US3484439A - Novel tetrahydro-s-triazin-2(1h)-ones - Google Patents
Novel tetrahydro-s-triazin-2(1h)-ones Download PDFInfo
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- triazin
- tetrahydro
- toluenesulfonyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/08—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Description
United States Patent 3,484,439 NOVEL TETRAHYDRO-s-TRIAZIN-2[1H]-0NES William E. McGonigal, Wilmington, DeL, assignor to E. I. du Pont de Nemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 571,697, Aug. 11, 1966. This application Oct. 21, 1968, Ser. No. 769,415
Int. Cl. C07d 55/12; A61k 27/00 U.S. Cl. 260-248 12 Claims ABSTRACT OF THE DISCLOSURE Certain tetrahydro s triazin 2[ 1H]-ones having the formula Pit-Z wherein R R and R are various organic radicals hereinafter defined are useful as hypoglycemic agents.
RELATED CASES This application is a continuation-in-part of copending Ser. No. 571,697, filed Aug. 11, 1966, now abandoned.
DESCRIPTION OF THE INVENTION General I This invention relates to novel substituted triazones, particularly to tetrahydro-s-triazin-Z[1H]-ones, and to their use as hypoglycemic agents.
The compounds of this invention have the formula:
where R1 is wherein n is 0, 1, or 2; R can be the same as R or hydrogen.
3,484,439 Patented Dec. 16, 1969 ICC The terms cycloalkyl," cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, and tricycloalkenyl as used herein are intended to include the respective group optionally substituted on the ring or on the ring portion of the group with substituents which will not interfere with the desired hypoglycemic activity of the compounds of the invention. Illustrative of such optional substituents, but not necessarily all inclusive, are alkyl or alkoxy groups containing one or two carbon atoms.
In accordance with the present invention, I have discovered that compounds of the above class are effective as hypoglycemic agents. These compounds are orally active antidiabetic agents useful for lowering blood sugar content in warm-blooded animals as evidence by in vivo tests in rats and dogs. The hypoglycemic activity of these com-- pounds can be readily demonstrated by animal tests which are known to correlate with antidiabetic activity in man, such as those reviewed by Auguste Lobatieres in chapter 37 Hypoglycemic Agents, vol. II, Academic Press, London (1964).
The preferred compounds because of their outstanding hypoglycemic activity include where Z is methyl, ethyl, acetyl, chlorine or bromine; R and R are the same or different and are alkyl of 3-6 carbon atoms, cycloalkyl of 5-7 ring carbon atoms, bicycloalkyl or bicycloalkenyl of 7 or 8 ring carbon atoms, tricycloalkyl of 10 ring carbon atoms.
Methods of preparation where R; and R have the same meaning as defined above. The reaction may be accomplished in the absence of solvent or in the presence of an inert anhydrous solvent such as dioxane, toluene or acetone. The reaction occurs readily at temperatures between 10 and 100 C.
Certain of the compounds of this invention can also be made by a second process, which uses a 1-arylsulfonyl-3- alkylurea, formaldehyde and an acid catalyst. This reabove equation are different, the product triazinone will be present as a mixture of our compounds as follows:
0 II II action is described by the following chemical equat1on:
0 t 6 H H+ R2 R3 2 R1SOzNHCNHRg 2 CHzO 0 ll f R1SO N N-Rz R1-SO2-NHz E20 CO3 R1SOz-N N-R2 R1SO2N N-R3 H N/ N/ R2 l I 4 where R and R have the same meaning as defined above. (3)
The reaction of a substituted sulfonyl urea is effected If desired, these compounds can be separated by fractional in solution of a suitable anhydrous solvent at temperatures crystallization, chromatography, or other known methods of 2050 C. with either paraformaldehyde or s-trioxane which will be obvious to those skilled in the art. as the source of formaldehyde. Suitable solvents for the This reaction is performed in the same manner as that reaction are dioxane, dimethylformamide or dimethyldescribed in the second method given above, except that sulfoxide. An acid catalyst is required for the reaction. an amine salt of the 1-arylsulfonyl-3-alkylurea is used Sulfuric acid and p-toluenesulfonic acid, for example, are instead of the urea. suitable catalysts. The water formed in the reaction should A better understanding of the invention will be gained be removed to achieve highest yields. Azeotropic distillafrom the following examples which are for the purpose of tion using benzene or contacting the reaction with a suitillustrating the various features thereof.
