United States Patent [19] [11] Patent Number: 6,080,860 Karimian Et Al

US006080860A United States Patent [19] [11] Patent Number: 6,080,860 Karimian et al. [45] Date of Patent: Jun. 27, 2000

[54] METHODS OF MAKING UREAS AND 1464583 2/1977 European Pat. Off. . GUANIDINES INCLUDING, TERAZOSIN, 2041932 9/1980 European Pat. Off. . PRAZOSIN, DOXAZOSIN, TIODAZOSIN, 0034471 2/1981 European Pat. Off. . TRIMAZOSIN, QUINAZOSIN AND 0227450 7/1987 European Pat. Off. . 0227451 7/1987 European Pat. Off. . BUNAZOSIN (EXEMPLARY OF 2 2231571 11/1990 European Pat. Off. . SUBSTITUTED QUINAZOLINE 2350101 4/1975 France . COMPOUNDS), AND MEOBENTINE, AND 2321890 8/1975 France . BETHANIDINE AND INTERMEDIATES 2457911 6/1975 Germany . THEREFOR 2707068 9/1977 Germany . 2725019 12/1977 Germany . [75] Inventors: Khashayar Karimian; Keshava 181743 12/1992 Hungary . Murthy; Darren Hall, all of Brantford, 1156973 8/1969 United Kingdom . Canada 1390014 4/1975 United Kingdom . 1390015 4/1975 United Kingdom . [73] Assignee: Brantford Chemicalss Inc., Brantford, 2021108 5/1979 United Kingdom . Canada PCT/CA93/ 00355 8/1993 WIPO . [21] Appl. No.: 08/939,414 OTHER PUBLICATIONS [22] Filed: Sep. 29, 1997 Synthetic Communications, vol. 18, No. 5, May 1988, US. pp. 525—530, A.V.N. Reddy, et al.: An Efficient Synthesis of Related US. Application Data 3,4—dihydro—4—imino—2(1H)—quinaZolines’ . Houben—Weyl: ‘Methoden der Organischen Chemie’, Band [62] Division of application No. 08/453,093, May 30, 1995, Pat. E4, 1983, pp. 352—364, published by Georg Thieme Verlag, No. 5,686,612, which is a continuation of application No. Stuttgart, DE. 08/004,114, Jan. 13, 1993, abandoned. Houben—Weyl: ’Methoden der Organischen Chemie’, Band [30] Foreign Application Priority Data E4, 1983, pp. 608—619, published by Georg Thieme Velag, Stuttgart, DE. Aug. 31, 1992 [CA] Canada ...... 2077252 Althius, TH. and Hess, H.J., “Synthesis and Identi?cation of [51] Int. Cl.7 ...... C07C 275/70; C07D 407/04; the Major Metabolites of PraZosin Formed in Dog and Rat”, C07D 241/04 Journal of Medicinal Chemistry vol. 20 p. 146 (1977). Reiter, J. and Pongo, L, “On TriaZoles. V[1,2],Synthesis of [52] US. Cl...... 544/291; 540/575; 544/284; 544/367; 544/374; 544/377; 544/379; 544/388; 1—and 2—R1—3—R2,R3—Amino—5—amino—1,2,4—triaZoles”, 544/390; 558/385; 558/386; 558/413; 558/417 Journal of Heterocyclic Chemistry vol. 23, p. 401 (1986). Curd, F.H.S., Landquist, J .K. and Rose, F.L., “Synthetic [58] Field of Search ...... 558/385, 386, Animalarials, Part XXXII. 2—p—Chloroanilino—4—[3—di— 558/413, 417; 540/575; 544/284, 291, 367, ethylaminoethylaminoquinaZolines containing Various Sub 374, 377 stituents in the QuinaZoline Nucleus”,Journal of the Chemi [56] References Cited cal Society, p. 1759 (1948). U.S. PATENT DOCUMENTS Primary Examiner—Richard L. Raymond Attorney, Agent, or F irm—Ivor M. Hughes; Neil H. Hughes; 3,511,836 5/1970 Maxwell et al...... 260/256.4 Marcelo K. Sarkis 3,949,089 4/1976 Maxwell et al...... 544/284 4,026,894 5/1977 Winn et al...... 260/256.4 Q [57] ABSTRACT 4,138,561 2/1979 Crenshaw et al...... 544/284 Novel methods for the synthesis of substituted ureas and 4,251,532 2/1981 Roteman ...... 544/291 4,672,116 6/1987 Bandurco et al...... 544/286 guanidines including TeraZosin, PraZosin, DoxaZosin, TiodaZosin, TrimaZosin, Quinasin and BunaZosin FOREIGN PATENT DOCUMENTS (exemplary of 2-amino substituted QuinaZolines), Meoben 1056831 6/1979 Canada . tine and Bethanidine and novel intermediates suitable for 1057754 7/1979 Canada . use in such methods of synthesis are taught. 1081229 7/1980 Canada . 1390015 4/1975 European Pat. Off. . 12 Claims, No Drawings 6,080,860 1 2 METHODS OF MAKING UREAS AND pounds comprise 2-amino-substituted quinaZolines (such as GUANIDINES INCLUDING, TERAZOSIN, teraZosin, praZosin, tiodaZosin, bunaZosin, quinaZosin and PRAZOSIN, DOXAZOSIN, TIODAZOSIN, trimaZosin and doXaZosin) and other guanidines (such as TRIMAZOSIN, QUINAZOSIN AND Meobentine and Bethanidine) Which are known medica BUNAZOSIN (EXEMPLARY OF 2 ments known to reduce blood pressure in hyperactive sub SUBSTITUTED QUINAZOLINE jects. COMPOUNDS), AND MEOBENTINE, AND BETHANIDINE AND INTERMEDIATES This invention also relates to a number of novel interme THEREFOR diates (including novel ureas and novel guanidines) that may 10 be used in the synthesis of for eXample the 2-amino - This application is a divisional of application Ser. No. substituted quinaZolines and guanidines and the methods of 08/453,093, ?led May 30, 1995, HOW US. Pat. NO. 5,686, the synthesis thereof, 612 Which application is a File Wrapper Continuation of _ _ _ _ Us application Ser_ No 08/004 114 ?led on Jan 13 1993 Some of these novel intermediates that are guan1d1nes HOW abandoned) ’ ’ ’ 15 may also be useful as accelerators in the manufacture of rubber and as activators for thiaZole accelerators. FIELD OF INVENTION This invention relates to novel processes of making ureas BACKGROUND OF THE INVENTION for eXample N-monosubstituted, N-N-disubstituted, N,N-N‘ trisubstituted, N,N-N‘,N‘-tetrasubstituted ureas and Anumber of medicines are guanidines. These guanidines guanidines and derivatives thereof. A number of such com- include cycliZed guanidines of the general formula 1.

