# US 5,703,109 A · Selective aromatase inhibiting compounds

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- Number: US 5,703,109 A
- Document ID: US5703109A
- Status: Granted
- Kind: A
- Application number: 08/436,389
- Filed: 1995-05-19
- Granted: 1997-12-30
- Earliest claimed: 1992-12-16
- Assignees: Orion-yhtyma Oy
- Inventors: Arto Johannes Karjalainen; Maria-Liisa Sodervall; Arja Marketta Kalapudas; Reino Olavi Pelkonen; Aire Maria Laine; Risto Arvo Sakari Lammintausta; Jarmo Sakari Salonen
- Web page: https://patentgrep.com/patent/US5703109A

## CPC

- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- A61P 3/06: Antihyperlipidemics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/08: of the prostate
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 233/56: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

New compounds of formula (I) wherein R.sub.1 is H, CH.sub.3, OCH.sub.3, NO.sub.2, NH.sub.2, CN, CF.sub.3, CHF.sub.2, CH.sub.2 F or halogen, R.sub.2 is a heterocyclyl radical selected from 1-imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl and isothiazolyl, R.sub.3 is H or OH, R.sub.4 is H, R.sub.5 is H or OH; or R.sub.4 is H and R.sub.3 and R.sub.5 combined form a bond; or R.sub.3 is H and R.sub.4 and R.sub.5 combined form --(O); R.sub.6 is methylene, ethylene, --CHOH--, --CH.sub.2 --CHOH--, --CHOH--CH.sub.2 --, --CH--CH-- or --C(--O)--; or R.sub.4 is H and R.sub.5 and R.sub.6 combined is --CH-- or --CH--CH.sub.2 --; stereoisomers thereof and non-toxic pharmaceutically acceptable acid addition salts thereof exhibit selective aromatase inhibiting properties, compared with their desmolase inhibiting properties. The compounds of the invention are valuable in the treatment of estrogen dependent diseases, e.g. breast cancer or benign prostatic hyperplasia (BPH).

## Claims

### Claim 1

A compound of formula (I) ##STR20## wherein R.sub.1 is H, CH.sub.3, OCH.sub.3, NO.sub.2, NH.sub.2, CN, CF.sub.3, CHF.sub.2, CH.sub.2 F or halogen; R.sub.2 is 1,2,4-triazolyl, R.sub.3 is H or OH, R.sub.5 is H or OH; R.sub.6 is methylene, ethylene, --CHOH--, --CH.sub.2 --CHOH-- or --CHOH--CH.sub.2 --; or a stereoisomer; or a non-toxic pharmaceutically acceptable acid addition salt thereof with the proviso that when R.sub.3 and R.sub.5 are H, R.sub.6 cannot be methylene or ethylene.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R.sub.3 is OH and R.sub.5 is H and R.sub.6 is methylene or ethylene.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R.sub.3, R.sub.4 and R.sub.5 are H and R.sub.6 is --CHOH--, --CH.sub.2 --CHOH-- or --CHOH--CH.sub.2 --.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R.sub.2 is 1-1,2,4-triazolyl.

### Claim 5 (depends on 1)

A compound according to claim 1 which is 1-›1-(4-cyano-phenyl)-3-(4-fluorophenyl)-2-hydroxypropyl!-1,2,4-triazole, a stereoisomer or a non-toxic pharmaceutically acceptable acid addition salt thereof.

### Claim 6 (depends on 1)

A compound according to claim 1 which is 1-›1-(4-cyano-phenyl)-4-(4-fluorophenyl)-2-hydroxybutyl!-1,2,4-triazole, a stereoisomer or a non-toxic pharmaceutically acceptable acid addition salt thereof.

### Claim 7 (depends on 1)

A compound according to claim 1 which is 1-›1-(4-cyano-phenyl)-3-(4-fluorophenyl)-3-hydroxypropyl!-1,2,4-triazole, a stereoisomer or a non-toxic pharmaceutically acceptable acid addition salt thereof.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.

### Claim 9 (depends on 1)

A method of inhibiting aromatase comprising administering to a subject in which such inhibition is desired, an mount of a compound as claimed in claim 1 to produce the desired inhibition.

### Claim 10

A process for the preparation of a compound of formula ##STR21## wherein R.sub.1 is H, CH.sub.3, OCH.sub.3, NO.sub.2, NH.sub.2, CN, CF.sub.3, CHF.sub.2, CH.sub.2 F or halogen, R.sub.2 is 1,2,4-triazolyl R.sub.6 is methylene or ethylene; or a stereoisomer; or a non-toxic pharmaceutically acceptable acid addition salt thereof which comprises reacting a compound of formula ##STR22## wherein R.sub.7 is CN or a functional group which may be converted to CN, with an ester of formula ##STR23## wherein R' is lower alkyl and n is 1 or 2, in the presence of a strong base, to give a compound of formula ##STR24## and further reducing this compound to give a compound of formula ##STR25## and converting R.sub.7 when not CN to CN and deprotecting the optional N-protection of the heterocyclyl group, and if desired separating and/or isolating stereoisomers thereof and/or converting the compounds of the invention to their non-toxic pharmaceutically acceptable acid addition salts or converting the acid addition salts to free compounds.

### Claim 11 (depends on 10)

A process according to claim 10 which comprises preparing 1-›1-(4-cyanophenyl)-3-(4-fluorophenyl)-2-hydroxypropyl!-1,2,4-triazole, a stereoisomer or a non-toxic pharmaceutically acceptable acid addition salt thereof.

### Claim 12 (depends on 10)

A process according to claim 10 which comprises preparing 1-›1-(4-cyanophenyl)-4-(4-fluorophenyl)-2-hydroxybutyl!-1,2,4-triazole, a stereoisomer or a non-toxic acid addition salt thereof.

### Claim 13 (depends on 1)

A compound according to claim 1, wherein R.sub.2 is halogen.

### Claim 14 (depends on 13)

A compound according to claim 13, wherein R.sub.1 is fluorine.

### Claim 15 (depends on 1)

A compound according to claim 1, wherein R.sub.3 is H, R.sub.5 is OH, R.sub.6 is methylene or ethylene.

### Claim 16 (depends on 15)

A compound according to claim 15, wherein R.sub.1 is halogen.