DE1817146A1 - 4-aminofuro [2,3-d] pyrimidines and their use as relaxants for smooth muscles - Google Patents

Description

Glias. Pfizer & Co., Ine. New York, N.Y., V.St.A.

4-An * inofuro / 2,3- * d7pyrimidine and their use as

Smooth muscle relaxants

The invention relates to smooth muscle helaxants, those due to a content of 4-aminofuro- / S, 3-d7-pyrimidines the general formulas

/ X

in which X and Y are identical or different and each have a hydrogen atom, an alkyl group with up to 4 carbon atoms, a phenyl or naphthyl group or X and Y together an alkylene group © with 4 The 6 carbon atoms or a benzo group,

R and H _{2 are} identical or different and each have a hydrogen atom, an alkyl group with up to 6 carbon atoms, an alkenyl group with up to 6 carbon atoms, a phenyl,

BAD OHlGiNAi.

IIaphthyl-, ß-hydroxyethy group ooer I. “unc. Y. ^ ₃ ζν-.ζΆ: \. & :. a .iorpholino-, thionorpholino- oter ^ i ^ crazi.r ... .. ^ vj '^ c ₃ where the piperazinoy group in ^J ! -otellurc el ure a cii. ; * e teasing off ator.i, an Alkylycuppe j dt bia to C ^ -Lbo. -er ;, jii.t Alkenyl ^ ruppe i.iit to su 6 C- / tons., one; lxr - "'i-'; ■« ■ haphthylyuppe is substituted,

? i ^ a Vlassstoffaton or an alkyl ruu; : 1, Li, au 6 carbon atoms,

Kjr |> rt _r ^and % the same or different jin · - ·. ..iü v / asserot off atom or an alley group rit lis;.: · '* - -'., -. -y. and

η mean a ^ anae number from 2 to 5, cc ".c: - (i? en pharmaceutically acceptable salts as Uirkstcff el-i-niii; -, io net, as well as compounds of the preceding ^{u f} _er .: anten -or: - In, in which, however, at least one of the two groups. I .. and ~, \ does not mean a hydrogen atom.

The unwanted and overi.ässice ilontraction eir.eö plate muscle can have a multitude of reasons uno. manifest themselves in a variety of symptoms, such as bronchial constrictions and high blood pressure. This. The problem is caused by different kinds of medicines, depending on the cause and focus of the disease.

It has now been found that the compounds according to the invention are at least partially effective. The relaxation agents for flat muscles, since they are unable to influence the aenosine 3 '>5''onophosphate 3: e3. In the smooth muscles This phenomenon is based on a bronchodilator and antihypertensive v.'irkunfj. II. Gehwald describes in Ciien.Ler., Volume 99, S. Ioo2_ (1966) the synthesis of certain basic aminofuro- / 2,3-d7pyrimidines. Ils was, however hitherto not known that these compounds have a valuable pharmaceutical activity.

909848/1378

Jic ei * fintajn "G; jciai-ISen connections are in relaxation verLraEpftei- Ilusboln, s.B. the lironchial muscles effective unt. can follow this «» .'eck alone or in combination nit cinoi- piiarrtaaeutiscii compatible tracer. i.-esoriders -uirlisa: ** sine the connections of the I'ori.iel I.

Zie furo- / C _a 5 "-" 7 ~ py "ii-iciine of the present jürfindun ^;» who "have a nieiii suLstituicrte- A :: inorruppeaer ^ ₁ -Htstellung, köraiGn iiacli the ;. ¥ ei * faliren von ßehwald her fees informs four, in which a uC-Lyörox ^ ketone rit ilalononitrile in Ge ^ envmrt a base Lont. then cyclized with Porn.ar.iid This method is however for the substituted

inctaiüen. ie compounds of formula II and those of]? orael I. in which R ^ and R _{2 are} not both hydrogen, not applicable. In order to obtain these substituted aninoderivatives, a conversion * which proceeds analogously to the J | e £ i £ @ en of üehwa.ld cannot be carried out using appropriately substituted compounds.

Ss MUPiäe found * that the substituted amino derivatives, nit 'iltisciahiae of Konso- and B. ^ jTjC-Tetrah ^ droleichen, synthetically produced according to the following reaction scheme

will know: ■

CH (CONlI ^) ₁

HO

YTl

The first stage of this reaction scheme consists in the condensation of a corresponding Φ -chloroketone or & -chloraldehyde of the allcenein formula:

! I

X-C-C- (Cl) -Y,

in which X and Y correspond to the substituents of the second product, with eii: ei: alonic acid ester. Liiaethylnalonat whose iTatriunsfil ^ facilitates I'ondensation is for this ^T Z.:. Ecl "^ oei; _r.et This Caiz Uird in the usual way under 7c-r ;; cndiai _L x ^ on ITatriurihydric in an inert. LoüunosriittG-lj irie zL Diiiethylfornaraid, Lenzol, i ^ ether or one; ar.t.cre-n-, non-hydroxyl-containing solvent produced, r.ao <A-Chlorl: eton or -aldcliyd l: ann then directly the Lc · Sun _w des Calzes des "ialons." Ureesters to control the reaction, preferably added dropwise. The use of about equi- molar amounts of substances gives satisfactory yields; to be critical.

6/1376

Ls is sufficient to simply cool the reaction mixture to room temperature after the addition, uj? To obtain the desired product, which can then be separated off according to the usual method. For example, are distillation or. Extraction excessive process. An eromketone or aldehyde can be used in place of the above-mentioned chlorine compounds.

To the reaction of the carbonyl groups with those in the following To prevent steps used to prevent reaction texlniiern, the i-ethylene ketal derivative of the original Condensation product produced. The ketal can by the usual acid-catalyzed reaction with XthyXenglykol in a common inert solvent such as benzene, Toluene or another solvent which forms an azeotropic mixture with water. A useful one The catalyst is p-toluenesulfonic acid. The time is not critical, but reflux temperature should be used to keep the water in the azeotropic mixture. Hours of reflux treatment in benzene were often found than necessary to obtain a satisfactory yield. The ketal can expediently by extraction be separated from a v / äs aqueous disodium bicarbonate solution. -. . -

The ilalonate ethylene ketal derivative thus obtained is then treated with excess ammonium hydroxide or liquid ammonia into the corresponding halon amide ketal convicted. This substance is then used in ethanol Hatriuinäthoxyd dissolved, preferably at least about 2 hol equivalents of sodium ethoxide in the solution are available. To this solution are added an ester of a Alkanoic acid IU-CO 'H, in which R, the desired substituent in the 2-position of the end product. For example, ethyl formate leads to an unsubstituted in the 2-position

909848/1570

BAD ORlQI

Tuted pyriiuidine and ethyl acetate gives a 2-methylpyriiridine. Rairz periodi ^ e reflux treatment of the received Mixture gives a satisfactory yield of 4,6-dihydroxypyrinidine, .With extended accordingly Reaction sides lower temperatures can be applied. Jas product can by failing the free

The blocking ketal group vf.rd removed by treatment with concentrated hydrochloric acid. The cyclization of the furo "/ 2 ₃ 3" d7-pyrimidine is then effected by heating the free carbonyl compound obtained in an excess of polyphosphoric acid. Reaction temperatures between about 130 and 150 ° C. and reaction times between about 15 and 10 minutes are appropriate. 3o-minute heating. about 140 ° C. was found to be sufficient to give the desired puro / 2 ₃ 3-d7-pyrir.iidin-'l-one, which is expediently obtained by precipitating the free base from aqueous solution.

The puro- / 2,3-d7-pyrimidin-4-one is obtained by treatment converted into the corresponding 4-chloro derivative with excess hot phosphorus oxychloride. 1/2 hour Refluxing the mixture provides a high yield of the chlorinated product which is also easy is obtained by precipitation of the free base from aqueous solution.

