Claims
- 1. A method for the treatment of chronic obstructive pulmonary disease which comprises administering to a mammal in need of such treatment an effective amount of a pharmacologically active compound of formula wherein the C(═NH)—NHR3 group may be in tautomeric or isomeric form; or a pharmaceutically acceptable salt thereof, in which:R1 is amino which is mono- or disubstituted by a substituent selected from an aliphatic hydrocarbon radical, an araliphatic hydrocarbon radical, an aromatic radical, and a cycloaliphatic hydrocarbon radical or is amino which is disubstituted by a divalent aliphatic hydrocarbon radical or a said radical interrupted by oxygen; R is hydrogen, halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy or is hydroxy which is etherified by an aliphatic, araliphatic or aromatic alcohol or by an aliphatic alcohol which is substituted by carboxy, by esterified carboxy or by amidated carboxy or which is esterified by an aliphatic or araliphatic carboxylic acid; R3 is hydrogen or an acyl radical which is derived from an organic carbonic acid, an organic carboxylic acid, a sulfonic acid, or a carbamic acid; X1 and X3, independently of one another, are oxygen (—O—) or sulphur (—S—); and X2 is a divalent aliphatic hydrocarbon radical which may be interrupted by an aromatic radical; wherein the phenyl rings of formula I may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; wherein aryl in the above definitions may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; wherein a cycloaliphatic hydrocarbon radical may be substituted by an aliphatic radical.
- 2. A method according to claim 1, in which:R1 is amino which is mono- or disubstituted by a substituent selected from lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl, phenyl, napthyl, indanyl, fluorenyl, cycloalkyl, and cycloalkenyl, cycloalkyl and cycloalkenyl each being unsubstituted or mono- or polysubstituted by lower alkyl, or is amino which is disubstituted by lower alkylene; R2 is hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, lower alkoxy substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- or di-lower alkylaminocarbonyl, lower alkanoyloxy, lower alkenoyloxy or phenyl-lower alkanyloxy; R3 is hydrogen, alkoxycarbonyl or alkenyloxycarbonyl, each of which is unsubstituted or substituted by phenyl, naphthyl, indanyl or fluorenyl, or is cycloalkoxycarbonyl being unsubstituted or mono- or polysubstituted by lower alkyl, or is lower alkanoyl or phenyl-lower alkanoyl, or is benzoyl, naphthoyl, indanoyl or fluorenoyl, or is C1-C7-alkanesulfonyl, phenyl-C1-C7alkanesulfonyl, C3-C7-cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which is substituted by lower alkyl, phenyl-lower alkyl or phenyl; X1 and X3, independently of one another, are O or S; and X2 is lower alkylene, lower alkylene-phenylene-lower alkylene or lower alkylene-naphthylene-lower alkylene; wherein the phenyl rings of formula I may be, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-lower alkanoyloxy; wherein the aromatic radicals in the above definitions may be, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-lower alkanoyloxy.
- 3. A method according to claim 1, in which:R1 is amino which is mono- or disubstituted by a substituent selected from C1-C7-alkyl, phenyl-C1-C7-alkyl, phenyl and C3-C6-cycloalkyl, C3-C6-cycloalkyl being unsubstituted or mono- or polysubstituted by C1-C7alkyl, or is amino which is disubstituted by C3-C6-alkylene; R2 is hydrogen, hydroxy, C1-C7-alkoxy, C1-C7-alkoxy substituted by carboxy or lower alkoxycarbonyl or phenyl-C1-C4 alkoxy; R3 is hydrogen, C1-C12-alkoxy-carbonyl, C2-C5-alkanoyl, phenyl-C2-C5-alkanoyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C1-C7-alkyl, or C1-C7 alkoxy, C3-C6-cycloalkylcarbonyl which is unsubstituted or substituted by C1-C7-alkyl, or is benzoyl, naphthoyl, indanoyl or fluorenoyl, or is C1-C7alkanesulfonyl, phenyl-C1-C7alkanesulfonyl, C3-C7-cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which is substituted by C1-C7-alkyl, phenyl-C1-C7-alkyl or phenyl; X1 and X3 each are —O—, or furthermore are, independently of one another, —O— or —S—; and X2 is C2-C7-alkylene or C2-C4-alkylene-phenylene-C2-C4-alkylene; wherein the phenyl rings of formula I may be unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C1-C7-alkyl, and C1-C7-alkoxy; wherein phenyl in the above definitions is unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C1-C7-alkyl, and C1-C7-alkoxy.
