# US 5,705,531 A · 1,5-disubstituted 7A-methylperhydroinden-3A-ol derivatives, useful in treating cardiovascular disorders, processes for their preparation and pharmaceutical compositions containing the same

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- Number: US 5,705,531 A
- Document ID: US5705531A
- Status: Granted
- Kind: A
- Application number: 08/556,854
- Filed: 1995-11-02
- Granted: 1998-01-06
- Earliest claimed: 1994-11-07
- Assignees: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
- Inventors: Alberto Cerri; Nicoletta Almirante; Giuseppe Bianchi; Patrizia Ferrari; Piero Melloni
- Web page: https://patentgrep.com/patent/US5705531A

## CPC

- C07D 239/22: with hetero atoms directly attached to ring carbon atoms
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- C07C 239/20: having oxygen atoms of hydroxylamino groups etherified
- C07C 251/36: with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 251/38: to carbon atoms of a saturated carbon skeleton
- C07C 251/58: of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 279/08: being further substituted by singly-bound oxygen atoms
- C07C 279/10: being further substituted by doubly-bound oxygen atoms
- C07C 281/16: Compounds containing any of the groups [IMAGE cpc-sch-C07C-0974.gif], e.g. aminoguanidine
- C07C 281/18: the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
- C07D 233/52: with hetero atoms directly attached to said nitrogen atoms
- C07B 2200/09: Geometrical isomers
- C07C 2601/14: The ring being saturated
- C07C 2602/24: the ring system containing nine carbon atoms, e.g. perhydroindane
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

1,5-Disubstituted 5a-methylperhydroinden-3a-ol derivatives of formula (I): ##STR1## where either the symbol - - - - represents a single bond, the group A is in cis configuration with respect to the 3a-hydroxy, 7a-methyl and 1-L groups, and A is (CH.dbd.CH).sub.m (CH.sub.2).sub.n OR, (CH.dbd.CH).sub.m (CH.sub.2).sub.n NR.sup.1 R.sup.2, (CH.dbd.CH).sub.m (CH.sub.2).sub.p B, OH, O(CH.sub.2).sub.q OR, O(CH.sub.2).sub.q NR.sup.1 R.sup.2 or O(CH.sub.2).sub.r B; q is an integer from 2 to 5; r is an integer from 1 to 2; or the symbol - - - - represents a double bond, A is oxygen, CH(CH.dbd.CH).sub.s (CH.sub.2).sub.n OR, CH(CH.dbd.CH).sub.s (CH.sub.2).sub.n NR.sup.1 R.sup.2 or CH(CH.dbd.CH).sub.s (CH.sub.2).sub.p B; and L is ›CH.dbd.C(R.sup.3)!.sub.s CH.dbd.NR.sup.4 or ›CH.dbd.C(R.sup.3)!.sub.s CH.sub.2 NHR.sup.4, in the E configuration, are useful for treating cardiovascular disorders such as heart failure and hypertension.

