US4490371A
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N,N-Disubstituted-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-B]quinazolinyl)oxyalkylamides
Assignee: Syntex USA LLC
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Filing: 1983-02-16
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Granted: 1984-12-25
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Expires: 2003-02-16
Abstract
Abstract Compounds according to the formula <IMAGE> (I) and the pharmaceutically acceptable acid addition salts thereof wherein: n is an integer of 1 to 6; R1 is hydrogen or alkyl of 1 to 4 carbons; R2 is hydrogen or R1 and R2 are combined to form an oxo group; R3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl or hydroxy lower alkyl; R4 is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is an amide forming group wherein the nitrogen substituents are: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 12 carbon atoms; cycloalkyl of 3 to 7 carbon atoms or cycloalkyl lower alkyl of 4 to 11 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, OH, -OCOR5, halo, -NH2, -N(R5)2, -NHCOR5, -COOH, or -COO(R5) group wherein R5 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an NH2, -N(R5)2, -NHCOR5, -COOH, or -COOR5 group wherein R5 is lower alkyl; morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (+/-)-decahydroquinolinyl or indolinyl. These compounds are cyclic AMP phosphodiesterase inhibitors useful as antithrombotic agents and the like in mammals.
Inventors
- 👤 Gordon H. Jones
- 👤 Michael C. Venuti
- 👤 Robert Alvarez
- 👤 John J. Bruno
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 10:23
CPC Classifications
C; C07; C07D; C07D295/00; C07D295/16; C07D295/18; C07D295/182; C07D295/185; A; A61; A61P; A61P35/00; A61P35/04; A61P43/00; A61P7/00; A61P7/02; A61P9/00; A61P9/04; C07C; C07C205/00; C07C205/27; C07C205/35; C07C205/36; C07C205/37; C07C205/44; C07C205/49; C07C205/56; C07D209/00; C07D209/02; C07D209/04; C07D209/08; C07D215/00; C07D215/02; C07D215/04; C07D215/08; C07D217/00; C07D217/02; C07D217/06; C07D487/00; C07D487/02; C07D487/04
Claims Analysis
Total Claims: 26
Claim 1
Independent Claim
256 words
A compound according to the formula ##STR12## and the pharmaceutically acceptable acid addition salts thereof wherein: n is an integer of 1 to 6; R 1 is hydrogen or alkyl of 1 to 4 carbons; R 2 is hydrogen or R 1 and R 2 are combined to form an oxo group; R 3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl or hydroxy lower alkyl; R 4 is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is an amide forming group wherein the nitrogen substituents are: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 12 carbon atoms; cycloalkyl of 3 to 7 carbon atoms or cycloalkyl lower alkyl of 4 to 11 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, OH, --OCOR 5 , halo, --NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COO(R 5 ) group wherein R 5 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COOR 5 group wherein R 5 is lower alkyl; morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (±)-decahydroquinolinyl or indolinyl.
Claim 2
Dependent Claim
256 words
A compound according to the formula ##STR12## and the pharmaceutically acceptable acid addition salts thereof wherein: n is an integer of 1 to 6; R 1 is hydrogen or alkyl of 1 to 4 carbons; R 2 is hydrogen or R 1 and R 2 are combined to form an oxo group; R 3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl or hydroxy lower alkyl; R 4 is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is an amide forming group wherein the nitrogen substituents are: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 12 carbon atoms; cycloalkyl of 3 to 7 carbon atoms or cycloalkyl lower alkyl of 4 to 11 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, OH, --OCOR 5 , halo, --NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COO(R 5 ) group wherein R 5 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COOR 5 group wherein R 5 is lower alkyl; morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (±)-decahydroquinolinyl or indolinyl.
Claim 3
Dependent Claim
28 words
A compound of claim 1 wherein R 1 , R 2 and R 3 are hydrogen, R 4 is hydrogen or methyl and n is 3 or 4.
Claim 4
Dependent Claim
72 words
A compound according to claim 2 wherein R 4 is hydrogen, n is 3 or 4 and A is nitrogen substituted with alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms or cycloalkyl lower alkyl of 7 to 11 carbon atoms.
Claim 5
Dependent Claim
17 words
A compound according to claim 3 which is N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazole[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 6
Dependent Claim
17 words
A compound according to claim 3 which is N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazole[2,1-b]quinazolin-7-yl)oxypentanamide and the pharmaceutically acceptable acid addition salts thereof.
Claim 7
Dependent Claim
17 words
A compound according to claim 3 which is N,N-dicyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazole[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 8
Dependent Claim
16 words
A compound of claim 3 which is N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 9
Dependent Claim
16 words
A compound of claim 3 which is N-cyclohexyl-N-(acetoxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 10
Dependent Claim
76 words
A compound of claim 2 wherein R 4 is hydrogen, n is 3 or 4 and A is nitrogen substituted with alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 12 carbon atoms, phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups.
Claim 11
Dependent Claim
16 words
A compound of claim 9 which is N,N-dibenzyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 12
Dependent Claim
16 words
A compound of claim 9 which is N-benzyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 13
Dependent Claim
16 words
A compound of claim 9 which is N-diphenylmethyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 14
Dependent Claim
16 words
A compound of claim 9 which is N-phenyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 15
Dependent Claim
30 words
A compound of claim 2 wherein R 4 is hydrogen, n is 3 and A is (±)-decahydroquinolinyl which is the compound (±)-decahydroquinolinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 16
Dependent Claim
30 words
A compound of claim 2 wherein R 4 is hydrogen, n is 3 and A is perhexylenyl which is the compound perhexylenyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide and the pharmaceutically acceptable acid addition salts thereof.
