IL28815A - 1,3-dioxolan-4-yl-alkyl guanidines and process for preparing same - Google Patents

Description

P. A. 28815/II 1.3-PI0X0l U?»¾~YI^M,KTL«GtJANI0INES AHP PHOCESS OH PREPARING SAME ο^^ι κη ·?^ρ*7Κ - ~ 4 - 3 i p K» - 1 «3 onayt'? -pvnni This invention relates to novel dioxolanyl -substituted guanidines , intermediates thereto and a process for their production. More particularly , it relates to 1 , 3 -dioxolan«4~yl~alkyl-guanidines having anti -hypertensive activity , 1 , 3 -dioa-ol?.n-4»yl..aIl¾''l-halides , -amines and -phthalimidQS usoful and to a process for their production.

The invention sought to be patented in one composition of matter juupaei resides in the concept of anti -hypertensive agents having the dioxolanyl - alky 1 -guanidine structure in which a 1 ; 3 -dioxolane group is attached by its 4-position ring carbon atom via a lower -alkylene bridge to the guanidine amino nitrogen atom. In another composition of matter aspect, it resides in the concept of 1 , 3 -dioxolan~ 4-yl~lower -alkyl amines having analgesic activity and which are useful as intermediates in the production of the 1 , 3 -dioxolan- -yl -lower -alky 1 -guanidines . I one process aspect , it resides in the concept of reacting a 1 , 3 -dioxolan - 4 -yl -substituted lower-alkyl amine with 2-alkyl~ 2 ~ thiopseudourea to produce a 1 , 3 -dioxolan~4-yl-lower-alkyl-gu?jiidine. In a further process aspect it resides in the concept of converting, by reaction with a metallo salt of phthalimide followed by hydrolysis , the halo group of a 1 , 3 -dioxolan-4-yl -lower -all y! halide to an amino group and then converting the amino group to a guanidine group by reaction with a thiopseudourea.

The tangible guanidine embodiments of this invention , in their free base and acid addition forms , are novel chemical compounds whose utility includes the inherent applied use characteristic of exhibiting pharmacological activity, including anti -hypertensive activity, as evidenced by pharmacological evaluation according to standard test procedures and evaluations.

Substituted guanidines having anti -hypertensive activity are known in the art. Examples of these are coumaranyl and indanyl substituted guanidines [U. S.3153057], benzodioxanyl guanidines, [Augstein and an Green, Nature, 201, 628 [1964]], and benzo-1, 3 -dioxolrl- 2 -guanidines [U.S 3149129].

The following is a description of methods for making the compounds of this invention, which reactions are illustrated schematically as follows.

STEP I STEP II II STEP III O i: I + 2H2NNH2 II . ΠΤ STEP IV NH, NH, -f- CH3SC . H2SO, CHoNHC H2SO4 2CH3SH II NH O NH R IV wherein X is a halogen other than fluorine preferably chlorine- M is an alkali metal , preferably sodium; and R and R' are each hydrogen or a sub-stituent as defined hereinbelow.

In Step I. virtually any non -reactive acidic substance can be used as catalyst. See F. F. Blicke and E. L Schumann J .Am. Chem . Soc. 76 , 1226 [1954]. Toluenesulfonic acid is preferred. Any inert solvent , e. g. , benzene , pentane or preferably toluene , which provides an azeotropic distillation mixture with water and which phase separates in the Dean -Stark trap can be used. Step I A is preferred over Step I B . In Step I B , neutral inert solvents are used, e. g. , CC14 or other chlorinated hydrocarbon.

In Step Π , dry solvents should be used. Ν, Ν-DialkyI acid amides , e. g. , dimethyl formamide and dimethyl acetamide , appear to catalyze the reaction. Alkanols , e. g. , ethanol, are also useful solvents . Sodium is the preferred metallo salt of the phthalimide , although other salts such as the more readily available potassium phthalimide may also be used.

In Step III, aqueous , hydrated or anhydrous hydrazine can be used. 95 percent ethanol is a useful solvent although any inert solvent for Intermediate II can be used. At least one mole and preferably two moles of hydrazine per mole of the substituted phthalimide is preferably employed . Hydrolysis in alcoholic ailkali -metal hydroxide is effective but gives lower yields than hydrazine. If desired product [ΙΠ] can readily be converted to a secondary lower alkyl substituted amine by methods commonly employed in the art prior to proceeding with Step IV.

Step IV is the preferred method of producing the final products of this invention. Possible variations are the use of other thiopseudoureas such as benzyl thiopseudourea [U. S. 3 027 370]; ammonia to promote the reaction [Fielding ' al , Brit. J. Pharmacol . 24 , 395 [1965]]; an acid addition P.A. 28815/IH ' J. Med. Chem.jS, 592 (1963) ϊ 2-methyl thioniidazoline (iihort et al. , J.Med.Chera.6, 283 1 63 ) and the use of 3.5-dimethyl-l-guanylpyrazole, (Can. J.Biochem. Physiol. 8, ^93 (i960) ; Scott et al., J.Am, Chem. Soc. ?¾, ¾053 (1953 ) ) ; cyanamide (Braun, J.AJTI. Chern. Soc . J5» 1291 (1933) ) or guanidine base and tosylate esters (Monroe, Chem. and Xnd. ¾31ISO 6 (l96¾ ) ) .