Treatment of the 4-chloro compound with an appropriately substituted amine leads to the desired 4-amino-furo _{-o / 2 a} 3-d7-pyrimidines of the formulas I and II. For example, diethylamine gives the ^ -dimethylamino derivative. In the Heroa position of the compounds of formula II, in which both ^ nitrogen atoms of the alkylenediamine at least one water '

**>Stoffatom'tragen can ^ ach of the nitrogens of the pyridine-pyrimidine Oi be bound. If the alkylenediamine is asymmetric, a mixture of two products is formed.

For example, N-methylethylenediamine would lead to a mixture of compounds of the formula II, which have as R |, / R _r /R.substituents V / hydrogen / hydrogen / methyl and ethyl / hydrogen / hydrogen.

The production of the desired amino derivative is expediently carried out in a medium such as refluxing ethanol, the amine, if it is a gas, being blown through the mixture, a reaction time of about one hour is sufficient at the reflux temperature of the ethanol , longer reaction times at lower temperatures being more appropriate. % The product is expediently obtained from the reaction mixture by recrystallizing the residue.

The 5,6,73 G "tetrahydrobenzofuro ~ 72 _a 3 · - d / -pyrimidines which have a substituted amino group in the '! -Position are obtained from the corresponding furo / 2,3-d7-pyrinidine- ¹ ! - on analogously to the process described above, that is, the furo- / 2,3-d / -pyrimidin-'t-one by treatment with phosphorus oxychloride into the ^ I-chloro derivative and the M -chloro derivative finally by treatment with öeri substituted \ anine converted into the desired ^ -anino compound j

will. The 5Jf's7aS-tetrahydrobenzofuro- / 2,3-d7-pyrimidine- i "

They can be used more effectively by nitric acid oxidation of the corresponding (unsubstituted) amino compound _; en received. This reaction, by adding ': ^T atriunnitrit to a solution of the amino compound in v / ässriger sulfuric acid are performed. The reagent should be added carefully in order to keep the reaction under control, for example by adding dropwise an aqueous solution of sodium nitrite. It can also be advantageous to use aas reaction mixture

46/137 6

ßAO ORKjiiNAL

IJ

to cool during the addition. Using a Excess of the reagent often leads to a good yield. Reaction time and reaction temperature are not critical, although as stated above became, because of the exothermic nature of the implementation a relatively low temperature is desirable. More hours are usually enough to make a satisfactory To obtain yield.

The productMi according to known processes, e. £. separated by precipitation, extraction and the like. That. Furo / may then, 2.3 ~ d7-pyrimidine are performed as described above in the 4-chlorofuro ~ / 2 _J 3-d7-pyrimidine ⁱ + -one.

Simple synthesis of the various Ji-Amino-benzofur..o- / 2 ₉ ;} - a7-pyrimidine consists in the dehydrogenation of the ^ corresponding j _s G> 7, 3-TetrahydrobenzofμΓ0- / 2,3-d7-pyrimi.dine , 2.L .. by '.Jx ¹ IiItzen with sulfur in Deealin, or wit Palladium / Xohle. The heating of a solution of the tetrahydrobenzo compound in dccalin and at least two equivalents of fine powdery powder leads to the development of hydrogen sulfide and the formation of the desired benzo compound, which can be obtained in the usual way, e.g. crystallization or precipitation can be purified by Umlo'istallisierung or 'Chromatographieren.

Lie erfino, uncleared compounds inhibit the activity of the cyclic 3 ', 5' - ucleotide phospliodiesterase, which is known as an enzyme, which converts adenosine 3 '»5' ~ ^ i.ionoplibsphat (cy'clisches 3 ', 5'- ALP) to Ade-nbsin-S ^ -riono - "^ · ^/ phosp'ha't (5 * -ΑΊΤΐΤ ¹ '! Rat'alysiert. Lei systems with PhDsphpu> 1 diesterase'al: tivitllt ^r , b'ei those it "desires a 'jjj high Spiager ^ nVyciiDchei. 3', 5'-Ai-? upright to'er-""can use the successful π verb indunge? ₇ with

BATH 0R «3 | n _Al>

They are so effective as inhibitors of the activity of the enzyme that concentrations of only 10% and lower are sufficient. The ability of erfindungsgenäßen compounds Snzymaktivität to herinenj is important because it is known that many tissue cyclic 3 '>5' Kucleotidphosphodiesteras? activity and that the ilononucleotide cyclic 3'35 '"AMP is an important regulator for numerous cell and tissue processes, such as the relaxation of smooth muscles, lipolysis and glycogenolysis.

The compounds of formula I ₉ in which R ^ and R_ each denote either a hydrogen atom or an alkyl group with up to 6 carbon atoms are preferred agents for inhibiting enzyme activity, especially when X and Y are a hydrogen atom or an alkyl -, phenyl or tetrahydrobenzo 'group ^ mean. Specific compounds which are particularly effective as phosphodiesterase inhibitors are ^ -diethylamino-6-phenyIfuro- / 2,3-d7-pyrinidine and 4-ethyamino-5 » 6 > 7 » 8-tetrahydrobenzofuro- / 2,3-d7 -pyrimidine and 4-diethylamino-5,6,7,8-tetrahydrobenzof uro- / 2 ₉ 3 * -d7-pyrimidine. The latter is particularly suitable for this purpose. .

The compounds according to the invention inhibit the enzyme activity in the smooth muscles, a phenomenon which is known to be related to the relaxation of the smooth muscles. 2 B. it was found that theophylline _s papaverine and many other kracipf solved i-Iittel for. the smooth musculature _r the'Phosphodiestierase 'in the smooth musculoskeletal system. inhibit literature. It was also found. That the compounds erfindungßgemäßen the smooth muscles aowoftl hei animals and in Standap € -in vitro Teats efttapänneni Of course, the effectiveness-del? respective connection with the different types of Mu $ k ^ lg®w ^e ^ ö ⁿ and the selection of the connection to ye3? abi? d | .öhendeji.

- Io -

from the tensioning tissue. However, the terbinunions according to the invention all cause a breach. ^ evor ^ u ^ be means for this "'./eel. üinc. j 7 i 3-t etraliyürobonsof uro- / 2,3-f.7-v-.yrimic.in,"

• 'l-Dii / efchyl-ar.tino-Cr. cthylfuro - / 2,3 ^< -d7 ~ pyrii..idin and

ur O- / 2 ₃ > -d7-pyriridine.

The erfindungsgenä.r> s compounds can be considered 'lelaxantien be administered for a specific tissue smooth Iluskels same W I / else like other previous ilittel for this purpose. In general, the compound will be administered with a pharmaceutical carrier, the choice of which will depend on; Yerabreichur.gsweg-e and. depends on normal pharmaceutical practice. For example, the compound can with various pharmaceutical acceptable inert carriers to form tablets, capsules, lozenges, pills, hard candies, powders, Sprühnitteln, aqueous suspensions, 'sions or solutions, injectable solutions, elixirs ^' syrups and the like are processed. Such carriers are solid diluents or filters, sterile

aqueous iledia and various non-toxic organic ones ^. Solvent * You can also use the oral preparations to be administered for this purpose Sweeteners or flavorings are added.

