N-Acylpiperidines of general structure ##STR1## are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis.

SUMMARY OF THE INVENTION 
This invention is concerned with novel compounds represented by structural 
formula I: 
##STR2## 
wherein X.sup.1, X.sup.2, R.sup.1a, R.sup.1b, R.sup.2a, R.sup.2b, R.sup.3, 
R.sup.4, R.sup.5, and R.sup.6 are hereinafter defined. 
The invention is also concerned with pharmaceutical formulations with these 
novel compounds as active ingredients and the use of the novel compounds 
and their formulations in the treatment of certain disorders. 
The compounds of this invention have activity as tachykinin receptor 
antagonists and are useful in the treatment of inflammatory diseases, pain 
or migraine, asthma and emesis. 
Also, some of these compounds are calcium channel blockers and are useful 
in the treatment of cardiovascular disorders such as angina, hypertension 
or ischemia. 
BACKGROUND OF THE INVENTION 
Analgesia has historically been achieved in the central nervous system by 
opiates and analogs which are addictive, and peripherally by 
cyclooxygenase inhibitors that have gastric side effects. Substance P 
antagonists may induce analgesia both centrally and peripherally. In 
addition, substance P antagonists are inhibitory of neurogenic intimation. 
The neuropeptide receptors for substance P (neurokinin-1; NK-1) are widely 
distributed throughout the mammalian nervous system (especially brain and 
spinal ganglia), the circulatory system and peripheral tissues (especially 
the duodenum and jejunum) and are involved in regulating a number of 
diverse biological processes. This includes sensory perception of 
olfaction, vision, audition and pain, movement control, gastric motility, 
vasodilation, salivation, and mictrition (B. Pernow, Pharmacol. Rev., 
1983, 35, 85-141 ). The NK1 and NK2 receptor subtypes are implicated in 
synaptic transmission (Laneuville et al., Life Sci., 42:1295-1305 (1988)). 
The receptor for substance P is a member of the superfamily of G 
protein-coupled receptors. This superfamily is an extremely diverse group 
of receptors in terms of activating ligands and biological functions. In 
addition to the tachykinin receptors, this receptor superfamily includes 
the opsins, the adrenergic receptors, the muscarinic receptors, the 
dopamine receptors, the serotonin receptors, a thyroid-stimulating hormone 
receptor, a luteinizing hormone-choriogonadotropic hormone receptor, the 
product of the oncogene ras, the yeast mating factor receptors, a 
Dictyostelium cAMP receptor, and receptors for other hormones and 
neurotransmitters (see A. D. Hershey, et al., J. Biol. Chem., 1991, 226, 
4366-4373). 
Substance P (also called "SP" herein) is a naturally occurring 
undecapeptide belonging to the tachykinin family of peptides, the latter 
being so-named because of their prompt contractile action on extravascular 
smooth muscle tissue. The tachykinins are distinguished by a conserved 
carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH.sub.2. In addition to SP 
the known mammalian tachykinins include neurokinin A and neurokinin B. The 
current nomenclature designates the receptors for SP, neurokinnin A, and 
neurokinin B as NK-1, NK-2, and NK-3, respectively. 
More specifically, substance P is a pharmacologically-active neuropeptide 
that is produced in mammals and possesses a characteristic amino acid 
sequence (Chang et al., Nature New Biol. 232, 86 (1971); D. F. Veber et 
al., U.S. Pat. No 4,680,283). 
Substance P acts as a vasodilator, a depressant, stimulates salivation and 
produces increased capillary permeability. It is also capable of producing 
both analgesia and hyperalgesia in animals, depending on dose and pain 
responsiveness of the animal (see R. C. A. Frederickson et al., Science, 
199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)) and plays a 
role in sensory transmission and pain perception (T. M. Jessell, Advan. 
Biochem. Psychopharmacol. 28, 189 (1981 )). For example, substance P is 
believed inter alia to be involved in the neurotransmission of pain 
sensations [Otsuka et al, "Role of Substance P as a Sensory Transmitter in 
Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous 
System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and 
Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS 
(Dec. 1987) 8 506-510]. In particular, substance P has been shown to be 
involved in the transmission of pain in migraine (see B. E. B. Sandberg et 
al., Journal of Medicinal Chemistry, 25, 1009 (1982)), and in arthritis 
(Levine et al. Science, (1984) 226 547-549). These peptides have also been 
implicated in gastrointestinal (GI) disorders and diseases of the GI 
tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's 
disease, etc. (see Mantyh et al., Neuroscience, 25 (3), 817-37 (1988) and 
D. Regoli in "Trends in Cluster Headache" Ed. F. Sicuteri et al., Elsevier 
Scientific Publishers, Amsterdam, 1987, pp. 85-95). 
Substance P may play a role in a neurogenic mechanism for arthritis (Kidd 
et al., "A Neurogenic Mechanism for Symmetric Arthritis" in The Lancet, 11 
Nov. 1989 and Gronblad et al., "Neuropeptides in Synovium of Patients with 
Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12) 
1807-10). Therefore, substance P may be involved in the inflammatory 
response in diseases such as rheumatoid arthritis and osteoarthritis 
(O'Byme et al., in Arthritis and Rheumatism (1990) 33 1023-8). 
Evidence for the usefulness of tachykinin receptor antagonists in pain, 
headache, especially migraine, Alzheimer's disease, multiple sclerosis, 
attenuation of morphine withdrawal, cardivascular changes, oedema, such as 
oedema caused by thermal injury, chronic inflammatory diseases such as 
rheumatoid arthritis, asthma/bronchial hyperreactivity and other 
respiratory diseases including allergic rhinitus, inflammatory diseases of 
the gut including ulcerative colitis and Crohn's disease, ocular injury 
and ocular inflammatory diseases, proliferative vitreoretinopathy, 
irritable bowel syndrome and disorders of bladder function including 
cystitis and bladder detruser hyperreflexia is reviewed in "Tachykinin 
Receptors and Tachykinin Receptor Antagonists," C. A. Maggi, R. 
Patacchini, P. Rovero and A. Giachetti, J. Auton. Pharmacol, (1993) 13, 
23-93. Neurokinin-1 receptor antagonists alone or in combination with 
bradykinin receptor antagonists may also be useful in the prevention and 
treatment of inflammatory conditions in the lower urinary tract, 
especially cystitis (Giuliani, et al., J. Urology, 150, 1014-1017 (1993)). 
Other disease areas where tachykinin antagonists are believed to be useful 
are allergic conditions (Hamelet et al., Can. J. Pharmacol. Physiol. 
(1988) 66 1361-7), immunoregulation (Lotz et al., Science (1988) 241 
1218-21, Kimball et al., J. Immunol. (1988) 141 (10) 3564-9 and A. 
Perianin, et al., Biochem, Biophys. Res Commun. 161, 520 (1989)) 
vasodilation, bronchospasm, reflex or neuronal control of the viscera 
(Mantyh et al., PNAS (1988) 85 3235-9) and, possibly by arresting or 
slowing .beta.-amyloid-mediated neurodegenerative changes (Yankner et al., 
Science, (1990) 250, 279-82) in senile dementia of the Alzheimer type, 
Alzheimer's disease and Downs Syndrome. Substance P may also play a role 
in demyelinating diseases such as multiple sclerosis and amyotrophic 
lateral sclerosis [J. Luber-Narod et. al., poster presented at C. I. N. P. 
XVIIIth Congress, 281th Jun.-2nd Jul., 1992, in press]. Antagonists 
selective for the neurokinin-1 (NK-1) and/or the neurokinin-2 (NK-2) 
receptor may be useful in the treatment of asthmatic disease (Frossard et 
al., Life Sci., 49, 1941-1953 (1991 ); Advenier, et al., Biochem. Biophys. 
Res. Comm., 184(3), 1418-1424 (1992)). Tachykinin antagonists may also be 
useful in the treatment of small cell carcinomas, in particular small cell 
lung cancer (SCLC) (Langdon et al., Cancer Research (1992) 52, 4554-7). 
