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Publication numberUS3862189 A
Publication typeGrant
Publication dateJan 21, 1975
Filing dateAug 14, 1973
Priority dateAug 14, 1973
Publication numberUS 3862189 A, US 3862189A, US-A-3862189, US3862189 A, US3862189A
InventorsCharles F Schwender
Original AssigneeWarner Lambert Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Aralkyl-substituted purines and pyrimidines as antianginal bronchodilator agents
US 3862189 A
Abstract
The present invention relates to compounds of formula I:
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Description  (OCR text may contain errors)

United States Patent n91 Schwender Jan. 21, 1975 1 ARALKYL-SUBSTITUTED PURINES AND PYRIMIDINES AS ANTIANGINAL BRONCHODILATOR AGENTS [75] Inventor: Charles F. Schwender, Lebanon,

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: Aug. 14, 1973 [21] Appl. No.: 388,290

[52] US. Cl 260/252, 260/253, 260/254, 260/256.4 N, 424/253 [51] Int. Cl C07d 57/38 [58] Field of Search 260/252, 253, 254

[56] References Cited UNITED STATES PATENTS 3,412,093 11/1968 Podesva et al 260/252 Primary Examiner-Donald G; Daus Assistant Examiner-Anne Marie T. Tighe Attorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow [57] ABSTRACT The present invention relates to compounds of for mula 1:

These compounds are useful as antianginal or bronchial dilator agents.

20 Claims, No Drawings ARALKYL-SUBSTITUTED PURIN AND PYRIMIDINES AS ANTIANGINAL BRONCHODILATOR AGENTS The present invention is concerned with novel compounds and. more particularly, the present invention is concerned with aralkyLsubstituted purines and pyrimidines having structural formula l:

wherein R is hydroxy, methoxy, mercapto, hydrazino, substituted hydrazino, chloro, amino, alkylamino, dialkylamino, hydroxyalkylamino, aralkylamino or substituted aralkylamino and R is phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety and at least two alkoxy, alkyl, halogen, hydroxy, nitro, amino, substituted amino, aminomethyl, acylamino, carboxy, carboxyalkyl or hydroxymethyl groups in the benzene ring or naphthylalkyl, tetrahydronaphthylalkyl, quinolylalkyl, tetrahydroquinolylalkyl or isoquinolylalkyl, each having 1 to 3 carbon atoms in the alkyl moiety and pharmaceutically acceptable acid addition salts thereof.

In addition, esters or amides of the above compounds utilizing alkanoyl or aralkanoyl, such as acetyl, propionyl, benzoyl, succinoyl and the like, and the pharmaceutieally acceptable acid addition salts are also within the scope of this invention.

In the above definitions for R the term alkyl means an aliphatic hydrocarbon having I to 6 carbon atoms, for example, methyl, propyl, isopropyl, isobutyl and the like. The term aryl denotes an aromatic hydrocarbon having 6 to l4 carbon atoms, for example, phenyl, naphthyl, anthryl and the like. The term aralkyl designates a combination of the hereinbefore defined alkyl and aryl groups. Substituted hydrazino denotes hydrazino substituted on either nitrogen atom or both nitrogen atoms by one or more alkyl or aryl groups.

In the above definitions for R the term alkyl stands for an aliphatic hydrocarbon of l to 6 carbon atoms, unless otherwise specified, and applies to the alkyl residues of the alkoxy and acyl moieties. Substituted amino includes within its scope amino groups substituted by alkyl and aryl groups defined in the preceding paragraph. Halogen encompasses all of the halo groups, chloro, bromo, iodo and fluoro.

Among the preferred compounds of this invention are those purine derivatives wherein R is chloro, amino, hydroxy, hydrazino, n-propylamino or 2- hydroxyethylamino and R is dimethoxybenzyl and R, is amino and R is dichlorobenzyl, 3,4-dimethylbenzyl.

The compounds of this invention exhibit a unique mode ofbiological action in that they produce selective dilation of certain coronary arteries causing a redistribution of blood flow towards isehemic areas of the heart enhancing perfusion and reducing anoxia which cause anginal pains. This biological activity is demonstrated in accordance with the procedure described in J. Pharmacol. Exp. Ther., l76,l84 (1971). Only nitroglycerin and some B-adrenergic blockers have been demonstrated to similarly redistribute blood flow to ischemic areas by large coronary artery dilation. See Eur. J. Pharmacol., I6, 271 (1971 The compounds of this invention offer an advantageous treatment of angina without interference with adrenergic control of the heart or without resorting to the use of nitrates.

