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Claims for Patent: 6,034,239

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Claims for Patent: 6,034,239

Title: Tricyclic compounds, their production and use
Abstract:A compound of the formula: ##STR1## wherein R.sup.1 is an optionally substituted hydrocarbon, amino or heterocyclic group; R.sup.2 is H or an optionally substituted hydrocarbon group; R.sup.3 is H or an optionally substituted hydrocarbon or heterocyclic group; X is CHR.sup.4, NR.sup.4, O or S in which R.sup.4 is H or an optionally substituted hydrocarbon group; Y is C, CH or N; ring A is optionally substituted 5- to 7-membered ring; ring B is an optionally substituted benzene ring; and m is 1 to 4, or a salt thereof, a process for producing it, an intermediate for the production and a pharmaceutical composition comprising it are provided.
Inventor(s): Ohkawa; Shigenori (Osaka, JP), Uchikawa; Osamu (Hyogo, JP), Fukatsu; Kohji (Hyogo, JP), Miyamoto; Masaomi (Hyogo, JP)
Assignee: Takeda Chemical Industries, Ltd. (Osaka, JP)
Application Number:08/812,168
Patent Claims: 1. A compound of the formula: ##STR74## wherein R.sup.1 represents an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group;

R.sup.2 represents a hydrogen atom or an optionally substituted hydrocarbon group;

R.sup.3 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;

X represents CHR.sup.4, NR.sup.4, O or S in which R.sup.4 represents a hydrogen atom or an optionally substituted hydrocarbon group;

Y represents C, CH or N, provided that when X is CH.sub.2, Y is C or CH;

......... represents a single bond or a double bond;

ring A represents an optionally substituted, 5- to 7-membered oxygen-containing heterocyclic ring;

ring B represents an optionally substituted benzene ring; and

m represents an integer of 1 to 4, or a salt thereof.

2. A compound as claimed in claim 1, wherein R.sup.1 is (i) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, C.sub.6-10 aryl-carbamoyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy and an optionally halogenated C.sub.1-6 alkyl-carbonylamino,

(ii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl and C.sub.6-14 aryl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy and an optionally halogenated C.sub.1-6 alkyl-carbonylamino, or

(iii) a 5- to 14-membered heterocyclic group containing, besides carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which group may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-6 alkynyl, C.sub.2-6 alkenyl, C.sub.7-11 aralkyl, C.sub.6-10 aryl, C.sub.1-6 alkoxy, C.sub.6-10 aryloxy, formyl, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, formyloxy, C.sub.1-6 alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, carboxyl, C.sub.1-6 alkoxy-carbonyl, C.sub.7-11 aralkyloxy-carbonyl, carbamoyl, an optionally halogenated C.sub.1-4 alkyl, oxo, amidino, imino, amino, mono-C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, 3- to 6-membered cyclic amino, C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl, di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl, C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10 arylsulfonyl;

R.sup.2 is (i) a hydrogen atom or (ii) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy and an optionally halogenated C.sub.1-6 alkyl-carbonylamino;

R.sup.3 is (i) a hydrogen atom, (ii) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy and an optionally halogenated C.sub.1-6 alkyl-carbonylamino or (iii) a 5- to 14-membered heterocyclic group containing, besides carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which group may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-6 alkynyl, C.sub.2-6 alkenyl, C.sub.7-11 aralkyl, C.sub.6-10 aryl, C.sub.1-6 alkoxy, C.sub.6-10 aryloxy, formyl, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, formyloxy, C.sub.1-6 alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, carboxyl, C.sub.1-6 alkoxy-carbonyl, C.sub.7-11 aralkyloxy-carbonyl, carbamoyl, an optionally halogenated C.sub.1-4 alkyl, oxo, amidino, imino, amino, mono-C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, 3- to 6-membered cyclic amino, C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl, di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl, C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10 arylsulfonyl;