2612:: gig 113g agent such as magneslum sulfate can be used EXAMPLE 1 The third method for the preparation of the novel com- Prep r ti n of 1(p-to 1uenesu1f0nyl)-3,5-di-(n-butyl) pounds of this invention involves the reaction of an amine tetfahYdf0-$-tT1aZ1H-2[lHl-one-first method Salt of a m g 1 fm 1a1dehyde m To a well stirred solution of 17.0 parts by weight of the presence of an acidic cata yst. T e chemlcal reaction 173,5 tri (n buty1)hexahydro s triazine and 87 Parts by )8 represented by the following chemical equation. Weight of anhydrous toluene is added, dropwisea 197 parts by weight of p-toluenesulfonylisocyanate. After the W initial heat evolution, the solution is maintained at 60 [R s02-NCNHR2] +[R3NH3] 2 01120 C. for six hours, The solvent is removed by stripping 0 under reduced pressure and the residue is recrystallized to H give essentially pure 1(p-to1uenesulfonyl)-3,5 di (nbutyl)tetrahydro-s-triazin-2 1H] -one. R SO N NR 2H 0 1 2 2 2 The following tetrahydro-s-tr1az1n-2[1H]-ones of this invention can be made similarly by substituting the ap- I propriate amount of the following hexahydro-s-triazine reagents or methylene amine reagents and sulfonylisocyanate reagents for 1,3,5-tri-(n-butyl)hexahydro-s-triwhere R R and R have the same meaning as defined azine and p-toluenesulfonylisocyanate employed as reabove. Actuallly, when R and R for the reactant in the actants hereinabove.
Hexahydro-s-triazine or N-methylene Example amine Sulfonylisocyanate Tetrahydro-s-triazin-2[1H]'one 2 1,3,5 trimethylhexahydro s triazine p Toluenesulionyl 1 (p-toluenesulfonyl) 3,5 dimethyl isoeyanate. tetrahydro-s-trianzin 2[lH]-one. 3 1,3,5 triethylhexahydro s-triavine .dn 1-(p-toluenesulfonyl)-3,5-diethyl-tetrahyd triazin-2[1H]-one. 1,3,5-tri(n-propy1)hexanydrol-(p-toluenesulfonyl)-3,5-di(n-propyl)- s-triazine. tetrahydro-s-triazin-2[1H]-one. 5 1,3,fi-triisopropylhexahydrol-(p-toluenesulfonyl)-3,5-diisopropyls-triazine. tetrahydro-s-triazin-ZllHl-one. 6 l,3,5-tri(see-butyl)hexahydrodo 1-(p-toluenesulfonyl)-3-5-di(seobutyl)- s-triazine. tetrahydro-s-triazin-2[1H]-0ne. 7 1,3,5-triisobutylhexahydrodo l-(p-toluenesulfonyl)-3,5-diisobutyls-triazine. tetrahydros-triazin-2llI-I1-one. 8 N-methylene-t-butylamine .d0 l-(p-toluenesulfonyl)-3,5-di (t-butyl)- tetrahydro-s-triazin-2I1H1-one. 9 1,3,5-tri(n-pentyl)hexahydrm d0 l-(p-toluenesulfonyl)-3,5-di(n-pentyl) s-triazine. totrahydro-s-triazin-2[lH]-one. 10 l,3,fi-trisopentylhexahydrodo 1-(p-toluenesulfonyl)-3,5-diis0pentyl-tetrahydros-triazine. s-triazin-2[1H]-one. 11 1,3,5-tris(l-methyl butyDhexa d0 l-(p-toluenesulfonyl)-3,5-bis(1-methyl hydro-s-triazine. butyl)tetrahydro-s-triazin-2[lH]-one. 12 N-methylene-neopentylamme ..d0 1-(p-toluenesulfonyl)-3,5-di(neopentyl)- tetrahydro-s-triazin-2[1H]-one. 13 1,3,5-t1is(1,2-dimethy1propyD- do l-(p-toluenesulfonyl)-3,5-bis(1,2-dimethylhexahydro-s-triazine. propyl)tetrahydro-s-triazin-2[1H]-one. 14 1,3,5-tris(1,3-dimethylbutyl)- -..d0 1-(p-tolueuesulfonyl)-3,5-bis(1,3-dirnethylhexahydr0-s-triazine. butyl) tetrahydro-s-triazin-Z[1H1-one. l5 1,3,5-tris(2,2,4-trimethylpenty1)- d0 1-(p-toluenesulfonyl)-3,5-bis(2,2,4-trihexahydro-s-triazine. n[ileltlliylpentyl)tetrahydro-s-triazin- 43116. 16 1,3,Mri(n-decyl) ...d0 1-(p-toluenesulfonyD-3,5-di(n-decyl)- hexahydro-s-triazlue. tetrahydro-s-triazin-2[1H]-one. 17 1,3,5-tricyclopropylhexahydl'o- ..d0 1-(p-t0luenesul1'onyl)-3,5-dicyclopropyls-trlazine. tetrahydro-s-triazin-Z[1H]-0ne.
