United States Patent (19) 11 Patent Number: 6,080,860 Karimian Et Al

Home , Quinazosin, Tiodazosin, Trimazosin

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.. 0227450 7/1987 European Pat. Off.. TRIMAZOSIN, QUINAZOSIN AND 0227451 7/1987 European Pat. Off.. BUNAZOSIN (EXEMPLARY OF 2 2231571 11/1990 European Pat. Off.. SUBSTITUTED QUINAZOLINE 235O101 4/1975 France. COMPOUNDS), AND MEOBENTINE, AND 2321890 8/1975 France. BETHANDINE 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/ OO355 8/1993 WIPO. 21 Appl. No.: 08/939,414 OTHER PUBLICATIONS 22 Filed: Sep. 29, 1997 Synthetic Communications, vol. 18, No. 5, May 1988, U.S. pp. 525-530, A.V.N. Reddy, et al.: An Efficient Synthesis of Related U.S. 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 ...... 2O77252 Althius, T.H. and Hess, H.J., “Synthesis and Identification of 51) Int. Cl." ...... C07C 275/70; CO7D 407/04; the Major Metabolites of Prazosin Formed in Dog and Rat', CO7D 241/04 Journal of Medicinal Chemistry vol. 20 p. 146 (1977). Reiter, J. and Pongo, L., “On Triazoles. V1,2,Synthesis of 52 U.S. Cl...... 544/291; 540/575; 544/284; 1-and 2-R-3-R.R-Amino-5-amino-1,2,4-triazoles", 544/367; 544/374; 544/377; 544/379; 544/388; Journal of Heterocyclic Chemistry vol. 23, p. 401 (1986). 544/390; 558/385; 558/386; 558/413; 558/417 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). Primary Examiner Richard L. Raymond U.S. PATENT DOCUMENTS Attorney, Agent, or Firm-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 O 57 ABSTRACT 4,138,561 2/1979 Crenshaw et al...... 544/284 4,251,532 2/1981 Roteman ...... 544/291 Novel methods for the synthesis of substituted ureas and 4,672,116 6/1987 Bandurco et al...... 544/286 guanidines including TeraZosin, PraZosin, Doxazosin, TiodaZosin, Trima Zosin, Quinasin and Buna Zosin 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. 1081,229 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- 5 ments known to reduce blood pressure in hyperactive Sub SUBSTITUTED QUINAZOLINE jects. COMPOUNDS), AND MEOBENTINE, AND BETHANDINE 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, filed May 30, 1995, now U.S. Pat. No. 5,686, the synthesis thereof. 612 which application is a File Wrapper Continuation of - 0 U.S. application Ser. No. 08/004,114, filed on Jan. 13, 1993 Some of these novel intermediates that are guanidines now abandoned) s---- is s is 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 A number 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 r 3 R1O Ns Nu N RO 2

NH2

COMPOUND R R. R. n. Rs PRAZOSIN H Me Me 1 / \

TERAZOSIN H Me Me 1

O O DOXAZOSIN H Me Me 1 1.O C O

TODAZOSIN H Me Me 1 N-N

os- O> SCH

TRIMAZOSN OMe Me Me 1 O 6,080,860

-continued

COMPOUND R OUINAZOSIN H

BUNAZOSIN H Me Me 2

Thus the include the following cyclized guanidines of general formula 2. 25

Cyclized Guanidines -continued R1O N N O TERAZOSIN s nV ls O DC N N R3 CHO ( )- 1) NH2 CHO R = R2 = Me; R = TERAZOSIN -C) DOXAZOSIN

R = R2 = Me; R = PRAZOSIN CHO

O CHO R = R2 = Me; R = DOXAZOSIN

50 TRIMAZOSIN CO O CH CHO N-C-O-CH-C-OH CH The following compounds are exemplary 55 CHO

PRAZOSIN OUINAZOSIN

60 CHO CHO N-CH-CH=CH

CHO CHO 6,080,860

-continued BUNAZOSIN

CHO Nn N ~- C-CH-CH-CH 5 N N CHO 2

NH 2 1O TODAZOSIN O CHO N O ---> ---SCH, N 15 CHO 2

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

N1 R's

R" n ul Y R's N N R / Y. '4

BETHANIDINE; R = R = H; R = R = Me; R = & MEOBENTINE; R = R = H; R = R = Me; R = \-()-ow wherein Me is CH (methyl).

METHOD 1 The prior art preparations of cyclized and uncylized 50 guanidines for example of Terazosin (R=tetrahydrofuryl), N X Prazosin (R=furyl), Doxazosin (R=1,4,-benzodioxan-2- R1O n R yl), and Meobentine (R'=4-methoxybenzyl, R=H, R's= + H-N He methyl, R=H, R's=CH-) are discussed below. 55 2 N R4 RO Compounds of general formulae 1 have been prepared by NH2 a number of approaches which may be classified into five general methods. 60 R RO N \ In method 1, a 4-amino-6,7-dimethoxy quinazoline that is 1. Substituted at C-2 position with a good leaving group X, is n YR condensed with a proper amine. Up to nine Steps are used to 2N Synthesize the 4-amino-6,7-dimethoxy quinazoline, Starting 65 RO from veratraldehyde J. Chem. Soc. 1759, (1948) and J. NH2 Med. Chem. 20, 146, (1977)). 6,080,860 7

X Reference METHOD 2 C Fr. Pat. 2321890

Fr. Pat. 235O1O1 RO NH 1. 2 R Can Pat. 1057754 -- Y-N?o He Can Pat. 1081,229 Ys Ger Pat. 2707O68 RO Z. 4 Ger Pat. 2725019 Eur Pat. OO34471 R U.S. Pat No. 4251532 RO1. N \ U.S. Pat No. 4O26894 N YR 15 Brit Pat. 1156973 2N RO Brit Pat. 2021108 SCH, Ger Pat. 2707O68 NH2 Brit Pat. 1156973 C-6(Z) Y Reference Brit Pat. 2021108 CN CN Brit Pat. 1390014 SO-alkyl Brit Pat. 2021108 Brit Pat. 1390015 Eur Pat. OO34471 CN HN-C=NH Brit Pat. 1156973 CN HN-C=NH Brit Pat. 1156973 25 (C1 instead of NH at C-1 position) Those fine chemical manufacturers Synthesizing praZoSin CN H-N=C-O-Alkyl Ger Pat. 2457911 CN H-N=C-S-Alkyl Ger Pat. 2457911 teraZosin, and doxazosin for the most part use this proceSS O-C-NH CN Ger Pat. 2457911 or a modification thereof. The major shortcoming of this HN=C-NH CN Ger Pat. 2457911 method (method 1) is the low yields (between about 5 and 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 In method 3,3,4-dimethoxy-6-cyanoaniline is converted the C-6 position with a nitrile, amide or amidine group is 35 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 reflux in the presence of ammonium chloride results in the insertion of the amine group. followed by ring closure to 40 afford Terazosin (Bel. Pat. PCT/F18200034, 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 R H Js R1O NH2 R1O N=C=S H. N. R1O N NS R4 R4 He S RO CN RO CN RO CN Me R R

R1O N \ 3 RO1. N \ 3 CHSH + N R4 NHCI N YR N S RO 2 RO CN Me 6,080,860 9 10 In method 4, N-cyano-N-(3,4-dimethoxyphenyl)-5- and the overall yield is approximately 5-25% F.H.S. 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 properamine (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, of highly toxic cyanogen bromide (Y=CN), followed by Eur. Pat. 0034471). The reported yields starting from the further modification of the activating group (Y=HN 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 \ R1O N SR R R1O N n i?.- - - - R. -N YR N RO NC 4 RO NC1

R3 R1O N \ N n R4 2N. RO NH2

In method 5, 2-chloro-4-amionquinazoline is initially 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.

