# US 5,344,834 A · Functionalized vinyl azoles and methods of use

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- Number: US 5,344,834 A
- Document ID: US5344834A
- Status: Granted
- Kind: A
- Application number: 07/802,639
- Filed: 1991-12-09
- Granted: 1994-09-06
- Earliest claimed: 1990-12-07
- Assignees: Schering Corporation
- Inventors: Peter Strehlke; Rolf Bohlmann; Martin Schneider; Yukishige Nishino; Hans-Peter Muhn-Seipoldy
- Web page: https://patentgrep.com/patent/US5344834A

## CPC

- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61P 9/08: Vasodilators for multiple indications
- 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 35/00: Antineoplastic agents
- 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)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Pharmaceutical preparations comprising functionalized vinyl azoles of formula I ##STR1## wherein the substituents are as defined herein, including novel compounds, as well as methods of use and methods of their preparation, are provided.

## Claims

### Claim 1

A pharmaceutical preparation comprising an effective amount of a vinyl azole of formula I ##STR17## wherein X is N or CH,
Y is S or CH.dbd.CH,
Z is cyano, and one of R.sup.1 or R.sup.2 is carboxyl unsterified or esterified with C.sub.1-10 straightchain, branched-chain or cyclic O-alkyl; or with O-aryl, wherein aryl is phenyl or naphthyl, unsubstituted or substituted by 1-3 C.sub.1-4 -alkyl or halogen; or with an O-aralkyl, wherein aryl and alkyl have the indicated meanings, carboxylic acid amide, wherein the carboxyl has the above-indicated meaning; unsubstituted or substituted with 1-2 same or different C.sub.1-10 straight-chain or branched-chain alkyl; or C.sub.6-10 aryl, unsubstituted or substituted by 1-3 C1-4 alkyl or halogen; and the amide N can also be part of a 5-8membered heterocyclic ring, containing no additional heteroatom or an additional ring heteroatom N, O or S, and the additional N is unsubstituted or substituted by R.sup.6, wherein R.sup.6 is H or C.sub.1-6 straight-chain or branched-chain alkyl, aldehyde, alkylketone --CO--R.sup.7, wherein R.sup.7 iS a straight-chain or branched-chain C.sub.1-10 alkyl or C.sub.3-12 cycloalkyl, arylketone --CO--R.sup.8, wherein R.sup.8 is phenyl, naphthyl or heteroaryl, unsubstituted or substituted 1-3 times by C.sub.1-4 alkyl, halogen, hydroxy or C.sub.1-4 alkoxy, sulfonamide, unsubstituted or substituted by R.sup.6, or cyano;
and the respective other R.sup.1 or R.sup.2 is hydrogen, C.sub.1-4 lower-alkyl or cycloalkyl, unsubstituted or substituted aryl, aralkyl, unesterified or esterified carboxyl, unsubstituted or substituted carboxylic acid amide, aldehyde, alkylketone or arylketone or cyano, each as defined above;
R.sup.1 and R.sup.2 together with the carbon atom on which they are bound form a 5-, 6- or 7-membered ring, which further contains a ketone, ester, lactone, lactam or imide, wherein at least one carbonyl is conjugated with a vinyl double bond; and
R.sup.3 is hydrogen; or
R.sup.3 together with R.sup.2 are
--O--C.dbd.O or --N--C.dbd.O, unsubstituted or substituted on the N,
wherein
the carbonyl is conjugated with a vinyl double bond, and a pharmaceutically acceptable excipient, wherein the preparation is in a unit dosage form for oral administration, is sterile for parenteral administration, or is a cream or ointment for topical administration.

### Claim 2 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein R.sup.1 or R.sup.2 is hydrogen.

### Claim 3 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein R.sup.1 and R.sup.2 together with the carbon on which they are bound form a 5-, 6- or 7-membered ring and R.sup.3 is hydrogen.

### Claim 4 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein R.sup.3 is hydrogen.

### Claim 5 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein R.sup.3 together with R.sup.2 are --O--C.dbd.O or --N--C.dbd.O .

### Claim 6 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein R.sup.1 and/or R.sup.2 are carboxyl esterified with a straight-chain or branchedchain or cyclic C.sub.1-10 O-alkyl, with O-aryl, and aryl is phenyl or naphthyl, unsubstituted or substituted one or more times by C.sub.1-4 lower-alkyl, F, CI, Br, I, or by O-aralkyl, wherein aryl and alkyl are as defined above.