1 R R

NHQ

COMPOUND R R1 R2 n R3 PRAZOSIN H Me Me 1 / \

TERAZOSIN H Me Me 1

O DOXAZOSIN H Me Me 1 $00 I j 0

TIODAZOSIN H Me Me 1 N_N O / h 0 SCH3

TRIMAZOSIN OMe Me Me 1 O

6,080,860 5 -continued BUNAZOSIN O

NH2 10 TIODAZOSIN

CH3O NYN 15 / N

NHZ

These guanidines also include uncycliZed guanidine of the general formula 3.

BETHANIDINE;

MEOBENTINE;

Wherein Me is CH3 (methyl).

METHOD 1 The prior art preparations of cycliZed and uncyliZed guanidines for eXample of TeraZosin (R3=tetrahydrofuryl), PraZosin (R3=furyl), DoXaZosin (R3=1,4,-b6I1ZOd1OXaI1-2 R10 yl), and Meobentine (R‘1=4-methoXybenZyl, R‘2=H, R‘3= methyl, R‘4=H, R‘5=CH3) are discussed beloW.

Compounds of general formulae 1 have been prepared by a number of approaches Which may be classi?ed into ?ve general methods. 60 R10 N N In method 1, a 4-amino-6,7-dimethoXy quinaZoline that is substituted at C-2 position With a good leaving group X, is condensed With a proper amine. Up to nine steps are used to R20 synthesiZe the 4-amino-6,7-dimethoXy quinaZoline, starting 65 from veratraldehyde [J. Chem. Soc. 1759, (1948) and J. Med. Chem. 20, 146, (1977)]. 6,080,860 7

X Reference METHOD 2 Cl Fr. Pat. 2321890 Fr. Pat. 2350101 R10 NHZ Can Pat. 1057754 Can Pat. 1081229 R Ger Pat. 2707068 R20 Z 4 10 Ger Pat. 2725019 Eur Pat. 0034471 U.S. Pat. No. 4251532 R10 N N U.S. Pat. No. 4026894 15 Brit Pat. 1156973 R20 Brit Pat. 2021108 SCH3 Ger Pat. 2707068 Brit Pat. 1156973 C—6(Z) Y Reference Brit Pat. 2021108 20 CN CN Brit Pat. 1390014 SO2alkyl Brit Pat. 2021108 Brit Pat. 1390015 Eur Pat. 0034471 Brit Pat. 1156973 Brit Pat. 1156973 25 Those ?ne chemical manufacturers synthesizing praZosin Ger Pat. 2457911 Ger Pat. 2457911 teraZosin, and doxaZosin for the most part use this process Ger Pat. 2457911 or a modi?cation thereof. The major shortcoming of this Ger Pat. 2457911 method (method 1) is the loW yields (between about 5 and 30 25%) Which may be ascribed to the large number of steps The processes taught by German Patent 2457911 propose involved. the use of highly toxic cyanogen bromide. The yields of the processes are poor at best and thus not attractive for com mercial production. In method 2, a 3,4-dimethoxyaniline that is substituted at 35 In method 3,3,4-dimethoxy-6-cyanoaniline is converted the C-6 position With a nitrile, amide or amidine group is to its corresponding isothiocyanate using thiophosgene. This condensed With an amine that is N-substituted With an is then condensed With a proper amine. The resulting thio appropriate functional group, Y. urea is then S-alkylated (e.g. methyl iodide). High tempera ture re?ux in the presence of ammonium chloride results in

40 the insertion of the amine group. folloWed by ring closure to afford TeraZosin (Bel. Pat. PCT/F 18200034, Eur. Pat. 00340471). However thiophosgene is extremely toxic and its use is not practical on commercial scale due to high cost and limited availability.