- 4. A method according to claim 1, in which —CO—R1 is located in position 4 (para) or 3 or 5 (meta) of the corresponding phenyl ring with respect to -X1—; R2— is located in position 2 (ortho) or 3 (meta) of the corresponding phenyl ring with respect to —X1—; and —C(═NH)—NHR3 is located in position 4 (para) of the corresponding phenyl ring with respect to —X3—.
- 5. A method according to claim 1, in which the compound of formula I is of formula IA wherein the C(═NH)—NHR3 group may be in tautomeric or isomeric form, and in which:R1 is di-C1-C4-alkylamino, C1-C4alkyl-(phenyl)amino, C1-C4alkyl-(phenyl-C1-C4-alkyl)-amino, di-C3-C6-cycloalkylamino, which is unsubstituted or substituted by C1-C4-alkyl, or 1-piperidino substituted by C1-C4-alkyl; R2 is hydrogen, C1-C4-alkoxy or C1-C4-alkoxy which is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by mono- or di-lower alkylaminocarbonyl; R3 is hydrogen, C1-C12-alkoxycarbonyl, phenyl-C1-C4-alkoxycarbonyl, C2-C5-alkanoyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C1-C4-alkyl or by C1-C4-alkoxy, C3-C6-cycloalkylcarbonyl which is unsubstituted or substituted by C1-C4-alkyl; X1 and X3 are —O—; X2 is C4-C7-alkylene; wherein the phenyl rings of formula IA may be unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C1-C4-alkyl, and C1-C4-alkoxy.
- 6. A method according to claim 5, in which:R1 is di-C1-C4-alkylamino, C1-C4-alkyl-(phenyl)-amino, C1-C4-alkyl-(phenyl-C1-C4-alkyl)-amino, di-C3-C6-cycloalkylamino, which is unsubstituted or substituted by C1-C4-alkyl, or 1-piperidino substituted by C1-C4-alkyl; R2 is hydrogen, C1-C4-alkoxy or C1-C4-alkoxy substituted by C1-C4-alkoxycarbonyl; R3 is hydrogen; or R3 is lower alkanoyl; X1 and X3 are —O—; and X2 is C4-C7-alkylene.
- 7. A method according to claim 5, in which:R1 is di-C1-C4-alkylamino; R2 is hydrogen, C1-C4-alkoxy or C1-C4-alkoxy substituted by C1-C4-alkoxycarbonyl or by aminocarbonyl; R3 is C1-C12-alkoxycarbonyl, phenyl-C1-C4-alkoxycarbonyl, C2-C5-alkanoyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C1-C4-alkyl, or C1-C4-alkoxy, C3-C6-cycloalkylcarbonyl which is unsubstituted or substituted by C1-C4-alkyl; X1 and X3 are —O—; and X2 is C4-C7-alkylene.
- 8. A method according to claim 5, in which:R1 is di-C1-C4-alkylamino; R2 is hydrogen, C1-C4-alkoxy or C1-C4-alkoxy substituted by C1-C4-alkoxycarbonyl or by aminocarbonyl; R3 is hydrogen or C1-C4-alkanoyl; X1 and X3 are —O—; and X2 is C4-C7-alkylene.
- 9. A method according to claim 5, in which R1 is di-isopropylamino, R2 is methoxy, R3 is hydrogen, X1 and X3 are —O— and X2 is pentylene.