R1O N Cl R1O N N n / V - HN NH -> s -n -H 2N 2 N N RO RO NH2 NH2 --O - Cylon "111-yul O RO Cls TERAZOSIN O OC OD. DOXAZOSIN O

AS in method 1, this process also fails to provide good go In method 4, the overall yield starting from N-cyano N'-((3, yields, because of the number of steps involved in the 4-dimethoxyphenyl)-S-methyl-isothiourea is reported to be ca. 63%. Nevertheless, the requirement of this isothiourea as preparation of the 2-chloroquinazoline Starting material. Starting material the preparation of which being very diffi cult and inefficient, renders the method unattractive. These methods suffer from various other shortcomings. Compounds of general formula 3 are Synthesized using For example, the use of 2-chloro-4-amino-6,7- 65 S-alkylated thiourea and the corresponding amine. The dimethoxyquinazoline (method 1 and 5) is prohibitive due to synthesis of Meobentine has been reported is U.S. 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 HCS I NH2 example a nucleophile (such as for example ammonia or an >=NCH, -- He amine) and HCHN OMe (ii) adding a desired radical to the results of Subparagraph CH (a) orb (i) if step (i) of Subparagraph (b) is carried out before 1. 3 this step (ii), and l (c) optionally, and if required, closing a ring to form for N NHMe example a 2-amino-Substituted quinazoline. H Other guanidines including quinazolines may also be manufactured according to the invention as would be under H3CO stood by perSons skilled in the art. Va: MEOBENTINE According to another aspect of the invention the desired 15 radical is ammonia or an amine radical. 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 EP is preferably POCl. EP may also comprise: PCls, tages described in the methods 2 and 3 (vide Sudra). POs, tosyl chloride (CH, SOCl) - TsCl- and in some It is therefore an object of this invention to provide instances mesyl chloride (CH, SOCl) -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 (e.g. Terazosin, Prazosin, Doxazosin, hetero radical containing oxygen to it for example by adding TiodaZosin, TrimaZosin. Quinasin and BunaZOsin) and for example uncyclized guanidines Such as those of general a carbonyl (c) to an amine; formula 3 (e.g. Meobentine and bethanidine). b) adding a desired radical to the results of (a); It is a further object of the invention to provide such c) adding a suitable electrophile (EP) to react with the 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 NH or an amine group: (therefore having the desired efficacy). 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 (f) with NH 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 (f) and (g): including cyclized guanidines for example 2-amino 50 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: 2-amino-Substituted quinazoline compounds (for example (a) (i) adding oxygen or a hetero radical containing 55 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 NH 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 (i) 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 NH 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 5 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 (b). In an exemplary method, an amine I (nitrile) is converted According to another aspect of the invention, Such a 1O 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 properamine III N-(tetrahydro-2-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-hydroxyethyl 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 2O cycloheptane (a 7-membered dinitrogen radical) in the case a method may comprise; of bunazosin in refluxing 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. POCl, PCls, tosyl chloride. phos oxygen of the urea to yield a reaction product as a leaving phorous pentoxide), resulting in the conversion of the oxy group Susceptible to replacement by an amine; 25 gen of the urea into a good leaving group (V). 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. 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 R1O N NH2

H-NECEO --> r O RO CN RO CN I Pyridine, reflux

N1 R R r R1O N R1O N Nu --- r EP = POCl3, PC, POs, TsCl O O RO C. CNNEPs RO CN IV V NH 6,080,860

-continued

RO CN RO

VII

In this scheme R may be hydrogen or lower alkoxy (for example methoxy), R and R may be lower alkyl (for 15 example methyl), n is a number Selected from 1 and 2 and R 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 iooxadiazole carbonyl), dialkyl hydroxy alkyl ester (for example 2,2-dimethyl hydroxy ethyl ester), alkene (for example propene) and alkyroyl (for example butyroyl). The following chart identifies combinations of substitu 25 ents for identified Medicines.

COMPOUND R R. R., n R. PRAZOSIN H Me Me 1

-continued

COMPOUND R R R n R. 40

TERAZOSIN H Me Me 1 TRIMAZOSIN OMe Me Me 1 O

45 arc.Me

50 DOXAZOSIN H Me Me 1 O OUINAZOSIN H Me Me 1 N-1s C 55

BUNAZOSIN H Me Me 2 O 60 TODAZOSIN H Me Me 1 N-N -.

65 Thus the following is specifically included 6,080,860 17 18

H R1O NH2 R1O N NH2 H-NRCRO --> r O RO CN RO CN II N O H1 n\ ls Pyridine, reflux N R III"

DOrsu R" IV EP = POCl3, PCls, POs, TsCl Er R1O N N O O n \\ NH R1O NSr.) N A NH2 N R" -- O N R" RO CN RO CNNEP V

R1O N N O

O RO Cls TERAZOSIN O OC OD. DOXAZOSIN O

45 The radical ls.O Tri R" and R"-C 50 HCHN NHCH, EP = POCl3 Ia preferably may be Substituted by other radicals as is apparent from examination of the Substituents for Rs. 55

Usual work up of the reaction mixture results in the EP R isolation of the desired product. Compounds II (including o1 II), IV (including IV). V (including V) and VI (including 1. NH2 VI) are novel and the processes of their manufacture are also 60 HCN NHCH R = H, OMe 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 POCl, HN PCls, etc, (see above) to form intermediate VIII in which the 1. oxygen function of the urea becomes a good leaving group. HCN NHCH Displacement of the oxygen by a proper amine III and R = OMe: MEOBENTINE Subsequent work-up results in the isolation of the desired R = H BETHANDINE 10 quinazoline VII (for example terazosin). Compounds II, VI and VIII are novel. Preferably EP is PCOl. The following reaction Scheme presents itself

R R H H R1O N NH2 R1O N NH2 1 Hebe Y O O R CN RO CNNEP O II VIII EP = POCl3, PCls, POs, TsCl y \ HN N-R

III

1 R 1 R R r N R r N R1O N N- R1O N N s a s 2N NH2 RO RO CN NH2 VII VI

R R R Rs

H Me Me 1. / \

H Me Me 1.

S-2O

H Me Me 1. O 6,080,860 22

-continued

R R H H R1O N NH2 R1O N NH2 1" Hehe NY O O R CN RO CNNEP O II VIII EP = POCl3, PCls, POs, TsCl y \ HN N-R

III

R3 R r 1 R r R1O N Nu R1O N Nu N -e- s 2N. NH2 RO RO CN NH2 VII VI

R R R R

H Me Me 1. N-N

a- O > SCH

OMe Me Me 1. O

alsO Me OH Me

Thus the following is specifically included 6,080,860

H H R1O N NH2 R1O N NH2

rO - EP -e- DOC YO RO CN RO CNNEP VIII II N O 1 H O N

III"

R1O N N O R1O N N O n n O O H 2N N NH 2 N RO RO CN NH2 VI" VII

(The tetrahydrofuryl radical may be substituted by furyl or group using an electrophile (EP) Such as POCl, PCls, 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 Rs.) 35 converted to its pharmaceutically acceptable salts (for In another method, for example the amine III is converted to its corresponding urea IX with cyanic acid. Again the example the hydrochloride or mesylate salt). The following oxygen function of the urea is converted to a good leaving reaction Scheme presents itself. 6,080,860 25

III IX

EP = POCl3, PCls, POs, MsCl, TsCl NH

RO CN

R1O Nn Nu 2N RO RO

VII VI

Me 1.