METHOD 3 R3 / H R10 NH2 R10 H—N R10 N N R4 _>

R20 CN R20 CN R20

R10

CH3SH + R20 R20 6,080,860 9 10 In method 4, N-cyano-N-(3,4-dimethoXyphenyl)-5- and the overall yield is approximately 5—25% Curd methylisothiourea [see J. Heterocycl. Chem. 23, 401 (1986) et. al., J. Chem. Soc. 1759 (1948) and J. Med. Chem. 20, 146 or Hungarian Pat. 181743] is condensed With a proper amine (1977)]. to afford a carboXamidine Which upon heating at high Activation of the amine group (method 2) requires the use temperature affords the desired product (Can. Pat. 2015066, 5 of highly toXic cyanogen bromide (Y=CN), folloWed by Eur. Pat. 0034471). The reported yields starting from the further modi?cation of the activating group (Y=H2N thioether is 63%. HoWever, the thioether itself is difficult to C=NH, HN=C-O-Alkyl). Use of ammonium thiocyanate, manufacture. folloWed by altylation of sulfur, Will result in Y=HN=C

METHOD 4 R3 H H / R10 N SR R10 N N\ l ’ l 4 Y + H—N R 3 —> R / N \R / N R20 NC 4 R20 NC4

R3 / R10 N N Y R4 / N R20 NH2

In method 5, 2-chloro-4-amionquinaZoline is initially 3O S-Alkyl. Nevertheless, the yields are generally loW (ca. condensed With piperaZine and the resulting amine is reacted 40%). In method 3, although the reported yield of praZosin With an acid chloride to afford the desired product (Brit. Pat. is high (ca. 68%), high toxicity and limited commercial 1156973). availability of thiophosgene renders the method unattractive.