- 10. A method according to claim 1, in which the compound of formula I is of formula IB wherein the C(═NH)—NHR3 group may be in tautomeric or isomeric form, and in which:R1 is di-C1-C4-alkylamino, C1-C4alkyl-(phenyl)amino, C1-C4-alkyl-(phenyl-C1-C4-alkyl)-amino, di-C3-C6-cycloalkylamino, which is unsubstituted or substituted by C1-C4-alkyl, or 1-piperidino substituted by C1-C4-alkyl; R2 is hydroxy or C1-C4-alkoxy which is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by mono- or di-lower alkylaminocarbonyl; R3 is hydrogen, C1-C12-alkoxycarbonyl, phenyl-C1-C4-alkoxycarbonyl, C2-C5-alkanoyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C1-C4-alkyl, or C1-C4-alkoxy, C3-C6-cycloalkylcarbonyl which is unsubstituted or substituted by C1-C4-alkyl; X1 and X3 are —O—; and X2 is C4-C7-alkylene; wherein the phenyl rings of formula IB may be unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C1-C4-alkyl, and C1-C4-alkoxy.
- 11. A method according to claim 10, in which:R1 is di-C1-C4-alkylamino, C1-C4-alkyl-(phenyl)-amino, C1-C4alkyl-(phenyl-C1-C4-alkyl)-amino, di-C3-C6-cycloalkylamino, which is unsubstituted or substituted by C1-C4-alkyl, or 1-piperidino substituted by C1-C4-alkyl; R2 is hydroxy or C1-C4-alkoxy substituted by C1-C4-alkoxycarbonyl, or by aminocarbonyl; R3 is hydrogen; or R3 is C2-C5-alkanoyl; X1 and X3 are —O—; and X2 is C4-C7-alkylene.
- 12. A method according to claim 10, in which:R1 is di-C1-C4-alkylamino; R2 is hydroxy or C1-C4-alkoxycarbonylmethoxy, or aminocarbonylmethoxy; R3 is hydrogen or C2-C5-alkanoyl; X1 and X3 are —O—; and X2 is C4-C7-alkylene.
- 13. A method according to claim 10, in which R1 is di-isopropylamino, R2 is hydroxy, R3 is hydrogen, X1 and X3 are —O— and X2 is pentylene.
- 14. A method according to claim 1, in which the compound of formula I or salt thereof is administered in combination with a pharmaceutically acceptable carrier.
- 15. A method according to claim 1, in which the disease is chronic bronchitis.
- 16. A method according to claim 9, in which the compound of formula I or salt thereof is administered in combination with a pharmaceutically acceptable carrier.
- 17. A method according to claim 9, in which the disease is chronic bronchitis.
- 18. A method according to claim 13, in which the compound of formula I or salt thereof is administered in combination with a pharmaceutically acceptable carrier.
- 19. A method according to claim 13, in which the disease is chronic bronchitis.
- 20. A medicament suitable for pulmonary administration comprising a compound of formula I as specified in claim 1, or a pharmaceutically acceptable salt thereof, or a mixture of said compound or salt with a pharmaceutically acceptable carrier therefor, the compound, salt or mixture being in inhalable form.
- 21. A medicament suitable for pulmonary administration comprising a compound of formula IA as specified in claim 5, or a pharmaceutically acceptable salt thereof, or a mixture of said compound or salt with a pharmaceutically acceptable carrier therefor, the compound, salt or mixture being in inhalable form.
Parent Case Info
This is a continuation of U.S. patent application Ser. No. 09/435,943 filed Nov. 9, 1999, pending, which is a continuation of U.S. patent application Ser. No. 09/210,634, filed Dec. 11, 1998, abandoned, which is a continuation of U.S. Patent Application No. 60/112,002, filed Dec. 12, 1997, which is a continuation of U.S. patent application No. Ser. 08/989,367, filed Dec. 12, 1997, now abandoned.
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Provisional Applications (1)
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60/112002 |
Dec 1997 |
US |
Continuations (3)
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09/435943 |
Nov 1999 |
US |
Child |
09/732453 |
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Parent |
09/210634 |
Dec 1998 |
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Child |
09/435943 |
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Parent |
08/989367 |
Dec 1997 |
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Child |
09/210634 |
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US |