The particular carrier used and the ratio of carrier to active ingredient are determined by the solubility and ^! chemical nature of the therapeutic compound "the overall \ ι chose Verabreiehungsweg and the needs of ordinary pharmacist Iselien practice determined" VJo these compounds, for example orally in the form of afclefcten ^ * "'"

Tt-lger, like s * B, lactose,

υηά i *

will use * ^ 9V9 & idL & äi & nm-

- li -

Such as, for example, starch, alginic acid and certain complex stearates can be used together with lubricants such as, for example, ilanesium stearate, sodium lauryl sulfate and talc to produce tablets for the oral administration of these compounds. Door the oral 'administration in the form of capsules In ₃ . Lactose and high molar polyethylene glycols are among the preferred pharmaceutically acceptable tracers. VJo what other suspensions are to be administered orally, the inventions can do. Compounds with dissolving or suspending agents can be combined. Even dilution - Λ f mitt el- such as Jlthanol, PropyleiiLlykol, glycerol and mixtures of these substances can be used in addition to other shake.

• For parenteral administration and inhalation, solutions or suspensions in sesame or almond nut oil or in aqueous propyl glycol solution can be used. Sterile, viscous solutions of the soluble acid addition salts described below can be used. These respective solutions are particularly suitable for intramuscular and subcutaneous injection. The aqueous solutions _s einscliließliclj derjenic.en the Eeureaddit ions salts in pure idestillierten. Water are also suitable for intravenous injection, provided that their value has been set accordingly beforehand; ^r urde. Such solutions should also, if necessary, be appropriately buffered and the "flow if; e ■" Äe.rdünhunr.-si.jittel should be accompanied by a sufficient ;. ί _? 8-1 · 5 ~ .odor Glukoselöaunj isotonic c ^e ~ mac]). T vi

iq .- ^ eiTlvipj ^ m ^ qp can be sent to patients nit iironchialverenGun'j., 4ur-ch Dispensers or other devices administered ve. rpenj .. ..that .possible that the!. "irkatpff in unr.ittalbaren ^ oi ^ takt init .cien constricted tissues of the

'90 9848/13 ^^ r ^ Vi, ^ at

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of the patient. ',,' ground as a spray in the form of a 1 percent. Solution administered, then a one to z; ieii.iali; _: , e actual j'.nwendunc preferred ..

The active ingredient should make such a JIen; depending on the preparation, because. °. a, -. eeicnctc Dosieruir ~ _, sfora is obtained. Obviously, different dosage regimes can be used simultaneously; administered. In certain cases, tubes with an actual off content of less than o ₅ oo5 Geu.f can be used, it wii'o. However bevorsu: t,; 'ubereitm: ;; he. 211 use ^ the iiicl'it ireni ^ er as 0.005 Get: .- '' öcz '.irLßtqffs included, ca otherwise the ^r ->"c; err er;. ^R _; e i'." .- <QW. 'ü £ i; . .; rc £ vrird. i'ie 1, 'irkun;¹; increases rit C.cr "..onzentration cec * irkstoffes. The preparation can Io ₃ 5o, 75" or 93 nehr ücwichtsprozent of ΐ / irkstoffes included.

ucr doctor bcstira.it _: the most suitable dosage depending on age, weight and external reaction of the jevieili ^ en] ³ r.tients as well as the iJatur and Ausi / aile eggs oynptoi-ie and ccn phc.rrnakolof_; ijcLen Ii ^ enschaftc -; * c.es jevieils zv, administering iiittels abhün ^ t.II-i all ^ ei.eine become /.ϊ:Γα: _ο small-doses at alli.iahlicher ttei, - erun ^ oer i ^ osicrun ₍ ^r ; administered until the optii. as ^ io. ^ el is reached. It is often found that ". when administered orally, greater amounts of active substances are required", u; ... c. to obtain the same gpior.el, uer achieved with a small parenterally administered Ilen ^ e ;; iro. Apparently leads to a dosage; from etvm Cjo2 to etv; a 2co rx; j of the '..' active ingredient per 1: ^, body £; possibly, the is administered in a single or in real ./dosierunssunss, su an effective ^ esserunc the Eronchialverenterunf;. Of course ^ i ^ t it is Linzelf all, where higher or lower dosage concentrations are desired, and cii e also fall into the Hahiaen of inventions.

903848/1376

ORIGINAL

1817U6

The compounds according to the invention can expediently be administered in the form of pharmaceutically acceptable salts. “Pharmaceutically acceptable” salts are understood as meaning salts which essentially have no greater toricity than the free compound. The pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of mineral acids, such as s.-Ij. Hydrochloric, hydrobromic, hydroiodic, phosphoric, ₃ iletaphosphor-, nitric and sulfuric acid, and salts of organic acids such as tartaric, acetic, citric, Ilalein-, üenzoe-, glycolic, gluconic,%

Gulon-j Bernstein "and aryl sulfonic acid such as p-toluenesulfonic acid.

The pharmaceutically incompatible salts are not suitable for therapy, but are valuable for obtaining and leiniguhg the new prebindings. They are also suitable for the production of therapeutically valuable, pharmaceutically acceptable salts. The more fermented salts of this group are obtained using hydrofluoric and perchloric acids. Ilydrofluoride are particularly valuable for Lerstellung the pharmaceutically acceptable salts, for example the hydrochlorides can j by solving the Lydrofluoride in hydrochloric acid and crystallization of the Eydrochlorids thus formed are obtained.

The ability of the present compounds to phosphodiesterase is not only limited to chemotherapeutic application, but is also of great use for various biological in vitro systems. In Cases in which one can see the properties of certain other enzyme systems than phosphodiesterase .determine will ', it is often impossible to have different effects without prior to loading inhibition of phosphodiesterase activity.

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watch and measure. For example, Jr Turtle and Ij.; .. iifonis, biochT] ocal and Biophysical Research Communications, j_d. 2C ₃ 3. 797 O- 67) an inhibitor for uie Phospiioc.iesteraseea 'activity, "to elucidate" certain "characteristics of the Ader.ylcyclase system. However, so far only two" substances have proven to be suitable for this field of application, namely the xanthines, theophylline and gaff a. The use of these two means, however, brings with it considerable disadvantages, which are mainly related to their potency and solubility properties. 'Jie erfiiidun ^ s ^ emiTen compounds have' zujcix.dest a similar potency as inhibitors of Phospliodiostei'aso and außerr.em ^ sor t rtie diversity of substituents' for a different ^T -öslichl: eit, a unterschicc, -liches Veri. ö.ieiij the muscles zv. diirchdrin ^ jen and for advantages in specific musculature weavers *. The compounds according to the invention therefore offer a wider range of conditions and processes, since it is not necessary to adapt these characteristics to the requirements of a specific inhibitor of phosphodiesterase.

The ability of inventive connections that ■ To inhibit phosphiiodiesterase enzyme, they macnt except c.-sr, for aie i ^ rhöhuni, c.er I. water permeability uhd den Με.ΐ? ίοηοη-transport of well-known membranes of animal origin, suitable.

^T ». ^T hen it is also desirable under bestimiuten Umstünden is aas cyclic 3 '> 5 ^T--AliP lTuk.leotid get from biological sources, then the erfindun ^ s ^ are emäßen connections to u, eviinnunk a larger ßtöffnende. Ms ;; was observed that theophylline de, n levels of the cyclic 3 ¹ >5'-AIIP; with certain iles around l. ^ oo; ' increased, una giq

Connections have a potential of

£ lcieher order of magnitude.

For diagnostic! - 'wake sur ^ eotij.-iaun ;; of the cyclic 3 ', 5' ~ / - ^T "'P-Gpie ^ clB in various animal oeVGbon, sine: the compounds are often valuable, everywhere -ro in experiments 2 to determine the content of cyclic:. · ~>', 5 '~ ΛΙΙΓ in tissue inhibitor of cyclic IS'j?' - is required ■ ITuQleqtiuphosphodiesterase ₅ can the _erfinuun;; safety-, er.aPen compounds beneficial use..

