Preparation UUD this Verbindunpen containing medicinal preparations.

At present, antidiabetic therapy "relies" on administration of either sulfonylharristoff or biguariide compounds. " 8ul \ Oiiylurea connections put insulin out of the Pancreas free, biguanide compounds inhibit glucose uptake from the small intestine and gluloneogenesis in the liver and increase peripheral glucose utilization under certain conditions.

309841/1168 OKüMAL IHSrüCTED-

It has been found mm, that a number of basic / ithe3 "n for the treatment of diabetes mellitus compared to the. Heretofore available sulfonylurea and 'biguanide compounds are the advantages. Preliminary tests have shown that this basic ether in Alloxan-Treated mice hypoglykanische' . Have activity. Further experiments with normal houses and other

their animals, such as rats, guinea pigs and squirrel monkeys, confirm this pre-smoking.

The invention thus relates to compounds of the general Formula (I) or (II) and their acid addition salts,

A - Py

in which Py is an optionally substituted 2-, 3- or 4-pyridyl radical, an N-oxidized or quaternary pyridyl radical and. A denotes a residue of the formulas (IIIA), (IIIB) or (HIC)

4- ALK-O -l · - -f- O-ALK ~] ~ - [- τAIK-O-ALK -} - (ΙΙΙΛ) (IIIB). (IIIC)

in which ALK is a straight-chain or linked alkylene radical with 1 to 6 carbon atoms, R ^ a carboxyl group or

30984 1 / -1 168

ORIGINAL INSPECTED

- - 3 -

a group dars-fcellt which is converted a carboxyl or acyl group in the human body la, P ^ ₁ * R and R. each one Wasserstoffatosi, a carboxyl group, a? A group that is converted into a carboxyl group in the human body, an acyl, optionally esterified hydroxyl, nitro or amino group, an alkoxy, ary! Alkoxy or aryloxy radical odex 'a halogenatoia, with the proviso that R Tea can be a methyl, cyano or methoxycarbonyl group, if Py is a 2-I ^ ridyl or 5-ethylpyrid-2-yl radical, A is a radical of the formula - ^ O-CH ₂ -7- and R ₂ , R, and R, are each a Viasserst-off- or Halogenatoia.

The invention also relates to a method for producing the Compounds of formula (I) or (TI), characterized is that nan a compound of formula (IV) with a compound the forrael (V) condenses,

(IV) B -. (AtK) -OH HO - (AtK) _1n "-Py (V)

α where and m each to have profiled 0 or 1, provided n + m / 0, AJQK and PY are as defined in the Pormeln (I) or (II) and B is a radical of formulas (IA) or (HA) ,

(IA) (IIA)

309841/1168

in which R ₁ , K ₂ > ^E ~ ^{and E} / are ^{as defined in} lOriacl '. (l) or (II).

This condensation reaction is carried out with the aid of a condensation agent such as a carbodiimide, for example DieyclohexylcarbodliEnd, or a carbonyldiiioidazole. But you can also use a halide, for example a chloride or broinide, the compound of the formula (IY) or (V) with a) salt, for example potassium or sodium salt, of the corresponding compound of the formula (V) or ( IV) implement "Preferably, the substituents in the phenyl and / or Pyridyl'ring schematically changed the coupling reaction. in the preparation of compounds of formula (τ) or (Ij) in which R, or any other substituent or a ivmid- _{If R 1} or any other substituent is a carboxyl group, it is therefore preferable to first prepare the corresponding compound in which R 1 or any other substituent is a carboxylic acid ester group and then convert this group into a carboxyl or amide group in a manner known per se. Further details of the process according to the invention can be found in the examples.

For the compounds of formula (i) or (II) already known from the literature, in which Py is a 2-pyridyl or 5-a'tbylpyrid ~ 2-yl radical, A is a group of the formula - / ~ 0- CH ₂ _ / - »R _{1 is} a methyl, cyano or methoxycarbonyl group and Rp, R-, and R, each a hydrogen or halogen atom, only one insecticidal or fungicidal effect is described. The hypoglycemic effect of the compounds of the formulas (I) and (II) is new and surprising.

3 0 9 841/1 368.

Pur afm Reut ALIC of the formula (IHA), (TIIB) or (IIIC), a methylene, ethyl acetate or n-propylene group is preferred.

It has been found that an M -oxidized or quart iiro pyridyl group reduces the hypoglycanic activity of compounds of the formula (I) or (II). An optionally substituted 2-, 3- or 4-pyridyl radical is therefore preferred for Py. 2- and 3-pyridyl radicals are particularly preferred. Examples of suitable substituents are halogen atoms, lower alkyl, alkoxy, aryloxy, aryalkoxy or acyl radicals, hydroxy, amino, nitro or carboxyl groups or their salt, ester or amide derivatives the substituents of the pyrid ^r ring in meta or para position to reads A. The ring is preferably substituted with carboxyl groups or with groups that are converted into a carboxyl or acyl group in the human body. Examples of such groups are SaI ^ e, ester or Araidderivate of carboxyl groups, alkyl, alkenyl or alkynyl, in particular those with an odd number of coolant atoms, and alkyl, alkenyl or alkynyl radicals, which with an alkoxy, aryloxy or arylalkoxy radical or an optionally esterified hydroxyl or carboxyl group or its salt, ester or amide derivative are substituted.

