CHOLECYSTOKININ ANTAGONISTS USEFUL IN THE TREATMENT OF PANIC ATTACKS

Abstract: Unnatural dipeptoids of alpha -substituted Try-Phe derivatives are useful as agents in the treatment of panic disorders. These dipeptoids are CCKB antagonists having utility in the prevention of panic attacks in patients prone to these attacks.

Description: CHOLECYSTOKININ i_NTAGONISTS USEFUL IN THE TREATMENT OF PANIC ATTACKS BACKGROUND OF THE INVENTION The neuropeptide cholecystokinin-8 (CCK-8) is an important neuromodulator and neurotransmitter in the brain . There are two types of CCK receptor which are currently referred to as CCK A and CCK B receptors . The major of the CCK receptor types in brain is the CCK B receptor (Review by Woodruff & Hughes, Annual Review of Pharmacology Toxicology 31 : 469-501 (1991 ) ) . The functional role of CCK in brain is not fully understood . Recently there has been evidence that CCK is involved in anxiety and that CCK B antagonists have an anxiolytic action in animal models of anxiety (Hughes , et al, Proc Natnl Acad Sci , USA 87 : 6728-6732 (1990) . It has recently been shown (de ontigny, C Arch Gen Psychiatry 46 : 511-517 (1989) ; Bradwejn J, Koszyckl, D, and Metesissian, G, Can J Psychiatr 35 : 83-85 (1990) that the injection of pentagastrin into human volunteers or into patients suffering from panic disorder precipitates a panic attack . Pentagastrin is a substance that stimulates CCK B receptors, i . e. , is a CCK B ant agonist . The injection of pentagastrin into the cerebral ventricles of the brain of rats precipitates the onset of an anxiogenic reaction . This anxiogenic response can be prevented by pretreatment of the rats with the CCK B antagonist CI-988 (Sing, et al - Proc Natnl Acad Sci USA 88 : 1130-1133 (1991) ) . The present invention relates to compounds known as dipeptoids and/ or their pharmaceutically acceptable salts for use in the prevention of panic attacks in patients prone to these attacks . Suitable compounds are cholecystokinin (CCK) B antagonists such as [R-(R*,R*) ]-4-[ [2-[ [3-(lH-indol-3-yl) -2-methyl-l-oxo- 2-[ [ (tricyclo[3.3.1.I 3 ' 7 ]dec-2-yloxy) carbonyl]amino] - propyl] amino]-1-phenylethyl] amino]-4-oxobutanoic acid. The compounds useful in this invention are fully described in 07/629,809, filed December 19, 1990. Methods of preparing the compounds, intermediates useful in their preparation, compositions containing the compounds, and uses of the compounds are disclosed. The uses disclosed include the treatment of obesity, hypersecretion of gastric acid in the gut, gastrin-dependent tumors, psychoses, anxiety, ulcer, depression, withdrawal response produced by chronic treatment or use followed by withdrawal from nicotine, diazepam, alcohol, cocaine, caffeine, or opioids. The disclosure of 07/629,809 is incorporated herein by reference. SUMMARY OF THE INVENTION The instant invention concerns a new method of treating panic disorders which comprises administering to a human in need of such treatment or therapeutically effective amount of a compound of formula H or a pharmaceutically acceptable salt thereof in unit dosage form. R 1 , A, R 2 , R 3 , R 4 , R 9 , and Ar are as defined below. The method of the invention is administering the compound in an amount of 0.1 to 20 g/kg of body weight. A preferred amount is from 1 to 10 mg/kg of body weight. Preferred compounds useful in this method are those of formula I wherein the cycloalkyl or polycycloalkyl has from about six to ten carbon atoms unsubstituted or substituted with one or more substituents, each substituent selected independently from: methyl, fluorine, chlorine, and bromine. Other preferred compounds useful in this method are those of formula I wherein R 1 is cycloalkyl or polycycloalkyl wherein the polycycloalkyl is selected from the group consisting of wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF 3 , NR 5 R 6 , -(CH 2 ) n C0 2 R * , CN, F, Cl, Br, OR * , SR * , wherein R * , R 5 and R° are as defined in Claim 1 and n is an integer of from 1 to 3. A is -NHCO-, OC(=0)-, -S0 2 -, -S (=0) -, -SCO- or -CH 2 C0-/ and Ar is 2- or 3-thienyl, 2- or 3-furanyl, 2-, 3-, or 4-ρyridinyl or an unsubstituted or substituted phenyl whose substituents if any are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl, nitro, OH, NH 2 , 0CF 3 , NHCOCH 2 CH 2 C0 2 H, or CH 2 CH 2 C0 2 H. More preferred compounds of the instant invention are those of formula I wherein in the compound of formula I R 1 is 2-adamantyl or 1-(S)-2-endobornyl; A is -NHC0-, -0C0-, -S0 2 -, -S (=0)-, or -CH 2 CO-; R 2 is -CH 3 , -CH 2 C0 2 H or -CH 2 C≡CH; R 3 is -(CH 2 ) n -B-D or H; R 4 is -(CH 2 ) n -B-D or H; and R s is hydrogen or methyl. Still more preferred compounds of the invention are those of formula I wherein in the compound of formula I R 1 is 2-adamantyl, 1- (S) -2-endobornyl, or 2-methyl cyclohexyl, A is -OC(=0)-/ R 2 is -CH 3 ; R 3 is H, CH 2 OH, CH 2 OCOCH 2 CH 2 C0 2 H, CH 2 OCOCH=CHC0 2 H, CH 2 NHC0CH 2 CN 2 C0 2 H, CH 2 NHCOCH=CHC0 2 H, or CH 2 C0 2 H; R 4 is H, -CH 2 SCH 2 C0 2 H, -CH 2 SCH 2 CH 2 C0 2 H, -NHCOCH=CKC0 2 H, -NHCOCH 2 CH 2 C0 2 H ( [D] configuration) or NHCOCH=CHC0 2 H [ ( [D] configuration) . Especially preferred compounds useful in preventing panic attacks or in treating the symptoms of panic are: (±) -trans-2-chlorocyclohexyl [1- (lH-indol-3- ylmethyl) -l-methyl-2-oxo-2- [ (2- phenylethyl) amino] ethyl] carbamate; 2-chlorocyclohexyl [2- [ [1- (hydroxymethyl) -2- phenylethyl] -amino] -1- (lH-indol-3-ylmethyl) -1-methyl- 2-oxoethyl] -carbamate; 2-[ [2-[ [ [ (2-chlorocyclohexyl) oxy] carbonyl] amino] - 3- (lK-indol-3-yl) -2-methyl-l-oxopropyl] amino] -3- phenylpropyl butanedioate; 2-[ [2-[ [ [ (2 -methyl cyclohexyl) oxy] carbonyl] amino] - 3- (lH-indol-3-yl) -2-methyl-l-oxopropyl] amino] — 3- phenylpropyl butanedioate; (±) -tricyclo [3.3.1.1 3 ' 7 ] dec-2-yl [1- (lH-indol-3- ylmethyl) -l-methyl-2-oxo-2- [ (2-phenylethyl) amino] - ethyl] carbamate; (+) or (-)-2-chlorocyclohexyl[l-(lH-indol-3- ylmethyl) -l-methyl-2-oxo-2- [ (2-phenylethyl) - amino ] ethyl ] carbamate ; tricyclo [3.3.1.1 3 ' 7 ] dec-2-yl [2-[[l- (hydroxy ethyl) -2 -phenylethyl] amino] -1- (lH-indol-3- ylmethyl) -l-methyl-2-oxoethyl] carbamate; 2- [ [3- (lH-indol-3-yl) -2-methyl-l-oxo-2- [ [ (tricyclo- [3.3.1.1 3 ' 7 ] dec-2-yloxy) carbonyl] amino] - propyl] amino] -3-phenylpropyl butanedioate; [R-(R*,R*) ]-4-[ [2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-t [ (-ricyclo[3.3.1.1 3,7 ]dec-2-yloxy)- carbonyl] amino] propyl] amino] -1 -phenylethyl] -amino] -4- oxobutanoic acid; [lS-[l«,2β[S* (S*) ],4oc]]-4-[[2-[ [3-(lH-indol-3- yl) -2-methyl-l-oxo-2-[ [ [ (1, 7, 7-trimethylbicyclo- [2.2. l]hept-2-yl) oxy] carbonyl] amino] propyl] amino] -1- phenylethyl ] amino ] -4-oxobut anoic acid; [R-[R*,S*-(E) ] ]-4-[ [2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2- [ [tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) carbonyl] amino] -propyl] amino] -3- phenylpropyl] amino] -4-oxo-2-butenoic acid; [R- (R*, S*) ] -4- [ [2- [ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl] amino ] -propyl ] amino] -3- phenylpropyl ] amino ] -4-oxo-butanoic acid; (R) -tricyclo [3.3.1.1 3 ' 7 ] dec-2-yl- [1- (lH-indol-3- ylmethyl) -l-methyl-2- [methyl- (2 -phenylethyl) amino] -2- oxoethylcarbamate ; [R- (R*, S*) ] -2- [ [2- [ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) carbonyl] amino] -propyl] amino] -3- phenylpropyl] sulf inyl] acetic acid; [R- (R* , S*) ] - [ [2- [ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1. l 3 ' 7 ]dec-2- yloxy) ] carbonyl] amino] -propyl] amino] -3- phenylpropyl ] sulfonyl] acetic acid; [R- (R*, S*) ] - [ [2- [ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) carbonyl] amino ] -propyl ] amino] -3- pheny lpropy 1 ] sulf inyl] acetic acid, ethyl ester; [R- (R*, S*) ] - [ [2- [ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2- [ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) ] carbonyl] amino] -propyl] amino] -3- pheny lpropy 1] sulfonyl] acetic acid; [R-[R*,R*-(E) ]]-4-[[2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl] amino] -propyl] amino]-1- phenylethyl]amino]-4-oxo-2-butenoic acid; [R- (R*,S*) ]-[ [2-[ [2-[3-(lH-indol-3-yl) -2-methyl- l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) - carbonyl] amino]-propyl] mino]-3- phenylpropyl]thio] acetic acid; [lS-[l«,2β[S*[S*(E)]] ,4«]]-4-[[2-[ [3-(lH-indol-3- yl) -2-methyl-l-oxo-2-[ [ [ (1,7,7- trimethylbicyclo [2.2. l]hept-2-yl) oxy] - carbonyl] amino] propyl] amino] -1 -phenylethyl] amino] -4- oxo-2— butenoic acid, methyl ester, (bicvclo system is lS-endo) ; [lS-[loe,2β[S*[S*(E)]_ ,4«] ] -4- [ [2- [ [3- (lH-indol-3- yl) -2-methyl-l-oxo-2- [ [ [ (1, 7, 7-trimethylbicyclo- [2.2.1]hept-2-yl) oxy] carbonyl] amino] propyl] amino] -1- phenylethyl] amino] -4-oxo-2-butenoic acid (bicyclo system is lS-endo) ; [R-(R*,R*) ]-3-[[2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) carbonyl] amino] -propyl] amino] -1— phenylethyl] amino] -3-oxoproρanoic acid; [R- (R*. S*) ] -3- (lH-indol-3-ylmethyl) -3-methyl- 4, 10-dioxo-6- (phenylmethyl) -ll-oxo-8-thia-2, 5- diazatridecanoic acid, tricyclo [3.3.1.1 3 ' 7 ] dec-2-yl or ester; [R- (R*, S*) ] -β- [ [3- (lH-indol-3-yl) -2-methyl-l-oxo- 2-[ [ (tricyclo [3.3.1. l 3 ' 7 ]dec-2-yloxy) - carbonyl] amino ] propyl ] amino ]benzenebutanoi c acid; [R- (R*, S*) ] -β- [ [3- (lH-indol-3-yl) -2-methyl-l-oxo- 2- [ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2-yloxy) - carbonyl] amino ] propyl ] amino] -4-iodo-benzenebutanoic acid, where the iodo group may be 1-125 or 1-127; [R-(R*,S*) ]-N-[3-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2- [ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) carbonyl] amino] -propyl] amino] -4-phenyl- butyl]glycine; and [R-[R*,S*-(E) ]]-4-[ [2-[[3-(lH-indol-3-yl)-2- methyl-2-[ [ (bicyclo[3.3.l]non-9-yloxy)carbonyl]amino]- 1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2- butenoic acid. A most preferred compound for treating panic disorder symptoms is 2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)carbonyl]- amino]prop l]amino]-1-phenylethyl butanedioate. DETAILED DESCRIPTION The compounds useful in the present invention are formed by the condensation of two modified amino acids and are therefore not peptides. Rather they are "dipeptoids", synthetic peptide-related compounds differing from natural dipeptides in that the substituent group R 2 is not hydrogen. The compounds of the present invention are represented by the formula or a pharmaceutically acceptable salt thereof wherein : R 1 is a cyclo- or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents , each independently selected from the group consisting of : a straight or branched alkyl of from one to six carbon atoms, halogen, CN, OR * , SR * , C0 2 R * , CF 3 , NR 5 R 6 , or (CH 2 ) π OR 5 wherein R * is hydrogen, straight or branched alkyl of from one to six carbon atoms, R 5 and R 6 are each independently hydrogen or alkyl of from one to six carbon atoms; and n is an integer from zero to six; A is (CH 2 ) n C0-, -S0 2 -, -S(=0)-, -NHCO-, 0 II -(CH 2 ) -0C-, -SCO-, 0-(CH 2 ) n C0- or -HC=CHCO- wherein n is an integer from zero to six; R 2 is a straight or branched alkyl of from one to six carbon atoms, -HC=CH 2 , -C≡CH, -CH 2 -CH=CH 2 , -CH 2 C≡CH, -(CH 2 ) n Ar, -(CH 2 ) n OR * , -(CH 2 ) n OAr, -(CH 2 ) rι C02 *, - (CH 2 ) π NR 5 R 6 wherein n, R' R 5 and R 6 are as defined above and Ar is as defined below; R 3 and R 4 are each independently selected from hydrogen, R^, and -(CH 2 ) n -B-D, wherein n' is an integer of from zero to three; B is a bond -OCO(CH 2 ) n -, -0(CH 2 ) n -, -S0 2 NH(CH 2 ) n -, -NHS0 2 (CH 2 ) n , -NHCO(CH 2 ) n -, CONH(CH 2 ) n -, NHCOCH=CH-, -COO(CH 2 ) n -, -CO(CH 2 ) n -, -S-(CH 2 ) n -, -SO(CH 2 ) n -, -S0 2 (CH 2 ) n -, -NHS0 2 -(CH 2 ) n -, -S0 2 NH-(CH 2 ) n -, -NHC0-C=C-, R 7 R 8 -C0NH-C=C-, H H ! I -C0NHC-C-, R 7 R 8 wherein R 7 and R 8 are independently selected from hydrogen and R 2 or together form a ring (CH 2 ) m wherein m is an integer of from 1 to 5 and n is as defined above ; D is -COOR', -CH 2 0R*, -CHR 2 0R*, — CH 2 SR , -CR 2 SR*, -CONR 5 R δ , -CN, -NR 5 R β , -OH, -H, and acid replacements such as tetrazole, and N — N Λi OR*, NR 5 R*, CH 3 , or Cl 1,2,4 oxadiazole s is an integer of from 0 to 2 wherein R * , R 2 , R 5 , R 6 and R 10 are as defined above; R 9 is H, or a straight or branched alkyl of from one to six carbon atoms, -(CH 2 ) n C0 2 R * , (CH 2 ) n OAr' , (CH 2 ) n Ar *' , (CH 2 ) n NR 5 R 6 , wherein n, R * , R 5 , and R 6 are as defined above or taken from R 3 and Ar* * is taken from Ar as defined below; R 12 and R 13 can each be independently hydrogen (in which case the carbon atom to which it is attached is a chiral center) or can each be taken with R 3 and R 4 respectively to form a moiety doubly bonded to the carbon atom (in which case the carbon atom is not chiral) ; and SUBSTITUTE SHEET Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety . Preferred Ar is 3-pyridyl, 4-pyridyl, 4-pyridyl N-oxide, l-nap thyl, 2-nap thyl, More preferred definitions of Ar are: HN— N Λ— N -N Still more preferred Ar is 2- or 3-thienyl, 2- or -furanyl, 2-, 3- or 4-pyridinyl or an unsubstituted r substituted benzene ring wherein E and F are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl, nitro, hydroxy, NH 2 , 0CF 3 , and R 3 as defined above . Preferred definition for R 3 is NHCOCH 2 CH 2 C0 2 H or CH 2 CH 2 C0 2 H . The indole portion of formula I can be mono or disubstituted by halogen; lower alkyl ; CF 3 ; lower 0 alkoxy; benzyloxy; hydroxy; 0-C-R 14 wherein R 14 is lower alkyl or phenyi ; -N0 2 ; NR 1 15 R 2 16 wherein τ_ 1= and R 2 16 are each independently hydrogen or lower alkyl ; -N-C-R 14 wherein R 14 is as defined above . II