R10 N\ C 1 R 1 O N\ N + HN NH —> \ /H N N N R20 / R20 /

NH2 NH2

R Cl R10 N N O R: 0* PRAZOSIN \Y \TL, i 0 R20 Ox TERAZOSIN NH2 0 @i o l DOXAZOSIN 0

As in method 1, this process also fails to provide good 60 In method 4, the overall yield starting from N-cyano N‘-((3, yields, because of the number of steps involved in the 4-dl6rglgthiiiyphf?lylD-s-gethyl-isothlollrgat?§ rfipcgtrfed to be preparation- of the 2 _ chloroqumaZolme- - starting- material.- Startingca. 0. material ever ethe ess, preparation e requiremen of Which o beingis 1so Veryiourea di?i_ as These methods Suffer from Various other Shortcomin S cult and inefficient, renders the method unattractive. g ' Compounds of general formula 3 are synthesiZed using For examplm the use of 2'Ch19rO'4'?1I_n_inO'6>7' 65 S-alkylated thiourea and the corresponding amine. The dIIIIfIIhOXYqIlIHaZOhHfI (IIleIhOd 1 and 5)1S PfOhlbltlVe due to synthesis of Meobentine has been reported is US. Pat. No. the fact its synthesis involves nine steps from veratraldehyde 3,949,089 as described beloW. 6,080,860 12 the oxygen—electrophile (O-EP) becomes a good leaving group that can be and is subsequently displaced by for H3CS I NHZ example a nucleophile (such as for example ammonia or an >=NCH3 + —> amine) and H3CHN 0M6 (ii) adding a desired radical to the results of subparagraph CH (a) or b if step of subparagraph (b) is carried out before / 3 this step (ii), and (c) optionally, and if required, closing a ring to form for )1 example a 2-amino-substituted quinaZoline. N NHMe H 10 Other guanidines including quinaZolines may also be manufactured according to the invention as Would be under H3CO stood by persons skilled in the art. VIa: MEOBENTINE According to another aspect of the invention the desired radical is ammonia or an amine radical. 15 The use of thiophosgene to manufacture thiourea is lim In this Way, greater yields and higher purity in the ited due to its high toxicity and commercial unavailability. manufacture of knoWn products can be achieved. Further Use of ammonium thiocyanate on the other hand followed more compounds of the invention may be conveniently by alkylation of the resulting thiourea generally affords loW prepared by a “one pot” synthesis. overall yields and therefore suffers from the same disadvan 20 EP is preferably POCl3. EP may also comprise: PCl5, tages described in the methods 2 and 3 (vide sudra). P205, tosyl chloride (CH3 SO2 Cl) —TsCl— and in some It is therefore an object of this invention to provide instances mesyl chloride (CH3 SO2 Cl) —MsCl—. improved more efficient methods for the synthesis of com Thus according to another aspect of the invention, such a pounds such as ureas and guanidines for example cycliZed method comprises; guanidines such as 2-amino substituted quinaZolines of 25 a) taking a knoWn intermediate and adding oxygen or a general formula 1 (eg TeraZosin, PraZosin, DoxaZosin, hetero radical containing oxygen to it for example by adding TiodaZosin, TrimaZosin. Quinasin and BunaZosin) and for a carbonyl (c) to an amine; example uncycliZed guanidines such as those of general b) adding a desired radical to the results of (a); formula 3 (eg Meobentine and bethanidine). c) adding a suitable electrophile (EP) to react With the It is a further object of the invention to provide such 30 improved more efficient processes Which produce the oxygen to yield a reaction product (O-EP) Which is a leaving desired compounds for example guanidines and ureas and in group susceptible to replacement by a nucleophile such as higher yields than in the prior art. ammonia or an amine; It is still a further object of the invention to provide such d) replacing the reaction product (leaving group) of (c) compounds for example quinaZolines of very high purity 35 With NH2 or an amine group: (therefore having the desired ef?cacy). e) closing a ring if required to produce a desired com It is still further object of this invention to provide pound. (manufacture) novel intermediates including ureas and In accordance With another aspect of the invention, such guanidines suitable for use to synthesiZe other guanidines a method may comprise; for example 2-amino-substituted quinaZolines including 40 f) taking an intermediate compound carrying oxygen (for TeraZosin. PraZosin, and DoxaZosin and other guanidines for example the results of subparagraph (a) of the previous example meobentine and Bethanidine. paragraph) and adding a suitable electrophile (EP) to react Further and other objects of the invention Will be realiZed With the intermediate at the site of the oxygen to yield a by those skilled in the art from the folloWing summary of the reaction product therebetWeen as a leaving group susceptible invention and detailed description of the embodiments 45 to replacement by a nucleophile such as ammonia or amine; thereof. g) replacing the reaction product (O-EP) (leaving group) SUMMARY OF THE INVENTION of With NH3 or ammonia group; According to one aspect of the invention a method of h) optionally adding a radical if desired before or after manufacture of compounds such as ureas and guanidines carrying out either or both of steps and (g): including cycliZed guanidines for example 2-amino i) closing a ring if required to produce a desired com substituted quinaZolines compounds (for example TeraZosin, pound. PraZosin, DoxaZosin, TiodaZosin, TrimaZosin, Quinasin and According to another aspect of the invention a method of BunaZosin) and for example uncyliZed guanidines such as manufacture of substituted ureas and guanidines including meobentine and Bethanidine are provided, comprising: 55 2-amino-substituted quinaZoline compounds (for example (a) adding oxygen or a hetero radical containing TeraZosin, PraZosin and DoxaZosin) is provided comprising; oxygen to an intermediate compound for example by adding (a) converting an amine to its corresponding urea; a carbonyl (c) to an amine in one embodiment in a form of (b) substituting the NH2 group of the substituted urea of converting an amine to its corresponding urea or (a) by an amine: (ii) starting With an intermediate compound containing 60 (c) reacting the resulting substituted urea With a suitable oxygen for example containing a carbonyl group in some electrophile (EP) to yield a reaction product in Which the embodiments connected to an amine or forming part of a oxygen of the urea reacts With the electrophile (EP) to urea, become a good leaving group that can be displaced by a and (b) carrying out in any order or (ii) of this nucleophile for example such as ammonia or an amine; subparagraph (b) 65 (d) replacing the reaction product betWeen the oxygen and (i) react the oxygen for example the oxygen of a carbonyl, EP (leaving group) of (c) by NH3 or an amine to provide for With a suitable electrophile (EP) in Which the combination of example unsymmetrically substituted guanidines; 6,080,860 13 14 (e) optionally, and if required closing the resulting sub compounds are disclosed. In one method, guanidine com stituted guanidine to provide 2-amino-substituted quinaZo pounds are synthesiZed starting for example from 3,4 lines such as TeraZosin, PraZosin, and DoxaZosin. dimethoxyanthranilonitrile I and the corresponding amine In this Way, greater yields and high purity of known III. The initial reactants are all available and are easily products can be achieved, for example steps (a) and (b) of manufactured as Would be understood by persons skilled in the immediately previous process being both converted in the art. very high yields of 85—95%. Furthermore compounds of the invention may be conveniently prepared by a “one pot” synthesis, starting from the substituted urea 10 In an exemplary method, an amine I (nitrile) is converted According to another aspect of the invention, such a to its corresponding urea II in high yields (85—90%) With method may comprise; sodium cyanate. The resulting urea is then condensed With a) taking a knoWn intermediate and converting it to a urea; a proper amine III [N-(tetrahydro-Z-furoyl) piperaZine in the b) adding a suitable electrophile (EP) to react With the case of TeraZosin, N-(2-furoyl) piperaZine in the case of oxygen of the urea to yield a reaction product as a leaving 15 PraZosin, N-(1,4-BenZodioxan-2-carbonyl) piperaZine in the group susceptible to replacement by an amine; case of DoxaZosin, MethylthiooxadiaZale carbonyl pipera c) replacing the leaving group of (b) With an amine; Zine in the case of TiodaZosin, 2,2-dimethyl-2-hydroxy ethyl d) closing a ring if required to produce a desired com ester piperaZine in the case of TrimaZosin, propene carbonyl pound. piperaZine in the case of QuinaZosin and butyroyl diaZo In accordance With another aspect of the invention, such 20 cycloheptane (a 7-membered dinitrogen radical) in the case a method may comprise; of bunaZosin] in re?uxing pyridine to afford IV (85—95% e) taking a knoWn intermediate and converting it to a urea; yield). The intermediate IV is then reacted With an appro f) adding a suitable electrophile (EP) to react With the priate electrophile (e.g. POCl3, PCIS, tosyl chloride. phos oxygen of the urea to yield a reaction product as a leaving phorous pentoxide), resulting in the conversion of the oxy 25 group susceptible to replacement by an amine; gen of the urea into a good leaving group Addition of g) displacing the leaving group of the reaction product of ammonia (e.g. ammonia gas or ammonium carbonate) Will (f) With an amine; then displace the activated oxygen function, forming the h) closing the ring if required to produce a desired corresponding guanidine VI. QuinaZoline ring system VII is compound. 30 then formed by the attack of the amino group of the The salts of the guanidines may also be produced for guanidine on the nitrile. This is a very facile reaction and in example TeraZosin hydrochloride and teraZosin hydrochlo fact intermediate VI Was not isolated. ride dihydrate and DoxaZosin Mesylate. In accordance With another aspect of the invention, exem plary novel processes of the manufacture of guanidine The folloWing reaction scheme thus presents itself