The following is a description of the compounds of this invention, which are exemplified by the following formula t wherein n is the integer 1 or 2; R and R* are each independently selected from the grou consisting of hydrogen, alkyl, cydoalkyl, phenyl and substi uted phenyl, said substituent being selected from the group consisting of halogen, alkyl of 1 to 8 car on atoms, alkoxy and t ihalomethyl and H and R1 can, together with 2-carbon atom of the dioxolane ring form a saturated c^rbocyclic ring or a substituted saturated carbocyclic ring aid sybstituen being selected from the group consisting of phenyl, lower alkoxy, alkyl and halogen; and is selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms.

P.A. 28815/11 saturated The tern "carbocyclic ring" means/cyclic systems all of whose rinf* members are carbon atoms* Such ring systems can be monocyclic or poly-cyclic, but preferably comprise no more than a total of 3 rings, i T.ndi.ng aromatic r ng systems,—e.jf. , of the benzene and aph halene seri s, saturated cycloalkyl ring systems, e.g., of the eyclohexane and cycloheptane series. Especially preferred are compounds containing a spirocyclic ring system wherein the 2-position carbon atom of the dloxolane ring is a carbon atom of a cycloalkyl ring substituent· The term "lower", e.g., when used in ••lower-alkylM, means containing up to eight carbon atoms, inclusive.

The utility of the compounds of this invention as pharmacologics is the result of the novel molecular combination of 1 ,3-dioxolane with guanldlne via a lower-alkylene group. While the manifestation of this activity varies in degree and character from member to member in this series in the usual manner expected of the compounds of any series having Pharmacologier.1 activity, the series ef compounds embraced within this invention are all useful as pharmacologics.

Because novelty and utility of the compounds are the result of the molecular combination of the 1,3-dioxola e structure joined by an alkylene bridge with the guanidine structure, embraced within the scope of the compounds h i g this structural combination are those having one or more, usually not more than four and preferably not more than three, simple substituents on the R and R' su stituents, when said substituents are phenyl or a saturated carbocyclic ring. Those which can be on a carbon atom thereof include halo, e.g. chloro and fluoro , lower—alky1 including methyl, ethyl, propyl and octyl, trifluoro-methyl , trichloromethyl , lower-alkoxy including raethoxy r a»* ethoxy and/aryi—4»-e4ud4«,g phenyl* Preferred classes of compounds within this invention are the 1,3-dioxolan-^-yl-lower-alkyl-guanidines meeting one or more of the following requirements! and tho dioKola.no ring oxygen atoms , the co mpounds are hydrocarbon a b (c) the lower -alky lene bridging group is methylene; d) the valences of the 2 -position dioxolane carbon atom are satisfied by non-aromatic hydrocarbon substituents , e. g. , lower -all y 1 , or more preferably by a single spiro carbocyclic ring which bears at most a single substituent which -is c preferably non -aromatic; (e) the compounds are in their acid addition salt form , preferably as their hydrochloride or sulfate.

The compounds of this invention possess assymmetric carbon atoms . They can thus exist as a mixture of its optical isomers or by conventional separation techniques , in the form of an optical isomer substantially free from the other isomers .

The following is a description of the method of using the compounds of this invention.

The 1 , 3 ™dioxolan-4~yl -lower -alky 1 -guanidines of this invention are useful in scientific research, particularly in the field of pharmacology. Their pharmacological activity renders them useful in modifying body functions in laboratory test animals and other mammals by a modification of nerve impulses , e. g. , the sympathetic nervous system. This activity mani fests itself in laboratory tests utilized to detect sympathetic nervous system blocking activity , i. e. , one or more of carotid occlusion , nictitating membrane and norepinephrine depletion tests .

In the Carotid Occlusion Test, a dog is anesthetized with 20 rag. / Kg. of thiopental and maintained with 60 mg. /Kg. of chloralose by IV injection. The femoral artery and vein' are catheterized and the common carotid arteries are isolated for bilateral clamping. After determining the control arterial pressor response to 30 seconds of carotid occlusion, the test com pound is administered and the response is again measured. The dose which produces approximately a 40 percent inhibition of the pressor response is used for potenc}^ comparison with other drugs.

In the Nicitating Membrane Test , a cat is anesthetized with Dial-urethane (0. 9 cc. /Kg. I. P. ) , with the femoral artery and vein catheterized. The nictitating membrane is drawn out and attached to a thread fastened to a force -displacem ent transducer. The pre -ganglionic nerve to the superior cervical ganglion is isolated for stimulation by supra maximal electrical shock. After determining the control response to pre -ganglionic stimulation , the drug is administered by intravenous injection and the dose which produces at least a 10 percent reduction in response is used for potency comparison with other test drugs .