It has furthermore been suggested that tachykinins have utility in the 
following disorders: depression, dysthymic disorders, chronic obstructive 
airways disease, hypersensitivity disorders such as poison ivy, 
vasospastic diseases such as angina and Reynauld's disease, fibrosing and 
collagen diseases such as scleroderma and eosinophillic fascioliasis, 
reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction 
disorders such as alcoholism, stress related somatic disorders, 
neuropathy, neuralgia, disorder related to immune enhancement or 
suppression such as systemic lupus erythmatosis (EPO Publication No. 
0,436,334) conjunctivitis, vernal conjunctivitis, contact dermatitis, 
atropic dermatitis, urticaria, and other eczematoid dermatitis (EPO 
Publication No. 0,394,989) and emesis (Trends Pharmacol, Sci., 9, 334-341 
(1988); Eur. J. Pharmacol., 249, R3-R4 (1993)). 
Substance P antagonists may be useful in mediating neurogenic mucus 
secretion in mammalian airways and hence provide treatment and symptomatic 
relief in diseases characterized by mucus secretion, in particular, cystic 
fibrosis [S. Ramnarine, et al., abstract presented at 1993 ALA/ATS Int'l 
Conference, 16-19 May, 1993, published in Am. Rev. of Respiratory Dis., 
May 1993, in press]. 
In the recent past, some attempts have been made to provide peptide-like 
substances that are antagonists for substance P and other tachykinin 
peptides in order to more effectively treat the various disorders and 
diseases listed above. See for example Lowe, Drugs of the Future, 17 (12) 
1115-1121 (1992) and European patent applications (EPO Publication Nos. 
0,347,802, 0,401,177 and 0,412,452) which disclose various peptides as 
neurokinin A antagonists. Also, PCT Patent Publication WO 93/14113 
discloses certain peptides as tachykinin antagonists. In addition, EPO 
Publication No. 0,336,230 discloses heptapeptides which are substance P 
antagonists useful in the treatment of asthma. Merck U.S. Pat. No. 
4,680,283 also discloses peptidal analogs of substance P. 
Certain inhibitors of tachykinins have been described in U.S. Pat. No. 
4,501,733, by replacing residues in substance P sequence by Trp residues. 
A further class of tachykinin receptor antagonists, comprising a monomeric 
or dimetic hexa- or heptapeptide unit in linear or cyclic form, is 
described in GB-A-2216529. 
The peptide-like nature of such substances make them too labile from a 
metabolic point of view to serve as practical therapeutic agents in the 
treatment of disease. The non-peptidic antagonists of the present 
invention, on the other hand, do not possess this drawback, as they are 
expected to be more stable from a metabolic point of view than the 
previously-discussed agents. 
It is known in the an that baclofen 
(.beta.-(aminoethyl)-4-chlorobenzenepropanoic acid) in the central nervous 
system effectively blocks the excitatory activity of substance P, but 
because in many areas the excitatory responses to other compounds such as 
acetylcholine and glutamate are inhibited as well, baclofen is not 
considered a specific substance P antagonist. Pfizer WIPO patent 
applications (PCT Publication Nos. WO 90/05525, WO 90/05729, WO 91/18899, 
WO 92/12151 and WO 92/12152) and publications (Science, 251,435-437 
(1991); Science, 251,437-439 (1991); J. Med. Chem., 35, 2591-2600 (1992)) 
disclose 2-arylmethyl-3-substituted amino-quinuclidine derivatives which 
are disclosed as being useful as substance P antagonists for treating 
gastrointestinal disorders, central nervous system disorders, inflammatory 
diseases and pain or migraine. A Glaxo European patent application (EPO 
Publication No. 0.360.390) discloses various spirolactam-substituted amino 
acids and peptides which are antagonists or agonists of substance P. A 
Pfizer WIPO patent application (PCT Publication No. WO 92/06079) discloses 
fused-ring analogs of nitrogen-containing nonaromatic heterocycles as 
useful for the treatment of diseases mediated by an excess of substance P. 
A Pfizer WIPO patent application (PCT Publication No. WO 9/15585 discloses 
1-azabicyclo[3.2.2]nonan-3-amine derivatives as substance P antagonists. A 
Pfizer WIPO patent application (PCT Publication No. WO 93/10073) discloses 
ethylenediamine derivatives as substance P antagonists. PCT Publication 
No. WO 93/01169 discloses certain aromatic compounds as tachykinin 
receptor antagonists. A Sanofi publication (Life Sci., 50, PL101-PL106 
(1992)) discloses a 4-phenyl piperidine derivative as an antagonist of the 
neurokinin A (NK2) receptor. 
Howson et al. (Biorg, & Med. Chem, Lett., 2 (6), 559-564 (1992)) disclose 
certain 3-amino and 3-oxy quinuclidine compounds and their binding to 
substance P receptors. EPO Publication 0,499,313 discloses certain 3-oxy 
and 3-thio azabicyclic compounds as tachykinin antagonists. U.S. Pat. No. 
3,506,673 discloses certain 3-hydroxy quinuclidine compounds as central 
nervous system stimulants. A Pfizer EPO Patent application (EPO 
Publication 0,436,334) discloses certain 3-aminopiperidine compounds as 
substance P antagonists. U.S. Pat. No. 5,064,838 discloses certain 
1,4-disubstituted piperidinyl compounds as analgesics. PCT Publication No. 
WO 92/12128 discloses certain piperidine and pyrrolidine compounds as 
analgesics. Peyronel, et al. (Biorg & Med. Chem, Lett., 2 (1), 37-40 
(1992)) disclose a fused ring pyrrolidine compound as a substance P 
antagonist. EPO Publication No. 0,360,390 discloses certain spirolactam 
derivatives as substance P antagonists. EPO Publication No. 0,532,456 
discloses certain 1acylpiperidine derivatives as substance P antagonists. 
EPO Publication No. 0,559,538 discloses quatemary salts of certain 
4-substituted piperidines as neurokinin antagonists. U.S. Pat. No. 
4,804,661 discloses certain piperazine compounds as analgesics. U.S. Pat. 
No. 4,493,578 discloses certain piperazine compounds useful in the 
treatment of pain. PCT Publication No. WO 92/01679 discloses certain 
1,4-disubstituted piperazines useful in the treatment of mental disorders 
in which a dopaminergic deficit is implicated. PCT Publication No. WO 
92/21360 and Mills, et al. (Bioorganic & Med. Chem. Lttrs., 3(12) 
2707-2712 (1993)) disclose certain 1,4-diacylpiperazine substance P 
receptor antagonists. 
