Pyrimido(4,5-d)pyridazine derivatives and process for producing them
United States Patent IWI Yurugi et al.  
 I 5] Apr. 29, 1975 U IYRIMlDUt-LS-B)PYRHIAZINE DERIVATIVES AND PROCESS FOR PROI)U(ING THEM [&#34;51 Inventors: Shojiro Yurugi. Kyulu. Shinturo Kikuchi. Hyngu hulh of Japan [731 Assigncc: Takcda Chemical Industries. Lld..  
 Osaka. Japan [III FiICd; DEC. 6. i972 III I App] Nli13i2-5ii4 Hill Foreign Applicalion Priority Data Duu h. W7] JupmL i i i i i i i i i i l, Jh-QHWh fill LLS. Cl. 2(1(i/246B;2h(i/256.4 F; 424/248 [il l lnl. (I i. C07d 87/40 [5X] Field oi Search IMO/150.4 F 246 B [57 ABSTRACT Nmul compounds of \hu formula:  
 27 Claims. No Drawings I IYRIMlDO(4.5-D)PYRIDAZINE DERIVATIVES AND PROCESS FOR PRODUCING THEM This invention relates to novel compounds ofthe formula tivherein R is phenyl \hich may be substituted by lower alkyl. R is a or b-ntembered heteroeyclic imino group \\hieh may be substituted by lower alkyl and R is alkyl which may be substituted by a pyridyl group or loner alltoxy. cycloalkyl. phenyl which may be substituted by In er alkyl or lower alkoxy. or aralkyl whose aryl moiety may be substituted by lower alkyl. loiver alkoxy or halogen) and their pharmaceutically acceptable acid salts. The present compounds are useful as diuretics With the purpose of developing no\el and useful diuretics. the present inventors ha\e synthesized a number of novel dcritatives of pyrimipy ridaline and tested diuretic activities of those derivatives. in the Course of their estcnsiie study. they found out that. hen a compound of the formula (wherein all the symbols have the meanings as defined ahovet is allowed to react with a (irignard reagent of the formula lwherein X is a halogen te.g.. chlorine. bromine or iodine] and R has the meaning as defined above reduction of the double bond between the 3- and l-positions ol&#39; the Compounds (ll) occurs simultaneously with the introduction of the R&#34; group into the 4-position. whereby the present Compounds (I) are obtained They found further that a similar reaction is conducted by employing a compound of the formula lwhercin M is an alkali metal te.g. Na. K or Li) and R&#34; has the meaning as defined above] in place of the Grignard reagent tlll).  
  They found further that the present Compounds tlt produce a remarkably durable diuretic activity at a considerably lt)\\&#39; dose. which is attributable to the presence of a single bond between 3- and 4-positions of the present Compound (II. On the basis of those findings mentioned above. they completed the present invention.  
  Principal object of the present invention is to pro\ lLlL&#39; the Compounds ll) as well as their pharmaceuticalh acceptable acid salts.  
  Second object of the present invention is to pro\ ide a useful process for producing the Compound llt.  
  Another object of the present invention is to pro\ idc pharmaceutical compositions containing the Compound tll as the main acti e ingredient.  
  The principal and the second objects are reali/cd by reacting a Compound (ll) with the (irignard reagent llllt or with a Compound (IV I.  
  The starting Compound (lll was synthesized also by the present inventors and as known in eg. the German tWcstt Pat. Application No. P 2040 577.4 \vliich was filed in the name of Takeda Chemical Industries. Ltd. of Osaka. Japan and has been opened to public inspection since May 6. IJ7l Referring to the above formulas. the lower .tlltyl which may attach to the phenyl group denoted by R may preferably be such ones as having l to 3 carbon atoms ie.g.. methyl. ethyl. propyl I.  
  The 5- or b-memhered heterocyclic imino group represented by R may for cutmple be morpholino. piperidino. pipera/ino. pyrrolidino and the like. Those hetcr ocyclic groups may be substituted by loner alkyl groups as mentioned for R group.  
  The alkyl designated by R&#34; may be saturated or unsaturated and preferably such ones as ha\ing l to 7 carbon atoms teg. methyl. ethyl. propyl. iso-propyl. butyl. isobutyl. amyl. hexyl I. Those alkyl groups may be substituted by pyridyl or lower also (e.g metho\ ethoxy. propoxy The cyeloalkyl denoted by R&#34; may for example be c clopropyl. cyclopcntyl or cyclohesyl. The aralkyl group denoted by R&#34; may for example be benzyl or phenethyl Those aralkyl groups maybe substituted by lower all\ \l (cg. methyl. ethyl. propyl or iso-propyll or lower alk&#39; ox) (cg. methoxy. ethoxy. proposy. iso proposy or methylenedioxy t.  