### Claim 7 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein R.sup.1 and/or R.sup.2 are carboxylic acid amide substituted one or two times by same or different straight-chain or branched-chain C.sub.1-10 -alkyl, C.sub.6-10 -aryl radicals, unsubstituted or substituted up to three times by alkyl or halogen, or wherein both alkyls on the amidic nitrogen together with the amidic nitrogen form a 5- to 8-membered heterocyclic ring, containing no additional heteroatoms or an additional ring heteroatom N, O or S, and, if there is an additional N in the ring, it is unsubstituted or substituted by R.sup.6, wherein R.sup.6 is H or straight-chain or branched-chain C.sup.6 -alkyl.

### Claim 8 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein R.sup.1 and/or R.sup.2 is alkylketone --CO--R.sup.7, and R.sup.7 is straight-chain or branched-chain C.sub.1-10 alkyl or C.sub.3-12 -cycloalkyl.

### Claim 9 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein R.sup.1 and/or R.sup.2 is arylketone --CO--R.sup.8, and R.sup.8 is phenyl, naphthyl or heteroaryl unsubstituted or substituted by alkyl, halogen, hydroxy or alkoxy.

### Claim 10 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein R.sup.1 or R.sup.2 is sulfonamide --SO.sub.2 NR.sup.9 R.sup.10, and R.sup.9 and R.sup.10 are each, independently, a straight-chain or branched-chain C.sub.1-10 -alkyl, C.sub.8-10 -aryl, unsubstituted or substituted one to three times by alkyl or halogen, or wherein both alkyls on the amidic nitrogen together with the amidic nitrogen form a 5- to 8-membered heterocyclic ring, containing no additional heteroatoms or an additional ring heteroatom N, O or S, and, if there is an additional N in the ring, it is unsubstituted or substituted by R.sup.6, wherein R.sup.6 is H or straight-chain or branched-chain C.sub.1-6 -alkyl.

### Claim 11 (depends on 6)

A pharmaceutical preparation according to claim 6, wherein the carboxyl is esterified with methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, cyclohexyloxy, cyclopentyloxy, phenyloxy, or 2,6-dichlorophenoxy.

### Claim 12 (depends on 7)

A pharmaceutical preparation according to claim 7, wherein the carboxylic acid amide is substituted with methyl, ethyl, propyl, phenyl or benzyl; two methyls, ethyls or propyls; phenyl and methyl; phenyl and ethyl; or benzyl and methyl; or wherein the substituents on the amidic nitrogen together with the amidic nitrogen form a pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring.

### Claim 13 (depends on 8)

A pharmaceutical preparation according to claim 8, wherein R.sup.7 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl or cyclohexyl.

### Claim 14 (depends on 9)

A pharmaceutical preparation according to claim 9, wherein R.sup.8 is phenyl, hydroxyphenyl, methoxyphenyl or chlorophenyl.

### Claim 15 (depends on 10)

A pharmaceutical preparation according to claim 10, wherein R.sup.9 and R.sup.10 are methyl, ethyl, propyl, phenyl or benzyl; two methyls, ethyls or propyls; phenyl and methyl; phenyl and ethyl; or benzyl and methyl; or wherein the substituents on the amidic nitrogen together with the amidic nitrogen form a pyrrolidine, piperidine, piperazine, Nmethylpiperazine, morpholine or thiomorpholine ring.

### Claim 16 (depends on 15)

A pharmaceutical preparation according to claim 15, wherein R.sup.9 and R.sup.10 is each alkyl.

### Claim 17 (depends on 3)

A pharmaceutical preparation according to claim 3, wherein R.sup.1 and R.sup.2 together with the carbon on which they are bound form a ##STR18## wherein n is 2 or 3 and W is hydrogen or C.sub.1-6 -alkyl.

### Claim 18 (depends on 5)

A pharmaceutical preparation according to claim 5, wherein R.sup.2 and R.sup.3 together with the aromatic ring containing Y form a ##STR19## wherein W is hydrogen or alkyl.

### Claim 19 (depends on 1)

A pharmaceutical preparation according to claim 1, wherein the vinyl azole is
3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylic acid methyl ester,
3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylic acidtert-butyl ester,
E-3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylic acid,
E-3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylic acid piperidide,
E-3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylic acid methylamide,
3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylonitrile,
4-[1-(1-imidazolyl)-3-oxo-l-butenyl]-benzonitrile,
3-[(4-cyanophenyl)-(1-imidazolyl)-methylene]dihydro-2(3H)-furanone,
3-(5-cyano-2-thienyl)-3-(1-imidazolyl)-acrylic acidtert-butyl ester,
3-(5-cyano-2-thienyl)-3-(1-imidazolyl)acrylonitrile,
3-(4-cyanophenyl)-3-(1,2,4-triazol-l-yl)-acrylic acid-tert-butyl ester,
3-(4-cyanophenyl)-3-(1,2,4-triazol-l-yl)acrylonitrile, or
7-cyano-4-(1-imidazolyl)-coumarin;

### Claim 20 (depends on 1)

A pharmaceutical preparation of claim 1, which is sterile.