DETAILED DESCRIPTION OF THE INVENTION 
The novel compounds of this invention are represented by structural formula 
I: 
##STR3## 
or a pharmaceutically acceptable salt thereof, wherein: R.sup.1a is 
selected from the group consisting of: 
1) H, 
2) C.sub.1-8 alkyl, 
3) phenyl, either unsubstituted or substituted with one or two substituents 
selected from the group consisting of: 
a) --C.sub.1-4 alkyl, 
b) -halo, 
c) --OH, 
d) --CF.sub.3, 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C.sub.1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
4) --C.sub.1-4 alkyl-phenyl, wherein the phenyl is either unsubstituted or 
substituted with one or two substituents selected from: 
a) --C.sub.1-4 alkyl 
b) -halo, 
e) --OH, 
d) --CF.sub.3 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl) 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
R.sup.1b is selected from the group consisting of: 
1) R.sup.1a 
2) --C.sub.3-7 cycloalkyl, and 
3) --CH.sub.2 -R.sup.1a; 
R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or 
substituted with one or two substituents selected from the group 
consisting of: 
1) --C.sub.1-4 alkoxy, 
2) -halo, 
3) --OH, 
4) --CF.sub.3, 
5) --NH.sub.2, 
6) --NH(C.sub.1-4 alkyl), 
7) --N(C.sub.1-4 alkyl).sub.2, 
8) --CO.sub.2 H, 
9) --CO.sub.2 (C.sub.1-4 alkyl), and 
10) --C.sub.1-6 alkyl, either unsubstituted or substituted with one or more 
substituents selected from the group consisting of: 
a) -halo, 
b) --OH, 
c) --CF.sub.3, 
d) --NH.sub.2, 
e) --NH(C.sub.1-4 alkyl), 
f) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl) 
g) --CO.sub.2 H, 
h) --CO.sub.2 (C.sub.1-4 alkyl), 
i) C.sub.1-4 alkoxy, 
j) --S(O).sub.x (C.sub.1-4 alkyl) wherein x is 0, 1 or 2, 
k) --C.sub.3-7 cycloalkyl; 
and the phenyl groups of R.sup.2a and R.sup.2b may be joined together at 
the ortho carbon atoms through a carbon-carbon single bond or C.sub.1-3 
alkylene to form a tricyclic group with the X.sup.2 to which they are 
attached; 
X.sup.1 is --N, --CH or O, and if X.sup.1 is O R.sup.1a is absent; 
X.sup.2 is --N or --CH; 
R.sup.3 is selected from the group consisting of: 
1) --CONR.sup.7 R.sup.8, and 
2) --CO.sub.2 R.sup.9; 
R.sup.4, R.sup.5 and R.sup.6 are H or are independently selected from the 
definitions of R.sup.3 ; 
R.sup.7 is C.sub.1-6 alkyl substituted with one or more substituents 
selected from the group consisting of: 
1) --NHR.sup.10, 
2) --NR.sup.10 R.sub.11, 
3) --NHCO(C.sub.1-6 alkyl), 
4) --NR.sup.10 CO.sub.2 R.sup.11, 
5) --N(R.sup.10)((C.sub.1-6 alkyl)CONHR.sup.11), 
6) --N(CO.sub.2 R.sup.10)((C.sub.1-6 alkyl)CONHR.sup.11), and 
7) --NR.sup.10 (C.sub.1-6 alkyl)CONHR.sup.11 ; 
R.sup.8 is H, C.sub.1-6 alkyl or is independently selected from the 
definitions of R.sup.7 ; 
R.sup.9 is H or --CH.sub.2 -phenyl, wherein the phenyl is either 
unsubstituted or substituted with one or more substituents selected from 
the group consisting of: 
1) --C.sub.1-4 alkoxy, 
2) -halo, 
3) --OH, 
4) --CF.sub.3 
5) --NH.sub.2, 
6) --NH(C.sub.1-4 alkyl) 
7) --N(C.sub.1-4 alkyl)2, 
8) --CO.sub.2 H, 
9) --CO.sub.2 (C.sub.1-4 alkyl), and 
10) --C.sub.1-6 alkyl, either unsubstituted or substituted with one or more 
substituents selected from the group consisting of: 
a) -halo, 
b) --OH, 
c) --CF.sub.3, 
d) --NH.sub.2, 
e) --NH(C.sub.1-4 alkyl), 
f) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl) 
g) --CO.sub.2 H, 
h) --CO.sub.2 (C.sub.1-4 alkyl, 
i) C.sub.1-4 alkoxy, 
j) --S(O).sub.x (C.sub.1-4 alkyl) wherein x is 0, 1 or 2, 
k) --C.sub.3-7 cycloalkyl; 
R.sup.10 is H, C.sub.1-6 alkyl, or --(C.sub.1-6 alkyl)-phenyl, wherein the 
phenyl is either unsubstituted or substituted with one or more 
substituents selected from the group consisting of: 
1) --C.sub.1-4 alkoxy, 
2) -halo, 
3) --OH, 
4) --CF.sub.3, 
5) --NH.sub.2, 
6) --NH(C.sub.1-4 alkyl), 
7) --N(C.sub.1-4 alkyl)2, 
8) --CO.sub.2 H, 
9) --CO.sub.2 (C.sub.1-4 alkyl), and 
10) --C.sub.1-6 alkyl, either unsubstituted or substituted with one or more 
substituents selected from the group consisting of: 
a) -halo, 
b) --OH, 
c) --CF.sub.3, 
d) --NH.sub.2, 
e) --NH(C.sub.1-4 alkyl), 
f) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl) 
g) --CO.sub.2 H, 
h) --CO.sub.2 (C.sub.1-4 alkyl), 
i) C.sub.1-4 alkoxy, 
j) --S(O).sub.x (C.sub.1-4 alkyl) wherein x is 0, 1 or 2, 
k) --C.sub.3-7 cycloalkyl; and 
R.sup.11 is H, C.sub.1-6 alkyl, or is independently selected from the 
definitions of R.sup.10. 
The compounds of the present invention have asymmetric centers and this 
invention includes all of the optical isomers and mixtures thereof. 
In addition compounds with carbon-carbon double bonds may occur in Z- and 
E- forms with all isomeric forms of the compounds being included in the 
present invention. 
When any variable (e.g., alkyl, aryl, R.sup.6, R.sup.7, R.sup.8, R.sup.9, 
R.sup.10, R.sup.11, R.sup.12, R.sup.13, etc.) occurs more than one time in 
any variable or in Formula I, its definition on each ocurrence is 
independent of its definition at every other occurrence. 
As used herein, the term "alkyl" includes those alkyl groups of a 
designated number of carbon atoms of either a straight, branched, or 
cyclic configuration. Examples of "alkyl" include methyl, ethyl, propyl, 
isopropyl, butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 
3-ethylbutyl, and the like. "Alkoxy" represents an alkyl group of 
indicated number of carbon atoms attached through an oxygen bridge, such 
as methoxy, ethoxy, propoxy, butoxy and pentoxy. "Alkenyl" is intended to 
include hydrocarbon chains of a specified number of carbon atoms of either 
a straight- or branched- configuration and at least one unsaturation, 
which may occur at any point along the chain, such as ethenyl, propenyl, 
butenyl, pentenyl, dimethylpentyl, and the like, and includes E and Z 
forms, where applicable. "Halogen" or "halo", as used herein, means 
fluoro, chloro, bromo and iodo. 
As will be understood by those skilled in the art, pharmaceutically 
acceptable salts include, but are not limited to salts with inorganic 
acids such as hydrochloride, sulfate, phosphate, diphosphate, 
hydrobromide, and nitrate or salts with an organic acid such as malate, 
maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, 
methanesulfonate, p-toluenesulfonate or pamoate, salicylate and stearate. 
Similarly pharmaceutically acceptable cations include, but are not limited 
to sodium, potassium, calcium, aluminum, lithium and ammonium. 
The term "aryl" means phenyl or naphthyl either unsubstituted or 
substituted with one, two or three substituents selected from the group 
consisting of halo, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, NO.sub.2, 
CF.sub.3, C.sub.1-4 -alkylthio, OH,--N(R.sup.6).sub.2, --CO.sub.2 R.sup.6, 
C.sub.1-4 -polyfluoroalkyl, C.sub.3-6 polyfluorocycloal and tetrazol-5-yl. 
The term "heteroaryl" means an unsubstituted, monosubstituted or 
disubstituted five or six membered aromatic heterocycle comprising from 1 
to 3 heteroatoms selected from the group consisting of O, N and S and 
wherein the substituents are members selected from the group consisting of 
--OH, --SH, --C.sub.1-4 -alkyl, --C.sub.1-4 -alkoxy, --CF.sub.3, halo, 
--NO2, --CO.sub.2 R.sup.6, --N(R.sup.6).sub.2 and a fused benzo group. 
One embodiment of the novel compounds of this invention is that wherein 
X.sup.1 and X.sup.2 are both N of structural formula: 
##STR4## 
or a pharmaceutically acceptable salt thereof. 