It viird an ^ eno: .i:.! En, cla. ^r . !. the Verbinounfjen the Toriaeln I u ^ id I in which JI a ΛIkο: rygruppe nit up to k carbon atoms> in particular means a Hethoxycruppe, v for chemotherapeutic like apeutic and biological "corner as well, are" ertvoll how the compounds of the formulas I and II, in which ~ * Z has the same meaning as above. ^T J: * ei also these yerbincuncen. in which X is an alcohol; es tsvreclä ^ äri ^, in the process use the diethyl acetal of chloroacetaldehyde su.

Tie nachfoisender: r> examples serve for further explanation the invention.

^ί ί-L · i:, ίethylauino-6 · -nethylftto- / 2. ^ ■ 3 * 'd7-pyril, ₁ idin .

..
/ .. IHi.ietliylauefconyli.;. Alonat ·

ZC ¹ I ₁ Z Dinethyl: .ialonat (2 ₃ ο lii) vairden drip-icing of a dispersion of atrium hydride in 1,5oo ccn di-diethylforuanid etched. To keep the temperature below 65 ° ε zn . "\ x of this solution were" 1.5 "g of freshly distilled chlorine tint (2.0 Hol) drop by drop, the temperature being kept below 65 ° C. The pale brown dispersion obtained was allowed to cool to room temperature and then poured into i 500 ccn / water. The aqueous solution from 909848/1376

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-IC-

then extracted with vior 2oo cc portions of ethylene chloride, the combined ethylene chloride extracts dried over sodium sulfate and evaporated. The oil obtained was distilled, and after a first run of dimethyl malonate, nan received 222 g of the desired product as a clear, colorless liquid.
(59 / "itSe yield) Boiling point: 135-146 ° C 12 now Hg, ηψ l, 44oo.

The sample purified by gas chromatography had an optical rotation of n ,, " ⁵ = 1.4379 ·
Analysis calculated for CoIx ₁₀ Or-: C = 51, oc; Ii = 6.43 .;

found: C = 'oil »111' ^ - 6.4n

B. Dime thy lace tony lr.ialonate ethylene ketal

A mixture of 174 g of diraethylacetonylraalonate (ο, 92β mol) from Section A, 57.3 g of ethylene glycol (0.926 ϊΐοΐ) and 100 mg of p-toluenesulfonic acid in 1, ooo ecm of benzene was stirred for 16 hours at reflux temperature in a water separator, in which 22, ο ecm Uasser xiurden xiurden. The solution obtained was allowed to cool and then poured into 500 ecm of a sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and then evaporated to give the desired product as an orange oil.
Yield: 205 g (95.4 %) ru ⁵ = 1.4543. A sample purified by gas chromatography had an optical rotation of n ^ - 1.4465 Analysis calculated for ^C j_ _o ^H ig ⁰ 5 ^{: c} = 51 j72; Ii = 6.94

β Found: C = 51, c5; K = 7.08

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C. Acetonylualonarnidäthylenenketal

ü) A solution of 200 g of diethylacetonylmalonate ethylene ketal (0.16 Hol) from Section E in 500 ccn of concentrated AM ionic hydroxide solution and 100 cen of methanol was stirred at room temperature for 20 hours. The ■ dispersion was filtered and 'washed with ethanol! To give the desired product as a white crystalline solid jf.

Yield: 99.0 g (57 %)

Melting point: 177-178 ⁰ C.

The filtrate was introduced into a guinmiartigeir riüefcständ%

concentrated, which was triturated with methanol, giving a further 26.0 g (15% yield) of the white Ia (E ¹ staline product with a melting point of 171-173 ° C. The total yield was 72: Zinc analysis sample was prepared by recrystallization from ethanol, melting point: 177-173 ° C.
Analysis calculated for C ^ ₁ ^ iT ₂ O, _} : C = 47.52; H = 6.90; 1T = 13.36 ^I.

found: C = 47.53; H = 7.12: M = 13.9;

D. 5-Acetony1 ~ 4,6- dihydroxypyrimidine ethylene ketal

Sine solution of! Tatriumäthoxyd in ethanol xfurde by adding 28 _'3 5 E (1.24 .lol) of metallic llatriums made to 1.2oo ecm viasserfreiei.i ethanol. To this solution x; urden 125.0 Z acetonylmalonamide ethyl ketal (0.62 mol) from section C was added, which almost completely dissolved. Then 92, og / -; Freshly distilled ethyl formate (1.24 Iol) was added, a precipitate immediately forming. The resulting dispersion was stirred under reflux for 1.5 hours, cooled and evaporated to remove most of the ethanol. The residue was dissolved in 1,500 ecm of water and the pii value was adjusted to 6 with concentrated hydrochloric acid. The mixture

90984871376

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-IG-

was filtered to give the desired product as white to separate crystalline solid.

Yield: 0.05 g (65 / '.')

Melting point: 200-220 ° C. (decomposition). An analytical sample was crystallized from dimethylformamide.

Analysis calculated for C ₀ II ₁₂ IT ₂ O ₂ ,: C = 50.94; Κ = 5.7ο Γ = 13.2ο

found: C = 50.62; l; = 5.33j 11 = 13.40

E. 5-Acetonyl-4,6-dihydro;: ypyrimidine

A solution of 83.0 g of 5-acetonyl-4,6-dihyaroxy.oyrimidinäthylenenketal (0.39 KoI) from section D in 175 ecm concentrated hydrochloric acid was stirred under reflux for 15 minutes. The resulting yellow solution was cooled to 0 C, and 800 ecm of ethanol were added. The mixture was filtered to separate the desired product as a beige crystalline solid.
Yield: 44.0 g (67 Ji)
Melting point: 240-24 ° C (decomposition) The analysis sample was recrystallized from V / water. Analysis calculated for CK ₀ UpO -.,: 0 = 50.005 H = Jf, Co; I. ' = 16.66

found: . 0 = 49.93; I: = 5 _a oo; ll = lC, k5

F. 6-Methylfno- / 2 ₃ 3-d7-pyrimidin- ^j i-one

2I0 ecm of polyphosphoric acid were mixed with 42 g of 5-acetonyl-3,4 ~ dihydroxypyrimidine (0.25 ilol) added from section ϊ-i, and the mixture was heated to 140 ° C. for 30 minutes. Laugh for 15 minutes everything had completely dissolved. The solution was cooled to room temperature and slowly with vigorously Stir poured into ice water, after neutralization with about 1 ounce of concentrated ammonium hydroxide the dispersion was filtered to separate the desired product as a beige crystalline pesticide.

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Yield: 33aο C ^(CC;);
Melting point: 228-230 ° C

G. 4-chloro-6-methylfuro- / 2 _a 3-d7-pyrinidine

A dispersion of 31, ο g ⁱ ! - chloro-6-nethyifuro- / 2,3 ~ d7-pyrinidine-- ^! The solution was cooled and concentrated. The backwater ¹ , concentrated AKimoniur.hydroxydlösung was slowly added to 5 ° o ecu and filtered to

- Desired product to be separated off as a crystalline solid. Yield: 35jO g. (1oo; ')
Fast point: Ö5-S3 ° (3.