R H R10 N\"/ NH2 0 R20 CN R20 CN II Pyridine, reflux

N/ R3 R (VA R10 N R10 N Nd <—EP T EP = POC13, PC13, P205, TsCl 0 0 H Y R20 CN R20 CN \EP IV V l NH3 6,080,860

-continued

R10 N R10

R20 R20

In this scheme R may be hydrogen or loWer alkoxy (for example methoxy), R1 and R2 may be loWer alkyl (for example methyl), n is a number selected from 1 and 2 and R3 may be selected from unsubstituted or substituted furoyl (for example furoyl or tetrahydrofuroyl), benZodioxanyl carbonyl (for example 1,4-benZodioxan-2-yl carbonyl), loWer alkylthiooxadiaZole carbonyl (for example methylth 20 iooxadiaZole carbonyl), dialkyl hydroxy alkyl ester (for example 2,2-dimethyl hydroxy ethyl ester), alkene (for example propene) and alkyroyl (for example butyroyl). 25 The following chart identi?es combinations of substitu ents for identi?ed Medicines.

COMPOUND R R1 R2 n R3

PRAZOSIN H Me Me 1

-continued

COMPOUND R R1 R2 n R3 40

TERAZOSIN H Me Me 1 TRIMAZOSIN OMe Me Me 1 0

AW:Me

DOXAZOSIN H Me Me 1 O QUINAZOSIN H Me Me 1

BUNAZOSIN H Me Me 2 0 60 TIODAZOSIN H Me Me 1 Am,

Thus the following is speci?cally included 6,080,860 17 18

H R10 NHZ R10 N NHZ + H—N= C = O —> T 0 R20 CN R20 CN II‘

N o

H/ \ l i H Pyridine, reflux

EP = POC13, PC15, P205, TsCl R1 R10 N N o O

R 0 CN R3" 2 R20

R10 ‘IE/NE l R3, = 0X PRAZOSIN / N N R3“ 0 R20 NH2 OX TERAZOSIN VII 0 @i o l DOXAZOSIN o

45 The radical O

R3“ and R3“ c 50 H3CHN NHcH3 Ia preferably may be substituted by other radicals as is apparent from examination of the substituents for R3. 55

Usual Work up of the reaction mixture results in the /EP R isolation of the desired product. Compounds II (including NH2 II‘), IV (including IV‘). V (including V‘) and VI (including 60 R _ H OM VI‘) are novel and the processes of their manufacture are also H3CN NHCH3 _ ’ 6 novel. IIa IIIa