It was found that substituents in position 2 of the phenyl ring reduce the hypoglycemic activity of the invention Reduce connections. Therefore, in the compounds of formula (i) or (II) IU and E, preferably water

30984 1/1168

ORIClIIAt INSPECTED

ser-stoffatoTue.

The compounds examined are strongly acidic. The prefer "· ten / Verüiuri'ui'igeu üov / ie their acid addition salts have the formula (Vl)

in the Py a 2 ", 3" or 4-pyriclyl radical, the. "" optionally in meta or para position to the group. Py ~ A bond with a C & rbuxylgrvippe · or its salt, ester or amide, a An alkyl radical with an odd number of carbon atoms or one with a carboxyl group, its salt, ester or air id. substituted alkyl radical with a straight line. Number of carbon atoms, is substituted, A is a residue of the formula (IIIA), (IHB) or (IHC) means.

.-4-0-AIK-J- 4- ALK-O -] - 4- A-DC-O-ALK 4- (HIA) (HIB) (HIC)

in which ALK is a straight-chain alkyl radical with 1 to 6, in particular 1 to 3 * carbon atoms and R and R,;] e a hydrogen atom or a carboxyl group whose salt, ester or amide or an alkyl radical with an odd number of carbon atoms or one with a carboxyl group whose salt,

with a straight Num &_# hl substituted on carbon atoms alkyl ester or amide / is', wherein at least one of _R and R, no Wasserst is off atom, with the

309841/1168

QfUQlHAL IMSPECTED -

M'cu; sgabe _} class veder R ₈ or E ^ is a methyl or l-lethoxycarbony'l group if Py is a 2-pyridyl or 5-ethylpyrid-2-yl radical and I. is a rust of J. -or τη el

The following compounds as well as their pharaoalcological compatible Acid.additiornjsal2: e are particularly preferred because their liyposslylcäi-iic Alibivity particularly high lot:

4-Mö fchylp} iencc-: y-3'-pyridylraethane 4 -n ~ prop; y! Phenoxy ~ 2 '-pyrid y line than 4-methyJ.benayloxy-2' -pyridylethane .1 - (4 ~ Met'hy Ibenssyl oxy) - '$ - (2' -pyridyl) -n-pr opari

4-Garboxypheiiccf.y-2 '-pj ^ r 4-CarboxyiTi8thylphenoxy-2' -pyriöylmethan 4 ~ carboxyätbylpheno> :. y-2 '-pyrid.yliaethan 4-Carboxyätliyläthylenpheiio: cy- ~ 2' -pyridylne '-Carboxyät} iyl-e, thylphenoxy-2' -pyridylmnethan 4-Carbi.miy3-phenoxy-2 '-pyridyliaethan 4-Carba.inylphenoxy ~ 3 ^T -pj'ridjrlinethan 4-CarbamyD. phenoxy-4 '-pyridyliaetham 4-garboxyethy] phenoxy-3'-pyridylnuthan 3- (6-methyl) -pyridoxy-4' -methylplienylmethane

3- (6-methyl) pyridoxy-4 ^! -carboxyethylpheny! methane.

309841/1168

CFTCi ^ AL. IKSrEGTED

For the production of the acid addition salts used v / earth acids, which form salts after reaction with the free base, whose anion is phai'makologisoh "compatible. Inorganic acids such as hydrochloric acid, Broiiiv / asöwrs'jof f ~ are particularly suitable acid j nitric acid, phosphoric acid and sulfuric acid as well organic acids such as vinegar, lemon, apple, wine and Lactic acid. If the compound of formula- (I) "or (II) in Form of their SaIg; it uses, - so is the "basic ether itself the active part of the therapeutically effective * !. Molecule *. By appropriate choice of salt, solubility, absorption or other properties the connection can be changed ".

As already mentioned, the functions according to the invention Compounds are hypoglycemic and are therefore a treatment for the Suitable for diabetes mellitus. Another benefit of many connections the formula. (i) or (II) is their hypolipemic Effect. As increased serum cholesterol and triglyceride levels often occur in diabetes patients int this hypolipäinisclie ·. Effect very welcome.

