US2711411A - B-bromotheophylijne salt of z-amino-z- - Google Patents

Description

Grote, Chattanooga, Tenn., assig'noi's fto The Chat tanooga Medicine Company, Chattanooga, Tenm, a corporation of Tennessee No Drawing.

Serial No. 3 21,498 1 Claim. c1. 260-253 Application November 19, 1952,

' symptomsg i V iproductiof h pr'sent'ai tg ftion; -in-.the-treatment-i e a vpremenstrual,:tension is--;that in mostjpatients 'it; pro The present invention relates, to a pharmaceutical compound having enhanced diuretic activity,- and more particularly, totthe compound: 8-bromotheophylline-2 amino-Z-methyl-l-propanol,which is a bromotheophylgline salt of 2-amino-2-methyl-l propanol. "These. compounds have the following'structural formulas:

I 8-bromotheophylline cH3-N-c =ofH 2-amino-2-methyl-1-propanol i CH3 NH! cq nr -cm-c-wmon 1 been combined withflvarioujs amines for/the purpose of solubilizing'the theophylline in. diuretic compositions Probably the. most commomde'rivatiye ofwthis-Ltypeuis theophylline-ethylene v diamine, xknown aunder theiconl mercial name Aminoph'yllineff.

w are also awarethat s. Patent Ne. i,404,319,

issued July 16, 1946, to Robert S; Shelton, discloses :and

claims the theophyllineisalti-of u2t-methyl-2-amino-l-l propanol, alleging ,thatmthis compoundgis superi or to Aminophylline as: a .therapeuticaage'nt y We .have now found't'hat, if the-theophylline oi this type ,of composition is-replaced :by a -halotheophylline;

particularly 8-bromotheophylline, 'not only is "the solu t of t8-bromotheophylline areg suspended in one l terliof water. "To this suspension are addecl eighty-ninegrams: V

bility of the resulting composition increased,- to a greater:

degree than occurs fromwthe; reaction between theophyl- 1 line and the same amine fcompound, particularly 2-x methyl-Z-amino-l-propanol but 1 the 1 resulting; salt-is fa1 superior as a diuretic compound to thepprevjiously known i n U l temvby t mw t Theremarkably increased diuretic properties;tofhthe 2 1 -1 9 halotheophylline-amine salt "of the 1 present; invention makes it a valuable-therapeutic agent in the relief of pre-} menstrual tension, a v condition upon which previously; 3 known derivatives of theophylline hadlittlepr no efiect.

diuretic compounds containing theophylline; 1;

A large percentage of women, estirnated at 3.010)

V 1-; .T bii'f Q '1" th?f qemolesula I I compoundg has b een formed-consisting oflone'mole bromoth a hylline combined jwith fone mole of g-amino extreme nervousness, swelling of the;ankles jncreased;

appetite, irritability; pelvic: pain, and 1 a feeling of tension. The severity of the-discomfornis:directly comw mensurate with the -ax nount of fluid .accurnulated sort; Pounds o i d-lwomenaw otze ime qm;

3 /2 to 4. pounds during the 7 week "preceding the are almost incapacitated gue to;v th symptoms'from water toxemia-.,- Z v V i The Compound. of the hprese ntq nvven on ly efiicient inthe relic F with premenstrual tension:

Patients to whom the com- -Lt ympt m :tasa t siit menstrual,periodgsi 's-- 5. v I, Ang objectaof the p esent mvention sis oaprovidea sal 2=amino+2-m ethy1 l -propanol, fOI' ause 3 intheire lief premenstrual;- tension without 1 {thev presence-11o side: tions usually associatedjwith -the- Jadmini eQphy lin a The salt. of these two compounds' maysbeScalIed -Z amino-Z-methyl-l-propanol '8 -bromotheophyllinate or turefis" well ifstirred and l if necessary completelsolutiou cow in testing the o ,be fexcreted' as urine overa;=four-h our period.

the, presentainvention is administered iapp .oxi week ;:b'eforethe Onset of menses rarely E gai ning treatment,

.One outstandin erapeu vents waterf accumulation without diuresisygifi the treat ment isastarted: 'earlygenoughgso thattheipatients -have-i no; symptoms ofdwa'tergtoxemia throughon their prettherapeutic product' comprising a .halotheophylline;-salt ofa' organic;.amine,;namely, the 8.-bromotheophylline fo si lne grams .Two hundred" all pared to Qthe or'etical -pro'pa nol accordingto'the"following formula 'c s'r-.CH. ;i cH,-QH q The compound decomposes rrather sharply atv 390. 'C.

i The solubility? j wat'er at; froom temperature exceeds 30 31100 c. to give also'lution'havinga pH otaroun e e 7 mpound ot thevpresent invention for, 1ts"d ur etic1 action, the ffollowing procedure 'wa'si'us edi When .rats are given-tap water perorallyQoh}the-;b'asi' rat, on theaverage' of s-1 00% of the waterso given will 1 f,":in"- j addition' to the watc the rats areeachlgiven' sub- 3 cutaneously /2 unit 'of pit're ssi'n, an anti-diuretic drug, only 42% of. the. .water,..on the average, will he ex: creted. In conducting this test, the drug to be tested is given in a dosage on the basis of 0.1 g. of the product per kilogram'body weight of-the rat and the product isadded inthis proportion to :the water and pitressin. In this way, the anti=pitressin action of each of the various compounds is tested in terms ofthc percent of water recovery from the rats. 1 3 a It was found that the diuretic activity of 8'-bromotheophyllineQemino-Lmethybl propanol was 116-; whereas the diuretic-activity of the corresponding theophylline salt: theophylline-Z-amino-2-methyl-l-propanol was only 66, under the same-test conditions. These results are even more startling when the molar proportions. of theophylline per so are considered since one gram of bromotheophylline is equivalent on this basis to only about gram of theophylline U. S. P.

