Claims
- 1. A compound having the Formula I:
- 2. The compound of claim 1, wherein
R1 is hydrogen, C1-6alkyl, C6-10 ar(C1-6)alkyl, R11SO2, R11OOC, R11CO or R11CH2, where R11 is hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C4-7 cycloalkyl(C1-4)alkyl, camphor-10-yl, or C6-10 aryl substituted by one or more C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C6-10 ar(C1-6)alkyl, C6-10 aryloxy (further optionally substituted by nitro, halo, or cyano), C6-10 aryldiazenyl (further optionally substituted by amino, C1-4 alkylamino or di (C1-4) alkylamino), C1-6 alkoxy, halo(C1-6)alkyl, halo(C1-6)alkoxy, C1-6 alkylcarbonylamino, C1-6 alkylsulfonyl, mono- or di-(C1-6)alkylamino, hydroxy, carboxy, cyano, nitro, halo, or a heteroaryl which is optionally substituted with one or more C1-6 alkyl, halo(C1-6)alkyl, or halo; and when R1 is R11CO, then R11 can also be N-attached pyrrolidinyl, piperidinyl or morpholinyl; R2 is one of hydrogen, C1-6 alkyl or benzyl; R3 is one of hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl, C2-10 aminoalkyl, C2-7 carboxyalkyl, mono(C1-4 alkyl)amino-(C1-8)alkyl, or di(C1-4 alkyl)amino(C1-8)alkyl; R4, R5 and R6 are independently hydrogen, C1-6 alkyl, C6-10 ar(C1-6)-alkyl, C6-10 aryl, C2-10 hydroxyalkyl or C2-7 carboxyalkyl; R7 is hydrogen or C1-6 alkyl; R8, R9 and R10 are independently hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano or —CO2Rw, where Rw, in each instance, is one of C1-4 alkyl, C4-7 cycloalkyl, phenyl, or benzyl; n is zero to 4; and m is zero to 4.
- 3. The compound of claim 1, wherein
R1 is hydrogen, t-butylcarbonyl, butylsulfonyl, propylsulfonyl, optionally substituted benzylsulfonyl, optionally substituted phenylsulfonyl, pentylsulfonyl, 4-tolylsulfonyl, naphthylsulfonyl or camphor-10-sulfonyl; R2 is hydrogen or C1-6 alkyl; R3 is methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl or 2-(dimethylamino)ethyl; R4, R5 and R6 independently represent hydrogen, methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl or 4-carboxybutyl; R7 is hydrogen or C1-6 alkyl; R8, R9 and R10 are each hydrogen; n is zero, 1, or 2; and m is zero, 1, or 2.
- 4. The compound of claim 1, wherein
R2 is hydrogen, alkyl, aryl, aralkyl, dialkylaminoalkyl, 1-morpholinoalkyl, 1-piperidinylalkyl, pyridinylalkyl, alkoxy(alkoxy)alkoxyalkyl, or (alkoxycarbonyl)oxyethyl.
- 5. The compound of claim 1, wherein
R1 is R11SO2, where R11 is hydrogen, alkyl, cycloalkyl, camphor-10-yl, alkenyl, alkynyl, heterocycle, aryl, aralkyl, or aralkenyl, any of which can be optionally substituted by one or more alkyl, alkenyl, aryl, aryloxy (further optionally substituted by nitro, halo, or cyano), aralkyl, aryldiazenyl (further optionally substituted by amino, alkylamino, or dialkylamino), alkoxy, haloalkyl, haloalkoxy, alkylcarbonylamino, alkylsulfonyl, mono- or di-alkylamino, hydroxy, carboxy, cyano, nitro, halo, or a heteroaryl which is optionally substituted with one or more alkyl, haloalkyl, or halo; R2, R3, R4, R5 and R6 are each hydrogen; R7, R8, R9 and R10 are each hydrogen; n is zero; and m is zero.
- 6. The compound of claim 5, wherein
R1 is R11SO2, where R11 is hydrogen, C1-6 alkyl, C4-7 cycloalkyl, camphor-10-yl, C2-6 alkenyl, C2-6 alkynyl, thienyl, thiazolyl, benzo[b]thiophenyl, pyrazolyl, chromanyl, imidazolyl, benzo[2,3-c]1,2,5-oxadiazole, C6-10 aryl, C6-10 ar(C1-6)alkyl, or C6-10 ar(C2-6)alkenyl, any of which can be optionally substituted by one or more C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C6-10 aryloxy (further optionally substituted by nitro, halo, or cyano), C6-10 ar(C1-6)alkyl, 4-dimethylaminophenyldiazenyl, C1-6 alkoxy, halo(C1-6)alkyl, halo(C1-6)alkoxy, C1-6alkylcarbonylamino, C1-6alkylsulfonyl, mono- or di-(C1-6)alkylamino, hydroxy, carboxy, cyano, nitro, halo, or pyrazolyl which is optionally substituted with one or more C1-6 alkyl, halo-(C1-6)alkyl, or halo.
- 7. The compound of claim 1, wherein R2 is hydrogen, C1-6 alkyl, or benzyl.
- 8. The compound of claim 1, wherein R3 is hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl, C2-10 aminoalkyl, C2-7 carboxyalkyl, mono(C1-4 alkyl)amino(C1-8)alkyl, or di(C1-4 alkyl)amino(C1-8)-alkyl.
