DEP0030375DA - Process for the preparation of new thiouracils - Google Patents

Description

Patent Attorney, JfcWns.Ε.Spbneman ^ ^he Chemical Foundation, Inc., New York City.

Hamburg 36

Neuer Wall 10, 4th floor Call 347900

Hamburg 30 ³ ° - 1948

New WaiN 0, Siedk

^ c .fs * U f (fe *

Method of manufacture « μ». newX Igjaa · »

Dies® invention relates to a method aur Her = "position of new. Medicines with an anti-thyroid effect ο

It is known that hyperthyroidism are characterized by a Ueberfunkticjn or thyroid dysfunction _i dodge the Grundumsata more or less affected. The thyroid itself is overactive and can be enlarged "The cells of the gland hyperplasia may have _similar hypertrophy and Hyparaemie. Until a few years ago, iodine was used in the form of Lugol's ⁹ solution for the treatment of hyperthyroidism "This iodine therapy was not satisfactory, however ₉ because the iodine administered only has a temporary effect"

In view of the short duration of iodine treatment, many researchers have looked for better remedies. So vidi de ces - "* r; t 'R _e H" "Ulliams _p Arch. Internal

.cii the function of the thyraoid with thiouracil i ^ rino. ¹ χ -; h better than diit inhibits iodine.

Medidinsi [194t]. ?? Γ'Λ ⁹ 95 that himself

further experimental and clinical investigations (J. Λ <, ^

Shirer and M "Cohen _p Annals of Internal Medicine / [19453 J;. 790} showed _? that thiouracil given-operatively in nichttoxischsn doses praeope ™, influenced the clinical hyperthyroidism. However, these authors point out - that the treated Thiouraeil "thyroid ^ due to increased vascularization and vulnerability _p the surgeon during the operation larger Difficult Celts prepared when treated with iodine gland * Nor could If proven _il that in severely toxic traps _s which prepared with thiouracil on the operation _'s ere a postoperative "Disease tsverlauf occur Rann _il comes sometimes a toxic Kri sis close"

One of the biggest Kachteile _a welcher- with thiouracils treatment associated "is the ongoing gland hyperemia shield ·». Experience has taught _£ that can iverden caused by the administration of thiouracil a DegenBration thyroid Bachelor "In view of this limitation in the use of this remedy and its s" ijen- effects ^ has the Medisin largely _for the iodine as the preferred agent in the preoperative treatment of thyrotoxicosis _? returned

DymziuxüIga is the problem of finding a non-toxic thyroid-inhibiting preparation _p which causes the above-mentioned ebyn effects, such as hyperaeraia and cell degeneration, only to a small extent or not _{at all 9} has not yet been solved. Due to extensive research, a class of compounds has now geTundsn _s satisfying ,, starting point "ar the notion ₈ that it must succeed the requirements referred to _/; by introducing geeignsber transmits ionelleij &'groups in the molecule of the Thiouracils _f whose metabolism lowering properties to ride and the genanntsn undesirable side effects au saus cha Iten or possible to Verraindern ₀ The core of the present invention is now _{i is} the finding that this objective Halogenderi ¹ Vaten of Thiouracils Di = © specificity of function is achieved _i, which is peculiar to this body class _s brings of course; uit is the j ,, the individual representatives in their sch iId d rüse nh emnend s η .virkung qualitative and quantitative difference comprise "

The new thiouracils are characterized e _f get to know said that in compounds of the formula

HI-CO

_"9 X represents a Halogenated and T is hydrogen or a Allqrlgrappe in the E a AUsyl- or aralkyl radical the radical E to form the split off in Hereaptograppe to check Isekamter manner.

The TCrfahrenBgenSss raw materials used may be obtained see ζ ".B * in the following way?

Hfein solves S ₀ B _e 2-Htothyithiourac 11 © tier 2-Aethylthioura "eil in a KsungCTittels ₁ as Elsesaig _g in blessing presence of a catalyst such as iron chloride _e The Ealcgenierung is then carried out by combining at room temperature za this LSsung a suitable Halogenierungsiaittel one _s as

Sch WQfeli ^v IO nochlorid or Chlorgaa dissolved in glacial acetic acid or carbon tetrachloride Sugibt ₀ To carry out the chlorination, 2 Holn a ^ fc. Chlorine slowly sur solution given "DI® temperature rises to approximately 60 to _i to (c & J ^ ®! ^ 25 $ sulfuric excess 1st added chlorine maintained on this Höh® Vzerdsn ,, The reaction is continued until no chlorine = hydrogen gas more arises ,