## Claims

### Claim 1

A 1,5 disubstituted 5a-methylperhydroinden-3a-ol derivative of formula (I), or a pharmaceutically acceptable salt thereof: ##STR7## wherein: either
the symbol - - - - represents a single bond,
the group A is in cis configuration with respect to the 3a-hydroxy, 7a-methyl and 1-L groups, and
A is (CH.dbd.CH).sub.m (CH.sub.2).sub.n OR, (CH.dbd.CH).sub.m (CH.sub.2).sub.n NR.sup.1 R.sup.2, (CH.dbd.CH).sub.m (CH.sub.2).sub.p B, OH, O(CH.sub.2).sub.q OR, O(CH.sub.2).sub.q NR.sup.1 R.sup.2 or O(CH.sub.2).sub.r B;
q is an integer from 2 to 5;
r is an integer from 1 to 2;
or
the symbol - - - - represents a double bond,
A is oxygen, CH(CH.dbd.CH).sub.s (CH.sub.2).sub.n OR, CH(CH.dbd.CH).sub.s (CH.sub.2).sub.n NR.sup.1 R.sup.2 or CH(CH.dbd.CH).sub.s (CH.sub.2).sub.p B;
R is hydrogen, unsubstituted C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkyl substituted by NR.sup.1 R.sup.2 ;
either
R.sup.1 and R.sup.2, which may be the same or different, are independently hydrogen or C.sub.1 -C.sub.4 alkyl;
B is a five-membered unsaturated or six-membered unsaturated or saturated monocarbocyclic ring and the monocarbocycle may be unsubstituted or substituted by one or more substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl, halogen, (CH.sub.2).sub.m OR, and (CH.sub.2).sub.m NR.sup.1 R.sup.2 ;
n is an integer from 1 to 6;
p is an integer from 0 to 2;
m is an integer from 0 to 2;
L is ›CH.dbd.C(R.sup.3)!.sub.s CH.dbd.NR.sup.4 or ›CH.dbd.C(R.sup.3)!.sub.s CH.sub.2 NHR.sup.4, in the E configuration;
s is 0 or 1;
R.sup.3 is hydrogen or CH.sub.3 ;
R.sup.4 is NHC(.dbd.NR.sup.5)NR.sup.6 R.sup.7 or OR.sup.8 ;
the symbol represents a Z or E configuration;
R.sup.5 is hydrogen or C.sub.1 -C.sub.4 alkyl, R.sup.6 and R.sup.7, which may be the same or different, are independently hydrogen, unsubstituted C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 substituted by NR.sup.9 R.sup.10 ;
R.sup.8 is hydrogen, CH.sub.3, unsubstituted C.sub.2 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkyl substituted with NR.sup.9 R.sup.10 or NHC(.dbd.NH)NH.sub.2 ; and
R.sup.9 and R.sup.10, which may be the same or different, are independently hydrogen or C.sub.1 -C.sub.4 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the symbol - - - - represents a single bond.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the symbol - - - - represents a double bond.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl.

### Claim 5 (depends on 1)

A compound according to claim 1, which is selected from:
(1S,3aS,5S,7aR)-1-›(E)-guanidinoimino!methyl-5-phenyl-7a-methylperhydroinde n-3a-ol
(1S,3aS,5S,7aR)-1-›(E)-hydroxyimino!methyl-5-phenyl-7a-methylperhydroinden- 3a-ol
(1S,3aS,5S,7aR)-1-›(E)-2-aminoethoxyimino!methyl-5-phenyl-7a-methylperhydro inden-3a-ol
(1S,3aS,5S,7aR)-1-›(E)-3-aminopropoxyimino!methyl-5-phenyl-7a-methylperhydr oinden-3a-ol
(1S,3aS,5S,7aR)-1-›(E)-4-aminobutoxyimino!methyl-5-phenyl-7a-methylperhydro inden-3a-ol
(1S,3aS,5S,7aR)-1-›(E)-2-dimethylaminoethoxyimino!methyl-5-phenyl-7a-methyl perhydroinden-3a-ol
(1S,3aS,5S,7aR)-1-›(E)-3-dimethylaminopropoxyimino!methyl-5-phenyl-7a-methy lperhydroinden-3a-ol
(1S,3aS,5S,7aR)-1-›(E)-4-dimethylaminobutoxyimino!methyl-5-phenyl-7a-methyl perhydroinden-3a-ol
(1S,3aS,5S,7aR)-1-›(E)-2-guanidinoethoxyimino!methyl-5-phenyl-7a-methylperh ydroinden-3a-ol
(1S,3aS,5S,7aR)-1-guanidinoaminomethyl-5-phenyl-7a-methylperhydroinden-3a-o
(1S,3aS,5S,7aR)-1-(2-aminoethoxyamino)methyl-5-phenyl-7a-methylperhydroinde n-3a-ol
(1S,3aS,5S,7aR)-1-(3-aminopropoxyamino)methyl-5-phenyl-7a-methylperhydroind en-3a-ol
(1S,3aS,5S,7aR)-1-(2-dimethylaminoethoxyamino)methyl-5-phenyl-7a-methylperh ydroinden-3a-ol
(1S,3aS,5S,7aR)-1-(3-dimethylaminopropoxyamino)methyl-5-phenyl-7a-methylper hydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E,E)-3-guanidinoimino -1-propenyl!-5-phenyl-7a-methylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E,E)-3-(2-aminoethoxyimino)-1-propenyl!-5-phenyl-7a-met hylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E,E)-3-(2-dimethylaminoethoxyimino)-1-propenyl!-5-pheny l-7a-methylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E)-3-guanidinoamino-1-propenyl!-5-phenyl-7a-methylperhy droinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E)(-3-(2-aminoethoxyamino!)-1-propenyl!-5-phenyl-7a-met hylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E)-3-(2-dimethylaminoethoxyamino)-1-propenyl!-5-phenyl- 7a-methylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E,E)-2-methyl-3-guanidinoimino-1-propenyl!-5-phenyl-7a- methylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E,E)-2-methyl-3-(2-aminoethoxyimino!)-1-propenyl!-5-phe nyl-7a-methylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E,E)-2-methyl-3-(2-dimethylaminoethoxyimino)-1-propenyl !-5-phenyl-7a-methylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E)-2-methyl-3-guanidinoamino-1-propenyl!-5-phenyl-7a-me thylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E)-2-methyl-3-(2-aminoethoxyamino!)-1-propenyl!-5-pheny l-7a-methylperhydroinden-3a-ol
(1R,3aS,5S,7aR)-1-›(E)-2-methyl-3-(2-dimethylaminoethoxyamino)-1-propenyl!- 5-phenyl-7a-methylperhydroinden-3a-ol.