OMe Me 1.

Me 1.

6,080,860 29 30 -continued R1O N N O R1O N N O Sr. O Sr. O N N N N RO 2 He- RO 2

NH2 NH2-HC12H2O VII XI

1O (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 r Compounds VI", IX" and X" are novel and the processes R1O N N of their manufacture are also novel. O RO CN Thus according to another aspect of the invention, com- 20 IX pounds of the formula HN N O N O Ran ||O 7eR O N N-C-N 25 y' \ X- N-R are provided wherein R is Selected from hydrogen, 3O HN \ / R 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 R and R are each selected from of the formula hydrogen, (provided R. and R are not hydrogen when R. 35 and R, 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 substituted carbonyl for example R carbonyl (wherein R is 40 Selected from furyl, tetrahydrofuryl, 1,4-benzosioxan-2-yl, alkylthiooxadiazole for example methylthiooxadiazole and alkyl (for example propyl), dialkyl hydroxy alkyl ester for are provided, wherein example, 2,2-dimethyl-2-hydroxy-ethyl ester, and alkene EP is an electrophile and together with the oxygen forms (for example propene). Exemplary of Such compounds are 45 a leaving group (preferably Substitutable by NH or an II, II", IV, IV, IX and IX set out below amine) (preferably EP being selected from POCl, P.O.s, II PCls, mesyl chloride and tosylchloride), R is selected from H hydrogen, alkyl (for example methyl) and a Substituted 50 phenyl radical Substituted by at least one of alkoxy (for R1O N NH2 example methoxy) and cyano, and R and R are each Selected from hydrogen, lower alkyl (for example methyl) a RODOC CN O 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 R1O N NH2 6-membered or 7-membered ring), the closed ring being O substituted by R-carbonyl (wherein R is selected from for RO CN 60 example furyl, tetrahydrofuryl, 1,4-benzodioxan-2-yl, IV alkylthiooxadiazole, for example methylthiooxadiazole, R1O N N O alkyl for example propyl, dialkyl hydroxy alkyl ester for example 2,2-dimethyl-2-hydroxy-ethyl ester and alkene (for \\lo example propene). O 65 RO Exemplary of such compounds are V, V, IIa. VIII, VIII', X and X" set out below. 6,080,860

V VI R1O N N O R1O N N O n a. ls Sr Yu On N R 5 NH2 N R RO CN EP RO CN V where R' is furyl, R tetrahydrofuryl or R (1 N1 1,4-benzodioxan-2-yl. 1O VI R1O N N n -R3 R (1 N O RO CNNEP R1O N Nu IIa 15 s EP NH2 o1 RO CN VI" R1O N N O HCN NHCH n 2O O VIII H NH2 N R1O N NH RO CN I O RO CN YEP 25 Additionally compounds VII and XI are of higher purity VIII R than prior art compounds and contain for example residues H of II, IV, V, VI, VIII, IX or X. R1O N NH 3O II R O RO CNNEP H X." R1O Y NH2 HN N O 35 O Nulls -o RO CN OYEP N IV 1 R R X H r NH y \ 40 R1O -- X- N-R O EP-O \ / RO CN 45 V According to another aspect of the invention compounds Y R of formula R ( r N R1O NN Nu

50 O RO CNNEP VI Y R are provided wherein R, is selected from a Substituted 55 R ( r N phenyl being Substituted by a radical Selected from at least R1O N Nu one of alkoxy (for example methoxy) and cyano and R, R, s together with the Nitrogen, form a closed ring preferably NH2 containing a second nitrogen (preferably being a 6–7 mem RO CN bered ring), the closed ring being Substituted by furoyl, 60 VIII tetrahydrofuroyl, 1,4-benzodioxan-2-yl carbonyl, methylth R iooxadiazole carbonyl, dialkyl hydroxy alkyl ester (for example 2, 2-dimethyl-2-hydroxy-ethyl ester), alkene (for example propene), alkoyl (for example butyroyl) 65 Exemplary of such compounds are compounds VI, VI' and VI" set out below 6,080,860

-continued DX II H O (/)n R1O N NH2 X- N-R 5 r HN \ / O RO CN X IV'

NH y \ R1O NH N O N N-R 1O O EP-O O N RO CN

Vil wherein the appropriate Substituents are Selected dependent 15 RO1. N n N O on the medicine for example See the chart below: \Y O O N RO CN YEP - 20 VI' COMPOUND R R. R., n R. R1O N N O n PRAZOSIN H Me Me 1 O / \ NH2 N RO CN O 25 VIII' O H R1O N NH TERAZOSIN H Me Me 1 DOC 3O O O RO CN YEP DX O HN N O DOXAZOSIN H Me Me 1 O 35 r \\ O DO O N O X' HN N O O 40 \) O TODAZOSIN H Me Me 1 N-N "Yep N

a- O> SCH 45 Where the medicine is Prazosin the residues II, IV, V, VI, TRIMAZOSIN OMe Me Me 1 O VIII, IX and/or X may be

als O Me 50 II OH H Me R1O s" OUINAZOSIN H Me Me 1 N-1s DOC O N 55 RO CN IV it BUNAZOSIN H Me Me 2 O RO N O --~. 1. DOS-Uy - " RO CN O will R1O N N O The combinations of these residues with VII and XI are \ \ f \ also new providing a product of higher purity. Thus for 65 On N example for Terazosin, the residues II, IV, V, VI, VIII, IX RO CN EP O and/or X are follows: 6,080,860 35 36 -continued -continued VI'll X R1O N N O "Sri On N R RO EP wherein VIII 1O ru O

15 In respect of the medicines TiodaZosin, TrimaZosin, Quinasin and BunaZosin, the residues are II, IV, V, VI, VIII, IX and/or X.

II X it R H R1O N NH2

O RO CN 25 IV 1. R

Where the medicine is doxazosin the residues II, IV, V, VI, R H r VIII, IX and/or X may be R1O - II O H RO CN V R1O N R 35 Y RODOC CN O R r IV R1O Nn Nu H O R1O r) All 40 RO CN SEP VI RO CN R (1, N -R3 Vl R1O N N O R1O N Nu 45 s O N R3 NH2 RO CNNEP RO CN VIII VI 50 R R1O N N O H