o Preferred substituents are : 5-fluoro, 5-chloro; 5-hydroxy; 5-methyl ; 5-methoxy; 5-benzyloxy; 5-CF 3 , 5-N0 2 ; and 5-NH 2 . The indole is numbered for purposes of the above substituents. Further, the indole can be substituted on the nitrogen by -[ (4-methylphenyl) sulfonyl] or by a methyl group. Preferred cycloalkyl or polycycloalkyl substituents have from six to ten carbon atoms. Preferred compounds of the instant invention are those wherein cycloalkyl is a substituted or unsubstituted and wherein polycycloalkyl is selected from wherein W, X, Y, and S are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF 3 , NR 5 R β , -(CH 2 ) n C0 2 R*, or CN, F, Cl, Sr, OR * , SR * , wherein R' is hydrogen or a straight or branched alkyl of from one to six carbon atoms and R 5 and R 6 are as defined above and n is an integer of rom 1 to 3. Other preferred compounds of the instant invention are those wherein R 1 is 2-adamantyl or 1- (S) -2-endobornyl; A is -NHC0-, -OCO-, -S0 2 -, -S (=0) - or -CH 2 C0-; R 2 is -CH 3 , -CH 2 C0 2 CH 3 or -CH 2 C≡CH; R 3 is -(CH 2 ) n ,-B-D or H; R 4 is -(CH 2 ) n ,-B-D or H; and R 9 is hydrogen or methyl. More preferred compounds of the instant invention are those wherein Rl is 2-adamantyl, 1- (S) -2-endobornyl, or 2-methylcyclohexyl; 0 II A is -0-C-, R 2 is -CH 3 ; R 3 is H, CH 2 0H, -CH 2 OCOCH 2 CH 2 C0 2 H, -CH 2 0C0CH=CHC0 2 H or -CH 2 NHCOCH 2 CH 2 C0 2 H, or -CH 2 NHC0CH=CHC0 2 H and R 4 is H, -CH 2 SCH 2 C0 2 H, -CH 2 SCH 2 CH 2 C0 2 H, -NHCOCH=CHC0 2 H, -NHCOCH 2 CH 2 C0 2 H ( [D] configuration or -NHCOCH=CHC0 2 H ( (D] con iguration) . The D and the L con igurations are possible at the chiral centers and are included in the scope of the invent ion : 1. Preferred is when R 2 -CH 3 [D] configuration; 2. Preferred is when R 3 is -CH 2 OCOCH 2 CH 2 C0 2 H or CH 2 C0 2 H or -CH 2 NHCOCH 2 CH 2 C0 2 H with the ID] configuration at the Trp oc-carbon atom and the [L] configuration at the Phe-α-carbon atom; and 3. Preferred is when R 4 is -NHCOCH 2 CH 2 C0 2 H [D] configuration or NHCOCH=CHC0 2 H[D] configuration with the ID) configuration at the Trp α-carbon atom. Most preferred compounds of the instant invention are: 1. [lS-[loe,2β[S*[S*(E) ]],4°c]]-4-[ [2-[ [3-(lH-indol-3- yl) -2-methyl-l-oxo-2-[[[(1,7,7-trimethylbicyclo- [2.2. l]hept-2-yl)oxy] carbonyl] amino]propyl]amino]-1- phenylethyl]amino]-4-oxo-2-butenoic acid, 2. [lS-[l ,2β[S*(S*)],4-_]]-4-[[2-[[3-(lH-indol-3- yl) -2-methyl-l-oxo-2-[ [ [ (1, 7, 7-trimethylbicyclo- [2.2.l]hept-2-yl)oxy] carbonyl] amino]propyl]methyl- amino]-1-phenylethyl]amino] -4-oxobutanoic acid, 3. [IS-[lee,2β [S* (S*) ] , ee] ]-4-[ [2-[ [3-(lH-indol-3- yl)-2-methyl-l-oxo-2-[ [ [ (1, 7,7-trimethylbicyclo- [2.2.l]hept-2-yl)amino]carbonyl] amino]propyl] amino]-1- phenylethyl]amino]-4-oxobu anoic acid, 4. [R-(R*,R*)]-4-[ [2-[ [3-(lH-indol-3yl)-2-methyl-l- oxo-2-[ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-ylsulfonyl) amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid, 5. [R-(R*,S*) ]-4-[ [2-[ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-ylsulfonyl) amino]- propyl]amino]-3-phenylpropy1]amino]-4-oxobutanoic acid, 6. [lR-[loc[R*(S*) ] ,2β]] and [IS-[1«[S* (R*) ] ,2β] ]-4- [ [2-[ [2-[ [ [ (2-fluorocyclohexyl) oxy]carbonyl]amino]-3- (lH-indol-3-yl)-2-methyl-l-oxopropyl]amino]-3- phen lpropy1]amino]—4-oxobutanoic acid, 7. [lR-[l~[R*(S*)],2β]] and [IS-[1-[S*(R*) ] ,2β] ]-4- [ [2-[ [2-[ [ [ (2-fluorocyclohexyl) oxy] carbonyl]amino] -3- (lH-indol-3-yl)-2-methyl-l-oxopropyl]methylamino]-3- phenylpropyl]amino]-4-oxobutanoic acid, 8. [lR-[lβ [R * (S * )],2β]] and [IS-[l«[S r (R * ) ] ,2β]-4- [ [2-[ [3- (lH-indol-3-yl)-2-methyl-l-oxo-2-[ [ [ [2- (tri- fluoromethyl)cyclohexyl] oxy] carbonyl]amino]propyl] - amino]-3-phenylpropy1] amino]-4-oxobut noic acid, 9. [lR-[loe[R * (S * )],2β]] and [IS-[1«[S * (R * ) ] ,2β] ] -4- [ [2-[ [3-(lH-indol-3-yl)-2-methyl-l-oxo-2-[ [ [ [2- (trifluoromethyl) cyclohexyl] oxy]carbonyl]amino]- propyl]methylamino] -3-phenylpropyl]amino]-4- oxobutanoic acid, 10. [R-(R * ,S*) ]-4-[ [2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]- amino]propyl]methylamino]-3-phenylpropyl] amino]-4- oxobutanoic acid, 11. [lS-[l«,2β[S * (R * ) ] ,4«] ]-[l-(lH-indol-3-ylmethyl)- l-methyl-2-oxo-2-[ [2-[ [l-oxo-3-(lH-tetrazol-5- yl) propyl] amino] -1- (phenylmethyl) ethyl ] amino] ethyl] - carbamic acid, 1 , 7 , 7-trimethylbicyclo [2 .2 . l ] hept-2-yl ester, 12. [lS- [l< * <, 2β [S * (R*) 1 f 4«] ] - [l- (lH-indol-3-ylmethyl) - l-methyl-2-oxo-2- [ [2- [ [l-oxo-3- (lH-tetrazol-5-yl) - propyl] amino]-2-phenylethyl] amino]ethyl]carbamic acid, 1,7, -trimethyl-bicyclo[2.2.1]hept-2-yl ester, 13. N-[2-methyl-N-[ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) - carbonyl]-D-tryptophyl]-L-phenylalanylglycine, 14. N-[2-methyl-N-[ (tricyclo[3.3.1.1 3 ' " ]dec-2-yloxy)- carbonyl]-D-tryptophyl]-L-phenylalanyl-β-alanine and 15. (R) -tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [1-(lH-indol-3- ylmethyl)-l-methyl-2-[methyl (2-phenylethyl)amino]-2- oxoethylcarbamate. In addition most especially preferred compounds of the instant invention are: 16. (±) -Trans-2-chlorocyclohexyl [1-(lH-indol-3-yl- methyl)-l-methyl-2-oxo-2-[ (2-phenylethyl)amino]ethyl]- carbamate, 17. 2-chlorocyclohexyl [2-[ [1-(hydroxymethyl) -2- phenylethyl]amino]-1-(lH-indol-3-ylmethyl) -l-methyl-2- oxoethyl]carbamate, 18. 2-[ [2-[ [ [ (2-chlorocyclohexyl)oxy] carbonyl] amino] - 3-(lH-indol-3-yl) -2-methyl-l-oxopropyl] amino]-3- phenylpropyl butanedioate, 19. 2-[ [2-[ [ [ (2-methylcyclohexyl)oxy] carbonyl] amino] - 3-(lH-indol-3-yl) -2-methyl-l-oxopropyl] amino]-3- phenylpropyl butanedioate, 20. (±) -tricyclo [3.3.1.1 3 ' 7 ]dec-2-yl [1- (lH-indol-3- ylmethyl) -l-methyl-2-oxo-2-[ (2-phenylethyl) amino]- eth 1carbamat , 21. tricyclo [3.3.1.1 3 ' 7 ]dec-2-yl [2-[[l- (hydroxymethyl) -2-phenylethyl] amino] -1- (lH-indol-3-yl- ethyl) -l-methyl-2-oxoethyl] carbamate, 22. 2-[ [3-(lH-indol-3-yl)-2-methyl-l-oxo-2- [ [ (tricyclo-[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl] amino] - propyl] amino] -3-phenylpropy1 butanedioate, 23. 