Title of Invention	A PROCESS FOR THE SYNTHESIS OF SUBSTITUTED 2,4,5-TRIAMINO-8-CHLOROPYRIMIDO-[4,5-B] QUINOLINES AS NOVEL ANTIMALARIALS
Abstract	A process for preparation of substituted 2,4,5-triamino-8-chloropyrimido-[4,5-blquinolines, formula (h) as given in the drawing (sheet no. 1) comprising the following steps, step (i) refluxing guanidine nitrate, formula (a) with malononitrile, formula (b) in presence of sodium alkoxide for four to eight hours to yield 2,4,6-triaminopyrimidine, formula (c), step (ii) condensing the resultant product of step (i) with 2,4-dichlorobenzoic acid, formula (d) in presence of freshly prepared copper powder at 145°-185°C for seven to nine hours to yield N-(2,4-diamino-6-pyrimidino)-4-chloroanthranilic acid, formula (e), step (iii) cyclizing the resultant product of step (ii) with concentrated sulphuric acid at 85°-100°C for four to six hours to yield 5-oxo-(10H)-2,4-diamino-8-chloropyrimido-[4,5-b]quinoline, formula (f), step (iv) chlorination of the product of step (iii) using redistilled phosphorous oxychloride at 110M50°C for six to nine hours to yield 2,4-diamino-5,8-dichloropyrimido-[4,5-b]quinoline, formula (g), step (v) condensing the product of step (iv) with amines (R-NH2) to yield compounds of general formula (h) wherein and R.2 = H, alkyl, aryl, heteroaryl, alkylaryl and R3 and R4 are identical or different and represent H, alkyl, aminoalkyl and heteroaryl.

Title of Invention

A PROCESS FOR THE SYNTHESIS OF SUBSTITUTED 2,4,5-TRIAMINO-8-CHLOROPYRIMIDO-[4,5-B] QUINOLINES AS NOVEL ANTIMALARIALS

Abstract

A process for preparation of substituted 2,4,5-triamino-8-chloropyrimido-[4,5-blquinolines, formula (h) as given in the drawing (sheet no. 1) comprising the following steps, step (i) refluxing guanidine nitrate, formula (a) with malononitrile, formula (b) in presence of sodium alkoxide for four to eight hours to yield 2,4,6-triaminopyrimidine, formula (c), step (ii) condensing the resultant product of step (i) with 2,4-dichlorobenzoic acid, formula (d) in presence of freshly prepared copper powder at 145°-185°C for seven to nine hours to yield N-(2,4-diamino-6-pyrimidino)-4-chloroanthranilic acid, formula (e), step (iii) cyclizing the resultant product of step (ii) with concentrated sulphuric acid at 85°-100°C for four to six hours to yield 5-oxo-(10H)-2,4-diamino-8-chloropyrimido-[4,5-b]quinoline, formula (f), step (iv) chlorination of the product of step (iii) using redistilled phosphorous oxychloride at 110M50°C for six to nine hours to yield 2,4-diamino-5,8-dichloropyrimido-[4,5-b]quinoline, formula (g), step (v) condensing the product of step (iv) with amines (R-NH2) to yield compounds of general formula (h) wherein and R.2 = H, alkyl, aryl, heteroaryl, alkylaryl and R3 and R4 are identical or different and represent H, alkyl, aminoalkyl and heteroaryl.