The dose-dependent properties of the according to the invention

Connections are different depending on the connection. The most active compound studied is lowering blood sugar levels in normal and alloxan treated mice at doses of 30 to 300 mg / kg. In mice, rats, guinea pigs and skulls, the hypoglycemic effect of the invention persists Connections in general between

2 and 6 hours. In the case of 4-C ^a rboxyäthylphenoxy-2 ^t -pyridyl-

30 9 841/1168

, VAL SUSPECTED-. . -

Raft than eats a: suitable dose range for humans, about 0.5 Ms: 0 mg / kg / day ¹ g, preferably a little more / a. 5 mg / kg / day »

Di e uj.'f.vndxin (iGgeri? .R? Gen connections, esp

4 ~ Carbo "yMtliylpheiioxy-2 ^f -pyridyl riotnaia, act on other V / ee than the sulfonylureas, - since they do not release insulin» V / ie the biguanides inhibit the compounds of the formula (l) odei '(II) oils clucose uptake of the small intestine; their effect on peripheral glultose degradation is, however, therapeutically satisfactory. The compounds of the formula (I) or (JT) that were criticized presumably cause lower lactic acidosis and possibly also lower gastrointestinal heating than the Bigusuide ..

The invention therefore also relates .Arsneipräparate, which by a content of a compound of formula (I) or (II) as V / irl?: Substance in combination nr.it pharjualcological. tolerable raw materials and / or dilution agents are marked.

As is customary, these Arisneiprepai ^ ate from a written or accompanied by a printed prescription or description of the use of this blood sugar medicinal product.

In order to isolate the medicinal products, the inventions are used 'Compounds of a pharmacologically acceptable carrier, a drink or a food incorporated. The medicinal preparations can be in the form of tablets, lozenges, powder, capsules, porridge, lozenges or candies are made up. The wan of the vehicle

. 3 09.841 / 1168

depends on the desired properties of the medicinal product. In f c-uten-Arsneipreparaten are used as a carrier Magnesium sal κ κ, starch, lactose, tails: or chalk / used » However, the arsieipreparations can also be easily digested in the form of a -Capsule, e.g. oiriGr gelatin capsule, which is the inven- contains, present, »also

a syrup, a solution or a sweet pen is suitable. Specific examples of liquid pharmacologically acceptable Diluents are ethyl alcohol, glycerine, sodium chloride solution and water, optionally conventional fragrances or May contain dyes. The invention " Connection can also 'in a food, 2.B. in a biscuit, be incorporated. ".

The examples illustrate the invention.

Example 1 4-Carboxyäthylphenoxy-2 '-pyridylmetha n.'

17.5 g of 2-hydroxymethylpyridine in 80 ml of ethyl acetate are mixed with 15 g of phosphorus oxychloride ^{at 0 ° C. while stirring.} The mixture is heated in a water bath for 1 hour and then left to stand at room temperature for 5 hours. The solvent is then distilled off under reduced pressure. The residue is dissolved in water and the solution is made alkaline with sodium carbonate solution. An oil is formed which is extracted with ether. The ether extracts are washed twice with water, washed and dried over MgSO.

309 8 41 /1.1 6 8.

The residue is distilled and the residue is fractionated. 14.56 (71 percent of theory) 2-Ohlorraethylpyridiu are obtained. A ρ solution of 2, B g 'sodium in 100 ml Ätb & uol is sunächot with

-ilthV-Lr-'rtcr
Ig ₅ T. j .; .4-H? /Cirox7/biiii^-Oi.-Kriure/ in 100 ml of ethanol and then with 15.0 g of 2 - Chloriaethylpyridin verseta + -; the mixture is refluxed for 4 hours, the sodium chloride is filtered off after cooling and the solvent is distilled off under reduced pressure. The remaining solid is recirculated from ethanol. 16.7 g (55 percent of the oil) of the desired compound are obtained, melting point 78 C.

According to Example 1, i.e. reaction of the Ijatrrum salt of a suitable pyridine derivative) with the chloride of a suitable

-säur'-fjotf: r

Hydroxybenzene /, are those listed in the table below Connections JTr. 1 to 11, 15, 16, 18, 20, 22, 23,? B, 28, 35 and 42 made. The structure of the compounds is v / ird

confirmed by Ele1nentara.nal3rof.nis IR and EMR spectra. IR Tni & x (KBr):? 991, 1710, 1270, 768 cd " ¹ .

mi-J '.- l,?! d (J, ^J i Hz, 1 arorpatlöchec proton); 1.9-3 H. (7 χ aromatic protons); 4.75 S (CH _p ); 5.65 q (J, 8 Hz,); P.6h t (J, 8 Hz., 0-

B cis ρ 1 e 1 2

.2.0 g of the compound prepared according to Example 1 v / ground with 50 ml of a 20 percent sodium hydroxide solution at reflux for 4 hours heated. Then the solution is cooled and made with glacial acetic acid acidified. The solid which separates out is filtered off, dried and recrystallized from ethanol. 1.6 g are obtained (90 percent of theory) of the desired compound, mp 24 ° C.