R.sup.4 is (i) a hydrogen atom or (ii) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-16 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy and an optionally halogenated C.sub.1-6 alkyl-carbonylamino;

ring A is a 5- to 7-membered heterocyclic group optionally containing, besides carbon atoms and an oxygen atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which group may be substituted by 1 to 4 substituents selected from the group consisting of (i) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy and an optionally halogenated C.sub.1-6 alkyl-carbonylamino, (ii) a halogen, (iii) C.sub.1-6 alkoxy, (iv) C.sub.6-10 aryloxy, (v) formyl, (vi) C.sub.1-6 alkyl-carbonyl, (vii) C.sub.6-10 aryl-carbonyl, (viii) formyloxy, (ix) C.sub.1-6 alkyl-carbonyloxy, (x) C.sub.6-10 aryl-carbonyloxy, (xi) carboxyl, (xii) C.sub.1-6 alkoxy-carbonyl, (xiii) C.sub.7-11 aralkyloxy-carbonyl, (xiv) carbamoyl, (xv) an optionally halogenated C.sub.1-4 alkyl, (xvi) oxo, (xvii) amidino, (xviii) imino, (xix) amino, (xx) mono-C.sub.1-4 alkylamino, (xxi) di-C.sub.1-4 alkylamino, (xxii) 3- to 6-membered cyclic amino, (xxiii) C.sub.1-3 alkylenedioxy, (xxiv) hydroxy, (xxv) nitro, (xxvi) cyano, (xxvii) mercapto, (xxviii) sulfo, (xxix) sulfino, (xxx) phosphono, (xxxi) sulfamoyl, (xxxii) mono-C.sub.1-6 alkylsulfamoyl, (xxxiii) di-C.sub.1-6 alkylsulfamoyl, (xxxiv) C.sub.1-6 alkylthio, (xxxv) C.sub.6-10 arylthio, (xxxvi) C.sub.1-6 alkylsulfinyl, (xxxvii) C.sub.6-10 arylsulfinyl, (xxxviii) C.sub.1-6 alkylsulfonyl and (xxxix) C.sub.6-10 arylsulfonyl; and

ring B is a benzene ring which may be substituted by 1 or 2 substituents selected from the group consisting of

(i) a halogen,

(ii) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C.sub.1-6 alkyl, C.sub.16 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy and an optionally halogenated C.sub.1-6 alkyl-carbonylamino,

(iii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl and C.sub.6-14 aryl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy and an optionally halogenated C.sub.1-6 alkyl-carbonylamino, (iv) a C.sub.1-6 alkanoylamino group, (v) a C.sub.1-6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxy, an optionally halogenated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, C.sub.6-10 aryl, C.sub.6-10 aryloxy and an optionally halogenated C.sub.1-6 alkyl-carbonylamino or (vi) a C.sub.1-3 alkylenedioxy group.

3. A compound as claimed in claim 1, wherein ##STR75## wherein R.sup.4' is an optionally substituted hydrocarbon group.

4. A compound as claimed in claim 1 which is a compound of the formula: ##STR76## wherein ring A' is an optionally substituted, oxygen-containing heterocyclic ring;

n is an integer of 0 to 2;

---- and .... are independently a single bond or a double bond.

5. A compound as claimed in claim 1, wherein R.sup.1 is

(i) an optionally substituted C.sub.1-6 alkyl group,

(ii) an optionally substituted C.sub.3-6 cycloalkyl group,

(iii) an optionally substituted C.sub.2-6 alkenyl group,

(iv) an optionally substituted C.sub.6-14 aryl group,

(v) an optionally substituted mono- or di-C.sub.1-6 alkylamino group,

(vi) an optionally substituted C.sub.6-14 arylamino group or

(vii) an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group.