sNH2 N N ls R R1O s RO CN O RO CNNEP 55 VIII DX H R1O N NH O y \ )- N-R O RO CNNEP 60 HN \ / X IX NH (in N N-R "st l EP-O O N R 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 (160.5g, 2.46 mol in 750 mL of deionized water) in 100 mL R is Methyl portions over a thirty minute period. Acetone (6000 mL) is R is Methyl added and the mixture is maintained at +5 C for an n is 1 additional 30 minutes. The product is filtered and the cake is and R is washed with acetone (2x150 mL) (293/7 grams, 79% yield). "H nmr (DMSO-d) d 8.19 (bs, 1H, NH); 7.48 (s, 1H, N-N C-5); 6.98 (s, 1H, C-2); 6.12 (bs, 2H, NH); 3.65 (s, 3H. OCH); 3.60 (s, 3H, OCH). 1O s' s EXAMPLE 2 4-(2-tetrahydrofuroyl)piperazine-1-ylformamide (IX) (b) TRIMAZOSIN R is methoxy (OMe) 15 4-(2-Tetrahydrofuroyl)piperazine (33.25 g, 180.7 mmol) R 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 R is with stirring. Sodium cyanate (13.1 g, 201.15 mmol) is added in Small portion to the Stirring Solution and heating is O continued for an additional 2 hours. The reaction mixture is concentrated under reduced pressure to yield a thick oil. als Me Chloroform (100 mL) is added to the oil and the solution is O heated to reflux. The hot Solution is filtered and the filtrate OH Me is dried over NaSO. 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 filtered, washed with ether (25 mL) and dried. The R is hydrogen product is used without further purification (33.8 g., 82.3% R is Methyl yield). R is Methyl "H nmr (CDC1) d 5.60 (bs, 2H, NH); 4.32 (t. J=7.0 Hz, and R is 1H. CH, C-2 (tetrahydrofuroyl)): 3.80 (t, J=6.0 Hz, 2H, CH, C-5 (tetrahydrofuroyl)): 3.70–280 (m, 8H, CH's (C-2. C-3, C-5, C-6 (piperazinyl))); 2.39-1.49 (m, 4H, CH's (C-3, C-4 (tetrahydrofuroyl)). 35 (d) BUNAZOSIN EXAMPLE 3 R is hydrogen R is Methyl 3,4-dimethoxy-6-4-(2-tetrahydrofuroyl) piperazine R is Methyl 1-ylcarbamido) benzonitrile (IV) and R 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 refluxed for 3 hours. The Solvent is then Vacuum distilled to a minimum Volume and then azeotroped --~. 45 with Small portions of water. The final 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 cmx2.5 cm). It is then eluted with ethyl acetate initially and the polarity is gradually increased with ethanol OEP 50 to a final solvent ratio of 80:20. Fractions containing the product (TLC: 80:20 ethylacetate:methanol, R=0.5) are NHCH 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). least one of the associated residues is new and provides 55 "H nmr (CDC1) d 7.35 (s, 1 H. 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 (tetrahydrofuroyl)); 3.89 (s, 3H, OCH); 3.80 (s, 3H. following exemplary methods of manufacture. OCH); 4.11-3.18 (m, 10H, CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 (tetrahydrofuroyl))); 2.22-1.49 (m, 4H, DETAILED DESCRIPTION OF PREFERRED 60 CH'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-ylcarbamidobenzonitrile (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 6,080,860 39 40 g, 13.9 mmol) (III) are suspended in 25 mL dry dimethyl (10 mL) and n-butanol (30 mL) are added to the aqueous formamide and the mixture is refluxed for 3 hours. The Solution and the mixture is heated to 60° C. The warm Solvent is then Vacuum distilled to a minimum Volume and mixture is basified to pH-10.0 with dropwise addition of then azeotroped with small portions of water. The final 10% NaOH. The layers are separated and the aqueous phase aqueous Solution is extracted with six portions (20 mL) of is further extracted with three portions (20 mL) of n-butanol. ethyl acetate. The organic layer is concentrated and applied The organic extractions are combined and filtered through a to a silica gel column (25 cmx2.5 cm). It is then eluted with bed of celite. The filtrate is dried over NaSO, concentrated ethyl acetate initially and the polarity is gradually increased under reduced pressure and applied to a Silica gel column (35 cmx5 cm). It is then eluted initially with ethyl acetate with ethanol to a final Solvent ratio of 80:20. Fractions and the polarity is gradually increased with ethanol to a final containing the product (TLC: 80:20 ethylacetate:methanol, solvent ratio of 80:20. Fractions containing the product R=0.5) are combined and the solvent evaporated. The pure (TLC: 80:20 ethyl acetate:methanol, R=0.37) are combined product is crystallized from a Small Volume of ethyl acetate and concentrated under reduced pressure. The pure product as light yellow needles (2.85 g, 60% yield). is crystallized from a minimum volume of ethyl acetate as "H nmr (CDC1) d 7.35 (s, 1H, ArH, C-2); 7.10 (bs, 1H, white crystals (3.02 g, 67% yield). NH; 6.85 (s, 1H, ArH, C-5); 4.58 (t, J=7.0 Hz, 1H, CH, C-2 15 "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, (tetrahydrofuroyl)); 3.89 (s, 3H, OCH); 3.80 (s, 3H, NH): 482-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 OCH); 4.11-3.18 (m, 1 OH, CH's (C-2, C-3, C-5, C-6 (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, (piperazinyl), C-5 (tetrahydrofuroyl))); 2.22-1.49 (m, 4H, CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 CH's (C-3, C-4 (tetrahydrofuroyl))). (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 EXAMPLE 5 (tetrahydrofuroyl))). EXAMPLE 7 3,4-dimethoxy-6-4-(2-tetrahydrofuroyl)piperazine 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino 1-ylcarbamidobenzonitrile (IV) 6,7-dimethoxyquinazoline (VII) 25 (3,4-Dimethoxy-6-cyanoaniline-1-ylformamide (2.75 g, The reaction mixture of Example 3 is cooled to 20 C. 12.5 mmol) (II) and 4-(2-tetrahydrofuroyl)piperazine (2.56 (after the three hour reflux). PCls (3.90 g, 18.75 mmol) is g. 13.9 mmol) (III) are suspended in 25 mL dry dichloro added and the resulting solution is heated to 80° C. and ethane and the mixture is refluxed for 3 hours. maintained for thirty minutes. The reaction mixture is Water (30 mL) is added and the mixture is stirred at room removed from the heat and allowed to cool to room temperature for 15 minutes. The layers are separated and the temperature.Compound V is the result. Anhydrous, NH aqueous phase is further extracted with five portions of gas is moderately purged through the reaction mixture and dichloroethane (20 mL). The organic layer is concentrated the internal temperature is allowed to rise independently to and applied to a silica gel column (25 cmx2.5 cm). It is then a maximum temperature (70° C-80° C). When the internal eluted with ethyl acetate initially and the polarity is gradu 35 temperature drops below the previously attained maximum ally increased with ethanol to a final solvent ratio of 80:20. temperature, the reaction mixture is slowly heated to 100° C. Fractions containing the product (TLC: 80:20 (alternatively (NH4)2CO can be used as a Source of ethylacetate:methanol, R=0.5) are combined and the solvent ammonia). The reaction mixture is cooled to 60° C. and then evaporated. The pure product is crystallized from a Small Vacuum distilled to a minimum Volume. The residual pyri volume of ethyl acetate as light yellow needles (1.18 g, 25% 40 dine is azeotroped off with small amounts of water. Water yield). (10 mL) and n-butanol (30 mL) are added to the aqueous "H nmr (CDC1) d 7.35 (s, 1H, ArH, C-2); 7.10 (bs, 1H, Solution and the mixture is heated to 60° C. the warm NH; 6.85 (s, 1H, ArH, C-5); 4.58 (t, J=7.0 Hz, 1H, CH, C-2 mixture is basified to pH-10.0 with dropwise addition of (tetrahydrofuroyl)); 3.89 (s, 3H, OCH); 3.80 (s, 3H, 10% NaOH. The layers are separated and the aqueous phase OCH); 4.11-3.18 (m, 10H, CH's (C-2, C-3, C-5, C-6 45 is further extracted with three portions (20 mL) of n-butanol. (piperazinyl), C-5 (tetrahydrofuroyl))); 2.22-1.49 (m, 4H, The organic extractions are combined and filtered through a CH's (C-3, C-4 (tetrahydrofuroyl))). bed of celite. The filtrate is dried over NaSO, concentrated under reduced pressure and applied to a Silica gel column EXAMPLE 6 (35 cmx5 cm). It is then eluted initially with ethyl acetate 50 and the polarity is gradually increased with ethanol to a final 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino solvent ratio of 80:20. Fractions containing the product 6,7-dimethoxyquinazoline (VII) (TLC: 80:20 ethyl acetate:methanol, R=0.37) are combined The reaction mixture of Example 3 is cooled to 20 C. and concentrated under reduced pressure. The pure product (after the three hour reflux). POCl (2.11g, 13.75 mmol) is is crystallized from a minimum volume of ethyl acetate as added and the resulting solution is heated to 70° C. and 55 white crystals (2.78 g, 59% yield). maintained for thirty minutes. The reaction mixture is "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5): 5.52 (bs, 2H, removed from the heat and allowed to cool to room NH): 482-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 temperature.Compound V is the result. Anhydrous, NH (s, 3H. OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 1 OH, gas is moderately purged through the reaction mixture and CH's (C-2, C-3. C-5, C-6 (piperazinyl), C-5 the internal temperature is allowed to rise independently to 60 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 a maximum temperature (70 C-80° C). When the Internal (tetrahydrofuroyl))). temperature drops below the previously attained maximum EXAMPLE 8 temperature, the reaction mixture is slowly heated to 100° C. (alternatively (NH)2 CO can be used as a source of 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino ammonia). The reaction mixture is cooled to 60° C. and then 65 6,7-dimethoxyquinazoline (VII) Vacuum distilled to a minimum Volume. The residual pyri The reaction mixture of Example 3 is cooled to 20 C. dine is azeotroped off with small amounts of water. Water (after the three hour reflux). POs (2.66 g., 18.75 mmol) is 6,080,860 41 42 added and the resulting solution is heated to 80° C. and pure product is crystallized from a minimum volume of maintained for thirty minutes. The reaction mixture is ethyl acetate as white crystals (0.23 g, 5% yield). removed from the heat and allowed to cool to room "H nmr (CDC1) d 6.98 (s.1H, ArH, C-5): 5.52 (bs, 2H, temperature.Compound V is the result. Anhydrous, NH NH): 482-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 gas is moderately purged through the reaction mixture and (s, 3H, OCH): 3.90 (s, 3H, OCH); 4.10-3.42 (m, 1 OH, the internal temperature is allowed to rise independently to CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 a maximum temperature (70 C-80° C). When the internal (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 temperature drops below the previously attained maximum (tetrahydrofuroyl))). temperature, the reaction mixture is slowly heated to 100° C. (alternatively (NH4)2CO can be used as a Source of EXAMPLE 10 ammonia). The reaction mixture is cooled to 60° C. and the Vacuum distilled to a minimum Volume. The residual pyri 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino dine is azeotroped off with small amounts of water. Water 6,7-dimethoxyquinazoline (VII) (10 mL) and n-butanol (30 mL) are added to the aqueous Solution and the mixture is heated to 60° C. The warm 15 Under an inert atmosphere (N) and anhydrous conditions mixture is basified to pH-10.0 with dropwise of 10% NaOH. 3,4-dimethoxy-6-cyanoanaline-1-ylformamide (2.21 g. 10 The layers are Separated and the aqueous phase is further mmol) is suspended in dry pyridine (10 mL). With vigorous extracted with three portions (20 mL) of n-butanol. The stirring POCl (1.9g. 12 mmol) is added and the solution is organic extracts are combined and filtered through a bed of heated to 60° C. and maintained for fifteen minutes. 