### Claim 21 (depends on 1)

A pharmaceutical preparation of claim 1, wherein, when one of R.sup.1 or R.sup.2 iS arylketone, the other is cycloalkyl, unsubstituted or substituted aryl, aralkyl, unesterified or esterified carboxyl, unsubstituted or substituted carboxylic acid amide, aldehyde, arylketone or cyano.

### Claim 22 (depends on 1)

A pharmaceutical preparation of claim 1, wherein the parenteral administration is in the form of a sterile depot injection.

### Claim 23 (depends on 1)

A pharmaceutical preparation of claim 1, wherein the parenteral administration is in the form of a sterile implant.

### Claim 24 (depends on 1)

A method of inhibiting estrogen biosynthesis comprising administering an effective amount of a pharmaceutical preparation of claim 1.

### Claim 25 (depends on 1)

A method of treating estrogen-induced or estrogen-dependent tumors, comprising administering an effective amount of a pharmaceutical preparation of claim 1.

### Claim 26 (depends on 1)

A method of treating estrogen-induced male infertility, comprising administering an effective amount of a pharmaceutical preparation of claim 1.

### Claim 27 (depends on 1)

A method of inhibiting ovulation, comprising administering an effective amount of a pharmaceutical preparation of claim 1.

### Claim 28

A vinyl azole of formula 1a ##STR20## wherein X is N or CH,
Y is S or CH.dbd.CH,
Z.sup.a is cyano and
R.sup.1a or R.sup.2a is carboxyl unesterified or esterified with C straightchain or branched-chain or cyclic 0-alkyl; or with O-aryl, wherein aryl is phenyl or naphthyl, unsubstituted or substituted 1-3 times by C.sub.1-4 -alkyl or halogen; or with O-aralkyl, wherein aryl and alkyl have the indicated meanings, carboxylic acid amide, wherein the carboxyl has the above-indicated meaning unsubstituted or substituted 1-2 times by same or different C.sub.1-10 straight-chain or branched-chain alkyl; or C.sub.6-10 aryl unsubstituted or substituted 1-3 times by C.sub.1-4 alkyl or halogen, and the amide N is optionally can be part of a 5-8membered heterocyclic ring, containing no additional heteroatom or an additional ring heteroatom N, O or S, and the additional N is unsubstituted or substituted by R.sup.6, wherein R.sup.6 is H or C.sub.1-6 straight-chain or branched-chain alkyl, aidehyde, arylketone -CO-R.sup.8, wherein R.sup.a is phenyl, naphthyl or heteroaryl, unsubstituted or substituted 1-3 times by C.sub.1-4 alkyl, halogen, hydroxy or C.sub.1-4 alkoxy, sulfonamide, unsubstituted or substituted by R.sup.6, or cyano and the respective other R.sup.TM or R.sup.2a is hydrogen, lower-alkyl or cycloalkyl, unsubstituted or substituted aryl, aralkyl, unesterified or esterified carboxyl, unsubstituted or substituted carboxylic acid amide, aldehyde, arylketone or cyano, each as defined above,
with the proviso that R.sup.TM and R.sup.2a are not simultaneously hydrogen and arylketone,
R.sup.2a and R.sup.2a together with the carbon on which they are bound form a 5-, 6- or 7-membered ring, which further contains a ketone, ester, lactone, lactam or imide, wherein at least one carbonyl is conjugated with a vinyl double bond; and
R.sup.3 [means]is hydrogen; or
R.sup.3 together with R.sup.2a are --OC --O--N--C .dbd.or unsubstituted or substituted on the N, wherein the carbonyl group is conjugated with a vinyl double bond.

### Claim 29 (depends on 28)

A pharmaceutical preparation comprising an effective amount of a compound of claim 28 and a pharmaceutically acceptable excipient.

### Claim 30 (depends on 28)

A vinyl azole of claim 28, wherein, when one of R.sup.1a or R.sup.2a is arylketone, the other is cycloalkyl, unsubstituted or substituted aryl, aralkyl, unesterified or esterified carboxyl, unsubstituted or substituted carboxylic acid amide, aldehyde, arylketone or cyano.