A first class of compounds within this embodiment are those compounds 
wherein: 
R.sup.1a is selected from the group consisting of: 
1) H, 
2) C.sub.1-8 alkyl, 
3) phenyl, either unsubstituted or substituted with one or two substituents 
selected from the group consisting of: 
a) --C.sub.1-4 alkyl, 
b) -halo, 
c) --OH, 
d) --CF.sub.3, 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C.sub.1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
4) --C.sub.1-4 alkyl-phenyl, wherein the phenyl is either unsubstituted or 
substituted with one or two substituents selected from: 
a) --C.sub.1-4 alkyl, 
b) -halo, 
e) --OH, 
d) --CF.sub.3 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl)2, 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C.sub.1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
R.sup.1b is selected from the group consisting of: 
1) R.sup.1a 
2) --C.sub.3-7 cycloalkyl, and 
3) --CH.sub.2 -R.sup.1a ; 
R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or 
substituted with one or two substituents selected from the group 
consisting of: 
1) --C.sub.1-4 alkoxy, 
2) -halo, 
3) --OH, 
4) --CF.sub.3, 
5) --NH.sub.2, 
6) --NH(C.sub.1-4 alkyl), 
7) --N(C.sub.1-4 alkyl)2, 
8) --CO.sub.2 H, 
9) --CO.sub.2 (C.sub.1-4 alkyl), and 
10) --C.sub.1-6 alkyl, either unsubstituted or substituted with one or more 
substituents selected from the group consisting of: 
a) -halo, 
b) --OH, 
c) --CF.sub.3, 
d) --NH.sub.2, 
e) --NH(C.sub.1-4 alkyl), 
f) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl) 
g) --CO.sub.2 H, 
h) --CO.sub.2 (C.sub.1-4 alkyl), 
i) C.sub.1-4 alkoxy, 
j) --S(O).sub.x (C.sub.1-4 alkyl) wherein x is 0, 1 or 2, and 
k) --C.sub.3-7 cycloalkyl; 
and the phenyl groups of R.sup.2a and R.sup.2b may be joined together at 
the ortho carbon atoms through a carbon-carbon single bond or C.sub.1-3 
alkylene to form a tricyclic group with the X.sup.2 to which they are 
attached; 
R.sup.3 is --CONR.sup.7 R.sup.8 ; 
R.sup.4, R.sup.5 and R.sup.6 are H; 
R.sup.7 is C.sub.1-6 alkyl substituted with one or more substituents 
selected from the group consisting of: 
1) --N(R.sup.10)(CH.sub.2 CONHR.sup.11), 
2) --N(CO.sub.2 R.sup.10)(CH.sub.2 CONHR.sup.11), and 
R.sup.8 is H. 
Specific compounds within this first class include: 
1) trans 1 -(N,N-diphenylaminocarbonyl )-2-(RS)-(2-(N(aminocarbonylmeth 
yl)amino)ethylaminocarbonyl)-4-(RS)-(N,N-dipentylaminocarbonyl)piperidine; 
2) trans 
1-(N,N-diphenylaminocarbonyl)-2-(RS)-(2-(N-(2methoxybenzyl)-(N-(aminocarbo 
nylmeth 
yl)amino)ethylaminocarbonyl)-4-(RS)-(N,N-dipentylaminocarbonyl)piperidine; 
3) trans 
1-(N-(3-chlorophenyl)-N-(phenyl)-aminocarbonyl)-2-(RS)-(2-(N-(benzyloxycar 
bonyl) 
-N-(aminocarbonylmethyl)amino)-ethylaminocarbonyl)-4-(RS)-(N,N-dipentylami 
nocarbonyl)piperidine; 
4) trans 
1-(N-(3-chlorophenyl)-N-(phenyl)-aminocarbonyl)-2-(RS)(2-N-(aminocarbonylm 
ethyl)amino)ethylaminocarbonyl)-4-(RS)-(N-N-dipentylaminocarbonyl)piperidin 
e; 
5) trans 
1-(N-(3-chlorophenyl)-N-(phenyl)-aminocarbonyl)-2-(RS)(2-(N-(2-methoxybenz 
yl)-(N-aminocarbonylmethyl)amino)ethylaminocarbonyl)-4-(RS)-(N,N-dipentylam 
inocarbonyl)piperidine; 
or a pharmaceutically acceptable salt thereof. 
A second class of compounds within this embodiment are those compounds 
wherein: 
R.sup.1a is selected from the group consisting of: 
1) H, 
2) C.sub.1-8 alkyl, 
3) phenyl, either unsubstituted or substituted with one or two substituents 
selected from the group consisting of: 
a) --C.sub.1-4 alkyl, 
b) -halo, 
c) --OH, 
d) --CF.sub.3, 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C.sub.1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
4) --C.sub.1-4 alkyl-phenyl, wherein the phenyl is either unsubstituted or 
substituted with one or two substituents selected from: 
a) --C.sub.1-4 alkyl, 
b) -halo, 
e) --OH, 
d) --CF.sub.3 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl).sub.2, 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C.sub.1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
R.sup.1b is selected from the group consisting of: 
1) R.sup.1a 
2) --C.sub.3-7 cycloalkyl, and 
3) --CH.sub.2 -R.sup.1a ; 
R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or 
substituted with one or two substituents selected from the group 
consisting of: 
1) --C.sub.1-4 alkoxy, 
2) -halo, 
3) --OH, 
4) --CF.sub.3, 
5) --NH.sub.2, 
6) --NH(C.sub.1-4 alkyl), 
7) --N(C.sub.1-4 alkyl).sub.2, 
8) --CO.sub.2 H, 
9) --CO.sub.2 (C.sub.1-4 alkyl), and 
10) --C.sub.1-6 alkyl, either unsubstituted or substituted with one or more 
substituents selected from the group consisting of: 
a) -halo, 
b) --OH, 
c) --CF.sub.3, 
d) --NH.sub.2, 
e) --NH(C.sub.1-4 alkyl), 
f) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl) 
g) --CO.sub.2 H, 
h) --CO.sub.2 (C.sub.1-4 alkyl), 
i) C.sub.1-4 alkoxy, 
j) --S(O).sub.x (C.sub.1-4 alkyl) wherein x is 0, 1 or 2, 
k) --C.sub.3-7 cycloalkyl; 
and the phenyl groups of R.sup.2a and R.sup.2b may be joined together at 
the ortho carbon atoms through a carbon-carbon single bond or C.sub.1-3 
alkylene to form a tricyclic group with the X.sup.2 to which they are 
attached; 
R.sup.3 is --CONR.sup.7 R.sup.8 ; 
R.sup.4, R.sup.5 and R.sup.6 are H; 
R.sup.7 is C.sub.1-6 alkyl substituted with --NR.sup.10 R.sup.11 ; 
R.sup.8 is H; 
R.sup.10 is --(C.sub.1-6 alkyl)-phenyl, wherein the phenyl is substituted 
with --C.sub.1-4 alkoxy, 
R.sup.11 is H, C.sub.1-6 alkyl, or is independently selected from the 
definitions of R.sup.10. 
Specific compounds within this second class include: 
1) trans 
1-(N,N-diphenylaminocarbonyl)-2-(RS)-(2-(N-(2methoxybenzyl)-N-methylamino) 
ethylaminocarbon-4-(RS)-(N,N-dipentylaminocarbonyl)piperidine; 
2) cis 
1-(N,N-diphenylaminocarbonyl)-2-(RS)-(2-(N-(2-methoxybenzyl)-N-methylamino 
)ethylaminocarbonyl (N,N-dipentylaminocarbonyl)piperidine; 
3) trans 
1-(N-(3-chlorophenyl)--N-(phenyl)-aminocarbonyl)-2-(RS)-(2-(N-(2-methoxybe 
nzyl)-N-methylmino)ethylaminocarbonyl)-4-(RS)-(N,N-dipentylaminocarbonyl)pi 
perdine; 
4) trans 
1-(N-(3-chlorophenyl)-N-(phenyl)-aminocarbonyl)-2-(RS)-(2-(N-(2-methoxyben 
zyl)-N-methylamino)ethylaminocarbonyl)-4-(RS)-(N,N-dibenzylaminocarbonyl)pi 
peridine; 
or a pharmaceutically acceptable salt thereof. 