In the Norepinephrine Depletion Test, albino guinea pigs weighing 200 to 300 g. are treated with the drug in three test groups , !, e. , control , 5 mg/Kg. I. P. , and 10 mg. /Kg. I. P. , and then sacrificed after 15 to 18 hours . Quickly the hearts were removed , flushed with saline , placed in a vial and frozen in a dry ice -acetone bath. The hearts are individually analyzed for norepinephrine by the method of J . R. Crout, J. Pharmacol. 132 , 269 (1961) and the level of depletion below control levels compared with other test drugs .

The compounds of this invention manifest fewer of the undesirable side effects of other known guanidyl anti -hypertensive agents , e. g. .diarrhea.

When the compositions of this invention are used as pharmaceuticals , they can be administered orally in the form of pills , tablets , capsules , e. g. , in admixture with talc , starch , sugar , milk sugar , or other inert, i. e. . nontoxic or pharmacologically acceptable pharmaceutical carrier , or in the form of aqueous solutions , suspension , encapsulated suspensions , gels , elixers , aqueous alcoholic, solutions , e. g. , in admixture with sugar or other sweetening agent , flavorings , colorants , thickeners , and other conventional pharma ceutical excipients . When injected subcutaneousl , intravenously or intra or peanut oil solution or suspension using excipients and carriers conventional for this mode of administration. The best route of administration and the best dosage will be apparent from the laboratory tests for activity and toxicity of the selected compound conventionally undertaken as part of the development phase of a pharmaceutical.

In the following preparations and examples , which are illustrative of the process and products of this invention , temperatures are in degrees centigrade.

STEP I.

Preparation Ka) : 2-Chloromethyl-l , 4-dioxaspiro [4 , 5] decane- The preparations of this intermediate compound are illustrative of the methods used to make each of the corresponding first step intermediates leading to the guanidines described in the Examples . The first procedure is preferred.

Procedure A.

In a reflux distillation apparatus (See F. F.-Blicke and E. L. Schumann, J. Am. Chem . Soc. 76 , 1226 (1954) equipped with a Dean-Stark trap was placed 442 g. of 3 -chloro-l , 2 -propanediol and 4 g. of -toluene sulfonic acid and 1300 ml. of toluene. After reflux had been established , 392 g. of cyclohexanone was added dropwise duri&g a period of 30 minutes . The mixture was then refluxed for 6 hours until water ceased to accumulate in the trap. A total of 68 ml, of water was collected. The solution was cooled and the pH adjusted to neutrality with sodium methylate and filtered. The filtrate was distilled , removing the toluene first and then 2 -chloromethyl-1 , 4-dioxaspiro [4 , 5]decane , N ? 1. 4754 , at 112 - 116°/14. 5 mm.

Procedure B.

Using the method of F. F. Blicke and F. E. Anderson, J. Am. Chem.

Soc.74, 1735 (1952), this reaction is generally applicable to this group of intermediates. In a reaction flask equipped with a large stirrer, ice bath, dropping funnel, and protected from moisture by drying tubes, was placed 200 g.of cyclohexanone, 200 g. of epichlorohydrin, and 500 ml. of anhydrous o carbon tetrachloride. When the solution had cooled to 10 , 67 g. of stannic chloride was added dropwise over a period of 2.5 hours with stirring. After another hour of stirring at room temperature, 69.8 g. of potassium o hydroxide in 300 ml. of water was added at a temperature of 5 to 10. After standing some hours, the aqueous phase was decanted and extracted with ether. The combined carbon tetrachloride and ether solutions were dried over anhydrous potassium carbonate and distilled. The portion boiling at 0 25 118 to 124 /15 mm. ,N 1.4750, was used.

Analysis: Calculated for C9H1SC102: CI, 18.6 Found: CI, 18.06.

; STEP II Preparation 1 fb : 2-( Phthalimidomethy )~l, 4-dioxaspiro [4.5] decane '— — I The preparation of this phthalimido derivative is illustrative of the general procedure which was satisfactory for all such intermediates. See J.H.Billman and R.Vincent Cash, J. Am. Chem. Soc.75, 2500 (1953).

A 9.1 g. portion of sodium hydride (52.3 percent in mineral oil suspension) was slurried with about 80 ml. of anhydrous dimethyl formamide, anu then 29.4 g. oi phthaliniide was li usf rred gra.claa.lly to the reaction mixture from an attached flask connected by tubing to form a closed system. After an additional period of about one hour at temperatures varying up to 70 , 38. 1 g. of 2~chloromethyl~l , 4-dioxaspiro [4. 5] decane was added together with 0. 5 g. of sodium iodide (optional) in 20 ml. of dry dimethylformamide , and the mixture was heated at reflux for 5 hours and then filtered hot leaving 10. 8 g. of sodium chloride on the filter. o Reaction is practically complete after 2 hours at reflux. Reaction at 125 appears to require at least 24 hours for a similar yield. The filtrate was evaporated at reduced pressure on the steam bath to an oily residue which was diluted with 200 ml. of benzene and filtered. The filtrate was washed once with 100 ml. of 1 percent aqueous sodium hydroxide and 3 times with 300 ml. of water. The benzene was removed at reduced pressure on the steam bath and the residue triturated with petroleum ether, whereupon it crystallized to give 2 -(phthalimido -methyl) -! , 4-dioxaspiro [4. 5] decane , melting at o 87-90 . Crystallization may also be induced with isopropanol.