2-[ [3-(lH-indol-3-yl)-2-methyl-l-oxo-2- [ [ (tricyclo[3.3.1. l 3 ' 7 ]dec-2-yloxy) carbonyl]- amino]prop l] amino]-1-phenylethyl butanedioate, 24. [R-(R*,R*) ]-4-[ [2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl] - amino]propyl] amino]-1-phenylethyl]amino]-4-oxobutanoic acid, 25. [lS-[l°c,2β[S * (S*) ],4oc] ]-4-[[2-[ [3- (lH-indol-3- yl)-2-methyl-l-oxo-2-[ [ [ (1, 7,7-trimethylbicyclo- [2.2.1]hept-2-yl) oxy]carbonyl]amino]propyl]amino]-1- phenylethyl] amino]-4-oxobutanoic acid, 26. [R-[R*,S * -(E) ] ]-4-[ [2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl]amino]propyl] amino]-3-phenylpropyl]- amino]-4-oxo-2-butenoic acid, 27. [R-(R*,S*) ]-4-[ [2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl] - amino]propyl]amino]-3-phenylpropyl] amino]-4- oxobutanoic acid, 28. (R)-tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [1- (lH-indol-3- ylmethyl)-l-methyl-2-[methyl (2-phenylethyl) amino]-2- oxoethylcarbamate, 29. [ -( * ,S * )]-[ [2-[ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) ]carbonyl]- amino]propyl] amino]-3-phenylpropyl] sulfinyl]- acetic acid, ethyl ester, 30. [R-(R * ,S * ) ]-[[2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3, ]dec-2-yloxy) Jcarbonyl]- amino]propyl] amino]-3-phenylpropyl] sulfonyl]- acetic acid, ethyl ester, 31. [R-(R * ,S * ) ]-[[2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) ]carbonyl]- amino]propyl] amino]-3-phenylpropyl] sulfinyl] - acetic acid, 32. [R-[R * ,R * -(E) ] ]-4-[ [2-[ [3- (lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- y lox ) ] carbon l ] amino ] propyl ] amino ] -1- phenylethyl] amino] -4-oxo-2-butenoic acid, 33 . [R- (R * , S * ) ] - [ [2- [ [2- [3- (lH-indol-3-yl) -2-methyl- l-oxo-2- [ [ (tricyclo [3 .3 . 1 . 1 3 ' 7 ] dec-2-yloxy) ] carbonyl] - amino] propyl] amino ] -3-phenylpropyl] thio] acetic acid, 34. [lS- [l«, 2β [S * [S * (E) ] ] , 4«] ] -4- [ [2- [ [3- (lH-indol-3- yl)-2-methyl-l-oxo-2-[[[(1,7,7-trimethylbicyclo- [2.2.l]hept-2-yl) oxy]carbonyl]amino]propyl]amino] -1- phenylethyl]ajπαino]-4-oxo-2-butenoic acid, methyl ester, (Bicyclo system is lS-endo) , 35. ]-4-[ [2-[ [3-(lH-indol-3- yl) -2-methyl-l-oxo-2-[ [ [ (1,7,7-trimethylbicyclo- [2.2.l]hept-2-yl) oxy]carbonyl]amino]propyl]amino]-1- phenylethyl] amino]-4-oxo-2-butenoic acid, (Bicyclo system is lS-endo) , 36. [R-(R*,R*) ]-3-[[2-[ [3- (lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.l 3 ' 7 ]dec-2- yloxy) ]carbonyl]amino]propyl]amino]-1- phenylethyl]cimino]-3-oxo—propanoic acid, 37. [R-(R * , S * ) ]-3-(lH-indol-3-ylmethyl)-3-methyl- 4, 10-dioxo-6-(phenylmethyl) -ll-oxo-8-thia-2,5- diazatridecanoic acid, tricyclo[3.3.1.l 3,7 ]dec-2-yl or ester, 38. [R-(R*,S * ) ]-β-[ [3-(lH-indol-3-yl)-2-methyl-l-oxo- 2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) ] carbonyl] amino]- propyl]amino]benzenebutanoic acid, 39. [R-(R * ,S * ) ]-N-[3-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3. l.l 3 ' 7 ]dec-2-yloxy) ] carbonyl]- amino]propyl] amino]-4-phenylbuty1]glycine, 40. [R-[R * ,S*-(E) ] ]-4-[[2-[[3-(lH-indol-3-yl)-2- methyl-2-[ [ (bicyclo [3.3.l]non-9-yloxy) carbonyl]amino]- 1-oxopropyl] -amino]-3-phenylprop 1] amino]-4-oxo-2- butenoic acid, 41. mono [R- (R*,R*) ] -2-[ [3-(lH-indol-3-yl) -2-methyl- l-oxo-2-[ [ (tricyclo [3.3.1.l 3 ' 7 ]dec-2- yloxy) carbonyl] amino] -1-phenylethyl butanedioate, 42. 3-[ [3-[ [3-(lH-indol-3-yl)-2-methyl-l-oxo-2- [ [ (tricyclo-[3.3.1.1 3 ' 7 ]dec-2-yloxy) ] carbonyl]- amino]propyl] amino]-l-oxo-2-phenylpropyl]amino]- propanoic acid (TRP is R, other center is RS) , 43. [1R-[1°=[R*(S*) ] ,2β] ]-4-[ [2-[ [3- (lH-indol-3-yl) -2- methyl-2-[ [ [ (2-methyl-l-cyclohexyl) oxy]carbonyl]- amino]-1—oxopropyl] -amino]-3-ρhenylpropyl]amino]-4- oxo-2-butenoic acid, (-) -Isomer, 44. [1R-[1«[R*(S * ) ],2β]]-4-[[2-[ [3-(lH-indol-3-yl) -2- methyl-2-[ [ [ (2-methyl-l-cyclohexyl) oxy]carbonyl]- amino]-1-oxopropyl]-amino]-3-phenylpropyl] amino]-4- oxobutanoic acid, (-) -Isomer, 45. [lR-[lo=[R*(S*) ],2β]]-4-[[2-[[3-(lH-indol-3-yl)-2- methyl-2-[ [ [ (2-methyl-l-cyclohexyl) oxy]carbonyl]- amino]-1-oxopropyl]-amino]-1-phenylethyl]amino]-4-oxo- 2-butenoic acid, (-) -Isomer, 46. [1R-[1«[R*(S * ) ] ,2β] ]-4-[ [2-[ [3-(lH-indol-3-yl) -2- methyl-2-[ [ [ (2-methyl-l-cyclohexyl) oxy]carbonyl]- amino]-1-oxopropyl] -amino]-1-phenylethyl]amino]-4- oxobutanoic acid, (-) -Isomer, 47. 2-methylcyclohexyl-[lR-[l~[R*(S*)]],2β]-[2-[[l- (hydroxymethyl) -2-phenylethyl]amino]-1-(lH-indol-3- ylmethyl) -l-methyl-2-oxoethyl]carbamate, 48. [R-[R*,S*-(E,E) ] ]-6-[ [3-(lH-indol-3-yl) -2-methyl- l-oxo-2-[ [ (tricyclo-[3.3.1.l 3 ' 7 ]dec-2- yloxy) carbonyl]amino]propyl] -amino]-7-phenyl-2, 4- heptadienoic acid, 49. [R-(R * ,R * ) ]-[2-[ [2-[ [1,4-dioxo-4- (lH-tetrazol-5- ylamino) -butyl]amino]-2-phenylethyl]amino]-1- (1H- indol-3-ylmethyl)-l-methyl-2-oxoethyl]carbamic acid, 50. tricyclo-[3.3.1.1 3 ' 7 ]dec-2-yl-[S-[R * , S*-(E) ] ]-12- (lH-indol-3-ylmethyl) -12-methyl-3, ll-dioxo-9- (phenylmethyl) -2-oxa-7, 10, 13-triazatetradec-4-en-14- oate, 51. [R-(R*,S * ) ]-3-[[2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo-[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]- amino]propyl]-amino]-3-phenylpropyl]amino]—3- oxopropanoic acid, 52. ethyl [R- (R*, S*) ]-[ [2-[ [2-[3- (lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' ]dec-2-yloxy) - carbonyl]amino]-propyl]amino]-3-phenylpropyl]thio]- acetate, 53. [R-(R*,S*) ]-β-[ [3-(lH-indol-3-yl)-2-methyl-l-oxo- 2-[ [tricyclo [3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl] amino]- propyl]amino]-4-iodo-benzenebutanoic acid, 54. [R- (R*,R*) ]-[2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[[ (1 (tricyclo[ [ (3.3.1.1 3 ' 7 ]dec-2-yloxy) - carbonyl] amino]-propyl]amino]-1-phenylethoxy]acetic acid, 55. [[3-[[3-(lH-indol-3-yl)-2-methyl-l-oxo-2- [ [tricyclo (3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]amino]- propyl]amino]-l-oxo-2-phenylpropyl]amino]acetic acid (TRP center is R, other center is RS) , 56. (R) -[ [ [2-[ [3-(lH-indol-3-yl)-l-oxo-2-methyl-2- [ [ (tricyclo[3.3.1.1 3,7 ]dec-2-yloxy) carbonyl] amino]- propyl]amino]-1-phenylethylidene]amino] oxy]acetic acid, 57. [R-(R*,S*) ]-β-[ [3-(lH-indol-3-yl) -2-methyl-1-oxo- 2-[[ (tricyclo[3.3.1.l 3 ' 7 ]dec-2- yloxy) carbonyl]amino] ropyl]-amino]benzenebutanoic acid, SUBSTITUTE SHEET 58. [R- (R* , S*) ] -N- [3- [ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2- [ [ (tricyclo- [3.3.1.1 3 ' 7 ] dec-2- yloxy ) carbonyl ] propyl ] amino] -4-phenylbutyl ] glycine , 59. 2- [ [ [2- [ [3- (lH-indol-3-yl) -2-methyl-l-oxo-2- [[ (tricyclo- [3.3.1. l 3 ' 7 ]dec-2- yloxy) carbonyl] amino] propyl] amino] -1- phenylethyl] amino] carbonyl] cyclopropanecarboxylic acid (cyclopropane ring is trans- (±) other centers are R) , 60. carbamic acid, [1- (lH-indol-3-ylmethyl) -1-methyl- 2-oxo-2-[ [2-[ [l-oxo-3-(lH-tetrazol-5-yl' 1 -r pyl] amino] - 2-phenylethyl] -amino] ethyl] -, tricycl _._ .3.1.1 3 ' 7 ] dec-2- yl ester, [R, (R*,S*]~, 61. benzeneheptanoic acid, <* • - [ [3- (lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) carbonyl] amino] -propyl] amino] -, [R- (R*, S*) ] -, 62. methyl- (±) -β- [ [ (2-phenylethyl) amino] carbonyl] -lβ- [ [ (tricyclo [3.3.1. l 3,7 ]dec-2-yloxy) carbonyl] amino] -1H- indole-3-but anoate , 63. [R- (R*, S*) ] -4- [ [2- (lH-indol-3-yl) -2-methyl-l-oxo- 2- [ [tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxylcarbonyl] amino] propyl] -amino] -3- phenylpropyl] amino] -4-oxo-2-butenoic acid, 64. bicyclo[2.2.1]heptane-2-acetic acid, 3-[[[[2-[[l- (hydroxymethyl) -2-phenylethyl] amino] -1- (lH-indol-3- ylmethyl) -l-methyl-2-oxoethyl] amino] carbonyl] oxy] - 4,7,7-trimethyl-, [1R- [1«, 2β, 3°=[R* (S*) ] , 4<=>c] ]-, 65. butanoic acid, 4-[ [2- [ [3- (lH-indol-3-yl) -2- methyl-2- [ [ [ (2-methyl-l-cyclohexyl) oxy] carbonyl] - amino] -1-oxopropyl] -amino] -1-phenylethyl] amino] -4-oxo- [1R-[1CC[R* (R*) ] 2β] ]-((-) -isomer) , 66. 