4-(2- celite. The filtrate is dried over NaSO, concentrated under Tetrahydrofuroyl)piperazine (2.20 g, 12 mmol) is added and reduced pressure and applied to a silica gel column (35 the reaction mixture is brought to reflux and maintained for cmx5 cm). It is then eluted initially with ethyl acetate and two hours. Compound V is produced but not isolated). The the polariyy is gradually increased with ethanol to a final Solvent is distilled off to a minimum volume and the residual solvent ratio of 80:20. Fractions containing the product pyridine is azeotroped off with Small portions of water. Water is added to the aqueous mixture to bring the reaction (TLC: 80:20 ethyl acetate:methanol, R=0.37) are combined 25 volume to 30 mL. Chloroform (30 mL) is then added to the and concentrated under reduced pressure. The pure product aqueous Solution and with Vigorous Stirring the mixture is is crystallized from a minimum volume of ethyl acetate as basified to pH=10 with dropwise addition of 10% NaOH. white crystals (0.71 g, 15% yield). The layers are Separated and the aqueous phase is further "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5): 5.52 (bs, 2H, extracted with four portions (10 mL) of chloroform. The NH): 482-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 organic extracts are combined and filtered through a bed of (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 1 OH, CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 celite. The filtrate is dried over NaSO, concentrated under (tetrahydrofuroyl))); 2.39–1.75 (m, 4H, CH's (C-3, C-4 reduced pressure and applied to a silica gel column (25 (tetrahydrofuroyl))). cmx2.5 cm). It is then eluted initially with ethyl acetate and 35 the polarity is gradually increased with ethanol to a final EXAMPLE 9 solvent ratio of 80:20. Fractions containing the product (TLC: 80:20 ethyl acetate:methanol, R=0.37) are combined 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino and concentrated under reduced pressure. The pure product 6,7-dimethoxyquinazoline (VII) is crystallized from a minimum Volume of ethyl accetate as The reaction mixture of Example 3 is cooled to 20 C. 40 white crystals (0.77 g. 20% yield). (after the three hour reflux). P-toluenesulfonyl chloride (3.57 "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5): 5.52 (bs, 2H, g, 18.75 mmol) is added and the resulting Solution is heated NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)): 3.98 to reflux and maintained for ninety minutes. The reaction (s, 3H, OCH): 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, mixture is removed from the heat and allowed to cool to CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 room temperature.Compound V is the result. Anhydrous 45 (tetrahydrofuroyl))); 2.39–1.75 (m, 4H, CH's (C-3. C-4 NH gas is moderately purged through the reaction mixture (tetrahydrofuroyl))). and the internal temperature is allowed to rise independently to a maximum temperature (70° C.-80° C.). When the EXAMPLE 11 internal temperature drops below the previously attained 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino maximum temperature, the reaction mixture is slowly heated 50 to 100° C. (alternatively (NH)CO can be used as a source 6,7-dimethoxyquinazoline (VII) of ammonia). The reaction mixture is cooled to 60° C. and Under an inert atmosphere (N2) and anhydrous conditions the vacuum distilled to a minimum volume. The residual 3,4-dimethoxy-6-cyanoanaline-1-ylformamide (2.21 g, 10 pyridine is azeotroped off with Small amounts of water. mmol) is suspended in dry pyridine (10 mL). With vigorous Water (10 mL) and n-butanol (30 mL) are added to the 55 stirring PCls (2.50 g, 12 mmol) is added and the solution is acqueous solution and the mixture is heated to 60° C. The heated to 60° C. and maintained for fifteen minutes. 4-(2- warm mixture is basified to pH-10.0 with dropwise addition Tetrahydrofuroyl)piperazine (2.20 g, 12 mmol) is added and of 10% NaOH. The layers are separated and the aqueous the reaction mixture is brought to reflux and maintained for phase is further extracted with three portions (20 mL) of two hours. Compound V was produced but not isolated. n-butanol. The organic extracts are combined and filtered 60 The Solvent is vacuum distilled off to a minimum volume through a bed of celite. The filtrate is dried over NaSO, and the residual pyridine is azeotroped off with Small concentrated under reduced pressure and applied to a Silica portions of water. Water is added to the aqueous mixture to gel column (35 cmx5 cm). It Is then eluted initially with bring the reaction volume to 30 mL. Chloroform (30 mL) is ethyl acetate and the polarity is gradually increased with then added to the aqueous Solution and with Vigorous ethanol to a final solvent ratio of 80:20. Fractions containing 65 stirring the mixture is basified to pH=10 with drowise the product (TLC:80:20 ethyl acetate:methanol, R=0.37) addition of 10% NaOH. The layers are separated and the are combined and concentrated under reduced preSSure. The aqueous phase is further extracted with four portions (10 6,080,860 43 44 mL) of chloroform. The organic extracts are combined and hours. Water (30 mL) is added and with vigorous stirring the filtered through a bed of celite. The filtrate is dried over mixture is basified to pH:10 with dropwise addition of 10% Na2SO, concentrated under reduced pressure and applied to NaOH. The layers are separated and the aqueous phase is a Silica gel column (25 cmx2.5 cm). It is then eluted initially further extracted with four portions (10 mL) of dichloroet with ethyl acetate and the polarity is gradually increased hane. The organic extracts are combined and filtered through with ethanol to a final Solvent ratio of 80:20. Fractions a bed of celite. The filtrate is dried over NaSO, concen containing the product (TLC: 80:20 ethyl acetate:methanol, trated under reduced pressure and applied to a Silica gel R=0.37) are combined and concentrated under reduced column (25 cmx2.5 cm). It is then eluted initially with ethyl preSSure. The pure product is crystallized from a minimum acetate and the polarity is gradually increased with ethanol volume of ethyl acetate as white crystals (0.60 g, 16% yield). to a final solvent ratio of 80:20. Fractions containing the "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, product (TLC: 80:20 ethyl acetate:methanol, R:0.37) are NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 combined and concentrated under reduced preSSure. The (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, pure product is crystallized from a minimum volume of CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 ethyl acetate as white crystals (0.38 g, 10% yield). (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 15 "H nmr (CDC1) d 6.98 (s, 1H. ArH, C-5); 5.52 cbs, 2H, (tetrahydrofuroyl))). NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 (s, 3H, OCH); 3.90 (s, 3H, OCH): 4.10-3.42 (m, 10H, EXAMPLE 12 CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino (tetrahydrofuroyl))). 6,7-dimethoxyquinazoline (VII) 3,4-Dimethoxy-6-cyanoanaline-1-ylformamide (2.21 g, EXAMPLE 1.4 10 mmol) is suspended in dry pyridine (10 mL) and with 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino Stirring p-toluenesulfonyl chloride (2.5g, 13 mmol) is added 25 6,7-dimethoxyquinazoline (VII) portionwise. The reaction mixture is heated on a water bath (60° C.) until complete dissolution is achieved 4-(2- 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g. Tetrahydrofuroyl)piperazine (2.20 g. 12 mmol) is added and 10 mmol) is suspended in dichloroethane (15 mL) and the mixture is brought to reflux and maintained for two heated until total dissolution is achieved. Triethylamine (2.0 hours. The solvent is vacuum distilled off to a minimum g, 20 mmol) is added and the solution is stirred for 5 Volume and the residual pyridine is azeotroped off with minutes. P-toluenesulfonyl chloride (3.92 g, 20 mmol) is Small portions of water. Water is added to the aqueous added and the reaction mixture is heated to reflux and mixture to bring the reaction volume to 30 mL. Chloroform maintained for 3 hours. Compound X is produced. 3,4- (30 mL) is then added to the aqueous solution and with Dimethoxyanthralinonitrile (1,78 g, 10 mmol) is added and vigorous stirring the mixture is basified to pH=10 with reflux is continued for an additional 24 hours. Compound dropwise addition of 10% NaOH. The layers are separated 35 VI is the result). Water (30 mL) is added and with vigorous and the aqueous phase is further extracted with four portions stirring the mixture is basified to pH=10 with dropwise (10 mL) of chloroform. The organic extracts are combined addition of 10% NaOH. The layers are separated and the and filtered through a bed of celite. The filtrate is dried over aqueous phase is further extracted with four portions (10 Na2SO, concentrated under reduced pressure and applied to mL) of dichloroethane. The organic extracts are combined a Silica gel column (25 cmx2.5 cm). It is then eluted initially 40 and filtered through a bed of celite. The filtrate is dried over with ethyl acetate and the polarity is gradually increased Na2SO, concentrated under reduced pressure and applied to with ethanol to a final Solvent ratio of 80:20. Fractions a Silica gel column (25 cmx2.5 cm). It is then eluted initially containing the product (TLC: 80:20 ethyl acetate:methanol, with ethyl acetate and the polarity is gradually increased with ethanol to a final Solvent ratio of 80:20. Fractions R=0.37) are combined and concentrated under reduced 45 preSSure. The pure product is crystallized from a minimum containing the product (TLC: 80:20 ethyl acetate:methanol, volume of ethyl acetate as white crystals (0.53 g, 14% yield). R=0.37) are combined and concentrated under reduced "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, preSSure. The pure product is crystallized from a minimum NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 volume of ethyl acetate as white crystals (0.76 g, 20% yield). (s.3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, 50 "H nmr (CDC1) d 6.98 (s.1H, ArH, C-5); 5.52 (bs, 2H, CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)), 3.98 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m. 10H, (tetrahydrofuroyl))). CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 (tetrahydrofuroyl))), 2.39-1.75 (m, 4H, CH's (C-3, C-4 EXAMPLE 13 55 (tetrahydrofuroyl))). 