Existing coronary vasodilators such as dipyridamole and chromonar dilate smaller vessels increasing coronary blood flow without redistributing flow to needed ischemic areas. In severe ischemia, dipyridamole actually induced anginal attacks in man since it diverted blood flow away from ischemic areas through its dilator action on smaller coronary vessels. See Ann. Rep. Med. Chem, 7, 69 (i972).

Experimentally, this blood flow redistribution is demonstrable in a dog by measuring changes in resistance to blood flow of larger coronary arteries (RL) relative to small vessel physical resistance to flow (RT), using the protocol described in J. Pharmacol. Exp. Ther.. 176, 184(1971).

Generally, the compounds of this invention at a dose of about 1-10 mg/kg were observed to effect a drop in the RLzRT ratio. Known coronary vasodilators such as dipyridamole and chromonar caused an increased RLzRT ratio reflecting a redistribution of blood flow away from ischemic tissues.

The compounds of this invention, particularly the preferred species, are indicated in the management of angina pectoris. A usual dose of l-lO mg/kg by injection or orally two or three times daily is suggested to prevent anginal attack. These compounds can be ad- ,ministered by combining with excipients such as lactose or water for injection.

In addition to the antianginal effects described above, the compounds of this invention were also observed to protect guinea pigs from histamine-induced bronchial spasm. Thus tested in accordance with the procedure described in J. Pharmacol. Exp. Ther., 90, 254 (1947) at a dose of 1-50 mg/kg intraperitoneally, they were effective to protect the guinea pigs against bronchial spasms which had been induced by the administration of one mg of histamine. At this dosage level, a mild cardiotonic effect was also observed. Hence, the compounds of this invention are also useful in the treatment of bronchial spasms such as in bronchial asthma. Generally'speaking, a dose of 1-50 mg/kg administered orally or by intramuscular injection is suggested.

According to the present invention, the above compounds are prepared by processes as illustrated in the following reaction scheme:

Method A N'H; Method B N/ k I m I N RZNHZ Nl/ \NHRZ (ECO) sCH l N II or R (MeO) CH III 2 Method C Method D Nucleophile N I to I 2 Referring now to the reaction scheme. in Method A 5-amino-4,6-dichloropyrimidine is condensed with a substituted amine in butanol and triethylamine. The resultant substituted amino pyrimidine II is cyclizcd with triethyl or trimethyl orthoformate to the 6- chloropurine derivative III as in Method B. Treating said 6-chloropurine derivative with ammonia as brought out in Method C, or an appropriate nucleophile as in Method D, gives the (a-substituted purine derivative l.

The starting material for the first process, S-amino- 4.6-dichloropyrimidine is available from commercial chemical suppliers such Krishell Laboratories, Inc. The amino compounds utilized in Method A, triethyland trimethyl orthoformate of Method B and the nucleophiles of Method D are available from the Aldrich Chemical Company or readily preparedby methods well known to those skilled in the art.

In addition, treatment of adenine with a substituted benzyl or aralkyl halide in the presence of a base such as sodium hydride gives the desired 9-substituted adenine directly. This reaction is illustrated by the following reaction scheme:

NH: Method E )I 51:? R x \N a, 2 R

Adenine, the starting material for the second process is commercially available from the Aldrich Chemical Company as are the requisite aralkyl halides. R- X.

The following experiments are general procedures for the preparation of the compounds olthis invention: all temperatures are in degrees Centigrade.

TABLE I Recrystallization R Formula Analysis* moC- Solvent Method Preparation Ci H ',ClN, 0; citNcl 188-191 MeOH/H=O A ocii ocii 8}: C H CINaO= cuacl 133-135 neon/1120 A OCH, 0011, v cuiiucmt CHNCl 219-223 MeOH/H;O A

C: 0 nac m ciiucl 197-19s.5 MOE/H 0 A *Cenpountls reported analyzed with in :OJrZ of theory.

percent); P l 21f' REFERENCES l. M. M. Winhury, B. B. Howe, H. R. Weiss. J. Pharmacol. Exp. Then, I76, 184 (1971).