2-butenoic acid, 4-[ [2- [ [3- (lH-indol-3-yl) -2- methyl-2- [ [ [ (2-methyl-l-cyclohexyl) oxy] carbonyl] - amino] -1-oxopropyl] -amino] -1-phenylethyl] aimino] -4-oxo- [ 1R- [ 1« [R* (R* ) ] , 2β ] ] - ( (-) -isomer) , 67. butanoic acid, 4-[ [2-[ [3- (lH-indol-3-yl) -2- methyl-2- [ [ [ (2-methyl-l-cyclohexyl) oxy] carbonyl] - amino] -1-oxopropyl] -amino] -3-pheny lpropy 1] amino] — 4— oxo-[lR-[l«[R*(S*) ] ,2β]]-( (-) -isomer) , and 68. 2-butenoic acid, 4-[ [2-[ [3-) lH-indol-3-yl) -2- methyl-2-[ [ [ (2-methyl-l-cyclohexyl) oxy] carbonyl] - amino] -1-oxopropyl] -amino]-3-phenylpropy1]amino]-4- oxo-[IR[l->=[R* (s*) ] ,2β] ]-( (-) -isomer) . Additionally preferred are the compounds: 69. [ [3-[ [3-(lK-indol-3-yl) -2-methyl-l-oxo-2- [ [tricyclo [3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]amino] - propyl] amino]-l-oxo-2-phenylpropyl] amino]acetic acid (TRP center is R, other center is RS) , 70. [R-(R*,R*) ]-[2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl] amino]propyl] amino] -1- phenylethoxy] acetic acid, 71. [1R-[lα,2B [R* (R*) ] ] ]-2-[ [ [2-[ [3-(lH-indol-3-yl)- 2-methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl] amino] ropyl]amino]-1- phenylethyl] amino] carbonyl]cyclopropane carboxylie acid, 72. [lS-[lα,2J_[S*(S*) ] ] ]-2-[[[2-[[3-(lH-indol-3-yl)- 2-methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl] amino]propyl] amino]-1- phenylethyl] amino] carbonyl] cyclopropane carboxylic acid, 73. [R-R*,R*) ]-3-[2-[ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2-yloxy) carbonyl] - amino] propyl] amino] -l-phenylethoxy]propanoic acid, 74. [R-(R*,R*) ]-mono 2- [ [3- (lH-indol-3-yl) -2-methyl- l-oxo-2-[ [ (tricyclo [3.3.1. I 3 ' 7 ] dec-2-yloxy) carbonyl] - amino] -1-phenylethyl butanedioic acid, 75. 3-[[3-[[3-(lH-indol-3-yl)-2-methyl-l-oxo-2- [ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2-yloxy) carbonyl] - amino]propyl] amino] -l-oxo-2-phenylpropyl] amino] - propanoic acid, (TRP is R, other center is RS) , 76. [R-(R*,S*) ]-β-[[3-(lH-indol-3-yl)-2-methyl-l-oxo- 2- [ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2-yloxy) carbonyl] - amino] propyl] amino] -4-iodobenzenebutanoic acid, 77. [lR-[lα[R*(S*) ],2β]]-4-[[2-[[3-(lH-indol-3-yl)-2- methyl-2- [ [ [ (2-methyl-l-cyclohexyl) oxy] carbonyl] - amino]-1-oxopropyl]amino]-3-phenylpropy1]amino]-4-oxo- 2-butenoic acid, ((-) -isomer) , 78. [lR-[lα[R* (S) ] , (S) *2β] ]-4-[ [2-[ [3- (lH-indol-3- yl) -2-methyl-2-[ [ [ (2-methyl-l- cyclohexyl) oxy] carbonyl] -amino]-1-oxopropyl] amino]-3- phenylpropyl] amino] -4-oxobutanoic acid, ( (-) -isomer) , 79. [lR-[lα[R*(R*) ] ,2β] ]-4-[ [2-[ [3-(lH-indol-3-yl)-2- methyl-2-[ [ [ (2-methyl-l-cyclohexyl) oxy]carbonyl]- amino]-1-oxopropyl]amino]-1-phenylethyl]amino] -4-oxo- 2-butenoic acid, ((-) -isomer) , 80. lR-[lα[R*(R*) ] ,2β] ]-4-[[2-[ [3- (lH-indol-3-yl) -2- methyl-2-[ [ [ (2-methyl-l-cyclohexyl) oxy]carbonyl]- amino]-1-oxopropyl] amino]-1-phenylethyl]amino] —4— oxobutanoic acid, ( (-) -isomer) , 81. [R-(R*,S*) ]-lδ-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.l 3,7 ]dec-2-yloxy) carbonyl]- amino]propyl] amino]benzeneheptanoic acid, 82. 2-[ [ [2-[ [3-(lH-indol-3-yl) -2-methyl-l-oxo-2- [ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]- amino]propyl] amino]-1-phenylethyl]amino]carbonyl]- cyclopropanecarboxylic acid (cyclopropyl ring is trans-(±), other centers are R) , 83. 2-methylcyclohexyl [lR-[lα[R* (S*) ] ] ,2β] -[2-[ [1- (hydroxymethyl)-2-phenylethyl]amino]-1-(lH-indol-3- ylmethyl) -l-methyl-2-oxoethyl]carbamate, ((-) -isomer, 84. [R-[R*,S*-(E,E) ] ]-6-[[3-(lH-indol-3-yl)-2-methyl- l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]- amino]propyl]amino]-7-phenyl-2,4-heptadienoic acid, 85. tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [2-[[l- (hydroxymethyl) -2-hydroxy-2-phenylethyl]amino]-1- (1H- indol-3-ylmethyl)-1-methylethyl]carbamate, 86. tricyclo[3.3.l.l 3 ' 7 ]dec-2-yl [R-(R*,R*) ]-[1-(1H- indol-3-ylmethyl)-l-methyl-2-oxo-2-[ [2-[ [l-oxo-3-(1H- tetrazol-5-yl)propyl] amino]-2-phenylethyl] amino]- ethyl]carbamate, 87. [R-(R*,S*) ]-2-[ [2-[ [3-(lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)carbonyl]- TE SHEET amino] propyl] amino] -3 -phenylpropyl] sulf inyl] acetic acid, 88. [R-(R*,S*)]-[ [2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1.1 3,7 ] dec-2-yloxy) ] carbonyl] - amino] propyl] amino] -3-phenylpropyl] sulfonyl] acetic acid, 89. Ethyl [R- (R*, S*) ] - [ [2- [ [3- (lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1. l 3,7 ]dec-2- yloxy) ] carbonyl] amino] propyl] amino] -3- phenylpropyl] sulfonyl] acetate, 90. 2-chlorocyclohexyl [2- [ [1- (hydroxymethyl) -2- phenylethyl] amino] -1- (lH-indol-3-ylmethyl) -l-methyl-2- oxoethyl] carbamate, Isomer II, ring centers are trans, trp center is D, other center is S) ( (-) or (+) form) , 91. [R-[R*,R*(E) ]]-4-[[2-[[3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- ylamino) carbonyl] amino] ropyl] amino] -1- phenylethyl] amino] -4-oxo-2-butenoic acid, 92. [R-(R*,R*)]-4-[ [2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2-yloxy) carbonyl] - amino]propyl] amino] -1 -phenylethyl] amino] -4-oxobutanoic acid, 93. [R- (R*, S*) ] -mono [2- [ [3- (lH-indol-3-yl) -2-methyl- l-oxo-2-[ [ (tricyclo[3.3.l.l 3 ' 7 ]dec-2-yloxy) carbonyl]- amino]propyl]amino]-3-phenylpropyl] butanedioate, 94. tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [R-(R*, S*) -2-[ [1- (hydroxymethyl)-2-phenylethyl]amino]-1-(lH-indol-3- ylmethyl)-l-methyl-2-oxoethyl]-carbamate, 95. [IS-[lα,2β[S* [S* (E) ] ] ,40] ]-4-[ [2-[ [3-(lH-indol-3- yl) -2-methyl-l-oxo-2-[ [ [ (1,7,7-trimethylbicyclo- [2.2.l]hept-2-yl) oxy] carbonyl] amino]-propyl] amino]-1- phenylethyl]amino]-4-oxo-2-butenoic acid (bicyclo system is lS-endo) , 96. [IS-[lα,2β[S* (S*) ] ,4α] ]-4-[ [2-[ [3-(lH-indol-3- yl) -2-methyl-l-oxo-2-[ [ [ (1,7,7-trimethylbicyclo- [2.2.1]hept-2-yl)oxy]carbonyl]-amino]propyl] amino]-1- phenylethyl] amino]-4-oxo-2-butenoic acid (bicyclo system is lS-endo) , 97. [R-[R*,S*-(E) ] ]-4-[ [2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) - carbonyl]amino]propyl]amino]-3-phenylpropy1] amino] -4- oxo-2-butenoic acid, 98. N-[2-methyl-N-[ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl]-D-tryptophyl] -L-phenylalanylglycine, 99. [R-(R*, S*) ]-4-[ [2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl] - amino]propyl] amino] -3-phenylpropy1]amino]-4- oxobutanoic acid, 100. [R-(R*,R*) ]-[2-[ [2-[ [l,4-dioxo-4-(lH-tetrazol-5- ylamino)butyl] amino]-2-phenylethyl]amino]-1- (lH-indol- 3-ylmethyl) -l-methyl-2-oxoethyl] carbamic acid, 101. [R-(R*,R*) ]-3-[[2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo [3.3.l.l 3,7 ]dec-2-yloxy) carbonyl] - amino]propyl] amino] -1-phenylethyl]amino]-3- oxopropanoic