30 98 4T / 116 8

C.TC.:,\\M INSPECTED

G em üs s Example-2, i.e. alkaline hydrolysis of a suitable. Ethyl ester s, the compounds Wr. 19, 24- ,. 25 and 27 manufactured. Here, too, the structure is given by -Elemeataraaa-

lysis, IR and! Tlili spectron confirmed.

IR> rr ^>: (Kßr) i -1690, 1600, 1? BO, 768 c? R ~ ^] . , · / NrIR Tf (CO ^ j ₂ SOj -.- I ₁ ^ c, (J, 4 H ^ 1 aromatic ;; proton)? 2 ~} M (7 x aromatic protons ^; 4.75 S '(CH ₀ ).

At s ρ i e 1 5

3 - (6-Kethyl) -pyridoxy-4-tolylme tha n

A solution of 1.2 g itfatriujn. in ethanol v / ill be successively with 5> 5 g ^ -hydroxy-ö-methylpyridiu in 1 ml ^ 0 J '; Iiano-l and 7 g V _s p-chloro Äthylbenzyl id. Versetat ", and then the mixture is refluxed for 5 hours. After cooling, the sodium chloride is filtered off and the solvent is distilled off under reduced pressure. The remaining pesticide is crystallized from ethanol. This gives 4, 6 g (42 percent of theory) of the

desired compound, m.p. 71 C- -

According to Example 3, the compounds Hr. 36 and. 37 manufactured. The structure is determined by elemental analysis, IR and

'BMR spectra confirmed. ''

IR VinaK (KBr) .: 2920, 1255, 1010, 810 cm ™ ¹ .

NMR T ^- (CD ₅ Cl ^):.-1.75 d ('J,;j> Hz, 1 aromatic. Proton); 2.58 2.97 M (6 χ aromatic protons); 4.88 S (CH _Q > j 5.60 q (J, 8 Hz, -OCH ₂ CHO; 7.50 S (CH,); 8.62 t (J ", ^ 8 Hk / O -CH ₂ -CH ₃ ).

B is ρ ie 1 i \

^ S C arb aiTi.y 1 ph en οχ ν -2 '- pyrj 07 Lttc than - hydrnchlo r id

13, 7 g of 4-Ilydroxvbenzamid are dissolved in 150 ml of 2, 3 g / sodium ent-- -haltendein isopropyl alcohol at 6O ⁰ C. 14.0 g of 2-picolyl chloride are then added to the solution, and so is the mixture

left 0 9 8 4 1/116

Left to stand at 100 ^{° C. for 5 hours.} Then the solution

medium distilled off and the residue dissolved in ethanol. The vnlik-3; '. Chcn substances are filtered off, the alcohol is abf ii'ti.Lpit _t T) sr remaining residue is in 2a Sal a acid £.; -'? Löet UYi-'ΐ ekle Löf: uug with Bola charcoal discolored. / inuohliGDöend v / ird clic L ';^;"ung a dry oingodainpft, the residue is κv.'eriKiUl from ethanol recrystallized. Mau receives 17.8 g (67-5 probate of theory) of the desired compound, Pp,? 0C to 210 ⁰ C.

Coiüäoü Example 4 produce the compounds No. _0, 30 and 31 '. The structure is confirmed by elemeutaranalyBen, IR- and IiK [I-Opel'tren.

• Example 5

3.0 g of the compound obtained according to Example 1 and 10 ral hydrasin hydrate are refluxed with 20 ml of ethanol. The white solution is filtered and cooled. The solid which separates out is filtered off, dried and recrystallized from ethanol. 2.0 g (71 percent of theory) of the desired compound are obtained, pp. 185 to 186 ⁰ O.

IR ymax. (KBr): 3360, 1620, 16000, - 60 cm " ¹ .

WiJi ΊΓ { CD,) _o S07: -0, ^} 4 S (NII), 1.37 d (J, ² I Hz, 1 aromatic

Protojt ^; 2.1-3 M (Γχ aronutic protons); 4.75 S (CH ₂ ) j. 5.55 S (NH ₂ ).

Example β 4- (1 - £ ~ ^> » 5 -Dimethylpyra ζ ol ^ -cg ^ ony lp henoxy-2 '~ pyr idylmetjian

3.58 g of the compound prepared according to Example 5 and 1.5 ml of acetylacetone are mixed together in 100 ml of ethanol for 3 hours heated to reflux. After that, the solution becomes dry

309841/1168

:. ι * - 231688 T ■■;

evaporated and -d -: - r RUrtKstand from Fetrolätaer (boiling range 60 to 80 ° C) recrystallized ;, iian receives '1.26 π (? δ percent of the ■ thεc-rie) cer recommended compound ,, Fp,' 106 " C.

