CN1964939B - Compounds and compositions for delivering active agents - Google Patents

Compounds and compositions for delivering active agents Download PDF

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Publication number
CN1964939B
CN1964939B CN2005800186141A CN200580018614A CN1964939B CN 1964939 B CN1964939 B CN 1964939B CN 2005800186141 A CN2005800186141 A CN 2005800186141A CN 200580018614 A CN200580018614 A CN 200580018614A CN 1964939 B CN1964939 B CN 1964939B
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compound
another embodiment
methyl
acid
solution
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CN1964939A (en
Inventor
M·I·格梅泽-欧雷兰那
D·克施内德纳
A·里奥内-贝
D·莫伊-舍曼
S·V·普兹泰
P·拉赛
邓炳华
J·J·韦德纳
宋建峰
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Emisphere Technologies Inc
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Emisphere Technologies Inc
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Abstract

Compounds and compositions for the delivery of active agents are provided. Methods of administration and preparation are provided as well.

Description

Transmit the compound and the compsn of promoting agent
The application requires the rights and interests of following patented claim: the U.S. Provisional Application that the U.S. Provisional Application of submitting on June 1st, 2004 is submitted to number on June 1st, 60/576,088,2004 number 60/576,397; The U.S. Provisional Application that the U.S. Provisional Application of submitting on June 1st, 2004 is submitted to number on May 14th, 60/576,105,2004 number 60/571,090; The U.S. Provisional Application that the U.S. Provisional Application of submitting on May 14th, 2004 is submitted to number on May 14th, 60/571,092,2004 number 60/571; The U.S. Provisional Application of submitting on May 14th, 195,2004 number 60/571,194; The U.S. Provisional Application that the U.S. Provisional Application of submitting on May 14th, 2004 is submitted to number on May 14th, 60/571,093,2004 number 60/571; The U.S. Provisional Application of submitting on May 14th, 055,2004 number 60/571,151; The U.S. Provisional Application that the U.S. Provisional Application of submitting on May 14th, 2004 is submitted to number on May 14th, 60/571,315,2004 number 60/571; The U.S. Provisional Application of submitting on May 14th, 144 and 2004 number 60/571,089, more than all patented claims incorporate this paper into as a reference.
Technical field
The present invention relates to target spot transmit promoting agent (biological example or chemical active agent) compound and compsn.These compounds are fit to form the non-covalent mixture that is applied to animal with oral or other approach with promoting agent very much.The present invention also discloses the preparation and the application process of said composition.
Background technology
The usual manner that transmits promoting agent often receives the serious restriction of biology, chemistry and physical barriers.Typically, these barriers are to be produced by the environment of transmission generation, the target spot environment and/or the target spot itself of transmission.The biological and chemical promoting agent is subject to the influence of this barrier especially.
In the animal transmittance process, this barrier is provided with by body at biological activity and chemically active pharmacology and therapeutical agent.The instance of physical barriers is skin, epithelium, lipid bilayer and multiple organ film, and agent is impermeable relatively to these barriers for certain activity, but arriving target spot, for example must pass this barrier before the recycle system.Chemical barrier is including, but not limited to variation and the degrading enzyme of pH in stomach and intestine (GI) road.
These barriers are particularly importants in the design of oral delivery system.The oral delivery of a lot of promoting agents so then can be used as the selection approach that is applied to animal if not biology, chemistry and physical barriers.In receiving the Orally administered multiple material that influences, do not comprise the biological or chemical bioactive peptide, for example thyrocalcitonin and Regular Insulin with being true to type; Polysaccharide, mucopolysaccharide for example is including, but not limited to heparin; Heparitin; Microbiotic; And other organic substance.These materials possibly become invalid fast by acidolysis, enzyme etc. in gi tract or destroy.In addition, the size of macromolecular drug and structure also can suppress to absorb.
The early stage method of Orally administered affected pharmacological agents depends on and uses adjuvant (for example Resorcinol and non-ionics jointly; For example polyoxyethylene oleyl ether and n-hexadecyl polyvinyl ether) increase the perviousness of intestines wall with manual work, and use the degraded of enzyme inhibitors (for example trypsin inhibitor, diisopropylphosphofluoridate (DFP) and Trypsin inhibitor,Trasylol) jointly with inhibitory enzyme.Liposome also has been described as the drug delivery system of Regular Insulin and heparin.But the widespread adoption of this drug delivery system is prevented from owing to such reasons: (1) this system needs the adjuvant or the suppressor factor of toxic dose; (2) the low-molecular-weight goods (being promoting agent) that is fit to can not obtain; (3) system shows poor stability and quality guaranteed period deficiency; (4) system is difficult to preparation; (5) system can not protect promoting agent (goods); (6) system changes promoting agent unfriendly; Or (7) system does not allow or promotes the absorption of promoting agent.
The proteinoid microballoon has been used to transmit medicine.See for example U.S. Patent number 5,401,516,5,443,841 and Re.35,862.In addition, the amino acid of some modifications has been used to transmit medicine.See for example U.S. Patent number 5,629,020,5; 643,957,5,766; 633,5; 776,888 and 5,866; 536, and International Patent Publication No. WO 98/49135, WO00/06534, WO00/07979, WO00/40203, WO00/47188, WO00/50386, WO00/59863, WO01/32130, WO01/32596, WO01/44199, WO01/51454, WO02/02509, WO02/15959, WO02/16309, WO02/20466, WO02/19969, WO02/69937, WO03/45306.
Recently, polymkeric substance is connected so that the polymkeric substance delivery agent to be provided with the amino acid or derivatives thereof of modification through linking group.The polymkeric substance of modifying can be any polymkeric substance, but preferred polymkeric substance is including, but not limited to polyoxyethylene glycol (PEG) and verivate thereof.See for example International Patent Publication No. WO 00/40203.
But, still need be prone to prepare and can be through simple, the cheap transfer system of the large-scale promoting agent of number of ways transmission.
Summary of the invention
The invention provides the compound and the compsn that help transmitting promoting agent.Delivery agent compound of the present invention comprises following compound and pharmacologically acceptable salt thereof:
Compd A
Wherein:
R 1Be-(CH 2) m-R 8, m=0 or 1 wherein;
R 2-R 6Be independently selected from hydrogen, hydroxyl, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, C 1-C 4Alkoxyl group and cyanic acid;
R 7Be selected from C 1-C 10Alkyl, C 2-C 10Alkenyl and C 2-C 10Alkynyl;
R 8Be selected from cyclopentyl, cyclohexyl and phenyl, wherein work as R 8When being phenyl, m=1; And
R 8Randomly by C 1-C 4Alkyl, C 1-C 4Alkoxyl group, halogen or hydroxyl or its combination replace.
In one embodiment, R 7Be C 1Alkyl.
In another embodiment, R 7Be C 2Alkyl.
In another embodiment, R 7Be C 3Alkyl.
In another embodiment, R 7Be C 4Alkyl.
In another embodiment, R 7Be C 5Alkyl.
In another embodiment, R 7Be C 6Alkyl.
In another embodiment, R 7Be C 7Alkyl.
In another embodiment, R 7Be C 8Alkyl.
Preferred compound is including, but not limited to following compound and pharmacologically acceptable salt thereof:
(compound 1)
(compound 2)
(compound 3)
(compound 4)
(compound 5)
Figure S05818614120061211D000053
(compound 6)
(compound 7)
(compound 8)
(compound 9)
Figure S05818614120061211D000064
(compound 10)
(compound 11)
(compound 12)
(compound 13)
(compound 14)
Figure S05818614120061211D000081
(compound 15)
Figure S05818614120061211D000082
(compound 16)
Figure S05818614120061211D000083
(compound 17)
(compound 18)
(compound 19)
Figure S05818614120061211D000092
(compound 20)
(compound 21)
(compound 22)
Other delivery agent compounds of the present invention comprise those compounds and the pharmacologically acceptable salt thereof of following formula:
(compd B)
Wherein:
R 1Be C 1-C 6Alkyl or C 2-C 6Alkenyl,
R 2-R 6Be independently selected from hydrogen, hydroxyl, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, C 1-C 4Alkoxyl group and cyanic acid, and
R 7Be selected from C 1-C 10Alkyl, C 2-C 10Alkenyl and C 2-C 10Alkynyl.
In one embodiment, R2-R6 is hydrogen, methyl, halogen, methoxyl group independently.
In another embodiment, R2-R6 is hydrogen, methyl, chlorine, methoxyl group independently.
In another embodiment, R2-R6 is hydrogen, methyl, fluorine, methoxyl group independently.
In another embodiment, R2-R6 is hydrogen, methyl, iodine, methoxyl group independently.
In another embodiment, R2-R6 is hydrogen, methyl, bromine, methoxyl group independently.
In another embodiment, R1 is C 1-C 3Alkyl.
In another embodiment, R1 is a methyl.
In another embodiment, R1 is an ethyl.
In another embodiment, R1 is a sec.-propyl.
In another embodiment, R2 is a methyl.
In another embodiment, R2 is a halogen.
In another embodiment, R2 is a chlorine.
In another embodiment, R2 is a fluorine.
In another embodiment, R4 is a methyl.
In another embodiment, R4 is a methoxyl group.
In another embodiment, R4 is a halogen.
In another embodiment, R4 is a chlorine.
In another embodiment, R4 is a fluorine.
In another embodiment, R4 is a cyanic acid.
In another embodiment, R7 is C 1Alkyl.
In another embodiment, R7 is C 2Alkyl.
In another embodiment, R7 is the C with methyl branch 2Alkyl.
In another embodiment, R7 is C 3Alkyl.
In another embodiment, R7 is the C with methyl branch 3Alkyl.
In another embodiment, R7 is C 4Alkyl.
In another embodiment, R7 is C 5Alkyl.
In another embodiment, R7 is C 6Alkyl.
In another embodiment, R7 is C 7Alkyl.
In another embodiment, R7 is C 8Alkyl.
Preferred compound is including, but not limited to following compound and pharmacologically acceptable salt thereof
Compound
23
6-(sec.-propyl-
Phenyl-amino first
Acyl group)-caproic acid
Compound
24
6-[sec.-propyl
(phenyl) ammonia
Base]-the 6-oxo
Caproic acid
Compound
25
Figure S05818614120061211D000113
5-[sec.-propyl
(phenyl) ammonia
Base]-the 3-methyl
-5-oxopentanoic acid
Compound
26
Figure S05818614120061211D000114
5-[ethyl (benzene
Base) amino]-3-
Methyl-5-oxo
Valeric acid
Compound
27
Figure S05818614120061211D000121
7-[methyl (benzene
Base) amino]-7-
The oxo enanthic acid
Compound
28
Figure S05818614120061211D000122
3-methyl-5-[first
Base (phenyl) ammonia
Base]-the 5-oxo
Valeric acid
Compound
29
Figure S05818614120061211D000123
4-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 4-oxo
Butyric acid
Compound
30
Figure S05818614120061211D000124
8-[methyl (4-first
The base phenyl) ammonia
Base]-the 8-oxo
Sad
Compound
31
Figure S05818614120061211D000125
8-[(4-methoxyl group
Phenyl) (methyl)
Amino]-8-oxygen
In generation, is sad
Compound
32
Figure S05818614120061211D000126
8-[ethyl (benzene
Base) amino]-8-
Oxo is sad
Compound
33
8-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 8-oxo
Sad
Compound
34
8-[(4-fluorobenzene
Base) (methyl) ammonia
Base]-the 8-oxo
Sad
Compound
35
Figure S05818614120061211D000132
10-[methyl (4-
Aminomethyl phenyl) ammonia
Base]-the 10-oxo
Capric acid
Compound
36
Figure S05818614120061211D000133
3-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 3-oxo
Propionic acid
Compound
37
Figure S05818614120061211D000134
3-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 3-oxo
Propionic acid
Compound
38
5-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 4-methyl
-5-oxopentanoic acid
Compound
39
Figure S05818614120061211D000136
10-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 10-oxo
Capric acid
Compound
40
4-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 4-oxo
Butyric acid
Compound
41
Figure S05818614120061211D000142
5-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 5-oxo
Valeric acid
Compound
42
Figure S05818614120061211D000143
7-[ethyl (2-first
The base phenyl) ammonia
Base]-the 7-oxo
Enanthic acid
Compound
43
6-[ethyl (2-first
The base phenyl) ammonia
Base]-the 6-oxo
Caproic acid
Compound
44
Figure S05818614120061211D000145
4-methyl-5-[first
Base (4-methylbenzene
Base) amino]-5-
Oxopentanoic acid
Compound
45
Figure S05818614120061211D000146
5-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 4-methyl
-5-oxopentanoic acid
Compound
46
8-[methyl (2-first
The base phenyl) ammonia
Base]-the 8-oxo
Sad
Compound
47
Figure S05818614120061211D000152
5-[ethyl (2-first
The base phenyl) ammonia
Base]-the 3-methyl
-5-oxopentanoic acid
Compound
48
5-[sec.-propyl
(phenyl) ammonia
Base]-the 4-methyl
-5-oxopentanoic acid
Compound
49
5-[ethyl (2-first
The base phenyl) ammonia
Base]-the 4-methyl
-5-oxopentanoic acid
Compound
50
Figure S05818614120061211D000155
4-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 3-methyl
-4-ketobutyric acid
Compound
51
Figure S05818614120061211D000156
9-[methyl (4-first
The base phenyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
52
Figure S05818614120061211D000161
8-[ethyl (2-first
The base phenyl) ammonia
Base]-the 8-oxo
Sad
Compound
53
Figure S05818614120061211D000162
8-[sec.-propyl
(phenyl) ammonia
Base]-the 8-oxo
Sad
Compound
54
9-[methyl (2-first
The base phenyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
55
Figure S05818614120061211D000164
6-[ethyl (benzene
Base) amino]-6-
The oxo caproic acid
Compound
56
Figure S05818614120061211D000165
7-[ethyl (2-first
The base phenyl) ammonia
Base]-the 7-oxo
Enanthic acid
Compound
57
Figure S05818614120061211D000171
9-[ethyl (2-first
The base phenyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
58
Figure S05818614120061211D000172
10-[ethyl (benzene
Base) amino]-10-
The oxo capric acid
Compound
59
6-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 6-oxo
Caproic acid
Compound
60
Figure S05818614120061211D000174
4-[sec.-propyl
(phenyl) ammonia
Base]-the 4-oxo
Butyric acid
Compound
61
Figure S05818614120061211D000181
5-[ethyl (benzene
Base) amino]-4-
Methyl-5-oxo
Valeric acid
Compound
62
Figure S05818614120061211D000182
4-[ethyl (2-first
The base phenyl) ammonia
Base]-the 4-oxo
Butyric acid
Compound
63
5-[methyl (4-first
The base phenyl) ammonia
Base]-the 5-oxo
Valeric acid
Compound
64
Figure S05818614120061211D000184
5-[methyl (2-first
The base phenyl) ammonia
Base]-the 5-oxo
Valeric acid
Compound
65
5-[sec.-propyl
(phenyl) ammonia
Base]-the 5-oxo
Valeric acid
Compound
66
5-[ethyl (benzene
Base) amino]-4-
Methyl-5-oxo
Valeric acid
Compound
67
Figure S05818614120061211D000192
5-[ethyl (benzene
Base) amino]-5-
Oxopentanoic acid
Compound
68
Figure S05818614120061211D000193
6-[methyl (4-first
The base phenyl) ammonia
Base]-the 6-oxo
Caproic acid
Compound
69
6-[methyl (2-first
The base phenyl) ammonia
Base]-the 6-oxo
Caproic acid
Compound
70
6-[ethyl (2-first
The base phenyl) ammonia
Base]-the 6-oxo
Caproic acid
Compound
71
Figure S05818614120061211D000196
7-[methyl (4-first
The base phenyl) ammonia
Base]-the 7-oxo
Enanthic acid
Compound
72
Figure S05818614120061211D000201
7-[methyl (2-first
The base phenyl) ammonia
Base]-the 7-oxo
Enanthic acid
Compound
73
5-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 5-oxo
Valeric acid
Compound
74
6-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 6-oxo
Caproic acid
Compound
75
Figure S05818614120061211D000204
7-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 7-oxo
Enanthic acid
Compound
76
7-[(4-cyanic acid benzene
Base) (methyl) ammonia
Base]-the 7-oxo
Enanthic acid
Compound
77
7-[(4-methoxyl group
Phenyl) (methyl)
Amino]-7-oxygen
For enanthic acid
Compound
78
8-[(4-cyanic acid benzene
Base) (methyl) ammonia
Base]-the 8-oxo
Sad
Compound
79
8-[(4-fluorobenzene
Base) (methyl) ammonia
Base]-the 8-oxo
Sad
Compound
80
Figure S05818614120061211D000213
9-[(2-fluorobenzene
Base) (methyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
81
Figure S05818614120061211D000214
9-[(4-fluorobenzene
Base) (methyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
82
7-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 7-oxo
Enanthic acid
Compound
83
Figure S05818614120061211D000216
8-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 8-oxo
Sad
Compound
84
9-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
85
9-[sec.-propyl
(phenyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
86
Figure S05818614120061211D000222
9-[ethyl (2-first
The base phenyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
87
10-[methyl (2-
Aminomethyl phenyl) ammonia
Base]-the 10-oxo
Capric acid
Compound
88
10-[sec.-propyl
(phenyl) ammonia
Base]-the 10-oxo
Capric acid
Compound
89
Figure S05818614120061211D000225
10-[ethyl (benzene
Base) amino]-10-
The oxo capric acid
Compound
90
Figure S05818614120061211D000226
9-[(4-cyanic acid benzene
Base) (methyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
91
Figure S05818614120061211D000231
9-[(4-methoxyl group
Phenyl) (methyl)
Amino]-9-oxygen
For n-nonanoic acid
Compound
92
10-[(4-cyanic acid
Phenyl) (methyl)
Amino]-10-oxygen
For capric acid
Compound
93
Figure S05818614120061211D000233
10-[(4-methoxy
The base phenyl) (first
Base) amino]-10-
The oxo capric acid
Compound
94
Figure S05818614120061211D000234
10-[(2-fluorobenzene
Base) (methyl) ammonia
Base]-the 10-oxo
Capric acid
Compound
95
Figure S05818614120061211D000235
10-[(4-fluorobenzene
Base) (methyl) ammonia
Base]-the 10-oxo
Capric acid
Compound
96
Figure S05818614120061211D000236
9-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 9-oxo
N-nonanoic acid
Compound
97
Figure S05818614120061211D000241
10-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 10-oxo
Capric acid
Compound
98
10-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 10-oxo
Capric acid
Compound
99
Figure S05818614120061211D000243
3-methyl-4-[first
Base (4-methylbenzene
Base) amino]-4-
Ketobutyric acid
Compound
100
3-methyl-4-[first
Base (2-methylbenzene
Base) amino]-4-
Ketobutyric acid
Compound
101
Figure S05818614120061211D000245
4-[sec.-propyl
(phenyl) ammonia
Base]-the 3-methyl
-4-ketobutyric acid
Compound
102
Figure S05818614120061211D000246
3-methyl-5-[first
Base (4-methylbenzene
Base) amino]-5-
Oxopentanoic acid
Compound
103
3-methyl-5-[first
Base (2-methylbenzene
Base) amino]-5-
Oxopentanoic acid
Compound
104
4-[ethyl (2-first
The base phenyl) ammonia
Base]-the 3-methyl
-4-ketobutyric acid
Compound
105
Figure S05818614120061211D000253
4-methyl-5-[first
Base (4-methylbenzene
Base) amino]-5-
Oxopentanoic acid
Compound
106
Figure S05818614120061211D000254
4-methyl-5-[first
Base (2-methylbenzene
Base) amino]-5-
Oxopentanoic acid
Compound
107
Figure S05818614120061211D000255
5-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 3-methyl
-5-oxopentanoic acid
Compound
108
4-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 3-methyl
-4-ketobutyric acid
Compound
109
Figure S05818614120061211D000261
5-[(4-chlorobenzene
Base) (methyl) ammonia
Base]-the 4-methyl
-5-oxopentanoic acid
Compound
110
5-[(4-chlorobenzene
Base) (ethyl) ammonia
Base]-the 3-methyl
-5-oxopentanoic acid
Other delivery agent compounds of the present invention comprise those compounds and the pharmacologically acceptable salt thereof of following formula:
Compound C
N=1 to 9, and
R 1To R 5Be hydrogen, C independently 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 2-C 4Alkenyl, halogen, hydroxyl ,-NH-C (O)-CH 3Or-O-C 6H 5
Preferred compound and the salt thereof of delivery agent compound including, but not limited to having following structural formula:
In one embodiment, n=2-8.
In another embodiment, n=8.