acid, 102. [R- (R*, S*) ] -3-[ [2-[ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl] - amino]propyl] amino]-3-phenylpropyl]amino] -3- oxopropanoic acid, 103. [R-[R*,S*[ (E) ]]-4-[[2-[[3-(lH-indol-3-yl)-2- methyl-2-[ [ (bicyclo[3.3.1]non-9-yloxy) carbonyl] amino]- 1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2- butenoic acid, 104. [R-[R*,S*) ]-5-[[2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl] - amino]propyl] amino]-3-phenylpropyl]amino]-5- oxopentanoic acid, 105. ethyl [R- (R*,S*) ]-[ [2-[ [3-(lE-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.l 3,7 ]dec-2-yloxy) - carbonyl]amino]propyl] amino]-3-phenylpropy1] sulfinyl]- acetate, 106. [R-(R*,R*- (E) ] ]-4-[ [2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy)carbonyl] amino]propyl] mino]-l- phenylethyl]amino]-4-oxo-2-butenoic acid, 107. [R-(R*,S*) ]-N-[3-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]- amino] ropyl]amino]-l-oxo-4-phenylbutyl]-β-alanine, 108. N-[N-[α-methyl-N-[ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl]-D-tryptophyl]- -phenylalanyl]-L- alanine, 109. [R-R*,S*) ]-3-[ [2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]- amino]propyl] amino]-3-phenylpropyl]thio]propanoic acid, 110. [R-(R*,S*) ]-[[2-[ [2-[3-(lH-indol-3-yl)-2-methyl- l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)carbonyl]- amino]propyl] amino]-3-phenylpropy1] hio] acetic acid, 111. [R-(R*, S*) ]-β-[ [3- (lH-indol-3-yl) -2-methyl-l-oxo- 2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl] amino]- propyl] amino]benzenebutanoic acid, 112. tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [R-(R*, S*) ]-3-(1H- indol-3-ylmethyl) -3-methyl-4,10-dioxo-6- (phenylmethyl) -ll-oxa-8-thia-2,5-diazatridecanoic acid, 113. Carbamic acid, [2-[ [1-(hydroxymethyl) -2- phenylethyl]amino]-1-methyl-l-[ (l-methyl-lH-indol-3- yl)methyl]-2-oxoethyl]-, tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl ester, [R- (R*,S*) ]-, 114. Glycine, N-[3- (lH-indol-3-yl)-2-methyl-l-oxo-2- [ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)carbonyl]amino]- propyl]-N- (2-phenylethyl) -, (±)-, 115. Glycine, N-[3-(lH-indol-3-yl)-2-methyl-l-oxo-2- [ [ (tricyclo[3.3.1.1 3,7 ]dec-2-yloxy)carbonyl]amino]- propyl]-N- (2-phenylethyl) -, methyl ester, (±) -, 116. Methyl (±)-7-[ [3- (lH-indol-3-yl) -2-methyl-l-oxo- 2-[ [ (tricyclo [3.3.1.l 3 ' 7 ]dec-2-yloxy) carbonyl] amino]- propyl] (2-phenylethyl) amino]heptanoate, 117. (±)-7-[ [3-(lH-indol-3-yl)-2-methyl-l-oxo-2- [ [t icyclo [3.3.l.l 3 ' 7 ]dec-2-yloxycarbony1]amino]- propyl] (2-phenylethyl) amino]heptanoic acid, 118. Carbamic acid, [2-[ [2-(1-cyclohexen-l-yl)ethyl]- amino]-1- (lH-indol-3-ylmethyl) -l-methyl-2-oxoethyl]-, (R)-, 119. Carbamic acid, [1- (lH-indol-3-ylmethyl) -1-methyl- 2-OXO-2- [ [2-(2-pyridinyl) ethyl] amino]ethyl] -, tricyclo [3.3. l.l 3 ' 7 ]dec-2-yl ester, (R)-, 120. Benzenebutanoic acid, 4-amino-β-[ [3-(lH-indol-3- yl) -2-methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl]amino]propyl] amino]-, [R-(R*, S*) ]-, 121. Acetic acid, [ [3-[ [3-(lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]- amino]propy1] amino]-2-phenylpropy1]thio]- (TRP center is R, other center is RS) , 122. 12-oxa-9-thia-2, 5-diazatetradecanoic acid, 3-(lH- indol-3-ylmethyl)-3-methyl-4,ll-dioxo-7-phenyl-, tricyclo [3.3.1.1 3,7 ]dec-2-yl ester (TRP center is R, other center is RS) , 123. Benzenebutanoic acid, γ-[ [ [3- (lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl] mino]propyl] amino]methyl]- (TRP center is R, other center is RS) , 124. 2-pentenoic acid, 5-[ [3-(lH-indol-3-yl) -2-methyl- l-oxo-2- [ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy] carbonyl]- amino]propyl]amino]-4-phenyl-, methyl ester (TRP center is R, other center is RS, double bond is (E)), 125. Benzenebutanoic acid, γ-[ [ [3- (lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl]amino]propyl]amino]methyl]-, methyl ester (TRP center is R, other center is RS) , 126. Butanoic acid, 4-[ [2-[2-[ [3-(lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl] amino] propyl] amino] ethyl ]phenyl] amino] - 4-oxo-, (R) -, 127. Carbamic acid, [1-(lH-indol-3-ylmethyl) -1-methyl- 2-oxo-2-[ [2-[ [[ (lH-l,2,4-triazol-5-ylthio)acetyl]- amino]-2-phenylethyl] mino]ethyl]-, tricyclo- [3.3.1.1 3 ' 7 ]dec-2-yl ester, [R-(R*,R*) ]-, 128. Carbamic acid, [2-[ [2-[ [ (lH-imidazol-2- ylthio) acetyl]amino]-2-phenylethyl] amino] -1-(IH-indol- 3-ylmethyl)-l-methyl-2-oxoethyl]-, tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl ester, [R- (R*,R*) ]-, 129. Butanoic acid, 4-[ [2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' ]dec-2- yloxy) carbonyl]amino]propyl] amino]-1- phenylethyl] amino] -4-oxo-, (Phenyl center R, other center S or R) (Diastereomer II) , 130. Butanoic acid, 4-[ [2-[ [3-(lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)- carbonyl] amino]propyl]amino]-1-phenylethyl]amino]-4- oxo- (Phenyl center R, other center R or S) (Diastereomer I) , 131. 13-oxa-2,5,8-triazatetradecanoic acid, 3-(lH- indol-3-ylmethyl) -3-methyl-4, 9, 12-trioxo-7, 14- diphenyl-, tricyclo[3.3.1.l 3,7 ]dec-2-yl ester (Phenyl center is R, other center is S or R) (Diastereomer 2) , 132. 13—oxa-2,5,8-triazatetradecanoic acid, 3-(lH- indol-2-ylmethyl) -3-methyl-4, 9, 12-trioxo-7, 14- diphenyl-, tricyclo[3.3.1.l 3 ' 7 ]dec-2-yl ester (Phenyl center is R, other center is R or S) (Diastereomer 1) , 133. Carbamic acid, [2-[ [1-(hydroxymethyl) -2- phenylethyl]amino]-1-(lH-indol-2-ylmethyl) -l-methyl-2- oxoethyl]-, tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl ester (Hydroxymethyl center is S, other center is R or S) (Diastereomer 1) , 134. Carbamic acid, [2-[ [1-(hydroxymethyl) -2- phenylethyl]amino]-1 (lH-indol-2-ylmethyl) -l-methyl-2- oxoethyl]-, tricyclo[3.3.l.l 3 ' 7 ]dec-2-yl ester (Hydroxymethyl center is S, other center is S or R) (Diastereomer 2) , and 135. Carbamic acid, [1-methyl-l-[ [1-[ (4-methylphenyl) - sulfonyl]-lH-indol-2-yl]methyl]-2-oxo-2-[ (2- phenylethyl) amino]ethyl] , tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl ester, (±)-. In addition to the compounds above, the compounds of the present invention include compounds of formula I wherein the indole moiety is a 2-indolyl. The compounds include solvates and hydrates and pharmaceutically acceptable salts of the compounds of formula I. Preferred pharmaceutically acceptable salts are benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, diethylamine, and tromethane. Especially preferred pharmaceutically acceptable salts are N-methylgluca ine and sodium. The compounds of the present invention can have multiple chiral centers including those designated in the above formula I by an t, Φ, Φ depending on their structures. For example, when R 3 taken with R 12 and R 4 taken with R 13 form double bonds to these carbon atoms they are no longer chiral. In addition, centers of asymmetry may exist on substituents R 1 , R 9 , R 3 , R 4 and/or -Ar. In particular the compounds of the present invention may exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual optical enantiomers. The present invention contemplates all such forms of the compounds. The mixtures of diastereomers are typically obtained as a result of the reactions described more fully below. Individual diastereomers may be separated from mixtures of the diastereomers by conventional techniques such as column chromatography or repetitive recrystallizations. Individual enantiomers may be separated by convention method well known in the art such as conversion to a salt with an optically active compound, followed by separation by chromatography or recrystallization and reconversion to the nonsalt form. The compounds of the present invention can be formed by coupling individual substituted oc-amino acids by methods well known in the art. (See, for example, standard synthetic methods discussed in the multi-volume treatise "The Peptides, Analysis, Synthesis, Biology," by Gross and Meienhofer, Academic Press, New York.) The individual substituted alpha amino acid starting materials are generally known or, if not known, may be synthesized and, if desired, resolved by methods within the skill of the art. (Synthesis of racemic [DL] -< * -methyl tryptophan methyl ester - see Brana, M. F., et al, J. Heterocyclic Chem. , 1980, 17:829.) For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceuti¬ cally acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. For preparing suppository preparations, a low- melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify. The powders and tablets preferably contain 5 to about 70% of the active component. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Liquid form preparations include solutions, suspensions, and emulsions. Sterile water or water- propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. Preferably the pharmaceutical preparation is in unit dosage form. In such form, the preparation is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a SUBSTITUTESHEET capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. The dipeptoids, their pharmaceutically acceptable salts, hydrates, and solvates are administered to mammals, e.g., humans. The diagnosis of the group of disorders covered herein is the predominant disturbance as in Panic Disorder as in the third edition-revised of the Diagnostic and Statistical Manual of Mental Disorders (DSM-111-R) , published by the American Psychiatric Association (1987) . Pharmaceutical Formulations In the following examples of pharmaceutical formulations according to the present invention, unless otherwise indicated, the term "Active Ingredient" represents a dipeptoid of the invention hereinbefore defined or a pharmaceutically acceptable salt thereof. The dose represents that appropriate for the base; if a salt is used the dose should of course be increased appropriately. EXAMPLE 1 Tablet T -. • _. Amount per Ingred i ent tablet ( mg ) Active Ingredient (compound of 60.0 Claim 9)* Lactose 125.0 Corn Starch 50.0 Polyvinylpyrrolidone 3.0 Stearic acid 1.0 Magnesium stearate 1.0 * [R-(R*,R*)]-4-[[2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)- carbonyl]amino]prop l]amino]-1-phenylethyl]- amino]-4-oxobutanoic acid EXAMPLE 2 Capsule Ingredient Amount per capsule (mg) Active Ingredient* 60.0 Lactose 174.0 Corn Starch 174.0 Stearic acid 2.0 * [R-(R*,R*) ]-4-[ [2-[ [3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) - carbonyl]amino]propyl]amino]-1-phenylethyl]- amino]-4-oxobutanoic acid EXAMPLE 3 Ampoule Ingredient Amount per ampoule Active Ingredient* 60.0 mg Water for injection, q.s. 1.0 mL * [R-(R*,R*) ]-4-[ [2-[[3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[[ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)- carbonyl]amino]propyl] amino]-1-phenylethyl]- amino]-4-oxobutanoic acid EXAMPLE 4 * [R-(R*,R*) ]-4-[ [2-[[3- (lH-indol-3-yl) -2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) - carbonyl] amino]propyl]amino]-1-phenylethyl]- amino]-4-oxobutanoic acid

Claims: CLAIMS 1. A method of treating a panic disorder in a human who has been identified as exhibiting panic disorder symptoms which comprises administering to said human a therapeutically effective amount of a compound of formula H or a pharmaceutically acceptable salt thereof wherein: R 1 is a cyclo- or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents, each independently selected from the group consisting of: a straight or branched alkyl of from one to six carbon atoms, halogen, CN, OR*, SR * , C0 2 R * , CF 3 , NR 5 R 5 , or (CH 2 ) n OR 5 wherein R* is hydrogen, straight or branched alkyl of from one to six carbon atoms, R = and R 6 are each independently hydrogen or alkyl of from one to six carbon atoms; and n is an integer from zero to six; A is (CH 2 ) n CC~, -S0 2 -, -S(=0)-, -NHCO-, 0 II -(CH 2 ) -0C-, -SCO-, 0-(CH 2 ) n CO- or -HC=CHC0- wherein n is an integer from zero to six; R 2 is a straight or branched alkyl of from one to six carbon atoms, -HC * =CH 2 , -C≡CH, -CH 2 -CH=CH 2 , -CH 2 C≡CH, -(CH 2 ) n Ar, -(CH 2 ) n OR*, -(CH 2 ) n 0Ar, -(CH 2 ) n C0 2 R*, -(CH 2 ) n NR 5 R 6 wherein n, R' R 5 and R 6 are as defined above and Ar is as defined below; R 3 and R 4 are each independently selected from hydrogen, R 2 , and -(CH 2 ) n -B-D, wherein n' is an integer of from zero to three; B is a bond -0C0(CH 2 ) n -, -0(CH 2 ) n -, -S0 2 NH(CH 2 ) n -, -NHS0 2 (CH 2 ) n , -NHCOfCH^-, C0NH(CH 2 ) n -, NHC0CH=CH-, -C00(CH 2 ) n -, -C0(CH 2 ) n -, -S-(CH 2 ) n -, -S0(CH 2 ) n -, -S0 2 (CH 2 ) n -, -NHS0 2 -(CH 2 ) n -, -S0 2 NH-(CH 2 ) n -, H H I I -C0NHC-C-, R 7 R 8 wherein R 7 and R 8 are independently selected from hydrogen and R 2 or together form a ring (CH 2 ) m wherein m is an integer of from 1 to 5 and n is as defined above; D is -COOR' , -CH 2 OR * -CHR 2 OR*, -CR 2 SR*, -CONR 5 R 6 , -CN, -NR 5 R 6 , -OH, -H, and acid replacements such as tetrazole, and N-N A N> ■ A OR * , NR 5 R* , CH 3 , or Cl 1 , 2 , oxadiazole s is an integer of from 0 to 2 wherein R*, R 2 , R 5 , R 6 and R 10 are as definod above; R 9 is H, or a straight or branched alkyl of from one to six carbon atoms, - (CH 2 ) n C0 2 R * , (CH 2 ) n OAr', (CH 2 ) n Ar', (CH 2 ) n NR 5 R 6 , wherein n, R * , R 5 , and R 6 are as defined above or taken from R 3 and Ar' is taken from Ar as defined below; R 12 and R 13 can each be independently hydrogen (in which case the carbon atom to which it is attached is a chiral center) or can each be taken with R 3 and R 4 respectively to form a moiety doubly bonded to the carbon atom (in which case the carbon atom is not chiral) ; and Ar is a mono— or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety. 2. A method according to Claim 1 wherein the amount is 0.25 to 15 mg/kg of body weight. 