Hexahydro-s-triazine or N-methylene Tetrahydro-s-triazin-2[1H]-one 69 1,3,5-tri(n-propyl)hexahydro-sp-trifiuoromethyl-benzene- 1(p-trifinoromethylbenzenesulfonyl)-3,5-di(ntriazine. sultonyl isocyanate. propyl)tetrahydro-s-triazin-2[1H]-one.
70 1,3,5-tricyclhexylhexahydro-sdo 1-(p-trifluoromethylbenzenesulfonyl)-3,5-
triazine. dicyclohexyltetrahydro-s-triazin-2[1H]-one.
71 1,3,fi-tricycloheptylhexahydro-s- ..do 1-(p-trifluoromethylbenzenesull'onyl)-3,5-
triazine. dicycloheptyltetrahydro-s-triazin2[lH]-one.
72 1,3,5-tri(n-bntyl)hexahydro-sp-methy1mercapto-benzenel-(p-mcthylmercaptobenzenesulf0nyl)-3,5-diiazine. sulfonyl isocyanate. (n-butyl)tetrahydro-s-triazin-2[1H]-one.
73 1,3,S-tricyclohexylhexahydro-sd0 1-(p-methylmercaptobenzenesull'onyl)-3,5-
triazine. dicyclohexyltetrahydro-s-triazin2[1H]-one.
74 do p-Ethylmercaptol-(p-ethylmercaptobenzenesulicnyl)-3,5-
benzenesulfonyl dieyclohexyltetrahydro-s-triazin-2[1H]-one. isocyanate.
75 do p-(Is0pr0py1thio)- l-[p-(isopropylthio)benzenesuIfony1]-3,5-
benzenesulfonyl dicyclohexyltetrahydro-s-triazin-2[1H]-one. isocyanate.
76 "do p-(n-Butylthio)- 1-[p-(n-butylthio)benzenesulfonyl]-3,5-
benzenesulfonyl dieyclohexyltetrahydro-s-triazin-3[1H]-one. isocyanate.
77 1,3,5tri(n-butyDhexahydro-sp-Methoxybenzenesuhonyl 1-(p-methoxybenzenesulfonyl)-3,5-di-(n-butyl) triazine. isocyanate. tetrahydro-s-triazin-Z[1H]-one.
78 1,3,5-tricye1ohexylhexahydro-sdo 1-(p-methoxybenzenesulfonyl)-3,5-ditriazine. cyclohexyltetrahydro-s-triazin-2[1H]-one.
79 "do p-(n-Butoxy)benzenel-lp-(n-butoxy)benzenesu1f0nyl]-3,5-
snlfonyl isocyanate. dicyclohexyltetrahydro-s-triazin-2[1H]-one.
80 do p-Fluorobenzenesulfonyl 1-(p-fluorobenzenesulfonyl)-3.5di-eyclohexy1- isocyanate. tetrahydr0-s-triazin-2[1Hl-one.
s1 1,3,5-tri-(n-buty1)hexahydro'sd0 1-(p-fluorobenzenesulfonyl)-3,5-di-(n-butyl) triazine. tetrahydr0-s-triazin-2[1H]-one.