This compound was also made by a similar procedure but using commercial potassium phthalimide reagent in place of the sodium phthalimide used in the procedure described above. 102 Grams of 2-chloromethyl-l , 4-dioxaspiro[4. 5] decane , 121g. of potassium phthalimide , 6 g. of potassium iodide , and 500 ml. of anhydrous dimethyl formarnide were mixed and refluxed gently for approximately 16 hours with the reflu condenser closed by a calcium chloride drying tube. The solution was filtered hot, and 48. 1 g. of potassium chloride was recovered. The filtrate was diluted with 500 ml. of water which precipitated an oil. The aqueous portion was extracted twice with 250 ml. portions of chloroform which were combined and mixed with the oily precitipate. and evaporated to an oil which crystallized when triturated with iso-propanol. The crude product was recrystallized from ethanol and the crystals washed with 50 ml. of 8 percent aqueous sodium hydroxide, followed by a wash with 50 ml. of water, and then dried to give 2- 0 (phthalimiclo -methyl 4-dioxaspiro[4.5] decane, melting at 91 - 92.

Analysis: Calculated for C17H19N04: C, 68.03; H, 6.38.

Found: C, 68.20; H, 6.52.

STEP ΠΙ Preparation 1 (c): 1, 4-Dioxaspiro[4.5]decane~2~methylamine Sulfate. .3 Grams of 2-phthalimidomethyl-l, 4-dioxaspiro[4.5] decane and 4.5 ml. of hydrazine (95 percent anhydrous) were heated at reflux in 300 ml. of ethanol with vigorous stirring for one hour. The cooled slurry was diluted with 200 ml. of dry ether , filtered, and the precipitate was washed twice with 100 ml. portions of ether. The combined filtrates and washes was evaporated to 100 ml. of residue and diluted with 100 ml. of fresh ether and refiltered. The filtrate was evaporated to an oily residue which was dissolved in 10 ml. water and adjusted to pH 6.0 with 50 percent sulfuric acid. A precipi- I tate formed and was filtered, washed with ether, and dried to give 1 ,4-dioxaspiro o [4.5] decane-2-methylamine sulfate , melting at 237.5 - 239.5.

Analysis: i Calculated for (C9H17N02)2- H2S04: C, 49.07; H, 8.24; N, 6.36;S, 7.28 Found: C, 48.75;H, 8.37; N 6.32; S, 6.98.

The oily residue is usually of suitable purity and is in the desired free base form for us e in the Step TV reaction , and the refore can be used as such. For further purification when necessary the amines can be distilled or converted to sulfate salts or both.

The following table gives the melting point and /or boiling point of the intermediates prepared by the above procedures and used to prepare the compounds of the examples having the same number which follow it. The amine intermediates (ΠΙ) also poss ess useful pharmacolo gical activity , especially analgesic activity and barbiturate potentiation activity . 04) HCl) TABLE II RV n • (b.p. (mm) base) f>-- P-CH3OC6H,," . ¾H5 H 2 (138-14570.6) 6. CH3 . H 2 (101-140° /O.7) 7. C2H5 rn-CF3C&Ms • H 2 (101-10370.5) 8. C2H5 p-CH3-C£H5 H 2 (123-12570.5) 9. C2H5 p-Cl-CSH5 H 2 (132-13570.6) 0. CH3 CH3 H 2 (77-78713.5) 1. C2K5 CSH5 H 3 (102-10870.3) 2. H s H . 1 178- J 72 (.li2SOj . C6H5 H .· 2 195.5-196° (KC1) 4. H p-ClC&HS K 1 166-168° (H2S0,J 5. H . 2 (110-112° /0.25 mm) 140-141.2° (bonzoa 6. °Λ H 2 ( 108- Π070. mm) 159-160.5 (bGnzoa 7. H 2 161.5- (bonzo, • * 163.0 ' - C6H5 H 2 (94-9771-0 nun) . '(C2H2}5- ' H • 2 ca.- 250° (H2S0J C6"s ' "C2"s C2«5. 1 176-177° (HC1) STEP IV Example 1: (1 , 4-Dioxaspiro[4. 5]decan~2-ylmethyl)guanidine Sulfate .

