# US 5,104,876 A · Benzopyrido piperidine, piperidylidene and piperazine compounds, compositions, methods of manufacture and methods of use

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- Number: US 5,104,876 A
- Document ID: US5104876A
- Status: Granted
- Kind: A
- Application number: 07/598,667
- Filed: 1990-10-26
- Granted: 1992-04-14
- Earliest claimed: 1988-04-28
- Assignees: Schering Corporation
- Inventors: John J. Piwinski; Jesse K. Wong; Michael J. Green; Ashit K. Ganguly; Frank J. Villani
- Web page: https://patentgrep.com/patent/US5104876A

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 491/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Novel benzopyrido piperidiene, piperidylidene and piperazine compounds of the generalized formula ##STR1## are disclosed as useful for the treatment of asthma, allergy and inflammation. Novel pharmaceutical compositions containing such compounds and processes for producing the compounds are also disclosed.

## Claims

### Claim 1

A compound represented by the structural formula ##STR97## or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d represents nitrogen or --NR.sup.11, where R.sup.11 is --O.sup.-, --CH.sub.3, or --(CH.sub.2).sub.p CO.sub.2 H where p is 1 to 3, and the remaining a, b, c and d groups are CH which may be optionally substituted with R.sup.1 or R.sup.2 ;
R.sup.1 and R.sup.2 may be the same or different and each independently represents halo, --CF.sub.3, --OR.sup.10, --C(O)R.sup.10, --S(O).sub.e R.sup.12 where e is 0, 1 or 2, --N(R.sup.10).sub.2, --NO.sub.2, SH, CN, --OC(O)R.sup.10, --CO.sub.2 R.sup.10, --OCO.sub.2 R.sup.12, --NR.sup.10 C(O)R.sup.10, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.12 alkenyl or C.sub.2 -C.sub.12 alkynyl, which alkyl or alkenyl groups may be substituted with halo, --OR.sup.10 or --CO.sub.2 R.sup.10, or R.sup.1 and R.sup.2 may together form a benzene ring fused to the pyridine ring;
R.sup.10 represents H, C.sub.1 -C.sub.20 alkyl or C.sub.6 -C.sub.15 aryl;
R.sup.12 represents C.sub.1 -C.sub.20 alkyl or C.sub.6 -C.sub.15 aryl;
R.sup.3 and R.sup.4 may be the same or different and each independently represents H or any of the substituents of R.sup.1 and R.sup.2, or
R.sup.3 and R.sup.4 may be taken together to represent a saturated or unsaturated C.sub.5 -C.sub.7 ring fused to the benzene ring;
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each independently represents H, --CF.sub.3, --CO.sub.2 R.sup.10, --C(O)R.sup.10, C.sub.1 -C.sub.20 alkyl or C.sub.6 -C.sub.15 aryl, which alkyl or aryl may be substituted with --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --NO.sub.2, --C(O)R.sup.10, --OC(O)R.sup.12, --OCO.sub.2 R.sup.12, --CO.sub.2 R.sup.10 and --OPO.sub.3 (R.sup.10).sub.2, or one of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 may be taken in combination with R as defined below to represent --(CH.sub.2).sub.r --where r is 1 to 4, said combination being optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --CF.sub.3 or C.sub.6 -C.sub.15 aryl, or R.sup.5 may be combined with R.sup.6 to represent .dbd.O or .dbd.S, and/or R.sup.7 may be combined with R.sup.8 to represent .dbd.O or .dbd.S;
T represents carbon or nitrogen, with the dotted line attached to T representing an optional double bond when T is carbon;
m and n are integers 0, 1, 2, or 3, such that the sum of m plus n equals 0 to 3;
when m plus n equals 1, X represents --O--, --S(O).sub.e --wherein e is 0, 1 or 2, --NR.sup.10 --, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, --C(S)NR.sup.10 --, --NR.sup.10 C(S)--, --CO.sub.2 --or --O.sub.2 C--, where R.sup.10 is a defined above;
when m plus n equals 2, X represents --O--, --S(O).sub.e --where e is 0, 1 or 2, or --NR.sup.10 ;
when m plus n represents 0, X can be any substituent for m plus n equalling 1 and X can also be a direct bond, cyclopropylene or propenylene;
when m plus n equals 3 then X equals a direct bond;
each R.sup.a may be the same of different, and each independently represents H, C.sub.1 -C.sub.6 alkyl or phenyl;
Z represents .dbd.O, .dbd.S or .dbd.NR.sup.13 with R.sup.13 equal to R.sup.10 or --CN, wherein R.sup.10 is as defined above, such that
(a) when Z is O, R may be taken in combination with R.sup.5, R.sup.6, R.sup.7 or R.sup.8 as defined above, or R represents H, C.sub.1 -C.sub.20 alkyl, C.sub.6 -C.sub.15 aryl, --SR.sup.12, --N(R.sup.10).sub.2, C.sub.3 -C.sub.20 cycloalkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl or --D wherein --D represents C.sub.3 -c.sub.15 heterocycloalkyl, ##STR98## wherein R.sup.3 and R.sup.4 are as previously defined and W is O, S or NR.sup.10, and where Y is N or NR.sup.11,
said cycloalkyl, alkyl, alkenyl and alkynyl being optionally substituted with from 1-3 groups selected from halo, --CON(R.sup.10).sub.2, C.sub.6 -C.sub.15 aryl, --CO.sub.2 R.sup.10, --OR.sup.14, --SR.sup.14, --N(R.sup.10).sub.2, --N(R.sup.10)CO.sub.2 R.sup.10, --COR.sup.14, --NO.sub.2 or --D, wherein --D and R.sup.10 are as defined above and R.sup.14 represents R.sup.10, --(CH.sub.2).sub.r OR.sup.10 or --(CH.sub.2).sub.q CO.sub.2 R.sup.10 wherein r is 1 to 4, q is 0 to 4; said alkenyl and alkynyl R groups not containing --OH, --SH or --N(R.sup.10).sub.2 on a carbon in a double or triple bond respectively; and
(b) when Z represents .dbd.S, R represents in addition to those R groups above, C.sub.6 -C.sub.15 aryloxy or C.sub.1 -C.sub.20 alkoxy; and
(c) where Z represents .dbd.NR.sup.50, R represents H, C.sub.1 -C.sub.20 alkyl, C.sub.6 -C.sub.15 aryl, N(R.sup.10).sub.2, C.sub.3 -C.sub.20 cycloalkyl, C.sub.2 -C.sub.12 alkenyl or C.sub.2 -C.sub.12 alkynyl.