82 l-(methyleneamino)pyrrolidine.. p-Toluenesulfonyl 1-(p-toluenesulionyl)-3,5-di(l-pyrrolidinyl) isoeyanate. tetrahydro-s-triazin-2[1H]-0ne.
83 1-(methyleneamino)piperidine d0 l-(p-toluenesulfonyl)-3,5-dipiperidlnotetrahydr0-s-triazin-2[1H]-one.
84 ..do p-Chlor benzenesulfonyl l-(p-chlorobenzenesulionyl)-3,5-dipiperidinoisocyanate. tetrahydro-2-triazin-2[1H]-one.
85 do p-A e yl enz nesulfonyl 1-(p-acetylbenzenesulfonyl)-3,fi-dipiperidinoisocyanate. tetrahydro-s-triazin-Z[lHl-one.
86 1-(methyleneamin0)-4,4- p-Tolnenesulfonyl 1-(p'toluenesulfonly)-3,5-bis(4,4-dimethy1- dimethylpiperidine. isocyanate. piperidino) tetrahydro-s-triazin-2[lHl-one.
87 l-(methyleneamino)hexahydro ...d0 l-(p-toluenesulfonyl)-3,5-di(1-hexahydroazeazepine. pinyl)tetrahydro-s-triazin-2[1Hl-one.
38 1,3,s-tris(4-ethoxyeyc1ohexyD- .d0 l-(p-toluenesulfonyl)-3,5-bis(4-ethoxyeyclohexahydro-s-triazine. hexyl)tetrahydro-s-triazin-ZHH]-one.
89 1,3,5-tris(Z-ethoxycyclohexyD- d0 1-(p-toluenesulfonyl)-3,5-bis(2-ethoxycyclohexahydro-striazine. hexyl) tetrahydm-S'triaZin-Z[1H]-one.
90 1,3,5-tris(2-methoxycyclohexy1)- --.--d l-(p-toluenesulfonyD-B,5-bis(2-methoxycyclohexahydros-triazine. hexyl)tetrahydr0-striazin-2[11H]-one.
EXAMPLE 91 fonyl)-3-(n-butyl)urea, 50 parts by weight of p-dloxane,
Preparation of l-(p-toluenesulfonyl) -3 ,5 -di- (n-butyl tetrahydro-s-triazin-2[1H]-onesecond method A mixture of 27 parts by weight of l-(p-toluenesulfonyl)-3-(n-butyl)urea, 7.3 parts by weight of paraformaldehyde, 50 parts by weight of p-dioxane, 0.2 parts by weight of p-toluenesulfonic acid monohydrate, and 174 parts by weight of benzene are heated to reflux under a Dean-Stark trap and maintained at that temperature until water is no longer evolved. The solution is cooled to 15 C. and washed with 2 N hydrochloric acid and saturated aqueous sodium bicarbonate. After drying with anhydrous magnesium sulfate, the solvents are removed by stripping under reduced pressure. The residue is recrystallized to give essentially pure 1-(p-toluenesulfonyl)-3,5- di- (n-butyl tetrahydro-s-triazine-2[ 1H] -one.
All of the compounds named in Examples 290 can be also prepared according to this procedure by substituting the appropriate urea for 1-(p-toluenesulfonyl)-3- (n-butyl)urea employed above. In addition, the following tetrahydro-s-triazin-2[1H]-ones of this invention can be prepared according to this procedure by substituting the following urea reagents for 1-(p-toluenesulfonyl-3-(nbutyl)-urea employed above.
174 parts by weight of benzene and 7.3 parts by weight of n-butylamine are stirred at room temperature. Next, 6.6 parts by weight of paraformaldehyde and 0.3 part by weight of p-toluenesulfonic acid monohydrate are added and the mixture is refluxed under a Dean-Stark trap until water is no longer evolved. The solvents are removed by stripping under reduced pressure and the residue is recrystallized to give essentially pure 1-(p-toluenesulfonyl)-3,5- din-butyl -tetrahydr0-s-triazin-s[ 1H] -one.