IR ^ sx (KBr) r 1700, 15 * 5, 926.7S8 c ^ ^] _r

Ki-fR "OTCDCl -, /: -l, ^ -: ':, 07 Π (8 χ ^ r> ηatU; before proton? *); 3 * 9ö Ä (CH) .;

B e i s ρ i e 1 7 4- (Äthoxyhippuryl o? .Y) -2 "♦ -pyridy'lm_eth.au

3.5 g GlyciuaLliylester-hydroclilorld are suspended in 75 ml Dioiiloriaetliarji, 3 »4 ml Träthylanrin v / erdeii ixin _f and the mixture w L ·. The mixture is then filtered and 5.1 g of dicyclohexylcarbohydrate are added with 5.7 g of the compound obtained in Example 2. The mixture is stirred for 16 hours at room temperature. Insoluble substances are then filtered off The solution is evaporated to dryness and the residue is recrystallized from ethanol. 3 »5 g (49 percent of theory) are obtained

desired. Compound, pp. 107-108 ° C.

IR % ay, (KEr): 3275, 2900, 17 ^ 0, 1500, 855, 772 cm " ^1. NMR T / XCTiJ) ₂ SO J Ί -1.35-3 M (8 χ aromatic protons); 4 , 75 S (CH ₂ ); 5.87 q (J, 8 Hz, 0-CH ₂ -CH ₅ ); NH overlaps in q at

₅ 5.87 ^; 6.72 S (CH ₀ ); 8.8 t (J, 8 Hz,. 0-CH ₀ CH,.).

Example 3 ~ (-6-HeJAyjO ^ y ^

23.68 g of p-toluic acid ethyl ester, 23.5 g of N-bromosucciriimide and 0.05 g of O ^ -azobutyronitrile become -together in-Tetx-chlorocarbon Heated to reflux for 2 hours. The reaction mixture is then cooled, the pesticide filtered off and the solvent evaporated. 36.05 g of P-carboxyethylbenzyl bromide are obtained. Of this, 13.7 g of a solution of 6.2 g of 3-hydroxy-6-iron, ethylpyridine in 130 ml of ethanol containing 1.3 g of sodium

309841/1168

Location! G:? IAL INSPECTED- .

■ - 15 -

The solution is heated on the beetroot for 3 hours. After cooling, the sodium chloride is filtered off, the solution is evaporated to dryness and the residue is crystallized from petroleum (boiling range 60 to 60 ° C). You get οϊ ' ^Λ ' G (53 percent dor theory) dca? gr.vmnought connection, Ppc 61 ⁰ C.

Example 9 sy "1-Ojc.Y) -2- (2 ^l -pyridyl ^ -. Hljaan

13.0 g of 2- (2-hydroxyethyl) pyridine v / erdcn in 50 ml? _f 3 g Hs-triumhaltendeia t-lethane dissolved and the solution evaporated under reduced οία Drude to Trocliene. The Hatrium- obtained Saj ζ is suspended in 50 ml of toluene "After the addition of 24.0 g ^ ■ bromo-pr-xylene v / ill be dan mixture 5 Stvmden s.uf 100 ⁰ C" heated "The solution is cooled, the The pesticide is filtered off and the solvent is removed under reduced pressure. The residue is dissolved in 2N hydrochloric acid and extracted with ethyl acetate. The aqueous phase is made alkaline with potassium carbonate solution and extracted with ethyl acetate. The ethyl acetate vial is washed with water and dried. The residue v / is distilled under reduced pressure. 3.0 g (14.8 percent of theory) of the desired compound, boiling point 115 ° to 118 ° C. at 0.15 mm, are obtained.

Following the procedure of Example 9, compounds Fr. 12 and 14 are prepared. The structure is determined by elemental analyzes, IK and WMi spectra confirmed.

309841/1 1 68

_C Ri «« i £ A. INSPECTED

Vmax (KBr) - 2.86ol 1593 * 1095, 805, 755 cm "" ¹ .

MM «J ^ (CDCI-.): -1.52 ύ (J _1. 4 Hz, 1 aromatic proton) 2.4-3.1 M - (7 x aromatic protons), · 5.55 S (CK _2. ) ; 6.15 t (J, 7 Hz, -CH ₂ -CH _2. ) .; 6.9 t (J, 7 Hz, -CH ₂ Cli ₂ -); 7.75 3 (CH ^>.