  The phenyl group denoted by R&#34; may be substituted by lower alkyl or lower alkosy. examples of which are mentioned just above.  
  In the present process. the Compound (ll) is reacted with the Grignard reagent ill) or the Compound tl\&#39;l The present reaction is conducted generally in the presence of a suitable solvent at a temperature not e\- ceeding about C. The solvent employable in the present process may for example be ethers teg methyl ether. ethyl ether. iso-propyl ether. amyl ether. dioxane or tetrahydrofuran). hyTtroc-arbons teg. henzene. toluene or xylene) or tertiary amines (eg. trt methyl amine. triethyl amine. pyridine. picoline. quintr line or isoquinoline l,  
  The Compound (lll l or (IV) is employed generally lll an amount of about 2 to about 4 moles per mole of the Compound ill).  
  The reaction completes generally in a range from about half an hour to a out 5 hours.  
  It is assumed that t. present reaction proceed through an intermediate compound of the formula (wherein Y means -MgX or M in which X and M have the meanings as defined above and the other symbols have the meanings as defined above).  
  it is further assumed that the Intermediate (V! can easily be convened to the Compound (I) upon hydrolysis with atmospheric moisture.  
  The Compound (I) can be isolated and purified by a per se conventional method such as extraction. crystallilation. etc. The Compound (I) can be converted to its acid salt by a per se conventional procedure. As an acid which may form the salts with the Compound (I) there may be counted for example organic acid (c.g.. acetic acid. fumaric acid. oxalic acid. malic acid or maleic acid) or inorganic acid (e.g.. hydrochloric acid or sull&#39;uric acid).  
  The Compound (I) shows remarkable diuretic activity in animals including human and is useful as diuretics.  
  Pharmacological advantages found in the Compound ill are. among others. as follows:  
  l. It can accelerate secretion of uine. while suppressing secretion of potassium ion in uine.  
  2. It can produce effective diuretic activity at a low dose.  
 3. The diuretic activity is considerably durable.  
 4, Side effects are very slight.  
  The present compounds can be administered orally or parcntcrally in the form of a suitable conventional pharmaceutical composition such as tablets. capsules. owder. granules. solution or suspension. The dosage may vary with kinds of host. type or severity of a dis- 4 ease to be treated. properties specific to various derivatives defined as Compound (I). etc. The dosage may for example be suitably selected from the range of about It) to about 200 mg. per day for an adult human.  
 EXAMPLE l In 25 ml. of dry ether is suspended 0.48 g. of magnesium. to which is added a small amount of iodine. To the mixture is added dropwise a solution of 2.5 g. of benzyl chloride in 25 ml. of ether. whereby a Grignard reagent is prepared. A solution of 3.7 g. of Z-phenyl- 5.S-dimorpholinopyrimidol4.5-dlpyridazinc in 50 ml. of tetrahydrol&#39;uran is added to the mixture containing the Grignard reagent. and this reaction mixture is heated at 40-50C for an hour.  
  The resultant mixture is poured onto 300 ml. of icewater and the mixture is shaken several times with 200 ml. of ethyl acetate. The ethyl acetate layer is separated. washed with water. dried and concentrated in vacuo. The residue ofan oily substance is recrystallized from ethanol to give 2-phenyl-3.4-dihydro-4-henzyl- 5.B-dimorpholinn-pyrimidol4.5-dlpyridazine as yellow prisms melting at ZIP-224C. Yield 2.6 g. (55.4%]  
 Anal. Calc. for C- ;H, .,N..O,:  
 Found C. 69.24; H. 6.49; N. l7.o4  
 EXAMPLES 2-20 Following a similar procedure to that in Example 1. Examples 2-20 are carried out as summarized in the Table l.  
 Table l-Continued Cult: fo: C ll tl il z &#34;L p (l yellow prism C 69.60 ii 6.60, N 1  
 , i I r Found: 9.25, .i 61;).  
 Momma-.4: In all .1 the &#39;Zxnmplcu listed above, the reaction to carried out. at 40-50% in f-r&#39;cr&#39;rhydrofuren.  
 Example 2l ca-gel with a mixture of acetone and benzene (I14 In volume).  
  To a suspension of 100 mg. of magnesium and 370 mg. of tricthylaminc in 2 ml of dry benzene is added gradually and dropwise a solution of 380 mg. of ethyl bromide in 10 ml. ol&#39;dry benzene, whereby a Grignard i H reagent is prepared. A solution of 680 mg. of Z-phenyl- 3 f 5 p py 5 xpy in [5 ml prism s melting ill l5! l fil The Cfybllllh hhUW I10 of chloroform is added to the Grignard reagent and the memo or when m&#39;xcd mm mixture is heated at 4()-50C for l hour. The resulting pmduc obwmcd m Example mixture is poured onto lOO ml. of ice-water and the mixture is shaken several times with ethyl acetate. The organic layer is separated, washed with water. dried Following a similar procedure to that in Example Ill and concentrated under reduced pressure. The residue Example 22 is carried out as summarized in the Tahitof an oily substance is columnchromatogruphcd on sili- 2.  