.Bine analysis sample was made from a liethanol-V / water mixture produced. Melting point 80-81 ° C

Analysis calculated for C ₇ K ₁ -II ₅ ClO: C = iJ9 _s 37j H-2 "991 " = 1 ^, 62 ^

' ^{D ά} Cl = 21 _s o3

found: - ΰ = ί} 9, υ ^2!; K = 2, CG | Π = 16.67;

Cl = 2o _s 7u

H * 4-pinethylajainO "C ~ men) bylfuro- / 2 ₃ 3 ~ d7-pyrimidine

In a refluxing dispersion of -: ₃ o r. ⁱ {-Chlor-5-methylfuro ~ / 2j3-d7 ~ pyriirddin (o _a o230 hol)

itt 3 in 100 ccn absolute ethanol was 3'o -minutes c Dinetliylasuin oine blown, and the solution obtained was heated for a further 30 'minutes. ITach evaporation to 'rroclcne _s was recrystallized from 75 cc of hexane llückstaucl to the analysenreinc Trodukt in the form of large beige iladeln

z, 7 ε (Sk ;; ig)

n :: t: "io7-lo9 ° C.
Analysis a calculated for C _n II ^ ₁ : ^T -, 0: C = Cl, ooj H = 6 _S 26; 17 = 23.72

found C = Cl, 2?; · E = 6.33; .: - = - 23.75

909848/1376

■ - 2 ο -

^ e i.spiel 2

Ilan proceeded according to Example 1 with the subordinate rule in section L an equivalent instead of di ^ etliylatins I-icncG Annoni-ak or an appropriately substituted anin den r.eaktionsGcr.iGC ^ sufjosetzt was. 'Those listed below Products were thereby obtained and from the advertised Solvent crystallized.

CL,

üsuiiysmittel f.d. uchmelpunkt,

Uiii crystallization

ι: t C ₂ II. E. UasGcr π -IT- (CI C ₂ L ₅ "•• 'ater ^C 2 C 5 > v i ₂ ) ₂ - liethanol / IJasser
benzene from HCl (SaIz) nc ₃ i: _7th
I. ' i-propyl ether Ii Eexan (CIi ₂ ) _o

177-179

2-C3

oil

'3-Sun

166-167 187-189

109-110

90-91

Iiethanol / IJaBGer Io3-lo4

909848/1376

BATH ORIGINAL

Example 3

Γ ^! οχΐ: Proceeded according to Example 1-P, with the difference that instead of chloroacetone "equivalent IIs: en 3-chloro-2-titanone and H-chloroacetophen-one were used ₃ where" methyl - ^ - methylacetonylalonate and dimethylphena-. Cyli.ialonab received. These two diethylalonates were added to the reaction flow of Example IB-H using -, JOTxOn _3, with an equivalent similar alumina or the corresponding anine being used in section B instead of dimethylamine. The products below were retained and recrystallized from the precipitated solvent.

lif \

IL

Solvent f.d, uncrystallization

Melting point C.

CT
J ■ IX; j ix cn CIi- CII 3 CIi ₃ CH ClI-, Ck 3 K Ii GAU
Ü "j α,
JLJ. H GK

. "ethanol / yasser I Ie t hano 1 / T / a s s er Γ ie than oil Methanol / ethanol / water

193-194

84-35 250-252 196-197 95-96

Example 4

flan proceeded according to, Example 1 using an equivalent Hen ^ e dee corresponding <& - G'hloroketons in Section A and an equivalent. Amount of ammonia or the corresponding amine in Section H and received the following products: 909840/137 *

i.

^h l

^U 2

Ii
nC

pt '

KJi--

n-C,

CII-, nC ₆ K _:

; ₂ ) ₂ cF- = c (cir ₃ ) ₂

CL ₀ CH = CL _n

i,

GIi ₃ CK-,
■ J 1-C ₃ II ₇ i-C A- CH-,
j C ₃ ^C 6 ^ll 5 H

ο

CII-, 3

-O-

Kj fix r- D 5

^C lo ^K 7 CL ₂ CH ₂ OL

CIi ₂ CIi ₂ OII

₂ ) ₂ -0

- (Gi. _O ) _, -5; ~ (Ch ₀ ) ρ -

CI-. S- (CI

^C lo ^H 7

- (UI. ") _O -i - (C -.-.

- (. cn.

c.

■ (CH ₀ ) _O -N

E ₂ ) ₂ -

909848/1376 ORIGINAL

■ "- ■ -. '■ .- ■■" - 23 - Example . 5

Repeating the procedure of Example 1 with the difference, since: "!, in section D in place of an equivalent amount / was used ithylacetat of Athylforniat and the desired one-ty-Dimethylanino 2 ₁ 6-dLnethy If uro- / 2 _s 3-d7 pyriirddin received.

Example 6 \

Man _: VQ drove according to example 3 ir.it the difference. c "af> instead of the ethyl formalinate iir. Section D an equivalent, low-ethylhutyrate was used and nan foli" oncO was preassembled:

YR ₁

CK ^ cii _r ir απ ..

CZ- CI_ CK-. Cl · -.

'5

CH-

CK,

Example J

; t '!, v'lanir.ou-raethy.If uro ~ / 2 ₅ 7-d7-pyrii :: id in

One follows "after. <? Ispiel 1 With c'ei. Difference, there." · Iu '/•.Bßclmitt-anötolle des Pinethylaiiins an equivalent ! 'eriL'e Diariiicr.ethar. uses v? urcTe and i.iah the desired,

909848/1376

4-aminomethyiamino-6-methylfuro- / 2 \ 3-d7-pyrimidine -

received.

Example 8 . ·

- ι

Han proceeded according to Example 3 with the difference that "in Section H an equivalent Hence l-amino ~ 2-dimethylaminoethyl or l-amino-2-methylaninoethane was used. and the following products were obtained:

3ii "CL,

X Y 3 9 i:
K S. H CII-
'J
CIU Γ'ΤΤ
3 CII-, ^0E 3. CE
3
H • j II J, - ■ E. ^C 6 ^I: 5 Ii . il CE _T ' CH-, ^C f ^K 5 Ii CE,
'j CH-,
j i: ^G S ^K 5 Il H example 4-amino-5 C-tetrahydrobenzofuro / 2J3-d7-pyrimidine

The desired product was obtained by ion denaction of -hydroxycyalphexanone with ilalononitrile and subsequent ring formation with rori :: ari-id according to the method of I '. Gehwald (Cheu.Der., Lu. TS ₃ C 1οο2-7, - ± * (· Χ.) Produced.

9098 ^ 8/1376

ßAD ORIGINAL

Leisjiel Io

3 ₃ 6., 7 j G-tetrahydrobensof uro- / 2 j 3 ~ d7-

Λ. 3j6,, 7jC-tetrahydrobengofuro- / 2 _a 5 ~ d.7'-pyrijiidin-4-one

loo - '! - ι: ino-3a 6 j 7,3-tdrahydrobonsofuro - / 2,3 "d7 ~ pyrii: iidin (ο _Λ 33 JoI) ₅ which was produced according to the method of Example 9" .roraen var ₅ was a cold solution of 1.25o ccr.i water and βοο ecu sulfuric acid added. "Jährend to uie temperature held at lo ° C, this solution was added dropwise 3o !!! long grooves 157 S NatriuRinitrit (2 ^ 3 HOI) in ä 3S0 Wassej ecm / zupesetzt. The mixture was stirred an additional hour and then to ⁰ The precipitate obtained was filtered off and the desired product was obtained.
Yield: 60 g (60; ■)

;. 179-13l ° C

liin Cfeniisch from 55 ₅ og 5>i> _J 7S8-l ¹ etrahydrobenzofurO- / 2 ₃ 3 "'d7-pyriiaidin-H-on (o ₃ 29 mole) from Section A and 5oo cc Pitosphoroxychlorid was stirred under reflux The solution obtained was cooled and concentrated, and the residue was slowly added to 1,000 ecm of cold concentrated ammonium hydroxide, after filtering the precipitate obtained, the desired product was obtained

Yield: 6 g (6o %) '

Melting point: 123-126 ⁰ C

liine analytical sample was recrystallized from ethanol; Melting point: 133-134 ° C. '