In the case of Meobentine and Bethanidine, urea Ia, for example, dimethyl urea, is reacted With Electrophile (EP) to 65 produce (IIa). Condensation of benZylamine (IIIa) With IIa affords Meobentine and Bethanidine. 6,080,860 19 20 -Continued Compounds IIa are neW and the processes of their manu facture are also novel. R In another method, for example the urea nitrile II is 5 initially activated With an electrophile (EP) such as POCl3, HN PCIS, etc, (see above) to form intermediate VIII in Which the oxygen function of the urea becomes a good leaving group. H3CN NHCH3 Displacement of the oxygen by a proper amine III and subsequent Work-up results in the isolation of the desired R = 0MB; MEOBENTINE R = H; BETHANIDINE 10 quinaZoline VII (for eXample teraZosin). Compounds II, VI and VIII are novel. Preferably EP is PCOl3. The folloWing reaction scheme presents itself

R R H H R10 N NH2 RIO N NHZ

T —>EP o 0 R2 CN R20 CN \EP 0 II VIII EP = POC13, PC15, P205, TsCl (/9n—\ HN N—R3

III

R3 R3 R (p N / R (p N / R10 N N\) R10 N Nd Y <— Y / N NHZ R20 R20 CN NHZ vn v1

R R1 R2 n R3

H Me Me 1 6,080,860 21 22

-continued

H R10 N NH2 R10

—> 0 R2 CN 0 R20 VIII EP = POC13, PC15, P205, TsCl

R10 R10

R20 R20 CN

VII VI

Me Me

OMe Me Me

OH Me

Me Me

Thus the following is speci?cally included 6,080,860

H H R10 N NH2 R10 N NH2

TO + EP _> U Y0 R20 CN R20 CN \EP VIIIv II' N O / H O N

IIIH

R10 N N 0 R10 N N O \ \ O O <— /N N NH 2 N R20 R20 CN

VIH VII

(The tetrahydrofuryl radical may be substituted by furyl or 30 group using an electrophile (EP) such as POCl3, PCIS, etc. 1,4-benZodioXan-2-yl to produce PraZosin and DoXaZosin, to form X. Displacement of the activated oXygen by the respectively. The tetrahydrofuryl radical, tetrahydrofuroyl amine function of I and subsequent Work-up results in the radical, and tetrahydrofuroyl piperaZine radical may also be isolation of the desired quinaZoline VII, Which may be substituted by the other radicals for example those for R3.) 35 converted to its pharmaceutically acceptable salts (for In another method, for example the amine III is converted eXample the hydrochloride or mesylate salt). The folloWing to its corresponding urea IX With cyanic acid. Again the reaction scheme presents itself. oxygen function of the urea is converted to a good leaving 6,080,860 25 26

EP = POC13, PC15, P205, MsCl, TsCl R R10: i NH R20 CN I

/N NHZ R20 R20 CN NHZ VII VI

R R1 R2 n R3

H Me Me 1 / \

H Me Me 1

H Me Me 1 0

$00

H Me Me 1 N—N O / I O SCH3

OMe Me Me 1 O

A O Me OH Me 6,080,860

-continued

( n O ( 1‘ EP 0 ( n HN N—R3 + H—N=C=O —> N N—R3 —> N N_R3

HI HZN EP—O IX

EP = POCl3, PC15, P205, MsCl, TsCl R R10 NHZ

R20 CN

R10 N N R10 N N Y <— Y / N NHZ R20 R20 CN NHZ VII VI

R1 R2 n R3

H Me Me 2 O N Me

Compounds IX, X and VI are novel and processes of their Thus the following is included manufacture are also novel.

/N O HZN N O H g% 0 T %L\ O N + H—N=C=O —> 0 N

III" IX"

EP = POC13, P205, PC15 EP MsCl, TsCl

R10 NHZ

R10 N\ N 0 R20 CN HN N O

NHZ N 0 N R20 CN \EP 6,080,860 29 30 -continued R10 N N 0 R10 N N O \_ O \_ O N N N N R20 / —> R20 /

NHZ NH2- HCI- 2H2O VII XI

10 (Once again the tetrahydrofuryl radical may be replaced -Continued by furyl or 1,4-benZodioxan-2-yl). The tetrahydrofuryl radi- IV cal and the tetrahydrofuroyl radicals may also be substituted /R3“ as is apparent. 15 R H (?n/\N Compounds VI“, IX“ and X“ are novel and the processes R10 N \H/ Nd of their manufacture are also novel. 0 R20 CN Thus according to another aspect of the invention, com- 20 IX pounds of the formula HZN N O \H/ \j\ 0 Ra\ /Rc O N N—C—N\ 25