Full Text	GRANTED 19/4/2004 FORM-2 THE PATENTS ACT, 1970 COMPLETE SPECIFICATION SECTION 10 TITLE : A PROCESS FOR THE SYNTHESIS OF SUBSTITUTED 2,4,5-TRIAMINO-8-CHLOROPYRIMIDO-[4,5-B] QUINOLINES AS NOVEL ANTIMALARIALS. APPLICANT (S) : CHELAKARA LAKSHMANAN VISWANATHAN, 1, LALIT, UTTAM SOCIETY, ST.ANTONY ROAD, CHEMBUR, MUMBAI 400 071, MAHARASHTRA, INDIA, JOSHIADVAIT ARUN, 108, PARIMAL SOCIETY, R.B. MEHTA ROAD, GHATKOPAR (E), MUMBAI 400 077, MAHARAHSTRA, INDIA & NARKHEDE SACHIN SURESH, C/O. S.G. NARKHEDE, SUHAS NAGAR, SOUTH OF NEB COLONY, JAMNER ROAD, BHUSAWAL 425 201. ALL INDIAN NATIONALS. The following Specification particularly describes the nature of this invention and the manner in which it is to be performed: - The present invention relates to the process for synthesis of a novel series of compounds with 2,4,5-triamino-8-chloropyrimido-[4,5-b]quinoline as the basic nucleus with a general formula as given below. in which where and R2 = H, alkyl, aryl, heteroaryl, alkylaryl and R3 and R4 are identical or different and independently of one another represent H, alkyl, aminoalkyl and heteroaryl. The process for the synthesis of substituted 2,4,5-triarnino-8-chloropyrirnido-[4,5-bjquinolines, formula (h), sheet no. 1, involved reacting guanidine nitrate, formula (a) with malononitrile, formula (b) in presence of alkali metal alkoxides in absolute alcohol to yield 2,4,6-triaminopyrimidine, formula (c), which was then condensed with 2,4-dichlorobenzoic acid, formula (d) in presence of copper catalyst(s) to form an intermediate, formula (e), which was cyclized with cone. H2SO4 and chlorinated with phosphorous oxychloride to yield 2,4-diamino-5,8-dichloropyrimido-[4,5-b]quinoline, formula (g), which on heating with substituted amines in solvents like pyridine, DMF and DMSO gave substituted 2,4,5-triamino-8-chloropyrimido-[4,5-b]quinolines, formula (h). The synthesized compounds were evaluated for antimalarial activity using Rane's test of blood schizonticidal activity in mice infected with Plasmodium berghei. All the compounds tested exhibited antimalarial activity. One of the compounds where exhibited mean survival time greater than 60 days at the doses studied (10, 20, 40, 80 & 160 mg/kg) while the standard drug chloroquine phosphate was studied at a single dose of 20 mg/kg and it exhibited a mean survival time of 16 days indicating that the above referred compound exhibits curative activity. On toxicological evaluation, the maximum tolerated dose for this compound was found to be 1.5 gms/kg when administered via the subcutaneous route in mice. Prior art: Synthesis of 3,10-disubstituted pyrimido-[4,5-b]quinoline has been reported (Ref: Yoneda F., "New synthesis of 5-deazaflavins", J. C. S., Chem. Commun., 1976, 203-204). For example, 3,10-dimethylpyrimido-[4,5-b]quinoline-3H,10H-2,4-dione was prepared by reacting 3-methyl-6-(N-methylanilino)uracil with a mixture of phosphorous oxychloride and N,N-dimethylforrnarnide at 90°C for 2 hours. The following example illustrates the process according to the present invention. Example 1: Synthesis of 5-[4'-aminobenzenesulfonamido]-2,4-diamino-8-chloropyrimido- [4,5-b]quinoline: Step (i): Synthesis of 2,4,6-triarninopyrimidine: To a solution of sodium ethoxide (0.2 M) in 150-170 ml absolute alcohol was added guanidine nitrate 25 gms (0.2 M) and malononitrile 13.5 gms (0.2 M). The mixture was refluxed for 4-8 hours. The reaction mixture was cooled and the product formed was filtered off, washed with three twenty milliliters of absolute alcohol and recrystallized using water as a solvent and dried. Yield: 20 gms (78%), m.p.: 249-251°C. Step (ii): Synthesis of N-(2,4-diamino-6-pyrirridino)-4-chloroanthranilic acid: A mixture of 2,4,6-triaminopyrimidine 10 gms (0.08 M), 15.2 gms (0.08 M) 2,4-dichlorobenzoic acid and 0.5-1 gm of freshly prepared copper powder was heated at 145— 185°C for 7-9 hours and the reaction mixture was extracted with dilute sodium hydroxide solution. The solution was filtered and the filtrate was neutralized with hydrochloric acid. The precipitate formed was filtered and washed with water till filtrate is neutral to litmus. The crude product formed was recrystallized from chloroform-benzene mixture (7:3). Yield: 14 gms (66.6%), mp.: 181°C. Step (iii): Synthesis of 5-oxo-(10H)-2,4-diarnino-8-chloropyrimido-[4,5-b]quinoline: N-(2,4-diamino-6-pyrimidino)-4--Moroanthranilic acid 10 gms (0.035 M) and 12-21 ml of concentrated sulphuric acid were heated at 85-100°C for 4-6 hours. The resulting solution was poured carefully into a mixture of crushed ice and water and the solution neutralized by using aqueous alkali. The product that precipitated was recrystallized using chloroform-benzene mixture (9:1) as the solvent. Yield: 7 gms (74%), mp.: 160°C. Step (iv): Synthesis of 2,4-diamino-5,8-dicholoropyrimido-[4,5-b]quinoline: The product of step (iii), 6 gms (0.02 M) and redistilled phosphorous oxychloride, 15-17 ml was heated at 110°C-150°C for 6-9 hours. Excess of phosphorous oxychloride was then removed under reduced pressure and ammonia-water mixture was added to the reaction mixture. The resulting solid was washed repeatedly with small portions of cold water and then recrystallized using benzene-chloroform (1:1) solvent system. Yield: 4.3 gms (67%), mp.: 151°C. Step (v): Synthesis of 5-[4'-aminobenzenesulfonamido]-2,4-diamino-8-chloropyrimido-[4,5-b]quinoline: A mixture of 4 gms (0.014 M) of 2,4-d-amino-5,8-dichloropyrimido-[4,5-b]quinoline and 2.4 gms (0.014 M) of 4-aminobenzenesulfonamide in 10-21 ml dry, distilled pyridine was stirred and refluxed for 3-6 hours. The resulting solution was then poured into 50 ml cold water. The solid that separated was filtered and recrystallized using water as the solvent. Yield: 3.5 gms (60%), mp.: 159°C. 4. We claim: where, 1. A process for preparation of substituted 2,4,5-triamino-8-chloropyrimido-[4,5-blquinolines, formula (h) as given in the drawing (sheet no. 1) comprising the following steps, step (i) refluxing guanidine nitrate, formula (a) with malononitrile, formula (b) in presence of sodium alkoxide for four to eight hours to yield 2,4,6-triaminopyrimidine, formula (c), step (ii) condensing the resultant product of step (i) with 2,4-dichlorobenzoic acid, formula (d) in presence of freshly prepared copper powder at 145°-185°C for seven to nine hours to yield N-(2,4-diamino-6-pyrimidino)-4-chloroanthranilic acid, formula (e), step (iii) cyclizing the resultant product of step (ii) with concentrated sulphuric acid at 85°-100°C for four to six hours to yield 5-oxo-(10H)-2,4-diamino-8-chloropyrimido-[4,5-b]quinoline, formula (f), step (iv) chlorination of the product of step (iii) using redistilled phosphorous oxychloride at 110M50°C for six to nine hours to yield 2,4-diamino-5,8-dichloropyrimido-[4,5-b]quinoline, formula (g), step (v) condensing the product of step (iv) with amines (R-NH2) to yield compounds of general formula (h) wherein and R.2 = H, alkyl, aryl, heteroaryl, alkylaryl and R3 and R4 are identical or different and represent H, alkyl, aminoalkyl and heteroaryl. 2. A method as claimed in claim 1, wherein 3. A method as claimed in claim 1, wherein the alkoxide is methoxide, ethoxide, propoxide or butoxide. 4. A method as claimed in claim 1, wherein the catalyst is activated copper bronze. 5. A method as claimed in claim 1, wherein the solvents used are anhydrous pyridine, DMF or DMSO. Dated this 16 th day of June / 2003. Signatures (Chelakara Lakshmanan Viswanathan) (Joshr Advait Arun) (Narkhede Sachin Suresh).