After this reaction has ended, the solution is cooled, whereupon part of the chlorinated compound precipitates out. The Miederschleg is separated from the clear solution and evaporated in vacuo until there is no more acetic acid. The residue is treated with susammen the precipitate with a mixture PvrldiWasser It can to evaporate and the residue obtained is purified by any Method® s "B ₀ by Urakristallisieren either from water _j, alcohol or Eisessigo

A yield of 20% 5 · = Ch 1 οr »2 = a 1 ky 11hiοurac 11 is obtained by this method. So 5 = Cblor-2 '= methyithiouracil _s 6 ~ methyl "5 ~ chlor- = 2-aethyithiouracil and 6-Met hy 1 - 5 c hlo r = 2" i so ρ r ο ρ y 11 hi our aci 1 shown - The 5 ~ chlorine »2 ° Tie thy Ithiouracil has a melting point of 25Ö-260 and contained in the analysis 20 _s 6 fo chlorine (over ₀ 20.02%) and

$ 15.80 nitrogen (calc. 15.87 ^). The 6-methyl-5-chloro-2-ethylthiouraeil melts at 185 degrees Celsius _and contains 17.50 $ chlorine, 17.32 $) and 13.7 $ nitrogen (calc. 13.69 ^). The 6-methyl = 5 ~ eMer «-2« = igopropylthiotira part has a scaling point of 160 ° and in the analysis contained 16,39 $ chlorine (calc. 16.21 $).

As mentioned earlier, * these alkylated halogenated thiouracils are used as starting materials for the preparation of the desired compounds used; this is achieved by splitting off the alkyl or aralkyl creations attached to the mercapto group achieved. This dealkylation or dealkylation can be carried out by any suitable method. Im beaondern may the following examples illustrate the process.

Example ii

5-chloro-2 ~ metnyl-thiourscil is dissolved in sied © © a nd glacial acetic acid derivative to which 25 vol. $ Essigsäureanliy & rid inflicted ₉ ". A 50 $ cent solution of Jodwasserst of f acid anhydride in glacial acetic acid and acetic acid is then passed through a reflux condenser to the reaction solution sugegebeiio The hydrogen iodide acid to slow ^ eg tropfenweisej be added to boiling at reflux solution. To complete the dealkylation, it is advantageous to approximately $ 10 üeberschuss to use than the stoichiometric amount of hydrogen iodide. When the addition is finished, it boils under reflux for another -y- hour. Another ₈ then cools the

the liquid and evaporates in a vacuum. The residue is washed with water, and any existing Üeberschuss of iodine by adding ve η little Ammoniurnhydroxyd to the water mixture and, if necessary, by heating away Beini followed by cooling and acidification with ^ ssigsäure fails the connection "You can by any method eg by Umkrlstall! » be cleaned ₀

In this process, the 5 "= chlorine- 2 = thi our ac 11 ° is obtained in high yield. It melts with decomposition at about 264 ° - When analyzed, it contained 21 _S, 8 $ chlorine C over ₀ 21.30 $), 17.29 $ nitrogen (over ₀ 17, -, 22 $) and 19.580 sulfur (over _c 19 _s 76 $} o

Bo auagehend of 6> = methyl = 5 ~ chlorine = 2 <= * aethy Ithiouracil by ö ^ ralky-regulation 6-: = thiouracils with thyroid-inhibiting action win, Sun is Sc - Get this general method, other two leave. M @ thj-l "5 ° chloro-" 2-thiouracil obtained in pure form . This product decomposes over 260 _s © s included in the analysis 20 %% chlorine (her. $ 20.20} "

The present invention encompasses _s as already mentioned earlier - not only the chlorine compounds of the 2 -Thiouracils ₈ but also other halogen derivatives such as t he corresponding bromine and iodine compounds. For example , you get that

£ = · B rom =? -1h 1 οUraC11 analogous to the 5 - = chlorine = 2 »thiouracil through

ilkylation of the ^ JUa «2wAe« teei ^ t ^^ ttk ^ used JJ- = bromine = ^ = Gje thyIthiourac i'lj nrfrt / a yield of about 1 * 9%> The fpXOdul · .t can be used in the same way as that described above © 5 ■ = chloro-2- • a Iky lthiouracil by bromination of 2-thiouracil., The 5- bromo-2-thiouracil melts with decomposition at 268-270 °; hat contained in the analysis _3ß? 70 # bromine (calc., 3NC _S 60 ^) _S $ 13.44 nitrogen (about ₀ 13, 52 $) and 15 33} $ sulfur (about 15 ο _s k / °) °