Analysis calculated for C ,, H _{s 0} N OCl: C = 57.56; Η = 4 »355Ν = 13.435

^{1σ 9 ά} 01 = 16.99

found: 0 = 57 ^ 35 H = 4 ₅ 29; H = 13 _a ^ oi

01 = 16.93

90 9 848/1376

pyrimidine

Into a stirred, refluxed dispersion of Io g il-chloro-5> 6a7a0-tetrahydrobenzofuro / 2,3-d7-pyrimidine (ο, ο ^ ίδ Zlol) from section B in loo ecm of absolute ethanol was 30 minutes long; Dimethylamine was blown in and the resulting solution was heated for a further 30 minutes. I: After evaporation to dryness, the residue was uncrystallized from an Ilothanol / Viasser and the desired product was obtained.
Melting point; 97 ~ 99 ° C

example Ϊ1

Ian proceeded according to Example Io with the difference that in section C instead of the dimethylamine an equivalent length of the corresponding amine was used ₃ and the following products were obtained:

II

II
H

R ₂ Solvent fd
Recrystallization rch-.ielapur CH ₃ Ilethcnol ^ Or: * "" · ■ s * ·. C ₂ H ₅ lie than oil : '.. '; ^: - C ₂ II ₅ lie than oil / V: ε. sr, he - .....--:. C ₆ H ₅ Ethanol CIi ₂ CH ₂ OH iithylacetate

909848/1376

BATH

> 27 -

Example 12

^ -Amino - 2-methyl-5 »6,7» 8th trahydrobenzof uro- / 2,3 ~ d7-pyrimldine """

■ f ■■ "-" ■ "■; ■" ■ ■ - ■.

The procedure was as in Example 9 with the difference that in step B, instead of: Formamide, an equivalent amount of acetamide '. was used.

Example ig

~ 5 » 6- ^ hexamethylene furo- / 2 ₃ 3-d7 "* pyrimidine

The procedure was as in Example 9 with the difference that in λ section A an equivalent amount of ^ hydroxycyclooctanone was used instead of ^ -hydroxycyclohexanone.

Example 15-B

4 ~ dieth ylai.i _i inoäthy.lami n _i or-5 _a 6 _Λ 7 » G-tetrahydrobenzof uro- / g, 3 ~ d7-pyrimidiii

Example 10 was followed with the difference that in section C an equivalent instead of the dimethylamine Iienge ß- (diethylaminoethyl) -amine was used, and obtained the desired product as Eq. The hydrochloric acid '

addition salt melted at 212 ° C. \ i

Pharmaceutically acceptable salts

The hydrochloric acid addition salts of the crind to the pure Puro / 2> 3 ~ §7-pyrinidines are produced by the fact that nan

909848/1376

BATH

1817148

an allcoliolisefcie solution of the bases, prepared according to the procedures of Examples 1-3 and. _S were äergestellt SH with wäßs-. mixed hydrochloric acid and the resulting solution "evaporated.", ...--

CIU

.CE-CH-,

CL,

H K

■ II L

^C "3 Ii CIi- CH ₃ CIi ₃ CH, CL, en. ^C 6 ^E 5 H C H H

R.

i:

Il

Γι

CIi,

6 5

_? .H"

cn, I

(CH ₂ ).-IT- (CiI ₂ ) ₂ -

Il

II

Sehmelapoint C

.227-228 '

I? D-IT!

221-223 17-4-176

H 273-276 CH, 257-259 Γ ^{; Τ} Ϊ 105-136 CIi ₃ 246-247 C ₂ K 2o3 ~ 2o5

90 9 848/1376

BATH

XY R ₁

E H

- (CHg) ₄ -. C, - (CHo) ₄ - H) ι, - II

R.
2. HCl salt _{or similar}
Melting point C. CE ₇ 210-212 C ₂ H ₅ 232-235 CU, 114-116 C ₂ H ₅ 1.57-159 ^C 6 ^H 5 191-193 CH ₂ CH ₂ OH 137

Other pharmaceutically acceptable acid addition salts λ

these three compounds were made using the same procedure using hydrogen bromide acid, hydrogen iodine off acid, nitric acid, sulfuric acid, citric acid, • Phosphoric acid, malic acid, tartaric acid and lactic acid instead made of hydrochloric acid.

Example 15 4-aminol3enzofuro / 2,3-d7-pyriniidin

£, ine solution of 13.9 c ^ -amino- ^ jö ^ jS-tetrahydrobenzofuro- / 2,3-d7-pyrii.iiain (o _s .lö hol) and 0 g of finely powdered sulfur (ο, 25 KoI) in loo ecm decalin was heated to 2oo ° C under nitrogen and. the temperature up to i

end of the evolution of hydrogen sulfide retained. Hexane was then added to the cooled reaction mixture, whereby the desired product precipitated which was filtered off became.

Example 16

! ■ lan proceeded according to Example 15 with the difference that £ instead of des Tetrahydrobenzofuro ~ / 2,3-d7-pyrimidine a equivalent quantity of the products of Examples lo-12 used was and received the following products:

«AD

909848/1376

CE

CIL

Π-

Xl 17th CE, F. ίί ^C 2 ^E 5 H " C ₂ E ₅ C ₂ H ₅ H M. ^C 6 ^H 5 - II H H en,
J example Tablets

A tab lettengrundiaasse ifurtie characterized 'Made that _a following xJestandtelle wiped in the indicated proportions by weight:

Sucrose, U.S.?. 80.3

Tapioca stalks e 13 _s 2

This tablet base was mixed with so much h-Asnlno-5 ₃ 6 , 7 _a S-tetrahydrobenzofuro / 2a3-d7-pyrimidine that tablets had a content of 2o _a loo and 25o no of the active ingredient per tablet received. The preparations ^T ./urd usual titmouse pressed into tablets, each of which is 3 £ o

Kg WOg. . .

903848/1378

OfUQtNAL

Example l £ . . :

Capsules

A .Cteiaiseh msröe from the following components lier £ est-ellt - - Caleiurearbonat _s TI..SP. 17th, c

ieat .. ü.C.P. 5 W, S. P, 5

Diosesa. Ge: tisch, liurüe soisriel ⁱ i'-rie

/ ^, J-oil-pyiriHidiii added> that capsules with a Qe stop at 2ο, loo and 25o jng of the active ingredient per capsule -er * · "The preparations" held "iur" len in the usual Lartgelatinekape-elii in an Ilqixje of 35c Hg per sapsel c

Injectable preparation

i.ooo L. ^ ~ ^ x :: ietlvip-- " ^! i * i'O ^ ß ~ Hc: v3ijJl ^- rurp- / 2 ₄ 3 ^ 7 Iiyc.i'-o-ci-loriä were r: it 2 ... SoC ^ "atriiiiacDcorbat iraii £ comparable -iäschfc mid £ ei'ahl3n.Das ^ e :: £ ilfleiie troelaie Go:. -iscii was in. _^:: -Villen, cerälltj -iiit I't" hjlcno: ^ d stez'ilized and the - "Lvip-ulle: * aii3Cülie-t-eiv. ^: sterile versciilossen .. to the intrevenüsen Vera ^ rcicliWK.,: Tir-ö.s -d.ci: öubstartE in the Arspullen so much. ".." ass-e: i ·· Eu ^ -es-et ^ t ₃ o 'aß-ΐαεη ■ a JLüsunc 0rl1ie.lt ₃ ς-ie Io r. ^ - ■ äesr ^.' iTiz & tGffez pi ^ o I; i llilit er ■ c er .injectable en Lohalthalt.