All of the compounds named in Examples l-97 can also be prepared according to this procedure by substituting the appropriate urea reagent, amine reagent and urea, n-butylamine, and paraformaldehyde respectively employed as reactants above.
EXAMPLE 99 Preparation of l-(p-toluenesulfonyl)-3-isopropyl-5-cyclohexyltetrahydro-s-triazin-Z[ 1H] -one and 1-( p-toluenesulfonyl) 3 cyclohexyl 5 isopropyltetrahydro-striazin2[1H]-one A mixture of 12.8 parts by weight of l-(p-toluenesulfonyl)-3-isopropylurea, 40 parts by weight of p-dioxane,
Example Sulionyl urea Tetrahydro-s-triazin-2[1H]-one 92 l-(p-aminob enzenesulfonyl) -3-(n-buty1) urea 1-(p-aminobenzenesulfonyl) -3,5-d1(n-butyl) tetrahydr0-s-tr1az1n-2[1H]-one. 93 1-(p-aminobenzenesulfonyl)-3-cyclohexylurea l-(p-aminobenzenesulfonyl)-3,5-d1cyclohexyltetrahydro-s-triazin-2[1H]-0ne. 94 1-(4-methyl-3-aminobenzenesulf0ny1)-3 1-(4-methyl-3-a1ninobenzenesulfonyl)43,5-
eyclohexylurea. dicyclohexyltetrahydr0-s-tr1azu1-2[1H]-one. 95 1-(4-methyl-3aminobenzenesult'onyl)-3- 1-(4-methy1-3'aminobenzenesulfonyl)-3,5-
eycloheptylurea. dicycloheptyltetrahydro-s-tr1az1n-2[1H]-one. 96 1-[4-(n-butyl)-3-aminobenzenesulfonyl]-3- 1-[4-(n-butyD-3-am1nobenzenesulfony1]-3,5-
cyclohexylurea. dicyclohexyltetrahydro-s-tr1azu1-2[1H]-one. 97 1-(3,4-dimethylbenzenesu1fonyl)-3- 1-(3,4-dimethylbenzenesulfonyD-3,5 d1eycl0- eyclohexylurea. hexyltetrahydro-s-tnaztn-2[1H]one.
EXAMPLE 98 Preparation of l-(p-toluenesulfonyl)-3,5-di-(n-butyl)- tetrahydro-s-triazin-Z 1H] -onethird method A mixture of 27 parts by weight of l-(p-toluenesul- 57 parts by weight of benzene and 50 parts by weight of cyclohexylamine are stirred at room temperature. Next, 3.3 parts by weight of paraformaldehyde and 0.3 part by weight of p-toluenesulfonic acid are added and the mixture is treated as described in Example 98. The crude syrupy residue contains the following four compounds in approximately equal amounts; 1-(p-toluenesulfonyl)-3,5- diisopropyltetrahydro-s-triazin 2[1H]-one, 1 (p-toluenesulfonyl) 3,5 dicyclohexyltetrahydro-s-triaziri 2- [1H]-one, 1 (p-toluenesulfonyl) 3 isopropyl 5 cyclohexyltetrahydro-s-triazin 2[1H] one and l-(p-toluenesulfonyl) 3 cyclohexyl 5 isopropyltetrahydro s triazin-2[1H]-one. These compounds can be obtained separately by either fractional crystallization or by chromatography of the crude mixture.
The following tetrahydro-s-triazin-2[1H]-ones of this invention can be made similarly by substituting the following sulfonylurea reagents and amine reagents for 1- more other metabolically, therapeutically or nutritionally beneficial ingredients.
These compositions will ordinarily contain from about 10 milligrams to about 500 milligrams of a compound of the invention. A preferred composition will contain from about milligrams to about 500 milligrams of such compound. The active compound will normally constitute from about 1% to 95% by weight of the total composition. Ordinarily, since it will be desired to administer the active compound according to this invention in fairly concentrated form, i.e. with only so much pharmaceutical carrier as is necessary or convenient to assist in administration, the active compound will constitute under most circumstances a fairly high proportion of the total composition.