A third class of compounds within this embodiment are those compounds 
wherein: 
R.sup.1a is selected from the group consisting of: 
1) H, 
2) C.sub.1-8 alkyl, 
3) phenyl, either unsubstituted or substituted with one or two substituents 
selected from the group consisting of: 
a) --C.sub.1-4 alkyl, 
b) -halo, 
c) --OH, 
d) --CF.sub.3, 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C.sub.1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
4) --C.sub.1-4 alkyl-phenyl, wherein the phenyl is either unsubstituted or 
substituted with one or two substituents selected from: 
a) --C.sub.1-4 alkyl, 
b) -halo, 
e) --OH, 
d) --CF.sub.3 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl).sub.2, 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C.sub.1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
R.sup.1b is selected from the group consisting of: 
1) R.sup.1a 
2) --C.sub.3-7 cycloalkyl, and 
3) --CH.sub.2 -R.sup.1a ; 
R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or 
substituted with one or two substituents selected from the group 
consisting of: 
1) --C.sub.1-4 alkoxy, 
2) -halo, 
3) --OH, 
4) --CF.sub.3, 
5) --NH.sub.2, 
6) --NH(C.sub.1-4 alkyl), 
7) --N(C.sub.1-4 alkyl)2, 
8) --CO.sub.2 H, 
9) --CO.sub.2 (C.sub.1-4 alkyl), and 
10) --C.sub.1-6 alkyl, either unsubstituted or substituted with one or more 
substituents selected from the group consisting of: 
a) -halo, 
b) --OH, 
c) --CF.sub.3, 
d) --NH.sub.2, 
e) --NH(C.sub.1-4 alkyl), 
f) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl) 
g) --CO.sub.2 H, 
h) --CO.sub.2 (C.sub.1-4 alkyl), 
i) C.sub.1-4 alkoxy, 
j) --S(O).sub.x (C.sub.1-4 alkyl) wherein x is 0, 1 or 2, 
k) --C.sub.3-7 cycloalkyl; and the phenyl groups of R.sup.2a and R.sup.2b 
may be joined together at the ortho carbon atoms through a carbon-carbon 
single bond or C.sub.1-3 alkylene to form a tricyclic group with the 
X.sup.2 to which they are attached; 
R.sup.3 is CONR.sup.7 R.sup.8 ; 
R.sup.4, R.sup.5 and R.sup.6 are H; 
R.sup.7 is C.sub.1-6 alkyl substituted with --NR.sup.1 OR.sup.11 ; 
R.sup.8 is H; 
R.sup.10 is C.sub.1-6 alkyl; 
R.sup.11 is H or C.sub.1-6 alkyl. 
Specific compounds within this third class include: 
1) trans 
1-(N,N-diphenylaminocarbonyl)-2-(RS)-(3(diethylamino)propylaminocarbonyl) 
-4-(RS)-(N,N-dipentylaminocarbonyl)piperidine; 
or a pharmaceutically acceptable salt thereof. 
A fourth class of compounds within this embodiment are those compounds 
wherein: 
R.sup.1a is selected from the group consisting of: 
1) H, 
2) C.sub.1-8 alkyl, 
3) phenyl, either unsubstituted or substituted with one or two substituents 
selected from the group consisting of: 
a) --C.sub.1-4 alkyl, 
b) -halo, 
c) --OH, 
d) --CF.sub.3, 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C.sub.1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
4) --C.sub.1-4 alkyl-phenyl, wherein the phenyl is either unsubstituted or 
substituted with one or two substituents selected from: 
a) --C.sub.1-4 alkyl, 
b) -halo, 
e) --OH, 
d) --CF.sub.3 
e) --NH.sub.2, 
f) --NH(C.sub.1-4 alkyl), 
g) --N(C.sub.1-4 alkyl).sub.2, 
h) --CO.sub.2 H, 
i) --CO.sub.2 (C.sub.1-4 alkyl), and 
j) --C.sub.1-4 alkoxy; 
R.sup.1b is selected from the group consisting of: 
1) R.sup.1a 
2) --C.sub.3-7 cycloalkyl, and 
3) --CH.sub.2 -R.sup.1a ; 
R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or 
substituted with one or two substituents selected from the group 
consisting of: 
1) --C.sub.1-4 alkoxy, 
2) -halo, 
3) --OH, 
4) --CF.sub.3, 
5) --NH.sub.2, 
6) --NH(C.sub.1-4 aklyl, 
7) --N(C.sub.1-4 alkyl)2, 
8) --CO.sub.2 H, 
9) --CO.sub.2 (C.sub.1-4 alkyl), and 
10) --C.sub.1-6 alkyl, either unsubstituted or substituted with one or more 
substituents selected from the group consisting of: 
a) -halo, 
b) --OH, 
c) --CF.sub.3, 
d) --NH.sub.2, 
e) --NH(C.sub.1-4 alkyl), 
f) --N(C.sub.1-4 alkyl)(C.sub.1-4 aklyl) 
g) --CO.sub.2 H, 
h) --CO.sub.2 (C.sub.1-4 alkyl), 
i) C.sub.1-4 alkoxy, 
j) --S(O).sub.x (C.sub.1-4 alkyl) wherein x is 0, 1 or 2, 
k) --C.sub.3-7 cycloalkyl; 
and the phenyl groups of R.sup.2a and R.sup.2b may be joined together at 
the ortho carbon atoms through a carbon-carbon single bond or C.sub.1-3 
alkylene to form a tricyclic group with the X.sup.2 to which they are 
attached; 
R.sup.3 is --CO.sub.2 R.sup.9 ; 
R.sup.4, R.sup.5 and R.sup.6 are H; 
R.sup.9 is H. 
Specific compounds within this fourth class include: 
1) trans 1 
-(N,N-diphenylaminocarbonyl)-4-(RS)-(N,N-dipentylaminocarbonyl)piperidine- 
2-(RS)-carboxylic acid; 
2) trans 1-(N-(3-chlorophenyl)-N-(phenyl)-aminocarbonyl)-4-(RS) 
(N,N-dipentylaminocarbonyl)piperidine-2-(RS)-carboxylic acid; 
or a pharmaceutically acceptable salt thereof. 
Especially preferred compounds include those of structural formula II: 
##STR5## 
or a pharmaceutically acceptable salt thereof, wherein: R.sup.1a is 
selected from the group consisting of: 
1) C.sub.5-6 alkyl, 
2) phenyl, 
3) --CH.sub.2 -phenyl, 
R.sup.1b is selected from the definitions of R.sup.1a ; 
R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or 
substituted with one substituent selected from the group consisting of: 
1) --OCH.sub.3, 
2) --Cl, 
3) --CF.sub.3, 
4) --CH.sub.3 ; 
R.sup.3 is selected from the group consisting of: 
1) --CONR.sup.7 R.sup.8, and 
2) --CO.sub.2 R.sup.9 ; 
R.sup.7 is C.sub.1-6 alkyl substituted with one or more substituents 
selected from the group consisting of: 
--NHR.sup.10, 
2) --NR.sup.10 R.sup.11, 
3) --NHCO (C.sub.1-6 alkyl), 
4) --NR.sup.10 CO.sub.2 R.sup.11, 
--N(CO.sub.2 R.sup.10)((C.sub.1-6 alkyl)CONHR.sup.11), 
5) --N(CO.sub.2 R.sup.10)((C.sup.1-6 alkyl)CONHR.sup.11), 
6) NR.sup.10 (C.sub.1-6 alkyl)CONHR.sup.11 ; 
R.sup.8 is H, C.sub.1-6 alkyl or is independently selected from the 
definitions of R.sup.7 ; 
R.sup.9 is H or --CH.sub.2 -phenyl, wherein the phenyl is either 
unsubstituted or substituted with one or more substituents selected from 
the group consisting of: 
1) --C.sub.1-4 alkoxy, 
2) -halo, 
3) --OH, 
4) --CF.sub.3 
5) --NH.sub.2, 
6) --NH(C.sub.1-4 alkyl), 
7) --N(C.sub.1-4 alkyl).sub.2, 
8) --CO.sub.2 H, 
9) --CO.sub.2 (C.sub.1-4 alkyl), and 
10) --C.sub.1-6 alkyl, either unsubstituted or substituted with one or more 
substituents selected from the group consisting of: 
a) -halo, 
b) --OH, 
c) --CF.sub.3, 
d) --NH.sub.2, 
e) --NH(C.sub.1-4 alkyl), 
f) --N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl) 
g) --CO.sub.2 H, 
h) --CO.sub.2 (C.sub.1-4 alkyl), 
i) C.sub.1-4 alkoxy, 
j) --S(O).sub.x (C.sub.1-4 alkyl) wherein x is 0, 1 or 2, 
k) --C.sub.3-7 cycloalkyl; 
R.sup.10 is --(C.sub.1-4 alkyl)-phenyl, wherein the phenyl is either 
unsubstituted or substituted with one or more substituents selected from 
the group consisting of: 
1) --OCH3, 
2) --Cl, 
3) --CF.sub.3, 
4) --CH.sub.3 ; and 
R.sup.11 is H, C.sub.1-6 alkyl, or is independently selected from the 
definitions of R.sup.10. 