A mixture of 10. 5 g. of 1 , 4-dioxaspiro [4. 5] decane-2-methylamine ' and 8. 6 g. of 2 -methyl ~2~thiopseudourea sulfate in 40 ml. of water was heated on the steam bath for 4 hours during which 2. 0 g. of methyl -mercaptan was collected in a dry ice bath connected to the reaction flask through a water cooled reflux condenser. The reaction mixture was then evaporated at 15 mm . pressure to a solid residue which was then dissolved in 80 ml . of 50/50 methanol -ethanol. The solution was filtered and evaporated to approximately 50 ml . volume and allowed to cool and crystallize , giving o a crop melting at 213. 5 to 215 of (1 , 4-dioxaspiro [4. 5]decan-2-ylmethyD -guanidine sulfate.

Analysis: Calculated for (C10H10N3O2)2' H2S04: C , 45. 79; H, 7 , 69; N, 16. 02;S, 6. 11. Found: C , 45. 97; H, 7. 99; N, 15. 76; S , 6. 14.

Another preparation which incorporated ammonia in the final crystal lization step gave a product with a higher melting point of 225-227° C but a slightly poorer analysis . A sample of this material, when recrystallized from water , resulted apparently in the formation of another crystal form , 0 melting at 243 -245 dec . This appears to be the stable form since recrystal -lization from methanol-ethanol did not alter the melting point.

This compound , in addition to pronounced anti -hypertensive activity , stimulates growth of the male accessory reproductive organs .

The compound of Example 1 is a potent sympathetic nerve ending blocker and depletes norepinephrine from the stores. Its anti -hypertensive properties have been demonstrated in renal hypertensive dogs . It appears superior to guanethidine or guanoxan in the following respects . First , it is well tolerated in large doses and doe s not induce diarrhea in any of the specie*s in which it was tested. Both guanethidine and guanoxan produce diarrhea. Second, both the compound of Example 1 and guanoxan cross the blood brain barrier and have been shown to deplete hypothalamic norepinephrine. Guanethidine does not penetrate the brain. Depletion of hypothalamic norepinephrine may contribute to the anti -hypertensive activity of the com -pound. Third , both the compound of Example 1 and guanoxan decrease the total catecholamine content of the adrenal gland . Guanethidine is devoid of this property . This is an additional characteristic which suggests that the compound of Example 1 may be superior to guanethidine as an antihypertensive agent.

Example 2 : (6-Chloro-l , 4-dioxaspiro [4. 5]decan«2«ylmethyl)guanidine Sulfate.

Following the procedure of Example 1 , 31 g. of 6~chloro --l , 4»dioxa~ spiro [4. 5]decane-2~methylamine , 23 g. of 2~niethyl-2~thiopseudourea sulfate , and 75 ml. of water were heated for 2 hours and then evaporated at reduced pressure and the residue was recrystallized from methanol twice to give (6-chloro-l , 4~dioxaspiro [4. 5] decan~2-ylmethyl)guanidine sulfate , melting at 232-234°.

Analysis: Calculated for (C30H18ClN3O2)2- H2SOy. C , 40. 47 ; H , 6. 45; N, 14. 16 Found: C , 40. 32; H, 6. 59; N, 14. 31 This compound possesses uterotrophic activity in addition to marked anti-hypertensive activity.

Example 3: (8-Methyl-l, 4~dioxaspiro[4.5]decan~2-ylmethyr)guanidine Sulfat.

In 30 ml. of water were dissolved 11.5 g. of 8-methyl-l, 4-di-oxaspiro[4.5]decane«2-methylamine sulfate, 6.8 g. of 2-methyl-2-thiopse-udourea sulfate, and 2.0 g. of sodium hydroxide. The solution was heated for 4.5 hours on the steam bath and was then evaporated at reduced pressure to a solid. This was dissolved in 90 ml. of an equal parts mixture of methanol -ethanol -water. The solution was filtered and then evaporated to about 2/3 volume and then allowed to stand. Three successive crops of crystals were o obtained at room temperature and at -j-2. These were combined and re-crystallized from 17 percent water in methanol to give (8 -methyl -1, 4-dioxa- o spiro[4.5]decan-2-ylmethyl) guanidine sulfate melting at 259 .

Analysis: Calculated for (CuH2lN3O2)2. H2S04: C, 47.81; H, 8.02; N, 15.21 Found: C, 47.91; H, 8.10; N, 14.96 This compound possesses anti -hypertensive activity.

Example 4: (7, 7, 9, 9-Tetramethyl-l, 4-dioxaspiro[4.5]decan-2~ylmethyl)« guanidine Sulfate.

Following the procedure of Example 1, 34 g. of 7, 7, 9, 9-tetra-methyl -I, 4-dioxaspiro[4.5]decane-2-methylamine and 23 g.of 2~rnethyl~2-thiopseudourea sulfate were dissolved in 50 ml. of v/ater and reacted for o 2 hours. The product melted at 254-256 after one recrystallization from methanol.

Analysis: Calculated for (C14H27N302)2. H2S04: C, 52.81; H, 8.86; N, 13. 20 Found: C, 52.81; H, 8.63; N, 13.11 This compound possesses anti -hypertensive activity.