909848/1376

T Jc

- Example 2g

•Suspension

. ". A suspension of ii <* eth / lardno -" - i; '~ i..cthylfuro ~ / 2,3-d7-pyriiii in the following Susej ^ ensctzun ^ was prepared:

Idrkstoff 25, oo. Q

7o ^ -ILO3 vr ^ scri ^ os "orbit 7 ^?! L _s 2f) g glycerine, ϋ.ί, .Γ.." 105.35 C '

Akazienjuüni (lo; "> ice Lös.unf. ') Iöo, o ecu Polyvinylpyrrolidon ο, 5 ί>

Distilliex'tes v / water ad 1 liter

Various fluids and geuclines were added to this suspension fabrics zuijesetstj ur.i their flavor ·; to improve. the Suspension contained about 25 i-icj of the active ingredient, per ililli * - liter,

Example 21

Ldsunc "■

l £ s tairde a solution of ⁱ ; -Aivdno-3-.C- _i > 7 _j > C ^Äi tetrahydrot) enzo ^ furo-72, J-dJ'-pyririidinliydrochlorid folcendef composition Iiex ^ qs fcellt: ■

active ingredient .- ;. ■■ .. Jo, 22 g

. WaGnesiur.iehloridhexahycirat 12.36 g I-lQiioätlianolaj.iiai-o, C5 ceia

Propylene Glycoi Ί> Ί & * ® Ζ

; Distilled water 5l, o g

The solution obtained from the solution had an active ingredient concentration from 5o m & / ecia ".unc. var to parenteral, in particular intrarcuscular Vcral-Reichunc suitable »

9 0 9 8 A 8/1 3 7 6

A second solution: a similar composition was made, which, however, contained 6oo ng of the active ingredient instead of 3o, 22 g. This diluted solution is for intranasal use administration

Example 22 Dronchial PTFE filtering effect

Conscious female ile pigs, those who had not been fed for 12 hours received oral or parenteral doses of the compound to be tested. Controls received doses of a saline solution that did not contain the compound being tested * Subsequently after this administration, each animal was treated with a histamine aerosol irritated.

The Piciz method consisted of getting an o, 4 / '- ige

2 ;; u.ssri ^ e Hiotaiiiinlösun ^ sprayed under a pressure of o, 35 kg / cm for one minute in aii 2o, 32 χ 2o, 32 χ 3o _s Hu cm large plastic container. Immediately after the container had been sprayed with the histamine, the animal was placed in clone containers. After the end of one stay, the respiratory condition, which is a reflex of the bronchial nerve, was evaluated. The evaluation grades were determined and classified as normal breathing (0), slightly increased kati.ien (1), laborious breathing (2), very laborious breathing and ataxia (3), as well as dextrusiveness (4). Each group consisted of 8 to 10 animals, and a control group consisting of approximately the same number of animals was used percentage protection indicated.

909848/1376

1817U6

The orally administered doses were: So mg / kg, and the animals were challenged oo l minutes later with histanin. The standard compound used, XiSr theophylline, which conferred 25% protection when a dose of £> o / kg was administered orally * and the animal was challenged one hour later. When the compounds listed below were administered according to the present methods and the animals challenged accordingly ₃ , the following percentage protection was found.

"Ρ Percentage ⁿ l" 2 protection

cn, κ ι: CH, 27

CK, H CH, CE, '23 ^ j? 3

CH, H nC, ü "n-CJi- 11 p. j 7 d 7

CH, HH CgK _r 7

cn,

CK, H - (CHO) ₂ -N- (CK _{2) 2-17}

CH- CIi, HL 13

CH, CK, II CH, 35

3 yy

CH, CH, CK-, CH, Io

CAIr. HE :. CK, 13

- (CH ₂ ) _2} - H 1; 3G

- / PTT ^ - "F f ¹ " ^ i "λ

909848/1376

Percentage R ₁ R ₂ protection

CA 23

Cl-. 7th

example

örido cut streiron of the trachea from left According to cier.i J.vr. Constantine in J, Pharia.PhaiUiacol. j Dd. 16, .'J. ^ 2'1 (19 ^ 5) described ed

drive groomed. The isometric relaxations were recorded using a unit for the displacement flow (110ail FT-c-3 from Grass Instrument Co., Quincy, Ila3oachuöetts), which was measured with a graph from Grass, I. -Iodell 7 »connected v; .ar (Gr neiit Go-. _S ^ uiiicy ₅ Hass.) *

Bie relative "..ΊΓίαιη ^ εη as" ielairans on the smooth IIusl: u ~ latnr jecer Uer ^ tested Verbiiiöuni, en v.airden as folct compared:

1. The; .irkunj alf3 Ilusirelrelaxsns a bath rdt o _? o3 / frg / ccn IsopxOtea ^ enol irurde for jeaen otreifen bestirant and proved to be suprana :: inal, This reaction was regarded as * Ka :: i! r.ale Reltixion des Γ-treifen,

2, .reitex ^ e - "- lo ^ .arithr.ischen / bstänaen angeoprineton lionsentr at ions * .; uruen bestirniit UNOE elaicioiien ir a jje ^ flat strip at Testvernir.dunren in öcn percentage of .elation un ^ eTiaiicleltj.! , c..that brought about by IsoOroterenol * - i ^ e leads -.iQi'dcr. was, Dui'ch /.btrajen c'er Dosierunnen [\ eg-Qn tie Oi-nzentvcZ- .'aximal relation; rd for each connection _o cii ^; e corresponding. "urve received *

3. The number given below for each individual compound was that concentration (expressed in / flg / ccm) of compound which was necessary to achieve 50 % of the maximum _{relaxation (EC n} .) Of the tracheal tube. As a result, the smaller the EC _r , the more effective the compound was as a P.elaxant for smooth

I'Iu skein.

4. Two standard compounds, namely theophylline (a known bronchial constricting agent) and papaverine, were also evaluated. . ■

The following compounds were tested to _{achieve corresponding EC r fourths:}

^ll 2

EC,

CIi, CH,

Theophylline
Papaverine ^
K I- Ii II H π II CII H C ₂ II Xj,

OHj

CH, 3

HS

27, ο 7, ο 3.3 2.6

1.2

1.1

909848 / 1.376

OHigi _NAl

1817 na

CH

CH,

EC,

- (CHg) ₁ ,

CH.

HC ₃ H ₇ "HC ₃ H ₇ 4, o CH
3 CH ₃ o, 42 II CH ₃ 1.7 CH ₃ CH ₃ O * - *
£ ~ - 3 * s H ■ H 3.2 H CIU 2.4 H C ₂ H ₅ 4.0 CH-
3 CH-, 1.2 C ₂ H ₅ C ₂ H ₅ o, 37 -. (0Hp) ₂ -I I- (CH ₂ ) ₂ -

CH-

Example 24 . _rT

'- phosphodiesterase Heramung The compounds of the invention were evaluated for their ability ^ dephosphorylierende the effect of cyclic 3', 5'-nucleotide phosphodiesterase to inhibit _9, umgev 5 ^f -AdenosinraorLophosphat to 5 ¹ -Adenosinmonophosphat / andelt is through the "3 '.

The cyclic 3'j5'-nucleotide phosphodiesterase was according to the method described by RW Butcher and E, W. Sutherland in J. Biol. Chem., Vol. 237 ₃ p. 1244 (1962) isolated; their purification process was carried out in the third stage, namely through ammonium sulfate fractionation, dialysis and freezing stages, but not through the ctoomatographic fraction stage.

90984871376

1817148

Two control compounds, namely papaverine and theophylline, both of which are known enzyme inhibitors, were tested along with each new compound. At least four substrates, each containing 3 ', 5 ⁿ -adenosine monophosphate, were therefore used with each new | Connection tested. One contained the new compound, another contained theophylline, another papaverine, and the last contained no phosphodiesterase inhibitor at all. Each substrate had a total volume of 2 ecm, was k χ Io molar with respect to 3 ¹ , 5'-adenosine monophosphate, contained 0.02 ecm cyclic 3 ', 5 ^T -uucleotide phosphodiesterase, HgSO ^, 0.2% / IIol ethylenediaminetetraacetic acid and a suitable one Buffer to keep the pH at 7.5. In those cases where the substrate also contained a new compound to be tested for inhibition of phosphodiesterase, or an inhibitory control compound, this compound was present at a molar concentration of Io.