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino EXAMPLE 1.5 6,7-dimethoxyquinazoline (VII) 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino 3,4-dimethoxy-6-cyanoanaline-1-ylformamide (2.21 g, 6,7-dimethoxyquinazoline (VII) 10 mmol) is suspended in dry dichloroethane (10 mL) and 60 triethylamine (2.0g, 20 mmol) is added and the Suspension A mixture of 3,4-dimethoxyanthranilonitrile (7.91 g, 44.5 is stirred for 10 minutes. P-toluenesulfonyl chloride (2.5 g. mmol), 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide 13 mmol) is added portionwise and the reaction mixture is (10.1 g, 44.5 mmol) and POs (32.0 g, 225 mmol) in dry heated to reflux and maintained for one hour. The mixture is pyridine (50 mL) is refluxed with stirring for 2.5 hours. The allowed to cool to room temperature and 4-(2- 65 reaction mixture is then allowed to cool to room temperature Tetrahydrofuroyl)piperazine (2.20 g, 12 mmol) is added and over a 1 hour period and then poured into a vessel containing the mixture is brought to reflux and maintained for two sodium bicarbonate (60 g). The reaction vessel is then 6,080,860 45 46 washed with four portions of water (50 mL) which are NaOH. The layers are separated and the aqueous phase is combined with bicarbonate mixture. The mixture is stirred further extracted with four portions (10 mL) of dichloroet for 30 minutes and filtered. The filtrate is then extracted with hane. The organic extractions are combined and filtered four portions of chloroform (100 ml). The organic layers are through a bed of celite. The filtrate is dried over NaSO, combined, dried over NaSO and concentrated under concentrated under reduced pressure and applied to a Silica reduced pressure. The orange oil obtained is applied to a gel column (25 cmx2.5 cm). It is then eluted Initially with silica gel column (25 cmx2.5 cm) and is eluted initially with ethyl acetate and the polarity is gradually increased with ethyl acetate and the polarity is gradually increased with ethanol to a final solvent ratio of 80:20. Fractions containing ethanol to a final solvent ratio of 80:20. Fractions containing the product (TLC: 80:20 ethyl acetate:methanol, R=0.37) the product (TLC: 80:20 ethyl acetate: methanol, R=0.37) are combined and concentrated under reduced preSSure. The are combined and concentrated under reduced preSSure. The pure product is crystallized from a minimum volume of pure product is crystallized from a minimum volume of ethyl acetate as white crystals (0.83 g, 22% yield). ethyl acetate as white crystals (2.05 g, 12% yield). "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 15 (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H. (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, CH's (C-2, C-3, C-5, C-6 piperazinyl), C-5 CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 tetrahydrofuroyl))). (tetrahydrofuroyl))). EXAMPLE 1.8 EXAMPLE 16 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino 2-4-2-Tetrahydrofuroylpiperazine-1-yl)-4-amino 6,7-dimethoxyquinazoline (VII) 6,7-dimethoxyquinazoline (VII) 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g, A mixture of 3,4-dimethoxy-6-cyanoaniline-1- 25 10 mmol) is suspended in dry pyridine (10 mL) and with ylformamide (10.6 g., 48 mmol) (II), 4-(2-tetrahydrofuroyl) stirring POCl (1.8 g., 12 mmol) is added and the reaction piperazine (8.8 g., 48 mmol) (III) and POs (36 g. 250 mmol) mixture is stirred for an additional ten minutes. 3,4- in dry pyridine (100 mL) is refluxed with stirring for 4 hours. Dimethoxyanthranilonitrile (1.78 g, 10 mmol) is added and The reaction mixture is then allowed to cool to room the mixture is brought to reflux and maintained for three temperature over a 1 hour period and then poured into a hours. The Solvent is vacuum distilled off to a minimum vessel containing Sodium bicarbonate (60 g). The reaction Volume and the residual pyridine is azeotroped off with vessel is then washed with four portions of water (50 mL) Small portions of water. Water is added to the aqueous which are combined with bicarbonate mixture. The mixture mixture to bring the reaction volume to 30 mL. Chloroform is stirred for 30 minutes and filtered. The filtrate is then (30 mL) is then added to the aqueous solution and with extracted with four portions of chloroform (100 ml). The 35 vigorous stirring the mixture is basified to pH=10 with organic layers are combined, dried over Na2SO and con dropwise addition of 10% NaOH. The layers are separated centrated under reduced pressure. The orange oil obtained is and the aqueous phase is further extracted with four portions applied to a Silica gel column (25 cmx2.5 cm) and is eluted (10 mL) of chloroform. The organic extracts are combined initially with ethyl acetate and the polarity is gradually 40 and filtered through a bed of celite. The filtrate is dried over increased with ethanol to a final Solvent ratio of 80:20. Na2SO, concentrated under reduced pressure and applied to Fractions containing the product (TLC: 80:20 ethyl acetate: a Silica gel column (25 cmx2.5 cm). It is then eluted initially methanol, R:0.37) are combined and concentrated under with ethyl acetate and the polarity is gradually increased reduced preSSure. The pure product is crystallized from a with ethanol to a final Solvent ratio of 80:20. Fractions minimum volume of ethyl acetate as white crystals (1.85g, 45 containing the product (TLC: 80:20 ethyl acetate:methanol, 10% yield). R=0.37) are combined and concentrated under reduced "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, preSSure. The pure product is crystallized from a minimum NH): 482-4-50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 volume of ethyl acetate as white crystals (0.26g, 7% yield). (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 cbs, 2H, CH-s (C-2, C-3, C-5, C-6 (piperazinyl), C-5 50 NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 (tetrahydrofuroyl))): 2.39–1.75 (m, 4H. CH's (C-3, C-4 (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 1 OH, (tetrahydrofuroyl))). CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 (tetrahydrofuroyl))); 2.39–1.75 (m, 4H, CH2's (C-3, C-4 EXAMPLE 1.7 (tetrahydrofuroyl))). 55 2-4-2-Tetrahydrofuroylpiperazine-1-yl)-4-amino EXAMPLE 1.9 6,7-dimethoxyquinazoline (VII) 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g, 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino 10 mmol) is suspended in dichloroethane (15 mL) and 6,7-dimethoxyquinazoline (VII) heated until total dissolution is achieved. Triethyline (2.0 g, 60 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g, 20 mmol) is added and the solution is stirred for 5 minutes. 10 mmol) is suspended in dichloroethane (15 mL) and with Methanesulfonyl chloride (2.29 g, 20 mmol) is added and stirring POCl (1.8 g. 12 mmol) is added and the reaction the reaction mixture is heated to reflux and maintained for 1 mixture is stirred for an additional ten minutes. 3,4- hour. 3,4-Dimethoxyanthranilonitrile (1.78 g, 10 mmol) is Dimethoxyanthranilonitrile (1.78 g. 10 mmol) Is added and added and reflux is continued for an additional 24 hours. 65 the mixture is brought to reflux and maintained for 24 hours. Water (30 mL) is added and with vigorous stirring the Water (30 mL) is added and with vigorous stirring the mixture is basified to pH:10 with dropwise addition of 10% mixture is basified to pH:10 with dropwise addition of 10% 6,080,860 47 48 NaOH. The layers are separated and the aqueous phase is AS many changes can be made to the examples without further extracted with four portions (10 mL) of dichloroet departing from the Scope of the invention, it is intended that hane. The organic extracts are combined and filtered through all material contained herein be interpreted as illustrative of a bed of celite. The filtrate is dried over NaSO, concen the invention and not in a limiting Sense. trated under reduced pressure and applied to a Silica gel column (25 cmx2.5 cm). It is then eluted initially with ethyl The embodiments of the invention in which an exclusive acetate and the polarity is gradually increased with ethanol property or privilege is claimed are as follows: to a final solvent ratio of 80:20. Fractions containing the 1. A compound of the formula: product (TLC: 80:20 ethyl acetate:methanol, R=0.45) are combined and concentrated under reduced preSSure. The pure product is crystallized from a minimum volume of R O R ethyl acetate as white crystals (0.30 g, 8% yield); aN N- y C "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, R^ Yp, NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 (s, 3H, OCH): 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, 15 CH's (C-2. C-3, C-5. C-6 (piperazinyl), C-5 wherein R is hydrogen, R, is selected from the group (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 consisting of hydrogen and a 2-cyano-4,5-dialkoxy phenyl (tetrahydrofuroyl))). group optionally Substituted in the 6-position by an alkoxy EXAMPLE 2.0 group, and R and R are each hydrogen, provided R. and R. are not hydrogen when R and R, are hydrogen, or R and 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino R together with the nitrogen to which they are attached 6.7-methoxyquinazoline (VII) form a 6- or 7-membered closed ring optionally containing 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g, a Second nitrogen, the closed ring being Substituted on the 10 mol) is suspended in dichloroethane (15 mL) and with 25 optional Second nitrogen by a member Selected from the Stirring, triethylamine (1.2 g, 12 mmol) is added and the group consisting of unsubstituted or Substituted furoyl, reaction mixture is stirred for 15 minutes. POCl (1.8 g. 12 benzodioxanyl carbonyl, alkylthiooxadiazole carbonyl, mmol) is added and the mixture is heated to reflux and hydroxy alkoxy carbonyl alkenyl and alkyroyl. maintained for ten minutes. The reaction is cooled to room temperature and 3,4-dimethoxyanthranilonitrile (1.78 g, 10 2. A compound of claim 1 of the formula: II mmol) is added and the mixture is brought to reflux and maintained for 24 hours. Water (30 mL) is added and with II vigorous stirring the mixture is basified to pH=10 with R dropwise addition of 10% NaOH. The layers are separated H and the aqueous phase is further extracted with four portions 35 R1O s (10 mL) of dichloroethane. The organic extracts are com bined and filtered through a bed of celite. The filtrate is dried RO r CN O over Na2SO, concentrated under reduced pressure and applied to a silica gel column (25 cmx2.5 cm). It is then 40 eluted initially with ethyl acetate and the polarity is gradu wherein R is Selected from the group consisting of hydrogen ally increased with ethanol to a final solvent ratio of 80:20. Fractions containing the product (TLC: 80:20 ethyl and alkoxy and R and R are each alkyl. acetate:methanol, R=0.37) are combined and concentrated 3. A compound of claim 1 of the formula: IV." under reduced preSSure. The pure product is crystallized 45 from a minimum Volume of ethyl acetate as white crystals IV" (0.35 g, 9.2% yeild). H "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, R1O N N O NH); 4.82–4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)): 3.98 r \) O O N (s, 3H, OCH), 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, 50 CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 RO CN (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 (tetrahydrofuroyl))). wherein R and R2 are each alkyl. EXAMPLE 21 55 4. A compound of claim 1 of the formula: IV." 2-4-2-Tetrahydrofuroylpiperazine-1-yl)-4-amino 6,7-dimethoxyquinazoline Hydrochloride Dihydrate IV it