  The cluate is concentrated under reduced pressure and the residue is recrystallized from ethanol to gite 2-phcnyl-3.4-dihydro-4-ethyl-5,8-  
 Example 22 ab 0 21 Example Ora-nerd reagent Stu-tin? compound a He. 11) Compound (Il obtained I 4 lllelting point; 3 x R] R2 31 R2 R -yi (Cl and nILllYSiT ianpenrancc I m 22 cflz clb-cl&#39;lz Br N 0 CR AM-CH 9.5 213-222 yellow prism l Remark: 1&#39;. the Sample noted above, the reaction is carried out at -50% for an hour in taizruhydrofuran Example 23 A solution of 3.8 g. of Z-phenyl-SJ- dimorpholinop rimidol4.5-dlpyridazinc in 50 ml of lelrahtdrnftlrall is added to a solution of hutyl lithium in So ml. of ether. which is prepared from 0.86 g. of lithium and (M45 g of hutyl bromide at l0&#34;C in the treams of nitrogen. The reaction mixture is stirred at room temperature for an hour and poured into 500 ml. of liter. The separated oil is extracted with eth \l acctalc. The curacl is dried UHJI anh \drous sodium sull.|lc. Al&#39;ter eutporation of the solvent in incur). the residue is purified by column chromatograph on silica-gel ith a mi\turc of benzene and acetone (4;] by volume) to afford Z-phcnyl-IiA-dihydro-4-butyl-S.7- tlimorpholinopyrimidol4.5-dlpyriduzinc as yellow prisms melting at l93-l95C. Yield: L? 3. (395i Examples 24 -27 Following the procedure ol&#39;Es-ample 23. these E\am- What vie claim is: l. A compound of the formula wherein R is phenyl or methylphenyl&#39;. R is morpholino. mcthylmorpholino. or piperidino. and R&#34; is alkyl of l lo 7 carbon atoms. all l. henz l. methylhcnvyl. methoxyhenz l. 3-4 mcthylenedioxy-henzyl. phenethyl.  
 phen \l or cyclohextl,  
 2. A compound according to claim 1. wherein the Z-phenyl-R.4-dih &#39;dro--l-henzyl-5.8-  
 compound is diintirpholiniipyrimido-l 4,5-d lpyridazinc.  
  5. A compound according to claim I. wherein the compound is 2-phen vl-3.4-dihydro-4-henzyl-5.li-hist2- melht&#39;lmorpholino )|1 rimidol 4.5-d l-pyridazinc.  
  9 l IS. A compound according to claim I. wherein the wherein R is phenyl or melh lphenyl. R is mor hocompound is 2-phenyl-3.4-dihydro4-t4- lino. methylmorpholino. or ptpcridino. and R is .||k \l mcthoxybenzyl l-S.8-dimorpholino-pyrimidol4.5- ofl to 7 carbon atoms. allyl. benz l. meth lbenz 1. medlpyridazinc, thoxybenzyl. 3.4 melh lencdinx -benzyl. pheneth l. I). A compound according to claim 1. wherein the phenyl or cyclohexyl which comprises the step of reactcompound is l-phenyl-3.4-dihydro-4-t 3.4- ng it mpound of the formula methylenedioxyhenzyl)-5.l&#39;ldimorpholinopyrimidol4.5-dlpyridazine.  
  20. A compound according to claim I, wherein the compound is Z-phenyl-3.4-dihydro-4-hcnzyl-5.8- h&#39;&#34; dipiperidinopyrimido-l4.5-dlpyridazine, i i l 21. A compound according to claim l, wherein the i3.- compound is 2-(3-tolyll-3.4-dihydro-4-benzyl-5.8- dimorpholinopyrimido-l4.5-dlpyridazine. 11  
  22. The compound as claimed in claim I. wherein R is phenyl.  
  23. The compound as claimed in claim 1. wherein R is morpholino.  
 24. The compound as claimed in claim I. wherein R&#34; wherein all the symbols have the meanings as defined above with a Grignard reagent of the formula &#39;7 is henzyl. 25. The compound as in claim 1 wherein R is mc- My thylmorpholino.  
  26. The compound as in claim I wherein R is piperiwherein X is halogen and R has the meaning as defined di N above or with a compound of the formula 27. A process for producing a compound of the formula R M wherein M is alkali metal and R&#34; has the mcanin as do R N f d b ,1 g  
 V \N inc a me I l Ht! ,7 is  
  g mc i t a E ii a