Full Text

GRANTED
19/4/2004

FORM-2 THE PATENTS ACT, 1970
COMPLETE
SPECIFICATION
SECTION 10

TITLE : A PROCESS FOR THE SYNTHESIS OF SUBSTITUTED 2,4,5-TRIAMINO-8-CHLOROPYRIMIDO-[4,5-B] QUINOLINES AS NOVEL ANTIMALARIALS.

APPLICANT (S) : CHELAKARA LAKSHMANAN VISWANATHAN,
1, LALIT, UTTAM SOCIETY, ST.ANTONY ROAD, CHEMBUR, MUMBAI 400 071, MAHARASHTRA, INDIA,
JOSHIADVAIT ARUN, 108, PARIMAL SOCIETY, R.B. MEHTA ROAD, GHATKOPAR (E), MUMBAI 400 077, MAHARAHSTRA, INDIA &
NARKHEDE SACHIN SURESH, C/O. S.G. NARKHEDE, SUHAS NAGAR, SOUTH OF NEB COLONY, JAMNER ROAD, BHUSAWAL 425 201. ALL INDIAN NATIONALS.
The following Specification particularly describes the nature of this invention and the
manner in which it is to be performed: -

The present invention relates to the process for synthesis of a novel series of compounds with 2,4,5-triamino-8-chloropyrimido-[4,5-b]quinoline as the basic nucleus with a general formula as given below.