Claim 17
Dependent Claim
264 words
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula ##STR13## and the pharmaceutically acceptable acid addition salts thereof wherein n is an integer of 1 to 6; R 1 is hydrogen or alkyl of 1 to 4 carbons; R 2 is hydrogen or R 1 and R 2 are combined to form an oxo group; R 3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl or hydroxy lower alkyl; R 4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is an amide forming group wherein the nitrogen substituents are: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 2 carbon atoms; cycloalkyl of 3 to 7 carbon atoms or cycloalkyl lower alkyl of 7 to 11 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, OH, --OCOR 5 , halo, --NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COO(R 5 ) group wherein R 5 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COOR 5 group wherein R 5 is lower alkyl; morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (±)-decahydroquinolinyl or indolinyl.
Claim 18
Dependent Claim
264 words
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula ##STR13## and the pharmaceutically acceptable acid addition salts thereof wherein n is an integer of 1 to 6; R 1 is hydrogen or alkyl of 1 to 4 carbons; R 2 is hydrogen or R 1 and R 2 are combined to form an oxo group; R 3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl or hydroxy lower alkyl; R 4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is an amide forming group wherein the nitrogen substituents are: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 2 carbon atoms; cycloalkyl of 3 to 7 carbon atoms or cycloalkyl lower alkyl of 7 to 11 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, OH, --OCOR 5 , halo, --NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COO(R 5 ) group wherein R 5 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COOR 5 group wherein R 5 is lower alkyl; morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (±)-decahydroquinolinyl or indolinyl.
Claim 19
Independent Claim
283 words
A method for inhibiting 3',5'-cyclic AMP phosphodiesterase which method comprises administering a cyclic AMP phosphodiesterase inhibiting amount of a compound of the formula ##STR14## and the pharmaceutically acceptable acid addition salts thereof either alone or in admixture with a pharmaceutically acceptable excipient wherein n is an integer of 1 to 6; R 1 is hydrogen or alkyl of 1 to 4 carbons; R 2 is hydrogen or R 1 and R 2 are combined to form an oxo group; R 3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl or hydroxy lower alkyl; R 4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is an amide forming group wherein the nitrogen substituents are: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 12 carbon atoms; cycloalkyl of 3 to 7 carbon atoms or cycloalkyl lower alkyl of 7 to 11 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, OH, --OCOR 5 , halo, --NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COO(R 5 ) group wherein R 5 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COOR 5 group wherein R 5 is lower alkyl; morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (±)-decahydroquinolinyl or indolinyl.
Claim 20
Independent Claim
283 words
A method for inhibiting 3',5'-cyclic AMP phosphodiesterase which method comprises administering a cyclic AMP phosphodiesterase inhibiting amount of a compound of the formula ##STR14## and the pharmaceutically acceptable acid addition salts thereof either alone or in admixture with a pharmaceutically acceptable excipient wherein n is an integer of 1 to 6; R 1 is hydrogen or alkyl of 1 to 4 carbons; R 2 is hydrogen or R 1 and R 2 are combined to form an oxo group; R 3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl or hydroxy lower alkyl; R 4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is an amide forming group wherein the nitrogen substituents are: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 12 carbon atoms; cycloalkyl of 3 to 7 carbon atoms or cycloalkyl lower alkyl of 7 to 11 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, OH, --OCOR 5 , halo, --NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COO(R 5 ) group wherein R 5 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an NH 2 , --N(R 5 ) 2 , --NHCOR 5 , --COOH, or --COOR 5 group wherein R 5 is lower alkyl; morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (±)-decahydroquinolinyl or indolinyl.
Claim 21
Dependent Claim
16 words
The method of claim 17 wherein the inhibition of said phosphodiesterase activity results in antithrombotic activity.
Claim 22
Dependent Claim
97 words
A compound of the formula ##STR15## and the pharmaceutically acceptable acid addition salts thereof wherein n is an integer of 1 to 6; R 1 is hydrogen or alkyl of 1 to 4 carbons; R 2 is hydrogen or R 1 and R 2 are combined to form an oxo group; R 3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl or hydroxy lower alkyl; R 4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; and Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy.
Claim 23
Dependent Claim
97 words
A compound of the formula ##STR15## and the pharmaceutically acceptable acid addition salts thereof wherein n is an integer of 1 to 6; R 1 is hydrogen or alkyl of 1 to 4 carbons; R 2 is hydrogen or R 1 and R 2 are combined to form an oxo group; R 3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl or hydroxy lower alkyl; R 4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; and Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy.
Claim 24
Dependent Claim
28 words
A compound of claim 19 wherein R 1 , R 2 and R 3 are hydrogen, R 4 is hydrogen or methyl and n is 3 or 4.
Claim 25
Dependent Claim
15 words
A compound according to claim 20 wherein the oxyalkyl acid is substituted at position 7.
Claim 26
Dependent Claim
10 words
A compound according to claim 21 which is 4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyric acid.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1987-12-25 | 1988-06-25 | 1988-12-25 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1991-12-25 | 1992-06-25 | 1992-12-25 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1995-12-25 | 1996-06-25 | 1996-12-25 | $7700.00 | Window Closed / Lapsed |