The 6 - = methyl, "5 - ^io bromo '= 2 = was thiouracil example =, by ^ alkylation of 6 = methyl-5 = bromo ° 2 ° methy3, thiouracil ± n the above-b" sehriebenen as obtained _e melts This compound under decomposition at 260 ° "It contained 36 ₃ lß $ bromine (over 36s ο 15 $ 5 <■

A particularly effective body is the 5-iodine, 2-thiouracile. It throws in the same way as the 5-bromine - => 2 => thiouraeil by alkylation of the corresponding fern sulfur) a IkyIierten -o) products shown, where,; adoch

before a ugsv / ei " ne an ar a .1 ky .1 - - sub statuierter Thi ourac il, * An ζ, Β?

the 5 '> jQd ™ 2 ~ hQnzylth ± Q \ tV8.cil used «This can be described in more detail by iodizing the 2- benzy-itbiouracil after coarse? Cfi procedure obtained

P, The 5-iodine ~ 2-benzylthiouracil is used in the for the

^ alkylation of 5 ^e chlorine = 2 "= methylthiouracils described rteise df" basylj-ert, but the precaution be observed must _f that the reaction temperature IOO ⁰ not übersteigtg for about IOO ⁰ the removal of iodine from the ring _e starts Upon drying of the final product may the temperature 60 ° not ülersteigen ,. Advantageously, however, is dried under vacuum over a drying agent ₁₁ VIIe Phoaphorpentoxyd ₀ It must be emphasized especially _p that the 5 = iodine ° 2 = thioura is light sensitive and therefore should not be unnecessarily exposed to the light it melts with decomposition at 270? ₈ in the analysis it contained 50 "00% of iodine (about ₀ 49 * 94 $! and 12.11% sulfur (calc. 12 * 62%} c

Higher yields of 5-iodine • = ^ thiouracil with de. _s obtained following modification of the method wherein, moreover, -a better Üeberwaehung. .the reaction possible ISTC The principle is that the hydrogen iodide developed in a particular reaction vessel and thiouracils fed in a controlled, the solution of iodine 5 ~ = 2 = benzyl-! is ο

^^ - ^^^^ m ^^ W ^^^ ¥ w ^ sm ^ $ M ^ c, The apparatus consists of a main reaction vessel with a reflux "cooler or another common, indirect heat exchanger to control the temperature" with the boiler is a Hauptraaktions ζ world there vessel Connected _i is shown in which the hydrogen iodide. This is _f fed through a suitable line of Reaktionslöaung ira Hauptreaktionokessel, The Jodwasserstoffgenerator is equipped "© that it comprises a controlled amount of. Can give off hydrogen iodide »This reaction vessel is connected to the initial reaction vessel in a closed system»

64j 4 g 5 "iodine" 2 ° benzyTthiouracil are in the main «=

r β akti ο nsge v brought and in 4OO cm glacial acetic acid, which 3

10 cur acetic anhydride contains,, dissolved. The Reaktlonsgefäss is almost connected to the reflux condenser "The second Gefäse or the generator includes 95 cm of acetic anhydride and w in a Zulaufgefässy * e KoBofeinem dropping funnel _y 75 crcr a 5Obigen solution of hydriodic acid This one is fairly slowly _s ScB ₀ dropwise sum of acetic anhydride," The mixture in the generator is immediately heiso and Jodwascerstoff which developed thereby is continuously gerad® by the Yerbindungsrohr out above the liquid level in the main reaction kettle * at the point where the hydrogen iodide is incident on the solution of 2 '= benzyl compound, is immediately a ring of 4ei5enzyliertem Product, formed .. Animal hydrogen iodide, which in the regenerator

remains ,, you then drives you. * ch heating from this no precipitate forms in the reaction vessel via "Once more in Rsaktionsgef AESS" is the reaction ended vapors _f which during the reaction develop ^ are cooled in the reflux condenser and back into the reaction vessel guided Oaa upper end of the reflux condenser is connected to a Qefäsä to protect against the humidity

The reaction vessel is cooled and the precipitate

"separated from the supernatant solution by lift-off or decantation, the precipitate of 5 ° iodine ~ 2» thiouracils is well washed. Stripped for the removal of still present starting product twice with heissera glacial acetic acid and then washed alternately with alcohol and water thoroughly. For further purification, the product obtained is dissolved in warm sodium hydroxide and after cooling it is precipitated again by careful acidification with acetic acid. In this way , 37 g of purified 5-iodo-2-thiouracil _{0 are obtained}

The liquid separated from the precipitate rlrd.

in vacuo _r evaporated to give 7 ₅ 4 g of unreacted 5 'iodine <= benaylthioiii 2 ^", acil surückgewinnt. This can self-

understandable

be used"

As already mentioned above. the 5-iodine 2-thiouracil is carefully dried, preferably in a vacuum over phosphorus ρ ent oxy dt.