O ( I. N N—R3 are provided Wherein Ra is selected from hydrogen, 3O HZN

Rb is selected from hydrogen, and a substituted phenyl radical substituted by at least one of alkoxy (for example According to another aspect of the invention compounds methoxy) and cyano, and RC and Rd are each selected from of the formula hydrogen, (provided RC and Rd are not hydrogen When Ru 35 and Rb are hydrogen) or may With the nitrogen be connected together to form a closed ring preferably containing at least a second nitrogen, (preferably being a 6-membered or 7-membered ring), the closed ring being substituted by Rb Rd substituted carbonyl for example R carbonyl (Wherein R is 40 selected from furyl, tetrahydrofuryl, 1,4-benZosioxan-2-yl, alkylthiooxadiaZole for example methylthiooxadiaZole and are provided, Wherein alkyl (for example propyl), dialkyl hydroxy alkyl ester for example, 2,2-dimethyl-2-hydroxy-ethyl ester, and alkene EP is an electrophile and together With the oxygen forms 45 (for example propene). Exemplary of such compounds are a leaving group (preferably substitutable by NH2 or an II, II‘, IV, IV‘, IX and IX‘ set out beloW amine) (preferably EP being selected from POCl3, P205, PCIS, mesyl chloride and tosyl chloride), Rb is selected from II H hydrogen, alkyl (for example methyl) and a substituted phenyl radical substituted by at least one of alkoxy (for R10 N\H/ NH2 example methoxy) and cyano, and RC and Rd are each selected from hydrogen, loWer alkyl (for example methyl) a R20 11 CN 0 substituted phenyl radical substituted by at least one alkoxy II (for example methoxy) and cyano or may With the nitrogen R 55 be connected together to form a closed ring preferably H containing at least a second nitrogen, (preferably being a R10 N\H/ NH2 6-membered or 7-membered ring), the closed ring being 0 substituted by R-carbonyl (Wherein R is selected from for R20 CN 60 example furyl, tetrahydrofuryl, 1,4-benZodioxan-2-yl, IV akylthiooxadiaZole, for example methylthiooxadiaZole, R10 N N o alkyl for example propyl, dialkyl hydroxy alkyl ester for T m 0 example 2,2-dimethyl-2-hydroxy-ethyl ester and alkene (for o N example propene). R20 CN 65 Exemplary of such compounds are V, V‘, IIa. VIII, VIII‘, X and X“ set out beloW. 6,080,860 31 32

R10 R10

R20 R20 Where R’ is furyl, tetrahydrofuryl or 1,4-benzodioxan-2-yl. 10 VI R10

R10 R20 Ha 15 R20 VI H R10 20 VIII’ R10 NYNH R20 R20 25 Additionally compounds VII and XI are of higher purity than prior art compounds and contain for example residues of II, IV, V, VI, VIII, IX or X. R10 NY NH

R10

35 HNYNm R20 N IV

40 R10

R20 CN

45 According to another aspect of the invention compounds of formula R10

50 R20 VI are provided Wherein Rb is selected from a substituted 55 phenyl being substituted by a radical selected from at least R10 one of alkoXy (for eXample methoXy) and cyano and RC, Rd together With the Nitrogen, form a closed ring preferably containing a second nitrogen (preferably being a 6—7 mem R20 bered ring), the closed ring being substituted by furoyl, 6O VIII tetrahydrofuroyl, 1,4-benZodioXan-2-yl carbonyl, methylth iooXadiaZole carbonyl, dialkyl hydroXy alkyl ester (for R10 eXample 2, 2-dimethyl-2-hydroXy-ethyl ester), alkene (for eXample propene), alkoyl (for eXample butyroyl) Exemplary of such compounds are compounds VI, VI‘ R20 and VI“ set out beloW

6,080,860 36 -c0ntinued -continued VI,” X, R10 N N O Y \ \ Wm l NHZ N / \ O\ N R3 EP R20 CN 0 Wherein VIII' H R10 N NHZ 10

R20 I I CN 0 \EP m

IX”, In respect of the medicines Tiodazosin, Trimazosin, Quinasin and Bunazosin, the residues are II, IV, V, VI, VIII, H2N\"/o N _ 'N%O IX and/0r X. O II X,” 20 R HN N. O H R10 N\“/NH2 o \ EP ‘N%0 0 R20 CN 25 IV

/ R3

Where the medicine is d0XaZ0sin the residues II, IV, V, VI, R H (Fn/\N VIII, IX and/0r X may be 30 R10 N\H/N\) H’ 0 H R20 CN V R10 N\"/NH2 R3 35 / R20 U CN 0 R (F)n/\N IV' R10 N\ Nd H 0 40 R20 CN \EP VI R20 CN /R3 R ( I. N V, R10 N N. o R10 N Nd 45 Y O N R3 NHZ R20 CN \EP R20 CN VIII VI' R R10 N N 0 H Y \\ i NH2 N R3 R10 NYNH R20 CN 0 R20 CN \EP 55 VIII’ IX H R10 N NH 0 ( n N N—R3 0 HZN R20 CN \EP 60 X IX’ NH ( n