6. A compound as claimed in claim 1, wherein R.sup.1 is an optionally halogenated C.sub.1-6 alkyl group.

7. A compound as claimed in claim 1, wherein R.sup.2 is a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group.

8. A compound as claimed in claim 1, wherein R.sup.2 is a hydrogen atom.

9. A compound as claimed in claim 1, wherein R.sup.3 is a hydrogen atom or an optionally substituted hydrocarbon group.

10. A compound as claimed in claim 1, wherein R.sup.3 is a hydrogen atom.

11. A compound as claimed in claim 1, wherein R.sup.4 is a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group.

12. A compound as claimed in claim 1, wherein X is CHR.sup.4.

13. A compound as claimed in claim 1, wherein X is CHR.sup.4 and ......... is a single bond.

14. A compound as claimed in claim 13, wherein X is CH.sub.2.

15. A compound as claimed in claim 1, wherein X is NR.sup.4.

16. A compound as claimed in claim 1, wherein Y is C or CH.

17. A compound as claimed in claim 1, wherein Y is CH.

18. A compound as claimed in claim 1, wherein m is 2.

19. A compound as claimed in claim 1, wherein ring A is a tetrahydrofuran ring.

20. A compound as claimed in claim 1, wherein ring A is unsubstituted.

21. A compound as claimed in claim 1, wherein ring B is unsubstituted.

22. A compound as claimed in claim 4, wherein n is 0 or 1.

23. A compound as claimed in claim 1 which is a compound of the formula: ##STR77## wherein R.sup.1b is C.sub.1-6 alkyl, X' is CH.sub.2, NH or NCHO,

......... is a single bond or double bond,

R.sup.3a is a hydrogen atom or phenyl,

E.sup.a is CH.sub.2 CH.sub.2, CH.dbd.CH, CH.sub.2 O, CH.dbd.N, CONH or CH.sub.2 NH,

n.sup.a is 0 or 1,

ring A" is a 5- or 6-membered oxgen-containing heterocyclic ring which may be substituted by 1 or 2 C.sub.1-6 alkyl optionally substituted by a hydroxy, and

ring B' is a benzene ring which may be substituted by a halogen.

24. A compound claimed in claim 23, wherein ......... is single bond and X' is NH.

25. A compound claimed in claim 1, which is (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide

26. A compound claimed in claim 1, which is N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]propionamide.

27. A compound claimed in claim 1, which is N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]butyramide.

28. A compound claimed in claim 1, which is N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide.

29. A compound claimed in claim 1, which is N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide.

30. A process for producing a compound as claimed in claim 1, which comprises:

reacting a compound of the formula (i): ##STR78## or a salt thereof, or (ii): ##STR79## or a salt thereof, with a compound of the formula:

or a salt or a reactive derivative thereof; and

if necessary, subjecting the resultant compound to reduction and/or alkylation.

31. A process for producing a compound as claimed in claim 4, which comprises:

subjecting to cyclization a compound of the formula: ##STR80## wherein R.sup.5 represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxy group, a nitro group, a cyano group or an optionally substituted amino group; L represents a leaving group, or a salt thereof; and

if necessary, subjecting the resultant compound to reduction.

32. A compound of the formula: ##STR81## wherein R.sup.3 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;

x represents CHR.sup.4, NR.sup.4, O or S in which R.sup.4 represents a hydrogen atom or an optionally substituted hydrocarbon group;

ring A represents an optionally substituted, 5- to 7-membered oxygen-containing heterocyclic ring;

ring B represents an optionally substituted benzene ring; and

m represents an integer of 1 to 4, or a salt thereof.

33. A compound of the formula: ##STR82## wherein X.sup.a represents CHR.sup.4a, NR.sup.4a, O or S in which R.sup.4a represents a hydrogen atom or an optionally substituted hydrocarbon group;

Y.sup.a represents C, CH or N, provided that when X.sup.a is NH or NCH.sub.3, Y.sup.a is CH or N;

.... represents a single bond or a double bond;

R.sup.3 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;

ring A represents an optionally substituted, 5- to 7-membered oxygen-containing heterocyclic ring;

ring B represents an optionally substituted benzene ring; and

m represents an integer of 1 to 4, or a salt thereof.

34. A pharmaceutical composition which comprises a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

35. A composition as claimed in claim 34 wherein said compound or said pharmaceutically acceptable salt has a binding affinity for melatonin receptor.

36. Method for treating or preventing diseases related to the action of melatonin in mammals which comprises administrating to a subject in need thereof a therapeutically effective amount of a composition as claimed in claim 35.

37. A method as claimed in claim 36 which regulates circadian rhythm.

38. A method as claimed in claim 36 which regulates sleep-awake rhythm.

39. A method as claimed in claim 36 which regulates time zone change syndrome.

40. A method as claimed in claim 36 which treats or prevents sleep disorders.

41. A process of manufacturing a pharmaceutical composition comprising the steps of selecting a compound or pharmaceutically acceptable salt of claim 1 and admixing said compound or salt with a pharmaceutically acceptable carrier.
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