Also other iodine derivatives the 2 "Thiouracilsa" B. that

6 = "Msthyl" 5 ^e j3d -'2 ~ thiouracil od.®? allgsmein in position 6 alkyliert® 5 = iodine "2" thiouracils have a scbilddrüsenhenaaende effect The 6 -Κ ο t hy 1 ■ = ^f: j ο d - 2 = = ■ thi our ac i 1 can Bicli starting from 6 --Methyl- "§ ~ j od» £ ~ alkyIthiouracil © n by - ^ alkylation in the above-described Vieise 'carter Beo ¹ Oachtomg of the special ones mentioned

PRESENTATION OF PRECAUTIONARY MEASURES. It melts at 270 ° with decomposition; as contained in the analysis of 47 »25% iodine CBER ₀ 47" 17%) °

The anti-thyroid effects of the various

New halogen derivatives found in animal experiments were carried out on rats after subcutaneous injection of equiüßolar concentrations of the compounds described in a non-toxic solvent such as sesara oil.

/ f

taken. The test substance was 2 · = thiouraeil in sesame oil Bis injections were carried out daily for 3 periods _i for 5, 10 and 15 consecutive days _i , on different groups of T.iereno At the end of each one of these perlodes the tiaras concerned were killed _} . prepared her thyroid removed and for the histological examinations and the Bestiiaraung the halogen content _r Tested were the Halogenhoraologen of Thiouraciis _r. all of which have a thyrostatic effect , the results of these investigations are given in the following TshsJfc Husazas5 © n;

Table 1.

Cell change Colloid-
change Hyperemia Iodine content
in γ pro
gland 2-thiouracil
(Control) Hypertrophy"
partial
degeneration reduced present 1 5 -Chlor = 2-
-thiouracil mäsßiga
hypertrophy reduced present 1 * 5 5 <= - Brosi "2 =
^ thiouracil racy hyper
trophy and
degeneration moderate
reduced present 5- iodine = 2 ~
-thiouracil none insignificant
reduced absent 1 = 2

From this table it can be seen ₂ that the cell degeneration of the thyroid gland with the halogen derivatives is lower in comparison with thiouracil itself. It is especially important to point out ₂ that after treatment with 5- iodine = 2 -thiouracil no fibrosis occurred at all. vvas concerns the iodine content of the thyroid, the average normal value ^ FCRR * "OK * ^%" € ^ # 5 Ks VCD ° 2 ~ is for this species of rat swi see 3-5 Y iodine. $ Ln gland ο All tested compounds, thiouracil _f reduce the iodine content of the thyroid gland ^

It is evident from the figures given, out j that the Grup described) e of connections a strong schilddrüsenhemreende effectively have "It's just if obvious that the jodsubstituierten 2-Thiouracils how the 5 ~ iodine _s thiouraeil 2 = ideal means ^ represent, as they thyroid function to inhibit ₅ hyperaemia to ver reduce assets and also lowering the iodine content below without simultaneously © fibrosis and cell degeneration ago »ITorisurufen ₀

Be able to i £ "thiouraci> Embrace _f determined as _£ previously shown that Alkylderivote these compounds inhibit thyroid function effectively, _0: Although the studies cited only the application of 5 ~ Haloge

While only certain examples of the characteristic group of compounds have been described _for the presently © Erfindimg generally comprises the Idfee _8, the effectiveness of the 2 - Thi our aci .1 s su low influenced by introduction of halogen atoms ₀

Claims (1)

Patent claims s I »Process for the production of new Shioiaracile _p dadureh gekenaselehnet ₉ that oan in connection with the formula Hf-CO
ES-Ιϊ <kg in which R is an AUqtI or aralkyl radical _p X is an IIalogenatoa raid Y is hydrogen or an Ali ^ l group, ₉ splits off the radical R to form the mercapto cap in a manner known per se 2 ο method according to claim I _s characterized in that that the remainder R is split off by treatment with any hydrogen acid _9, preferably at a temperature of at most ICKD ⁰ _{9 »} 3. Yerfahren according to claims 1 and 2 characterized ₉ j DAEs oan emanating from a Yerbindung the above formula, in which I is a IJethylgruppe means. 4 β Process according to claims _{1-5 9,} characterized in that the benzyl group is split off in the 5 "-iodo-2-bensyl-thiouraeil _{" u} Pc ^l e η ta η wait D '. AA:, ν, F .. S A. ? R, emann