In another embodiment, n=7.
In another embodiment, n=6.
In another embodiment, n=5.
In another embodiment, n=4.
In another embodiment, n=3.
In another embodiment, n=2 and remaining R group are H.
In another embodiment, n=8 and remaining R group are H.
In another embodiment, n=7 and remaining R group are H.
In another embodiment, n=6 and remaining R group are H.
In another embodiment, n=5 and remaining R group are H.
In another embodiment, n=4 and remaining R group are H.
In another embodiment, n=3 and remaining R group are H.
In another embodiment, n=2 and remaining R group are H.
In another embodiment, R1 and R5 are hydrogen.
In another embodiment, R1 and R5 are hydrogen and n=2.
In another embodiment, R3 is a hydroxyl.
In another embodiment, R3 is hydroxyl and N=8.
In another embodiment, R1 is a hydroxyl.
In another embodiment, R1 is hydroxyl and N=8.
In another embodiment, R3 is a methoxyl group.
In another embodiment, R3 is methoxyl group and N=2.
In another embodiment, R3 is methoxyl group and N=3.
In another embodiment, R2 and R4 are halogen and N=2.
In another embodiment, R2 and R4 are fluorine.
In another embodiment, R2 and R4 are fluorine and N=2.
In another embodiment, R1 and R3 are methyl.
In another embodiment, R1 and R3 are methyl and N=2.
In another embodiment, R2 and R4 are methyl, and R3 is methoxyl group and N=4.
In another embodiment, R3 is a sec.-propyl.
In another embodiment, R3 is sec.-propyl and N=3.
In another embodiment, R1 is a methoxyl group.
In another embodiment, R1 is methoxyl group and N=2.
In another embodiment, R3 is a halogen.
In another embodiment, R3 is halogen and N=2.
In another embodiment, R3 is fluorine and N=2.
In another embodiment, R3 is a methoxyl group.
In another embodiment, R3 is methoxyl group and N=4.
In another embodiment, R2 and R4 are methyl.
In another embodiment, R2 and R4 are methyl and N=2.
In another embodiment, R2 and R4 are methyl and N=4.
In another embodiment, R2 and R4 are methyl and N=6.
In another embodiment, R2 and R3 are methyl and N=4.
In another embodiment, R2 and R3 are methyl and N=2.
In another embodiment, R1 and R4 are methyl and N=2.
In another embodiment, R1 and R4 are halogens.
In another embodiment, R1 and R4 are halogen and N=2.
In another embodiment, R1 and R4 are halogen and N=4.
In another embodiment, R1 and R4 are chlorine.
In another embodiment, R1 and R4 are chlorine and N=2.
In another embodiment, R1 and R4 are chlorine and N=4.
In another embodiment, R1 and R4 are hydroxyls.
In another embodiment, R1 and R4 are hydroxyl and N=8.
In another embodiment, compound 117,118,119,120,121,122,123,124,125,126,128,129,130,132,133,134,136 and/or 138 is got rid of from Compound C.
Preferred compound is including, but not limited to following compound.
Compound 111
Figure S05818614120061211D000291
Compound 112
Compound 113
Figure S05818614120061211D000293
Compound 114
Figure S05818614120061211D000294
Compound 115
Compound 116
Compound 117
Figure S05818614120061211D000302
Compound 118
Compound 119
Compound 120
Figure S05818614120061211D000311
Compound 121
Compound 122
Figure S05818614120061211D000313
Compound 123
Figure S05818614120061211D000314
Compound 124
Figure S05818614120061211D000315
Compound 125
Figure S05818614120061211D000321
Compound 126
Figure S05818614120061211D000322
Compound 128
Figure S05818614120061211D000323
Compound 129
Figure S05818614120061211D000324
Compound 130
Figure S05818614120061211D000331
Compound 132
Compound 133
Figure S05818614120061211D000333
Compound 134
Figure S05818614120061211D000334
Compound 136
Figure S05818614120061211D000341
Compound 138
Other delivery agent compounds of the present invention comprise those compounds and the pharmacologically acceptable salt thereof of following formula:
(Compound D)
R1 to R4 is hydrogen, C independently 1-C 4Alkyl, C 2-C 4Alkenyl, halogen, C 1-C 4Alkoxyl group or hydroxyl.
In one embodiment, R1 and R4 are hydrogen, methyl, methoxyl group, halogen or sec.-propyl independently.
In one embodiment, R1 to R4 is a hydrogen.
In another embodiment, R2 and R4 are halogens, are preferably bromine or are preferably chlorine, or be preferably iodine, or be preferably fluorine.
In another embodiment, R2 and R4 are halogens, be preferably bromine or be preferably chlorine, or be preferably iodine, and R1 and R3 are hydrogen.
In another preferred embodiment, R2 and R4 are sec.-propyls.
In another preferred embodiment, R2 and R4 are sec.-propyls, and R1 and R3 are hydrogen.
In another preferred embodiment, R4 is a methyl.
In another preferred embodiment, R4 is that methyl and R1 and R3 are hydrogen.
In another preferred embodiment, R3 is a halogen, is preferably chlorine.
In another preferred embodiment, R3 is a halogen, and being preferably chlorine and R1, R2 and R4 is hydrogen.
In another preferred embodiment, R3 is a methoxyl group.
In another preferred embodiment, R3 is a methoxyl group, and R1, R2 and R4 are hydrogen.
In another preferred embodiment, R2 is a halogen, is preferably bromine.
In another preferred embodiment, R2 is a halogen, is preferably bromine, and R1, R2 and R4 are hydrogen.
In another preferred embodiment, R2 is a halogen, is preferably chlorine.
In another preferred embodiment, R2 is a halogen, is preferably chlorine, and R1, R3 and R4 are hydrogen.
In another preferred embodiment, R2 is a methoxyl group.
In another preferred embodiment, R2 is a methoxyl group, and R1, R3 and R4 are hydrogen.
In another preferred embodiment, R2 is a methyl.
In another preferred embodiment, R2 is a methyl, and R1, R3 and R4 are hydrogen.
Preferred compound and the salt thereof of delivery agent compound including, but not limited to having following structural formula:
Figure S05818614120061211D000351
Compound 140
3-(2-hydroxyl-benzamido-)-butyric acid
Compound 141
3-(3,5-two bromo-2-hydroxyl-benzamido-s)-Ding
Acid
Figure S05818614120061211D000361
Compound 142
3-(3,5-two chloro-2-hydroxyl-benzamido-s)-Ding
Acid
Compound 143
3-(2-hydroxyl-3,5-two iodo-benzamido-s)-Ding
Acid
Compound 144
3-(2-hydroxy-3-methyl-benzamido-)-Ding
Acid
Figure S05818614120061211D000364
Compound 145
3-(4-chloro-2-hydroxyl-benzamido-)-butyric acid
Figure S05818614120061211D000365
Compound 146
3-(2-hydroxyl-4-methoxyl group-benzamido-)-
Butyric acid
Compound 147
3-(5-bromo-2-hydroxyl-benzamido-)-butyric acid
Figure S05818614120061211D000372
Compound 148
3-(5-chloro-2-hydroxyl-benzamido-)-butyric acid
Compound 149
3-(2-hydroxy-5-methyl oxygen base-benzamido-)-
Butyric acid
Compound 150
3-(2-hydroxy-5-methyl base-benzamido-)-Ding
Acid
Figure S05818614120061211D000381
Compound 151
3-(2-hydroxyl-3,5-di-isopropyl-benzene carbon amide
Base)-butyric acid
Other delivery agent compounds of the present invention comprise those compounds and the pharmacologically acceptable salt thereof of following formula:
(compd E)
Wherein
One of R1 to R5 has following universal architecture
-(CH 2) n-COOH
N=0 to 6 wherein;
Remaining four groups of R1 to R5 are hydrogen, C independently 1-C 4Alkyl, C 2-C 4Alkenyl, halogen, C 1-C 4Alkoxyl group or hydroxyl; And
R6 to R10 is hydrogen, C independently 1-C 4Alkyl, C 2-C 4Alkenyl, halogen, C 1-C 4Alkoxyl group or hydroxyl.
In one embodiment, n=0 to 4.
In another embodiment, n=0.
In another embodiment, n=1.
In another embodiment, to be preferably be hydrogen, halogen, methyl and methoxyl group to R1-R10 independently.
In another embodiment, to be preferably be chlorine, halogen, methyl and methoxyl group to R1-R10 independently.
In another embodiment, as universal architecture-(CH 2) nWhen-COOH connected in the R1 position, remaining R group was a hydrogen.
In another embodiment, as universal architecture-(CH 2) nWhen-COOH connected in the R1 position, remaining R group was hydrogen and n=0.
In another embodiment, as universal architecture-(CH 2) nWhen-COOH connected in the R1 position, remaining R group was hydrogen and n=1.
In another embodiment, as universal architecture-(CH 2) nWhen-COOH connected in the R3 position, remaining R group was a hydrogen.
In another embodiment, as universal architecture-(CH 2) nWhen-COOH connected in the R3 position, remaining R group was hydrogen and n=0.
In another embodiment, as universal architecture-(CH 2) nWhen-COOH connected in the R3 position, remaining R group was hydrogen and n=1.
In another embodiment, as universal architecture-(CH 2) nR5 was a methoxyl group when-COOH connected in the R2 position.
In another embodiment, as universal architecture-(CH 2) nR5 was a methoxyl group when-COOH connected in the R2 position, and remaining R group is a hydrogen.
In another embodiment, as universal architecture-(CH 2) nR5 was a methoxyl group when-COOH connected in the R2 position, and n=0.
In another embodiment, as universal architecture-(CH 2) nR5 was a methoxyl group when-COOH connected in the R2 position, and n=0, and remaining R group is a hydrogen.
In another embodiment, as universal architecture-(CH 2) nR1 and R5 were methyl when-COOH connected in the R3 position.
In another embodiment, as universal architecture-(CH 2) nR1 and R5 were methyl when-COOH connected in the R3 position, and remaining R group is a hydrogen.
In another embodiment, as universal architecture-(CH 2) nR1 and R5 were methyl when-COOH connected in the R3 position, and n=0.
In another embodiment, as universal architecture-(CH 2) nR1 and R5 were methyl and n=0 when-COOH connected in the R3 position, and remaining R group is a hydrogen.
In another embodiment, as universal architecture-(CH 2) nR1 or R5 were methoxyl group and n=0 when-COOH connected in the R3 position.
In another embodiment, as universal architecture-(CH 2) nR1 or R5 were methoxyl group and n=0 when-COOH connected in the R3 position, and remaining R group is a hydrogen.
In another embodiment, as universal architecture-(CH 2) nR2 or R4 were halogens when-COOH connected in the R3 position, were preferably chlorine.
In another embodiment, as universal architecture-(CH 2) nR2 or R4 were halogens when-COOH connected in the R3 position, were preferably chlorine, and remaining R group is a hydrogen.
In another embodiment, as universal architecture-(CH 2) nR2 or R4 were halogens when-COOH connected in the R3 position, were preferably chlorine and n=0.
In another embodiment, as universal architecture-(CH 2) nR2 or R4 were halogens when-COOH connected in the R3 position, were preferably chlorine and n=0, and remaining R group is a hydrogen.
In one embodiment, compound 152,153,154,155,156,157 and/or 158 is got rid of from compd E.
Preferred compound is including, but not limited to following compound and pharmacologically acceptable salt thereof:
Figure S05818614120061211D000401
Compound 152
2-benzyloxy phenylacetic acid
Compound 153
3-benzyloxy-4-methoxybenzoic acid
Compound 154
4-benzyloxy-3, the 5-mesitylenic acid
Figure S05818614120061211D000412
Compound 155
(4-benzyloxy-3-methoxyl group-phenyl)-acetate
Compound 156
4-(benzyloxy)-2-chloro-benzoic acid
Figure S05818614120061211D000414
Compound 157
4-benzyloxy-phenylformic acid
Figure S05818614120061211D000421
Compound 158
(4-benzyloxy-phenyl)-acetate
Figure S05818614120061211D000422
Compound 159
2-benzyloxy phenylformic acid
Other delivery agent compounds of the present invention comprise those compounds and the pharmacologically acceptable salt thereof of following formula:
Compound F 17-hydroxy-corticosterone
Wherein
N=1 to 9; And
R 1To R 9Be hydrogen, C independently 1-C 4Alkyl, C 2-C 4Alkenyl, halogen, C 1-C 4Alkoxyl group or hydroxyl.
According to an embodiment preferred, n=3 to 7, preferably, and in a preferred embodiment, n=3, preferably, and in another preferred embodiment, n=4; Preferably, in another preferred embodiment, n=5; Preferably, in another preferred embodiment, n=6; Preferably, in another preferred embodiment, n=7.
According to another embodiment preferred, R 1To R 8Be hydrogen.
According to another embodiment preferred, R 3Be halogen, preferably, in one embodiment, R 3Be chlorine, preferably, in another embodiment, R 3It is bromine.
According to another embodiment preferred, R 2It is methoxyl group.
According to another embodiment preferred, R 2It is methyl.
According to another embodiment preferred, R 3It is methoxyl group.
According to another embodiment preferred, R 3It is methyl.
According to another embodiment preferred, R 6It is methoxyl group.
According to another embodiment preferred, R 9Be hydrogen.
According to another embodiment preferred, R 9It is hydroxyl.
According to another embodiment preferred, R 9Being halogen, preferably, is chlorine in one embodiment.
According to another embodiment preferred, R 3And R 6It all is methoxyl group.
According to another embodiment preferred, R 3And R 6All be that methoxyl group and remaining R group are hydrogen.
According to another embodiment preferred, R 2Be methyl and R 3Be chlorine.
According to another embodiment preferred, R 2Be methyl and R 3Be that chlorine and remaining R group are hydrogen.
According to another embodiment preferred, R 2Be methyl and R 9Be chlorine.
According to another embodiment preferred, R 2Be methyl and R 9Be that chlorine and remaining R group are hydrogen.
According to another embodiment preferred, R 3Be methyl and R 9Be chlorine.
According to another embodiment preferred, R 3Be methyl and R 9Be that chlorine and remaining R group are hydrogen.
Preferred compound and the salt thereof of delivery agent compound including, but not limited to having following structural formula:
Compound 160
6-(2-(2-hydroxy benzoyl) phenoxy) caproic acid
Figure S05818614120061211D000441
Compound 161
8-(2-(2-hydroxy benzoyl) phenoxy) Sodium octoate
Figure S05818614120061211D000442
Compound 162
5-(2-(2-hydroxy benzoyl)-4-methoxyl group phenoxy) valeric acid
Figure S05818614120061211D000443
Compound 163
5-(2-(2-hydroxy benzoyl) phenoxy) valeric acid
Figure S05818614120061211D000444
Compound 164
5-(2-(2-hydroxy-5-methyl oxygen base benzoyl-)-4-methoxyl group phenoxy) valeric acid
Figure S05818614120061211D000451
Compound 165
4-(2-(2-hydroxy benzoyl)-5-methoxyl group phenoxy) butyric acid
Compound 166
4-(2-(2-hydroxy benzoyl) phenoxy) butyric acid
Figure S05818614120061211D000453
Compound 167
4-(2-chlorobenzene formacyl-4-methylphenoxy) butyric acid
Figure S05818614120061211D000454
Compound 168
4-(2-benzoyl--5-methoxyl group phenoxy) butyric acid
Compound 169
4-(2-benzoyl--4-chlorophenoxy) butyric acid
Figure S05818614120061211D000462
Compound 170
4-(2-benzoyl--4-bromine phenoxy) butyric acid
Compound 171
4-(2-(2-chlorobenzene formacyl-5-methylphenoxy) butyric acid
Figure S05818614120061211D000464
Compound 172
4-(2-(2-chlorobenzene formacyl-4-methylphenoxy) butyric acid
Figure S05818614120061211D000471
Compound 173
4-(2-benzoyl--4-chloro-5-methylphenoxy) butyric acid
Compound 174
3-(5-chloro-2-(2-hydroxybenzoyl) amino) propionic acid
Other delivery agent compounds of the present invention comprise those compounds and the pharmacologically acceptable salt thereof of following formula:
(compound G)
Wherein
R1 to R5 is hydrogen, C independently 1-C 4Alkyl, C 2-C 4Alkenyl, halogen, C 1-C 4Alkoxyl group, hydroxyl or-O-(CH 2) n-COOH (wherein n to 12);
R 1To R 5In at least one has following universal architecture
-O-(CH 2) n-COOH
N=1 to 12 wherein; And
R6 to R10 is hydrogen, C independently 1-C 4Alkyl, C 2-C 4Alkenyl, halogen, C 1-C 4Alkoxyl group or hydroxyl.
Preferably, only one of R1 to R5 has formula-O-(CH 2) n-COOH.In other words, four groups among the R1 to R5 are hydrogen, C independently 1-C 4Alkyl, C 2-C 4Alkenyl, halogen, C 1-C 4Alkoxyl group or hydroxyl, and a remaining group is-O-(CH among the R1 to R5 2) n-COOH (wherein n is 1 to 12).
N=1 to 12 in a preferred embodiment.
N=1 to 10 in another preferred embodiment.
N=1 to 6 in another preferred embodiment.
N=1 to 4 in another preferred embodiment.
N=10 in another preferred embodiment.
N=4 in another preferred embodiment.
N=1 in another preferred embodiment.
As universal architecture-(CH 2) nWhen-COOH connected in the R1 position, every other R group was a hydrogen.
As universal architecture-(CH 2) nWhen-COOH connected in the R1 position, every other R group was hydrogen and n=3.
As universal architecture-(CH 2) nWhen-COOH connected in the R3 position, every other R group was a hydrogen.
As universal architecture-(CH 2) nWhen-COOH connected in the R3 position, every other R group was hydrogen and n=1.
As universal architecture-(CH 2) nWhen-COOH connected in the R3 position, every other R group was hydrogen and n=4.
As universal architecture-(CH 2) nWhen-COOH connected in the R3 position, every other R group was hydrogen and n=10.
Preferred compound is including, but not limited to following compound and pharmacologically acceptable salt thereof:
Figure S05818614120061211D000481
Compound 175
4-(2-benzyloxy-phenoxy)-butyric acid
Compound 176
(4-benzyloxy-phenoxy)-acetate
Figure S05818614120061211D000492
Compound 177
11-(2-benzyloxy phenoxy) 11
Acid
Figure S05818614120061211D000493
Compound 178
5-(4-benzyloxy-phenoxy)-valeric acid
Also can use the mixture of these delivery agent compounds.
The present invention also provides the compsn that comprises delivery agent compound of the present invention and at least a promoting agent.Compare with using the promoting agent that does not contain the delivery agent compound, these compsns are passed to promoting agent in the biosystem of selection with the promoting agent bioavailability that increases or improve.
The present invention also provides the dosage unit form that comprises compsn.Dose unit can be with liquid or solid, and for example tablet, capsule or granule comprise the form of powder or sachet.
Another embodiment is the method that promoting agent is applied to animal, and this method is applied to animal through the compsn that will comprise at least a delivery agent compound of the present invention and promoting agent.That route of administration comprises is oral, colonic and lung approach.
Another embodiment is through using the present composition is treated disease or obtained the physiological action of expection in animal method.
Another embodiment is that compsn of the present invention is applied to animal that can from compsn, be benefited and/or the animal that needs promoting agent.
Another embodiment is through at least a delivery agent compound of the present invention and at least a promoting agent being mixed with the method for the present composition.
Detailed Description Of The Invention
Definition
The singulative that uses in this paper and the accessory claim comprises the indication things of plural number, only if context offers some clarification on.Therefore; For example relate to " molecule " and comprise one or more these molecules; " a kind of reagent " comprises one or more this different reagent; And relate to " this method " or " said method " and comprise and relate to suitable step known to a person of ordinary skill in the art and method, these methods can be the improvement or the replacement of the method described among this paper.
Term " polymorphic form " refers to distinct form on the crystallography of material.
The term that uses among this paper " hydrate " comprises with the material of molecular form bonded water and (ii) comprises the crystalline material of one or more crystal water molecules or comprise the crystalline material of free-water including, but not limited to (i).
The term that uses among this paper " solvolyte " is including, but not limited to the molecule of solvent or molecule or the ionic molecule or the ion complex of ion and delivery agent.
Term " delivery agent " refers to disclosed herein or incorporates this paper any delivery agent compound as a reference into, comprises its pharmacologically acceptable salt.
" pharmaceutical composition of significant quantity " is in for some time, and the amount of effective treatment or prophylactic pharmaceutical composition in the object of using for example provides therapeutic action in the spacing of doses of expection.
Term " treatment " refers to the tendency that prevention ground prevented, cures, fully recovers, alleviates, alleviates, changes, corrects, improves, improves or influenced the symptom of illness (for example disease), illness or illness takes place.
" delivery agent of significant quantity " is the amount of delivery agent of absorption that promotes the promoting agent of desired amount.
Term " object " comprises Mammals, for example rodent, cow, pig, dog, cat, primate and particularly people.
The term that uses among this paper " AUC " meaning is the area under plasma concns-time curve, and this area is through going through complete spacing of doses, and for example 24 hours trapezoidal rules at interval calculate.
Term " on average " is before the pharmacokinetics value time (for example average peak), and except as otherwise noted, it represents the arithmetical av of pharmacokinetics value.
The term " about " used among this paper meaning be designated value 10% in, be preferably in 5%, more preferably in 1% of designated value.In addition, the term " about " meaning is to drop on the value in the acceptable limit of error on the science of such offset, and it depends on the qualitative degree of the method that available instrument provides.
" indication " meaning is chemoprophylaxis of using or the purposes of treating disease, and can use with " treatment " exchange.
The term that uses among this paper " substituted " is including, but not limited to the replacement of substituent any one or any combination below the usefulness: halogen, hydroxyl, C 1-C 4Alkyl and C 1-C 4Alkoxyl group.
Term " alkyl ", " alkoxyl group ", " alkenyl ", " alkylene group ", " alkyl (arylidene) " and " aryl (alkenyl) " are respectively including, but not limited to linearity or branched-chain alkyl, alkoxyl group, alkenyl, alkylene group, alkyl (arylidene) and aryl (alkenyl).
" peptide YY " or " PYY " refer to obtain from any species or deutero-peptide YY polypeptide.Therefore; Term " PYY " comprises that human total length, 36 amino acid whose peptides are as (it is the PCT text of U.S. Patent Publication 2002/0141985 at international publication number WO02/47712; It incorporates this paper into as a reference) SEQ ID NO:2 and Tatemoto, Proc Natl Acad Sci U.S.A.79:2514-8 lists in 1982; And the transmutation of species of PYY, comprise for example like murine, hamster, chicken, ox, rat and dog PYY." PYY agonist " meaning is to cause that PYY reduces any compound of the effect of nutritional utilization degree; The compound (1) that for example has following character has activity and (2) in Y receptor assay (embodiment 10 of WO02/47712 and U.S. Patent Publication 2002/0141985) or competitive binding analysis and come from and have some tissues that enrich the Y acceptor in ingestion of food, stomach emptying, pancreatic secretion or weight loss analysis (describing among the embodiment 1,2,5 or 6 in WO02/47712 and U.S. Patent Publication 2002/0141985); Comprise that for example the PYY or PYY [3-36] specificity of the mark of area postrema combine (embodiment 9 of WO02/47712 and U.S. Patent Publication 2002/0141985), wherein the PYY agonist is not the pancreas polypeptide.Preferably, binding affinity is greater than about 1 μ M in this is analyzed for the PYY agonist, and more preferably its avidity is greater than about 1nM about 5 nM extremely.
This agonist can comprise polypeptide or chemistry or the small molecules with function PYY zone, PYY active fragments.The PYY agonist can be peptide class or non-peptide compound; And comprise " PYY agonist analogue "; This analogue refers to any compound similar with PYY on the structure, and it is typically owing to causing that the acceptor of biological respinse combines or interact with it directly or indirectly in addition to have the PYY activity with its interaction with pyy receptor or other acceptors or pyy receptor itself.This compound comprises PYY verivate, PYY fragment, has the PYY molecule more than 36 amino acid whose prolongations, the substituted PYY molecule that has the PYY molecule that is less than 36 amino acid whose brachymemmas and have one or more different aminoacids, perhaps any combination of above molecule.This compound also can be modified through the method for for example Pegylation, amidation, glycosylation, acidylate, sulfation, phosphorylation, acetylize and cyclisation.
One of this PYY agonist analogue is PYY [3-36], through being accredited as the SEQ ID NO:3 of WO02/47712 and U.S. Patent Publication 2002/0141985; Eberlein, people such as Eysselein., Peptides 10:797-803 (1989) and Grandy, people such as Schimiczek. and, Regul Pept 51:151-9 (1994).Polypeptide with bracket inner digital refers to has the polypeptide that comprises the brachymemma of the full-length peptide sequence of amino acid sites in the bracket.Therefore, PYY [3-36] has the identical sequence of the amino acid 3 to 36 of PYY.PYY [3-36] comprises about 40% total peptide YY-appearance immunocompetence and under fasting state, comprises about 36% total plasma peptides YY immunocompetence in the intestines extract of people and dog, and after the meal a little more than 50%.It obviously is dipeptidyl peptidase-IV (DPP4) the shearing product of peptide YY.It is the selective ligands of Y2 and Y5 acceptor that peptide YY [3-36] is in the news, and it demonstrates the uniqueness on the pharmacology in the neuropeptide tyrosine analogue of preferred N end brachymemma (being its C end fragment).The PYY agonist can combine with pyy receptor with higher and lower affinity, in vivo or externally demonstrate the long or short transformation period, or has higher or lower validity than natural PYY.
Other PYY agonists that are fit to comprise the PYY agonist that those are described in international publication number WO98/20885, it incorporates this paper into as a reference.
The term that uses among this paper " heparin " refers to the heparin of form of ownership, including, but not limited to unfraction heparin, heparitin, dermatan, chrondroitin, low molecular weight heparin (for example booth is pricked heparin (tinzaparin) (comprising Tinzaparin sodium)), super low molecular heparin and ultra-low molecular weight heparin.Limiting examples comprises unfraction heparin, and for example (heparin sodium USP for example is available from ScientificProtein Labs of Waunakee, WI) for heparin sodium.Heparin has about 1,000 or 5,000 to about 30,000 daltonian molecular weight usually.Term " low molecular weight heparin " be commonly referred to as wherein heparin at least about 80% (weight) have about 3000 and about 9000 dalton between the heparin of molecular weight.The limiting examples of low molecular weight heparin comprises booth bundle heparin, enoxaparin (enoxaprin) and reaches heparin (daltiparin).Booth is used to treat the acute lower limb vein thrombus that has or not pulmonary infarction when pricking heparin by U.S.Food&Drug Administration approval and Warnerin combined utilization.PharmionCorporation TMBooth is pricked the sodium salt of heparin at trade mark Innohep of Boulder, can obtain under the CO.Term " super low molecular heparin " be commonly referred to as wherein heparin at least about 80% (weight) have about 1500 and about 5000 dalton between the heparin of molecular weight.The limiting examples of super low molecular heparin is a shellfish rice heparin (bemiparin).Term " ultra-low molecular weight heparin " be commonly referred to as wherein heparin at least about 80% (weight) have about 1000 and about 2000 dalton between the heparin of molecular weight.The limiting examples of ultra-low molecular weight heparin is fondiparinux.
Delivery agent
Delivery agent of the present invention can be the form of free acid or pharmacologically acceptable salt.The pharmacologically acceptable salt that is fit to is including, but not limited to organic and inorganic salt, for example an alkali metal salt, for example sodium, potassium and lithium salts; Alkaline earth salt, for example magnesium, calcium or barium salt; Ammonium salt; Basic aminoacids, for example Methionin or l-arginine; And organic amine, for example dimethyl amine or pyridine.In one embodiment, salt is sodium salt.Salt can be unit price or a polyvalent salt, for example single sodium salt and disodium salt.Salt can be solvolyte also, comprises alcohol solvent compound, and hydrate.The limiting examples of pharmacologically acceptable salt comprises the salt with following material: sodium, hydrochloric acid, sulfuric acid, phosphoric acid, Hydrocerol A, acetate, vitriol, phosphoric acid salt, muriate, bromide, iodide, acetate, propionic salt, Hydrogen bromide, sodium hydroxide, Pottasium Hydroxide, volatile caustic and salt of wormwood.These salt can prepare by means commonly known in the art.For example sodium salt can be through being dissolved in delivery agent in the ethanol and adding the aqueous sodium hydroxide solution preparation.Delivery agent can be through recrystallization purifying or on one or more solid phase chromatogram upholders, and level branch independent or that front and back link to each other carries out purifying.The recrystallization solvent system that is fit to is including, but not limited to acetonitrile, methyl alcohol and THF.Level is divided and can carried out under the following condition: (i) aluminum oxide for example on the chromatogram upholder that is fit to; Using methyl alcohol/n-propyl alcohol mixture is moving phase; (ii) using trifluoroacetic acid/acetonitrile mixture through reverse-phase chromatography is moving phase, or (iii) answers water or suitable damping fluid as moving phase through ion-exchange chromatography.When carrying out anion-exchange chromatography, be preferably and use 0-500mM sodium-chlor gradient.
Delivery agent can comprise the polymkeric substance that links to each other with linking group, this linking group is selected from-NHC (O) NH-,-C (O) NH-,-NHC (O) ,-OOC-,-COO-,-NHC (O) O-,-OC (O) NH-,-CH 2NH-NHCH 2-,-CH 2NHC (O) O-,-OC (O) NHCH 2-,-CH 2NHCOCH 2O-,-OCH 2C (O) NHCH 2-,-NHC (O) CH 2O-,-OCH 2C (O) NH-,-NH-,-O-and C-C, condition is that the polymkeric substance delivery agent is not polypeptide or polyamino acid.Polymkeric substance can be any polymkeric substance, and including, but not limited to alternating copolymer, segmented copolymer and random copolymers, it is application safety in Mammals.Preferred polymkeric substance including, but not limited to Vilaterm, polyacrylic ester, Rohm tech inc, gather (oxygen ethene), gather (propylene), W 166, polyoxyethylene glycol (PEG) and the verivate of these polymkeric substance and the combination of these polymkeric substance.The typical scope of the molecular weight of polymkeric substance is about 100 to about 200,000 dalton.The molecular weight preferable range of polymkeric substance is about 200 to about 10,000 dalton.In one embodiment, the molecular weight ranges of polymkeric substance be about 200 to about 600 dalton and more preferably scope be about 300 to about 550 dalton.U.S. Patent number 6,627,228 quote in full and incorporate this paper into as a reference.
The amount of delivery agent is the delivery agent significant quantity and can confirms according to those methods well known in the art for concrete compsn in solid composite medicament.Usually, the weight ratio scope of delivery agent and promoting agent is about 0.1: 1 to about 1000: 1 and is preferably about 1: 1 to about 300: 1.Weight ratio will change according to the concrete indication of promoting agent and administering active agents.
Describe in following patent for other delivery agents that are fit to of the present invention: U.S. Patent number 6,846,844,6,699,467,6,693,208,6,693,073,6,663,898,6,663,887,6; 646,162,6,642,411,6,627,228,6,623,731,6,610,329,6,558,706,6,525; 020,6,461,643,6,461,545,6,440,929,6,428,780,6,413,550,6,399,798,6; 395,774,6,391,303,6,384,278,6,375,983,6,358,504,6,346,242,6,344; 213,6,3.31,318,6,313,088,6,245,359,6,242,495,6,221,367,6,180,140,5; 541,155,5,693,338,5,976,569,5,643,957,5,955,503,6,100,298,5,650; 386,5,866,536,5,965,121,5,989,539,6,001,347,6,071,510 and 5,820,881.Delivery agent of the present invention is also described in following patent: U.S. Patent Application Publication 20050009748; 20040110839; 20040106825; 20040068013; 20040062773; 20040022856; 20030235612; 20030232085; 20030225300; 20030198658; 20030133953; 20030078302; 20030072740; 20030045579; 20030012817; 20030008900; 20020155993; 20020127202; 20020120009; 20020119910; 20020102286; 20020065255; 20020052422; 20020040061; 20020028250; 20020013497; 20020001591; 20010039258 and 20010003001.Delivery agent of the present invention is also described in following patent: international publication number WO2005/020925; WO2004/104018; WO2004/080401; WO2004/062587; WO2003/057650; WO2003/057170; WO2003/045331; WO2003/045306; WO2003/026582; WO2002/100338; WO2002/070438; WO2002/069937; WO02/20466; WO02/19969; WO02/16309; WO02/15959; WO02/02509; WO01/92206; WO01/70219; WO01/51454; WO01/44199; WO01/34114; WO01/32596; WO01/32130; WO00/07979; WO00/59863; WO00/50386; WO00/47188; WO00/40203 and WO96/30036.Each USP more than listed and the patented claim of the U.S. and International Publication are incorporated this paper into as a reference.These delivery agents can be through method preparation as known in the art, the method for for example describing in those patents mentioned in front and the disclosed patented claim.For example, SNAC can prepare by means commonly known in the art, and for example those are at U.S. Patent number 5,650, and 386 and 5,866,536, and the method for describing in the U.S. Patent Application Publication 2002/0065255.
Promoting agent
Be fit to be applied to promoting agent of the present invention and comprise biologically active agent and chemical active agent, including, but not limited to sterilant, pharmaceutical prepn and therapeutical agent.The promoting agent that is fit to comprises that those are caused by acidolysis, enzyme effect etc. in gi tract that curative effect reduces, invalid or ruined promoting agent.Physico-chemical property (comprising size, structure or electric charge) suppresses or stops the macromolecular substance that absorbs when also comprising that those work as oral administration as the promoting agent that is fit to.
For example, as restricted when oral bioavailability or when not existing, get in the body and maybe can comprise the material of being benefited the transmission from the pharmacokinetics of improving.These materials are to be fit to be applied to biological or chemical promoting agent of the present invention, and including, but not limited to macromole, for example peptide comprises protein or polypeptide, comprises dipeptides; Hormone; And carbohydrate, comprise monose, polysaccharide, comprise the mixture of disaccharides, mucopolysaccharide; Glucide; Lipoid; And little polarity organic molecule (promptly have molecular weight 500 dalton or be lower than 500 daltonian polarity organic molecules); Nucleosides, other organic cpds; And do not have oral administration biaavailability or have the concrete compound of limited oral administration biaavailability, comprise those itself can not and/or be subject to the compound of the chemical cracking of acid and enzyme in the gi tract through (or only the part through application dosage) gastrointestinal mucosa; Or any combination of these compounds.
Other instance comprises its synthetic, source natural or reorganization including, but not limited to following instance:
Amylin and amylin agonist;
Thyroliberin;
Antigen;
Antimicrobial drug comprises microbiotic, antiseptic-germicide and anti-mycotic agent; Antibiotic limiting examples comprises microbiotic, sterilization microbiotic, lipopeptide antibiotics and the cyclic peptide microbiotic that acts on gram-positive microorganism, for example daptomycin (daptomycin) and analogue thereof;
Antimigraine, for example BIBM-4096BS and other calcitonin gene related protein antagonist, GR-43175 SUMATRIPTAN SUCCINATE;
Antiviral drug comprises acycloguanosine, valacyclovir (valacyclovir);
Atrionatriuretic factor;
Diphosphonate comprises Alendronate (alendronate), clodronate salt (clodronate), etridronate salt (Etidronate), ibandronate (ibandronate), because of card phosphonate (incadronate), YM 529 (minodronate), neridronic acid salt (neridronate), olpadronate (olpadronate), pamldronate (pamidronate), risedronate (risedronate), Tiludronate (tiludronate), Zoledronic acid salt (zoledronate), EB1053 and YH529;
Thyrocalcitonin comprises salmon calcitonin see calcimar, eel thyrocalcitonin, pig thyrocalcitonin and HCT;
Cholecystokinin (CCK) and CCK agonist comprise CCK-8;
Sodium Cromoglicate (Sodium Cromoglicate or sodium cromoglycate);
S-Neoral;
(DFO) desferrioxamines;
Hempoietine;
Exendin and exendin peptide agonists comprise Exendin-3, Exendin-4;
Filgrastim (filgrastim);
Follicle stimulating hormone (Puregon and natural follicle stimulating hormone);
Glucagon-like peptide 1 (GLP-1), hyperglycemic-glycogenolytic factor and glucagon-like peptide 2 (GLP-2);
Glucocerebrosidase;
Gonadotropin releasing hormone;
Somatotropin releasing factor;
Growth hormone releasing hormone;
Figure S05818614120061211D000571
Comprise these compounds secretogogue, the verivate modified of analogue, fragment, stand-in or polyoxyethylene glycol (PEG); Or any combination of these materials.
Transfer system
Compsn of the present invention comprises one or more delivery agent compounds of the present invention, and one or more promoting agents.In one embodiment; One or more delivery agent compounds; Or the salt of these compounds, or these compound or its salts form the polyamino acid or the peptide of one or more units, can use compsn as delivery agent through before using, mixing with formation with promoting agent.
Use compsn and can be the form of liquid.Solution medium can be water (for example for salmon calcitonin see calcimar, Rat parathyroid hormone 1-34 and Hempoietine), 25% aqueous solution of propylene glycol (for example for heparin) and phosphoric acid buffer (for example for the recombinant human somatropin).Other excipient substance comprises polyoxyethylene glycol.Medicament solution can prepare through only before using, the delivery agent compound solution being mixed with activator solution.In addition, delivery agent compound (or promoting agent) solution can mix with the promoting agent (or delivery agent compound) of solid form.Delivery agent compound and promoting agent also can be used as dry powder blend.Delivery agent compound and promoting agent also can mix in the preparation process.
Medicament solution can randomly comprise additive for example phosphate-buffered salt, Hydrocerol A, terepthaloyl moietie or other dispersion agent.Can mix stabilising additive in the solution, preferred concentration range is between about 0.1% and 20% (w/v).
In addition, use compsn and can be solid form, for example tablet, capsule or granule, for example powder or sachet.Solid dosage can be mixed with the promoting agent of solid form through the compound with solid form and prepared.In addition, solid can obtain from the solution of compound and promoting agent through method as known in the art, and this method is freeze-dried (freeze-drying), deposition, crystallization and solid dispersed for example.
The compsn of using of the present invention also can comprise one or more enzyme inhibitorss.This enzyme inhibitors is including, but not limited to compound for example actinonine or table actinonine and their verivate.Other enzyme inhibitors is including, but not limited to pressing down enzyme peptide (Trasylol) and Bowman-Birk suppressor factor.
Being applied to the amount of using the promoting agent in the compsn of the present invention is the amount for the effectively concrete promoting agent of target indication.The amount of promoting agent typically is pharmacology, biology, therapeutics or chemical significant quantity in the compsn.But its amount can be lower than above-mentioned amount when compsn is used for dosage unit form, maybe can comprise pharmacology, biology, therapeutics or chemical significant quantity separately because dosage unit form can comprise multiple delivery agent compound/surfactant composition.Then, total significant quantity can be used with the accumulation unit of the promoting agent that comprises total significant quantity.
The total amount of the promoting agent of using can be confirmed through those methods as known in the art.But; Because compsn of the present invention can more effectively transmit promoting agent than the compsn that only comprises promoting agent; So can be applied to the biological or chemical promoting agent of patient, and still can obtain level and/or therapeutic action in the same blood than the lower amount of those biological or chemical promoting agents of using in front dosage unit form or the transfer system.
The transmission of present disclosed delivery agent compound promoted biological and chemical promoting agent; Particularly in oral, nose, hypogloeeis, stomach, intestines, comprise in the duodenum, jejunum and ileum transmission, subcutaneous, oral cavity, colonic, rectum, vagina, mucous membrane, lung, through skin, intracutaneous, non-enteron aisle, intravenously, intramuscular and vision system, and pass through hemato encephalic barrier.
Dosage unit form also can comprise a kind of of following material or combination: vehicle, thinner, disintegrating agent, lubricant, softening agent, tinting material, correctives, odor mask, sugar, sweeting agent, salt and excipient substance; Including, but not limited to water, 1, any combination of 2-Ucar 35, ethanol, sweet oil or these auxiliary materials.
Compound of the present invention and compsn are used for using the biological or chemical promoting agent to any animal, and this animal is including, but not limited to birds chicken for example; Mammals, for example rodent, cow, pig, dog, cat, primate, particularly people; And insect.
This system is particularly conducive to and is delivered in promoting agent to arrive target area (promptly transmitting the zone that the promoting agent of compsn discharges) preceding and in the animal body that promoting agent is used, suffer from environment damage or show as the chemistry or the biologically active agent of lower effect.Especially, compound of the present invention and compsn are used for Orally administered promoting agent, and particularly those are not normal oral transferable promoting agents, or those need improve the promoting agent of transmission.
The compsn of inclusion compound and promoting agent have with promoting agent pass to selection biosystem effect and the effect that increases or improve the bioavailability of compound active agent is arranged with respect to the promoting agent of using no delivery agent.Transmission can improve in the following manner: go through for some time and transmit more promoting agent; Or in the concrete time cycle, transmit promoting agent (for example booster action or delay are transmitted), or transmit promoting agent (transmission that for example continues) in the specific time or the for some time of going through.
Another embodiment of the invention is through the physiological action of in animal, using combination treatment of the present invention or preventing disease or obtaining to expect, the method for the physiological action of for example listing in those tables below.Preferably, use the compsn of the significant quantity of disease that is used to treat or prevents to expect or the physiological action that obtains expection.The concrete indication of promoting agent can be found in the document below: (1) the Physicians ' Desk Reference (58th Ed., 2004, Medical EconomicsCompany, Inc.; Montvale, NJ) with (2) Fauci, AS; Deng the people., Harrison ' s Principlesof Internal Medicine (14th Ed., 1998; McGraw-Hill Health ProfessionsDivision, New York), the two all incorporates this paper into as a reference.Promoting agent in the following table comprises its analogue, fragment, stand-in and polyethyleneglycol modified verivate.
Promoting agent Disease or physiological action
Amylin and amylin agonist; Fat
Thyroliberin; Hypercholesterolemia (reducing cholesterol)
Antigen; Infect
Antiviral drug comprises acycloguanosine, valacyclovir; Virus infection comprises I type and II type herpes simplex
Tethelin (comprising recombinant human growth hormone and somatotropin releasing factor and analogue thereof) Retardation of growth
Interferon, rabbit comprises α, β and γ Virus infection comprises chronic cancer, hepatitis and multiple sclerosis
Interleukin-(for example interleukin 1, interleukin II, interleukin 11, interleukin II 1) Virus infection; Cancer; Cell-mediated immunity and graft-rejection;
Regular Insulin; Insulin-like growth factor I GF-1 Mellitus
Heparin Treatment and prevention thrombosis comprise (deep-vein thrombosis formation); The prevention hemopexis
Thyrocalcitonin comprises salmon calcitonin see calcimar, eel thyrocalcitonin, pig thyrocalcitonin and HCT; Osteoporosis; Osteopathia; Bone pain; Pain relieving (comprising the pain relevant) with osteoporosis or cancer
Cholecystokinin (CCK) and CCK agonist comprise CCK-8; Fat
Hempoietine Anaemia; The relevant anaemia of HIV/HIV-treatment; Chemotherapy inductive anaemia
Atrionatriuretic factor Vasorelaxation
Antigen Infect
CPHPC Reduce amyloid deposition and frequent (but not always) systemic amyloidosis relevant with alzheimer's disease, type ii diabetes and other based on amyloid disease
(antibody comprises Retuxin, TNF-α soluble receptors to monoclonal antibody; ) The prevention transplant rejection; Cancer; Be used for analyzing to detect disease
Leptin (OB albumen) Fat
Somatostatin/Sostatin Hemorrhagic ulcer; Erosive gastritis; Varix occurs; Diarrhoea; Acromegaly; The adrenotrophic hormone pituitary adenoma; Secretion pancreas knurl (secretorypancreatic tumors); Carcinoid syndrome; Reduce the relevant illness in eye of outstanding/Tiroidina; Reduce macula oedema/retinopathy
Proteinase inhibitor HIV infection/AIDS
Thyroliberin Hypercholesterolemia (reducing cholesterol)
Gonadotropin releasing hormone Ovulation function disorderly (induction of ovulation)
Pitocin Childbirth dysfunction (stimulate and shrink)
R-hLH; Follicle stimulating hormone Regulate reproductive function
Glucocerebrosidase Gaucher disease (metabolism lipoprotein)
TSF Thrombopenia
Filgrastim (granulocyte colony-stimulating factor); GM-CSF, (reorganization granulocyte-macrophage colony stimutaing factor) Shorten time length that chemotherapy inductive neutrophilic leukocyte reduces and therefore treatment or preventing infection in patients undergoing chemotherapy; Suppress the growth of MycobacteriumIntracellular Avium or kill Mycobacterium Intracellular Avium infection (MAC)
Prostaglandin(PG) Hypertension
S-Neoral Graft-rejection
Beta-hypophamine Nocturnal enuresis; Antidiuretic
Sodium Cromoglicate Asthma; Transformation reactions
Vancomyein Treatment or prevent antimicrobial inductive to infect is including, but not limited to methicillin resistance Staphalococcus aureus and Staph.epidermiditis
Gallium nitrate Osteoporosis; Paget; Suppress osteoclast; Promote scleroblast active, hypercalcemia comprises the hypercalcemia that cancer is relevant, and urethra (urinary tract) is pernicious; Antitumor, cancer comprises urethra and bladder cancer; Lymphoma; Pernicious (comprising bladder cancer); White blood disease; Handle bone and shift (with relevant pain); Multiple myeloma; Weaken immunne response, comprise the allograft rejection reaction; Disturb iron metabolism; Promote cell migration; Trauma repair; Weaken or treatment branch Pseudomonas, including, but not limited to the course of infection of Mycobacterium Tubercolosis and Mycobacterium Avium complex body
(DFO) desferrioxamines The iron overload
Rat parathyroid hormone 1-34 (PTH) comprises its fragment. Osteoporosis; Osteopathia
Antimicrobial drug Infect, including, but not limited to gram positive bacteria infection
VITAMINs Treatment and prevention vitamin deficiency
Diphosphonate comprises Alendronate, clodronate salt, etridronate salt, ibandronate, because of card phosphonate, YM 529, neridronic acid salt, olpadronate, pamldronate, risedronate, Tiludronate, Zoledronic acid salt, EB1053 and YH529; Osteoporosis; Paget; Osteoma and transfer (and ache related); Mammary cancer; Comprise assisting therapy as breast carcinoma of early stage; Handle bone and shift (and ache related), comprise that the bone relevant with mammary cancer, prostate cancer and lung cancer shifts; Suppress osteoclast; Promote scleroblast active; Treat and/or prevent BMD (bmd) loss; Multiple myeloma; Prevent the bone complication relevant with pernicious osteolysis; Fibrous dysplasia; Paediatrics osteogenesis defective (pediatric osteogenesisimperfecta); Hypercalcemia, urethra (urinary tract) is pernicious; Reflection sympathetic nerve dystropy syndrome, the acute back pain after the vertebra comminuted fracture, the chronic inflammatory joint disease, the kidney osteopathy, the extrosseous calcification, pain relieving, poisoning by vitamin D, ossified around the joint
Antimigraine; For example BIBM-4096BS, BIBN4096BS-(1-piperidyl urea .N-[2-[[5-amino-1-[[4-(4-pyridyl)-1-piperazinyl] carbonyl] amyl group] amino]-1-[(3; 5-two bromo-4-hydroxy phenyls) methyl]-the 2-oxoethyl]-4-(1,4-dihydro-2-oxo--3 (2H-quinazolyl)-[R-(R ＊，S ＊)]-) and other calcitonin gene related protein antagonist, GR-43175 SUMATRIPTAN SUCCINATE; Migraine; The CGRP antagonist
Hyperglycemic-glycogenolytic factor Improve glycemic control (for example treating hypoglycemia and control hypoglycemic reaction), obesity; The diagnosis of the radioassay of stomach, duodenum, small intestine and colon is auxiliary; Treat cardiovascular agent including, but not limited to calcium channel blocker, the acute poisoning of Beta receptor blockers
GLP-1, Exendin-3, Exendin-4 Mellitus; Improve glycemic control (for example treating hypoglycemia and control hypoglycemic reaction), obesity
DPP IV (DPP-4) suppressor factor Mellitus; Improve glycemic control (for example treating hypoglycemia), obesity
Vaccine comprises the vaccine of those anti-anthraxs or yersinia pestis, influenza and bleb. Prevent or minimize disease or infection
Peptide YY (PYY) and PYY appearance peptide Obesity, mellitus, eating disorder, insulin resistance syndrome
For example, one embodiment of the invention are to suffer from or the patient's of easy infection mellitus method through the insulinize of using pharmaceutical prepn of the present invention.Other promoting agent comprises on those promoting agent of listing in table, can with pharmaceutical prepn combined utilization of the present invention.
After using, the promoting agent that is present in compsn or the dosage unit form absorbs the entering circulation.The bioavailability of material can be through measuring known pharmacologically active in the blood, and for example the increase of the blood coagulation time that causes of heparin or circulation calcium level that thyrocalcitonin causes reduce and easily estimate.In addition, can directly measure the cyclical level of promoting agent itself.
Additive
Solid composite medicament of the present invention and unit dosage can comprise other promoting agent and pharmaceutically acceptable additive, for example any combination of vehicle, carrier, thinner, stablizer, softening agent, tackiness agent, glidant, disintegrating agent, swelling agent, lubricant, softening agent, tinting material, membrane-forming agent, correctives, odor mask, sugar, sweeting agent, sanitas, excipient substance, tensio-active agent and above any material.Preferably, these additives are pharmaceutically useful additives, for example those Remington ' s, The Science and Practice of Pharmacy,(Gennaro, A.R., ed., 20 ThEdition, 2003, Mack Pub.Co.) the middle additive of describing, it incorporates this paper into as a reference.
The tackiness agent that is fit to is including, but not limited to starch, gelatin, sugar (for example sucrose, syrup and lactose), monocalcium phosphate, natural and synthetic is gummy (for example gum arabic), sodium-alginate, CMC 99.5, methylcellulose gum, Vinylpyrrolidone polymer, polyoxyethylene glycol, TKK 021 and paraffin.
The glidant that is fit to is including, but not limited to talcum powder and silicon-dioxide (for example fumed silica and colloidal silica).
The disintegrating agent that is fit to is including, but not limited to starch, sodium starch glycollate, Sodium Croscarmellose, PVPP, clay, Mierocrystalline cellulose (the for example Mierocrystalline cellulose of purifying, methylcellulose gum and Xylo-Mucine), alginates, pregelatinized corn starch and natural gum (for example agar, X 5363, carob bean gum, POLY-karaya, pectin and tragakanta).Preferred disintegrating agent is a sodium starch glycollate.
The swelling agent that is fit to is including, but not limited to starch (for example Starch rice), Microcrystalline Cellulose, lactose (a for example Lactose hydrate), sucrose, glucose, N.F,USP MANNITOL, calcium sulfate, sulfuric acid dicalcium and sulfuric acid DFP.
The lubricant that is fit to is including, but not limited to Triple Pressed Stearic Acid, stearate (for example calcium stearate and Magnesium Stearate), talcum powder, boric acid, Sodium Benzoate, sodium acetate, sodium fumarate, sodium-chlor, polyoxyethylene glycol, hydrogenated cottonseed oil and Viscotrol C.
The tensio-active agent that is fit to comprises but is not limited to sodium lauryl sulphate, hydroxylation soybean lecithin, Spheron MD 30/70 and propylene oxide and epoxyethane block copolymer.
Formulation
The solid composite medicament of the present invention that comprises promoting agent and delivery agent can be formulated as solid unit dosage form.Formulation can be for example tablet, sachet or capsule, for example hard or Gelseal.Formulation can provide delivery agent, heparin and optional other promoting agent fast, continue or controlled release.
Solid composite medicament of the present invention and solid unit dosage form can be according to following preparations.The delivery agent (for example passed through 35 mesh sieves pulverize) of processing solid form has relatively little and is preferably the powder of homogeneous granules size to provide.With for example vee-blender or less instrument delivery agent is mixed so that powdered mixture to be provided with delivery agent and optional weighting agent and/or wetting agent then.
The wetting agent mixture is separately through being mixed with wetting agent, heparin and delivery agent.Mixture also can for example comprise water.Wetting heparin when the prescription of selective wetting mixture mixes with aforesaid powdered mixture with box lunch.According to an embodiment preferred, the wetting agent mixture also can so be prepared, and promptly when mixing with powdered mixture, is partly dissolved delivery agent.
Under mixing continuously, powdered mixture joins in the wetting agent mixture with the form of small amount of incremental.Add the back at all powdered mixture and mix time enough (for example 15 minutes) continuously to obtain uniform compsn.The compsn that produces is typically semisolid, colloid or liquid.
Then, compsn can be formulated as formulation through method as known in the art, for example capsule.According to an embodiment preferred, the compsn of generation is packaged as soft gelatin capsule or hard gelatin capsule (for example No. 0 Licap Capsugel hard gelatin capsule).Other methods that are fit to are at U.S. Patent number 6,605, and 298,6,458,383,6,261,601,5,714,477 and 3,510,561; U.S. Patent Application Publication 2003/0077303 and 2001/0024658; And describe among the international publication number WO88/10117, these all documents are incorporated this paper into as a reference.
Embodiment
Following examples are used to the present invention is described and do not constitute restriction.All unless otherwise indicated per-cent is weight percent.
Unless otherwise indicated; It is at 300MHz
Figure S05818614120061211D000661
spectrometer (Bruker-Physik AG that the proton nuclear magnetic resonance of the compound of listing below (1H NMR) is analyzed; Silberstreifen; GERMANY) or 400MHz JEOL spectrometer (JEOL USA, Inc., Peabody; MA), application methyl-sulphoxide (DMSO-d6) carries out as solvent.
Liquid chromatography/mass spectrometry (LC-MS) analyze with Agilent Technologies (Palo Alto, California), LC/MSD 1100 (single-stage quadrupole) carries out, it has following parameter:
Mobile phase A: 50: 950: 5 acetonitriles: water: acetate (v/v/v).
Mobile phase B: 950: 50: 5 acetonitriles: water: acetate (v/v/v).
Gradient elution: 4 minutes linear gradient 0-100%B; The total time of every pin is 11 minutes.
Sampling volume: 5 μ L.
Chromatographic column: ZORBAX Rapid Resolution Cartridge, SB-C18,2.1 * 30mm, 3.5 μ m.
Particle diameter, catalog number (Cat.No.) #873700-902.
Column temperature: 40 ℃.
UV detects at 244nm.
The MSD parameter:
Source: API-ES, anodal sweep parameter:
Mass range: 125.00-600.00
Ionization voltage: 60V is separated in collision
Gain: 1.0EMV
Threshold value: 150
The spray chamber:
Gas temperature: 350deg.D
Dry gas: 12.0L/ minute
Nozzle pressure: 40psig
Capillary voltage: 4000V just/negative
The preparation of embodiment 1 compound 1-22
Compound 1-22 is according to U.S. Patent number 6,384, and 278 method prepares, and it quotes in full incorporates this paper into as a reference.
In YLENE, with the substituted aniline of suitable N mix with suitable dicarboxylic acid monoesters and in the presence of boric acid catalyst the heating.With the midbody acid amide hydrolysis to obtain final product.
Embodiment 2 compound 23-34 and 59 preparation
Exsiccant 200mL 3 neck round-bottomed flasks are equipped with the magnetic stirring bar of polytetrafluorethylecoatings coatings and the dean stark trap of vacuum jacket layer, and the reflux exchanger that is fit to nitrogen inlet tube is equipped with at this water trap top.In reaction vessel, pack into N-sec.-propyl-N-phenyl amine (8.11g, 60mmol), boric acid (0.93g, 15mmol) and YLENE (88mL).Adding a 7-oxyethyl group-7-oxo enanthic acid in the reaction mixture that stirs (11.29g, 60mmol).The application of heat cover extremely refluxes reaction mass heated.Azeotropic water begins to separate and be collected in the dean stark trap.Reflux after 16 hours, water is collected, and allow reactant to be cooled to the envrionment temperature reaction.Reaction mixture is diluted with ETHYLE ACETATE (100mL), and with the 2N HCl aqueous solution (50mL) washing, and then wash with saturated sodium hydrogen carbonate solution (60mL).Under vacuum, remove most of organic solvent.In residue, add 2N aqueous sodium hydroxide solution (60mL).Mixture was 60 ℃ of heating 4 hours.Then be cooled to room temperature, mixture washs with 60mL ETHYLE ACETATE.After separating from organic layer carefully, water evaporates to remove all residual ETHYLE ACETATE.Ice is joined in the aqueous solution, and (2N 60mL), produces the white solid deposition then to add the HCl aqueous solution.Continue to stir other 30 minutes, use the sinter funnel collecting precipitation then.With the white solid of collecting successfully water and hexane wash, then room temperature, vacuum held 12 hours, obtain 7-[sec.-propyl (phenyl) amino]-7-oxo enanthic acid of 7.49g (45%), be white solid.HPLC: at 4.83 minutes was unimodal; Mp:62-63 ℃. 1H NMR(DMSO-d6，)δ：0.95-0.97(d，6H)，1.08-1.10(m，2H)，1.34-1.40(m，4H)，1.76-1.79(m，2H)，2.09-2.13(m，2H)，4.81-4.85(m，1H)，7.18-7.20(m，2H)，7.44-7.46(m，3H)。Quality (M+1): 278.Analyze C 16H 23NO 3Calculated value: C, 69.29; H, 8.36; N, 5.05.Measured value: C, 69.06; H, 8.45; N, 4.99.
Compound 24-34 and 59 uses identical process with suitable feedstock production.
Compound (24)
HPLC: at 4.43 minutes was unimodal.Quality (M+1): 264. 1H NMR(400 MHz，DMSO-d 6)δ：0.95(d，6H)，1.30(m，2H)，1.40(m，2H)，1.80(m，2H)，2.00(m，2H)，4.80(m，1H)，7.15(m，2H)，7.40(m，3H)。 13C NMR(100MHz，DMSO-d 6)δ：21.0，24.0，24.5，33.0，34.0，45.0，128.0，129.0，130.0，138.5，170.5，174.0。
Compound (25)
HPLC: at 4.62 minutes was unimodal.Quality (M+1): 264. 1H NMR(400MHz，DMSO-d 6)δ：0.78(d，3H)，0.94-0.95(d，6H)，1.70-1.72(m，1H)，1.80-1.92(m，2H)，2.08-2.15(m，1H)，2.20-2.30(m，1H)，4.75-4.90(m，1H)，7.10-7.20(m，2H)，7.35-7.50(m，3H)。 13C NMR(100MHz，DMSO-d 6)δ：19.5，21.0，27.0，40.5，41.0，45.0，128.0，129.0，130.5，138.5，170.0，174.0。
Compound (26)
HPLC: at 4.19 minutes was unimodal.Quality (M+1): 250. 1H NMR(400MHz，DMSO-d 6)δ：0.65(d，3H)，0.84-0.86(t，3H)，1.80-1.90(m，3H)，2.01-2.12(m，2H)，3.49-3.53(q，2H)，7.09-7.11(d，2H)，7.20-7.25(m，1H)，7.30-7.32(m，2H)。 13C NMR(100MHz，DMSO-d 6)δ：9.18，15.87，17.30，23.35，39.50，123.98，124.72，125.92，138.39，166.17，168.27，169.80。
Compound (27)
HPLC: at 3.92 minutes was unimodal.Quality (M+1): 250. 1H NMR(400MHz，DMSO-d 6)δ：1.13(m，2H)，1.37-1.46(m，4H)，1.99(m，2H)，2.10-2.15(t，2H)，3.15(s，3H)，7.29-7.37(m，3H)，7.42-7.47(m，2H)。
Compound (28)
HPLC: at 3.72 minutes was unimodal.Quality (M+1): 236. 1H NMR(400 MHz，DMSO-d 6)δ：0.79-0.81(d，3H)，1.93-2.02(m，3H)，2.16-2.30(m，2H)，3.15(s，3H)，7.27-7.37(m，3H)，7.43-7.48(m，2H)。
Compound (29)
HPLC: at 3.88 minutes was unimodal.Quality (M+1): 242. 1H NMR(400 MHz，DMSO-d 6)δ：2.21(m，2H)，2.49(m，2H)，3.13(s，3H)，7.37(m，2H)，7.58(m，2H)，12.10(br.，1H)。
13C NMR(100MHZ，DMSO-d 6)δ：28.81，29.0，36.5，129.32，129.58，132.0，142.66，170.58，173.63。
Compound (30)
HPLC: at 4.82 minutes was unimodal.Quality (M+1): 278. 1H NMR(400MHz，DMSO-d 6)δ：1.02(m，4H)，1.32(m，4H)，1.86(m，2H)，2.05(m，2H)，2.21(s，3H)，3.00(s，3H)，7.00(m，2H)，7.12(m，2H)，11.85(br.，1H)。
Compound (31)
HPLC: at 4.44 minutes was unimodal.Quality (M+1): 294. 1H NMR(400 MHz，DMSO-d 6)δ：1.10(m，4H)，1.39(m，4H)，1.93(m，2H)，2.11(m，2H)，3.07(s，3H)，3.75(s，3H)，6.96(m，2H)，7.20(m，2H)，11.93(br.，1H)。
Compound (32)
HPLC: at 4.81 minutes was unimodal.Quality (M+1): 278. 1H NMR(400 MHz，DMSO-d 6)δ：0.97(t，3H)，1.10(m，4H)，1.39(m，4H)，1.90(m，2H)，2.13(m，2H)，3.58-3.63(q，2H)，7.09-7.24(d，2H)，7.34(m，1H)，7.41-7.45(m，2H)。
Compound (33)
HPLC: at 5.48 minutes was unimodal.Quality (M+1): 312. 1H NMR(400 MHz，DMSO-d 6)δ：0.96(t，3H)，1.10(m，4H)，1.40(m，4H)，1.91(m，2H)，2.12(m，2H)，3.60(q，2H)，7.27(d，2H)，7.46(m，2H)，11.93(br.，IH)。
Compound (34)
HPLC: at 4.52 minutes was unimodal.Quality (M+1): 282. 1H NMR(400 MHz，DMSO-d 6)δ：1.09(m，4H)，1.39(m，4H)，1.93(m，2H)，2.10-2.14(m，2H)，3.09(s.3H)，3.75(s 3H)，7.19(m，2H)，7.30(m，2H)，11.91(br.，1H)。
Compound (59)
HPLC: at 4.71 minutes was unimodal.Quality (M+1): 284. 1H NMR(400 MHz，DMSO-d 6)δ：0.90(t，3H)，1.35-1.37(m，4H)，1.87(t，2H)，2.04(t，2H)，3.52-3.57(q，2H)，7.25(m，2H)，7.43(m，2H)，11.94(s，1H)。
The preparation of embodiment 3 compound 111-139
(compound 111) 4-oxo-4-phenyl-butyric acid:
(available from Sigma-Aldrich Co., St.Louis MO) joins in the 10mL water with 10g (56mmol) 3-benzoyl-propionic acid.Stir the mixture and add 28mL 2N sodium hydroxide (aqueous solution).With the solution stirring 2 hours that generates and after the solution freeze-drying, collect solid product. 1H NMR (d6-DMSO): δ 7.9, d, 2H, (aryl H); δ 7.6, t, 1H, (aryl H); δ 7.5, t, 2H, (aryl H); δ 3.1, t, the 2H (CH of carbonyl α position 2); δ 2.2, t, the 2H (CH of COOH α position 2); Because the existence of water does not observe the COOH peak in the sample.
(compound 113) 10-(4-hydroxyl-phenyl)-10-oxo-capric acid:
Under rare gas element, the sebacic acid of in the 500mL flask that reflux exchanger is installed, packing into (20g, 296mmol) and diacetyl oxide (280mL, 2.96mol).Mixture heating up is to refluxing 5 hours.Under reduced pressure remove acetate and excessive acetic anhydride via.Product can be used and need not to be further purified.
Under rare gas element, in the 500mL flask that mechanical stirrer is installed, add oxa-ring undecane-2, the 11-diketone (20g, 108.5mmol), (10.22g is 108.5mmol) with 200mL dithiocarbonic anhydride for phenol.(72.34g 542mmol) and with reactant stirred 72 hours to add aluminum chloride (III).Dithiocarbonic anhydride is decanted, and add ice carefully up to most of mixture dissolving.Insoluble substance is through the suction filtration collection and with 2 * 100mL water washing.Then solid is dissolved in the 100mL 1M aqueous sodium hydroxide solution, uses the acidifying of 1M aqueous hydrochloric acid then up to pH=7.5.The solid by filtration that forms is removed and mother liquor is continued acidifying up to pH=2.5.The crude product deposition is through the filtration collection and with 1 * 100mL water washing.Crude product is dissolved in the 100mL 1M aqueous sodium hydroxide solution, removes up to pH=7.5 and with sedimentary contaminant filter with the acidifying of 1M aqueous hydrochloric acid carefully then.With the further acidifying of mother liquor up to pH2.Crude product is through the filtration collection and with 2 * 50mL water washing.Product is recrystallization from acetone.Isolating product (1.2g, 4%) is collected through filtering.Measured value: C 69.00, H 7.81%; C 16H 22O 4Theoretical value is C:69.04, H:7.97%. 1H NMR (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 10.3, bs, 1H (aryl-hydroxyl); δ 7.8d, 2H (aryl H); δ 6.8, d, 2H, (aryl H); δ 2.9, t, the 2H (CH of carbonyl α position 2); δ 2.2, t, the 2H (CH of COOH α position 2); δ 1.5, multiplet, the 4H (CH of carbonyl β position 2CH with COOH β position 2), δ 1.3, multiplet, 8H (remaining CH 2).
(compound 114) 10-(2-hydroxyl-phenyl)-10-oxo-capric acid:
In the flask of 100mL, add methylene dichloride (50mL), 9-bromine nonyl alcohol (7.63g, 34.2.mmol) and trimethylsilyl chloride (4.5mL, 35.5mmol) and allow it under nitrogen, to stir 20 minutes.(5.0mL 35.9mmol) and with the reaction mixture that generates at room temperature stirred 2 hours to add triethylamine then.Then reaction mixture is diluted, filters with 80 mL hexanes, under reduced pressure concentrate then.The residue that generates with the dilution of 80mL hexane, filters once more, under reduced pressure concentrates then, obtains the yellow liquid of 9.7g (96%), and it can be used and need not to be further purified.
Under rare gas element, 5.69g (19.3mmol) (9-bromo-oxygen in ninth of the ten Heavenly Stems base)-trimethylammonium-silane is added drop-wise to comprises MAGNESIUM METAL 99 (0.59g in 50mL flask 24.3mmol), adds the 20mL THF and is used to begin Grignard with the fritter iodine crystal and reacts.In the 100mL flask, (2.1mL, 20mL tetrahydrofuran solution 19.7mmol) cools off with outside ice bath will to contain salicylic aldehyde under rare gas element.(20.0mL 20mmol) handles with 1.0M two (trimethyl silyl) lithamide with refrigerative aldehyde solution then.Stir after 1 hour, the Grignard reactant is cooled off with outside ice bath.Then under constant stirs, go through refrigerative Grignard was added drop-wise in the aldehyde solution through sleeve pipe in 5 minutes.Make reaction mixture temperature to the room temperature of generation and continue stirred overnight.Reactant is poured onto in the ETHYLE ACETATE of 40mL and and handles with the saturated sodium bicarbonate aqueous solution of 15mL.With the organic layer separation and with two part of 4% aqueous hydrochloric acid washing of 2 * 25mL, then with a brine wash of 1 * 20mL.Organic layer filters and under reduced pressure removes and desolvate through dried over sodium sulfate.The residue that residual salicylic aldehyde is removed and generated through the Kugelrohr distillation can be used and need not to be further purified.
1-(2-hydroxyl-phenyl)-undecane-1 of in the 100mL flask, packing into, (5.0g is 18.9mmol) with the 50mL N for the 11-glycol.To wherein add pyridine
Figure S05818614120061211D000711
dichromate (32.9g, 87.5mmol).(adition process is slightly generated heat).With reaction mixture stirred overnight at room temperature.Be poured onto in the 50mL ETHYLE ACETATE reaction mixture and with 200mL water, 30mL 4% aqueous hydrochloric acid, 30mL water and final 30mL brine wash.Organic layer stirred 15 minutes with 10g silica gel then, used dried over sodium sulfate, filtered and under reduced pressure removed and desolvate.With off-white color crude product recrystallization from ethanol/water.Product (0.5g, 10%) is separated, be the off-white color solid, mp85-87 ℃.Combustion analysis: measured value: C69.01, H8.36%; C 16H 22O 4Theoretical value is C:69.54, H:8.02%. 1H NMR (d6-DMSO): δ 12.0, s, 1H (COOH); δ 7.9 dd, 1H (aryl H); δ 7.5, dt, 1H, (aryl H); δ 6.9, complicated multiplet, 2H (aryl H), 3.1, t, the 2H (CH of carbonyl α position 2); δ 2.2, t, the 2H (CH of COOH α position 2); δ 1.6, multiplet, the 2H (CH of carbonyl β position 2), δ 1.5, multiplet, the 2H (CH of COOH β position 2), δ 1.3, multiplet, 8H (remaining CH 2).
(compound 115) 4-(4-methoxyl group-phenyl)-4-oxo-butyric acid:
Under rare gas element (nitrogen), 5.25mL (48.3mmol) phenylmethylether of in the 500mL round-bottomed flask of magnetic stirring bar is installed, packing into, 4.83g (48.3mmol) Succinic anhydried, 125mL sym.-tetrachloroethane and 125mL oil of mirbane.The ice bath that reaction vessel usefulness is outside cools off and stirred 30 minutes.(14.2g, 106.4mmol), this solution becomes dark red brown then in yellow solution, to add aluminum chloride.Ice bath is removed, and at room temperature reactant was stirred 36 hours.Reactant is cooled off with outside ice bath once more.Through being poured onto in the 100mL beaker that is filled with ice, 1 N hydrogen chloride solution prepares acidic solution.This solution is joined in the reaction mixture carefully, and beginning is to drip up to reactant to become clarification and have white precipitate.Behind this point, carefully add a ice/acid mixture of 10mL with detection reaction, add remaining ice/acid mixture then.Add second part of 100mL ice/acid mixture, the ice bath of outside is removed and white emulsion was stirred 2 hours.Collect the deposition in the emulsion through suction filtration.This solid is dissolved in the 300mL 0.3M sodium hydroxide, with 100mL ETHYLE ACETATE washing, and with the 1M hcl acidifying extremely～pH1.The white precipitate that vacuum filtration is collected is with 3 * 100mL deionized water wash and drying.Product (4.7g, 47%) is separated, be white solid, mp149-150 ℃.Combustion analysis: measured value: C63.52, H5.78%; C 11H 12O 4Theoretical value is C:63.45, H:5.81%. 1H NMR (d6-DMSO): δ 12.2, s, 1H (COOH); δ 7.9d, 2H (aryl H); δ 7.0, d, 2H, (aryl H); δ 3.8, s, 3H (H of OMe); δ 3.2, t, the 2H (CH of carbonyl α position 2); δ 2.5, t, the 2H (CH of COOH α position 2).
(compound 116) 5-(4-methoxyl group-phenyl)-5-oxo-valeric acid:
Replace Succinic anhydried except using Pyroglutaric acid, compound 116 is according to the similar method preparation of compound 115, mp141-142 ℃.Measured value: C64.65, H6.34%; C 12H 14O 4Theoretical value is C:64.85, H:6.35%. 1H NMR (d6-DMSO): δ 12.2, s, 1H (COOH); δ 7.9 d, 2H (aryl H); δ 7.0, d, 2H, (aryl H); δ 3.8, s, 3H (H of OMe); δ 3.0, t, the 2H (CH of carbonyl α position 2); δ 2.3, t, the 2H (CH of COOH α position 2); δ 1.8 quintets, 2H (two CH 2Between CH 2).
Compound 117 available from Aldrich (St.Louis, MO), catalog number (Cat.No.) 514683.
Compound 118 available from Aldrich (St.Louis, MO), catalog number (Cat.No.) B12687.
Compound 119 available from Aldrich (St.Louis, MO), catalog number (Cat.No.) S346810.
Compound 120 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7013D.
Compound 121 is available from Reike, Aldrich (St.Louis, MO), catalog number (Cat.No.) 7148C and
(compound 121) 5-(4-sec.-propyl-phenyl)-5-oxo-pentanoate sodium-salt:
In the 250mL flask, (5g 21.3mmol) is dissolved in the 75mL ethanol with 5-(4-sec.-propyl-phenyl)-5-oxo-valeric acid.Add sodium hydroxide (0.85g, 21.3mmol) and under decompression on the Rotary Evaporators with the reactant stirred overnight.Solid is dry and can use and need not to be further purified under vacuum.Measured value C60.24, H6.66, Na9.21%; C 14H 17O 3The Na theoretical value is C:61.28, H:6.98, Na8.38%.
1H NMR (D2O): δ 7.7, d, 2H (aryl H); δ 7.2 d, 2H (aryl H); δ 2.9, t, the 2H (CH of carbonyl α position 2); δ 2.8, multiplet, 1H, (CH of sec.-propyl); δ 2.1, t, the 2H (CH of COOH α position 2); δ 1.8, q, the 2H (CH of carbonyl and COOH β position 2), δ 1.1, d, the 6H (CH of sec.-propyl 3).
Compound 122 available from Aldrich (St.Louis, MO), catalog number (Cat.No.) B13802.
Compound 123 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7060B.
Compound 124 available from Fischer-Scientific (Hampton, NH), Acros, catalog number (Cat.No.) 17.522.62.
Compound 125 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7011D.
Compound 126 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7036B.
Compound 128 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7012D.
Compound 129 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7012B.
Compound 130 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7055B.
Compound 132 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7005b.
Compound 133 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7036F.
Compound 134 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7144D.
Compound 136 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7144B.
Compound 138 is available from Reike, and Aldrich (St.Louis, MO), catalog number (Cat.No.) 7036D.
(compound 139) 10-(2,5-dihydroxyl-phenyl)-10-oxo-capric acid:
Under rare gas element, the sebacic acid of in the 500mL flask that reflux exchanger is installed, packing into (20g, 296mmol) and diacetyl oxide (280mL, 2.96mol).With mixture heating up to refluxing 5 hours.Under reduced pressure remove acetate and excessive acetic anhydride via.Product can be used and need not to be further purified.
Under rare gas element, in the 500mL flask that mechanical stirrer is installed, add the oxa-ring undecane-2 of front preparation, (37.95g, 206mmol), 1, (20g is 103mmol) with 200mL dithiocarbonic anhydride for 4-diacetoxyl-benzene for the 11-diketone.(68.7g 515mmol) and with reactant stirred 72 hours to add aluminum chloride (III).Dithiocarbonic anhydride is decanted, and the careful ice that adds is up to most of mixture dissolving.Collect insoluble material and with 2 * 100mL water washing through suction filtration.Be dissolved in solid in the 50mL 1M aqueous sodium hydroxide solution then and stirred 1 hour.With the aqueous hydrochloric acid of 1M with the solution acidifying up to pH=2.Be dissolved in acetonitrile (50mL) and the methylene dichloride (15mL) once more and allow it to go through slow deposition of 1 week through filter to collect the crude product deposition and will precipitate.Through the brown ceramic powder that filter to collect produces and from 10: 3 acetate: recrystallization the water.Through filtering product (0.8g, 3%) is separated.Measured value: C65.55, H7.69%; C 16H 22O 5Theoretical value is C:65.29, H:7.53%. 1H NMR (d6-DMSO): δ 12.0, s, 1H (COOH); δ 11.4, s, 1H (aryl-hydroxyl); δ 9.2, s, 1H (aryl-hydroxyl); δ 7.2 d, 1H (aryl H); δ 7.0, dd, 1H, (aryl H); δ 6.8, d, 1H (aryl H), 3.0, t, the 2H (CH of carbonyl α position 2); δ 2.2, t, the 2H (CH of COOH α position 2); δ 1.6, multiplet, the 2H (CH of carbonyl β position 2), δ 1.5, multiplet, the 2H (CH of COOH β position 2), δ 1.3, multiplet, 8H (remaining CH 2).
The preparation of embodiment 4-compound 140-151
Usually, compound prepares according to four-step method.At first, suitable substituted salicylic acid and 3-propalanine ethyl ester are mixed with ethylene dichloride (EDC)/hydroxybenzotriazole (HOBt)/methylene dichloride (DCM).Second step, and adding deacidite A-15/A-21 (available from Rohm and Haas, Philadelphia, PA).The 3rd step is after the partially disposed, with product and trimethyl silicane potassium alcoholate (KOTMS)/THF (THF) reaction.The 4th step, and adding IRC-50 resin (Rhohm & Haas, Philadelphia, PA).
In each scintillation vial, add Whitfield's ointment (4.57mmol), DCM (10mL), EDC (1.05g, 5.48mmol), HOBt (838mg, 5.48mmol), DMF (2mL) and ethyl-3-propalanine ester (600mg, 4.57mmol).All little bottle caps is tight, be placed on the J-Kem reaction block (J-KemScientific Inc., St.Lois, MO) on, jolting and the heating (150rpm, 35 ℃) spend the night.Based on TLC, all reactants have a significant point.In each bottle, add Amberlyst-21 and Amberlyst-15 resin (about 2.5g, 11mmol) and continuous at ambient temperature jolting spend the night.Reactant is filtered, with DCM (2 * 5mL) washing resins, and filtrating of each reaction collection is incorporated in the new scintillation vial.Filtrating is blown under nitrogen gas stream to the about 2mL of volume.
The THF that contains trimethyl silicane potassium alcoholate (KOTMS) (10mL, 12mmol) solution that in each bottle, add 1.2 M.But in some reaction, add more THF if desired to obtain the slurry of jolting.All little bottle caps is tight, be placed on the J-Kem reaction block jolting and heating (150rpm, 60 ℃, 6 hours).With the reaction block cooling, and (3g is 30mmol) to handle sylvite in each bottle, to add the IRC-50 resin.Add DCM if desired so that resin suspends and is prone to jolting.The reactant jolting is spent the night.Reactant is filtered, and (2 * 5mL) washing resins wash with dissolved solids with DMF if desired, and filtrating that each reaction is collected is incorporated in the scintillation vial new, taring with DCM.This some taking-up small portion filtrating and with 1: 1 ACN/H 2The O dilution is to carry out LC-MS.Under nitrogen gas stream, filtrating is dried up.For removing the DMF of trace, bottle is put in 50 ℃ the vacuum constant temperature case.
Analyze based on LC-MS, some reaction mixtures comprise quite a large amount of esters.These materials are handled with KOTMS once more.The THF (8mL, 9.6mmol) solution that in each bottle, add 1.2M KOTMS.All little bottle caps is tight, put into the Pierce reaction block, stir and heating (60 ℃, 5 hours).With the reaction block cooling, and (2g is 20mmol) to handle sylvite in each bottle, to add the IRC-50 resin.Add DCM if desired so that resin suspends and is prone to stirring.Going through weekend stirs reactant.Reactant filters through unmodified packed column, and (1 * 5mL), (3 * 7mL) washing resins and silica gel and the filtrating that each reaction is collected are incorporated in the scintillation vial new, taring 2: 5 MeOH/DCM then with DCM.This some taking-up small portion filtrating and with 1: 1 ACN/H 2The O dilution is to carry out LC-MS.Under nitrogen gas stream, filtrating is dried up.
Come from the every other reaction mixture that KOTMS for the first time handles and put into 10: 1DCM/MeOH and filter through unmodified packed column, with more 10: 1 DCM/MeOH wash-outs.This some taking-up small portion filtrating and with 1: 1 ACN/H 2The O dilution is to carry out LC-MS.Under nitrogen gas stream, filtrating is dried up.
The selectivity preparation of compound 140-151
In the round-bottomed flask of 1L, add 3, and 5-di-isopropyl Whitfield's ointment (25.0g, 112.5mmol), HOBt (20.6g, 135.0mmol), (18.0g is 123.7mmol) with diox (400mL) for ethyl-3-propalanine ester.The mixture that produces stirs at ambient temperature.Add a part of EDC (25.9g, 135.0mmol) and continuously stirring spend the night.Show HOBt, perhaps initial Whitfield's ointment and a kind of new main product of trace at the HPLC of the reaction mixture of this point.Add another part EDC (5g, 26.0mmol) and continuously stirring spend the night.The HPLC of another time shows basically not change.React water (400mL) cancellation and remove diox with Rotary Evaporators.Oil/the water mixture that produces is poured onto in the separating funnel of 1L and adds DCM (400mL).Form a large amount of white solids.Adding EtOAc attempts making two separate and not success.Separating funnel is fallen dry doubling and on Rotary Evaporators, remove organism.With EtOAc (500mL, 200mL then) extraction water/oil mixt.With the EtOAc layer that merges with the HCl aqueous solution (10%, 2 * 200mL), the NaOH aqueous solution (10%, 2 * 200mL) and salt solution (50mL, 200mL then) wash.Organism is through Na 2SO 4Dry and more than rotary evaporation, remove to obtain to comprise the brown oil of a small amount of white solid.HPLC analysis revealed white solid is residual HOBt, and brown oily matter is the product of expection.With the sucking-off from flask of brown oily matter, avoid the sucking-off white solid as far as possible.Brown oil is put among the EtOAc (500mL), with NaOH (10%, 2 * 200mL) washing and through Na 2SO 4Dry.EtOAc is removed on Rotary Evaporators to obtain brown oil.Show a main peak and do not have HOBt at the HPLC of this point.
With the oil of viscosity be dissolved among the THF (200mL) and add KOTMS (31.7g, 247.4mmol).The viscous mixt stirred overnight that produces.HPLC shows that it is a peak that reaction is accomplished.Add the IRC-50 resin (37g, 370mmol, 1.5eq.) with 100mL DCM so that resin suspends stirred for several hour then.Filter, with DCM (3 * 50mL) washing resins and on Rotary Evaporators, concentrating with the acquisition brown oil.Trial from ACN/ acetone recrystallization and the success.The solvability that is based on this point can clear and definite material mainly be a sylvite.Oily matter is put into H 2Among the O/ACN, heat up to clarification, filtered while hot, and be cooled to envrionment temperature.With the solid precipitation that the HCl aqueous solution is handled and separation produces, grind into powder is to obtain E1528:9.13g with filtrating, and the HPLC RT is 6.7 minutes 100%; KF 0.47, and NMR is consistent with structure, and the ultimate analysis theoretical value is C:66.11; H:8.21, N:4.54, measured value C:65.62; H:8.19, N:4.46.
Compound number and title molecular weight MS (M+H) are pure based on LC-MS's
The approximate per-cent of degree
Compound 140 223.2306 224 83
3-(2-hydroxyl-benzamido-)-butyric acid
Compound 141 381.0326 382 71
3-(3,5-two bromo-2-hydroxyl-benzamido-s)-butyric acid
Compound 142 292.1206 292 77
3-(3,5-two chloro-2-hydroxyl-benzamido-s)-butyric acid
Compound 143 475.0234 476 82
3-(2-hydroxyl-3,5-two iodo-benzamido-s)-butyric acid
Compound 144 237.2577 238 75
3-(2-hydroxy-3-methyl-benzamido-)-butyric acid
Compound 145 257.6756 258 82
3-(4-chloro-2-hydroxyl-benzamido-)-butyric acid
Compound 146 253.2571 254 75
3-(2-hydroxyl-4-methoxyl group-benzamido-)-butyric acid
Compound 147 302.1316 303 82
3-(5-bromo-2-hydroxyl-benzamido-)-butyric acid
Compound 148 257.6756 258 78
3-(5-chloro-2-hydroxyl-benzamido-)-butyric acid
Compound 149 253.2571 254 77
3-(2-hydroxy-5-methyl oxygen base-benzamido-)-butyric acid
Compound 150 237.2577 238 82
3-(2-hydroxy-5-methyl base-benzamido-)-butyric acid
Compound 151 307.3931 308 89
3-(2-hydroxyl-3,5-di-isopropyl-benzamido-)-butyric acid
Embodiment 5 obtains compound 152-160
Compound 152-available from Transworld Chemical (South Melborne, AUSTRALIA).
Compound 153-available from Lancaster (Windham, NH).
Compound 154-available from Avocado (Heysham, Lancashire, ENGLAND).
Compound 155-is available from Aldrich, and catalog number (Cat.No.) 42919 (St.Louis, MO).
Compound 156-available from Sigma-Aldrich (St.Louis, MO).
Compound 157-available from Sigma (St.Louis, MO).
Compound 158-available from Matrix Scientific (Columbia, SC).
Compound H PLC HPLC KF value melting range value CHNC CHNC CHNF CHNF
Method
RT
C H C H
152 5.41 0
0.1%TF 0 69.76 5.46 in 153 5.1 minutes
A
0.1%TF 0 74.98 6.29 in 154 6.2 minutes
A
155 5.21 0
0.1%TF 0 in 156 5.82 minutes
A
157 5.42 0 184-186 73.67 5.3 72.56 4.91
158 5.47 0 110-112 74.36 5.82 74.39 5.66
159 5.56 minutes 63.47 5.39 62.65 5.13
1 60 5.30 0.3 67-70 73.45 5.32 73.08 5
Compound 160:
(10.37g 184.8mmol) grinds to powder and joins and contains 75mL methyl-sulphoxide and 2-hydroxy-benzoic acid methyl esters (7.03g is in 250mL flask 46.2mmol) with Pottasium Hydroxide with mortar and pestle.In this mixture, add bromotoluene (7.91g, 46.2mmol) and allowed under agitation to mix 4 hours.Add entry (100mL) and reactant was stirred 30 minutes in addition.Then reactant is cooled to 0 ℃ and with concentrated hydrochloric acid it is acidified to pH1 with outside ice bath.With mixture with 3 * 230mL ethyl acetate extraction.Merge organic layer and under reduced pressure remove and desolvate.The yellow liquid that produces is dissolved in the ETHYLE ACETATE (50mL) and with 2 * 30mL water, uses 2 * 30mL brine wash then.Organic layer through dried over sodium sulfate, is filtered and under reduced pressure removes and desolvate.With the yellow liquid that produces dry a few days under vacuum, form white crystals shape solid.Collect solid product and further dry under vacuum.Separated product (8.04g, 76%) is a white crystals shape solid, mp67-70 ℃.Combustion analysis: measured value: C73.08, H5.37%; C 14H 12O 3Theoretical value is C73.45, H5.32%.
The preparation of embodiment 6 compound 160-167
According to the flow preparation compound F 17-hydroxy-corticosterone of routine, wherein with the 2-hydroxy benzophenone in the presence of alkali with the alkylation of bromine alkyl ester, then using trimethyl silanol potassium is with the ester moiety cracking.
(compound 160) 6-(2-(2-hydroxy benzoyl) phenoxy) caproic acid:
The 10.32g (48.2mmol) 2 that in the 250mL round-bottomed flask that magnetic stirring bar and reflux exchanger are installed, packs into, 2 '-dihydroxy benzophenone and 100mL methyl-sulphoxide (DMSO).In clear soln, add the Pottasium Hydroxide ground to powder (2.91g, 51.9mmol).Reaction mixture is heated to 45 ℃, dissolves up to most of solid.(11.04g, 49.5mmol) 6-bromine n-caproic acid ethyl ester is handled with 8.80mL with the red slurry that produces.After stirring 20 hours under 25 ℃, clarifying reaction mixture is diluted with 1% aqueous hydrochloric acid and methyl tert-butyl ether (MTBE).With two separate.The organic phase water (2 * 50mL) and salt solution (1 * 40mL) washing is through dried over sodium sulfate and concentrate.Residue is put into 100mL THF (THF) and (15.09g 118mmol) handles with the trimethyl silicane potassium alcoholate.Orange solution was stirred 20 hours down at 25 ℃, be diluted to pH 7.5 and wash with MTBE with 4% aqueous hydrochloric acid.Organic phase extracts with 3% sodium bicarbonate aqueous solution.The water that merges is acidified to pH2 with 4% aqueous hydrochloric acid and extracts with 60mL MTBE.(1 * 40mL) washing is through dried over sodium sulfate and concentrated with salt solution for organic phase.Residue is used 80% hexane/ethyl acetate (adding 0.5% acetate) through purification by flash chromatography.Separated product (4.2g, 27%) is the off-white color solid, mp89-91 ℃.Combustion analysis: measured value: C69.50, H6.04%; C 19H 20O 5Theoretical value is C:69.50, H:6.14%. 1H NMR (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 11.5, bs, 1H (OH); δ 7.5, t, 2H, (aryl H); δ 7.4, dd, 1H (aryl H); δ 7.3, dd, 1H (aryl H); δ 7.15, d, 1H (aryl H); δ 7.1, t, 1H (aryl H); δ 7.0, d, 1H (aryl H); δ 6.9, t, 1H (aryl H); δ 3.9, t, the 2H, (CH of O α position 2); δ 2.05, t, the 2H (CH of COOH α position 2); δ 1.4, m, 4H (other two CH 2); δ 1.0, p, 2H (chain intermediary CH 2).
Below compound use identical method from suitable feedstock production: compound 161, compound 162, compound 163, compound 164, compound 165, compound 166 and compound 167.
(compound 161) 8-(2-(2-hydroxy benzoyl) phenoxy) Sodium octoate: title compound is from 2; 2 '-dihydroxy benzophenone and 8-bromine ethyl octylate begin preparation; Be translated into sodium salt then as follows: (3.56 g 9.99mmol) are dissolved in the 40mL Virahol, and handle with sodium hydroxide solution (1.7mL) with free acid; This sodium hydroxide solution with sodium hydroxide (0.90g, 22.5mmol) and water (3.7mL) preparation.Add Virahol and MTBE and cause solid precipitation.This mixture heating up is caused the most solid dissolving.Remaining solid by filtration is removed.Off-white color solid by filtration with the dry ice cooling forms is separated and drying under reduced pressure.Combustion analysis: measured value: C65.02%, H6.22%; C 21H 23O 5The Na theoretical value is C66.00, H6.65%. 1HNMR (d6-DMSO): δ 12.6, bs, 1H (OH); δ 7.41, t, 1H, (aryl H); δ 7.31, t, 1H (aryl H); δ 7.27, dd, 1H (aryl H); δ 7.15, dd, 1H (aryl H); δ 7.03, d, 1H (aryl H); δ 6.97, t, 1H (aryl H); δ 6.91, d, 1H (aryl H); δ 6.65, t, 1H (aryl H); δ 3.83, t, the 2H, (CH of O α position 2); δ 1.82, t, the 2H (CH of COONa α position 2); δ 1.3, m, 4H (other two CH 2); δ 1.0, m, 6H (chain intermediary CH 2). 13C NMR(d6-DMSO)：198.59，177.35，161.35，156.10，134.56，131.98，131.78，129.55，128.57，123.57，120.18，118.00，117.09，112.51，67.74，37.87，28.83，28.35，28.27，25.84，24.87。
(compound 162) 5-(2-(2-hydroxy benzoyl)-4-methoxyl group phenoxy) valeric acid (disclosing main isometry volume data): LC-MS analyzes: confirm m+1 peak (345). 1H NMR analyzes: (d6-DMSO): δ 12.4, bs, 1H (COOH); δ 11.9, bs, 1H (OH); δ 7.47, t, 1H, (aryl H); δ 7.26, dd, 1H (aryl H); δ 7.14, d, 1H (aryl H); δ 7.13, d, 1H (aryl H); δ 7.03, t, 1H (aryl H); δ 6.49, d, 1H (aryl H); δ 6.42, dd, 1H (aryl H); δ 3.95, t, the 2H, (CH of O α position 2); δ 3.79, s, 3H, (CH 3O); δ 2.07, t, the 2H (CH of COOH α position 2); δ 1.48, p, the 2H (CH in the chain 2); δ 1.34, p, the 2H (CH in the chain 2). 13C NMR(d6-DMSO)：199.60，174.18，165.97，163.34，155.14，135.14，131.77，128.29，127.83，120.46，114.06，112.69，107.41，100.70，67.51，55.76，33.05，27.80，20.77。
(compound 163) 5-(2-(2-hydroxy benzoyl) phenoxy) valeric acid: LC-MS analyzes: confirm m+1 peak (315). 1H NMR analyzes: (d6-DMSO): δ 11.9, bs, 1H (COOH); δ 11.5, bs, 1H (OH); δ 7.50, dt, 1H, (aryl H); δ 7.48, dt, 1H, (aryl H); δ 7.35, dd, 1H (aryl H); δ 7.25, dd, 1H (aryl H); δ 7.14, d, 1H (aryl H); δ 7.06, t, 1H (aryl H); δ 6.96, d, 1H (aryl H); δ 6.85, t, 1H (aryl H); δ 3.93, t, the 2H, (CH of O α position 2); δ 2.06, t, the 2H (CH of COOH α position 2); δ 1.42, p, the 2H (CH in the chain 2); δ 1.29, p, the 2H (CH in the chain 2). 13C NMR(d6-DMSO)：200.59，174.15，160.43，155.71，135.94，132.69，132.22，128.58，128.02，121.50，120.46，119.06，117.30，112.67，67.50，33.05，27.75，20.70。
(compound 164) 5-(2-(2-hydroxy-5-methyl oxygen base benzoyl-)-4-methoxyl group phenoxy) valeric acid: LC-MS analyzes: confirm m+1 peak (375). 1H NMR analyzes: (d6-DMSO): δ 12.4, bs, 1H (COOH); δ 12.0, bs, 1H (OH); δ 7.25, d, 1H, (aryl H); δ 7.21, d, 1H, (aryl H); δ 6.66, d, 1H (aryl H); δ 6.62, dd, 1H (aryl H); δ 6.48, d, 1H (aryl H); δ 6.42, dd, 1H (aryl H); δ 3.96, t, the 2H, (CH of O α position 2); δ 3.81, s, 3H, (CH 3O); δ 3.80, s, 3H, (CH 3O); δ 2.08, t, the 2H (CH of COOH α position 2); δ 1.48, p, the 2H (CH in the chain 2); δ 1.34, p, the 2H (CH in the chain 2). 13C NMR(d6-DMSO)：198.85，174.20，165.62，164.14，162.54，157.11，135.18，130.22，120.60，114.44，107.04，105.51，100.63，99.24，67.55，55.69，55.48，33.06，27.75，20.77。
(compound 166) 4-(2-(2-hydroxy benzoyl) phenoxy) butyric acid: LC-MS analyzes: confirm m+1 peak (333). 1H NMR analyzes: (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 7.46, m, 2H (aryl H); δ 7.33, dt, 1H (aryl H); δ 7.29, d, 1H (aryl H); δ 6.82, t, 1H (aryl H); δ 3.77, t, the 2H, (CH of O α position 2); δ 1.85, t, the 2H (CH of COOH α position 2); δ 1.35, p, 2H (chain intermediary CH 2). 13C NMR(d6-DMSO)：200.47，173.92，160.40，155.57，135.97，132.64，132.27，128.64，128.00，121.52，120.56，119.10，117.34，112.62，66.99，29.55，23.92。
(compound 167) 4-(2-chlorobenzene formacyl-4-methylphenoxy) butyric acid: LC-MS analyzes: confirm m+1 peak (333). 1H NMR analyzes: (d6-DMSO): δ 12.4, bs, 1H (COOH); δ 12.0, bs, 1H (OH); δ 7.23, d, 1H (aryl H, the ortho position of O); δ 3.74, t, the 2H, (CH of O α position 2); δ 2.25, s, 3H, (CH 3); δ 1.84, t, the 2H (CH of COOH α position 2); δ 1.33, p, 2H (chain intermediary CH 2). 13C NMR(d6-DMSO)：198.76，173.97，165.63，164.10，162.58，156.99，135.11，130.29，120.55，114.45，107.14，105.67，100.67，99.16，67.03，55.69，55.50，29.56，23.85。
The preparation of embodiment 7 compound 168-173
(compound 168) 4-(2-benzoyl--5-methoxyl group phenoxy) butyric acid: in the 100mL mini-block pipe that magnetic stirring bar is installed, pack into 4.56g (20.0mmol) 2-hydroxyl-4-methoxyl group benzophenone, 2.70mL (3.68g, 18.9mmol) 4-bromo-butyric acid ethyl ester and 40mL N (DMF).In clear soln, add salt of wormwood (2.96g, 21.4mmol).Reaction mixture is heated to 80 ℃.After stirring 20 hours under 25 ℃, with clarifying reaction mixture dilute with water.The solid by filtration that produces is separated.Solid is dissolved in the 30mL THF (THF) and with 3.10g (24.0mmol) trimethyl silicane potassium alcoholate handles.Orange solution stirred 20 hours down at 25 ℃, was diluted to pH7.5 and washed with MTBE with 4% aqueous hydrochloric acid.Organic phase extracts with 3% sodium bicarbonate aqueous solution.The water that merges is extracted to pH2 and with 60mL MTBE with 4% hcl acidifying.(1 * 40mL) washing is through dried over sodium sulfate and concentrated with salt solution for organic phase.The solid that produces grinds purifying through using the MTBE/ hexane.More product separates from mother liquor.LC-MS analyzes: confirm m+1 peak (315). 1H NMR analyzes: (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 7.6, d, 2H, (phenyl H, the ortho position of CO); δ 7.56, t, 1H (phenyl H, the contraposition of CO); δ 7.44, t, 2H (phenyl H, position between CO); δ 7.35, d, 1H (aryl H, the ortho position of CO); δ 6.64, m, 2H (aryl H, position between CO); δ 3.88, t, the 2H, (CH of O α position 2); δ 3.82, s, 3H, (CH 3O); δ 1.84, t, the 2H (CH of COOH α position 2); δ 1.53, p, 2H (chain intermediary CH 2). 13C NMR(d6-DMSO)：195.08，173.91，163.17，158.33，138.84，132.37，131.37，128.67，128.24，120.87，105.87，99.02，66.89，55.53，29.45，23.79。
Other delivery agent prepares with identical method: compound 169, compound 170, compound 171, compound 172 and compound 173.
(compound 169) 4-(2-benzoyl--4-chlorophenoxy) butyric acid: LC-M analyzes: confirm m+1 peak (319). 1H NMR analyzes: (d6-DMSO): δ 11.9, bs, 1H (COOH); δ 7. δ 4, d, 2H, (phenyl H, the ortho position of CO); δ 7.59, t, 1H (phenyl H, the contraposition of CO); δ 7.51, dd, 1H (aryl H, the contraposition of CO); δ 7.45, t, 2H (phenyl H, position between CO); δ 7.3 δ, d, 1H (aryl H, the ortho position of CO); δ 7.14, d, 1H (aryl H, position between CO); δ 3.87, t, the 2H, (CH of O α position 2); δ 1.84, t, the 2H (CH of COOH α position 2); δ 1.53, p, 2H (chain intermediary CH 2). 13CNMR(dδ-DMSO)：194.37，173.82，154.74，13δ.9δ，133.42，131.5δ，130.05，128.97，128.δ2，128.29，124.48，114.61，67.38，29.37，23.79。
(compound 170) 4-(2-benzoyl--4-bromine phenoxy) butyric acid: LC-M analyzes: confirm m+1 peak (363). 1H NMR analyzes: (d6-DMSO): δ 11.9, bs, 1H (COOH); δ 7.6, m, 3H, (aryl H); δ 7.60, t, 1H (phenyl H, the contraposition of CO); δ 7.49, dd, 1H (aryl H, the ortho position of CO); δ 7.46, t, 2H (phenyl H, position between CO); δ 7.09, d, 1H (aryl H, position between CO); δ 3.89, t, the 2H, (CH of O α position 2); δ 1.82, t, the 2H (CH of COOH α position 2); δ 1.53, p, 2H (chain intermediary CH 2). 13C NMR(d6-DMSO)：194.28，173.81，155.19，136.97134.48，133.42，131.06，130.48，128.97，128.62，115.08，112.02，67.33，29.35，23.77。
(2-(2-chlorobenzene formacyl-5-methylphenoxy) butyric acid: LC-M analyzes (compound 171) 4-: confirm m+1 peak (333). 1H NMR analyzes: (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 7.54, d, 1H (aryl H); δ 7.4, m, 2H (aryl H); δ 7.33, dt, 1H (aryl H); δ 7.29, d, 1H (aryl H); δ 6.86, m, 2H (aryl H, the ortho position of O); δ 3.77, t, the 2H, (CH of O α position 2); δ 2.31, s, 3H, (CH 3); δ 1.85, t, the 2H (CH of COOH α position 2); δ 1.35, p, 2H (chain intermediary CH 2). 13C NMR(d6-DMSO)：193.31，173.81，158.34，145.98，141.38，130.99，130.56，129.48，129.43，128.38，127.00，123.95，121.46，113.43，66.95，29.65，23.70，21.48。
(2-(2-chlorobenzene formacyl-4-methylphenoxy) butyric acid: LC-M analyzes (compound 172) 4-: confirm m+1 peak (333). 1H NMR analyzes: (d6-DMSO): δ 11.95, bs, 1H (COOH); δ 7.43, m, 3H, (aryl H); δ 7.34, m, 3H (aryl H); δ 6.92, d, 1H (aryl H, the ortho position of O); δ 3.74, t, the 2H, (CH of O α position 2); δ 2.25, s, 3H, (CH 3); δ 1.84, t, the 2H (CH of COOH α position 2); δ 1.33, p, 2H (chain intermediary CH 2). 13C NMR(d6-DMSO)：193.92，173.81，156.15，140.95，135.37，131.24，130.40，129.65，129.56，129.49，128.62，127.02，126.45，112.95，67.07，29.65，23.75，19.80。
(compound 173) 4-(2-benzoyl--4-chloro-5-methylphenoxy) butyric acid: LC-M analyzes: confirm m+1 peak (333). 1H NMR analyzes: (d6-DMSO): δ 11.9, bs, 1H (COOH); δ 7. δ 1, d, 2H, (phenyl H, the ortho position of CO); δ 7.57, t, 1H (phenyl H, the contraposition of CO); δ 7.44, t, 2H (phenyl H, position between CO); δ 7.33, s, 1H (aryl H, the ortho position of O); δ 7.14, s, 1H (aryl H, position between O); δ 3.87, t, the 2H, (CH of O α position 2); δ 2.33, s, 3H, (CH 3); δ 1.81, t, the 2H (CH of COOH α position 2); δ 1.49, p, 2H (chain intermediary CH 2). 13C NMR(dδ-DMSO)：194.31，173.83，154.78，139.80，137.39，133.17，128.91，128.84，128.51，127.55，124.69，115.57，67.32，29.37，23.80，20.03。
The selectivity preparation of compound F 17-hydroxy-corticosterone
Compound F 17-hydroxy-corticosterone can prepare according to the Friedel-Crafts acidylate selectivity of aromatic compound:
Get suitable fortified phenol, and it is mixed with suitable bromo-ester, use K 2CO 3As alkali, with product and suitable fragrant acyl chlorides at AlCl 3Down reaction of existence; Or get suitable substituted salicylic acid, and itself and suitable bromo-ester are reacted, K used 2CO 3As alkali.Product is converted into acyl chlorides SOCl 2, then with itself and suitable substituted benzene at AlCl 3Down reaction of existence.
The preparation of embodiment 8 compounds 174
Compound 174 minutes three steps preparation:
A.O-ethanoyl-5-chloro-salicylic acid
10g (57.9mmol) 5-chloro-salicylic acid is weighed in the 100mL round-bottomed flask, then add diacetyl oxide (12.8mL, 115.9mmol).Mixture stirred 5 minutes, added the vitriol oil (2) then.Reactant was refluxed 3 hours.Through HPLC monitoring reaction process.Reaction mixture is cooled to room temperature and is poured onto in the beaker that contains 2 N HCl (200mL) so that the product deposition is separated out.Collect product through vacuum filtration.Show the existence of impurity through the purity test of HPLC.To be deposited in stirred overnight in the 200mL round-bottomed flask that water (150mL) is housed.Collect insoluble solid through vacuum filtration.Determination of foreign matter through HPLC shows there is not impurity in the crude product.The product dried in vacuum is spent the night to obtain 12gO-ethanoyl-5-chloro-salicylic acid (56mmol, 97% productive rate).
B.O-ethanoyl-5-chlorine water poplar acyl chlorides
With THIONYL CHLORIDE 97 (～100mL) pack in the 250mL round-bottomed flask and in ice bath, stirred 15 minutes.(6.0g 27.9mmol) slowly joins in the refrigerative THIONYL CHLORIDE 97 with O-ethanoyl-5-chloro-salicylic acid.DMF (2) is joined in the reaction mixture to help the dissolving of acid.With the reactant stirred overnight to obtain uniform solution.Excessive THIONYL CHLORIDE 97 distills in a vacuum to be removed.Remaining residue dried in vacuum is spent the night.
C.3-(N-2-hydroxyl-5-chlorobenzene formacyl) alanine
(2.5g 28.0mmol) weighs in the 250mL round-bottomed flask with Beta-alanine.Methylene dichloride (100mL) is joined in the flask and mixture was stirred 5 minutes.With trimethylchlorosilane (δ .06g.55.7mmol) be added drop-wise in the flask.Reaction mass heated is to refluxing 1.5 hours.Allow mixture to be cooled to room temperature and to put into ice bath 15 minutes.(8.5g 84.0mmol) slowly joins in the refrigerative flask with triethylamine.(7.6g 27.9mmol) is dissolved in the methylene dichloride (30mL) and goes through and joined in the reactant in 0.5 hour with O-ethanoyl-5-chlorine water poplar acyl chlorides.Reactant stirred overnight and permission is warm to room temperature.Confirm reaction process through HPLC.The solvent vaporising under vacuum.Remaining residue 2N NaOH (～stirred 2 hours in 100mL) and slowly be heated to 60 ℃.Solution is cooled to room temperature, filters through gravity filtration then.Filtrating forms up to deposition with the slow acidifying of dense HCl.When mixture is collected crude product during at pH 6.Product is used MeOH-H 2The O recrystallization.Show the existence of impurity through the purity test of HPLC.Product through repeatedly purifying and re-crystallization step up to obtaining pure compound.With end product stirred overnight in methylene dichloride, through filter to collect and under vacuum dried overnight to obtain pale pink powder (3.98g, 16.3mmol, 58.5% productive rate); Mp 181-183 ℃; 1H NMR (DMSO-d6) δ 2.47-2.58 (t, 2H), 3.44-3.54 (q, 2H), 6.93-6.98 (d, 1H), 7.39-7.44 (dd, 1H), 7.91-7.96 (d, 1H), 8.93-9.01 (t, 1H), 12.1-12.3 (s, 1H).KF value=1.615%.Analyze C 10H 10NO 4Cl*0.2220H 2O calculated value: C, 48.50, H, 4.25, N, 5.66.Measured value: C, 48.20; H, 4.03; N, 5.43.
The preparation of embodiment 9 compound 175-178
Compound 175-4-(2-benzyloxy-phenoxy)-butyric acid:
Under rare gas element, in the 250mL flask that reflux exchanger, magnetic stirring apparatus are installed, add 2-benzyloxy-phenol (8.0g, 40mmol), 4-bromo-butyric acid ethyl ester (5.7mL, 40mmol), salt of wormwood (7.2g, 52mmol) and ethanol (100mL).Reaction mixture is heated with stirring to backflow 8 hours.Reactant is cooled to room temperature and removes insoluble by product through suction filtration.In filtrating, add 2 N aqueous sodium hydroxide solutions (30mL).With solution be heated to 50 ℃ 2 hours.Solution is cooled to room temperature, under reduced pressure removes ethanol and the solution that produces is adjusted to pH9.With ETHYLE ACETATE (2 * 30mL) wash water solution and under reduced pressure remove residual ETHYLE ACETATE.With outside ice bath solution is cooled to 0 ℃, with the 6N aqueous hydrochloric acid it is acidified to pH2 then.Through the product of suction filtration collecting precipitation and dry under vacuum.Product (7.2g, 63%) is separated, be white powder. 1H-NMR (400MHz, DMSO-d6): δ 12.0, s, 1H (COOH); δ 7.4, multiplet, 5H (benzyl aryl H); δ 7.0, multiplet, 2H (aryl H); δ 6.9, multiplet, 2H (aryl H); δ 5.0, s, 2H (benzyl CH 2); δ 4.0, t, the 2H (CH of phenoxy α position 2); δ 2.4, t, the 2H (CH of COOH α position 2); δ 1.9, multiplet, 2H (remaining CH 2).
Compound 1 76-(4-benzyloxy-phenoxy)-acetate is available from Lancaster.
Compound 177-11-(2-benzyloxy phenoxy) undeeanoic acid:
(4.2g is 74.91mmol) with the 100mL methyl-sulphoxide for the Pottasium Hydroxide of the fresh grinding of adding in the 250mL Erlenmeyer flask.Add 2-benzyloxy-phenol (5g, 24.97mmol) with 11-bromine methyl undecylate (7g, 25.07mmol) and allow mixture stirred overnight at room temperature.Add entry (75mL) and solution is heated to 85 ℃, and stirred 3 hours.Reactant is cooled to room temperature and is acidified to pH 2 with concentrated hydrochloric acid.Acidifying solution is cooled to 4 ℃ reaches 2 hours, then through the suction filtration collecting precipitation.Product is recrystallization from ethanol/water.Product (8.88g, 93%) is separated, be the light brown solid, mp 62-63 ℃.Combustion analysis: measured value: C 74.71 H 8.08%; C 24H 32O 4Theoretical value C 74.97, and H 8.39%.
Compound 178-5-(4-benzyloxy-phenoxy)-valeric acid:
Under rare gas element, in the three-necked bottle that reflux exchanger is installed, add 4-benzyloxy-phenol (30.64g, 150mmol), 5-bromine Valeric acid ethylester (31.99g, 150mmol), (22.80g is 165mmol) with the 270mL 2-butanone for salt of wormwood.Reaction mixture is heated to backflow 23 hours, and ETHYLE ACETATE (150mL) dilution and extraction from water (500mL) are used in cooling then.Organic layer water (1 * 250mL) and salt solution (1 * 250mL) washing and under reduced pressure remove and desolvate.With the oily matter that produces under vacuum dry 4 days, form white crystal during this period.White crystal is dissolved in the ETHYLE ACETATE (100mL), and (3 * 50mL) wash, and under reduced pressure remove and desolvate with the 1N aqueous sodium hydroxide solution.With the oily matter that produces under vacuum dried overnight to produce white crystal.With product from 1: 1 ethanol: recrystallization and collect and dry under vacuum the water through suction filtration.This product can be used and need not to be further purified.
In the 1L round-bottomed flask that reflux exchanger is installed, add 5-(4-benzyloxy-phenoxy)-Valeric acid ethylester (15.13,46mmol) with 2N aqueous sodium hydroxide solution (47mL).Allow mixture to stir 30 minutes.Add entry (200mL).Mixture stirred to be heated to then in 20 minutes reflux 2 hours to form brown solution.Make solution be cooled to room temperature rapidly through adding ice.With 2N aqueous hydrochloric acid (50mL) with acidifying of refrigerative solution and the white precipitate that collect to produce through suction filtration, water (2 * 100mL), hexane (2 * 100mL) washings, and under vacuum dried overnight.With the powder porphyrize and with hexane (1 * 250mL) and ether (1 * 250mL) washing to obtain white powder.In the 1L beaker with powder dissolution in the mixing solutions of ETHYLE ACETATE (300mL) and ether (200mL).With solution heating 10 minutes, add methyl alcohol (5mL), reheat 10 minutes filters to obtain clarifying yellow solution through siliceous earth column then.Product is through slowly adding the hexane crystallization.At first the crystal of results is through filtering collection and in mother liquor, adding hexane (200mL).Under reduced pressure to be concentrated into volume be 400mL and allow to leave standstill with solution then.Through filter to collect second batch of crystal and with first merging.Product (8.92g, 65%) is separated, be the crystalline thing of white, mp127-128 ℃.Combustion analysis: measured value C71.01H 6.98%; C 18H 20O 4Theoretical value C71.98, H6.71%;
The compound sequence number The HPLC RT The KF value The melting range value CHNC C CHNC H CHNF C CHNF H
175 5.93 minute
176 5.54 0 69.76 5.46
176 5.54 0 69.76 5.46
177 9.19 0 63-63 74.97 8.39 74.71 8.08
178 6.12 0 127-128 71.98 6.71 71.01 6.98
The Peroral solid dosage form transmission of embodiment 10 PYY [3-36] in rat
(PYY is available from Bachem California Inc.of Torrance, CA) for PYY [3-36] storing solution (80mg/mL) that application prepares with deionized water.
Like following explanation, add the PYY (about 1 μ L) of about 0.08mg/ sheet (about 0.3mg/kg) and mix with about 13.5 or the free acid or the sodium salt of the delivery agent compound of 27mg/ sheet (50 or 100mg/kg).Handle the Shang Chong of the manual tabletting machine of Carver4350, following dashing and punch die with Magnesium Stearate (0.1%), this tabletting machine has Natoli Engineering Company, Inc. (St.Charles, the capsule sheet shape model of Missouri) selling.With about 13.58 or the mixed powder of about 27.08mg insert in the punch die and under about 1000psi bar pressure, prepare miniature pearl tablet.The solid dosage that produces for 27.08mg size is the size of No. 9 capsules of about standard (the about 2.65mm of diameter and be about 8.40mm), and for the about 2.65mm of 13.58mg solid diameter be about 4.20mm.
With male Sprague Dawley rat (about 260 to about 280g) overnight fasting, the CO through standard then 2The technology that sucks is anaesthetized generation in about 10 to 30 seconds with it and is shorter than 1 minute approximately, is preferably about 10 to about 30 seconds narcosis.
Use the oral administration pipe.The pharynx of this delivery tube being inserted in the mouth of rat and picking one's way across rat and the about 8cm of esophagus be about 15cm extremely, and it depends on the weight (typically about 11cm) of rat.Piston through depressing the oral administration pipe is discharged into solid dosage in oesophagus end and/or the stomach.
Typically in time=0, collected blood sample behind the eye socket in 15,30,60 and 90 minutes.Using P YY [3-36] radioimmunoassay (catalog number (Cat.No.) #RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont, CA) quantitative blood-serum P YY concentration.Calculate the result's of every treated animal MV for each time point.Listed the peak (being blood-serum P YY [3-36] average peak concentration ± standard deviation (SD)) of these MVs below.
Table 1. PYY [3-36] is Orally administered in rat
The delivery agent compound Application process Compound dosage (mg/kg) PYY (3-36) dosage (mg/kg) Average serum peak value (pg/mL) ± SD of PYY
The 23-sodium salt Oral, solid dosage, 1 of every animal 100 0.3 427.4±258.7
The 121-sodium salt Oral, solid dosage, 1 of every animal 100 0.3 897.1±257.3
The 121-free acid Oral, solid dosage, 1 of every animal 50 0.3 161.7±148.5
The 174-sodium salt Oral, solid dosage, 1 of every animal 100 0.3 675±427.1
The 174-free acid Oral, solid dosage, 1 of every animal 100 0.3 0
The liquid oral transmission of embodiment 11 PYY [3-36] in rat
(available from Bachem California Inc.of Torrance, oral gavage (PO) CA) gives drug solns following for preparation delivery agent compound and peptide YY residue 3-36 (PYY [3-36]) in deionized water.
Prepare PYY [3-36] storing solution (80mg/mL) with deionized water.The composition for oral administration that comprises 200mg/kg delivery agent compound and 0.3mg/kg PYY prepares in the aqueous solution.The solution of compound 23 prepares so that the free acid delivery agent is converted into its sodium salt with a normal sodium hydroxide.
Weight is maximum 24 hours of male Sprague-Dawley rat fasting before test of 240-320g and before using test subject, draws piperazine (1.5mg/kg) through intramuscularly administration of ketamine to (44mg/kg) and rope.Then, the administered through oral gavage uses test subject for the animal of anesthesia.Use a kind of medicament solution for the administration group of 5 animals.For oral gavage (PO), the Rusch8French conduit of 11cm is connected to the 1mL syringe that has the micropipet tip.This syringe comes filling to give drug solns through the conduit draw solution, then conduit is dried.Conduit is put into esophagus, outside front tooth, reserve the 1cm pipe.Use through the piston of depressing syringe to drug solns.
Collect blood sample continuously from caudal artery or through cardiac puncture, typically in time=0,15,30,45,60 and 90 minutes.Using P YY [3-36] radioimmunoassay (catalog number (Cat.No.) #RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont, CA) quantitative blood-serum P YY concentration.Calculate the result's of every treated animal MV for each time point.Listed the peak (being blood-serum P YY [3-36] average peak concentration ± standard deviation (SD)) of these MVs in the table 2 below., animal in blood, do not detect tangible PYY [3-36] when only using PYY [3-36] oral administration.
Table 2. PYY [3-36] Orally administered in rat (liquid)
Compound Application process Compound dosage (mg/kg) PYY (3-36) dosage (mg/kg) Average serum peak value (pg/mL) ± SD of PYY
23 Oral (liquid dosages) 200 0.3 788.198±50.59
151 Oral (liquid dosages) 200 0.3 801.96±290.61
158 Oral (liquid dosages) 200 0.3 1065±75.352
160 Oral (liquid dosages) 200 0.3 370.39±306.29
160 Oral (liquid dosages) 200 0.3 631.96±316.16
160 Oral (liquid dosages) 200 0.3 705.106±75.906
161 Oral (liquid dosages) 200 0.3 340.95±228.946
174 Oral (liquid dosages) 200 0.3 1262.26±313.58
Embodiment 12 biosynthetic human insulin's in rat oral delivery
(Aurora OH), is bulk powder to Regular Insulin (people's reorganization) available from ICN Biomedicals.In order to prepare storing solution, it is 15mg/mL that Regular Insulin is dissolved in the deionized water (pH～6.5) to obtain concentration.Storing solution is kept being chilled in-20 ℃ up to application with every part of 1.0mL.For giving drug solns, in deionized water, be 200mg/mL to obtain final concentration with the delivery agent compound dissolution.Through adding a normal sodium hydroxide free acid form of delivery agent is converted into sodium salt.With solution vortex, ultrasonic and heating, and if desired, the sodium hydroxide that adds other μ L amount is to obtain consistent solvability.Through adding hydrochloric acid or sodium hydrate regulator solution to pH3.5-8.5.Joining in the delivery agent solution Regular Insulin storing solution (typically 66.7 μ L) to obtain final concentration then is 0.5mg/mL.Behind dissolving and the adding medicine, solution is adjusted to final volume through adding deionized water.
Regular Insulin is applied to male Sprague-Dawley rat separately or with Emisphere delivery agent combination administered through oral gavage (PO).Typically, rat is before administration fasting 18-24 hour.For administration, Rusch 8 French conduits are cut into long 11cm and are applicable to the 1mL syringe.Syringe is inserted to drug solns and dried the excessive solution of conduit.Conduit is inserted in the mouth of rat and stretch into esophagus (10.0cm).Rat is kept vertical position, medicament solution is discharged through the piston of depressing syringe.
Sample collection and processing: Regular Insulin
During blood sample collection, before each sampling time point, immediately rat of short duration (～10 seconds) is exposed in the carbonic acid gas up to weak.For blood sample collection, with recess behind the kapillary insertion eye socket of 77-mm.Typically, before administration, collected blood sample after (time 0) and the administration in 15,30,45 and 60 minutes.With sample collection in comprising setting accelerator (red cap; Serum separator tube)
Figure S05818614120061211D000901
pipe (TerumoCorporation; Tokyo, Japan) in.Allow sample solidify at 4 ℃～20 minutes.After solidifying, sample is at 6 ℃, 10, under the 000rpm centrifugal 4 minutes so that separation of serum.Serum is collected in the eppendorf pipe and freezing up to analysis down at-20 ℃.
Sample collection and processing: full blood glucose
In order to confirm the drug effect reaction; After administration of insulin or Regular Insulin and delivery agent, use hand-held blood glucose meter (OneTouch Ultra; (Johnson&Johnson; New Brunswick, New Jersey)) mensuration whole blood blood sugar.Recess behind the eye socket (see sample collection and processing: Regular Insulin) or caudal artery (being that tail is cut off) collect sample.Cut off for tail, the Applied Anatomy blade cuts off the tip of tail at the most advanced and sophisticated about 5mm of distance place.After abandoning the First Blood, (OneTouch Ultra LifeScan) and usually reads the blood glucose reading through instrument with small amount of sample (～5-10 μ L) contact blood glucose meter test bar.For each ensuing sampling time point, the most advanced and sophisticated clot that forms of tail is destroyed and collects fresh sample.Typically, before administration, collected sample after (time 0) and the administration in 15,30,45 and 60 minutes.
Table 3. Oral insulin (liquid dosages) is applied to rat
Compound Application process Delivery agent compound dosage (mg/kg) Insulin dose (mg/kg) Largest percentage ± SD with respect to contrast decline
24 Oral (liquid dosages) 200 0.5 -14.73±17.64
25 Oral (liquid dosages) 200 0.5 -14.81±12.99
26 Oral (liquid dosages) 200 0.5 -25.93±14.86
27 Oral (liquid dosages) 200 0.5 -25.40±30.61
28 Oral (liquid dosages) 200 0.5 -11.41±18.92
29 Oral (liquid dosages) 200 0.5 -29.25±6.97
140 Oral (liquid dosages) 100 1 Cmax＝81.16± 114.98μIU/mL
141 Oral (liquid dosages) 100 1 Cmax＝204.05± 60.88μIU/mL
142 Oral (liquid dosages) 100 1 Cmax＝118.16± 72.75μIU/mL
145 Colonic (liquid dosages) 50 0.1 Cmax＝15.03± 7.80μIU/mL
145 Oral (liquid dosages) 100 1 Cmax＝3.92± 5.62μIU/mL
160 Oral (liquid dosages) 200 0.5 Cmax＝74±7.5 μIU/mL
165 Oral (liquid dosages) 200 0.5 -33.0
166 Oral (liquid dosages) 200 0.5 -5.7
167 Oral (liquid dosages) 200 0.5 -21.2
167 Oral (liquid dosages) 200 0.5 -17.7
167 Oral (liquid dosages) 200 0.5 -26.2
167 Oral (liquid dosages) 200 0.5 -17.8
167 Oral (liquid dosages) 200 0.5 -22.7
Embodiment 13 people's insulin zinc-oral delivery
Preparation delivery agent compound and people's insulin zinc in deionized water (minimum 26IU/mg, available from Calbiochem-Novabiochem Corp, La Jolla, oral administration CA) (PO) compsn.500mg delivery agent compound is joined in the 1.5mL water.Through the solution that stir to produce and add a normal sodium hydroxide free acid of delivery agent compound is converted into sodium salt.With the solution vortex, heating (about 37 ℃) and ultrasonic then.With NaOH or HCl with pH regulator to about 7 to 8.5.If desired, add other NaOH obtaining consistent solvability, and again with pH regulator to about 7 to 8.5.Add entry then and make about 2.4mL of TV and vortex.To come from Regular Insulin storing solution (15mg/mL; By the preparation of 0.5409g Regular Insulin and 18mL deionized water, with HCl and NaOH be adjusted to pH 8.15 and with 40mL concentrated hydrochloric acid, 25mL 10N NaOH and 50mL1N NaOH acquisition settled solution) about 1.25mg Regular Insulin join in the solution and pass through the turned upside down mixing.The dosage of final delivery agent compound, the dosage and the dose volume amount of Regular Insulin have been listed.
The male Sprague-Dawley rat fasting of the about 200-250g of weight 24 hours and in administration with need keep anaesthetizing preceding 15 minutes administration of ketamine to (44mg/kg) and CHLORPROMAZINE HCL (1.5mg/kg) once more.Use a kind of medicament solution for the administration group of 5 animals.For oral administration, the Rusch 8French conduit of 11cm is connected to the 1mL syringe that has the micropipet tip.This syringe comes filling to give drug solns through the conduit draw solution, then conduit is dried.Conduit is put into esophagus, outside front tooth, reserve the 1cm pipe.Use through the piston of depressing syringe to drug solns.
Collect blood sample continuously from caudal artery, typically in time=15,30,60,120 and 180 minutes.With Regular Insulin ELISA test kit (test kit #DSL-10-1600; DiagnosticSystems Laboratories; Inc.; Webster TX) confirms serum insulin level, revises standard method so that the linearity range of the typical curve of sample volume of using in optimization sensitivity and present method and concentration.Measure every animal in five animals of each administration group in the serum insulin human concentration (μ U/mL) of each time point.Five values of each time point on average and with serum insulin concentration are mapped to the time.(previous test shows that independent oral administration insulin human does not have measurable insulin human's level).Peak (peak value) and TG-AUC (AUC) are listed in the following table 4.For BloodGlucose the ONE TOUCH (Life Scan; Johnson&Johnson; NewBrunswick, New Jersey) per-cent that changes from baseline.
Table 4. Regular Insulin-oral delivery
The delivery agent compound Delivery agent compound dosage (mg/kg) Insulin dose (mg/kg) Volume dose (ml/kg) C max(glucose) (μ U/mL) AUC Glucose (% contrast)
123 200 0.50 107.3 7440
125 200 0.50 98.3 7687.5
123 200 0.50 100.3 7447.5
115 200 0.50 83.3 3232.5
116 200 0.50 89.5 3292.5
118 200 0.50 90.5 4327.5
124 200 0.50 87.8 1582.5
134 200 0.50 81.5 3817.5
136 200 0.50 91.5 4507.5
138 200 0.50 93.4 6907.5
124 200 0.50 59.9 112.5
152 200 0.5 -29.3％
153 200 0.5 -7.1％
154 200 0.5 -7.9％
159 200 0.5 -6.6％
159 200 0.5 9.1 -36.5％
Embodiment 14 Regular Insulin-lung transmission
Preparation delivery agent compound and insulin human's pharmaceutical composition in water.Typically, 1.5mg delivery agent compound is joined in the deionized water so that volume is 1.0mL, and with the solution vortex.Use the sodium salt of delivery agent or through stirring the solution that produces and adding a normal sodium hydroxide (10N) and dilute with water is converted into sodium salt with free acid.With the solution vortex, heating (about 37 ℃) and ultrasonic then.With NaOH or HCl with pH regulator between about 7.0 to 8.5.75 μ L insulin human storing solutions (2mg/mL) are joined in the solution.(storing solution prepares according to following method: in 0.02g Regular Insulin, add the solution of 3mL pH3.0 HCl in deionized water.The pH of the solution that produces is adjusted to (about 2.6) below 3.0 with HCl and NaOH and clarifies up to solution.With NaOH and HCl pH is risen to 7.6 then.Use the deionized water of pH7.5 to make final volume be 10mL.Final pH is 7.59).Adding entry then, to make TV be 2.0mL, and solution is turned upside down for several times gently.This solution can be applied to medication immediately, or this solution can be put into 37 ℃ of water-baths 1 hour before administration.Final delivery agent compound dosage, insulin dose and volume dose are listed in following table 5.
Typical administration and sampling method are following.The male Sprague-Dawley rat fasting of weight 200-250g 24 hours and in administration with need keep preceding 15 minutes administration of ketamine to (44mg/kg) of the anesthesia ketamine and the 1.5mg/kg CHLORPROMAZINE HCL of same amount (use) and CHLORPROMAZINE HCL (3.0mg/kg) once more.Use a kind of medicament solution for the administration group of 5 animals.The control group of giving 5 animals is administration of insulin only.With the rodentine conduit instillator that lamp is installed (available from Penn Century, Inc., Pittsburgh, PA) medicament solution is filled and is inserted in the larynx and gets into esophagus (visually confirming) up to pin.Use through depressing piston to drug solns.
Collect blood sample continuously from caudal artery, typically after administration 5,15,30,60 and 120 minutes.With Regular Insulin ELISA test kit (test kit #DSL-10-1600; DiagnosticSystems Laboratories; Inc.; Webster TX) confirms serum insulin level, revises standard method so that the linearity range of the typical curve of sample volume of using in optimization sensitivity and present method and concentration.Measure every animal in five animals of each administration group in the serum insulin human concentration (μ U/mL) of each time point.Five values of each time point on average and with serum insulin concentration are mapped to the time.The ratio of the TG-AUC of test group and control group (AUC) is listed below.Maximum serum insulin concentration (the C of test group and control group Max) ratio also list below.
Table 5. The lung transmission of Regular Insulin
Transmit thinner
Delivery agent compound dosage insulin dose
Volume dose (mL/kg)
C max
Compound
(mg/kg) (mg/kg)
174 0.4 16 0.03 18.36±19.18
Embodiment 15 oral and colonic heparin transmission
In the aqueous solution of 25% Ucar 35, prepare the oral gavage (PO) and/or the colonic (IC) that comprise delivery agent compound and heparin sodium USP and give drug solns.Use the sodium salt of compound.Typically, delivery agent compound and heparin (about 166-182IU/mg) pass through vortex mixed with the form of dried powder.This drying composite is dissolved in the 25%v/v aqueous solution of propylene glycol vortex and put it into (about 37 ℃) in the ultrasonic device.With NaOH (2N) aqueous solution with pH regulator to about 7 (6.5-8.5).Will be ultrasonic to produce settled solution to drug solns.Final volume is adjusted to 3.0mL.The dosage of final delivery agent compound, the dosage and the volume dose of heparin are listed in following table 6.
Typical administration and sampling method are following.The male Sprague-Dawley rat fasting of weight 275-350g 24 hours and before administration, use ketamine (88mg/kg) anesthesia immediately at intramuscular.Use a kind of medicament solution for the administration group of 5 rats.For oral gavage (PO) administration, the Rusch 8 French conduits of 11cm are connected to the 1mL syringe that has the micropipet tip.This syringe comes the filling medicament solution through the conduit draw solution, then conduit is dried.Conduit is put into esophagus, outside the front tooth of rat, reserve the 1cm pipe.Solution is used through the piston of depressing syringe.For colonic (IC) administration, the 8fr Rusch conduit of 7.5cm is connected to the 1mL syringe that has the micropipet tip.Be inserted in colon up to pipe no longer visible through anus delivery catheter.Slowly with the administration injection of solution in colon.
Behind administration of ketamine to (88mg/kg), typically in time=0.25, collected the blood sample of Citrate trianion in 0.5,1.0 and 1.5 hour through cardiac puncture.According to Henry; J.B., Clinical Diagnosisand Management by Laboratory Methods, Philadelphia; PA, the method for W.B.Saunders (1979) is confirmed the activity of heparin through using activated partial thromboplastin time (APTT).Previous research shows that baseline value is about 20 seconds.Every group of 5 rats are average in the result of each time point.Peak is listed in following table 6.
Table 6. Oral/colonic the transmission of heparin
The delivery agent applied volume dosage compound heparin equal peak value of dosage APTT (sec) ± SD pH
Compound method (mL/kg) dosage (mg/kg) (mg/kg)
114 IC 1 50 25 42.90±8.70 7.61
140 IC 1 50 25 23.49±6.12 7.67
141 IC 1 50 25 52.40±21.54 7.62
143 IC 1 50 25 114.69±121.62 7.18
145 IC 1 50 25 134.42±99.03 6.93
151 PO 3 300 100 252.09±107.13
151 IC 1 50 25 2.36 ± 1.27 (anti-Xa factor) 7.06
151 IC 1 25 25 3.39 ± 3.07 (anti-Xa factor) 7.23
160 IC, 1 50 25 131 ± 154 (T Max=90 minutes)
Embodiment 16 Rat parathyroid hormone 1-34 transmission (PTH 1-34) are oral/the colonic transmission
The oral gavage (PO) of preparation delivery agent compound and human parathyroid hormone residue 1-34 (PTH) and/or colonic (IC) are given drug solns in water.Use the sodium salt of delivery agent compound.Typically, the solution and the stirring of preparation compound in water add a normal sodium hydroxide (1.0N) when the preparation sodium salt.Through with compound and PTH storing solution (PTH is available from Eli Lilly and Co., Indianapolis, IN) (typically concentration is 5mg PTH/mL) is mixed with final medicament solution and is diluted to the volume (being generally 3.0mL) of expection.The dosage of final compound, the dosage of PTH and volume dose are listed in following table 7.
Typical administration and sampling method are following.The male Sprague-Dawley rat fasting of weight 200-250g 24 hours and at preceding 15 minutes administration of ketamine to (44mg/kg) of administration and CHLORPROMAZINE HCL (1.5mg/kg).Use a kind of medicament solution for the administration group of 5 rats.For oral gavage (PO) administration, the Rusch 8 French conduits of 11cm are connected to the 1mL syringe that has the micropipet tip.This syringe comes the filling medicament solution through the conduit draw solution, then conduit is dried.Conduit is put into esophagus, outside the front tooth of rat, reserve the 1cm pipe.Solution is used through the piston of depressing syringe.For colonic (IC) administration, the Rusch conduit of 7.5cm (French 8 or 6) is applicable to the syringe that has Eppendorf micropipet tip.This syringe comes the filling medicament solution through the conduit draw solution.Conduit is dried.The K-Y jelly is applied to tip, avoids contacting, and be inserted in colon up to pipe no longer visible through anus pipe with managing eye.Through depressing the piston injection solution of syringe, and remove pipe.
Collect blood sample continuously from caudal artery, for oral, typically in time=0,15,30,45,60 and 90 minutes and for the IC administration, typically in time=0,10,20,30,60 and 90 minutes.(test kit #RIK 6101 is available from Peninsula Laboratories, Inc.San Carlos, CA) quantitative serum PTH concentration through PTH radioimmunoassay test kit.Previous research shows that baseline value is about 0.Every group of 5 rats are average in the result of each time point.Peak is listed in following table 7.
Table 7. PTH's is oral in rat/the colonic transmission
The delivery agent compound Application process Volume dose (mL/kg) Compound dosage (mg/kg) PTH dosage (μ g/kg) Serum [PTH] average peak ± SD pH
113 Oral 1 100 200 780.77±439.92 8.18
113 Oral 1 100 200 53.51±39.55 8.09
114 Oral 1 100 200 135.78±136.97 8.41
Embodiment 17 Interferon, rabbit-oral delivery
( is available from InterMune for preparation delivery agent compound and Alfacon-1 (IFN) in deionized water; Inc.of Brisbane, CA) give drug solns.With a normal sodium hydroxide free acid of delivery agent compound is converted into sodium salt.Typically, preparation delivery agent compound solution and stirring in water add a normal sodium hydroxide (1.0N) when the preparation sodium salt.With the mixture vortex and put into ultrasonic device (about 37 ℃).With the NaOH aqueous solution with pH regulator to about 7.0 to 8.5.With the mixture vortex to produce uniform suspension or solution, also using ultrasound and heating if desired.If desired, add other NaOH, to obtain uniform solvability, again with pH regulator to about 7.0 to 8.5.The volume (being generally 3mL) that delivery agent compound solution and IFN storing solution (about 22.0 to 27.5mg/mL in phosphate-buffered salt) is mixed and be diluted to expection.Final delivery agent compound and dosage and the dose volume of IFN are listed in following table 8.
Typical administration and sampling method are following.The male Sprague-Dawley rat fasting of weight 200-250g 24 hours and in administration with need keep anaesthetizing preceding 15 minutes administration of ketamine to (44mg/kg) and CHLORPROMAZINE HCL (1.5mg/kg) once more.Use a kind of medicament solution for the administration group of 5 rats.The Rusch 8 French conduits of 11cm are connected to the 1mL syringe that has the micropipet tip.This syringe comes the filling medicament solution through the conduit draw solution, then conduit is dried.Conduit is put into esophagus, outside front tooth, reserve the 1cm pipe.Use through the piston of depressing syringe to drug solns.
Collect blood sample continuously from caudal artery, typically in time=0,15,30,45,60 and 90 minutes.(catalog number (Cat.No.) #KHC4012 is available from Biosource International, Camarillo, CA) quantitative serum I FN concentration for the Cytoscreen immunoassay kits of people's IFN-α in application.Previous research shows that baseline value is about 0.Every treated animal is average in the result of each time point.The peak of these MVs (being serum I FN average peak concentration) is listed in following table 8.
Table 8. Interferon, rabbit-oral delivery
The delivery agent compound Delivery agent compound dosage (mg/kg) IFN dosage (mg/kg) Volume dose (mL/kg) Serum [IFN] average peak (ng/mL) ± SD pH
141 200 1 1 0.73±0.44 8.29
147 200 1 1 1.27±0.60 8.45
174 200 1 1 0.5±0.57
174 200 1 1 0.18±0.17
174 200 1 1 3.96±2.72
174 200 1 1 17.4±9.12
The oral delivery of embodiment 18 salmon calcitonin see calcimars (sCT)
The composition for oral administration of preparation delivery agent compound and salmon calcitonin see calcimar (sCT) in water.Typically, 450mg delivery agent compound is added in the 2.0mL water.Use the sodium salt of compound or through stirring the solution that produces and adding a normal sodium hydroxide (1.0N) and dilute with water is converted into sodium salt with free acid.With the solution vortex, heating (about 37 ℃) and ultrasonic then.With NaOH or HCl with pH regulator to about 7 (6.5 to 8.5).The storing solution that will contain 90 μ g sCT is added in the solution.Add entry then so that TV is about 3mL (solvability that depends on the delivery agent compound changes).The dosage of final delivery agent compound, dosage and the volume dose of sCT are listed in following table 9.
The male Sprague-Dawley rat fasting of weight 200-250g 24 hours and at preceding 15 minutes administration of ketamine to (44mg/kg) of administration and CHLORPROMAZINE HCL (1.5mg/kg).Use a kind of drug solns of giving for the administration group of 5 rats.For oral administration, the Rusch 8French conduit of 11cm is connected to the 1mL syringe that has the micropipet tip.This syringe comes filling to give drug solns through the conduit draw solution, then conduit is dried.Conduit is put into esophagus, outside the front tooth of rat, reserve the 1cm pipe.Solution is used through the piston of depressing syringe.
Collect blood sample continuously from caudal artery, typically in time=0,10,20,30,60 and 90 minutes.Through (test kit #EIAS-6003 is available from Peninsula Laboratories with the EIA test kit; Inc., San Carlos, CA) mensuration is confirmed serum sCT; The standard method of revising test kit is following: hatch 2 hours (jolting in the dark) with 50 μ L peptide antibodies; Wash plate adds serum and dilute with the biotinylation peptide and with the 4mL damping fluid, and in the dark jolting is spent the night.Baseline value according to some acquisition in time=0 is regulated numeral.Every treated animal is average in the result of each time point.Peak is listed in following table 9.
Table 9 The oral delivery of salmon calcitonin see calcimar (sCT)
The delivery agent compound Volume dose (mL/kg) Compound dosage (mg/kg) SCT dosage (μ g/kg) Serum sCT average peak (pg/mL) ± SD (SE)
174 150 30 1 182.83±184.82
174 150 30 1 198.21±205.15
174 150 30 1 70.81±118.47
Oral/colonic transmission of embodiment 19 recombinant human somatropins (rhGH)
In phosphate buffered saline buffer the oral gavage (PO) of preparation delivery agent compound and rhGH and/or colonic (IC) to drug solns (rhGH is available from Novartis, Basel, Switzerland).Through sodium salt with a free acid and a normal sodium hydroxide reaction acquisition delivery agent compound.Through compound is prepared final medicament solution with the volume (being generally 3mL) that rhGH storing solution (15mg rhGH/mL) mixes and be diluted to expection.The dosage of compound and rhGH is listed in following table 10.
Typical administration and sampling method are following.The male Sprague-Dawley rat fasting of weight 200-250g 24 hours and at preceding 15 minutes administration of ketamine to (44mg/kg) of administration and CHLORPROMAZINE HCL (1.5mg/kg).Use a kind of medicament solution for the administration group of 5 rats.For oral gavage (PO) administration, the Rusch 8 French conduits of 11cm are connected to the 1mL syringe that has the micropipet tip.This syringe comes the filling medicament solution through the conduit draw solution, then conduit is dried.Conduit is put into esophagus, outside the front tooth of rat, reserve the 1cm pipe.Solution is used through the piston of depressing syringe.For colonic (IC) administration, the Rusch conduit of 7.5cm (French 8 or 6) is applicable to the syringe that has Eppendorf micropipet tip.This syringe comes the filling medicament solution through the conduit draw solution.Conduit is dried.The K-Y jelly is applied to tip, avoids contacting, be inserted in colon up to pipe no longer visible through anus pipe with managing eye.Through depressing the piston injection solution of syringe, and remove pipe.
Recess is collected blood sample continuously behind caudal artery or the eye socket, typically for oral in time=0,15,30,45,60 and 90 minutes and for the IC administration in time=0,10,20,30,60 and 90 minutes.With sample collection in comprising setting accelerator (red cap; Serum separator tube) pipe (Terumo Corporation; Tokyo, Japan) in.Allow sample solidify at 4 ℃～20 minutes.(test kit #K1F4O15 is available from GenzymeCorporation Inc., and Cambridge MA) carries out quantitatively serum rhGH concentration through rhGH immunoassay test kit.5 duplicate samples of each time cycle are concentrated.Previous research shows that baseline value is about 0.
Every group peak concentration is listed in following table 10.
Table 10. RhGH's is oral in rat/the colonic transmission
Delivery agent chemical combination applied volume dosage compound rhGH serum rhGH average peak
Object space method (mL/kg) dosage (mg/kg) dosage (mg/kg) (ng/mL)
160 PO 1 200 3 -
161 PO 1 200 3 1.033 (± 2.31) (T Max=15 minutes
Clock)
174 PO 1 200 3 57.42
All publications, document, patent and disclosed patented claim are incorporated this paper into as a reference.

Claims (5)

1. compound, this compound is selected from:
Compound 23 or its sodium salt
Compound 24
Figure FSB00000867111200012
Compound 25
Figure FSB00000867111200013
Compound 26
Compound 27
Figure FSB00000867111200015
Compound 28
2. compsn, said composition comprises:
(A) at least a biologically active agent; And
(B) compound of claim 1,
Wherein said biologically active agent is PYY, PYY agonist or Regular Insulin.
3. the compsn of claim 2, wherein said biologically active agent is PYY [3-36].
4. the compsn of claim 2, wherein said biologically active agent is a Recombulin.
Among the claim 2-4 each compsn in the purposes of preparation in the medicine.
CN2005800186141A 2004-05-14 2005-05-16 Compounds and compositions for delivering active agents Expired - Fee Related CN1964939B (en)

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US57131504P 2004-05-14 2004-05-14
US57109204P 2004-05-14 2004-05-14
US57119404P 2004-05-14 2004-05-14
US57114404P 2004-05-14 2004-05-14
US57108904P 2004-05-14 2004-05-14
US57109004P 2004-05-14 2004-05-14
US60/571,151 2004-05-14
US60/571,055 2004-05-14
US60/571,144 2004-05-14
US60/571,195 2004-05-14
US60/571,089 2004-05-14
US60/571,194 2004-05-14
US60/571,090 2004-05-14
US60/571,092 2004-05-14
US60/571,315 2004-05-14
US60/571,093 2004-05-14
US60/576,088 2004-06-01
US60/576,397 2004-06-01
US60/576,105 2004-06-01
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Citations (1)

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US3072473A (en) * 1959-10-07 1963-01-08 Us Rubber Co Plant growth regulants

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3072473A (en) * 1959-10-07 1963-01-08 Us Rubber Co Plant growth regulants

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