(XI) H Terazosin free base (VII, 3.87g, 10 mmol) was suspended 60 R1O N N O in 20 mL hot isopropanol and concentrated hydrochloric \) O acid (5 mL) was added. A solution was obtained which was O N concentrated to dryneSS under reduced pressure. Isopropanol RO CN (20 mL) was then added and the resulting Suspension was brought to reflux and then cooled to room temperature. The 65 slurry was filtered and washed with a small volume of isopropanol. Yield 4.1 g (90% yield), mp. 271-273. wherein R and R are each alkyl. 6,080,860 49 SO 5. A compound of claim 1 of the formula IV: group consisting of hydrogen, alkyl and a group 2-cyano 4,5-dialkoxy phenyl group optionally Substituted in the IV 6-position by an alkoxy group and wherein R and R are R each Selected from the group consisting of hydrogen, pro R r 3 Vided R. and R are not hydrogen when R, is hydrogen, and lower alkyl or R and R together with the nitrogen to which R1O Hs - they are attached form a closed heterocyclic ring optionally O containing a Second nitrogen, the closed heterocyclic ring RO CN being Substituted on the optional Second nitrogen by a member Selected from the group consisting of unsubstituted or Substituted furoyl, benzodioxanyl carbonyl, lower alky wherein R, R, R n and R are Selected from the chart as lthiooxadiazole carbonyl, hydroxy alkoxy carbonyl, alkenyl follows: and alkyroyl. 15 7. A compound of claim 6 of the formula V" R R R Rs vil H Me Me 1. f \ R1O N N O N O O O N O RO CN n EP

