Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-12-20
2004-09-07
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S105000, C544S132000, C544S173000, C544S350000, C544S353000, C544S366000, C544S374000, C544S360000, C544S384000, C544S389000, C544S396000
Reexamination Certificate
active
06787543
ABSTRACT:
TECHNICAL FIELD
The present invention relates to new benzhydryl derivatives and a salt thereof.
More particularly, it relates to new benzhydryl derivatives and a salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same as a medicament.
Accordingly, one object of the present invention is to provide new and useful benzhydryl derivatives and a salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like.
Another object of the present invention is to provide a process for the preparation of said benzhydryl derivatives and a salt thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said benzhydryl derivatives and a pharmaceutically acceptable salt thereof.
Still further object of the present invention is to provide a use of said benzhydryl derivatives or a pharmaceutically acceptable salt thereof as Tachykinin antagonist, especially Substance P antagonist, Neurokinin A antagonist or Neurokinin B antagonist, useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, couph, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g., migraine, headache, toothache, cancerous pain, back pain, etc.); and the like in human being or animals.
DISCLOSURE OF INVENTION
The object compound of the present invention can be represented by the following general formula (I):
in which R
1
and R
2
are independently hydrogen, halogen, lower alkoxy, lower alkyl or mono(or di or tri)halo(lower)alkyl,
R
10
is hydrogen or lower alkyl optionally substituted with lower alkoxy, carbamoyl or phenyl,
R
11
, R
12
, R
13
and R
14
are independently hydrogen, lower alkoxycarbonyl or lower alkyl optionally substituted with hydroxy or lower alkoxy, and
R
10
and R
14
optionally forming —(CH
2
)
i
—CHR
15
—(CH
2
)
j
—, —(CH
2
)
i
—NR
16
—(CH
2
)
j
—, —(CH
2
)
i
—O—CH
2
—CO— or —(CH
2
)
i
—O—(CH
2
)
j
—, wherein i and j are independently 1 or 2, R
15
is hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino or di(lower)alkylamino and R
16
is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, benzyloxycarbonyl, lower alkylsulfonyl or mono(or di or tri)halo(lower)alkylsulfonyl, or
R
12
and R
13
optionally forming —(CH
2
)
i
—CHR
15
—(CH
2
)
j
—, wherein i, j and R
15
are defined as above, or
R
13
and R
14
optionally forming oxo or two to five methylenes,
in which R
3
, R
4
and R
5
are independently hydrogen; halogen; lower alkyl; mono(or di or tri)halo(lower)alkyl; cyano; lower alkoxycarbonyl; lower alkylthio; lower alkylsulfonyl; hydroxy; lower alkoxy optionally substituted with lower alkoxy, lower alkoxycarbonyl, carbamoyl, cyano, phenyl or one, two or three halogen(s); lower alkenyloxy; cyclo(lower)alkyloxy; nitro; lower alkylamino; di(lower)alkylamino; or imidazolyl, pyrazolyl, thienyl, thiazolyl, furyl, tetrazolyl, pyridyl or phenyl, each of which may have a substituent selected from a group which consists of lower alkyl, mono(or di or tri)halo(lower)alkyl, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkylamino and di(lower)alkylamino, and
R
6
and R
7
are independently hydrogen or halogen, and
R
8
is hydrogen or lower alkyl.
It is to be noted that the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention
It is further to be noted that isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.
It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
According to the present invention, the object compound (I) or a salt thereof can be prepared by processes which are illustrated in the following schemes.
wherein
Z, R
1
, R
2
, R
8
and R
16
are each as defined above, and
W
1
is a leaving group.
As to the starting compounds (II) and (III), some of them are novel and can be prepared by the procedures described in the Preparations and Examples mentioned later or similar manners thereto.
Suitable salts of the starting and object compounds are conventional non-toxic and pharmaceutically acceptable salt and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), or a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.), or the like.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term “lower” is intended to mean 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise indicated.
Suitable “halogen” and “halogen” moiety in the terms “mono(or di or tri)halo(lower)alkyl”, “mono(or di or tri)halo(C
1
-C
4
)alkyl”, etc. may include fluorine, chlorine, bromine and iodine.
Suitable “lower alkyl” and “lower alkyl” moiety in the terms “mono(or di or tri)halo(lower)alkyl”, “lower alkylamino”, etc. may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like, in which the preferred one is C
1
-C
4
alkyl and the most preferred one is methyl, ethyl or isopropyl.
Suitable “mono(or di or tri)halo(lower)alkyl” and “mono(or di or tri)halo(lower)alkyl” moiety in the term “mono(or di or tri)halo(lower)alkylsulfonyl” may include chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 or 2-chloroethyl, 1 or 2-bromoethyl, 1 or 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and the like.
Suitable “cyclo(lower)alkyl” and “cyclo(lower)alkyl” moiety in the term “cyclo(lower)alkyloxy” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Suitable “lower alkenyl” moiety in the term “lower alkenyloxy” may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)-butenyl, and the like, in which more preferable example may be C
2
-C
4
alkenyl.
Suitable “lower alkoxy” and “lower alkoxy” moiety in the terms “lower alkoxycarbonyl”, etc. may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like, in which the preferred one is C
1
-C
4
alkoxy and
Azami Hidenori
Eikyu Yoshiteru
Kasahara Chiyoshi
Morita Masataka
Nakai Kazuo
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Ramsuer Robert W.
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