3. A method according to Claim 1 wherein the amount is 1 to 10 mg/kg of body weight. . A method according to Claim 1 wherein in the compound of formula I the cycloalkyl or polycycloalkyl has from about six to ten carbon atoms unsubstituted or substituted with one or more substituents, each substituent selected S independent ly fro : methyl, fluorine, chlorine, and bromine . A method according to Claim 1 wherein in the compound of formula I R 1 is cycloalkyl or polycycloalkyl wherein the polycycloalkyl is selected from the group consisting of wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF 3 , NR-R 6 , -(CH 2 ) r C0 2 R * , CN, F, Cl, Br, OR * , SR*, wherein R * , R 5 and R 6 are as defined in Claim 1 and n is an integer of from 1 to 3; A is -NHC0-, OC(=0)-, -S0 2 -, -S (=0) -, -SCO- or -CH 2 CO-; and Ar is 2- or 3-thienyl, 2- or 3-furanyl, 2-, 3- or 4-pyridinyl or an unsubstituted or substituted phenyl whose substituents if any are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl nitro, OH, NH 2 , OCF 3 , NHCOCH 2 CH 2 C0 2 H, or A method according to Claim 1 wherein in the compound of formula I: R 1 is 2-adamantyl or 1-(S) -2-endobornyl; A is -NHCO-, -OCO-, -S0 2 -, -S (=0) - or -CH 2 CO-; R 2 is -CH 3 , -CH 2 C0 2 H or -CH 2 C≡CH; R 3 is - (CH 2 ) n , -B-D or H; R 4 is - (CH 2 ) n -B-D or H; and R 9 is hydrogen or methyl . 7. A method according to Claim 1 wherein in the compound of formula I: R 1 is 2-adamantyl, 1-(S)-2-endobornyl, or 2-methyl cyclohexyl, A is -0C(=0)-: R 2 is -CH 3 ; R 3 i- _i, CH 2 0H, CH 2 θCOCH 2 CH 2 C0 2 H, CH 2 0COCH=CHCO 2 H, C " 2 NHCOCH 2 CH 2 C0 2 H, CH 2 NHC0CH=CHCO 2 H, or CH 2 C0 2 H; -NHCOCH=CHC0 2 H, -NHCOCH 2 CH 2 C0 2 H ( [D] configuration) or NHCOCH=CHC0 2 H ([D] configuration) . 8. A method according to Claim 1 wherein the compound is selected from: (±) -trans-2-chlorocyclohexyl[l-(lH-indol-3- ylmethyl)-l-methyl-2-oxo-2-[ (2- phenylethyl) amino]ethyl] carbamate; 2-chlorocyclohexyl[2-[ [1- (hydroxymethyl) -2- phenylethyl]-amino]-1-(lH-indol-3-ylmethyl) -1- methyl-2-oxoethyl]-carbamate; 2-[ [2-[ [ [ (2-chlorocyclohexyl) oxy] carbonyl]- amino]-3-(l__-indol-3-yl) -2-methyl-l- oxopropyl] amino]-3-phenylpropyl butanedioate; 2-[ [2-[ [ [ (2-methylcyclohexyl) oxy]carbonyl]- amino]-3-(lH-indol-3-yl) -2-methyl-l-oxopropyl]- amino]-3-phenylprop 1 butanedioate; (±) -tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [1-(1H- indol-3-ylmethyl)-l-methyl-2-oxo-2-[ (2- phenylethyl) amino]-ethyl]carbamate; (+) or (-)-2-chlorocyclohexyl[l-(lH-indol-3- ylmethyl)-l-methyl-2-oxo-2-[ (2-phenylethyl) - amino]ethyl] carbamate; tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl [2-[ [1- (hydroxymethyl)-2-phenylethyl]amino]-1-(lH-indol- 3-ylmethyl)-l-methyl-2-oxoethyl] carbamate; 2-[ [3-(lH-indol-3-yl) -2-methyl-l-oxo-2- [ [ (tricyclo-[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]- amino]propyl]amino]-3-phenylprop l butanedioate; [R-(R*,R*) ]-4-[[2-[[3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) -carbonyl] amino]propyl]amino]-1- phenylethyl]-amino]-4-oxobutanoic acid; [1S-[1°=,2β[S*(S*) ] ,4°=] ]-4-[[2-[ [3-(lH-indol- 3-yl) -2-methyl-l-oxo-2-[ [ [ (1,7,7-trimethyl- bicyclo-[2.2.l]hept-2-yl) oxy] carbonyl]amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid; [R-[R*, S*- (E) ] ]-4-[ [2-[ [3-(lH-indol-3-yl) -2- methyl-l-oxo-2-[ [tricyclo [3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl]amino]-propyl] amino]—3- phenylpropyl] amino]-4-oxo-2-butenoic acid; [R-(R*,S*) ]-4-[ [2-[ [3-(lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl] amino]-propyl] amino]—3- phen lpropy1]amino]-4-oxo-butanoic acid; (R)-tricyclo [3.3.1.1 3 ' 7 ]dec-2-yl-[1- (1H- indol-3-ylmethyl) -l-methyl-2-[methyl-(2- phenylethyl) amino]-2-oxoethylcarbamate; [R-(R*,S*) ]-2-[ [2-[ [3-(lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl]amino]-propyl]amino]—3- phenylpropyl] sulfinyl]acetic acid; [R-(R*,S*) ]-[ [2-[ [3- (lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo[3.3.l.l 3 ' 7 ]dec-2- yloxy) ]carbonyl]amino]-propyl]amino]—3- phenylpropyl] sulfonyl]acetic acid; [R-(R*,S*) ]-[[2-[[3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl]amino]-propyl]amino]-3- phenylpropyl]sulfinyl]acetic acid, ethyl ester; [R-(R*,S*) ]-[ [2-[ [3-(lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.l 3 ' 7 ]dec-2- yloxy) ] carbonyl] amino] —propyl] amino] — 3- pheny lpropy 1] sulfonyl] acetic acid; [R- [R*,R*- (E) ] ] -4- [ [2- [ [3- (lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) carbonyl] amino] -pr opy 1 ] amino ] -1- phenylethy 1 ] amino ] -4-oxo-2-butenoic acid; [R- (R*, S*) ] - [ [2- [ [2- [3- (lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) -carbonyl] amino] -propyl] amino] -3- phenylpropyl ] thio] acetic acid; [lS-[l~,2β[S*[S*(E)]],4°c]]-4-[[2-[[3-(lH- indol-3-yl) -2-methyl-l-oxo-2-[ [[(1,7,7- trimethylbicyclo[2.2.1]hept-2-yl) oxy]- carbonyl]amino]propyl]amino]-1-phenylethyl]- amino]-4-oxo-2-butenoic acid, methyl ester, (bicyclo system is lS-endo) ; [IS-[lo,2β[S*[S* (E) ] ] , 4~] ]-4-[ [2-[ [3- (1H- indol-3-yl) -2-methyl-l-oxo-2-[ [ [ (1, 7, 7-trimethyl- bicyclo-[2.2. l]hept-2-yl) oxy] carbonyl] amino] - propyl] amino] -1-phenylethyl] amino] -4-oxo-2- butenoic acid (bicyclo system is lS-endo) ; [R-(R*,R*)]-3-[[2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.1 3 ' 7 ] dec-2- yloxy) carbonyl] amino] -propyl] amino] — 1- phenylethyl] amino] -3-oxopropanoic acid; [R- (R* , S * ) ] -3- (lH-indol-3-ylmethyl ) -3- methyl-4, 10-dioxo-6- (phenylmethyl) -ll-oxo-8-thia- 2, 5-diazatridecanoic acid, tricyclo [3.3. l.l 3 ' 7 ] - dec-2-yl or ester; [R- (R*, S*) ] -β-[ [3- (lH-indol-3-yl) -2-methyl- l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' ]dec-2-yloxy)- carbonyl]amino]propyl]amino]benzenebutanoic acid; [R-(R*,S*) ]-β-[[3-(lH-indol-3-yl)-2-methyl- l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)- carbonyl]amino]propyl] amino]-4-iodo- benzenebutanoic acid, where the iodo group may be 1-125 or 1-127; SUBSTITUTE SHEET [R-(R*,S*) ]-N-[3-[ [3-(lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- 100 yloxy) carbonyl]amino]-propyl] amino]-4-phenyl- butyl]glycine; and [R-[R*,S*-(E) ] ]-4-[ [2-[ [3- (lH-indol-3-yl)-2- methyl-2-[ [ (bicyclo[3.3.1]non-9-yloxy)carbonyl]- amino]-1-oxopropyl]amino]-3-phenylpropyl] amino]- 105 4-oxo-2-butenoic acid. 9. A method of treating panic disorder in a human who has been identified as exhibiting panic disorder symptoms which comprises administering to said human a therapeutically effective amount 5 of [R-(R*,R*) ]-4-[[2-[[3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy) carbonyl]amino]propyl]amino] -1- phenylethyl]amino]-4-oxobutanoic acid, or a pharmaceutically acceptable salt thereof.

Inventors: WOODRUFF GEOFFREY NEIL, WOODRUFF, GEOFFREY, NEIL
Applicants: WARNER LAMBERT CO, WARNER-LAMBERT COMPANY
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61P25, C07D209, C07D401, C07D403, C07D407, C07D409, C07D471