The useful activities of the compounds of this invention are demonstrated 
and exemplified by the following assays. 
TACHYKININ ANTAGONISM ASSAY 
The compounds of this invention are useful for antagonizing tachykinins, in 
particular substance P and neurokinin A in the treatment of 
gastrointestinal disorders, central nervous system disorders, inflammatory 
diseases, pain or migraine and asthma in a mammal in need of such 
treatment. This activity can be demonstrated by the following assay. 
A. Receptor Expression in COS 
To express the cloned human neurokinin-1 receptor (NK1R) transiently in 
COS, the cDNA for the human NK1R was cloned into the expression vector 
pCDM9 which was derived from pCDM8 (INVITROGEN) by inserting the 
ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) 
into the Sac II site. Transfection of 20 ug of the plasmid DNA into 10 
million COS cells was achieved by electroporation in 800 ul of 
transfection buffer (135 mM NaCl, 1.2 mM CaCl.sub.2, 1.2 mM MgCl.sub.2, 
2.4 mM K.sub.2 HPO.sub.4, 0.6 mM KH.sub.2 PO.sub.4, 10 mM glucose, 10 mM 
HEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (IBI, New 
Haven, Conn.). The cells were incubated in 10% fetal calf serum, 2 mM 
glutamine, 100U/ml penicillinstreptomycin, and 90% DMEM media (GIBCO, 
Grand Island, N.Y.) in 5% CO.sub.2 at 37.degree. C. for three days before 
the binding assay. 
B. Stable Expression in CHO 
To establish a stable cell line expressing the cloned human NK1R, the cDNA 
was subcloned into the vector pRcCMV (INVITROGEN). Transfection of 20 ug 
of the plasmid DNA into CHO cells was achieved by electroporation in 800 
ul of transfection buffer supplemented with 0.625 mg/ml Herring sperm DNA 
at 300 V and 950 uF using the IBI GENEZAPPER (IBI). The transfected cells 
were incubated in CHO media [10% fetal calf serum, 100 U/ml 
penicillin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine 
(ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, Kans.), 0.7 mg/ml G418 
(GIBCO)]in 5% CO.sub.2 at 37.degree. C. until colonies were visible. Each 
colony was separated and propagated. The cell clone with the highest 
number of human NK1R was selected for subsequent applications such as drug 
screening. 
C. Assay Protocol using COS or CHO 
The binding assay of human NK1R expressed in either COS or CHO cells is 
based on the use of .sup.125 I-substance P (.sup.125 I-SP, from DU PONT, 
Boston, Mass.) as a radioactively labeled ligand which competes with 
unlabeled substance P or any other ligand for binding to the human NK1R. 
Monolayer cell cultures of COS or CHO were dissociated by the 
non-enzymatic solution (SPECIALTY MEDIA, Lavallette, N.J.) and resuspended 
in appropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM 
MnCl.sub.2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 
mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ul of the cell suspension 
would give rise to about 10,000 cpm of specific .sup.125 I-SP binding 
(approximately 50,000 to 200,000 cells). In the binding assay, 200 ul of 
cells were added to a tube containing 20 ul of 1.5 to 2.5 nM of .sup.125 
I-SP and 20 11 of unlabeled substance p or any other test compound. The 
tubes were incubated at 4.degree. C. or at room temperature for 1 hour 
with gentle shaking. The bound radioactivity was separated from unbound 
radioactivity by GF/C filter (BRANDEL, Gaithersburg, M.d.) which was 
pre-wetted with 0.1% polyethylenimine. The filter was washed with 3 ml of 
wash buffer (50 mM Tris pH 7.5, 5 mM MnCI.sub.2, 150 mM NaCl) three times 
and its radioactivity was determined by gamma counter. 
The activation of phospholipase C by NK1R may also be measured in CHO cells 
expressing the human NK1R by determining the accumulation of inositol 
monophosphate which is a degradation product of IP.sub.3. CHO cells are 
seeded in 12-well plate at 250,000 cells per well. After incubating in CHO 
media for 4 days, cells are loaded with 0.025 uCi/ml of .sup.3 
H-myoinositol by overnight incubation. The extracellular radioactivity is 
removed by washing with phosphate buffered saline. LiCl is added to the 
well at final concentration of 0.1 mM with or without the test compound, 
and incubation is continued at 37.degree. C. for 15 min. Substance P is 
added to the well at final concentration of 0.3 nM to activate the human 
NK1R. After 30 min of incubation at 37.degree. C., the media is removed 
and 0.1N HCl is added. Each well is sonicated at 4.degree. C. and 
extracted with CHCl.sub.3 /methanol (1:1). The aqueous phase is applied to 
a 1 ml Dowex AG 1X8 ion exchange column. The column is washed with 0.1N 
formic acid followed by 0.025M ammonium formate-0.1N formic acid. The 
inositol monophosphate is eluted with 0.2M ammonium formate-0.1N formic 
acid and quantitated by beta counter. 
The compounds of the present invention are useful in the prevention and 
treatment of a wide variety of clinical conditions which are characterized 
by the presence of an excess of tachykinin, in particular substance P, 
activity. 
These conditions may include disorders of the central nervous system such 
as anxiety, depression, psychosis and schizophrenia; neurodegenerative 
disorders such as AIDS related dementia, senile dementia of the Alzheimer 
type, Alzheimer's disease and Down's syndrome; demyelinating diseases such 
as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS; Lou 
Gehrig's disease) and other neuropathological disorders such as peripheral 
neuropathy, for example AIDS related neuropathy, diabetic neuropathy, 
chemotherapy-induced neuropathy, and postherpetic and other neuralgias; 
respiratory diseases such as chronic obstructive airways disease, 
bronchopneumonia, chronic bronchitis, bronchospasm and asthma; airways 
disease modulated by neurogenic inflammation; diseases characterized by 
neurogenic mucus secretion, such as cystic fibrosis; diseases associated 
with decreased glandular secretions, including lacrimation, such as 
Sjogren's syndrome, hyperlipoproteinemias IV and V, hemochromatosis, 
sarcoidosis, or amyloidosis; inflammatory diseases such as inflammatory 
bowel disease, irritable bowel syndrome, psoriasis, fibrositis, ocular 
intimation, osteoarthritis and rheumatoid arthritis; allergies such as 
eczema and rhinitis; hypersensitivity disorders such as poison ivy; 
ophthalmic diseases such as conjunctivitis, vemal conjunctivitis, dry eye 
syndrome, and the like; cutaneous diseases such as contact dermatitis, 
atropic dermatitis, urticaria, and other eczematoid dermatitis; oedema, 
such as oedema caused by thermal injury; addiction disorders such as 
alcholism; stress related somatic disorders; reflex sympathetic dystrophy 
such as shoulder/hand syndrome; dysthymic disorders; adverse immunological 
reactions such as rejection of transplanted tissues and disorders related 
to immune enhancement or suppression, such as systemic lupus 
erythematosis; gastrointestinal (GI) disorders and diseases of the GI 
tract such as disorders associated with the neuronal control of viscera 
such as ulcerative colitis, Crohn's disease and incontinence; emesis, 
including acute, delayed, post-operative, late-phase, and anticipatory 
emesis, for example, induced by chemotherapy, radiation, toxins, 
pregnancy, vestibular disorder, motion, post-opearative sickness, surgery, 
gastrointestinal obstruction, reduced gastrointestinal motility, visceral 
pain, migraine, opioid analgesics and variations in intercranial pressure 
(except quaternary salts); disorders of bladder function such as bladder 
detrusor hyperreflexia; fibrosing and collagen diseases such as 
scleroderma and eosinophilic fascioliasis; disorders of blood flow caused 
by vasodilation and vasospastic diseases such as angina, migraine and 
Reynaud's disease; and pain or nociception, for example, chronic pain or 
that attributable to or associated with any of the foregoing conditions 
especially the transmission of pain in migraine. Hence, these compounds 
may be readily adapted to therapeutic use for the treatment of 
physiological disorders associated with an excessive stimulation of 
tachykinin receptors, especially neurokinin-1, and as neurokinin-1 
antagonists in the control and/or treatment of any of the aforesaid 
clinical conditions in mammals, including humans. 