2. M. M. Winbury. H. R. Weiss and B. B. Howe. Eur. J. PharmaeoL, 16. 271 (1971).

3. H. R. Weiss and M. M. Winhury, Fed. Proc., 30 (2) 631 (1971). 4. O. Mantcro and F. Conti, Circulatory Drugs, A. Bcrtelli. ed. pp

| 18-123. NorthHolland, Amsterdam, The Netherlands, 1969.

5. C. F. Schwcnder. Antianginal Agents, Ann. Rep. Med. Chem, 7. 69. R. V. Heinzelmann, ed. Academic Press. New York, 1972.

6. O. H. Siegmuhd, H. R. Granger and A. M. Lands. J. Pharmacol. Exp. Ther., 90. 254 (1947).

METHOD A crystallized by trituration with water. The crude yellow' solid was recrystallized from methanol-water to give 1.61 g (90.1 percent), mp 185-l88, of crystalline product. The analytical sample was obtained by recrystallization from methanol-water; yield, 1.36 g (76.9

METHOD B 6-Chloro-9-(3.4-dimethoxybenzyl)purine. To a suspension of 15.6 g (52.8 mmols) of 5-amino-4-chloro-6- (3.4-dimethoxybenzylamino)-pyrimidine in 100 ml of triethyl orthoformate was added 149 mg 1.36 mmols) oi ethanesulfonic acid and the resulting mixture was heated at 80 for min. Upon cooling and addition of hexane to the reaction mixture, a yellow precipitate formed which was collected by filtration; yield, 15.4 g (95.6 percent) mp l '59l63. Recrystallization from EtOH H O gave the analytical sample;-yield 13.2 g (82.2 percent) mp l60l64.

METHOD C METHOD D 6-Propylamino-9-veratrylpurine. A reaction mixture containing 5.14 g (16.8 mmol) of 6-chloro-9- veratrylpurine. 7.0 ml (84.9 mmol) of propylamine and 60 ml of EtOH was refluxed for 2.5 hrs. Evaporation of the reaction mixture gave a residual solid which was recrystallized from acetone togive the crude product; yield 4.78 g (87.0 percent) mp 1l.7-120. Further re crystallizations of the crude white material from acetone gave the analytical materialymp 122-l25.

METHOD E 9-(3,4-Dimethylbenzyl)adenine (W10,813). An ice cold suspension containing adenine (10.0 g, 74 mmol), 3.74 g (89.0 mmol) of NaH (57 percent suspension in oil) and 120 ml of'DMF was allowed to reach RT and stirred for one additional hourf3,4-Dimethylbenzyl chloride 13.7g 89 mmol) was'added to the reaction I amino and R is l-naphthylmethyl.

crystallization from methanol; mp 21 1-213.

Anal. Calcd for C,,H,,-,N C, 66.38; H, 5.97; N, 27.65. Found: C, 66.38; H, 6.l0; N, 27.80.

' I claim:

1. A compound of the formula 1:

wherein R, is, chlori fl hydi'oiy mercapto, alkoxy of l to 6 carbon atoms, hydrazino, amino, amino substituted by one or two alkyl groups each of l to 6 carbon atoms, amino substituted by l-naphthylmethyl or benzyl, or hydroxy-alkylamino of l to 6 carbon atoms and R 15 l-naphthylmethyl; phenylmethyl. and phenylethyl substituted on the phenyl group by two or three alkoxy groups of l to 6 carbon atoms, 2 or 3 alkyl groupsot 1 to 6 carbon atoms, or two chloros and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 in which R, is methoxy and R is 3,4-dimethoxybenzyl.

3. A compound according to claim 1 in which R, is mercapto and R is 3,4-dimethoxybenzyl.

4. A compound according to claim 1 in which R, is l-naphthylmethylamino and R is 3,4- dimethoxybenzyl.

5. A compound according to claim 1 in which R, is amino and R is 3,4-dimethoxybenzyl 6. A compound according to claim 1 in which R, is hydroxy and R is 3,4-dimeth'oxybenzyl.

7. A compound according to claim 1 in which R, is benzylamino'and R is 3,4-dimethoxybenzyl.

8. A compound according to claim I in which R, is 2-hydroxyethylamino and R is 3.4-dimethoxybenzyl.

9. A compound according to claim 1 in which R, is chloro and R is 3,4-dimethoxyhenzyl.

10. A compound according to claim 1 in which'R, is hydrazino and R is 3,4-dimethoxybenzyl.

ll. A compound according to claim 1 in which R, is l-propylamino and R is 3,4-dimethoxybenzyl.