(p-toluenesulfonyl)-3-isopropylurea and cyclohexylamine 15 This invention will be further understood by reference employed as reactants above. to the following additional examples:
Example Sulfonylurea Amine Tetrahydr0-s-triazin-2flH]-one 100-...- l-(p-toluenesulfonyl)-3-(n-butyl)- Cyclohexylamine l-(p-toluenesulfonyl)-3-(n-butyl)-5-cyc1ohexyl urea. tetrahydro-s-triazin-2[1H]-one.
1-(p-toluenesu1fonyl)-3-cycl0hexy1-5-(n-buty1)- tetrahydro-s-triazm-2[1Hl one. 101 l-(p-chlorobenzenesulfonyl)-3- do 1-(p-chlorobenzenesulfonyl)-3-(n-propyl)5- (n-propyDurea. cyelohexyltetrahydro-s-triazin 2-[1H]one.
1-(p-chlorobenzenesulfonyl)-3-cyclohexyl-5- (n-propyl)tetrahydm-S'triaZin-ZDH]-one. 102 1-(p-acetylbenzenesulfonyl)-3- Cyclopentylamine l-(p-aeetylbenzenesulionyl)-3-cyc1ohexy1-5r cyclohexylurea. cyclopentyltetrahyd.ros-triazin-2[1H]-one.
l-(p-acetylbenzenesuli'onyl)-3-cyelopenty1-5- cyclohexyltetrahydro-s-triazin-2[1H]-oiie. 103 l-(p-toluenesullonyl)-3-(n-buty1)- l-adamatylamiue l-(p-toluenesulfonyl-B-(ri-butyl)-5(1-adamantyl) urea. tetrahydro-s-triazin-zllfl]brie.
l-(p-toluenesulfonyl)-3-(1-adarnanty1)-5-(i1-but3 1) tetrahydro-s-triazin-2[1H]-one. 104 l-(p-toluenesulfonyl)-3-(n-butyl)- Ammonia 1-(p-toluenesulfouyl)-3-(ri-butyD-tetrahydro-surea. trlazin-2[1H]one.
For 'Examples 100, 101, 102, and 103, as in the case of EXAMPLE 105 f lz i 1 1 5 pzq y g l lg reaction 15 a g fi One-hundred (100) milligrams of l-(p-toluenesulourb e ra y tug-21132111 133 if lzi f 1 w w fonyl)-3,5-di-(n butyl)-tetrahydro-s-triazin-2[1H]-one, can 6 separae mm one ano er so eslre 2.5 milligrams of gelatin, 2.5 milligrams of magnesium Utility of compounds stearate and 100 milligrams of mannitol are mixedand The compounds of this invention can be administered g 2 i fi i g' g g f machme' orally and will be used in an amount effective to reduce tionel a e m y e u a e y com/en blood sugar level in the recipient. Ordinarily, doses will a pr 6 u EXAMPLE 106 range from 0.005 to 5 grams per day. Administration can be spread out over several times per day, as with The procedure of Example 144 is followed, using 100 meals, or otherwise, as convenient. The exact dosage milligrams of l-(p-toluenesulfonyl l)-3,5-diisopropylwithin the recited range will depend on the severity of tetrahydro-s-triazin-2[1H]-one in place of the compound the affliction, on concurrent treatments, on the physiology of that example. The tablets may be surface-coated if of the recipient, on other attendant circumstances, and desired. on the nature of the effect desired. EXAMPLE 107 The compounds can be used according to this invention in a composition which comprises the active com- 1 h P E Examlile 144 follozved substlfiitmg pound together with an inert non-toxic pharmaceutical 00 i grams 0 carrier. The composition can take the form of tablet, prop}, 13 for the actwe powder, capsule or other dosage forms. The compounds gredlengfo lfhat exam]? The ta lets may be surface can be admixed with solid diluents and/ or tableting adcoated deslred' juvants such a lactose, mannitol, corn starch, magnesium EXAMPLE 108 stearate talc gelatm; gums the A plurality of unit capsules is prepared by filling Any the tabletlng mammals used In Pharmaceuucid standard two-piece hard gelatin capsules weighing about andfietermarygractlqes i be Where there 1s 50 milligrams each #3 with milligrams of powdered no ncompatibility with either the active compound of l (p toluenesulfonyl) 3,5 di (n hexyl)tetrahydm s the invention or its biological activity. 