For example, the compounds of the present invention may suitably be used in 
the prevention or treatment of disorders of the central nervous system 
such as anxiety, psychosis and schizophrenia; neurodegenerative disorders 
such as senile dementia of the Alzheimer type, Alzheimer's disease and 
Down's syndrome; respiratory diseases, particularly those associated with 
excess mucus secretion, such as chronic obstructive airways disease, 
broncho-pneumonia, chronic bronchitis, cystic fibrosis and asthma, and 
bronchospasm; inflammatory diseases such as inflammatory bowel disease, 
osteoarthritis and rheumatoid arthritis; adverse immunological reactions 
such as rejection of transplanted tissues; gastrointestinal (GI) disorders 
and diseases of the GI tract such as disorders associated with the 
neuronal control of viscera such as ulcerative colitis, Crohn's disease 
and incontinence; disorders of blood flow caused by vasodilation; and pain 
or nociception, for example, that attributable to or associated with any 
of the foregoing conditions or the transmission of pain in migraine (both 
prophylaxis and acute treatment). 
As calcium channel blocking agents some of the compounds of the present 
invention are useful in the prevention of treatment of clinical conditions 
which benefit from inhibition of the transfer of calcium ions across the 
plasma membrane of cells. These include diseases and disorders of the 
heart and vascular system such as angina pectoris, myocardial infarction, 
cardiac arrhythmia, cardiac hypertrophy, cardiac vasospasm, hypertension, 
cerebrovascular spasm and other ischemic disease. Furthermore, these 
compounds may be capable of lowering elevated intraocular pressure when 
administered topically to the hypertensive eye in solution in a suitable 
ophthalmic vehicle. Also, these compounds may be useful in the reversal of 
multidrag resistance in rumor cells by enhancing the efficacy of 
chemotherapeutic agents. In addition, these compounds may have activity in 
blocking calcium channels in insect brain membranes and so may be useful 
as insecticides. 
The compounds of the present invention are particularly useful in the 
treatment of pain or nociception and/or inflammation and disorders 
associated therewith such as, for example: neuropathy, such as diabetic or 
peripheral neuropathy and chemotherapy-induced nemopathy; postherpetic and 
other neuralgias; asthma; osteoarthritis; rheumatoid arthritis; and 
especially migraine. The compounds of the present invention are also 
particularly useful in the treatment of diseases characterized by 
neurogenic mucus secretion, especially cystic fibrosis. 
In the treatment of the clinical conditions noted above, the compounds of 
this invention may be utilized in compositions such as tablets, capsules 
or elixirs for oral administration, suppositories for rectal 
administration, sterile solutions or suspensions for parenteral or 
intramuscular administration, and the like. 
The pharmaceutical compositions of this invention can be used in the form 
of a pharmaceutical preparation, for example, in solid, semisolid or 
liquid form, which contains one or more of the compounds of the present 
invention, as an active ingredient, in admixture with an organic or 
inorganic carder or excipient suitable for external, enteral or parenteral 
applications. The active ingredient may be compounded, for example, with 
the usual non-toxic, pharmaceutically acceptable carders for tablets, 
pellets, capsules, suppositories, solutions, emulsions, suspensions, and 
any other form suitable for use. The carders which can be used are water, 
glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium 
trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, 
urea and other carders suitable for use in manufacturing preparations, in 
solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, 
thickening and coloring agents and perfumes may be used. The active object 
compound is included in the pharmaceutical composition in an amount 
sufficient to produce the desired effect upon the process or condition of 
the disease. 
For preparing solid compositions such as tablets, the principal active 
ingredient is mixed with a pharmaceutical carder, e.g. conventional 
tableting ingredients such as corn starch, lactose, sucrose, sorbitol, 
talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and 
other pharmaceutical diluents, e.g. water, to form a solid preformulation 
composition containing a homogeneous mixture of a compound of the present 
invention, or a non-toxic pharmaceutically acceptable salt thereof. When 
referring to these preformulation compositions as homogeneous, it is meant 
that the active ingredient is dispersed evenly throughout the composition 
so that the composition may be readily subdivided into equally effective 
unit dosage forms such as tablets, pills and capsules. This solid 
preformulation composition is then subdivided into unit dosage forms of 
the type described above containing from 0.1 to about 500 mg of the active 
ingredient of the present invention. The tablets or pills of the novel 
composition can be coated or otherwise compounded to provide a dosage form 
affording the advantage of prolonged action. For example, the tablet or 
pill can comprise an inner dosage and an outer dosage component, the 
latter being in the form of an envelope over the former. The two 
components can be separated by an enteric layer which serves to resist 
disintegration in the stomach and permits the inner component to pass 
intact into the duodenum or to be delayed in release. A variety of 
materials can be used for such enteric layers or coatings, such materials 
including a number of polymeric acids and mixtures of polymeric acids with 
such materials as shellac, cetyl alcohol and cellulose acetate. 
The liquid forms in which the novel compositions of the present invention 
may be incorporated for administration orally or by injection include 
aqueous solution, suitably flavoured syrups, aqueous or oil suspensions, 
and flavoured emulsions with edible oils such as cottonseed oil, sesame 
oil, coconut oil or peanut oil, as well as elixirs and similar 
pharmaceutical vehicles. Suitable dispersing or suspending agents for 
aqueous suspensions include synthetic and natural gums such as tragacanth, 
acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, 
polyvinylpyrrolidone or gelatin. 
Compositions for inhalation or insuffiation include solutions and 
suspensions in pharmaceutically acceptable, aqueous or organic solvents, 
or mixtures thereof, and powders. The liquid or solid compositions may 
contain suitable pharmaceutically acceptable excipients as set out above. 
Preferably the compositions are administered by the oral or nasal 
respiratory route for local or systemic effect. Compositions in preferably 
sterile pharmaceutically acceptable solvents may be nebulized by use of 
inert gases. Nebulized solutions may be breathed directly from the 
nebulizing device or the nebulizing device may be attached to a face mask, 
tent or intermittent positive pressure breathing machine. Solution, 
suspension or powder compositions may be administered, preferably orally 
or nasally, from devices which deliver the formulation in an appropriate 
manner. 
For the treatment of the clinical conditions and diseases noted above, the 
compounds of this invention may be administered orally, topically, 
parenterally, by inhalation spray or rectally in dosage unit formulations 
containing conventional non-toxic pharmaceutically acceptable carriers, 
adjuvants and vehicles. The term parenteral as used herein includes 
subcutaneous injections, intravenous, intramuscular, intrastemal injection 
or infusion techniques. 
For the treatment of certain conditions it may be desirable to employ a 
compound of the present invention in conjunction with another 
pharmacologically active agent. For example, for the treatment of 
respiratory diseases such as asthma, a compound of the present invention 
may be used in conjunction with a bronchodilator, such as a .beta..sub.2 
-adrenergic receptor agonist or tachykinin antagonist which acts at 
neurokinin-2 receptors. Also, for the treatment of conditions that require 
antagonism of both neurokinin-1 and neurokinin-2, including disorders 
associated with bronchoconstriction and/or plasma extravasation in 
airways, such as asthma, chronic bronchitis, airways disease, or cystic 
fibrosis, a compound of the present invention may be used in conjunction 
with a tachykinin antagonist which acts at neurokinin-2 receptors, or with 
tachykinin receptor antagonist which acts at both neurokinin-1 and 
neurokinin-2 receptors. Similarly, for the prevention or treatment of 
emesis a compound of the present invention may be used in conjunction with 
other anti-emetic agents, especially 5HT.sub.3 receptor antagonists, such 
as ondansetron, granisetron, tropisetron, decadron, and zatisetron. 