in which

where

and

R2 = H, alkyl, aryl, heteroaryl, alkylaryl
and
R3 and R4 are identical or different and independently of one another represent H, alkyl, aminoalkyl and heteroaryl.
The process for the synthesis of substituted 2,4,5-triarnino-8-chloropyrirnido-[4,5-bjquinolines, formula (h), sheet no. 1, involved reacting guanidine nitrate, formula (a) with malononitrile, formula (b) in presence of alkali metal alkoxides in absolute alcohol to yield 2,4,6-triaminopyrimidine, formula (c), which was then condensed with 2,4-dichlorobenzoic acid, formula (d) in presence of copper catalyst(s) to form an intermediate, formula (e), which was cyclized with cone. H2SO4 and chlorinated with phosphorous oxychloride to yield 2,4-diamino-5,8-dichloropyrimido-[4,5-b]quinoline, formula (g), which on heating with substituted amines in solvents like pyridine, DMF and DMSO gave substituted 2,4,5-triamino-8-chloropyrimido-[4,5-b]quinolines, formula (h).

The synthesized compounds were evaluated for antimalarial activity using Rane's test of blood schizonticidal activity in mice infected with Plasmodium berghei. All the compounds tested exhibited antimalarial activity. One of the compounds where

exhibited mean survival time greater than 60 days at the doses studied (10, 20, 40, 80 & 160 mg/kg) while the standard drug chloroquine phosphate was studied at a single dose of 20 mg/kg and it exhibited a mean survival time of 16 days indicating that the above referred compound exhibits curative activity. On toxicological evaluation, the maximum tolerated dose for this compound was found to be 1.5 gms/kg when administered via the subcutaneous route in mice.
Prior art:
Synthesis of 3,10-disubstituted pyrimido-[4,5-b]quinoline has been reported (Ref: Yoneda F., "New synthesis of 5-deazaflavins", J. C. S., Chem. Commun., 1976, 203-204). For example, 3,10-dimethylpyrimido-[4,5-b]quinoline-3H,10H-2,4-dione was prepared by reacting 3-methyl-6-(N-methylanilino)uracil with a mixture of phosphorous oxychloride and N,N-dimethylforrnarnide at 90°C for 2 hours.
The following example illustrates the process according to the present invention.
Example 1: Synthesis of 5-[4'-aminobenzenesulfonamido]-2,4-diamino-8-chloropyrimido-
[4,5-b]quinoline:
Step (i): Synthesis of 2,4,6-triarninopyrimidine:
To a solution of sodium ethoxide (0.2 M) in 150-170 ml absolute alcohol was added
guanidine nitrate 25 gms (0.2 M) and malononitrile 13.5 gms (0.2 M). The mixture was
refluxed for 4-8 hours. The reaction mixture was cooled and the product formed was filtered
off, washed with three twenty milliliters of absolute alcohol and recrystallized using water as a
solvent and dried.
Yield: 20 gms (78%), m.p.: 249-251°C.

Step (ii): Synthesis of N-(2,4-diamino-6-pyrirridino)-4-chloroanthranilic acid: A mixture of 2,4,6-triaminopyrimidine 10 gms (0.08 M), 15.2 gms (0.08 M) 2,4-dichlorobenzoic acid and 0.5-1 gm of freshly prepared copper powder was heated at 145— 185°C for 7-9 hours and the reaction mixture was extracted with dilute sodium hydroxide solution. The solution was filtered and the filtrate was neutralized with hydrochloric acid. The precipitate formed was filtered and washed with water till filtrate is neutral to litmus. The crude product formed was recrystallized from chloroform-benzene mixture (7:3). Yield: 14 gms (66.6%), mp.: 181°C.
Step (iii): Synthesis of 5-oxo-(10H)-2,4-diarnino-8-chloropyrimido-[4,5-b]quinoline: N-(2,4-diamino-6-pyrimidino)-4--Moroanthranilic acid 10 gms (0.035 M) and 12-21 ml of concentrated sulphuric acid were heated at 85-100°C for 4-6 hours. The resulting solution was poured carefully into a mixture of crushed ice and water and the solution neutralized by using aqueous alkali. The product that precipitated was recrystallized using chloroform-benzene mixture (9:1) as the solvent. Yield: 7 gms (74%), mp.: 160°C.
Step (iv): Synthesis of 2,4-diamino-5,8-dicholoropyrimido-[4,5-b]quinoline: The product of step (iii), 6 gms (0.02 M) and redistilled phosphorous oxychloride, 15-17 ml was heated at 110°C-150°C for 6-9 hours. Excess of phosphorous oxychloride was then removed under reduced pressure and ammonia-water mixture was added to the reaction mixture. The resulting solid was washed repeatedly with small portions of cold water and then recrystallized using benzene-chloroform (1:1) solvent system. Yield: 4.3 gms (67%), mp.: 151°C.
Step (v): Synthesis of 5-[4'-aminobenzenesulfonamido]-2,4-diamino-8-chloropyrimido-[4,5-b]quinoline:
A mixture of 4 gms (0.014 M) of 2,4-d-amino-5,8-dichloropyrimido-[4,5-b]quinoline and 2.4 gms (0.014 M) of 4-aminobenzenesulfonamide in 10-21 ml dry, distilled pyridine was stirred and refluxed for 3-6 hours. The resulting solution was then poured into 50 ml cold water. The solid that separated was filtered and recrystallized using water as the solvent. Yield: 3.5 gms (60%), mp.: 159°C.