Eleme n ta ranalyse;

C % ■ - H $ N ^

calc .: 79.29 7.48 6.17

found · .: "78.62 -..- '7.4o 5.60

found ..: 78.46 7.59 5.97

309 841/116 8

Example 10 4-Methylp hono yy-2 ^f - py ridy line than-N ~ ο xi ^ hyj r ο ohl_qrj_d_

5.0 g of 4-methylphenoxy-2 ^l -pyridylmethane are suspended in 10 ml of acetic acid and 3.8 ml of 30% hydrogen peroxide. The solution is heated to 70 ° C. for 4 hours. After cooling, the solid is filtered off, washed with acetic acid and recrystallized from ethanol after adding ether. 5.5 g (87 percent of theory) of the desired compound, melting point 126 to 127 ^° C., are obtained. ·

"Example 11

4-meth yl-phenoxy-1'-methylenca rboxyä thyl ~ pyridi nium-2'-ylmet hanbrom id

1.9 g 4-methylphenoxy-2 ~ ^l pyridylmethan and 1.7 g of ethyl bromoacetate are heated for 4 hours at 80 ⁰ C in 20 ml nitropropane. The solution is then cooled and filtered, the solid is washed with ether and dried under reduced pressure. 2.3 g (63 percent of theory) of the desired compound, melting point 187 to 192 ^° C., are obtained

Table I contains data on structure and hypoglycemic Effect of a representative number of compounds. The hypoglycemic effect was measured on those treated with alloxan.

ι '

Mice for sure. The values listed were obtained by measuring the lowering of blood sugar after intraperitoneal administration a 300 mg / kg dose set in carboxymethyl cellulose.

309841/1168. ..

Evaluation B key

<5 / α ■ 3 = 25 - 40 = '5 - 15 Io Λ ' > 40 = 15 - 25 Io - ■

309841/1168

T a "b e 1 1 e I

A -? Y

~ ^{Seii:; e 18} ~

link

Py

Hypoglycanic effect

3-methylphe: noxy-2'-pyridylmeth.an hydrochloric!

-OGK ₂ -

H2-pyridyl

4-MethylpherLoxy ~

2'-pyridylmethane -OGH ₂ - OH ₃ hydrochloride

H 2-pyridyl

3 4-methylphenoxy
3'-pyridylmethane -OCH ₂ - GH ₃ ■ H H H E. 3-pyridyl 4th . _ 4th 4-methylphenoxy
4'-pyridylmethane -OCH ₂ - CH ^ ■ H H H H 4-pyridyl 2 OO 5 4-1thylphenoxy-
2'-pyridylinethane -OGH ₂ - CH ₃ H H H H 2-pyridyl 1

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_m

P; "Cd

I. ; ■ £ O CM O O O - O I. id Cv! O PI "ί

CM

ϊχί

C_1 O

• Μ rf ο -P fj- φ ω rf H P ^ M. • Η ο f-i ft I. ο
ι CM

to r: a w

• Η, "-
H P

O O

P..q
Γ4 ϊθ

m pi

-si- pi

OJ

tsO

• Η

fl
O

T ¹

W.
O
OJ

Ό

H-H

+> Pi

O Q

ti xi

O Q> 43 O

ft 13

O
OJ

ri

OJ

IN THE

OJ O . OJ

O
O

OJ

-H

H f-f

Λ ft

ρ ι

^ 2 H rf

fi ο α? oi rfrf

O (DP
Λ Ο

OJ

33.

OJ O O

I I

HH

Ρ, Ό

O -rl

h 5h

ft t> s

hf

> sCM MI ο tn

hod ei Ö.53 O Φ 4 ^>

OJ OJ

-H

'Cl • Η

P: I.

OJ

CM O O

OJ

I. O C. J I. O Π3 O , - H fH O •H I. 1> 5 {>> I. rf Π3 I. • 4 ^ •H ft P, ω Sh O I. P. !> s M.
■ O ft ft, OJ
I. I rQ I. O k 54 OJ ω M. «}
O I. • rl
■ O I. pi
Q) "5 O M. rf Γι. 1 si O P, 05 O) H si
4 ³ rf S. co Q) rf O _p I. r-l G)

• rl

CM

O U OJ

.l ftÖ

OJ

309841/1 168

Table I - continued

link

Py

Hypoglyc

mix

effect

4-carboxyethylene

■ - '■ phenoxy-2' -pyridyl 'methane',:

OCKo-CH = GH-OO ₀ HH * H · H K, 2-pyridyl

26 4-Carbooxyethyläthylenphenpxy-
; a'-pyridylae-chan.

■> 27 4-ß-Car "b-oxyätliyl-

- * ■■. phenoxy ¹ -? - ¹ -pyridyl-

^ -. methane ', \ ■

OCH ₂ - -CH = CH-CO ₂ C ₂ H ₅ H: 'H 2-? Yridy.l

OCH ₂ -

CH ₂ CH ₂ CO ₂ E

H 2-pyridyl

co 28- 4- • ß-Oar'boxyäthyl-

ethylphenoxy-2'- ·. ,. pyridy-ljne-than

00Hg- ¹ ^ -OH ₉ CK ₂ OQ ₂ O ₂ Hr-E HH

H 2-pyridyl

■ 4-cartoainylphenoxy 2 '-pyri.yylinethane,

.- .. hydrochloride ■. .. ■■

OCH ₂ - -CONH ₂

H- .H H 2-pyridyl

4-carbanylphenoxv 3'-pyridyl-iethp.n.