Example 5: (8-Methoxy-l, 4-dioxaspiro[4.5]decan-2-ylmethyl)guanidine Sulfate.

By the procedure of Example 1, 37.6 g. of 8-methoxy-l, 4-dioxaspiro[4.5]decane-2-methylamine was reacted with 23 g.of 2-methyl-2-thiopseudourea sulfate. The recrystallization of the product from iso-propanol was very slow. A second and third crops were obtained by dilution of the mother liquor with ether. The crops were combined and recrystallized from isopropanol and then from methanol. The impure product was then dissolved in aqueous caustic at pH 11. The solution was then washed with ether and finally readjusted to pH 7.4. The water was removed at reduced pressure and the residue was recrystallized from ethanol by ether dilution to give (8-methoxy-l, 4-dioxaspiro [4.5]decan-2-ylmethyl')guanidine sulfate melting at 216-218.

Analysis: Calculated for ((^H^NgO^. H2SO4: C, 45.19; H, 7.59; N, 14.37 Found: C, 44.96; H, 7.73; N, 14.51.

This compound possesses anti -hypertensive activity.

Example 6 : (6-Phenyl-l , 5]decan-2-ylmethy guanidine Sulfate.

Following the procedure of Example l 39 g. of 6-phenyl-l ,4-dioxaspiro[4.5]decane-2-methylamine was reacted with 23 g.of 2-methyl-2-thiopseudourea sulfate to give a crystalline residue after removal of the reaction solvent at reduced pressure. The residue was washed with concentrated aqueous potassium bicarbonate and then triturated first with ether and then with ether -ethanol to give (6-phenyl-l, 4-dioxaspiro[4.5] o decan-2-ylmethyl)guanidine sulfate, melting at 244-245 dec.

Analysis: Calculated for (C1CH23N302)2.H2S04: C, 56.79; H, 7.15; N, 12.42; S, 4.74 Found: C, 53.01; H, 7.23; N, 12.37; S, 4.51 This compound possesses anti -hypertensive activity.

Example 7: (1, 4»Dioxaspiro[4.6jundecan~2~ylmethyl)guamdine Sulfate.

By the procedure described in Example 1, 28 g.of 1, 4-dioxaspiro-[4.6]undecane«2-methylamine v/as reacted with 20 g. of 2-methyl-2~thiopseudo-urea sulfate in 50 ml. of water for approximately 2 hours during which a heavy precipitate formed. It was separated and recrystallized from methanol twice to give (1, 4~dioxaspiro[4.6jundecan-2~ylmethyl)guanidine sulfate, m. p. 255,- 256°.

Analysis: Calculated for (C11H2lN302)2. H2S04: C, 47.81; H, 8.02; N, 15.21; S, 5.80 Found: , C, 47.85; H, 8.01; N, 16.02; S, 5.71 This compound, in addition to strong anti -hypertensive activity, blocks the cardiac -conditioning response and has anti -inflammatory activity by the limb volume test.

Example 8: (1, 4-Dioxaspiro[4.7Jdodecan»2-ylmethyl)guanidine Sulfate.

Following the procedure of Example 1, 32 g. of 1, 4~dioxaspiro[4.7]·-dodecane-2-methylamine, 23 g.of 2~methyl~2~thiopseudourea sulfate, and 75 ml. of water were heated for 1.5 hours and then allowed to stand overnight when a heavy prec.ipita.te formed and v/as filtered off. It v/as recrystallized from methanol, to give (1, 4~dioxaspi.ro [4.7 ] dodeean -2 -ylme thyDguanictine Analysis: Calculated for (Cl2H23N302)2. H2S04: C, 49.64; H, 8.33; N, 14.47 Found: C, 49.41; H, 8.12; N, 14.61 This compound possesses anti -inflammatory activity in addition to anti --hypertensive activity.

Example 9: [Spiro(L 3~dioxolane-2, 2' -indan) -4~ylmethyl]guanidine Sulfate.

According to the procedure of Example 1, 20 g. of spirofl, 3-dioxo-lane~2, 2' -indan) -4-methylamine, 14 g. of 2 -methyl -2 -thiopseudourea sul¬ fate, and 65 ml. of water were heated on the steam bath and upon cooling a heavy precipitate formed which was filtered from the mother liquor and recrystallized from 200 ml. of ethanol to give [spiro(l, 3-dioxolane~2, 2' - o indan) -4~ylmethy]]-guanidine sulfate, melting at 234-235 .

Analysis: Calculated for (C13H17N302)2.H2S04: C, 52.69; H. 6.12; N. 14.18 Found: C, 52.50; H, 6.06; N, 14.29 This compound possesses anti -hypertensive activity.

Example 10 : (1, 4-Dioxaspiro[4, 4]non-2-ylmethyl)guanidine Sulfate.