Likewise, for the prevention or treatment of migraine a compound of the 
present invention may be used in conjunction with other anti-migraine 
agents, such as ergotamines or 5HT.sub.1 agonists, especially sumatriptan. 
For the prevention or treatment of inflammatory conditions in the lower 
urinary tract, especially cysfitis, a compound of the present invention 
may be used in conjunction with an antiinflammatory, such as a bradykinin 
receptor antagonist. The compound of the present invention and the other 
pharmacologically active agent may be administered to a patient 
simultaneously, sequentially or in combination. 
The compounds of this invention may be administered to patients (animals 
and human) in need of such treatment in dosages that will provide optimal 
pharmaceutical efficacy. The dose will vary from patient to patient 
depending upon the nature and severity of disease, the patient's weight, 
special diets then being followed by a patient, concurrent medication, and 
other factors which those skilled in the art will recognize. 
In the treatment of a condition associated with an excess of tachykinins, 
an appropriate dosage level will generally be about 0.001 to 50 mg per kg 
patient body weight per day which can be administered in single or 
multiple doses. Preferably, the dosage level will be about 0.005 to about 
25 mg/kg per day; more preferably about 0.01 to about 10 mg/kg per day; 
and even more preferably about 0.05 to about 1 mg/kg per day. For example, 
in the treatment of conditions involving the neurotransmission of pain 
sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, 
preferably about 0.005 to 10 mg/kg per day, and especially about 0.01 to 5 
mg/kg per day. The compounds may be administered on a regimen of 1 to 4 
times per day, preferably once or twice per day. 
Several methods for preparing the compounds of this invention are 
illustrated in the following Schemes and Examples wherein R.sup.1, 
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 , R.sup.9, 
R.sup.10 and R.sup.11 are as defined above. 
TABLE 1 
______________________________________ 
ABBREVIATIONS USED IN SCHEMES AND EXAMPLES 
______________________________________ 
Reagents: 
Et.sub.3 N triethylamine 
Ph.sub.3 P triphenylphosphine 
TFA trifluoroacetic acid 
NaOEt sodium ethoxide 
DCC N,N'-dicyclohexylcarbodiimide 
DCU N,N'-dicyclohexylurea 
CDI 1,1'-carbonyldiimidazole 
MCPBA m-chloroperbenzoic acid 
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene 
Cbz-Cl benzyl chloroformate 
ACE-Cl alpha-chloroethyl chloroformate 
iPr.sub.2 NEt or DIEA 
N,N-diisopropylethylamine 
NHS N-hydroxysuccinimide 
DIBAL diisobutylaluminum hydride 
Me.sub.2 SO.sub.4 
dimethyl sulfate 
HOBt 1-hydroxybenzotriazole hydrate 
EDAC 1-ethyl-3-(3-dimethylaminopropyl)carbo- 
diimide hydrochloride 
Solvents: 
DMF dimethylformamide 
THF tetrahydrofuran 
MeOH methanol 
EtOH ethanol 
AmOH n-amyl alcohol 
AcOH acetic acid 
MeCN acetonitrile 
DMSO dimethylsulfoxide 
Others: 
Ph phenyl 
Ar aryl 
Me methyl 
Et ethyl 
iPr isopropyl 
Am n-amyl 
Cbz carbobenzyloxy (benzyloxy-carbonyl) 
BOC tert-butoxycarbonyl 
PTC phase transfer catalyst 
cat. catalytic 
FAB-MS fast atom bombardment mass spectrometry 
rt room temperature 
______________________________________ 
##STR6## 
The compounds of the present invention in which X.sup.2 =N can be prepared 
according to the procedure given in Scheme 1. Esterification of the 
commercially available cis-piperidine-2,4dicarboxylic acid under acidic 
conditions yields the diester 1. Acylation on nitrogen with, for example, 
N,N-diphenylcarbamyl chloride (R.sup.1a =R.sup.1b =Ph) provides the urea 
2. Exposure of the diester 2 to one equivalent of aqueous base followed by 
acidification produces a mixture of the 4-carboxylic acid 3 and the 
2-carboxylic acid 4, along with lesser quantities of the diacid. During 
the base hydrolysis step, epimerization to the more stable trans 
2,4-disubstituted piperidine takes place. The extent of epimerization is 
dependent in part on the composition of the solvent: the lower the 
concentration of water present, the greater the degree of epimerization. 
If product enriched in cis-isomer is desired, the hydrolysis can be run in 
water with a minimum of organic solvent present, and the reaction should 
be stopped before completion. 
The products 3 and 4 can be separated and carded on separately as shown in 
Schemes 2 and 3. In each case, the free acid is converted to the 
corresponding amide under standard conditions, the remaining ester is 
hydrolysed, for example to give 5, and the revealed acid is functionalized 
to provide the product 6. 
The side chains of interest can be prepared by several routes. For example, 
the ethylenediamine derivatives can be synthesized according to Scheme 4 
if R.sup.10 and R.sup.11 do not contain groups susceptible to reduction 
with lithium aluminum hydride. If the N-methyl amide is not desired, the 
primary amine 7 can be used directly in the coupling reaction with the 
piperidine substrates. 
For preparation of the N-methylcarboxamide containing sidechains, the 
chemistry shown in Scheme 5 can be employed. Monoprotection with an 
acylating agent such as di-t-butyl carbonate followed by alkylation of the 
remaining basic nitrogen with iodoacetamide is followed by orthogonal 
protection, for example by CBZ chloride, to give the doubly protected 
intermediate 8. This compound can then be selectively deprotected to yield 
the desired side chain 9. 
After coupling 9 to 5 with a suitable condensing agent, for example, EDAC 
in the presence of HOBt in methylene chloride with a base present such as 
DIEA to free 9 from its salt, the product 10 can be deprotected under 
hydrogenolytic conditions to give the tetra-amide 11. Alternatively, if 
groups incompatible with reducing conditions are present, HBr in acetic 
acid can be employed to cleave the CBZ protecting group. The amine 11 can 
be optionally alkylated, for example with a benzyl chloride derivative, to 
provide the product 12. 
The object compounds of Formula I obtained according to the reactions as 
explained above can be isolated and purified in a conventional manner, for 
example, extraction, precipitation, fractional crystallization, 
recrystallization, chromatography, and the like. 
The compounds of the present invention are capable of forming salts with 
various inorganic and organic acids and bases and such salts are also 
within the scope of this invention. Examples of such acid addition salts 
include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, 
citrate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, 
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, 
hydroiodide, methanesulfonate, lactate, maleate, methanesulfonate, 
2-naphthalenesulfonate, oxalate, pamoate, persulfate, pierate, pivalate, 
propionate, succinate, tartrate, tosylate, and undecanoate. Base salts 
include ammonium salts, alkali metal salts such as sodium, lithium and 
potassium salts, alkaline earth metal salts such as calcium and magnesium 
salts, salts with organic bases such as dicyclohexylamine salts, 
N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine 
and so forth. Also, the basic nitrogen-containing groups may be 
quaternized with such agents as: lower alkyl halides, such as methyl, 
ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates 
like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such 
as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; 
aralkyl halides like benzyl bromide and others. The non-toxic 
physiologically acceptable salts are preferred, although other salts are 
also useful, such as in isolating or purifying the product. 
The salts may be formed by conventional means, such as by reacting the free 
base form of the product with one or more equivalents of the appropriate 
acid in a solvent or medium in which the salt is insoluble, or in a 
solvent such as water which is removed in vacuo or by freeze drying or by 
exchanging the anions of an existing salt for another anion on a suitable 
ion exchange resin. 
Although the reaction schemes described herein are reasonably general, it 
will be understood by those skilled in the art of organic synthesis that 
one or more functional groups present in a given compound of formula I may 
render the molecule incompatible with a particular synthetic sequence. In 
such a case an alterative route, an altered order of steps, or a strategy 
of protection and deprotection may be employed. In all cases the 
particular reaction conditions, including reagents, solvent, temperature, 
and time, should be chosen so that they are consistent with the nature of 
the functionality present in the molecule.