OCH ₂ -

-CONH

H, 2-pyridyl

Table I - continued;

link

R ^!

4-CarbarcyIphenoxy-4'idlth

pyy hydrochloride

-OGH ₂ -

-00IiH

Z-

4- (A "thoxyhippuryl ~ methane

OCH ₀ - 0Hp ₅

(m lim ff.

* ^ 33 4- (1 -β * 5-Dinotliyl-Γ * pyraisolT ^ oarlionyl «-

phenoxy-2'-pyridyl methane

-OCH ₂ -

2-r'71-icSyl

2-Iyrictyl

4-CarbonylhyuraE-ino-phenoxy-2'-pyridylmethane

-OCH ₂ -

O It

-C-NKNH,

2-

H · pyridyl

3-oxyethylphenoxy-4'-pyrid- y! methane

-OCH ₀ -

4-

H ti pyridyl

co "cn

36 . link Tabel Ι - Gone settlement R ² H H R ⁵ - So ite 25 - "ö
*. ^ " 37 2-pyridoxy-4'-
tolylnethan A. E ¹ H ■ H H .H ■ Py Hypoglyca
niche
Effect ZZ
"ύ
m
q 3-pyridoxy-4'-
tolylmethane -CH ₂ O- H H 2-pyridyl 1 H
S. -CH ₂ Ο J 2-Pyriajl 3 ■■ ·.

■ ^ 38 3- (6-methyl) -

o> pyridoxy-4'-

oo tolylsiethan

-CH ₂ O-

3 -. (6-Methyl) -pyrido2cy-4'-carboxyethylplienylinethane

-CH ₂ O-

CO ₂ C ₂ H ₅

Ii

'4-methylphenoxy-2'-pyridylmethane. N-oxide hydrochloride -OCH ₀ -,

CH

fl J

O) CO OO

4-methylphenoxy-1 '-r.ethylencarb- oxyäthyl-pyridiniuni-2 '-ylid

-OCHo-

CE,

3r CHgC02C2J

-P • Η G)

• Η PS

Ai f-i

^ • r-i Γ-i; - ~

! ■ "; O OJ

P., s1

ϊ> .ϋ

Lu co

PI

pi

pi

CM

Ρί

HD

Ό ¹

• Η U

pi

4 =

¹ A ο

, α U co
O

OJ

O O Ό

m ίΰ

CvJ ϋ

OJ

Ι-ρϊ HM

CO tJ

J M · Η

t <- \ QV

I ■ Ö "H

O rf -H

ft

OO UU Ό

3 0 9 8 A _{1/1 1 6 8 OR! C; N} al iNS

Application example ■

According to the table above, a. Series of fertilizers selected, im die hypoglyfcamisehe v / irlcung at uurnalcu Mice. The compounds were either orally " or administered intraperitoneally «. Simultaneously became the scxi-.zität certain * With the selected compounds · it is the connections Fr, 2, 3, 6, 8, 11, 16, 19, 2o, 21, 32, 38 and 42.

. After checking the received Krgebnisse with these compounds, the compound No. 21 (4- Carboxyäthy] phGiioxy-2 · -. Pyridylmethan j selected for further determinations piping connection is characterized by gerrtige oral Toxisitä / t and has even at low doses. good hypoglylemic activity, that is, inheritance has an excellent therapeutic index. Further biological data on this compound are summarized in Table II.

ORKSKAL .K8PKIH) . 309 841/1168

Taliello II

Q!: Ler "dose" administered

! lit AlXo; -: un intraperi-

hs'lui ·: O. e'3 to tone al

'iüuGf .: 300 oral 50

300 oral 32

LiOl Jliäl C; 300 ■ 100 orally 64 Again 2 250 do aohx-iQJ nchen orally 30th 1 So ten) :: C] -f ~ orally 25th get'iir- ' ape sis 3unci Lii ^ n; ^! : J.ü)

309841/1168

ORlGiMAL! NSPECTED

Claims (1)