Following the procedure of Example 1, 35 g. of 1, 4-dioxaspiro [4..4]~ f nonane-2-methylamine and 21 g. of 2-methyl-2~thiopseudourea sulfate were reacted in 30 ml. of water. Evaporation at reduced pressure and re- evaporation after adding propanol to the residue gave an amorphous product which crystallized when stirred with 50 ml. of ethanol. The mixture was diluted with 200 ml. of dry ether and filtered. The crude product was recrystal 1* zed f o ethanol n then from ms^hn ; Ο1 to gi e (Ϊ 4 -d'* eff spiro f ^ 4 ηοη·- 0 2 -ylmethyl)-guanidine sulfate, melting at 205 dec.

Analysis:' Calculated for (CgH17N302)2. H2S04: C, 42.97; H, 7.01; N, 16.92; S, 6.45 Found: C, 43.64; H, 7.15; N, 16.86; S, 6.54 This compound possesses anti -hypertensive activity.

Example 11: (1, 3 ~Dioxolan~4- lmethyl)guanidine Sulfate.

Using the procedure of Example 1, 15.3 g. of 1,3- dioxolane-4- methylamine was reacted with 13.9 g.of 2~methyl-2~thiopseudourea sulfate. The reaction mixture was evaporated at reduced pressure on the steam bath to a colorless amorphous semi -solid. It was dissolved in 170 ml. of methanol and re -evaporated to an amorphous solid at high vacuum. This material was triturated with anhydrous ether to give an amorphous solid which was pulverized and triturated with fresh anhydrous ether to give a white powder which o o softened at approximately 60 and melted at 100 with decomposition.

Analysis: Calculated for (C5HnN3O2)2. H2S04: C, 30.92; H, 6.23; N, 21.64 Found: C, 30.7; H, 6.0; N, 20.8 This compound, in addition to anti -hypertensive activity, is a lipase inhibitor.

Example 12: (2, 2-Dimethyl-l, 3~dioxolan-4~ylmethyl)guanidine Sulfate.

By the procedure fof Example 1, 29.5 g. of 2, 2 -dimethyl -1, 3-dioxolane- 4 -methylamine was reacted with 21 g.of 2-methyl~2-thiopseudourea sulfate. The crude product was recrystallized twice from propanol without prior treatment with ether. It was finally recrystallized from 95 percent ethanol to give o (2, 2-dimethyl-l, 3-dioxolan-4»ylmethyl)guanidine sulfate, melting at 181.

Analysis: Calculated for (C7H15N302)2. H2S04: C, 37.83; H, 7.26; N, .18.91 Found: C, 37.84; H, 7.20; N, 18.66 This compound possesses anti -hypertensive activity.

Example 13: (2, 2-Diethyl-l, 3 ~dioxolan~4-ylmethyl)guanidine Sulfate.

Following the procedure of Example 1, 20 g. of 2, 2 -diethyl -1, 3 -dioxolane-4-methylamine and 14 g.of 2-methyl-2-thiopseudourea sulfate were reacted in 25 ml. of water. The product precipitated as a crystalline solid upon cooling the reaction mixture and was filtered. It was reci'ystal-lized from ethanol to give (2, 2 -diethyl -1, 3-dioxolan-4~ylmethyl)guahidine sulfate, melting at 229-231°.

Analysis: Calculated for (C9H19N302), . H2S04: C, 43.19; H, 7.65; N, 16.79 Found: C, 43.19; H, 7.61; N, 16.62 This compound possesses anti -hypertensive activity.

Example 14: (.2, 2-Diisopropyl-l, 3~dioxolan-4-ylmethyl)guanidine Hydrochloride.

A mixture of 5.2 g.of 2, 2-diisopropyl-l, 3~dioxolane»4~methylamine and 4.0 g.of 2-methyl-2~thiopseudourea hydrochloride in 25 ml. of water was heated on the steam bath for one hour. Then the solvent was evaporated at reduced pressure and the residue was dissolved in 25 ml. of hot isopropanol and the solution was re -evaporated to a residue at reduced pressure. The o residue was again dissolved in isopropanol and set aside at -{-2 for 3 days and a precipitate of 0.8 g. was filtered off. The filtrate was concentrated partially and allowed to stand for several days when it became crystalline.

The mass was washed with hot ethylacetate, filtered, and dried to give crystals o melting at 143-145 , of(2, 2-diisopropyl-L 3-dioxolan~4-ylmethylguanidin.e hydrochloride.

Calculated for C11H23N302. HC1: C, 49.71: H , 9.10 ; N, 15.81 This compound possesses anti -hypertensive activity .

Example 15: (2, 2-Dipropyl-l, 3~dioxolan~4-ylme thyl)guanidine Sulfate.

