Substituted benzolactam compounds as substance P antagonists

Details Substituted benzolactam compounds as substance P antagonists Substituted benzolactam compounds as substance P antagonists

2000-06-28

2001-09-11

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

Reexamination Certificate

active

06288225

ABSTRACT:

TECHNICAL FIELD
This invention relates to substituted benzolactam and cyclicthioamide compounds of interest to those in the field of medical chemistry and chemotherapy. More particularly, it is concerned with a series of substituted benzolactam and cyclicthioamide compounds, including their pharmaceutically acceptable salts, which are of special value in view of their ability to antagonize substance P. These compounds are of use in treating gastrointestinal disorders, central nervous system (CNS) disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine, angiogensis or the like, especially CNS disorders in a mammalian subject, especially humans.
BACKGROUND ART
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specially, substance P is a pharmaceutically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine, as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, and in gastrointestinal disorders and diseases of GI tract, like ulcerative colitis and Cromhn's diseases, etc. It is also reported that the tachykinin antagonists are useful for the treatment of allergic conditions, immunoregulation, vasodilation, bronchospasm, reflex or neuronal control of the viscera and senile dementia of the Alzheimer type, emesis, sunburn and
Helicobacter pylori
infection.
International Publication No. WO 94/13663 discloses a wide variety of azaheterocyclic compounds as tachykinin antagonists such as substance P antagonists. However, none of the compounds specifically disclosed in the references have good activity against CNS disorders with decreased adverse effects (e.g., Ca
2+
channel binding affinity).
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides substituted benzolactam and cyclicthioamide compounds of the following chemical formula (I):
and its pharmaceutically acceptable salts, wherein
W is methylene, ethylene, propylene, vinylene, —CH
2
—O—, —O—CH
2
—, —CH
2
—S— or —S—CH
2
—;
R
1
, R
2
and R
3
are independently hydrogen, C
1
-C
3
alkyl, C
1
-C
3
alkoxy or halo C
1
-C
3
alkyl, provided that when W is methylene, both R
2
and R
3
are not hydrogen;
X is halo, C
1
-C
3
alkoxy, C
1
-C
3
alkyl, halo C
1
-C
3
alkoxy or C
1
-C
3
alkenyl;
Y is imino or oxy;
Q is oxygen or sulfur; and
T is (2S,3S)-2-diphenylmethylquinuclidin-3-yl, (2S,3S)-2-phenylpiperidin-3-yl or (2S,3S)-2-diphenylmethyl-1-azanorbornan-3-yl.
Also, this invention includes an intermediate compound useful for preparation of the compounds of formula (I), which is (2S,3S)-3-amino-1-(tert-butoxycarbonyl)-2-phenylpiperidine.
The compounds of the present invention of formula (I) exhibit good antagonist activity toward Substance P, particularly good activity agaisnt CNS disorders with decreased side effects (e.g., Ca
2+
channel affinity), and are thus useful for treatment of a gastrointestinal disorder, a central nervous system disorder, an inflammatory disease, emesis, urinary incontinence, pain, migraine or angiogensis in a mammalian subject, especially human.
Accordingly, the present invention provides a pharmaceutical composition for the treatment of a gastrointestinal disorder, a central nervous system disorder, an inflammatory disease, emesis, urinary incontinence, pain, migraine or angiogensis in a mammalian subject, which comprises a therapeutically effective amount of a compound of the formula (I) together with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
In this specification,
the term “halo C
1
-C
3
alkyl” is used herein to mean a C
1
-C
3
alkyl radical substituted with one or more halogens (e.g., Cl, F, I or Br) including, but not limited to, chloromethyl, trifluoromethyl, 2,2,2-trichloroethyl and the like; and
the term “halo C
1
-C
3
alkoxy” is used herein to mean a C
1
-C
3
alkoxy radical substituted with one or more halogens (e.g., Cl, F, I or Br) including, but not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and the like.
A preferred group of compounds of this invention includes the compounds of formula (I) wherein R
1
, R
2
and R
3
are independently hydrogen, C
1
-C
3
alky, C
1
-C
3
alkoxy or halo C
1
-C
3
alkyl, provided that when W is methylene, both R
2
and R
3
are not hydrogen; X is C
1
-C
3
alkoxy or halo C
1
-C
3
alkoxy; Y is imino; and T is (2S,3S)-2-diphenylmethylquinuclidin-3-yl or (2S,3S)-2-phenylpiperidin-3-yl.
A particularly preferred group of compounds of the invention includes the compounds of formula (I), wherein R
1
is methyl, isopropyl, methoxy or 2,2,2-trifuluoroethyl; R
2
and R
3
are independently hydrogen, methyl or trifluoromethyl, provided that when W is methylene, both R
2
and R
3
are not hydrogen; and X is methoxy, isopropoxy, difluoromethoxy or trifuluoromethylmethoxy. When W is methylene, T—Y—CH
2
— and X are preferably at 5- or 6-position on the benzolactam ring.
When W is ethylene or vinylene, T—Y—CH
2
— and X are preferably at 6- or 7-position on the benzolactam ring. When W is —CH
2
—O—, —O—CH
2
—, —CH
2
—S— or —S—CH
2
—, X and T—Y—CH
2
— are preferably at 6- or 7-position on the benzoxadine and benzothiadine ring. When W is propylene, X and T—Y—CH
2
— are preferably 7- or 8-position on the benzazepin ring, respectively.
Preferred individual compounds of this invention are the following:
(2S,3S)-3-(6-methoxy-1,3,3-trimethyloxindol-5-yl)methylamino-2-phenylpiperidine or its salts;
(2S,3S)-3-(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methylamino-2-phenylpiperidine or its salts;
(2S,3S)-3-(6-isopropoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methylamino-2-phenylpiperidine or its salts;
(2S,3S)-3-(1-isopropyl-6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methylamino-2-phenylpiperidine or its salts;
(2S,3S)-3-[(6-methoxy-1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride or its salts;
(2S,3S)-3-[(7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino-2-phenylpiperidine dihydrochloride or its salts; and
(2S,3S)-3-[(6-methoxy-1-methyl-2-oxo-4H-3,1-benzothiazin-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride or its salts.
Particularly preferred individual compounds of this invention are the following:
(2S,3S)-2-diphenylmethyl-3-(6-methoxy-1,3,3-trimethyloxindol-5-yl)methylamino-1-azabicyclo[2.2.2]octane or its salts;
(2S,3S)-2-diphenylmethyl-3-(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methylamino-1-azabicyclo[2.2.2]octane or its salts;
(2S,3S)-2-diphenylmethyl-3-(6-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)methylamino-1-azabicyclo[2.2.2]octane or its salts;
(2S,3S)-3-[(6-methoxy-1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride or its salts; and
(2S,3S)-3-[(6-methoxy-1-methyl-2-oxo-4H-3,1-benzothiazin-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride or its salts.
General Synthesis
The compounds of the formula (I) of this invention may be prepared as described in the following reaction schemes.
Unless otherwise indicated, in the reaction schemes that follow, R
1
, R
2
, R
3
, X, Y, Z, W, Q and T are defined as above.
Scheme A-I illustrates a method for preparing compounds of the formula (I) by reductive amination of a compound of the formula (II) with a compound of the formula: T—NH
2
(Y═NH). The reduction can be carried out by catalytic hydrogenatio

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