N N—R3 HZNTN l EP—O o ‘N R3 65

Wherein for the medicine: 6,080,860 37 38 (a) TIODAZOSIN To this solution is added a suspension of sodium cyanate R is H (160.5 g, 2.46 mol in 750 mL of deioniZed Water) in 100 mL R1 is Methyl portions over a thirty minute period. Acetone (6000 mL) is R2 is Methyl added and the mixture is maintained at +5 ° C for an n is 1 additional 30 minutes. The product is ?ltered and the cake is and R3 is Washed With acetone (2x150 mL) (293/7 grams, 79% yield). 1H nmr (DMSO-d6) d 8.19 (bs, 1H, NH); 7.48 (s, 1H, C-5); 6.98 (s, 1H, C-2); 6.12 (bs, 2H, NHZ); 3.65 (s, 3H. OCH3); 3.60 (s, 3H, OCH3). 10 EXAMPLE 2 4-(2-tetrahydrofuroyl)piperaZine-1 -ylformamide (b) TRIMAZOSIN (IX) R is methoxy (OMe) 15 4-(2-Tetrahydrofuroyl)piperaZine (33.25 g, 180.7 mmol) R1 is Methyl (III) is dissolved in 165 mL Water. 5N Hydrochloric acid R is Methyl (34.5 mL) is added and the suspension is heated to 70° C. and R3 is With stirring. Sodium cyanate (13.1 g, 201.15 mmol) is added in small portion to the stirring solution and heating is 20 O continued for an additional 2 hours. The reaction mixture is concentrated under reduced pressure to yield a thick oil. A Me Chloroform (100 mL) is added to the oil and the solution is O heated to re?ux. The hot solution is ?ltered and the ?ltrate OH Me is dried over Na2SO4. The dried solution is concentrated 25 under reduced pressure to a thick yelloW oil. Ether (50 mL) is added to the oil and White crystals precipitated out. The (c) QUINAZOSIN product is ?ltered, Washed With ether (25 mL) and dried. The R is hydrogen product is used Without further puri?cation (33.8 g, 82.3% R1 is Methyl yield). R2 is Methyl 30 1H nmr (CDCl3) d 5.60 (bs, 2H, NHZ); 4.32 (t. J=7.0 HZ, and R3 is 1H. CH, C-2 (tetrahydrofuroyl)): 3.80 (t, J=6.0 HZ, 2H, CH2, C-5 (tetrahydrofuroyl)): 3.70—2.80 (m, 8H, CH2’s (C-2. C-3, C-5, C-6 (piperaZinyl))); 2.39—1.49 (m, 4H, CH2’s (C-3, C-4 (tetrahydrofuroyl)). 35 (d) BUNAZOSIN EXAMPLE 3 R is hydrogen 3,4-dimethoxy-6-[4-(2-tetrahydrofuroyl) piperaZine R1 is Methyl 1-ylcarbamido] benZonitrile (IV) R2 is Methyl and R3 is 40 3,4-Dimethoxy-6-cyanoaniline-1-ylformamide (2.75 g, 12.5 mmol) (II) and 4-(2-tetrahydrofuroyl) piperaZine (2.56 O g, 13.9 mmol) (III) are suspended in 25 mL dry pyridine and the mixture is re?uxed for 3 hours. The solvent is then vacuum distilled to a minimum volume and then aZeotroped 2%,, 45 With small portions of Water. The ?nal aqueous solution is extracted With six portions (20 mL) of ethyl acetate. The Where the medicine is Meobentine or Bethanidine, the organic layer is concentrated and applied to a silica gel residue includes IIa. column (25 cm><2.5 cm). It is then eluted With ethyl acetate initially and the polarity is gradually increased With ethanol 50 to a ?nal solvent ratio of 80:20. Fractions containing the product (TLC: 80:20 ethylacetate:methanol, Rf=0.5) are combined and the solvent evaporated. The pure product is crystalliZed from a small volume of ethyl acetate as light Thus the combinations of the above medicines With at yelloW needles (4.27 g, 85% yield). 55 least one of the associated residues is neW and provides 1H nmr (CDCl3) d 7.35 (s, 1H. ArH, C-2); 7.10 (bs, 1H, medicine having a very high purity. NH; 6.85 (s, 1H, ArH, C-5): 4.58 (t. J=7.0 HZ, 1H, CH, C-2 The invention Will noW be illustrated With respect to the (tetrahydrofurOyD); 3.89 (s, 3H, OCH3); 3.80 (s, 3H. folloWing exemplary methods of manufacture. OCH3); 4.11—3.18 (m, 10H, CH2’s (C-2, C-3, C-5, C-6 (piperaZinyl), C-5 (tetrahydrofuroyl))); 2.22—1.49 (m, 4H, DETAILED DESCRIPTION OF PREFERRED 60 CH2’s (C-3, C-4 (tetrahydrofuroyl))). EMBODIMENTS OF THE INVENTION EXAMPLE 4 EXAMPLE 1 3,4-dimethoxy-6-[4-(2-tetrahydrofuroyl)piperaZine 3,4-Dimethoxy-6-cyanoaniline-1-ylformamide (II) 65 1-ylcarbamido]benZonitrile (IV) 3,4-Dimethoxyanthraniloniltrile (300 g, 1.69 mol) is 3,4-Dimethoxy-6-cyanoaniline-1-ylformamide (2.75 g, taken in glacial acetic acid (1500 mL) and cooled to +5 ° C. 12.5 mmol) (II) and 4-(2-tetrahydrofuroyl)piperaZine (2.56