By the procedure of Example 1, 17.4 g. of 2, 2-dipropyl-l, 3-dioxolane 4-methylamine and 20.8 g. of 2--metlryl-2-thiopseudourea sulfate in 30 ml. of water were reacted for 3 hours and the volatile material was then removed at reduced pressure. The residue was treated with 50 ml. of ethanol and re-evaporated to a heavy sirup which was dissolved in 100 ml. hot isopropanol, filtered, and diluted with about 200 ml. of ethyl acetate to give a crystalline precipitate. This crop was recrystallized from 30 ml. of water to give (2, 2- o dipropyl-1, 3»dioxolan-4"ylmethyl)guanidine sulfate melting at 175-178.

Analysis: Calculated for (CUH23N302)2. H2S04: C, 47.46; H, 8.69; N, 15.10 Found: C, 47.16; H, 8.35; N, 15.18 This compound possesses anti -hypertensive activity.

Example 16: (2, 2-Diphenyl-l, 3-dioxolan~4-ylrnethyl)guanidine Sulfate. 9.1 Grams of 2, 2-diphenyl-l, 3-.dioxolane~4-methylami.ne hydro¬ chloride was suspended in 20 ml. of 10 percent aqueous sodium hydroxide and extracted with two 40 ml. portions of ether. The combined extracts were dried and evaporated to an oil which was treated with 4.8 g. of 2-methyl~2- thiopseudou ea sulfate as described in Example 1 for a period of 2 hours.

The reaction mixture was evaporated at reduced pressure to a while solid which was then recyrstallized from approximately 250 ml. of 50/50 ethanol - water 3 times to give(2, 2-diphenyl-l, 3 -dioxolan-4-ylmethyl guanidine sulfate m.p.229°.

Analysis: Calculated for (C17H19N302)2. H2S04: C, 58.94; H, 5.82; , 12.13 Found: C, 59.00; H. 6.08: N. 12.20 This compound, in addition to mild anti -hypertensive activity, has anti -inflammatory activity, is a lipase inhibitor and decreases postprandial lipemia of rats.

Example 17: (2, 2-I)icyclohcxyl-l, 3-dioxolan~4-ylme thyDguanidine Hydrochloride.

A solution of 27 g.of 2, 2-dieyclohexyl-l, 3-dioxolane-4-methyl- amine in 40 ml. of ethanol was mixed with 13 g.of 2~methyl-2~thiopseudo~ urea hydrochloride dissolved in 60 ml. of ethanol in a flask connected by a closed system through a Avate -cooled reflux condenser to a dry ice trap. The flask was then heated on the steam bath to reflux for 3 hours during which time 2.5 g.of methylmercaptan was collected. The reaction mixture was then diluted with 75 ml. of ether. Two liquid phases formed and the aqueous phase, a heavy sirup, was separated. It was diluted with water and washed 0 with fresh ether and then allowed to stand at ~{- 2 for two clays when a precipitate was separated. It was recrystallized from 25 ml. of water and then from methanol -ethyl -acetate to give (2, 2-dicyclohexyl-l, 3-dioxolan~4- o ylmethyl)guanidine hydrochloride, melting at 86-90 .

Analysis: Calculated for C„H31N3O2. HC1: C, 58.85; H, 9.59; N, 12.11 Found: ! C, 57.4 ;K, 9.4 ; N, 12.09 This compound possesses lipase inhibiting as well as anti -hypertensive activity.

Obvious variations

Claims (1)

1. WHAT IS CLAIMED A of the wherein n is the 1 or ft and are each independently selected the group consisting of phenyl and substituted said substituent being selected from the of 1 to 8 atoms group consisting of and tri alomethyl and and together with the eaturated atom of the dioxolane form saturated ring or a substituted ring said substituent bein selected the group consisting of lower alkyl and and is the group consisting of hydrogen and 1 to 8 carbon A compound of Claim 1 wherein n A compound of 1 wherein the carbon atom of the dioxolane ring bears as its sole substituents one to two hydrocarbon A compound of Claim 3 wherein bridge A compound of Claim wherein the substituents each are A compound of Claim 1 wherein the carbon atom is part of a spirocyclic compound of Claim 6 wherein n Λ compound of Claim 1 wherein the carbon atom of the dioxolane is part of a cycloalkane of carbon A compound of 8 or an acid addition salt A compound of Claim 8 guanidine or an acid addition salt A compound of Claim 8 or an acid addition salt A process for producing a compound of Claim which comprises reactin a compound of the formula with a and n are as defined in Claim A process to Claim 12 wherein the of the amine is A process according to Claim 12 wherein the carbon atom of the dioxolane as its sole substltuents from one to two hydrocarbon A process according to Claim the substituents each are A process according to 13 wherein the carbon atom of the dioxolane ring is part of a cycloalkane ring of carbon A process according Claim 16 cycloalkane ring contain 6 carbon A process according to Claim 16 the cycloalkane ring contains 7 carbon A pharmaceutical preparation comprising as active ingredient a guanidine as defined in Claim An reparation comprising as active ingredient a guanidine of the formula defined in claim 1 or as claimed in any of claims 2 to 11 An antihypertensive comprising a guanidine as claimed in any of claims 1 to 11 in unit dosage insufficientOCRQuality