4. We claim:
where,

1. A process for preparation of substituted 2,4,5-triamino-8-chloropyrimido-[4,5-blquinolines, formula (h) as given in the drawing (sheet no. 1) comprising the following steps, step (i) refluxing guanidine nitrate, formula (a) with malononitrile, formula (b) in presence of sodium alkoxide for four to eight hours to yield 2,4,6-triaminopyrimidine, formula (c), step (ii) condensing the resultant product of step (i) with 2,4-dichlorobenzoic acid, formula (d) in presence of freshly prepared copper powder at 145°-185°C for seven to nine hours to yield N-(2,4-diamino-6-pyrimidino)-4-chloroanthranilic acid, formula (e), step (iii) cyclizing the resultant product of step (ii) with concentrated sulphuric acid at 85°-100°C for four to six hours to yield 5-oxo-(10H)-2,4-diamino-8-chloropyrimido-[4,5-b]quinoline, formula (f), step (iv) chlorination of the product of step (iii) using redistilled phosphorous oxychloride at 110M50°C for six to nine hours to yield 2,4-diamino-5,8-dichloropyrimido-[4,5-b]quinoline, formula (g), step (v) condensing the product of step (iv) with amines (R-NH2) to yield compounds of general formula (h) wherein

and
R.2 = H, alkyl, aryl, heteroaryl, alkylaryl
and
R3 and R4 are identical or different and represent H, alkyl, aminoalkyl and heteroaryl.

2. A method as claimed in claim 1, wherein

3. A method as claimed in claim 1, wherein the alkoxide is methoxide, ethoxide, propoxide or butoxide.
4. A method as claimed in claim 1, wherein the catalyst is activated copper bronze.
5. A method as claimed in claim 1, wherein the solvents used are anhydrous pyridine, DMF or DMSO.
Dated this 16 th day of June / 2003.
Signatures
(Chelakara Lakshmanan Viswanathan)
(Joshr Advait Arun)
(Narkhede Sachin Suresh).

Documents:

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627-mum-2003-claims(granted)-(19-04-2004).pdf

627-mum-2003-correspondence(16-06-2003).pdf

627-mum-2003-correspondence(ipo)-(03-05-2007).pdf

627-mum-2003-form 1(16-06-2003).pdf

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627-mum-2003-form 2(granted)-(19-04-2004).pdf

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Patent Number

206568

Indian Patent Application Number

627/MUM/2003

PG Journal Number

30/2007

Publication Date

27-Jul-2007

Grant Date

03-May-2007

Date of Filing

16-Jun-2003

Name of Patentee

CHELAKARA LAKSHMANAN VISWANATHAN

Applicant Address

1, LALIT, UTTAM SOCIETY, ST. ANTONY ROAD, CHEMBUR, MUMBAI.

Inventors:

#	Inventor's Name	Inventor's Address
1	CHELAKARA LAKSHMANAN VISWANATHAN	1, LALIT, UTTAM SOCIETY, ST. ANTONY ROAD, CHEMBUR, MUMBAI - 400 071.
2	JOSHI ADVAIT ARUN	108, PARIMAL SOCIETY, R.B.MEHTA ROAD, GHATKOPAR(E), MUMBAI.
3	NARKHEDE SACHIN SURESH	C/O S.G.NARKHEDE, SUHAS NAGAR, SOUTH OF NEB COLONY, JAMNER ROAD, BHUSAWAL

PCT International Classification Number

A61K 31/47

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA