JP2002515503A - Novel 1,3,8-triazaspiro [4,5] decanone with high affinity for opioid receptor subtypes - Google Patents

Abstract

(57) Abstract The present invention relates to the use of small organic compounds that act as ligands for opioid receptors for the treatment of vasomotor disorders. In particular, the present invention provides a compound of the general formula (Ia) or (Ib) wherein R ¹ is selected from among phenyl, arylalkyl or thienyl; R ² is aminophenyl, C _1-6 monoalkylaminophenyl, C _1-6 dialkyl Aminophenyl, cyanophenyl, C _2-6 alkylphenyl, naphthyl, tetrahydronaphthyl, furanyl, indanyl, benzothienyl or benzofuranyl, wherein R ³ is hydrogen, C _1-6 alkyl, phenyl, benzyl, or acetyl There; R ⁴ is hydrogen or _{(CH 2) m - (CHR} 9) - (CH 2) be a _p -AR ^11; R ⁵ is hydrogen or C _1-4 alkyl; z is CHR ¹⁰ (wherein R ¹⁰ is hydrogen, C _1-6 alkyl, phenyl or arylalkyl), or z are C _2-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene; Is a triazaspiro compound of 1 or 2 or a pharmaceutically acceptable salt thereof, which comprises migraine, non-insulin dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence and / or vasomotor disorders, especially For the treatment of disorders of peripheral vasomotor action known as hot flashes or hot flushes.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to the use of small organic compounds that act as opioid receptor ligands for the treatment of vasomotor disorders. In particular, the invention is for the treatment of migraine, non-insulin-dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence and / or vasomotor disorders, especially hot flush or hot flash. Of the general formula Ia or Ib. The invention also includes pharmaceutical compositions comprising these compounds and methods of using said compounds and their pharmaceutical compositions.

[0002] Background of the Invention "hot flashes" is a sudden transient sense to change from warmth to intense heat sensation,
And typically accompanied by flushing and sweating. It is a classic menopausal sign, and a dominant complaint of menopausal women.

A positive correlation between the plasma concentration of calcitonin gene-related peptide (CGRP) and the frequency of hot flashes in women has recently been reported (Chen et al., 1993, Lan).
cet (342) 49), which is a potential vasodilator effect of CGRP (Brain et al., 1985,
Nature, (313) 54-56). In addition, a positive correlation between CGRP antagonists and diabetes, septic shock and inflammation has been described (Feurstein, G, Willette, R and Aiyar, N., 1995,
Can. J. Physiol. Pharmacol. 73: 1070-1074).

[0004] Recently, a novel heptadecapeptide, nociceptin, has been discovered (Meunier et a
l., 1995, Nature (377) 532-535, Reinscheid et al., 1995, Science (270) 7
92-794). Nociceptin and its analogs were disclosed in WO 97/07212, EP 813065 and WO 97/07208. These peptides and their inhibitors are said to be useful in antagonizing the physiological effects of opioids in animals and in treating / reducing hyperalgesia, neuroendocrine secretion, stress, motor activity, anxiety, etc. ing.

[0005] Jenck, F. and others have also found that Orphanin FQ acts as an anxiolytic drug that reduces behavioral responses to stress (PNAS Vol. 94).
, 1997). Triaza-spiro compounds have been disclosed by Janssen in U.S. Pat. No. 3,238,
It is known to be a vasodilator and a morphine-like analgesic, as disclosed in US Pat. No. 216 and 3,155,670.

[0006] SUMMARY OF THE INVENTION triaza - a member of a new group of spiro compounds has a high affinity for nociceptin receptor, which, as a control agent of vasomotor action of the peripheral known as hot flashes, them useful It was clear what they were doing.

The present invention provides a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof as disclosed below, which comprises type II diabetes, septic shock, inflammation, incontinence and vasomotor disorders, Especially for the manufacture of a pharmaceutical composition for the treatment of peripheral vasomotor effects known as hot flashes or hot flushes. Further objects will become apparent from the description below.

[0008] DETAILED DESCRIPTION OF THE INVENTION The present invention, migraine, non-insulin-dependent diabetes mellitus (II diabetes), sepsis, inflammation, incontinence, vasomotor disorders, especially hot flashes or peripheral vasomotor known as hot flushes The use of opioid receptors for the treatment of a disease selected from its effects and / or for the manufacture of a pharmaceutical composition for reducing withdrawal symptoms, especially withdrawal symptoms occurring during withdrawal from substance abuse. It relates to the use of small organic compounds that act as ligands.

In another aspect, the invention relates to the manufacture of a pharmaceutical composition of a small organic compound, or a pharmaceutically acceptable salt thereof, acting as a ligand for a nociceptin receptor having a molecular weight of 1000 or less, for the treatment of vasomotor disorders. For use for. In yet another aspect, the invention relates to the manufacture of a pharmaceutical composition for the treatment of vasomotor disorders of a small organic compound, or a pharmaceutically acceptable salt thereof, acting as a ligand for a nociceptin receptor having a molecular weight of 600 or less. Regarding the use of

In yet another aspect, the present invention provides a small organic compound, or a pharmaceutically acceptable salt thereof, that acts as a ligand for a nociceptin receptor having 5 or fewer amide bonds,
It relates to the use for the manufacture of a pharmaceutical composition for the treatment of vasomotor disorders. In yet another aspect, the present invention relates to the manufacture of a pharmaceutical composition for the treatment of vasomotor disorders of a small organic compound having no amide bond and acting as a ligand for the nociceptin receptor, or a pharmaceutically acceptable salt thereof. For use for.

In yet another aspect, the present invention provides a ligand for the nociceptin receptor,
The use of said compound comprising a triaza-spiro compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of vasomotor disorders. In yet another aspect, the invention relates to a small organic compound or a pharmaceutically acceptable salt thereof, having an IC ₅₀ of 1 μM or less, that acts as a ligand for the nociceptin receptor.
It relates to the use for the manufacture of a pharmaceutical composition for the treatment of vasomotor disorders.

In a second aspect, the present invention provides a compound of general formula I

[0013]

Embedded image｛Where, R¹ Is phenyl, arylalkyl or thienyl, which is one or more
Halogen, cyano, nitro, trifluoromethyl, C_1-6 Alkyl, hydroxy
Si, C_1-6 Alkoxy or NR⁶ R⁸ (Where R⁶ And R⁸ Is independently hydrogen or
C_1-6 Alkyl), or R¹ Is C_1-6 Archi
R; R^Two Is aminophenyl, C_1-6 Monoalkylaminophenyl, C_1-6 Dialki
L-aminophenyl, cyanophenyl, C_2-6 Alkylphenyl, naphthyl, tet
Lahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoin
Drill, benzothienyl, benzofuranyl, coumarinyl, wherein said group is one or more
Represents multiple halogens, amino, nitro, trifluoromethyl, C_1-6 Alkyl, ar
Droxy, C_1-6 Alkoxy, C (O) R⁷ (Where R⁷ Is -OH, C_1-6 A
Lucoxy or -NR¹²R¹³Where R¹²And R¹³Is independently hydrogen or C _1-6 Alkyl)) or R^Two Is phenyl, phenoxy, benzodioxinyl or cyanodiphenylmethyl
Any one of these may be one or more of halogen, cyano, nitro,
Trifluoromethyl, C_1-6 Alkyl, hydroxy, C_1-6 Alkoxy, C (O
) R⁷ (Where R⁷ Is -OH, C_1-6 Alkoxy or -NR¹²R¹³And this
Where R¹²And R¹³Is independently hydrogen or C_1-6 Optionally substituted with alkyl)
Where R¹ Is not phenyl and R^Three Is not methyl or hydrogen,
Or R^Four Is hydrogen, acetyl, methyl, hydroxymethyl, ethyl, 2-sia
Not ethyl, propionyl or methoxymethyl; R^Three Is hydrogen, C_1-6 R is alkyl, phenyl, benzyl or acetyl;^Four Is hydrogen or (CH_Two )_m − (CHR⁹ )-(CH_Two )_p -AR¹¹〔here
m and p are independently 0-4;⁹ Is hydrogen, C_1-6 Alkyl, phenyl or
Arylalkyl, R¹¹Is C_1-6 Alkyl, hydroxy, C_1-6 Alkoki
Guanidino, OCH_Three Or NH_Two A C-terminal consisting of
An amino acid residue having a group or 2 to 4 peptidyl residues;¹¹Is the group NR¹⁴ R^FifteenWhere R¹⁴And R^FifteenIs independently hydrogen, C_1-6 Alkyl, (
CH_Two )_q R¹⁶(Where q may be 0-6 and R¹⁶Is C3-C7
Membered cycloalkyl ring, optionally substituted aromatic or heteroaromatic ring, 1 or
Is an aliphatic ring containing a plurality of hetero atoms, an alkoxy or aryloxy group, an amino
Or a guanidino group); A is -CH_Two Or -C = O;
Where R¹¹A is a -C = O group when is an amino acid or a peptidyl residue]
R^Five Is hydrogen or C_1-4 Z is CHR^Ten(Where R^TenIs hydrogen, C_1-6 Alkyl, phenyl or aryl
Or z is C_2-8 Alkylene, C_2-8 Alkenylene
Or C_2-8 N is 1 or 2; or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, R ¹ is phenyl, arylalkyl or thienyl, which is one or more of halogen, cyano, nitro, trifluoromethyl, C _1-6 alkyl, hydroxy, C _{1-. 6} alkoxy or NR ⁶ R ⁸ (where R ⁶
And R ⁸ are independently hydrogen or C _1-6 alkyl);
Alternatively, R ¹ is C _1-6 alkyl.

R^Two Is aminophenyl, C_1-6 Monoalkylaminophenyl, C_1-6 Dialki
L-aminophenyl, cyanophenyl, C_2-6 Alkylphenyl, naphthyl, tet
Lahydronaphthyl, furanyl, indanyl, benzothienyl, benzofuranyl
Wherein said group is one or more of halogen, cyano, nitro, trifluoromethyl
, C_1-6 Alkyl, hydroxy, C_1-6 Alkoxy, C (O) R⁷ (Where R ⁷ Is -OH, -NR¹²R¹³Where R¹²And R¹³Is independent of hydrogen
Is C_1-6 Alkyl or C_1-6 Alkoxy)), or
Is R^Two Is phenyl, provided that R¹ Is not phenyl and R^Three Is methyl or water
Not prime, or R^Four Is hydrogen, acetyl, methyl, hydroxymethyl, ethyl
Not 2-cyanoethyl, propionyl or methoxymethyl.

R ³ is hydrogen, C _1-6 alkyl, phenyl, benzyl or acetyl. R ⁴ is hydrogen or (CH ₂ ) _m- (CHR ⁹ )-(CH ₂ ) _p -AR ¹¹ wherein m and p are independently 0 to 4, R ⁹ is hydrogen, C _1-6 alkyl , Phenyl or arylalkyl, R ¹¹ is C _1-6 alkyl, hydroxy, C _1-6 alkoxy, guanidino, an amino acid residue having a C-terminal group consisting of OCH ₃ , or NH ₂ or R ¹¹ may be a group NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 alkyl, (2-4 peptidyl residues;
CH _{2) q} R ¹⁶ (wherein, q may be from 0 to 6, and R ¹⁶ is C3-C7
A cycloalkyl ring, optionally substituted aromatic or heteroaromatic ring, aliphatic ring containing one or more heteroatoms, alkoxy or aryloxy group, amino or guanidino group); be -CH ₂ or -C = O;
However, when R ¹¹ is an amino acid or a peptidyl residue, A is a —C ＝ O group.
It is.

R ⁵ is hydrogen or C _1-4 alkyl. z is CHR ¹⁰ where R ¹⁰ is hydrogen, C _1-6 alkyl, phenyl or arylalkyl, or z is C _2-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene is there. n is 1 or 2.

The present invention is directed to a compound as described above or a pharmaceutically acceptable salt thereof. In another aspect of the invention, R¹ Is C_1-6 Alkyl, phenyl, aryl
Kill or thienyl. In yet another aspect of the invention, R^Two Is aminophenyl, C_1-6 Monoalkyl
Aminophenyl, C_1-6 Dialkylaminophenyl, cyanophenyl, C_2-6 A
Alkylphenyl, naphthyl, tetrahydronaphthyl, furanyl, indanyl,
Benzothienyl, benzofuranyl, wherein said group is one or more halogen,
No, nitro, trifluoromethyl, C_1-6 Alkyl, hydroxy, C_1-6 Arco
Kishi, C (O) R⁷ Where R is⁷ Is -OH, -NR¹²R ¹³ Where R¹²And R¹³Is independently hydrogen or C_1-6 Alkyl or C _1-6 Alkoxy.

In yet another aspect of the invention, R ² is cyanophenyl or naphthyl;
Said groups may be substituted by one or more of fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C (O) R ⁷ , And R ⁷ is —OH, C _1-6 alkoxy or —NR ¹² R ¹³ ,
R ¹² and R ¹³ are independently hydrogen or C _1-6 alkyl.

In a preferred embodiment of the present invention, n is 2. Another preferred embodiment of the present invention comprises formula Ia wherein R ¹ , R ² , R ³
, R ⁴ , R ⁵ , z and n are defined as above. In yet another preferred embodiment of the invention, R ¹ is phenyl; in yet another preferred embodiment of the invention, the compound is selected from: (4-oxo-8-phenethyl-1-) Phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetic acid methyl ester, (1a) {8- [2- (1,3-dioxo-1,3-dihydro-iso) Indole-2-
Yl) -ethyl] -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl} -acetic acid methyl ester, (1b) [8- (3-cyano- 3,3-Diphenyl-propyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (1c) [8- (4 -Nitro-benzyl) -4-oxo-1-phenyl-1,3,8-
Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (1d) [4-oxo-1-phenyl-8- (3-phenyl-propyl) -1,3,8
-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (1e
) [4-oxo-8- (3-phenoxy-propyl) -1-phenyl-1,3,
8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (1
f) [4-oxo-8- (4-phenoxy-butyl) -1-phenyl-1,3,8
-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (1 g
) [8- (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl)
-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] deca-
3-yl] -acetic acid methyl ester, (1h) {8- [5- (1,3-dioxo-1,3-dihydro-isoindole-2-
Yl) -pentyl] -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl} -acetic acid methyl ester, (1i) (8-naphthalen-1-ylmethyl -4-oxo-1-phenyl-1,3,8
-Triaza-spiro [4.5] dec-3-yl) -acetic acid methyl ester, (1j
) {8- [2- (4-Fluoro-phenoxy) -ethyl] -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl} -acetic acid methyl ester , (1k) [8- (6,7-dimethoxy-2-oxo-2H-chromen-4-ylmethyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] deca -3-yl] -acetic acid methyl ester, (11) [8- (2-naphthalen-1-yl-methyl) -4-oxo-1-phenyl-
1,3,8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (1m) [8- (3-cyano-benzyl) -4-oxo-1-phenyl-1,3 , 8-
Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (1n) 3- (3-methoxycarbonylmethyl-4-oxo-1-phenyl-1,3,3
8-Triaza-spiro [4.5] dec-8-ylmethyl) -benzoic acid methyl ester, (1o) [8- (4-bromo-benzyl) -4-oxo-1-phenyl-1,3,8-
Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (1p) [8- (3,4-dichloro-benzyl) -4-oxo-1-phenyl-1,3
, 8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (
1q) (8-anthracen-9-ylmethyl-4-oxo-1-phenyl-1,3,3
8-Triaza-spiro [4.5] dec-3-yl) -acetic acid methyl ester, (1
r) 5-guanidino-2- (S)-[2- (8-naphthalen-1-ylmethyl-4
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] pentanoic acid methyl ester, N- (2-guanidino-ethyl) -2- (8-naphthalen-1-ylmethyl-
4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] deca-3
-Yl) -acetamide, 3- (7-amino-heptyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one, 3- (1H-Imidazol-4-yl) -2- (S)-[2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] Deca-3-yl) -acetylamino] -propionamide, 5-guanidino-2- (S)-[2- (8-naphthalen-1-ylmethyl-4)
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] -pentanoic acid amide, 5-guanidino-2- (R)-[2- (8-naphthalen-1-ylmethyl-4)
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] -pentanoic acid amide, N- (3-guanidino-propyl) 2- (8-naphthalen-1-ylmethyl-
4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] deca-3
-Yl) -acetamide, 3- (5-amino-pentyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-4-one, N- (3-Amino-propyl) -2- (8-naphthalen-1-ylmethyl-4
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetamide, N- (2-amino-ethyl) -2- (8-naphthalen-1-ylmethyl-4-
Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetamide, N- [7- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl −
1,3,8-triaza-spiro [4.5] dec-3-yl) -heptyl] -guanidine, 3-ethyl-8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-
Triaza-spiro [4.5] decan-4-one, 2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3
, 8-Triaza-spiro [4.5] dec-3-yl) -N- (tetrahydro-furan-2-ylmethyl) acetamide, 2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl- 1,3
, 8-Triaza-spiro [4.5] dec-3-yl) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl] -acetamide, 6-amino-2- (S)- [2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetylamino] -hexanoic acid amide, N -Carbamoylmethyl-2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl)
-Acetamide, 2- (S)-[2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl)- Acetylamino] -phenyl-acetamide, 6-amino-2- (S)-(2- {6-amino-2- (S)-[2- (8-naphthalen-1-ylmethyl-4-oxo-1-) Phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetylamino] -hexanoylamino} -acetylamino) -hexanoic acid amide, 5-guanidino-2- (S)- {2- [2- (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetylamino] -acetylamino ｝ -Pentanoic acid amide or 5-g Anidino-2- (S)-(2- {2- [2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5]
] Dec-3-yl) -acetylamino] -acetylamino｝ -acetylamino)
Pentanoic acid amides.

In a most preferred embodiment of the present invention, said compound is selected from: (4-oxo-8-phenethyl-1-phenyl-1,3,8-triaza-spiro [4.5] Deca-3-yl) -acetic acid methyl ester, [8- (2-naphthalen-1-yl-ethyl) -4-oxo-1-phenyl-
1,3,8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [8- (4-bromo-benzyl) -4-oxo-1-phenyl-1,3,8-
Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [8- (3,4-dichloro-benzyl) -4-oxo-1-phenyl-1,3
, 8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, 5-guanidino-2- (S)-[2- (8-naphthalen-1-ylmethyl-4)
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] -pentanoic acid amide, 5-guanidino-2- (R)-[2- (8-naphthalen-1-ylmethyl-4)
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] -pentanoic acid amide or 3- (7-amino-heptyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-4 -ON.

In a third aspect, the present invention provides compounds of the general formula I

[0023]

Embedded image Wherein R ¹ is phenyl, arylalkyl or thienyl, which is one or more of halogen, cyano, nitro, trifluoromethyl, C _1-6 alkyl, hydroxy, C _1-6 alkoxy or NR ⁶ R ⁸ Wherein R ⁶ and R ⁸ are independently hydrogen or C _1-6 alkyl, or R ¹ is C _1-6 alkyl; R ² is phenyl, phenoxy, benzo dioxinyl, cyano diphenylmethyl, aminophenyl, C _1-6 monoalkylamino phenyl, C _1-6 dialkylamino, phenyl, naphthyl, tetrahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, at coumarinyl Wherein said group is one or more of halogen, cyano, nitro, trifluoromethyl, C _1-6 Alkyl, hydroxy, C _1-6 alkoxy, C (O) R ^7, wherein R ⁷ is —OH, C _1-6 alkoxy or —NR ¹² R ¹³ , wherein R ¹² and R ¹³ are independent and may be substituted by hydrogen or C _1-6 alkyl) and; R ³ is hydrogen, C _1-6 alkyl, phenyl, benzyl or acetyl; R ⁴ is hydrogen or (CH _{2) m} - ( _{^{CHR 9) - (CH 2)}} p -AR 11 [wherein m and p are 0-4 independently, R ⁹ is hydrogen, C _1-6 alkyl, phenyl or arylalkyl, R ¹¹ is C _1-6 alkyl, hydroxy, C _1-6 alkoxy, guanidino, an amino acid residue having a C-terminal group consisting of either OCH ₃ or NH ₂ or 2 to 4 peptidyl residues; ¹¹ may be a group NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 alkyl, (
CH _{2) q} R ¹⁶ (wherein, q may be from 0 to 6, and R ¹⁶ is C3-C7
A cycloalkyl ring, optionally substituted aromatic or heteroaromatic ring, aliphatic ring containing one or more heteroatoms, alkoxy or aryloxy group, amino or guanidino group); be -CH ₂ or -C = O;
However, when R ¹¹ is an amino acid or a peptidyl residue, A is a —C ＝ O group.
Or R ⁵ is hydrogen or C _1-4 alkyl; z is CHR ¹⁰ (where R ¹⁰ is hydrogen, C _1-6 alkyl, phenyl or arylalkyl), or z is C _2-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene; wherein n is 1 or 2; or a pharmaceutically acceptable salt thereof, comprising migraine, non-insulin dependent intrinsic For the treatment of diabetes (type II diabetes), sepsis, inflammation, incontinence, vasomotor disorders, especially peripheral vasomotor effects known as hot flashes or hot flushes, and / or withdrawal symptoms, especially drug abuse. Comprising the use for the reduction of withdrawal symptoms resulting from withdrawal from a drug.

In another aspect of the invention, the composition is in a form suitable for oral, nasal, transdermal, pulmonary, or parenteral administration. In a further aspect of the invention, the compound of formula Ia or Ib is present in an amount of 1 per patient.
About 0.01 to about 5000 mg per day, preferably about 1 per patient per day
It is administered as a dose ranging from about 1000 mg to about 1000 mg, especially about 10 to 100 mg per patient per day, for example about 100 mg per patient per day.

In a fourth aspect, the present invention relates to the treatment or prevention of migraine, type II diabetes, sepsis, inflammation, incontinence and / or vasomotor inflammation, especially peripheral vasomotor effects known as hot flashes or pigment flushing. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof.

In a fifth aspect, the invention relates to a pharmaceutical composition comprising a triaza-spiro compound having high affinity for the nociceptin receptor, or a pharmaceutically acceptable salt thereof. In a sixth aspect, the invention relates to a method of treating withdrawal symptoms, especially withdrawal symptoms that occur during withdrawal from drug abuse.

An effective, eg, therapeutically effective, amount of a compound of Formula Ia or Ib is the form of administration in the desired therapy, the form to be administered, the subject to be treated and the weight of the subject to be treated, And the preferences and experience of the attending physician or veterinarian. As used herein, the term “patient” comprises any mammal that can benefit from treatment or prevention of vasomotor disorders, eg, a human, especially if said mammal is female, eg, female. It is. However, "patient" does not limit women.

As used herein, the term “small organic compound” means a compound having a molecular weight of 1000 or less and having 5 or less amide bonds or no amide bonds. As used herein, the term "triaza-spiro" refers to a compound of the formula having various substituents as defined above.

[0029]

Embedded image Means the compound of As used herein, the term “high affinity” means an IC ₅₀ of 1 μM or less.

As used herein, the term “arylalkyl” includes straight or branched, saturated carbon chains containing 1 to 6 carbon atoms that are substituted with an aromatic hydrocarbon, eg, Benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- (
1-naphthyl) ethyl and the like. As used herein, the term “C _1-6 alkyl” refers to a branched or straight chain alkyl group or a cycloalkyl having 5 or 6 carbons in the ring.
Typical C _1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl,
Including isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

As used herein, the term “C _1-6 alkoxy”, alone or in combination, refers to a designated linear or branched or cyclic arrangement linked through the oxygen of an ether. It is meant to include those C _1-6 alkyl groups of length, which have free valence bonds derived from the oxygen of the aforementioned ethers. Examples of straight chain alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Examples of branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy and isohexoxy. Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

As used herein, the term “halogen” refers to fluorine, chlorine, bromine or iodine. As used herein, the term "amino acid residue or peptidyl residue" is also meant to comprise a natural or synthetic amino acid linked to the compound by an amide bond.

As used herein, the term “C _2-8 alkylene” refers to a branched or straight-chain alkyl group having from one to the indicated number of carbon atoms. Typical _C2-8 alkylene groups include, but are not limited to, ethylene, n-propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, hexylene, isohexylene, and the like.

As used herein, the term “C _2-8 alkenylene” refers to an olefinically unsaturated, branched or straight-chain group having at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenylene, allylene, isopropenylene, 1,3-butadienylene, 1-butenylene, hexenylene, pentenylene, and the like.

As used herein, the term “C _2-8 alkynylene” refers to an unsaturated, branched or straight-chain group having at least one triple bond. Examples of such groups include, but are not limited to, 1-propynylene, 1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene, and the like. As used herein, the term "ligand" is also meant to comprise a compound that has an active, partially active or antagonistic activity that specifically binds to a receptor protein.

As used herein, the term “treatment” is also meant to comprise a prophylactic treatment. The preparation of the compound of formula Ia may include, but is not limited to, the following method: A :

[0037]

Embedded image A compound of formula (II) wherein R¹ , R^Three , R^Four , R^Five And n are as described above.
A) is a compound of formula (III) wherein R^Two And z are as described above.
X is a suitable leaving group such as halogen, p-toluenesulfonate or mesyl
Which is the default). This alkylation reaction is carried out in a solvent such as an alcohol.
Seton, dibutyl ether, 2-butanone, methyl ethyl ketone, ethyl acetate,
In tetrahydrofuran (THF) or toluene, a base such as sodium hydride
And the reflux temperature of the solvent used in the presence of a catalyst, for example an alkali metal iodide.
, For example, for 1 to 120 hours. The compound of formula (II)
For example, US Pat. No. 3,238,2.
No.16. Compound of formula (III) is commercially available
Or can be produced by methods known to those skilled in the art. B :

[0038]

Embedded image Compounds of formula (II), wherein R ¹ , R ³ , R ⁴ , R ⁵ , and n are as described above, are prepared according to formula (IV), wherein R ² is as described above, and Linker y is one carbon atom shorter than linker z, where z is as described above, and can form an imine of formula (V). The reaction is
It can be carried out in a suitable solvent, for example a lower aliphatic alcohol, for example ethanol or ether, for example tetrahydrofuran, or a mixture thereof. In the second stage, the iminium derivative of formula (V) formed is subsequently converted to a suitable reducing reagent,
For example, by addition of a hydride, for example sodium cyanoborohydride or sodium borohydride, for example for 1 to 120 hours at 20 ° C. to reflux temperature, the formula (Ia)
To an amine.

The compounds of formula (Ia) are also described, for example, in F. Zaragoza and S.V. Petersen Tetrahed
ron,52, 10823 (1996), in a similar manner.
Can be. In this case, R in the compound of formula (II)^Four Is (CH_Two )_m − (CHR ⁹ )-(CH_Two )_p -C (O) R^7b(Where m, p and R⁹ Is as described above
Yes, and R^7bIs a resin-O- or resin-NH- residue).

The above reaction is followed by cleavage from the resin to form a compound of formula (Ia). The cleavage conditions used will depend on the type of resin used, and are generally known to those skilled in the art. C :

[0041]

Embedded image The compound of formula (VI) wherein R ¹ , R ² , R ³ , R ⁵ , z and n are as described above is N 3 and a suitable base such as sodium hydride, n-butyllithium or Can be deprotonated with potassium tert-butoxide in an aprotic solvent, such as dimethylformamide or dimethylsulfoxide,
And subsequently, it can be reacted with a reagent of formula (VII), wherein R ⁴ and X are as described above. The above reaction can be carried out at a temperature from 0 ° C. to the reflux temperature, preferably at room temperature, for 1 to 24 hours to form a compound of formula (Ia). D :

[0042]

Embedded image The compound of formula (Ia) is further converted to a compound of formula (VIII) wherein R ¹ , R ² , R ³ , R ⁵ ,
Reacting a compound of the formula (IX), wherein R ⁹ has a residue which couples to the resin, by reacting a compound of the formula R ⁹ , m, p, n and z as defined above. It can be synthesized and subsequently cleaved from the resin as an ester or amide moiety. The coupling reaction between (VIII) and (IX) is carried out in a suitable solvent, for example dimethylformamide or N-methylpyrrolidone, for example a coupling reagent from carbodiimides, benzotriazole and any base, for example a constrained amide. This can be done using a tertiary amine. These amide couplings are well described in the literature and are generally known. Formula (IX)
May be a commercially available resin, or may be prepared from such a commercially available resin using common alkylation, reductive amination, or acylation methods. can do.

In the present invention, the compounds of the formula Ia or Ib can be prepared in the form of pharmaceutically acceptable salts, for example bases or acid addition salts, in particular acid addition salts, which comprises organic and inorganic acids. Contains salt. Examples of such salts are organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, Including salts such as salicylic acid.
Suitable inorganic acid addition salts include salts such as hydrochloric, hydrobromic, sulfuric, and phosphoric acids. Examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts described in the Journal of Pharmaceutical Science , 66, 2 (1977), known to those skilled in the art .

Further contemplated pharmaceutically acceptable acid addition salts are the hydrides which the compounds of formula Ia or Ib can form. The above-mentioned acid addition salts can be obtained as a direct product of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing a suitable acid, and the salt is isolated by evaporation of the solvent or other separation of the salt and solvent. be able to.

The compounds of formula Ia or Ib of the present invention can form solvates with standard low molecular weight solvents using methods known to those skilled in the art. The compound of formula Ia or Ib can be administered in pharmaceutically acceptable acid addition salt form. It is believed that such salt forms exhibit approximately the same activity as the free base form.

Pharmaceutical compositions for use according to the invention comprise one or more of the formulas Ia as active ingredient
Or a compound of Ib, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. Pharmaceutical compositions comprising a compound of formula Ia or Ib of the present invention, prior art, for example, Remi ngton:. The Science and Practice of Pharmacy, 19 th Ed, can be prepared according to what is described in 1995. The compositions may be presented in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or topical applications.

A typical composition comprises a compound of Formula Ia or Ib or a pharmaceutically acceptable acid addition salt thereof, which is a carrier or diluent or may be diluted with a carrier,
It is associated with a pharmaceutically acceptable excipient or enclosed in a carrier, which can be in the form of a capsule, sachet, paper or other container. In preparing the compositions described above, conventional techniques for the manufacture of pharmaceutical compositions can be used. For example, the active compound will usually be mixed with or diluted with a carrier, or enclosed in a carrier which may be in the form of an ampoule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material, which acts as an excipient, excipient or solvent for the active compound. The active compound may be adsorbed on a granular solid container, such as a sachet. Examples of suitable carriers are water, saline, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil,
Gelatin, lactose, china clay, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, lower alkyl ethers of stearic acid or cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol Fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release agent known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax. The formulations also include wetting agents, emulsifying and suspending agents,
Preservatives, sweetening or flavoring agents may be included. The rapid application of the active ingredient after administration to the patient by applying a formulation according to the invention to the patient, by applying methods known in the art.
It can be prepared to provide sustained or delayed release.

The pharmaceutical compositions described above can be sterilized and mixed, if desired, with adjuvants, emulsifiers, salts which affect osmotic pressure, buffers and / or coloring substances and the like. Does not react harmfully with compounds. The route of administration in the present case may be any route which effectively delivers the active compound to a suitable or desired site of action, for example oral, nasal, pulmonary, transdermal or parenteral, for example rectal , Depot, subcutaneous, intravenous, urethral, intramuscular, intranasal, ophthalmine solution or ointment.

If a solid carrier is used for oral administration, the preparation may be tabletted and placed in a hard gelatin capsule in powder or pill form, or it may be in the form of a troche or lozenge There is. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsifier, soft gelatin capsule or sterile injectable solution such as an aqueous or non-aqueous liquid suspension or solution.

For nasal administration, the preparation may comprise a compound of formula Ia or Ib dissolved or suspended in a liquid carrier, especially an aqueous carrier for spray application. The carrier may include solubilizers, for example, propylene glycol, surfactants, adsorption enhancers, for example, lecithin (phosphatidylcholine) or cyclodextrin, or preservatives, for example, additives such as parabens.

Particularly suitable for parenteral application are injectable solutions or suspensions,
Preferred is an aqueous liquid having the active compound dissolved in polyhydroxylated castor oil. Tablets, dragees or capsules with talc and / or carbohydrate carriers or binders are particularly suitable for oral application. Preferred carriers for tablets, dragees, or capsules include lactose, corn starch, and / or potato starch. Syrups or elixirs can be used where sweetened excipients can be applied.

Typical tablets that can be manufactured by conventional tableting techniques are: Core: Active compound (as an independent compound or a salt thereof) 100 mg Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, Microcristo (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Coating: HPMC about 9 mg ^* Mywacet 9-40T May contain about 0.9 mg. ^* Acylated monoglycerides used as plasticizers for film coating.

Any novel feature or combination of features described herein is considered essential to the invention.

Pharmacological action : Female Sprague Dawley rats (300 ± 25 g) were anesthetized with sodium pentobarbital (50 mg / kg ip) and a polyethylene catheter was placed in both femoral veins. It was set up for intravenous administration of drugs, such as nociceptin and analogs, and in the aorta of the left thigh to measure aortic blood pressure and heart rate. The trachea is intubated with a polyethylene tube and N
As described by uki Y et al., rats were pithed, aerated and drug-treated (Effects of Dorsal Rhizotomy on Depressor Response to Spinal Cord Stimu).
lation Mediated by Endogenous Calcitonin Gene-related Peptide in the Pit
hed Rat. J. Neurosurg. 1993; 79: 899-904).

Examples : The preparation of the compounds of the formula Ia or Ib and the preparations containing them are further illustrated in the following examples, which should not be construed as limiting.

Hereinafter, TLC is thin layer chromatography, CDCl ₃ is deuteriochloroform, and DMSO-d ₆ is hexadeuteriodimethylsulfoxide. The structure of the compound is confirmed by either elemental analysis or NMR, wherein peaks due to the characteristic protons of the title compound are at appropriate positions. ¹ H NMR shifts (δ _H ) are given in parts per million (ppm).

The HPLC-MS analysis was performed using the following method using PE Sciex API 10
Performed on a 0LC / MS system. Method 1 : Positive ion spray with Waters ™ 3 mm × 150 mm 3.5 μ C-18 symmetric column and flow rate of 20 μL / min. The column is 5-90% A
Using a linear gradient from 85 to 0% B and 10% C at a flow rate of 1 ml / min within 15 minutes (solvent A = acetonitrile, solvent B = water and solvent C = 0.1% trifluoroacetic acid) /water). Method 2 : YMC ODS-A 120Ås-5μ 3 mm × 50 mm column and 20
Cation spray with flow rate of μL / min. The column is 5 to 90% A, 85 to
Eluted within 7.5 minutes with a linear gradient of 0% B and 10% C at a flow rate of 1.5 ml / min (solvent A = acetonitrile, solvent B = water and solvent C = 0.5% triethylamine). Fluoroacetic acid / water).

M. p. Is the melting point and is given in ° C. and is not exact. Column chromatography is described in J. Org. Chem. (1978), 43, 2923-292 described in WC Still et al.
5 was performed on Merck silica gel 60 (Art. 9385). The compounds used as starting materials are either known compounds or compounds which can easily be prepared by methods known per se.

Example 1 8-alkylated 4-oxo-1-phenyl-1,3,8-triaza-spiro [4
. 5] Dec-3-yl) -acetic acid methyl ester (Method A)

[0060]

Embedded image Wang resin (2.17 g, 2.0 mmol) was placed in a solid synthetic flask equipped with a glass frit and swelled in dry dimethylformamide (15 ml) for 15 minutes. Excess solvent is removed by suction and dimethylformamide (
8.0 ml) of Fmoc-3-carboxymethyl-1-phenyl-1,3,8-
A solution of triaza-spiro [4.5] decan-4-one (2.05 g, 4.0 mmol) was added. The mixture was shaken for 5 minutes and dried pyridine (0.53 ml)
And 2,6-dichlorobenzoyl chloride (0.54 ml, 4.0 mmol) were added and the mixture was shaken for 20 hours. The solution was removed by suction and the resin was washed with dimethylformamide (2 × 10 ml) and 1,2-dichloroethane (4 × 10 ml). Dichloromethane (8 ml), pyridine (0.81 ml, 10 mmol) and benzoyl chloride (0.81 ml, 7.0 mmol) were added to the resin and the mixture was shaken for 2 hours. The solution is removed by suction and the resin is washed with dichloromethane (4 × 10 ml)
, Methanol (2 x 10 ml) and N, N-dimethylformamide (2 x 10 ml)
And washed.

The resin was shaken with 20% piperidine / N, N-dimethylformamide (10 ml) for 30 minutes to remove the Fmoc group. The solution was removed by suction and the resin was washed with N, N-dimethylformamide (2 × 10 ml), dichloromethane (
(4 × 10 ml) and methanol (3 × 10 ml) and dried. This resulted in Wang resin (2.53 g) combined with 3-carboxy-1-phenyl-1,3,8-triaza-spiro [4.5] decane-4-one (0.67 mmol / g). .

The following solid phase synthesis method was described by F. Zaragoza and SV Petersen,
An analogous procedure was performed using the apparatus of Tetrahedron, 52 , 10823 (1996). An equal amount of the above resin (67 mg, 0.045 mmol) was placed in a Teflon tube equipped with a frit on a mechanical shaker. Dimethyl sulfoxide (1 ml), the appropriate alkyl bromide R ² -z-X (0.225mmol) and diisopropylethylamine (0.02
(9 g, 0.225 mmol) was added to the resin. The tube was heated to 60 ° C. and shaken for 16 hours. The resin was discharged and dimethyl sulfoxide (2 × 1 ml)
), Dichloromethane (4 x 1 ml) and methanol (2 x 1 ml).

A solution of sodium methoxide (0.009 mmol) in a 4: 1 mixture of tetrahydrofuran / methanol (2 ml) was added to the resin and the suspension was heated to 50 ° C.
For 16 hours. The mixture was neutralized by addition of acetic acid solution (0.01 mmol) in a 4: 1 mixture of tetrahydrofuran / methanol (1 ml), the solution was drained and the resin was washed with tetrahydrofuran (1 ml). The combined filtrate was concentrated in vacuo to yield the title compound.

[0064]

Embedded image

[0065]

Embedded image Example 2 8-alkylated-4-oxo-1-phenyl-1,3,8-triaza-spiro [
4.5] Dec-3-yl) -acetic acid methyl ester (Method B)

[0066]

Embedded image 3-Carboxy-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one) (0.88 mmol / g) is bound and analogously as described in the previous example. The prepared Wang resin was used for this library of compounds. An equivalent amount of the resin (62 mg, 0.055 mmol) was placed in a Teflon tube equipped with a frit on a mechanical shaker. The resin is swollen for 0.5 hours in 2 ml of dry tetrahydrofuran, the solvent is removed by suction, and each aldehyde (0.275 mmol) dissolved in 1 ml of tetrahydrofuran is added and 5
0% v / v acetic acid (0.225 ml) was added. The mixture was placed in a nitrogen atmosphere at room temperature for 0.1 hour.
Shake for 5 hours. Sodium cyanoborohydride solution (tetrahydrofuran, 0
. 1M in 2 ml) and shaken at room temperature for 16 hours. The resin is discharged and tetrahydrofuran (2 × 1 ml), water (2 × 1 ml), tetrahydrofuran (2 × 1 ml)
, Dichloromethane (2 x 1 ml) and tetrahydrofuran / methanol 4: 1 (2
× 1 ml). A solution of sodium methoxide (0.009 mmol) in a mixture of tetrahydrofuran / methanol 4: 1 (2 ml) was added to the resin and the suspension was stirred at 50 ° C. for 16 hours. The mixture was neutralized by the addition of a solution of acetic acid (0.01 mmol) in a 4: 1 (1 ml) mixture of tetrahydrofuran / methanol,
The solution was drained and the resin was washed with tetrahydrofuran (1 ml).
The combined filtrate was concentrated in vacuo to yield the title compound.

[0067]

Embedded image

[0068]

Embedded image

[0069]

Embedded image

[0070]

Embedded image Example 3 2- (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,3
8-Triaza-spiro [4.5] dec-3-yl) -propionic acid ethyl ester hydrochloride

[0071]

Embedded image 60% sodium hydride (0.156 g, 3.9 mmol) was added to dry heptane (5 ml)
) And stirred under nitrogen for 5 minutes. The solvent was decanted and dry dimethylformamide (2 ml) was added. Dry dimethylformamide (11 ml)
8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-
Triazaspiro [4.5] decan-4-one (1.115 g, 3.0 mmol) was added dropwise while cooling in an ice bath. The mixture was stirred at 0 ° C. for 1 hour. Deprotonated 1-phenyl-8-naphthalen-1-ylmethyl-1,3,8-
An aliquot of the resulting solution of triazaspiro [4.5] decan-4-one (2.3
ml, 0.5 mmol) was added to ethyl-2-bromopropionate and the mixture was stirred at room temperature overnight. Water (15 ml) and ethyl acetate (15 ml) were added and the mixture was shaken, the organic layer was separated and subsequently washed with water (2 × 10 ml) and brine (10 ml). The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and dichloromethane 1: 4 to give the pure base, which was dissolved in tetrahydrofuran (3 ml) and excess in ether Hydrogen chloride solution was added. Crystallization occurred by careful addition of ether (6 ml). The residue was collected by filtration and dried and the title compound (217
mg, 85% yield). M. p. 175-181 ° C. Theory for C ₂₉ H ₃₃ N ₃ O ₃ , HCl: C, 68.56%; H, 6.75%; N, 8.27%; found C; 68.36%; H, 7.03%; N, 7.93%.

[0072] By a similar fabrication method, the following compounds were prepared: 3-methyl-2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-3,8-triaza - spiro [ 4.5] dec-3-yl) - butyric Echirue ester hydrochloride

[0073]

Embedded image LC / MS (Method 2): m / e = 500.2 (MH +); RT = 6.60 min _{C 31 H 37 N 3 O 3} , HCl, 0.25H 2 O of theory: C, 69.45 %; H, 7.14%; N, 7.84%; Found: C; 68.87%; H, 7.18%; N, 7.77%. 2- (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8- triaza-spiro [4.5] dec-3-yl) -hexanoic acid ethyl ester hydrochloride

[0074]

Embedded image M. p. 169 ° -177 ° C. Theory for C ₃₂ H ₃₉ N ₃ O ₃ , HCl, 0.75 H ₂ O: C, 68.19%; H, 7.42%; N, 7.45%; Found: C; 67.92%; H, 7.47%; N, 7.34%. 5- (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8- triaza-spiro [4.5] dec-3-yl) -pentanoic acid ethyl ester hydrochloride

[0075]

Embedded image LC / MS (Method 2): m / e = 500.2 (MH +); RT = 6.08 min _{C 31 H 37 N 3 O 3} , HCl, 1.25H 2 O of theory: C, 66.12 %; H, 7.34%; N, 7.46%; Found: C; 66.23%; H, 7.13%; N, 7.34%. 4- (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8- triaza-spiro [4.5] dec-3-yl) -butyric acid ethyl ester hydrochloride

[0076]

Embedded image M. p. _{200-203 ℃ C 30 H 35 N 3} O 3, HCl, 0.3 tetrahydrofuran theory: C, 68.92%; H, 7.12%; N, 7.73%; Found: C; 68 H, 7.08%; N, 7.64%.

Example 4 8-Naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-4-one

[0078]

Embedded image 1-phenyl-1,3,8-triaza-spiro [4.5] decane-4-one (
185.04 g, 0.76 mol) were suspended in 2-butanone (3600 ml).
1- (chloromethyl) nafretane (169.21 g, 0.91 mol), dry potassium carbonate (345.42 g, 2.50 mol) and sodium iodide (113.9)
1 g, 0.76 mol) was added and the mixture was heated at reflux for 24 hours. The solvent was evaporated in vacuo and the residue was taken up in water (2000 ml) and diethyl ether (20
00 ml). The precipitate formed was collected by filtration and treated with water (800 ml).
), Toluene (600 ml) and ice-cold acetone (2 x 200 ml) and dried to give the title compound as a powder (191.20 g, 68).
% Yield). M. p. _{207-215 ℃ C 24 H 25 N 3} O of theory C, 77.60%; H, 6.78 %; N, 11.31%; Found: C; 77.23%; H, 6.90 %; N, 11.29%.

Example 5 (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8- triaza-spiro [4.5] dec -3-yl) -acetic acid methyl ester

[0080]

Embedded image Sodium hydride (60%, 12.96 g, 0.324 mol) was stirred with dry n-heptane under nitrogen, and the solvent was decanted from the precipitated hydride. Ice-cold dimethylformamide (600 ml) was added and the resulting solution was allowed to stand for 0.5 h during the reaction of 8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza in dimethylformamide (900 ml). To a stirred solution of -spiro [4.5] decan-4-one (prepared as described in Example 4) at 0-5 ° C.
After stirring for a further 0.5 hour, a solution of methyl bromoacetate (54.84 g, 0.348 mol) in dimethylformamide (20 ml) was added under ice cooling. The reaction mixture was allowed to warm to room temperature while stirring for an additional hour and then ethyl acetate (8
00 ml) and ice water (1900 ml) with vigorous stirring. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x400ml). The combined organic layers were washed successively with water (2 × 300 ml) and brine (2 × 250 ml) and dried over magnesium sulfate. The solution was concentrated in vacuo, ethyl acetate (30 ml) was added to the warm residue with stirring, and crystallization was achieved by cooling to room temperature. The product was filtered, washed on the filter with ice-cold ethyl acetate, and dried to give the title compound (111.06 g, 83% yield) as a powder. M. p. _{122-135 ℃ C 27 H 29 N 3} O 3 of theory: C, 73.11%; H, 6.59%; N, 9.47%; Found: C; 72.84%; H, 6 .71%; N, 9.36%.

Example 6 (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8- triaza-spiro [4.5] dec -3-yl) -acetic acid

[0082]

Embedded image (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8
-Triaza-spiro [4.5] dec-3-yl) -acetic acid methyl ester (44.
40 g, 0.1 mol, prepared as described above) were combined with 2N sodium hydroxide (165 ml).
, 0.33 mol) and ethanol (500 ml) and stirred at room temperature for 16 hours. Dichloromethane (700 ml) was added and the pH was adjusted to 5, 6N
Prepared by the addition of hydrochloric acid. The organic layer was separated, washed with water (2 × 200 ml) and concentrated in vacuo to 300 ml. Water (300 ml) and dichloromethane (
100 ml) was added and the slurry was stirred overnight. The product was collected by filtration, water (4 × 100 ml), dichloromethane (2 × 50 ml) and acetone (2 × 5
0 ml) and dried to give the title compound as a powder (4
4.6 g, 97% yield). ¹ H NMR (200 MHz, DMSO-d ₆ ) δ 1.62 (d, 2H);
56 (q, 2H), 2.88 (m, 4H), 4.03 (s, 2H), 4.07 (
s, 2H), 4.68 (s, 2H), 6.78 (t, 1H), 6.84 (d, 2
H), 7.23 (d, 2H), 7.40-7.70 (m, 4H), 7.90 (d
d, 2H), 8.42 (d, 1H). C ₂₆ H ₂₇ N ₃ O ₃ , 1.25H ₂ O requires C, 69.08%; H, 6.58%; N, 9.30%; found: C; 68.89%; H , 6.39%; N, 9.13%.

[0083] Example 7 (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza - spiro [4.5] dec-3-yl) - acetyl glycine methyl ester le

[0084]

Embedded image Wang resin coupled to Fmoc-glycine (88 mg, 0.045 mmol)
Placed in a Teflon tube with a frit on a mechanical shaker. The resin was swollen in dimethylformamide (1.5 ml) for 1 hour. The solvent is removed by aspiration and the resin is washed with 20 ml of N, N-dimethylformamide (1.5 ml).
Stirred with% piperidine for 30 minutes. The solution was removed by aspiration and the resin was washed with N, N-dimethylformamide (3 × 1.5 ml). (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] deca-dimethylformamide (1.6 ml)
To a solution of 3-yl) -acetic acid (0.0773 g, 0.18 mmol) was added diisopropylcarbodiimide (29 μl, 0.18 mmol) and 1-hydroxy-1H-benzotriazole (0.0243 g, 0.18 mmol), and The mixture was stirred at room temperature for 0.5 hours. The resulting solution and diisopropylethylamine (31 μl,
0.18 mmol) was added to the resin and it was stirred at room temperature overnight. The resin was filtered and dimethylformamide (2 x 1.5 ml), dichloromethane (4
× 1.5 ml), methanol (2 × 1.5 ml) and tetrahydrofuran / methanol 4: 1 (2 × 1.5 ml). Tetrahydrofuran / methanol 4: 1
A solution of sodium methoxide (0.009 mmol) in a mixture of (2 ml) was added to the resin and the suspension was stirred at 50 ° C. for 16 hours. The mixture was neutralized by the addition of an acetic acid solution (0.01 mmol) in a mixture of tetrahydrofuran / methanol 4: 1 (1 ml), the solution was drained and the resin was treated with tetrahydrofuran (
1 ml). The combined filtrate was concentrated in vacuo to give the title compound.

The following compounds were similarly synthesized using the method described above:

[0086]

Embedded image

[0087]

Embedded image Example 8 5-guanidino- (S) -2- [2- (8-naphthalen-1-ylmethyl-7 -oxo-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetyl Amino] -pentanoic acid amide, difluoroacetic acid salt

[0088]

Embedded image One equivalent (1.0 g, 0.69 mmol) of Rink Amide (AM) resin (0
. 69 mmol / g, purchased from Novabiochem) with piperidine / N, N-
Suspended in dimethylformamide (20%) (all volumes calculated as 10 mg / g resin) and shaken for 0.5 h on a mechanical shaker. The resin was filtered, rinsed with N, N-dimethylformamide, suspended in piperidine / N, N-dimethylformamide (20%) and shaken for 0.5 hours. The resin was filtered and washed as follows: 3 × N, N-dimethylformamide / water (90%)
2.times.ethanol, 3.times.N, N-dimethylformamide, 5.times.methylene chloride. The resin was dried in vacuo and suspended in N, N-dimethylformamide. Fm
oc-Arg (Pbf). OH (1.7 g, 0.17 mmol, 4 equiv), EDAC
(N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride)
(0.51 g, 2.68 mmol, 4 eq.), And HOBT (1-hydroxybenzotriazole) (0.36 g, 2.68 mmol, 4 eq.), And quench the reaction with 1
Shaking was performed for 6 hours. The resin is filtered and washed successively with 3 × N, N-dimethylformamide / water (90%), 3 × N, N-dimethylformamide, 3 × methylene chloride, and piperidine / N, N- Dimethylformamide (20%
) And shaken for 0.5 h. The resin was filtered and washed as follows: 3 × N, N-dimethylformamide / water (90%), 2 × ethanol, 3 × N, N-dimethylformamide, 5 × methylene chloride. The resin is dried in vacuo and suspended in N, N-dimethylformamide and (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-
Spiro [4.5] dec-3-yl) -acetic acid (1.08 g, 2.51 mmol, 3.6)
Eq), and EDAC (0.47 g, 2.51 mmol, 3.6 eq), H
OBT (0.33 g, 2.51 mmol, 3.6 eq) followed, and the reaction was stirred at room temperature for 20 hours. The resin was mixed with 3 × N, N-dimethylformamide / water (90
%), 3 × N, N-dimethylformamide, 3 × methylene chloride and dried in vacuo. The resin was suspended in trifluoroacetic acid / water (95%) and shaken for 2 hours. The filtrate is collected and cyclohexane / ether (50%
), A white precipitate was observed. The white solid was collected using centrifugation and washed with 3x cyclohexane / ether (50%). This was dissolved in a minimum amount of acetonitrile / water (10%) and lyophilized to give the title compound (273 mg, 50% yield) as a white powder. HPLC retention time = 11.01 min (5 μm C18 4 x 250 mm column, 0
. Elution at 35 ° C. with a 20-80% gradient of 1% trifluoroacetic acid / acetonitrile and 0.1% trifluoroacetic acid / water over 30 minutes). LC / MS (method 2): m / e = 585.4 (MH +); RT = 4.43 min 5-guanidino- (R) -2- [2- (8-naphthalen-1-ylmethyl-7 -oxo) -1,3,8-Triaza-spiro [4.5] dec-3-yl) -acetylamino] -pentanoic acid amide, ditrifluoroacetate Resin (0.6
9 mmol / g) (0.200 g, 0.138 mmol, 1 equivalent), Fmoc-D-Ar
g (Pbf). Prepared using OH (0.358 g, 0.552 mmol, 4 equiv) and purified to give the title compound (73 mg, 59% yield) as a white powder. This powder appeared to be a salt with 2 equivalents of trifluoroacetic acid.
LC / MS (method 2): m / e = 585.2 (MH ⁺ ); RT = 4.42 min ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.4 (bm, 3H), 1.
7 (bm, 1H), 1.8-1.9 (bm, 2H), 2.8 (bm, 2H), 3
. 1 (m, 2H), 3.4-3.5 (bm, 4H), 3.7 (bm, 1H), 4
. 1 (s, 2H), 4.2 (m, 1H), 4.6 (m, 2H), 4.8-4.9
(Bm, 1H), 6.6-7.4 (bm, 4H), 6.7 (m, 1H), 6.9
(M, 2H), 7.1 (s, 1H), 7.2 (t, J = 9 Hz, 2H), 7.4
(S, 1H), 7.0-7.2 (m, 4H), 7.9 (bs, 1H), 8.0 (
m, 2H), 8.4 (t, J = 9 Hz, 2H), 10.2 (bs, 1H). ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 24.62, 25.94, 28
. 61, 42.37, 48.19, 51.63, 57.22, 63.14, 11
4.17, 118.02, 123.53, 124.84, 125.77, 126
. 57, 128.31, 128.70, 131.64, 132.97, 141.
91, 156.23, 166.06, 172.62, 6 carbons were ambiguous.

Example 9A N-benzyl-2- (8-naphthalen-1-ylmethyl-4-oxo-phenyl- 1,3,8-triaza-spiro [4.5] dec-3-yl) -acetamide

[0090]

Embedded image To a suspension of a commercially available aminomethylated polystyrene resin (Novabiochem) (20 g, 16 mmol) in dimethylformamide (70 ml) was added
Commercially available BAL-Linker (P) in 0 ml of dimethylformamide
erSeptive Biosystems GMBH) (12.88 g, 48
. 0 mmol) and 1-hydroxybenzotriazole (7.26 g, 48.0 mmol)
) Was added. To this was added N, N'-diisopropylcarbodiimide (6.06 g,
48.0 mmol) followed by N, N-diisopropylethylamine (6.19 g, 4
8.0 mmol) was added. The reaction was stirred at room temperature for 20 hours. The resin was filtered and washed as follows: 3x dimethylformamide (50ml), 3x tetrahydrofuran (50ml), 3x dichloromethane (50ml), 3x ether (
50 ml). The resin was dried in vacuo and isolated: 23.92 g. IR spectroscopy showed a stretch band of the aldehyde at 1674 cm ^-1 . To a portion of this resin (0.200 g, 0.160 mmol) in 1,2-dichloroethane (8 ml) at room temperature was added benzylamine (0.171 g, 1.60 mmol) followed by sodium triacetoxyborohydride (0. .339 g, 1.60 mmol). The reaction solution is
Shake for hours at room temperature, filter and wash as follows: 3x dimethylformamide / water (90/10) (8ml); 3x dimethylformamide (8ml); 3x
Dichloromethane (8 ml). The resin was suspended in dimethylformamide and (8-
Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetic acid (0.274 g, 0.640 mmol)
), 1-hydroxybenzotriazole (0.099 g, 0.640 mmol) and N, N'-diisopropylcarbodiimide (0.081 g, 0.640 mmol). The reaction was shaken for 20 hours at room temperature. The resin was filtered, suspended in dimethyl sulfoxide and heated to 40 ° C. for 1 hour. The resin was filtered again, suspended in dimethyl sulfoxide (8 ml) and heated to 40 ° C. for 1 hour. The resin is filtered and as follows: 3 × dimethylformamide / water (9
0/10) (8 ml); 3 × dimethylformamide (8 ml); 3 × dichloromethane (8 ml) and air-dried. The resin was treated with trifluoroacetic acid / water (95
/ 5) (8 ml) for 1 hour at room temperature. The filtrate was collected and concentrated in vacuo to give the desired product.

The above examples and the following compounds were synthesized in a similar manner using the methods described above and the appropriate amine.

[0092]

Embedded image

[0093]

Embedded image

[0094]

Embedded image Example 10A 2- (S) - [2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza - spiro [4.5] dec-3-yl) - Asechirua Mino] -5-ureido - pentanoic acid amide

[0095]

Embedded image Link Amide (AM) resin (Novabiochem) (0.200
g, 0.138 mmol) in dimethylformamide / piperidine (80/20) (8
ml) and shaken for 30 minutes at room temperature. The resin was filtered and rinsed with dimethylformamide (8 ml) and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows. : 3 × dimethylformamide / water (90/10) (8 ml
), 3x dimethylformamide (8ml), 3x dichloromethane (8ml). The resin was suspended in dimethylformamide (8 ml) and treated with Fmoc-L-2-amino-5.
-Ureido-n-valeric acid (L-Fmoc-Cit-OH) (0.227 g,
0.552 mmol) and 1-hydroxybenzotriazole (0.085 g, 0.
552 mmol) was added. N, N'-diisopropylcarbodiimide (0.071
g, 0.552 mmol) and the reaction was shaken for 20 hours at room temperature. The resin was filtered and washed as follows: 3 × dimethylformamide / water (9
0/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml). The above resin was dissolved in dimethylformamide / piperidine (80/20) (8 ml).
) And shaken for 30 minutes at room temperature. The resin was filtered and rinsed with dimethylformamide (8 ml) and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows 3 × dimethylformamide / water (90/10) (8
ml), 3x dimethylformamide (8ml), 3x dichloromethane (8ml). The resin was suspended in dimethylformamide (8 ml); (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5]
Dec-3-yl) -acetic acid (0.269 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N, N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol). added. The reaction mixture was shaken at room temperature for 20 hours and filtered. The resin was treated with dimethyl sulfoxide (8
ml) and heated to 40 ° C. for 1 hour. Filtering the resin again,
Suspended in dimethyl sulfoxide (8 ml) and heated to 40 ° C. for another hour. The resin is filtered and as follows: 3 × dimethylformamide / water (
90/10) (8 ml); 3 × dimethylformamide (8 ml); 3 × dichloromethane (8 ml) and air-dried. The resin was treated with trifluoroacetic acid / water (95
/ 5) (8 ml) for 2 hours at room temperature. The filtrate was collected and concentrated in vacuo to give the desired product.

The above examples and the following examples also use the method described above, as well as the appropriate LF
Synthesized using moc-protected amino acids. For example, 10b and 10c are TFA
The water / water cleavage filtrate was added dropwise at 0 ° C. to a solution of heptane / ether (50/50) (10 ml). Compound 10b precipitated and was recovered as a white solid. For example, at 10c an oily residue is formed, the heptane / ether solution is decanted, the residue is dissolved in water / acetonitrile (90/10) (10 ml),
It was then lyophilized to give a white powder.

[0097]

Embedded image

[0098]

Embedded image Example 11A 5-guanidino-2- (S)-{2- [2- (8-naphthalen-1-ylmethyl -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] deca - 3-yl) - acetylamino] - acetylamino} - pentanoic acid amide

[0099]

Embedded image Link Amide (AM) resin (Novabiochem) (0.200
g, 0.138 mmol) in dimethylformamide / piperidine (80/20) (8
ml) and shaken for 30 minutes at room temperature. The resin is filtered and rinsed with dimethylformamide and again dimethylformamide / piperidine (80
/ 20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows: 3 × dimethylformamide / water (90/10) (8 ml), 3 ×
Dimethylformamide (8 ml), 3x dichloromethane. The resin was suspended in dimethylformamide (8 ml) and L-Fmoc-Arg (Pbf) -OH (0.3
58 g, 0.552 mmol) and 1-hydroxybenzotriazole (0.085
g, 0.552 mmol). N, N'-diisopropylcarbodiimide (0
. (071 g, 0.552 mmol) was added and the reaction was shaken for 20 hours at room temperature. The resin was filtered and washed as follows: 3x dimethylformamide / water (90/10) (8ml), 3x dimethylformamide (8ml), 3x dichloromethane (8ml). The resin was treated with dimethylformamide / piperidine (80/2
0) (8 ml) and shaken for 30 minutes at room temperature. Filtering the resin,
It was then rinsed with dimethylformamide and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows: 3 × dimethylformamide / water ( 90/10) (
8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml). The resin was suspended in dimethylformamide (8 ml) and Fmoc. Gly. OH (
0.163 g, 0.552 mmol), 1-hydroxybenzotriazole (0.0
85 g, 0.552 mmol) and N, N'-diisopropylcarbodiimide (0.
(071 g, 0.552 mmol). The reaction was shaken at room temperature for 20 hours.
The resin was filtered and washed as follows: 3x dimethylformamide / water (80/20) (8ml); 3x dimethylformamide (8ml); 3x dichloromethane (8ml). The resin was treated with dimethylformamide / piperidine (80/20) (
8 ml) and shaken for 30 minutes at room temperature. The resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows: × dimethylformamide / water (90/10) (8 ml)
3x dimethylformamide (8ml), 3x dichloromethane (8ml). The resin was suspended in dimethylformamide (8 ml); (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl). -Acetic acid (0.269 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N, N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) were added. The reaction mixture was shaken at room temperature for 20 hours and filtered and as follows: 3x dimethylformamide / water (90/10) (8ml); 3x dimethylformamide (8ml); 3x dichloromethane (8ml) Washed and air dried. The resin is trifluoroacetic acid /
Treated with water (95/5) (8 ml) for 2 hours at room temperature. The filtrate was collected and added dropwise to cyclohexane / ether at 0 ° C., causing a white precipitate to form.

The above examples and the following examples were prepared according to this method using the appropriate amino acids as described in the table below.

[0101]

Embedded image

[0102]

Embedded image Example 12 5-guanidino-2-(S) - (2- {2- [2- (8-naphthalen-1-yl-methyl-4-oxo-1-phenyl-1,3,8-triaza - spiro [4 .5] Dec-3-yl) -acetylamino] -acetylamino} -acetylamino) -pentanoic acid amide

[0103]

Embedded image Link Amide (AM) resin (Novabiochem) (0.200
g, 0.138 mmol) in dimethylformamide / piperidine (80/20) (8
ml) and shaken for 30 minutes at room temperature. The resin is filtered and rinsed with dimethylformamide and again dimethylformamide / piperidine (80
/ 20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows: 3 × dimethylformamide / water (90/10) (8 ml), 3 ×
Dimethylformamide (8 ml), 3 x dichloromethane (8 ml). The resin was suspended in dimethylformamide (8 ml) and L-Fmoc-Arg (Pbf) -OH
(0.358 g, 0.552 mmol) and 1-hydroxybenzotriazole (0
. 085 g, 0.552 mmol). N, N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) was added and the reaction was shaken for 20 hours at room temperature. The resin was filtered and washed as follows: 3x dimethylformamide / water (90/10) (8ml), 3x dimethylformamide (8ml), 3
X dichloromethane (8 ml). The resin was treated with dimethylformamide / piperidine (8
0/20) (8 ml) and shaken for 30 minutes at room temperature. The resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows: × dimethylformamide / water (90/1
0) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml)
). The resin was suspended in dimethylformamide (8 ml); Fmoc-Gly-
Gly-OH (0.195 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N, N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) were added, and the reaction solution was added. Shake at room temperature for 20 hours. The resin was filtered and washed as follows: 3x dimethylformamide / water (90/10) (8ml), 3x dimethylformamide (8ml), 3x dichloromethane (8ml). The resin was treated with dimethylformamide / piperidine (80 /
20) (8 ml) and shaken for 30 minutes at room temperature. The resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature;
The resin was washed as follows: 3 × dimethylformamide / water (90/10)
(8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
Suspending the resin in dimethylformamide (8 ml); (8-naphthalene-1-
Ilmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.
5] Dec-3-yl) -acetic acid (0.269 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N, N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) ) Was added. The reaction mixture was shaken at room temperature for 20 hours, filtered and washed as follows: 3x dimethylformamide / water (90/10) (8ml); 3x dimethylformamide (8ml)
3x dichloromethane (8ml). The resin was treated with trifluoroacetic acid / water (95/5)
(8 ml) for 2 hours at room temperature. The filtrate is collected and added dropwise to cyclohexane / diethyl ether (50/50) at 0 ° C., causing a white precipitate to form,
This was collected and washed with a cyclohexane / diethyl ether solution. 32
. 5 mg of product was recovered.

Theoretical MW = 698, LCMS (method 2), retention time = 4.20 min, MH +
= 699. Example 13 3- (7-amino-heptyl) -8- naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza - spiro [4.5] decane-4-one, ditrifluoroacetate

[0105]

Embedded image 60% sodium hydride (0.156 g, 3.9 mmol) in dry heptane (5
ml) and stirred under nitrogen for 5 minutes. Decant the solvent and add
Then dry dimethylformamide (4 ml) was added. Dry dimethylformamide (
8-naphthalen-1-ylmethyl-1-phenyl-1,3 dissolved in 11 ml).
, 8-Triazaspiro [4.5] decan-4-one (1.115 g, 3.0 mmol)
) Was added dropwise while cooling in an ice bath. The mixture is stirred at 0 ° C. for 1 hour
Was. The resulting deprotonated 1-phenyl-8-naphthalen-1-ylmethyl
-1,3,8-Triazaspiro [4.5] decan-4-one was dissolved in dimethyl
1,7-Dibromoheptane (3.88 g, 15 mmol) in formamide (3 ml)
Was added dropwise at room temperature to the stirred solution and stirring was continued for 1 hour. Next, the mixing
The material was diluted with water (50ml) and extracted with ethyl acetate (2x30ml). together
Layer was washed successively with water (2 × 20 ml) and brine (2 × 20 ml), _Four Dehydrated above and evaporated in vacuo. Residue is tetrahydrofuran (10ml)
And a mixture of ether (10 ml) and the hydrochloride salt in excess ether
Of hydrochloric acid solution was added dropwise. Precipitate in tetrahydrofuran
And a 1: 1 mixture of ether and dried and dried to give 3- (7-bromo-
(Butyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-tri
Aza-spiro [4.5] decan-4-one (1.192 g, 68% yield) was powdered.
I gave as the end. LC / MS (method 2): m / e = 550.2 (MH⁺ ); RT
= 6.74 minutes.

¹ H NMR (200 MHz, CDCl ₃ ) d1.4 (bm, 6H), 1.5-
1.9 (m, 6H), 3.3-3.6 (m, 8H), 3.92 (broad d
d, 2H), 4.70 (s, 4H), 6.86 (t, 1H), 7.15 (d, 2H).
H), 7.35 (t, 2H), 7.5-7.7 (m, 3H), 7.92 (dd,
2H), 8.15 (d, 1H), 8.38 (d, 1H). The above bromide (0.38 g, 0.65 mmol) was dissolved in 5 M ammonia solution / ethanol (7.5 ml) and heated in an autoclave at 100 ° C. for 16 hours. The solution was evaporated in vacuo and the residue was purified by preparative HPLC to give C
Purified using an 18-silica column. The column was eluted within 15 minutes with a linear gradient of 10-90% acetonitrile and 90-10% 0.1% trifluoroacetic acid. The purified fractions were evaporated in vacuo, dissolved in water / acetonitrile and lyophilized to give the title compound (0.238 g, 51% yield) as a powder. LC / MS (Method 2): m / e = 485.4 (MH ⁺ ); RT = 4.77 min Theoretical values for C ₃₁ H ₄₀ N ₄ O, 2CF ₃ CO ₂ H, 0.5 H ₂ O: C H, 6.00%; N, 7.76%; Found: C; 58.20%; H, 6.13%; N, 7.23%.

The following compounds were synthesized using the method described above and the appropriate dihaloalkane: 3- (5-aminopentyl) -8-naphthalen-1-ylmethyl-1-phenyl- 1,3,8- triaza - spiro [4.5] decane-4-one, ditrifluoroacetate

[0108]

Embedded image LC / MS (Method 2): m / e = 457.4 (MH ⁺ ); RT = 5.17 min Theoretical value for C ₂₉ H ₃₆ N ₄ O, 2CF ₃ CO ₂ H: C, 57.89%; H, 5.59%; N, 8.18%; Found: C; 57.57%; H, 5.54%; N, 8.05%. 3- (9-Aminononiru) -8-naphthalen-1-ylmethyl-1-phenyl - 1,3,8-triaza - spiro [4.5] decane-4-one ditrifluoroacetic vinegar salt

[0109]

Embedded image LC / MS (Method 2): m / e = 513.6 (MH +); RT = 5.03 min C ₃₃ H ₄₄ N ₄ O, theoretical values _{2.4CF 3 CO 2 H: C,} 57.73 %; H, 5.95%; N, 7.12%; Found: C; 57.75%; H, 6.07%; N, 7.17%.

[0110] Example 14 3- (3-dimethylaminopropyl) -8- naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza - spiro [4.5] decane-4-one dihydrochloride

[0111]

Embedded image 3- (3-chloropropyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4, prepared using the method described in Example 13.
. 5] Decan-4-one (0.145 g, 0.30 mmol) was added to a 33% dimethylamine / ethanol solution. Sodium iodide (0.045 g, 0.3 mmol)
Was added and the mixture was stirred at room temperature for 24 hours. The salts were separated by filtration and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on silica gel using dichloromethane / ethyl acetate 1: 1 containing 2.5% triethylamine as eluent. The purified fractions collected were evaporated down i. Vac., The residue was dissolved in tetrahydrofuran (5 ml) and the hydrochloride was precipitated by the dropwise addition of an excess of hydrochloric acid / ether solution. The precipitate was collected by filtration and dried to give the title compound (148 mg, 93% yield) as a powder. LC / MS (method 2): m / e = 457.4 (MH ⁺ ); RT = 4.47 min Theoretical value for C ₂₉ H ₃₆ N ₄ O, 2HCl, 2H ₂ O: C, 61.59%; H, 7.48%; N, 9.60%; Found: C; 61.56%; H, 7.23%; N, 9.30%.

The following compounds were synthesized using the methods described above. 3- (3,7-dimethyl-aminopropyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza - spiro [4.5] decane-4-one dihydrochloride The compound Example 13 3- (7-bromo-heptyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-4-one prepared by the method described in And synthesized. LC / MS (Method 2): m / e = 513.6 (MH ⁺ ); RT = 4.77 min ¹ H NMR (400 MHz, CDCl ₃ ) d1.4 (m, 6H), 1.65 (
m, 2H), 1.74 (d, 2H), 1.87 (m, 2H), 2.80 (s, 6
H), 3.35-3.55 (m, 6H), 3.90 (m, 2H), 4.72 (s
, 4H), 6.85 (t, 1H), 7.13 (d, 2H), 7.35 (t, 2H).
), 7.55-7.70 (m, 3H), 7.95 (t, 2H), 8.17 (d,
1H), 8.33 (d, 1H), 12.4 (broad s, 1H), 12.7.
(Broad s, 1H).

Example 15 N- (5- (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl- 1,3,8-triazaspiro [4.5] dec-3-yl) -pentyl) guanidine

[0114]

Embedded image 3- (5-aminopentyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one, prepared as described in Example 13, Ditrifluoroacetate (0.137 g, 0.2 mmol) was dissolved in dimethylformamide (1 ml) and diisopropylethylamine (0.
(233 g, 1.8 mmol) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.060 g, 0.3 mmol). The mixture was stirred at room temperature for 1 hour and the addition of an equal amount of 3,5-dimethylpyrazole-1-carboxamidine nitrate was repeated. After stirring for 16 hours, the mixture was diluted with water (10 ml) and extracted with ether (5 × 10 ml). The aqueous layer and the insoluble syrup were extracted with dichloromethane (10 ml) and the dichloromethane solution was washed with water (5 × 10 ml), dried over MgSO ₄ and concentrated in vacuo to give the title compound (0. 04
7 g, 5.2%) as an amorphous powder. LC / MS (Method 2): m / e = 499.2 (MH ⁺ ); RT = 4.70 min ¹ H NMR (400 MHz, DMSO-d ₆ ) d1.3 (m, 2H), 1.4.
5-1.65 (m, 7H), 2.48 (m, 1H), 2.32 (m, 4H), 3
. 09 (t, 2H), 3.35 (t, 2H), 3.95 (s, 2H), 4.68
(S, 2H), 6.79 (t, 1H), 6.88 (d, 2H), 7.23 (t,
2H), 7.50 (d, 2H), 7.59 (dt, 2H), 7.88 (dd, 1
H), 7.95 (d, 1H), 8.40 (d, 1H).

The following compounds were synthesized using the method described above: N- (5- (8-Naphthalen-1-ylmethyl-4-oxo-phenyl- 1,3,8-triazaspiro [4.5] deca -3-yl) heptyl) guanidine

[0116]

Embedded image LC / MS (Method 2): m / e = 527.2 (MH ⁺ ); RT = 4.90 min ¹ H NMR (200 MHz, DMSO-d ₆ ) d1.2-1.4 (m, 6H).
, 1.45-1.70 (m, 6H), 2.5-2.9 (m, 6H), 3.15 (
m, 2H), 3.35 (t, 2H), 3.95 (s, 2H), 4.62 (s, 2
H), 6.80 (m, 3H), 7.23 (t, 2H), 7.30-7.7 (m,
5H), 7.75 (m, 2H), 8.40 (d, 1H).

[0117] Example 16 N-(2-aminoethyl) -2- (8-naphthalen-1-ylmethyl-4-Oki Seo-1-phenyl-1,3,8-triazaspiro [4.5] dec-3 yl) A acetamide dihydrochloride

[0118]

Embedded image Tetrahedron Let
ters, 1995, 36 , p. 8677, and treated with 1,2-diaminoethane. The resulting resin (2.87 g, 2.5 mmol) was placed in a solid synthetic flask equipped with a glass frit and dried in dry dimethylformamide (50 ml).
Swelled for a minute and the excess solvent was removed by suction. In a flask for separation, (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) in dimethylformamide (30 ml). -To a suspension of acetic acid (4.88 g, 10 mmol) was added 1-hydroxybenzotriazole (1.35 g, 10 mmol) and diisopropylcarbodiimide (
1.26 g, 10 mmol). The mixture was stirred at room temperature for 1 hour and then the above resin was added. Diisopropylamine (1.29 g, 10 mmol) was added and the mixture was shaken on a shaker for 16 hours. The solution was removed by suction, and the resin was washed with dimethylformamide (2 × 50 ml), dimethylsulfoxide (2
× 50 ml), dichloromethane (4 × 50 ml), methanol (3 × 50 ml) and dichloromethane (1 × 50 ml). Dichloromethane / trifluoroacetic acid (
25 ml) was added and the resin was shaken for 30 minutes. The solution was drained and the resin was washed with dichloromethane (2 × 25 ml). The combined filtrate was concentrated in vacuo and the residue was taken up in dichloromethane (50 ml) and saturated NaHC
He was shaken together with the O ₃ solution (25ml). The organic layer was washed with water (20 ml) and brine (20 ml).
) And concentrated in vacuo. The residue was dissolved in tetrahydrofuran and a hydrochloric acid / ether solution was added. The precipitate formed was collected by filtration and dried to give the title compound (0.67 g, 49%) as a powder. LC / MS (method 2): m / e = 472.2 (MH ⁺ ); RT = 4.27 min Theoretical values for C ₂₈ H ₃₃ N ₅ O ₂ , 2HCl, 3H ₂ O: C, 56.19% H, 6.90%; N, 11.70%; Found: C, 56.03%; H, 6.45%; N, 11.34%.

[0119] The following compounds were synthesized using the methods hereinbefore: N- (3- aminopropyl) -2- (8-naphthalen-1-ylmethyl-4-o Kiso-1-phenyl-1,3 , 8-Triazaspiro [4.5] dec-3-yl) acetamide dihydrochloride

[0120]

Embedded image 1,3-Diaminopropyl Wang resin was prepared using the method described above. LC / MS (Method 2): m / e = 486.4 (MH +); RT = 4.27 min _{C 29 H 35 N 5 O 2} , 2HCl, 2.75H 2 O of theory: C, 57. H, 7.64%; N, 11.52%; Found: C; 57.16%; H, 7.72%; N, 11.20%.

Example 17 N- (2-guanidinoethyl) -2- (8-naphthalen-1-ylmethyl-4- oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-3-yl ) Acetamide hydrochloride

[0122]

Embedded image N- (2-aminoethyl) -2- (8) in dimethylformamide (1.5 ml)
-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-3-yl) acetamide dihydrochloride (0.203 g,
0.40 mmol) in a solution of diisopropylethylamine (0.046 g, 3.6).
mmol) and 1-H-pyrazole-1-carboxamidine hydrochloride (0.088 g,
0.60 mmol) was added. The mixture is stirred at room temperature for 1 hour and the same amount of 1-H-
Pyrazole-1-carboxamidine hydrochloride was added. The reaction was stirred for a further 48 hours, water (10 ml) was added and the solution was washed with ether (5 × 10 ml). The aqueous layer was adjusted to pH 1 with dilute hydrochloric acid, washed with dichloromethane (20 ml), adjusted to pH 8 with dilute sodium hydroxide solution and extracted with dichloromethane (3 × 5 ml). The organic layer was concentrated to 5 ml and left in the refrigerator for crystallization. The precipitate was filtered and dried to give the title compound (135mg, 66%) as a powder. LC / MS (Method 2): m / e = 514.4 (MH +); RT = 4.37 min _{C 29 H 35 N 7 O 2} , HCl, 0.7H 2 O of theory: C, 61. H, 6.70%; N, 17.42%; Found: C; 61.95%; H, 6.52%; N, 17.30%.

[0123] Example 18 6-Amino-2- (S) - (2- (S) - {6-Amino-2- [2- (8-naphthoquinone array type 1-ylmethyl-4-oxo-1-phenyl - 1,3,8-Triaza- spiro [4.5] dec -3-yl) -acetylamino] -hexanoylamino } -acetylamino) -hexanoic acid amide

[0124]

Embedded image Link Amide (AM) resin (Novabiochem) (0.200
g, 0.138 mmol) in dimethylformamide / piperidine (80/20) (8
ml) and shaken for 30 minutes at room temperature. The resin was filtered and rinsed with dimethylformamide (8 ml) and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows. : 3 × dimethylformamide / water (90/10) (8 ml
), 3x dimethylformamide (8ml), 3x dichloromethane (8ml). The resin was suspended in dimethylformamide (8 ml) and L-Fmoc-Lys (Boc
) -OH (0.258 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N, N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) were added and the reaction mixture was added. Was shaken for 20 hours at room temperature. The resin was filtered and washed as follows: 3x dimethylformamide / water (90/10) (8ml), 3x dimethylformamide (8ml), 3
X dichloromethane (8 ml). The resin was treated with dimethylformamide / piperidine (8
0/20) (8 ml) and shaken for 30 minutes at room temperature. The resin was filtered and rinsed with dimethylformamide (8 ml) and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows Performed: 3 × dimethylformamide / water (
90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml). The resin was suspended in dimethylformamide (8 ml);
Gly-OH (0.163 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N, N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) are added, and the reaction mixture is added. For 20 hours
Shake at room temperature. The resin was filtered and washed as follows: 3x dimethylformamide / water (90/10) (8ml), 3x dimethylformamide (8ml)
3x dichloromethane (8ml). The resin was suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature. The resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows: × dimethylformamide / water (90
/ 10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (
8 ml). The resin was suspended in dimethylformamide (8 ml); L-Fmoc-
Lys (Boc) -OH (0.258 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N, N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) were added, The reaction was shaken for 20 hours at room temperature. The resin was filtered and washed as follows: 3
X dimethylformamide / water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml). The resin is dimethylformamide /
Suspended in piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature. The resin was filtered and rinsed with dimethylformamide (8 ml) and again suspended in dimethylformamide / piperidine (80/20) (8 ml) and shaken for 30 minutes at room temperature; the resin was washed as follows 3 × dimethylformamide / water (90/10) (8 ml), 3 × dimethylformamide (8 ml), 3
X dichloromethane (8 ml). The resin was suspended in dimethylformamide (8 ml); (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,3
8-Triaza-spiro [4.5] dec-3-yl) -acetic acid (0.269 g, 0.1.
552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552
mmol) and N, N'-diisopropylcarbodiimide (0.071 g, 0.55
2 mmol) was added. The reaction mixture was shaken at room temperature for 20 hours, filtered and washed as follows: 3x dimethylformamide / water (90/10) (8ml); 3x dimethylformamide (8ml); 3x dichloromethane (8ml) . The resin was treated with trifluoroacetic acid / water (95/5) (8 ml) for 2 hours at room temperature. The filtrate was collected and added dropwise to heptane / ether at 0 ° C. to form a white precipitate, which was collected and washed with a heptane / diethyl ether solution. 13.7 mg of the product was isolated. Theory MW = 741, LCMS (method 2) retention time = 3.80 minutes, MH + =
742 is shown.

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] December 2, 1999 (1999.12.2)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image｛Where, R¹ Is phenyl, arylalkyl or thienyl, which is one or more
Halogen, cyano, nitro, trifluoromethyl, C_1-6 Alkyl, hydroxy
Si, C_1-6 Alkoxy or NR⁶ R⁸ (Where R⁶ And R⁸ Is independently hydrogen or
C_1-6 Alkyl), or R¹ Is C_1-6 Archi
R; R^Two Is aminophenyl, C_1-6 Monoalkylaminophenyl, C_1-6 Dialki
L-aminophenyl, cyanophenyl, C_2-6 Alkylphenyl, naphthyl, tet
Lahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoin
Drill, benzothienyl, benzofuranyl, coumarinyl, wherein said group is one or more
Represents multiple halogens, cyano, nitro, trifluoromethyl, C_1-6 Alkyl, ar
Droxy, C_1-6 Alkoxy, C (O) R⁷ (Where R⁷ Is -OH, C_1-6 A
Lucoxy or -NR¹²R¹³Where R¹²And R¹³Is independently hydrogen or C _1-6 Alkyl)) or R^Two Is phenyl, phenoxy, benzodioxinyl or cyanodiphenylmethyl
Any one of these may be one or more of halogen, cyano, nitro,
Trifluoromethyl, C_1-6 Alkyl, hydroxy, C_1-6 Alkoxy, C (O
) R⁷ (Where R⁷ Is -OH, C_1-6 Alkoxy or -NR¹²R¹³And this
Where R¹²And R¹³Is independently hydrogen or C_1-6 Optionally substituted with alkyl)
Where R¹ Is not phenyl and R^Three Is not methyl or hydrogen,
Or R^Four Is hydrogen, acetyl, methyl, hydroxymethyl, ethyl, 2-sia
Not ethyl, propionyl or methoxymethyl; R^Three Is hydrogen, C_1-6 R is alkyl, phenyl, benzyl or acetyl;^Four Is hydrogen or (CH_Two )_m − (CHR⁹ )-(CH_Two )_p -AR¹¹〔here
m and p are independently 0-4;⁹ Is hydrogen, C_1-6 Alkyl, phenyl or
Arylalkyl, R¹¹Is C_1-6 Alkyl, hydroxy, C_1-6 Alkoki
Guanidino, OCH_Three Or NH_Two A C-terminal consisting of
An amino acid residue having a group or 2 to 4 peptidyl residues;¹¹Is the group NR¹⁴ R^FifteenWhere R¹⁴And R^FifteenIs independently hydrogen, C_1-6 Alkyl, (
CH_Two )_q R¹⁶(Where q may be 0-6 and R¹⁶Is C3-C7
Membered cycloalkyl ring, optionally substituted aromatic or heteroaromatic ring, 1 or
Is an aliphatic ring containing a plurality of hetero atoms, an alkoxy or aryloxy group, an amino
Or a guanidino group); A is -CH_Two Or -C = O;
Where R¹¹A is a -C = O group when is an amino acid or a peptidyl residue]
R^Five Is hydrogen or C_1-4 Z is CHR^Ten(Where R^TenIs hydrogen, C_1-6 Alkyl, phenyl or aryl
Or z is C_2-8 Alkylene, C_2-8 Alkenylene
Or C_2-8 N is 1 or 2; or a pharmaceutically acceptable salt thereof.

Embedded image｛Where, R¹ Is phenyl, arylalkyl or thienyl, which is one or more
Halogen, cyano, nitro, trifluoromethyl, C_1-6 Alkyl, hydroxy
Si, C_1-6 Alkoxy or NR⁶ R⁸ (Where R⁶ And R⁸ Is independently hydrogen or
C_1-6 Alkyl), or R¹ Is C_1-6 Archi
R; R^Two Is aminophenyl, C_1-6 Monoalkylaminophenyl, C_1-6 Dialki
L-aminophenyl, cyanophenyl, C_2-6 Alkylphenyl, naphthyl, tet
Lahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoin
Drill, benzothienyl, benzofuranyl, coumarinyl, wherein said group is one or more
Represents multiple halogens, cyano, nitro, trifluoromethyl, C_1-6 Alkyl, ar
Droxy, C_1-6 Alkoxy, C (O) R⁷ (Where R⁷ Is -OH, C_1-6 A
Lucoxy or -NR¹²R¹³Where R¹²And R¹³Is independently hydrogen or C _1-6 Alkyl)) or R^Two Is phenyl, phenoxy, benzodioxinyl or cyanodiphenylmethyl
Any one of these may be one or more of halogen, cyano, nitro,
Trifluoromethyl, C_1-6 Alkyl, hydroxy, C_1-6 Alkoxy, C (O
) R⁷ (Where R⁷ Is -OH, C_1-6 Alkoxy or -NR¹²R¹³And this
Where R¹²And R¹³Is independently hydrogen or C_1-6 Optionally substituted with alkyl)
Where R¹ Is not phenyl and R^Three Is not methyl or hydrogen,
Or R^Four Is hydrogen, acetyl, methyl, hydroxymethyl, ethyl, 2-sia
Not ethyl, propionyl or methoxymethyl; R^Three Is hydrogen, C_1-6 R is alkyl, phenyl, benzyl or acetyl;^Four Is hydrogen or (CH_Two )_m − (CHR⁹ )-(CH_Two )_p -AR¹¹〔here
m and p are independently 0-4;⁹ Is hydrogen, C_1-6 Alkyl, phenyl or
Arylalkyl, R¹¹Is C_1-6 Alkyl, -OH, amino acid residue, NR ¹⁴ R^FifteenOr C_1-6 Alkoxy, where R¹⁴And R^FifteenIs independently hydrogen or C _1-6 Alkyl and A is -CH_Two Or -C = O; provided that R¹¹But
A is a -C = O group when it is a amino acid residue];^Five Is hydrogen or C_1-4 Z is CHR^Ten(Where R^TenIs hydrogen, C_1-6 Alkyl, phenyl or aryl
Or z is C_2-8 Alkylene, C_2-8 Alkenylene
Or C_2-8 N is 1 or 2; or a pharmaceutically acceptable salt thereof.

Embedded image Wherein R ¹ is phenyl, arylalkyl or thienyl, which is one or more of halogen, cyano, nitro, trifluoromethyl, C _1-6 alkyl, hydroxy, C _1-6 alkoxy or NR ⁶ R ⁸ Wherein R ⁶ and R ⁸ are independently hydrogen or C _1-6 alkyl, or R ¹ is C _1-6 alkyl; R ² is phenyl, phenoxy, benzo dioxinyl, cyano diphenylmethyl, aminophenyl, C _1-6 monoalkylamino phenyl, C _1-6 dialkylamino, phenyl, naphthyl, tetrahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, at coumarinyl Wherein said group is one or more of halogen, cyano, nitro, trifluoromethyl, C _1-6 Alkyl, hydroxy, C _1-6 alkoxy, C (O) R ^7, wherein R ⁷ is —OH, C _1-6 alkoxy or —NR ¹² R ¹³ , wherein R ¹² and R ¹³ are independent and may be substituted by hydrogen or C _1-6 alkyl) and; R ³ is hydrogen, C _1-6 alkyl, phenyl, benzyl or acetyl; R ⁴ is hydrogen or (CH _{2) m} - ( _{^{CHR 9) - (CH 2)}} p -AR 11 [wherein m and p are 0-4 independently, R ⁹ is hydrogen, C _1-6 alkyl, phenyl or arylalkyl, R ¹¹ is C _1-6 alkyl, hydroxy, C _1-6 alkoxy, guanidino, an amino acid residue having a C-terminal group consisting of either OCH ₃ or NH ₂ or 2 to 4 peptidyl residues; ¹¹ may be a group NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 alkyl, (
CH _{2) q} R ¹⁶ (wherein, q may be from 0 to 6, and R ¹⁶ is C3-C7
A cycloalkyl ring, optionally substituted aromatic or heteroaromatic ring, aliphatic ring containing one or more heteroatoms, alkoxy or aryloxy group, amino or guanidino group); be -CH ₂ or -C = O;
However, when R ¹¹ is an amino acid or a peptidyl residue, A is a —C ＝ O group.
R ⁵ is hydrogen or C _1-4 alkyl; z is CHR ¹⁰ where R ¹⁰ is hydrogen, C _1-6 alkyl, phenyl or arylalkyl, or z is C _{2 -8} alkylene, C _2-8 alkenylene or C _2-8 alkynylene; wherein n is 1 or 2｝ or a pharmaceutically acceptable salt thereof, comprising migraine, non-insulin dependent diabetes mellitus For the treatment of (type II diabetes), sepsis, inflammation, incontinence, vasomotor disorders, especially peripheral vasomotor actions known as hot flashes or hot flushes, and / or from withdrawal symptoms, especially drug abuse. Use to reduce withdrawal symptoms that occur during withdrawal.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/06 A61P 25/06 25/30 25/30 29/00 29/00 31/04 31/04 43 / 00 43/00 111 111 C07D 487/10 C07D 487/10 (31) Priority claim number PA 1998 00729 (32) Priority date May 26, 1998 (1998. 5.26) (33) Priority claim Country Denmark (DK) (31) Priority claim number PA 1998 00927 (32) Priority date July 10, 1998 (Jul. 10, 1998) (33) Priority claim country Denmark (DK) (31) Priority Claim number PA 1999 00111 (32) Priority date January 29, 1999 (Jan. 29, 1999) (33) Priority claiming country Denmark (DK) (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE , AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW , MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Holberg, Rolf Denmark, Dako-3490 Kvist Gard, Nibobai 6 (72) Inventor Tomsen, Christian Denmark, Deco-4671 Streby, Kistbeien 321 F term (reference) 4C050 AA04 BB05 CC04 EE03 FF01 GG03 HH02 HH04 4C065 AA16 BB06 CC01 DD03 EE02 HH09 JJ01 KK09 LL04 PP03 PP07 PP09 4C086 AA01 ZAB ZAA ZAB ZAA ZC42

Claims (21)

[Claims] 1. Use of a small organic compound that acts as a ligand for an opioid receptor, comprising migraine, non-insulin dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence, vasomotor disorders, especially hot flashes flush) or hot flush (
Pharmaceutical compositions for the treatment of diseases selected from peripheral vasomotor effects known as hot flash) and / or for reducing withdrawal symptoms, especially withdrawal symptoms occurring during withdrawal from substance abuse. Use for the manufacture of things. 2. Use of a small organic compound acting as a ligand of a nociceptin receptor having a molecular weight of 1000 or less, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating vasomotor disorders. The use according to claim 1. 3. Use of a small organic compound acting as a ligand for a nociceptin receptor having a molecular weight of 600 or less, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating vasomotor disorders. The use according to any one of claims 1-2. 4. Use of a small organic compound acting as a ligand of a nociceptin receptor having 5 or less amide bonds, or a pharmaceutically acceptable salt thereof,
Use according to any one of claims 1 to 3 for the manufacture of a pharmaceutical composition for the treatment of a vasomotor disorder. 5. Use of a small organic compound having no amide bond and acting as a ligand of a nociceptin receptor, or a pharmaceutically acceptable salt thereof, for producing a pharmaceutical composition for treating vasomotor neuropathy. Use according to any one of claims 1 to 3 for the use. 6. 7. A compound comprising a triaza-spiro compound, which acts as a ligand for the nociceptin receptor, or a pharmaceutically acceptable salt thereof.
Use according to any one of the preceding claims, for the manufacture of a pharmaceutical composition for the treatment of vasomotor disorders. 8. Use of a small organic compound or a pharmaceutically acceptable salt thereof acting as a ligand of the nociceptin receptor, having an IC ₅₀ of 1 μM or less, which is a pharmaceutical composition for the treatment of vasomotor neuropathy. Use according to any one of claims 1 to 5 for the manufacture. 9. A compound of the general formula I｛Where, R¹ Is phenyl, arylalkyl or thienyl, which is one or more
Halogen, cyano, nitro, trifluoromethyl, C_1-6 Alkyl, hydroxy
Si, C_1-6 Alkoxy or NR⁶ R⁸ (Where R⁶ And R⁸ Is independently hydrogen or
C_1-6 Alkyl), or R¹ Is C_1-6 Archi
R; R^Two Is aminophenyl, C_1-6 Monoalkylaminophenyl, C_1-6 Dialki
L-aminophenyl, cyanophenyl, C_2-6 Alkylphenyl, naphthyl, tet
Lahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoin
Drill, benzothienyl, benzofuranyl, coumarinyl, wherein said group is one or more
Represents multiple halogens, cyano, nitro, trifluoromethyl, C_1-6 Alkyl, ar
Droxy, C_1-6 Alkoxy, C (O) R⁷ (Where R⁷ Is -OH, C_1-6 A
Lucoxy or -NR¹²R¹³Where R¹²And R¹³Is independently hydrogen or C _1-6 Alkyl)) or R^Two Is phenyl, phenoxy, benzodioxinyl or cyanodiphenylmethyl
Any one of these may be one or more of halogen, cyano, nitro,
Trifluoromethyl, C_1-6 Alkyl, hydroxy, C_1-6 Alkoxy, C (O
) R⁷ (Where R⁷ Is -OH, C_1-6 Alkoxy or -NR¹²R¹³And this
Where R¹²And R¹³Is independently hydrogen or C_1-6 Optionally substituted with alkyl)
Where R¹ Is not phenyl and R^Three Is not methyl or hydrogen,
Or R^Four Is hydrogen, acetyl, methyl, hydroxymethyl, ethyl, 2-sia
Not ethyl, propionyl or methoxymethyl; R^Three Is hydrogen, C_1-6 R is alkyl, phenyl, benzyl or acetyl;^Four Is hydrogen or (CH_Two )_m − (CHR⁹ )-(CH_Two )_p -AR¹¹〔here
m and p are independently 0-4;⁹ Is hydrogen, C_1-6 Alkyl, phenyl or
Arylalkyl, R¹¹Is C_1-6 Alkyl, hydroxy, C_1-6 Alkoki
Guanidino, OCH_Three Or NH_Two A C-terminal consisting of
An amino acid residue having a group or 2 to 4 peptidyl residues;¹¹Is the group NR¹⁴ R^FifteenWhere R¹⁴And R^FifteenIs independently hydrogen, C_1-6 Alkyl, (
CH_Two )_q R¹⁶(Where q may be 0-6 and R¹⁶Is C3-C7
Membered cycloalkyl ring, optionally substituted aromatic or heteroaromatic ring, 1 or
Is an aliphatic ring containing a plurality of hetero atoms, an alkoxy or aryloxy group, an amino
Or a guanidino group); A is -CH_Two Or -C = O;
Where R¹¹A is a -C = O group when is an amino acid or a peptidyl residue]
R^Five Is hydrogen or C_1-4 Z is CHR^Ten(Where R^TenIs hydrogen, C_1-6 Alkyl, phenyl or aryl
Or z is C_2-8 Alkylene, C_2-8 Alkenylene
Or C_2-8 N is 1 or 2; or a pharmaceutically acceptable salt thereof. 9. A compound of the general formula｛Where, R¹ Is phenyl, arylalkyl or thienyl, which is one or more
Halogen, cyano, nitro, trifluoromethyl, C_1-6 Alkyl, hydroxy
Si, C_1-6 Alkoxy or NR⁶ R⁸ (Where R⁶ And R⁸ Is independently hydrogen or
C_1-6 Alkyl), or R¹ Is C_1-6 Archi
R; R^Two Is aminophenyl, C_1-6 Monoalkylaminophenyl, C_1-6 Dialki
L-aminophenyl, cyanophenyl, C_2-6 Alkylphenyl, naphthyl, tet
Lahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoin
Drill, benzothienyl, benzofuranyl, coumarinyl, wherein said group is one or more
Represents multiple halogens, cyano, nitro, trifluoromethyl, C_1-6 Alkyl, ar
Droxy, C_1-6 Alkoxy, C (O) R⁷ (Where R⁷ Is -OH, C_1-6 A
Lucoxy or -NR¹²R¹³Where R¹²And R¹³Is independently hydrogen or C _1-6 Alkyl)) or R^Two Is phenyl, phenoxy, benzodioxinyl or cyanodiphenylmethyl
Any one of these may be one or more of halogen, cyano, nitro,
Trifluoromethyl, C_1-6 Alkyl, hydroxy, C_1-6 Alkoxy, C (O
) R⁷ (Where R⁷ Is -OH, C_1-6 Alkoxy or -NR¹²R¹³And this
Where R¹²And R¹³Is independently hydrogen or C_1-6 Optionally substituted with alkyl)
Where R¹ Is not phenyl and R^Three Is not methyl or hydrogen,
Or R^Four Is hydrogen, acetyl, methyl, hydroxymethyl, ethyl, 2-sia
Not ethyl, propionyl or methoxymethyl; R^Three Is hydrogen, C_1-6 R is alkyl, phenyl, benzyl or acetyl;^Four Is hydrogen or (CH_Two )_m − (CHR⁹ )-(CH_Two )_p -AR¹¹〔here
m and p are independently 0-4;⁹ Is hydrogen, C_1-6 Alkyl, phenyl or
Arylalkyl, R¹¹Is C_1-6 Alkyl, -OH, amino acid residue, NR ¹⁴ R^FifteenOr C_1-6 Alkoxy, where R¹⁴And R^FifteenIs independently hydrogen or C _1-6 Alkyl and A is -CH_Two Or -C = O; provided that R¹¹But
A is a -C = O group when it is a amino acid residue];^Five Is hydrogen or C_1-4 Z is CHR^Ten(Where R^TenIs hydrogen, C_1-6 Alkyl, phenyl or aryl
Or z is C_2-8 Alkylene, C_2-8 Alkenylene
Or C_2-8 N is 1 or 2; or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 8, wherein R ¹ is C _1-6 alkyl, phenyl, arylalkyl or thienyl. 11. R ² is aminophenyl, C _1-6 monoalkylamino phenyl, C _1-6 dialkylamino, phenyl, cyanophenyl, C _2-6 alkyl phenyl, naphthyl, tetrahydronaphthyl, anthryl, furanyl, indanyl, indolyl , Isoindolyl, benzothienyl, benzofuranyl, coumarinyl, wherein said group is one or more of fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C ( O) R ⁷ (wherein, R ⁷ is -OH, a C _1-6 alkoxy or -NR ¹² R ^13, where R ¹² and R ¹³ are independently hydrogen or C _1-6 alkyl) May be substituted or R ² is phenyl, phenoxy, benzodioxinyl or cyanodiphenylmethyl; Has one or more fluorine, chlorine, bromine, cyano,
Nitro, trifluoromethyl, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C (O) R ⁷ (where R ⁷ is —OH, C _1-6 alkoxy or —NR ¹² R ¹³ ; Wherein R ¹² and R ¹³ are independently hydrogen or C _1-6 alkyl, provided that R ¹ is not phenyl, R ³ is not methyl or hydrogen, or R ⁴ is hydrogen, acetyl, methyl, hydroxymethyl, ethyl, 2
A compound according to any one of claims 8 to 10 or a pharmaceutically acceptable salt thereof, which is not cyanoethyl, propionyl or methoxymethyl. 12. R^Four Is hydrogen or (CH_Two )_m − (CHR⁹ )-(CH_Two ) _p -AR¹¹(Where m and p are independently 0-4 and R⁹ Is hydrogen, C_{1- 6} Alkyl, phenyl or arylalkyl;¹¹Is -OH, NR¹⁴R^Fifteen Or C_1-6 Alkoxy, where R¹⁴And R^FifteenIs hydrogen or C_1-6 With alkyl
And A is C = O).
Or a pharmaceutically acceptable salt thereof. 13. (4-oxo-8-phenethyl-1-phenyl-1,3,13.
8-Triaza-spiro [4.5] dec-3-yl) -acetic acid methyl ester, {8- [2- (1,3-dioxo-1,3-dihydro-isoindole-2-
Yl) -ethyl] -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl} -acetic acid methyl ester, [8- (3-cyano-3,3 -Diphenyl-propyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [8- (4-nitro-benzyl)- 4-oxo-1-phenyl-1,3,8-
Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [4-oxo-1-phenyl-8- (3-phenyl-propyl) -1,3,8
-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [4-oxo-8- (3-phenoxy-propyl) -1-phenyl-1,3,
8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [4-oxo-8- (4-phenoxy-butyl) -1-phenyl-1,3,8
-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [8- (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl)
-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] deca-
3-yl] -acetic acid methyl ester, {8- [5- (1,3-dioxo-1,3-dihydro-isoindole-2-
Yl) -pentyl] -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl} -acetic acid methyl ester, (8-naphthalen-1-ylmethyl-4-) Oxo-1-phenyl-1,3,8
-Triaza-spiro [4.5] dec-3-yl) -acetic acid methyl ester, {8- [2- (4-fluoro-phenoxy) -ethyl] -4-oxo-1-phenyl-1,3,8 -Triaza-spiro [4.5] dec-3-yl} -acetic acid methyl ester, [8- (6,7-dimethoxy-2-oxo-2H-chromen-4-ylmethyl) -4-oxo-1-phenyl -1,3,8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [8- (2-naphthalen-1-yl-methyl) -4-oxo-1-phenyl-
1,3,8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [8- (3-cyano-benzyl) -4-oxo-1-phenyl-1,3,8-
Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, 3- (3-methoxycarbonylmethyl-4-oxo-1-phenyl-1,3,3
8-triaza-spiro [4.5] dec-8-ylmethyl) -benzoic acid methyl ester, [8- (4-bromo-benzyl) -4-oxo-1-phenyl-1,3,8-
Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [8- (3,4-dichloro-benzyl) -4-oxo-1-phenyl-1,3
, 8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, (8-anthracen-9-ylmethyl-4-oxo-1-phenyl-1,3,3
8-Triaza-spiro [4.5] dec-3-yl) -acetic acid methyl ester, 5-guanidino-2- (S)-[2- (8-naphthalen-1-ylmethyl-4)
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] pentanoic acid methyl ester, N- (2-guanidino-ethyl) -2- (8-naphthalen-1-ylmethyl-
4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] deca-3
-Yl) -acetamide, 3- (7-amino-heptyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one, 3- (1H-Imidazol-4-yl) -2- (S)-[2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] Deca-3-yl) -acetylamino] -propionamide, 5-guanidino-2- (S)-[2- (8-naphthalen-1-ylmethyl-4)
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] -pentanoic acid amide, 5-guanidino-2- (R)-[2- (8-naphthalen-1-ylmethyl-4)
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] -pentanoic acid amide, N- (3-guanidino-propyl) 2- (8-naphthalen-1-ylmethyl-
4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] deca-3
-Yl) -acetamide, 3- (5-amino-pentyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-4-one, N- (3-Amino-propyl) -2- (8-naphthalen-1-ylmethyl-4
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetamide, N- (2-amino-ethyl) -2- (8-naphthalen-1-ylmethyl-4-
Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetamide, N- [7- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl −
1,3,8-triaza-spiro [4.5] dec-3-yl) -heptyl] -guanidine, 3-ethyl-8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-
Triaza-spiro [4.5] decan-4-one, 2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3
, 8-Triaza-spiro [4.5] dec-3-yl) -N- (tetrahydro-furan-2-ylmethyl) acetamide, 2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl- 1,3
, 8-Triaza-spiro [4.5] dec-3-yl) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl] -acetamide, 6-amino-2- (S)- [2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetylamino] -hexanoic acid amide, N -Carbamoylmethyl-2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl)
-Acetamide, 2- (S)-[2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl)- Acetylamino] -phenyl-acetamide, 6-amino-2- (S)-(2- {6-amino-2- (S)-[2- (8-naphthalen-1-ylmethyl-4-oxo-1-) Phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetylamino] -hexanoylamino} -acetylamino) -hexanoic acid amide, 5-guanidino-2- (S)- {2- [2- (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetylamino] -acetylamino ｝ -Pentanoic acid amide, 5-gua Nidino-2- (S)-(2- {2- [2- (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5]
] Dec-3-yl) -acetylamino] -acetylamino｝ -acetylamino)
-Pentanoic acid amide, (4-oxo-8-phenethyl-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl) -acetic acid methyl ester, [8- (2-naphthalene -1-yl-ethyl) -4-oxo-1-phenyl-
1,3,8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [8- (4-bromo-benzyl) -4-oxo-1-phenyl-1,3,8-
Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, [8- (3,4-dichloro-benzyl) -4-oxo-1-phenyl-1,3
, 8-Triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester, 5-guanidino-2- (S)-[2- (8-naphthalen-1-ylmethyl-4)
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] -pentanoic acid amide, 5-guanidino-2- (R)-[2- (8-naphthalen-1-ylmethyl-4)
-Oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-
Yl) -acetylamino] -pentanoic acid amide or 3- (7-amino-heptyl) -8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-4 The compound according to any one of claims 8 to 12, wherein the compound is selected from -one. 14. A medicament comprising as active ingredient a compound according to any one of claims 8 to 13 together with a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent. Composition. 15. A method as claimed in any one of claims 8 to 13 which is suitable for use in the treatment of migraine, non-insulin dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence and / or vasomotor disorders. A pharmaceutical composition comprising any of the compounds described in 1 to 4 together with a pharmaceutically acceptable carrier or diluent. 16. An oral dosage unit form or a form suitable for oral, nasal, transdermal, pulmonary, parenteral dosage units comprising from 0.1 to about 1 per patient per day.
The pharmaceutical composition according to claim 14 or 15, comprising 000 mg. 17. The method according to claim 8, for the manufacture of a medicament for the treatment of migraine, non-insulin-dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence and / or vasomotor disorders. Use of the compound according to claim 1. 18. Use of a compound according to any one of claims 8 to 13 for the manufacture of a medicament for the treatment of vasomotor disorders, in particular hot flashes. 19. A method for treating hot flashes in a subject in need of treatment, the method comprising:
14. A method comprising administering to said subject some of the compounds of any of claims 8 to 13 that are effective in reducing such illness. 20. A method for treating hot flashes in a subject in need of treatment,
14. A method comprising administering some of the compounds of claims 8-13 to the subject in the form of a pharmaceutical composition thereof, wherein the compounds are effective in reducing such illness, wherein the agent is pharmaceutically acceptable. Carrier or diluent is present together). 21. A compound of the general formula I Wherein R ¹ is phenyl, arylalkyl or thienyl, which is one or more of halogen, cyano, nitro, trifluoromethyl, C _1-6 alkyl, hydroxy, C _1-6 alkoxy or NR ⁶ R ⁸ Wherein R ⁶ and R ⁸ are independently hydrogen or C _1-6 alkyl, or R ¹ is C _1-6 alkyl; R ² is phenyl, phenoxy, benzo dioxinyl, cyano diphenylmethyl, aminophenyl, C _1-6 monoalkylamino phenyl, C _1-6 dialkylamino, phenyl, naphthyl, tetrahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, at coumarinyl Wherein said group is one or more of halogen, cyano, nitro, trifluoromethyl, C _1-6 Alkyl, hydroxy, C _1-6 alkoxy, C (O) R ^7, wherein R ⁷ is —OH, C _1-6 alkoxy or —NR ¹² R ¹³ , wherein R ¹² and R ¹³ are independent and may be substituted by hydrogen or C _1-6 alkyl) and; R ³ is hydrogen, C _1-6 alkyl, phenyl, benzyl or acetyl; R ⁴ is hydrogen or (CH _{2) m} - ( _{^{CHR 9) - (CH 2)}} p -AR 11 [wherein m and p are 0-4 independently, R ⁹ is hydrogen, C _1-6 alkyl, phenyl or arylalkyl, R ¹¹ is C _1-6 alkyl, hydroxy, C _1-6 alkoxy, guanidino, an amino acid residue having a C-terminal group consisting of either OCH ₃ or NH ₂ or 2 to 4 peptidyl residues; ¹¹ may be a group NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 alkyl, (
CH _{2) q} R ¹⁶ (wherein, q may be from 0 to 6, and R ¹⁶ is C3-C7
A cycloalkyl ring, optionally substituted aromatic or heteroaromatic ring, aliphatic ring containing one or more heteroatoms, alkoxy or aryloxy group, amino or guanidino group); be -CH ₂ or -C = O;
However, when R ¹¹ is an amino acid or a peptidyl residue, A is a —C ＝ O group.
R ⁵ is hydrogen or C _1-4 alkyl; z is CHR ¹⁰ where R ¹⁰ is hydrogen, C _1-6 alkyl, phenyl or arylalkyl, or z is C _{2 -8} alkylene, C _2-8 alkenylene or C _2-8 alkynylene; wherein n is 1 or 2｝ or a pharmaceutically acceptable salt thereof, comprising migraine, non-insulin dependent diabetes mellitus For the treatment of (type II diabetes), sepsis, inflammation, incontinence, vasomotor disorders, especially peripheral vasomotor actions known as hot flashes or hot flushes, and / or from withdrawal symptoms, especially drug abuse. Use to reduce withdrawal symptoms that occur during withdrawal.