### Claim 6 (depends on 1)

The compound of claim 1, wherein B is selected from the group consisting of phenyl, cyclopentyl and cyclohexyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the NR.sup.6 R.sup.7 group is selected from the group consisting of amino, methylamino, dimethylamino, pyrrolidinyl, piperidinyl, 2-dimethylaminoetil and 2-diethylaminoetil.

### Claim 8

A composition, comprising:
(a) a pharmaceutically acceptable carrier and/or diluent; and
(b) a 1,5 disubstituted 5a-methylperhydroinden-3a-ol derivative of formula (I), or a pharmaceutically acceptable salt thereof: ##STR8## wherein: either
the symbol - - - - represents a single bond,
the group A is in cis configuration with respect to the 3a-hydroxy, 7a-methyl and 1-L groups, and
A is (CH.dbd.CH).sub.m (CH.sub.2).sub.n OR, (CH.dbd.CH).sub.m (CH.sub.2).sub.n NR.sup.1 R.sup.2, (CH.dbd.CH).sub.m (CH.sub.2).sub.p B, OH, O(CH.sub.2).sub.q OR, O(CH.sub.2).sub.q NR.sup.1 R.sup.2 or O(CH.sub.2).sub.r B;
q is an integer from 2 to 5;
r is an integer from 1 to 2;
or the symbol - - - - represents a double bond,
A is oxygen, CH(CH.dbd.CH).sub.s (CH.sub.2).sub.n OR, CH(CH.dbd.CH).sub.s (CH.sub.2).sub.n NR.sup.1 R.sup.2 or CH(CH.dbd.CH).sub.s (CH.sub.2).sub.p B;
R is hydrogen, unsubstituted C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkyl substituted by NR.sup.1 R.sup.2 ;
either
R.sup.1 and R.sup.2, which may be the same or different, are independently hydrogen or C.sub.1 -C.sub.4 alkyl;
B is a five-membered unsaturated or six-membered unsaturated or saturated monocarbocyclic ring, and the monocarbocycle may be unsubstituted or substituted by one or more substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl, halogen, (CH.sub.2).sub.m OR, and (CH.sub.2).sub.m, NR.sup.1 R.sup.2 ;
n is an integer from 1 to 6;
p is an integer from 0 to 2;
m is an integer from 0 to 2;
L is ›CH.dbd.C(R.sup.3)!.sub.s CH.dbd.NR.sup.4 or ›CH.dbd.C(R.sup.3)!.sub.s CH.sub.2 NHR.sup.4, in the E configuration;
s is 0 or 1;
R.sup.3 is hydrogen or CH.sub.3 ;
R.sup.4 is NHC(.dbd.NR.sup.5)NR.sup.6 R.sup.7 or OR.sup.8 ;
the symbol represents a Z or E configuration;
R.sup.s is hydrogen or C.sub.1 -C.sub.4 alkyl, R.sup.6 and R.sup.7 which may be the same or different, are independently hydrogen, unsubstituted C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 substituted by NR.sup.9 R.sup.10 ; R.sup.8 is hydrogen, CH.sub.3, unsubstituted C.sub.2 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkyl substituted with NR.sup.9 R.sup.10 or NHC(.dbd.NH)NH.sub.2 ; and
R.sup.9 and R.sup.10, which may be the same or different, are independently hydrogen or C.sub.1 -C.sub.4 alkyl.