0 triazimzufiyone' Compounds of the invention can be put in dosage forms with or without adjuvants. For example, in a preferred EXAMPLE 109 aspect of this invention, a compound with or without a 1 f 1 b further adjuvant can be placed in a conventional pharmap ura lty g 1 es limpared' ceutical capsule, such as a gelatin capsule, and be ad- 5 Stan aFd.two'Plece at ge atm capsu es (#3 slze) Wlth i 100 milligrams of powdered 1-(p-chlorobenzenesulfonyl)- ministered inthat form. 5 1 h d 2 1H Compositions containing compounds of the invention SOPIOPY tetra y will include the presence of the active compound in a EXAMPLE 110 powder packet, or such composition can be prepared in the form of a suspension in a material in which the active 70 An effective hypoglycemic oral suspension is prepared by admixing 1 part by weight of l-(p-toluenesulfonyD- 3,5-di (n-propy1) -tetrahydro-s-triazin-2 1H] -one, 5 parts by weight of Acacia, N.F., 1.5 parts by weight of Cyclamate Sodium, NE, and 92.5 parts by weight of water.
1 1 EXAMPLE 1 11 The procedure of Example 110 is followed, using 1 part by weight of l-(p-toluenesulfonyl)-3,5-dicyclohexyltetrahydro-s-triazin-2[1H]-one in place of the active ingredient of that example.
The disclosure herein should not be considered a recommendation to utilize the disclosed invention in any way without full compliance with US. Food and Drug Laws.
I claim: 1. A compound of the formula:
R SO N N-Rz where:
R is selected from the group consisting of wherein X is selected from the group consisting of hydrogen, alkyl of 1-4 carbon atoms, alkoxy of l-4 carbon atoms, alkylthio of 1-4 carbon atoms, alkanoyl of 2-4 carbon atoms, trifiuoromethyl, chlorine, fluorine, bromine and amino, and Y is selected from the group consisting of hydrogen and alkyl of 1-4 carbon atoms;
R is selected from the group consisting of alkyl of 2-1() carbon atoms, cycloalkyl of 3-8 ring carbon atoms, cycloalkenyl of 3-8 ring carbon atoms, bicycloalkyl of 7-10 ring carbon atoms, bicycloalkenyl of 7-10 ring carbon atoms, tricycloalkyl of 8-11 ring carbon atoms, tricycloalkenyl of 8-10 ring carbon atoms,
wherein n is 0, 1, or 2;
R is selected from the group consisting of R and hydrogen.
2. A compound of the formula Z AM TR.
where:
Z is selected from the group consisting of methyl,
acetyl, chlorine and bromine;
R and R are selected from the group consisting of alkyl of 3-6 car-bonatorns, cycloalkyl of 5-7 ring carbons, bicycloalkyl and bicycloalkenyl of 7-8 ring carbons and tricycloalkyl of 10 ring carbons.
3. l-(p-toluenesulfonyl) 3,5 di-(n-butyl)tetrahydros-triazin-2[1H]-one.
4. 1 (p chlorobenzenesulfonyl) 3,5 di(n propyl) tetrahydro-s-triazin-2[ 1H] -one.
5. 1 (p toluenesulfonyl) 3,5 dicyclohexyltetrahydro-s-triazin-2[1H]-one.
6. 1-(p toluenesulfonyl) 3,5 di(1-adamantyl)tetrahydro-s-triazin-2 1H] -one.
7. 1 (p chlorobenzenesulfonyl) 3,5 di(l-adamantyl) tetrahydro-s-triazin-Z 1H] -one.
8. 1 (p toluenesulfonyl) 3,5 dipiperidinotetrahydro-s-triazin-2[1H]-one.
9. 1 (p toluenesulfonyl) 3,5 dicycloheptyltetrahydro-s-triazin-Z[1H1-one,
10. 1 (p toluenesulfonyl) 3,5 di(n-propyl)tetrahydro-s-triazin-2[1H]-one.