Amore elaborate series of tests were run substantially as the test hereinbefore described wasrun; and the results obtained are shown on the table (below), wherein column (1) shows the dosage of the theophylline or brornotheophyll-ine used in each test, and column (2) showsthe percentage water recovery calculated-by dividing the total volume of water given to a cage (of 4 rats each, which is the number of rats employed toobtain each test figure on the table) into the volumeof urine collected in the following 4 hours. Columns ('3); (4), (5) and (6) show, respectively, the total sodium (Na), potassium- (K), chloride (Cl), and sodium plus potassium, in milli-eq'uivalent weights, per cage of four rats that was found'in the urine recovered during the 4-hour period. Section A shows the results using plain tap water; Section B shows the results using plain tap water plus the subcutaneous pitressin injection hereinbefore described; Section C shows the results using plain water plus pitressin as in'Section'B and also using the amounts of the theophylline salt specified; and Section 'D compares with Section C, using in this instance the brornotheophylline saltof the invention instead of the theophylline salt.

Table SECTION AWATER I Average H d! D SECTION n wsman. rr'rnussny Average.. 1a 2. 3. 22

SECTION O-WATER, PITRESSIN, THEOPHYLLINE 2-AMINO- -METHYL-1-PROPANOL Averag e 64 1.32 0.69 1.72 2.51.

T ableContinued Z'AMIN O-2-METHYL-l-PROPANOL Col. 1 Colt: Col; 3 001. 4 Col. 5 Col. 6

- I. "TottilMlllieiiulvalent Weight s Percent DoseDrugmgJcc. Water t 1 Recovery p v' K" I 761 Nakand 4.84 5.20 4.85 4.23 6.85 as. 3. 7a 2.02 a. as s. so 122 1. as 1.71 2. 22 3.117 126 14s 1.56 2.06 3.04 122 a. as 1. 4a a. 5.21; 112 3.4a l.58 3.24 I 5.01

- sst 2.10 ass 5.71 as 5.00 2.40 was 2.40 as 4530 2.25 4.18 v 6.55 2187 1.94 2.05 4.81. 118 4. 69 2. 17 4. 4s a as 111 3. rs 2. 0s a. 56 5. as

Average 122 l. 93 1. 80 2. O2 3. 73

39 It will be seen from the table-above that in. each instance,

35 be administered to the rats without introducing considerable toxic symptoms in the'test'animals. it is thus clear that the hromotheophylline'drug gives superior as well as different results, inthat it can'be given in large dosages.

40 Ithas also been found that the instant bromotheophyl- 1 line salt gives a unique physiologicalaction that is-different from the general action characteristic of theophylline drugs. It has been established that the major effect of xanthine drugs, including theophylline, is on the cir- 45 culation, which, in turn, causes increased transport conditions connected with'the waste materials including water and salt. Under appropriate conditions the renal circulation becomes affected, and a diuretic efiect may be obtained; but such action, whether or not directly on the renal cells, is, clearly not the major action of these drugs. 1

In viewof the fact that the increased renal functionresults, if at all in the case of these drugs, from changes inthe generalized transport situation, it follows that the renal action induced is variable, depending uponmany 5 other factors afiecting the'transport situation whichmay divert major transport effects to other areas of the body, such as the skin.

Tests have revealed that both the theophylline and the bromot-heophylline drugs show an increase intotal weight no loss in a test animal, but that with'the theophylline drug tl1eloss'-may- -be extra-renal as'well-asrena}, whereas in the case of'the instant bromotheophylline drug the losses are almost exclusively renal. Extra-renal weight loss, known to befdue largely totranspiration through the 5.3 skin-,is-markediy increased under theophyllineaction in hot weather to such an extent that the renal action may be decreased, or evenmarkedly inhibited, as compared to normal controls. Using-the bromotheophylline drug,

however, this action does not take place, thereby showing p u thatthis drugpossess'es a unique focussin'g or localizing effect upon kidney function. This function is" valuable because it'providesa new standardizing agent for corn parative studies on kidney function. Also, tests show that fin hot weather the salt diuresis effectedby-thebremo- 76 theophylline drug is consistently high (compared to the The diuretic activity of a compound, as measured by 5 the above test, is a good indication of its eifectiveness in the relief of premenstrual tension among human females.

The relief of premenstrual tension by the diuretic compound of the present invention may be' explained when it is appreciated that premenstrual tension is a symptomcomplex related to abnormal water storage during the premenstrual period and is essentially a Water toxemia. The intensity of these symptoms varies directly as the amount of water retained, and relief of the symptoms accompanies the diuresis.

6 It will be understood that modifications and variations may be efiected without departing from the scope of the novel concepts of the-present invention.

We claim'as our invention: 7

The S-bromotheophylline Saltof Z-aminO-Z-rnethyl-I propanol. v p I I 7 References Cited in'the' file of this patent 'UNITED STATES PATENTS 2,576,106 Cusicr Nov; 27, 1951 'oTHER REFERENCES