12. A compound according to claim 1 in which R, is chloro and R is 2-(3,4-dimethoxyphenyl)ethyl.

13. A compoundaccording to claim 1' in which R, is amino and R is 2-( 3,4-dimethoxyphenyl)ethyl.

14. A compound according to claim 1 in which R, is chloro and R is l-naphthylmethyl'.

l5. A compound according to claim 1 in which R, is

. l6. A compound according to claim 1 in which R, is propylamino and R is l-naphthylmethyl.

17. A compound according to claim 1 in which R, is l-hydroxyethylamino and R is l-naphthylmethyl.

18. A compound according to claim 1 in which R, is amino and R is 3,4-dimethylbenzyl..

19. A compound according to claim 1 in which R, is chloro and R is 3,4-dichlorobenzyl.

20. A compound according to claim 1 in which R, is

r, amino and R is 3,4-dichlorobenzyl.-

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3412093 *Dec 15, 1966Nov 19, 1968Delmar ChemNew adenine derivatives and method for their preparation
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3996361 *Dec 10, 1974Dec 7, 1976Boehringer Mannheim G.M.B.H.Antiedematous, reducing capillary permeability
US4221909 *Sep 15, 1978Sep 9, 1980Sloan-Kettering Institute For Cancer ResearchP-Acetamidobenzoic acid salts of 9-(hydroxyalkyl) purines
US4221910 *Sep 15, 1978Sep 9, 1980Newport Pharmaceuticals International, Inc.9-(Hydroxy alkyl)purines
US4241063 *Aug 6, 1979Dec 23, 1980Bristol-Myers CompanyPurine derivatives and their use as bronchodilators
US4269839 *Sep 13, 1979May 26, 1981Bristol-Myers CompanyMuscle relaxants and antispasmodic agents; respiratory system disorders
US4278675 *Sep 13, 1979Jul 14, 1981Bristol-Myers CompanyBronchodilating process
US4340726 *Mar 14, 1980Jul 20, 1982Newport Pharmaceuticals International, Inc.Purine compounds having immunomodulator, antiviral antitumor and enzyme inhibitor altivity
US4407802 *Sep 28, 1981Oct 4, 1983Merck & Co., Inc.Treatment of coccidiosis
US4634706 *Oct 25, 1984Jan 6, 1987Sankyo Company LimitedGriseolic acid derivatives, and their use as enzyme inhibitors
US4666914 *May 13, 1985May 19, 1987Schering CorporationAnti-inflammatory and anti-allergic substituted-2,3-dihydro-6-(hydroxy)pyrimido[2,1-f]-purine-4,8(1H,9H)-diones
US4816458 *Dec 19, 1986Mar 28, 1989Schering CorporationTopical administering
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US6316456 *Nov 29, 1996Nov 13, 2001Centre National De La Recherche ScientifiquePurine derivatives having, in particular, antiproliferative properties, and their biological uses
US6660745May 9, 2000Dec 9, 2003Mitsubishi Chemical CorporationPhosphodiesterase inhibitors; treatment of asthma, chronic obstructive pulmonary disease, inflammatory disorders
US6734187Jul 23, 2002May 11, 2004Mitsubishi Chemical CorporationPurine derivatives and medicaments comprising the same as active ingredient
US6919455Aug 1, 2003Jul 19, 2005Mitsubishi Chemical Corporation4-((9-((3-Cyclopentyloxy-4-methoxy)benzyl)-6,8 dimethylpurin)-2-yl-3-oxypropyl)pyridine N-oxide chemical intermediate; phosphodiesterase inhibitors; antiasthmatic and antiinflammatory agents; chronic obstructive pulmonary disease
US8163762Dec 23, 2009Apr 24, 2012Centre National De La Recherche Scientifique (Cnrs)Purine derivatives having, in particular, anti-proliferative properties, and their biological uses
US8680108Dec 17, 2010Mar 25, 2014Incyte CorporationSubstituted fused aryl and heteroaryl derivatives as PI3K inhibitors
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WO1999024432A1 *Nov 12, 1998May 20, 1999Akira AmenomoriPurine derivatives and medicine containing the same as the active ingredient
Classifications
U.S. Classification544/264, 544/277, 544/265, 514/826
International ClassificationC07D239/48, C07D473/00
Cooperative ClassificationC07D473/00, Y10S514/826, C07D239/48
European ClassificationC07D239/48, C07D473/00