Each substrate was incubated for 30 minutes at 30 ° C., after which the reaction was terminated by boiling for 10 minutes. At this point in time, 1 mg of lyophilized Crotolusatrorvenunij das dissolved in 1 ecm of a buffer with a pK-l / ert = 7 * 5 x? Ar _{3 was} added, and the new mixture was incubated at 30 ° C. for 30 minutes. This reaction was also interrupted by boiling for 10 minutes. The venum reacted with 5'-adenosine monophosphate, the dephospliorylation product, releasing inorganic phosphates. A low final concentration of inorganic phosphate therefore indicated that a small amount of 5'-Ad.enosine monophosphate had formed and that the phosphodiesterase activation was inhibited. The inorganic phosphorus compound was colorimetrically according to that of CH. Fiske and Y. S ü ar ow in J ». Biol. Chem., Volume 66,

909848/1376

S, 375 (1925) described method bestirnt. The percentage reduction was higher than the difference ■ between the inorganic phosphate concentration in the the substrate containing the inhibitory compound and the Concentration in the substrate containing an inhibitor, divided by the concentration in the substrate with no inhibitor. The effect of the present compounds in relation to theophylline was determined by varying the concentration of the inhibitor and by applying Standard method of statistical analysis determined, as described by D., J. Finney in Statistical Method in Liological Assay, Charles Griffin & Co., Ltd., London, 1952.

The following compounds were rated:

CL-

Uiricune im

Percentage of inhibition to theophylline

Theophylline L. 5-15 H H CH ₃ 2 Ii H ^C 2 ^H 5 IC II H ^C 2 ^I: 5 26th H C ₂ H ₅ n-C-JU il6 II n-CX
ο 7 75 II - j ' ^{2 2} 13th II - (ClI ₂ ). CL ₂ CH = CK ₂ 13th , -JT- (CII ₂ ) - - (CE ₂ ). 9

n ₀

egg: _

909848/1376

Ι, ο

9.7

181 7 U.S.

- ho - ■

Viirkung in

Percentage ratio H ₁ R ₀ '. Identification of theophylline »

c :: ₇ . cn, cn-, cn, 57 14.9

CGII _r 'fl Cl-7 _CH? '7o 12.8

C ₆ H ₅ HC ₂ K ₅ C ₂ II ₅ 5C 23.3

CgH _n - L CH _T CK-, '43

- (Clig) 2 | ~ "- h K 31 ■

- ■ (CII ₂ );, - Π Ch, .52 13.1

- (CK ₂ ) _{i (} - I; C ₂ Ii ₅ 7o 25.1 »(CII ₂ ) _{i (} - CL ₃ CII ₃ 67 15.3 - (CII ₂ J ₁ , - C ₂ K ₅ C ₂ II ₅ 97 lho, 5

- (CIl ₂ J ₂ -LI- (CK ₂ J ₂ - 29 1.5 "

- (c: i ₂ ) ₂ -: :-( CK ₂ J ₂ - 32 1.9

CO ₂ -C ₂ K ₅ '

II 3 ', ^' - diOCII ^ -benzyl 25 o, 4

^Jz tr ^v

I ₂ CH ₂ OH

2) if I- CK ₂ CII ₂ OK 65 9.5

- (CK ₂ J ₁ .- CK ₂ CK ₂ II (C ₂ K ₅ J ₂ IC 0.8

909848/1376

Claims (2)

Patent claims » ί. Smooth muscle relaxants, labeled. ■ also a content of 4-aminofuro- / 2,3-d7-pyrimidines of the general formulas: or in which ' X and Y are the same or different and are hydrogen atom, an alkyl group with Ms to 4 carbon atoms, phenyl or naphthyl group or X and Y together represent an alkylene group with 4 to 6 carbon atoms or a benzo group, Ε., And Rp are the same or different and are hydrogen atom, an alkyl group with up to 6 carbon atoms, an alkenyl group with up to 6 carbon atoms, a phenyl, Taphthyl, ß-hydroxyethyl group or R ^ and Rp together a morpholino, thiomorpholino or piperazino group, where the piperazino group. in 4 position by a Hydrogen atom, an alkyl group with up to 6 carbon atoms, Alkenyl group with up to 6 carbon atoms, a phenyl or naphthyl group is substituted, R, a hydrogen atom or an alkyl group with bia to 6 carbon atoms,. . R., Rj- and Rg are the same or different and a Hydrogen atom or an alkyl group with up to 6 carbon atoms and η is an integer from 2 to 5 or their pharmaceutically acceptable salts as active ingredients. 90984 8/1376 BATH '. 2. Means according to claim 1, characterized in that it · contains a pharmaceutically acceptable carrier. 3. Composition according to claim 1, characterized in that it contains the compound of formula I as active ingredient. where R ₁ and Rp are identical or different and represent a hydrogen atom or an alkyl group with Ms to 6 carbon atoms. 4 · Means according to claim 1, characterized in that it as active ingredient 4-Mäthylamino-6-phenylfuro- / S, 3-d / -pyrimidin contains. 5. Composition according to claim 1, characterized in that it is the active ingredient 4-Ä'thylamino-5,6,7,8-tetrahydrobenzofuro- / 2,3-d7-pyrimidine contains. 6. Composition according to claim 1, characterized in that it is the active ingredient 4-diethylamino-5,6,7,8-tetrahydrobenzo- / 2,3-d7-pyrimidine contains. 7. Composition according to claim 1, characterized in that it contains ^s as active ingredient 4-amino-5,6,7,8-tetrahydrobeifo'furo - ^, 3-d7-pyrimidine. 8. Composition according to claim 1, characterized in that it as active ingredient 4-bimethylamino-6-methylfuro- / S, 3-d7-pyrimidine contains. ".... ^^ 9f means according to claim 1, characterized in that it ! as active ingredient 4-methylamino ~ 6-methylfuro- ^ 2,3-d7-pyrimidine contains. 90984871376 1817H6 10! Agent according to Claim 1, characterized in that the active ingredient is 4-methylamino-5,6-dimethylfuro- / S, 3-d7-pyrimidine contains. 11. Compounds of the general formulas: or II in which X, Y, R- ,, R ,, R, -, Rg and η have the above meaning and Ri and RA the meaning of R., and Rp have, but at least one of the two groups Ri and RA is not a hydrogen atom, and their pharmaceutically acceptable salts. 12 «Compounds according to claim 10 of the formula I ¹ , in which R ¹ -j and R ' ₂ denote a hydrogen atom or an alkyl group with up to 6 carbon atoms. 13. Compound according to claim 11, in which R ¹ ^ and R ^f ₂ each denote an ethyl group, R denotes a hydrogen atom, X denotes a phenyl group and Y denotes a hydrogen atom. 14. A compound according to claim 11, in which H ¹ , a hydrogen atom, R ^f p an ethyl group, R, a hydrogen atom and X and Ϋ together denote a butylene group. 909848/1376 BATH 15 · Compound according to claim 11, in which R * ^ and R ' ₂ each represent an ethyl group, R ^ a hydrogen atom and X and Y together represent a butylene group. 16. The compound of claim 11, wherein R '^ and R'p each a methyl group, R ^ a hydrogen atom, X a Methyl group and Y eh hydrogen atom. 17 · Compound according to claim 11, in which R ^1. , Eir Wp s ε only o'ff atom, R ¹ O a methyl group, R, a hydrogen atom, X a methyl group and Y a hydrogen / re ^. 18 · Compound according to claim 11, in which R'-, a hydrogen atom, 11'2 a methyl group and X and Y each represent a methyl group. For Chas, Pfizer & Co. Ine, New York ,, N.Y., V.St.A. Pike attorney Sü9S / i8 / 1 37 6