H Me Me 1. 25

O wherein -O-EP is the reaction product of the urea oxygen and an electrophile, EP, and is a leaving group Substitutable O by NH2 or a primary or Secondary amino group and wherein H Me Me 1. O R and R2 are each alkyl. 8. A compound of claim 6 of the formula V" C C will O 35 R1O N N O H Me Me 1 O n O RO CNYO EP N O - O s 40 O OMe Me Me 1. O wherein -O-EP is the reaction product of the urea oxygen lsO Me OH 45 and an electrophile, EP, and is a leaving group Substitutable Me by -NH2 or a primary or Secondary amino group and wherein R and R2 are each alkyl. H Me Me 1. N-1s 9. A compound of claim 6 of the formula V 50 H Me Me 2 O

R1O N N 55 s O RO CN YEP

60 wherein -O-EP is the reaction product of the urea oxygen wherein -O-EP is the reaction product of the urea oxygen and an electrophile, EP, EP and is a leaving group Substi and an electrophile, EP and forms a leaving group Substi tutable by -NH2 or a primary or Secondary amino group tutable by -NH2 or a primary or Secondary amino group 65 wherein EP is selected from POCl, PCls, POs, mesyl and wherein R, R., R., n and R are Selected from the chart chloride and tosyl chloride, wherein R, is selected from the as follows: 6,080,860 S1 52

II R R R. R. n Rs H R1O N NH2 H Me Me 1 W \ 5 O O RO CN O H Me Me 1 1O in the presence of Pyridine- 0 and compound (III) of the formula

O III O 15 y \ H Me Me 1 HN N-R,

.DO 20 to give compound (IV) of the formula O IV H Me Me 1 O R y \ N-N H W \ 25 R1O N N N-R

O SCH 3 rO RO CN OMe Me Me 1. O

ls O Me wherein R, R, R2, n and R, are defined in the chart as OH follows: Me

H Me Me 1. N-1s 35 R R. R. n Rs H Me Me 2 O H Me Me 1 W \ --~. 40 O O 10. A process comprising: H Me Me 1. I R 45 O R1O NH2 O

O RO CN 50 O with a compound of the formula H-N=C=O to give O compound (II) of the formula O

55 H Me Me 1 N-N II / \ R H O > R1O N NH2 O SCH

RO CN OMe Me Me 1 O als Me wherein R is Selected from hydrogen and alkoxy and R and O ~kOH R2 are each alkyl. 65 Me 11. A process comprising: refluxing compound (II) of the formula 6,080,860

-continued R R. R. n Rs

H Me Me 1. N-1s

H Me Me 2 O

12. The process comprising: reacting compound (IV) of 15 the formula

IV R y V R1O N N N-R

O RO CN

25 in the presence of an electrophile, EP, wherein EP is selected from the group consisting of POCl, PO, PCls and TSC1, to OMe give compound (V) of the formula

R yn V R1O N N N-R s V W O RO CN YEP

40 wherein -O-EP is the reaction product of the urea oxygen and EP and is a leaving group Substitutable by -NH2 or a primary or Secondary amino group and wherein R. R, R2, n and R are defined in the chart as follows: