CN1413206A - Non peptide tachykinin receptor antagonists - Google Patents
Non peptide tachykinin receptor antagonists Download PDFInfo
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- CN1413206A CN1413206A CN00817549A CN00817549A CN1413206A CN 1413206 A CN1413206 A CN 1413206A CN 00817549 A CN00817549 A CN 00817549A CN 00817549 A CN00817549 A CN 00817549A CN 1413206 A CN1413206 A CN 1413206A
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Abstract
Compounds of Formula (I) are specific tachykinin receptor antagonists where R, m, X, R1, R2, n, Y, R3, R4, R5, and R6 are as described in the specification. The compounds are useful agents for treating conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth.
Description
Background technology of the present invention
The Mammals tachykinin is shared common C-end sequence Phe-X-G1y-Leu-Met-NH
2The little peptide (Nakanishi S., Physiol Rev., 67:117,1987) of gang.Very definite now, Substance P, neurokinin A (NKA) and neurokinin B (NKB) are distributed in periphery and central nervous system (CNS) widely, and wherein they appear to be called NK at least three kinds
1, NK
2And NK
3Acceptor type interaction (GuardS. waits the people, Neurosci.Int., 18:149,1991) is arranged.Substance P shows for NK
1The affinity that acceptor is the highest, and NKA and NKB preferentially respectively with NK
2And NK
3Receptors bind.All three kinds of acceptors are cloned and are checked order, and are shown as ' super family (superfamily) ' the acceptor member (Nakanishi S., Annu.Rev.Neurosci., 14:123,1991) that G albumen connects.
Since 1991, the report (IDrugs, Vol.1, No.1, p.73-91,1998) of many high affinity non-peptide tachykinin receptor antagonists has been arranged.
There have been a large amount of evidences to show that the neuropeptide of tachykinin and various biology activity comprise pain conduction, neuronal excitation, salivation, vascularization, vasorelaxation, smooth muscle contraction, bronchoconstriction, immune activation and neuron inflammation-related (Pernow B, Pharmacol.Rev.35:85,1983).
Therefore, can be at NK
1The compound of the antagonistic substance P of acceptor place effect can be effective to treatment or prevent various CNS obstacles to comprise pain (struvite, surgery with neuropathic), anxiety, fear, dysthymia disorders, be accompanied by the severe dysthymia disorders of anxiety, schizophrenia, neurodynia, anxiety, sexual dysfunction, amphicheirality's mental disorder, dyskinesia, cognitive disorder and habituation obstacle; Chronic obstructive pulmonary disease (COPD) and psoriasis; Gastrointestinal disorders comprises colitis, Crohn disease, irritable bowel syndrome and satiety; Transformation reactions is eczema and rhinitis for example; Vascular disorder is angina (angina) and migraine for example; The obstacle of europathology comprises scleroderma and vomiting.
The present invention's general introduction
The invention provides tachykinin receptor antagonists; These compounds are proved to be high selectivity and functional tachykinin receptor antagonists.These compounds are at C ● the replacement at carbon place is unique.
Compound of the present invention is the compound of formula (I):
Or its pharmacologically acceptable salts, R wherein, M, X, R1, R2, n, Y, R3, R4, R5 and R6 are as described below:
● and ▲ all steric isomers of expression; R is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Quinolyl
Isoquinolyl
Naphthyl,
Benzofuryl,
Benzo [1,3] dioxole
Benzothienyl or,
Benzimidazolyl-, they each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3Or
OCF
3；
M is the integer of 1-3;
X is NR8 or NHCONH, and wherein R8 is the alkyl of H or 1-3 carbon atom; R1 is (CH
2)
pY wherein p be 0 to 3 and Y be OH, OCH
3, F, CF
3, CO
2H, N (CH
3)
2, NHCH
3, NH
2, COCF
3, COCH
3Or NO
2
N is 1 to 2 integer;
R2 is naphthyl or indyl, and it is unsubstituted or is replaced by following group N-: hydroxyl, alkyl, formyl radical, CH
2OH, CH
2N (CH
3)
2,
Or
Z is NR3 or O, and wherein R3 is H or C1-C4 alkyl;
R4 and R5 independently are hydrogen separately, or (CH
2)
pR7 is wherein:
P is 1 to 3 integer, and
R7 is H, CH
3, CN, OH, OCH
3, CO
2CH
3, NH
2, NHCH
3, or N (CH
3)
2
R6 is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Pyrryl,
Pyrazolyl,
Imidazolyl,
Quinolyl,
Isoquinolyl,
Naphthyl,
Indyl,
Benzofuryl,
Benzothienyl (benzothiophenyl),
Benzimidazolyl-, or
Benzoxazolyl, wherein aforementioned every each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3，
NO
2，
N(CH
3)
2，
OCF
3，
SONH
2，
NH
2，
CONH
2，
CO
2CH
3Or
CO
2H，
Or R6 is:
The straight chained alkyl of 1 to 3 carbon,
The branched-chain alkyl of 3 to 8 carbon,
The cycloalkyl of 5 to 8 carbon or
Heterocyclylalkyl, each can by at the most one or two be selected from following substituting group and replace:
OH，
CO
2H，
N(CH
3)
2，
NHCH
3With
CH
3Or
R5 and R6 when connecting by a key, can form a ring.
Preferred compound of the present invention is these compounds with following formula (I), wherein:
● be R or S, and ▲ be R or S;
-R is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Quinolyl
Isoquinolyl
Benzofuryl,
Benzo [1,3] dioxole
Benzothienyl or
Benzimidazolyl-, they each be unsubstituted, or by following base
Single group-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3Or
OCF
3；
M is 1 to 3 integer;
X be NR8 or NHCONH wherein R8 be the alkyl of H or 1-3 carbon atom;
R1 is (CH
2)
pY wherein p is that 0-3 and Y are OH, F, CF
3, OCH
3, CO
2H, N (CH
3)
2, NHCH
3, NH
2, COCF
3, COCH
3Or NO
2
N is 1 to 2 integer;
R2 is naphthyl or indyl, and it is unsubstituted or is replaced by following group N-: hydroxyl, and alkyl,
Formyl radical, CH
2OH, CH
2N (CH
3)
2,
Or
Z is NR3 or O, and wherein R3 is H or CH
3
R4 and R5 independently are hydrogen separately, CH
3Or CH
2OH;
R6 is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Pyrryl,
Cyclohexyl or
Benzimidazolyl-,
Wherein aforementioned each group is unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3，
NO
2, or
N(CH
3)
2。
Preferred compound of the present invention is these compounds with following formula (I), wherein:
● be R or S, and ▲ be R or S; R is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Benzofuryl,
Benzo [1,3] dioxole
Benzothienyl or,
Benzimidazolyl-, they each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3Or
OCF
3；
M is the integer of 1-3;
X is NR8 or NHCONH, and wherein R8 is the alkyl of H or 1-3 carbon atom; R1 is (CH
2)
pY wherein p be 0 to 3 and Y be OH, OCH
3, F, CF
3, CO
2H, N (CH
3)
2, NHCH
3, NH
2, COCF
3, COCH
3Or NO
2
N is 1 to 2 integer;
R2 is an indyl unsubstituted or that replaced by alkyl or formyl radical N-;
Z is NR3 or O, and wherein R3 is H or CH
3
R4 and R5 independently are hydrogen, CH separately
3Or CH
2OH;
R6 is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Pyrryl,
Cyclohexyl, or
Benzimidazolyl-, wherein each is unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3，
NO
2, or
N(CH
3)
2。
Most preferred compound of the present invention is:
2-[(cumarone-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methoxymethyl-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)];
2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide (S, S);
2-[(cumarone-2-ylmethyl)-amino]-2-methylol-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)];
2-(3-cumarone-2-ylmethyl-urea groups)-2-methylol-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)];
2-(3-cumarone-2-ylmethyl-urea groups)-3-(1H-indol-3-yl)-2-methoxymethyl-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)];
(R)-C-[(cumarone-2-ylmethyl)-amino]-dimethylamino-C-(1-methylol-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl)-propionic acid amide;
(R)-C-[(cumarone-2-ylmethyl)-amino]-dimethylamino-C-(1-dimethylaminomethyl-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl) propionic acid amide.
The invention provides a kind of compound of general formula I and pharmaceutical preparation of pharmaceutically acceptable carrier, thinner or mixed with excipients of comprising in addition.
The mammiferous NK that the present invention also provides a kind of antagonism to treat
1The method of acceptor comprises the formula I compound that gives the Mammals significant quantity.
The present invention further provides a kind of and is used for the treatment of or prevents various CNS obstacles to comprise pain (struvite, surgery with neuropathic), anxiety, fear, dysthymia disorders, be accompanied by the severe dysthymia disorders of anxiety, schizophrenia, neurodynia, nervous, sexual dysfunction, amphicheirality's mental disorder, dyskinesia, cognitive disorder, fat and habituation obstacle; Struvite disease is sacroiliitis for example, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; Gastrointestinal disorders comprises colitis, Crohn disease, irritable bowel syndrome and satiety; Transformation reactions is eczema and rhinitis for example; Vascular disorder is angina and migraine for example; The obstacle of europathology comprises the method for scleroderma and vomiting, comprises the formula I compound of the Mammals significant quantity that needs treatment.
Compound of the present invention, NK
1Receptor antagonist, the medicament that can be used as anti-angiogenic formation, the present invention further provides a kind of treatment or the prevention situation relevant with unusual neovascularization, rheumatoid arthritis for example, the method of atherosclerosis and growth of tumour cell, this method comprise the formula I compound of the Mammals significant quantity that needs treatment.
The present invention further is provided at NK under the situation of for example ulcerative colitis and Crohn disease
1The medicament of acceptor in-vivo imaging.
The compound that the present invention further provides claim 1 is used for for example pain (struvite, surgery with neuropathic) of prevention or treatment CNS obstacle, anxiety in preparation, fear, dysthymia disorders is accompanied by the severe dysthymia disorders of anxiety, schizophrenia, neurodynia, anxiety, sexual dysfunction, amphicheirality's mental disorder, dyskinesia, cognitive disorder, fat and habituation obstacle; Struvite disease is sacroiliitis for example, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; Gastrointestinal disorders comprises colitis, Crohn disease, irritable bowel syndrome and satiety; Transformation reactions is eczema and rhinitis for example; Vascular disorder is angina and migraine for example; The obstacle of europathology comprises scleroderma and vomiting; The situation relevant with unusual neovascularization be the purposes in the medicine of rheumatoid arthritis, atherosclerosis and growth of tumour cell for example.
The invention still further relates to the method for a kind of preparation ((S)-2-benzylidene amino)-3-(1H-indol-3-yl)-methyl propionate, this method comprises that the reaction of (S)-tryptophan methyl ester and phenyl aldehyde reclaims target product then.
The present invention also further relates to a kind of method for preparing alpha-alpha-dimethyl amino methyl tryptophan methyl ester, wherein, obtain racemic alpha-alpha-dimethyl amino methyl tryptophan methyl ester with ((S)-2-benzal-amino)-3-(1H-indol-3-yl)-methyl propionate and the reaction of 1-dimethylaminomethyl benzotriazole.
The invention also discloses a kind of method, wherein the racemize methyl esters that obtains is separated into (R)-and (S)-enantiomorph.
Another embodiment of the present invention is 2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide (S, S) preparation is wherein with (S)-2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-propionic acid is two-hydrochloride with (S)-reaction of α-Jia Jibianji amine.
Further embodiment of the present invention is (R)-C-[(cumarone-2-ylmethyl)-amino]-preparation of dimethylamino-C-(1-methylol-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl)-propionic acid amide, wherein with 2-[(cumarone-2-ylmethyl)-amino]-(S is S) with hexamethyldisilane base amination potassium and formaldehyde reaction for 2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide.
The invention still further relates to (R)-C-[(cumarone-2-ylmethyl)-amino]-preparation of dimethylamino-C-(1-dimethylaminomethyl-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl)-propionic acid amide, wherein with 2-[(cumarone-2-ylmethyl)-amino]-(S is S) with hexamethyldisilane base amination lithium and Eschenmoser reactant salt for 2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide.
Brief description of drawings
Fig. 1 shows the evaluation of the compound of embodiment 2 in carrageenin-inductive allergy model of cavy.
Detailed description of the invention
The invention provides tachykinin receptor antagonists; These compounds are proved to be high selectivity and functional tachykinin receptor antagonists. These compounds are at C ● the replacement at carbon place is unique.
Compound of the present invention is these compounds of formula (I):
Or the acceptable salt of its pharmacy, R wherein, M, X, R1, R2, n, Y, R3, R4, R5 and R6 are as described below:
● and ▲ all stereoisomers of expression; R is phenyl,
Pyridine radicals,
Thienyl,
Furyl,
Quinolyl
Isoquinolyl
Naphthyl,
Benzofuranyl,
Benzo [1,3] dioxole
Benzothienyl or,
Benzimidazolyl, they each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl,
Halogen,
CF
3Or
OCF
3；
M is the integer of 1-3;
X is NR8 or NHCONH, and wherein R8 is the alkyl of H or 1-3 carbon atom; R1 is (CH2)
pY wherein p be 0 to 3 and Y be OH, OCH3，F，CF
3，CO
2H，N(CH
3)
2，
NHCH
3，NH
2，COCF
3，COCH
3Or NO2；
N is 1 to 2 integer;
R2 is naphthyl or indyl, and it is unsubstituted or is replaced by following group N-: hydroxyl, alkyl, formoxyl, CH2OH，
CH
2N(CH
3)
2，
Or
Z is NR3 or O, and wherein R3 is H or C1-C
4Alkyl;
R4 and R5 independently are hydrogen separately, or (CH2)
pR7 is wherein:
P is 1 to 3 integer, and
R7 is H, CH3，CN，OH，OCH
3，CO
2CH
3，NH
2，NHCH
3, or N (CH3)
2；
R6 is phenyl,
Pyridine radicals,
Thienyl,
Furyl,
Pyrrole radicals,
Pyrazolyl,
Imidazole radicals,
Quinolyl,
Isoquinolyl,
Naphthyl,
Indyl,
Benzofuranyl,
Benzothienyl,
Benzimidazolyl, or
Benzoxazolyl, wherein aforementioned every each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl,
Halogen,
CF
3，
NO
2，
N(CH
3)
2，
OCF
3，
SONH
2，
NH
2，
CONH
2，
CO
2CH
3Or
CO
2H，
Or R6 is:
The straight chained alkyl of 1 to 3 carbon,
The branched alkyl of 3 to 8 carbon,
The cycloalkyl of 5 to 8 carbon or
Heterocyclylalkyl, each can be by one or two are selected from following substituting group and replace at the most:
OH，
CO
2H，
N(CH
3)
2，
NHCH
3With
CH
3 Or
R5 and R6 when connecting by a key, can form a ring.
Preferred compound of the present invention is these compounds with following formula (I), wherein:
● be R or S, and ▲ be R or S;
-R is phenyl,
Pyridine radicals,
Thienyl,
Furyl,
Quinolyl
Isoquinolyl
Benzofuranyl,
Benzo [1,3] dioxole
Benzothienyl or
Benzimidazolyl, they each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl,
Halogen,
CF
3Or
OCF
3；
M is 1 to 3 integer;
X be NR8 or NHCONH wherein R8 be the alkyl of H or 1 to 3 carbon atom;
R1 is (CH2)
pY wherein p be 0 to 3 and Y be OH, F, CF3，OCH
3，CO
2H，
N(CH
3)
2，NHCH
3，NH
2，COCF
3，COCH
3Or NO2；
N is 1 to 2 integer;
R2 is naphthyl or indyl, and it is unsubstituted or is replaced by following substituting group N-: hydroxyl, alkyl, formoxyl, CH2OH
CH
2N(CH
3)
2，
Or
Z is NR3 or O, and wherein R3 is H or CH3，
R4 and R5 independently are hydrogen separately, CH3Or CH2OH；
R6 is phenyl,
Pyridine radicals,
Thienyl,
Furyl,
Pyrrole radicals,
Cyclohexyl or
Benzimidazolyl,
Wherein aforementioned each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl,
Halogen,
CF
3，
NO
2, or
N(CH
3)
2。
Preferred compound of the present invention is these compounds with following formula (I), wherein:
● for R orS, and ▲ be R orS R is phenyl,
Pyridine radicals,
Thienyl,
Furyl,
Benzofuranyl,
Benzo [1,3] dioxole
Benzothienyl,
Benzimidazolyl, they each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl,
Halogen,
CF
3Or
OCF
3；
M is the integer of 1-3;
X is NR8 or NHCONH, and wherein R8 is the alkyl of H or 1-3 carbon atom; R1 is (CH2)
pY wherein p be 0 to 3 and Y be OH, OCH3，F，CF
3，CO
2H，
N(CH
3)
2，NHCH
3，NH
2，COCF
3，COCH
3Or NO2；
N is 1 to 2 integer;
R2 is indyl unsubstituted or that replaced by alkyl or formoxyl N-;
Z is NR3 or O, and wherein R3 is H or CH3；
R4 and R5 independently are hydrogen separately, CH3Or CH2OH；
R6 is phenyl,
Pyridine radicals,
Thienyl,
Furyl,
Pyrrole radicals,
Cyclohexyl, or
Benzimidazolyl, wherein each is unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl,
Halogen,
CF
3，
NO
2, or
N(CH
3)
2。
Most preferred compound of the present invention is:
2-[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methoxy-N-(1-phenyl-ethyl)-propionamide [S-(R*，R
*)]；
2-[(benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide (S, S);
2-[(benzofuran-2-ylmethyl)-amino]-2-methylol-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide [S-(R*，R
*)]；
2-(3-benzofuran-2-ylmethyl-urea groups)-2-methylol-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide [S-(R*，R
*)]; 2-(3-benzofuran-2-ylmethyl-urea groups)-3-(1H-indol-3-yl)-2-methoxy-N-(1-phenyl-ethyl)-propionamide [S-(R*，R
*)]；
(R)-C-[(benzofuran-2-ylmethyl)-amino]-dimethylamino-C-(1-methylol-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl)-propionamide;
(R)-C-[(benzofuran-2-ylmethyl)-amino]-dimethylamino-C-(1-dimethylaminomethyl-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl) propionamide.
The invention still further relates to the pro-drug of formula I compound such as can (seeing the people such as Bundgaard, Acta Pharma Suec., 1987 by those pro-drugs that those skilled in the art expect; 24:233-246.) for example suitable part can be connected with the nitrogen-atoms that the nitrogen-atoms that links thing X, Z link thing, or when R2 is indyl, be connected with nitrogen-atoms on the indyl of R2.
The invention provides in addition a kind of compound and pharmaceutically acceptable carrier that comprises general formula I, the pharmaceutical preparation of diluent or mixed with excipients.
The mammiferous NK that the present invention also provides a kind of antagonism to treat1The method of acceptor comprises the formula I compound that gives the mammal effective dose.
The present invention further provides a kind of and is used for the treatment of or prevents various CNS obstacles to comprise pain (struvite, surgery with neuropathic), anxiety, fear, depression is accompanied by the major depression of anxiety, schizophrenia, neuralgia, anxiety, sex dysfunction, amphicheirality's phrenoblabia, dyskinesia, cognitive disorder, fat and habituation obstacle; Struvite disease is arthritis for example, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; Gastrointestinal disorders comprises colitis, Crohn's disease, irritable bowel syndrome and satiety; Allergy is eczema and rhinitis for example; Vascular disorder is angina and antimigraine for example; The obstacle of europathology comprises the method for chorionitis and vomiting, comprises the formula I compound of the mammal effective dose that needs treatment.
Compound of the present invention, NK1Receptor antagonist, can be used as the medicament of anti-angiogenic formation, the present invention further provides a kind for the treatment of or the prevention situation relevant with unusual neovascularization, rheumatoid arthritis for example, the method of atherosclerotic and growth of tumour cell, the method comprise the formula I compound of the mammal effective dose that needs treatment.
The present invention further is provided at NK in the situation of for example ulcerative colitis and Crohn's disease1The medicament of acceptor in-vivo imaging.
The compound that the present invention further provides formula I is for the preparation of prevention or treatment CNS obstacle pain (struvite, surgery with neuropathic) for example, anxiety, fear, depression is accompanied by the major depression of anxiety, schizophrenia, neuralgia, anxiety, sex dysfunction, amphicheirality's phrenoblabia, dyskinesia, cognitive disorder, fat and habituation obstacle; Struvite disease is arthritis for example, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; Gastrointestinal disorders comprises colitis, Crohn's disease, irritable bowel syndrome and satiety; Allergy is eczema and rhinitis for example; Vascular disorder is angina and antimigraine for example; The obstacle of europathology comprises chorionitis and vomiting; The situation relevant with unusual neovascularization be rheumatoid arthritis for example, the purposes in the medicine of atherosclerotic and growth of tumour cell.
In whole application, following abbreviation has following implication:
The CBZ benzyloxycarbonyl group
The CNS central nervous system
The COPD chronic obstructive pulmonary disease
DCC 1,3-dicyclohexyl carbodiimide
The DIPEA DIPEA
DMAP N, N-dimethyl-4-aminopyridine
DMF N, dinethylformamide
DMPU N, N '-dimethyl-N, N '-propylidene urea
HBTU O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate
The HRMS high resolution mass spec
LHMDS hexamethyldisilane base amination lithium
The Met methionine(Met)
PEI gathers (ethyleneimine)
The Sar sarkosine
S.c. subcutaneous
SEM-Cl 2-(trimethyl silyl) ethoxymethyl chloride
The RT room temperature
The TBAF tetrabutylammonium fluoride
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
TIPS triisopropyl silyl
Tris three (methylol) aminomethane
The Trp tryptophane
The following further definition of the compound of general formula I.
Term " alkyl " is meant the straight or branched hydrocarbon with 1 to 12 carbon atom and comprises, for example, and methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, undecyl, dodecyls etc. are unless specifically describe in addition.
Term " cycloalkyl " is meant the stable hydrocarbon ring that contains 3 to 12 carbon atoms, cyclopropyl for example, and cyclobutyl, cyclopentyl, cyclohexyl, except as otherwise noted.
Term " alkoxyl group " is meant the aforesaid alkyl that connects by Sauerstoffatom.
Term " halogen " is meant chlorine, bromine, fluorine or iodine.
Have 4 to 6 atoms of total and be unsubstituted by the ring that is connected to form with R5 and R6.
The compound of formula I can form the acceptable acid salt of pharmacy.All these forms is all within the present invention the scope.
The acceptable acid salt of the pharmacy of formula I compound comprises and derives from for example hydrochloric acid of nontoxic mineral acid, nitric acid, phosphoric acid, sulfuric acid, Hydrogen bromide, hydroiodic acid HI, hydrofluoric acid, the salt of phosphoric acid etc. and derive from nontoxic organic acid, for example aliphatics single-and dicarboxylic acid, the paraffinic acid of phenyl-replacement, hydroxyl-paraffinic acid, the chain docosandioic acid, the salt of aromatic acid, aliphatics and aromatic sulfonic acid etc.Thereby this salt comprises vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, nitrate, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, fluorochemical, acetate, trifluoroacetate, propionic salt, octylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chloro benzoate, tolyl acid salt, dinitro-benzoate, phthalate, benzene sulfonate, tosylate, phenylacetate, Citrate trianion, lactic acid salt, tartrate, mesylate etc.Amino acid salts for example arginic acid salt etc. also can be expected.For example, see Berge S.M., et al, PharmaceuticalSalts, J.Pharm.Sci., 66:1-19 (1977) is hereby incorporated by.
The acid salt of described basic cpd is by free alkali form is contacted with the required acid of q.s, prepares in the mode of the preparation salt of routine.Preferably, the compound of formula I can be by with the processing of required aqueous acid, so that the pH value that obtains is less than four, and changes hydrochlorate into.Can come absorption compound by solution by the C18 post,,, separate by concentrating under reduced pressure then, with postlyophilization with polar organic solvent wash-out compounds such as methyl alcohol, acetonitrile, its aqueous mixture for example with a large amount of water washings.Contact with alkali by salt form and can produce free alkali form again, then with the mode separated free alkali of routine.For example the solvability in polar solvent is slightly different in some physicals for free alkali form and their corresponding salt forms, but is that the free alkali of the object of the invention is suitable accordingly in salt aspect other and they.
Some compound of the present invention can non-solvent compound form and solvate forms, comprise that hydrate forms exists.In general, solvate forms, the form that comprises hydrate forms and non-solvent compound is of equal value, and all comprises within the scope of the invention.
Some compound of the present invention has one or more chiral centres and each center can R (D) or the existence of S (L) configuration.The present invention includes all enantiomorphs and epimer with and suitable mixture.
Compound of the present invention can multiple oral and parenteral formulation preparation and administration.Thereby compound of the present invention can pass through drug administration by injection, promptly in intravenously, intramuscular, intracutaneous, subcutaneous, the duodenum or the intraperitoneal administration.In addition, compound of the present invention can pass through inhalation, for example intranasal administration.In addition, compound of the present invention can be through percutaneous drug delivery.Be obviously for those skilled in the art, following formulation both can comprise the compound of formula I, also can comprise the corresponding pharmacologically acceptable salts of formula I compound as active ingredient.
For the pharmaceutical composition of preparation The compounds of this invention, pharmaceutically acceptable carrier both can be that solid also can be a liquid.Solid formulation comprises powder, pill, tablet, capsule, cachet, suppository and dispersible granula.Solid carrier can be one or more material, can be used as thinner, seasonings, tackiness agent, sanitas, tablet disintegrant, or encapsulated raw material.
In powder, carrier is finely divided solid, and it is the mixture with finely divided active ingredient.
In tablet, active ingredient is mixed in the proper ratio with the carrier with necessary bond property, and add and be pressed into required shape and size.
Powder and tablet preferably contain 5% or 10% to about 70% active compound.Appropriate carriers is a magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gel, tragacanth, methylcellulose gum, Xylo-Mucine, low-melting paraffin, theobroma oil etc.Terms " formulation " be meant comprise active compound with as the preparation of carrier with encapsulated raw material that a kind of capsule is provided, wherein have or do not have the active ingredient of other carrier, center on by carrier, thereby carrier interrelates with it.Similarly, comprise cachet and dragee.Can use tablet, powder, capsule, pill, cachet and dragee are as being suitable for oral solid dosage.
For preparation suppository, can at first melt low-melting paraffin, for example the mixture of glycerin fatty acid ester or theobroma oil is evenly dispersed in active ingredient wherein by stirring then.Then the uniform mixture of fusing is poured into the mould of suitable size, cooling is solidified then.
Liquid formulation comprises solution, suspension and emulsion, for example, and water or water propylene glycol solution.For parenteral injecting fluid medicament, can be in the solution of the polyoxyethylene glycol aqueous solution, to prepare.
The aqueous solution that is suitable for orally using can be by also adding the appropriate colouring agent with solubilization of active ingredient, spices, stable and thickening material preparation as required in water.
The aqueous suspension that is suitable for orally using can be by with finely divided active ingredient and heavy-gravity raw material, for example natural or synthetic gum, and resin, sodium carboxymethylcellulose pyce, carboxymethyl cellulose, and other well-known suspension agent disperses to prepare in water.
Also comprise solid formulation, promptly be meant before using and change the solid formulation that is used for oral liquid formulation soon into.This liquid form comprises solution, suspension, and emulsion.These preparations can contain tinting material except this active ingredient, spices, stablizer, buffer reagent, artificial and natural sweetener, dispersion agent, thickening material, dissolved medicament etc.
Pharmaceutical preparation is preferably the form with unit dosage form.In this form, preparation is divided into again the dosage unit of the active ingredient that contains appropriate amount.Presented in unit dosage form can be a kind of packaged preparation, contains the preparation of independent quantities in the packing, for example the powder in Bao Zhuan tablet, capsule and threading bottle or the ampoule.Presented in unit dosage form can also be a capsule, tablet, and cachet or dragee itself, or it can be the packaged form of any of these of appropriate amount.
The amount of active ingredient can be different in the dosage unit preparation, or can be preferably 0.5 milligram and change in 100 nanogram ranges according to the effectiveness of specific application and active ingredient at 0.1 milligram to 200 milligrams.If required, composition can also contain the therapeutical agent of other compatibility.
In therepic use, high selectivity and emulative NK
1Receptor antagonist and compound of the present invention are to arrive about 500 milligrams/kilogram initial dosage administration about 0.01 milligram of every day.About 0.01 milligram to about 100 milligrams/kilogram of preferred per daily dose scope.Yet dosage can be according to the compound of the seriousness of patient's needs, the situation of being treated and use and is different.Be used for particular case suitable dosage determine it is within the scope known to those skilled in the art.Usually, at first use smaller dose begin treatment less than optimum compound dosage.Then increase dosage slightly, until reaching optimum in this case effect.For convenience's sake, can be separately with the total dose of every day, if desired in the daytime with a few part administrations.
The compound of formula I or be used for synthetic their intermediate product, particularly wherein R2 is the indyl compound, wherein indyl is unsubstituted or by hydroxyl, alkyl, formyl radical, CH
2OH, CH
2N (CH
3)
2,
Or
N-replaces, can be by any several organic chemistry synthetic method preparations well known to those skilled in the art.Can on the racemic reactants basis, synthesize,, can they be split by ordinary method if desired to form the The compounds of this invention of racemic form.Perhaps, can prepare The compounds of this invention with the optically active form with the reactant and the asymmetric reaction of enantiomorph.
The method of reaction scheme 1 is the method that is used for the intermediate product of synthetic compound of the present invention.
Reaction scheme 1 has been described the synthetic of trinucleated intermediate product 1, and intermediate product 1 may be synthetic The compounds of this invention, especially one of key intermediate of the compound of embodiment 1 to 7.
Reaction scheme 1
Intermediate 1
Wherein P1 is a for example benzyloxycarbonyl of N-protected base, alkyl oxy carbonyl (for example, methyl, ethyl, haloalkyl), aryl sulfonyl (for example tolyl, phenyl), alkyl sulphonyl (methyl, ethyl), RCO-.
I) vinyl carbinol, DCC, DMAP, CH
2Cl
2, 89%
ii)TFA，52％
Iii) P1-C1, Na
2CO
3(aqueous solution), dioxane, 92%
In this is synthetic:
-in step I) in form the allyl ester of P1-Trp with DCC and DMAP reaction;
-at step I i) in, with the compound that obtains TFA cyclisation; And
-with second protecting group indole nitrogen is protected in ii) in step I then.
P1 is a benzyloxycarbonyl in the preferred embodiment of the invention.
Other intermediate that is used for synthetic The compounds of this invention can obtain shown in reaction scheme 2.
Reaction scheme 2:
R1 wherein, R4, R5, R6 and P1 are as previously defined.
In this is synthetic:
-in step I) in three ring intermediate asymmetric alkylations;
-at step I i) in, the product that obtains is for example used the TFA open loop;
-remove allyl ester in step I in ii);
-step I v) in, the acid that obtains is used and suitable amine coupling; And
-remove the terminal protecting group of N-in v) in step, obtain the intermediate that needs.
Following reaction scheme 2.1 is for example understood the synthetic of intermediate 2 and 3.
In this is synthetic:
-with three ring intermediates, 1 asymmetric alkylation;
-then with the product that obtains TFA open loop;
-remove allyl ester then, and
-with the HBTU activation, with acid and the coupling of Alpha-Methyl benzylamine that obtains;
-remove the terminal protecting group of benzyloxycarbonyl N-with palladium hydroxide/charcoal then, form intermediate 2 and 3.
Reaction scheme 2.1:
Wherein Z is a for example benzyloxycarbonyl of N-protected base, alkyl oxy carbonyl (for example, methyl, ethyl, haloalkyl), aryl sulfonyl (for example tolyl, phenyl), alkyl sulphonyl (methyl, ethyl), RCO-.
i)LHMDS，RX，DMPU，THF
Ii) TFA, CH
2Cl
2Or H
2SO
4, MeOH, H
2O
Iii) Pd (PPh
3)
4, morpholine, THF
Iv) amine, HBTU, DIPEA, DMF
v)Pd(OH)
2/C，EtOH
In the preferred embodiment of the invention, Z is a benzyloxycarbonyl.
Can shown in reaction scheme 3, obtain to be used for other intermediate of synthetic The compounds of this invention.
Reaction scheme 3:
P1 wherein, R4, R5, R6 be as former definition, and wherein P2 and P3 are protecting groups, and P2 is SEM, and P3 is TIPS, TBS, TBDMS, or DPS or ether group MOM for example, THP.
In this is synthetic:
-in step I) in introduce hydroxy functional group;
-at step I i) in open loop and remove protecting group on the hydroxy functional group;
-with suitable protecting group hydroxylic moiety is protected in ii) in step I.
-remove allyl ester in step I in v);
-step v) in, acid is used and suitable amine coupling;
-step vi) in, remove the terminal protecting group of N-, obtain the intermediate that needs.
In the preferred embodiment of the invention, P2 is that SEM and P3 are TIPS.
Following reaction scheme 3.1 is for example understood the synthetic of intermediate 4.
In this method:
-by intermediate 1 and LHMDS reaction, then introduce the hydroxy functional group of protection with the SEM-Cl reaction;
-open loop is also removed protecting group with TFA in methylene dichloride;
-then hydroxylic moiety is protected with TIPS in DMF by TIPS-Cl;
-remove allyl ester then, and
-with acid and the coupling of usefulness HBTU activatory α-Jia Jibianji amine.
-remove the terminal protecting group of carbobenzoxy-(Cbz) N-with palladium hydroxide/charcoal then, form intermediate 4.
Reaction scheme 3.1:
Intermediate 4
Wherein Z is a for example benzyloxycarbonyl of N-protected base, alkyl oxy carbonyl (for example, methyl, ethyl, haloalkyl), aryl sulfonyl (for example tolyl, phenyl), alkyl sulphonyl (methyl, ethyl), RCO-.I) LHMDS, SEM-Cl, THFii) TFA, CH
2Cl
2Iii) imidazoles, TIPS-Cl, CH
2Cl
2Iv) Pd (PPh
3)
4, morpholine, THFv) amine, HBTU, DIPEA, DMFvi) Pd (OH)
2/ C, EtOH
Z is a benzyloxycarbonyl in the preferred embodiment of the invention.
The method of synthetic The compounds of this invention is shown in reaction scheme 4.
Reaction scheme 4
Wherein R9 is as defined above R1 or (CH
2)
pP3, wherein p is 0 to 3 integer, and P3 is as defined above; R wherein, m, R4, R5 and R6 as defined above, and wherein R ' is a hydroxyl, alkyl, formyl radical, CH
2OH, CH
2N (CH
3)
2,
Or
The step I of-present method) amino need be reduced to secondary amine.
-have only when R9 be (CH
2)
pJust need step I i during P3).In this second step, remove protecting group by routine side known to those skilled in the art.
Most preferred is that wherein R is the compound of benzofuryl.
Following reaction scheme 4.1 has provided the synthetic of embodiment 1,2 and 3 compounds.
Embodiment 1 and 2 be by cumarone-2-formaldehyde respectively with intermediate 2 and 3 and sodium triacetoxy borohydride 1, reduction amination preparation in the 2-ethylene dichloride.
Embodiment 3 prepares with similar method, has added one and has gone on foot the step of removing the TIPS protection in tetrahydrofuran (THF) with TBAF.
Reaction scheme 4.1:
Intermediate 4, R=TIPSO a), R=TIPSO embodiment 3
Intermediate 2, R=OMe embodiment 1, R=OMe
Intermediate 3, R=NMe
2Embodiment 2R=NMe
2
I) cumarone-2-formaldehyde, NaBH (Oac)
3, (CH
2Cl)
2
ii)TBAF，THF
Following reaction scheme 4.2 is for example understood compound synthetic of embodiment 4 and 5.
Embodiment 4 is by intermediate 2 and (2-benzofuryl) methyl isocyanate prepared in reaction in tetrahydrofuran (THF).
Embodiment 5 prepares with similar method, has added one and has gone on foot the step of removing the TIPS protection in tetrahydrofuran (THF) with TBAF.
Reaction scheme 4.2:
Embodiment 5
I) (2-cumarone) methyl isocyanate, THF
ii)TBAF，THF
Another method of the present invention is used on the N atom of indyl of R2 and introduces substituting group, reaction scheme 5.
Reaction scheme 5:
R1 wherein, R4, R5, R6, R and m as defined above, R ' is a hydroxyl, alkyl, formyl radical, CH
2OH, CH
2N (CH
3)
2,
Or
In this is synthetic:
-in step I) in carry out reaction with hexamethyldisilane base amination potassium.
-at step I i) in carry out reaction with formaldehyde or Eschenmoser salt.
These two reactions can also as reaction scheme 2.1 (more than) shown in merge into one ' step ' LHMDS for example, RX, THF.
Following reaction scheme 5.1 is for example understood the synthetic of embodiment 6 and 7 compounds.
Compound and hexamethyldisilane amine potassium and formaldehyde among THFs the prepared in reaction of embodiment 6 by using embodiment 2 down at-78 ℃.
Embodiment 7 prepares with similar method, but replaces ketone with Eschenmoser salt
Reaction scheme 5.1:
Embodiment 6, R=OH
Embodiment 7, R=N (CH
3)
2
I) hexamethyldisilane base amination potassium, embodiment 2, THF (78 ℃)
Ii) formaldehyde or Eschenmoser salt
Can shown in reaction scheme 6, obtain to be used for other alternative intermediate of synthetic The compounds of this invention.
Reaction scheme 6:
Wherein R1 such as previous description and R ' are hydroxyls, alkyl, formyl radical, CH
2OH, CH
2N (CH
3)
2,
Or
In this is synthetic:
-in step I) in reaction with phenyl aldehyde takes place.This is that a kind of imines forms reaction, wherein uses dehydrated reagent (MgSO for example
4), molecular sieve or azeotropy process (dean stark trap) remove the by product that anhydrates.
-at step I i) in the reaction of α amino-alkylation takes place;
-carry out the hydrolysis of benzyl imines in ii) in step I;
-mutually in carry out the separation of racemoid at two corresponding diastereomer chirality HPLC in step I in v).
Can also racemoid be separated into two corresponding diastereomers reacting post crystallization with chiral acid.
Following reaction scheme 6.1 is for example understood the synthetic of intermediate 6.
Reaction scheme 6.1
Found and opposite with literature reference do not used the protecting group chemical treatment and prepare the method for alpha-alpha-dimethyl amino methyl tryptophan methyl ester; can be from Schiff's base ((S)-2-benzylidene amino)-3-(1H-indol-3-yl)-methyl propionate, the α amino-alkylation of the 1-dimethylaminomethyl benzotriazole that realization needs.
Surprisingly, the method esterification that alpha-alpha-dimethyl amino methyl tryptophane can only be exceedingly difficult with routine.We are surprised to find that ((S)-2-benzal-amino)-3-(1H-indol-3-yl)-methyl propionate (Schiff's base) now; it can ((S)-Trp-OMe) be with step preparation by cheap (S)-tryptophan methyl ester; can change racemic alpha-alpha-dimethyl amino methyl tryptophan methyl ester into without the protecting group chemical treatment by reacting with 1-dimethylaminomethyl benzotriazole.
People know can be used as by N-(alpha-aminoalkyl)-benzotriazole derivatives that benzotriazole, aldehyde and uncle or secondary amine are very easy to preparation amino-alkylation reagent (see A.Katritzky etc., Tetrahedron, 46, No.24,8153-8160/1990).
People such as J.H.Bruckhalter described 1-dimethylaminomethyl benzotriazole preparation (J.A.C.S., 74,3868-3369/1952).
B.E.Love and B.T.Nguyeri (Synlett, 1123, October, 1998) have described the reaction of 1-methylamino Methylbenzotriazole and indoles.As principal reaction, on the indole nitrogen atom, amino-alkylation takes place, and the amino-alkylation that carries out in the 3-position is side reaction.
Surprisingly, under the situation that is used for tryptophan derivative of the present invention (Schiff's base), only occur on α-C atom with the reaction of the amino-alkylation of 1-dimethylaminomethyl-benzotriazole.Completely different with above-mentioned reference, do not observe the alkylation on the indole nitrogen atom.
In addition, we find racemic alpha-alpha-dimethyl amino methyl tryptophan methyl ester to be separated into enantiomorph by the method for enzymatic or the method for formation diastereoisomeric salt.More unexpected is to tell two kinds of enantiomorphs on mutually at preparative scale chirality HPLC, i.e. (S)-enantiomorph and (R)-enantiomorph.
Then, can be with racemic alpha-alpha-dimethyl amino methyl tryptophan methyl ester further with ordinary method and second kind of chiral component reaction, obtain the mixture of diastereomer, the mixture of this diastereomer can be that the compound of two diastereomers separates by crystallization.
Can be by following alternative method, reaction scheme 7 obtains other compound of the present invention.
Reaction scheme 7:
Wherein R ' is a hydroxyl, alkyl, formyl radical, CH
2OH, CH
2N (CH
3)
2,
Or
And R1 wherein, m, R, R4, R5, R6 are as described previously.
In this is synthetic:
-in step I) in amino is reduced to secondary amine.
-at step I i) in the appropriate solvent system with alkali (LiOH, NaOH, KOH) hydrolysis methyl esters
-step I iii) in, acid is used and suitable amine coupling.
Following reaction scheme 7.1 is for example understood the another kind of synthesis method of the compound of embodiment 2.
Reaction scheme 7.1
I) cumarone-2-formaldehyde, sodium triacetoxy borohydride, (CH
2Cl)
2
Ii) NaOH, 1,4-diox/water.
Iii) HBTU, amine, DIPEA, DMF.
Can obtain the compound of embodiment 6 and 7 from the method for listing by reaction scheme 5.1 with the compound of described method synthetic embodiment 2.
The present invention further illustrates by following figure and embodiment, but restriction anything but.
Embodiment
Embodiment 1
2-[(cumarone-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methoxymethyl-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)]
Step 1
With (R)-N-CBZ-tryptophane (1.00 grams, 29.6mmol), N, (640 milligrams of N '-dicyclohexylcarbodiimide, 31.1mmol), N, (36 milligrams of N-dimethyl-4-aminopyridines, 2.96mmol) and the solution stirring of methylene dichloride (10 milliliters) 10 minutes, add then vinyl carbinol (0.22 milliliter, 32.5mmol).After 30 minutes, filtering mixt, and remove in a vacuum and desolvate.Obtain limpid oil with chromatography (n-heptane solution of 33%EtOAc) purified product, it leaves standstill curing.Recrystallization (EtOAc/ heptane) obtains amorphous solid (1.00 grams, 89%); Mp 83-85 ℃; δ
H3.32 (2H, d, IndCH
2, J5.2Hz), 4.56 (2H, bs, CH
2O), 4.74 (1H, dt, α-H, J7.8,7.8Hz), 5.11 (2H, m, CH
2O), 5.20-5.32 (3H, m, NH ,=CH
2), 5.82 (1H, m, CH), 6.96 (1H, d, arom, J2.0Hz), 7.08 (1H, t, arom, J7.4Hz), 7.18 (1H, d, arom, J7.2Hz), 7.34 (6H, m, arom), 7.52 (1H, d, arom, J8.0Hz), 8.04 (1H, bs, NH);
ν
max?3410，3361，3060，1713，1512，1205，743cm
-1；
M/z 378 (MH
+, 18%), 130 (100%); Analytical calculation value C
22H
22N
2O
4C 69.82, H
5.86, N 7.40% experimental value C 69.88, H 5.86, and N 7.44%; [α]
D 20(c=0.75, MeOH) :+
14.5°.
Step 2
(17.25g 45.6mmol) is dissolved in the trifluoroacetic acid (100mL), and stirring at room 3 hours with the ester that obtained.Enriched mixture (～50 milliliters) in a vacuum is added drop-wise to it NaHCO that has stirred preferably then
3(15%, 1l) and in the mixture of methylene dichloride (500 milliliters).After the adding, use saturated NaHCO
3, salt water washing organic layer and dry (MgSO
4).With chromatography (20-50%Et
2The n-heptane solution of O) purified product obtains limpid oil (8.90 grams, 52%); δ
H2.64 (2H, m, CH
2), 3.83-4.25 (3H, m, CH, CH
2O), 4.58 (0.5H, dd, a-H, J1.9,8.3Hz), 4.68 (0.5H, m, α-H), 4.75 (0.5H, bs, 0.5NH), 5.05-5.26 (4.5H, m, CH
2O ,=CH
2, 0.5NH), 5.50 (1H, m, CH=), 5.60 (1H, t, CH, J6.4Hz), 6.58 (1H, m, arom), 6.67 (1H, m, arom), 7.01 (2H, m, arom), 7.28-7.40 (4H, m, arom), 7.41 (1H, m, arom); ν
Max3400,1702,1416,747cm
-1M/z 378 (MH
+, 90%), 130 (100%);
Analytical calculation value C
22H
22N
2O
4C 69.82, and H 5.86, N 7.40% experimental value C 69.54, and H 5.85, and N 7.79%; [α]
D 20(c=1.62, MeOH) :-144.9 °.
Step 3: intermediate 1
Under 0 ℃, to the amine that stirs (8.90 grams, 23.5mmol), Na
2CO
3.10H
2(13.43 grams 47.0mmol), 1, add benzyl chloroformate (8.01 restrain 47.0mmol, 6.7 milliliters) to O in the mixture of 4-diox (100 milliliters) and water (10 milliliters).The mixture that obtains is risen to room temperature and stirred 16 hours.Remove in a vacuum and desolvate, then product is extracted among the EtOAc, water, 10%HCl, salt water washing organism, and dry (MgSO
4).Obtain limpid oil (10.39 grams, 86%) with chromatography (n-heptane solution of 25%EtOAc) purified product; δ
H2.55 (1H, m, CH
2), 2.65 (1H, d, CHH, J13.2Hz), 3.85 (1H, dd, OCHH J5.2,13.2Hz), 4.01 (1H, t, CH, J7.0Hz), 4.12 (1H, m, OCHH), 4.69 (1H, t, α-H, J8.0Hz), 4.80-5.24 (6H, m, 2x CH
2O ,=CH
2), 5.50 (1H, m, CH=), 6.51 (1H, d, CH, J6.0Hz), 6.98 (1H, t, arom, J7.4Hz), 7.10 (1H, m, arom), 7.19 (1H, t, arom, J7.6Hz), 7.27-7.38 (10H, m, arom), 7.63 (1H, bs, arom); ν
Max3065,3033,1716,1483,1416,1266,1173,753cm
-1M/z 513 (MH
+, 100); [α]
D 20(c=0.11, MeOH) :+2.6 °.
Step 4
Under-78 ℃, at exsiccant N
2Protection down to intermediate 1 (2.00 grams, 3.91mmol), DMPU (0.47 milliliter adds LHMDS (7.81 milliliters, 7.81mmol, the THF solution of 1M) in THF 3.91mmol) (30 milliliters) solution.In this temperature after 2 hours, add the iodomethyl methyl ether (1.34 grams, 7.81mmol), and with the mixture ambient temperature overnight that heats up.Remove in a vacuum and desolvate, then product is extracted among the EtOAc, with 10%HCl, salt water washing, and dry (MgSO
4).Realize purifying with chromatography (n-heptane solution of 15-20 EtOAc), obtain limpid oil (1.66 grams, 76%); δ
H2.52 (1H, dd, CHH, J1.2,13.2Hz), 2.82 (1H, dd, CHH, J8.0,13.6Hz), 3.26 (3H, s, OCH
3), 3.58 (1H, d, CHHO, J7.6Hz), 3.78 (1H, dddd, OCHH, J1.6,1.6,5.6,13.2Hz), 3.90 (1H, t, CH, J7.0Hz), 4.06 (1H, bs, CHHO), 4.17 (1H, dd, OCHH, J5.6,13.2Hz), 4.96-5.16 (6H, m, 2x CH
2O ,=CH
2), 5.38 (1H, m ,=CH), 6.44 (1H, d, CH, J6.0Hz), 6.99 (1H, m, arom), 7.08 (1H, d, arom, J7.2Hz), 7.19 (1H, t, arom, J7.6Hz), 7.25-7.34 (10H, m, arom), 7.59 (1H, d, arom, J8.0Hz); ν
Max1717,1483,1412,1335,1274,751cm
-1M/z 557 (MH
+, 100%);
Analytical calculation value C
32H
32N
2O
7C 69.05, and H 5.80, N 5.03% experimental value C 68.82, and H 5.52, and N 4.88%; [α]
D 20(c=0.75, MeOH) :+9.6 °.
Step 5
To above-mentioned oil (1.66 grams add trifluoroacetic acid (2 milliliters) in methylene dichloride 3.07mmol) (10 milliliters) solution, and with the solution that obtains stirring at room 24 hours.Remove in a vacuum and desolvate, then resistates is diluted with EtOAc, use saturated NaHCO
3, salt water washing organism, and dry (MgSO
4).Obtain limpid oil (1.19 grams, 72%) with chromatography (n-heptane solution of 15%EtOAc) purified product; δ
H3.32 (3H, s, OCH
3), 3.24 (1H, d, IndCHH, J14.4Hz), 3.60 (1H, d, IndCHH, J14.4Hz), 3.77 (1H, d, CHHO, J9.2Hz), 4.13 (1H, d, CHHO, J9.2Hz), 4.49 (1H, dd, OCHH, J4.8,12.8Hz), 4.61 (1H, dd, OCHH, J5.2,12.8Hz), 5.09 (2H, s, CH
2O), 5.11 (1H, d ,=CHH J10.8Hz), 5.28 (1H, d ,=CHH, J17.2Hz), 5.41 (2H, dd, CH
2O, J12.0,14.8Hz), 5.75 (2H, m ,=CH, NH), 7.14 (1H, t, arom, J8.0Hz), 7.28-7.47 (13H, m, arom), 8.15 (1H, bd, arom, J6.4Hz); ν
Max3418,3352,1736,1501,1456,1399,1250,1087,749cm
-1M/z 557 (MH
+, 100%); [α]
D 20(c=0.67, MeOH) :+13.0 °.
Step 6
(1.14 grams add tetrakis triphenylphosphine palladium (O) (50 milligrams, 43 μ mol) to the amino ester that replaces to α in THF 2.11mmol) (10 milliliters) solution, (1.84 grams 21.1mmol), and at room temperature stirred mixture 30 minutes to add morpholine after 5 minutes.Add EtOAc, with 10%HCl, salt water washing organism, and dry (MgSO
4).Except that after desolvating, obtain transparent glass attitude material (1.11 grams, 100%) in a vacuum; δ
H3.33 (1H, d, IndCHH, J14.7Hz), 3.37 (3H, s, OCH
3), 3.60 (1H, d, IndCHH, J14.4Hz), 3.84 (1H, d, CHHO, J9.3Hz), 3.99 (1H, d, CHHO, J8.8Hz), 5.09 (2H, s, CH
2O), 5.40 (2H, s, CH
2O), 5.71 (1H, s, NH), 7.14 (1H, t, arom, J7.6Hz), 7.27-7.52 (13H, m, arom), 8.18 (1H, dd, arom, J6.8,6.8Hz); ν
Max3411,1732,1456,1399,1250,1086,748cm
-1M/z (MH
+, 100%); HRMS C
29H
29N
2O
7Theoretical value 517.1975 experimental values 499.187 (MH-H
2O
+).
Step 7
With acid (1.01 grams, 2.02mmol), (766 milligrams of HBTU, 2.02mmol), (0.70 milliliter of DIPEA, 2.02mmol) mixture in DMF (10 milliliters) at room temperature stirred 10 minutes, add (244 milligrams of (S)-methyl-benzyl amine then, 2.02mmol) and DIPEA (0.70 milliliter, 2.02mmol), and with the solution stirring that obtains 8 hours.Remove and desolvate, then product is extracted among the EtOAc, with 10%HCl, 10%K
2CO
3, the salt water washing, and dry (MgSO
4).Chromatogram is purified and is obtained transparent glass shape thing, and its recrystallization (EtOAc/ heptane) is obtained transparent glass shape thing (1.04 grams, 78%); δ
H1.37 (3H, d, CHCH
3, J6.8Hz), 3.35 (3H, s, OCH
3), 3.39 (1H, d, IndCHH, J15.2Hz), 3.47 (1H, d, CHHO, J9.2Hz), 3.66 (1H, d, IndCHH, J14.4Hz), 4.16 (1H, d, CHHO, J8.0Hz), 4.98 (1H, m, CHCH
3), 5.03 (2H, bs, CH
2O), 5.40 (2H, bs, CH
2O), 6.02 (1H, bs, NH), 7.147.53 (20H, m, arom, NH), 8.14 (1H, bs, arom); ν
Max3350,1732,1653,1488,1455,1398,1249,1084,748cm
-1M/z 620 (MH
+, 100%); Analytical calculation value C
37H
37N
3O
6: C 71.71, and H 6.02, N 6.78% experimental value: C71.85, and H 6.04, and N 6.59%; [α]
D 20(c=0.53, MeOH) :-21.7 °.
Step 8: intermediate 2
At 30 ℃, and hydrogenation acid amides under the pressure of 50psi (345kpa) (980 milligrams, 1.63mmol), the mixture of 10% palladium hydroxide/carbon and methyl alcohol (20 milliliters).After 90 minutes, mixture desolvated by diatomite filtration and removing in a vacuum, to obtain pink colour foam (630 milligrams, quantitative); δ
H(DMSO-d
6) 1.36 (3H, d, CHCH
3, J6.8Hz), 3.26 (3H, s, OCH
3), 3.37 (2H, s, IndCH
2), 3.66 (1H, d, CHHO, J10.0Hz), 4.17 (1H, d, CHHO, J10.0Hz), 4.90 (1H, dq, CHCH
3, J6.8,6.8Hz), 7.00-7.38 (8H, m, arom), 7.70 (1H, d, arom, J7.6Hz), 8.17 (3H, bs, NH, NH
2), 8.94 (1H, d, arom, J7.6Hz), 11.17 (1H, d, NH, J1.2Hz); ν
Max3419,3213,3057,1667,1494,1458,1106,746cm
-1HRMS C
21H
26N
3O
2Theoretical value 352.2025 experimental values 352.2025 (MH
+); Analytical calculation value C
21H
25N
3O
2.0.4H
2O:C 70.33, and H 7.25, and N 11.72% experimental value: C 70.32, and H 6.94, and N 11.66%; [α]
D 19(c=0.66, MeOH) :-9.2 °.
Step 9
1, in the 2-ethylene dichloride (2 milliliters) cumarone-2-formaldehyde (83 milligrams, 568 μ mol), intermediate 2 (200 milligrams, 406 μ mol) and sodium triacetoxy borohydride (172 milligrams, 811 μ mol) were at room temperature stirred 16 hours.Use CH
2Cl
2The diluted mixture thing, with 0.5M NaOH, salt water washing, and dry (MgSO
4).Obtain transparent glass shape thing (60 milligrams, 44%) with chromatography (n-heptane solution of 5-15%EtOAc) purified product; Mp 50-53 ℃; δ
H1.45 (3H, d, CHCH
3, J6.8Hz), 2.15 (1H, bs, NH), 3.15 (2H, dd, IndCH
2, J14.6,51.6Hz), 3.39 (3H, s, OCH
3), 3.69 (2H, dd, CH
2O), J9.6,44.0Hz), 3.92 (2H, dd, CH
2N, J13.8,67.6Hz), 5.02 (1H, dq, CHCH
3, J7.6,7.6Hz), 6.49 (1H, s, arom), 6.59 (1H, s, NH, J2.0Hz), 7.03-7.27 (10H, m, arom), 7.39 (1H, m, arom), 7.50 (1H, m, arom), 7.57 (1H, d, arom, J8.6Hz), 7.77 (1H, d, arom, J8.4Hz), 7.85 (1H, s, NH); ν
Max3338,2925,1659,1512,1455,1106,742cm
-1M/z 482 (MH
+, 100%);
Analytical calculation value C
30H
31N
3O
3C 74.82, and H 6.49, N 8.73% experimental value C 74.57, and H 6.36, and N 8.74%; [α]
D 19(c=0.31, MeOH) :-37.7 °.
Embodiment 2
2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide (S, S)
Step 1
Method such as embodiment 1, step 4 obtain limpid oil (1.90g, 76%);
δ
H?2.23(6H，s，2x?CH
3)，2.40(1H，d，IndCHH，?J13.2Hz)，2.66(1H，d，CHHN，J
14.4Hz)；3.00(1H，dd，IndCHH，J8.2，13.4Hz)，3.29(1H，bs，CHHN)，3.69
(1H，dddd，OCHH，J1.6，2.9，5.8，13.3Hz)，3.94(1H，t，CH，J7.0Hz)，4.11(1H，
bs，CHHN)，4.93-5.33(7H，m，2x?CH
2O，＝CH，＝CH
2)，6.40(1H，d，CH，J6.4
Hz)，6.99(1H，t，arom，J7.4Hz)，7.06(1H，d，arom，J7.6Hz)，7.18(1H，t，arom，
J7.6Hz)，7.26-7.37(10H，m，arom)，7.58(1H，bs，arom)；
ν
max?2947，1717，1483，1412，1331，1267，1043，1020，750cm
-1；
HRMS C
33H
36N
3O
6Theoretical value 570.2604 experimental values 570.2604 (MH
+, 100%);
[α]
D 19(c＝0.49，MeOH)：-0.4°.
Step 2
Method such as embodiment 1, step 5 obtain faint yellow gluey thing (3.46g, 59%);
δ
H?2.26(6H，s，2x?CH
3)，2.83(1H，d，CHHN，J13.6Hz)，3.23(1H，d，IndCHH，J
14.4Hz)，3.32(1H，d，CHHN，J13.6Hz)，3.64(1H，dd，IndCHH，J14.4Hz)，
4.49(1H，d，CHHO，J13.2Hz)，4.59(1H，d，CHHO，J6.0Hz)，5.08(2H，dd，
CH
2O，J12.4，27.6Hz)，5.23(1H，d，＝CHH，J10.4Hz)，5.34(1H，d，＝CHH，J
14.4Hz)，5.41(2H，s，CH
2O)，5.85(1H，m，＝CH)，6.00(1H，s，NH)，7.14(2H，
m，arom)，7.25-7.48(12H，m，arom)，8.15(1H，bd，arom，J6.4Hz)；
ν
max?3418，1736，1456，1248，1084，1037，748cm
-1；
m/z?570(MH
+，100％)；
[α]
D 19(c＝O.27，MeOH)：-12.6°.
Step 3
Method such as embodiment 1, step 6, obtain weak yellow foam shape thing (690 milligrams, quantitative .);
Because impurity and zwitter-ion make δ
HNonsensical.
ν
max?3373，1731.1633，1485，1456，1401，1388，1248cm
-1；
HRMS C
30H
32N
3O
6Theoretical value 530.2291 experimental values 530.229 (MH
+).
Step 4
Method such as embodiment 1, step 7 obtain white crystals (Et0Ac/ heptane) (150mg, 34%); Mp 102-107 ℃; δ
H1.38 (3H, d, CHCH
3, J6.8Hz), 2.14 (6H, s, 2x CH
3), 2.43 (1H, d, CHHN, J14.4Hz), 3.35 (1H, d, CHHN, J14.4Hz), 3.38 (1H, d, IndCHH, J15.2Hz), 3.63 (1H, d, IndCHH, J15.2Hz), 4.98 (1H, dq, CHCH
3, J7.2,7.2Hz), 5.02 (2H, dd, CH
2O, J12.4,28.8Hz), 5.40 (2H, s, CH
2O), 6.40 (1H, s, NH), 7.15-7.55 (19H, m, arom, NH), 8.16 (H, s, arom), 8.28 (1H, s, arom); ν
Max3373,1732,1666,1486,1250,1077,747cm
-1M/z 633 (MH
+, 100%), 486 (37%); Analytical calculation value C
38H
40N
4O
5C 72.13, H6.36, and N 8.86% experimental value C 71.77, H 6.16, and N 8.66%; [α]
D 20(c=0.36, MeOH) :-34.6 °
Step 5 intermediate 3
Method such as embodiment 1, step 8, obtain transparent glass shape thing (342 milligrams, quantitative .);
δ
H?1.43(3H，d，CHCH
3，J7.6Hz)，2.32(6H，s，2xNCH
3)2.46(1H，d，CHHN，J
12.4Hz)，2.83(1H，d，IndCHH，J14.4Hz)，3.13(1H，d，CHHN，J12.4Hz)，3.20
(1H，d，IndCHH，J14.4Hz)，5.00(1H，dq，CHCH
3，J7.6，7.6Hz)，6.74(1H，s，
arom)，7.04-7.26(7H，m，arom)，7.33(1H，d，arom，J7.6Hz)，7.61(1H，d，arom，
J7.8Hz)，7.89(1H，bs，NHInd)，8.14(1H，d，NH)；
[α]
D 19(c＝0.56，MeOH)：4.5°.
Step 6
Method such as embodiment 1, step 9 obtain yellow glass shape thing (30 milligrams, 19%);
δ
H?1.44(3H，d，CHCH
3，J7.0Hz)，1.59(1H，bs，NH)，2.34(6H，s，N(CH
3)
2)，
2.67(1H，d，CHHN，J13.4Hz)，2.96(1H，d，CHH，J13.4Hz)，3.06(1H，d，
IndCHH，J15.2Hz)，3.29(1H，d，IndCHH，J15.2Hz)，3.99(2H，dd，CH
2N，J
14.0，24.4Hz)，5.00(1H，m，CHCH
3)，6.45(1H，s，arom)，6.90(1H，d，arom，J
7.4Hz)，7.02(2H，m，arom)，7.08-7.26(7H，m，arom)，7.31(1H，m，arom)，7.42
(1H，d，arom，J8.0Hz)，7.49(1H，m，arom)，7.64(1H，d，arom，J8.0Hz)，7.80
(1H，bs，NH
Ind)，7.99(1H，d，NH，J8.0Hz)；
ν
max?3312，1655，1454，741cm
-1；
m/z495.3(MH
+，100％)；
Embodiment 3
2-[(cumarone-2-ylmethyl)-amino]-2-methylol-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)]
Step 1.
Under-78 ℃, at exsiccant N
2Protection is down to intermediate 1 (2.00 grams, 3.91mmol) DMPU (0.47 milliliter adds LHMDS (7.81 milliliters, 7.81mmol, the THF solution of 1M) in THF 3.91mmol) (30 milliliters) solution.In this temperature after 2 hours, (1.22 grams 7.81mmol), and are warming up to ambient temperature overnight with mixture to add iodoethane.Remove in a vacuum and desolvate, then product is extracted among the EtOAc, with 10%HCl, salt water washing, and dry (MgSO
4).Realize purifying with chromatography (n-heptane solution of 15-20 EtOAc), obtain limpid oil (1.53 grams, 61%);
δ
H?0.04(9H，s，Si(CH
3)
3)，0.85(2H，t，CH
2Si，J8.0Hz)，2.52(1H，d，IndCHH，J
13.2Hz)，2.84(1H，dd，IndCHH，J7.6，13.2Hz)，3.47(2H，t，OCH
2，J8.0Hz)，
3.58(1H，d，CHH，J9.6Hz)，3.78(1H，dd，OCHH，J5.6？，13.2Hz)，3.90(1H，t，
CH，J7.0Hz)，4.15(2H，m，OCHH，CHH)，4.96-5.15(6H，m，2x?CH
2O，CH
2＝)，
5.38(1H，m，CH＝)，6.44(1H，d，CH，J6.0Hz)，7.00(1H，t，arom，J6.4Hz)，7.07
(1H，d，arom，J7.6Hz)，7.19(1H，t，arom，J7.6Hz)，7.26-7.34(10H，m，arom)，
7.60(1H，d，arom，J7.6Hz)；
ν
max?2952，1720，1483，1412，1275，838，751cm
-1；
HRMS C
36H
43NO
7Si theoretical value 643.2840 experimental values 643.2840;
[α]
D 21(c＝0.45，MeOH)：+13.9°.
Step 2.
To above-claimed cpd (1.66 grams add trifluoroacetic acid (2 milliliters) in methylene dichloride 3.07mmol) (10 milliliters) solution, and with the solution that obtains stirring at room 24 hours.Remove in a vacuum and desolvate, then resistates is diluted with EtOAc, use saturated NaHCO
3, salt water washing organism, and dry (MgSO
4).Obtain faint yellow oily thing (910 milligrams, 71%) with chromatography (n-heptane solution of 15%EtOAc) purified product; δ
H3.01 (1H, bs, OH), 3.24 (1H, d, IndCHH, J14.7Hz), 3.54 (1H, d, IndCHH, J14.7Hz), 4.01 (1H, m, CHHO), 4.35 (1H, m, CHHO), 4.56 (2H, m, CH
2O), 5.08 (1H, s, CH
2O), 5.22 (2H, m, CH
2=), 5.42 (1H, s, CH
2O), 5.73 (1H, s, NH), 5.79 (1H, m, CH=), 7.16 (1H, t, arom, J7.2Hz), 8.14 (1H, bs, arom); ν
Max3413,1732,1456,1399,1251,1085,749cm
-1HRMS C
31H
31N
2O
7Theoretical value 543.2130 experimental values 543.2130; [α]
D 19(c=0.2, MeOH) :+2.4 °.
Step 3.
(606 milligrams, (351 milligrams, 5.24mmol), (1.42 restrain, 2.62mmol) then to add amino acid to add imidazoles in DMF 3.14mmol) (5 milliliters) solution to tri isopropyl chlorosilane.The mixture that obtains is warmed up to 80 ℃ kept 36 hours, remove in a vacuum then and desolvate, and resistates is diluted with EtOAc, with 10%HCl, salt water washing, and dry (MgSO
4).Obtain limpid oil with the raw material in chromatography (n-heptane solution of 10%EtOAc) the purifying crude product, it leaves standstill curing.(1.36g，74％)；
Fusing point 72-74 ℃ (pentane/Et
2O);
δ
H?1.02(18H，s，6xCH
3)，1.26(3H，m，3xCH)，3.17(1H，d，IndCHH，J14.4Hz)，
3.67(1H，s，IndCHH，J14.4Hz)，4.09(1H，d，CHHO，J9.2Hz)，4.49(3H，m，
CH
2O，CHHO)，5.05(2H，s，CH
2O)，5.20(2H，m，CH
2＝)，5.41(2H，s?CH
2O)，
5.83(2H，m，CH＝，NH)，7.13(1H，t，J7.6Hz)，7.26-7.48(13，m，arom)，8.17
(1H，bs，arom)；
ν
max?3422，2944，2866，1741，1248，1086cm
-1；
Analytical calculation value C
40H
50N
2O
7Si C 68.74, H 7.21, N 4.01% experimental value C 68.79, H 7.06,
N?4.08％；
m/z?699.2(MH
+).
Step 4.
(1.14 grams add tetrakis triphenylphosphine palladium (O) (50 milligrams, 43 μ mol) in THF 2.11mmol) (10 milliliters) solution to allyl ester; Add after 5 minutes morpholine (1.84 grams, 21.1mmol), and with mixture stirring at room 30 minutes.Add EtOAc, with 10%HCl, salt water washing organism, and dry (MgSO
4).Except that after desolvating, obtain transparent jelly (845 milligrams, 94%) in a vacuum;
δ
H?1.03(21H，m，Si(CHMe
2)
3)，3.31(1H，d，IndCHH，J14.8Hz)，3.63(1H，d，
IndC
HH，J14.8Hz)，4.30(2H，s，CH
2O)，5.05(2H，s，CH
2O)，5.39(2H，d，
CH
2O，J2.8Hz)，5.76(1H，s，NH)，7.12(1H，t，arom，J7.6Hz)，7.26-7.47(13H，
m，arom)，8.17(1H，bs，arom)；
ν
max?3411，2944，2866，1733，1456，1400，1249，1086，746cm
-1；
m/z?659.2(MH
+，100％)；
Analytical calculation value C
37H
46N
3O
7Si C 67.45, H 7.04, N 4.25% experimental value C, 67.83, H
6.94，N?4.24％；[α]
D 21(c＝0.40，MeOH)：-1.0°.
Step 5.
With acid (1.01 grams, 2.02mmol), (766 milligrams of HBTU, 2.02mmol), (0.70 milliliter of DIPEA, 2.02mmol) mixture in DMF (10 milliliters) at room temperature stirred 10 minutes, add (244 milligrams of (S)-methyl-benzyl amine then, 2.02mmol) and DIPEA (0.70 milliliter, 2.02mmol), and with the solution stirring that obtains 8 hours.Remove and desolvate, then product is extracted among the EtOAc, with 10%HCl, 10%K
2CO
3, the salt water washing, and dry (MgSO
4).Chromatogram is purified and is obtained transparent glass shape thing (533 milligrams, 92%); δ
H1.05 (21H, bs, Si (CHMe
2)), 1.35 (3H, d, CHCH
3, J7.2Hz), 3.40 (1H, d, IndCHH, J13.6Hz), 3.78 (1H, d.IndCHH, J13.6Hz), 3.80 (1H, m, CHHO), 4.65 (1H, m, CHHO), 4.93 (1H, m, CHCH
3), 5.03 (2H, s, CH
2O), 5.40 (2H, d, CH
2O, J5.2Hz), 6.20 (1H, bs, NH), 7.17-7.46 (18H, m, arom), 8.18 (1H, bs, arom); ν
Max3372,2944,1733,1674,1486,1456,1398,1249,1077cm
-1M/z 620 (MH
+, 100%);
Analytical calculation value C
45H
55N
3O
6Si.0.5H
2O C 70.10, H 7.32, N 5.45% experimental value C 70.27, H 7.12, and N 5.25%; [α]
D 19(c=0.62, MeOH) :-24.6 °.
Step 6. intermediate 4
At 30 ℃, and hydrogenation acid amides under the pressure of 50psi (345kpa) (980 milligrams, 1.63mmol), the mixture of 10% palladium hydroxide/carbon and methyl alcohol (20 milliliters).After 90 minutes, mixture desolvated by diatomite filtration and removing in a vacuum, to obtain white jelly (325 milligrams, quantitative); δ
H1.10 (21H, m, Si (CHMe
2)
3), 1.40 (3H, s, CHCH
3, J6.8Hz), 1.61 (2H, bs, NH
2), 3.02 (1H, d, IndCHH, J14.4Hz), 3.32 (1H, d, IndCHH, J14.4Hz), 3.76 (1H, d, CHHO, J8.8Hz), 4.10 (1H, d, CHH, J8.8Hz), 5.01 (1H, m CHCH
3), 6.68 (1H, s, NH), 7.03 (3H, m, arom), 7.17-7.24 (4H, m, arom), 7.32 (1H, d, arom, J7.6Hz), 7.58 (1H, d, arom, J8.0Hz), 7.83 (2H, bs, arom, NH); ν
Max3304,2942,2866,1651,1512,1104,741cm
-1M/z 494 (MH
+); Analytical calculation value C
29H
43N
3O
2Si.0.3H
2O C 69.78, H 8.80, N 8.42% experimental value C 69.84, H 8.49, and N 8.11%; [α]
D 19(c=0.49, MeOH) :-37.7 °.
Step 7.
Method such as embodiment 2, step 6 obtain the loose crystallization (103mg, 41%) of white;
mp?110-111℃；
δ
H?1.17(21H，m，Si(CHMe
2)
3)，1.36，(3H，d，CHCH
3，J6.8Hz)，2.23(1H，bs，
NH)，3.17(2H，dd，IndCH
2，J14.8，29.2Hz)，3.92(1H，d，CHHN，J14.0Hz)，
4.07(1H，d，CHHN，J14.0Hz)，4.09(1H，d，CHHO，J10.0Hz)，4.23(1H，d，
CHHO，J10.0Hz)，4.92(1H，dt，CHCH
3，J7.2，7.2Hz)，6.72(1H，s，arom)，6.73
(1H，d，NH，J2.4Hz)，6.94(2H，m，arom)，7.05(1H，m，arom)，7.18(7H，m，
arom)，7.37(1H，m，arom)，7.49(1H，m，arom)，7.58(2H，2xd，arom，J8.0Hz)，
7.69(1H，s，NH)；
ν
max?3306，2942，2866，1657，1512，1455，1100，741cm
-1；
M/z 624.1 (MH
+); Analytical calculation value C
38H
39N
3O
3Si C 73.15, H 7.92, and N 6.73%
Experimental value C 73.48, H 7.81, and N 6.73%;
[α]
D 19(c＝0.49，MeOH)：-22.0°
Step 8.
Handle THF (1 milliliter) solution of the intermediate (103 milligrams, 1.65 μ mol) of TIPS-protection with TBAF (1M THF solution, 331 μ mol, 0.33 milliliter), and with the solution that obtains stirring at room 1 hour.Solution is diluted with EtOAc, with salt water washing and dry (MgSO
4).Obtain white foam shape thing (29 milligrams, 38%) with chromatography (n-heptane solution of 20-40%EtOAc) purified product; Mp 53-56 ℃; δ
H1.52 (3H, d, CHCH
3, J7.2Hz), 2.00 (1H, bs, NH), 2.98 (1H, d, IndCHH, J14.6Hz), 3.45 (1H, d, IndCHH, J14.6Hz), 3.75 (1H, d, CHHO, J10.4Hz), 3.81 (1H, bs, OH), 3.85 (2H, dd, CH
2N, J14.2,24.3Hz), 4.07 (1H, d, CHHO, J10.4Hz), 5.12 (1H, dq, CHCH
3, J7.2,7.2Hz), 6.45 (1H, s, arom), 7.01 (1H, d, arom, J2.0Hz), 7.09-7.40 (9H, m, arom, NH), 7.51 (1H, m, arom), 7.77 (1H, d, arom, J7.6Hz), 8.00 (1H, d, arom, J8.0Hz), 8.13 (1H, s, NH); ν
Max3312,1646,1514,1455,740cm
-1M/z 468.1 (MH
+, 100%);
Analytical calculation value C
29H
29N
3O
3.0.5H
2O C:73.09, H 6.34, N 8.82% experimental value C 73.02, H 6.19, N 8.92%.
Embodiment 4.
2-(3-cumarone-2-ylmethyl-urea groups)-3-(1H-indol-3-yl)-2-methoxymethyl-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)]
THF (2 milliliters) solution of intermediate 2 (142 milligrams, 288 μ mol) and (2-benzofuryl) methyl isocyanate (50 milligrams, 288 μ mol) was stirred 2 hours under nitrogen atmosphere.Remove in a vacuum and desolvate, and, obtain white solid (109 milligrams, 72%) with chromatography (n-heptane solution of 20-25%EtOAc) purified product; Mp 78-82 ℃; δ
H(DMSO) 1.38 (3H, d, CH
3CH, J6.8Hz), 3.37 (3H, s, CH
3O), 3.42,3.68 (2H, dd, IndC
H 2, J14.8Hz), 3.52,4.27 (2H, dd, CH
2O, J13.4Hz), 4.38 (2H, 2, dd, CH
2N, J6.0,16.0Hz), 4.93 (1H, dq, CHCH
3, J7.2Hz), 5.26 (1H, t, NH, J5.8Hz), 5.68 (1H, s, NH), 6.67 (1H, d, NH, J2.4), 7.06 (1H, dt, arom, J1.2,8.0Hz), 7.15 (1H, dt, arom, J1.0,68.Hz), 6.52 (1H, s, arom), 7.20-7.32 (8H, m, arom), 7.41 (2H, m, arom), 7.51 (1H, m, arom), 7.60 (1H, d, arom, J7.6Hz), 7.65 (1H, d, arom, J7.6Hz), 10.80 (1H, bs, NH); ν
Max3327,1644,1557,1455,1253,1106,741cm
-1
Analytical calculation value C
31H
32N
4O
4.0.2C
7H
16: C 71.45, and H 6.51, N 10.29% experimental value C 71.34, and H 6.38, and N 10.02%; [α]
D 19(c0.34, MeOH) :-19.4 °.
Embodiment 5
2-(3-cumarone-2-ylmethyl-urea groups)-2-methylol-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)]
Step 1.
Method such as embodiment 4 obtain transparent glass shape thing (110 milligrams, 57%);
δ
H?1.07(21H，m，18xCH
3)，1.21(3H，d，CH
3CH，J7.2Hz)，3.42(1H，d，
IndCH
H，J14.8Hz)，3.78(1H，d，CHHO，J10.0Hz)，4.03(1H，d，IndC
HH，J
14.8Hz)，4.12(1H，m，CHHN，4.30(1H，dd，CHHN，J6.0，15.6Hz)，4.69(1H，
dq，CHCH
3，J7.2Hz)，4.89(1H，d，CHHO，J9.6Hz)，5.73(1H，t，NH，J5.6
Hz)，6.10(1H，d，NH，J2.4Hz)，7.05-7.25(9H，m，arom)，7.33(1H，m，arom)，
7.43(1H，m，arom)，7.62(1H，d，arom，J8.0Hz)，7.91(1H，d，arom，J8.0Hz)
IndNH？；
ν
max?3337，1634，1548，1495，1455，1060，741cm
-1；
HRMS C
39H
51N
4O
4Si667.368 experimental value 667.3680 (MH
+);
[α]
D 19(c0.70，MeOH)：-18.9°.
Step 2.
With TBAF (0.33 milliliter, 330 μ mol 1M/THF) handle THF (1 milliliter) solution of the alcohol (110 milligrams, 165 μ mol) of TIPS-protection, and with solution stirring at room 10 minutes.With EtOAc diluted mixture thing, with 10%HCl, salt water washing, and dry (MgSO
4).Obtain transparent glass shape thing (20 milligrams, 24%) with chromatography (n-heptane solution of 20-70%EtOAc) purified product; Mp 82-82 ℃; δ
H(DMSO) 1.27 (3H, d, CH
3CH, J6.8Hz), 3.27 (2H, dd, IndC
H 2, J14.8,38.0Hz) 3.79 (1H, dd, CHHO, J5.8,12.0Hz), 4.07 (1H, dd, CHHO, J7.0,11.6Hz), 4.29 (1H, dd, CHHN, J5.6,16.0Hz), 4.33 (1H, dd, CHHN, J5.6,16.4Hz), 4.91 (1H, dq, CHCH
3, J6.8,6.8Hz), 4.93 (1H, bs, OH), 5.95 (1H, t, NHCH
2, J5.4Hz), 6.02 (1H, s, NH), 6.43 (1H, s, arom), 6.68 (1H, d, NH, J6.0Hz), 7.04 (1H, m, arom), 7.09-7.27 (8H, m, arom), 7.35 (1H, d, arom, J8.0Hz), 7.47 (2H, m, arom), 7.54 (1H, s, arom), 8.01 (1H, d, NH, J7.6Hz) IndH? ν
Max3346,1644,1557,1455,1253,742cm
-1M/z 448 (M
+-61,100%), 101 (16%); Analytical calculation value C
30H
30N
4O
4.0.5 EtOAc:C 69.30, and H 6.18, N 10.10% experimental value C 69.18, and H 6.03, and N 10.29%; [α]
D 19(c0.46, MeOH) :-15.6 °.
Embodiment 6
(R)-C-[(cumarone-2-ylmethyl)-amino]-dimethylamino-C-(1-methylol-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl)-propionic acid amide
Under-78 ℃, at N
2(1.0 grams add hexamethyldisilane base amination potassium (4.4 milliliters, 2.02mmol, the toluene solution of 0.5M) in THF 2.02mmol) (15 milliliters) solution to embodiment 2 down in protection.Continue to stir 10 minutes in this temperature, add formaldehyde (about 250 milligrams, the 15 milliliters) solution of prepared fresh then, and continue to stir 3 hours down at-78 ℃.With EtOAc diluted mixture thing, use saturated NaHCO
3, the salt water washing, and dry (MgSO
4).With the chromatography (CH of 0-1% methyl alcohol
2Cl
2Solution) purified product obtains yellow foam (182 milligrams, 17%).MS?m/z?525.6(MH
+，BP)；IRν3353，1646，1454，1040，741cm
-1；
1H?NMRδ1.42(3H，d，CHCH
3，J7.2Hz)，2.33(6H，s，N(CH
3)
2)，2.55(1H，bs，NH)，2.65(1H，d，CHHN，J13.6Hz)，2.97(2H，2xd，CHHN，CHHInd，J15.6Hz)，3.25(1H，d，CHHInd，J15.6Hz)，3.94(2H，dd，CH
2N，J13.6，19.6Hz)，4.98(1H，dq，CHCH
3，J7.6Hz)，5.26(2H，bs，CH
2O)，6.44(1H，s，ar)，6.84(1H，s，ar)，7.05(2H，m，ar)，7.12-7.26(7H，m，ar)，7.41(2H，m，ar)，7.51(1H，d，ar，J5.6Hz)，7.60(1H，d，ar，J8.0Hz)，8.00(1H，d，NH，J7.2).
Embodiment 7
(R)-C-[(cumarone-2-ylmethyl)-amino]-dimethylamino-C-(1-dimethylaminomethyl-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl)-propionic acid amide
At-78 ℃, at N
2(500 milligrams add hexamethyldisilane base amination lithium (1.1 milliliters, 1.01mmol, the THF solution of 1M) in THF 1.01mmol) (5 milliliters) solution to embodiment 2 are descended in protection.Continue to stir 15 minutes in this temperature, add Eschenmoser salt (37 milligrams 2.02mmol), and-78 ℃ of lasting down stirrings 1 hour, are warming up to ambient temperature overnight with mixture then then.With EtOAc diluted mixture thing, use saturated NaHCO
3, the salt water washing, and dry (MgSO
4).With the chromatography (CH of 0-2% methyl alcohol
2Cl
2Solution) purified product obtains yellow jelly (68 milligrams, 12%).MS?m/z?552(MH
+，BP)；IRν3366，1661，1494，1454，740cm
-1；
1H?NMR?δ1.42(3H，d，CHCH
3，J7.2Hz)，2.15?33(6H，s，N(CH
3)
2)，2.33(6H，s，N(CH
3)
2)，2.66(1H，d，CHHN，J13.6Hz)，2.95(1H，d，CHHN，J13.6Hz)，3.03(1H，d，CHHInd，J15.6Hz)，3.30(1H，d，CHHInd，J15.2Hz)，3.95(2H，dd，CH
2N，J14.0，25.2Hz)，4.50(2H，s，NCH
2N)，4.98(1H，dq，CHCH
3，J7.2Hz)，6.43(1H，s，ar)，6.94(1H，s，ar)，7.01(2H，m，ar)，7.08(1H，t，ar，J7.6Hz)，7.16-7.26(6H，m，ar)，7.35(1H，d，ar，J8.4Hz)，7.38(1H，d，ar，J8.0Hz)，7.48(1H，d，ar，8.0Hz)，7.61(1H，d，ar，J7.6Hz)，8.00(1H，d，NH，J7.6Hz).
Embodiment 8
2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide (S, alternative synthesis S)
Embodiment 8.A: intermediate 5 synthetic
1) (S)-preparation of 2-(Ben Yajiaji-amino)-3-(1H-indol-3-yl)-methyl propionate (schiff alkali).
245 gram (S)-tryptophan methyl esters and 118 gram phenyl aldehydes are dissolved in 1837 milliliters of methylene dichloride, and mix with 245 gram exsiccant sal epsom.Reaction mixture was stirred 4 hours at ambient temperature.After leaching this sal epsom, solvent is steamed on rotatory evaporator.Stay very heavy-gravity material (364 gram), can be in next step direct use.
2) preparation of racemic alpha-alpha-dimethyl aminomethyl tryptophan methyl ester
In reaction flask, 117.9 gram diisopropylamines are dissolved in 1170 milliliters of anhydrous tetrahydro furans with the nitrogen inflation of removing moisture content.Under-30 ℃, in about 1 hour, drip 728 milliliters of 1.6M butyllithium/hexane solutions of adding.Behind the stir about 15 minutes, under-30 ℃, in 1 hour, drip the Schiff alkali that adding 340 grams are dissolved in preparation among 1020 milliliters of embodiment 1 in the anhydrous tetrahydro furan.Behind the restir 15 minutes, under-30 ℃, in 1 hour, drip adding 205 grams and be dissolved in 1025 milliliters of 1-dimethylaminomethyl-benzotriazoles in the anhydrous tetrahydro furan.
Subsequently, reaction mixture is risen to envrionment temperature.During stirring at ambient temperature about 16 hours, produce thick slurry.
With under ice-cooled,, add 1544 milliliters of frozen water solution of 386 milliliter of 37% hydrochloric acid so that the reaction vessel temperature is no more than 25 ℃ mode.Tell the tetrahydrofuran (THF) phase, with 500 milliliters of ethyl acetate extraction waters five times.
Water is covered with 500 milliliters of ethyl acetate, and under agitation restrain the yellow soda ash batch mixing with 247.Tell organic phase in each case, extract water once more twice with 500 milliliters of ethyl acetate.In each case with the organic phase that merges with 300 milliliters of saturated sodium-chloride water solution washed twice.
Behind anhydrous sodium sulfate drying, filtering solution is to transparent and evaporation in a vacuum.
Remaining 242 gram (79.1% theoretical amount) brown, heavy-gravity resistates.Analyze according to HPLC, this thick product contains 62% the target product of having an appointment.In order to purify again,, obtain 94 gram (30.7% theoretical amount) racemic alpha-alpha-dimethyl amino methyl tryptophan methyl esters with thick product ether recrystallization; Fusing point: 105 ℃; HPLC purity 96.2, rel.%.
3) racemic alpha-alpha-dimethyl amino methyl tryptophan methyl ester is separated into two enantiomeric compounds.
On preparation HPLC instrument, on chirality phase Chiracel OJ 20 μ m, separate the racemic alpha-alpha-dimethyl amino methyl tryptophan methyl ester of 15 grams that obtains among the embodiment 2, tell 6.2 gram (R)-enantiomorphs and 6.45 gram (S) enantiomorphs.
Embodiment 8.B:2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide (S, S) synthetic
Step 1:(S)-2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-methyl propionate
At room temperature, with (S)-2-amino-2-dimethylaminomethyl-3-(1H-indol-3-yl)-methyl propionate (5.69 grams, 20.7mmol), cumarone-2-formaldehyde (4.77 the gram, 32.7mmol) and sodium triacetoxy borohydride (9.24 grams, 43.6mmol) 1, stirred 8 hours in the 2-ethylene dichloride (100 milliliters).Use CH
2Cl
2The diluted mixture thing, with NaOH (0.5M), salt water washing, and dry (MgSO
4).Except that after desolvating, use the heptane wash raw material, stay fawn-coloured solid (6.45 grams, 77%).
δ
H?2.27(6H，s，N(CH
3)
2)，2.74(2H，dd，CH
2N，J13.6，20.4Hz)，3.27(2H，s，
CH
2Ind)，3.63(3H，s，OMe)，4.08(2H，dd，CH
2N，J14.0，38.8Hz)，6.57(1H，s，
arom)，7.09-7.34(6H，m，arom)，7.42(1H，m，arom)，7.51(1H，m，arom)，7.63
(1H，d，arom，J8.0Hz)，8.03(1H，s，NH).
ν
max?1718，142，1174，742cm
-1；
m/z?406(MH
+，100)；
Step 2:(S)-2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-propionic acid dihydrochloride
With (S)-2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-methyl propionate (6.35 grams, 15.7mmol) and (608 milligrams in sodium hydroxide, 15.7mmol) 1,4-diox/aqueous solution under refluxad heated 4 days.Remove and to desolvate, then mixture use the 10%HCl acidifying, remove once more and desolvate, stay brown foam (～10 restrain,＞quantitative).δ
H(DMSO-d
6)2.18(6H，s，N(CH
3)
2)，2.48(2H，s，CH
2N)，J13.6，20.4Hz)，3.01(2H，s，CH
2Ind)，3.88(2H，dd，CH
2N)，6.57(1H，d，arom，J0.4Hz))，6.89(1H，m，arom)，6.96(1H，m，arom)，7.14-7.28(4H，m，arom)，7.45(1H，m，arom)，7.52(1H，m，arom)，7.57(1H，d，arom，J8.0Hz)，10.69(1H，s，NH).
Step 3:(S)-2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-((S)-1-phenyl-ethyl)-propionic acid amide
In DMF (75 milliliters), with (S)-2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-propionic acid dihydrochloride (6.13 grams, suppose 15.7mml), HBTU (5.95 the gram, 15.7mmol), (S)-α-Jia Jibianji amine (2.85 the gram, 23.6mmol) and DIPEA (10.13 the gram, 78.5mmol) at room temperature stir 6 hours.Remove and desolvate, in EtOAc, handle raw material then, use 15%K
2CO
3, the salt water washing, and dry (MgSO
4).Obtain yellow solid with chromatography (the C7 solution of 20-50%EtOAc) purified feed stock, it is obtained yellow powder with heptane wash.By RP-HPLC (0-100%MeOH/ water) once more the part of purification of impure obtain further product white-yellowish solid.
Total recovery (1.91g, 25%).
Data are seen embodiment 2.
Embodiment 9
With NK
1The combination of acceptor
Compound of the present invention is high selectivity and emulative NK
1Receptor antagonist.As described belowly them have been estimated at NK
1Combination in the acceptor.
Method
In RPMI 1640 substratum that replenish with 10% foetal calf serum and 2mM glutamine, make the growth of human lymphoma IM9 cell, and remain on 5%CO
2Under the atmosphere.By being replayed, cell to milliliter every 175cm2 flask of concentration 4～800 ten thousand/40, made passage in every 3-4 days.By testing required cell in 3 minutes results of 1000g centrifugation.Sedimentary cell is being measured damping fluid (50 millimeters Tris HCl, pH value 7.4,3mM MnCl
2, 0.02%BSA, 40 mg/ml bacitracins, 2 mg/ml chymostatins, 2mM phosphamide element, 4 mg/ml leupeptins) in the resuspending washing once, and be resuspending, repeated centrifugation separating step afterwards in the mensuration damping fluid of 2.5 * 106 cells/ml in concentration.Under the situation of the test compound that is with or without different concns, use [
125I] Bolton-Hunter Substance P (0.05-0.1nM) is at 21 ℃ of following hatching cells (200 milliliters) 50 minutes.By 1mM[Sar
9, Met (O
2) 11) Substance P defines nonspecific combination (observe into total binding 10%) under this condition.With the Brandel cell harvestor by with 0.2%PEI preimpregnation 1-2 hour GF under vacuum, filter termination reaction fast on the C nutsche filter.Wash nutsche filter with 6 * 1 milliliters of ice-cold TrisHCl (50mM, pH value 7.4), and measure the radioactivity combination with gamma counter.In RS1 or Graphpad lnplot, carry out interpretation of result with the iteration curve-fitting method.
Table I: vitro human NK as a result
1Receptors bind is measured
| Embodiment No. | ?NK 1In conjunction with IC 50(nM) |
| ?1 | ?6.56 |
| ?2 | ?0.89 |
| ?3 | ?1.41 |
| ?4 | ?4.93 |
| ?5 | ?1.07 |
| ?6 | ?28.8 |
| ?7 | ?6.96 |
Because these compounds are NK
1The effective part of acceptor, they can be effectively replace Substance P in its position, therefore can be used for treating other the biological conditions by the Substance P mediation.Therefore, these can be at NK
1The compound of the effect of antagonistic substance P can be effective to treatment or prevent that various CNS obstacles from comprising pain (struvite, surgery with neuropathic pain), anxiety on the acceptor, fear, dysthymia disorders has the severe dysthymia disorders of anxiety, schizophrenia, neurodynia, anxiety, sexual disorder, amphicheirality's mental disorder, dyskinesia, cognitive disorder and habituation obstacle; Struvite disease is sacroiliitis for example, asthma, bronchitis, COPD and psoriasis; The stomach and intestine disorder comprises colitis, Crohn disease, irritable bowel syndrome and satiety; Anaphylaxis is eczema and rhinitis for example; Vascular disorder is angina and migraine for example; The obstacle of neuropathology comprises scleroderma and vomiting.Compound of the present invention, NK
1Receptor antagonist also is effective angiogenesis inhibitor medicament, is used for the treatment of the situation relevant with unusual neovascularization for example rheumatoid arthritis, atherosclerosis and growth of tumour cell.They also can be used as uses NK
1The medicament of acceptor in-vivo imaging is for example under the illness of ulcerative colitis and Crohn disease.
Embodiment 10
The carrageenin inductive allergy model of cavy
Method
Male Dunkin Hartley cavy (200-250 gram) is divided into 4 groups, carries out 12 hours illumination/dark cycle (turning on light at 7:00), food and water arbitrarily absorb.
Carrageenin-inductive allergy:
By injecting in the right back pawl toe, cavy is carried out carrageenin (100 μ l, 20 mg/ml) administration.With " intelligent anesthesia test device (Incapacitance tester) " (LintonInstruments, U.K.) in the test of bearing a heavy burden, measure their allergy:
Animal is placed instrument, and note the heavy burden that it applies by rear solid end.Every interval was once measured in one minute, measures three times, and calculating mean value.Be adjusted to 4 seconds for the cavy measuring interval.(baseline) carries out animal experiment with different interval, injection back before the injection carrageenin.Before giving carrageenin 1 hour, the subcutaneous compound that gives embodiment 2, dosage are 1 ml/kg (in PEG 200 vehicle).With the allergy of heavy burden test evaluation.
The heavy burden of calculating between homonymy and the offside pawl is poor, carries out One-way ANOVA then, then for each research time-carry out the Dunnett check, (
*P＜0.05,
*P＜0.01 is different from the animal that vehicle is treated significantly).
(n, every group=6-19) mean deviation is come ecbatic with the heavy burden ± SEM (gram) of the pawl of homonymy and offside.
The result
In the rear solid end middle toe, inject the allergy that carrageenin (100 μ l, 20 mg/ml) is induced cavy, as by the heavy burden test evaluation.Give with carrageenin before the compound (0.1 and 1mg/kg, in PEG 200 vehicle) of 1 hour subcutaneous injection embodiment 2, but dose-dependently prevent to the formation (Fig. 1) of carrageenin allergy after 3 hours.
As mentioned above, the compound of formula I preferably uses with the form of pharmaceutical preparation.The following examples further illustrate concrete preparation provided by the present invention.
Embodiment 11
Tablet
| ????????????????? Composition | ???? Consumption |
| 2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide (S, S) | ????50mg |
| Yam starch | ????100mg |
| Talcum powder | ????50mg |
| Magnesiumcarbonate | ????20mg |
| Dextrose | ????20mg |
| 240 milligrams |
Mentioned component is mixed and tablet forming.This tablet of the people who is put to the test every day one to four time, be used for the treatment of the illness relevant for example rheumatoid arthritis, atherosclerosis and growth of tumour cell with unusual neovascularization.
Embodiment 12
Parenteral injection
| ???????????????????? Composition | ?? Consumption |
| 2-(3-cumarone-2-ylmethyl-urea groups)-3-(1H-indol-3-yl)-2-methoxymethyl-N-(1-phenyl-ethyl)-propionic acid amide [S-(R *，R *)] | 20 milligrams |
| Citric acid monohydrate | 0.75 milligram |
| Sodium phosphate | ??4.5mg |
| Sodium-chlor | ??9mg |
| Water for injection | To 10ml |
Sodium phosphate, citric acid monohydrate compound and sodium-chlor are dissolved in a part of water.Active ingredient is dissolved in this solution, adds to volume required then.
Embodiment 13
Parenteral injection
| ?????????????????? Composition | ???? Consumption |
| 2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide (S, S) | 20 milligrams |
| The citric acid monohydrate compound | 0.75 milligram |
| Sodium phosphate | 4.5 milligram |
| Sodium-chlor | ????9mg |
| Water for injection | To 10ml |
With sodium phosphate, citric acid monohydrate compound and sodium-chlor are dissolved in a part of water.Active ingredient is dissolved in this solution, adds to volume required then.
Claims (18)
1. the compound of formula I or its pharmacologically acceptable salts,
Wherein:
● and ▲ all steric isomers of expression;
R is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Quinolyl
Isoquinolyl
Naphthyl,
Benzofuryl,
Benzo [1,3] dioxole
Benzothienyl or,
Benzimidazolyl-, they each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3Or
OCF
3；
M is the integer of 1-3;
X is NR8 or NHCONH, and wherein R8 is the alkyl of H or 1-3 carbon atom;
R1 is (CH
2)
pY wherein p be 0 to 3 and Y be OH, OCH
3, F, CF
3, CO
2H, N (CH
3)
2, NHCH
3, NH
2, COCF
3, COCH
3Or NO
2
N is 1 to 2 integer;
R2 is naphthyl or indyl, and it is unsubstituted or is replaced by following group N-: hydroxyl, alkyl, formyl radical, CH
2OH,
CH
2N(CH
3)
2，
Z is NR3 or O, and wherein R3 is H or C
1-C
4Alkyl;
R4 and R5 independently are hydrogen separately, or (CH
2)
pR7 is wherein:
P is 1 to 3 integer, and
R7 is H, CH
3, CN, OH, OCH
3, CO
2CH
3, NH
2, NHCH
3, or N (CH
3)
2
R6 is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Pyrryl,
Pyrazolyl,
Imidazolyl,
Quinolyl,
Isoquinolyl,
Naphthyl,
Indyl,
Benzofuryl,
Benzothienyl,
Benzimidazolyl-, or
Benzoxazolyl, wherein aforementioned every each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3，
NO
2，
N(CH
3)
2，
OCF
3，
SONH
2，
NH
2，
CONH
2，
CO
2CH
3Or
CO
2H，
Or R6 is:
The straight chained alkyl of 1 to 3 carbon,
The branched-chain alkyl of 3 to 8 carbon,
The cycloalkyl of 5 to 8 carbon or
Heterocyclylalkyl, each can by at the most one or two be selected from following substituting group and replace:
OH，
CO
2H，
N(CH
3)
2，
NHCH
3With
CH
3Or
R5 and R6 when connecting by a key, form a ring.
2. the compound of formula I, wherein:
● be R or S, and ▲ be R or S;
-R is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Quinolyl
Isoquinolyl
Benzofuryl,
Benzo [1,3] dioxole
Benzothienyl or
Benzimidazolyl-, they each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3Or
OCF
3；
M is 1 to 3 integer;
X be NR8 or NHCONH wherein R8 be the alkyl of H or 1-3 carbon atom;
R1 is (CH
2)
pY wherein p is that O-3 and Y are OH, F, CF
3, OCH
3, CO
2H, N (CH
3)
2, NHCH
3, NH
2, COCF
3, COCH
3Or NO
2
N is 1 to 2 integer;
R2 is naphthyl or indyl, and it is unsubstituted or is replaced by following group N-: hydroxyl, and alkyl,
Formyl radical, CH
2OH, CH
2N (CH
3)
2,
Z is NR3 or O, and wherein R3 is H or CH
3
R4 and R5 independently are hydrogen separately, CH
3Or CH
2OH;
R6 is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Pyrryl,
Cyclohexyl or
Benzimidazolyl-,
Wherein aforementioned each be unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3，
NO
2, or
N(CH
3)
2。
3. the compound of formula I, wherein:
● be R or S, and ▲ be R or S;
R is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Benzofuryl,
Benzo [1,3] dioxole
Benzothienyl or,
Benzimidazolyl-, they each be unsubstituted, or by following group list-, two-or three-replace:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3Or
OCF
3；
M is the integer of 1-3;
X is NR8 or NHCONH, and wherein R8 is the alkyl of H or 1-3 carbon atom;
R1 is (CH
2)
pY wherein p be 0 to 3 and Y be OH, OCH
3, F, CF
3, CO
2H, N (CH
3)
2, NHCH
3, NH
2, COCF
3, COCH
3Or NO
2
N is 1 to 2 integer;
R2 is an indyl unsubstituted or that replaced by alkyl or formyl radical N-;
Z is NR3 or O, and wherein R3 is H or CH
3
R4 and R5 independently are hydrogen separately, CH
3Or CH
2OH;
R6 is a phenyl,
Pyridyl,
Thienyl,
Furyl,
Pyrryl,
Cyclohexyl, or
Benzimidazolyl-,
Wherein each is unsubstituted, or by following group list-, two or trisubstituted:
Alkyl,
Hydroxyl,
Alkoxyl group,
Halogen,
CF
3，
NO
2Or
N(CH
3)
2。
4. according to the compound of claim 1, be selected from:
2-[(cumarone-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methoxymethyl-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)],
2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide (S, S),
2-[(cumarone-2-ylmethyl)-amino]-2-methylol-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)],
2-(3-cumarone-2-ylmethyl-urea groups)-2-methylol-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)],
2-(3-cumarone-2-ylmethyl-urea groups)-3-(1H-indol-3-yl)-2-methoxymethyl-N-(1-phenyl-ethyl)-propionic acid amide [S-(R
*, R
*)],
(R)-C-[(cumarone-2-ylmethyl)-amino]-dimethylamino-C-(1-methylol-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl)-propionic acid amide,
(R)-C-[(cumarone-2-ylmethyl)-amino]-dimethylamino-C-(1-dimethylaminomethyl-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl) propionic acid amide.
5. mammiferous NK that antagonism need be treated
1The method of acceptor comprises the compound of the claim 1 that gives the Mammals significant quantity.
6. a treatment and prevent the method for following disease:
-CNS obstacle is pain (struvite, surgery with neuropathic) for example, anxiety, and fear, dysthymia disorders is accompanied by the severe dysthymia disorders of anxiety, schizophrenia, neurodynia, anxiety, sexual dysfunction, amphicheirality's mental disorder, dyskinesia, cognitive disorder, fat and habituation obstacle;
-struvite disease is sacroiliitis for example, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis;
-gastrointestinal disorders comprises colitis, Crohn disease, irritable bowel syndrome and satiety;
-transformation reactions is eczema and rhinitis for example;
-vascular disorder is angina and migraine for example;
The obstacle of-europathology comprises scleroderma and vomiting;
And
-the situation relevant, for example rheumatoid arthritis, atherosclerosis and growth of tumour cell with unusual neovascularization
This method comprises the compound of the claim 1 of the Mammals significant quantity that needs treatment.
7. the compound according to claim 1 is used as medicine.
8. one kind comprises the compound of claim 1 and the pharmaceutical preparation of at least a pharmacy acceptable diluent, carrier or mixed with excipients.
9. one kind comprises the compound of claim 3 and the pharmaceutical preparation of at least a pharmacy acceptable diluent, carrier or mixed with excipients.
A treatment relevant with unusual neovascularization the illness method of rheumatoid arthritis, atherosclerosis and growth of tumour cell for example.
11. NK under the situation of for example ulcerative colitis and Crohn disease
1The method of acceptor in-vivo imaging.
12. the compound of claim 1 is used for for example pain (struvite, surgery with neuropathic) of prevention or treatment CNS obstacle, anxiety, fear in preparation, dysthymia disorders, be accompanied by the severe dysthymia disorders of anxiety, schizophrenia, neurodynia, nervous, sexual dysfunction, amphicheirality's mental disorder, dyskinesia, cognitive disorder, fat and habituation obstacle; Struvite disease is sacroiliitis for example, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; Gastrointestinal disorders comprises colitis, Crohn disease, irritable bowel syndrome and satiety; Transformation reactions is eczema and rhinitis for example; Vascular disorder is angina and migraine for example; The obstacle of europathology comprises scleroderma and vomiting; The situation relevant with unusual neovascularization be rheumatoid arthritis for example, the purposes in the medicine of atherosclerosis and growth of tumour cell.
13. a method for preparing ((S)-2-benzylidene amino)-3-(1H-indol-3-yl)-methyl propionate, this method comprise that the reaction of (S)-tryptophan methyl ester and phenyl aldehyde reclaims target product then.
14.-plant the method for preparing alpha-alpha-dimethyl amino methyl tryptophan methyl ester, wherein, obtain racemic alpha-alpha-dimethyl amino methyl tryptophan methyl ester with ((S)-2-benzal-amino)-3-(1H-indol-3-yl)-methyl propionate and the reaction of 1-dimethylaminomethyl benzotriazole.
15. according to the method for claim 14, wherein the racemize methyl esters that obtains is separated into (R)-and (S)-enantiomorph.
16. one kind prepares 2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide (S, S) method is wherein with (S)-2-[(cumarone-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-indol-3-yl)-propionic acid dihydrochloride with (S)-α-Jia Jibianji amine reaction.
17. (R)-C-[(cumarone-2-ylmethyl)-amino]-preparation method of dimethylamino-C-(1-methylol-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl)-propionic acid amide, wherein with 2-[(cumarone-2-ylmethyl)-amino]-(S is S) with hexamethyldisilane base amination potassium and formaldehyde reaction for 2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide.
18. (R)-C-[(cumarone-2-ylmethyl)-amino]-preparation method of dimethylamino-C-(1-dimethylaminomethyl-1H-indol-3-yl methyl)-N-((S)-1-phenyl-ethyl)-propionic acid amide, wherein with 2-[(cumarone-2-ylmethyl)-amino]-(S is S) with hexamethyldisilane base amination lithium and Eschenmoser reactant salt for 2-dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionic acid amide.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17154099P | 1999-12-22 | 1999-12-22 | |
| US60/171,540 | 1999-12-22 | ||
| EP00103665.6 | 2000-02-22 | ||
| EP00103665A EP1127875A1 (en) | 2000-02-22 | 2000-02-22 | Process for the preparation of alpha-dimethylaminomethyl-tryptophan methyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1413206A true CN1413206A (en) | 2003-04-23 |
Family
ID=26070578
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00817549A Pending CN1413206A (en) | 1999-12-22 | 2000-12-21 | Non peptide tachykinin receptor antagonists |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP1244653A1 (en) |
| JP (1) | JP2003518111A (en) |
| KR (1) | KR20020062364A (en) |
| CN (1) | CN1413206A (en) |
| AP (1) | AP2002002556A0 (en) |
| AU (1) | AU2370801A (en) |
| BG (1) | BG106804A (en) |
| BR (1) | BR0016626A (en) |
| CA (1) | CA2399584A1 (en) |
| IL (1) | IL150203A0 (en) |
| IS (1) | IS6395A (en) |
| MA (1) | MA26854A1 (en) |
| MX (1) | MXPA02006282A (en) |
| NO (1) | NO20022942D0 (en) |
| OA (1) | OA12129A (en) |
| PL (1) | PL357650A1 (en) |
| SK (1) | SK8862002A3 (en) |
| WO (1) | WO2001046176A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2129381A1 (en) | 2007-01-24 | 2009-12-09 | Glaxo Group Limited | Pharmaceutical compositions comprising 3, 5-diamin0-6- (2, 3-dichl0phenyl) -l, 2, 4-triazine or r (-) -2, 4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethyl pyrimidine and an nk1 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994004494A1 (en) * | 1992-08-13 | 1994-03-03 | Warner-Lambert Company | Tachykinin antagonists |
| AU2180600A (en) * | 1998-12-18 | 2000-07-12 | Warner-Lambert Company | Non-peptide nk1 receptors antagonists |
-
2000
- 2000-12-21 OA OA1200200196A patent/OA12129A/en unknown
- 2000-12-21 BR BR0016626-0A patent/BR0016626A/en not_active Application Discontinuation
- 2000-12-21 WO PCT/EP2000/013349 patent/WO2001046176A2/en active Search and Examination
- 2000-12-21 CA CA002399584A patent/CA2399584A1/en not_active Abandoned
- 2000-12-21 JP JP2001547086A patent/JP2003518111A/en active Pending
- 2000-12-21 SK SK886-2002A patent/SK8862002A3/en unknown
- 2000-12-21 AP APAP/P/2002/002556A patent/AP2002002556A0/en unknown
- 2000-12-21 IL IL15020300A patent/IL150203A0/en unknown
- 2000-12-21 KR KR1020027008007A patent/KR20020062364A/en not_active Application Discontinuation
- 2000-12-21 CN CN00817549A patent/CN1413206A/en active Pending
- 2000-12-21 PL PL00357650A patent/PL357650A1/en not_active Application Discontinuation
- 2000-12-21 MX MXPA02006282A patent/MXPA02006282A/en unknown
- 2000-12-21 EP EP00987477A patent/EP1244653A1/en not_active Withdrawn
- 2000-12-21 AU AU23708/01A patent/AU2370801A/en not_active Abandoned
-
2002
- 2002-05-24 IS IS6395A patent/IS6395A/en unknown
- 2002-06-10 BG BG106804A patent/BG106804A/en unknown
- 2002-06-14 MA MA26689A patent/MA26854A1/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| KR20020062364A (en) | 2002-07-25 |
| WO2001046176A2 (en) | 2001-06-28 |
| BG106804A (en) | 2003-03-31 |
| OA12129A (en) | 2006-05-05 |
| MA26854A1 (en) | 2004-12-20 |
| CA2399584A1 (en) | 2001-06-28 |
| WO2001046176A3 (en) | 2002-07-04 |
| EP1244653A1 (en) | 2002-10-02 |
| IL150203A0 (en) | 2002-12-01 |
| MXPA02006282A (en) | 2004-09-06 |
| AU2370801A (en) | 2001-07-03 |
| IS6395A (en) | 2002-05-24 |
| BR0016626A (en) | 2002-11-05 |
| NO20022942L (en) | 2002-06-19 |
| PL357650A1 (en) | 2004-07-26 |
| SK8862002A3 (en) | 2002-11-06 |
| AP2002002556A0 (en) | 2002-06-30 |
| JP2003518111A (en) | 2003-06-03 |
| NO20022942D0 (en) | 2002-06-19 |
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