in which I ³ Y is an optionally substituted 2-, 3- or 4-pyridyl radical. a! -oxidized "or quaternary 3? yridyl ~ radical and A is a radical of the formula (HlA) ₅ (IUB) or (IHC) ' 4-ALK-O-J- -f- O-ALK · -] - -f-ALK-O-'ALK-J- (IHA) (HID) (.11IC) in which AlK is a straight-chain or branched alkylene radical with 1 to 6 carbon atoms, R ^ a carboxyl group or a group which is converted into a carboxyl or ayl group in the human body, Rp, R ₇ and R. each one Hydrogen atom, a carboxyl group, a group that is converted into a carboxyl group in the human body, an acyl, optionally esterified hydroxyl, nitro or amino group, an alkoxy, aryl 309841/1 168 ORIGINAL INSPECTED '" o ^ ä ¹ ™ or -Aryj-oxyrefci; oöcr mean an Hs-logenatoM, with the Massgalie that S. lc a methyl, cyano or. Kethoxycarbonyl group can be, if Py eiu 2-Fyx-idylodor 5-Äthylpyrid-2-yl-Ees, A is a best of the formula - ^ "" 0-CHg _- T "- wad Rg, R and R * each one Hydrogen or Ralogena-fcom are * 2 »Compounds according to claim 1 of Fcu'f.e.-l (Vl) sovJ.e whose S Mure ad αχ in the Py a 2-,;> - or ^ -Pyrirjyj.reöt, öer optionally.lr; In insta or paca style. Group Py-A-Binding rides fcinör carboxyl group or their tails, udders or Amide is an alkyl structure with an odd number of carbon atoms or one with a Carboxy.! group, whose Salt, lister or anvide-substituted alkyl radical with a; straight number of carbon atoms, is substituted, A is a residue of the formulas (ΙΙΪΛ), (ΙΙΪΒ) or (IIIC), 4-0-ΛΙΚ - ^ - - {- ALK - 0 4- Hr AIJC-Q-ALK "3- ■ (UTA) (IXIB) (IIIC) in dr.non ALK a straight-chain alkyl base with 1 to 6, in particular 1 bi.s ? j, carbon atoms and R_ and R, each one to!: or a carboxyl group whose salt, Ester or amide or an alkyl radical with an odd one Number of carbon atoms or one with a carboxyl 309841/1168 " ORIGINAL INSFEGTED is group, its salt, Enter od ^ r amide substituted Alkylrent rnden GC with a "Arizehl to Kohlenstoffatonien, wherein at least one dor radicals R and R to _1, no Wassere:. 'T-atom is specified with aer Με that υeder R nor K cine et D Is methyl "or methoxycarbony! Group ", vie.nn ~ - "v" is a 2-pyridyl or 5 ~ Sthylpyrid "2-yl-Rer.t and A cj.n rust of the formula ~ Ip-OlI ₀ J - -' is. 3. 4-Methylrherjoxy-3'-pyridylnothane '. 4. 4-n-Propylpheneoxy-2'-pyridymethane. 5. ^ -Methylbenzyloxy-S'-pyridj'lfithan. "." 6.] - (^ -Methylbonzyloxy) -3- (2'-pyridyl) ~ n-propane 7 »A-Hydroxyiiieth ^ Lphenoxy- ^ ¹ ~ pj? Ridy Im ethane • 8, - ^ -Carbox-yphenoxy - ^^ - pyridvlrnethaii 9. ^ -carboxy-methylphynoxy-2'-pyrldylmethane 10. 4-Carboxyäthylphenoxy-2 ^t -pyridy! Methane 11. 4-Carbo> r / ethyl-ethylene-pbeno;.: Y-2'-pyridylmethane 12. 4-beta-carboxyethyl-2-äthylpheriGxy ^T -pyridylmethan 15. 4-Carbamylphenoxy-2 ^I -pyridylrnethan 14. 4-Carbainylphenoxy-. "5 '-pyridylmethane 15, 4-carbamylphenoxy «4 ⁽ -pyridylmethane 36. 4-carboxyethylphenoxy-3'-pyridylmethane Ι? · 3- (6-methyl) -pyridoxy - 4'-methylphenylmethane l8. 3- (6-methyl) pyridoxy ~ 4 ^I -carboxyethylpheny! Methane 309841/1168 ORlOf ^ AL IMSPECTED " 19 «Procedure for making the connections according to -AJ ^ pi'Uch 1 bio l8, thereby g e k c η η s c lehne t, dans condensing a compound of formula (IV) with a compound üer formula (V). · B- (ALK) _n -OH H0- (ALK) _m -Py (IV). - (V) in which η and ni each have the value 0 or 1, provided now / ο, ALK and Py as in formula (-1) or (II) are defined and B is a radical of the formula (IA.) or (UA), (IA). (ILA) in which R ₁ , R ₂ , R, and R. are as defined in formula (I) or (II) = 309841 / Ί168 ORlGlHAt lf4SFEGTED 20. The method according to claim 1, characterized in that da.GS one in the way of carbodiiniid or carbonyldiimidazole condensed· 21. The method according to claim 1 and 2 _} characterized »that a halide, preferably a chloride or bromide, 'a compound of formula (IV) or (V) with a salt, preferably an ITa tr ium-- odei ^ potassium salt, the corresponding compound of the formula (V) or .. (IV) 22. Medicinal preparation - 'identified by a content a.n one Link . according to claim. 1 as an active ingredient in combination with pharmacologically compatible carriers and / or diluents .. 30 9 841/1168 ORIGINAL lh4SPECTED '