11. A process for the preparation of a compound ofthe formula:
where:
R is selected from the group consisting of wherein X is selected from the group consisting of hydrogen, alkyl of l-4 carbon atoms, alkoxy of 1-4 carbon atoms, alkylthio of 1-4 carbon atoms, alkanoyl of 2-4 carbon atoms, trifiuoromethyl, chlorine, fluorine and bromine, and Y is selected from the group consisting of hydrogen and alkyl of l-4 carbon atoms;
R is selected from the group consisting of alkyl of 2-10 carbon atoms, cycloalkyl of 3-8 ring carbon atoms, cycloalkenyl of 3-8 ring carbon atoms, bicycloalkyl of 7-10 ring carbon atoms, bicycloalkenyl of 7-10 ring carbon atoms, tricycloalkyl of 8-11 ring carbon atoms, tricycloalkenyl of 8-10 ring carbon atoms,
wherein n is 0, 1, or 2; comprising reacting at a temperature in the range of from 10 to C., an aryl sulfonyl isocyanate of the formula where R is as defined above with a substituted methylene amine selected from the group consisting of where R is as defined above in a molar ratio of said aryl sulfonyl isocyanate to said methylene amine of 1:2 in case of the amine being Formula a above and 1: /a in the case of the amine being Formula 12 above.
12. A process for the preparation of a compound of the formula:
where:
R is selected from the group consisting of wherein X is selected from the group consisting of hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, alkylthio of l-4 carbon atoms, alkanoyl of 2-4 carbon atoms, trifluoromethyl, chlo- *rine, fluorine and bromine, and Y is selected from the group consisting of hydrogen and alkyl of 1-4 carbon atoms,
13 R is selected from the group consisting of alkyl of 2-10 carbon atoms, cycloalkyl of 3-8 ring carbon atoms, cycloalkenyl of 3-8 ring carbon atoms, bicycloalkyl of 7-10 ring carbon atoms, bicycloalkenyl of 7-10 ring carbon atoms, tricycloalkyl of 8-11 ring carbon atoms, tricycloalkenyl of 8-10 ring carbon atoms,
wherein n is 0, 1, or 2; comprising reacting a substituted sulfonyl urea of the formula Where R and R are defined as above in solution of an References Cited UNITED STATES PATENTS Burke 260-248 Martone 260-248 XR George et a1 260248 Schafer et a1 260248 NORMA S. MILESTONE, Primary Examiner J. M. FORD, Assistant Examiner U.S. C1. X.R.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76941568A | 1968-10-21 | 1968-10-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3484439A true US3484439A (en) | 1969-12-16 |
Family
ID=25085380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US769415A Expired - Lifetime US3484439A (en) | 1968-10-21 | 1968-10-21 | Novel tetrahydro-s-triazin-2(1h)-ones |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3484439A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4084054A (en) * | 1976-03-22 | 1978-04-11 | Imc Chemical Group, Inc. | Substituted triazones |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2304624A (en) * | 1940-04-25 | 1942-12-08 | Du Pont | 5-substituted tetrahydrotriazone |
| US2641584A (en) * | 1951-10-26 | 1953-06-09 | Du Pont | Adhesive compositions, including an amylaceous material and a triazone |
| US3108101A (en) * | 1963-10-22 | Process for-the synthesis of triazines | ||
| US3379725A (en) * | 1964-04-09 | 1968-04-23 | Bayer Ag | Substituted hexahydro-1, 3, 5-triazines |
-
1968
- 1968-10-21 US US769415A patent/US3484439A/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3108101A (en) * | 1963-10-22 | Process for-the synthesis of triazines | ||
| US2304624A (en) * | 1940-04-25 | 1942-12-08 | Du Pont | 5-substituted tetrahydrotriazone |
| US2641584A (en) * | 1951-10-26 | 1953-06-09 | Du Pont | Adhesive compositions, including an amylaceous material and a triazone |
| US3379725A (en) * | 1964-04-09 | 1968-04-23 | Bayer Ag | Substituted hexahydro-1, 3, 5-triazines |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4084054A (en) * | 1976-03-22 | 1978-04-11 | Imc Chemical Group, Inc. | Substituted triazones |
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