### Claim 2 (depends on 1)

A compound as defined in claim 1 wherein d represents nitrogen or NO, and the a, b and c groups are CH which may be substituted with R.sup.1 or R.sup.2.

### Claim 3 (depends on 1)

A compound as defined in claim 1 further characterized by one of R.sup.3 and R.sup.4 being halo, alkyl, --CF.sub.3 or --OR.sup.10.

### Claim 4 (depends on 3)

A compound as defined in claim 3 further characterized by R.sup.5, R.sup.6, R.sup.7 and R.sup.8 being H or alkyl.

### Claim 5 (depends on 4)

A compound as defined in claim 4 further characterized by m plus n equalling 1, and X representing --O--, --S(O).sub.e --, where e is 0, 1 or 2.

### Claim 6 (depends on 4)

A compound as defined in claim 4 above further characterized by m plus n being zero, and X representing a direct bond, cyclopropylene, propenylene, --O--or --S(O).sub.e --with e equal to 0, 1 or 2.

### Claim 7 (depends on 4)

A compound as defined in claim 4 above further characterized m plus n equalling 3 and X being a direct bond.

### Claim 8 (depends on 1)

A compound as defined in claim 1 further characterized by T being carbon and the dotted line attached to T representing a double bond.

### Claim 9 (depends on 1)

A compound as defined in claim 1 further characterized by T being nitrogen.

### Claim 10 (depends on 1)

A compound as defined in claim 1 further characterized by Z being O and R representing H, alkyl, or D.

### Claim 11 (depends on 1)

A compound as defined in claim 1 having the name:
1-acetyl-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine;
1-acetyl-4-(8-chloro-5,11-dihydro[1]benzoxepino [4,3]pyridin-11-ylidene)piperidine;
1-acetyl-4-(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)piperidine;
4(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)-1-piperidine carboxaldehyde;
1-acetyl-4-(5H-[1]benzopyrano[2,3-b]pyridin-5-ylidene)piperidine;
1-acetyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12-ylidene )piperidine;
1-methoxyacetyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12- ylidene)piperidine;
11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4, 3-b]pyridine;
11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4, 3-b]pyridine 1,6-dioxide;
11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4, 3-b]pyridine 6,6-dioxide;
11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4, 3-b]pyridine -6-oxide;
11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4, 3-b]pyridine -1,6,6-trioxide;
1-acetyl-4-(9H-indeno[2,1-b]pyridin-9-yl)piperazine; and
1-(4-pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta[1,2b]pyridin-1 2-ylidene)piperidine N'-oxide.

### Claim 12 (depends on 1)

A method of treating asthma, allergy and/or inflammation comprising administering to a mammal in need of such treatment an antiallergic effective amount of a compound as defined in claim 1.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a compound of formula I as defined in claim 1 in combination with a pharmaceutically acceptable carrier wherein the active compound in a unit dose is about 0.01 mg to 2000 mg.