- 9. The compound of claim 8, wherein R3 is methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl or 2-(dimethylamino)ethyl.
- 10. The compound of claim 1, wherein R4, R5 and R6 are independently hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl or C2-7 carboxyalkyl.
- 11. The compound of claim 10, wherein R4, R5, and R6 are independently hydrogen, methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl or 4-carboxybutyl.
- 12. The compound of claim 10, wherein R4, R5 and R6 are each hydrogen.
- 13. The compound of claim 1, wherein R7 is hydrogen or C1-6 alkyl.
- 14. The compound of claim 1, wherein R8, R9 and R10 are independently hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano or CO2Rw, where Rw, in each instance, is one of C1-4 alkyl, C4-7 cycloalkyl, phenyl, or benzyl.
- 15. The compound of claim 14, wherein R8, R9 and R10 are independently hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, —CO2CH3, —CO2CH2CH3 or —CO2CH2CH2CH3.
- 16. The compound of claim 14, wherein R8, R9 and R10 are each hydrogen.
- 17. The compound of claim 1, wherein n is zero to 6, and m is zero to 4.
- 18. The compound of claim 17, wherein n is zero, 1, or 2; and m is zero, 1 or 2.
- 19. The compound of claim 1, which is one of:
(3S)-7-[3-(Amidinoaminooxy)propoxy]-2-[(2,5-dimethoxyphenyl)-sulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (3S)-7-[3-(Amidinoaminooxy)propoxy]-2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (3S)-7-[3-(Amidinoaminooxy)propoxy]-2-(2-naphthylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (3S)-7-[3-(Amidinoaminooxy)propoxy)]-2-{[2-(methylsulfonyl)-phenyl]sulfonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (3S)-7-[3-(Amidinoaminooxy)propoxy]-2-(butylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (3S)-7-[3-(Amidinoaminooxy)propoxy]-2-[(2,6-dichlorophenyl)-sulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (3S)-7-[3-(Amidinoaminooxy)propoxy]-2-[(2-methyl-5-nitrophenyl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (3S)-7-[3-(Amidinoaminooxy)propoxy]-2-{[(7,7-dimethyl-2-oxobicyclo[2.2.1]heptyl)methyl]sulfonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
- 20. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
- 21. A method of treating αvβ3 integrin- and αvβ5 integrin-mediated pathological conditions selected from the group consisting of tumor growth, metastasis, osteoporosis, restenosis, inflammation, macular degeneration, diabetic retinopathy, rheumatoid arthritis and sickle cell anemia, in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 22. A method of treating tumor growth in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 23. A method of treating osteoporosis in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 24. A method of treating restenosis in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 25. A method of treating inflammation in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 26. A method of treating macular degeneration in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 27. A method of treating diabetic retinopathy in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 28. A method of treating rheumatoid arthritis in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 29. A method of treating sickle cell anemia in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 30. A process for preparing a tetrahydroisoquinoline-3-carboxylicacid alkoxyguanidine compound of claim 1, comprising:
reacting a compound of Formula II: 22or a salt, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, m and n are as defined in claim 1, with a deprotection reagent and a guanidinylating reagent, to form a compound of Formula III: 23or a salt, hydrate, solvate or prodrug thereof, where R1, R2, R3, R4, R5, R6, R8, R9, m and n are as defined in claim 1.
- 31. The process of claim 30, wherein said deprotection reagent is hydrazine, or methylamine.
- 32. The process of claim 30, wherein said guanidinylating reagent is aminoiminosulfonic acid, 1H-pyrazole-1-carboxamidine hydrochloride, N,N′-bis(tert-butoxycarbonyl)-S-methylisothiourea, or N—R8, N—R9-1H-pyrazole-1-carboxamidine, where R8 and R9 are defined as in claim 1.
- 33. A compound having the Formula II:
- 34. The compound of claim 1, wherein R7 is hydrogen.
- 35. A method for treating a central nervous system (CNS) related disorder, selected from the group consisting of: neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia, surgery, neurodegenerative diseases, adverse consequences of overstimulation of one or more excitatory amino acids, anxiety, convulsions, chronic pain, psychosis, schizophrenia, anesthesia, and opiate tolerance, in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of claim 1.
- 36. The method according to claim 35, wherein said CNS related disorder is neuronal loss associated with stroke.
- 37. The method according to claim 35, wherein said CNS related disorder is ischemia.
- 38. The method according to claim 35, wherein said CNS related disorder is CNS trauma.
- 39. The method according to claim 35, wherein said CNS related disorder is hypoglycemia.
- 40. The method according to claim 35, wherein said CNS related disorder is the result of surgery.
- 41. The method according to claim 35, wherein said CNS related disorder is a neurodegenerative disease.
- 42. The method according to claim 41, wherein said neurodegenerative disease is selected from Alzheimer's disease and Parkinson's disease.
- 43. The method according to claim 35, wherein said CNS related disorder is schizophrenia.
Parent Case Info
[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 09/921,759, filed Aug. 6, 2001, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 60/223,478, filed Aug. 7, 2000, now abandoned, both of which are incorporated by reference herein in their entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60223478 |
Aug 2000 |
US |
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
09921759 |
Aug 2001 |
US |
Child |
09969181 |
Oct 2001 |
US |